Tapan Majumdar - Academia.edu (original) (raw)

Papers by Tapan Majumdar

Heart & Lung, 2013

Pulmonary nocardiosis is an uncommon opportunistic infection affecting mainly immunocompromised p... more Pulmonary nocardiosis is an uncommon opportunistic infection affecting mainly immunocompromised patients. We herein present a case of nocardiosis without profound underlying immunodeficiency. A female, 84-years' old patient with stage IV chronic obstructive pulmonary disease (COPD) is presented. No profound causes of immunodeficiency existed, such as HIV infection, diabetes mellitus, malignancy, alcoholism, chemotherapy or previous corticosteroid intake. The patient recovered after treatment with trimethoprim/sulfamethoxazole for 6 months. One year after infection resolution, stimulation of the patient's blood monocytes with Nocardia antigens revealed defective production of tumor necrosis factor-alpha, interleukin (IL)-6 and IL-17. We provide preliminary evidence for a link between defective innate immune responses and predisposition for Nocardia infections. Further studies must be conducted in order to fully investigate this mechanism of infection acquisition.

John Wiley & Sons, Inc. eBooks, May 18, 2006

John Wiley & Sons, Inc. eBooks, Aug 30, 2013

Journal of Pharmacological and Toxicological Methods, May 1, 2007

During the last decade, quantification of low molecular weight molecules using liquid chromatogra... more During the last decade, quantification of low molecular weight molecules using liquid chromatography-tandem mass spectrometry in biological fluids has become a common procedure in many preclinical and clinical laboratories. This overview highlights a number of issues involving "small molecule drugs", bioanalytical liquid chromatography-tandem mass spectrometry, which are frequently encountered during assay development. In addition, possible solutions to these issues are proposed with examples in some of the case studies. Topics such as chromatographic peak shape, carry-over, cross-talk, standard curve non-linearity, internal standard selection, matrix effect, and metabolite interference are presented. Since plasma is one of the most widely adopted biological fluid in drug discovery and development, the focus of this discussion will be limited to plasma analysis. This article is not intended to be a comprehensive overview and readers are encouraged to refer to the citations herein.

Pulmonary Pharmacology & Therapeutics, Apr 1, 2016

Purpose: QMF149 is a fixed-dose combination of the long-acting b 2 agonist, indacaterol and the c... more Purpose: QMF149 is a fixed-dose combination of the long-acting b 2 agonist, indacaterol and the corticosteroid, mometasone furoate that is currently under development for treatment of patients with asthma and chronic obstructive pulmonary disease. We describe here a study designed to assess any pharmacokinetic (PK) and/or biopharmaceutical interaction between indacaterol and mometasone furoate when administered via the Breezhaler ® device, either alone or in a free or fixed combination (QMF149) in healthy adult subjects. Methods: In this randomized, open-label, four-way crossover study, subjects were randomized to receive indacaterol acetate 150 mg, mometasone furoate 320 mg, alone and as free combination of the individual components, or QMF149 (indacaterol acetate 150 mg/mometasone furoate 320 mg) once daily for 14 days in each period, followed by a 7-day washout between periods. PK profiles were characterized on Day 14 up to 168 h post-dose. Results: Indacaterol AUC 0-24h,ss and C max,ss after administration of QMF149 were 13% [ratio: 1.13; 90%CI: 1.09, 1.17] and 18% [ratio: 1.18; 90%CI: 1.12, 1.25] higher, respectively, than indacaterol monotherapy. Mometasone furoate AUC 0-24h,ss and C max,ss after administration of QMF149 were 14% [ratio: 1.14; 90%CI: 1.09, 1.20] and 19% [ratio: 1.19; 90%CI: 1.13, 1.26], higher, respectively than mometasone furoate monotherapy. The majority (three of four comparisons between QMF149 and monotherapy) of the 90% confidence intervals of the between-treatment ratios for AUC 0-24h,ss and C max,ss were within the 0.80 to 1.25 interval and therefore fulfilled bioequivalence criteria. The 90% confidence interval for C max,ss for MF for the QMF149 vs. monotherapy comparison was [1.13, 1.26]. Although no definitive data can be provided on the basis of the present study results, it is unlikely that the small observed differences in expsoure are clinically meaningful. Multiple inhaled doses of indacaterol and mometasone furoate, when administered alone, in free combination or as QMF149 were well tolerated. Conclusions: The QMF149 fixed dose combination treatment showed comparable systemic exposure to the free combination and monotherapy treatments in terms of AUC 0-24h,ss and C max,ss for both indacaterol and mometasone furoate, indicating an absence of clinically relevant PK or biopharmaceutical interactions. These data support further development of QMF149 without dose adjustment.

International Journal of Clinical Pharmacology and Therapeutics, Mar 5, 2015

Pradigastat, a novel diacylglycerol acyltransferase 1 inhibitor, has been studied in familial chy... more Pradigastat, a novel diacylglycerol acyltransferase 1 inhibitor, has been studied in familial chylomicronemia syndrome. To evaluate the effects of supra-therapeutic concentrations of pradigastat on the QTc interval, two studies were conducted. The first study assessed the safety, tolerability and pharmacokinetics of single escalating intravenous doses of pradigastat (10, 30, 100 and 115mg over 60 minutes) in healthy adults. Single IV doses were safe, well tolerated, and at the higher doses resulted in supra-therapeutic pradigastat exposure. The second was a parallel, 3-arm thorough QTc study where healthy male subjects were randomized to pradigastat (115mg IV), moxifloxacin (400mg oral, positive control), or placebo. Following IV administration, pradigastat exposure peaked at 4 times the therapeutic concentration, and did not prolong the baseline adjusted and placebo corrected QTc interval. During the 60 minute pradigastat infusion, a number of infusion reactions and a small mean decrease in QTc were observed. Both effects disappeared when the infusion was stopped, suggesting that an infusate excipient may have been responsible. As expected, moxifloxacin This article is protected by copyright. All rights reserved. significantly increased the QTc interval at multiple time points, confirming the study's sensitivity to detect a true positive effect. Pradigastat is therefore unlikely to increase the risk of dysrhythmias associated with QTc prolongation in humans.

