Amitava Chakrabarti

A Comparative Evaluation of Amitriptyline and Duloxetine in Painful Diabetic Neuropathy: A randomized, double-blind, cross-over clinical trial

OBJECTIVE To compare the efficacy and safety of duloxetine and amitriptyline in painful diabetic neuropathy (PDN). RESEARCH DESIGN AND METHODS In this randomized, double-blind, cross-over, active-control trial, 58 patients received amitriptyline and duloxetine orally once daily at bedtime, each for 6 weeks with optional dose uptitration fortnightly. Single-blinded placebo washout was given for 2 weeks between the two treatments and a single-blinded placebo run-out phase of 4 weeks was given at the end of the treatment period. Pain relief was measured by the patient’s global assessment of efficacy, using a visual analog scale (0–100) as a primary end point, and overall improvement and adverse events were assessed as secondary outcome measures. Median pain score reductions of >50%, 25–50%, and <25% were considered good, moderate, and mild responses, respectively. RESULTS There was a significant improvement in pain with both treatments compared with their baseline values (P < 0.001 for both). Good, moderate, and mild pain relief was achieved in 55, 24, and 15% of patients, respectively, on amitriptyline and 59, 21, and 9% of patients, respectively, on duloxetine. There were no significant differences in various other outcome measures between the groups. Of the reported adverse events, dry mouth was significantly more common with amitriptyline than duloxetine (55 vs. 24%; P < 0.01). Although, numerically, more patients preferred duloxetine, overall this was not statistically significant (48 vs. 36%; P = 0.18). CONCLUSIONS Both duloxetine and amitriptyline demonstrated similar efficacy in PDN. A large, multicentric clinical trial in other populations could possibly demonstrate the superiority of either drug.

Pantoprazole Improves Glycemic Control in Type 2 Diabetes: A Randomized, Double-Blind, Placebo-Controlled Trial

OBJECTIVE Proton pump inhibitors, by elevating plasma gastrin, can influence glucose-insulin homeostasis. Because there are no controlled clinical trials, the present study was planned to evaluate the effect of pantoprazole, a proton pump inhibitor, on glucose-insulin homeostasis in patients with type 2 diabetes (T2DM). RESEARCH DESIGN AND METHODS IN this 12-wk, randomized, double-blind, placebo-controlled study, patients with T2DM were allocated to either the pantoprazole or placebo treatment in an equal ratio. Alterations in glycosylated hemoglobin (HbA1c), fasting plasma glucose, insulin, and gastrin were measured at baseline and at 12 wk. RESULTS Thirty-one eligible patients were randomized to receive either the pantoprazole (n = 16) or placebo (n = 15). Twelve weeks of pantoprazole therapy significantly increased plasma gastrin and insulin levels and improved β-cell function (P < 0.05 for all parameters), along with a significant decrease in HbA1c (7.6 ± 1.17 to 6.8 ± 1.16; P < 0.001). The decrease in HbA1c correlated with an increase in gastrin and insulin (r = 0.54, P =0.010; and r = 0.67, P =0.01, respectively). CONCLUSIONS Pantoprazole therapy increases plasma gastrin and insulin levels, thereby improving the glycemic control in T2DM. The effect of pantoprazole on glucose-insulin homeostasis requires further study.

Neuroprotective effect of progesterone on acute phase changes induced by partial global cerebral ischaemia in mice

The possible neuroprotective effect of progesterone, a steroid hormone, on acute phase changes in a mouse model of cerebral ischaemia induced by bilateral common carotid artery occlusion (BCAO) was studied. A total of 72 male mice were included in the study. The BCAO model was used to induce partial global cerebral ischaemia. Morphological assessment included measurement of infarct size and brain oedema. Post‐ischaemic seizure susceptibility was assessed using a subconvulsive dose of pentylenetetrazole (30 mgkg−1 i.p.). Biochemical estimations included tumour necrosis factor α (TNF‐α) levels and enzyme parameters such as lipid peroxidation, superoxide dismutase, catalase and glutathione peroxidase, and protein estimation. BCAO induced a significant infarct size and oedema in the saline‐treated control group, along with an increase in oxidative stress, indicated by increased lipid peroxidation and decreased levels of antioxidants such as superoxide dismutase, catalase and glutathione peroxidase. Progesterone (15 mgkg−1 i.p.) administration showed a neuroprotective effect by significantly reducing the cerebral infarct size as compared with the control group. Post‐ischaemic seizure susceptibility was also reduced as the number of positive responders decreased. Brain oedema subsided, but not significantly. Progesterone significantly reduced TNF‐α levels compared with the ischaemia group. Progesterone improved levels of all the anti‐oxidants, indicating activity against oxidative stress induced by BCAO. The results demonstrate the neuroprotective effect of progesterone against ischaemic insult, suggesting a role for the steroid as a neuroprotective agent.

