ACS Publications. Most Trusted. Most Cited. Most Read
Evaluation of Subetadex-α-methyl, a Polyanionic Cyclodextrin Scaffold, as a Medical Countermeasure against Fentanyl and Related Opioids
More

OR SEARCH CITATIONS

My Activity
Publications

Figure 1Loading Img
Download Hi-Res ImageDownload to MS-PowerPointCite This:ACS Cent. Sci. 2024, XXXX, XXX, XXX-XXX
  • Open Access
Article

Evaluation of Subetadex-α-methyl, a Polyanionic Cyclodextrin Scaffold, as a Medical Countermeasure against Fentanyl and Related Opioids
Click to copy article linkArticle link copied!

  • Michael A. Malfatti*
    Michael A. Malfatti
    Physical and Life Sciences Directorate  and  Biosciences and Biotechnology Division, Lawrence Livermore National Laboratory, Livermore, California 94550, United States
    *Phone: +1 925 422 5732. Email: [email protected]
    More by Michael A. Malfatti
    Orcidhttps://orcid.org/0000-0003-2431-9115
  • Heather A. Enright
    Heather A. Enright
    Physical and Life Sciences Directorate  and  Biosciences and Biotechnology Division, Lawrence Livermore National Laboratory, Livermore, California 94550, United States
    More by Heather A. Enright
  • Summer McCloy
    Summer McCloy
    Physical and Life Sciences Directorate  and  Biosciences and Biotechnology Division, Lawrence Livermore National Laboratory, Livermore, California 94550, United States
    More by Summer McCloy
  • Esther A. Ubick
    Esther A. Ubick
    Physical and Life Sciences Directorate  and  Biosciences and Biotechnology Division, Lawrence Livermore National Laboratory, Livermore, California 94550, United States
    More by Esther A. Ubick
  • Edward Kuhn
    Edward Kuhn
    Physical and Life Sciences Directorate  and  Biosciences and Biotechnology Division, Lawrence Livermore National Laboratory, Livermore, California 94550, United States
    More by Edward Kuhn
  • Alagu Subramanian
    Alagu Subramanian
    Physical and Life Sciences Directorate,  Biosciences and Biotechnology Division,  Global Security Directorate  and  Forensic Science Center, Lawrence Livermore National Laboratory, Livermore, California 94550, United States
    More by Alagu Subramanian
    Orcidhttps://orcid.org/0009-0007-7716-7801
  • Victoria Hio Leong Lao
    Victoria Hio Leong Lao
    Physical and Life Sciences Directorate  and  Biosciences and Biotechnology Division, Lawrence Livermore National Laboratory, Livermore, California 94550, United States
    More by Victoria Hio Leong Lao
  • Doris Lam
    Doris Lam
    Physical and Life Sciences Directorate  and  Biosciences and Biotechnology Division, Lawrence Livermore National Laboratory, Livermore, California 94550, United States
    More by Doris Lam
  • Nicholas A. Be
    Nicholas A. Be
    Physical and Life Sciences Directorate  and  Biosciences and Biotechnology Division, Lawrence Livermore National Laboratory, Livermore, California 94550, United States
    More by Nicholas A. Be
  • Saphon Hok
    Saphon Hok
    Global Security Directorate  and  Forensic Science Center, Lawrence Livermore National Laboratory, Livermore, California 94550, United States
    More by Saphon Hok
  • Edmond Y. Lau
    Edmond Y. Lau
    Physical and Life Sciences Directorate  and  Biosciences and Biotechnology Division, Lawrence Livermore National Laboratory, Livermore, California 94550, United States
    More by Edmond Y. Lau
  • Derrick C. Kaseman
    Derrick C. Kaseman
    Physical and Life Sciences Directorate,  Forensic Science Center  and  Materials Science Division, Lawrence Livermore National Laboratory, Livermore, California 94550, United States
    More by Derrick C. Kaseman
    Orcidhttps://orcid.org/0000-0003-2076-1264
  • Brian P. Mayer
    Brian P. Mayer
    Physical and Life Sciences Directorate,  Global Security Directorate  and  Forensic Science Center, Lawrence Livermore National Laboratory, Livermore, California 94550, United States
    More by Brian P. Mayer
    Orcidhttps://orcid.org/0000-0003-1967-9802
  • Carlos A. Valdez*
    Carlos A. Valdez
    Physical and Life Sciences Directorate,  Biosciences and Biotechnology Division  and  Forensic Science Center, Lawrence Livermore National Laboratory, Livermore, California 94550, United States
    *Phone: +1 925 423 1804. Email: [email protected]
    More by Carlos A. Valdez
Open PDFSupporting Information (1)

ACS Central Science

Cite this: ACS Cent. Sci. 2024, XXXX, XXX, XXX-XXX
Click to copy citationCitation copied!
https://doi.org/10.1021/acscentsci.4c00682
Published October 23, 2024

© 2024 The Authors. Published by American Chemical Society. This publication is licensed under

CC-BY 4.0 .

Abstract

Click to copy section linkSection link copied!
High Resolution Image
Download MS PowerPoint Slide

Subetadex-α-methyl (SBX-Me), a modified, polyanionic cyclodextrin scaffold, has been evaluated for its utilization as a medical countermeasure (MCM) to neutralize the effects of fentanyl and related opioids. Initial in vitro toxicity assays demonstrate that SBX-Me has a nontoxic profile, comparable to the FDA-approved cyclodextrin-based drug Sugammadex. Pharmacokinetic analysis showed rapid clearance of SBX-Me with an elimination half-life of ∼7.4 h and little accumulation in major organs. SBX-Me was also evaluated for its ability to counteract the effects of fentanyl, carfentanil, and remifentanil in rats. Recovery times in rats exposed to sublethal fentanyl doses were found to be shorter when treated with SBX-Me after opioid exposure. The recovery times were reduced from ∼35 to ∼17 min for fentanyl, ∼172 to ∼59 min for carfentanil, and ∼18 to ∼12 min for remifentanil. SBX-Me increased the elimination half-life for fentanyl and remifentanil from 5.37 to 6.42 h and 8.24 to 9.74 h, respectively. These data support SBX-Me as a solid platform from which further research can be launched for the development of a MCM against the effects of fentanyl and its analogs. Furthermore, the data suggests that SBX-Me and other analogs are attractive candidates as broad spectrum opioids targeting MCMs.

This publication is licensed under

CC-BY 4.0 .
  • cc licence
  • by licence
© 2024 The Authors. Published by American Chemical Society

Subjects

what are subjects

Synopsis

Subetadex-α-methyl, a chemically modified polyanionic cyclodextrin, can bind and sequester synthetic opioids as a way to neutralize their toxic effects.

Introduction

Click to copy section linkSection link copied!
The global opioid pandemic has forced government agencies worldwide, as well as law enforcement entities, to strengthen their efforts in effectively combating the illicit manufacture and distribution of these lethal substances. (1,2) One of the most common and often encountered synthetic opioid species is fentanyl, created in the laboratory of Paul Janssen over 60 years ago in an effort to discover more potent anesthetic compounds based on the meperidine scaffold (3,4) (Figure 1). Since its discovery in 1960, fentanyl has been the subject of numerous structure–activity relationship studies that have yielded more powerful analogs, some of which have found beneficial clinical applications (5,6) while others have become primary players in the world of illegal consumption. (7−10) Another alarming part of the epidemic is the ease by which some of these analogs can be synthesized following protocols found openly on the Internet and in the scientific literature. (11−14) Given the scale of this epidemic, drug and law enforcement agencies have established several ways of addressing the problem in order to mitigate its impact in society (15) from developing more sensitive and rapid analytical detection techniques (16,17) to the development of antidotes like naloxone and naltrexone. (18−20) Another one deals with the development of medical countermeasures (MCMs) in the form of pretreatment methods that can provide an immediate layer of protection pre-exposure to the opioid. (21,22)

Figure 1

Figure 1. Structures of (A) fentanyl and its more and equally powerful analogs: carfentanil and remifentanil. Potencies of each relative to morphine are provided in brackets; (B) the original meperidine scaffold from which fentanyl originated via SAR studies along with the structure of morphine and the current state-of-the-art antidotes for overdose treatment: naloxone and naltrexone.

High Resolution Image
Download MS PowerPoint Slide
Two main characteristics for the development of a successful MCM include high specificity for the opioid and a large circulation half-life (preferably ∼5–6 days). Efforts toward attaining these goals have revolved around employing host molecules that could in principle capture synthetic opioids in their interior thereby neutralizing their effects on their biological target. (20) One such class of host systems has been the cucurbit[n]urils, introduced by the Isaacs group at the University of Maryland for opioid-binding purposes, that has provided promising MCM candidates. (23,24) Another set of similar hosts based on a cyclic carbohydrate backbone are the cyclodextrins (CDs), which unfortunately have been underexplored as MCM scaffolds for counter-fentanyl applications. (22,25)
Cyclodextrins are cyclic oligosaccharide structures composed of glucose units joined together via α-1,4-glycosidic linkages (Figure 2a). These linkages give rise to a well-defined three-dimensional structure with a flexible cavity resembling that of a truncated cone open at both ends featuring a hydrophilic exterior and a much less hydrophilic interior. (26−28) Historically, CDs have been attractive molecular scaffolds for their propensity to form inclusion complexes with organic molecules in host:guest interactions governed by mainly dispersion forces. In addition, CDs have raised interest in research and development ventures by serving as inexpensive, commercially available starting scaffolds that via established chemical modifications can be converted into new CDs with enhanced binding profiles. This type of host:guest association has found numerous applications in the pharmaceutical field, as the bioavailability, solubility, and stability of commonly used drugs have been enhanced because of their complexation with CDs. (29) Thus, hydrophobic organic molecules of the right size will tend to form inclusion complexes with CDs at various binding strengths. For example, previous work in our lab resulted in the production of polyanionic β-CDs with enhanced binding affinity toward fentanyl relative to the native β-CD such as Subetadex (SBX) and Subetadex+1 (SBX+1) (Figure 2a). (30) The work described herein summarizes the evaluation of another polyanionic β-CD based on SBX called Subetadex-α-methyl (SBX-Me), for its effectiveness in binding three synthetic opioids: fentanyl, carfentanil and remifentanil. These three synthetic opioids were chosen based on their toxicity profile, ease of manufacture, and propensity for illicit use. Although remifentanil is a fast-acting drug that quickly gets metabolized and may not pose the same safety concerns as fentanyl and carfentanil, it is still a powerful opioid with serious toxic side effects if the dose is not controlled. At higher doses acute overdose can be manifested by respiratory arrest. The polyanionic nature of SBX-Me originates from its pendant 2-methyl-3-thiopropanoic acid chains that line up its upper rim and due to their electrostatic interactions remain separated from each other (Figure 2b). As a result of this modification and newly given physical characteristic, the inner cavity of SBX-Me is expanded and can not only accommodate larger guests in its interior but also provide additional dispersion interactions that increase the strength of the host:guest inclusion complex with, for example fentanyl and analogs with longer features such as butyrylfentanyl or valerylfentanyl (Figure 2b). Relative to SBX, SBX-Me is a CD that possesses a chiral center on the thioalkylcarboxylate chains by the presence of the α-methyl group. As the starting thioalkylcarboxylic acid methyl ester used in the synthesis was racemic in nature, SBX-Me is a mixture of several isomers bearing the same molecular weight but providing very similar binding to the synthetic opioids used in this work.

Figure 2

Figure 2. (A) Structure of β-cyclodextrin (β-CD) indicating the α-1,4-glycosidic linkages in a head to tail fashion between glucose units generate their cyclic nature along with three anionic β-CDs that have been evaluated as potential MCMs against fentanyl including SBX-Me. (B) Full structure of SBX-Me showing the anionic pendant units that serve to elongate and expand its hydrophobic interior and increase its hosting capability toward fentanyl and other synthetic opioids. Note that the opioid, fentanyl in this case, can bind in two orientations.

High Resolution Image
Download MS PowerPoint Slide

Results and Discussion

Click to copy section linkSection link copied!
Development of effective MCMs against synthetic opioids like those belonging to the fentanyl class of compounds has become the focus of intense research by academic and industrial groups. The realization that a global pandemic involving these deadly substances is not only on the rise (31) but without any potentially powerful solutions for its control has prompted the discovery and evaluation of not only effective treatments but also means by which a protective layer can be provided to an individual prior to an exposure to these compounds. (32) Desirable characteristics for a MCM must include high specificity for the target toxic substance, blood circulation times in the order of 5–6 days and low systemic toxicity. Other more minor characteristics but not necessarily detrimental for eliminating a MCM from consideration include ease and inexpensive production cost for eventual mass production. To this end, an approach that has received heavy attention for this purpose is the use of molecular hosts that can encapsulate the fentanyl before it reaches its biological target. In this area, CDs have become a natural platform for this application based on their rich history as host molecules for a myriad of small molecules ranging from pharmaceutical drugs, (33−35) toxic chemicals (36−38) and biological molecules. (39) In addition, the low toxicity associated with CDs and chemically modified analogs have increased their applications in the clinic, with Sugammadex (SGX) becoming the prime example of an FDA-approved CD drug for the reversal of anesthesia in patients suffering from its prolonged effects hours after a surgery. (40−44)
To this end, we embarked on a program to evaluate polyanionic CD analogs of SGX to find a candidate that could bind fentanyl and related analogs more tightly. These studies led to the discovery of polyanionic CD scaffolds with powerful binding constants for fentanyl such as Subetadex (SBX, Ka = 49,000 M–1). For polyanionic CD analogs that demonstrated favorable binding constants (Ka = 49,000 M–1 – Ka = 66,500 M–1 (30)) initial in vitro assessments were conducted to evaluate potential toxicity; these assays were based on reported literature that have demonstrated that CDs can sequester cholesterol and induce hemolysis in vitro for various cells. These assays included: hemolytic activity, cholesterol and phospholipid solubilization. For our initial assessments, we benchmarked the outcomes for our CD analogs to FDA approved and clinically used SGX, given its FDA approval and use in the clinic. The results from these initial in vitro assessments of SBX and related analogs (30) are shown in Figure 3. Hemolytic activity was assessed in human erythrocytes for 10, 1, and 0.1 mg/mL of SBX/analog/SGX and is shown in Figure 3, panels A-C (10, 1, and 0.1 mg/mL), respectively. At the highest concentration (10 mg/mL), significant differences were noted between SBX (534.2% ± 110.1), SBX+1 (338.1% ± 68.9) and SBX-Me (7.7% ± 13.8), as well as when comparing both SBX and SBX+1 to SGX (p-values shown in Figure 3) when normalized to SGX. For lower concentrations (1 and 0.1 mg/mL), no statistical significance was noted between any groups except SBX+1 vs SBX-Me at 1 mg/mL (p < 0.05). Cholesterol solubilization is shown in Figure 3D, where when normalized to SGX, SBX-Me demonstrated the lowest solubilization (8.2% ± 6.1) compared to both SBX (10.4% ± 3.6) and SBX+1 (16.1% ± 5.5). Finally, in panel E, phospholipid solubilization is shown. Statistical differences were noted when comparing SBX (374.7% ± 78.4) and SBX+1 (562.1% ± 70.4) to SGX; no significant difference was observed when comparing SBX-Me to SGX. These initial in vitro results together with NMR results clearly showing a strong binding between SBX-Me and fentanyl (See SI for discussion and experimental data) demonstrated that the most favorable CD analog compared to SGX was SBX-Me. Considering the strong binding affinity for SBX-Me and fentanyl together with the similar nontoxic profile compared to SGX, SBX-Me was advanced for further in vivo evaluation. As a side note it is important to mention that SBX-Me bears a chiral center in its pendant thioalkylcarboxylate chains. As the synthesis of SBX-Me involved the use of a racemic mixture of the mercaptoalkylcarboxylic acid methyl ester, the SBX-Me used in this work is actually a mixture of several isomers. However, we do not anticipate that the nature of the stereocenter in the alkyl chains will have a profound effect on the overall binding of the CD to the opioids. Nevertheless, enantiomerically pure versions of the methyl esters of the mercaptoalkylcarboxylic acids are commercially available and may be used to provide enantiomerically pure SBX-Me.

Figure 3

Figure 3. In vitro assessment of SBX and related CDs. (A–C) Hemolytic activity at 2 h; SBX, SBX+1, SBX-Me, and SGX at 10 (A), 1 (B) and 0.1 (C) mg/mL concentrations. Data is expressed as a percentage relative to the positive control (complete hemolysis). (D) Cholesterol solubilization data (n = 2/CD). (E) Release of phospholipids from hemoglobin-free human erythrocyte ghosts treated with the CDs. CD concentration was 25 mg/mL, and 2% Triton X-100 was used as a positive control. For all assays, data is normalized to SGX and is presented as the mean (±) of the standard error of the mean (SEM). A one-way ANOVA with Tukey post-test was run on all data with statistical significance noted for comparisons where *p < 0.05, **p < 0.01, and ***p < 0.001.

High Resolution Image
Download MS PowerPoint Slide

Pharmacokinetics of SBX-Me

Pharmacokinetic parameters of 14C-SBX-Me were evaluated for both IV and IM dose routes. Mean plasma concentrations over time of SBX-Me are illustrated in Figure 4 and the mean PK parameters are presented in Table 1. The plasma concentration versus time curve for both dose routes were similar following first order kinetics. A comparison of PK parameters from IV administration versus IM administration of a 16 mg/kg dose of SBX-Me showed a significant lower maximum observed concentration (Cmax), following the IM exposure (Table 1). Intramuscular exposed animals had a longer distribution half-life (t1/2dist) of 0.83 h. compared to the IV exposure of 0.33 h. The elimination half-life (t1/2elim) was twice as long in the IM exposed animals when compared to the IV exposures (Table 1). The observed tmax from the IM exposure was 0.3 h indicating rapid absorption from the injection site into the plasma compartment (data not shown). Total clearance of SBX-Me from plasma (CL) was 220.5 and 306.4 mL/h/kg and the apparent volume of distribution (Vd) was 2349.2 and 5896.3 mL/kg for the IV and IM doses respectively, suggesting rapid and extensive distribution beyond the plasma compartment. The lower CL and Vd in the IV exposed animals indicate a higher proportion of the compound remained in the plasma of the IV exposed animals. The mean AUC0-t was 66.9 and 42.0 ± 2.41 μg•h/mL for the IV and IM dose route, respectively (Table 1). Based on the difference in AUC0-t between the two dose routes the absolute bioavailability (F) was determined to be 0.63, indicating abundant absorption into the systemic circulation after an IM exposure.

Figure 4

Figure 4. Mean plasma concentration–time profiles of SBX-Me following (A) single intravenous (IV) or (B) intramuscular (IM) administration of 16 mg/kg 14C-SBX-Me to male Sprague–Dawley rats. Data are expressed as the mean of 5 animals ± the standard error.

High Resolution Image
Download MS PowerPoint Slide
Table 1. Mean Pharmacokinetic Parameters of SBX-Me Following a Single Administration of 16 mg/kg 14C-SBX-Me to Male Sprague Dawley Ratsa
dose (mg/kg)Cmax (μg/mL)t1/2dist (h)t1/2elim (h)AUC0-t (μg·h/mL)AUC0-inf (μg·h/mL)Vd (mL/kg)CL (mL/h/kg)
16, IV49.8 ± 4.40.33 ± 0.327.38 ± 0.4666.9 ± 4.7672.7 ± 4.542349.2 ± 231220.5 ± 13.9
16, IM14.7 ± 2.60.83 ± 0.1814.71 ± 2.642.0 ± 7.7156.5 ± 20.55896.3 ± 523306.4 ± 102
a

Data are expressed as the mean of 5 animals ± the standard deviation. IV: intravenous, IM: intramuscular.

Pharmacokinetics of SBX-Me with Opioid Challenge

To determine if opioids affect the kinetics of SBX-Me, the pharmacokinetic parameters of SBX-Me were evaluated after an IV exposure of either fentanyl, carfentanil or remifentanil followed by treatment with an IM dose of 14C-SBX-Me in Sprague–Dawley rats. Mean plasma concentrations over time of SBX-Me are illustrated in Figure 5 and the mean PK parameters are presented in Table 2. The plasma concentration versus time curve for SBX-Me with and without fentanyl, carfentanil or remifentanil were similar following first order kinetics. Results show that there was no significant change in SBX-Me plasma concentration or PK parameters indicating that the three opioids that were evaluated do not significantly interfere with SBX-Me pharmacokinetics or clearance.

Figure 5

Figure 5. Mean plasma concentration–time profiles of an IM exposure of 14C-SBX-Me (16 mg/kg) after an IV exposure to fentanyl (50 μg/kg), carfentanil (5 μg/kg), or remifentanil (5 μg/kg) in male Sprague–Dawley rats. Inset is a zoom in of earlier time points (0–2 h). Data are expressed as the mean of n = 5 animals ± the standard error.

High Resolution Image
Download MS PowerPoint Slide
Table 2. Mean Pharmacokinetic Profiles of an IM Exposure of 14C-SBX-Me after an IV Exposure to Fentanyl, Carfentanil, or Remifentanil in Male Sprague Dawley Ratsa
dosebCmax (μg/mL)t1/2dist (h)t1/2elim (h)tmax (h)AUC0-t (μg·h/mL)AUC0-inf (μg·h/mL)Vd (mL/kg)CL (mL/h/kg)
SBX-Me14.7 ± 2.60.83 ± 0.1814.71 ± 2.60.3 ± 0.042.0 ± 7.7156.5 ± 20.505896.3 ± 523306.4 ± 102
SBX-Me + fentanyl18.2 ± 5.900.70 ± 0.2414.1 ± 2.720.45 ± 0.163.3 ± 13.8082.2 ± 23.304071.3 ± 553.6207.7 ± 63.4
SBX-Me + carfentanil17.5 ± 3.171.27 ± 0.6210.2 ± 2.040.40 ± 0.1154.8 ± 8.4262.8 ± 13.233783.8 ± 270.5263.5 ± 56.6
SBX-Me + remifentanil18.7 ± 2.110.57 ± 0.0610.1 ± 1.060.40 ± 0.1146.9 ± 2.6053.7 ± 3.764448.7 ± 453.2263.3 ± 80.8
a

Data are expressed as the mean of 5 animals ± the standard deviation.

b

14C-SBX-Me dose = 16 mg/kg (IM); Fentanyl dose = 50 μg/kg (IV); Carfentanil dose = 5 μg/kg (IV); Remifentanil dose = 5 μg/kg (IV).

