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BMC Nephrology Jun 2024Tubular biomarkers, which reflect tubular dysfunction or injury, are associated with incident chronic kidney disease and kidney function decline. Several tubular... (Randomized Controlled Trial)
Randomized Controlled Trial
Changes in tubular biomarkers with dietary intervention and metformin in patients with autosomal dominant polycystic kidney disease: a post-hoc analysis of two clinical trials.
BACKGROUND
Tubular biomarkers, which reflect tubular dysfunction or injury, are associated with incident chronic kidney disease and kidney function decline. Several tubular biomarkers have also been implicated in the progression of autosomal dominant polycystic kidney disease (ADPKD). We evaluated changes in multiple tubular biomarkers in four groups of patients with ADPKD who participated in one of two clinical trials (metformin therapy and diet-induced weight loss), based on evidence suggesting that such interventions could reduce tubule injury.
METHODS
66 participants (26 M/40 F) with ADPKD and an estimated glomerular filtration rate (eGFR) ≥ 30 ml/min/1.73m who participated in either a metformin clinical trial (n = 22 metformin; n = 23 placebo) or dietary weight loss study (n = 10 daily caloric restriction [DCR]; n = 11 intermittent fasting [IMF]) were included in assessments of urinary tubular biomarkers (kidney injury molecule-1 [KIM-1], fatty-acid binding protein [FABP], interleukin-18 [IL-18], monocyte chemoattractant protein-1 [MCP-1], neutrophil gelatinase-associated lipocalin [NGAL], clusterin, and human cartilage glycoprotein-40 [YKL-40]; normalized to urine creatinine), at baseline and 12 months. The association of baseline tubular biomarkers with both baseline and change in height-adjusted total kidney volume (HtTKV; percent change from baseline to 12 months) and estimated glomerular filtration rate (eGFR; absolute change at 12 months vs. baseline), with covariate adjustment, was also assessed using multiple linear regression.
RESULTS
Mean ± s.d. age was 48 ± 8 years, eGFR was 71 ± 16 ml/min/1.73m, and baseline BMI was 30.5 ± 5.9 kg/m. None of the tubular biomarkers changed with any intervention as compared to placebo. Additionally, baseline tubular biomarkers were not associated with either baseline or change in eGFR or HtTKV over 12 months, after adjustments for demographics, group assignment, and clinical characteristics.
CONCLUSIONS
Tubular biomarkers did not change with dietary-induced weight loss or metformin, nor did they associate with kidney disease progression, in this cohort of patients with ADPKD.
Topics: Humans; Metformin; Polycystic Kidney, Autosomal Dominant; Male; Female; Biomarkers; Middle Aged; Kidney Tubules; Caloric Restriction; Adult; Glomerular Filtration Rate; Lipocalin-2; Chemokine CCL2; Fatty Acid-Binding Proteins; Hepatitis A Virus Cellular Receptor 1; Chitinase-3-Like Protein 1; Hypoglycemic Agents
PubMed: 38918734
DOI: 10.1186/s12882-024-03643-6 -
Asian Pacific Journal of Cancer... Jun 2024The 2x2 factorial design is an effective method that allows for multiple comparisons, especially in the context of interactions between different interventions, without... (Randomized Controlled Trial)
Randomized Controlled Trial
OBJECTIVE
The 2x2 factorial design is an effective method that allows for multiple comparisons, especially in the context of interactions between different interventions, without substantially increasing the required sample size. In view of the considerable preclinical evidence for Curcumin and Metformin in preventing the development and progression of head and neck squamous cell carcinoma (HNSCC), this study describes the protocol of the clinical trial towards applying the drug combination in prevention of second primary tumors.
METHODS
We have applied the trial design to a large phase IIB/III double-blind, multi-centric, placebo-controlled, randomized clinical trial to determine the safety and efficacy of Metformin and Curcumin in the prevention of second primary tumours (SPT) of the aerodigestive tract following treatment of HNSCC (n=1,500) [Clinical Registry of India, CTRI/2018/03/012274]. Patients recruited in this trial will receive Metformin (with placebo), Curcumin (with placebo), Metformin, and Curcumin or placebo alone for a period of 36 months. The primary endpoint of this trial is the development of SPT, while the secondary endpoints are toxicities associated with the agents, incidence of recurrence, and identifying potential biomarkers. In this article, we discuss the 2x2 factorial design and how it applies to the head and neck cancer chemoprevention trial.
