Aniket Kumar

Time for clinical trials of epigenetic drugs in psychiatric disorders

We read with great interest the Editorial by van Gerven and Cohen [1], in which they discussed the issue of the dearth of new drugs in clinical psychopharmacology despite the fact that the currently used drugs are often not effective and based on mechanisms that were largely already known in the 1970s. These mechanisms almost exclusively involve the primary neurotransmitters and their receptors. As stated by the authors, however, psychiatric disorders are complex, and cannot be explained adequately only in terms of changes in neurotransmission. In this context, we wish to discuss the relevance of epigenetic therapy in clinical psychopharmacology. Epigenetic therapy, a new development in pharmacology, refers to the correction of epigenetic defects [2, 3]. Such defects involve changes in gene expression without changes in DNA sequence [2, 3]. They include abnormalities in patterns of DNA methylation, histone modifications and abnormalities in RNA-mediated regulation of gene expression [4]. Although there are several classes of epigenetic drugs under investigation, at present most attention is being paid to two drug classes: DNA methyltransferase (DNMT) inhibitors and histone deacetylase (HDAC) inhibitors [2, 3]. There is increasing evidence that epigenetic defects play a major role in the pathogenesis of psychiatric disorders, with some epigenetically modified genes having been implicated in the pathogenesis of these disorders [4, 5]. Interestingly, some of the genes found to be epigenetically modified in patients with psychiatric disorders code for enzymes [6] and receptors [7] involved in the activity of the primary neurotransmitters. There is evidence suggesting that epigenetic drugs may be useful in treating psychiatric disorders. Thus, several psychotropic drugs currently in clinical use have been shown to exhibit epigenetic effects in addition to their commonly understood mechanisms of action [3]; however, epigenetic effects are not the main actions of these drugs. An example of such a drug is the mood stabilizer valproate, which in addition to its well-known actions on nerve conduction, also inhibits HDAC [2, 3]. Epigenetic drugs have also been found to be effective in preclinical trials in the treatment of psychiatric disorders. For example, Tremolizzo et al. [8] showed in a methionine-induced epigenetic mouse model of schizophrenia that valproate enhanced acetylated histone 3 content, prevented methionine-induced hypermethylation of the promoter of the RELN gene, the gene that encodes the protein reelin, and corrected behavioural abnormalities in the mice. Kundakovic et al. [9] found, using cultured NT-2 neuronal precursor cells, that the DNMT inhibitors doxorubicin, azacytidine and zebularine inhibited DNMT1, leading to the activation of the expression of the RELN and glutamic acid decarboxylase 1 (GAD1) genes, both of which have been found to be epigenetically modified in postmortem brains of patients with schizophrenia and bipolar disorder [4]. To our knowledge, except for valproate, no epigenetic drug has undergone clinical trials in patients with psychiatric disorders. As the use of epigenetic drugs in patients with psychiatric disorders appears to be promising, we suggest that it is time for clinical trials of epigenetic drugs in these disorders. Epigenetic therapy may fulfil the need for newer and more effective drugs in clinical psychopharmacology.

Tramadol inhibits the contractility of isolated caprine detrusor muscle.

The atypical opioid analgesic tramadol has been shown to provide beneficial clinical and urodynamic effects in patients with detrusor overactivity. The effect of tramadol on isolated detrusor muscle has not been studied. This study investigated the ability of tramadol to inhibit acetylcholine (ACh)-induced contractility of the isolated caprine (goat) detrusor muscle. The effect of three concentrations (30, 100 and 300 μm) of tramadol on 10 caprine detrusor strips contracted by the addition of 100, 200 or 400 μm ACh was studied. The sensitivity of tramadol-induced inhibition of ACh responses to treatment with the β-adrenoceptor antagonist propranolol (1 μm) and the opioid receptor antagonist naloxone (100 μm) was also studied. Tramadol caused a concentration-dependent inhibition of ACh-induced detrusor contraction that was reversed by raising the concentration of ACh. Propranolol, but not naloxone, reversed the tramadol-induced inhibition of contractions to ACh in the detrusor. These results suggest that tramadol inhibits ACh-induced contractility of the isolated detrusor. They also suggest that tramadol does so by an indirect anticholinergic mechanism involving the stimulation of β-adrenoceptors. Tramadol may be useful in managing clinical conditions requiring relaxation of the detrusor muscle. Although the concentrations of tramadol needed to relax the detrusor were relatively high, these could be clinically attained via intravesical administration.

