Randomized, Double-blind, Phase III Trial of Lobeglitazone Add-on to Metformin in Type 2 Diabetes (SENSITIZE INDIA).

BACKGROUND: The efficacy and safety of lobeglitazone sulfate has been reported only in the Korean population, and no study has been conducted in India. MATERIALS AND METHODS: In this 16-week randomized, double-blind, and multicenter study, the efficacy and safety of lobeglitazone sulfate 0.5 mg were evaluated with pioglitazone 15 mg. Type 2 diabetes mellitus (T2DM) patients with ≥7.5% glycated hemoglobin (HbA1c) ≤10.5% and on stable metformin dose were assigned to both treatment arms. The primary outcome was a mean change in HbA1c. Safety assessments included adverse events (AE), home-based glucose monitoring, vital parameters, electrocardiogram (ECG), and laboratory assessments. RESULTS: A total of 328 subjects were randomized equally in two groups. A statistically significant reduction in HbA1c at week 16 in the lobeglitazone group with the least square (LS) mean change: 1.01 [standard error (SE): 0.09] (p < 0.0001) was seen. The LS mean difference between the two groups was 0.05 (SE: 0.12) [95% confidence interval (CI): -0.18, 0.27], which was statistically significant (p = 0.0013). Statistically significant reductions were also observed in fasting and postprandial glucose. Treatment-emergent Aes (TEAE) were comparable between both groups. CONCLUSION: Lobeglitazone 0.5 mg once daily was found to be efficacious and safe in the treatment of T2DM in the Indian population. Lobeglitazone significantly improved glycemic parameters and was noninferior to pioglitazone; hence, it could be a promising insulin sensitizer in T2DM management in India.

Correction to "SARS-CoV-2 accelerated clearance using a novel nitric oxide nasal spray (NONS) treatment: A randomized trial".

[This corrects the article DOI: 10.1016/j.lansea.2022.100036.].

SARS-CoV-2 accelerated clearance using a novel nitric oxide nasal spray (NONS) treatment: A randomized trial.

Background: Additional outpatient therapies which are readily accessible will be essential to reduce COVID-19 illness progression in high risk individuals. Especially as the virus continues to mutate with greater transmissibility despite increased global vaccination. Methods: A randomized, double-blind, multicentre, parallel group, placebo-controlled phase III clinical trial evaluated the ability of nitric oxide (NO) to rapidly eradicate nasal SARS-CoV-2 RNA. Adults (18-70 years) with mild symptomatic COVID-19 were randomized, confirmed by laboratory SARS-CoV-2 reverse transcription polymerase chain reaction (RT-PCR) nasal swab. Randomisation was 1:1, NONS (N = 153) vs placebo (N = 153). NO generated by a nasal spray (NONS) was self-administered six times daily as two sprays per nostril (0⋅45 mL of solution/dose) for seven days. Patients at high risk of illness progression, defined as unvaccinated, ≥ 45 years of age or having comorbidities, were the primary analysis population. Findings: Overall, mean SARS-CoV-2 RNA concentrations (6·96 log10 copies/mL in the NONS group and 7·16 log10 copies/mL in the placebo group) were comparable at baseline. Primary endpoint mean treatment difference SARS-CoV-2 RNA change from baseline to the end of treatment (EOT) was -0·52 copies/mL (SE 0·202, 95% CI -0·92 to -0·12; p = 0·010) with NONS compared to placebo. Secondary endpoint assessments demonstrated a greater proportion of patients receiving NONS (82·8%) cleared SARS-CoV-2 (RT-PCR negative) by EOT compared to placebo (66·7%, p = 0·046), with no virus RNA detected a median of four days earlier compared to placebo (three vs seven days; p = 0·044). Interpretation: Use of NONS in patients recently infected with SARS-CoV-2 accelerates nasal virus clearance. Funding: Funding provided by Glenmark Pharmaceuticals Limited. Study medication provided by SaNOtize.