European Journal of Clinical Pharmacology, Mar 1, 2015

Purpose The purpose of this study was to evaluate the effect of pradigastat, a diacylglycerol acy... more Purpose The purpose of this study was to evaluate the effect of pradigastat, a diacylglycerol acyltransferase-1 inhibitor, on the pharmacokinetics of acetaminophen, a gastric emptying marker. Methods Twenty-five healthy subjects were enrolled and received 1000 mg acetaminophen with meal in period 1, pradigastat (100 mg×3 days followed by 40 mg×7 days, 1 h before meal) in period 2, and 1000 mg acetaminophen at −2, −1, 0, +1, and +3 h with respect to meal timing in presence of steady-state pradigastat (40-mg maintenance dose) during periods 3-7. Results The geometric mean ratio and 90 % confidence interval of Cmax and AUC of acetaminophen were within 80-125 % suggesting that the rate ad extent of acetaminophen were not affected when given at various time points with respect to pradigastat/meal timing. The acetaminophen Tmax was also not impacted under all treatment conditions but increased from 0.75 to 2.00 h when administered 1 h after food. Conclusion In the presence of steady-state pradigastat, the pharmacokinetics of acetaminophen is unchanged, when given before, with, or 3 h after a meal. However, when given 1 h after a meal, the T max of acetaminophen was delayed by ∼1.25 h without affecting C max or AUC.

Biopharmaceutics & Drug Disposition, Jun 5, 2015

Pradigastat, a diacylglycerol acyltransferase 1 inhibitor, is being developed for the treatment o... more Pradigastat, a diacylglycerol acyltransferase 1 inhibitor, is being developed for the treatment of familial chylomicronemia syndrome. The results of two studies that evaluated the effect of food on the oral bioavailability of pradigastat using randomized, open‐label, parallel group designs in healthy subjects (n = 24/treatment/study) are presented. In study 1, a single dose of 20 mg pradigastat was administered under the fasted condition or with a high‐fat meal. In study 2, a single dose of 40 mg pradigastat was administered under the fasted condition or with a low‐ or high‐fat meal. At the 20 mg dose, the pradigastat Cmax and AUClast increased by 38% and 41%, respectively, with a high‐fat meal. When 40 mg pradigastat was administered with a low‐fat meal, the Cmax and AUClast increased by 8% and 18%, respectively, whereas with a high‐fat meal the increase was 20% and 18%, respectively. The population pharmacokinetic analysis with the pooled data from 13 studies indicated that administration of pradigastat with a meal resulted in an increase of 30% in both the Cmax and AUC parameters. Based on these results, food overall increased pradigastat exposure in the range of less than 40%, which is not considered clinically significant. Both 20 and 40 mg doses of pradigastat were well tolerated under fasted or fed conditions. Copyright © 2015 John Wiley & Sons, Ltd.

Xenobiotica, Dec 12, 2016

1. Pradigastat is a potent and specific diacylglycerol acyltransferase-1 (DGAT1) inhibitor effect... more 1. Pradigastat is a potent and specific diacylglycerol acyltransferase-1 (DGAT1) inhibitor effective in lowering postprandial triglycerides (TG) in healthy human subjects and fasting TG in familial chylomicronemia syndrome (FCS) patients. 2. Here we present the results of human oral absorption, metabolism and excretion (AME), intravenous pharmacokinetic (PK), and in vitro studies which together provide an overall understanding of the disposition of pradigastat in humans. 3. In human in vitro systems, pradigastat is metabolized slowly to a stable acyl glucuronide (M18.4), catalyzed mainly by UDP-glucuronosyltransferases (UGT) 1A1, UGT1A3 and UGT2B7. M18.4 was observed at very low levels in human plasma. 4. In the human AME study, pradigastat was recovered in the feces as parent drug, confounding the assessment of pradigastat absorption and the important routes of elimination. However, considering pradigastat exposure after oral and intravenous dosing, this data suggests that pradigastat was completely bioavailable in the radiolabeled AME study and therefore completely absorbed. 5. Pradigastat is eliminated very slowly into the feces, presumably via the bile. Renal excretion is negligible. Oxidative metabolism is minimal. The extent to which pradigastat is eliminated via metabolism to M18.4 could not be established from these studies due to the inherent instability of glucuronides in the gastrointestinal tract.

The Journal of Clinical Pharmacology, May 27, 2015

RCT-18 is a novel recombinant fusion protein that blocks the activity of a B-lymphocyte stimulato... more RCT-18 is a novel recombinant fusion protein that blocks the activity of a B-lymphocyte stimulator and a proliferation-inducing ligand. This was a randomized, single-blind, and placebo-controlled phase 1 study in 12 patients with systemic lupus erythematosus. Eligible patients were randomized 3:1 to receive multiple subcutaneous doses of RCT-18 for 4 weeks (180 mg, once weekly) or placebo and monitored over an 84-day observation period for pharmacokinetics, pharmacodynamics, immunogenicity, safety, and clinical activity. After multiple-dose RCT-18, the maximal serum concentration (C max) of total and free RCT-18 was reached within 1 to 2 days. Mean elimination half-life for total RCT-18 and free RCT-18 was 11.4 to 26.4 days and 2.4 to 26.5 days, respectively. Slight accumulation was found after multiple subcutaneous administrations. The average accumulation ratios of AUC and C max after the fourth administration of RCT-18 were 2.0 and 1.7 for total RCT-18, and 1.8 and 1.6 for free RCT-18. The formation and elimination of BLyS-RCT-18 complex were much slower, with a time to C max of 14 to 46 days. Pharmacokinetic characteristics of RCT-18 in SLE patients were similar to those in patients with rheumatoid arthritis. No positive reaction was detected in the immunogenicity assessments. RCT-18 was biologically active, according to serum immunoglobulin and B-cell levels. Treatment-related IgM and IgA reduction was found during this study. CD19 + , IgD + , and CD27 + B-cell counts were increased after administration and decreased subsequently. SLE patients treated with RCT-18 were more prone to infections, including moderate and severe infections. Lower dosages of RCT-18 should be considered in further clinical development.

