Debasish Hota

Evaluation of antihyperalgesic effect of curcumin on formalin-induced orofacial pain in rat.

The present study was planned to evaluate the role of curcumin in the formalin‐induced orofacial pain in rats that mimics typical human orofacial pain. Adult Wistar rats of either sex received an injection of 50 µL of 5% v/v subcutaneous formalin injection into one vibrissal pad and consequent facial grooming behavior was monitored. Animals exhibited two distinct periods of nocifensive grooming: (a) an acute phase lasting 0–6 min; and (b) a tonic phase lasting 6–45 min. The analgesic response of curcumin was observed at doses of 25, 50, 100, 200, 400 and 600 mg/kg i.p., administered 15 min prior to formalin injection. Another group received subanalgesic dose of diclofenac (0.2 mg/kg) and curcumin 25 mg/kg. Curcumin and diclofenac were administered 15 and 5 min prior to formalin injection respectively. Curcumin produced a dose‐dependent inhibition of facial grooming in both acute and tonic phases compared to vehicle and potentiated the subanalgesic dose of diclofenac. The study results for the first time demonstrated the per se antinocifensive effect of curcumin and also exhibited a synergistic interaction with the subanalgesic dose of an NSAID in the facial pain model. More studies are necessary to elucidate the mechanisms of curcumin in this model of pain. Copyright

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.

Pharmacokinetic interaction of single dose of piperine with steady-state carbamazepine in epilepsy patients.

Piperine, the active principle of piper species, is commonly used as a spice and adjuvant in various traditional systems of medicine. It has been known as a bioavailability‐enhancer. The present study aimed at evaluating the effect of piperine on the steady‐state pharmacokinetics of a single dose of carbamazepine in poorly controlled epilepsy patients on carbamazepine monotherapy. Patients (n = 10 each) receiving either 300 mg or 500 mg dose of carbamazepine twice daily were selected. After administration of carbamazepine, venous blood samples were collected at 0, 0.5, 1, 2, 4, 6, 9, 12 h. Subsequently, piperine (20 mg p.o.) was administered along with carbamazepine and samples were collected similarly. The pharmacokinetic parameters were compared by Students t‐test. Piperine significantly increased the mean plasma concentrations of carbamazepine at most of the time points in both dose groups. There was a significant increase in AUC0‐12hr (p < 0.001), average Css (p < 0.001), t1\2el (p < 0.05) and a decrease in Kel (p < 0.05), in both the dose groups, whereas changes in Ka and t1\2a were not significant. Cmax (p < 0.01) and tmax (p < 0.01) were increased significantly following piperine administration in the 500 mg dose group; however, these parameters were not significant in the lower dose group. Piperine could significantly enhance the oral bioavailability of carbamazepine, possibly by decreasing the elimination and/or by increasing its absorption. Copyright

Preoperative statin therapy is associated with lower requirement of renal replacement therapy in patients undergoing cardiac surgery: a meta-analysis of observational studies

OBJECTIVES Acute kidney injury (AKI) following cardiac surgery is a common complication associated with serious morbidity and mortality. Activation of inflammatory cascade and vascular endothelial dysfunction plays a vital role during the perioperative period leading to AKI. Statins are known to suppress inflammation and improve endothelial dysfunction over and above the cholesterol lowering efficacy. METHODS Observational studies with a defined population in terms of preoperative statin therapy and no preoperative statin therapy undergoing cardiac surgery (CABG, isolated valve surgery or both) and with reported data on the incidence of acute renal failure/injury and/or mortality were identified and analysed for inclusion in the analysis. Outcomes evaluated were occurrence of postoperative acute kidney injury/failure, requirement of any postoperative renal replacement therapy and short-term all-cause mortality rate. A meta-analysis was conducted and a pooled estimate of odds ratio (OR) was calculated using the inverse variance method. RESULTS A total of 17 studies with a total population of 24 998 statin users and 22 082 non-statin users were included in the final analysis. PST resulted in a significantly lower incidence of renal replacement therapy in patients undergoing CABG (OR: 0.56 [0.41-0.76]) but not in isolated valve surgery (OR: 1.80 [0.73-4.44]). Also preoperative statin therapy resulted in a significantly lower postoperative mortality (0.72 [0.61-0.84]) irrespective of the type of surgery. There was no effect of preoperative statin therapy on the incidence of AKI in any of the sub-group of the patients. CONCLUSIONS Patients undergoing CABG might derive benefit from preoperative statin therapy in terms of reducing the need for postoperative renal replacement therapy and mortality. However, the uncertainty concerning the reno-protective efficacy of preoperative statin therapy in patients undergoing isolated valve surgery needs further investigation.

