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Biomedical subjects

C L Kaul

Publications and source records attributed to C L Kaul.

At least 37 records · Page 2Linked to original sources
PubMed2001

Antituberculosis drugs and new drug development.

Tuberculosis affects more than 8 million people and has serious repercussions on economic, psychologic, and social status. Since its declaration as a global emergency in 1993 by the World Health Organization, significant development in the treatment and control of tuberculosis has been the implementation of the short-course directly observed treatment along with fixed dose combinations of existing drugs. However, the currently available therapeutic regimens have inherent disadvantages of long treatment duration, patient noncompliance, and risk of drug resistance. Hence, new antituberculosis drugs that are potent, are active against resistant strains and latent forms, and reduce the treatment period are needed to combat this disease. In this review, the authors discuss new chemical entities that in their opinion have a potential to become new antituberculosis drugs. This article emphasizes the role of biopharmaceutics and pharmacokinetics as an indispensable part in the development of new antituberculosis drugs to overcome the common hurdles such as exorbitant cost, time, and attrition rate involved in the process.

Animals↗
PubMed2001

Pharmacokinetic study of paclitaxel as a 3-hour infusion in an Indian population: 135 mg/m2 vs. 175 mg/m2.

The objective of this clinical study was to determine the pharmacokinetic parameters of paclitaxel at doses of 135 and 175 mg/m2 when given as a 3-hour infusion in an Indian population. Twelve cancer patients of both sexes participated in the study and a parallel experimental design was adopted for the assignment of doses to patients. A solid phase extraction technique was used for sample clean-up followed by a reversed phase HPLC assay for the analysis of paclitaxel in plasma samples. Pharmacokinetic parameters such as Cmax, AUC0-infinity, T1/2 beta, AUMC0-infinity, VSS, VZ and CLT were determined by a compartment model-independent method using a PCNONLIN package. Teff and AUCeff were also calculated and compared at the two doses by considering a plasma concentration of > or = 0.05 microM as threshold. The mean Cmax and AUC0-infinity values were 2.57 microM and 12.06 microM at the 135 mg/m2 dose level while at the 175 mg/m2 dose the values increased to 4.96 microM and 9.52 microM.h/l, respectively. It was found that the 135 mg/m2 dose resulted in greater mean CLT and VSS values than the 175 mg/m2 dose. The disposition of paclitaxel was found to be nonlinear and the pertinent pharmacokinetic parameters were comparable to those from previous clinical studies. It was concluded from the present study that further clinical trials of paclitaxel alone or in combination with other drugs should be undertaken cautiously, taking into consideration its nonlinear pharmacokinetics which necessitate proper adjustment of the infusion schedule and/or dose to avoid any adverse consequences to the patient.

Adult↗
PubMed2001

The role of aldose reductase inhibitors in diabetic complications: recent trends.

Pharmacological intervention of hyperglycemia-induced diabetic complications would be of great clinical significance since it is very difficult to maintain normoglycemia by any means in patients with diabetes mellitus. Several factors and pathways are involved in diabetic complications. One of the major contributory factors is aldose reductase. The beneficial effects of aldose reductase inhibitors in animal models have been reported. The clinical efficacy of these agents, however, is far from satisfactory and the reasons for this may vary. Recent advances in understanding the structure-based functioning, physiological and pathophysiological role of aldose reductase, the use of transgenic animal models and the abundant availability of human aldose reductase have greatly influenced the design and development of its inhibitors, which are highly selective, specific, potent and less toxic. Concurrently, other mechanisms involved in diabetic complications are being explored as targets for better therapeutic agents.

Aldehyde Reductase↗
PubMed2001

Bioequivalence of isoniazid in a two drug fixed dose combination and in a single drug dosage form.

To increase the patient compliance and reduce the risk of drug resistant strains, WHO and IUATLD recommend the use of Fixed Dose Combination (FDC) tablets as a routine therapeutic regimen in Directly Observed Treatment Shortcourse (DOTS). But the main issue in the use of FDC is the quality of the formulation. At present WHO and IUATLD suggest the bioequivalence assessment of only rifampicin from FDC compared to separate formulations. For the therapeutic effectiveness all the components of the FDCs should be bioavailable at tissue site. Also, the primary and acquired resistance rate of isoniazid is much higher compared to other anti-tubercular drugs. Hence, a comparative bioavailability study of isoniazid from a two drugs FDC compared to a separate formulation was carried out on a group of 12 healthy volunteers. When evaluated by normal or log transformed confidence interval, Two Way ANOVA and Hauschke analysis, the bioequivalence limits for AUC0-8 and AUC0-24 were within 0.8-1.25. For Cmax and Tmax, these limits were within 0.7-1.43. Hence, isoniazid from a FDC formulation was found to be bioequivalent to a separate formulation at same dose levels.