Randomized, double-blind, placebo-controlled trial of ISC 17536, an oral inhibitor of transient receptor potential ankyrin 1, in patients with painful diabetic peripheral neuropathy: impact of preserved small nerve fiber function.

ABSTRACT: Patients with chronic pain syndromes, such as those with painful peripheral neuropathy due to diabetes mellitus, have limited treatment options and suffer ongoing attrition of their quality of life. Safer and more effective treatment options are needed. One therapeutic approach encompasses phenotypic characterization of the neuropathic pain subtype, combined with the selection of agents that act on relevant mechanisms. ISC 17536 is a novel, orally available inhibitor of the widely expressed pain receptor, transient receptor potential ankyrin 1, which mediates nociceptive signaling in peripheral small nerve fibers. In this randomized, placebo-controlled, proof-of-concept trial, we assessed the safety and efficacy of 28-day administration of ISC 17536 in 138 patients with chronic, painful diabetic peripheral neuropathy and used quantitative sensory testing to characterize the baseline phenotype of patients. The primary end point was the change from baseline to end of treatment in the mean 24-hour average pain intensity score based on an 11-point pain intensity numeric rating scale. The study did not meet the primary end point in the overall patient population. However, statistically significant and clinically meaningful improvement in pain were seen with ISC 17536 in an exploratory hypothesis-generating subpopulation of patients with preserved small nerve fiber function defined by quantitative sensory testing. These results may provide a mechanistic basis for targeted therapy in specific pain phenotypes in line with current approaches of "precision medicine" or personalized pain therapeutics. The hypothesis is planned to be tested in a larger phase 2 study.

Comparative efficacy and safety of glycopyrronium/formoterol fixed-dose combination versus glycopyrronium monotherapy in patients with moderate-to-severe COPD.

Background: The safety and efficacy of fixed-dose combination (FDC) of glycopyrronium bromide 12.5 µg/formoterol fumarate 12 µg (GB/FF) twice daily as dry powder inhalers (DPIs) compared to glycopyrronium 50 µg monotherapy (GLY) once daily as DPI in subjects with moderate-to-severe chronic obstructive pulmonary disease (COPD) were evaluated. Methods: This was a phase-3, randomized, double-blind, active-controlled, parallel-group, superiority study conducted in India. COPD patients aged ≥40 to ≤65 years, current or ex-smokers with FEV1/FVC <0.70, using ICS, LAMA, or LABA for ≥1 month were included. Subjects were randomized (1:1) to GB/FF or GLY for 12 weeks. The primary efficacy endpoint was the change from baseline in peak FEV1 at the end of 12 weeks. The study is registered with the Clinical Trials Registry of India (CTRI/2017/02/007814). Results: Between March 2017 and July 2018, 331 patients were enrolled and randomized into GB/FF FDC (165 patients) and GLY monotherapy (166 patients) groups. At week 12, the difference in change from baseline in the peak FEV1 for GB/FF DPI versus GLY was 0.115 L (SE = 0.02; 95% CI = 0.061, 0.170; P < 0.0001). Trough FEV1 increased significantly in the GB/FF group compared to the GLY group with a treatment difference of 0.078 L (SE = 0.02; 95% CI = 0.015, 0.14; P = 0.01). There were no significant differences in adverse events between the groups. Conclusion: FDC of GB/FF (12.5/12 µg twice daily) as a DPI provides superior bronchodilation and lung function improvement over GLY (50 µg once daily) monotherapy. It is safe and well tolerated in symptomatic COPD patients.

Efficacy and safety of single-inhaler triple therapy of glycopyrronium, formoterol and fluticasone in patients with COPD: a double-blind, randomised controlled trial.