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.

Evaluation of analgesic efficacy, gastrotoxicity and nephrotoxicity of fixed-dose combinations of nonselective, preferential and selective cyclooxgenase inhibitors with paracetamol in rats

Nonsteroidal anti-inflammatory drugs (NSAIDs) are combined with paracetamol (PCM) with a view to enhance analgesic efficacy and reduce gastric toxicity. However, there are reports of enhanced nephrotoxicity with nonselective NSAID with PCM combinations. The present study investigated the analgesic efficacy, gastrotoxicity and nephrotoxicity of nonselective, preferential and selective cyclooxygenase inhibitors and their combination with PCM in rats. Graded doses of ibuprofen, meloxicam and celecoxib alone and their combination with fixed dose of PCM were administered to the rats by gavage for 14 days. The results showed that PCM potentiated the analgesic effect of all three classes of NSAIDs significantly as evidenced by increase in tail-flick latency in radiant heat method. Dose-dependent gastromucosal damage was produced by all the drugs, which was augmented significantly with PCM in the form of decreased total carbohydrate/protein ratio of mucin and increased gastric ulcer index. It was further confirmed by histopathology of rats stomach. The renal histopathology was conducted to evaluate inflammation, tubular damage, papillary necrosis, and interstitial changes. Increased nephrotoxicity was observed with all NSAIDs in dose-dependent manner and in combination with PCM. Our study revealed the augmented analgesia as well as enhanced gastrotoxicity and nephrotoxicity with all three major NSAIDs classes when combined with PCM. These findings highlighted the need for large pharmacoepidemiological studies to evaluate the magnitude of gastrotoxicity and nephrotoxicity in population who are on long-term treatment with NSAID combinations.

Patterns of prescription drug use and incidence of drug–drug interactions in patients reporting to medical emergency

Pharmaco‐epidemiological studies detailing prescribing patterns of physicians are very few from developing countries. The present study describes the patterns of prescription of drugs by physicians working in different clinical settings in India and explores using the prescriptions the incidence of potential drug–drug interactions (DDI). This study was a cross‐sectional observational study. The prescriptions of patients for any chronic medical condition and drug therapy received at the first point of contact with health care services for present medical emergency were analyzed for information. The prescriptions were also analyzed for potential DDI. Data were expressed as mean ± SD or median and inter‐quartile range. Multiple logistic regression was used for variables likely to be associated with incidence of DDI. Of total 710 patients, 565 prescriptions were available for analysis. Of the chronic diseases, hypertension (17.7%) and diabetes mellitus (16.8%) were the commonest. Alcoholic liver disease had maximum average number of drugs prescribed (3.9). Supplements were the most commonly prescribed pharmacological agents for chronic disease (142/796). Patients in 35–50 years of age consumed maximum average number of drugs (1.9). Antibiotics were the most frequently prescribed agents (148/1240) followed by supplements (122/1240). We noted 296 mild and moderate potential DDI. Literacy of patients and polypharmacy were the factors associated significantly with DDI. Patients in India do not consume large number of allopathic medicines. The practice of prescribing supplements and antibiotics needs to be reviewed. Potential DDI are not an important problem. Prescription policies need significant revision.

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.

Research methodological issues in evaluating herbal interventions

Randomized controlled trials provide the best evidence, and is seen as the gold standard for allopathic research. Herbal therapies are not an integral part of conventional care although they are still used by patients in their health care management. These medicines need to be subjected to rigorous research to establish their effectiveness and safety. Clearly defined treatments are required and should be recorded in a manner that enables other suit - ably trained researchers to reproduce them reliably. Quality control of herbal products is also a prerequisite of credible clinical trials. Methodological strategies for investigating the herbal interventions and the issues regarding appropriate patient selection, randomization and blind- ing, placebo effects and choice of comparator, occupational standardization and the selection of appropriate study endpoints to prove efficacy are being discussed. This paper will review