A Comparison between Single and Double-Dose Intravenous Ketamine Administration in Bipolar Mood Disorder: A Double-Blind Controlled Clinical Trial.

Objective: As glutamatergic system dysfunction is involved in bipolar depression pathophysiology, the glutamate receptor modulators such as Ketamine have been applied as complementary medication for mood stabilizers. While the treatment is currently just the intravenous injection of a single dose, and there is no robust conclusion on Ketamine effectiveness or its side effects in bipolar patients, this study aimed to consider single- and double-dose intravenous injections of Ketamine in bipolar patients compared to the placebo. Method : In a randomized, double-blind controlled clinical trial, 30 patients diagnosed with bipolar I and II disorders according to DSM-IV-TR (SCID-I) were randomly divided into three groups: the first group received an intravenous injection of Ketamine (0.5 mg/kg) and placebo with a three-day interval, the second group received two doses of Ketamine (0.5 mg/kg) in the same interval, and the third group received two placebo injections. Patients were assessed for depression, anxiety, and mania at various time points, including before the injection, 60 minutes after the injection, on the first, third, fifth, seventh, and 14th day, as well as at the end of the first month using the Hamilton Depression Rating Scale, Beck Anxiety Inventory, and Young Mania Scale, respectively. Data were analyzed using ANOVA and Repeated measure tests. Results: The mean age of patients was 36.8 ± 7.9 years, with 18 females (60%) and 12 (40%) males. Depression and anxiety showed significant differences in both the single- and double-dose Ketamine groups over time (P < 0.01). Moreover, mania displayed significant changes during the study time in the single- and double-dose Ketamine groups, as well as the in the control group. However, during the study time, there were no significant differences observed in depression, anxiety, and mania among the three groups (P = 0.198, P = 0.416, and P = 0.540, respectively). Patients did not indicate any side effects during the study. Conclusion: Intravenous Ketamine administration may relieve depressive manifestations in bipolar patients. The findings suggest that a double dose of Ketamine does not lead to greater improvement than a single dose.

Protective effects of Biebersteinia multifida on sub-chronic toxicity of DZN in male Wistar rats: biochemical, hematological, and oxidative stress indices.

The protective effect of Biebersteinia Multifida on diazinon-induced toxicity in male Wistar rats was investigated over 8 weeks. Impacts of diazinon (10 mg/kg daily), Biebersteinia Multifida (500 mg/kg daily), and coadministration of them on oxidative stress parameters besides hematological and biochemical indices were assessed in various groups. The gas chromatography-mass spectrometry analysis was performed to identify the antioxidant components of plant extract by comparing the mass spectra and retention indices with those given in the literature. Pseudocholinesterase level demonstrated a significant attenuation in the Biebersteinia Multifida+diazinon-treated group in comparison to the diazinon group at the end of the 8th week. Statistical significant differences in hematological and biochemical indices were detectable when the diazinon group was compared to Biebersteinia Multifida+diazinon-treated rats. While diazinon destroyed hepatic and renal functions, Biebersteinia Multifida protected the liver and kidney from diazinon toxic effects by normalizing related function indices at the end of the 8th week. By diminishing malondialdehyde and enhancing the ferric-reducing power, Biebersteinia Multifida minimized the hazardous effect of diazinon-induced oxidative stress. Following these results, the beneficial effects of Biebersteinia Multifida in reducing the toxicity of diazinon should be taken into consideration.

Frequency and Predictors of Opioid Use in Rheumatoid Arthritis and Seronegative Spondyloarthropathy Patients.

Background: Pain is one of the most challenging symptoms in patients with rheumatoid arthritis (RA) and spondyloarthropathies (SpAs), and pain relief is one of the top priorities for improving health-related quality of life. When medication therapy does not significantly reduce pain, chronic opioid consumption becomes more prominent in such patients. This study aimed to evaluate the state of opioid use in RA and SpA patients. Methods: This cross-sectional study was performed on 316 patients with RA and spondyloarthropathies (SpAs) from January to March 2014. The convenience sampling method was used to select the participants, and by obtaining verbal consent, everyone was given 15 minutes to complete a checklist independently. Demographic and opioid use data were evaluated in terms of opioid use and its predictors. In this regard, univariate and multivariate logistic regressions were used to evaluate the predictors of opioid consumption in patients. All analyses were conducted using SPSS 21 and the significance level was set at P<0.05. Findings: About 9.5% of all participants, including 8.8% of RA and 22.6% of SpA cases, were opioid abusers. In the first step of the analysis, it was observed that opioid abuse was significantly higher in men, married participants, urban residents, patients with no biological therapy, and patients with a negative family history of addiction. The most prevalent ways of drug abuse were smoking and ingestion. The results of univariate logistic regression analysis revealed SpA and other factors significantly increase the chance of opioid abuse. Furthermore, multivariate logistic regression analysis showed male gender (OR=10.4) and negative family history of addiction (OR=3.19) significantly affected addiction in RA and SpA patients with a 95% confidence interval. Conclusion: Lack of suitable responsiveness to medication therapy to relieve pain, inconsistent pain evaluation, and shame of asking direct questions about addiction in RA and SpA patients may lead to opioid consumption in some cases. Seronegative SpA may make patients more prone to addiction. However, in this study, male gender and no family history of addiction were related to opioid abuse.

