3-Year Follow-up of Lower Risk Cannabis Use Patterns: Evidence from a Longitudinal Survey

Objectives:Following recommendations from the Lower Risk Cannabis Use Guidelines, we evaluated how lower risk cannabis use (late initiation and low use frequency) was associated with the risk of developing cannabis abuse/dependence over a 3-year follow-up period compared to 12-month abstinence (controls) or higher risk cannabis use (early initiation and higher use frequency). We also explored the effect of cannabis quantity.Methods:Data were obtained from the U.S. nationally representative survey, National Epidemiologic Survey on Alcohol and Related Conditions wave I (2001 to 2002) and wave II (2004 to 2005), which included 31,464 respondents with no lifetime history of cannabis abuse/dependence at the first interview. We applied multiple logistic regression and propensity score matching analyses to examine the association between different use patterns at wave I and cannabis abuse/dependence at wave II, adjusting for covariates. Lower risk cannabis use and the transition to higher use frequency were also assessed.Results:For propensity score analysis, lower risk cannabis use at wave I was associated with higher risk of cannabis use/dependence at wave II compared to controls (odds ratio [OR]: 4.27; 95% confidence interval [95% CI], 1.57 to 11.61); however, there was no association with use frequency increase (OR: 2.52; 95% CI, 0.88 to 7.17). Higher risk use had a greater risk of cannabis use/dependence than controls (OR: 6.27; 95% CI, 2.56 to 15.38) and lower risk use (OR: 2.69; 95% CI, 1.12 to 6.47). Logistic regression analyses showed similar results, except that lower risk use was significantly associated with use frequency increase (OR: 2.49; 95% CI, 1.22 to 5.08). For the lower risk use group, 1 to 3 joints/day of use was significantly associated with cannabis abuse/dependence.Conclusions:We found that following recommended use patterns can significantly lower one’s risk of cannabis abuse/dependence. However, risk of cannabis abuse/dependence is still 4 times higher than staying abstinent. Updated recommendations on safe cannabis exposure levels are needed to guide cannabis use in the general population after cannabis legalization.     

Insulin and glucose metabolism with olanzapine and a combination of olanzapine and samidorphan: exploratory phase 1 results in healthy volunteers

A combination of olanzapine and samidorphan (OLZ/SAM) received US Food and Drug Administration approval in May 2021 for the treatment of adults with schizophrenia or bipolar I disorder. OLZ/SAM provides the efficacy of olanzapine, while mitigating olanzapine-associated weight gain. This exploratory study characterized the metabolic profile of OLZ/SAM in healthy volunteers to gain mechanistic insights. Volunteers received once-daily oral 10 mg/10 mg OLZ/SAM, 10 mg olanzapine, or placebo for 21 days. Assessments included insulin sensitivity during an oral glucose tolerance test (OGTT), hyperinsulinemic-euglycemic clamp, other measures of glucose/lipid metabolism, and adverse event (AE) monitoring. Treatment effects were estimated with analysis of covariance. In total, 60 subjects were randomized (double-blind; placebo, n = 12; olanzapine, n = 24; OLZ/SAM, n = 24). Olanzapine resulted in hyperinsulinemia and reduced insulin sensitivity during an OGTT at day 19, changes not observed with OLZ/SAM or placebo. Insulin sensitivity, measured by hyperinsulinemic-euglycemic clamp, was decreased in all treatment groups relative to baseline, but this effect was greatest with olanzapine and OLZ/SAM. Although postprandial (OGTT) glucose and fasting cholesterol concentrations were similarly increased with olanzapine or OLZ/SAM, other early metabolic effects were distinct, including post-OGTT C-peptide concentrations and aspects of energy metabolism. Forty-nine subjects (81.7%) experienced at least 1 AE, most mild or moderate in severity. OLZ/SAM appeared to mitigate some of olanzapine’s unfavorable postprandial metabolic effects (e.g., hyperinsulinemia, elevated C-peptide) in this exploratory study. These findings supplement the body of evidence from completed or ongoing OLZ/SAM clinical trials supporting its role in the treatment of schizophrenia and bipolar I disorder.Subject terms: Medical research, Developmental biology     

Structure of polystyrene-block-poly(ethylene oxide) diblock copolymer micelles in water

Micellization in water of two homologous series of AB-type diblock copolymers, composed of polystyrene (PS) as the A block and poly(ethylene oxide) (PEO) as the B block, were investigated by small-angle X-ray scattering (SAXS) and dynamic light scattering (DLS). The copolymers have molecular weights M _n in the range 2 000—34 800, and have in a given series, the same number of repeating units of the PS block, (N_PS = 10 and 38), and a variable number of repeating units of the PEO block (N_PEO values in the range 23–704). In order to avoid secondary association of micelles, a dialysis technique was used to prepare the micellar systems, in the case of copolymers having high M _n values of the PS block. The experimental micelle properties such as the core radius R_c and the aggregation number N of non-equilibrium structures, so called “frozen micelles”, obtained by dialysis, were found to be independent of the copolymer characteristics. However, for equilibrium structures, obtained by direct solubilization of the copolymers (N_PS = 10) in water, R_c and N were found to decrease with increasing N_PEO for the homologous series.     