BACKGROUND: The aim of this work was to investigate the safety and efficacy of single-inhaler triple therapy with 12.5 µg glycopyrronium (GB)/12 µg formoterol fumarate (FF)/250 µg fluticasone propionate (FP), compared to 50 µg GB co-administered with a fixed dose of 12 µg FF/250 µg FP in subjects with COPD. METHODS: This was a phase 3, randomised, double-blind, active-control, parallel-group, noninferiority study conducted at 20 sites across India. COPD patients aged ≥40 to ≤75 years, with forced expiratory volume in 1 s (FEV1)/forced vital capacity (FVC) <0.70, using mono/dual therapy with inhaled corticosteroids (ICSs), long-acting muscarinic antagonists (LAMAs), or long-acting ß-agonists (LABAs) for ≥1 month, were included. Subjects were randomised 1:1 to GB/FF/FP or GB+FF/FP for 12 weeks. The primary efficacy end-point was the change from baseline in trough FEV1 at the end of 12 weeks. The study is registered with the Clinical Trials Registry of India (identifier number: CTRI/2019/01/017156). RESULTS: Between 23 March 2019 and 14 February 2020, 396 subjects were enrolled, with 198 patients each in the fixed-triple (GB/FF/FP) and open-triple (GB+FF/FP) groups. The difference in least-square mean (LSM) changes in pre-dose FEV1 from baseline at 12 weeks was noninferior between the groups (p<0.05). The LSM change from baseline in post-dose FEV1 was comparable (p=0.38). A superiority test showed comparable efficacy (p=0.12) for the difference in mean change from baseline in trough FEV1 between the groups. Adverse events (mild or moderate) were recorded in 25.3% and 24.9% of subjects in the GB/FF/FP and GB+FF/FP groups. CONCLUSIONS: Fixed triple therapy with GB/FF/FP provides comparable bronchodilation and lung function improvement as open-triple therapy. It is safe and well tolerated in symptomatic COPD patients with a history of exacerbations.

Efficacy and safety of favipiravir, an oral RNA-dependent RNA polymerase inhibitor, in mild-to-moderate COVID-19: A randomized, comparative, open-label, multicenter, phase 3 clinical trial.

OBJECTIVE: To assess the efficacy and safety of favipiravir in adults with mild-to-moderate coronavirus disease 2019 (COVID-19). METHODS: In this randomized, open-label, parallel-arm, multicenter, phase 3 trial, adults (18-75 years) with RT-PCR confirmed COVID-19 and mild-to-moderate symptoms (including asymptomatic) were randomized 1:1 to oral favipiravir (day 1: 1800 mg BID and days 2-14: 800 mg BID) plus standard supportive care versus supportive care alone. The primary endpoint was time to the cessation of viral shedding; time to clinical cure was also measured. RESULTS: From May 14 to July 3, 2020, 150 patients were randomized to favipiravir (n = 75) or control (n = 75). Median time to the cessation of viral shedding was 5 days (95% CI: 4 days, 7 days) versus 7 days (95% CI: 5 days, 8 days), P = 0.129, and median time to clinical cure was 3 days (95% CI: 3 days, 4 days) versus 5 days (95% CI: 4 days, 6 days), P = 0.030, for favipiravir and control, respectively. Adverse events were observed in 36% of favipiravir and 8% of control patients. One control patient died due to worsening disease. CONCLUSION: The lack of statistical significance on the primary endpoint was confounded by limitations of the RT-PCR assay. Significant improvement in time to clinical cure suggests favipiravir may be beneficial in mild-to-moderate COVID-19.

Efficacy and Safety of Remogliflozin Etabonate, a New Sodium Glucose Co-Transporter-2 Inhibitor, in Patients with Type 2 Diabetes Mellitus: A 24-Week, Randomized, Double-Blind, Active-Controlled Trial.

