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Frontiers in Biophysics 2024P-glycoprotein (Pgp) is known for its dichotomous roles as both a safeguarding efflux transporter against xenobiotics and as a catalyst for multidrug resistance. Given...
P-glycoprotein (Pgp) is known for its dichotomous roles as both a safeguarding efflux transporter against xenobiotics and as a catalyst for multidrug resistance. Given the susceptibility of numerous therapeutic compounds to Pgp-mediated resistance, compliance with Food and Drug Administration (FDA) guidelines mandates an in-depth transport assay during drug development. This study introduces an innovative transport assay that aligns with these regulatory imperatives but also addresses limitations in the currently established techniques. Using Pgp-reconstituted liposomes and employing surface plasmon resonance (SPR), this study developed a distinct method of measuring the relative transport rates of Pgp substrates in a controlled microenvironment. The Pgp substrates selected for this study-quinidine, methadone, and desipramine-resulted in transport ratios that corroborate with trends previously observed. To assess the kinetics of Pgp-mediated transport, the results were analyzed by fitting the data to both currently proposed Pgp substrate translocation models-the vacuum cleaner and flippase models. While the resulting kinetic analysis in this study lends support predominantly to the vacuum cleaner model, this study most notably developed a novel method of assessing Pgp-mediated transport rates and real-time kinetics using surface plasmon resonance.
PubMed: 38645731
DOI: 10.3389/frbis.2024.1367511 -
Drug and Alcohol Dependence Jun 2024We introduce the concept of harm reduction capital (HRCap) as the combination of knowledge, resources, and skills related to substance use risk reduction, which we...
LatinX harm reduction capital, medication for opioid use disorder, and nonfatal overdose: A structural equation model analysis among people who use drugs in Massachusetts.
BACKGROUND
We introduce the concept of harm reduction capital (HRCap) as the combination of knowledge, resources, and skills related to substance use risk reduction, which we hypothesize to predict MOUD use and opioid overdose. In this study, we explored the interrelationships between ethnicity, HRCap, nonfatal overdose, and MOUD use among PWUD.
METHODS
Between 2017 and 2019, people who currently or in the past used opioids and who lived in Massachusetts completed a one-time survey on substance use history, treatment experiences, and use of harm reduction services. We fit first-order measurement constructs for positive and negative HRCap (facilitators and barriers). We used generalized structural equation models to examine the inter-relationships of the latent constructs with LatinX self-identification, past year overdose, and current use of MOUD.
RESULTS
HRCap barriers were positively associated with past-year overdose (b=2.6, p<0.05), and LatinX self-identification was inversely associated with HRCap facilitators (b=-0.49, p<0.05). There was no association between overdose in the past year and the current use of MOUD. LatinX self-identification was positively associated with last year methadone treatment (b=0.89, p<0.05) but negatively associated with last year buprenorphine treatment (b=-0.68, p<0.07). Latinx PWUD reported lower positive HRCap than white non-LatinX PWUD and had differential utilization of MOUD.
CONCLUSION
Our findings indicate that a recent overdose was not associated with the current use of MOUD, highlighting a severe gap in treatment utilization among individuals at the highest risk. The concept of HRCap and its use in the model highlight substance use treatment differences, opportunities for intervention, and empowerment.
Topics: Humans; Massachusetts; Male; Female; Hispanic or Latino; Harm Reduction; Adult; Opioid-Related Disorders; Drug Overdose; Middle Aged; Latent Class Analysis; Buprenorphine; Young Adult; Opiate Overdose; Drug Users; Opiate Substitution Treatment
PubMed: 38643530
DOI: 10.1016/j.drugalcdep.2024.111293 -
The International Journal on Drug Policy May 2024Long-acting injectable depot buprenorphine has become an important treatment option for the management of opioid dependence. However, little is known about patients'...
