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Biomedical subjects

L Iyer

Publications and source records attributed to L Iyer.

36 records · Page 2Linked to original sources
PubMed1998

Clinical pharmacology of camptothecins.

Camptothecins (CPTs) are a unique class of chemotherapeutic agent which inhibit DNA synthesis by inhibiting topoisomerase I activity. Structure-activity studies on the original CPT alkaloid led to the development of the new analogues irinotecan (CPT-11), topotecan, and 9-aminocamptothecin, which have improved water solubility and lower toxicity. CPT analogues exhibit interesting pharmacokinetic/pharmacodynamic and metabolic properties that are of major research and clinical interest. This review describes the clinical pharmacology of these 3 CPT analogues. Specific areas such as absorption after extravascular administration, pharmacokinetic/pharmacodynamic variability, metabolism, and administration in special populations are discussed.

Animals↗
PubMed1998

Pharmacogenetics and cancer chemotherapy.

Cancer chemotherapy is limited by significant inter-individual variations in responses and toxicities. Such variations are often due to genetic alterations in drug metabolising enzymes (pharmacokinetic polymorphisms) or receptor expression (pharmacodynamic polymorphisms). Pharmacogenetic screening prior to anticancer drug administration may lead to identification of specific populations predisposed to drug toxicity or poor drug responses. The role of polymorphisms in specific enzymes, such as thiopurine S-methyltransferases (TPMT), dihydropyrimidine dehydrogenase (DPD), aldehyde dehydrogenases (ALDH), glutathione S-transferases (GST), uridine diphosphate glucuronosyl-transferases (UGTs) and cytochrome P450 (CYP 450) enzymes in cancer therapy are discussed in this review.

Acetyltransferases↗
PubMed1996

Study of pathogenicity markers of staphylococci isolated from clinical specimens.

A total of 165 strains of coagulase positive staphylococci (CPS) and 39 strains of coagulase negative Staphylococci (CNS) isolated from various clinical specimens studied for biochemical and enzyme profile showed overlapping of the key characters of pathogenicity. Anaerobic mannitol fermentation (69.20%), phosphatase (58.97%) and penicillinase (58.97%) production was remarkable amongst CNS. Both CPS and CNS showed increased resistance to penicillin and other antimicrobials. Besides increased frequency of isolation of CNS from pathological specimens, they elaborate singly or in combination, the recognized virulence factors.

Coagulase↗
PubMed1995

Impact of biotechnology in the diagnostic and therapeutic management of cardiovascular disorders.

Although biotechnology has been useful in the development of new diagnostic methods and drugs for the management of cardiovascular disorders, there are several issues which raise certain questions on the global use of biotechnology based drugs and diagnostic methods (Piascik, 1991; Fareed, 1993a; Fareed, 1994a). The cost is rather prohibitive in the development of this type of technology. Most diagnostic methods and drugs developed utilizing biotechnology based methods are relatively expensive. The second important consideration is the equivalence of the newer biotechnology derived drugs to the natural products. Many of the biotechnology derived drugs are obtained in prokaryotic systems (E. coli). Post-transcriptional modifications such as glycosylation are often important in determining the function of various proteins. On the other hand, biotechnology based diagnostic methods exhibit somewhat different specificity in comparison to conventional methods. Thus, it is rather important to assess the developments in this area in a careful manner. Furthermore, validation of the clinical, diagnostic and therapeutic efficacy of biotechnology derived diagnostic devices and drugs is a prerequisite for their use in cardiovascular medicine.

Amino Acid Sequence↗
PubMed1995

Development and validation of two enzyme-linked immunosorbent assay (ELISA) methods for recombinant hirudin.

Recombinant hirudin is currently being developed as a potential prophylactic and therapeutic antithrombotic drug in various clinical indications such as angina and deep venous thrombosis. In this report, we have discussed the production of specific polyclonal antibodies to recombinant hirudin (rH) and the development of two ELISA methods to measure rH concentrations in biological fluids: a sandwich and a competitive ELISA method. Intra- and inter-assay variations in the two methods are extremely low (3-7%). The competitive ELISA method is rapid, simple and highly reproducible. Saturation binding curves, selection of appropriate incubation times, recovery of different hirudin variants and reactivity in the presence of thrombin are discussed. The methods can be easily adapted to monitor hirudin concentrations in the clinical laboratory for diagnostic purposes as well as for performing pharmacokinetic studies.

