Nusrat Shafiq

Pilot trial: Pioglitazone versus placebo in patients with plaque psoriasis (the P6).

Background  Disordered differentiation and hyperproliferation of keratinocytes with inflammation are the hallmarks of psoriasis. Ligand activation of peroxisome proliferator receptor‐γ (a class of nuclear receptors) by thiazolidinediones can normalize the histologic features of psoriasis.

Clinical Profile of Idiopathic Chronic Pancreatitis in North India

BACKGROUND & AIMS Tropical pancreatitis, a form of idiopathic chronic pancreatitis (ICP) with unique features, has been described in South and North India. We investigated the clinical profile of ICP patients in North India. METHODS Detailed demographic data were recorded; hematological and biochemical analyses were performed on samples from 155 patients (mostly from North India) who had been diagnosed with chronic pancreatitis. Ultrasonography and computed tomography were performed on all patients. Magnetic resonance cholangiopancreatography, endoscopic retrograde cholangiopancreatography, glucose tolerance tests, and fecal fat studies were performed on some patients. Patients were divided into groups based on early- or late-onset ICP (before or after 35 years of age). RESULTS ICP was reported in 41.3% of patients and alcoholic chronic pancreatitis in 38.1%. The mean age of ICP patients was 33.0 +/- 13.0 years and the mean duration of symptoms at the time of presentation was 40.2 +/- 34.4 months. Pain was the dominant symptom in patients with early- (95.1%) and late-onset (100%) ICP; pseudocyst was the most common local complication. Diabetes was observed in 17.1% of patients with early-onset ICP and 34.8% with late-onset ICP. Pancreatic calcification was noted in 46.3% of patients with early-onset and 47.8% with late-onset ICP. Pseudocyst and segmental portal hypertension occurred more frequently in non-calcific ICP, whereas diabetes mellitus and abnormal fecal fat excretion occurred more frequently in patients with calcific ICP. CONCLUSIONS In North India, ICP differs from the classical tropical pancreatitis described in the literature. It is associated with a higher prevalence of pain and lower frequencies of diabetes, calcification, and intraductal calculi.

PHARMACOKINETICS AND TISSUE DISTRIBUTION STUDIES OF ORALLY ADMINISTERED NANOPARTICLES ENCAPSULATED ETHIONAMIDE USED AS POTENTIAL DRUG DELIVERY SYSTEM IN MANAGEMENT OF MULTI-DRUG RESISTANT TUBERCULOSIS

Sustained release nanoformulations of second line anti-tubercular drugs can help in reducing their dosing frequency and improve patient’s compliance in multi-drug resistant tuberculosis (MDR TB). The objective of the current study was to investigate the pharmacokinetics and tissues distribution of ethionamide encapsulated in poly (DL-lactide-co-glycolide) (PLGA) nanoparticles. The drug loaded nanoparticles were 286 ± 26 nm in size with narrow size distribution, and zeta-potential was −13 ± 2.5 mV. The drug encapsulation efficiency and loading capacity were 35.2 ± 3.1%w/w and 38.6 ± 2.3%w/w, respectively. Ethionamide-loaded nanoparticles were administered orally to mice at two different doses and the control group received free (unencapsulated) ethionamide. Ethionamide-loaded PLGA nanoparticles produced sustained release of ethionamide for 6 days in plasma against 6 h for free ethionamide. The Ethionamide was detected in organs (lung, liver, and spleen) for up to 5–7 days in the case of encapsulated ethionamide, whereas free ethionamide was cleared within 12 h. Ethionamide-loaded PLGA nanoparticles exhibited significant improvement in pharmacokinetic parameters, i.e. Cmax, tmax, AUC0–∞, AUMC0–∞, and MRT of encapsulated ethionamide as compared with free ethionamide. Drug in nanoparticles also exhibited a dose proportional increase in the AUC0–∞ values. The pharmacodynamic parameters such as AUC0–24/MIC, Cmax/MIC, and Time > MIC were also improved. PLGA nanoparticles of ethionamide have great potential in reducing dosing frequency of ethionamide in treatment of MDR TB.

Effect of HDL-Raising Drugs on Cardiovascular Outcomes: A Systematic Review and Meta-Regression