Clinical pharmacology in drug development, Jul 3, 2016

Pradigastat, a novel diacylglycerol acyltransferase 1 inhibitor, has been studied in familial chy... more Pradigastat, a novel diacylglycerol acyltransferase 1 inhibitor, has been studied in familial chylomicronemia syndrome. To evaluate the effects of supra-therapeutic concentrations of pradigastat on the QTc interval, two studies were conducted. The first study assessed the safety, tolerability and pharmacokinetics of single escalating intravenous doses of pradigastat (10, 30, 100 and 115mg over 60 minutes) in healthy adults. Single IV doses were safe, well tolerated, and at the higher doses resulted in supra-therapeutic pradigastat exposure. The second was a parallel, 3-arm thorough QTc study where healthy male subjects were randomized to pradigastat (115mg IV), moxifloxacin (400mg oral, positive control), or placebo. Following IV administration, pradigastat exposure peaked at 4 times the therapeutic concentration, and did not prolong the baseline adjusted and placebo corrected QTc interval. During the 60 minute pradigastat infusion, a number of infusion reactions and a small mean decrease in QTc were observed. Both effects disappeared when the infusion was stopped, suggesting that an infusate excipient may have been responsible. As expected, moxifloxacin This article is protected by copyright. All rights reserved. significantly increased the QTc interval at multiple time points, confirming the study's sensitivity to detect a true positive effect. Pradigastat is therefore unlikely to increase the risk of dysrhythmias associated with QTc prolongation in humans.

Indian Journal of Dermatology, Venereology, and Leprology, 2017

References 1. Moisini I, Davidson A. BAFF: A local and systemic target in autoimmune diseases. Cl... more References 1. Moisini I, Davidson A. BAFF: A local and systemic target in autoimmune diseases. Clin Exp Immunol 2009;158:155‐63. 2. Matsushita T, Hasegawa M, Matsushita Y, Echigo T, Wayaku T, Horikawa M, et al. Elevated serum BAFF levels in patients with localized scleroderma in contrast to other organ‐specific autoimmune diseases. Exp Dermatol 2007;16:87‐93. 3. Mejri K, Abida O, Kallel‐Sellami M, Haddouk S, Laadhar L, Zarraa IR, et al. Spectrum of autoantibodies other than anti‐desmoglein in pemphigus patients. J Eur Acad Dermatol Venereol 2011;25:774‐81. 4. Asashima N, Fujimoto M, Watanabe R, Nakashima H, Yazawa N, Okochi H, et al. Serum levels of BAFF are increased in bullous pemphigoid but not in pemphigus vulgaris. Br J Dermatol 2006;155:330‐6. 5. Abida O, Zitouni M, Kallel‐Sellami M, Mahfoudh N, Kammoun A, Ben Ayed M, et al. Tunisian endemic pemphigus foliaceus is associated with the HLA‐DR3 gene: Anti‐desmoglein 1 antibody‐positive healthy subjects bear protective alleles. Br J Dermatol 2009;161:522‐7. 6. Nagel A, Podstawa E, Eickmann M, Müller HH, Hertl M, Eming R. Rituximab mediates a strong elevation of B‐cell‐activating factor associated with increased pathogen‐specific IgG but not autoantibodies in pemphigus vulgaris. J Invest Dermatol 2009;129:2202‐10. 7. Malheiros D, Petzl‐Erler ML. Individual and epistatic effects of genetic polymorphisms of B‐cell co‐stimulatory molecules on susceptibility to pemphigus foliaceus. Genes Immun 2009;10:547‐58. 8. Mahieu MA, Strand V, Simon LS, Lipsky PE, Ramsey‐Goldman R. A critical review of clinical trials in systemic lupus erythematosus. Lupus 2016;25:1122‐40. How to cite this article: Mejri K, Sellami MK, Zaraa IR, Laadhar L, Lahmar H, Mokni M, et al. High B‐cell‐activating factor levels in endemic Tunisian pemphigus. Indian J Dermatol Venereol Leprol 2017;83:496‐9.

Research Reviews Journal of Microbiology and Biotechnology, Jan 4, 2014

The increasing tendency of oxyimino-cephalosporin resistance in Escherichia coli represents a cli... more The increasing tendency of oxyimino-cephalosporin resistance in Escherichia coli represents a clinical threat. Clavulanic acid-inhibitory extended-spectrum β-lactamases (ESBLs)

Journal of clinical and diagnostic research : JCDR, 2015

High morbidity and mortality rates are associated with Methicillin-resistant Staphylococcus aureu... more High morbidity and mortality rates are associated with Methicillin-resistant Staphylococcus aureus (MRSA) because of development of multidrug resistance. Staphylococcus aureus (S. aureus) has the ability to colonize and form biofilms on biomaterials which is causing resistance towards antimicrobials and thus making them difficult to eradicate from the infected hosts. Culture isolation, identification was done following standard protocol and antibiogram of the isolates were done. The detection of MRSA, Macrolide-Lincosamide-Streptogramin B resistance (MLSB), vancomycin resistance phenotypes were done by using cefoxitin disc diffusion test, D zone test and vancomycin E test. Biofilm was detected by Congo red agar method. A total of 100 (31.7%) S. aureus strains were isolated from 315 clinical specimens. The prevalence of MRSA was 47% (47/100) with 85.1% were homogeneous MRSA and 14.9% were heterogeneous. Out of 47 MRSA strains, 63.8% were Hospital acquired-MRSA (HA-MRSA) infections wh...