CONCLUSION
2x2 factorial design is an effective trial design for chemoprevention clinical trials where the effectiveness of multiple interventions needs to be tested parallelly.
Topics: Humans; Metformin; Curcumin; Head and Neck Neoplasms; Double-Blind Method; Neoplasms, Second Primary; Male; Female; Squamous Cell Carcinoma of Head and Neck; Antineoplastic Combined Chemotherapy Protocols; Middle Aged; Adult; Follow-Up Studies; Prognosis; Research Design; Aged; Randomized Controlled Trials as Topic
PubMed: 38918654
DOI: 10.31557/APJCP.2024.25.6.1935 -
Ochsner Journal 2024Buprenorphine/naloxone (Suboxone) is widely considered the first-line treatment for opioid use disorder (OUD), which causes significant morbidity and mortality in the... (Review)
Review
Buprenorphine/naloxone (Suboxone) is widely considered the first-line treatment for opioid use disorder (OUD), which causes significant morbidity and mortality in the United States, but prior to 2023, practitioners interested in prescribing buprenorphine/naloxone for OUD needed a special Drug Enforcement Administration certification (the X-Waiver) that imposed a patient cap and other limitations. The Consolidated Appropriations Act of 2023 considerably decreased the restrictions on prescribing practitioners. Buprenorphine/naloxone can now be prescribed like any other prescription opioid, excluding methadone. The historic context for the opioid crisis, OUD, the X-Waiver, and additional initiatives that may be needed beyond legislative change to effectively address OUD are the subjects of this review. To develop this review of the opioid crisis, OUD, and OUD treatment, we conducted a literature search of the PubMed database and constructed a timeline of the opioid crisis and changes in OUD treatment, specifically the X-Waiver, to characterize the historic context of OUD and the X-Waiver against the background of the opioid crisis. The opioid crisis has had pervasive public health and economic impacts in the United States. Major changes to the treatment of OUD have occurred as a result of the Drug Addiction Treatment Act of 2000 that imposed the X-Waiver and the Consolidated Appropriations Act of 2023 that repealed the X-Waiver. The repeal of the X-Waiver is predicted to increase the accessibility of buprenorphine/naloxone in the United States. However, additional work beyond legislative change, including institutional support and reduction of stigma and disparities, is needed to substantially improve outcomes for OUD patients.
PubMed: 38912181
DOI: 10.31486/toj.23.0074 -
Advances in Drug and Alcohol Research 2024The Methadone Maintenance Treatment (MMT) program has been proven to be beneficial in reducing illicit opioid use, increasing access to and retention of HIV treatment...
The Methadone Maintenance Treatment (MMT) program has been proven to be beneficial in reducing illicit opioid use, increasing access to and retention of HIV treatment and other therapies, and reducing HIV transmission, and other drug-related morbidities and mortalities. However, determinants of treatment retention and outcomes for opioid-dependent persons accessing MMT in Kenya are limited. We sought to identify factors contributing to poor treatment outcomes among opioid-dependent persons enrolled in the Mombasa MMT program, between 2017 and 2019. We conducted a retrospective records review for opioid-dependent persons receiving Methadone treatment in the Kisauni MAT clinic enrolled during 2017-2019. We defined poor clinical or health-related treatment outcome as any client Lost-To-Follow-Up (LTFU), turned HIV or Viral hepatitis positive, and/or missed two or more antiretroviral therapy (ART) appointments intake during MMT. Variables abstracted from clinical and pharmacological MMT service delivery tools included socio-demographic characteristics, clinical history, risk factors, and MMT outcomes. Data were analyzed using . We calculated Prevalence Odds Ratios (POR) and 95% Confidence Intervals (CI) to identify factors associated with adverse health outcomes. Of the total 443 eligible records, the mean age was 37 years (SD ± 7.2) and males comprised 90.7%. The majority of females clients, 79.1% (34/43), were aged ≤35 years, 7.0% (3/43) had no education, 32.6% (14/43) were employed, 39.5% (17/43) were HIV positive and 18.6% (8/43) were HCV-positive. Overall, adverse treatment outcomes were at 27.5% (122/443), namely: LTFU at 22.8% (101/443), new HIV cases at 1.0% (4/391), HCV at 1.2% (5/405), and Hepatitis B Virus (HBV) at 1.2% (5/411), and 1.1% (5/443) died. Of HIV-infected clients linked to Comprehensive Care Clinic (CCC), 3.6% (2/56) defaulted from ART, and 25% (2/8) had detectable Viral Load of those retested. Lack of formal education (POR: 2.7, 95% CI: 1.3-5.7), unemployment (POR: 2.4, 95% CI: 1.4-4.0), and being a Non-Injector (POR: 1.7, 95% CI: 1.0-2.9) were negatively associated with treatment retention. Females were younger, and more educated with higher HIV and HCV prevalence. Being a Non-injector, unemployment, and lack of formal education may increase the likelihood of poor treatment outcomes among MMT clients. Closer monitoring of MMT clients with these characteristics is recommended with the integration of CCC into MMT services.