Background Substantial residual cardiovascular risk remains after optimal LDL lowering in patients of established coronary artery disease. A number of therapeutic agents that raise HDL-C have been tested in clinical trials to cover this risk. However, the results of clinical trials are conflicting. Objectives To determine whether raising HDL-C with pharmacologic therapies translates into beneficial cardiovascular outcomes and to find out if this change was proportional to the percentage change in HDL levels. Methods Electronic and printed sources were searched up to August, 2013 for randomised controlled trials (RCTs) using at least one of the HDL raising therapies for secondary prevention of adverse cardiovascular events over optimal LDL levels. Data from eligible studies were pooled for the following outcomes: all cause mortality, cardiovascular disease mortality, hospitalization for unstable angina, non-fatal myocardial infarction, coronary revascularization and ischemic stroke. Mantel Haensnzel fixed effect model was used preferentially. Meta-regression was done to see the correlation of change in HDL levels and cardiovascular outcomes. Pooled odds ratios with 95% confidence interval (CI) were calculated. Results A total of 12 RCTs including 26,858 patients with follow up period ranging from 1 year to 6.2 years were included in the analysis. Pooled analysis showed no significant difference in all-cause mortality between the treatment and control group (Pooled OR 1.07; 95% CI 0.98–1.16, p = 0.15). No significant difference was found between the groups for any of the secondary outcomes. Similarly no correlation was seen between percentage change in HDL and adverse cardiovascular outcomes on meta-regression analysis. Conclusion Increasing HDL levels via pharmacological manipulation beyond optimal lipid lowering therapy for secondary prevention is not beneficial.

Triple antiplatelet therapy vs. dual antiplatelet therapy in patients undergoing percutaneous coronary intervention: an evidence-based approach to answering a clinical query.

AIMS Outcomes of patients undergoing percutaneous coronary intervention (PCI) with drug-eluting stents (DES) and bare metal stents (BMS) have not been evaluated separately for specific dual and triple antiplatelet agent use. The purpose of this meta-analysis was to determine whether triple antiplatelet therapy (combination of clopidogrel, aspirin and cilostazol) has any advantage in efficacy compared with standard dual antiplatelet therapy (aspirin and clopidogrel) in patients undergoing PCI. METHODS Electronic and printed sources were searched till May 2008 for randomized controlled clinical trials (RCTs) of cilostazol in combination with aspirin and clopidogrel. Pooled weighted mean difference (WMD) and pooled odds ratio (OR) with 95% confidence intervals (CIs) were calculated. RESULTS A total of four RCTs including 1457 patients with a median follow-up period of 6-9 months were included in the analysis. The rates of major adverse cardiac and/or cerebrovascular events (MACE/MACCE), stent thrombosis and bleeding were not significantly different between triple and dual antiplatelet therapy groups. Pooled analysis showed that cilostazol was associated with significantly decreased incidence of in segment restenosis (ISR) (OR 0.51, 95% CI 0.38, 0.68; P < 0.00001), increased minimum luminal diameter (MLD) (WMD 0.16, 95% CI 0.10, 0.22; P < 0.00001) for both DES and BMS and also individually. However, the rates of target vessel revascularization (OR 0.45, 95% CI 0.25, 0.83; P = 0.01 and late lumen loss (pooled WMD 0.14, 95% CI 0.2, 0.07; P = 0.001) were decreased significantly only in the DES group receiving triple therapy. CONCLUSIONS Cilostazol appears to be effective in reducing the rates of ISR without any significant benefit for MACE/MACCE.

Optimization, in vitro–in vivo Evaluation, and Short-term Tolerability of Novel Levofloxacin-loaded PLGA Nanoparticle Formulation

A novel poly(lactic-co-glycolic acid) (PLGA)-based nanoformulation of levofloxacin was developed for multidrug-resistant tuberculosis with the purpose of achieving sustained release in plasma. After lyophilization of levofloxacin-loaded nanoparticles, the average size, charge, and polydispersity index were 268 ± 18 nm, -10.2 ± 1.5 mV, and 0.15 ± 0.03, respectively. The maximum drug encapsulation efficiency and loading capacity were 36.9 ± 6.1% (w/w) and 7.2 ± 1.2 mg/100 mg nanopowder, respectively. Biphasic extended-release profile was produced in vitro. Scanning electron microscopy and Fourier transform infrared studies showed spherical shape of drug-loaded nanoparticles and no drug-polymer interactions were observed. After single oral administration in mice, levofloxacin-loaded PLGA nanoparticles produced sustained release of levofloxacin for 4 days in plasma against 24 h for free levofloxacin. Levofloxacin was detected in organs (lung, liver, and spleen) for up to 4-6 days in case of levofloxacin-loaded nanoparticles, whereas free levofloxacin was cleared within 24 h. This novel formulation did not show any significant adverse effects on body weight and clinical signs in mice. No treatment-related changes were found in hematological and biochemical parameters and on histopathological evaluation. These results indicate the feasibility of development of an orally efficacious safe formulation of levofloxacin with sustained-release properties.

