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N V Nagaraja

Publications and source records attributed to N V Nagaraja.

14 recordsLinked to original sources
PubMed2004

Population pharmacokinetics of methylprednisolone in accident victims with spinal cord injury.

OBJECTIVE: High-dose methylprednisolone (MP) is used to treat acute spinal cord injury (ASCI). The objective of the present study was to determine the pharmacokinetics of the pro-drug methylprednisolone hemisuccinate (MPHS) and MP in accident victims with ASCI. METHODS: The patients (n = 26) were treated with a bolus intravenous loading dose of 30 mg/kg MPHS within 2 h after injury and this was followed by a maintenance infusion of 5.4 mg/kg/h up to 24 h. Blood, CSF and saliva samples were collected up to 48 h after the initial dose and the samples were analyzed by HPLC. Concentration-time data of MPHS and MP were analyzed using population pharmacokinetic analysis with NONMEM software. RESULTS: MPHS and MP could be monitored in plasma and CSF. MP but not MPHS was present in saliva. High variability was seen in the MPHS levels in CSF. The pharmacokinetics of the pro-drug and the metabolite were adequately described by a 2-compartment model with exponential distribution models assigned to the interindividual and the residual variability. At steady state, the average measured MP concentration in plasma was 12.3+/-7.0 microg/ml and 1.74+/-0.85 microg/ml in CSF. The CSF levels of MP could be modeled as a part of the peripheral compartment. CONCLUSION: This study demonstrated that CSF concentrations of MP were sufficiently high after i.v. administration and reflected the concentrations of unbound drug in plasma. Salivary levels of MP were about 32% of the plasma level and may serve as an easily accessible body fluid for drug level monitoring.

Accidents↗
PubMed2001

Optimization of contraceptive dosage regimen of Centchroman.

Centchroman (Ormeloxifene), a non-steroidal oral contraceptive, is used at a dose of 30 mg once a week. To prevent failures in the beginning of the therapy, it is recommended that a dose of 30 mg twice a week for 12 weeks be administered to build up adequate blood levels. The present study was undertaken to simplify the dosing schedule without sacrificing the purpose of twice a week dosing regimen, using modeling and measurement approaches. The drug was given to 60 female volunteers who were divided into seven groups: group I, 30 mg weekly; group II, 30 mg twice a week; group III, 30 mg twice a week for 12 weeks followed by 30 mg weekly; group IV, 30 mg twice a week for 6 weeks followed by 30 mg weekly; group V, 60 mg weekly; and groups VI and VII, single 60 mg loading dose followed by 30 mg weekly doses. The blood samples were collected and analyzed by HPLC. In group I, mean trough concentrations of centchroman and its active metabolite, 7-desmethyl centchroman, were comparable to the steady-state trough concentrations in groups III, IV, VI, and VII. The metabolite to parent drug ratio remained constant in all the groups. The pharmacokinetic parameters in group VII were comparable to those reported after a single 30 mg dose. Dosage regimen VI was more convenient and provided better pregnancy protection (Pearl index 1.18; unpublished report) than regimen III, which is currently on the market and, thus, could be effectively used for contraception.

Centchroman↗
PubMed2001

Population pharmacokinetics of intramuscular quinine in children with severe malaria.

We present the first population pharmacokinetic analysis of quinine in patients with Plasmodium falciparum malaria. Ghanaian children (n = 120; aged 12 months to 10 years) with severe malaria received an intramuscular loading dose of quinine dihydrochloride (20 mg/kg of body weight). A two-compartment model with first-order absorption and elimination gave post hoc estimates for pharmacokinetic parameters that were consistent with those derived from non-population pharmacokinetic studies (clearance [CL] = 0.05 liter/h/kg of body weight; volume of distribution in the central compartment [V(1)] = 0.65 liter/kg; volume of distribution at steady state = 1.41 liter/kg; half-life at beta phase = 19.9 h). There were no covariates (including age, gender, acidemia, anemia, coma, parasitemia, or anticonvulsant use) that explained interpatient variability in weight-normalized CL and V(1). Intramuscular quinine was associated with minor, local toxicity in some patients (13 of 108; 12%), and 11 patients (10%) experienced one or more episodes of postadmission hypoglycemia. A loading dose of intramuscular quinine results in predictable population pharmacokinetic profiles in children with severe malaria and may be preferred to the intravenous route of administration in some circumstances.

Acidosis, Lactic↗
PubMed2000

Population pharmacokinetic/pharmacodynamic modeling of cetrorelix, a novel LH-RH antagonist, and testosterone in rats and dogs.

