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Biomedical subjects

D R Krishna

Publications and source records attributed to D R Krishna.

At least 19 recordsLinked to original sources
PubMed2005

Cytochrome P450 3A: genetic polymorphisms and inter-ethnic differences.

Ethnicity is a demographic variable that plays an important role in interindividual variability of drug metabolism and response. The genetic variations of drug-metabolizing enzymes exhibiting interindividual differences of drug metabolism also show differences between populations. The reason for this is that the frequency of a polymorphism is found to differ between populations. The other reason is that different variants are seen in different populations. Most drugs are biotransformed in the body by cytochrome P450. The CYP3A isozymes are responsible for the metabolism of 50-60% of all currently prescribed drugs. Studies have shown that there is variability in CYP3A activity and also inter-ethnic differences in CYP3A-mediated drug metabolism. The purpose of this review is to focus on the genetic polymorphism and ethnic variations in CYP3A-mediated oxidative drug metabolism.

Cytochrome P-450 CYP3A↗
PubMed2003

Selective activation of anthracycline prodrugs for use in conjunction with ADEPT.

A major limitation in the chemotherapy of cancer results from the lack of tumor specificity displayed by most anticancer drugs. In this regard, a great deal of research has been focused on the development of new chemotherapeutic agents that are able to effectively exploit the differences between neoplastic and normal tissues. Several cancerous tissues and tumors are rich in certain lysosomal enzymes as compared with those found in the normal tissues. Thus, a prodrug can be designed to selectively target such tumor cells where it can be activated to antineoplastic agent by tumor-associated antigen-targeted monoclonal antibody-enzyme conjugate (antibody directed enzyme prodrug therapy strategy) or by the action of an enzyme present at high levels in tumor tissues (prodrug monotherapy strategy). This approach protects the normal cells from the cytotoxic effects of the drug. In the last few years, a number of new MAb-based reagents has been clinically approved (Rituxan, Herceptin and Panorex), and several others are now in advanced clinical trials. This review focuses on the design of several different enzyme/prodrug combinations with an emphasis on mechanistic insight and clinical activity.

Anthracyclines↗
PubMed2003

HPLC determination of valproic acid in human serum.

A HPLC method for the determination of valproic acid (VA) in human serum using diazepam as internal standard (I.S.) is described. The eluates were separated with a C18 250 x 4.6 mm internal diameter reversed phase column maintained at a temperature of 50 degrees C. A mobile phase consisting of acetonitrile and 0.05 M phosphate buffer (pH 3.0) 45:55 v/v was used at a flow rate of 1.2 ml/min. Wavelength was switched from 360 nm to 210 nm during valproic acid retention. The method was linear over a concentration range of 20 to 160 microg/ml for valproic acid. Recovery was greater than 94% over a concentration range of 20 to 120 microg/ml and the limit of quantitation was 1 microg/ml. The intra day and inter day relative standard deviation (R.S.D.) measured at 20, 60, 80 and 120 microg/ml ranged from 1.46 to 5.34% and 0.83 to 5.03% respectively. The method is simple, rapid, accurate and sensitive and it was used for Therapeutic Drug Monitoring (TDM) in Indian epileptic patient population. The results obtained with this method correlated well with clinical practice.

Anticonvulsants↗
PubMed2002

Validated HPLC method for the determination of tinidazole in human serum and its application in a clinical pharmacokinetic study.

A high performance liquid chromatographic (HPLC) method for the determination of tinidazole in human serum using metronidazole as internal standard (IS) is described. Protein precipitation is used for the preparation of sample. Mobile phase consisting of 0.002 M phosphate buffer, methanol and acetonitrile mixture (85:7.5:7.5/v/v/v) was used at a flow rate of 1 ml/min on a C18 column. The eluate was monitored using an UV/Vis detector set at 320 nm. Ratio of peak area of analyte to IS was used for quantification of serum samples. The absolute recovery was greater than 95% over a concentration range of 0.5 to 30 micrograms/ml and the limit of quantitation was 0.05 microgram/ml. The intra-day relative standard deviation (RSD) measured at 0.5, 5, 15 and 30 micrograms/ml ranged from 0.36 to 6.14%. The inter-day RSD ranged from 1.14 to 4.21%. The method is simple, sensitive and has been successfully used in a pharmacokinetic study conducted in healthy human volunteers.

