Effect of citalopram and sertraline on the expression of miRNA- 124, 132, and 16 and their protein targets in patients with depression

Objective(s): This study aimed to evaluate the effect of SSRIs on the expression of miRNAs and their protein targets.Materials and Methods: In a 100 day open-label study of citalopram (n=25) and sertraline (n=25), levels of miRNA 16, 132, and 124 and glucocorticoid receptor (GR), Brain-derived neurotrophic factor (BDNF), and serotonin transporter (SERT) protein expression were measured by QRT-PCR and western blot in healthy control (n=20), patients with depression at the baseline, and same patients after 100 days of treatment.Results: Expression levels of GR and BDNF proteins were lower in the depressed group before treatment as compared with the healthy group (P<0.0001). The SERT level was higher among the depressed group before treatment in comparison with the healthy group (P<0.0001). The level of GR and BDNF significantly increased, and SERT expression decreased after receiving sertraline (P<0.05). When the depressed group received citalopram, only SERT and GR were altered (P<0.05). Among the microRNAs’ expression investigated, mir-124 and mir-132 were higher, and mir-16 was lower among the depressed compared with the healthy group (P<0.0001). Individuals receiving citalopram only showed an increase in the expression of mir-16 while administration of sertraline led to a significant increase in the expression of mir-16 and a decrease in mir-124 and mir-132 (P<0.05).Conclusion: This elucidated the relationship between antidepressant treatment and the expression of different microRNA that control gene expression in various pathways involved in depressed patients.  Receiving SSRI can affect the level of these proteins and their relevant microRNAs

Future of cholesteryl ester transfer protein (CETP) inhibitors: A pharmacological perspective

In almost 30 years since the introduction of HMG-CoA reductase inhibitors (statins), no other class of lipid modulators has entered the market. Elevation of high-density lipoprotein-cholesterol (HDL-C) via inhibiting cholesteryl ester transfer protein (CETP) is an attractive strategy for reducing the risk of cardiovascular events in high-risk patients. Transfer of triglyceride and cholesteryl ester (CE) between lipoproteins is mediated by CETP; thus inhibition of this pathway can increase the concentration of HDL-C. Torcetrapib was the first CETP inhibitor evaluated in phase III clinical trials. Because of off-target effects, torcetrapib raised blood pressure and increased the concentration of serum aldosterone, leading to higher cardiovascular events and mortality. Torcetrapib showed positive effects on cardiovascular risk especially in patients with a greater increase in HDL-C and apolipoprotein A-1 (apoA-1) levels. The phase III clinical trial of dalcetrapib, the second CETP inhibitor that has entered clinical development, was terminated because of ineffectiveness. Dalcetrapib is a CETP modulator that elevated HDL-C levels but did not reduce the concentration of low-density lipoprotein cholesterol (LDL-C). Both heterotypic and homotypic CE transfer between lipoproteins are mediated by some CETP inhibitors, including torcetrapib, anacetrapib, and evacetrapib, while dalcetrapib only affects the heterotypic CE transfer. Dalcetrapib has a chemical structure that is distinct from other CETP inhibitors, with a smaller molecular weight and a lack of trifluoride moieties. Moreover, dalcetrapib is a pro-drug that must be hydrolyzed to a pharmacologically active thiol form. Two other CETP inhibitors, anacetrapib and evacetrapib, are currently undergoing evaluation in phase III clinical trials. Both molecules have shown beneficial effects by increasing HDL-C and decreasing LDL-C concentration. The success of anacetrapib and evacetrapib remains to be confirmed upon the completion of phase III clinical trials in 2017 and 2015, respectively. Generally, the concentration of HDL-C has been considered a biomarker for the activity of CETP inhibitors. However, it is not clear whether a fundamental relationship exists between HDL-C levels and the risk of coronary artery diseases. The most crucial role for HDL is cholesterol efflux capacity in which HDL can reverse transport cholesterol from foam cells in atherosclerotic plaques. In view of the heterogeneity in HDL particle size, charge, and composition, the mere concentration of HDL-C may not be a good surrogate marker for HDL functionality. Recent clinical studies have reported that increased HDL functionality inversely correlates with the development of atherosclerotic plaque. Future development of CETP inhibitors may therefore benefit from the use of biomarkers of HDL functionality. © 2013 Springer International Publishing Switzerland. Reference:

