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Current Topics in Medicinal Chemistry 2017We have recently reported the synthesis and antiproliferative potential of a series of biaryl type α-noscapine congeners. Among them, 9-(3-pyridyl) noscapine 3f... (Review)
Review
We have recently reported the synthesis and antiproliferative potential of a series of biaryl type α-noscapine congeners. Among them, 9-(3-pyridyl) noscapine 3f (9-PyNos, henceforth), which was synthesized by adding pyridine unit to the tetrahydroisoquinoline part of natural α-noscapine core, was found to be the most effective one to inhibit proliferation of a variety of cancer cell lines. However, details of its interactions with its cellular target, tubulin, remain poorly understood. In this report, we examined the nature of interactions of 9-PyNos with tubulin based on the methodologies of spectrofluorimetry, circular dichroism, and turbidimetry techniques. Far-UV circular dichroism spectra indicated perturbation of tubulin secondary structure in the presence of 9-PyNos, not amounting, however, to the perturbation induced by noscapine. The noscapinoid nevertheless altered the surface configuration of the protein considerably, as indicated by an anilinonaphthalene sulphonate binding assay, and promoted colchicine binding to tubulin, the latter indicating its adjacent binding site with colchicine. 9-PyNos however, did not alter microtubule assembly considerably. Investigating the possible reason behind this apparent lack of strong inhibition of microtubule assembly, we found that the binding interactions of tubulin with 9-PyNos do not involve modification of cysteine residues of tubulin. Taken together, our data suggest that the antiproliferative mechanism of action of 9-PyNos involves disruption of structural integrity of tubulin without strong inhibition of tubulin assembly.
Topics: Humans; Molecular Structure; Noscapine; Structure-Activity Relationship; Tubulin; Tubulin Modulators
PubMed: 28056737
DOI: 10.2174/1568026617666170104150304 -
World Journal of Urology Jun 2021Patients presenting with acute renal colic may be at risk of opiate abuse. We sought to analyze prescribing patterns and identify risk factors associated with prolonged...
PURPOSE
Patients presenting with acute renal colic may be at risk of opiate abuse. We sought to analyze prescribing patterns and identify risk factors associated with prolonged opiate use during episodes of acute renal colic.
METHODS
Retrospective study of patients presenting with both a stone confirmed on imaging and an acute pain episode from 6/2017-2/2020. Opiate prescription data was obtained from a statewide prescribing database. Primary outcome was an opiate refill or new opiate prescription prior to resolution of the stone episode (either passage or surgery). Univariate and multivariate linear regression analysis was performed.
RESULTS
A total of 271 patients met inclusion criteria. Mean age was 52 years and 48% had a history of nephrolithiasis. 180 (66%) patients filled a new opiate prescription during their acute stone episode. Thirty-eight (14%) patients had an existing opiate prescription within 3 months of their stone episode. Seventy-four (27%) patients refilled an opiate prescription prior to stone passage or surgery. Larger stone size, need for surgery, prolonged time to treatment, existing opiate prescription, new opiate prescription at presentation, and greater initial number of pills prescribed were associated with increased risk of requiring a refill prior to stone resolution.
CONCLUSIONS
Patients prescribed new opiates for acute nephrolithiasis and those with an existing opioid prescription are likely to require refills before resolution of the stone episode. Larger stones that require surgery (not spontaneous passage) also increase the risk. Timely treatment of these patients and initial treatment with non-narcotics may reduce the risk of prolonged opiate use.
Topics: Adult; Aged; Analgesics, Opioid; Duration of Therapy; Female; Humans; Male; Middle Aged; Nephrolithiasis; Opiate Alkaloids; Renal Colic; Retrospective Studies; Time Factors
PubMed: 32740804
DOI: 10.1007/s00345-020-03386-7 -
The Analyst Sep 2020Increasing global production, trafficking and consumption of drugs of abuse is an emerging threat to people's health and safety. Electrochemical approaches have been...