BACKGROUND
Long-acting injectable depot buprenorphine has become an important treatment option for the management of opioid dependence. However, little is known about patients' experiences of depot buprenorphine and its embodied effects. This qualitative study aims to explore patients' experiences of depot buprenorphine treatment, including how it feels within the body, experiences of dosing cycles across time, and how this form of treatment relies on wider ecologies of care beyond the clinical encounter.
METHODS
Participants were recruited from sites in Sydney, regional New South Wales, and Melbourne, Victoria, Australia. Thirty participants (16 men, 14 women) participated in semi-structured interviews. Participants had histories of both heroin and prescription opioid consumption, and opioid agonist therapy including daily dosing of buprenorphine and methadone.
RESULTS
Our analysis illuminates: (1) how patients' expectations and concerns about treatment are linked to past embodied experiences of withdrawal and uncertainty about the effectiveness of depot buprenorphine; (2) the diverse meanings patients attribute to the depot buprenorphine substrate 'under the skin'; and, (3) how depot buprenorphine is embedded within wider ecologies of care, such as counselling and social supports.
CONCLUSION
Our analysis destabilises commonplace assumptions about a linear, causal relationship between the pharmacological action of depot buprenorphine and experiences of treatment. Instead, it highlights patients' variable experiences of depot buprenorphine, tracing the everyday practices, embodied feelings, expectations and wider networks of care that shape patient experiences. We conclude with some reflections on the implications of our analysis for alcohol and other drug treatment, specifically how they might inform the design of client education materials and care.
Topics: Humans; Buprenorphine; Male; Female; Opioid-Related Disorders; Adult; Opiate Substitution Treatment; Delayed-Action Preparations; Middle Aged; Australia; Qualitative Research; Narcotic Antagonists; Interviews as Topic; Methadone
PubMed: 38636315
DOI: 10.1016/j.drugpo.2024.104399 -
International Journal of Molecular... Mar 2024Bile has emerged as an alternative matrix for toxicological investigation of drugs in suspected forensic cases of overdose in adults and intoxications in children....
Bile has emerged as an alternative matrix for toxicological investigation of drugs in suspected forensic cases of overdose in adults and intoxications in children. Toxicological investigation consists in screening and, subsequently, confirming the result with specific techniques, such as liquid chromatography with tandem mass spectrometry (LC-MS/MS). As there is no screening test on the market to test postmortem bile specimens, the novelty of this study was in investigating the applicability of a chemiluminescence immunoassay, designed for other matrices and available on the market, on bile and validate its use, testing the agreement with LC-MS/MS analysis. Bile specimens were obtained from 25 forensic cases of suspected death from overdose and intoxication. Sample preparation for bile screening consists simply in centrifugation and dilution. Confirmation analysis allows simultaneous identification of 108 drugs and was validated on bile. Kappa analysis assessed a perfect agreement (0.81-1) between the assays for benzodiazepines, methadone, opiates, cocaine, oxycodone, cannabinoids, buprenorphine and pregabalin; a substantial agreement (0.41-0.6) was reported for barbiturates. No agreement was assessed for amphetamines, due to an abundance of putrefactive amines in postmortem specimens. In conclusion, this fast and easy immunoassay could be used for initial screening of bile specimens, identifying presence of drugs, except amphetamines, with reliability.
Topics: Adult; Child; Humans; Bile; Chromatography, Liquid; Luminescence; Reproducibility of Results; Tandem Mass Spectrometry; Drug Overdose; Amphetamines
PubMed: 38612632
DOI: 10.3390/ijms25073825 -
Scientific Reports Apr 2024The simultaneous identification of drugs has considerable difficulties due to the intricate interplay of analytes and the interference present in biological matrices. In...
