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Translational Research : the Journal of... Feb 2024To investigate the role of S-palmitoylation in pyroptosis following acute myocardial infarction (AMI). Myocardial ischemic injury is mainly related to the death of...
To investigate the role of S-palmitoylation in pyroptosis following acute myocardial infarction (AMI). Myocardial ischemic injury is mainly related to the death of terminally differentiated cardiomyocytes. Pyroptosis is a new form of programmed cell death and recently is identified a potential mechanism of cardiomyocyte loss. However, the role of S-palmitoylation in pyroptosis following MI remains elusive. AMI was mimicked by permanent left anterior descending artery ligation. The palmitoylated proteins labeled by Click-iT palmitic acid were precipitated using streptavidin magnetic bead conjugate. The short-term palmitic acid dietary intake by modified western diet with palm oil for 7 days is compared with modified western diet with olive oil. Palmitoylation is increased in myocardial infarction and anoxic cardiomyocytes. Pyroptosis, but not apoptosis and necrosis, is more relevant with palmitoylation in the process of myocardial ischemia injury. The gasdermin D (GSDMD) Cys192 palmitoylation promotes its cytomembrane localization by ZDHHC14. GSDMD Cys192 palmitoylation aggravates in vitro cardiomyocyte pyroptosis. The short-term palmitic acid dietary intake or ML348 deteriorates myocardial pyroptosis, infarct size and cardiac function in AMI mice by GSDMD palmitoylation. Disulfiram antagonizes Cys192 palmitoylation of GSDMD-N-terminal and reduces myocardial pyroptosis and injury in AMI mice. We identifies ZHDDC14 induced palmitoylation as a crucial node for modulating GSDMD-N-terminal cytomembrane localization and establishes Disulfiram targeting GSDMD Cys192 palmitoylation as a potential clinical intervention for myocardial pyroptosis.
Topics: Mice; Animals; Disulfiram; Intracellular Signaling Peptides and Proteins; Gasdermins; Lipoylation; Palmitic Acid; Myocardial Infarction
PubMed: 37769810
DOI: 10.1016/j.trsl.2023.09.007 -
Neuropsychopharmacology Reports Dec 2023Habitual behaviors, rather than goal-oriented behaviors, mainly characterize drinking patterns in patients with alcohol use disorder (AUD). However, few studies have...
BACKGROUND
Habitual behaviors, rather than goal-oriented behaviors, mainly characterize drinking patterns in patients with alcohol use disorder (AUD). However, few studies have focused on the influence of drinking behavior on AUD relapse. This prospective study examined associations between drinking behavior patterns and alcohol-use relapse using the 20-item questionnaire for drinking behavior patterns (DBP-20).
METHODS
We enrolled patients with AUD and compared the cohort's demographic data and 6-month outcomes based on the DBP-20 and the Alcohol Use Disorders Identification Test between two groups (alcohol use relapse vs. abstinence). We also assessed the results for significant factors related to relapse.
RESULTS
We included 105 patients with AUD. More patients in the relapse group (n = 63) were active smokers and lived alone, while fewer took medication with cyanamide or disulfiram than those in the abstinence group (n = 42). The DBP-20 automaticity subscale score was higher in the relapse group than that in the abstinence group. Current smoker, living alone, and automatic drinking habits were significantly associated with AUD relapse.
CONCLUSIONS
Automaticity may be a risky drinking behavior that leads to future relapse in patients with AUD, justifying behavioral strategies to combat automatic drinking for relapse prevention.
Topics: Humans; Alcoholism; Prospective Studies; Alcohol Drinking; Disulfiram; Recurrence
PubMed: 38069609
DOI: 10.1002/npr2.12405 -
PLOS Global Public Health 2023Males have a higher prevalence of cardiovascular (CVD) risk factors such as alcohol use, hypercholesterolemia, hypertension, obesity, and smoking based on limited data...
Potential risk factors for cardiovascular diseases and associated sociodemographic characteristics: A cross-sectional evaluation of a large cohort of women living with HIV in north-central Nigeria.