Increasing global production, trafficking and consumption of drugs of abuse is an emerging threat to people's health and safety. Electrochemical approaches have been proved to be useful for on-site analysis of drugs of abuse. However, less attention has been focused on the analysis of polydrug samples, even though these samples pose severe health concerns, especially when stimulants and depressants are combined, as is the case of speedball, a mixture of cocaine and heroin. In this work, we provide solutions for the selective detection of cocaine (stimulant) in polydrug samples adulterated with heroin and codeine (depressants). The presence of either one of these compounds in cocaine street samples leads to an overlap with the cocaine signal in square-wave voltammetry measurements at unmodified carbon screen-printed electrodes, leading to inconclusive screening results in the field. The provided solutions to this problem consist of two parallel approaches: (i) cathodic pretreatment of the carbon screen-printed electrode surface prior to measurement under both alkaline and neutral conditions and (ii) electropolymerization of orthophenylenediamine on graphene modified carbon screen-printed electrodes prior to measurement under neutral conditions. Both strategies allow simultaneous detection of cocaine and heroin in speedball samples as well as simultaneous detection of cocaine and codeine. Implementing these strategies in portable devices holds great potential for significantly improved accuracy of on-site cocaine screening in polydrug samples.
Topics: Central Nervous System Stimulants; Cocaine; Codeine; Electrochemical Techniques; Electrodes; Heroin; Humans
PubMed: 32840270
DOI: 10.1039/d0an01097a -
Molecules (Basel, Switzerland) Feb 2021Codeine is derived from morphine, an opioid analgesic, and has weaker analgesic and sedative effects than the parent molecule. This weak opioid is commonly used in... (Review)
Review
Codeine is derived from morphine, an opioid analgesic, and has weaker analgesic and sedative effects than the parent molecule. This weak opioid is commonly used in combination with other drugs for over-the-counter cough relief medication. Due to the psychoactive properties of opioid drugs, the easily obtained codeine often becomes subject to misuse. Codeine misuse has emerged as a concerning public health issue due to its associated adverse effects such as headache, nausea, vomiting, and hemorrhage. Thus, it is very important to develop reliable analytical techniques to detect codeine for both quality control of pharmaceutical formulations and identifying drug misuse in the community. This review aims to provide critical outlooks on analytical methods applicable to the determination of codeine.
Topics: Chemistry Techniques, Analytical; Codeine; Humans
PubMed: 33557168
DOI: 10.3390/molecules26040800 -
Forensic Science International Feb 2019Papaver somniferum (opium poppy) is one of the world's oldest medicinal plants which are widely used for medicinal, nutritive and scientific purposes. Turkey is one of...
Papaver somniferum (opium poppy) is one of the world's oldest medicinal plants which are widely used for medicinal, nutritive and scientific purposes. Turkey is one of the major legal opium poppy producer countries in the world and the seed paste of the poppies is consumed in great deal, even more than 100g per meal. The main objective of this study is to investigate the influence of poppy seed paste ingestion on urine tests for opiates whether or not could lead to opiate positive urine test results. For this purpose, a variety of poppies were used and the morphine content of white, yellow and blue-black poppies were determined as 1.9, 4.0 and 2.6mg/kg, respectively. 100g of these seed pastes were consumed in the breakfast by ten healthy adults enrolled in the study over three days and urine samples were collected before and after the breakfast. Opiate screening analysis was carried out by enzyme immunoassay method and the results were evaluated by two different cut-off values (300 and 2000ng/mL). Morphine confirmation analysis was made by GC-MS system and the chromatographic method was validated in terms of selectivity, extraction efficiency, linearity (25-2000ng/ml), intra-assay precision, accuracy, limit of detection (LOD) and limit of quantitation (LOQ) (3 and 10ng/ml), carryover, matrix effect, dilution integrity and stability. According to cut-off value 300ng/ml, opiate concentrations were found positive up to 48h. For cut-off value 2000ng/mL; this time was up to 12h in collected urine samples after consumption of three different colored poppy seed pastes. In all urine samples, thebaine was detected while the heroin abuse metabolite 6-acetyl morphine (6-AM) was not. Urine drug testing legislation was revised on 2016 in Turkey and opiate screening cut-off values increased from 300 to 2000ng/mL. Overall results have shown that poppy seed paste as food consumption could lead to opiate positive urine test result even if increased cut off levels are used. It can also be deduced that thebaine can be taken as supportive biomarker for poppy seed paste consumption. Awareness of interpretation of urine test results and defining the procedures especially for forensic drug testing must be done in legal aspect to ensure justice for each individual (workplace, traffic, court etc.).