Geocarto International, 2006

Recent advancements in remote sensing techniques have made it possible to monitor and understand ... more Recent advancements in remote sensing techniques have made it possible to monitor and understand the activities of polar ice sheets, which exert profound influence in controlling global climate. Techniques such as laser altimetry, radar altimetry, InSAR, GPS etc. have been used for generation of DEMs, calculation of ice-sheet mass balance, retrieval of snow-water equivalent and other snow/ice related studies. In the present study, DEMs were generated using SEASAT altimeter data over parts of Antarctica and the maximum height variations in the studied area have been observed as high as 3200 m. From the analysis of the surface slopes, an attempt was made to qualitatively estimate the magnitude and direction of the ice-sheet movement vectors. Coupled with temporal data, both field and satellite derived, the results obtained can be used for modelling of ice-sheet mass balance over Antarctica.

Annals of Tropical Medicine & Parasitology, 2004

ABSTRACT Renal failure was experimentally induced in 36 hamsters by intraperitoneal injection wit... more ABSTRACT Renal failure was experimentally induced in 36 hamsters by intraperitoneal injection with uranyl nitrate (5 mg/kg Twenty-four h later [during acute renal failure (ARF), as indicated by the serum concentrations of creatinine and urea nitrogen] or 72 h later [during chronic renal failure (CRF)] these hamsters plus 18. uninjected. control hamsters were each given a single, intramuscular dose of sodium stibogluconate (120 mg pentavalent antimony/kg). The pharmacokinetic parameters for the antimonial drug were calculated using a non-compartmental model. Urine was collected for 72 h after similar treatment with the antimonial drug. from another 30 hamsters (10 controls. 10 with ARF, and 10 with CRF), so that the fraction of the antimony administered that was subsequently excreted in the urine could be estimated. Compared with the controls, both the hamsters with ARF and those with CRF had significantly higher maximum concentrations of antimony (C-max), significantly larger 'areas under the curve' for the plots of blood concentration. v. time, and significantly longer plasma half-lives (P< 0.001 for each). The mean (S.D.) Values Of C-max, for example were more than three-fold higher in the hamsters with ARF [467.5 (59.04)μg/ml] or CRF [461.1 (68.9)μg/ml) dian in the controls [154.01 (17.3) μg/ml]. The systemic clearance of antimony was also significantly lower in the hamsters with CRF than in the control animals [0.051 (0.002) v. 0.296 (0.047) litres/h/kg: P<0.01]. In addition. the fraction of the antimony administered that was excreted in urine was significantly lower in the animals with ARF (0.25) or CRF (0.08) than in the controls (0.37), indicating significant dysfunction of the kidneys in the hamsters injected with uranyl nitrate. It seems clear that, if severe toxicity is to be avoided, patients with renal dysfunction requiring treatment (for leishmaniasis) with sodium stibogluconate should be given lower doses than similar Cases with normal function.

Best Practices, Experimental Protocols, and Regulations, 2013

Xenobiotica; the fate of foreign compounds in biological systems, Jan 12, 2016

1. Pradigastat is a potent and specific diacylglycerol acyltransferase-1 (DGAT1) inhibitor effect... more 1. Pradigastat is a potent and specific diacylglycerol acyltransferase-1 (DGAT1) inhibitor effective in lowering postprandial triglycerides (TG) in healthy human subjects and fasting TG in familial chylomicronemia syndrome (FCS) patients. 2. Here we present the results of human oral absorption, metabolism and excretion (AME), intravenous pharmacokinetic (PK), and in vitro studies which together provide an overall understanding of the disposition of pradigastat in humans. 3. In human in vitro systems, pradigastat is metabolized slowly to a stable acyl glucuronide (M18.4), catalyzed mainly by UDP-glucuronosyltransferases (UGT) 1A1, UGT1A3 and UGT2B7. M18.4 was observed at very low levels in human plasma. 4. In the human AME study, pradigastat was recovered in the feces as parent drug, confounding the assessment of pradigastat absorption and the important routes of elimination. However, considering pradigastat exposure after oral and intravenous dosing, this data suggests that pradigas...

Journal of Pharmaceutical and Biomedical Analysis, Sep 30, 2000

Clinical pharmacology in drug development, Jan 8, 2016

Pradigastat, a novel diacylglycerol acyltransferase 1 inhibitor, has been studied in familial chy... more Pradigastat, a novel diacylglycerol acyltransferase 1 inhibitor, has been studied in familial chylomicronemia syndrome. To evaluate the effects of supratherapeutic concentrations of pradigastat on the QTc interval, 2 studies were conducted. The first study assessed the safety, tolerability, and pharmacokinetics of single escalating intravenous doses of pradigastat (10, 30, 100, and 115 mg over 60 minutes) in healthy adults. Single intravenous doses were safe, well tolerated, and at the higher doses resulted in supratherapeutic pradigastat exposure. The second was a parallel, 3-arm thorough QTc study in which healthy male subjects were randomized to pradigastat (115 mg intravenously), moxifloxacin (400 mg oral, positive control), or placebo. Following intravenous administration, pradigastat exposure peaked at 4 times the therapeutic concentration and did not prolong the baseline-adjusted and placebo-corrected QTc intervals. During the 60-minute pradigastat infusion, a number of infus...

