A placebo-controlled study of nefazodone for the treatment of chronic posttraumatic stress disorder: a preliminary study

Nefazodone is a unique serotonergic antidepressant that acts as both a presynaptic serotonin reuptake inhibitor and a postsynaptic 5-hydroxytryptamine 2A receptor antagonist. Based on the positive results of open-label trials of nefazodone, including one from our group, we tested nefazodone's efficacy in the treatment of posttraumatic stress disorder (PTSD) under placebo-controlled conditions. Forty-one patients with chronic PTSD, predominantly male combat veterans, were enrolled in a randomized, double-blind, placebo-controlled 12-week trial of nefazodone. The primary outcome measure was the Clinician-Administered PTSD Scale. Fifteen patients were randomized to placebo and 26 were randomized to nefazodone. In a repeated-measures analysis of variance with last observation carried forward, patients on nefazodone showed a significant improvement in the percentage change of Clinician-Administered PTSD Scale Total score from baseline compared with those on placebo (P = 0.04; effect size = 0.6). Sample size was not powered to test group differences in the Clinician-Administered PTSD Scale criterion B, C, or D subscale. However, the criterion D subscale showed significant improvement in patients treated with nefazodone compared with those treated with placebo (P = 0.007). In addition, the Hamilton Rating Scale for Depression showed significant improvement compared with placebo (P = 0.008). The nefazodone group also reported an improvement on the PTSD Checklist (self-report scale; P = 0.08) and the Clinician-Administered Dissociative States Scale (P = 0.06). This pilot study supports the efficacy of nefazodone for the treatment of PTSD. However, larger placebo-controlled studies in more diverse patient population are warranted.     

Short- and long-term effect of simvastatin therapy on the heterogeneity of cardiac repolarization in diabetic patients

The interlead variability of QT interval in the 12-lead electrocardiogram, QT dispersion (QTd), has been shown to reflect dispersion of ventricular refractoriness and may provide a measure of arrhythmogenic potential in diabetic patients. QTd and heart rate corrected QTd (QTcd) were also proposed to be accurate predictors of cardiac death in patients with diabetes. In recent years, experimental and clinical evidence demonstrates that statins exert antiarrhythmic properties. Therefore, in the present study, we have examined whether simvastatin treatment has any effect on the QTd and QTcd in patients with diabetes mellitus. Sixty type 2 diabetic patients without known coronary artery disease and low-density lipoprotein cholesterol >100mg/dl and 30 age and sex-matched non-diabetic controls were included in a prospective study. Out of 60 diabetic patients, 30 were treated with simvastatin 40 mg/day for 1 year and the remaining 30 subjects were served as diabetic controls. No lipid lowering therapy was administered to the diabetic and the non-diabetic controls. QTd and QTcd of treated diabetics and the non-diabetic controls were measured at baseline, 6, 12 weeks and at 1 year. QTd and QTcd of the diabetic controls were obtained at baseline, 6 and 12 weeks. Both QTd and QTcd were significantly greater in patients with the diabetes than in the non-diabetic controls at baseline (52+/-13 ms vs. 41+/-12 ms, p<0.001 and 62+/-17 ms vs. 42+/-11 ms, p<0.001, respectively). Simvastatin therapy significantly decreased both QTd and QTcd at the end of first year compared to baseline (51+/-15 ms vs. 33+/-11 ms, p<0.001 and 60+/-18 ms vs. 38+/-12 ms, p<0.001, respectively). No significant change were found in QTd and QTcd in the non-diabetic (p=0.29 and p=0.87 by ANOVA, respectively) and in the diabetic controls (p=0.72 and p=0.57, by ANOVA, respectively). This study suggests for the first time that simvastatin treatment in diabetic patients with hyperlipidemia is associated with an improvement in the heterogeneity of cardiac repolarization. This may be one of the mechanisms for the reduction in clinical events reported in the survival studies with statins. Further prospective randomized studies are warranted to confirm our findings.     

Health literacy and logical inconsistencies in valuations of hypothetical health states: results from the Canadian EQ-5D-5L valuation study

Objectives

To examine the association of health literacy with logical inconsistencies in time trade-off valuations of hypothetical health states described by the EQ-5D-5L classification system.