Antitrichomonal Agents↗
PubMed2002

Validated HPLC method for determination of chlorzoxazone in human serum and its application in a clinical pharmacokinetic study.

A high performance liquid chromatographic (HPLC) method for the determination of chloroxazone in human serum using phenacetin as internal standard (IS) is described. Protein precipitation is used for preparation of the sample. A mobile phase consisting of acetonitrile and 0.5% acetic acid in water mixture (40:60 v/v) was used at a flow rate of 1 ml/min on a C18 column. The eluate was monitored using an UV/VIS detector set at 287 nm. Ratio of peak area of analyte to IS was used for quantification of serum samples. The absolute recovery was greater than 96% over a concentration range of 1 to 100 micrograms/ml and the limit of quantitation was 0.05 microgram/ml. The intra-day relative standard deviation (RSD) measured at 1, 10, 50, and 100 micrograms/ml ranged from 0.9 to 5.1%. The inter-day RSD ranged from 0.6 to 3.0%. The method is simple, sensitive and has been successfully used in pharmacokinetic study conducted in healthy human volunteers.

Adult↗
PubMed2001

Assessment of antioxidant activity of some antileprotic drugs.

DPPH (alpha,alpha-diphenyl-beta-picryl hydrazyl) (CAS 217-591-8), a stable free radical can be used to determine the antioxidant activity (AOA) of some drugs. In the present study the DPPH method was used for the first time to test AOA of dapsone (CAS 80-08-0), clofazimine (CAS 2030-63-9) and rifampicin (CAS 13282-42-1) in vitro and deproteinated blood method. Ascorbic acid (CAS 50-81-7) was used as a control in the study, which showed concentration-dependent antioxidant activity. Rifampicin showed a per se effect but it showed concentration dependent decrease in the DPPH absorbance. Ascorbic acid, dapsone and rifampicin showed DPPH scavenging activity both in vitro and deproteinated blood method. Clofazimine did not have any influence on DPPH. This method may be extended to different drugs for testing their AOA in biological fluids.

Adult↗
PubMed2001

Influence of rice bran oil on serum lipid peroxides and lipids in human subjects.

To study the effect of rice bran oil (RBO) on serum lipids and lipid peroxides in human volunteers. Nine healthy volunteers, aged between 42 to 57 years were given 75 ml of RBO thrice daily as the cooking medium with break fast, lunch and dinner for a period of 50 days. At the beginning and at the end of 50 days, 5 ml of blood were drawn from an ante cubital vein. Serum lipids and lipid peroxides levels were estimated from the blood sample. There was a significant decrease in the levels of lipid peroxides, triglycerides, LDL, VLDL, and total cholesterol in human volunteers who switched over to RBO. RBO has evidently antioxidant and antilipidemic activities in human subjects.

Adult↗
PubMed1999

Does pH 6 beta-galactosidase activity indicate cell senescence?

Apparently two forms of beta-galactosidase (beta-GAL) in cells or tissue sections can be detected by enzyme histochemical staining (X-GAL). Using a sensitive and specific HPLC method we have determined the pH dependent activity of beta-GAL in cell lines of lung carcinoma (A549), colon carcinoma (Caco2-TC7), promyelocytic leukemia (HL60), hepatoma (HepG2) and human liver homogenates. The HPLC method has been validated and the influence of pH and substrate concentration was studied. There was a good linear correlation between HPLC and quantitative enzyme histochemistry (pH 4.5: r = 0.985; pH 6.0: r = 0.967). Both, pH 4.5 beta-GAL and pH 6 beta-GAL could be demonstrated in all biological material tested and pH 6 beta-GAL activity was always lower (25-50%) than pH 4.5 activity. In Caco2-TC7 cells both activities increased by a factor of 10 from day 3 to day 17 after seeding. In addition, since the beta-GAL activity decreased with increase in pH both in human liver homogenates (independent of the age of the donor) as well as in tumor cell lysates in a similar fashion we believe that the activity at pH 6 can hardly be considered as an exclusive 'senescence marker'. In addition, the more sensitive HPLC method could demonstrate activity in cells that showed negative reaction with X-GAL.