Tissue Distribution of SBX-Me

When adjusted to total tissue weight, at the Cmax, the liver contained the highest proportion of the dose with a mean of 5.2% of the administered dose followed by the kidney at 2.5%. All other tissues contained less than 1% of the administered dose (See Supporting Information). No SBX-Me was detected in the brain. In the heart and lung SBX-Me was rapidly eliminated from the tissue whereas in the liver, kidney, and spleen elimination was significantly slower over the course of the experiment. As expected, the levels of SBX-Me in the tissues from the IM exposed animals were lower compared to the IV dosed animals (See Supporting Information). (45,46) There was no significant difference in tissue distribution or concentration of SBX-Me in the presence of the opioids when compared to the results obtained from exposure to SBX-Me alone (See Supporting Information). The relatively higher levels and slower elimination rate of SBX-Me in the kidneys could increase the potential for toxic effects since previous studies have shown that certain cyclodextrins have been shown to induce nephrotoxic properties. Some α- and β-CDs have been shown to be nephrotoxic by manifesting a series of alterations in the vacuolar organelles of the proximal tubule after parenteral administration. (47) Additionally, Sugammadex caused a histopathological degeneration in the kidneys when administered to rats at therapeutic dose levels. However, these changes did not cause any deterioration in renal function and were deemed to not be a safety concern. (48)

Pharmacokinetics of Opioids

To determine if SBX-Me affects the pharmacokinetics of the studied opioids, the pharmacokinetic parameters of fentanyl, carfentanil, and remifentanil were evaluated after exposure to 14C-fentanyl, 14C-carfentanil, or 14C-remifentanil and treatment with SBX-Me. Mean plasma concentrations over time of fentanyl, carfentanil, and remifentanil are illustrated in Figure 6 and the mean PK parameters are presented in Table 3. The plasma concentration versus time curve for fentanyl, carfentanil, and remifentanil were similar following first order kinetics. Both the distribution and elimination half-lives were similar for both fentanyl and carfentanil treatment groups even thought there was a 10-fold difference in dose between fentanyl and carfentanil. The elimination half-life for remifentanil was about 35% longer than the other two opioids. The elimination rate constants (CL/Vd) for fentanyl and carfentanil were similar at 0.107 and 0.109, respectively indicating similar rates of movement throughout the body. The elimination rate constant for remifentanil was smaller at 0.071. The observed increase in the elimination half-lives of 6.42 ± 0.38 h and 9.74 ± 0.96 h for fentanyl and remifentanil with SBX-Me treatment respectively, were statistically different when compared to the elimination half-lives for fentanyl (5.37 ± 0.52 h) and remifentanil (8.24 ± 0.69 h) exposure without SBX-Me treatment, indicating that the presence of SBX-Me may alter the elimination half-lives of these opioids (Table 4). It is presumed that the lack of significance in the elimination half-lives from carfentanil was due to the relatively large variation between the individual animals from these treatments resulting in an increase in the standard deviation between the treatment groups.

Figure 6

Figure 6. Mean plasma concentration–time profiles of (A) fentanyl, (B) carfentanil, and (C) remifentanil following single intravenous (IV) administrations of 14C-fentanyl (50 mg/kg), 14C-carfentanil (5 mg/kg), or 14C-remifentanil (50 mg/kg) and (IM) administrations of 16 mg/kg SBX-Me to male Sprague–Dawley rats. Insets are a zoom in of earlier time points (t = 0–2 h.). Data are expressed as the mean of n = 5 animals ± the standard error.

High Resolution Image
Download MS PowerPoint Slide
Table 3. Mean Pharmacokinetic Parameters of Fentanyl, Carfentanil, and Remifentanil with and without SBX-Me Treatment in Male Sprague Dawley Ratsa
treatment groupbCinitial (μg/mL)t1/2dist (h)t1/2elim (h)AUC0-t (ng·h/mL)AUC0-inf (ng·h/mL)Vd (mL/kg)CL (mL/h/kg)
Fentanyl51.6 ± 7.630.35 ± 0.045.37 ± 0.5289.85 ± 9.0992.8 ± 8.363893.5 ± 911502.1 ± 99.2
Fentanyl + SBX-Me64.4 ± 13.520.30 ± 0.036.42 ± 0.38c116.64 ± 7.31124.18 ± 6.953749.62 ± 399403.6 ± 23.1
Carfentanil11.76 ± 1.610.40 ± 0.097.93 ± 2.0618.72 ± 2.5820.66 ± 2.112834 ± 926255.5 ± 25.4
Carfentanil + SBX-Me13.6 ± 3.650.35 ± 0.056.28 ± 2.1118.42 ± 1.6720.35 ± 1.702249.45 ± 819246.8 ± 20.2
Remifentanil6.88 ± 1.630.27 ± 0.028.24 ± 0.694.08 ± 0.694.34 ± 0.7214118 ± 29981186 ± 244.3
Remifentanil + SBX-Me5.36 ± 0.670.26 ± 0.029.74 ± 0.96c3.56 ± 0.273.94 ± 0.3917908 ± 6991282 ± 120.8
a

Data are expressed as the mean of 5 animals ± the standard deviation.

b

14C-Fentanyl dose = 50 mg/kg (IV),14C-carfentanil dose = 5 mg/kg (IV),14C-remifentanil dose = 5 mg/kg (IV), and SBX-Me dose = 16 mg/kg (IM).

c

Statistically different from the opioid exposure group without SBX-Me treatment. p < 0.05.

Table 4. Recovery Times in Male Rats after Exposure to Fentanyl, Carfentanil, and Remifentanil with and without Treatment with SBX-Me
treatmentatime to recovery
fentanyl35 min
fentanyl + SBX-Me17 min
carfentanil172 min
carfentanil + SBX-Me59 min
remifentanil18 min
remifentanil + SBX-Me12 min
a

Fentanyl dose = 50 mg/kg (IV), carfentanil dose = 5 mg/kg (IV), remifentanil dose= 5 mg/kg (IV), and SBX-Me dose = 16 mg/kg (IM).

Tissue Distribution of Fentanyl and Its Derivative

Both fentanyl and carfentanil were detected in all tissues examined (See Supporting Information). Opioid levels rapidly declined from each tissue over the time course of the experiment with background levels returning at approximately 24 h. SBX-Me did not appear to have any effect on the tissue disposition of the opioids.

Metabolism of SBX-Me/Fentanyls

HPLC analysis of urine from rats exposed to 16 mg/kg 14C-SBX-Me revealed that SBX-Me was excreted unchanged over the 24-h period at a retention of 3–4 min which corresponded to the retention time of an SBX-Me standard. Exposure to fentanyl, carfentanil, or remifentanil did not alter the SBX-Me urinary profiles of the animals. Analysis of the urine of rats exposed to 50 μg/kg 14C-fentanyl, 5 μg/kg 14C-carfentanil or 5 μg/kg 14C-remifentanil followed 1 min later with SBX-Me revealed changes in the metabolic profiles of the opioids suggesting the formation of an opioid/SBX-Me complex. Urinary radioprofiles showed a shift in the HPLC retention time of 14C-fentanyl from 8 min to 3–4 min (See Supporting Information). Likewise, a similar shift for carfentanil and remifentanil was observed (from 13 min to 3–4 min and from 14 to 4 min, respectively). The radioactive peaks detected at 3–4 min corresponded to the retention time of 14C-SBX-Me suggesting that the opioids formed a complex with SBX-Me in vivo and were excreted in the urine with a retention time similar to SBX-Me (Supporting Information).

Effect of SBX-me on Fentanyl Intoxication Recovery Time

In addition to the PK/ADME studies, SBX-Me was evaluated in vivo for its ability to counteract the effects of fentanyl, carfentanil and remifentanil in rats. Animals were observed after opioid exposure for any physiological changes and the time to recovery from opioid intoxication with and without SBX-Me treatment. Recovery was determined when animals could right themselves and freely move about their cages. For all three opioids tested, treatment with SBX-Me decreased the time it took animals to recover compared to animals that did not receive the CD (Table 4). The observed recovery times were reduced from ∼35 to ∼17 min for fentanyl, from ∼172 to ∼59 min for carfentanil and from ∼18 to ∼12 min for remifentanil. These results indicate that SBX-Me can decrease the effects of opioid intoxication by aiding in the recovery after sublethal exposures to the three opioids tested.

Discussion

A new, polyanionic, cyclodextrin scaffold known as Subetadex-α-methyl (SBX-Me) has been identified and subsequently evaluated for use as a potentially useful medical countermeasure to combat the effects of fentanyl and related opioids. Preliminary in vitro toxicity assays including hemolytic activity and cholesterol binding propensity for SBX-Me demonstrated its nontoxic profile relative to other promising CD analogs promoting it into the next phase involving in vivo PK and biodistribution studies. Initially, PK studies, employing a 14C-radiolabeled version of SBX-Me, showed a rapid clearance of SBX-Me with an elimination half-life of t1/2 ∼ 7.4 h with little accumulation in major organs (e.g., heart, liver, spleen, kidney and lung). SBX-Me was not detected in the brain. Metabolism and clearance analysis showed that SBX-Me was excreted in the urine unchanged. Subsequent in vivo experiments demonstrated the ability of SBX-Me to alter the PK parameters and metabolic profiles of fentanyl, carfentanil, and remifentanil when administered after opioid exposure in Sprague–Dawley rats. Treatment with SBX-Me caused an increase in the elimination half-lives of the opioids, matching them closely to the elimination half-life of the SBX-Me itself strongly suggesting the formation of a SBX-Me:fentanyl complex. This concept was further reinforced with the observation from the HPLC urinary metabolic profiles showing altered opioid retention times matching that of SBX-Me after SBX-Me treatment. By altering the PK profile (i.e., increasing the half-life) the rate and extent of absorption of the opioid can be altered which can alter the dose that reaches the target tissues potentially leading to decreased toxicity. Furthermore, by forming an SBX-Me/opioid complex the change in metabolism and clearance can influence the concentration of the opioid in the body and the duration of its exposure to various organs and tissues which could ultimately alter the toxicity profile of the compound. The PK and metabolism result together with the decrease in recovery times from animals treated with SBX-Me suggest that this cyclodextrin may influence the toxicity profile of these synthetic opioids by sequestering the free opioid, preventing the drug from interacting with the target receptors therefore neutralizing its effects, which would serve to lower the effective lethal dose of fentanyls leading to a reduced risk from exposure. This proposed mechanism is different compared to conventional treatments where a competitive antagonist (i.e naloxone) competes with the opioids for binding sites on the receptors (49) but is similar to that of the related cyclodextrin Sugammadex in which the neuromuscular blocking agent rocuronium is deactivated by encapsulation by the cyclodextrin. (50) In contrast, the present finding that fentanyl and carfentanil was detected in brain tissue when dosed together with SBX-Me dissuades the argument that an SBX-Me/opioid complex is formed since data shows that SBX-Me alone was not detected in brain tissue. To speculate, SBX-Me may limit the amount of drug getting to the brain but not totally eliminate brain penetration by sequestering some of the free opioid before it crosses the blood–brain barrier. More studies are needed to fully elucidate the toxicity profile of SBX-Me, and interactions between SBX-Me and this class of opioids, and their effects on SBX-Me/opioid biodisposition and brain penetration. These additional studies should include determining the crystal structure of the fentanyl-SBX-Me inclusion complex to better understand the host–guest interactions. (51) These studies can provide direct insight into the binding mechanism of the fentanyl molecule and cyclodextrin and the functional mechanism of the inclusion complex which can influence stability, solubility and drug efficacy. Previous studies have determined the crystal structure of an inclusion complex of β-cyclodextrin and fentanyl, and together with molecular confirmational calculations showed that fentanyl is totally contained within the β-cyclodextrin cavity and that the phenylethyl part of fentanyl existed in several conformations. (51) Overall, the results presented herein collectively present SBX-Me as a plausible starting platform for further development as a MCM in the treatment of fentanyl poisoning. Due to its ability to sequester not only fentanyl but other synthetic opioids such as carfentanil and remifentanil and confer some degree of protection in animals, it is hoped that after additional studies SBX-Me can be further advanced as a potential broad spectrum MCM against a variety of synthetic opioids.

Materials and Methods

Click to copy section linkSection link copied!

Chemicals and Reagents

Reagents and solvents were purchased and used as received. Acetone, methanol, N-methyl-2-pyrrolidinone (NMP), sodium hydroxide and hydrogen sulfide were purchased from VWR (Radnor, PA.). Heptakis-6-deoxy-6-bromo-β-cyclodextrin was purchased from Arachem/Cyclodextrin Shop (Tilberg, Netherlands). 2-Methyl methacrylate was purchased from BeanTown Chemicals (Hudson, NH.). 1-Hydroxybenzotriazole (HOBT), diisopropylcarbodiimide (DIC) and anhydrous dimethylformamide were purchased from Sigma-Aldrich (St. Louis, MO.). 14C-Radiolabeled versions of 2-methyl methacrylic acid and propionic acid were purchased from American Radiolabeled Chemicals, Inc., (St. Louis, MO). Thiol-mediated displacement reactions on the C6-per-brominated β-cyclodextrin followed by methyl ester hydrolysis was accomplished with a modified version of the originally published protocol. (40,52) For the synthesis of the cold and 14C-radiolabeled mercaptoalkylcarboxylic acid methyl ester intermediates, thin layer chromatography (TLC) was used to monitor their production using Merck kieselgel 60-F254 glass sheets and detection accomplished with development of color using ceric ammonium molybdate (CAM) and iodine vapor. (53,54) The three 14C-radiolabeled fentanyls (fentanyl, carfentanil, remifentanil) were synthesized as previously reported (13) but using the final acylation step to introduce the 14C-radiolabel onto the opioids. Multimilligram (∼200–300 mgs) synthesis of SBX-Me was accomplished in similar fashion as for the synthesis of SBX, (30) and then purchased in multigram quantities (2 × 10G) from Cyclolab Kft. (Budapest, Hungary). The purification of all intermediates, regular as well as 14C-radiolabeled, was accomplished by flash column chromatography using a Biotage Isolera purification system using Biotage Sfär silica high-capacity duo cartridges (10 G).

Synthesis of 14C-Fentanyl, 14C-Carfentanil, and 14C-Remifentanil

The syntheses involve acylation as the last step in order to minimize handling of the valuable 14C-radiolabeled propionic acid, and also to minimize the loss of any radiolabeling efficiency in the final product during the early steps due to either low reaction yields or competing side reactions. Thus, reaction between 4-ANPP and 14C-labeled propionic acid (radiolabel at the carbonyl atom) using HOBT/DIC (1-hydroxybenzotriazole and diisopropylcarbodiimide) as coupling reagents provides the 14C-radiolabeled fentanyl. For the remaining two opioids, carfentanil and remifentanil, the 14C-radiolabel was introduced analogously at the acylation step using the precursors on Scheme 1a. The only differences lie in the amount of time for the reaction to take place. All the 14C-radiolabeled opioids were purified using flash column silica gel chromatography (DCM → 3:7 MeOH/DCM).

Scheme 1

Scheme 1. Synthesis of (a) 14C-Labeled Fentanyl, Carfentanil, and Remifentanil and (b) 14C-Labeled SBX-Me (SBX-Me*)a
High Resolution Image
Download MS PowerPoint Slide

aThe asterisk (*) shows the carbon atom where the 14C-label is in each molecule.

Synthesis of 14C-SBX-Me (SBX-Me*)

As there are no commercial vendors for 14C-radiolabeled 2-methyl methacrylate, a synthetic route was devised for its production from the commercially available 14C-radiolabeled 2-methyl methacrylic acid. The synthesis of 14C-radiolabeled 3-mercapto-2-methyl methylpropanoate is outlined in Scheme 1b, and it involves the conversion of 14C-radiolabeled 2-methyl methacrylic acid to its acyl chloride using thionyl chloride and esterification with methanol. With the 14C-radiolabeled 2-methyl methacrylate, several conditions were tested for the Michael addition using the mercapto anion (See Supporting Information). The most optimal conditions for the synthesis of 14C-radiolabeled 3-mercapto-2-methyl methylpropanoate involved the heating (80 °C) of the methyl methacrylate in wet DMF in the presence of Na2S to furnish the desired 14C-radiolabeled side chain in 77% yield after purification. Reaction of 14C-radiolabeled 3-mercapto-2-methyl methylpropanoate with the C6-deoxy-6-heptabromo-β-CD in NMP at 55 °C overnight to provide the 14C-radiolabeled SBX-Me (SBX-Me*) as an off-white flaky solid after two alternating rounds of precipitation from MeOH, water, and acetone respectively. The methyl ester hydrolysis was accomplished using a 1 M NaOH/H2O solution and stirring overnight at ambient temperature followed by precipitation using acetone to yield white flakes that were collected by centrifugation (Scheme 1b). Additionally, the white solid was resuspended, washed with MeOH (2 × 50 mL) and collected by centrifugation. Lastly, the solid was vacuum filtered, washed with MeOH (2 × 20 mL), and dried under vacuum for 2 h. This method of purification is the same that we have used in the synthesis of SBX and previously described SBX analogs. (30)

EI-GC-MS Analysis Method

A 6890 Agilent GC with 5975 MS detector equipped with a split/splitless injector was used for analysis of all intermediate small molecules. The GC column used for the analysis was an Agilent HP-5 ms UI capillary column (30 m × 0.25 mm id ×0.25 μm film thickness). Ultrahigh purity helium, at 0.8 mL/min, served as the carrier gas. The inlet was operated in pulsed splitless mode (25 psi for 1 min, followed by a 50 mL/min purge flow), with the injector temperature set at 250 °C and the injection volume was 1 μL. The oven temperature program was as follows: 40 °C, held for 3 min, increased at 8 °C/min to 300 °C, held for 3 min. The MS ion source and quadrupole temperatures were 230 and 150 °C, respectively. Electron ionization (EI) was used with an ionization energy of 70 eV. The MS was operated to scan from m/z = 29 to 600 in 0.4 s with a solvent delay of 3.5 min as previously described. (55,56)

In Vitro Assays

Assays included hemolytic activity, cholesterol solubilization and solubilization of phospholipids. The concentration range of the CDs in the in vitro assays were based on reported literature values from previous studies with known CD analogs. (57−59) A one-way ANOVA with Tukey post-test was run on all data with statistical significance noted for comparisons where p < 0.05.

Hemolytic Activity

Hemolytic activity was assessed using established protocols. (57) Erythrocytes were separated from citrated human blood (500g, 5 min, 3X PBS wash) and resuspended in PBS. The CDs, SBX, SBX-Me, Sugammadex (SGX), and SBX+1 (where the side chains possess and additional methylene unit relative to SBX) were added to the cell suspension (16% v/v in PBS), gently mixed and incubated at 37 °C. At 2 h, samples were centrifuged at 500 x g and supernatants were collected. The absorbance of hemoglobin was measured in the supernatant using λ = 577 nm with λ = 655 nm as a reference wavelength. The percent of hemolysis is expressed as the ratio of hemoglobin in each sample supernatant relative to hemoglobin concentration after complete hemolysis of cells in Triton x-100.

Cholesterol Solubilization

Cholesterol solubilization was assessed using established protocols. (58) The CDs (SBX, SBX-Me, SGX, and SBX+1) were dissolved in PBS (10 mM) and an excess of cholesterol (100 mM) was added. Suspensions were mixed at room temperature for 12 h. After incubation, suspensions were filtered (Co-star, SpinX, 0.22 μm filters) and the cholesterol contents of filtrates were determined by ultrahigh performance liquid chromatography (UPLC) using the following method: isocratic, flow rate of 0.250 mL/min, mobile phase: acetonitrile/isopropanol (50/50), column: Phenomenex C18 Synergi Max RP 250 × 4.6, column temperature of 55 °C, UVmax of λ = 207 nm. Percent solubilization is calculated based on the peak areas from the CD/cholesterol solution evaluated relative to the cholesterol standard solution and all data (n = 2/CD) are normalized to SGX.

Solubilization of Phospholipids

Phospholipid solubilization was assessed using established protocols. (59) To assess the solubilization of phospholipids for CDs, hemoglobin-free human erythrocyte ghosts were used since hemoglobin interferes with the colorimetric assay for phospholipoids. Ghost cell suspensions (0.250 mL) were added to a Tris-HCl (10 mM) buffer containing the CDs (SBX-Me, SBX, SGX, and SBX+1). The samples were incubated in a 37 °C water bath for 1 h. and then centrifuged at 2000g for 20 min at 4 °C. The amount of phospholipid in the supernatant was determined using the commercially available Phospholipid Assay Kit (MAK122, Sigma-Aldrich, St Louis, MO, λ = 570 nm).

In Vivo Assessment

Animal experiments were conducted at the Lawrence Livermore National Laboratory (LLNL) AAALAC accredited animal care facility. The protocol for the animal experiments was reviewed and approved by the LLNL Institutional Animal Care and Use Committee (IACUC) prior to the initiation of the study. All experiments were performed in accordance with relevant guidelines set forth by the Guide for the Care and Use of Laboratory Animals (Eighth Ed.). In addition, the study was carried out in compliance with the ARRIVE guidelines. Male Sprague–Dawley rats weighing 250–300 g were obtained from Envigo Laboratories (Indianapolis, IN.). Rats were housed individually in polystyrene cages containing hardwood bedding and kept on a 12-h. light/dark cycle in a ventilated room maintained at 24 °C. Food and water were provided ad libitum.

Pharmacokinetics of SBX-Me

To evaluate the pharmacokinetics (PK) of SBX-Me, male Sprague–Dawley rats were administered a single intravenous (IV) or intramuscular (IM) dose of 14C-SBX-Me dissolved in sterile saline at a concentration of 16 mg/kg, which is the therapeutic dose for the FDA-approved cyclodextrin SGX. At the designated time points of 0.08, 0.25, 0.5, 1, 2, 4, 8, and 24 h. postexposure, whole blood was collected, and the plasma was separated within 1 h of collection by centrifugation. The volume of plasma obtained was recorded and the sample was stored at −80 °C until analysis. Total radiocarbon content of the plasma samples was quantified by accelerator mass spectrometry (AMS) as described previously. (60)
The plasma PK parameters of SBX-Me were calculated by noncompartmental analysis using PK Solutions software (Summit Research Services, Montrose, CO.). A two-stage approach was used to independently fit the plasma concentration data from each rat, and then determine the individual means ± standard errors. The half-life (t1/2) and the initial concentration observed in plasma (C0) were determined from the concentration-versus-time data. The area under the concentration vs time curve (AUC) was calculated for the intervals from time zero to time t (AUC0-t), where t is the time of the last measurable concentration (24 h.), and for time zero to infinity (AUC0-inf), using the linear trapezoidal method. The volume of distribution (Vd) was determined on the basis of the AUC determination and reflects the Vd during the elimination phase. The clearance (CL) calculation is based on the AUC00-inf. These parameters provided valuable information on bioavailability, the effect of dose route on clearance, and the effect of dose on the extent of absorption beyond the central compartment. To assess the effect these three fentanyls have on SBX-Me pharmacokinetics, the above procedure was repeated except that one minute prior to the 14C-SBX-Me dose animals received an IV dose of either fentanyl (50 μg/kg), carfentanil (5 μg/kg), or remifentanil (5 μg/kg) through an implanted jugular vein catheter. The dose concentrations of the opioids were chosen to provide a nonlethal maximum observed anesthetic effect. (61−63)

Biodistribution of SBX-Me

Biodistribution of SBX-Me was determined as described previously. (63) Briefly, rats (n = 5 per time point) were administered a single IM dose of 16 mg/kg 14C-SBX-Me with or without an IV dose of fentanyl (50 μg/kg), carfentanil (5 μg/kg), or remifentanil (5 μg/kg), as described above. Following dose administration, animals were euthanized by CO2 asphyxiation at 0.08, 0.25, 0.5, 1, 2, 4, 8, and 24 h. post dose. Immediately following euthanasia, whole animal perfusion (heparinized (50 K U/L) PBS), was performed to ensure all the blood was removed from the tissues prior to collection. After perfusion, tissues (brain, liver, kidney, heart, spleen and lung) were excised from the carcass and rinsed twice in PBS. All tissues were then stored in glass vials (28 × 60 mm) at −80 °C until analysis for carbon-14 content by AMS. (64) To assess metabolism of 14C-SBX-Me a subset of animals was placed in metabolism cages and urine was collected for 24 h. after 14C-SBX-Me administration. The collected urine was analyzed by reversed-phase HPLC to determine the presence of SBX-Me metabolites or breakdown products.