BACKGROUND: Metformin is the first-line treatment for type 2 diabetes mellitus (T2DM), but many patients either cannot tolerate it or cannot achieve glycemic control with metformin alone, so treatment with other glucose-lowering agents in combination with metformin is frequently required. Remogliflozin etabonate, a novel agent, is an orally bioavailable prodrug of remogliflozin, which is a potent and selective sodium-glucose co-transporter-2 inhibitor. OBJECTIVE: Our objective was to evaluate the efficacy and safety of remogliflozin etabonate compared with dapagliflozin in subjects with T2DM in whom a stable dose of metformin as monotherapy was providing inadequate glycemic control. METHODS: A 24-week randomized, double-blind, double-dummy, active-controlled, three-arm, parallel-group, multicenter, phase III study was conducted in India. Patients aged ≥ 18 and ≤ 65 years diagnosed with T2DM, receiving metformin ≥ 1500 mg/day, and with glycated hemoglobin (HbA1c) levels ≥ 7 to ≤ 10% at screening were randomized into three groups. Every patient received metformin ≥ 1500 mg and either remogliflozin etabonate 100 mg twice daily (BID) (group 1, n = 225) or remogliflozin etabonate 250 mg BID (group 2, n = 241) or dapagliflozin 10 mg once daily (QD) in the morning and placebo QD in the evening (group 3, n = 146). The patients were followed-up at weeks 1 and 4 and at 4-week intervals thereafter until week 24. The endpoints included mean change in HbA1c (primary endpoint, noninferiority margin = 0.35), fasting plasma glucose (FPG), postprandial plasma glucose (PPG), bodyweight, blood pressure, and fasting lipids. Treatment-emergent adverse events (TEAEs), safety laboratory values, electrocardiogram, and vital signs were evaluated. RESULTS: Of 612 randomized patients, 167 (group 1), 175 (group 2), and 103 (group 3) patients with comparable baseline characteristics completed the study. Mean change ± standard error (SE) in HbA1c from baseline to week 24 was - 0.72 ± 0.09, - 0.77 ± 0.09, and - 0.58 ± 0.12% in groups 1, 2, and 3, respectively. The difference in mean HbA1c of group 1 versus group 3 (- 0.14%, 90% confidence interval [CI] - 0.38 to 0.10) and group 2 versus group 3 (- 0.19%; 90% CI - 0.42 to 0.05) was noninferior to that in group 3 (p < 0.001). No significant difference was found between group 1 or group 2 and group 3 in change in FPG, PPG, and bodyweight. The overall incidence of TEAEs was comparable across study groups (group 1 = 32.6%, group 2 = 34.4%, group 3 = 29.5%), including adverse events (AEs) of special interest (hypoglycemic events, urinary tract infection, genital fungal infection). Most TEAEs were mild to moderate in intensity, and no severe AEs were reported. CONCLUSION: This study demonstrated the noninferiority of remogliflozin etabonate 100 and 250 mg compared with dapagliflozin, from the first analysis of an initial 612 patients. Remogliflozin etabonate therefore may be considered an effective and well-tolerated alternative treatment option for glycemic control in T2DM. TRIAL REGISTRATION: CTRI/2017/07/009121.

An Open-Label, Single-Period, Two-Stage, Single Oral Dose Pharmacokinetic Study of Remogliflozin Etabonate Tablet 100 and 250 mg in Healthy Asian Indian Male Subjects Under Fasting and Fed Conditions.