Methods

Data from the EQ-5D-5L Canadian Valuation study were used. Health literacy was assessed using the Brief Health Literacy Screen. A health state valuation was considered logically inconsistent if a respondent gave the same or lower value for a very mild health state compared to the value given to 55555, or gave the same or lower value for a very mild health state compared to value assigned to the majority of the health states that are dominated by the very mild health state.

Results

Average age of respondents (N?=?1209) was 48 (SD?=?17) years, 45% were male, 7% reported inadequate health literacy, and 11% had a logical inconsistency. In adjusted analysis, participants with inadequate health literacy were 2.2 (95%CI: 1.2, 4.0; p?=?0.014) times more likely to provide an inconsistent valuation compared to those with adequate health literacy. More specifically, those who had problems in “understanding written information” and “reading health information” were more likely to have a logical inconsistency compared to those who did not. However, lacking “confidence in completing medical forms” was not associated with logical inconsistencies.

Conclusions

Health literacy was associated with logical inconsistencies in valuations of hypothetical health states described by the EQ-5D-5L classification system. Valuations studies should consider assessing health literacy, and explore better ways to introduce the valuation tasks or use simpler approaches of health preferences elicitation for individuals with inadequate health literacy.

     

Lack of MERS Coronavirus Neutralizing Antibodies in Humans,Eastern Province,Saudi Arabia

We used a lentiviral vector bearing the viral spike protein to detect neutralizing antibodies against Middle East respiratory syndrome coronavirus (MERS-CoV) in persons from the Eastern Province of Saudi Arabia. None of the 268 samples tested displayed neutralizing activity, which suggests that MERS-CoV infections in humans are infrequent in this province.     

Advance medical directives: a proposed new approach and terminology from an Islamic perspective

Advance directives are specific competent consumers’ wishes about future medical plans in the event that they become incompetent. Awareness of a patient’s autonomy particularly, in relation to their right to refuse or withdraw treatment, a right for the patient to die from natural causes and interest in end of life issues were among the main reasons for developing and legalizing advance medical directives in developed countries. However, in many circumstances cultural and religious aspects are among many factors that can hamper implementation of advance directives. Islam and Muslims in general have a good understanding of death and dying. Islam allows the withholding or withdrawal of treatments in some cases where the intervention is considered futile. However, there is lack of literature and debate about such issues from an Islamic point of view. This article provides the Islamic perspective with regards to advance medical directive with the hope that it will generate more thoughts and evoke further discussion on this important topic.     

Inhibition of monoacylglycerol lipase reduces nicotine withdrawal

Background and Purpose

Abrupt discontinuation of nicotine, the main psychoactive component in tobacco, induces a withdrawal syndrome in nicotine-dependent animals, consisting of somatic and affective signs, avoidance of which contributes to drug maintenance. While blockade of fatty acid amide hydrolase, the primary catabolic enzyme of the endocannabinoid arachidonoylethanolamine (anandamide), exacerbates withdrawal responses in nicotine-dependent mice, the role of monoacylglycerol lipase (MAGL), the main hydrolytic enzyme of a second endocannabinoid 2-arachidonylglycerol (2-AG), in nicotine withdrawal remains unexplored.

Experimental Approach

To evaluate the role of MAGL enzyme inhibition in nicotine withdrawal, we initially performed a genetic correlation approach using the BXD recombinant inbred mouse panel. We then assessed nicotine withdrawal intensity in the mouse after treatment with the selective MAGL inhibitor, JZL184, and after genetic deletion of the enzyme. Lastly, we assessed the association between genotypes and smoking withdrawal phenotypes in two human data sets.

Key Results

BXD mice displayed significant positive correlations between basal MAGL mRNA expression and nicotine withdrawal responses, consistent with the idea that increased 2-AG brain levels may attenuate withdrawal responses. Strikingly, the MAGL inhibitor, JZL184, dose-dependently reduced somatic and aversive withdrawal signs, which was blocked by rimonabant, indicating a CB₁ receptor-dependent mechanism. MAGL-knockout mice also showed attenuated nicotine withdrawal. Lastly, genetic analyses in humans revealed associations of the MAGL gene with smoking withdrawal in humans.