Evaluation of the ability of clinical research participants to comprehend informed consent form

BACKGROUND The comprehension of informed consent is an integral part of clinical trials. Though India is rapidly becoming a hub of clinical trials very few studies have dealt with the issue of comprehension of informed consent by the patients participating in these trials. METHODS Patients who were invited to participate in a phase 3 multicentric trial of a novel lipid lowering agent were evaluated for comprehension score. The participants were explained about the structured consent form which included the question on background details for the study, design of the study, rights of the patients and miscellaneous aspects pertinent to the clinical trial. The questionnaire comprised of 24 items and each correct answer was assigned a score of 1. Total comprehension score (CS) was obtained by summing all the scores. RESULTS Participants were from diverse socio economic and educational backgrounds. The mean +/- SD CS achieved by the participants was 13.4 +/- 2.9; median 14(6 to 20). The highest correct responses were obtained for questions on background details (38%). For most of the categories the mean CS was more than 50%. Aspects related to design were mostly difficult to comprehend. No significant difference in the CS was noted between participants from different educational and socioeconomic groups. 8 patients refused to give consent, fear of adverse drug reactions (n = 3) and inability to follow up (n = 5) were the reasons cited by the patients. CONCLUSION In conclusion, CS of patients in trials conducted in developing countries can be reasonably good if the investigators explain the consent form in simple language to the participants and CS is not related to the educational status of the participants. Moreover, though a larger majority of patients agree to participate after knowing study details, some patients exercise their right to refuse.

Thiazolidinediones for plaque psoriasis: a systematic review and meta-analysis

Background There is some evidence for the role of inflammation and insulin resistance in the pathophysiology of plaque psoriasis. Thiazolidinediones are antidiabetic drugs that act by improving insulin sensitivity and also possess anti-inflammatory effects. Evidence from in vitro, animal and human studies has accumulated suggesting that these drugs may be of use in psoriasis. Objective This systematic review and meta-analysis was performed to assess the efficacy of thiazolidinediones on psoriasis severity. Study selection Randomised, open-label or single blind or double blind, published as well as unpublished, studies of thiazolidinedione administration compared with placebo, given to patients with plaque psoriasis for at least 8 weeks were considered for inclusion in this review. The primary outcomes were as follows: mean or mean percent change in Psoriasis Area and Severity Index (PASI) from baseline to end of treatment with pioglitazone, proportion of patients showing >75% improvement in PASI score, and proportion of patients showing >50% improvement in PASI score. Data analysis was done using Revman 5. Findings Twenty-seven relevant citations were identified. Two studies each for pioglitazone and rosiglitazone were included in the meta-analysis. There was a significantly greater mean decrease in PASI scores from baseline to end of treatment (−4.24 (95% CI −5.35 to −3.12)) in the pioglitazone group as compared to placebo. There was a non-significant improvement in PASI50/70 in the pooled analysis of rosiglitazone trials. Conclusion Pioglitazone appears to have efficacy for the treatment of psoriasis. The clinical significance of the effect and role in management of psoriasis deserve further study.

Effects of three different doses of a fruit extract of Terminalia chebula on metabolic components of metabolic syndrome, in a rat model

There is documented evidence of the use of Terminalia chebula for various ailments in the Ayurvedic literature. The extract has been shown to possess glucose lowering activity and to improve insulin sensitivity in animal models of type 2 diabetes mellitus. The present study was carried out to study the dose response relationship of this extract in a rat model of metabolic syndrome. Six groups of rats were fed a high fructose diet (HFD) for a period of 20 days to induce metabolic syndrome. Three doses of fruit extract of T. chebula 50, 100 and 200 mg/kg were administered orally and pioglitazone 2.7 mg/kg was used as a positive control. Blood samples were collected at days 0, 20 and 40 from the tail vein. Systolic blood pressure (SBP) was measured using the tail cuff method and an oral glucose tolerance test (OGTT) was done on the day of blood collection. Administration of HFD for 20 days significantly increased fasting blood glucose (FBG), SBP and the area under the curve of OGTT. On day 40 the FBG in the 50, 100 and 200 mg/kg group was 97.33 ± 5.82 (NS), 86.83 ± 5.08 (p = 0.038) and 85.67 ± 6.74 (p = 0.15), respectively. These results show that the fruit extract of T. chebula exerts a significant and dose‐dependent glucose lowering effect in the rat model of metabolic syndrome. Copyright

Probiotics in Treatment of Allergic Rhinitis

Many randomized controlled trials (RCTs) have been done on role of probiotics as a treatment modality in allergic rhinitis. We conducted a review on the same. A systematic search of published literature was done. RCTs comparing effect of probiotics with placebo were included. A predefined set of outcome measures were assessed. Continuous data were expressed as pooled standardized mean difference (SMD) with 95% confidence interval (CI). Dichotomous data were expressed as odds ratio with 95% CI. P value < 0.05 was considered significant. RevMan version 5 was used for all the analyses. Seven RCTs were eligible for inclusion. Probiotic intake improved quality of life score in patients with allergic rhinitis [SMD -1.17 (95% CI -1.47, -0.86; P < 0.00001)]. Other parameter that improved with probiotic intake was decrease in the number of episodes of rhinitis per year. There was no significant change in blood or immunologic parameters in the probiotic group, SMD -0.10 (95% CI -0.26, 0.06; P = 0.22). Adverse events were not significant. Probiotic therapy might be useful in rhinitis, but the present data do not allow any treatment recommendations.