BACKGROUND AND OBJECTIVE: Remogliflozin etabonate is an orally available prodrug of remogliflozin, an inhibitor of renal sodium glucose co-transporter-2 (SGLT2) with antihyperglycemic activity. The present study was conducted to characterize the pharmacokinetic and safety profile of remogliflozin etabonate under fasting and fed conditions at single oral doses of 100 and 250 mg in healthy Asian Indian adults. METHODS: Sixty-five healthy, adult Asian Indian male subjects were enrolled in an open-label, two-stage, single-period pharmacokinetic study. Remogliflozin was given under fasting and/or fed conditions as a single oral dose of 100 or 250 mg. The plasma concentrations of remogliflozin etabonate, remogliflozin, and the metabolite GSK279782 were quantified by validated liquid chromatography-tandem mass spectrometry (LC-MS/MS) method. Pharmacokinetic parameters were determined from the plasma concentration-time profile by non-compartmental analysis. Safety was assessed through monitoring of adverse events. Descriptive statistics were calculated and reported for all parameters. RESULTS: The plasma concentration profiles showed rapid absorption of the prodrug remogliflozin etabonate and rapid conversion to the active moiety, remogliflozin, which is then further metabolized to another active metabolite, GSK279782. The geometric mean maximum concentration (Cmax) and area under the plasma concentration-time curve (AUC) were comparable for all three analytes between the fasted and fed state. The fed/fasted ratio for Cmax ranged from 0.77 to 1.44 at the 100 mg dose, and from 0.80 to 1.12 at the 250 mg dose. The fed/fasted ratio for AUC was 1.22 and 1.35 at 100 and 250 mg, respectively. An early time to Cmax (tmax) was observed for all three analytes while being administered in the fasted state. Both the Cmax and AUClast of all the three analytes increased in a dose-proportional manner under the fasted and fed states. The terminal half-life for remogliflozin ranged from 1.53 to 2.07 h. All three analytes had comparable terminal half-lives irrespective of dose levels or dietary conditions. CONCLUSIONS: Following single oral administration at 100 and 250 mg, remogliflozin etabonate showed favorable, linear pharmacokinetics. There were no clinically relevant food effects on the pharmacokinetics at both the 100 and 250 mg dose levels. Remogliflozin etabonate was well-tolerated without any safety concerns or hypoglycemic events. CLINICAL TRIAL REGISTRATION: Clinical Trial Registry-India identifier number CTRI/2017/10/010043.

In vivo phenotyping of cytochrome 450 isoforms involved in the metabolism of anti-HIV and anti-tubercular drugs in human using cocktail approach: An LC-MS/MS analysis.

PURPOSE: In vivo phenotyping of CYP isoforms involved in the metabolism of anti-HIV and antitubercular drugs is important to determine therapeutic dose levels in HIV/AIDS-TB coinfections. In this study, we used a cocktail of bupropion, losartan and dapsone for in vivo phenotyping of CYP2B6, CYP2C9 and N-acetyltransferase-2 (NAT2) in plasma. CYP2B6 is the main catalyst of anti-HIV efavirenz, while NAT2 is involved in antitubercular drug isoniazid metabolism. CYP2C9 has a significant association with antitubercular drug-induced reactions. The activity level of these isoforms has a significant bearing on therapeutic dose in rapid and poor metabolizers. METHODS: Briefly, a cocktail of probe drugs was administered to human volunteers and the drugs and metabolites were determined by an inhouse LC-MS/MS method in 250 µl plasma. The mobile phase and drug/metabolite extraction methods were optimized before analysis. Retention time, Cmax and tmax were calculated from the same sample and the values were used for phenotyping the isoforms. RESULTS: Retention time of drugs and metabolites was calculated. The method was sensitive (4.5-8.2 %CV) and no interfering peak was observed in any batch. %Accuracy of the calibrator and QC was 85-115%. %CV of storage stability testing was within FDA approved limits. Cmax and tmax were comparable to the values reported for individual drugs. CONCLUSIONS: This study advocates the use of a cocktail of bupropion, losartan and dapsone for in vivo phenotyping of CYP2B6, CYP2C9 and NAT2, which is important in determining therapeutic dose levels of anti-HIV and anti-TB drugs in HIV/AIDS-TB coinfections.

Genotype-phenotype correlation of cytochrome P450 2C9 polymorphism in Indian National Capital Region.