Topics: Adult; Female; Food; Gas Chromatography-Mass Spectrometry; Humans; Immunoenzyme Techniques; Limit of Detection; Male; Morphine; Papaver; Seeds; Time Factors; Turkey
PubMed: 30579243
DOI: 10.1016/j.forsciint.2018.11.026 -
Therapeutic Drug Monitoring Apr 2020In the United States, drug addiction has become a nationwide health crisis. Recently, buprenorphine (BUP), a maintenance therapy approved by the Food and Drug...
BACKGROUND
In the United States, drug addiction has become a nationwide health crisis. Recently, buprenorphine (BUP), a maintenance therapy approved by the Food and Drug Administration, has been increasingly used in pregnant women for the treatment of opioid use disorder. Pregnancy is associated with various anatomic and physiological changes, which may result in altered drug pharmacokinetics (PKs). Previously, we reported that dose-adjusted plasma concentrations of BUP are lower during pregnancy than after pregnancy. The mechanism(s) responsible for this difference has not yet been defined. Our study aimed to evaluate alterations in cytochromes P450 (CYP)- and uridine diphosphate glucunosyltransferases (UGT)-mediated metabolism of BUP during pregnancy to determine the mechanism(s) responsible for this observation.
METHODS
Data from 2 clinical studies were included in the current analysis. Study 1 was a prospective, open-labeled, nonrandomized longitudinal BUP PK study in pregnant women with a singleton gestation, stabilized on twice-daily sublingual BUP opioid substitution therapy. Each subject participated in up to 3 studies during and after pregnancy (the second, third trimester, and postpartum). The design of study 2 was similar to study 1, with patients evaluated at different time points during the pregnancy (first, second-half of pregnancy), as well as during the postpartum period. In addition, the dosing frequency of BUP study 2 participants was not restricted to twice-daily dosing. At each study visit, blood samples were collected before a BUP dose, followed by multiple collection times (10-12) after the dose, for up to 12 hours or till the end of the dosing interval. Plasma concentrations of BUP and 3 metabolites were quantified using validated ultraperformance liquid chromatography-tandem mass spectrometric assays.
RESULTS
In total, 19, 18, and 14 subjects completed the PK study during 1/2 trimester, third trimester, and postpartum, respectively. The AUC ratios of norbuprenorphine and norbuprenorphine glucuronide to buprenorphine, a measure of CYP3A mediated N-demethylation, were 1.89, 1.84, and 1.33 during the first and second, third trimesters, and postpartum, respectively. The AUC ratios of buprenorphine glucuronide to BUP, indicative of UGT activity, were 0.71, 2.07, and 0.3 at first/second trimesters, third trimester, and postpartum, respectively. Linear mixed-effect modeling analysis indicated that the AUC ratios of CYP- and UGT-mediated metabolism of BUP were significantly higher during pregnancy compared with postpartum.
CONCLUSIONS
The CYP and UGT activities were significantly increased as determined by the metabolic ratios of BUP during pregnancy compared with the postpartum period. The increased UGT activity appeared to account for a substantial part of the observed change in metabolic activity during pregnancy. This is in agreement with the need for BUP dose increment in pregnant women to reach similar BUP exposure and therapeutic effect as in nonpregnant subjects.