The simultaneous identification of drugs has considerable difficulties due to the intricate interplay of analytes and the interference present in biological matrices. In this study, we introduce an innovative electrochemical sensor that overcomes these hurdles, enabling the precise and simultaneous determination of morphine (MOR), methadone (MET), and uric acid (UA) in urine samples. The sensor harnesses the strategically adapted carbon nanotubes (CNT) modified with graphitic carbon nitride (g-CN) nanosheets to ensure exceptional precision and sensitivity for the targeted analytes. Through systematic optimization of pivotal parameters, we attained accurate and quantitative measurements of the analytes within intricate matrices employing the fast Fourier transform (FFT) voltammetry technique. The sensor's performance was validated using 17 training and 12 test solutions, employing the widely acclaimed machine learning method, partial least squares (PLS), for predictive modeling. The root mean square error of cross-validation (RMSECV) values for morphine, methadone, and uric acid were significantly low, measuring 0.1827 µM, 0.1951 µM, and 0.1584 µM, respectively, with corresponding root mean square error of prediction (RMSEP) values of 0.1925 µM, 0.2035 µM, and 0.1659 µM. These results showcased the robust resiliency and reliability of our predictive model. Our sensor's efficacy in real urine samples was demonstrated by the narrow range of relative standard deviation (RSD) values, ranging from 3.71 to 5.26%, and recovery percentages from 96 to 106%. This performance underscores the potential of the sensor for practical and clinical applications, offering precise measurements even in complex and variable biological matrices. The successful integration of g-CN-CNT nanocomposites and the robust PLS method has driven the evolution of sophisticated electrochemical sensors, initiating a transformative era in drug analysis.
Topics: Morphine; Uric Acid; Nanotubes, Carbon; Reproducibility of Results; Nanocomposites; Electrochemical Techniques
PubMed: 38582770
DOI: 10.1038/s41598-024-58843-9 -
Addiction Science & Clinical Practice Apr 2024Long-acting injectable buprenorphine (LAIB) formulations are a novel treatment approach in opioid agonist treatment (OAT), which provide patients with a steady dose...
BACKGROUND
Long-acting injectable buprenorphine (LAIB) formulations are a novel treatment approach in opioid agonist treatment (OAT), which provide patients with a steady dose administered weekly or monthly and thus reduce the need for frequent clinic visits. Several studies have analyzed patient experiences of LAIB but the perspective of OAT staff is unknown. This study aimed to explore how healthcare staff working in OAT clinics in Sweden perceive and manage treatment with LAIB.
METHODS
Individual qualitative interviews were conducted with OAT physicians (n = 10) in tandem with nine focus group sessions with OAT nurses and other staff categories (n = 41). The data was analyzed with thematic text analysis.
RESULTS
Five central themes were identified in the data: (1) advantages and disadvantages of LAIB, (2) patient categories that may or may not need LAIB, (3) patients' degrees of medication choice, (4) keeping tabs, control and treatment alliance, and (5) LAIB's impact on risk and enabling environments in OAT. Overall staff found more advantages than disadvantages with LAIB and considered that patients with ongoing substance use and low adherence were most likely to benefit from LAIB. However, less frequent visits were viewed as problematic in terms of developing a treatment alliance and being able to keep tabs on patients' clinical status. Clinics differed regarding patients' degrees of choice in medication, which varied from limited to extensive. LAIB affected both risk and enabling environments in OAT.
CONCLUSIONS
LAIB may strengthen the enabling environment in OAT for some patients by reducing clinic visits, exposure to risk environments, and the pressure to divert medication. A continued discussion about the prerequisites and rationale for LAIB implementation is needed in policy and practice.
Topics: Humans; Buprenorphine; Opiate Substitution Treatment; Opioid-Related Disorders; Delivery of Health Care; Qualitative Research; Analgesics, Opioid; Methadone
PubMed: 38581022
DOI: 10.1186/s13722-024-00458-6 -
Veterinary Anaesthesia and Analgesia 2024To evaluate cardiovascular effects of oral tasipimidine on propofol-isoflurane anaesthesia with or without methadone and dexmedetomidine at equianaesthetic levels.
OBJECTIVE
To evaluate cardiovascular effects of oral tasipimidine on propofol-isoflurane anaesthesia with or without methadone and dexmedetomidine at equianaesthetic levels.