Subchronic neurotoxicity of diazinon in albino mice: Impact of oxidative stress, AChE activity, and gene expression disturbances in the cerebral cortex and hippocampus on mood, spatial learning, and memory function.

Diazinon (DZN) with prominent neurotoxic effects perturbs CNS function via multiple mechanisms. This investigation intends to explore mood, spatial learning, and memory dysfunction, acetylcholine esterase (AChE) activity, and neurodegeneration-related gene expression in the cortex and hippocampus regions of mice exposed to DZN for 63 consecutive days (subchronic exposure). Adult male albino mice were orally given sublethal DZN (DZNL = 0.1 mg/kg, DZNM = 1 mg/kg and DZNH = 10 mg/kg). All mice in the DZNH group died within 3 weeks postexposure. DZNL and DZNM caused body and brain weight loss (p < 0.05). Completing 9 weeks of DZN exposure, a marked decline in AChE activity and oxidative stress level was indicated in both brain regions (p < 0.05). Also, synaptophysin, vesicular acetylcholine transferase, and glutamate decarboxylase gene expressions were affected in both brain regions (p < 0.05). Furthermore, the present study revealed that DZN administration increased anxiety and depressive-like behaviors (p < 0.0001). Spatial learning and short- and long-memory were severely affected by DZNL and DZNM treatments (p < 0.0001). Taken together, subchronic exposure to low and medium doses of DZN can cause AChE inhibition, oxidative damage, and neurotransmitter disturbances in brain cells and induce neurodegeneration. These changes would impair mood, spatial learning, and memory function.

Assessment of the Efficacy of Withania somnifera Root Extract in Patients with Generalized Anxiety Disorder: A Randomized Double-blind Placebo- Controlled Trial.

BACKGROUND: Anxiety disorders are the most universal psychiatric problems in the general population. Due to their chronic nature, these diseases are managed with a multi-drug regimen lasting for a long period of time. Medication discontinuation leads to 25% and 80% recurrence in the first month and the first year, respectively. Despite several treatment approaches, there is no specific and optimal method for patient management. Therefore, it is necessary to find some new therapeutic approaches with fewer side effects. Withania somnifera is a plant with GABAergic property responsible for its anxiolytic effect. The aim of this study was to investigate the effect of W. somnifera root extract as an alternative therapy to reduce standard Generalized Anxiety Disorder (GAD) symptoms. METHODS: Forty patients who met the inclusion criteria (with a confirmed diagnosis of GAD as stated in the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision (DSM-IV-TR) took part in this randomized double-blind placebo-controlled trial and were randomly selected for participation in the treatment group (W. somnifera extract, 1g/day; n = 22) or the placebo group (n = 18). All patients were under treatment with Selective Serotonin Reuptake Inhibitors (SSRIs) and were prescribed one capsule of the extract or placebo per day for six weeks. The Hamilton anxiety rating scale (HAM-A) was used to assess the severity of GAD symptoms at baseline as well as the second and sixth weeks of the trial. RESULTS: Comparison of the HAM-A scores during the course of the trial revealed a significant amelioration ofHAM-A score in the treatment group versus placebo (14 and 8 units reduction, respectively (P < 0.05)). Moreover, there was a significant difference in the reduction of GAD score between the second (P =0.04) and sixth week (P =0.02) in the treatment group. The extract was safe and no adverse effect was observed during the trial. CONCLUSION: W. somnifera extract offers some potential advantages as a safe and effective adjunctive therapy to SSRIs in GAD. The clinical trial protocol has been registered under the Iranian Registry of Clinical Trials (IRCT20180615040105N1).

Estimation of Abbreviated Mycophenolic Acid Area Under the Concentration- Time Curve during Stable Post-transplant Period by Limited Sampling Strategy.