PURPOSE: Population models for the pharmacokinetic-pharmacodynamic relationship for cetrorelix (CET), a luteinising hormone-releasing hormone (LH-RH) antagonist, and the pharmacodynamic response on testosterone production were investigated in rats and dogs. METHODS: The plasma concentrations of CET and testosterone were determined after intravenous and subcutaneous injections. The population PK/PD-models were developed using P-PHARM software. RESULTS: Absolute bioavailability of cetrorelix was 100% in rats and 97% in dogs. In rats, the pharmacokinetics was explained by a two-compartment model with saturable absorption, while a three-compartment model was used in dogs. Testosterone suppression in both species was described by a sigmoid E(max) model with maximum effect (E(max)) considered as total hormonal suppression. The duration of testosterone suppression in rats was longer at higher doses. The population elimination half-lives after iv-dose were 3.0 h in rats and 9.3 h in dogs. Population mean estimates of IC50 were 1.39 and 1.24 ng/ml in rats and dogs, respectively. CONCLUSIONS: A population pharmacokinetic model was developed to explain the dissolution rate limited absorption from the injection site. The suppression of testosterone could be described by an indirect inhibitory sigmoid E(max) model. In both species 1-2 ng/ml CET in plasma was necessary to suppress testosterone production.

Animals↗
PubMed2000

Pharmacokinetic and pharmacodynamic modeling of cetrorelix, an LH-RH antagonist, after subcutaneous administration in healthy premenopausal women.

PURPOSE: The purpose of this study was the development of pharmacokinetic and pharmacodynamic models for the luteinizing hormone (LH) suppression and subsequent shift in LH surge and follicle-stimulating hormone by cetrorelix in women. BACKGROUND: Cetrorelix is a potent luteinizing hormone-releasing hormone (LH-RH) antagonist and is used for the prevention of the premature ovulation indicated by an LH surge in in vitro fertilization. The pharmacokinetic and pharmacodynamic relationship for the suppression and the shift in the LH surge has not yet been established. METHODS: In a placebo-controlled study, single subcutaneous doses of 1, 3, and 5 mg of cetrorelix were given to 36 subjects on day 8 of the natural menstrual cycle. Cetrorelix, LH, follicle-stimulating hormone, estradiol, and progesterone were determined. RESULTS: Cetrorelix pharmacokinetics were described by a 2-compartment model with a terminal half-life of 56.9 +/- 27.1 hours. Mean shift in LH surge was by 4.1, 7.5, and 9.3 days with the 1-, 3-, and 5-mg doses, respectively. An indirect response sigmoid Emax model was developed for the suppression of LH and the shift in the LH surge. The inhibitory concentration of 50% (for LH suppression) and median effective concentration (for surge shift) estimates were 3.6 ng/mL and 1.6 ng/mL, respectively. The suppression of follicle-stimulating hormone was described by a similar Emax model, with an inhibitory concentration of 50% of 7.25 ng/mL. CONCLUSIONS: A pharmacokinetic and pharmacodynamic model was developed for the transient initial suppression of LH and the subsequent shift in the LH surge after 3 single subcutaneous doses of cetrorelix without ovarian stimulation. A separate model was developed for the suppression of follicle-stimulating hormone by cetrorelix. The shift in the LH surge could be adequately described by the model.

Adult↗
PubMed2000

Pharmacokinetic-pharmacodynamic modeling of testosterone and luteinizing hormone suppression by cetrorelix in healthy volunteers.

Cetrorelix (CET), a potent luteinizing hormone-releasing hormone (LH-RH) antagonist, was recently approved for the prevention of premature ovulation in patients undergoing a controlled ovarian stimulation (COS), followed by oocyte pickup and assisted reproductive techniques (ART), and is currently under clinical trials for benign prostate hyperplasia, endometriosis, and tumors sensitive to sex hormones. CET suppresses luteinizing hormone (LH), follicle-stimulating hormone (FSH), and testosterone (T) in men. The purpose of this study was to evaluate the pharmacokinetics and absolute bioavailability of 3 mg intravenously and subcutaneously administered CET in healthy male and female volunteers and to develop a pharmacokinetic-pharmacodynamic (PK-PD) model to link the plasma concentrations of CET to the T and LH suppression in males. Following intravenous (IV) (n = 5) and subcutaneous (SC) (n = 6) administration of CET acetate, CET and hormone plasma levels were measured by radioimmunoassay (RIA) and enzyme immunoassay (EIA) methods, respectively. Pharmacokinetics of CET was explained by a three-compartment model for the IV route and by a two-compartment model with first-order absorption for the SC route. Average absolute bioavailability after SC administration was 85%. There were no differences in the pharmacokinetics between male and female subjects (ANOVA, p > 0.05). Single IV and SC doses of CET caused immediate and distinct suppression of LH, FSH, and T levels by 80%, 45% and 95% of their baseline levels, respectively. The duration of hormone suppression was longer for the SC route. An indirect-response PK-PD Emax model was developed to link the measured CET plasma concentrations with the respective T or LH levels. In addition, the circadian rhythm of T levels was accounted by including a cosine function in a second separate PD model. The PD model with cosine function was applied to T baseline levels as well as to the suppressed concentrations after CET dosing. The two models adequately described the PK-PD relationship between plasma levels of CET and T suppression following IV and SC dosing. The EC50 values (mean +/- SD) for the suppression of T were similar (p > 0.05) between the two routes of administration and the two models.