Biodisposition of Fentanyl, Carfentanil, and Remifentanil

To assess the affect SBX-Me has on opioid biodisposition animals were exposed to an IV dose of either 14C-fentanyl (50 μg/kg), 14C-carfentanil (5 μg/kg), or 14C-remifentanil (5 μg/kg) through an implanted jugular vein catheter followed one minute later with an IM dose of SBX-Me (16 mg/kg). At the designated time points of 0.08, 0.25, 0.5, 1, 2, 4, 8, and 24 h. postexposure, blood and urine was collected, for PK and metabolism analysis of each opioid, as described above.

Safety Statement

The synthesis of synthetic opioids should be executed by specially trained personnel and always involve the use of the appropriate personal protective equipment (PPE) that includes lab coat, nitrile gloves underneath butyl gloves, face shield, and eye protection. All the synthetic steps leading to the formation of the final opioid should take place in a well-ventilated chemical fume hood for maximum shielding from the chemicals. In addition, Narcan antidote should always be present nearby for rapid use when these synthetic and analytical standard preparations are taking place.

Supporting Information

Click to copy section linkSection link copied!

The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/acscentsci.4c00682.

  • Complete synthetic methods and characterization of SBX-Me, 14C-radiolabeled SBX-Me, fentanyl, carfentanil, and remifentanil; NMR spectra of SBX-Me; experimental methods and additional data including tissue distribution profiles and metabolism studies (PDF)

Terms & Conditions

Most electronic Supporting Information files are available without a subscription to ACS Web Editions. Such files may be downloaded by article for research use (if there is a public use license linked to the relevant article, that license may permit other uses). Permission may be obtained from ACS for other uses through requests via the RightsLink permission system: http://pubs.acs.org/page/copyright/permissions.html.

Author Information

Click to copy section linkSection link copied!
  • Corresponding Authors
    • Michael A. Malfatti - Physical and Life Sciences Directorate  and  Biosciences and Biotechnology Division, , , , and , Lawrence Livermore National Laboratory, Livermore, California 94550, United States;  Orcidhttps://orcid.org/0000-0003-2431-9115;  Email: [email protected]
    • Carlos A. Valdez - Physical and Life Sciences Directorate,  Biosciences and Biotechnology Division  and  Forensic Science Center, , , , and , Lawrence Livermore National Laboratory, Livermore, California 94550, United States;  Email: [email protected]
  • Authors
    • Heather A. Enright - Physical and Life Sciences Directorate  and  Biosciences and Biotechnology Division, , , , and , Lawrence Livermore National Laboratory, Livermore, California 94550, United States
    • Summer McCloy - Physical and Life Sciences Directorate  and  Biosciences and Biotechnology Division, , , , and , Lawrence Livermore National Laboratory, Livermore, California 94550, United States
    • Esther A. Ubick - Physical and Life Sciences Directorate  and  Biosciences and Biotechnology Division, , , , and , Lawrence Livermore National Laboratory, Livermore, California 94550, United States
    • Edward Kuhn - Physical and Life Sciences Directorate  and  Biosciences and Biotechnology Division, , , , and , Lawrence Livermore National Laboratory, Livermore, California 94550, United States
    • Alagu Subramanian - Physical and Life Sciences Directorate,  Biosciences and Biotechnology Division,  Global Security Directorate  and  Forensic Science Center, , , , and , Lawrence Livermore National Laboratory, Livermore, California 94550, United States;  Orcidhttps://orcid.org/0009-0007-7716-7801
    • Victoria Hio Leong Lao - Physical and Life Sciences Directorate  and  Biosciences and Biotechnology Division, , , , and , Lawrence Livermore National Laboratory, Livermore, California 94550, United States
    • Doris Lam - Physical and Life Sciences Directorate  and  Biosciences and Biotechnology Division, , , , and , Lawrence Livermore National Laboratory, Livermore, California 94550, United States
    • Nicholas A. Be - Physical and Life Sciences Directorate  and  Biosciences and Biotechnology Division, , , , and , Lawrence Livermore National Laboratory, Livermore, California 94550, United States
    • Saphon Hok - Global Security Directorate  and  Forensic Science Center, , , , and , Lawrence Livermore National Laboratory, Livermore, California 94550, United States
    • Edmond Y. Lau - Physical and Life Sciences Directorate  and  Biosciences and Biotechnology Division, , , , and , Lawrence Livermore National Laboratory, Livermore, California 94550, United States
    • Derrick C. Kaseman - Physical and Life Sciences Directorate,  Forensic Science Center  and  Materials Science Division, , , , and , Lawrence Livermore National Laboratory, Livermore, California 94550, United States;  Orcidhttps://orcid.org/0000-0003-2076-1264
    • Brian P. Mayer - Physical and Life Sciences Directorate,  Global Security Directorate  and  Forensic Science Center, , , , and , Lawrence Livermore National Laboratory, Livermore, California 94550, United States;  Orcidhttps://orcid.org/0000-0003-1967-9802
  • Notes
    This document (LLNL-JRNL-853702) was prepared as an account of work sponsored by an agency of the United States government. Neither the United States government nor Lawrence Livermore National Security, LLC, nor any of their employees makes any warranty, expressed or implied, or assumes any legal liability or responsibility for the accuracy, completeness, or usefulness of any information, apparatus, product, or process disclosed, or represents that its use would not infringe privately owned rights. Reference herein to any specific commercial product, process, or service by trade name, trademark, manufacturer, or otherwise does not necessarily constitute or imply its endorsement, recommendation, or favoring by the United States government or Lawrence Livermore National Security, LLC. The views and opinions of authors expressed herein do not necessarily state or reflect those of the United States government or Lawrence Livermore National Security, LLC, and shall not be used for advertising or product endorsement purposes.
    The authors declare no competing financial interest.

Acknowledgments

Click to copy section linkSection link copied!

This work was performed under the auspices of the U.S. Department of Energy by Lawrence Livermore National Laboratory under contract DE-AC52-07NA27344 and was accomplished with a grant awarded to C.A.V. by the Defense Threat and Reduction Agency (DTRA) (CB10740). Work was performed in part at the National User Resource for Biological Accelerator Mass Spectrometry at LLNL which is supported by the National Institutes of Health (NIH), National Institute of General Medical Sciences (NIGMS) under grant R24GM137748. The authors greatly appreciate Dr. Carolyn Koester and Mr. Armando Alcaraz for their critical reading of the manuscript.

Dedication

Click to copy section linkSection link copied!

This article is dedicated to the memory of our colleague Victoria Hio Leong Lao.

References

Click to copy section linkSection link copied!

This article references 64 other publications.