Identification of polymorphism of cytochrome P450 2C9 (CYP2C9) enzymes in different ethnic populations is important to understand the differences in clinical responses to drugs. This study determines the CYP2C9 genetic polymorphism in Indian National Capital Region and correlates the phenotype-genotype. Losartan (25 mg) was administered to 107 volunteers to assess CYP2C9 activity, and, on the basis of results, volunteers were categorized as rapid and poor metabolizers. Molecular typing of CYP2C9*1 (wild type), CYP2C9*2, and CYP2C9*3 (the most common variant) was carried out by single-base primer extension technology for 37 subjects, of which 9 were poor metabolizers, and 28 were rapid metabolizers. 14.28 % of the studied population was identified as poor metabolizer for the category of drugs metabolized by CYP2C9. Significant difference was observed between the mean ratio (drug/metabolite) of poor (11.38 ± 5.88) and rapid (1.18 ± 1.11) drug metabolizers. The study suggests that phenotyping of CYP2C9 is desirable before enrollment of subjects for clinical trials or for deciding drug dose regimen as 14.28 % of study population was found to be poor metabolizer for the category of drugs metabolized by CYP2C9. This study establishes phenotype-genotype correlation, and proposes to use genotyping or phenotyping to evaluate the status of drug metabolizing capacity of CYP2C9 as a primary screening procedure before enrolling subjects in clinical trials or in clinical practice.

Prevalence of poor and rapid metabolizers of drugs metabolized by CYP2B6 in North Indian population residing in Indian national capital territory.

Identification of poor and rapid metabolizers for the category of drugs metabolized by cytochrome P450 2B6 (CYP2B6) is important for understanding the differences in clinical responses of drugs metabolized by this enzyme. This study reports the prevalence of poor and rapid metabolizers in North Indian population residing in the National Capital Territory. The prevalence of poor and rapid metabolizers was determined in the target population for the category of drugs metabolized by CYP2B6 by measuring plasma bupropion, a drug metabolized by CYP2B6, and its metabolite. Bupropion (75 mg) was administered to 107 volunteers, and the drug (bupropion) and its metabolite (hydroxybupropion) were determined simultaneously by LCMS/MS in the plasma. CYP2B6 activity was measured as hydroxybupropion/bupropion ratio, and volunteers were categorized as rapid or poor metabolizers on the basis of cutoff value of log (hydroxybupropion/bupropion). Significant differences were observed between the mean metabolite/drug ratio of rapid metabolizers (Mean = 0.59) and poor metabolizers (Mean = 0.26) with p<0.0001. Results indicate that 20.56% individuals in the target population were poor metabolizers for the category of drugs metabolized by CYP2B6. Cutoff value defined in this study can be used as a tool for evaluating the status of CYP2B6 using bupropion as a probe drug. The baseline information would be clinically useful before administering the drugs metabolized by this isoform.

Comparative evaluation of US Food and Drug Administration and pharmacologically guided approaches to determine the maximum recommended starting dose for first-in-human clinical trials in adult healthy men.

The authors compared US Food and Drug Administration (FDA) and 9 pharmacologically guided approaches (PGAs; simple allometry, maximum life span potential [MLP], brain weight, rule of exponent [ROE], two 2-sp methods and 3 one-sp methods) to determine the maximum recommended starting dose (MRSD) for first-in-human clinical trials in adult healthy men using 10 drugs. The ROE method as suggested by Mahmood and Balian1 gave the best prediction accuracy for a pharmacokinetic (PK) parameter. Values derived from clearance were consistently better than volume of distribution (Vd)-based methods and had lower root mean square error (RMSE) values. A pictorial method evaluation chart was developed based on fold errors for simultaneous evaluation of various methods. The one-sp method (rat) and the US FDA methods gave the highest prediction accuracy and low RMSE values, and the 2-sp methods gave the least prediction accuracy with high RMSE values. The ROE method gave more consistent predictions for PK parameters than other allometric methods. Despite this, the MRSD predictions were not better than US FDA methods, probably indicating that across-species variation in clearance may be higher than variation in no observed adverse effect level (NOAEL) and that PGA methods may not be consistently better than the NOAEL based methods.

Pharmacokinetics and bioequivalence study of three oral formulations of valsartan 160 mg: a single-dose, randomized, open-label, three-period crossover comparison in healthy Indian male volunteers.