Adult↗
PubMed1998

Transdermal delivery of isosorbide 5-mononitrate from a new membrane reservoir and matrix-type patches.

Isosorbide 5-mononitrate (5-ISMN) has a direct relaxing effect on vascular smooth muscle. In the present study we developed matrix and reservoir-type transdermal patches of 5-ISMN. We investigated the usefulness of a new film-forming material isolated from the roots of Salacia macrosperma to serve as rate-controlling membrane for the reservoir-type patches. Matrix-type patches were formulated using polyvinyl chloride. Permeation studies through rat skin were conducted on both types of patches using Teflon cells. The mean +/- SD flux values from the matrix- and reservoir-type patches were 99.55 +/- 22.89 and 31.82 +/- 8.31 micrograms/cm2.hr, respectively.

Administration, Cutaneous↗
PubMed1998

Pro- and anti-oxidant effects of some antileprotic drugs in vitro and their influence on super oxide dismutase activity.

The effect of ofloxacin (CAS 82419-36-1), dapsone (CAS 80-08-0), rifampicin (CAS 13282-46-1) and clofazimine (CAS 2030-63-9) on the generation of superoxide anions was studied in vitro. The drugs were incubated with a superoxide generating system (photochemical reaction between riboflavin and dianisidine). The change in optical density was measured. The optical density was increased with dapsone and ofloxacin and decreased in presence of clofazimine and rifampicin. This result indicates that ofloxacin and dapsone have an antioxidant property, whereas clofazimine and rifampicin behave as pro-oxidants.

Antioxidants↗
PubMed1997

Characterization of clofazimine metabolites in humans by HPLC-electrospray mass spectrometry.

Clofazimine (CAS 2030-63-9) is an important drug used in the treatment of leprosy. Its important metabolites are investigated by thin layer chromatography (TLC), HPLC (diode array) and HPLC-electrospray mass spectrometry. The resulting analytical data, extraction, isolation and characterization methods are presented. Their applicability is described for human urine analysis.

Adult↗
PubMed1995

In vitro protein binding and tissue distribution of D(+) usnic acid.

In vitro protein binding of D(+) usnic acid in rabbit plasma and purified bovine serum albumin was investigated by equilibrium dialysis. The drug was highly protein bound, approximately 99.2%, and the extent of protein binding remained constant at usnic acid concentrations in the range of 1-5 micrograms/ml. The extent of binding, however, tended to decrease at low albumin concentrations and higher drug concentrations; Scatchard plot analysis indicated the existence of two classes of binding sites with association constants of 34.3 x 10(-6) and 1.43 x 10(-6) M respectively. Tissue distribution studies of usnic acid were undertaken in rats following i.p. administration. Usnic acid was well distributed into well perfused organs. The tissue/plasma ratio in lungs was high, which could be advantageous in a therapeutic agent for pulmonary tuberculosis.

Animals↗
PubMed1995

Tissue distribution and deposition of clofazimine in rat following subchronic treatment with or without rifampicin.

Tissue distribution and deposition characteristics of clofazimine (CAS 2030-63-9), an antileprotic drug in rats have been investigated following controlled sub-chronic administration (p.o.) for a period of 1-2 months. The drug was administered alone at a dose of 20 mg/kg body weight and in combination with rifampicin (CAS 13292-46-1) (20 mg/kg p.o.). Various tissues (liver, lung, spleen, small intestine, brain, heart, kidney, skin, stomach and subcutaneous fat) were analyzed for clofazimine in all the treated groups. High levels (range 0.9-3.6 mg/g of wet tissue) were observed in tissues having reticuloendothelial components. In other tissues the levels were relatively lower (range 3-114 micrograms/g of wet tissue). Histopathological studies revealed that clofazimine is deposited in many tissues in the form of reddish-orange crystals. Concomitant treatment with rifampicin did not significantly alter tissue distribution or deposition profile of clofazimine nor did it influence the histopathology.

Animals↗
PubMed1994

Pharmacokinetics and effects on intracranial pressure of sufentanil in head trauma patients.