  1. 1
    Shipton, E. A.; Shipton, E. E.; Shipton, A. J. A Review of the Opioid Epidemic: What Do We Do About It?. Pain Ther 2018, 7, 23– 36,  DOI: 10.1007/s40122-018-0096-7
    Google Scholar
    1
    A Review of the Opioid Epidemic: What Do We Do About It?
    Shipton Edward A; Shipton Elspeth E; Shipton Ashleigh J
    Pain and therapy (2018), 7 (1), 23-36 ISSN:2193-8237.
    The opioid epidemic, with its noticeable increase in opioid prescriptions and related misuse, abuse and resultant deaths in the previous 12 years, is a particularly North American phenomenon. Europe, and particularly low- and middle-income countries, appear to be less influenced by this problem. There is undisputable value in using opioids not only in the treatment of acute pain, but in cancer pain as well. However, opioids are progressively being prescribed more and more for chronic non-cancer pain, despite inadequate data on their efficacy. In this paper, we describe the current prevalence of opioid misuse in a number of countries and the rationale for the commencement of opioid therapy. The safe initiation and monitoring of opioid therapy as well as the need for concurrent use of interdisciplinary multimodal therapy is discussed. The possible consequences of long-term use and predictors of high opioid use and overdose are presented. In particular, the management of opioid use disorders and the prevention of opioid abuse and dependence in the young, the old and the pregnant are discussed. Measures to prevent overprescribing and to alleviate risk are described, including the tapering of opioids and the use of opioid deterrents. Finally, the paper looks at the future development of pioneering medications and technologies to potentially treat abuse. In those parts of the world with an opioid epidemic, coroners and medical examiners, private and public health agencies, and agencies that enforce the law need to cooperate in an effort to slow down and reverse the indiscriminate use of prescribing opioids in the long-term for chronic non-cancer pain. Ongoing research is needed to create ways to minimise risks of opioid use, and to provide evidence for effective strategies for treating chronic pain.
    >> More from SciFinder ®
    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC1MnpsFGhsA%253D%253D&md5=106224b0b69f5164ee8a9abed3856f8c
  2. 2
    Skolnick, P. The Opioid Epidemic: Crisis and Solutions. Annu. Rev. Pharmacol. Toxicol. 2018, 58, 143– 159,  DOI: 10.1146/annurev-pharmtox-010617-052534
    Google Scholar
    2
    The Opioid Epidemic: Crisis and Solutions
    Skolnick, Phil
    Annual Review of Pharmacology and Toxicology (2018), 58 (), 143-159CODEN: ARPTDI; ISSN:0362-1642. (Annual Reviews)
    The widespread abuse of prescription opioids and a dramatic increase in the availability of illicit opioids have created what is commonly referred to as the opioid epidemic. The magnitude of this epidemic is startling: About 4% of the adult US population misuses prescription opioids, and in 2015, more than 33,000 deaths were attributable to overdose with licit and illicit opioids. Increasing the availability of medication-assisted treatments (such as buprenorphine and naltrexone), the use of abuse-deterrent formulations, and the adoption of US Centers for Disease Control and Prevention prescribing guidelines all constitute short-term approaches to quell this epidemic. However, with more than 125 million Americans suffering from either acute or chronic pain, the development of effective alternatives to opioids, enabled at least in part by a fuller understanding of the neurobiol. bases of pain, offers the best long-term soln. for controlling and ultimately eradicating this epidemic.
    >> More from SciFinder ®
    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXhsF2hurzP&md5=af8d4dfe44cab36c82163e4e06e9ac61
  3. 3
    Janssen, P. A. J.; Eddy, N. B. Compounds related to pethidine-IV. New general chemical methods of increasing the analgesic activity of pethidine. J. Med. Chem. 1960, 2, 31– 45,  DOI: 10.1021/jm50008a003
    Google Scholar
    There is no corresponding record for this reference.
  4. 4
    Stanley, T. H. The history and development of the fentanyl series. J. Pain Symptom Manag. 1992, 7, S3– S7,  DOI: 10.1016/0885-3924(92)90047-L
    Google Scholar
    4
    The history and development of the fentanyl series
    Stanley T H
    Journal of pain and symptom management (1992), 7 (3 Suppl), S3-7 ISSN:0885-3924.
    In the last two decades, opioid analgesics have assumed an important place in general anesthetic practice in the United States. Part of the reason for this has been the introduction of the potent new agonists fentanyl, sufentanil, and alfentanil. Because of problems with morphine-oxygen anesthesia (incomplete amnesia, occasional histamine-related reaction, marked increases in intra- and postoperative respiratory depression), a suitable alternative was sought but not found among existing opioids. A breakthrough came in 1960, when fentanyl was synthesized, laying the foundation for a better understanding of the structure-activity relationships of narcotic analgesics and stimulating interest in developing compounds with even greater potency and safety margins. Investigators interested in opioid anesthesia began to study fentanyl in animals and then in humans. Fentanyl (50-100 micrograms/kg) with oxygen (100%) was evaluated as an anesthetic in patients undergoing mitral valve and coronary artery surgery. Changes in cardiovascular dynamics with induction doses ranging from 8 to 30 micrograms/kg consisted of small decreases in heart rate and arterial blood pressure. All other cardiovascular variables studied, including cardiac output, remained unchanged, even with additional doses up to 100 micrograms/kg. It was determined that fentanyl had use as a narcotic anesthetic, despite its potential for cardiovascular depression and stimulation, respiratory depression, muscle rigidity, and, occasionally, incomplete anesthesia. Since the introduction of fentanyl, two other potent synthetic opioids have been introduced into clinical practice--sufentanil and alfentanil.
    >> More from SciFinder ®
    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADyaK38zovVOmtA%253D%253D&md5=1fa4059345eb76873c75c413a859ab94
  5. 5
    Vardanyan, R. S.; Hruby, V. J. Fentanyl-related compounds and derivatives: current status and future prospects for pharmaceutical applications. Future Med. Chem. 2014, 6, 385– 412,  DOI: 10.4155/fmc.13.215
    Google Scholar
    5
    Fentanyl-related compounds and derivatives: current status and future prospects for pharmaceutical applications
    Vardanyan, Ruben S.; Hruby, Victor J.
    Future Medicinal Chemistry (2014), 6 (4), 385-412CODEN: FMCUA7; ISSN:1756-8919. (Future Science Ltd.)
    A review. Fentanyl and its analogs have been mainstays for the treatment of severe to moderate pain for many years. In this review, the authors outline the structural and corresponding synthetic strategies that were used to understand the structure-biol. activity relationship in fentanyl-related compds. and derivs. and their biol. activity profiles. The authors discuss how changes in the scaffold structure can change biol. and pharmacol. activities. Finally, recent efforts to design and synthesize novel multivalent ligands that act as mu and delta opioid receptors and NK-1 receptors are discussed.
    >> More from SciFinder ®
    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXksV2qtLk%253D&md5=4f28b2139ff80d66cf4ad55a691e6c4b
  6. 6
    Armenian, P.; Vo, K. T.; Barr Walker, J.; Lynch, K. L. Fentanyl, fentanyl analogs and novel synthetic opioids: A comprehensive review. Neuropharmacology 2018, 134, 121– 132,  DOI: 10.1016/j.neuropharm.2017.10.016
    Google Scholar
    6
    Fentanyl, fentanyl analogs and novel synthetic opioids: A comprehensive review
    Armenian, Patil; Vo, Kathy T.; Barr-Walker, Jill; Lynch, Kara L.
    Neuropharmacology (2018), 134 (Part_A), 121-132CODEN: NEPHBW; ISSN:0028-3908. (Elsevier B.V.)
    Deaths from opioid use are increasing in the US, with a growing proportion due to synthetic opioids. Until 2013, sporadic outbreaks of fentanyl and fentanyl analogs contaminating the heroin supply caused some deaths in heroin users. Since then, fentanyl has caused deaths in every state and fentanyl and its analogs have completely infiltrated the North American heroin supply. In 2014, the first illicit pills contg. fentanyl, fentanyl analogs, and other novel synthetic opioids such as U-47700 were detected. These pills, which look like known opioids or benzodiazepines, have introduced synthetic opioids to more unsuspecting customers. As soon as these drugs are regulated by various countries, new compds. quickly appear on the market, making detection difficult and the no. of cases likely underreported. Std. targeted anal. techniques such as GC-MS (gas chromatog. mass spectrometry) and LC-MS/MS (liq. chromatog. tandem mass spectrometry) can detect these drugs, but novel compd. identification is aided by nontargeted testing with LC-HRMS (liq. chromatog. high resoln. mass spectrometry). Fentanyl, fentanyl analogs and other novel synthetic opioids are all full agonists of varying potencies at the μ-opioid receptor, leading to typical clin. effects of miosis and respiratory and central nervous system depression. Due to their high affinity for μ-opioid receptors, larger doses of naloxone are required to reverse the effects than are commonly used. Synthetic opioids are an increasingly major public health threat requiring vigilance from multiple fields including law enforcement, government agencies, clin. chemists, pharmacists, and physicians, to name a few, in order to stem its tide.
    >> More from SciFinder ®
    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXhslSktbrM&md5=10085cfb511f8fd6316ffba4d39dcdef
  7. 7
    Dismukes, L. C. How Did We Get Here? Heroin and Fentanyl Trafficking Trends: A Law Enforcement Perspective. N. C. Med. J. 2018, 79, 181– 184,  DOI: 10.18043/ncm.79.3.181
    Google Scholar
    There is no corresponding record for this reference.
  8. 8
    Tamama, K.; Lynch, M. J. Newly Emerging Drugs of Abuse. Handb. Exp. Pharmacol. 2019, 258, 463– 502,  DOI: 10.1007/164_2019_260
    Google Scholar
    There is no corresponding record for this reference.
  9. 9
    Reuter, P.; Pardo, B.; Taylor, J. Imagining a fentanyl future: Some consequences of synthetic opioids replacing heroin. Int. J. Drug Policy 2021, 94, 103086,  DOI: 10.1016/j.drugpo.2020.103086
    Google Scholar
    There is no corresponding record for this reference.
  10. 10
    Kilmer, B.; Pardo, B.; Caulkins, J. P.; Reuter, P. How much illegally manufactured fentanyl could the U.S. be consuming?. Am. J. Drug Alcohol Abuse 2022, 48, 397– 402,  DOI: 10.1080/00952990.2022.2092491
    Google Scholar
    There is no corresponding record for this reference.
  11. 11
    Gupta, P. K.; Ganesan, K.; Pande, A.; Malhotra, R. C. A convenient one pot synthesis of fentanyl. J. Chem. Res. 2005, 2005, 452– 453,  DOI: 10.3184/030823405774309078
    Google Scholar
    There is no corresponding record for this reference.
  12. 12
    Siegfried. Synthesis of Fentanyl; 2014; https://erowid.org/archive/rhodium/chemistry/fentanyl.html (accessed Apr 23, 2023).
    Google Scholar
    There is no corresponding record for this reference.
  13. 13
    Valdez, C. A.; Leif, R. N.; Mayer, B. P. An efficient, optimized synthesis of fentanyl and related analogs. PLoS One 2014, 9, e108250  DOI: 10.1371/journal.pone.0108250
    Google Scholar
    13
    An efficient, optimized synthesis of fentanyl and related analogs
    Valdez, Carlos A.; Leif, Roald N.; Mayer, Brian P.
    PLoS One (2014), 9 (9), e108250/1-e108250/8, 8 pp.CODEN: POLNCL; ISSN:1932-6203. (Public Library of Science)
    An efficient synthesis of fentanyl and its analogs I [R1 = CH2CH2Ph, CH2CH2-2-thienyl, R2 = Me, Et] along with their hydrochloride and citric acid salts was described. The three-step synthetic route starting with 4-piperidone was subject to optimization studies furnishing a process that generated the target fentanyls in high yields (73-78%). The strategy offered an opportunity for gram-scale efficient prodn. of fentanyl analogs.
    >> More from SciFinder ®
    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXhslaqtrzJ&md5=ec30c9ce64dc9babfaff4da55772f486
  14. 14
    Walz, A. J.; Hsu, F.-L. An operationally simple synthesis of fentanyl citrate. Org. Prep. Proced. Int. 2017, 49, 467– 470,  DOI: 10.1080/00304948.2017.1374129
    Google Scholar
    There is no corresponding record for this reference.
  15. 15
    Pardo, B.; Taylor, J.; Caulkins, J. A.; Kilmer, B.; Reuter, P.; Stein, B. D. The Future of Fentanyl and Other Synthetic Opioids; RAND Corporation, 2019.
    Google Scholar
    There is no corresponding record for this reference.
  16. 16
    Busardò, F. P.; Carlier, J.; Giorgetti, R.; Tagliabracci, A.; Pacifici, R.; Gottardi, M.; Pichini, S. Ultra-High-Performance Liquid Chromatography-Tandem Mass Spectrometry Assay for Quantifying Fentanyl and 22 Analogs and Metabolites in Whole Blood, Urine, and Hair. Front. Chem. 2019, 7, 184,  DOI: 10.3389/fchem.2019.00184
    Google Scholar
    16
    Ultra-high-performance liquid chromatography-tandem mass spectrometry assay for quantifying fentanyl and 22 analogs and metabolites in whole blood, urine, and hair
    Busardo, Francesco Paolo; Carlier, Jeremy; Giorgetti, Raffaele; Tagliabracci, Adriano; Pacifici, Roberta; Gottardi, Massimo; Pichini, Simona
    Frontiers in Chemistry (Lausanne, Switzerland) (2019), 7 (), 184CODEN: FCLSAA; ISSN:2296-2646. (Frontiers Media S.A.)
    In this study, we aimed to develop a new method for detecting the newest fentanyl analogs with a high sensitivity, in whole blood, urine, and hair. We developed comprehensive ultra-high-performance liq. chromatog.-tandem mass spectrometry method for quantifying fentanyl and 22 analogs and metabolites. Urine samples were simply dild. before injection; a liq.-liq. extn. was performed for blood testing; and a solid phase extn. was performed in hair. Av. blood concns. were 7.84 ± 7.21 and 30.0 ± 18.0μg/L for cyclopropylfentanyl and cyclopropyl norfentanyl, resp., 4.08 ± 2.30μg/L for methoxyacetylfentanyl, 40.2 ± 38.6 and 44.5 ± 21.1μg/L for acetylfentanyl and acetyl norfentanyl, resp., 33.7 and 7.17μg/L for fentanyl and norfentanyl, resp., 3.60 and 0.90μg/L for furanylfentanyl and furanyl norfentanyl, resp., 0.67μg/L for sufentanil, and 3.13 ± 2.37μg/L for 4-ANPP. Av. urine concns. were 47.7 ± 39.3 and 417 ± 296μg/L for cyclopropylfentanyl and cyclopropyl norfentanyl, resp., 995 ± 908μg/L for methoxyacetylfentanyl, 1,874 ± 1,710 and 6,582 ± 3,252μg/L for acetylfentanyl and acetyl norfentanyl, resp., 146 ± 318 and 300 ± 710μg/L for fentanyl and norfentanyl, resp., 84.0 and 23.0μg/L for furanylfentanyl and furanyl norfentanyl, resp., and 50.5 ± 50.9μg/L for 4-ANPP. Av. hair concns. were 2,670 ± 184 and 82.1 ± 94.7 ng/g for fentanyl and norfentanyl, resp., and 10.8 ± 0.57 ng/g for 4-ANPP.
    >> More from SciFinder ®
    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1MXhtlOmsrfO&md5=d60dac197273bc67517ce9dbf96082f0
  17. 17
    Valdez, C. A. Gas Chromatography-Mass Spectrometry Analysis of Synthetic Opioids Belonging to the Fentanyl Class: A Review. Crit. Rev. Anal. Chem. 2022, 52, 1938– 1968,  DOI: 10.1080/10408347.2021.1927668
    Google Scholar
    There is no corresponding record for this reference.
  18. 18
    Van Dorp, E. L. A.; Yassen, A.; Dahan, A. Naloxone treatment in opioid addiction: the risks and benefits. Expert Opin. Drug Saf. 2007, 6, 125– 132,  DOI: 10.1517/14740338.6.2.125
    Google Scholar
    18
    Naloxone treatment in opioid addiction: the risks and benefits
    van Dorp, Eveline L. A.; Yassen, Ashraf; Dahan, Albert
    Expert Opinion on Drug Safety (2007), 6 (2), 125-132CODEN: EODSA9; ISSN:1474-0338. (Informa Healthcare)
    A review. Naloxone is a non-selective, short-acting opioid receptor antagonist that has a long clin. history of successful use and is presently considered a safe drug over a wide dose range (up to 10 mg). In opioid-dependent patients, naloxone is used in the treatment of opioid-overdose-induced respiratory depression, in (ultra)rapid detoxification and in combination with buprenorphine for maintenance therapy (to prevent i.v. abuse). Risks related to naloxone use in opioid-dependent patients are: (i) the induction of an acute withdrawal syndrome (the occurrence of vomiting and aspiration is potentially life threatening); (ii) the effect of naloxone may wear off prematurely when used for treatment of opioid-induced respiratory depression; and (iii) in patients treated for severe pain with an opioid, high-dose naloxone and/or rapidly infused naloxone may cause catecholamine release and consequently pulmonary edema and cardiac arrhythmias. These risks warrant the cautious use of naloxone and adequate monitoring of the cardiorespiratory status of the patient after naloxone administration where indicated.
    >> More from SciFinder ®
    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2sXjtFKns7s%253D&md5=e7ff48833854deffe0f8bf91520adf02
  19. 19
    Carpenter, J.; Murray, B. P.; Atti, S.; Moran, T. P.; Yancey, A.; Morgan, B. Naloxone Dosing After Opioid Overdose in the Era of Illicitly Manufactured Fentanyl. J. Med. Toxicol. 2020, 16, 41– 48,  DOI: 10.1007/s13181-019-00735-w
    Google Scholar
    There is no corresponding record for this reference.
  20. 20
    Britch, S. C.; Walsh, S. L. Treatment of opioid overdose: current approaches and recent advances. Psychopharmacology (Berl.) 2022, 239, 2063– 2081,  DOI: 10.1007/s00213-022-06125-5
    Google Scholar
    20
    Treatment of opioid overdose: current approaches and recent advances
    Britch Stevie C; Walsh Sharon L; Britch Stevie C; Walsh Sharon L; Walsh Sharon L; Walsh Sharon L; Walsh Sharon L
    Psychopharmacology (2022), 239 (7), 2063-2081 ISSN:.
    BACKGROUND: The USA has recently entered the third decade of the opioid epidemic. Opioid overdose deaths reached a new record of over 74,000 in a 12-month period ending April 2021. Naloxone is the primary opioid overdose reversal agent, but concern has been raised that naloxone is not efficacious against the pervasive illicit high potency opioids (i.e., fentanyl and fentanyl analogs). METHODS: This narrative review provides a brief overview of naloxone, including its history and pharmacology, and the evidence regarding naloxone efficacy against fentanyl and fentanyl analogs. We also highlight current advances in overdose treatments and technologies that have been tested in humans. RESULTS AND CONCLUSIONS: The argument that naloxone is not efficacious against fentanyl and fentanyl analogs rests on case studies, retrospective analyses of community outbreaks, pharmacokinetics, and pharmacodynamics. No well-controlled studies have been conducted to test this argument, and the current literature provides limited evidence to suggest that naloxone is ineffective against fentanyl or fentanyl analog overdose. Rather a central concern for treating fentanyl/fentanyl analog overdose is the rapidity of overdose onset and the narrow window for treatment. It is also difficult to determine if other non-opioid substances are contributing to a drug overdose, for which naloxone is not an effective treatment. Alternative pharmacological approaches that are currently being studied in humans include other opioid receptor antagonists (e.g., nalmefene), respiratory stimulants, and buprenorphine. None of these approaches target polysubstance overdose and only one novel approach (a wearable naloxone delivery device) would address the narrow treatment window.
    >> More from SciFinder ®
    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BB2Mvjslaksw%253D%253D&md5=251cb14d61e83fcc0f4e49769bd33038
  21. 21
    Yeung, D. T.; Bough, K. J.; Harper, J. R.; Platoff, G. E., Jr. National Institutes of Health (NIH) executive meeting summary: Developing medical countermeasures to rescue opioid-induced respiratory depression (a Trans-Agency Scientific Meeting)-August 6/7, 2019. J. Med. Toxicol. 2020, 16, 87– 105,  DOI: 10.1007/s13181-019-00750-x
    Google Scholar
    There is no corresponding record for this reference.
  22. 22
    France, C. P.; Ahern, G. P.; Averick, S.; Disney, A.; Enright, H. A.; Esmaeli-Azad, B.; Federico, A.; Gerak, L. A.; Husbands, S. M.; Kolber, B.; Lau, E. Y.; Lao, V.; Maguire, D. R.; Malfatti, M. A.; Martinez, G.; Mayer, B. P.; Pravetoni, M.; Sahibzada, N.; Skolnick, P.; Snyder, E. Y.; Tomycz, N.; Valdez, C. A.; Zapf, J. Countermeasures for preventing and treating opioid overdose. Clin. Pharmacol. Therap. 2021, 109, 578– 590,  DOI: 10.1002/cpt.2098
    Google Scholar
    There is no corresponding record for this reference.
  23. 23
    Deng, C. L.; Murkli, S. L.; Isaacs, L. D. Supramolecular hosts as in vivo sequestration agents for pharmaceuticals and toxins. Chem. Soc. Rev. 2020, 49, 7516– 7532,  DOI: 10.1039/D0CS00454E
    Google Scholar
    23
    Supramolecular hosts as in vivo sequestration agents for pharmaceuticals and toxins
    Deng, Chun-Lin; Murkli, Steven L.; Isaacs, Lyle D.
    Chemical Society Reviews (2020), 49 (21), 7516-7532CODEN: CSRVBR; ISSN:0306-0012. (Royal Society of Chemistry)
    A review. Pharmaceutical agents, drugs of abuse, and toxic substances have a large impact, pos. and neg., on modern society. Efforts to mitigate the side effects of pharmaceuticals and counteract the life threatening effects of drugs of abuse and toxins can occur either by pharmacodynamic (PD) approaches based on bioreceptor·drug antagonism or by pharmacokinetic (PK) approaches that seek to reduce the concn. of free drug. In this tutorial review, we present the use of supramol. hosts (cyclodextrins, calixarenes, (acyclic) cucurbiturils, and pillararenes) as in vivo sequestration agents for neuromuscular blockers, drugs of abuse (methamphetamine and fentanyl), anesthetics, neurotoxins, the pesticide paraquat, and heparin anti-coagulants by the PK approach. The review presents the basic phys. and mol. recognition features of the supramol. hosts and some of the principles used in their selection and structural optimization for in vivo sequestration applications. The influence of host·guest complexation on other relevant in vivo properties of drugs (e.g. distribution, circulation time, excretion, redox properties) is also mentioned. The article concludes with a discussion of future directions.
    >> More from SciFinder ®
    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3cXitVertL7P&md5=f1921dfb6696c71c06cda54cd873d659
  24. 24
    Thevathasan, T.; Grabitz, S. D.; Santer, P.; Rostin, P.; Akeju, O.; Boghosion, J. D.; Gil, M.; Isaacs, L.; Cotten, J. F.; Eikermann, M. Calabadion 1 selectively reverses respiratory and central nervous system effects of fentanyl in rat model. Br. J. Anaesth. 2020, 125, e140– e147,  DOI: 10.1016/j.bja.2020.02.019
    Google Scholar
    There is no corresponding record for this reference.
  25. 25
    Mayer, B. P.; Kennedy, D. J.; Lau, E. Y.; Valdez, C. A. Solution-state structure and affinities of cyclodextrin:fentanyl complexes by nuclear magnetic resonance spectroscopy and molecular dynamics simulation. J. Phys. Chem. B 2016, 120, 2423– 2433,  DOI: 10.1021/acs.jpcb.5b12333
    Google Scholar
    There is no corresponding record for this reference.
  26. 26
    Dodziuk, H. Rigidity versus flexibility. A review of experimental and theoretical studies pertaining to the cyclodextrin nonrigidity. J. Mol. Struct. 2002, 614, 33– 45,  DOI: 10.1016/S0022-2860(02)00236-3
    Google Scholar
    There is no corresponding record for this reference.
  27. 27
    Crini, D. Review: A history of cyclodextrins. Chem. Rev. 2014, 114, 10940– 10975,  DOI: 10.1021/cr500081p
    Google Scholar
    27
    Review: A History of Cyclodextrins
    Crini, Gregorio
    Chemical Reviews (Washington, DC, United States) (2014), 114 (21), 10940-10975CODEN: CHREAY; ISSN:0009-2665. (American Chemical Society)
    A discussion of the history of cyclodextrins is presented, describing the 120 years from discovery to development to the process of application.
    >> More from SciFinder ®
    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXhsFyrsLnP&md5=eefa7d9c4e06e877eb846a5857423ddb
  28. 28
    Lachowicz, M.; Stanczak, A.; Kolodziejczyk, M. Characteristic of Cyclodextrins: Their Role and Use in the Pharmaceutical Technology. Curr. Drug Targets 2020, 21, 1495– 1510,  DOI: 10.2174/1389450121666200615150039
    Google Scholar
    There is no corresponding record for this reference.
  29. 29
    Brewster, M. E.; Loftsson, T. Cyclodextrins as pharmaceutical solubilizers. Adv. Drug Delivery Rev. 2007, 59, 645– 666,  DOI: 10.1016/j.addr.2007.05.012
    Google Scholar
    29
    Cyclodextrins as pharmaceutical solubilizers
    Brewster, Marcus E.; Loftsson, Thorsteinn
    Advanced Drug Delivery Reviews (2007), 59 (7), 645-666CODEN: ADDREP; ISSN:0169-409X. (Elsevier B.V.)
    A review. Cyclodextrins are useful functional excipients that have enjoyed widespread attention and use. The basis for this popularity from a pharmaceutical standpoint, is the ability of these materials to interact with poorly water-sol. drugs and drug candidates resulting in an increase in their apparent water soly. The mechanism for this solubilization is rooted in the ability of cyclodextrin to form non-covalent dynamic inclusion complexes in soln. Other solubilizing attribute may include the ability to form non-inclusion based complexes, the formation of aggregates and related domains and the ability of cyclodextrins to form and stabilize supersatd. drug solns. The increase in soly. also can increase dissoln. rate and thus improve the oral bioavailability of BCS Class II and IV materials. A no. of cyclodextrin-based products have reached the market based on their ability to camouflage undesirable physicochem. properties. This review is intended to give a general background to the use of cyclodextrin as solubilizers as well as highlight kinetic and thermodn. tools and parameters useful in the study of drug solubilization by cyclodextrins.
    >> More from SciFinder ®
    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2sXpsFGks7g%253D&md5=50d40a75c10a799ae9487597c3d49495
  30. 30
    Mayer, B. P.; Kennedy, D. J.; Lau, E. Y.; Valdez, C. A. Evaluation of polyanionic cyclodextrins as high affinity binding scaffolds for fentanyl. Sci. Rep. 2023, 13, 2680,  DOI: 10.1038/s41598-023-29662-1
    Google Scholar
    There is no corresponding record for this reference.
  31. 31
    Lavonas, E. J.; Dezfulian, C. Impact of the Opioid Epidemic. Crit. Care Clin. 2020, 36, 753– 769,  DOI: 10.1016/j.ccc.2020.07.006
    Google Scholar
    There is no corresponding record for this reference.
  32. 32
    Fan, Y.-Z.; Liu, W.-G.; Yong, Z.; Su, R.-B. Pre-treatment with Tandospirone attenuates fentanyl-induced respiratory depression without affecting the analgesic effects of fentanyl in rodents. Neurosci. Lett. 2022, 771, 136459,  DOI: 10.1016/j.neulet.2022.136459
    Google Scholar
    There is no corresponding record for this reference.
  33. 33
    Kurkov, S. V.; Loftsson, T. Cyclodextrins. Int. J. Pharm. 2013, 453, 167– 180,  DOI: 10.1016/j.ijpharm.2012.06.055
    Google Scholar
    33
    Cyclodextrins
    Kurkov, Sergey V.; Loftsson, Thorsteinn
    International Journal of Pharmaceutics (Amsterdam, Netherlands) (2013), 453 (1), 167-180CODEN: IJPHDE; ISSN:0378-5173. (Elsevier B.V.)
    A review. Although cyclodextrins (CDs) have been studied for over 100 years and can be found in at least 35 pharmaceutical products, they are still regarded as novel pharmaceutical excipients. CDs are oligosaccharides that possess biol. properties that are similar to their linear counterparts, but some of their physicochem. properties differ. CDs are able to form water-sol. inclusion complexes with many poorly sol. lipophilic drugs. Thus, CDs are used to enhance the aq. soly. of drugs and to improve drug bioavailability after, for example, oral administration. Through CD complexation, poorly sol. drugs can be formulated as aq. parenteral solns., nasal sprays and eye drop solns. These oligosaccharides are being recognized as non-toxic and pharmacol. inactive excipients for both drug and food products. Recently, it has been obsd. that CDs and CD complexes in particular self-assemble to form nanoparticles and that, under certain conditions, these nanoparticles can self-assemble to form microparticles. These properties have changed the way we perform CD research and have given rise to new CD formulation opportunities. Here, the pharmaceutical applications of CDs are reviewed with an emphasis on their solubilizing properties, their tendency to self-assemble to form aggregates, CD ternary complexes, and their metab. and pharmacokinetics.
    >> More from SciFinder ®
    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38XhtVKntLbJ&md5=77681b35e026a98bc5a7c24e649e49a2
  34. 34
    Tian, B.; Hua, S.; Liu, J. Cyclodextrin-based delivery systems for chemotherapeutic anticancer drugs: A review. Carbohydr. Polym. 2020, 232, 115805,  DOI: 10.1016/j.carbpol.2019.115805
    Google Scholar
    34
    Cyclodextrin-based delivery systems for chemotherapeutic anticancer drugs: A review
    Tian, Bingren; Hua, Shiyao; Liu, Jiayue
    Carbohydrate Polymers (2020), 232 (), 115805CODEN: CAPOD8; ISSN:0144-8617. (Elsevier Ltd.)
    A review. Cancer is increasingly becoming a serious threat to human life and health. Therefore, the development of safe and effective therapeutic agents against the disease is of crucial significance. Cyclodextrins (CDs) are cyclic oligosaccharides obtained by the enzymic hydrolysis of starch, and constitute a class of cyclic oligosaccharides with external hydrophilic and internal hydrophobic properties and have been used widely in cancer therapy. Cyclodextrin has been extensively applied in nanomedicine therapy, gene therapy, cell therapy, immunotherapy, and chemotherapy. In this review, we summarize chemotherapy drugs for cancer treatment, classify various CD-based drug delivery systems, and describe their chemotherapy release and cancer treatment performance. In addn., current challenges and new opportunities for CD-based chemotherapeutic agents delivery systems are discussed.