Adolescent↗
PubMed2000

Renin release and the sympathetic nervous system.

This review describes the pharmacological aspects of renin release with special emphasis on the role of sympathetic nervous system, catecholamines, adrenoceptor blocking drugs, humoral agents, adrenalectomy and chemical sympathectomy. The effect of antihypertensive drugs and other pharmacological agents on plasma renin activity and the role of renin levels in their antihypertensive effects are also discussed. The role of renin inhibitors as a possible therapeutic class of antihypertensive agents, which could eventually expand the spectrum of antihypertensive therapy and improve our understanding of the role of the renin angiotensin system, is also addressed.

Journal Article↗
PubMed2000

Bioequivalence of rifampicin when administered as a fixed-dose combined formulation of four drugs versus separate formulations.

A bioequivalence study of the antitubercular drug rifampicin in a four-drug combination (rifampicin, isoniazid, pyrazinamide and ethambutol) and separate formulations of the drugs at the same dose levels was carried out in a group of 22 healthy male volunteers. The investigation was designed as an open crossover study. The drugs were administered once in individual formulations and once in a fixed-dose combination. The WHO-approved protocol was followed according to which six blood samples were collected over a period of 8 h for each volunteer and each experimental session. Pooled urine samples were also collected during the study. Rifampicin and desacetyl rifampicin concentrations in both plasma and urine samples were assessed. Various pharmacokinetic parameters such as AUC0-8 h, Cmax and Tmax were calculated for both rifampicin and desacetyl rifampicin. The results indicated that combined (the four-drug combination) and separate formulations are bioequivalent for rifampicin.

Adult↗
PubMed2000

Evaluation of rifampicin bioequivalence in fixed-dose combinations using the WHO/IUATLD recommended protocol.

For an accurate assessment of rifampicin bioequivalence from fixed-dose combinations (FDCs), and to reduce the time and cost constraints associated with bioequivalence studies, the World Health Organization and the International Union Against Tuberculosis and Lung Disease have developed a simplified screening protocol. This study was undertaken with the objective of testing the applicability of this protocol for all types of FDCs. Data were obtained for volunteers common to three studies, and pharmacokinetic parameters were evaluated by different statistical tests. From the results, it has been demonstrated that the simplified screening protocol is suitable for evaluating the bioequivalence of rifampicin in all the types of FDCs available on the market.

Adult↗
PubMed1999

Determination of rifampicin and its main metabolite in plasma and urine in presence of pyrazinamide and isoniazid by HPLC method.

A reversed phase HPLC method is described for the simultaneous estimation of rifampicin and its major metabolite desacetyl rifampicin, in the presence of isoniazid and pyrazinamide, in human plasma and urine. The assay involves simple liquid extraction of drug, metabolite and internal standard (rifapentine) from biological specimens and their subsequent separation on a C18 reversed phase column and single wavelength UV detection. In plasma as well as in urine samples, all the three compounds of interest eluted within 17 min. Using methanol-sodium phosphate buffer (pH 5.2; 0.01 M) (65:35, v/v) as mobile phase under isocratic conditions, it was established that isoniazid, pyrazinamide and ascorbic acid (added to prevent oxidative degradation of analytes) did not interfere with the analyte peaks. Recoveries (extraction efficiency) for drug were greater than 90% in both plasma and urine, whereas for metabolite the values were found to be 79 and 86% in plasma and urine, respectively. The plasma and urine methods were precise (total coefficient of variation ranged from 5 to 23%) and accurate (-7 to 5% of the nominal values) for both the analytes. Individual variance components, their estimates and their contribution to the total variance were also determined. Using the same method, unknown samples supplied by WHO were assayed and good correlations were obtained between the found and intended values. The method developed proved to be suitable for simultaneous estimation of rifampicin and desacetyl rifampicin in plasma and urine samples.

Antibiotics, Antitubercular↗
PubMed1999

The WHO simplified study protocol in practice: investigation of combined formulations supplied by the WHO.