Heart & Lung, 2013

Pulmonary nocardiosis is an uncommon opportunistic infection affecting mainly immunocompromised p... more Pulmonary nocardiosis is an uncommon opportunistic infection affecting mainly immunocompromised patients. We herein present a case of nocardiosis without profound underlying immunodeficiency. A female, 84-years' old patient with stage IV chronic obstructive pulmonary disease (COPD) is presented. No profound causes of immunodeficiency existed, such as HIV infection, diabetes mellitus, malignancy, alcoholism, chemotherapy or previous corticosteroid intake. The patient recovered after treatment with trimethoprim/sulfamethoxazole for 6 months. One year after infection resolution, stimulation of the patient's blood monocytes with Nocardia antigens revealed defective production of tumor necrosis factor-alpha, interleukin (IL)-6 and IL-17. We provide preliminary evidence for a link between defective innate immune responses and predisposition for Nocardia infections. Further studies must be conducted in order to fully investigate this mechanism of infection acquisition.

John Wiley & Sons, Inc. eBooks, May 18, 2006

John Wiley & Sons, Inc. eBooks, Aug 30, 2013

Journal of Pharmacological and Toxicological Methods, May 1, 2007

During the last decade, quantification of low molecular weight molecules using liquid chromatogra... more During the last decade, quantification of low molecular weight molecules using liquid chromatography-tandem mass spectrometry in biological fluids has become a common procedure in many preclinical and clinical laboratories. This overview highlights a number of issues involving "small molecule drugs", bioanalytical liquid chromatography-tandem mass spectrometry, which are frequently encountered during assay development. In addition, possible solutions to these issues are proposed with examples in some of the case studies. Topics such as chromatographic peak shape, carry-over, cross-talk, standard curve non-linearity, internal standard selection, matrix effect, and metabolite interference are presented. Since plasma is one of the most widely adopted biological fluid in drug discovery and development, the focus of this discussion will be limited to plasma analysis. This article is not intended to be a comprehensive overview and readers are encouraged to refer to the citations herein.

Pulmonary Pharmacology & Therapeutics, Apr 1, 2016

Purpose: QMF149 is a fixed-dose combination of the long-acting b 2 agonist, indacaterol and the c... more Purpose: QMF149 is a fixed-dose combination of the long-acting b 2 agonist, indacaterol and the corticosteroid, mometasone furoate that is currently under development for treatment of patients with asthma and chronic obstructive pulmonary disease. We describe here a study designed to assess any pharmacokinetic (PK) and/or biopharmaceutical interaction between indacaterol and mometasone furoate when administered via the Breezhaler ® device, either alone or in a free or fixed combination (QMF149) in healthy adult subjects. Methods: In this randomized, open-label, four-way crossover study, subjects were randomized to receive indacaterol acetate 150 mg, mometasone furoate 320 mg, alone and as free combination of the individual components, or QMF149 (indacaterol acetate 150 mg/mometasone furoate 320 mg) once daily for 14 days in each period, followed by a 7-day washout between periods. PK profiles were characterized on Day 14 up to 168 h post-dose. Results: Indacaterol AUC 0-24h,ss and C max,ss after administration of QMF149 were 13% [ratio: 1.13; 90%CI: 1.09, 1.17] and 18% [ratio: 1.18; 90%CI: 1.12, 1.25] higher, respectively, than indacaterol monotherapy. Mometasone furoate AUC 0-24h,ss and C max,ss after administration of QMF149 were 14% [ratio: 1.14; 90%CI: 1.09, 1.20] and 19% [ratio: 1.19; 90%CI: 1.13, 1.26], higher, respectively than mometasone furoate monotherapy. The majority (three of four comparisons between QMF149 and monotherapy) of the 90% confidence intervals of the between-treatment ratios for AUC 0-24h,ss and C max,ss were within the 0.80 to 1.25 interval and therefore fulfilled bioequivalence criteria. The 90% confidence interval for C max,ss for MF for the QMF149 vs. monotherapy comparison was [1.13, 1.26]. Although no definitive data can be provided on the basis of the present study results, it is unlikely that the small observed differences in expsoure are clinically meaningful. Multiple inhaled doses of indacaterol and mometasone furoate, when administered alone, in free combination or as QMF149 were well tolerated. Conclusions: The QMF149 fixed dose combination treatment showed comparable systemic exposure to the free combination and monotherapy treatments in terms of AUC 0-24h,ss and C max,ss for both indacaterol and mometasone furoate, indicating an absence of clinically relevant PK or biopharmaceutical interactions. These data support further development of QMF149 without dose adjustment.

International Journal of Clinical Pharmacology and Therapeutics, Mar 5, 2015

Pradigastat, a novel diacylglycerol acyltransferase 1 inhibitor, has been studied in familial chy... more Pradigastat, a novel diacylglycerol acyltransferase 1 inhibitor, has been studied in familial chylomicronemia syndrome. To evaluate the effects of supra-therapeutic concentrations of pradigastat on the QTc interval, two studies were conducted. The first study assessed the safety, tolerability and pharmacokinetics of single escalating intravenous doses of pradigastat (10, 30, 100 and 115mg over 60 minutes) in healthy adults. Single IV doses were safe, well tolerated, and at the higher doses resulted in supra-therapeutic pradigastat exposure. The second was a parallel, 3-arm thorough QTc study where healthy male subjects were randomized to pradigastat (115mg IV), moxifloxacin (400mg oral, positive control), or placebo. Following IV administration, pradigastat exposure peaked at 4 times the therapeutic concentration, and did not prolong the baseline adjusted and placebo corrected QTc interval. During the 60 minute pradigastat infusion, a number of infusion reactions and a small mean decrease in QTc were observed. Both effects disappeared when the infusion was stopped, suggesting that an infusate excipient may have been responsible. As expected, moxifloxacin This article is protected by copyright. All rights reserved. significantly increased the QTc interval at multiple time points, confirming the study's sensitivity to detect a true positive effect. Pradigastat is therefore unlikely to increase the risk of dysrhythmias associated with QTc prolongation in humans.