    >> More from SciFinder ®
    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3cXksFagsQ%253D%253D&md5=9ea031e01e998ee2345a695fb448d2c1
  35. 35
    Challa, R.; Ahuja, A.; Ali, J.; Khar, R. K. Cyclodextrins in drug delivery: an updated review. AAPS PharmSciTech 2005, 6, E329– E357,  DOI: 10.1208/pt060243
    Google Scholar
    35
    Cyclodextrins in drug delivery: an updated review
    Challa Rajeswari; Ahuja Alka; Ali Javed; Khar R K
    AAPS PharmSciTech (2005), 6 (2), E329-57 ISSN:.
    The purpose of this review is to discuss and summarize some of the interesting findings and applications of cyclodextrins (CDs) and their derivatives in different areas of drug delivery, particularly in protein and peptide drug delivery and gene delivery. The article highlights important CD applications in the design of various novel delivery systems like liposomes, microspheres, microcapsules, and nanoparticles. In addition to their well-known effects on drug solubility and dissolution, bioavailability, safety, and stability, their use as excipients in drug formulation are also discussed in this article. The article also focuses on various factors influencing inclusion complex formation because an understanding of the same is necessary for proper handling of these versatile materials. Some important considerations in selecting CDs in drug formulation such as their commercial availability, regulatory status, and patent status are also summarized. CDs, because of their continuing ability to find several novel applications in drug delivery, are expected to solve many problems associated with the delivery of different novel drugs through different delivery routes.
    >> More from SciFinder ®
    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BD2Mnms1Klsw%253D%253D&md5=ccb8423f272e82320890839bf3d29616
  36. 36
    Duri, S.; Tran, C. D. Supramolecular composite materials from cellulose, chitosan, and cyclodextrin: facile preparation and their selective inclusion complex formation with endocrine disruptors. Langmuir 2013, 29, 5037– 5049,  DOI: 10.1021/la3050016
    Google Scholar
    36
    Supramolecular Composite Materials from Cellulose, Chitosan, and Cyclodextrin: Facile Preparation and Their Selective Inclusion Complex Formation with Endocrine Disruptors
    Duri, Simon; Tran, Chieu D.
    Langmuir (2013), 29 (16), 5037-5049CODEN: LANGD5; ISSN:0743-7463. (American Chemical Society)
    We developed a simple 1-step method of prepg. high-performance supramol. polysaccharide composites from cellulose (CEL), chitosan (CS), and (2,3,6-tri-O-acetyl)-α-, β-, and γ-cyclodextrin (α-, β-, and γ-TCD). [BMIm+Cl-], an ionic liq. (IL), was used as a solvent to dissolve and prep. the composites. Because a majority (>88%) of the IL used was recovered for reuse, the method is recyclable. XRD, FTIR, NIR, and SEM were used to monitor the dissoln. process and to confirm that the polysaccharides were regenerated without any chem. modifications. It was found that unique properties of each component including superior mech. properties (from CEL), excellent adsorption for pollutants and toxins (from CS), and size/structure selectivity through inclusion complex formation (from TCDs) remain intact in the composites. Specifically, the results from kinetics and adsorption isotherms show that whereas CS-based composites can effectively adsorb the endocrine disruptors (polychlrophenols, bisphenol A), their adsorption is independent of the size and structure of the analytes. Conversely, the adsorption by γ-TCD-based composites exhibits a strong dependence on the size and structure of the analytes. For example, whereas all three TCD-based composites (i.e., α-, β-, and γ-TCD) can effectively adsorb 2-, 3-, and 4-chlorophenol, only the γ-TCD-based composite can adsorb analytes with bulky groups including 3,4-dichloro- and 2,4,5-trichlorophenol. The equil. sorption capacities for the analytes with bulky groups by the γ-TCD-based composite are much higher than those by CS-based composites. Together, these results indicate that the γ-TCD-based composite with its relatively larger cavity size can readily form inclusion complexes with analytes with bulky groups, and through inclusion complex formation, it can strongly adsorb many more analytes and has a size/structure selectivity compared to that of CS-based composites that can adsorb the analyte only by surface adsorption.
    >> More from SciFinder ®
    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXktlyltbs%253D&md5=4ab0a50329359d23acf12b54e386f9c9
  37. 37
    Mayer, B. P.; Albo, R. L. F.; Hok, S.; Valdez, C. A. NMR spectroscopic investigation of inclusion complexes between cyclodextrins and the neurotoxin tetramethylenedisulfotetramine. Magn. Reson. Chem. 2012, 50, 229– 235,  DOI: 10.1002/mrc.3803
    Google Scholar
    37
    NMR spectroscopic investigation of inclusion complexes between cyclodextrins and the neurotoxin tetramethylenedisulfotetramine
    Mayer, Brian P.; Albo, Rebecca L. F.; Hok, Saphon; Valdez, Carlos A.
    Magnetic Resonance in Chemistry (2012), 50 (3), 229-235CODEN: MRCHEG; ISSN:0749-1581. (John Wiley & Sons Ltd.)
    The binding stoichiometry, strength and structure of inclusion complexes formed between the neurotoxin tetramethylenedisulfotetramine (TETS) and both native and modified cyclodextrins (CyDs) were investigated using NMR spectroscopy. Of all six examd. cases, native β-cyclodextrin (β-CyD) and its chem. modified counterpart heptakis-(2,3,6-tris-(2-hydroxypropyl))-β-cyclodextrin (2HP-β-CyD) were found to assoc. most strongly with TETS as reflected in the magnitude of their binding consts. (K = 537 ± 26 M-1 for β-CyD and K = 514 ± 49 M-1 for 2HP-β-CyD). Two-dimensional rotating-frame Overhauser effect spectroscopy NMR expts. confirm close proximity of the TETS mol. to both β-CyD and 2HP-β-CyD as intermol., through-space interactions between the H3 and H5 protons located in the interior of the CyD cavity and the methylene protons of TETS were identified. Copyright © 2012 John Wiley & Sons, Ltd.
    >> More from SciFinder ®
    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38XjtVOlsbg%253D&md5=48741087771c075a1c6cceeb69a58650
  38. 38
    Dernaika, H.; Chong, S. V.; Artur, C. G.; Tallon, J. L. Spectroscopic Identification of Neurotoxin Tetramethylenedisulfotetramine (TETS) Captured by Supramolecular Receptor β-Cyclodextrin Immobilized on Nanostructured Gold Surfaces. J. Nanomat. 2014, 2014, 207258,  DOI: 10.1155/2014/207258
    Google Scholar
    There is no corresponding record for this reference.
  39. 39
    Mahammad, S.; Parmryd, I. Cholesterol depletion using methyl-β-cyclodextrin. Methods Mol. Biol. 2015, 1232, 91– 102,  DOI: 10.1007/978-1-4939-1752-5_8
    Google Scholar
    39
    Cholesterol Depletion Using Methyl-β-cyclodextrin
    Mahammad, Saleemulla; Parmryd, Ingela
    Methods in Molecular Biology (New York, NY, United States) (2015), 1232 (Methods in Membrane Lipids), 91-102CODEN: MMBIED; ISSN:1940-6029. (Springer)
    Cholesterol is an essential component of mammalian cells. It is the major lipid constituent of the plasma membrane and is also abundant in most other organelle membranes. In the plasma membrane cholesterol plays crit. phys. roles in the maintenance of membrane fluidity and membrane permeability. It is also important for membrane trafficking, cell signalling, and lipid as well as protein sorting. Cholesterol is essential for the formation of liq. ordered domains in model membranes, which in cells are known as lipid nanodomains or lipid rafts. Cholesterol depletion is widely used to study the role of cholesterol in cellular processes and can be performed over days using inhibitors of its synthesis or acutely over minutes using chem. reagents. Acute cholesterol depletion by methyl-β-cyclodextrin (MBCD) is the most widely used method and here we describe how it should be performed to avoid the common side-effect cell death.
    >> More from SciFinder ®
    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28XjtVyrsLk%253D&md5=1fe62a1e81f2dd607d204f66c69e0a9d
  40. 40
    Adam, J. M.; Bennett, D. J.; Bom, A.; Clark, J. K.; Feilden, H.; Hutchinson, E. J.; Palin, R.; Prosser, A.; Rees, D. C.; Rosair, G. M.; Stevenson, D.; Tarver, G. J.; Zhang, M.-Q. Cyclodextrin-derived host molecules as reversal agents for the neuromuscular blocker rocuronium bromide: Synthesis and structure-activity relationships. J. Med. Chem. 2002, 45, 1806– 1816,  DOI: 10.1021/jm011107f
    Google Scholar
    40
    Cyclodextrin-Derived Host Molecules as Reversal Agents for the Neuromuscular Blocker Rocuronium Bromide: Synthesis and Structure-Activity Relationships
    Adam, Julia M.; Bennett, D. Jonathan; Bom, Anton; Clark, John K.; Feilden, Helen; Hutchinson, Edward J.; Palin, Ronald; Prosser, Alan; Rees, David C.; Rosair, Georgina M.; Stevenson, Donald; Tarver, Gary J.; Zhang, Ming-Qiang
    Journal of Medicinal Chemistry (2002), 45 (9), 1806-1816CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)
    A series of mono- and per-6-substituted cyclodextrin derivs. were synthesized as synthetic receptors (or host mols.) of rocuronium bromide, the most widely used neuromuscular blocker in anesthesia. By forming host-guest complexes with rocuronium, these cyclodextrin derivs. reverse the muscle relaxation induced by rocuronium in vitro and in vivo and therefore can be used as reversal agents of the neuromuscular blocker to assist rapid recovery of patients after surgery. Because this supramol. mechanism of action does not involve direct interaction with the cholinergic system, the reversal by these compds. is not accompanied by cardiovascular side effects usually attendant with acetylcholinesterase inhibitors such as neostigmine. The structure-activity relationships are consistent with this supramol. mechanism of action and are discussed herein. These include the effects of binding cavity size and hydrophobic and electrostatic interaction on the reversal activities of these compds.
    >> More from SciFinder ®
    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD38XitFahs78%253D&md5=4f120b5717a6e876c7859b0ff6f5ab26
  41. 41
    de Boer, H. D.; van Egmong, J.; van de Pol, F.; Bom, A.; Booij, L. H. D. J. Sugammadex, a new reversal agent for neuromuscular block induced by rocuronium in anaesthesized Rhesus monkey. Br. J. Anesth. 2006, 96, 473– 479,  DOI: 10.1093/bja/ael013
    Google Scholar
    There is no corresponding record for this reference.
  42. 42
    Donati, F. Sugammadex: a cyclodextrin to reverse neuromuscular blockade in anaesthesia. Expert Opin. Pharmacother. 2008, 9, 1375– 1386,  DOI: 10.1517/14656566.9.8.1375
    Google Scholar
    There is no corresponding record for this reference.
  43. 43
    Schaller, S. J.; Lewald, H. Clinical pharmacology and efficacy of sugammadex in the reversal of neuromuscular blockade. Expert Opin. Drug Metab. Toxicol. 2016, 12, 1097– 1108,  DOI: 10.1080/17425255.2016.1215426
    Google Scholar
    There is no corresponding record for this reference.
  44. 44
    Bostan, H.; Kalkan, Y.; Tomak, Y.; Tumkaya, L.; Altuner, D.; Yilmaz, A.; Erdivanli, B.; Bedir, R. Reversal of Rocuronium-Induced Neuromuscular Block with Sugammadex and Resulting Histopathological Effects in Rat Kidneys. Renal Failure 2011, 33, 1019– 1024,  DOI: 10.3109/0886022X.2011.618972
    Google Scholar
    There is no corresponding record for this reference.
  45. 45
    Van Ommen, B.; De Bie, A. T. H. J.; Bår, A. Disposition of 14C- α-cyclodextrin in germ-free and conventional rats. Regul. Toxicol. Pharmacol. 2004, 39, S57– S66,  DOI: 10.1016/j.yrtph.2004.05.011
    Google Scholar
    There is no corresponding record for this reference.
  46. 46
    De Bie, A. T. H. J.; Van Ommen, B.; Bår, A. Disposition of [14C] γ-cyclodextrin in germ free and conventional rats. Regul. Toxicol. Pharmacol. 1998, 27, 150– 158,  DOI: 10.1006/rtph.1998.1219
    Google Scholar
    There is no corresponding record for this reference.
  47. 47
    Bostan, H.; Kalkan, Y.; Tomak, Y.; Tumkaya, L.; Altuner, D.; Yılmaz, A.; Erdivanli, B.; Recep Bedir, R. Reversal of Rocuronium-Induced Neuromuscular Block with Sugammadex and Resulting Histopathological Effects in Rat Kidneys. Renal Failure 2011, 33 (10), 1019– 1024,  DOI: 10.3109/0886022X.2011.618972
    Google Scholar
    There is no corresponding record for this reference.
  48. 48
    Irie, T.; Uekama, K. Pharmaceutical applications of cyclodextrins. III. Toxicological issues and safety evaluation. J. Pharm. Sci. 1997, 86, 147– 62,  DOI: 10.1021/js960213f
    Google Scholar
    48
    Pharmaceutical applications of cyclodextrins. III. Toxicological issues and safety evaluation
    Irie, Tetsumi; Uekama, Kaneto
    Journal of Pharmaceutical Sciences (1997), 86 (2), 147-162CODEN: JPMSAE; ISSN:0022-3549. (American Chemical Society)
    A review, with 201 refs., summarizing recent findings on the safety profiles of 3 natural cyclodextrins (α-, β- and γ-cyclodextrins) and several chem. modified cyclodextrins.
    >> More from SciFinder ®
    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK2sXhtVOgsLY%253D&md5=7482185501b59f3716b2c4ee435bd383
  49. 49
    Saari, T. I.; Strang, J.; Dale, O. Clinical Pharmacokinetics and Pharmacodynamics of Naloxone. Clin Pharmacokinet 2024, 63, 397– 422,  DOI: 10.1007/s40262-024-01355-6
    Google Scholar
    There is no corresponding record for this reference.
  50. 50
    Golembiewski, J. Sugammadex. Journal of PeriAnesthesia Nursing 2016, 31, 354– 357,  DOI: 10.1016/j.jopan.2016.05.004
    Google Scholar
    There is no corresponding record for this reference.
  51. 51
    Ogawa, N.; Nagase, H.; Loftsson, T.; Endo, T.; Takahashi, C.; Kawashima, Y.; Ueda, H.; Yamamoto, H. Crystallographic and theoretical studies of an inclusion complex of β-cyclodextrin with fentanyl. Int. J. Pharm. 2017, 531, 588– 594,  DOI: 10.1016/j.ijpharm.2017.06.081
    Google Scholar
    There is no corresponding record for this reference.
  52. 52
    Cameron, K. S.; Clark, J. K.; Cooper, A.; Fielding, L.; Palin, R.; Rutherford, S. J.; Zhang, M.-Q. Modified γ-Cyclodextrins and their rocuronium complexes. Org. Lett. 2002, 4, 3403– 3406,  DOI: 10.1021/ol020126w
    Google Scholar
    52
    Modified γ-Cyclodextrins and Their Rocuronium Complexes
    Cameron, K. S.; Clark, J. K.; Cooper, A.; Fielding, L.; Palin, R.; Rutherford, S. J.; Zhang, M.-Q.
    Organic Letters (2002), 4 (20), 3403-3406CODEN: ORLEF7; ISSN:1523-7060. (American Chemical Society)
    A series of per-6-substituted cyclodextrin derivs. was synthesized as synthetic host mols. for rocuronium, a steroidal muscle relaxant. By forming host-guest complexes with rocuronium, these cyclodextrin derivs. reverse the muscle relaxation induced by rocuronium in vitro and in vivo. The isothermal micro-calorimetry data are consistent with the biol. data supporting the encapsulation mechanism of action. Binary and biphasic complexes are reported with NMR expts. clearly showing free and bound rocuronium.
    >> More from SciFinder ®
    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD38Xms12ru7s%253D&md5=7743629838a2dbe675ee925c336b3625
  53. 53
    Valdez, C. A.; Saavedra, J. E.; Showalter, B. M.; Davies, K. M.; Wilde, T. C.; Citro, M. L.; Barchi, J. J.; Deschamps, J. R.; Parrish, D.; El-Gayar, S.; Schleicher, U.; Bogdan, C.; Keefer, L. K. Hydrolytic reactivity trends among potential prodrugs of the O2-glycosylated diazeniumdiolate family. Targeting nitric oxide to macrophages for antileishmanial activity. J. Med. Chem. 2008, 51, 3961– 3970,  DOI: 10.1021/jm8000482
    Google Scholar
    53
    Hydrolytic Reactivity Trends among Potential Prodrugs of the O2-Glycosylated Diazeniumdiolate Family. Targeting Nitric Oxide to Macrophages for Antileishmanial Activity
    Valdez, Carlos A.; Saavedra, Joseph E.; Showalter, Brett M.; Davies, Keith M.; Wilde, Thomas C.; Citro, Michael L.; Barchi, Joseph J., Jr.; Deschamps, Jeffrey R.; Parrish, Damon; El-Gayar, Stefan; Schleicher, Ulrike; Bogdan, Christian; Keefer, Larry K.
    Journal of Medicinal Chemistry (2008), 51 (13), 3961-3970CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)
    Glycosylated diazeniumdiolates of structure R2NN(O)=NO-R' (R' = a saccharide residue) are potential prodrugs of the nitric oxide (NO)-releasing but acid-sensitive R2NN(O)=NO- ion. Moreover, cleaving the acid-stable glycosides under alk. conditions provides a convenient protecting group strategy for diazeniumdiolate ions. Here, we report comparative hydrolysis rate data for five representative glycosylated diazeniumdiolates at pH 14, 7.4, and 3.8-4.6 as background for further developing both the protecting group application and the ability to target NO pharmacol. to macrophages harboring intracellular pathogens. Confirming the potential in the latter application, adding R2NN(O)=NO-GlcNAc (where R2N = diethylamino or pyrrolidin-l-yl and GlcNAc = N-acetylglucosamin-l-yl) to cultures of infected mouse macrophages that were deficient in inducible NO synthase caused rapid death of the intracellular protozoan parasite Leishmania major with no host cell toxicity.
    >> More from SciFinder ®
    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1cXmvVGrtrs%253D&md5=fb8c04ad34641b18500a9275da8ec09e
  54. 54
    Showalter, B. M.; Reynolds, M. M.; Valdez, C. A.; Saavedra, J. E.; Davies, K. M.; Klose, J. R.; Chmurny, G. N.; Citro, M. L.; Barchi, J. J.; Merz, S.; Meyerhoff, M. E.; Keefer, L. K. Diazeniumdiolate ions as leaving groups in anomeric displacement reactions: A protection-deprotection strategy for ionic diazeniumdiolates. J. Am. Chem. Soc. 2005, 127, 14188– 14189,  DOI: 10.1021/ja054510a
    Google Scholar
    54
    Diazeniumdiolate Ions as Leaving Groups in Anomeric Displacement Reactions: A Protection-Deprotection Strategy for Ionic Diazeniumdiolates
    Showalter, Brett M.; Reynolds, Melissa M.; Valdez, Carlos A.; Saavedra, Joseph E.; Davies, Keith M.; Klose, John R.; Chmurny, Gwendolyn N.; Citro, Michael L.; Barchi, Joseph J., Jr.; Merz, Scott I.; Meyerhoff, Mark E.; Keefer, Larry K.
    Journal of the American Chemical Society (2005), 127 (41), 14188-14189CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)
    Diazeniumdiolate ions [R2N-N(O):N-O-] are of growing interest pharmacol. for their ability to generate up to two molar equivalents of bioactive nitric oxide (NO) spontaneously on protonating the amino nitrogen. Accordingly, their stability increases as the pH is raised. Here we show that the corresponding β-glucosides [R2N-N(O):N-O-Glc] decreased in stability with pH; when R2N was diethylamino, the rate equation was kobs = ko + kOH- [OH-], where ko = 7.8 × 10-7 s-1 and kOH- = 5.3 × 10-3 M-1 s-1. The primary products were 1,6-anhydroglucose and the regenerated R2N-N(O):N-O- ion. The results were qual. similar to those of β-glucosyl fluoride and p-nitrophenoxide, whose hydrolyzes have been rationalized as proceeding via a glycal oxide intermediate. This chem. offers a convenient strategy for protecting heat- and acid-sensitive diazeniumdiolate ions during manipulations that would otherwise destroy them. As an example, a poly(urethane) film that generated NO in physiol. buffer at a surface flux comparable to that of the mammalian vascular endothelium was prepd. by glucosylating the ionic diazeniumdiolate group attached to the diol monomer before reacting it with the bis-isocyanate, then removing the saccharide with base when the protecting group was no longer needed.
    >> More from SciFinder ®
    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2MXhtVarurvI&md5=39ade2581dfd6632e7c5fcd2f6fcf253
  55. 55
    Albo, R. L. F.; Valdez, C. A.; Leif, R. N.; Mulcahy, H. A.; Koester, C. Derivatization of pinacolyl alcohol with phenyldimethylchlorosilane for enhanced detection by gas chromatography-mass spectrometry. Anal. Bioanal. Chem. 2014, 406, 5231– 5234,  DOI: 10.1007/s00216-014-7625-y
    Google Scholar
    There is no corresponding record for this reference.
  56. 56
    Valdez, C. A.; Leif, R. N.; Sanner, R. D.; Corzett, T. H.; Dreyer, M. L.; Mason, K. E. Structural modification of fentanyls for their retrospective identification by gas chromatographic analysis using chloroformate chemistry. Sci. Rep. 2021, 11, 22489,  DOI: 10.1038/s41598-021-01896-x
    Google Scholar
    There is no corresponding record for this reference.
  57. 57
    Roka, E.; Ujhelyi, Z.; Deli, M.; Bocsik, A.; Fenyvesi, E.; Szente, L.; Fenyvesi, F.; Vecsernyes, M.; Varadi, J.; Feher, P.; Gesztelyi, R.; Felix, C.; Perret, F.; Bacskay, I. K. Evaluation of the Cytotoxicity of α-Cyclodextrin Derivatives on the Caco-2 Cell Line and Human Erythrocytes. Molecules 2015, 20, 20269– 20285,  DOI: 10.3390/molecules201119694
    Google Scholar
    There is no corresponding record for this reference.
  58. 58
    Kiss, T.; Fenyvesi, F.; Bacskay, I.; Varadi, J.; Fenyvesi, E.; Ivanyi, R.; Szente, L.; Tosaki, A.; Vecsernyes, M. Evaluation of the cytotoxicity of β-cyclodextrin derivatives: Evidence for the role of cholesterol extraction. Eur. J. Pharm. Sci. 2010, 40, 376– 380,  DOI: 10.1016/j.ejps.2010.04.014
    Google Scholar
    58
    Evaluation of the cytotoxicity of β-cyclodextrin derivatives: Evidence for the role of cholesterol extraction
    Kiss, T.; Fenyvesi, F.; Bacskay, I.; Varadi, J.; Fenyvesi, E.; Ivanyi, R.; Szente, L.; Tosaki, A.; Vecsernyes, M.
    European Journal of Pharmaceutical Sciences (2010), 40 (4), 376-380CODEN: EPSCED; ISSN:0928-0987. (Elsevier B.V.)
    Several β-cyclodextrin (β-CD) derivs. have been synthesized recently to improve the physicochem. properties and inclusion capacities of the parent mol., however, there is limited information available about their cytotoxic effects. In this study we investigated the cytotoxic and hemolytic properties of various β-CDs in correlation with their cholesterol-solubilizing capacities to expose the mechanism of toxicity. MTT cell viability test, performed on Caco-2 cells showed significant differences between the cytotoxicity of β-CD derivs. Cell toxicity of methylated-β-CDs was the highest, while ionic derivs. proved to be less toxic than methylated ones. Most of the second generation β-CD derivs., having both ionic and Me substituents showed less cytotoxicity than the parent compds. both on Caco-2 cells and human erythrocytes. Inclusion of cholesterol into the ring of randomly methylated-β-CD and heptakis(2,6-di-O-methyl)-β-CD abolished the cell toxicity indicating the role of cholesterol extn. in cytotoxicity. These data demonstrate the correlation between the cytotoxic effect, hemolytic activity and the cholesterol complexation attributes of β-CD derivs. and we propose that cholesterol-solubilizing properties can be a predictive factor for β-CD cell toxicity.
    >> More from SciFinder ®
    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3cXmslOhur4%253D&md5=6ba4779af8594b1e6ed15e8fb5700a82
  59. 59
    Kainu, V.; Hermansson, M.; Somerharju, P. Introduction of phospholipids to cultured cells with cyclodextrin. J. Lipid Res. 2010, 51, 3533– 3541,  DOI: 10.1194/jlr.D009373
    Google Scholar
    59
    Introduction of phospholipids to cultured cells with cyclodextrin
    Kainu, Ville; Hermansson, Martin; Somerharju, Pentti
    Journal of Lipid Research (2010), 51 (12), 3533-3541CODEN: JLPRAW; ISSN:0022-2275. (American Society for Biochemistry and Molecular Biology, Inc.)
    Previous studies indicate that methyl-β-cyclodextrin (meβ-CD) can greatly enhance translocation of long-chain phospholipids from vesicles to cells in culture, which is very useful when studying, e.g., phospholipid metab. and trafficking. However, the parameters affecting the transfer have not been systematically studied. Therefore, we studied the relevant parameters including meβ-CD and vesicle concn., incubation time, phospholipid structure, and cell type. Because meβ-CD can ext. cholesterol and other lipids from cells, thereby potentially altering cell growth or viability, these issues were studied as well. The results show that efficient incorporation of phospholipid species with hydrophobicity similar to that of natural species can be obtained without significantly compromising cell growth or viability. Cellular content of phosphatidyl-serine, -ethanolamine, and -choline could be increased dramatically, i.e., 400, 125, and 25%, resp. Depletion of cellular cholesterol could be prevented or alleviated by inclusion of the proper amt. of cholesterol in the donor vesicles. In summary, meβ-CD mediates efficient transfer of long-chain (phospho) lipids from vesicles to cells without significantly compromising their growth or viability. This lays a basis for detailed studies of phospholipid metab. and trafficking as well as enables extensive manipulation of cellular phospholipid compn., which is particularly useful when investigating mechanisms underlying phospholipid homeostasis.
    >> More from SciFinder ®
    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3cXhsFWitLvJ&md5=d8a184625e9c3bce9ac033fccd862f6a
  60. 60
    Ognibene, T. J.; Bench, G.; Vogel, J. S.; Peaslee, G. F.; Murov, S. A high-throughput method for the conversion of CO2 obtained from biochemical samples to graphite in septa-sealed vials for quantification of 14C via accelerator mass spectrometry. Anal. Chem. 2003, 75, 2192– 02198,  DOI: 10.1021/ac026334j
    Google Scholar
    60
    A high-throughput method for the conversion of CO2 obtained from biochemical samples to graphite in septa-sealed vials for quantification of 14C via accelerator mass spectrometry
    Ognibene, Ted J.; Bench, Graham; Vogel, John S.; Peaslee, Graham F.; Murov, Steve
    Analytical Chemistry (2003), 75 (9), 2192-2196CODEN: ANCHAM; ISSN:0003-2700. (American Chemical Society)
    The growth of accelerator mass spectrometry as a tool for quant. isotope ratio anal. in the biosciences necessitates high-throughput sample prepn. A method has been developed to convert CO2 obtained from carbonaceous samples to solid graphite for highly sensitive and precise 14C quantification. Septa-sealed vials are used along with com. available disposable materials, eliminating sample cross contamination, minimizing complex handling, and keeping per sample costs low. Samples contg. between 0.25 and 10 mg of total carbon can be reduced to graphite in ∼4 h in routine operation. Approx. 150 samples per 8-h day can be prepd. by a single technician.
    >> More from SciFinder ®
    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD3sXisFCltbk%253D&md5=b3aefc406eea96be5033b882879797a4
  61. 61
    Ohtsuka, H.; Fujita, K.; Kobayashi, H. Pharmacokinetics of Fentanyl in Male and Female Rats after Intravenous Administration. Arzneimittel-Forschung(Drug Research) 2007, 57 (5), 260– 263,  DOI: 10.1055/s-0031-1296615
    Google Scholar
    There is no corresponding record for this reference.
  62. 62
    Bergh, M. S.-S.; Bogen, I. L.; Garibay, N.; Baumann, M. H. Evidence for nonlinear accumulation of the ultrapotent fentanyl analog, carfentanil, after systemic administration to male rats. Neuropharmacology 2019, 158, 107596,  DOI: 10.1016/j.neuropharm.2019.04.002
    Google Scholar
    62
    Evidence for nonlinear accumulation of the ultrapotent fentanyl analog, carfentanil, after systemic administration to male rats
    Bergh, Marianne Skov-Skov; Bogen, Inger Lise; Garibay, Nancy; Baumann, Michael H.
    Neuropharmacology (2019), 158 (), 107596CODEN: NEPHBW; ISSN:0028-3908. (Elsevier B.V.)
    The current opioid overdose crisis is being exacerbated by illicitly manufd. fentanyl and its analogs. Carfentanil is a fentanyl analog that is 10,000-times more potent than morphine, but limited information is available about its pharmacol. The present study had two aims: (1) to validate a method for quantifying carfentanil and its metabolite norcarfentanil in small-vol. samples, and (2) to use the method for examg. pharmacodynamic-pharmacokinetic relationships in rats. The anal. method involved liq.-liq. extn. of plasma samples followed by quantitation of carfentanil and norcarfentanil using ultra-high-performance liq. chromatog. coupled to tandem mass spectrometry (UHPLC-MS/MS). The method was validated following SWGTOX guidelines, and both analytes displayed limits of detection and quantification at 7.5 and 15 pg/mL, resp. Male Sprague-Dawley rats fitted with jugular catheters and temp. transponders received s.c. carfentanil (1, 3 and 10 μg/kg) or saline. Repeated blood specimens were obtained over 8 h, along with pharmacodynamic measures including core temp. and catalepsy scores. Carfentanil produced dose-related hypothermia and catalepsy that lasted up to 8 h. Carfentanil Cmax occurred at 15 min whereas metabolite Cmax was at 1-2 h. Concns. of both analytes increased in a dose-related fashion, but area-under-the-curve values were much greater than predicted after 10 μg/kg. Plasma half-life for carfentanil increased at higher doses. Our findings reveal that carfentanil produces marked hypothermia and catalepsy, which is accompanied by nonlinear accumulation of the drug at high doses. We hypothesize that impaired clearance of carfentanil in humans could contribute to life-threatening effects of this ultrapotent opioid agonist.
    >> More from SciFinder ®
    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1MXnsVertLk%253D&md5=3aca8d1fa597d52f447b53513678e224
  63. 63
    Burkle, H.; Dunbar, S.; Van Aken, H. PhD. Remifentanil: A Novel, Short-Acting, mu-Opioid. Anesthesia Analgesia 1996, 83 (3), 646– 651,  DOI: 10.1097/00000539-199609000-00038
    Google Scholar
    There is no corresponding record for this reference.
  64. 64
    Malfatti, M. A.; Enright, H. A.; Be, N. A.; Kuhn, E. A.; Hok, S.; McNerney, M. W.; Lao, V.; Nguyen, T. H.; Lightstone, F. C.; Carpenter, T. S.; Bennion, B. J.; Valdez, C. A. The biodistribution and pharmacokinetics of the oxime acetylcholinesterase reactivator RS194B in guinea pigs. Chem. Bio. Interact. 2017, 277, 159– 167,  DOI: 10.1016/j.cbi.2017.09.016
    Google Scholar
    There is no corresponding record for this reference.