Males have a higher prevalence of cardiovascular (CVD) risk factors such as alcohol use, hypercholesterolemia, hypertension, obesity, and smoking based on limited data available from two tertiary health centers in Nigeria. Increasing age and lower educational level influence smoking among the same population in northeastern and northwestern Nigeria. Specifically in women living with HIV (WLHIV), the association between demographic characteristics and CVD risk factors has not been described. In a multi-center cross-sectional study, we documented the association of sociodemographic characteristics with potential CVD risk factors among a large cohort of WLHIV attending five treatment sites in north-central Nigeria. This was a cross-sectional study among 5430 women of reproductive age who received antiretrovirals at five selected treatment sites in Benue State, Nigeria. We performed multivariable regression of sociodemographic characteristics on potential cardiovascular risk factors, namely, smoking, alcohol consumption, and contraceptive use. We found participants' mean age was 33.2 (standard deviation: 6.1) years. Prevalence of smoking, alcohol consumption, and contraceptive use were 0.6%, 11%, and 7% respectively. Older WLHIV (≥ 40 years) had a negative association with contraceptive use (aOR: 0.58, 95%CI: 0.42-0.81). Being educated WLHIV had a positive association with contraceptive use (aOR: 1.34, 95%CI: 1.02-1.76) and a negative association with tobacco smoking (aOR: 0.37, 95%CI: 0.16-0.83). Being a farmer had a negative association with alcohol consumption (aOR: 0.43, 95%CI: 0.35-0.52) and contraceptive use (aOR: 0.61, 95%CI: 0.48-0.76). Compared to being married, being in a single relationship had positive association with alcohol consumption (aOR: 1.30, 95%CI: 1.08-1.56) while parenting was associated with 165% higher odds of contraceptive use (aOR: 2.65, 95%CI: 1.73-4.06). In conclusion, the low prevalence of smoking exists among women living with HIV on antiretroviral treatment. Older age, farming and being married are potential deterrents to lifestyle risk factors for cardiovascular diseases among this population. To improve HIV-related treatment efforts and outcomes, implementing interventions aimed at lifestyle behavioral modification among this population has the potential to reduce cardiovascular disease risks.
PubMed: 38051752
DOI: 10.1371/journal.pgph.0002667 -
Chemical Communications (Cambridge,... Jun 2024The enantioselective synthesis of pharmacologically important 14-hydroxy-6-oxomorphinans is described. 4,5-Desoxynaltrexone and 4,5-desoxynaloxone were prepared using...
The enantioselective synthesis of pharmacologically important 14-hydroxy-6-oxomorphinans is described. 4,5-Desoxynaltrexone and 4,5-desoxynaloxone were prepared using this route and their biological activities against the opioid receptors were measured.
Topics: Stereoisomerism; Morphinans; Naltrexone; Molecular Structure; Narcotic Antagonists; Receptors, Opioid
PubMed: 38787679
DOI: 10.1039/d4cc01788a -
International Journal of Obesity (2005) May 2024This study aimed to assess the cost-effectiveness of weight-management pharmacotherapies approved by Canada Health, i.e., orlistat, naltrexone 32 mg/bupropion 360 mg...
OBJECTIVES
This study aimed to assess the cost-effectiveness of weight-management pharmacotherapies approved by Canada Health, i.e., orlistat, naltrexone 32 mg/bupropion 360 mg (NB-32), liraglutide 3.0 mg and semaglutide 2.4 mg as compared to the current standard of care (SoC).
METHODS
Analyses were conducted using a cohort with a mean starting age 50 years, body mass index (BMI) 37.5 kg/m, and 27.6% having type 2 diabetes. Using treatment-specific changes in surrogate endpoints from the STEP trials (BMI, glycemic, blood pressure, lipids), besides a network meta-analysis, the occurrence of weight-related complications, costs, and quality-adjusted life-years (QALYs) were projected over lifetime.