Antibody Specificity↗
PubMed1995

Colonisation factors amongst clinical isolates of enterotoxigenic Escherichia coli.

The production of heat-labile (LT) and heat-stable (ST) enterotoxins, colonisation factor antigens (CFAs) and haemagglutinins was investigated amongst 310 Escherichia coli (E. coli) isolates obtained from 62 children under the age of five, with diarrhoea. Twenty-one isolates were found to produce enterotoxins, of which fifteen (71%) isolates produced ST only, 2 (10%) produced LT only and 4 (19%) produced both LT and ST. However, none of the isolates demonstrated any of the common CFAs identified to date, but 8 out of the 21 isolates demonstrated haemagglutination with rabbit, sheep or human group A erythrocytes, suggesting the presence of putative CFAs, yet unidentified.

Bacterial Proteins↗
PubMed1993

Studies on the pharmacokinetics and pharmacodynamics of recombinant hirudin (rHV2-Lys 47) after intravenous and subcutaneous administration in dogs.

In recent years, the pharmacological and biochemical characterization of hirudins has taken a major upswing due to the availability of this natural polypeptide in recombinant form. Despite this, the current knowledge on the pharmacokinetics and pharmacodynamics of recombinant hirudin (rH) appears to be incomplete. The present study was designed to investigate the relationship between plasma concentrations of rH with corresponding antithrombin responses after intravenous (i.v.) and subcutaneous (s.c.) administration in dogs. Four male, Mongrel dogs were each injected with an i.v. (bolus) dose (1 mg/kg) of one specific variant of rH, i.e. rH with a lysine residue in position 47 (rHV2-Lys 47). The dogs were injected with a s.c. dose (1 mg/kg) of rHV2-Lys 47 after one week. After each dose, blood was collected at different time intervals, plasma separated and stored at -70 degrees C. Plasma concentrations of rHV2-Lys 47 were determined using an enzyme-linked immunosorbent assay (ELISA) method and pharmacokinetic parameters were determined using standard non-compartmental methods. The ex vivo antithrombin activity of the drug was measured using activated partial thromboplastin time (APTT), calcium-thrombin time (Ca++TT) and a chromogenic anti-IIa assay. The results from this study indicate that the pharmacokinetic behavior of rHV2-Lys 47 is strongly influenced by the route of administration. In all three functional assays used, a significant correlation was obtained after i.v. administration between plasma concentrations and corresponding responses over the time period of the study when compared to s.c. administration. The results are indicative of a probable structural and functional modification of this rH variant after s.c. administration which may be responsible for the altered pharmacokinetics and pharmacodynamics after s.c. dosing.

Animals↗
PubMed1993

Alteration of pharmacokinetics and pharmacodynamics of recombinant hirudin (rHV2-Lys 47) after repeated intravenous administration in dogs.

Native hirudin is a heterogenous polypeptide obtained from the medicinal leech, Hirudo medicinalis. Recent advances in molecular biological techniques have led to the availability of large amounts of hirudin in the recombinant form. Recombinant hirudins (rH) are currently being investigated for potential use in the prophylaxis and treatment of deep venous thrombosis (DVT), in disseminated intravascular coagulation (DIC) and during cardiovascular bypass surgery. In this study, one specific variant of rH with a lysine residue in position 47 (rHV2-Lys 47) was administered in dogs in a multiple dose regimen of 2 mg/kg (i.v. bolus) for three weeks with a dosing interval of one week. After each dose, blood samples were collected at regular time intervals, plasma separated and stored at -4 degrees C. Concentrations of rHV2-Lys 47 in each sample were determined using an enzyme-linked immunosorbent assay (ELISA). Ex vivo antithrombin responses measured included activated partial thromboplastin time (APTT), calcium-thrombin time (Ca++TT-10 NIH units/ml) and a chromogenic anti-IIa assay. It was the purpose of this study to detect any sensitization or desensitization of antithrombin responses when rHV2-Lys 47 is used in a repeated fashion such as would be expected in the prophylaxis of DVT. The results indicated that there was no attenuation in the responses; however, there was a sensitization of response as measured by the Ca++TT (10 NIH units/ml). These findings could have major implications in the clinical use of rH where this drug is expected to be used in a multiple dose regimen.

Animals↗
PubMed1992

Prior chronic exposure to cocaine inhibits the serotonergic stimulation of ACTH and secretion of corticosterone.