Adult↗
PubMed2000

Tissue distribution and excretion of CDRI-81/470 in rats.

Methyl-N[5 [[4-(2-pyridinyl)-1-piperazinyl]carbonyl]- 1H-benzimidazol-2-yl] carbamate (CDRI-81/470) is a broad spectrum anthelmintic agent, effective against both intestinal and systemic parasitism. Tissue distribution and excretion of CDR1-81/470 were studied in rats after a single oral dose of 100 mg kg(-1) CDRI-81/470. One of the metabolites was identified in pilot studies as its N-decarboxylate derivative and characterized by synthesis. HPLC assay methods for the simultaneous estimation of CDRI-81/470 and its N-decarboxylate derivative in tissues, bile, urine, and faeces were developed and validated. The parent compound was quantitated in all major tissues and organs up to 48 h post-dose. Among the tissues other than serum, the highest concentrations of CDRI-81/470 were found in liver, whereas only trace levels were found in brain. Approximately 3% of the administered dose was excreted unchanged in urine at 120 h postdose, whereas approximately 7% was recovered in faeces. The contribution of the biliary route for the excretion of parent compound was less than 0.5%. The N-decarboxylate derivative was quantitated in faeces (1-4%) and bile ( < 0.1%) but was absent in serum, tissues, and urine. An additional metabolite was isolated from bile and characterized as the pyridinyl-5-hydroxy derivative of CDRI-81/470. CDRI-81/470 showed rapid absorption and distribution into all major organs and tissues, and underwent extensive metabolism in rats. Two metabolites in bile were identified and characterized by synthesis.

Animals↗
PubMed2000

Population pharmacokinetics of digoxin in Korean patients.

AIM: Digoxin possesses a narrow therapeutic index and shows a large inter-patient pharmacokinetic variability. The purpose of this study was to develop a population model for the pharmacokinetics of digoxin in Korean patients. METHODS: Plasma concentrations of digoxin after multiple administration at varying dosing schedules in Korean patients were used for population modeling. Data analysis was performed with the P-Pharm software. The data were best fitted by a one-compartment model. The effect of demographic and clinical factors like sex, age, weight, disease state, and renal function on the pharmacokinetic parameters of digoxin was investigated. RESULTS: The study indicated that the clearance of digoxin was influenced by creatinine clearance, while body weight and creatinine clearance were the covariates for its volume of distribution. The population mean estimates for CL and V were 4.4 l/h and 535 l, respectively. Absorption rate constant was lower in females and in the presence of concomitant drug treatment. CONCLUSION: A population pharmacokinetic model for the digoxin pharmacokinetics in a section of Korean patients was developed. The relationships between the pharmacokinetic parameters and the demographic data and the patient-specific covariates were established.

Adult↗
PubMed2000

In vitro recovery of triamcinolone acetonide in microdialysis.

The purpose of this study was to assess the factors affecting the calibration of the microdialysis probe for the in vitro recovery of triamcinolone acetonide (TA). Recoveries of TA were determined in microdialysis, retrodialysis, and no-net flux methods. Experiments were performed at room temperature or 37 degrees C while the reservoir medium was either stirred or unstirred. The effect of the viscosity of the medium on the recovery was studied using methylcellulose gel spiked with TA. Recovery was also calculated by the no-net-flux method in Ringer's solution and in plasma. Stirring the medium increased the recovery of TA by 30%. The recovery was higher at 37 degrees C under stirred or unstirred conditions and was same in either direction of dialysis. Increasing viscosity of the reservoir medium decreased the recovery (55% in Ringer's solution to 14% in 20% methylcellulose gel). Recovery from spiked plasma under stirred conditions was only 15% and this shift which was also seen in no-net-flux method was accounted for by the protein binding. Binding of TA, determined by ultrafiltration, was 20% in 5% gel and 81% in plasma. The recovery determined by the no-net-flux method was similar to the retrodialysis result. Stirring, temperature, viscosity and protein binding in the reservoir medium affected the in vitro recovery of TA.