Cited By

Click to copy section linkSection link copied!

This article is cited by 1 publications.

  1. Noriko Ogawa. The Utility of Cyclodextrin for Countering μ-Opioid Receptor Drug Overdoses. ACS Central Science 2024, Article ASAP.
Download PDF
Go to ACS Central Science
Get e-Alerts
Get e-Alerts

ACS Central Science

Cite this: ACS Cent. Sci. 2024, XXXX, XXX, XXX-XXX
Click to copy citationCitation copied!
https://doi.org/10.1021/acscentsci.4c00682
Published October 23, 2024

© 2024 The Authors. Published by American Chemical Society. This publication is licensed under

CC-BY 4.0 .

Article Views

1362

Altmetric

-

Citations

1
Learn about these metrics

Article Views are the COUNTER-compliant sum of full text article downloads since November 2008 (both PDF and HTML) across all institutions and individuals. These metrics are regularly updated to reflect usage leading up to the last few days.

Citations are the number of other articles citing this article, calculated by Crossref and updated daily. Find more information about Crossref citation counts.

The Altmetric Attention Score is a quantitative measure of the attention that a research article has received online. Clicking on the donut icon will load a page at altmetric.com with additional details about the score and the social media presence for the given article. Find more information on the Altmetric Attention Score and how the score is calculated.

  • Abstract

    High Resolution Image
    Download MS PowerPoint Slide

    Figure 1

    Figure 1. Structures of (A) fentanyl and its more and equally powerful analogs: carfentanil and remifentanil. Potencies of each relative to morphine are provided in brackets; (B) the original meperidine scaffold from which fentanyl originated via SAR studies along with the structure of morphine and the current state-of-the-art antidotes for overdose treatment: naloxone and naltrexone.

    High Resolution Image
    Download MS PowerPoint Slide

    Figure 2

    Figure 2. (A) Structure of β-cyclodextrin (β-CD) indicating the α-1,4-glycosidic linkages in a head to tail fashion between glucose units generate their cyclic nature along with three anionic β-CDs that have been evaluated as potential MCMs against fentanyl including SBX-Me. (B) Full structure of SBX-Me showing the anionic pendant units that serve to elongate and expand its hydrophobic interior and increase its hosting capability toward fentanyl and other synthetic opioids. Note that the opioid, fentanyl in this case, can bind in two orientations.

    High Resolution Image
    Download MS PowerPoint Slide

    Figure 3

    Figure 3. In vitro assessment of SBX and related CDs. (A–C) Hemolytic activity at 2 h; SBX, SBX+1, SBX-Me, and SGX at 10 (A), 1 (B) and 0.1 (C) mg/mL concentrations. Data is expressed as a percentage relative to the positive control (complete hemolysis). (D) Cholesterol solubilization data (n = 2/CD). (E) Release of phospholipids from hemoglobin-free human erythrocyte ghosts treated with the CDs. CD concentration was 25 mg/mL, and 2% Triton X-100 was used as a positive control. For all assays, data is normalized to SGX and is presented as the mean (±) of the standard error of the mean (SEM). A one-way ANOVA with Tukey post-test was run on all data with statistical significance noted for comparisons where *p < 0.05, **p < 0.01, and ***p < 0.001.

    High Resolution Image
    Download MS PowerPoint Slide

    Figure 4

    Figure 4. Mean plasma concentration–time profiles of SBX-Me following (A) single intravenous (IV) or (B) intramuscular (IM) administration of 16 mg/kg 14C-SBX-Me to male Sprague–Dawley rats. Data are expressed as the mean of 5 animals ± the standard error.

    High Resolution Image
    Download MS PowerPoint Slide

    Figure 5

    Figure 5. Mean plasma concentration–time profiles of an IM exposure of 14C-SBX-Me (16 mg/kg) after an IV exposure to fentanyl (50 μg/kg), carfentanil (5 μg/kg), or remifentanil (5 μg/kg) in male Sprague–Dawley rats. Inset is a zoom in of earlier time points (0–2 h). Data are expressed as the mean of n = 5 animals ± the standard error.

    High Resolution Image
    Download MS PowerPoint Slide

    Figure 6

    Figure 6. Mean plasma concentration–time profiles of (A) fentanyl, (B) carfentanil, and (C) remifentanil following single intravenous (IV) administrations of 14C-fentanyl (50 mg/kg), 14C-carfentanil (5 mg/kg), or 14C-remifentanil (50 mg/kg) and (IM) administrations of 16 mg/kg SBX-Me to male Sprague–Dawley rats. Insets are a zoom in of earlier time points (t = 0–2 h.). Data are expressed as the mean of n = 5 animals ± the standard error.

    High Resolution Image
    Download MS PowerPoint Slide

    Scheme 1

    Scheme 1. Synthesis of (a) 14C-Labeled Fentanyl, Carfentanil, and Remifentanil and (b) 14C-Labeled SBX-Me (SBX-Me*)a
    High Resolution Image
    Download MS PowerPoint Slide

    aThe asterisk (*) shows the carbon atom where the 14C-label is in each molecule.

  • References

    This article references 64 other publications.