Allopregnanolone, the active metabolite of progesterone protects against neuronal damage in picrotoxin-induced seizure model in mice

Progesterone exerts anti-seizure effect against several chemoconvulsants. However, there is no published report on the interaction between progesterone and picrotoxin (PTX). The present study evaluated the effects of progesterone and its active metabolite, allopregnanolone against PTX-induced seizures, brain lipid peroxidation and DNA fragmentation in male mice. Finasteride, a 5alpha-reductase inhibitor and indomethacin, an inhibitor of 3infinity-hydroxysteroid dehydrogenase were assessed against progesterones effects on PTX-induced seizures, brain lipid peroxidation and DNA fragmentation. PTX produced clonic-tonic seizures in mice with CD50 and CD97 of 2.4 and 4.0mg/kg, i.p. respectively. Progesterone significantly countered PTX-induced seizures, with ED50 of 78.30mg/kg and ED97 of 200mg/kg. Progesterone antagonized PTX-induced DNA fragmentation. Finasteride (200mg/kg) and indomethacin (1mg/kg) reversed the anti-seizure and anti-DNA fragmentation effects of progesterone. Allopregnanolone, also protected against PTX-induced seizures and DNA fragmentation. There was no significant change in the brain lipid peroxidation parameters in any of the treatment groups. It may be concluded that progesterone protects against PTX-induced seizures and DNA fragmentation through its active metabolites allopregnanolone and 5alpha-pregnan-3,20-dione. However, it appears from the present study that, the neuroprotection with progesterone is primarily on account of allopregnalone. The therapeutic potential of allopregnanolone deserves to be evaluated clinically.

Dose-finding study with nimodipine: a selective central nervous system calcium channel blocker on aminophylline induced seizure models in rats.

Nimodipine, a dihydropyridine derivative central nervous system (CNS) selective calcium channel blocker was studied at four different dosage schedules in five different models of seizures in rats. At a dose of 5 mg/kg, i.p. with pretreatment time of 15 min, nimodipine significantly antagonized aminophylline (175 and 200 mg/kg, i.p.), electroshock (150 mA for 0.2 s), pentylenetetrazole (60 and 75 mg/kg, i.p.), aminophylline (100 mg/kg i.p.) + electroshock (66mA for 0.2 s), and aminophylline (100 mg/kg, i.p.) + pentylenetetrazole (40 mg/kg, i.p.) induced seizures in rats. No hemodynamic alteration was observed with this dose of nimodipine. However, 2 mg/kg, i.p. (pretreatment time of 15 min and 30 min) and 5 mg/kg, i.p. (pretreatment time of 30 min) doses of nimodipine failed to demonstrate any significant anticonvulsant effect. The study highlighted the critical role of calcium ion flux into the neurons for the genesis of seizure activity to aminophylline, electroshock, and pentylenetetrazole in rats. Furthermore, the critical dose requirement for nimodipine could be explained on the basis of its short half-life and shorter duration of protection against seizures. Therefore, nimodipine may be tried clinically as an anticonvulsant in patients who are on aminophylline because of bronchial asthma or chronic obstructive pulmonary disease, when such patients have concomitant epilepsy or other seizure prone neurological deficits or are scheduled to undergo electroshock therapy.

Off-Label, Low-Dose Naltrexone for Refractory Painful Diabetic Neuropathy.

Dear Editor, Naltrexone is a long-acting, potent, competitive opioid antagonist approved for the treatment of alcohol and opioid dependence at a dose of 50 mg/day [1]. Recently, naltrexone in 1–5 mg OD, typically referred to as low-dose naltrexone (LDN) [2], has been reported to treat chronic pain and autoimmune disorders. Pilot trials of LDN in Crohn’s disease, multiple sclerosis, cancer-related pain, and fibromyalgia have recently been conducted with success [3]. Here, we report a case in which off-label LDN was used for the treatment of painful diabetic neuropathic pain refractory to most available therapy. In April 2012, a 76-year-old male with a 30-year history of type-2 diabetes and 7 years of diabetic neuropathic symptoms presented in the endocrinology clinic with complaints of burning pain in both legs below the mid-calf level. He described that the pain began insidiously, occurring off and on and associated with certain degree of numbness. Subsequently, both the frequency of …

Nicotine Reversal of Anticonvulsant Action of Topiramate in Kainic Acid–Induced Seizure Model in Mice