Topics: Adult; Buprenorphine; Cytochrome P-450 CYP3A; Cytochrome P-450 Enzyme System; Female; Glucuronosyltransferase; Humans; Longitudinal Studies; Narcotic Antagonists; Opiate Substitution Treatment; Opioid-Related Disorders; Postpartum Period; Pregnancy; Pregnancy Trimesters; Young Adult
PubMed: 31929398
DOI: 10.1097/FTD.0000000000000724 -
Critical Reviews in Toxicology Nov 2018Individuals who receive buprenorphine treatment for opioid use disorder in office-based settings may be at risk for, or have a history of, polysubstance use. Urine drug... (Review)
Review
Individuals who receive buprenorphine treatment for opioid use disorder in office-based settings may be at risk for, or have a history of, polysubstance use. Urine drug testing is an important clinical tool for monitoring medication adherence and patient stability; and screening for illicit drug use and dangerous drug-drug interactions. This article is intended to educate practitioners in office-based opioid treatment settings on selecting appropriate substances for a definitive drug testing panel that are known to be used concurrently, sequentially, or in combination with buprenorphine for opioid use disorder. It is also intended to educate such practitioners on selecting appropriate testing technology to reduce risks to the health and safety of patients prescribed buprenorphine for opioid use disorder. In developing this article, the author conducted a search from May 2018 through December 2017 of peer-reviewed and government-supported articles in electronic databases. The literature showed that several common substances are often abused in conjunction with certain other substances, increasing the risk of serious adverse events, including death. Whether used on their own, concurrently, sequentially, or in combination, substances of abuse carry significant health risks. Definitive urine drug testing, given its high specificity and sensitivity, can accurately identify the use of specific prescription medications and illicit substances that, especially when taken with buprenorphine or other substances, may cause harm to a patient. When testing for buprenorphine and other opioids; sedatives, hypnotics, and anxiolytics; cocaine; amphetamines; and PCP and other club drugs, providers in office-based opioid treatment settings are strongly advised to use definitive urine drug tests as the primary testing methodology. In addition, practitioners must be able to identify all other substances that a patient may be consuming, taking into consideration the patient's historical and current drugs of choice, given that concurrent use with buprenorphine or other substances may cause serious adverse events. This article highlights the pressing market demand for comprehensive, definitive urine drug testing at a more reasonable cost.
Topics: Buprenorphine; Drug Interactions; Humans; Illicit Drugs; Opiate Substitution Treatment; Opioid-Related Disorders; Substance Abuse Detection
PubMed: 30794024
DOI: 10.1080/10408444.2018.1553935 -
Molecules (Basel, Switzerland) Dec 2022The design of enantiopure stereoisomers of N-2-phenylcyclopropylmethyl-substituted ortho-c oxide-bridged phenylmorphans, the E and Z isomers of an N-cinnamyl moiety, and...
The design of enantiopure stereoisomers of N-2-phenylcyclopropylmethyl-substituted ortho-c oxide-bridged phenylmorphans, the E and Z isomers of an N-cinnamyl moiety, and N-propyl enantiomers were based on combining the most potent oxide-bridged phenylmorphan (the ortho-c isomer) with the most potent N-substituent that we previously found with a 5-(3-hydroxy)phenylmorphan (i.e., N-2-phenylcyclopropyl methyl moieties, N-cinnamyl, and N-propyl substituents). The synthesis of the eight enantiopure N-2-phenylcyclopropylmethyl ortho-c oxide-bridged phenylmorphans and six additional enantiomers of the N-substituted ortho-c oxide-bridged phenylmorphans (N-E and Z-cinnamyl compounds, and N-propyl compounds) was accomplished. The synthesis started from common intermediates (3R,6aS,11aS)-10-methoxy-1,3,4,5,6,11a-hexahydro-2H-3,6a-methano-benzofuro[2,3-c]azocine (+)-6 and its enantiomer, (3S, 6aR, 11aR)-(-)-6, respectively. The enantiomers of ±-6 were obtained through salt formation with (S)-(+)- and (R)-(-)-p-methylmandelic acid, and the absolute configuration of the (R)-(-)-p-methylmandelate salt of (3S, 6aR, 11aR)-(-)-6 was determined by single-crystal X-ray analysis. The enantiomeric secondary amines were reacted with N-(2-phenylcyclopropyl)methyl derivatives, 2-(E)-cinnamyl bromide, and (Z)-3-phenylacrylic acid. These products led to all of the desired N-derivatives of the ortho-c oxide-bridged phenylmorphans. Their opioid receptor binding affinity was measured. The compounds with MOR affinity < 50 nM were examined for their functional activity in the forskolin-induced cAMP accumulation assay. Only the enantiomer of the N-phenethyl ortho-c oxide-bridged phenylmorphan ((-)-1), and only the (3S,6aR,11aR)-2-(((1S,2S)-2-phenylcyclopropyl)methyl)-1,3,4,5,6,11a-hexahydro-2H-3,6a-methanobenzofuro[2,3-c]azocin-10-ol isomer ((+)-17), and the N-phenylpropyl derivative ((-)-25) had opioid binding affinity < 50 nM. Both (-)-1 and (-)-25 were partial agonists in the cAMP assay, with the former showing high potency and low efficacy, and the latter with lower potency and less efficacy. Most interesting was the N-2-phenylcyclopropylmethyl (3S,6aR,11aR)-2-(1S,2S)-enantiomer ((+)-17). That compound had good MOR binding affinity (Ki = 11.9 nM) and was found to have naltrexone-like potency as a MOR antagonist (IC50 = 6.92 nM).