Evaluation of the Correlation between the rs4918 Polymorphism of AHSG Gene and Coronary Artery Calcification in Patients with Coronary Artery Disease

Objectives: Fetuin-A is a circulating calcification inhibitor that prevents coronary artery calcification (CAC) by increasing calcium phosphate solubility and inhibiting VSMC differentiation and apoptosis. In this study, we investigated the correlation between rs4918 and CAC in patients with coronary artery disease (CAD). Methods: Forty-two healthy individuals and eighty-one CAD patients were recruited in the present study. The CAC score (CACS) was measured by CT angiography and the genotype analysis of rs4918 single-nucleotide polymorphism SNP was performed by the polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) technique. Results: The CACS was significantly higher in CAD patients compared to healthy individuals (p &lt; 0.001); however, there was no significant difference between the mean CACS in the presence and absence of rs4918 (p = 0.792). The mean calcium score of the left main coronary artery (LMCA) was significantly lower in carriers of the rs4918 allele (p = 0.036). The frequency of rs4918 SNP was almost similar in the control group and CAD patients (p = 0.846). Conclusions: in patients with CAD, we found no significant association between rs4918 SNP and CACS, indicating that carriers of this allele are not at increased risk of developing cardiovascular diseases compared with those without

Estimating the Optimal Dosage of Sodium Valproate in Idiopathic Generalized Epilepsy with Adaptive Neuro-Fuzzy Inference System

Epilepsy is a clinical syndrome in which seizures have a tendency to recur. Sodium valproate is the most effective drug in the treatment of all types of generalized seizures. Finding the optimal dosage (The lowest effective dose) of sodium valproate is a real challenge to all neurologists. In this study, a new approach based on Adaptive Neuro-Fuzzy Inference System (ANFIS) was presented for estimating the optimal dosage of sodium valproate in IGE patients.   40 patients with Idiopathic Generalized Epilepsy, who were referred to the neurology department of Mashhad University of Medical Sciences between the years 2006-2011,were included in this study. The function Adaptive Neuro-Fuzzy Inference System (ANFIS) constructs a Fuzzy Inference System (FIS) whose membership function parameters are tuned (adjusted) using either a back-propagation algorithm alone, or in combination with a least squares type of method (hybrid algorithm). In this study, we usedhybrid method for adjusting the parameters.The R-square of the proposed system was %598 and thePearson correlation coefficient was significant (P 0.05) . Although the accuracy of the model was not high, it wasgood enough to be applied for treating the IGE patients with sodium valproate. This paper presented a new application of ANFIS for estimating the optimal dosage of s odium valproate in IGE patients. Fuzzy set theory plays an important role in dealing with uncertainty when making decisions in medical applications. Collectively, it seems that ANFIS has a high capacity to be applied in medical sciences, especially neurology

The Role of Antioxidants in the Management of Obsessive-Compulsive Disorder

Obsessive-compulsive disorder (OCD) is a chronic neuropsychiatric disorder that has a significant effect on the quality of life. The most effective treatment for OCD is the combination of selective serotonin reuptake inhibitors (SSRI) with cognitive behavior therapy (CBT). However, several adverse effects have been linked with this usual pharmacotherapy, and it is unsuccessful in many patients. The exact pathophysiology of OCD is not completely known, though the role of oxidative stress in its pathogenesis has been proposed recently. This review presents an overview of animal and human studies of antioxidant treatment for OCD. The use of antioxidants against oxidative stress is a novel treatment for several neurodegenerative and neuropsychiatric disorders. Among antioxidants, NAC was one of the most studied drugs on OCD, and it showed a significant improvement in OCD symptoms. Thus, antioxidants could be promising as an adjuvant treatment for OCD. However, a limited number of human studies are conducted on these agents, and for better judgment, human studies with a large sample size are necessary

Statin Therapy in Post-Operative Atrial Fibrillation: Focus on the Anti-Inflammatory Effects