RESULTS
From a societal perspective, at a willingness-to-pay (WTP) threshold of CAD 50 000 per QALY, semaglutide 2.4 mg was the most cost-effective treatment, at an incremental cost-utility ratio (ICUR) of CAD 31 243 and CAD 29 014 per QALY gained versus the next best alternative, i.e., orlistat, and SoC, respectively. Semaglutide 2.4 mg extendedly dominated other pharmacotherapies such as NB-32 or liraglutide 3.0 mg and remained cost-effective both under a public and private payer perspective. Results were robust to sensitivity analyses varying post-treatment catch-up rates, longer treatment durations and using real-world cohort characteristics. Semaglutide 2.4 mg was the preferred intervention, with a likelihood of 70% at a WTP threshold of CAD 50 000 per QALY gained. However, when the modeled benefits of weight-loss on cancer, mortality, cardiovascular disease (CVD) or osteoarthritis surgeries were removed simultaneously, orlistat emerged as the best value for money compared with SoC, with an ICUR of CAD 35 723 per QALY gained.
CONCLUSION
Semaglutide 2.4 mg was the most cost-effective treatment alternative compared with D&E or orlistat alone, and extendedly dominated other pharmacotherapies such as NB-32 or liraglutide 3.0 mg. Results were sensitive to the inclusion of the combined benefits of mortality, cancer, CVD, and knee osteoarthritis.
Topics: Humans; Cost-Benefit Analysis; Canada; Middle Aged; Obesity; Female; Anti-Obesity Agents; Male; Orlistat; Quality-Adjusted Life Years; Liraglutide; Diabetes Mellitus, Type 2; Bupropion; Naltrexone; Glucagon-Like Peptides
PubMed: 38291203
DOI: 10.1038/s41366-024-01467-w -
Journal of Substance Use and Addiction... Nov 2023Few studies investigate the natural history of patients on long-term treatment for opioid use disorder (OUD). We evaluated the long-term efficacy, safety, and... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
Few studies investigate the natural history of patients on long-term treatment for opioid use disorder (OUD). We evaluated the long-term efficacy, safety, and tolerability experience of monthly extended-release buprenorphine (BUP-XR) in participants seeking treatment for OUD, via integrated analysis of phase 3 studies.
METHODS
Study 1 was a 24-week randomized, double-blind, placebo-controlled trial of participants receiving monthly injections of BUP-XR (300 mg × 2, 100 mg × 4 [n = 203] or 300 mg × 6 [n = 201]) or placebo (n = 100). Study 2 was a 48-week, open-label trial enrolling 257 participants who completed study 1 and 412 de novo participants, to receive 6 and 12 BUP-XR injections, respectively. Study 3 was a 24-week, open-label extension enrolling 208 participants who completed study 2 for 6 additional injections. We assessed opioid abstinence as the proportion of urine opioid negative participants by visit and the percentage of each participant's negative opioid assessments during the first 6 months.
RESULTS
In total, 916 participants were treated with BUP-XR or placebo. By the end of 18 months, 92.7 % of the de novo cohort and 81.8 % of the study 1 cohort were urine negative for opioids. Among early nonresponders (percentage of abstinence ≤20 %), 73.1 % were urine negative after 18 months. The longer treatment period was well tolerated, with no new safety concerns, and a low incidence of opioid withdrawal signs and symptoms, and hepatic disorder.
CONCLUSIONS
Extending BUP-XR treatment beyond 6 months sustained improvement in opioid abstinence and was well tolerated, supporting clinical benefit up to 18 months.
TRIAL REGISTRATION
NCT02357901 (study 1); NCT02510014 (study 2); NCT02896296 (study 3).
Topics: Humans; Buprenorphine; Analgesics, Opioid; Narcotic Antagonists; Naltrexone; Opioid-Related Disorders; Injections, Subcutaneous
PubMed: 37657559
DOI: 10.1016/j.josat.2023.209155 -
The Lancet. Rheumatology Jan 2024
Topics: Humans; Fibromyalgia; Naltrexone
PubMed: 38258679
DOI: 10.1016/S2665-9913(23)00297-7 -
International Journal of Pharmaceutical... 2023Naltrexone is a competitive opioid receptor antagonist indicated to treat opioid and alcohol dependence. In the U.S., naltrexone is commercially available as 50-mg...
