AhR Activation in Pharmaceutical Development: Applying Liver Gene Expression Biomarker Thresholds to Identify Doses Associated With Tumorigenic Risks in Rats.

BackgroundA considerable proportion of patients suffering from schizophrenia show suboptimal responses to oral antipsychotics due to inadequate adherence. Hence, they are likely to benefit from switching to a long-acting injectable formulation. These post hoc analyses assessed the clinical effects of switching to olanzapine long-acting injection (OLAI) from either oral olanzapine (OLZ) or other antipsychotics (non-OLZ).MethodsPost hoc analyses were done based on two randomized studies (one short-term, one long-term) conducted in patients suffering from schizophrenia and treated with OLAI. The short-term study was an 8-week placebo-controlled, double-blind trial in acute patients, and the long-term study was a 2-year, oral olanzapine-controlled, open-label, follow-up of stabilized outpatients.ResultsThese analyses used data from 62 OLAI-treated patients (12 switched from OLZ, 50 from non-OLZ) from the short-term study and 190 OLAI-treated patients (56 switched from OLZ, 134 from non-OLZ) from the long-term study. Kaplan–Meier survival analyses of time to all-cause discontinuation of OLAI treatment did not differ significantly between OLZ and non-OLZ patients in the short-term study (P=0.209) or long-term study (P=0.448). Similarly, the proportions of OLZ and non-OLZ patients that discontinued OLAI were not statistically different in the short-term (16.7% versus 36.0%, respectively; P=0.198) or long-term (57.1% versus 47.8% respectively; P=0.238) studies. In the short-term study, no significant differences were detected between the patient groups in mean change in Positive and Negative Syndrome Scale (PANSS) total score (−13.4 OLZ versus −20.8 non-OLZ; P=0.166). In the long-term study, mean change in PANSS total score (3.9 OLZ versus −3.6 non-OLZ; P=0.008) was significantly different between the non-OLZ and OLZ groups. Rates of treatment-emergent adverse events were similar in OLZ and non-OLZ groups per study.ConclusionThese post hoc analyses suggest that no significant differences in clinical effectiveness were seen after switching from non-OLZ or OLZ to OLAI. However, these findings should be interpreted with care, due to small sample sizes and differences in patients’ clinical profiles.

Safety evaluation of Lactobacillus pentosus strain b240

Objective:Mood disorders are often associated with poor glycemic control, and antidepressant treatments for mood and pain disorders can alter plasma glucose levels in patients with diabetes. A previous meta-analysis from three studies showed that duloxetine modestly increased fasting plasma glucose (FPG) and HbA1c levels in patients with diabetic peripheral neuropathic pain (DPNP). This meta-analysis examined whether there were any short- and long-term effects of duloxetine (20–120 mg/day) on glycemic control in patients with diagnoses other than DPNP.Research design and methods:Short-term data (9–27 weeks): seven studies of duloxetine in general anxiety disorder, fibromyalgia, and chronic lower back pain (CLBP). Long-term data: 41-week, uncontrolled extension of the short-term CLBP study and 52-week study in patients with recurrence of major depressive disorder.Main outcome measures:Baseline-to-endpoint changes in FPG and HbA1c levels.Results:In short-term studies, patients were randomly assigned to placebo (n = 1098) or duloxetine (n = 1563). Mean baseline-to-endpoint changes in FPG and HbA1c did not significantly differ in duloxetine-treated patients compared with placebo-treated patients. In the 41-week study (n = 181), duloxetine-treated patients experienced a small but significant within-group baseline-to-endpoint increase in HbA1c (mean change = 0.1%; p < 0.001). This result was in contrast to absence of effect on mean baseline-to-endpoint within-group changes in FPG (p = 0.326) in that study, and to absence of between-treatment changes in FPG (p = 0.744) and HbA1c (p = 0.180) in the 52-week placebo-controlled study.Conclusion:Duloxetine treatment did not significantly alter FPG and HbA1c levels compared with placebo treatment in the short-term studies. A small but statistically significant within-group increase in HbA1c was found in the 41-week study, but not in between-treatment group differences in the 52-week study. Neither of the long-term studies showed significant changes in the FPG levels. The small, non-reproducible HbA1c increase in one study of patients without DPNP may have resulted from patients with unrecognized diabetes in these trials.