Background: Atrial fibrillation (AF) occurring after cardiac surgery, post-operative AF (POAF), is a serious and common complication of this treatment. POAF may be life-threatening and the available preventive strategies are insufficient or are associated with significantly increased risk of adverse effects, especially in long-term use. Therefore, more appropriate treatment strategies are needed. Methods: In this paper, the efficacy, safety, and other aspects of using statins in the prevention of POAF focusing on their anti-inflammatory effects are reviewed. Results: Recent studies have suggested that inflammation has a significant role in POAF, from the first AF episode to its serious complications including stroke and peripheral embolism. On the other hand, statins, the most widely used medications in cardiovascular patients, have pleiotropic effects, including anti-inflammatory properties. Therefore, they may potentially be effective in POAF prevention. Statins, especially atorvastatin, appear to be an effective option for primary prevention of POAF, especially in patients who had coronary artery bypass grafting (CABG), a cardiac surgery treatment associated with inflammation in the heart muscle. However, several large studies, particularly with rosuvastatin, did not confirm the beneficial effect of statins on POAF. One large clinical trial reported higher risk of acute kidney injury (AKI) following high-dose rosuvastatin in Chinese population. In this study, rosuvastatin reduced the level of C-reactive protein (CRP) but did not reduce the rate of POAF. Conclusion: Further studies are required to find the most effective statin regimen for POAF prevention with the least safety concern and the highest health benefits

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\u27s 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

Evaluating the Effects and Safety of Intravenous Lipid Emulsion on Haloperidol-Induced Neurotoxicity in Rabbit

There are many reports on the effect of intravenous lipid emulsion (ILE) as an antidote in drugs related toxicities. We determined the effects of ILE on neurotoxicity of haloperidol (HA), a highly lipophilic antipsychotic, as a model of antipsychotics poisoning. We used six groups of five male rabbits. Two groups received distilled water intravenously followed by infusions of either 18 mL/kg of normal saline or ILE 20%, after 30 minutes. The third group received 18 mL/kg of normal saline after HA (2.6 mg/kg) administration. The three other groups received ILE 20% solution (6, 12, and 18 mL/kg) following HA injection. Catalepsy scores, temperature, pupil size, and mortality rate were measured at 0, 0.5, 1, 2, 3, 4, 8, and 24 hours after HA administration began. Blood and tissue samples were taken from all animals at 24 hours or at death time for biochemical, cell count, and pathological studies. ILE reversed cataleptic scores, miotic pupils, and hypothermia of HA intoxication much faster than normal saline ( &lt; 0.001). Biochemical complications and mortality rate of the animals were significantly higher in the HA + 18 mL/Kg ILE group. ILE reversed sings of HA neurotoxicity; however, synergistic effect of high dose of ILE and HA increased complications and mortality

Prospective Drug Use Evaluation of Meropenem in a Teaching Referral Hospital, Mashhad, Iran

Introduction: Inappropriate use of antibiotic, leads to microbial resistance, nosocomial infections and increased hospital costs. Therefore, it is necessary to control and evaluate the use of these medications, especially broad-spectrum antibiotics. This study evaluated the pattern of meropenem utilization in Imam Reza hospital, Mashhad, Iran. Methods: First, a guideline for proper indications of meropenem was designed and finalized based on the clinical pharmacists and infectious disease specialist’s comments. One hundred patients were chosen randomly from different wards of the hospital and their data were recorded in predesigned questionnaires. Then, the pattern of meropenem consumption was analyzed according to the guideline. Results: This study was performed in 100 patients, including 48 women and 52 men. In 13 cases (13%), patients had no approved indication for meropenem. The initial regimens were changed in 6 cases (6%) based on culture results and in 73 cases (73%) relied on clinical response. In 64 cases (64%), administrated doses were compatible with prepared guideline. Renal dose adjustment was acceptable based on guideline only in 30% of patients with renal impairment (30 patients out of 100). Hyper-sensitivity reaction, one of the adverse reactions of meropenem, was seen in 1 patient (1%). Conclusion: According to the results, considerable errors occurred in meropenem administration and dosing. Therefore, it is necessary to design and implement a localized guideline for meropenem consumption in Imam Reza hospital of Mashhad, Iran