The effect of long-term pretreatment with cocaine on serotonergic regulation of ACTH (adrenocorticotropic hormone; corticotropin) and secretion of corticosterone in rats was investigated. The following observations were made: (1) Pretreatment with cocaine had no significant effect on basal levels of ACTH and corticosterone in plasma. However, cocaine caused a reduction in the ability of the 5-HT (5-hydroxytryptamine, serotonin) releaser p-chloroamphetamine (PCA) to increase corticosterone in plasma, 42 hr after the last injection of cocaine. (2) Exposure to cocaine for 7 days was sufficient to produce a maximal inhibition of the PCA-induced increase in ACTH in plasma. (3) The inhibitory effect of cocaine on PCA-induced release of ACTH was more marked than on corticosterone. (4) Conversely, the dose-dependent stimulatory effect of two 5-HT1 agonists, RU 24969 (5-methoxy-3-(1,2,3,4-tetrahydro-4-pyridinyl)-1H-indole) and m-CPP (m-chlorophenylpiperazine), on ACTH and corticosterone was not reduced by 7 days of exposure to cocaine. Taken together, these findings indicate that pretreatment with cocaine reduced the function of serotonergic nerve-terminals but not postsynaptic receptors, that stimulate ACTH and secretion of corticosterone.

Adrenocorticotropic Hormone↗
PubMed1991

An objective perspective on recombinant hirudin: a new anticoagulant and antithrombotic agent.

Leeches have been in medical use for many years. Hirudin, the anticoagulant obtained from the medicinal leech has been purified, characterized and can now be produced by recombinant (r) technology. R-hirudin is a potent inhibitor of thrombin and is therefore a potentially valuable anticoagulant and antithrombotic drug. This article reviews the current status of r-hirudin in this role and compares the pharmacokinetics, mechanism of action and clinical efficacy of this agent with heparin. The methods available for laboratory assessment and clinical monitoring of r-hirudin and the possible ways of antagonizing its effects are also discussed. Finally, the potential clinical applications of r-hirudin are outlined, although further laboratory and clinical studies, together with a fall in the cost of this compound are required before r-hirudin can be more widely accepted as an anticoagulant and antithrombotic agent.

Amino Acid Sequence↗
PubMed1985

The genotoxicity of 2-bromoacrolein and 2,3-dibromopropanal.

2-Bromoacrolein (2-BA) and 2,3-dibromopropanal (2,3-DBPA), an identified and a postulated reactive metabolite of tris(2,3-dibromopropyl)phosphate (Tris-BP), respectively, were found to cause mutations in Salmonella typhimurium TA 100 both in the absence and presence of a metabolic system. 2-BA, as well as 2,3-DBPA, caused extensive DNA single-stranded breaks as evidenced by alkaline elution of DNA from exposed Reuber hepatoma cells in culture. The data with Syrian hamster embryo cells suggest that both 2-BA and 2,3-DBPA were more potent than Tris-BP in transforming these cells in culture. On the other hand, neither 2-BA, nor 2,3-DBPA, was found to cause increased unscheduled DNA repair synthesis in isolated rat hepatocytes in monolayer cultures, whereas Tris-BP had a significant effect at low concentrations (10-50 microM). There was no correlation between the observed mutagenic effects of 2-BA and 2,3-DBPA and their alkylating activities using the nitrobenzyl-pyridine test. The genotoxic effects associated with 2-BA and its detection in microsomal incubations makes it a likely candidate for a role in the mutagenicity of Tris-BP.

Acrolein↗
PubMed1984

Activation mechanism of tris(2,3-dibromopropyl)phosphate to the potent mutagen, 2-bromoacrolein.

The potent mutagen 2- bromoacrolein is formed from the carcinogenic flame retardant tris(2,3-dibromopropyl)phosphate (Tris-BP) on incubation with hepatic microsomes. Substitution of deuterium for hydrogen at the terminal carbon atoms (C-3) of Tris-BP significantly decreased both the mutagenic response and the formation rate of 2- bromoacrolein . Mass spectral analysis of the 2- bromoacrolein that was formed from the selectively deuterated analogs of Tris-BP revealed that the primary mechanism for the formation of 2- bromoacrolein involves an initial oxidative dehalogenation at C-3 followed by a beta-elimination reaction.

Acrolein↗