Administration, Topical↗
PubMed1999

Determination of antifilarial compound UMF-078 and its metabolites in plasma by high-performance liquid chromatography.

UMF-078, methyl (+/-)-[5-(alpha-amino-4-fluorobenzyl)benzimidazol-2-yl]carba mate, is a new antifilarial compound being developed by the World Health Organization. In the present study, a HPLC method for the simultaneous estimation of UMF-078 and its metabolites (flubendazole, decarbamoylated flubendazole, UMF060 and decarbamoylated UMF-060) in plasma was developed, validated and applied to pharmacokinetic studies. Linearity was observed between 20 and 1000 ng/ml for decarbamoylated UMF-060 and between 10 and 500 ng/ml for other analytes. Recoveries were consistent over the concentration ranges studied for all the analytes. Variations in intra- and inter-batch accuracy and precision were within acceptable limits of +/-20% at the lowest limit of quantitation, whereas at higher concentrations it was +/-15%. The analytes showed stability up to two freeze-thaw cycles in plasma. No degradation was observed for any of the analytes even after 72 h of storing the dry plasma extracts at -30 degrees C. The assay method was employed to study the pharmacokinetics of hydrochloride salt of UMF-078 in rats. The parent compound and its metabolites viz: decarbamoylated UMF-060, UMF-060 and flubendazole were quantitated in serum and the compounds could be monitored up to 168 h post-dose.

Animals↗
PubMed1999

Choosing the calibration model in assay validation.

Data transformations and weighting schemes are normally used to obtain the best-fit of standard curves in bioanalysis and the calibration model is usually selected during prevalidation. In the present study, a comparison has been made between unweighted and weighted (1/x, 1/x2, and 1/square root of x) regression models with or without an intercept in achieving the best-fit for the standard curve of CDRI compound 81/470, a new anthelmintic agent, in cow milk. Validation samples in milk at the LLOQ, medium, and high concentrations were also analysed by each of the calibration models. An unweighted regression equation with an intercept overestimated the concentrations at the LLOQ. An unweighted equation without intercept and weighted equations with or without an intercept significantly minimized the bias at the LLOQ without distorting the results at higher concentrations. Hence, an unweighted equation for a straight line passing through the origin was found to be the best model for a standard curve of 81/470 in milk. Similar results were obtained for 81/470 and UMF-078 in serum and plasma, respectively. Bioanalysts should routinely test these models to obtain the best fit model for their calibration curves as part of their assay validation not during prevalidation.

Animals↗
PubMed1997

Estimation of anthelmintic compound 81/470 in cow's milk by high-performance liquid chromatography: method development and validation.

CDRI compound 81/470 is a new broad spectrum anthelmintic agent and is being developed for veterinary use. HPLC assay method for 81/470 in cow milk was developed and validated. The sample preparation consisted of protein precipitation, followed by extraction with ether. Separation was achieved on a C18 column using acetonitrile-buffer (pH 6, 50 mM) mobile phase and the compound was quantitated using fluorescence detector. The recovery of 81/470 was above 90% and was consistent over the calibration range of 10-1000 ng ml-1. Accuracy and precision were determined by analyzing replicate samples and were found to be within acceptable limits. Five freeze-thaw cycles of spiked milk and storage of processed dry residues at -30 degrees C for 7 days did not have any detrimental effect on the stability of 81/470.

Animals↗
PubMed1995

Sensitive high-performance liquid chromatographic method for the determination of methyl N-[5-[[4-(2-pyridinyl)-1-piperazinyl]carbonyl]-1H-benzimidazol-2-yl d carbamate in rat blood.

A sensitive high-performance liquid chromatographic assay has been developed and validated for the determination of methyl N-[5-[[4-(2-pyridinyl)-1-piperazinyl]carbonyl]-1H-benzimidazol-2-y l d carbamate (CDRI compound 81/470) in normal rat blood. The method described herein is simple, with improved selectivity and sensitivity over a previously reported HPLC method. The limit of quantitation is 10 ng/ml (method 1) and 2.5 ng/ml (method 2) in blood, as compared with 40 ng/ml for the previous method. The standard curve in blood is linear over the concentration range 10-1000 ng/ml in method 1 and 2.5-1000 ng/ml in method 2 and the extraction recovery is higher than 80% for both methods.

Animals↗