A double-blind, double-dummy, randomized, prospective pilot study of the partial mu opiate agonist, buprenorphine, for acute detoxification from heroin

The optimum dose of buprenorphine for acute inpatient heroin detoxification has not been determined. This randomized, double-blind, double-dummy, pilot study compares two buprenorphine sublingual tablet dosing schedules to oral clonidine. Heroin users (N = 30) who met DSM-IV criteria for opioid dependence and achieved a Clinical Opiate Withdrawal Scale (COWS) score of 13 (moderate withdrawal), were randomized to receive higher dose buprenorphine (HD, 8-8-8-4-2 mg/day on days 1-5), lower dose buprenorphine (LD, 2-4-8-4-2 mg/day on days 1-5), or clonidine (C, 0.2-0.3-0.3-0.2-0.1 mg QID on days 1-5). COWS scores were obtained QID. Twenty-four hours after randomization, the percentages of subjects who achieved suppression of withdrawal, as defined by four consecutive COWS scores <12, were: C = 11%, LD = 40%, and HD = 60%. Generalized estimating equation regression models, controlling for baseline COWS and time, indicated that COWS scores over the course of 5 days were lower in both LD and HD compared to C (chi(2)(2) = 13.28, P = 0.001). Similar analyses examining scores over time on the Adjective Rating Scale for Withdrawal (ARSW) and on a Visual Analog Scale of Opiate Craving (VAS) indicated an overall treatment effect on the VAS accounted for by a significant difference between HD and C, but no overall treatment effect on the ARSW. There were no discontinuations due to treatment-related adverse events. Both HD and LD regimens are safe and efficacious treatment for opioid detoxification, but HD demonstrated superiority to C on a greater number of measures.     

The Addiction Severity Index medical and psychiatric composite scores measure similar domains as the SF-36 in substance-dependent veterans: concurrent and discriminant validity

BACKGROUND: Recently attention has focused on the assessment of functional health status in substance-dependent individuals. The addiction severity index (ASI) is a widely used assessment instrument that includes scales to reflect current medical and psychiatric status. This study examines the concurrent validity of these ASI composite scores in relation to the short form 36-item health survey (SF-36), a well-established measure of health-related quality of life/functional health status. METHODS: Veterans (n=674) were assessed at admission to substance dependence treatment. Correlations were performed between ASI composite scores and SF-36 scales and the physical and mental summary components (PSC and MSC, respectively). Areas under receiver operating characteristic (ROC) curves determined the descriminative ability of the ASI composites to ascertain impairment. RESULTS: The ASI medical composite score demonstrated robust correlations with the four SF-36 scales that relate to physical health and with the PCS. The ASI psychiatric composite score had robust correlations with the four SF-36 scales related to mental health and with the mental component summary (MCS). ROC curves indicated that the ASI medical (AUC=0.83) and psychiatric composites (AUC=0.90) accurately detected subjects with impairment. CONCLUSIONS: ASI medical and psychiatric composite scores provide effective initial screening for patients with impaired functional status as measured by the corresponding SF-36 component summary scores.     

Drug repurposing and emerging adjunctive treatments for schizophrenia

Introduction: Schizophrenia is a frequent disorder, which substantially impairs patients’ quality of life. Moreover, the burden of illness for patients, their families and for the society, in general, is substantial. Nevertheless, the understanding of the pathophysiology of this syndrome, concise diagnostic methods and more effective and tolerable treatments are still lacking. Thus, innovative approaches and the exploration of new territories are required.

Areas covered: An overview of repurposed drugs and emerging treatments for schizophrenia is presented, focusing on randomized, controlled trials and meta-analyses.

Expert opinion: Despite many years of drug research, several needs in the treatment of schizophrenia including the safety and tolerability, stage-dependent and personalized approaches, as well as drug delivery and sustainability have not been addressed sufficiently. Given the current failure of a number of mechanistically new drugs, repurposed compounds may serve as alternative and/or adjunctive agents for schizophrenic patients and for treatment refractory patients in particular. Anti-inflammatory drugs (e.g., acetylsalicylic acid, celecoxib and minocycline), as well as N-acetylcysteine, a precursor of the major antioxidant glutathione, hormones (e.g., estrogen, raloxifene and oxytocin), glutamatergic (e.g., glycine and d-serine) and nicotinergic compounds, ‘nutraceuticals’ (e.g., ω-3 fatty acids) and cannabidiol, an endocannabinoidmodulator, represent promising agents in this field.     

High-Dose Menaquinone-7 Supplementation Reduces Cardiovascular Calcification in a Murine Model of Extraosseous Calcification

Cardiovascular calcification is prevalent in the aging population and in patients with chronic kidney disease (CKD) and diabetes mellitus, giving rise to substantial morbidity and mortality. Vitamin K-dependent matrix Gla-protein (MGP) is an important inhibitor of calcification. The aim of this study was to evaluate the impact of high-dose menaquinone-7 (MK-7) supplementation (100 µg/g diet) on the development of extraosseous calcification in a murine model. Calcification was induced by 5/6 nephrectomy combined with high phosphate diet in rats. Sham operated animals served as controls. Animals received high or low MK-7 diets for 12 weeks. We assessed vital parameters, serum chemistry, creatinine clearance, and cardiac function. CKD provoked increased aortic (1.3 fold; p < 0.05) and myocardial (2.4 fold; p < 0.05) calcification in line with increased alkaline phosphatase levels (2.2 fold; p < 0.01). MK-7 supplementation inhibited cardiovascular calcification and decreased aortic alkaline phosphatase tissue concentrations. Furthermore, MK-7 supplementation increased aortic MGP messenger ribonucleic acid (mRNA) expression (10-fold; p < 0.05). CKD-induced arterial hypertension with secondary myocardial hypertrophy and increased elastic fiber breaking points in the arterial tunica media did not change with MK-7 supplementation. Our results show that high-dose MK-7 supplementation inhibits the development of cardiovascular calcification. The protective effect of MK-7 may be related to the inhibition of secondary mineralization of damaged vascular structures.     