SETTING: The benefits of fixed-dose combination (FDC) formulations of rifampicin, isoniazid and pyrazinamide over individual formulations are well recognised. OBJECTIVES: To evaluate the comparative bioavailability of antituberculosis drugs in FDC formulations and the same doses in separate formulations of antituberculosis drugs, using a simplified protocol developed by the World Health Organization (WHO). METHODS: Twenty healthy volunteers were included in the study and evaluated for bioequivalence of rifampicin in a cross-over experimental design. After administration of drugs the plasma concentration of rifampicin and desacetyl-rifampicin was measured repeatedly up to 8 hours in both plasma and urine. Various pharmacokinetic parameters of rifampicin, such as Cmax, Tmax, elimination rate constant, area under the curve (AUC) up to 8 hours and absorption efficiency were calculated. RESULTS: No significant differences were observed between the FDCs and separate formulations when Cmax, Tmax, AUC and absorption efficiencies were compared by parametric test and Hauschke's analysis. CONCLUSION: The WHO simplified protocol is suitable for evaluating bioequivalence of antituberculosis drugs.

Adolescent↗
PubMed1999

Bioequivalence study of rifampicin in fixed-dose combination of rifampicin and isoniazid vs. separate formulations.

The benefits of fixed-dose combinations of antituberculosis agents are well recognized by the World Health Organization (WHO) and International Union Against Tuberculosis and Lung Disease (IUATLD) and preferred over separate formulations. Therefore, a comparative bioequivalence study of rifampicin and isoniazid together in a fixed-dose combination and separately (at the same dose levels) was performed on a group of 12 healthy subjects. The study was designed as a single-blind, crossover experiment. Nine blood samples were collected from each subject over a period of 24 h. The plasma concentrations of rifampicin were assessed by a method developed in this laboratory. Various pharmacokinetic parameters of rifampicin such as AUC, Cmax, Tmax and t1/2 were also calculated. The study demonstrates that a fixed-dose combination (test formulation) and separate formulations (standard formulations) are bioequivalent for rifampicin.

Adult↗
PubMed1999

Insulin resistance: current therapeutic approaches.

Insulin resistance, an impaired biological response to either exogenous or endogenous insulin occurs in a majority of the diabetic population with type II diabetes. One of the current approaches for treating insulin resistance associated with NIDDM is the use of insulin sensitizing agents. Elucidation of the mechanism(s) of these agents may provide new targets for which selective ligands with better efficacy and low toxicity can be found.

Journal Article↗
PubMed1997

Evaluation of BTS 67 582, a novel antidiabetic agent, in normal and diabetic rats.

1. The effect of BTS 67 582, a novel antidiabetic agent, has been evaluated on plasma glucose and plasma insulin in normal and streptozotocin-induced diabetic rats. 2. BTS 67 582 (3 to 300 mg kg-1, p.o.) caused a dose- and time-dependent reduction in plasma glucose and an increase in plasma insulin in both fasted and glucose-loaded normal rats. The ED50 for the glucose lowering effect of BTS 67 582 in fasted rats was 37.6, 18.4 and 18.5 mg kg-1 at 1, 2 and 4 h after administration respectively. 3. In streptozotocin-induced (50 mg kg-1, i.v.) diabetic rats, BTS 67 582 (37-147 mg kg-1, p.o.) caused significant reductions of plasma glucose following a glucose load, whereas glibenclamide (100 mg kg-1, p.o.) was ineffective. BTS 67 582 significantly increased plasma insulin compared to controls whereas glibenclamide did not. 4. BTS 67 582 did not displace [3H]-glibenclamide from its binding sites in rat brain, guinea-pig ventricle or the HIT-T15 insulinoma beta-cell line. BTS 67 582 does not therefore appear to modulate its action via an effect on the 'sulphonylurea' receptor. 5. In fasted rats, the glucose lowering effect of BTS 67 582 (100 mg kg-1 p.o.) and glibenclamide (1 mg kg-1, p.o.) were antagonized by diazoxide (30 mg kg-1, i.p.). In addition BTS 67 582, like glibenclamide, caused a dose-dependent rightward shift of cromakalim-induced relaxation of noradrenaline precontracted rat aortic strips, suggesting the involvement of KATP channels. 6. In summary, BTS 67 582 produces a blood glucose-lowering effect in normal and streptozotocin-induced diabetic rats associated with increased insulin concentrations. This effect appears to be due to a blockade of ATP-sensitive potassium channel activity via a different binding site to that of glibenclamide.

Animals↗
PubMed1996

A simple quantitative in vitro macrophage migration assay.