Naltrexone is a competitive opioid receptor antagonist indicated to treat opioid and alcohol dependence. In the U.S., naltrexone is commercially available as 50-mg tablets, and the adult dosage strength typically ranges between 50 mg once daily and 100 mg once daily. However, there is evidence to suggest that naltrexone prescribed in low doses, about 1/10th of the daily standard dosage, may be effective in managing a myriad of chronic conditions, including pain refractory to conventional pharmacological treatments. The U.S. Food and Drug Administration recently granted an orphan drug designation for low-dose naltrexone for the treatment of complex regional pain syndrome. This article provides a case study of a patient who was treated with a low dose of naltrexone for pain associated with the diagnosis of idiopathic hypereosinophilic syndrome.
Topics: Adult; Humans; Naltrexone; Pain Management; Narcotic Antagonists; Pain; Analgesics, Opioid
PubMed: 38100664
DOI: No ID Found -
Clinical Therapeutics Nov 2023Alcohol consumption, even minimal, can exacerbate the disulfiram-like reaction (also referred to as acetaldehyde syndrome) that occurs with the use of medications that... (Review)
Review
Alcohol consumption, even minimal, can exacerbate the disulfiram-like reaction (also referred to as acetaldehyde syndrome) that occurs with the use of medications that impede the breakdown of acetaldehyde. Such medications include Ginaton, a proprietary tablet formulation of Ginkgo biloba extract commonly used in Europe, Asia, and the United States for cardiovascular and nervous system health. This article details such a case from China. Healthcare providers should be proactive in educating patients about the potential adverse reactions related to using Ginaton and the importance of avoiding alcohol consumption while using it. Patients should also be advised to disclose their alcohol-consumption habits and seek medical advice before initiating treatment with any medication or supplement during treatment with Ginaton.
Topics: Humans; Acetaldehyde; Disulfiram; Drugs, Chinese Herbal; Heart
PubMed: 37722955
DOI: 10.1016/j.clinthera.2023.08.013 -
The Journal of Adolescent Health :... Nov 2023Alcohol use disorder (AUD) is a pediatric-onset condition needing timely, effective treatment. Medications for AUD are part of nationally recommended treatments for...
PURPOSE
Alcohol use disorder (AUD) is a pediatric-onset condition needing timely, effective treatment. Medications for AUD are part of nationally recommended treatments for youth. This study measured receipt of medications and behavioral health services for AUD and subsequent retention in care.
METHODS
This retrospective cohort study used claims data from > 4.7 million publicly insured youth aged 13-22 years in 15 states from 2014-2019. Timely treatment was defined as receipt of medication (naltrexone, acamprosate, or disulfiram) and/or behavioral health services within 30 days of incident AUD diagnosis. Associations of age and other characteristics with timely treatment were identified using modified Poisson regression. Retention in care (i.e., no period ≥ 60 days without claims) was studied using Cox regression.
RESULTS
Among 14,194 youth with AUD, 10,851 (76.4%) received timely treatment. Only 2.1% of youth received medication (alone or in combination); nearly all (97.9%) received behavioral health services only. Older (aged 16-17 years) and younger adolescents (aged 13-15 years) were 0.13 (95% confidence interval [CI], 0.07-0.26) and 0.24 (95% CI, 0.11-0.51) times as likely, respectively, to receive medications than young adults aged ≥ 21 years. Median retention in care for youth receiving medications was 119 days (interquartile range, 54-321) compared with 108 days (interquartile range, 43-243) for behavioral health services alone (p = .126). Young adults aged ≥ 18 years were 1.12 (95% CI, 1.06-1.18) times as likely to discontinue treatment compared with adolescents aged < 18 years.
DISCUSSION
This study found that more than seven in 10 youth received AUD treatment but only two in 100 received medications. Future studies should further characterize the effectiveness of medications and determine whether low rates of receipt represent underuse.
Topics: Young Adult; United States; Humans; Adolescent; Child; Alcoholism; Medicaid; Retrospective Studies; Retention in Care; Naltrexone
PubMed: 37256254
DOI: 10.1016/j.jadohealth.2023.03.005