European Journal of Clinical Pharmacology, Mar 1, 2015

Purpose The purpose of this study was to evaluate the effect of pradigastat, a diacylglycerol acy... more Purpose The purpose of this study was to evaluate the effect of pradigastat, a diacylglycerol acyltransferase-1 inhibitor, on the pharmacokinetics of acetaminophen, a gastric emptying marker. Methods Twenty-five healthy subjects were enrolled and received 1000 mg acetaminophen with meal in period 1, pradigastat (100 mg×3 days followed by 40 mg×7 days, 1 h before meal) in period 2, and 1000 mg acetaminophen at −2, −1, 0, +1, and +3 h with respect to meal timing in presence of steady-state pradigastat (40-mg maintenance dose) during periods 3-7. Results The geometric mean ratio and 90 % confidence interval of Cmax and AUC of acetaminophen were within 80-125 % suggesting that the rate ad extent of acetaminophen were not affected when given at various time points with respect to pradigastat/meal timing. The acetaminophen Tmax was also not impacted under all treatment conditions but increased from 0.75 to 2.00 h when administered 1 h after food. Conclusion In the presence of steady-state pradigastat, the pharmacokinetics of acetaminophen is unchanged, when given before, with, or 3 h after a meal. However, when given 1 h after a meal, the T max of acetaminophen was delayed by ∼1.25 h without affecting C max or AUC.

Biopharmaceutics & Drug Disposition, Jun 5, 2015

Pradigastat, a diacylglycerol acyltransferase 1 inhibitor, is being developed for the treatment o... more Pradigastat, a diacylglycerol acyltransferase 1 inhibitor, is being developed for the treatment of familial chylomicronemia syndrome. The results of two studies that evaluated the effect of food on the oral bioavailability of pradigastat using randomized, open‐label, parallel group designs in healthy subjects (n = 24/treatment/study) are presented. In study 1, a single dose of 20 mg pradigastat was administered under the fasted condition or with a high‐fat meal. In study 2, a single dose of 40 mg pradigastat was administered under the fasted condition or with a low‐ or high‐fat meal. At the 20 mg dose, the pradigastat Cmax and AUClast increased by 38% and 41%, respectively, with a high‐fat meal. When 40 mg pradigastat was administered with a low‐fat meal, the Cmax and AUClast increased by 8% and 18%, respectively, whereas with a high‐fat meal the increase was 20% and 18%, respectively. The population pharmacokinetic analysis with the pooled data from 13 studies indicated that administration of pradigastat with a meal resulted in an increase of 30% in both the Cmax and AUC parameters. Based on these results, food overall increased pradigastat exposure in the range of less than 40%, which is not considered clinically significant. Both 20 and 40 mg doses of pradigastat were well tolerated under fasted or fed conditions. Copyright © 2015 John Wiley & Sons, Ltd.

Xenobiotica, Dec 12, 2016

1. Pradigastat is a potent and specific diacylglycerol acyltransferase-1 (DGAT1) inhibitor effect... more 1. Pradigastat is a potent and specific diacylglycerol acyltransferase-1 (DGAT1) inhibitor effective in lowering postprandial triglycerides (TG) in healthy human subjects and fasting TG in familial chylomicronemia syndrome (FCS) patients. 2. Here we present the results of human oral absorption, metabolism and excretion (AME), intravenous pharmacokinetic (PK), and in vitro studies which together provide an overall understanding of the disposition of pradigastat in humans. 3. In human in vitro systems, pradigastat is metabolized slowly to a stable acyl glucuronide (M18.4), catalyzed mainly by UDP-glucuronosyltransferases (UGT) 1A1, UGT1A3 and UGT2B7. M18.4 was observed at very low levels in human plasma. 4. In the human AME study, pradigastat was recovered in the feces as parent drug, confounding the assessment of pradigastat absorption and the important routes of elimination. However, considering pradigastat exposure after oral and intravenous dosing, this data suggests that pradigastat was completely bioavailable in the radiolabeled AME study and therefore completely absorbed. 5. Pradigastat is eliminated very slowly into the feces, presumably via the bile. Renal excretion is negligible. Oxidative metabolism is minimal. The extent to which pradigastat is eliminated via metabolism to M18.4 could not be established from these studies due to the inherent instability of glucuronides in the gastrointestinal tract.

The Journal of Clinical Pharmacology, May 27, 2015

RCT-18 is a novel recombinant fusion protein that blocks the activity of a B-lymphocyte stimulato... more RCT-18 is a novel recombinant fusion protein that blocks the activity of a B-lymphocyte stimulator and a proliferation-inducing ligand. This was a randomized, single-blind, and placebo-controlled phase 1 study in 12 patients with systemic lupus erythematosus. Eligible patients were randomized 3:1 to receive multiple subcutaneous doses of RCT-18 for 4 weeks (180 mg, once weekly) or placebo and monitored over an 84-day observation period for pharmacokinetics, pharmacodynamics, immunogenicity, safety, and clinical activity. After multiple-dose RCT-18, the maximal serum concentration (C max) of total and free RCT-18 was reached within 1 to 2 days. Mean elimination half-life for total RCT-18 and free RCT-18 was 11.4 to 26.4 days and 2.4 to 26.5 days, respectively. Slight accumulation was found after multiple subcutaneous administrations. The average accumulation ratios of AUC and C max after the fourth administration of RCT-18 were 2.0 and 1.7 for total RCT-18, and 1.8 and 1.6 for free RCT-18. The formation and elimination of BLyS-RCT-18 complex were much slower, with a time to C max of 14 to 46 days. Pharmacokinetic characteristics of RCT-18 in SLE patients were similar to those in patients with rheumatoid arthritis. No positive reaction was detected in the immunogenicity assessments. RCT-18 was biologically active, according to serum immunoglobulin and B-cell levels. Treatment-related IgM and IgA reduction was found during this study. CD19 + , IgD + , and CD27 + B-cell counts were increased after administration and decreased subsequently. SLE patients treated with RCT-18 were more prone to infections, including moderate and severe infections. Lower dosages of RCT-18 should be considered in further clinical development.