Conclusions and Implications

Overall, our findings suggest that MAGL inhibition maybe a promising target for treatment of nicotine dependence.     

Does moxifloxacin alter oxidant status in the cornea? An experimental study

Objective: In this experimental study, we investigated the possible effects of intracameral moxifloxacin on oxidative stress parameters and endothelial cell morphology in corneal tissue.

Methods: In total, 30 rats were randomly assigned to three groups of 10 rats: the sham group (Group 1, n?=?10); the control group (Group 2), where balanced salt solution (BSS) was administered at a dose of 0.01?cc (n?=?10); and the treatment group (Group 3), where moxifloxacin was administered at a dose of 0.05?mg/0.01?cc (n?=?10). Total antioxidant status (TAS) and total oxidant status (TOS) in corneal tissue and blood samples were measured and the oxidative stress index (OSI) was calculated. Also, corneal tissue histopathology was evaluated with caspase-3 and caspase-8 staining. Apoptotic activity was also evaluated.

Results: In blood samples, TAS, TOS, and OSI levels were not statistically significantly different (all p?>?0.05). Compared with the sham and control groups, TOS and OSI levels in cornea tissue were significantly different in the moxifloxacin group (all p?p?>?0.05). Compared with the sham and control groups, apoptotic activity was higher in the moxifloxacin group, in both immunohistochemical staining for caspase-3 and caspase-8.

Conclusions: Intracameral moxifloxacin injection seems to be safe systemically, but it may have toxic effects on corneal tissues, as suggested by oxidative stress parameters and a histopathological evaluation.     

Chlorinated pesticide residues in human breast milk collected from southern Jordan in 2012/2013

Chlorinated pesticide residues in human breast milk from five southern Jordan districts were analyzed in 2012/2013. The total number of samples from all districts was 100. The number of samples gathered from each district was collected according to their population densities. The present study shows that 59% of the samples which contained pesticides’ residues were p,p’-DDE, 30% contained β-HCH, 10% contained p,p′-DDT, 6% contained α-HCH, 2% contained heptachlor and 1% contained endrin. These human milk samples were free of aldrin, dieldrin, α-endosulfan, β-endosulfan, HCB, γ-HCH, o,p′-DDD, o,p′-DDT and o,p′-DDE. The levels of the six mentioned compounds detected in all mother’s milk samples were higher in Ghor El-Safi district compared with the other four districts. In this study, it is recommended to continue the pesticides residues monitoring in all parts of Jordan, particularly in Ghor El-Safi district and other regions in the cultivated Jordan Valley.     

Systemic delivery of β-blockers via transdermal route for hypertension

Hypertension is the most common cardiovascular disease worldwide. Moreover, management of hypertension requires long-term treatment that may result in poor patient compliance with conventional dosage forms due to greater frequency of drug administration. Although there is availability of a plethora of therapeutically effective antihypertensive molecules, inadequate patient welfare is observed; this arguably presents an opportunity to deliver antihypertensive agents through a different route. Ever since the transdermal drug delivery came into existence, it has offered great advantages including non-invasiveness, prolonged therapeutic effect, reduced side effects, improved bioavailability, better patient compliance and easy termination of drug therapy. Attempts were made to develop the transdermal therapeutic system for various antihypertensive agents, including β-blockers, an important antihypertensive class. β-blockers are potent, highly effective in the management of hypertension and other heart ailments by blocking the effects of normal amounts of adrenaline in the heart and blood vessels. The shortcomings associated with β-blockers such as more frequent dose administration, extensive first pass metabolism and variable bioavailability, make them an ideal candidate for transdermal therapeutic systems. The present article gives a brief view of different β-blockers formulated as transdermal therapeutic system in detail to enhance the bioavailability as well as to improve patient compliance. Constant improvement in this field holds promise for the long-term success in technologically advanced transdermal dosage forms being commercialized sooner rather than later.