BACKGROUND: The Area Under the Concentration-time curve (AUC) of Mycophenolic Acid (MPA), is a valid prognosticator of the risk of rejection and the gold standard in its Therapeutic Drug Monitoring (TDM), over time post-transplantation. OBJECTIVE: This study aimed to investigate MPA pharmacokinetic parameters and develop a Limited Sampling Strategy (LSS) to estimate an abbreviated MPA AUC, in the stable phase post-renal transplantation. METHODS: In this study, 19 patients with normal graft function (glomerular filtration rate >70 ml/min) who fulfilled the inclusion and exclusion criteria were involved. Blood samples at various times were taken in the stable phase after transplantation. MPA plasma concentration was measured by reverse-phase high-performance liquid chromatography. MPA AUC0-12h was calculated using the linear trapezoidal rule. Multiple stepwise regression analysis was used to determine the minimal time points of MPA levels that could be used to yield model equations best fitted to MPA AUC 0-12h. The findings of this study were compared with the results of our previous study, which was done similarly in the early phase post-renal transplantation. RESULTS: The results demonstrated that the MPA-AUC and clearance were not affected over time, but MPA-tmax was significantly lower in the stable phase in comparison with the early phase (P=0.001). The best regression equation for AUC estimation in the stable phase was AUC=9.57*C6+27.238 (r2=0.907). The validation of the method was performed using the jackknife method. The mean prediction error of these models was not different from zero (P > 0.05) and had a high root mean square prediction error (7.91). CONCLUSION: In conclusion, the pharmacokinetics of MPA could be affected by time after transplantation, making it essential to develop a limited sampling strategy as an efficacious approach for therapeutic drug monitoring during the stable post-transplant period.

Curcumin effects on myeloperoxidase, interleukin-18 and matrix metalloproteinase-9 inflammatory biomarkers in patients with unstable angina: A randomized clinical trial.

OBJECTIVE: Inflammation along with oxidative stress plays an important role in the development, progression, instability and rupture of coronary atherosclerotic plaques. Several studies introduced curcumin (diferuloylmethane) as a wonderful chemical in Curcuma longa (turmeric) with appropriate anti-inflammatory and antioxidant effects. The effect of curcumin on inflammatory biomarkers was assessed in several clinical trials. This study was designed to evaluate the effect of curcumin on three pro-inflammatory biomarkers in patients with unstable angina. MATERIALS AND METHODS: Forty patients with unstable angina who met the inclusion criteria, participated in this double-blind randomized clinical trial. Patients were randomly divided into two groups. The patients in the treatment group received nanocurcumin 80 mg per day for 5 days and the control group received placebo 80 mg per day for five days. Blood samples were obtained before the administration, and also 1, 2 and 4 days after taking the treatment. Serum concentrations of Myeloperoxidase (MPO), matrix metalloproteinase-9 (MMP-9) and interleukin 18 (IL-18) biomarkers were measured by ELISA. RESULTS: There was no significant difference in concentration of these biomarkers before the administration and 1, 2 and 4 days after the start of the trial, between the two groups; however, the concentration of IL-18 on the first day significantly varied between the groups. CONCLUSION: Based on the findings of this study, administration of nanocurcumin capsules at the dose of 80 mg per day for 5 days, did not significantly decrease inflammatory biomarkers in patients with unstable angina.

Mechanisms behind the atherothrombotic effects of acrolein, a review.

Cardiovascular diseases (CVDs) are the leading cause of death worldwide. The majority of cardiovascular complications are secondary to atherosclerosis. Extensive evidence has showed that environmental pollutants such as cigarette smoke and automobile exhaust increase the risk of developing atherosclerosis. Acrolein, a highly reactive unsaturated aldehyde, is found as a contaminant in air, food and water. Investigations during the last decades have shown that acrolein via various mechanisms such as oxidative stress, enhancement of inflammatory processes and the activation of matrix metalloproteases can initiate and accelerate atherosclerotic lesions formation. Furthermore, exposure to acrolein has been suggested to induce or exacerbate systemic dyslipidemia, an important risk factor for the development of atherosclerosis. Finally, there are reports which indicate acrolein can increase platelet activation and stimulation of the coagulation cascade which subsequently leads to thrombosis. Even a modest reduction of pollutants such as acrolein can have substantial effects on population health. Public health efforts to reduce acrolein exposures from known sources may lower the prevalence of vascular disease. This review focuses on the potential pathways and mechanisms behind the acrolein-induced atherothrombotic effects.