Clinical pharmacology in drug development, Jul 3, 2016

Pradigastat, a novel diacylglycerol acyltransferase 1 inhibitor, has been studied in familial chy... more Pradigastat, a novel diacylglycerol acyltransferase 1 inhibitor, has been studied in familial chylomicronemia syndrome. To evaluate the effects of supra-therapeutic concentrations of pradigastat on the QTc interval, two studies were conducted. The first study assessed the safety, tolerability and pharmacokinetics of single escalating intravenous doses of pradigastat (10, 30, 100 and 115mg over 60 minutes) in healthy adults. Single IV doses were safe, well tolerated, and at the higher doses resulted in supra-therapeutic pradigastat exposure. The second was a parallel, 3-arm thorough QTc study where healthy male subjects were randomized to pradigastat (115mg IV), moxifloxacin (400mg oral, positive control), or placebo. Following IV administration, pradigastat exposure peaked at 4 times the therapeutic concentration, and did not prolong the baseline adjusted and placebo corrected QTc interval. During the 60 minute pradigastat infusion, a number of infusion reactions and a small mean decrease in QTc were observed. Both effects disappeared when the infusion was stopped, suggesting that an infusate excipient may have been responsible. As expected, moxifloxacin This article is protected by copyright. All rights reserved. significantly increased the QTc interval at multiple time points, confirming the study's sensitivity to detect a true positive effect. Pradigastat is therefore unlikely to increase the risk of dysrhythmias associated with QTc prolongation in humans.

Indian Journal of Dermatology, Venereology, and Leprology, 2017

References 1. Moisini I, Davidson A. BAFF: A local and systemic target in autoimmune diseases. Cl... more References 1. Moisini I, Davidson A. BAFF: A local and systemic target in autoimmune diseases. Clin Exp Immunol 2009;158:155‐63. 2. Matsushita T, Hasegawa M, Matsushita Y, Echigo T, Wayaku T, Horikawa M, et al. Elevated serum BAFF levels in patients with localized scleroderma in contrast to other organ‐specific autoimmune diseases. Exp Dermatol 2007;16:87‐93. 3. Mejri K, Abida O, Kallel‐Sellami M, Haddouk S, Laadhar L, Zarraa IR, et al. Spectrum of autoantibodies other than anti‐desmoglein in pemphigus patients. J Eur Acad Dermatol Venereol 2011;25:774‐81. 4. Asashima N, Fujimoto M, Watanabe R, Nakashima H, Yazawa N, Okochi H, et al. Serum levels of BAFF are increased in bullous pemphigoid but not in pemphigus vulgaris. Br J Dermatol 2006;155:330‐6. 5. Abida O, Zitouni M, Kallel‐Sellami M, Mahfoudh N, Kammoun A, Ben Ayed M, et al. Tunisian endemic pemphigus foliaceus is associated with the HLA‐DR3 gene: Anti‐desmoglein 1 antibody‐positive healthy subjects bear protective alleles. Br J Dermatol 2009;161:522‐7. 6. Nagel A, Podstawa E, Eickmann M, Müller HH, Hertl M, Eming R. Rituximab mediates a strong elevation of B‐cell‐activating factor associated with increased pathogen‐specific IgG but not autoantibodies in pemphigus vulgaris. J Invest Dermatol 2009;129:2202‐10. 7. Malheiros D, Petzl‐Erler ML. Individual and epistatic effects of genetic polymorphisms of B‐cell co‐stimulatory molecules on susceptibility to pemphigus foliaceus. Genes Immun 2009;10:547‐58. 8. Mahieu MA, Strand V, Simon LS, Lipsky PE, Ramsey‐Goldman R. A critical review of clinical trials in systemic lupus erythematosus. Lupus 2016;25:1122‐40. How to cite this article: Mejri K, Sellami MK, Zaraa IR, Laadhar L, Lahmar H, Mokni M, et al. High B‐cell‐activating factor levels in endemic Tunisian pemphigus. Indian J Dermatol Venereol Leprol 2017;83:496‐9.

Research Reviews Journal of Microbiology and Biotechnology, Jan 4, 2014

The increasing tendency of oxyimino-cephalosporin resistance in Escherichia coli represents a cli... more The increasing tendency of oxyimino-cephalosporin resistance in Escherichia coli represents a clinical threat. Clavulanic acid-inhibitory extended-spectrum β-lactamases (ESBLs)

Journal of clinical and diagnostic research : JCDR, 2015

High morbidity and mortality rates are associated with Methicillin-resistant Staphylococcus aureu... more High morbidity and mortality rates are associated with Methicillin-resistant Staphylococcus aureus (MRSA) because of development of multidrug resistance. Staphylococcus aureus (S. aureus) has the ability to colonize and form biofilms on biomaterials which is causing resistance towards antimicrobials and thus making them difficult to eradicate from the infected hosts. Culture isolation, identification was done following standard protocol and antibiogram of the isolates were done. The detection of MRSA, Macrolide-Lincosamide-Streptogramin B resistance (MLSB), vancomycin resistance phenotypes were done by using cefoxitin disc diffusion test, D zone test and vancomycin E test. Biofilm was detected by Congo red agar method. A total of 100 (31.7%) S. aureus strains were isolated from 315 clinical specimens. The prevalence of MRSA was 47% (47/100) with 85.1% were homogeneous MRSA and 14.9% were heterogeneous. Out of 47 MRSA strains, 63.8% were Hospital acquired-MRSA (HA-MRSA) infections wh...