INTRODUCTION Tobacco smoking is a widespread phenomenon, and nicotine is the addictive component of tobacco. Nicotine acts through nicotinic cholinergic receptors and has been associated with different types of psychophysical disorders in human beings. The present study had explored the proconvulsive action of nicotine and its effect on the antiseizure efficacy of topiramate against kainic acid (KA)-induced seizures in mice. METHODS The study had evaluated the dose-response curves for nicotine and KA and for KA in nicotine-pretreated mice and for topiramate against KA-induced seizures. Mecamylamine was used to antagonize the nicotinic receptor-mediated actions of nicotine. CD50 (convulsive dose in 50% of animals) for KA and nicotine and ED50 (effective dose in 50% of animals as anticonvulsant) for topiramate were determined. Brain lipid peroxidation studies were also undertaken in the treated mice. RESULTS Nicotine significantly potentiated the convulsive action of KA acid and reduced the CD50 (95% confidence limits [CL]) value for KA from 2.6 mg/kg (2.3-3.1) to 1.4 mg/kg (0.9-2.1), intraperitoneally (i.p.). Topiramate pretreatment significantly inhibited KA-induced seizures and brain lipid peroxidation with ED50 (95% CL) value of 21.90 mg/kg (17.3-28.2), i.p. Nicotine pretreatment caused dose-dependent antagonism to the antiseizure and antilipid peroxidative actions of topiramate. Mecamylamine had antagonized the proconvulsant action of nicotine. CONCLUSION The study highlights the fact that intake of nicotine, through agonism to nAChR, might predispose epileptic patients to lower seizure threshold and induce a state of refractoriness to the protective effects of the antiepileptic drugs, resulting in possible breakthrough seizure attacks.

Evaluation of Lercanidipine in Paclitaxel-Induced Neuropathic Pain Model in Rat: A Preliminary Study

Objective. To demonstrate the antinociceptive effect of lercanidipine in paclitaxel-induced neuropathy model in rat. Materials and Methods. A total of 30 rats were divided into five groups of six rats in each group as follows: Gr I: 0.9% NaCl, Gr II: paclitaxel + 0.9% NaCl, Gr III: paclitaxel + lercanidipine 0.5 μg/kg, Gr IV: paclitaxel + lercanidipine 1 μg/kg, and Gr V: paclitaxel + lercanidipine 2.5 μg/kg. Paclitaxel-induced neuropathic pain in rat was produced by single intraperitoneal (i.p.) injection of 1 mg/kg of paclitaxel on four alternate days (0, 2, 4, and 6). The tail flick and cold allodynia methods were used for assessing the pain threshold, and the assessments were done on days 0 (before first dose of paclitaxel) and on days 7, 14, 21, and 28. Results. There was a significant decrease (P < 0.001) in the tail flick and cold allodynia latency in the paclitaxel-alone group from day 14 onward when compared with day 0. In the lercanidipine groups, the decrease in the tail flick and cold allodynia latency was not observed in 1.0 and 2.5 μg/kg groups and it was statistically significant (P < 0.01) when compared with paclitaxel-alone group.

Antioxidant effect of isoflavones: A randomized, double-blind, placebo controlled study in oophorectomized women

Background: One of the postulated mechanism for cardioprotective potential of isoflavones is their ability to exert antioxidant action. However, various reports give conflicting results in this area. Aim: The present study was conducted with an objective to probe into the cardioprotective mechanism of isoflavones by evaluating their antioxidant potential in oophorectomized women. Materials and Methods: This was a randomized, double-blind, parallel, placebo controlled study. A total of 43 women were randomized to receive 75 mg/day isoflavones tablet or placebo for 12 weeks. Red blood cell antioxidant parameters including lipid peroxidation, superoxide dismutase (SOD), catalase and glutathione peroxidase (GSH-Px) were determined at baseline and at the end of the study. Results: After 12 weeks of administration of isoflavones, there was no statistically significant difference in lipid peroxidation (P value for isoflavones: 0.37; for placebo: 0.37), catalase (P value for isoflavones: 0.35; for placebo: 0.84), SOD (P value for isoflavones: 0.41; for placebo: 0.28) and GSH-Px (P value for isoflavones: 0.92; for placebo: 0.29). There was no statistically significant difference in the proportion of patients experiencing adverse events in the two groups (P -1.00). Conclusion: The study strengthens the concept that the cardioprotective mechanism of isoflavones might be due to some other reason apart from the antioxidant pathway.

Intestinal inflammation and seizure susceptibility: understanding the role of tumour necrosis factor-α in a rat model

Objectives The aim of the study was to evaluate the correlation between colitis and susceptibility to seizures.