STUDY DESIGN
Prospective, placebo-controlled, blinded, experimental trial.
ANIMALS
A group of seven adult Beagle dogs weighing (mean ± standard deviation) 12.4 ± 2.6 kg and a mean age of 20.6 ± 1 months.
METHODS
The dogs underwent four treatments 60 minutes before induction of anaesthesia with propofol. PP: placebo orally and placebo (NaCl 0.9%) intravenously (IV); TP: tasipimidine 30 μg kg orally and placebo IV; TMP: tasipimidine 30 μg kg orally and methadone 0.2 mg kg IV; and TMPD: tasipimidine 30 μg kg orally with methadone 0.2 mg kg and dexmedetomidine 1 μg kg IV followed by 1 μg kg hour. Isoflurane in oxygen was maintained for 120 minutes at 1.2 individual minimum alveolar concentration preventing motor movement. Cardiac output (CO), tissue blood flow (tbf), tissue oxygen saturation (stO) and relative haemoglobin content were determined. Arterial and mixed venous blood gases, arterial and pulmonary artery pressures and heart rate (HR) were measured at baseline; 60 minutes after oral premedication; 5 minutes after IV premedication; 15, 30, 60, 90 and 120 minutes after propofol injection; and 30 minutes after switching the vaporiser off. Data were analysed by two-way anova for repeated measures; p < 0.05.
RESULTS
Tasipimidine induced a significant 20-30% reduction in HR and CO with decreases in MAP (10-15%), tbf (40%) and stO (43%). Blood pressure and oxygenation variables were mainly influenced by propofol-isoflurane-oxygen anaesthesia, preceded by short-lived alterations related to IV methadone and dexmedetomidine.
CONCLUSIONS AND CLINICAL RELEVANCE
Tasipimidine induced mild to moderate cardiovascular depression. It can be incorporated into a common anaesthetic protocol without detrimental effects in healthy dogs, when anaesthetics are administered to effect and cardiorespiratory function is monitored.
Topics: Animals; Dogs; Dexmedetomidine; Propofol; Methadone; Female; Isoflurane; Heart Rate; Male; Blood Pressure; Hypnotics and Sedatives; Quinolizines; Anesthetics, Intravenous; Anesthetics, Inhalation; Premedication; Pyrazoles
PubMed: 38580536
DOI: 10.1016/j.vaa.2024.03.005 -
JMIR Public Health and Surveillance Apr 2024In the United States, both drug overdose mortality and injection-involved drug overdose mortality have increased nationally over the past 25 years. Despite documented...
BACKGROUND
In the United States, both drug overdose mortality and injection-involved drug overdose mortality have increased nationally over the past 25 years. Despite documented geographic differences in overdose mortality and substances implicated in overdose mortality trends, injection-involved overdose mortality has not been summarized at a subnational level.
OBJECTIVE
We aimed to estimate the annual number of injection-involved overdose deaths in each US state from 2000 to 2020.
METHODS
We conducted a stratified analysis that used data from drug treatment admissions (Treatment Episodes Data Set-Admissions; TEDS-A) and the National Vital Statistics System (NVSS) to estimate state-specific percentages of reported drug overdose deaths that were injection-involved from 2000 to 2020. TEDS-A collects data on the route of administration and the type of substance used upon treatment admission. We used these data to calculate the percentage of reported injections for each drug type by demographic group (race or ethnicity, sex, and age group), year, and state. Additionally, using NVSS mortality data, the annual number of overdose deaths involving selected drug types was identified by the following specific multiple-cause-of-death codes: heroin or synthetic opioids other than methadone (T40.1, T40.4), natural or semisynthetic opioids and methadone (T40.2, T40.3), cocaine (T40.5), psychostimulants with abuse potential (T43.6), sedatives (T42.3, T42.4), and others (T36-T59.0). We used the probabilities of injection with the annual number of overdose deaths, by year, primary substance, and demographic groups to estimate the number of overdose deaths that were injection-involved.