Use of recombinant hirudin as antithrombotic treatment in patients with heparin-induced thrombocytopenia

Heparin-induced thrombocytopenia is a rare but severe complication of heparin therapy that can result in severe venous or arterial thromboembolic events and whose treatment remains partially unanswered. Recombinant hirudin is potentially effective as an antithrombotic treatment in the management of heparin-induced thrombocytopenia, given its potent antithrombin effects without known interaction with platelets. We report the results obtained with intravenous recombinant hirudin (HBW 023) administered on a compassionate basis to patients suffering from heparin-induced thrombocytopenia. Six patients suffering from heparin-induced thrombocytopenia were submitted to intravenous recombinant hirudin (HBW 023) administered at a dose of 0.05 mg/kg/hr after an initial bolus injection of 0.07 mg/kg in the case of a venous thromboembolic event, and at a dose of 0.15 mg/kg/hr with the same initial bolus injection in the case of an arterial thromboembolic event. Whenever possible, oral anticoagulation with acenocoumarol was introduced at the same time as recombinant hirudin, which was interrupted as soon as the international normalized ratio reached 3. Clinical events, particularly thromboembolism and bleeding, were noted; activated partial thromboplastin time (aPTT), and platelet count were assessed throughout the administration of recombinant hirudin. Heparins responsible for heparin-induced thrombocytopenia were porcine sodium or calcium heparinate in four cases, nadroparin in one case, and enoxaparin in one case. Thrombocytopenia was discovered on routine systematic platelet count in two patients and after the occurrence of arterial and venous thromboembolism in two patients, respectively. After discontinuation of heparin and the onset of recombinant hirudin, clinical evolution was uneventful in all patients, with no recurrence of thromboembolism, limb amputation, or hemorrhagic complication. The aPTT ratio varied from 1.8 to 3.5 (median 2.4) throughout administration of recombinant hirudin. Platelet count rose from nadir (median value 60 × 10⁹ 15 to 90) to above 100 × 10⁹/L in every patient within 3–6 days (median 5), after discontinuation of heparin. Intravenous administration of recombinant hirudin ensured safe anticoagulation in patients with heparin-induced thrombocytopenia and made it possible to wait for oral anticoagulation to become efficient and platelet count to return to normal values without occurrence or recurrence of thromboembolism.     

Methotrexate in rheumatoid arthritis. a five-year prospective multicenter study

Objective. To evaluate the efficacy and tolerability of oral methotrexate (MTX) in rheumatoid arthritis (RA) in a long-term prospective trial. Methods. One hundred twenty-three patients with RA who completed a 9-month multicenter randomized trial comparing MTX and auranofin enrolled in this 5-year prospective study of MTX. Results. Significant (P = 0.0001) improvement compared with baseline was noted in all clinical disease variables, functional status, and the Westergren erythrocyte sedimentation rate (ESR). “Marked improvement” occurred in 87 (71%) and 85 (69%) of the patients, respectively, in the joint pain/tenderness index and the joint swelling index at the last evaluable visit. Forty-four patients (36%) withdrew during the study. Eight (7%) withdrew due to lack of efficacy, and 8 (7%) due to adverse experiences, including 1 patient with cirrhosis. At 5 years, 64% of patients were still taking MTX and completed the study. Conclusion. This large prospective study of long-term MTX treatment demonstrates sustained clinical response and improvement in the Westergren ESR and functional assessment scores, with an acceptable toxicity profile.     

Methotrexate concentrations in synovial membrane and trabecular and cortical bone in rheumatoid arthritis patients

Objective. To determine methotrexate (MTX) concentrations in the synovial membrane (SM) and cortical and trabecular bone of rheumatoid arthritis (RA) patients. Methods. Ten RA patients (9 women, 1 man; mean ± SD age 49.2 ± 10.6, mean disease duration 13.2 ± 9.9 years) undergoing surgical procedures for rheumatoid articular lesions participated in this study. Mean ± SD MTX treatment duration was 26.4 ± 21.3 months. The day preceding surgery, 10 mg of MTX was administered intramuscularly. During surgery, a mean ± SD of 19.7 ± 2.6 hours after MTX administration, SM, bone fragments, and blood were collected simultaneously. MTX was assayed by fluorescence polarization immunoassay in plasma and tissues. Results. The mean ± SD plasma concentration was 0.0252 ± 0.01 nmoles/ml at the time of tissue sampling. The mean MTX concentration in SM was 0.285 ± 0.159 nmoles/gm. The mean MTX concentrations in trabecular and cortical bone were 0.292 ± 0.164 and 0.286 ± 0.126 nmoles/gm, respectively. Conclusion. After intramuscular administration, high MTX concentrations are found in SM and cortical and trabecular bone of RA patients.