PurposeTo assess the safety and efficacy of the serotonin–norepinephrine reuptake inhibitor desvenlafaxine in adults with painful diabetic peripheral neuropathy (DPN).ClinicalTrials.gov identifiersNCT00283842, NCT01050218.Patients and methodsThis was a 13-week, randomized, double-blind, placebo-controlled, fixed-dose study of desvenlafaxine in adults with painful DPN. The primary efficacy endpoint was change from baseline in numeric rating scale (NRS) score. Patients who completed the 13-week trial could continue in a 9-month open-label, flexible-dose extension study.ResultsA total of 412 patients were randomized to treatment with placebo or desvenlafaxine 50, 100, 200, or 400 mg/day. Of those, 240 patients continued in the extension study. After a planned interim analysis, conducted when the first 225 patients had completed 6 weeks of treatment in the short-term study, randomization to the 50 mg or 400 mg doses was stopped. At week 13, the mean change from baseline in NRS score was significantly greater compared with placebo in the desvenlafaxine 200 mg (difference [95% confidence interval {CI}]: 1.10 [0.50 to 1.70]; P<0.001) and 400 mg groups (0.91 [95% CI: 0.23 to 1.59]; P=0.027); differences from placebo were not statistically significant for the 50 mg (0.58 [95% CI: −0.08 to 1.25]) and 100 mg (0.59 [95% CI: –0.03 to 1.21]) groups. Nausea and dizziness were the most common treatment-emergent adverse events reported in the short-term study, and the most common adverse events leading to discontinuation in the short-term study and the extension. Adverse events rates were dose-dependent in the short-term studies.ConclusionDesvenlafaxine was effective in relieving pain associated with DPN at doses of 200 and 400 mg/day, and improved activity impairment at all doses assessed. Desvenlafaxine was generally well-tolerated in the short-term and long-term studies.

Short term and long term studies on individual and combined toxicities of copper, zinc and lead to Scenedesmus quadricauda

Biochemical markers of bone resorption are useful for evaluating metabolic bone diseases. A three-center study was performed in 253 men, 21-86 yr of age, to determine the normal range of urinary N-telopeptide of type I collagen (NTX/creatinine) in a nonfasting, second void, morning specimen, to define the biological variability and to examine the relationship between NTX/creatinine and age. Men with disorders or taking medications known to alter bone turnover, or with a serum creatinine level greater than 2 mg/dL were excluded. Results are expressed as nanomoles of bone collagen equivalents (BCE) per mmol creatinine. In a subset of individuals over age 30 yr, additional second void morning urine specimens were obtained at 2, 3, and 4 days (short term study) and at 2, 3, and 4 months (long term study) after the first specimen. After collection, samples were shipped to one laboratory for analysis. Multiple samples from the same subject were analyzed in separate assays. It was found that urinary NTX/ creatinine was significantly higher in 45 men, aged 21-30 yr, than in 206 men, aged 31-86 yr (48 +/- 22 vs. 33 +/- 15 nmol/L BCE/mmol/L creatinine; P < 0.00001). Values did not otherwise change with age. The range of values in men aged 21-30 yr was 4-92 nmol/L BCE/mmol/L creatinine. The range for men over age 30 yr was 3- 63 nmol/L BCE/mmol/L creatinine, essentially the same as that previously reported for premenopausal women. The coefficient of variation was determined in each individual for the short term (n = 36) and long term studies (n = 35) and averaged 18% and 19%, respectively. There was no correlation between short term and long term coefficient of variations. In summary, urinary NTX/creatinine is higher in men aged 21-30 yr than in men over age 30 yr and may reflect continued skeletal maturation. Intrasubject variability of urinary NTX/creatinine in short term and long term studies has been defined for clinical purposes.

PURPOSEThe purpose of this study was to analyze the current literatures and to assess outcomes of implant treatment in patients with generalized aggressive periodontitis.MATERIALS AND METHODSStudies considered for inclusion were searched in Pub-Med. The literature search for studies published in English between 2000 and 2012 was performed. Our findings included literature assessing implant treatment in patients with a history of generalized aggressive periodontitis (GAP). All studies were screened according to inclusion criteria. The outcome measures were survival rate of superstructures, marginal bone loss around implant and survival rate of implants. All studies were divided into two follow-up period: short term study (< 5 years) and long term study (≥ 5 years).RESULTSSeven prospective studies were selected, including four short-term and three long-term studies. The survival rates of the superstructures were generally high in patients with GAP, i.e. 95.9 - 100%. Marginal bone loss around implant in patients with GAP as compared with implants in patients with chronic periodontitis or periodontally healthy patients was not significantly greater in short term studies but was significantly greater in long term studies. In short term studies, the survival rates of implants were between 97.4% and 100% in patients with GAP-associated tooth loss, except one study. The survival rates of implants were between 83.3% and 96% in patients with GAP in long term studies.CONCLUSIONImplant treatment in patients with GAP is not contraindicated provided that adequate infection control and an individualized maintenance program are assured.