Ten patients with head trauma received an intravenous bolus of sufentanil (2 micrograms kg-1) followed at 30 min by infusion of sufentanil (median 150 micrograms h-1) and midazolam (median 9.0 mg h-1) over 48 h. Median (range) values of pharmacokinetic parameters for sufentanil were: t1/2,z = 16 (7-49) h; CL = 1215 (519-2550) ml min-1; CLR = 7 (2-38) ml min-1; Vss = 10.0 (6.8-24.2) 1 kg-1. Decreases in intracranial pressure (ICP) (from 16.1 +/- 1.7 to 10.8 +/- 1.3 mm Hg; P < 0.05) and mean arterial blood pressure (MAP) (from 85.5 +/- 3.9 to 80.2 +/- 4.9 mm Hg; P < 0.05) were observed within 15 min of the bolus injection of sufentanil and remained unchanged thereafter. Thus, cerebral perfusion pressure (CPP = MAP-ICP) was stable.

Adolescent↗
PubMed1994

Extrahepatic metabolism of drugs in humans.

Although the liver plays the major role in drug metabolism [e.g. by oxidative cytochrome P450 (CYP)-dependent phase I and conjugation or phase II reactions], drug metabolising enzymes are also present at other sites. Depending on the particular drug and enzymes involved, these extrahepatic organs and/or tissues can contribute to the elimination of drugs and, thus, should be considered in any discussion of drug disposition. By the use of relatively new techniques in molecular biology, e.g. immunoblotting with antibodies directed to various CYP isoenzymes, the tissue and organ distribution of these drug metabolising enzymes can be determined. In addition, microsomal and cytosolic enzyme activity and capacity can be directly assessed in vitro by incubation of the enzymes with the drugs of interest. Both approaches have demonstrated the presence of 3 CYP families at different extrahepatic sites, such as the mucosa of the gastrointestinal tract, kidney, lung, brain or skin. Enzymes including epoxide hydrolases, hydrolysing enzymes, glutathione S-transferases, UDP-glucuronosyltransferases, sulphotransferases, N-acetyltransferases, and methyltransferases are discussed. Indirect evidence of extrahepatic drug metabolism can be generated from pharmacokinetic studies whenever total body clearance exceeds liver blood flow, or when severe liver dysfunction or anhepatic conditions do not affect metabolic clearance. Indeed, extrahepatic metabolism has been demonstrated for numerous drugs. Therefore, the metabolic profile and sites of enzymatic reactions for each drug should be determined.

Brain↗
PubMed1993

Comparative evaluation of ulcer prevention efficacy of orally, rectally and sublingually administered omeprazole in three acute gastric ulcer models in rats.

Ulcer prevention efficacy of orally, rectally and sublingually administered omeprazole was evaluated and compared using ulcer index and percentage inhibition of ulcerogenicity in three different acute gastric ulcer models viz, indomethacin, 0.6N HCl and aspirin (after pylorus ligation) induced ulcers in rats. The ulcer prevention efficacy after oral, rectal and sublingual administration were statistically significant (P < 0.01) in all the models. The differences in ulcer index and percentage inhibition of ulcerogenicity for rectal and sublingual administration were insignificant (P < 0.05) in indomethacin and HCl induced ulcers and were significant (P < 0.05) in aspirin induced ulcers. The ulcer prevention activity was significantly higher (P < 0.05) after rectal and sublingual routes when compared to oral administration in all three models evaluated. Results revealed a faster onset and higher extent of pharmacodynamic activity of omeprazole after rectal and sublingual administration.

Administration, Oral↗
PubMed1993

Determination of ivermectin in human plasma by high-performance liquid chromatography.

A specific reversed-phase HPLC-assay with sensitive fluorometric detection has been developed to measure the potent new antiparasitic agent ivermectin (CAS 70288-86-7) in human plasma (and urine). The lower limit of the method was 1 ng/ml and the intra-/interassay variability averaged 4.5/6.9%, respectively. The assay was applied for measuring plasma (urine) concentrations of ivermectin upto 56 (72 h) following a single oral dose of 6 and 12 mg. No unchanged or conjugated ivermectin could be detected in urine. Plasma concentrations increased linearly with dose but elimination half-life (12.6/13.4 h) was independent of the administered dose. Thus, the method is applicable for monitoring plasma levels during clinical and pharmacokinetic trials with ivermectin to evaluate its most efficacious dosage regimen.

Adult↗