A retrospective study on non-drug related poisoning in the community among children from south India

ABSTRACT Objectives: This retrospective study was performed to determine the incidence, demographic distribution, types and outcomes across various non-drug related poisonings among children attending a tertiary care center in south India. Methods: All children from 0-16 years who presented to the Paediatric Emergency Department, Christian Medical College, Vellore with non-drug related poisoning from October 2004 to September 2013 were included. Results: Out of the total 997 cases of poisoning, 629 (63.1%) cases were contributed by chemicals and plants: mainly hydrocarbons (kerosene) 309 (49.1%); organophosphates 72 (11.5%); corrosive acids and alkalis 57 (9.1%); insecticides 51 (8.1%); and plant poisons 20 (3.2%). Males (62.79%) and children < 5 years (77.42%) were mostly affected. Although many children developed complications requiring intensive care unit admissions, the total mortality was only 9 (1.4%). The incidence of poisoning showed a decreasing trend over the last 4 years. Conclusion: This study for the first time gives an elaborative insight on non-drug related pediatric poisoning from a tertiary care center in south India for almost a decade.

Retraction: Association Between 5-HTR2C -759C/T (rs3813929) and -697G/C (rs518147) Gene Polymorphisms and Risperidone-Induced Insulin Resistance Syndrome in an Indian Population

The above article from the Journal of Clinical Pharmacology, first published online on 22 September 2017 in Wiley Online Library (wileyonlinelibrary.com), has been retracted by agreement among the authors, the journal Editor in Chief, Joseph Bertino, and Wiley Periodicals, Inc. The retraction has been agreed upon due to the article having been submitted by the lead author without agreement from all co‐authors. Having been alerted to this irregularity, the journal was also advised by the Senior Author of inaccuracies in the genotyping data.

Drug prescribing pattern in pregnancy in a secondary care hospital in south India: a retrospective study.

Background In pregnancy drug treatment presents a special concern due potential teratogenic effects and physiologic alterations in mother. This retrospective study was performed to evaluate the drug prescribing pattern in pregnancy among pregnant women in a secondary care hospital in India. Materials and methods This cross-sectional retrospective study was done for 3 months using pre-formatted forms and patient’s records. Results A total of 326 drugs, including 46 different types of drugs, were prescribed to 606 gravid women. Eight different types of medications were started before being seen at the antenatal clinic. Most of these drugs fall under US FDA pregnancy categories B and C and few under categories A, X and N. Conclusion This study reflects a good, safe and rational medication practice during pregnancy in various common disorders in a secondary care hospital and can be cited as an example to similar primary and secondary care hospitals.

Prevalence of Hepatotoxicity From Antituberculosis Therapy: A Five-Year Experience From South India.

Background: Antituberculosis (ATT) drug-induced liver injury (DILI) is a common and serious adverse effect of tuberculosis (TB) treatment. This retrospective study was carried out to study the prevalence of DILI among patients who had received anti-TB medications and to study some of the known risk factors responsible for causing DILI. Materials and Methods: This longitudinal descriptive study was performed to evaluate cases of DILI with predefined criteria. Patients of all ages, diagnosed and treated for smear positive pulmonary TB from January 1, 2008 to December 31, 2012 and those who came for regular follow-up were included in the study. Multiple logistic regression analysis was performed to determine the association of different risk factors and DILI. The confounders considered were age, sex, weight, body mass index, doses of drugs (fixed or per kg), ATT regimens (daily or intermittent), and treatment categories. Results: Of the 253 patients analyzed, 24 (9.48%) developed DILI. Associations of different risk factors were insignificant; including chronic alcohol consumption, hepatitis B infection, hepatitis C infection, HIV infection, and existing chronic TB. Conclusion: DILI was not significantly associated with known risk factors in our settings.

Inhibitory effect of curcumin on the contractility of isolated caprine detrusor muscle.

Curcumin is a naturally occurring compound which has been used in traditional medicine in India for a long time. This study investigated the ability of curcumin to inhibit the contractility of isolated caprine (goat) detrusor muscle. The ability of three concentrations of curcumin (30, 100 and 300 µM) to inhibit the 100 µM acetylcholine-induced contractility of the isolated caprine urinary bladder detrusor muscle was investigated. The effect of raising the concentration of acetylcholine from 100, 200 and 400 µM to overcome the curcumin-induced inhibition of detrusor contractility and the effects of the reversal agents tetraethylammonium, a potassium channel blocker (100 µM), glibenclamide, an ATP-sensitive potassium channel blocker (10 µM), and propranolol, a beta adrenergic receptor blocker (1 µM), on the inhibitory effect of detrusor contractility was also studied. Curcumin caused a concentration-dependent inhibition of acetylcholine-induced contractility of the isolated detrusor muscle which was statistically significant at all three concentrations of curcumin used. This inhibition was partially overcome by raising the concentration of ACh to 200 and 400 µM. The inhibition was overcome by the concurrent administration of tetraethylammonium. Glibenclamide reversed the inhibitory effect of 100 µM curcumin, but not that of 300 µM curcumin. Propranolol reversed the inhibitory effect of 100 µM curcumin but not that of 300 µM curcumin. These results suggest that curcumin inhibited the contractions of the isolated detrusor muscle. The results further suggest that the inhibitory effect is mediated by various mechanisms: stimulation of beta adrenergic receptors; an anticholinergic effect; and the opening of ATP-sensitive potassium channels.