    1. 1
      Shipton, E. A.; Shipton, E. E.; Shipton, A. J. A Review of the Opioid Epidemic: What Do We Do About It?. Pain Ther 2018, 7, 23– 36,  DOI: 10.1007/s40122-018-0096-7
      1
      A Review of the Opioid Epidemic: What Do We Do About It?
      Shipton Edward A; Shipton Elspeth E; Shipton Ashleigh J
      Pain and therapy (2018), 7 (1), 23-36 ISSN:2193-8237.
      The opioid epidemic, with its noticeable increase in opioid prescriptions and related misuse, abuse and resultant deaths in the previous 12 years, is a particularly North American phenomenon. Europe, and particularly low- and middle-income countries, appear to be less influenced by this problem. There is undisputable value in using opioids not only in the treatment of acute pain, but in cancer pain as well. However, opioids are progressively being prescribed more and more for chronic non-cancer pain, despite inadequate data on their efficacy. In this paper, we describe the current prevalence of opioid misuse in a number of countries and the rationale for the commencement of opioid therapy. The safe initiation and monitoring of opioid therapy as well as the need for concurrent use of interdisciplinary multimodal therapy is discussed. The possible consequences of long-term use and predictors of high opioid use and overdose are presented. In particular, the management of opioid use disorders and the prevention of opioid abuse and dependence in the young, the old and the pregnant are discussed. Measures to prevent overprescribing and to alleviate risk are described, including the tapering of opioids and the use of opioid deterrents. Finally, the paper looks at the future development of pioneering medications and technologies to potentially treat abuse. In those parts of the world with an opioid epidemic, coroners and medical examiners, private and public health agencies, and agencies that enforce the law need to cooperate in an effort to slow down and reverse the indiscriminate use of prescribing opioids in the long-term for chronic non-cancer pain. Ongoing research is needed to create ways to minimise risks of opioid use, and to provide evidence for effective strategies for treating chronic pain.
      >> More from SciFinder ®
      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC1MnpsFGhsA%253D%253D&md5=106224b0b69f5164ee8a9abed3856f8c
    2. 2
      Skolnick, P. The Opioid Epidemic: Crisis and Solutions. Annu. Rev. Pharmacol. Toxicol. 2018, 58, 143– 159,  DOI: 10.1146/annurev-pharmtox-010617-052534
      2
      The Opioid Epidemic: Crisis and Solutions
      Skolnick, Phil
      Annual Review of Pharmacology and Toxicology (2018), 58 (), 143-159CODEN: ARPTDI; ISSN:0362-1642. (Annual Reviews)
      The widespread abuse of prescription opioids and a dramatic increase in the availability of illicit opioids have created what is commonly referred to as the opioid epidemic. The magnitude of this epidemic is startling: About 4% of the adult US population misuses prescription opioids, and in 2015, more than 33,000 deaths were attributable to overdose with licit and illicit opioids. Increasing the availability of medication-assisted treatments (such as buprenorphine and naltrexone), the use of abuse-deterrent formulations, and the adoption of US Centers for Disease Control and Prevention prescribing guidelines all constitute short-term approaches to quell this epidemic. However, with more than 125 million Americans suffering from either acute or chronic pain, the development of effective alternatives to opioids, enabled at least in part by a fuller understanding of the neurobiol. bases of pain, offers the best long-term soln. for controlling and ultimately eradicating this epidemic.
      >> More from SciFinder ®
      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXhsF2hurzP&md5=af8d4dfe44cab36c82163e4e06e9ac61
    3. 3
      Janssen, P. A. J.; Eddy, N. B. Compounds related to pethidine-IV. New general chemical methods of increasing the analgesic activity of pethidine. J. Med. Chem. 1960, 2, 31– 45,  DOI: 10.1021/jm50008a003
      There is no corresponding record for this reference.
    4. 4
      Stanley, T. H. The history and development of the fentanyl series. J. Pain Symptom Manag. 1992, 7, S3– S7,  DOI: 10.1016/0885-3924(92)90047-L
      4
      The history and development of the fentanyl series
      Stanley T H
      Journal of pain and symptom management (1992), 7 (3 Suppl), S3-7 ISSN:0885-3924.
      In the last two decades, opioid analgesics have assumed an important place in general anesthetic practice in the United States. Part of the reason for this has been the introduction of the potent new agonists fentanyl, sufentanil, and alfentanil. Because of problems with morphine-oxygen anesthesia (incomplete amnesia, occasional histamine-related reaction, marked increases in intra- and postoperative respiratory depression), a suitable alternative was sought but not found among existing opioids. A breakthrough came in 1960, when fentanyl was synthesized, laying the foundation for a better understanding of the structure-activity relationships of narcotic analgesics and stimulating interest in developing compounds with even greater potency and safety margins. Investigators interested in opioid anesthesia began to study fentanyl in animals and then in humans. Fentanyl (50-100 micrograms/kg) with oxygen (100%) was evaluated as an anesthetic in patients undergoing mitral valve and coronary artery surgery. Changes in cardiovascular dynamics with induction doses ranging from 8 to 30 micrograms/kg consisted of small decreases in heart rate and arterial blood pressure. All other cardiovascular variables studied, including cardiac output, remained unchanged, even with additional doses up to 100 micrograms/kg. It was determined that fentanyl had use as a narcotic anesthetic, despite its potential for cardiovascular depression and stimulation, respiratory depression, muscle rigidity, and, occasionally, incomplete anesthesia. Since the introduction of fentanyl, two other potent synthetic opioids have been introduced into clinical practice--sufentanil and alfentanil.
      >> More from SciFinder ®
      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADyaK38zovVOmtA%253D%253D&md5=1fa4059345eb76873c75c413a859ab94
    5. 5
      Vardanyan, R. S.; Hruby, V. J. Fentanyl-related compounds and derivatives: current status and future prospects for pharmaceutical applications. Future Med. Chem. 2014, 6, 385– 412,  DOI: 10.4155/fmc.13.215
      5
      Fentanyl-related compounds and derivatives: current status and future prospects for pharmaceutical applications
      Vardanyan, Ruben S.; Hruby, Victor J.
      Future Medicinal Chemistry (2014), 6 (4), 385-412CODEN: FMCUA7; ISSN:1756-8919. (Future Science Ltd.)
      A review. Fentanyl and its analogs have been mainstays for the treatment of severe to moderate pain for many years. In this review, the authors outline the structural and corresponding synthetic strategies that were used to understand the structure-biol. activity relationship in fentanyl-related compds. and derivs. and their biol. activity profiles. The authors discuss how changes in the scaffold structure can change biol. and pharmacol. activities. Finally, recent efforts to design and synthesize novel multivalent ligands that act as mu and delta opioid receptors and NK-1 receptors are discussed.
      >> More from SciFinder ®
      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXksV2qtLk%253D&md5=4f28b2139ff80d66cf4ad55a691e6c4b
    6. 6
      Armenian, P.; Vo, K. T.; Barr Walker, J.; Lynch, K. L. Fentanyl, fentanyl analogs and novel synthetic opioids: A comprehensive review. Neuropharmacology 2018, 134, 121– 132,  DOI: 10.1016/j.neuropharm.2017.10.016
      6
      Fentanyl, fentanyl analogs and novel synthetic opioids: A comprehensive review
      Armenian, Patil; Vo, Kathy T.; Barr-Walker, Jill; Lynch, Kara L.
      Neuropharmacology (2018), 134 (Part_A), 121-132CODEN: NEPHBW; ISSN:0028-3908. (Elsevier B.V.)
      Deaths from opioid use are increasing in the US, with a growing proportion due to synthetic opioids. Until 2013, sporadic outbreaks of fentanyl and fentanyl analogs contaminating the heroin supply caused some deaths in heroin users. Since then, fentanyl has caused deaths in every state and fentanyl and its analogs have completely infiltrated the North American heroin supply. In 2014, the first illicit pills contg. fentanyl, fentanyl analogs, and other novel synthetic opioids such as U-47700 were detected. These pills, which look like known opioids or benzodiazepines, have introduced synthetic opioids to more unsuspecting customers. As soon as these drugs are regulated by various countries, new compds. quickly appear on the market, making detection difficult and the no. of cases likely underreported. Std. targeted anal. techniques such as GC-MS (gas chromatog. mass spectrometry) and LC-MS/MS (liq. chromatog. tandem mass spectrometry) can detect these drugs, but novel compd. identification is aided by nontargeted testing with LC-HRMS (liq. chromatog. high resoln. mass spectrometry). Fentanyl, fentanyl analogs and other novel synthetic opioids are all full agonists of varying potencies at the μ-opioid receptor, leading to typical clin. effects of miosis and respiratory and central nervous system depression. Due to their high affinity for μ-opioid receptors, larger doses of naloxone are required to reverse the effects than are commonly used. Synthetic opioids are an increasingly major public health threat requiring vigilance from multiple fields including law enforcement, government agencies, clin. chemists, pharmacists, and physicians, to name a few, in order to stem its tide.
      >> More from SciFinder ®
      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXhslSktbrM&md5=10085cfb511f8fd6316ffba4d39dcdef
    7. 7
      Dismukes, L. C. How Did We Get Here? Heroin and Fentanyl Trafficking Trends: A Law Enforcement Perspective. N. C. Med. J. 2018, 79, 181– 184,  DOI: 10.18043/ncm.79.3.181
      There is no corresponding record for this reference.
    8. 8
      Tamama, K.; Lynch, M. J. Newly Emerging Drugs of Abuse. Handb. Exp. Pharmacol. 2019, 258, 463– 502,  DOI: 10.1007/164_2019_260
      There is no corresponding record for this reference.
    9. 9
      Reuter, P.; Pardo, B.; Taylor, J. Imagining a fentanyl future: Some consequences of synthetic opioids replacing heroin. Int. J. Drug Policy 2021, 94, 103086,  DOI: 10.1016/j.drugpo.2020.103086
      There is no corresponding record for this reference.
    10. 10
      Kilmer, B.; Pardo, B.; Caulkins, J. P.; Reuter, P. How much illegally manufactured fentanyl could the U.S. be consuming?. Am. J. Drug Alcohol Abuse 2022, 48, 397– 402,  DOI: 10.1080/00952990.2022.2092491
      There is no corresponding record for this reference.
    11. 11
      Gupta, P. K.; Ganesan, K.; Pande, A.; Malhotra, R. C. A convenient one pot synthesis of fentanyl. J. Chem. Res. 2005, 2005, 452– 453,  DOI: 10.3184/030823405774309078
      There is no corresponding record for this reference.
    12. 12
      Siegfried. Synthesis of Fentanyl; 2014; https://erowid.org/archive/rhodium/chemistry/fentanyl.html (accessed Apr 23, 2023).
      There is no corresponding record for this reference.
    13. 13
      Valdez, C. A.; Leif, R. N.; Mayer, B. P. An efficient, optimized synthesis of fentanyl and related analogs. PLoS One 2014, 9, e108250  DOI: 10.1371/journal.pone.0108250
      13
      An efficient, optimized synthesis of fentanyl and related analogs
      Valdez, Carlos A.; Leif, Roald N.; Mayer, Brian P.
      PLoS One (2014), 9 (9), e108250/1-e108250/8, 8 pp.CODEN: POLNCL; ISSN:1932-6203. (Public Library of Science)
      An efficient synthesis of fentanyl and its analogs I [R1 = CH2CH2Ph, CH2CH2-2-thienyl, R2 = Me, Et] along with their hydrochloride and citric acid salts was described. The three-step synthetic route starting with 4-piperidone was subject to optimization studies furnishing a process that generated the target fentanyls in high yields (73-78%). The strategy offered an opportunity for gram-scale efficient prodn. of fentanyl analogs.
      >> More from SciFinder ®
      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXhslaqtrzJ&md5=ec30c9ce64dc9babfaff4da55772f486
    14. 14
      Walz, A. J.; Hsu, F.-L. An operationally simple synthesis of fentanyl citrate. Org. Prep. Proced. Int. 2017, 49, 467– 470,  DOI: 10.1080/00304948.2017.1374129
      There is no corresponding record for this reference.
    15. 15
      Pardo, B.; Taylor, J.; Caulkins, J. A.; Kilmer, B.; Reuter, P.; Stein, B. D. The Future of Fentanyl and Other Synthetic Opioids; RAND Corporation, 2019.
      There is no corresponding record for this reference.
    16. 16
      Busardò, F. P.; Carlier, J.; Giorgetti, R.; Tagliabracci, A.; Pacifici, R.; Gottardi, M.; Pichini, S. Ultra-High-Performance Liquid Chromatography-Tandem Mass Spectrometry Assay for Quantifying Fentanyl and 22 Analogs and Metabolites in Whole Blood, Urine, and Hair. Front. Chem. 2019, 7, 184,  DOI: 10.3389/fchem.2019.00184
      16
      Ultra-high-performance liquid chromatography-tandem mass spectrometry assay for quantifying fentanyl and 22 analogs and metabolites in whole blood, urine, and hair
      Busardo, Francesco Paolo; Carlier, Jeremy; Giorgetti, Raffaele; Tagliabracci, Adriano; Pacifici, Roberta; Gottardi, Massimo; Pichini, Simona
      Frontiers in Chemistry (Lausanne, Switzerland) (2019), 7 (), 184CODEN: FCLSAA; ISSN:2296-2646. (Frontiers Media S.A.)
      In this study, we aimed to develop a new method for detecting the newest fentanyl analogs with a high sensitivity, in whole blood, urine, and hair. We developed comprehensive ultra-high-performance liq. chromatog.-tandem mass spectrometry method for quantifying fentanyl and 22 analogs and metabolites. Urine samples were simply dild. before injection; a liq.-liq. extn. was performed for blood testing; and a solid phase extn. was performed in hair. Av. blood concns. were 7.84 ± 7.21 and 30.0 ± 18.0μg/L for cyclopropylfentanyl and cyclopropyl norfentanyl, resp., 4.08 ± 2.30μg/L for methoxyacetylfentanyl, 40.2 ± 38.6 and 44.5 ± 21.1μg/L for acetylfentanyl and acetyl norfentanyl, resp., 33.7 and 7.17μg/L for fentanyl and norfentanyl, resp., 3.60 and 0.90μg/L for furanylfentanyl and furanyl norfentanyl, resp., 0.67μg/L for sufentanil, and 3.13 ± 2.37μg/L for 4-ANPP. Av. urine concns. were 47.7 ± 39.3 and 417 ± 296μg/L for cyclopropylfentanyl and cyclopropyl norfentanyl, resp., 995 ± 908μg/L for methoxyacetylfentanyl, 1,874 ± 1,710 and 6,582 ± 3,252μg/L for acetylfentanyl and acetyl norfentanyl, resp., 146 ± 318 and 300 ± 710μg/L for fentanyl and norfentanyl, resp., 84.0 and 23.0μg/L for furanylfentanyl and furanyl norfentanyl, resp., and 50.5 ± 50.9μg/L for 4-ANPP. Av. hair concns. were 2,670 ± 184 and 82.1 ± 94.7 ng/g for fentanyl and norfentanyl, resp., and 10.8 ± 0.57 ng/g for 4-ANPP.
      >> More from SciFinder ®
      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1MXhtlOmsrfO&md5=d60dac197273bc67517ce9dbf96082f0
    17. 17
      Valdez, C. A. Gas Chromatography-Mass Spectrometry Analysis of Synthetic Opioids Belonging to the Fentanyl Class: A Review. Crit. Rev. Anal. Chem. 2022, 52, 1938– 1968,  DOI: 10.1080/10408347.2021.1927668
      There is no corresponding record for this reference.
    18. 18
      Van Dorp, E. L. A.; Yassen, A.; Dahan, A. Naloxone treatment in opioid addiction: the risks and benefits. Expert Opin. Drug Saf. 2007, 6, 125– 132,  DOI: 10.1517/14740338.6.2.125
      18
      Naloxone treatment in opioid addiction: the risks and benefits
      van Dorp, Eveline L. A.; Yassen, Ashraf; Dahan, Albert
      Expert Opinion on Drug Safety (2007), 6 (2), 125-132CODEN: EODSA9; ISSN:1474-0338. (Informa Healthcare)
      A review. Naloxone is a non-selective, short-acting opioid receptor antagonist that has a long clin. history of successful use and is presently considered a safe drug over a wide dose range (up to 10 mg). In opioid-dependent patients, naloxone is used in the treatment of opioid-overdose-induced respiratory depression, in (ultra)rapid detoxification and in combination with buprenorphine for maintenance therapy (to prevent i.v. abuse). Risks related to naloxone use in opioid-dependent patients are: (i) the induction of an acute withdrawal syndrome (the occurrence of vomiting and aspiration is potentially life threatening); (ii) the effect of naloxone may wear off prematurely when used for treatment of opioid-induced respiratory depression; and (iii) in patients treated for severe pain with an opioid, high-dose naloxone and/or rapidly infused naloxone may cause catecholamine release and consequently pulmonary edema and cardiac arrhythmias. These risks warrant the cautious use of naloxone and adequate monitoring of the cardiorespiratory status of the patient after naloxone administration where indicated.
      >> More from SciFinder ®
      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2sXjtFKns7s%253D&md5=e7ff48833854deffe0f8bf91520adf02
    19. 19
      Carpenter, J.; Murray, B. P.; Atti, S.; Moran, T. P.; Yancey, A.; Morgan, B. Naloxone Dosing After Opioid Overdose in the Era of Illicitly Manufactured Fentanyl. J. Med. Toxicol. 2020, 16, 41– 48,  DOI: 10.1007/s13181-019-00735-w
      There is no corresponding record for this reference.
    20. 20
      Britch, S. C.; Walsh, S. L. Treatment of opioid overdose: current approaches and recent advances. Psychopharmacology (Berl.) 2022, 239, 2063– 2081,  DOI: 10.1007/s00213-022-06125-5
      20
      Treatment of opioid overdose: current approaches and recent advances
      Britch Stevie C; Walsh Sharon L; Britch Stevie C; Walsh Sharon L; Walsh Sharon L; Walsh Sharon L; Walsh Sharon L
      Psychopharmacology (2022), 239 (7), 2063-2081 ISSN:.
      BACKGROUND: The USA has recently entered the third decade of the opioid epidemic. Opioid overdose deaths reached a new record of over 74,000 in a 12-month period ending April 2021. Naloxone is the primary opioid overdose reversal agent, but concern has been raised that naloxone is not efficacious against the pervasive illicit high potency opioids (i.e., fentanyl and fentanyl analogs). METHODS: This narrative review provides a brief overview of naloxone, including its history and pharmacology, and the evidence regarding naloxone efficacy against fentanyl and fentanyl analogs. We also highlight current advances in overdose treatments and technologies that have been tested in humans. RESULTS AND CONCLUSIONS: The argument that naloxone is not efficacious against fentanyl and fentanyl analogs rests on case studies, retrospective analyses of community outbreaks, pharmacokinetics, and pharmacodynamics. No well-controlled studies have been conducted to test this argument, and the current literature provides limited evidence to suggest that naloxone is ineffective against fentanyl or fentanyl analog overdose. Rather a central concern for treating fentanyl/fentanyl analog overdose is the rapidity of overdose onset and the narrow window for treatment. It is also difficult to determine if other non-opioid substances are contributing to a drug overdose, for which naloxone is not an effective treatment. Alternative pharmacological approaches that are currently being studied in humans include other opioid receptor antagonists (e.g., nalmefene), respiratory stimulants, and buprenorphine. None of these approaches target polysubstance overdose and only one novel approach (a wearable naloxone delivery device) would address the narrow treatment window.
      >> More from SciFinder ®
      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BB2Mvjslaksw%253D%253D&md5=251cb14d61e83fcc0f4e49769bd33038
    21. 21
      Yeung, D. T.; Bough, K. J.; Harper, J. R.; Platoff, G. E., Jr. National Institutes of Health (NIH) executive meeting summary: Developing medical countermeasures to rescue opioid-induced respiratory depression (a Trans-Agency Scientific Meeting)-August 6/7, 2019. J. Med. Toxicol. 2020, 16, 87– 105,  DOI: 10.1007/s13181-019-00750-x
      There is no corresponding record for this reference.
    22. 22
      France, C. P.; Ahern, G. P.; Averick, S.; Disney, A.; Enright, H. A.; Esmaeli-Azad, B.; Federico, A.; Gerak, L. A.; Husbands, S. M.; Kolber, B.; Lau, E. Y.; Lao, V.; Maguire, D. R.; Malfatti, M. A.; Martinez, G.; Mayer, B. P.; Pravetoni, M.; Sahibzada, N.; Skolnick, P.; Snyder, E. Y.; Tomycz, N.; Valdez, C. A.; Zapf, J. Countermeasures for preventing and treating opioid overdose. Clin. Pharmacol. Therap. 2021, 109, 578– 590,  DOI: 10.1002/cpt.2098
      There is no corresponding record for this reference.
    23. 23
      Deng, C. L.; Murkli, S. L.; Isaacs, L. D. Supramolecular hosts as in vivo sequestration agents for pharmaceuticals and toxins. Chem. Soc. Rev. 2020, 49, 7516– 7532,  DOI: 10.1039/D0CS00454E
      23
      Supramolecular hosts as in vivo sequestration agents for pharmaceuticals and toxins
      Deng, Chun-Lin; Murkli, Steven L.; Isaacs, Lyle D.
      Chemical Society Reviews (2020), 49 (21), 7516-7532CODEN: CSRVBR; ISSN:0306-0012. (Royal Society of Chemistry)
      A review. Pharmaceutical agents, drugs of abuse, and toxic substances have a large impact, pos. and neg., on modern society. Efforts to mitigate the side effects of pharmaceuticals and counteract the life threatening effects of drugs of abuse and toxins can occur either by pharmacodynamic (PD) approaches based on bioreceptor·drug antagonism or by pharmacokinetic (PK) approaches that seek to reduce the concn. of free drug. In this tutorial review, we present the use of supramol. hosts (cyclodextrins, calixarenes, (acyclic) cucurbiturils, and pillararenes) as in vivo sequestration agents for neuromuscular blockers, drugs of abuse (methamphetamine and fentanyl), anesthetics, neurotoxins, the pesticide paraquat, and heparin anti-coagulants by the PK approach. The review presents the basic phys. and mol. recognition features of the supramol. hosts and some of the principles used in their selection and structural optimization for in vivo sequestration applications. The influence of host·guest complexation on other relevant in vivo properties of drugs (e.g. distribution, circulation time, excretion, redox properties) is also mentioned. The article concludes with a discussion of future directions.
      >> More from SciFinder ®
      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3cXitVertL7P&md5=f1921dfb6696c71c06cda54cd873d659
    24. 24
      Thevathasan, T.; Grabitz, S. D.; Santer, P.; Rostin, P.; Akeju, O.; Boghosion, J. D.; Gil, M.; Isaacs, L.; Cotten, J. F.; Eikermann, M. Calabadion 1 selectively reverses respiratory and central nervous system effects of fentanyl in rat model. Br. J. Anaesth. 2020, 125, e140– e147,  DOI: 10.1016/j.bja.2020.02.019
      There is no corresponding record for this reference.
    25. 25
      Mayer, B. P.; Kennedy, D. J.; Lau, E. Y.; Valdez, C. A. Solution-state structure and affinities of cyclodextrin:fentanyl complexes by nuclear magnetic resonance spectroscopy and molecular dynamics simulation. J. Phys. Chem. B 2016, 120, 2423– 2433,  DOI: 10.1021/acs.jpcb.5b12333
      There is no corresponding record for this reference.
    26. 26
      Dodziuk, H. Rigidity versus flexibility. A review of experimental and theoretical studies pertaining to the cyclodextrin nonrigidity. J. Mol. Struct. 2002, 614, 33– 45,  DOI: 10.1016/S0022-2860(02)00236-3
      There is no corresponding record for this reference.
    27. 27
      Crini, D. Review: A history of cyclodextrins. Chem. Rev. 2014, 114, 10940– 10975,  DOI: 10.1021/cr500081p
      27
      Review: A History of Cyclodextrins
      Crini, Gregorio
      Chemical Reviews (Washington, DC, United States) (2014), 114 (21), 10940-10975CODEN: CHREAY; ISSN:0009-2665. (American Chemical Society)
      A discussion of the history of cyclodextrins is presented, describing the 120 years from discovery to development to the process of application.
      >> More from SciFinder ®
      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXhsFyrsLnP&md5=eefa7d9c4e06e877eb846a5857423ddb
    28. 28
      Lachowicz, M.; Stanczak, A.; Kolodziejczyk, M. Characteristic of Cyclodextrins: Their Role and Use in the Pharmaceutical Technology. Curr. Drug Targets 2020, 21, 1495– 1510,  DOI: 10.2174/1389450121666200615150039
      There is no corresponding record for this reference.
    29. 29
      Brewster, M. E.; Loftsson, T. Cyclodextrins as pharmaceutical solubilizers. Adv. Drug Delivery Rev. 2007, 59, 645– 666,  DOI: 10.1016/j.addr.2007.05.012
      29
      Cyclodextrins as pharmaceutical solubilizers
      Brewster, Marcus E.; Loftsson, Thorsteinn
      Advanced Drug Delivery Reviews (2007), 59 (7), 645-666CODEN: ADDREP; ISSN:0169-409X. (Elsevier B.V.)
      A review. Cyclodextrins are useful functional excipients that have enjoyed widespread attention and use. The basis for this popularity from a pharmaceutical standpoint, is the ability of these materials to interact with poorly water-sol. drugs and drug candidates resulting in an increase in their apparent water soly. The mechanism for this solubilization is rooted in the ability of cyclodextrin to form non-covalent dynamic inclusion complexes in soln. Other solubilizing attribute may include the ability to form non-inclusion based complexes, the formation of aggregates and related domains and the ability of cyclodextrins to form and stabilize supersatd. drug solns. The increase in soly. also can increase dissoln. rate and thus improve the oral bioavailability of BCS Class II and IV materials. A no. of cyclodextrin-based products have reached the market based on their ability to camouflage undesirable physicochem. properties. This review is intended to give a general background to the use of cyclodextrin as solubilizers as well as highlight kinetic and thermodn. tools and parameters useful in the study of drug solubilization by cyclodextrins.
      >> More from SciFinder ®
      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2sXpsFGks7g%253D&md5=50d40a75c10a799ae9487597c3d49495
    30. 30
      Mayer, B. P.; Kennedy, D. J.; Lau, E. Y.; Valdez, C. A. Evaluation of polyanionic cyclodextrins as high affinity binding scaffolds for fentanyl. Sci. Rep. 2023, 13, 2680,  DOI: 10.1038/s41598-023-29662-1
      There is no corresponding record for this reference.
    31. 31
      Lavonas, E. J.; Dezfulian, C. Impact of the Opioid Epidemic. Crit. Care Clin. 2020, 36, 753– 769,  DOI: 10.1016/j.ccc.2020.07.006
      There is no corresponding record for this reference.
    32. 32
      Fan, Y.-Z.; Liu, W.-G.; Yong, Z.; Su, R.-B. Pre-treatment with Tandospirone attenuates fentanyl-induced respiratory depression without affecting the analgesic effects of fentanyl in rodents. Neurosci. Lett. 2022, 771, 136459,  DOI: 10.1016/j.neulet.2022.136459
      There is no corresponding record for this reference.
    33. 33
      Kurkov, S. V.; Loftsson, T. Cyclodextrins. Int. J. Pharm. 2013, 453, 167– 180,  DOI: 10.1016/j.ijpharm.2012.06.055
      33
      Cyclodextrins
      Kurkov, Sergey V.; Loftsson, Thorsteinn
      International Journal of Pharmaceutics (Amsterdam, Netherlands) (2013), 453 (1), 167-180CODEN: IJPHDE; ISSN:0378-5173. (Elsevier B.V.)
      A review. Although cyclodextrins (CDs) have been studied for over 100 years and can be found in at least 35 pharmaceutical products, they are still regarded as novel pharmaceutical excipients. CDs are oligosaccharides that possess biol. properties that are similar to their linear counterparts, but some of their physicochem. properties differ. CDs are able to form water-sol. inclusion complexes with many poorly sol. lipophilic drugs. Thus, CDs are used to enhance the aq. soly. of drugs and to improve drug bioavailability after, for example, oral administration. Through CD complexation, poorly sol. drugs can be formulated as aq. parenteral solns., nasal sprays and eye drop solns. These oligosaccharides are being recognized as non-toxic and pharmacol. inactive excipients for both drug and food products. Recently, it has been obsd. that CDs and CD complexes in particular self-assemble to form nanoparticles and that, under certain conditions, these nanoparticles can self-assemble to form microparticles. These properties have changed the way we perform CD research and have given rise to new CD formulation opportunities. Here, the pharmaceutical applications of CDs are reviewed with an emphasis on their solubilizing properties, their tendency to self-assemble to form aggregates, CD ternary complexes, and their metab. and pharmacokinetics.
      >> More from SciFinder ®
      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38XhtVKntLbJ&md5=77681b35e026a98bc5a7c24e649e49a2
    34. 34
      Tian, B.; Hua, S.; Liu, J. Cyclodextrin-based delivery systems for chemotherapeutic anticancer drugs: A review. Carbohydr. Polym. 2020, 232, 115805,  DOI: 10.1016/j.carbpol.2019.115805
      34
      Cyclodextrin-based delivery systems for chemotherapeutic anticancer drugs: A review
      Tian, Bingren; Hua, Shiyao; Liu, Jiayue
      Carbohydrate Polymers (2020), 232 (), 115805CODEN: CAPOD8; ISSN:0144-8617. (Elsevier Ltd.)
      A review. Cancer is increasingly becoming a serious threat to human life and health. Therefore, the development of safe and effective therapeutic agents against the disease is of crucial significance. Cyclodextrins (CDs) are cyclic oligosaccharides obtained by the enzymic hydrolysis of starch, and constitute a class of cyclic oligosaccharides with external hydrophilic and internal hydrophobic properties and have been used widely in cancer therapy. Cyclodextrin has been extensively applied in nanomedicine therapy, gene therapy, cell therapy, immunotherapy, and chemotherapy. In this review, we summarize chemotherapy drugs for cancer treatment, classify various CD-based drug delivery systems, and describe their chemotherapy release and cancer treatment performance. In addn., current challenges and new opportunities for CD-based chemotherapeutic agents delivery systems are discussed.
      >> More from SciFinder ®
      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3cXksFagsQ%253D%253D&md5=9ea031e01e998ee2345a695fb448d2c1
    35. 35
      Challa, R.; Ahuja, A.; Ali, J.; Khar, R. K. Cyclodextrins in drug delivery: an updated review. AAPS PharmSciTech 2005, 6, E329– E357,  DOI: 10.1208/pt060243