The effects of curcumin on the prevention of atrial and ventricular arrhythmias and heart failure in patients with unstable angina: A randomized clinical trial.

OBJECTIVE: Inflammation along with oxidative stress has an important role in the pathophysiology of unstable angina which leads to acute myocardial infarction, arrhythmias and eventually heart failure. Curcumin has anti-inflammatory and anti-oxidant effects and thereby, it may reduce cardiovascular complications. This randomized controlled trial aimed to investigate the effects of curcumin on the prevention of atrial and ventricular arrhythmias and heart failure in patients with unstable angina. MATERIALS AND METHODS: Forty patients with unstable angina who met the trial inclusion and exclusion criteria, participated in this double-blind randomized clinical trial. The patients were randomized into two groups: curcumin (80 mg/day for 5days) and placebo (80 mg/day for 5days). Cardiac function was evaluated by two-dimensional echocardiography devices at baseline (immediately after hospitalization) and 5 days after the onset of the trial. Atrial and ventricular arrhythmias were recorded by Holter monitors in cardiology ward, Ghaem academic hospital, Mashhad, Iran. Progression to heart failure, myocardial infarction, and pulmonary and cardiopulmonary resuscitation events as well as mortality were recorded daily throughout the study. RESULTS: There were no significant differences between the two groups in atrial and ventricular arrhythmias (p=0.2), and other echocardiographic parameters (Ejection fraction, E, A, E/A ratio, Em, and pulmonary artery pressure) at baseline and five days after the start of the trial. CONCLUSION: Nanocurcumin administered at the dose of 80 mg/day for five days had no effect in the incidence of cardiovascular complications in patients with unstable angina.

Protective effects of glycyrrhizin on sub-chronic diazinon-induced biochemical, hematological alterations and oxidative stress indices in male Wistar rats.

The aim of this study was to elucidate the protective effect of glycyrrhizin on diazinon-induced changes in body and organ weights, blood hematology, lipid profile, biochemistry parameters and tissue markers of oxidative stress in male Wistar rats over a 7-week period. Rats were orally given sublethal dose of diazinon (10 mg/kg daily; 0.008 LD50), while glycyrrhizin (25 mg kg-1 daily) was given alone or in combination with diazinon. At the end of 7th week, statistically significant decrease of pseudocholinesterase activity was detected when diazinon- and glycyrrhizin + diazinon-treated groups were compared to the control group. Diazinon treated rats showed weight loss and organ weight changes which were comparable to other groups. There was a statistically significance in hematological indices except mean corpuscular hemoglobin (MCH) when diazinon treated group was compared to glycyrrhizin + diazinon treated rats. Glycyrrhizin protected the liver and kidney from diazinon toxic effects with significantly decrease in serum aspartate aminotransferase, alanine aminotransferase, alkaline phosphatase and lactate dehydrogenase activities as well as ameliorated hepatic and renal function indices (such as bilirubin, total protein, albumin, BUN, creatinine glucose). In addition, glycyrrhizin minimized the hazardous effect of diazinon on plasma lipids and lipoproteins. The protective effects of glycyrrhizin were confirmed by tissue markers of oxidative stress analysis as glycyrrhizin in combination diminished malondialdehyde and glycyrrhizin alone or in combination enhanced thiol group and the ferric reducing power. In accordance to these results, our observations demonstrated the beneficial effects of glycyrrhizin in reducing the toxicity of diazinon.

Application of G-CSF in Congestive Heart Failure Treatment.

INTRODUCTION: Congestive Heart Failure (CHF) is a disorder in which the heart is unable to supply enough blood for body tissues. Since heart is an adaptable organ, it overcomes this condition by going under remodeling process. Considering cardiac myocytes are capable of proliferation after MI, stimulation of neovascularization as well as their regeneration might serve as a novel target in cardiac remodeling prevention and CHF treatment. Granulocyte Colony-Stimulating Factor (G-CSF), is a hematopoietic cytokine that promotes proliferation and differentiation of neutrophils and is involved in cardiac repair after MI. So far, this is the first review to focus on GCSF as a novel treatment for heart failure. METHODS: We conducted a search of some databases such as PubMed for articles and reviews published between 2003 and 2017, with different keywords including "G-CSF", "congestive heart failure", "new therapies for CHF", "filgrastim", "in vivo study". RESULTS: GCSF exerts its beneficial effects on cardiac repair through either stem cell mobilization or direct angiogenesis promotion. All of which are capable of promoting cardiac cell repair. CONCLUSION: GCSF is a promising target in CHF-therapy by means of cardiac repair and remodeling prevention through multiple mechanisms, which are effective enough to be used in clinical practice.