Geocarto International, 2006

Recent advancements in remote sensing techniques have made it possible to monitor and understand ... more Recent advancements in remote sensing techniques have made it possible to monitor and understand the activities of polar ice sheets, which exert profound influence in controlling global climate. Techniques such as laser altimetry, radar altimetry, InSAR, GPS etc. have been used for generation of DEMs, calculation of ice-sheet mass balance, retrieval of snow-water equivalent and other snow/ice related studies. In the present study, DEMs were generated using SEASAT altimeter data over parts of Antarctica and the maximum height variations in the studied area have been observed as high as 3200 m. From the analysis of the surface slopes, an attempt was made to qualitatively estimate the magnitude and direction of the ice-sheet movement vectors. Coupled with temporal data, both field and satellite derived, the results obtained can be used for modelling of ice-sheet mass balance over Antarctica.

Annals of Tropical Medicine & Parasitology, 2004

ABSTRACT Renal failure was experimentally induced in 36 hamsters by intraperitoneal injection wit... more ABSTRACT Renal failure was experimentally induced in 36 hamsters by intraperitoneal injection with uranyl nitrate (5 mg/kg Twenty-four h later [during acute renal failure (ARF), as indicated by the serum concentrations of creatinine and urea nitrogen] or 72 h later [during chronic renal failure (CRF)] these hamsters plus 18. uninjected. control hamsters were each given a single, intramuscular dose of sodium stibogluconate (120 mg pentavalent antimony/kg). The pharmacokinetic parameters for the antimonial drug were calculated using a non-compartmental model. Urine was collected for 72 h after similar treatment with the antimonial drug. from another 30 hamsters (10 controls. 10 with ARF, and 10 with CRF), so that the fraction of the antimony administered that was subsequently excreted in the urine could be estimated. Compared with the controls, both the hamsters with ARF and those with CRF had significantly higher maximum concentrations of antimony (C-max), significantly larger 'areas under the curve' for the plots of blood concentration. v. time, and significantly longer plasma half-lives (P< 0.001 for each). The mean (S.D.) Values Of C-max, for example were more than three-fold higher in the hamsters with ARF [467.5 (59.04)μg/ml] or CRF [461.1 (68.9)μg/ml) dian in the controls [154.01 (17.3) μg/ml]. The systemic clearance of antimony was also significantly lower in the hamsters with CRF than in the control animals [0.051 (0.002) v. 0.296 (0.047) litres/h/kg: P<0.01]. In addition. the fraction of the antimony administered that was excreted in urine was significantly lower in the animals with ARF (0.25) or CRF (0.08) than in the controls (0.37), indicating significant dysfunction of the kidneys in the hamsters injected with uranyl nitrate. It seems clear that, if severe toxicity is to be avoided, patients with renal dysfunction requiring treatment (for leishmaniasis) with sodium stibogluconate should be given lower doses than similar Cases with normal function.

Best Practices, Experimental Protocols, and Regulations, 2013

Xenobiotica; the fate of foreign compounds in biological systems, Jan 12, 2016

1. Pradigastat is a potent and specific diacylglycerol acyltransferase-1 (DGAT1) inhibitor effect... more 1. Pradigastat is a potent and specific diacylglycerol acyltransferase-1 (DGAT1) inhibitor effective in lowering postprandial triglycerides (TG) in healthy human subjects and fasting TG in familial chylomicronemia syndrome (FCS) patients. 2. Here we present the results of human oral absorption, metabolism and excretion (AME), intravenous pharmacokinetic (PK), and in vitro studies which together provide an overall understanding of the disposition of pradigastat in humans. 3. In human in vitro systems, pradigastat is metabolized slowly to a stable acyl glucuronide (M18.4), catalyzed mainly by UDP-glucuronosyltransferases (UGT) 1A1, UGT1A3 and UGT2B7. M18.4 was observed at very low levels in human plasma. 4. In the human AME study, pradigastat was recovered in the feces as parent drug, confounding the assessment of pradigastat absorption and the important routes of elimination. However, considering pradigastat exposure after oral and intravenous dosing, this data suggests that pradigas...

Journal of Pharmaceutical and Biomedical Analysis, Sep 30, 2000

Clinical pharmacology in drug development, Jan 8, 2016

Pradigastat, a novel diacylglycerol acyltransferase 1 inhibitor, has been studied in familial chy... more Pradigastat, a novel diacylglycerol acyltransferase 1 inhibitor, has been studied in familial chylomicronemia syndrome. To evaluate the effects of supratherapeutic concentrations of pradigastat on the QTc interval, 2 studies were conducted. The first study assessed the safety, tolerability, and pharmacokinetics of single escalating intravenous doses of pradigastat (10, 30, 100, and 115 mg over 60 minutes) in healthy adults. Single intravenous doses were safe, well tolerated, and at the higher doses resulted in supratherapeutic pradigastat exposure. The second was a parallel, 3-arm thorough QTc study in which healthy male subjects were randomized to pradigastat (115 mg intravenously), moxifloxacin (400 mg oral, positive control), or placebo. Following intravenous administration, pradigastat exposure peaked at 4 times the therapeutic concentration and did not prolong the baseline-adjusted and placebo-corrected QTc intervals. During the 60-minute pradigastat infusion, a number of infus...