PubMed: 38912085
DOI: 10.3389/adar.2024.11791 -
Cureus May 2024In this case report, we present the case of a 60-year-old Caucasian male with a history of depression, anxiety, opioid dependence, and idiopathic polyneuropathy,...
In this case report, we present the case of a 60-year-old Caucasian male with a history of depression, anxiety, opioid dependence, and idiopathic polyneuropathy, admitted to an inpatient psychiatric unit for suicidal ideation. The patient's symptoms were characterized by months of intractable nausea, severe anxiety, suicidal ideation (SI), and significant unintentional weight loss in the context of methadone-assisted treatment. Over nine days in the hospital, a treatment strategy was developed and refined, which eventually achieved sustained relief from nausea and significant improvement in anxiety. The most effective pharmacological interventions included mirtazapine, scopolamine, and gabapentin.
PubMed: 38910692
DOI: 10.7759/cureus.60855 -
Biological & Pharmaceutical Bulletin 2024Guanfacine, used as a medication for attention-deficit/hyperactivity disorder (ADHD), leads to a high incidence of somnolence, in contrast to methylphenidate, which...
Guanfacine, used as a medication for attention-deficit/hyperactivity disorder (ADHD), leads to a high incidence of somnolence, in contrast to methylphenidate, which leads to a high incidence of insomnia. The impact of somnolence on continuing guanfacine treatment is unclear. Therefore, we investigated the reasons for discontinuing guanfacine and analyzed the factors associated with discontinuation caused by somnolence. We surveyed 96 patients under guanfacine from July 2017 to December 2021 at the Saga University Hospital. Patients who discontinued guanfacine by the end date of our study were divided into a median early and late group. We compared the reasons for discontinuation in both groups. Of all patients, 47 continued and 49 discontinued guanfacine. A higher percentage of patients discontinued guanfacine caused by somnolence for ≤70 d than for >70 d of treatment (44.0 vs. 8.3%; p = 0.008). When stratified by the concomitant use of other ADHD drugs, somnolence resulted in a higher discontinuation rate for ≤70 d than for >70 d of treatment without concomitant use (55.0 vs. 7.1%; p = 0.009). Nonetheless, concomitant use resulted in no difference. In conclusion, somnolence affects the early discontinuation of guanfacine as an ADHD drug. The combination of methylphenidate or atomoxetine may decrease withdrawal caused by somnolence.
Topics: Guanfacine; Humans; Attention Deficit Disorder with Hyperactivity; Male; Female; Child; Adolescent; Sleepiness; Adrenergic alpha-2 Receptor Agonists; Methylphenidate
PubMed: 38910124
DOI: 10.1248/bpb.b24-00147 -
Clinica Chimica Acta; International... Jun 2024The number of xylazine-involved overdose deaths tremendously increased from 2019 onwards in the US. This is due to the "tranq-dope" trend consisting in mixing opioids...
BACKGROUND AND AIMS
The number of xylazine-involved overdose deaths tremendously increased from 2019 onwards in the US. This is due to the "tranq-dope" trend consisting in mixing opioids with the sedative to reduce drug manufacturing costs and enhance their effects. In this study, we report the first fatality involving xylazine-adulterated heroin in the EU.
MATERIALS AND METHODS
The subject was a 33-year-old Caucasian male with a documented history of drug abuse who was found dead in a public area with puncture marks at the elbow. Peripheral blood and urine were collected at the autopsy and analyzed by liquid chromatography-high-resolution tandem mass spectrometry (LC-HRMS/MS) after protein precipitation.
RESULTS
6-Monoacetylmorphine, total/free morphine, and codeine blood concentrations of 20.3, 236/105, and 38.3 ng/mL, respectively, indicated recent heroin consumption. Methadone blood concentration was below 10 ng/mL. Alprazolam, nordiazepam, and flurazepam blood concentrations were 23.9, 61.4, and 55.0 ng/mL, respectively. Benzoylecgonine blood concentration was below 5 ng/mL. Xylazine blood and urine concentrations were 105 and 72.6 ng/mL, respectively.