Topics: Crystallography, X-Ray; Oxides; Morphinans; Isomerism; Receptors, Opioid, mu
PubMed: 36557961
DOI: 10.3390/molecules27248808 -
European Heart Journal Dec 2022Atrial fibrillation (AF) is now regarded as a preventable disease, requiring a search for modifiable risk factors. With legalization of cannabis and more lenient laws...
AIMS
Atrial fibrillation (AF) is now regarded as a preventable disease, requiring a search for modifiable risk factors. With legalization of cannabis and more lenient laws regarding the use of other illicit substances, investigation into the potential effects of methamphetamine, cocaine, opiate, and cannabis exposure on incident AF is needed.
METHODS AND RESULTS
Using Office of Statewide Health Planning and Development databases, a longitudinal analysis was performed of adult Californians ≥18 years of age who received care in an emergency department, outpatient surgery facility, or hospital from 1 January 2005 to 31 December 2015. Associations between healthcare coding for the use of each substance and a new AF diagnosis were assessed. Among 23,561,884 patients, 98 271 used methamphetamine, 48 701 used cocaine, 10 032 used opiates, and 132 834 used cannabis. Of the total population, 998 747 patients (4.2%) developed incident AF during the study period. After adjusting for potential confounders and mediators, use of methamphetamines, cocaine, opiates, and cannabis was each associated with increased incidence of AF: hazard ratios 1.86 [95% confidence interval (CI) 1.81-1.92], 1.61 (95% CI 1.55-1.68), 1.74 (95% CI 1.62-1.87), and 1.35 (95% CI 1.30-1.40), respectively. Negative control analyses in the same cohort failed to reveal similarly consistent positive relationships.
CONCLUSION
Methamphetamine, cocaine, opiate, and cannabis uses were each associated with increased risk of developing incident AF. Efforts to mitigate the use of these substances may represent a novel approach to AF prevention.
Topics: Adult; United States; Humans; Atrial Fibrillation; Cannabis; Methamphetamine; Opiate Alkaloids; Cocaine; Incidence; Risk Factors
PubMed: 36257330
DOI: 10.1093/eurheartj/ehac558 -
Analytical Chemistry Jun 2019Electrochemical strategies to selectively detect heroin in street samples without the use of complicated electrode modifications were developed for the first time. For...
Electrochemical strategies to selectively detect heroin in street samples without the use of complicated electrode modifications were developed for the first time. For this purpose, heroin, mixing agents (adulterants, cutting agent, and impurities), and their binary mixtures were subjected to square wave voltammetry measurements at bare graphite electrodes at pH 7.0 and pH 12.0, in order to elucidate the unique electrochemical fingerprint of heroin and mixing agents as well as possible interferences or reciprocal influences. Adjusting the pH from pH 7.0 to pH 12.0 allowed a more accurate detection of heroin in the presence of most common mixing agents. Furthermore, the benefit of introducing a preconditioning step prior to running square wave voltammetry on the electrochemical fingerprint enrichment was explored. Mixtures of heroin with other drugs (cocaine, 3,4-methylenedioxymethamphetamine, and morphine) were also tested to explore the possibility of their discrimination and simultaneous detection. The feasibility of the proposed electrochemical strategies was tested on realistic heroin street samples from forensic cases, showing promising results for fast, on-site detection tools of drugs of abuse.
Topics: Electrochemistry; Electrodes; Graphite; Heroin; Hydrogen-Ion Concentration
PubMed: 31117413
DOI: 10.1021/acs.analchem.9b01796