Epigenetic Drugs for Mood Disorders

There is increasing evidence that changes in epigenetic mechanisms of gene expression are involved in the pathogenesis of mood disorders. Such evidence stems from studies conducted on postmortem brain tissues and peripheral cells or tissues of patients with mood disorders. This article describes and discusses the epigenetic changes in the mood disorders (major depressive disorder and bipolar disorder) found to date. The article also describes and discusses preclinical drug trials of epigenetic drugs for treating mood disorders. In addition, nonrandomized and randomized controlled trials of nutritional drugs with effects on epigenetic mechanisms of gene expression in patients with major depressive disorder and bipolar disorder are discussed. Trials of epigenetic drugs and nutritional drugs with epigenetic effects are showing promising results for the treatment of mood disorders. Thus, epigenetic drugs and nutritional drugs with epigenetic effects could be useful in the treatment of patients with these disorders.

Estimation of actual strengths of different brands of commonly available paracetamol tablets in India and comparing them with the corresponding label information

There are reported cases in India where some brands of paracetamol do not contain the quantity of paracetamol listed on the label, leading to dosage errors. Thus there is a need for greater stringency in the manufacturing process, ensuring that the correct amount of the drug is included in each dose form. We performed a study evaluating the actual strengths of different brands of commonly available paracetamol tablets (using spectrophotometry), comparing the actual content of the active ingredient with the corresponding label information of these medications and calculating the degree of variation. Eight different brands (designated as brands A–H) of paracetamol tablets were assessed, with different batches of each brand obtained from local chemist shops. A previously established and validated method of paracetamol assay using spectrophotometry was used for the analysis. Different concentrations of standard solutions of pure paracetamol (Sigma Aldrich, St Louis, MO, USA) were prepared in distilled water, ranging from 10 to 450 lg/mL. Standards were diluted 1:5 with distilled water and 0.5 mL of dilutions were reacted with 0.5 mL of hydrochloric acid for 10 min in a boiling water bath. Then samples were allowed to cool and 2.5 mL phenol reagent (30 mL liquid phenol/L) and 2.5 mL of ammonia reagent (175 mL 33% ammonia/L) were added respectively and reaction mixtures were mixed well. Similar procedures were repeated for each of the test samples (commercial preparations). Finally, the blue colour developed was quantified in terms of concentrations in a spectrophotometer (LabIndia Analytical Instruments Pvt. Ltd., Gurgaon, India) at 620 nm at 10–30 min after addition of the last reagent. Results were analysed using a Kruskal-Wallis test using the ‘R’ program (3.1.0) for statistical analysis and a value p < 0.05 was considered significant. Not all brands conformed to the acceptable 10% variation in content uniformity stipulated in the British and United States Pharmacopeia standards. However, the inter-brand and inter-batch variation in measured strengths was not statistically significant. The coefficients of variation (inter-batch within brands) of brands A, B, C, D, E, F, G and H were 0.02809, 0.07321, 0.07891, 0.07230, 0.12304, 0.04281, 0.04612 and 0.02680, respectively. The inter-brand comparison of actual strength is provided in Figure 1. A previous study conducted in India found that the physical parameters like hardness, friability, disintegration time and sedimentation properties of various products also showed wide variations from the standard values. It was concluded that there was evidence that the relevant manufacturing standards are not strictly

Prostacyclin and Interaction with Diacylglycerol Lipase and CDP Diacylglycerol; Possibility of De Novo Synthesisof Prostacyclin or Related Congeners by Novel Mechanisms

Prostacyclin is a strong cardioprotective hormone released by the endothelium of the blood vessels. Prostacyclin is present in equilibrium with several vasoactive agents in cardiovascular system. In recent years, prostacyclin (PGI2) has also been shown to enhance differentiation and inhibit proliferation in vascular smooth muscle cells. In addition to these well-described homeostatic roles within the cardiovascular system, prostacyclin (PGI2) also plays an important role as an inflammatory mediator. In this review, the focus on the contribution of prostacyclin (PGI2) as both a patho-physiological mediator in three major inflammatorymediated disease processes, namely rheumatoid arthritis, where it promotes disease progression , along with pulmonary vascular disease and atherosclerosis, where it inhibits disease progression. On the other hand, CDP-DAG synthases (CDS) are enzymes that catalyze the conversion of phosphatidic acid (PA) to CDPdiacylglycerol (CDP-DAG). Both PA and CDP-DAG serve critical roles in cellular functions.This article reviews the possibility of interaction with CDP diacylglycerol and it appears that de novo synthesis of PGI2 or its congeners occurs in specialized cells under patho-physiological conditions.