An in vitro macrophage chemotaxis model using mouse peritoneal non-elicited resident macrophage cells and chemotaxins containing mediators of non-specific elicitors such as oyster glycogen or sodium caseinate has been described. Macrophage cells accumulation in mouse peritoneal cavity was maximum at 48 hr after injecting (i.p.) oyster glycogen (2.5%) or sodium caseinate (12%), 0.5 ml/mouse. Chemotaxins containing mediators were prepared from these mice by peritoneal lavage and termed as routine 'diluted' cocktail and 'concentrated (3 times)' cocktail. Chemotaxis assays were carried out in a modified Boyden chamber using a 48-well microchemotaxis assembly. In vitro results showed higher macrophage chemotaxis response against the 'concentrated' cocktails as compared to routine 'diluted' cocktail. Macrophages exhibited cell density dependent increase in the responsiveness to chemoattractant and macrophage cell density of 4 x 10(6) per ml concentration in the upperwell was found to be optimum. Macrophage responsiveness was seen better with sodium caseinate cocktail as compared to oyster glycogen in vitro as well as in vivo. DMSO (Dimethyl Sulphoxide) solvent (0.25% conc.) did not interfere with normal macrophage chemotaxis. Both CO2 incubator (5% CO2 in air) and BOD incubator with humidified chamber favoured chemotaxis. In vitro test system described can be used as a model to study the effect of anti-inflammatory compounds directly on the macrophage chemotaxis.

Animals↗
PubMed1995

A comparative study of experimental caecal amoebiasis and the evaluation of amoebicides.

Caecal amoebiasis models (mouse, hamster and rat) were compared for amoebic infection and chemotherapeutic evaluation using a pathogenic strain of Entamoeba histolytica of human origin. Caecal infection in the hamster was of the acute type, with a large number of amoebae in the caecal tissue, whereas the amoebae in rats were seen in the lumen, on the mucosal surface. Amoebic lesions in the mouse caecum were of moderate severity. The mouse model responded to both metronidazole (tissue amoebicide) and diloxanide furoate (luminal amoebicide), whereas the hamster model only responded well to metronidazole and the rat model only to diloxanide furoate. Using the mouse as a primary screening model, a new oxadiazole compound, BTI 2405E, was found to have tissue and luminal amoebicidal activity. In rodent caecal models, a single dose of BTI 2405E was found to be more effective than one of metronidazole or diloxanide furoate. The mouse model appears to be the most useful for primary screening of anti-amoebic compounds.

Amebicides↗
PubMed1993

Activity of a new oxadiazole compound, against experimental infections with Entamoeba histolytica and Giardia lamblia in animal models.

BTI 2286E(+/-)-E-3-(4-methylsulphinylstyryl)-1,2,4-oxadiazole has demonstrated potent amoebicidal activity in a single-dose treatment against Entamoeba histolytica infection in the livers of golden hamsters and the caeca of mice, hamsters and rats. It has intra luminal activity against Entamoeba criceti, a natural infection in golden hamster, and anti-giardial activity against Giardia lamblia infection in suckling mice. BTI 2286E is more potent than metronidazole in extra intestinal, intra luminal amoebiasis models and has significant advantages in that it is non-mutagenic in the Ames test and has a shorter duration of effective treatment.

Amebicides↗
PubMed1993

Pharmacokinetics and amoebicidal activity of (+-)-(E)-3-(4- methylsulphinylstyryl)-1,2,4-oxadiazole (BTI 2286E) and its sulphone metabolite (BTI 2571E) in the golden hamster, Mesocricetus auratus.

BTI 2286E is a 1,2,4-oxadiazole with amoebicidal activity. Three groups of golden hamsters received single doses of BTI 2286E or its sulphone metabolite BTI 2571E as either BTI 2286E 60 mg/kg po or BTI 2571E 60 mg/kg po or BTI 2571E 60 mg/kg ip. Blood samples were collected up to 8 h post-dose and plasma concentrations of BTI 2286E and BTI 2571E were assayed by HPLC. BTI 2286E was rapidly absorbed, extensively metabolized during first pass and rapidly eliminated with a plasma elimination half-life of 1.32 h. Conversion to BTI 2571E was the major pathway of elimination. BTI 2571E had approximately 40% bioavailability after oral administration. After intraperitoneal administration its absorption was slow and prolonged, with an apparent elimination half-life of 2.77 h, considerably longer than the elimination half-life of 0.67 h observed when BTI 2571E was formed as a metabolite, in vivo. The amoebicidal activity of both the compounds was evaluated in the acute hamster hepatic model of amoebiasis. Both BTI 2286E and BTI 2571E were administered as single graded po or ip dose, and their dose-response profiles were characterized. BTI 2571E exhibited poor activity after oral administration (ED50 70 mg/kg) probably due to poor bioavailability, but after intraperitoneal administration its activity (ED50 40 mg/kg) was comparable to that of BTI 2286E after po or ip administration.

Administration, Oral↗