Oral toxicity of 1,2-dichloropropane: Acute, short-term, and long-term studies in rats

Objective: To analyze the effect of brexpiprazole on metabolic parameters and body weight in adults with schizophrenia, including clinically relevant sub-groups of patients, based on data from two pivotal phase 3 studies (NCT01393613; NCT01396421) and a long-term extension study (NCT01397786).Methods: The short-term studies were randomized, double-blind, placebo-controlled, fixed-dose (2 and 4 mg/day), 6-week phase 3 studies. The long-term study was an open-label 52-week study, recruiting de novo patients and those completing either short-term study. Maximum exposure to brexpiprazole was 58 weeks. Fasting metabolic parameters and weight were measured throughout the studies. Metabolic values were characterized as normal, borderline, or high (cholesterol, triglycerides, and glucose) and low or normal (HDL), using commonly reported thresholds. The incidences of all possible shifts in metabolic parameters were measured from baseline to any time post-baseline during the first 6 weeks, first 6 months, and last 6 months of treatment.Results: In short-term studies, the proportion of brexpiprazole-treated patients with unfavorable shifts in metabolic parameters was low and like that of placebo-treated patients; the incidence of these shifts was not dose-dependent. During both short- and long-term treatment, the incidence of unfavorable shifts with brexpiprazole was lower than that of favorable shifts. During short-term studies, the mean increase in body weight was 1.2 kg with brexpiprazole treatment and 0.2 kg with placebo. The mean increase in body weight during long-term treatment was 3.2 kg at week 58.Conclusions: Brexpiprazole treatment was associated with moderate weight gain and small changes in metabolic parameters during both short- and long-term treatment.

Review efficacy, safety, and tolerability of brexpiprazole in patients with schizophrenia in short- and long-term phase 3 studies. Patients experiencing a current exacerbation of schizophrenia received brexpiprazole in two fixed-dose (2 and 4 mg), 6-week, placebo-controlled studies, one flexible-dose (2-4 mg), 6-week, placebo-control and active reference study, and one fixed-dose (1-4 mg), 52-week, placebo-controlled maintenance study. The efficacy of brexpiprazole was demonstrated in the two short-term fixed-dose studies with statistically significant improvements from baseline in Positive and Negative Syndrome Scale (PANSS) total score compared with placebo. In the flexible-dose short-term study, treatment with brexpiprazole resulted in numerically greater improvements in PANSS total score than with placebo that approached statistical significance (p=0.056). A meta-analysis of these short-term studies showed a mean change in PANSS total score of -20.1, reflecting a clinically meaningful reduction in symptoms. In the maintenance study, brexpiprazole had a beneficial effect relative to placebo on time to exacerbation of psychotic symptoms/impending relapse (p<0.0001). For all studies, brexpiprazole demonstrated clinically meaningful treatment effects on the Personal and Social Performance scale. Brexpiprazole had a favourable safety profile, with a relatively low prevalence of activating and sedating side effects. Weight gain in the short-term studies was ~1 kg greater than placebo. No safety concerns were observed with brexpiprazole in laboratory values, electrocardiogram, or vital signs. Overall, the results indicate brexpiprazole, used either short-term or as part of a long-term maintenance treatment programme, is an efficacious therapy option in adults with schizophrenia and has a favourable safety/tolerability profile.

