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Biomedical subjects

Gopal Krishna

Publications and source records attributed to Gopal Krishna.

6 recordsLinked to original sources
PubMed2005

Nano-assembly of manganese peroxidase and lignin peroxidase from P. chrysosporium for biocatalysis in aqueous and non-aqueous media.

Development, characterization, and activity studies of nano-assemblies of lignin peroxidase (LiP), and manganese peroxidase (MnP) from Phanerochaete chrysosporium on flat surfaces as well as colloidal particles have been investigated. These assemblies of LiP and MnP were fabricated with polyelectrolytes-poly(ethylenimine) (PEI), poly(dimethyldiallylammonium chloride) (PDDA), and poly(allylamine) (PAH)-using a layer-by-layer self-assembly technique (LbL). Characterization of these assemblies on flat surfaces was monitored using quartz crystal microbalance (QCM), while assemblies on microparticles such as melamine formaldehyde (MF) were carried out with zeta potential analyzer (ZPA). A unique dynamic adsorption-desorption of the enzyme layers is observed during the assembly. All the nano-assemblies of LiP and MnP can effectively oxidize veratryl alcohol (VA) to its aldehyde for an extended period of time. The effect of different polyions and the number of polyion layers on the activities of LiP and MnP nano-assembly was also examined. It is observed that drying of enzyme layer during the assembly and the use of non-aqueous media, such as acetone can significantly reduce the activity of the enzymes. Enzyme activity reaches a minimum when the concentration of acetone is increased to 30%; however, the activity can be restored to its original value by increasing the concentration of aqueous media. Preliminary studies using assemblies of LiP and MnP on MF microparticles further demonstrate the feasibility of developing potential systems for degradation of environmental pollutants.

Adsorption↗
PubMed2005

Oral bioavailability of posaconazole in fasted healthy subjects: comparison between three regimens and basis for clinical dosage recommendations.

BACKGROUND AND OBJECTIVE: Posaconazole is a potent, extended-spectrum triazole antifungal agent currently in clinical development for the treatment of invasive fungal infections. This study was conducted to compare the bioavailability and resulting serum concentrations of posaconazole 800 mg following administration of three different dose regimens to fasting adults. STUDY DESIGN: This was a randomised, open-label, three-way crossover study. METHODS: Subjects fasted 12 hours before and 48 hours after the administration of posaconazole oral suspension (800 mg) given as a single dose (regimen A), 400 mg every 12 hours (regimen B) or 200 mg every 6 hours (regimen C). Plasma posaconazole concentrations were determined for 48 hours after the initial dose and subjects completed a 1-week washout period between treatment regimens. A one-compartment oral model with first-order rate of absorption and first-order rate of elimination was fitted to the plasma concentration-time data. Differences in exposure were investigated by allowing the bioavailability fraction to vary among regimens. STUDY PARTICIPANTS: A total of 18 healthy men were enrolled in and completed the study. MAIN OUTCOME MEASURES AND RESULTS: Posaconazole relative bioavailability was estimated to be significantly different among regimens (p < 0.0001) and increased with the number of doses, such that regimen B/regimen A = 1.98 +/- 0.35, representing a 98% increase, and regimen C/regimen A = 3.20 +/- 0.69, or a 220% increase. With use of the one-compartment model, the population steady-state values for area under the concentration-time curve over 24 hours were predicted to be 3900, 7700 and 12 400 microg.h/L, with average plasma concentrations of 162, 320 and 517 microg/L for regimens A, B and C, respectively. CONCLUSION: These data suggest that divided daily dose administration (every 12 or 6 hours) significantly increases posaconazole exposure under fasted conditions.

Administration, Oral↗
PubMed2004

Neonatal anesthesia.