      35
      Cyclodextrins in drug delivery: an updated review
      Challa Rajeswari; Ahuja Alka; Ali Javed; Khar R K
      AAPS PharmSciTech (2005), 6 (2), E329-57 ISSN:.
      The purpose of this review is to discuss and summarize some of the interesting findings and applications of cyclodextrins (CDs) and their derivatives in different areas of drug delivery, particularly in protein and peptide drug delivery and gene delivery. The article highlights important CD applications in the design of various novel delivery systems like liposomes, microspheres, microcapsules, and nanoparticles. In addition to their well-known effects on drug solubility and dissolution, bioavailability, safety, and stability, their use as excipients in drug formulation are also discussed in this article. The article also focuses on various factors influencing inclusion complex formation because an understanding of the same is necessary for proper handling of these versatile materials. Some important considerations in selecting CDs in drug formulation such as their commercial availability, regulatory status, and patent status are also summarized. CDs, because of their continuing ability to find several novel applications in drug delivery, are expected to solve many problems associated with the delivery of different novel drugs through different delivery routes.
      >> More from SciFinder ®
      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BD2Mnms1Klsw%253D%253D&md5=ccb8423f272e82320890839bf3d29616
    36. 36
      Duri, S.; Tran, C. D. Supramolecular composite materials from cellulose, chitosan, and cyclodextrin: facile preparation and their selective inclusion complex formation with endocrine disruptors. Langmuir 2013, 29, 5037– 5049,  DOI: 10.1021/la3050016
      36
      Supramolecular Composite Materials from Cellulose, Chitosan, and Cyclodextrin: Facile Preparation and Their Selective Inclusion Complex Formation with Endocrine Disruptors
      Duri, Simon; Tran, Chieu D.
      Langmuir (2013), 29 (16), 5037-5049CODEN: LANGD5; ISSN:0743-7463. (American Chemical Society)
      We developed a simple 1-step method of prepg. high-performance supramol. polysaccharide composites from cellulose (CEL), chitosan (CS), and (2,3,6-tri-O-acetyl)-α-, β-, and γ-cyclodextrin (α-, β-, and γ-TCD). [BMIm+Cl-], an ionic liq. (IL), was used as a solvent to dissolve and prep. the composites. Because a majority (>88%) of the IL used was recovered for reuse, the method is recyclable. XRD, FTIR, NIR, and SEM were used to monitor the dissoln. process and to confirm that the polysaccharides were regenerated without any chem. modifications. It was found that unique properties of each component including superior mech. properties (from CEL), excellent adsorption for pollutants and toxins (from CS), and size/structure selectivity through inclusion complex formation (from TCDs) remain intact in the composites. Specifically, the results from kinetics and adsorption isotherms show that whereas CS-based composites can effectively adsorb the endocrine disruptors (polychlrophenols, bisphenol A), their adsorption is independent of the size and structure of the analytes. Conversely, the adsorption by γ-TCD-based composites exhibits a strong dependence on the size and structure of the analytes. For example, whereas all three TCD-based composites (i.e., α-, β-, and γ-TCD) can effectively adsorb 2-, 3-, and 4-chlorophenol, only the γ-TCD-based composite can adsorb analytes with bulky groups including 3,4-dichloro- and 2,4,5-trichlorophenol. The equil. sorption capacities for the analytes with bulky groups by the γ-TCD-based composite are much higher than those by CS-based composites. Together, these results indicate that the γ-TCD-based composite with its relatively larger cavity size can readily form inclusion complexes with analytes with bulky groups, and through inclusion complex formation, it can strongly adsorb many more analytes and has a size/structure selectivity compared to that of CS-based composites that can adsorb the analyte only by surface adsorption.
      >> More from SciFinder ®
      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXktlyltbs%253D&md5=4ab0a50329359d23acf12b54e386f9c9
    37. 37
      Mayer, B. P.; Albo, R. L. F.; Hok, S.; Valdez, C. A. NMR spectroscopic investigation of inclusion complexes between cyclodextrins and the neurotoxin tetramethylenedisulfotetramine. Magn. Reson. Chem. 2012, 50, 229– 235,  DOI: 10.1002/mrc.3803
      37
      NMR spectroscopic investigation of inclusion complexes between cyclodextrins and the neurotoxin tetramethylenedisulfotetramine
      Mayer, Brian P.; Albo, Rebecca L. F.; Hok, Saphon; Valdez, Carlos A.
      Magnetic Resonance in Chemistry (2012), 50 (3), 229-235CODEN: MRCHEG; ISSN:0749-1581. (John Wiley & Sons Ltd.)
      The binding stoichiometry, strength and structure of inclusion complexes formed between the neurotoxin tetramethylenedisulfotetramine (TETS) and both native and modified cyclodextrins (CyDs) were investigated using NMR spectroscopy. Of all six examd. cases, native β-cyclodextrin (β-CyD) and its chem. modified counterpart heptakis-(2,3,6-tris-(2-hydroxypropyl))-β-cyclodextrin (2HP-β-CyD) were found to assoc. most strongly with TETS as reflected in the magnitude of their binding consts. (K = 537 ± 26 M-1 for β-CyD and K = 514 ± 49 M-1 for 2HP-β-CyD). Two-dimensional rotating-frame Overhauser effect spectroscopy NMR expts. confirm close proximity of the TETS mol. to both β-CyD and 2HP-β-CyD as intermol., through-space interactions between the H3 and H5 protons located in the interior of the CyD cavity and the methylene protons of TETS were identified. Copyright © 2012 John Wiley & Sons, Ltd.
      >> More from SciFinder ®
      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38XjtVOlsbg%253D&md5=48741087771c075a1c6cceeb69a58650
    38. 38
      Dernaika, H.; Chong, S. V.; Artur, C. G.; Tallon, J. L. Spectroscopic Identification of Neurotoxin Tetramethylenedisulfotetramine (TETS) Captured by Supramolecular Receptor β-Cyclodextrin Immobilized on Nanostructured Gold Surfaces. J. Nanomat. 2014, 2014, 207258,  DOI: 10.1155/2014/207258
      There is no corresponding record for this reference.
    39. 39
      Mahammad, S.; Parmryd, I. Cholesterol depletion using methyl-β-cyclodextrin. Methods Mol. Biol. 2015, 1232, 91– 102,  DOI: 10.1007/978-1-4939-1752-5_8
      39
      Cholesterol Depletion Using Methyl-β-cyclodextrin
      Mahammad, Saleemulla; Parmryd, Ingela
      Methods in Molecular Biology (New York, NY, United States) (2015), 1232 (Methods in Membrane Lipids), 91-102CODEN: MMBIED; ISSN:1940-6029. (Springer)
      Cholesterol is an essential component of mammalian cells. It is the major lipid constituent of the plasma membrane and is also abundant in most other organelle membranes. In the plasma membrane cholesterol plays crit. phys. roles in the maintenance of membrane fluidity and membrane permeability. It is also important for membrane trafficking, cell signalling, and lipid as well as protein sorting. Cholesterol is essential for the formation of liq. ordered domains in model membranes, which in cells are known as lipid nanodomains or lipid rafts. Cholesterol depletion is widely used to study the role of cholesterol in cellular processes and can be performed over days using inhibitors of its synthesis or acutely over minutes using chem. reagents. Acute cholesterol depletion by methyl-β-cyclodextrin (MBCD) is the most widely used method and here we describe how it should be performed to avoid the common side-effect cell death.
      >> More from SciFinder ®
      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28XjtVyrsLk%253D&md5=1fe62a1e81f2dd607d204f66c69e0a9d
    40. 40
      Adam, J. M.; Bennett, D. J.; Bom, A.; Clark, J. K.; Feilden, H.; Hutchinson, E. J.; Palin, R.; Prosser, A.; Rees, D. C.; Rosair, G. M.; Stevenson, D.; Tarver, G. J.; Zhang, M.-Q. Cyclodextrin-derived host molecules as reversal agents for the neuromuscular blocker rocuronium bromide: Synthesis and structure-activity relationships. J. Med. Chem. 2002, 45, 1806– 1816,  DOI: 10.1021/jm011107f
      40
      Cyclodextrin-Derived Host Molecules as Reversal Agents for the Neuromuscular Blocker Rocuronium Bromide: Synthesis and Structure-Activity Relationships
      Adam, Julia M.; Bennett, D. Jonathan; Bom, Anton; Clark, John K.; Feilden, Helen; Hutchinson, Edward J.; Palin, Ronald; Prosser, Alan; Rees, David C.; Rosair, Georgina M.; Stevenson, Donald; Tarver, Gary J.; Zhang, Ming-Qiang
      Journal of Medicinal Chemistry (2002), 45 (9), 1806-1816CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)
      A series of mono- and per-6-substituted cyclodextrin derivs. were synthesized as synthetic receptors (or host mols.) of rocuronium bromide, the most widely used neuromuscular blocker in anesthesia. By forming host-guest complexes with rocuronium, these cyclodextrin derivs. reverse the muscle relaxation induced by rocuronium in vitro and in vivo and therefore can be used as reversal agents of the neuromuscular blocker to assist rapid recovery of patients after surgery. Because this supramol. mechanism of action does not involve direct interaction with the cholinergic system, the reversal by these compds. is not accompanied by cardiovascular side effects usually attendant with acetylcholinesterase inhibitors such as neostigmine. The structure-activity relationships are consistent with this supramol. mechanism of action and are discussed herein. These include the effects of binding cavity size and hydrophobic and electrostatic interaction on the reversal activities of these compds.
      >> More from SciFinder ®
      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD38XitFahs78%253D&md5=4f120b5717a6e876c7859b0ff6f5ab26
    41. 41
      de Boer, H. D.; van Egmong, J.; van de Pol, F.; Bom, A.; Booij, L. H. D. J. Sugammadex, a new reversal agent for neuromuscular block induced by rocuronium in anaesthesized Rhesus monkey. Br. J. Anesth. 2006, 96, 473– 479,  DOI: 10.1093/bja/ael013
      There is no corresponding record for this reference.
    42. 42
      Donati, F. Sugammadex: a cyclodextrin to reverse neuromuscular blockade in anaesthesia. Expert Opin. Pharmacother. 2008, 9, 1375– 1386,  DOI: 10.1517/14656566.9.8.1375
      There is no corresponding record for this reference.
    43. 43
      Schaller, S. J.; Lewald, H. Clinical pharmacology and efficacy of sugammadex in the reversal of neuromuscular blockade. Expert Opin. Drug Metab. Toxicol. 2016, 12, 1097– 1108,  DOI: 10.1080/17425255.2016.1215426
      There is no corresponding record for this reference.
    44. 44
      Bostan, H.; Kalkan, Y.; Tomak, Y.; Tumkaya, L.; Altuner, D.; Yilmaz, A.; Erdivanli, B.; Bedir, R. Reversal of Rocuronium-Induced Neuromuscular Block with Sugammadex and Resulting Histopathological Effects in Rat Kidneys. Renal Failure 2011, 33, 1019– 1024,  DOI: 10.3109/0886022X.2011.618972
      There is no corresponding record for this reference.
    45. 45
      Van Ommen, B.; De Bie, A. T. H. J.; Bår, A. Disposition of 14C- α-cyclodextrin in germ-free and conventional rats. Regul. Toxicol. Pharmacol. 2004, 39, S57– S66,  DOI: 10.1016/j.yrtph.2004.05.011
      There is no corresponding record for this reference.
    46. 46
      De Bie, A. T. H. J.; Van Ommen, B.; Bår, A. Disposition of [14C] γ-cyclodextrin in germ free and conventional rats. Regul. Toxicol. Pharmacol. 1998, 27, 150– 158,  DOI: 10.1006/rtph.1998.1219
      There is no corresponding record for this reference.
    47. 47
      Bostan, H.; Kalkan, Y.; Tomak, Y.; Tumkaya, L.; Altuner, D.; Yılmaz, A.; Erdivanli, B.; Recep Bedir, R. Reversal of Rocuronium-Induced Neuromuscular Block with Sugammadex and Resulting Histopathological Effects in Rat Kidneys. Renal Failure 2011, 33 (10), 1019– 1024,  DOI: 10.3109/0886022X.2011.618972
      There is no corresponding record for this reference.
    48. 48
      Irie, T.; Uekama, K. Pharmaceutical applications of cyclodextrins. III. Toxicological issues and safety evaluation. J. Pharm. Sci. 1997, 86, 147– 62,  DOI: 10.1021/js960213f
      48
      Pharmaceutical applications of cyclodextrins. III. Toxicological issues and safety evaluation
      Irie, Tetsumi; Uekama, Kaneto
      Journal of Pharmaceutical Sciences (1997), 86 (2), 147-162CODEN: JPMSAE; ISSN:0022-3549. (American Chemical Society)
      A review, with 201 refs., summarizing recent findings on the safety profiles of 3 natural cyclodextrins (α-, β- and γ-cyclodextrins) and several chem. modified cyclodextrins.
      >> More from SciFinder ®
      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK2sXhtVOgsLY%253D&md5=7482185501b59f3716b2c4ee435bd383
    49. 49
      Saari, T. I.; Strang, J.; Dale, O. Clinical Pharmacokinetics and Pharmacodynamics of Naloxone. Clin Pharmacokinet 2024, 63, 397– 422,  DOI: 10.1007/s40262-024-01355-6
      There is no corresponding record for this reference.
    50. 50
      Golembiewski, J. Sugammadex. Journal of PeriAnesthesia Nursing 2016, 31, 354– 357,  DOI: 10.1016/j.jopan.2016.05.004
      There is no corresponding record for this reference.
    51. 51
      Ogawa, N.; Nagase, H.; Loftsson, T.; Endo, T.; Takahashi, C.; Kawashima, Y.; Ueda, H.; Yamamoto, H. Crystallographic and theoretical studies of an inclusion complex of β-cyclodextrin with fentanyl. Int. J. Pharm. 2017, 531, 588– 594,  DOI: 10.1016/j.ijpharm.2017.06.081
      There is no corresponding record for this reference.
    52. 52
      Cameron, K. S.; Clark, J. K.; Cooper, A.; Fielding, L.; Palin, R.; Rutherford, S. J.; Zhang, M.-Q. Modified γ-Cyclodextrins and their rocuronium complexes. Org. Lett. 2002, 4, 3403– 3406,  DOI: 10.1021/ol020126w
      52
      Modified γ-Cyclodextrins and Their Rocuronium Complexes
      Cameron, K. S.; Clark, J. K.; Cooper, A.; Fielding, L.; Palin, R.; Rutherford, S. J.; Zhang, M.-Q.
      Organic Letters (2002), 4 (20), 3403-3406CODEN: ORLEF7; ISSN:1523-7060. (American Chemical Society)
      A series of per-6-substituted cyclodextrin derivs. was synthesized as synthetic host mols. for rocuronium, a steroidal muscle relaxant. By forming host-guest complexes with rocuronium, these cyclodextrin derivs. reverse the muscle relaxation induced by rocuronium in vitro and in vivo. The isothermal micro-calorimetry data are consistent with the biol. data supporting the encapsulation mechanism of action. Binary and biphasic complexes are reported with NMR expts. clearly showing free and bound rocuronium.
      >> More from SciFinder ®
      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD38Xms12ru7s%253D&md5=7743629838a2dbe675ee925c336b3625
    53. 53
      Valdez, C. A.; Saavedra, J. E.; Showalter, B. M.; Davies, K. M.; Wilde, T. C.; Citro, M. L.; Barchi, J. J.; Deschamps, J. R.; Parrish, D.; El-Gayar, S.; Schleicher, U.; Bogdan, C.; Keefer, L. K. Hydrolytic reactivity trends among potential prodrugs of the O2-glycosylated diazeniumdiolate family. Targeting nitric oxide to macrophages for antileishmanial activity. J. Med. Chem. 2008, 51, 3961– 3970,  DOI: 10.1021/jm8000482
      53
      Hydrolytic Reactivity Trends among Potential Prodrugs of the O2-Glycosylated Diazeniumdiolate Family. Targeting Nitric Oxide to Macrophages for Antileishmanial Activity
      Valdez, Carlos A.; Saavedra, Joseph E.; Showalter, Brett M.; Davies, Keith M.; Wilde, Thomas C.; Citro, Michael L.; Barchi, Joseph J., Jr.; Deschamps, Jeffrey R.; Parrish, Damon; El-Gayar, Stefan; Schleicher, Ulrike; Bogdan, Christian; Keefer, Larry K.
      Journal of Medicinal Chemistry (2008), 51 (13), 3961-3970CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)
      Glycosylated diazeniumdiolates of structure R2NN(O)=NO-R' (R' = a saccharide residue) are potential prodrugs of the nitric oxide (NO)-releasing but acid-sensitive R2NN(O)=NO- ion. Moreover, cleaving the acid-stable glycosides under alk. conditions provides a convenient protecting group strategy for diazeniumdiolate ions. Here, we report comparative hydrolysis rate data for five representative glycosylated diazeniumdiolates at pH 14, 7.4, and 3.8-4.6 as background for further developing both the protecting group application and the ability to target NO pharmacol. to macrophages harboring intracellular pathogens. Confirming the potential in the latter application, adding R2NN(O)=NO-GlcNAc (where R2N = diethylamino or pyrrolidin-l-yl and GlcNAc = N-acetylglucosamin-l-yl) to cultures of infected mouse macrophages that were deficient in inducible NO synthase caused rapid death of the intracellular protozoan parasite Leishmania major with no host cell toxicity.
      >> More from SciFinder ®
      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1cXmvVGrtrs%253D&md5=fb8c04ad34641b18500a9275da8ec09e
    54. 54
      Showalter, B. M.; Reynolds, M. M.; Valdez, C. A.; Saavedra, J. E.; Davies, K. M.; Klose, J. R.; Chmurny, G. N.; Citro, M. L.; Barchi, J. J.; Merz, S.; Meyerhoff, M. E.; Keefer, L. K. Diazeniumdiolate ions as leaving groups in anomeric displacement reactions: A protection-deprotection strategy for ionic diazeniumdiolates. J. Am. Chem. Soc. 2005, 127, 14188– 14189,  DOI: 10.1021/ja054510a
      54
      Diazeniumdiolate Ions as Leaving Groups in Anomeric Displacement Reactions: A Protection-Deprotection Strategy for Ionic Diazeniumdiolates
      Showalter, Brett M.; Reynolds, Melissa M.; Valdez, Carlos A.; Saavedra, Joseph E.; Davies, Keith M.; Klose, John R.; Chmurny, Gwendolyn N.; Citro, Michael L.; Barchi, Joseph J., Jr.; Merz, Scott I.; Meyerhoff, Mark E.; Keefer, Larry K.
      Journal of the American Chemical Society (2005), 127 (41), 14188-14189CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)
      Diazeniumdiolate ions [R2N-N(O):N-O-] are of growing interest pharmacol. for their ability to generate up to two molar equivalents of bioactive nitric oxide (NO) spontaneously on protonating the amino nitrogen. Accordingly, their stability increases as the pH is raised. Here we show that the corresponding β-glucosides [R2N-N(O):N-O-Glc] decreased in stability with pH; when R2N was diethylamino, the rate equation was kobs = ko + kOH- [OH-], where ko = 7.8 × 10-7 s-1 and kOH- = 5.3 × 10-3 M-1 s-1. The primary products were 1,6-anhydroglucose and the regenerated R2N-N(O):N-O- ion. The results were qual. similar to those of β-glucosyl fluoride and p-nitrophenoxide, whose hydrolyzes have been rationalized as proceeding via a glycal oxide intermediate. This chem. offers a convenient strategy for protecting heat- and acid-sensitive diazeniumdiolate ions during manipulations that would otherwise destroy them. As an example, a poly(urethane) film that generated NO in physiol. buffer at a surface flux comparable to that of the mammalian vascular endothelium was prepd. by glucosylating the ionic diazeniumdiolate group attached to the diol monomer before reacting it with the bis-isocyanate, then removing the saccharide with base when the protecting group was no longer needed.
      >> More from SciFinder ®
      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2MXhtVarurvI&md5=39ade2581dfd6632e7c5fcd2f6fcf253
    55. 55
      Albo, R. L. F.; Valdez, C. A.; Leif, R. N.; Mulcahy, H. A.; Koester, C. Derivatization of pinacolyl alcohol with phenyldimethylchlorosilane for enhanced detection by gas chromatography-mass spectrometry. Anal. Bioanal. Chem. 2014, 406, 5231– 5234,  DOI: 10.1007/s00216-014-7625-y
      There is no corresponding record for this reference.
    56. 56
      Valdez, C. A.; Leif, R. N.; Sanner, R. D.; Corzett, T. H.; Dreyer, M. L.; Mason, K. E. Structural modification of fentanyls for their retrospective identification by gas chromatographic analysis using chloroformate chemistry. Sci. Rep. 2021, 11, 22489,  DOI: 10.1038/s41598-021-01896-x
      There is no corresponding record for this reference.
    57. 57
      Roka, E.; Ujhelyi, Z.; Deli, M.; Bocsik, A.; Fenyvesi, E.; Szente, L.; Fenyvesi, F.; Vecsernyes, M.; Varadi, J.; Feher, P.; Gesztelyi, R.; Felix, C.; Perret, F.; Bacskay, I. K. Evaluation of the Cytotoxicity of α-Cyclodextrin Derivatives on the Caco-2 Cell Line and Human Erythrocytes. Molecules 2015, 20, 20269– 20285,  DOI: 10.3390/molecules201119694
      There is no corresponding record for this reference.
    58. 58
      Kiss, T.; Fenyvesi, F.; Bacskay, I.; Varadi, J.; Fenyvesi, E.; Ivanyi, R.; Szente, L.; Tosaki, A.; Vecsernyes, M. Evaluation of the cytotoxicity of β-cyclodextrin derivatives: Evidence for the role of cholesterol extraction. Eur. J. Pharm. Sci. 2010, 40, 376– 380,  DOI: 10.1016/j.ejps.2010.04.014
      58
      Evaluation of the cytotoxicity of β-cyclodextrin derivatives: Evidence for the role of cholesterol extraction
      Kiss, T.; Fenyvesi, F.; Bacskay, I.; Varadi, J.; Fenyvesi, E.; Ivanyi, R.; Szente, L.; Tosaki, A.; Vecsernyes, M.
      European Journal of Pharmaceutical Sciences (2010), 40 (4), 376-380CODEN: EPSCED; ISSN:0928-0987. (Elsevier B.V.)
      Several β-cyclodextrin (β-CD) derivs. have been synthesized recently to improve the physicochem. properties and inclusion capacities of the parent mol., however, there is limited information available about their cytotoxic effects. In this study we investigated the cytotoxic and hemolytic properties of various β-CDs in correlation with their cholesterol-solubilizing capacities to expose the mechanism of toxicity. MTT cell viability test, performed on Caco-2 cells showed significant differences between the cytotoxicity of β-CD derivs. Cell toxicity of methylated-β-CDs was the highest, while ionic derivs. proved to be less toxic than methylated ones. Most of the second generation β-CD derivs., having both ionic and Me substituents showed less cytotoxicity than the parent compds. both on Caco-2 cells and human erythrocytes. Inclusion of cholesterol into the ring of randomly methylated-β-CD and heptakis(2,6-di-O-methyl)-β-CD abolished the cell toxicity indicating the role of cholesterol extn. in cytotoxicity. These data demonstrate the correlation between the cytotoxic effect, hemolytic activity and the cholesterol complexation attributes of β-CD derivs. and we propose that cholesterol-solubilizing properties can be a predictive factor for β-CD cell toxicity.
      >> More from SciFinder ®
      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3cXmslOhur4%253D&md5=6ba4779af8594b1e6ed15e8fb5700a82
    59. 59
      Kainu, V.; Hermansson, M.; Somerharju, P. Introduction of phospholipids to cultured cells with cyclodextrin. J. Lipid Res. 2010, 51, 3533– 3541,  DOI: 10.1194/jlr.D009373
      59
      Introduction of phospholipids to cultured cells with cyclodextrin
      Kainu, Ville; Hermansson, Martin; Somerharju, Pentti
      Journal of Lipid Research (2010), 51 (12), 3533-3541CODEN: JLPRAW; ISSN:0022-2275. (American Society for Biochemistry and Molecular Biology, Inc.)
      Previous studies indicate that methyl-β-cyclodextrin (meβ-CD) can greatly enhance translocation of long-chain phospholipids from vesicles to cells in culture, which is very useful when studying, e.g., phospholipid metab. and trafficking. However, the parameters affecting the transfer have not been systematically studied. Therefore, we studied the relevant parameters including meβ-CD and vesicle concn., incubation time, phospholipid structure, and cell type. Because meβ-CD can ext. cholesterol and other lipids from cells, thereby potentially altering cell growth or viability, these issues were studied as well. The results show that efficient incorporation of phospholipid species with hydrophobicity similar to that of natural species can be obtained without significantly compromising cell growth or viability. Cellular content of phosphatidyl-serine, -ethanolamine, and -choline could be increased dramatically, i.e., 400, 125, and 25%, resp. Depletion of cellular cholesterol could be prevented or alleviated by inclusion of the proper amt. of cholesterol in the donor vesicles. In summary, meβ-CD mediates efficient transfer of long-chain (phospho) lipids from vesicles to cells without significantly compromising their growth or viability. This lays a basis for detailed studies of phospholipid metab. and trafficking as well as enables extensive manipulation of cellular phospholipid compn., which is particularly useful when investigating mechanisms underlying phospholipid homeostasis.
      >> More from SciFinder ®
      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3cXhsFWitLvJ&md5=d8a184625e9c3bce9ac033fccd862f6a
    60. 60
      Ognibene, T. J.; Bench, G.; Vogel, J. S.; Peaslee, G. F.; Murov, S. A high-throughput method for the conversion of CO2 obtained from biochemical samples to graphite in septa-sealed vials for quantification of 14C via accelerator mass spectrometry. Anal. Chem. 2003, 75, 2192– 02198,  DOI: 10.1021/ac026334j
      60
      A high-throughput method for the conversion of CO2 obtained from biochemical samples to graphite in septa-sealed vials for quantification of 14C via accelerator mass spectrometry
      Ognibene, Ted J.; Bench, Graham; Vogel, John S.; Peaslee, Graham F.; Murov, Steve
      Analytical Chemistry (2003), 75 (9), 2192-2196CODEN: ANCHAM; ISSN:0003-2700. (American Chemical Society)
      The growth of accelerator mass spectrometry as a tool for quant. isotope ratio anal. in the biosciences necessitates high-throughput sample prepn. A method has been developed to convert CO2 obtained from carbonaceous samples to solid graphite for highly sensitive and precise 14C quantification. Septa-sealed vials are used along with com. available disposable materials, eliminating sample cross contamination, minimizing complex handling, and keeping per sample costs low. Samples contg. between 0.25 and 10 mg of total carbon can be reduced to graphite in ∼4 h in routine operation. Approx. 150 samples per 8-h day can be prepd. by a single technician.
      >> More from SciFinder ®
      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD3sXisFCltbk%253D&md5=b3aefc406eea96be5033b882879797a4
    61. 61
      Ohtsuka, H.; Fujita, K.; Kobayashi, H. Pharmacokinetics of Fentanyl in Male and Female Rats after Intravenous Administration. Arzneimittel-Forschung(Drug Research) 2007, 57 (5), 260– 263,  DOI: 10.1055/s-0031-1296615
      There is no corresponding record for this reference.
    62. 62
      Bergh, M. S.-S.; Bogen, I. L.; Garibay, N.; Baumann, M. H. Evidence for nonlinear accumulation of the ultrapotent fentanyl analog, carfentanil, after systemic administration to male rats. Neuropharmacology 2019, 158, 107596,  DOI: 10.1016/j.neuropharm.2019.04.002
      62
      Evidence for nonlinear accumulation of the ultrapotent fentanyl analog, carfentanil, after systemic administration to male rats
      Bergh, Marianne Skov-Skov; Bogen, Inger Lise; Garibay, Nancy; Baumann, Michael H.
      Neuropharmacology (2019), 158 (), 107596CODEN: NEPHBW; ISSN:0028-3908. (Elsevier B.V.)
      The current opioid overdose crisis is being exacerbated by illicitly manufd. fentanyl and its analogs. Carfentanil is a fentanyl analog that is 10,000-times more potent than morphine, but limited information is available about its pharmacol. The present study had two aims: (1) to validate a method for quantifying carfentanil and its metabolite norcarfentanil in small-vol. samples, and (2) to use the method for examg. pharmacodynamic-pharmacokinetic relationships in rats. The anal. method involved liq.-liq. extn. of plasma samples followed by quantitation of carfentanil and norcarfentanil using ultra-high-performance liq. chromatog. coupled to tandem mass spectrometry (UHPLC-MS/MS). The method was validated following SWGTOX guidelines, and both analytes displayed limits of detection and quantification at 7.5 and 15 pg/mL, resp. Male Sprague-Dawley rats fitted with jugular catheters and temp. transponders received s.c. carfentanil (1, 3 and 10 μg/kg) or saline. Repeated blood specimens were obtained over 8 h, along with pharmacodynamic measures including core temp. and catalepsy scores. Carfentanil produced dose-related hypothermia and catalepsy that lasted up to 8 h. Carfentanil Cmax occurred at 15 min whereas metabolite Cmax was at 1-2 h. Concns. of both analytes increased in a dose-related fashion, but area-under-the-curve values were much greater than predicted after 10 μg/kg. Plasma half-life for carfentanil increased at higher doses. Our findings reveal that carfentanil produces marked hypothermia and catalepsy, which is accompanied by nonlinear accumulation of the drug at high doses. We hypothesize that impaired clearance of carfentanil in humans could contribute to life-threatening effects of this ultrapotent opioid agonist.
      >> More from SciFinder ®
      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1MXnsVertLk%253D&md5=3aca8d1fa597d52f447b53513678e224
    63. 63
      Burkle, H.; Dunbar, S.; Van Aken, H. PhD. Remifentanil: A Novel, Short-Acting, mu-Opioid. Anesthesia Analgesia 1996, 83 (3), 646– 651,  DOI: 10.1097/00000539-199609000-00038
      There is no corresponding record for this reference.
    64. 64
      Malfatti, M. A.; Enright, H. A.; Be, N. A.; Kuhn, E. A.; Hok, S.; McNerney, M. W.; Lao, V.; Nguyen, T. H.; Lightstone, F. C.; Carpenter, T. S.; Bennion, B. J.; Valdez, C. A. The biodistribution and pharmacokinetics of the oxime acetylcholinesterase reactivator RS194B in guinea pigs. Chem. Bio. Interact. 2017, 277, 159– 167,  DOI: 10.1016/j.cbi.2017.09.016
      There is no corresponding record for this reference.

  • Supporting Information

    Supporting Information

    The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/acscentsci.4c00682.

    • Complete synthetic methods and characterization of SBX-Me, 14C-radiolabeled SBX-Me, fentanyl, carfentanil, and remifentanil; NMR spectra of SBX-Me; experimental methods and additional data including tissue distribution profiles and metabolism studies (PDF)


    Terms & Conditions

    Most electronic Supporting Information files are available without a subscription to ACS Web Editions. Such files may be downloaded by article for research use (if there is a public use license linked to the relevant article, that license may permit other uses). Permission may be obtained from ACS for other uses through requests via the RightsLink permission system: http://pubs.acs.org/page/copyright/permissions.html.