Hypovolaemia has been implicated as a major causal factor of morbidity during haemodialysis (HD). A model biofeedback control system for intra-HD blood volume (BV) changes modelling has been developed (Hemocontrol), Hospal Italy) to prevent destabilizing hypovolaemia. It is based on an adaptive controller incorporated in a HD machine (Integra), Hospal Italy). The Hemocontrol biofeedback system (HBS) monitors BV contraction during HD with an optical device. HBS modulates BV contraction rates by adjusting the ultrafiltration rate (UFR) and the refilling rate by adjusting dialysate conductivity (DC) in order to obtain the desired pre-determined BV trajectories. Nineteen hypotension-prone uraemic patients (seven males, 12 females; mean age 64.5+/-3.0 SEM years; on maintenance HD for 80.5+/-13.2 months) volunteered for the present prospective study that compared the efficacy and safety of bicarbonate HD treatment equipped with HBS, as a whole, with the gold-standard bicarbonate treatment equipped with a constant UFR and DC (BD). The study included three phases: Medium-term studies started with one period of 6 months of BD and always had a follow-up period of HBS treatment ranging from 14 to 30 months (mean 24.0+/-1.6); short-term studies started in September 1999, when all patients went back to BD treatment for a wash-out period of 4 weeks and a short-term study period of a further 3 weeks (phase A). Afterwards, they once again started HBS treatment for a wash-out period of 4 weeks and a short-term study period of a further 3 weeks (phase B). Every patient underwent acute studies during a single HD run, once during phase A and once in phase B. Resistance (R) and reactance (Xc) measurements were obtained utilizing a single-frequency (50 kHz) tetrapolar bioimpedance analysis (BIA). Extracellular fluid volume (ECV) was calculated from R, Xc, and height and body weight measurements using the conventional BIA regression equations. The overall occurrence of symptomatic hypotension and muscle cramps was significantly less in HBS treatment in both medium- and short-term studies. Self-evaluation of intra- and inter-HD symptoms (worst score=0, best score=10) revealed a statistically significant difference, as far as post-HD asthenia was concerned (6.2+/-0.2 in HBS treatment vs 4.3+/-0.1 in BD treatment, P<0.0001). No difference was observed between the two treatments when comparing pre- and post-HD lying blood pressure, heart rate, body weights and body weight changes in medium- and short-term studies. The residual BV%/ Delta ECV% ratio, expression of the vascular refilling, was significantly higher during HBS treatment in acute studies. HBS treatment is effective in lowering hypovolaemia-associated morbidity compared with BD treatment; this could be related to a greater ECV stability. Furthermore, HBS is a safe treatment in the medium-term because these results are not achieved through potentially harmful changes in blood pressure, body weight, and serum sodium concentration.

Role of ligamentum teres cardiopexy during laparoscopic sleeve gastrectomy in patients with obesity with gastroesophageal reflux disease: a short-term retrospective study.

Adeno-associated virus (AAV)-mediated clustered regularly interspaced short palindromic repeats (CRISPR) editing holds promise to restore missing dystrophin in Duchenne muscular dystrophy (DMD). Intramuscular coinjection of CRISPR-associated protein 9 (Cas9) and guide RNA (gRNA) vectors resulted in robust dystrophin restoration in short-term studies in the mdx mouse model of DMD. Intriguingly, this strategy failed to yield efficient dystrophin rescue in muscle in a long-term (18-month) systemic injection study. In-depth analyses revealed a selective loss of the gRNA vector after long-term systemic, but not short-term local injection. To determine whether preferential gRNA vector depletion is due to the mode of delivery (local vs. systemic) or the duration of the study (short term vs. long term), we conducted a short-term systemic injection study. The gRNA (4e12 vg/mouse in the 1:1 group or 1.2e13 vg/mouse in the 3:1 group) and Cas9 (4e12 vg/mouse) vectors were coinjected intravenously into 4-week-old mdx mice. The ratio of the gRNA to Cas9 vector genome copy dropped from 1:1 and 3:1 at injection to 0.4:1 and 1:1 at harvest 3 months later, suggesting that the route of administration, rather than the experimental duration, determines preferential gRNA vector loss. Consistent with our long-term systemic injection study, the vector ratio did not influence Cas9 expression. However, the 3:1 group showed significantly higher dystrophin expression and genome editing, better myofiber size distribution, and a more pronounced improvement in muscle function and electrocardiography. Our data suggest that the gRNA vector dose determines the outcome of systemic AAV CRISPR therapy for DMD.

Improving atherogenic risk factors with flax seed bread

The use of angiotensin converting enzyme inhibitors and calcium channel blockers, as monotherapies and in combination, is common in the management of hypertension. Clinical studies have documented the augmentation of blood pressure reduction when these agents are combined compared with the individual agents, in short-term studies. In the present investigation, 93 patients with stage 3-4 essential hypertension, who successfully completed a short-term double-blind study, participated in a 40-week open-label treatment phase. The patients were maintained on their previous doses of enalapril/diltiazem ER (E/D) with or without additional antihypertensive medications. Doses of medication could be adjusted as necessary for blood pressure control. Of the 93 patients, 68% were male and 82% were white; they averaged 52.7 years of age and had a baseline mean sitting blood pressure (SiBP) of 167/111 mmHg. The use of E/D alone (n = 14) reduced mean SiBP by 14.5/14.4 mmHg from baseline, whereas the use of E/ D with other agents (n = 79) decreased it by 27/20.5 mmHg from baseline. E/D alone or in combination with other drugs was well-tolerated, and no serious adverse events were noted. This long-term open-label study demonstrated that the E/D combination alone or with the addition of other antihypertensive drugs was effective, safe, and well-tolerated after prolonged administration.