Antidotes for aluminum phosphide poisoning - An update.

Aluminum phosphide (AlP), an inexpensive solid fumigant, is frequently used for grain conservation despite its alleged high toxicity. Increased utilization of AlP for agricultural and non-agricultural purposes during the last four decades has resulted in increment of AlP-attributed poisoning numbers. Moreover, due to its limitless accessibility in developing countries, AlP has been increasingly used for suicide. Moisture-exposed AlP undergoes a chemical reaction producing phosphine gas, which in turn inhibits cytochrome oxidase and impedes cellular oxygen consumption. Lethality remains elevated reaching rates of >50% and no effective antidote is available. Nevertheless, experimental and clinical studies suggested that magnesium sulfate, melatonin, N-acetylcysteine, glutathione, sodium selenite, vitamin C and E, triiodothyronine, liothyronine, vasopressin, milrinone, Laurus nobilis L., 6-aminonicotinamide, boric acid, acetyl-L-carnitine and coconut oil, may serve as antidotes by reducing the deleterious oxidative properties of AlP. This article reviews the afore-mentioned chemicals suggested to specifically treat AlP poisoning and discusses their protective mechanisms and main outcomes.

Captopril Attenuates Diazinon-Induced Oxidative Stress: A Subchronic Study in Rats.

BACKGROUND: Diazinon (DZN) is an organophosphate pesticide commonly used for pest control in agriculture. It may engender a variety of negative effects in non-target species, including humans and animals. The objective of the present study was to evaluate the ameliorative properties of captopril (CAP), as a thiol containing an angiotensin-converting enzyme inhibitor, against DZN-induced oxidative stress. METHODS: Twenty-eight male Wistar rats were divided randomly into 4 groups. All the rats were treated orally via gavage once a day for 7 weeks: control (corn oil), CAP (10 mg/kg), DZN (10 mg/kg), and CAP+DZN combination (as mentioned above). Oxidative stress indices in blood serum, liver and kidney homogenates (malondialdehyde [MDA], total thiol groups, and total antioxidant capacity), and erythrocyte hemolysis (superoxide dismutase [SOD] and glutathione peroxidase) were evaluated. Statistical analysis was performed using GraphPad Prism software, version 6.0 (GraphPad, San Diego, CA, USA), by ANOVA, followed by the Tukey post hoc analysis. RESULTS: The MDA content and SOD activity increased significantly in the DZN group compared with those in the control group. Treatment with CAP in the DZN-exposed group significantly decreased (P<0.05) the MDA concentration and the SOD activity. The total thiol groups were decreased in the DZN group and elevated again by CAP treatment. CONCLUSION: The co-administration of CAP and DZN was able to attenuate lipid peroxidation and enzyme changes caused by DZN.

Clinical Pharmacokinetics and Pharmacodynamics of Antihyperglycemic Medications in Children and Adolescents with Type 2 Diabetes Mellitus.

The incidence of type 2 diabetes mellitus (T2DM) among children and adolescents has been rising. This condition is associated with obesity, and it's prevalence is higher among minority or female youth. Lifestyle modification including diet and exercise is only successful in a small proportion of patients; therefore, pharmacotherapy approaches are needed to treat T2DM among youth. Currently, in the USA, only metformin and insulin are approved for the treatment of T2DM in children. However, several antihyperglycemic agents including exenatide, glimepiride, glyburide, liraglutide, pioglitazone, and rosiglitazone are also used off-label in this population. Moreover, a number of clinical trials are ongoing that are aimed at addressing the safety and efficacy of newer antihyperglycemic agents in this population. Little is known about the safety, efficacy, or pharmacokinetics of antihyperglycemic agents in children or adolescents. Our ability to predict the pharmacokinetics of these agents in youth is hampered first by the lack of information about the expression and activity of drug-metabolizing enzymes and transporters in this population and second by the presence of comorbid conditions such as obesity and fatty liver disease. This article reviews the prevalence of obesity and T2DM in children and adolescents (youth). We then summarize published studies on safety and effectiveness of antihyperglycemic medications in youth. Drug disposition may be affected by age or puberty and thus the expression and activity of different pathways for drug metabolism and xenobiotic transporters are compared between youth and adults followed by a summary of pharmacokinetics studies of antihyperglycemic agents currently used in this population.