RESULTS
In 2020, there were 91,071 overdose deaths among adults recorded in the United States, and 93.1% (84,753/91,071) occurred in the 46 jurisdictions that reported data to TEDS-A. Slightly less than half (38,253/84,753, 45.1%; 95% CI 41.1%-49.8%) of those overdose deaths were estimated to be injection-involved, translating to 38,253 (95% CI 34,839-42,181) injection-involved overdose deaths in 2020. There was large variation among states in the estimated injection-involved overdose death rate (median 14.72, range 5.45-31.77 per 100,000 people). The national injection-involved overdose death rate increased by 323% (95% CI 255%-391%) from 2010 (3.78, 95% CI 3.33-4.31) to 2020 (15.97, 95% CI 14.55-17.61). States in which the estimated injection-involved overdose death rate increased faster than the national average were disproportionately concentrated in the Northeast region.
CONCLUSIONS
Although overdose mortality and injection-involved overdose mortality have increased dramatically across the country, these trends have been more pronounced in some regions. A better understanding of state-level trends in injection-involved mortality can inform the prioritization of public health strategies that aim to reduce overdose mortality and prevent downstream consequences of injection drug use.
Topics: Adult; Humans; United States; Drug Overdose; Analgesics, Opioid; Cocaine; Public Health; Methadone
PubMed: 38578676
DOI: 10.2196/49527 -
BJA Open Jun 2024This retrospective study evaluated the efficacy and safety of intraoperative methadone compared with short-acting opioids.
BACKGROUND
This retrospective study evaluated the efficacy and safety of intraoperative methadone compared with short-acting opioids.
METHODS
Patients undergoing cardiac surgery with cardiopulmonary bypass (=11 967) from 2018 to 2023 from a single health system were categorised into groups based on intraoperative opioid administration: no methadone (Group O), methadone plus other opioids (Group M+O), and methadone only (Group M).
RESULTS
Patients in Groups M and M+O had lower mean pain scores until postoperative day (POD) 7 compared with Group O after adjusting for covariates (<0.01). Both Groups M and M+O had lower total opioid administered compared with Group O for all days POD0-POD6 (all <0.001). The median number of hours until initial postoperative opioid after surgery was 2.55 (inter-quartile range [IQR]=1.07-5.12), 6.82 (IQR=3.52-12.98), and 7.0 (IQR=3.82-12.95) for Group O, Group M+O, and Group M, respectively. The incidence of postoperative complications did not differ between groups.
CONCLUSIONS
Intraoperative administration of methadone was associated with better pain control without significant side-effects after cardiac surgery.
PubMed: 38560623
DOI: 10.1016/j.bjao.2024.100270 -
Cureus Feb 2024Methadone is a synthetic full µ-opioid receptor agonist and N-methyl-D-aspartate antagonist given to patients who have recently stopped using illicit opioids or are...
Methadone is a synthetic full µ-opioid receptor agonist and N-methyl-D-aspartate antagonist given to patients who have recently stopped using illicit opioids or are tapering off chronic opioid pain medication. Maintenance treatment with methadone is today the most widespread and effective way to treat opiate addiction, which achieves abstinence, decreases morbidity and mortality, improves quality of life, and reduces crime genesis, among other benefits. It is also approved by the Food and Drug Administration for treating moderate-to-severe pain that remains unresponsive to nonopioid medications. Patients sometimes abruptly discontinue the medication for several reasons and sometimes suffer distressing but non-life-threatening withdrawal symptoms. More common withdrawal symptoms include anxiety, agitation, rhinorrhea, nausea, and vomiting, like other opioid agonist medications. Psychosis has been reported in some rare cases of methadone withdrawal. However, more research is required because, although psychotic symptoms have been described in different case reports after the reduction or withdrawal of methadone, they have not been sufficient. This case report contributes to the literature on rare manifestations of psychosis in patients who abruptly discontinue the use of methadone.
PubMed: 38558723
DOI: 10.7759/cureus.55256