CONCLUSION
The combination of central nervous system depressants, i.e., opioids, benzodiazepines, and xylazine, was the principal cause of death by cardiorespiratory failure. The case was promptly reported to the UE Early Warning System on drugs.
PubMed: 38909977
DOI: 10.1016/j.cca.2024.119826 -
Substance Abuse Treatment, Prevention,... Jun 2024Research demonstrates gaps in medications for opioid use disorder uptake (MOUDs; methadone, buprenorphine, and naltrexone) especially among adolescents. These gaps may...
Attitudes toward and training in medications for opioid use disorders: a descriptive analysis among employees in the youth legal system and community mental health centers.
BACKGROUND
Research demonstrates gaps in medications for opioid use disorder uptake (MOUDs; methadone, buprenorphine, and naltrexone) especially among adolescents. These gaps may be partly attributable to attitudes about and training in MOUDs among youth-serving professionals. We extended prior research by conducting descriptive analyses of attitudes regarding effectiveness and acceptability of MOUDs, as well as training in MOUDs, among youth legal system (YLS) employees and community mental health center (CMHC) personnel who interface professionally with youth.
METHODS
Using survey data from participants (n = 181) recruited from eight Midwest counties, we examined: (1) differences in MOUD attitudes/training by MOUD type and (2) by respondent demographics, and (3) prediction of MOUD attitudes/training by participant-reported initiatives to implement evidence-based practices (EBPs), workplace culture around EBPs, and workplace stress. Attitudes and training were measured in reference to five MOUD types (methadone, oral buprenorphine, injectable buprenorphine, oral naltrexone, injectable naltrexone) on three subscales (effectiveness, acceptability, training).
RESULTS
Wilcoxon signed-rank tests demonstrated that most outcomes differed significantly by MOUD type (differences observed among 22 of 30 tests). Kruskal-Wallis tests suggested MOUD differences based on demographics. For methadone, CMHC providers endorsed greater perceived effectiveness than YLS providers and age explained significant differences in perceived effectiveness. For buprenorphine, CHMC providers viewed oral or injectable buprenorphine as more effective than YLS employees, respondents from more rural counties viewed oral buprenorphine as more effective than those from less rural counties, and age explained differences in perceived effectiveness. For naltrexone, perceived gender differed by gender. Hierarchical ordinal logistic regression analysis did not find an association between personal initiatives to implement EBPs, workplace culture supporting EBPs, or workplace stress and effectiveness or acceptability of MOUDs. However, personal initiatives to implement EBPs was associated with training in each MOUD.
CONCLUSIONS
These results highlight a few key findings: effectiveness/acceptability of and training in MOUDs largely differ by MOUD type; setting, rurality, age, gender, and education explain group differences in perceived effectiveness of and training in MOUDs; and implementing EBPs is associated with training in MOUDs. Future research would benefit from examining what predicts change in MOUD attitudes longitudinally.
Topics: Humans; Male; Female; Adult; Opioid-Related Disorders; Opiate Substitution Treatment; Attitude of Health Personnel; Naltrexone; Buprenorphine; Methadone; Community Mental Health Centers; Adolescent; Middle Aged; Young Adult; Narcotic Antagonists
PubMed: 38907286
DOI: 10.1186/s13011-024-00614-w -
Scientific Reports Jun 2024Cardiac ischemic preconditioning (Pre) reduces cardiac ischemia-reperfusion injury (IRI) by stimulating opioid receptors. Chronic use of opioids can alter the signaling...
Cardiac ischemic preconditioning (Pre) reduces cardiac ischemia-reperfusion injury (IRI) by stimulating opioid receptors. Chronic use of opioids can alter the signaling pathways. We investigated the effects of chronic methadone use on IRI and Pre. The experiments were performed on isolated hearts of male Wistar rats in four groups: IRI, Methadone + IRI (M-IRI), Pre + IRI (Pre-IRI), Methadone + Pre + IRI (M-Pre-IRI). The infarct size (IS) in the Pre-IRI group was smaller than the IRI group (26.8% vs. 47.8%, P < 0.05). In the M-IRI and M-Pre-IRI groups, the infarct size was similar to the IRI group. Akt (Ak strain transforming) phosphorylation in the Pre-IRI, M-IRI, and M-Pre-IRI groups was significantly higher than in the IRI group (0.56 ± 0.15, 0.63 ± 0.20, and 0.93 ± 0.18 vs 0.28 ± 0.17 respectively). STAT3 (signal transducer and activator of transcription 3) phosphorylation in the Pre-IRI and M-Pre-IRI groups (1.38 ± 0.14 and 1.46 ± 0.33) was significantly higher than the IRI and M-IRI groups (0.99 ± 0.1 and 0.98 ± 0.2). Thus, chronic use of methadone not only has no protective effect against IRI but also destroys the protective effects of ischemic preconditioning. This may be due to the hyperactivation of Akt and changes in signaling pathways.