The potential of flavanol and procyanidin intake to influence age-related vascular disease

Advancing age is an independent major risk factor for cardiovascular disease (CVD). Age-associated impairments in the control of inflammation, excessive oxidative stress, and reduced cellular repair can all contribute to the development and progression of CVD. Current recommendations for both the primary and secondary prevention of CVD promote lifestyle modifications that include the adoption of healthy dietary patterns, such as the consumption of diets rich in plant foods, as these have been associated with a lower lifetime risk for the development of CVD. The potential for a diet rich in plant foods to be cardiovascular protective is also supported by prospective studies that suggest the intake of foods providing high amounts of certain phytochemicals, in particular flavanols and procyanidins, reduce the risk for CVD. These observations are further supported by a number of dietary intervention trials that show improvements in vascular function and reduced platelet reactivity following the consumption of high flavanol foods. In the current article we review a selection of these studies, and comment on some of the potential mechanisms that have been postulated to underlie the health effects of flavanol and procyanidin-rich foods.     

Evaluation of the sensitizing potential of antibiotics in vitro using the human cell lines THP-1 and MUTZ-LC and primary monocyte-derived dendritic cells

Since the 7th amendment to the EU cosmetics directive foresees a complete ban on animal testing, alternative in vitro methods have been established to evaluate the sensitizing potential of small molecular weight compounds. To find out whether these novel in vitro assays are also capable to predict the sensitizing potential of small molecular weight drugs, model compounds such as beta-lactams and sulfonamides - which are the most frequent cause of adverse drug reactions - were co-incubated with THP-1, MUTZ-LC, or primary monocyte‐derived dendritic cells for 48 h and subsequent expression of selected marker genes (IL-8, IL-1β, CES1, NQO1, GCLM, PIR and TRIM16) was studied by real time PCR. Benzylpenicillin and phenoxymethylpenicillin were recognized as sensitizing compounds because they are capable to induce the mRNA expression of these genes in moDCs and, except for IL-8, in THP-1 cells but not in MUTZ-LC. Ampicillin stimulated the expression of some marker genes in moDCs and THP-1 cells. SMX did not affect the expression of these genes in THP-1, however, in moDCs, at least PIR was enhanced and there was an increase of the release of IL-8. These data reveal that novel in vitro DC based assays might play a role in the evaluation of the allergenic potential of novel drug compounds, but these systems seem to lack the ability to detect the sensitizing potential of prohaptens that require metabolic activation prior to sensitization and moDCs seem to be superior with regard to the sensitivity compared with THP-1 and MUTZ-3 cell lines.     

Prevalence, predictors, and service utilization of patients with recurrent use of Veterans Affairs substance use disorder specialty care

Although substance use disorders (SUDs) are chronic conditions for many patients, the prevalence, predictors, and health care utilization patterns of those who reenter SUD specialty care are understudied. We identified 1,640 patients who initiated SUD specialty care at 1 Veterans Affairs (VA) medical center and categorized them, using their subsequent 24 and prior 60 months receipt of VA SUD care, as index episode only (35.7%, 33.5–38.1), index and prior episode(s) (24.6%, 22.5–22.7), and index and postindex episodes (39.6%, 37.3–42.0). Compared with the index episode-only group, the postindex episode(s) group had modestly higher percentages of men, divorced/separated, and alcohol use, cocaine use, bipolar disorder, and psychotic disorders. Patients with postindex episodes averaged 2 times more postindex emergency visits and mental health hospitalizations than patients with an index only episode. Results document the prevalence, overall health care utilization, and limited predictability of SUD treatment reentry and support development of new models of care for these complex patients.     

Participation in mindfulness-based stress reduction is not associated with reductions in emotional eating or uncontrolled eating

The adverse health effects and increasing prevalence of obesity in the United States make interventions for obesity a priority in health research. Diet-focused interventions generally do not result in lasting reductions in weight. Behavioral interventions that increase awareness of eating cues and satiety have been postulated to result in healthier eating habits. We hypothesized that participation in a program called mindfulness-based stress reduction (MBSR) would positively influence the eating behaviors and nutritional intake of participants through changes in emotional eating (EE), uncontrolled eating (UE), and type and quantity of food consumed. Forty-eight veterans at a large urban Veterans Administration medical center were assessed before MBSR, after MBSR, and 4 months later. For all participants (N = 48), MBSR participation was not associated with significant changes in EE or UE. In addition, there were no significant differences in the intake of energy, fat, sugar, fruit, or vegetables at either follow-up time point as compared with baseline. Enhanced mindfulness skills and reduced depressive symptoms were seen over time with medium to large effect sizes. Changes in mindfulness skills were significantly and negatively correlated with changes in EE and UE over time. Overall, there was no evidence that participation in MBSR was associated with beneficial changes in eating through reductions in disinhibited eating or significant changes in dietary intake. Randomized studies are needed to further define the relationship between mindfulness program participation and eating behaviors.