BACKGROUND: Valsartan is a selective angiotensin II type 1 receptor blocker indicated for the treatment of hypertension. Although the bioavailability and pharmacokinetic properties of valsartan have been well characterized, a literature search did not identify any reports concerning the bioavailability of valsartan in the Indian population. OBJECTIVE: This study was undertaken to compare the pharmacokinetic properties of 2 branded generic valsartan formulations (tests A and B) with a branded innovator product (reference) in healthy Indian male subjects. METHODS: This single-dose, randomized, open-label, 3-period crossover study compared the pharmacokinetic properties of 3 marketed brands of valsartan 160-mg tablets in healthy Indian male volunteers aged 18 to 45 years under fasting conditions. Subjects were assigned to receive, in randomized order, a single oral dose of 1 of 2 test formulations (A or B) or a reference formulation of valsartan 160 mg. Each study period was separated by a 5-day washout period. Blood samples were collected at prespecified times over a period of 24 hours after administration. An HPLC method was used for the estimation of plasma valsartan concentrations. A noncompartmental method was employed to determine the pharmacokinetic properties (C(max), T(max), AUC(0-t), AUC(0-infinity), and t(1/2)) to test for bioequivalence. The predetermined regulatory range of 90% CI for bioequivalence was 80% to 125%. Tolerability was assessed using physical examination, including vital sign measurement, and direct questioning. RESULTS: The study was conducted in 18 subjects (mean age, 24.8 years; weight, 54.5 kg; and height, 164.67 cm). For test formulation A versus the reference formulation, the 90% CIs of the least squares mean test/reference ratios of C(max), AUC(0-t), and AUC(0-infinity) were 81.18% to 115.74%, 77.27% to 108.75%, and 79.32% to 108.70%, respectively. For test B versus reference, the corresponding values were 84.69% to 120.73%, 83.72% to 117.84%, and 84.40% to 115.67%. No adverse events were found or reported by subjects throughout the study. CONCLUSIONS: In this single-dose study in a small sample of healthy Indian male subjects, test formulation B of valsartan 160 mg was considered bioequivalent to the reference formulation as per predetermined regulatory criteria, whereas test formulation A was not. All 3 formulations were well tolerated.

The effects of rosuvastatin on the serum cortisol, serum lipid, and serum mevalonic acid levels in the healthy Indian male population.

In this open-label, balanced, randomized, placebo-controlled, parallel study, healthy male volunteers were randomly divided into two groups. Each group received either a single oral dose of rosuvastatin 20 mg or placebo. Estimations were done at predose on day 1 of dosing (baseline) and 24 h postdose after days 7 and 14. Serum cortisol and serum lipid levels were estimated using enzyme-linked immunosorbent assay kits and serum mevalonic acid (MVA) levels were measured using validated liquid chromatography-tandem mass spectrometry method. Rosuvastatin produced a statistically significant (P < 0.05) decrease in total cholesterol, low-density lipoprotein cholesterol, very low-density lipoprotein cholesterol, and triglycerides. However, the increase in high-density lipoprotein cholesterol and decrease in cortisol and MVA were not statistically significant when compared to the placebo-treated group. The study showed that rosuvastatin at a dose of 20 mg/day for a period of 14 days was very potent as cholesterol-lowering agent, without any significant change in serum cortisol level in the healthy Indian male population.

A single-dose, randomized, open-label, two-period crossover bioequivalence study of a fixed-dose pediatric combination of lamivudine 40-mg, nevirapine 70-mg, and stavudine 10-mg tablet for oral suspension with individual liquid formulations in healthy adult male volunteers.