The physiology of the preterm and term neonate is characterized by a high metabolic rate, limited pulmonary, cardiac and thermoregulatory reserve, and decreased renal function. Multisystem immaturity creates important developmental differences in drug handling and response when compared to the older child or adult. Neonatal anesthetic management requires an understanding of the pharmacophysiologic limitations of the neonate as well as the pathophysiology of coexisting surgical disease. This review addresses the pertinent aspects of neonatal physiology and pharmacology, general considerations in the anesthetic care of surgical neonates, and concludes with a brief review of the anesthetic management of neonates with necrotizing enterocolitis, diaphragmatic hernia, and tracheoesophageal fistula.

Anesthesia↗
PubMed2004

Pharmacodynamics of a new triazole, posaconazole, in a murine model of disseminated candidiasis.

Previous in vivo studies have characterized the pharmacodynamic characteristics of two triazole compounds, fluconazole and ravuconazole. These investigations demonstrated that the 24-h area under the concentration-time curve (AUC)/MIC ratio is the critical pharmacokinetic-pharmacodynamic (PK-PD) parameter associated with treatment efficacy. Further analysis demonstrated that a free-drug triazole 24-h AUC/MIC ratio of 20 to 25 was predictive of treatment success in both experimental models and clinical trials. We used a neutropenic murine model of disseminated Candida albicans infection to similarly characterize the time course activity of the new triazole, posaconazole. The PK-PD parameters (percent time above MIC, AUC/MIC ratio, and peak serum drug level/MIC ratio) were correlated with in vivo efficacy, as measured by organism number in kidney cultures after 48 h of therapy. Kinetics and protein binding following oral posaconazole dosing were performed in neutropenic infected mice. Peak levels and AUC from 0 h to infinity values were nonlinear over the 16-fold dose range studied. Serum drug elimination half-life ranged from 12.0 to 17.7 h. Protein binding was 99%. Single dose postantifungal effect studies demonstrated prolonged suppression of organism regrowth after serum posaconazole levels had fallen below the MIC. Treatment efficacy with the four dosing intervals studied was similar, supporting the AUC/MIC ratio as the PK-PD parameter predictive of efficacy. Nonlinear regression analysis also suggested that the AUC/MIC ratio was strongly predictive of treatment outcomes (AUC/MIC ratio R(2) = 83%; peak serum drug/MIC ratio R(2) = 85%; time that serum levels of posaconazole remained above the MIC R(2) = 65%). Similar studies were conducted with 11 additional C. albicans isolates with various posaconazole susceptibilities (MIC, 0.015 to 0.12 micro g/ml) to determine if a similar 24-h AUC/MIC ratio was associated with efficacy. The posaconazole free-drug AUC/MIC ratios were similar for all of the organisms studied (6.12 to 26.7, mean +/- SD = 16.9 +/- 7.8, P value, 0.42). These free-drug AUC/MIC ratios are similar to those observed for other triazoles in this model.

Animals↗
PubMed2002

The use of in vitro metabolic stability for rapid selection of compounds in early discovery based on their expected hepatic extraction ratios.

PURPOSE: The in vivo hepatic extraction ratio of cynomolgus monkeys was correlated with the corresponding in vitro extraction ratios that were determined in monkey microsomal incubations. METHOD: For compounds that are eliminated mainly through liver phase I metabolism, the extraction ratio calculated from liver microsomal stability studies should correlate with their in vivo hepatic extraction ratios and also with their oral bioavailability in monkey. We used both well-stirred and parallel tube models of intrinsic clearance for the correlation. We also calculated extraction ratios for compounds within a given therapeutic area from fraction absorbed values that were estimated from the Caco-2 absorption model. RESULT: The present data show that in vitro extraction ratios in monkey microsomes are predictive of the in vivo hepatic extraction ratios in monkeys. All compounds with high extraction ratio (>70%) in vivo were successfully classified as high-extraction-ratio compounds based on the in vitro monkey microsomal stability data. From the results of this study, it appears that the parallel tube model provided a slightly better classification than the well-stirred model. CONCULUSIONS: The present method appears to be a valuable tool to rapidly screen and prioritize compounds with respect to liver first-pass metabolism in monkeys at an early phase of drug discovery.

Animals↗