Topics: Animals; Methadone; STAT3 Transcription Factor; Male; Proto-Oncogene Proteins c-akt; Phosphorylation; Rats; Rats, Wistar; Myocardial Reperfusion Injury; Ischemic Preconditioning, Myocardial; Signal Transduction; Reperfusion Injury
PubMed: 38906975
DOI: 10.1038/s41598-024-65349-x -
JAMA Network Open Jun 2024An intermittent fasting plan consisting of 2 nonconsecutive fasting days and 5 days of habitual intake per week and meal replacement diet (5:2 MR) could provide... (Randomized Controlled Trial)
Randomized Controlled Trial
IMPORTANCE
An intermittent fasting plan consisting of 2 nonconsecutive fasting days and 5 days of habitual intake per week and meal replacement diet (5:2 MR) could provide additional benefits to patients with type 2 diabetes.
OBJECTIVE
To evaluate the effect of the 5:2 MR on glycemic control among patients with early type 2 diabetes compared with metformin and empagliflozin.
DESIGN, SETTING, AND PARTICIPANTS
The EARLY (Exploration of Treatment of Newly Diagnosed Overweight/Obese Type 2 Diabetes Mellitus) study is a randomized, open-label, active parallel-controlled clinical trial conducted between November 13, 2020, and December 29, 2022, in 9 centers across China. A total of 509 eligible patients underwent screening, out of which 405 were randomly assigned to 3 groups and included in the intention-to-treat analysis.
INTERVENTIONS
Patients were randomly allocated in a 1:1:1 ratio to receive either metformin, empagliflozin, or 5:2 MR. The treatment was 16 weeks, with an 8-week follow-up.
MAIN OUTCOMES AND MEASURES
The primary end point was the change in hemoglobin A1c (HbA1c) level from baseline to 16 weeks. Secondary end points included changes in body weight, anthropometric measurements, and biochemical parameters.
RESULTS
Of the 405 randomized participants (265 men [65.4%]; mean [SD] age, 45.5 [11.0] years; mean [SD] body mass index, 29.5 [4.1]; and mean [SD] HbA1c level, 7.9% [0.6%]), 332 completed the 16-week treatment. From baseline to week 16, participants in the 5:2 MR group showed the greatest reduction in HbA1c (least-squares mean [LSM], -1.9% [SE, 0.2%]), significantly greater than patients receiving metformin (LSM, -1.6% [SE, 0.2%]; adjusted LSM difference, -0.3% [95% CI, -0.4% to -0.1%]) and empagliflozin (LSM, -1.5% [SE, 0.2%]; adjusted LSM difference, -0.4% [95% CI, -0.6% to -0.2%]). At week 16, the mean weight loss in the 5:2 MR group (LSM, -9.7 kg [SE, 2.2 kg]) was greater than that in the metformin group (LSM, -5.5 kg [SE, 2.3 kg]) and empagliflozin group (LSM, -5.8 kg [SE, 2.3 kg]).
CONCLUSIONS AND RELEVANCE
This randomized clinical trial of Chinese adults with overweight or obesity and with early type 2 diabetes found that 5:2 MR could improve glycemic outcomes and weight loss in the short term compared with metformin or empagliflozin, making it a promising initial intervention and early management for type 2 diabetes.
TRIAL REGISTRATION
Chinese Clinical Trial Registry Identifier: ChiCTR2000040656.
Topics: Humans; Male; Female; Middle Aged; Diabetes Mellitus, Type 2; Fasting; Metformin; Glucosides; Benzhydryl Compounds; Glycemic Control; Adult; Glycated Hemoglobin; Hypoglycemic Agents; China; Blood Glucose; Intermittent Fasting
PubMed: 38904963
DOI: 10.1001/jamanetworkopen.2024.16786