BACKGROUND: Because of the lack of suitable pediatric antiretroviral (ARV) agents, adult fixed-dose ARVs are commonly used in children. This practice poses concerns about dose inaccuracy, which may lead to resistance or toxicity. OBJECTIVE: The objective of the present study was to evaluate the bioequivalence of a new pediatric fixed-dose combination (FDC) ARV tablet for oral suspension as compared with individual liquid formulations. METHODS: The FDC ARV tablet for oral suspension contained lamivudine 40 mg, nevirapine 70 mg, and stavudine 10 mg. This formulation was compared with 4 mL of lamivudine 10 mg/mL, 7 mL of nevirapine 50 mg/5 mL, and 10 mL of stavudine 1 mg/mL. This was an open-label, balanced, randomized, 2-treatment, 2-period, 2-sequence, single-dose crossover study in 36 Indian male volunteers under fasting conditions. Blood samples were collected before dosing and at 0.167, 0.25, 0.333, 0.5, 0.667, 0.833, 1, 1.25, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 6, 12, 16, 24, 36, 48, 72, 96, 120, 144, 168, and 192 hours after dosing in each period. RESULTS: The mean (SD) age, weight, and height of the Indian volunteers were 24.78 (5.31) years (range, 18-38 years), 57.06 (8.59) kg (range, 45-77 kg), and 165.14 (5.34) cm (range, 156-176 cm), respectively. The mean (SD) values for T(max), C(max), and AUC(0-t) for the FDC and the individual liquid formulations, respectively, were as follows: lamivudine, 0.71 (0.22) and 0.89 (0.50) hour, 594 (167) and 514 (139) ng/mL, 2382 (617) and 2227 (666) ng /mL per hour; nevirapine, 1.7 (1.1) and 2.5 (1.2) hours, 1248 (275) and 1185 (238) ng/mL, 70,372 (14,869) and 71,278 (17,435) ng/ mL per hour; and stavudine, 0.44 (0.11) and 0.43 (0.11) hour, 348 (82) and 395 (107) ng/mL, and 576 (113) and 631 (142) ng/mL per hour. The ratios and 90% CIs for the least-squares mean Cmax and AUC values were found to be within the prespecified range of 80% to 125% for each component. CONCLUSION: The FDC pediatric formulation of lamivudine, nevirapine, and stavudine was bioequivalent to the individual liquid formulations in these fasting, healthy Indian men.

Pharmacodynamic evaluation of warfarin and rosuvastatin co-administration in healthy subjects.

OBJECTIVE: To determine whether co-administration of rosuvastatin alters the pharmacodynamics of warfarin, thereby requiring additional monitoring of the anticoagulant effects of warfarin. METHODS: In this open-labeled, placebo-controlled, randomized, two-period, crossover trial with a washout period of 15 days, 12 healthy male volunteers were administered daily oral doses of 5 mg warfarin for 14 days. Either rosuvastatin 40 mg/day (treatment A) or placebo (treatment B) was concomitantly administered on days 8-14. The pharmacodynamic parameters prothrombin time (PT) and international normalized ratio (INR) were evaluated on all 14 days pre-dose during both study periods. On the 8th, 10th, 12th, and 14th days of each study period, PT and INR were also measured at 4 h post-dose of rosuvastatin or placebo. Bleeding time and clotting time were assessed on the 1st, 8th, and 14th days pre-dose. RESULTS: Data of 10 subjects have been analyzed. No significant effect of rosuvastatin was seen on the steady-state pharmacodynamics of warfarin during concomitant administration. CONCLUSION: Rosuvastatin did not significantly alter the anticoagulant effects of warfarin in this study.

Screening of early detection of lung cancer.

Methods for detecting early lung cancers, carcinoma in situ, and dysplastic lesions of the tracheobronchial tree ultimately aim to eradicate them before they become invasive. This approach is being developed to detect early stage lung cancer, when treatment is more likely to be curative. This review describes the recent developments in lung cancer screening and the possible impact on management of lung cancer.

DOTS versus self administered therapy (SAT) for patients of pulmonary tuberculosis: a randomised trial at a tertiary care hospital.

Tuberculosis is a major public health problem in a developing country like India, it is made worse by poor adherence to and frequent interruption of treatment. Treatment of tuberculosis requires strict discipline in order to eradicate mycobacteria and to cure the disease. In the present study we have conducted a randomized control trial, to compare the effectiveness of Directly Observed Therapy Short Course (DOTS) versus Self Administered Therapy (SAT) in a tertiary care hospital.