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Biomedical subjects

R Zacest

Publications and source records attributed to R Zacest.

At least 19 recordsLinked to original sources
PubMed1991

In vivo covalent binding of clofibric acid to human plasma proteins and rat liver proteins.

Recent studies have shown that acyl-glucuronide conjugates are chemically reactive electrophilic metabolites that can undergo transacylation reactions resulting in intra-molecular rearrangement, hydrolysis and covalent binding of aglycone to albumin both in vitro and in vivo. The hypolipidaemic agent clofibrate is eliminated almost entirely as clofibric acid glucuronide in humans and rats. The formation of clofibric acid-protein adducts was investigated in 14 patients receiving 0.5-2.0 g/day of clofibrate for hypercholesterolaemia, and in liver homogenates from 20 rats administered 280 mg/kg/day of clofibric acid for up to 21 days. Total clofibric acid concentrations in the patients ranged from 0 to 114 mg/L. Covalently bound clofibric acid-protein adducts were detected in all patients, even in one subject in whom there was no measurable plasma clofibric acid. Concentrations ranged from 2.2 to 53.4 ng/mg protein and, in eight patients receiving 1.0 g/day of clofibrate, were correlated (P less than 0.05) with renal function as assessed by creatinine clearance. Clofibric acid-protein adducts were also present in rat liver homogenates, and increased with increasing duration of treatment (P less than 0.0001), from a mean (SE) of 10.1 (0.7) to 32.3 (1.6) ng/mg protein. The covalent binding of drugs to tissue macromolecules has traditionally been associated with toxicity. Further research is required to elucidate the role of acyl-glucuronide conjugates in the formation of drug-protein adducts and their biological consequences.

Animals↗
PubMed1991

Improved high-performance liquid chromatography assay for atenolol in plasma and urine using fluorescence detection.

An improved assay for racemic atenolol (AT) concentrations in human plasma and urine is described using a high-performance liquid chromatographic method with fluorescence detection. The method has a sensitivity limit of 0.5 micrograms/L in plasma with acceptable within- and between-run reproducibilities, and demonstrated linearity at concentrations up to 2,000 micrograms/L. A pilot clinical evaluation of the assay was undertaken on 56 trough plasma specimens from 36 outpatients on established AT therapy. Atenolol concentrations in these patients showed large variations at all prescribed doses, including undetectable levels in four patients (revealing unsuspected noncompliance). Because of its sensitivity and applicability to urinary analysis, the method can be used for pharmacokinetic studies and, under certain circumstances, may be valuable in clinical therapeutic drug monitoring.

Adult↗
PubMed1985

Synthesis, formulation, and clinical pharmacological evaluation of hydralazine pyruvic acid hydrazone in two healthy volunteers.

Hydralazine pyruvic acid hydrazone [2-(phthalazin-1-yl hydrazono)propionic acid; 1] is a major plasma metabolite of hydralazine in humans. A number of in vitro and animal studies have suggested that this hydrazone may have cardiovascular activity and could account for the prolonged antihypertensive effect of hydralazine in humans in the absence of detectable plasma levels of the parent drug. To study this possibility, the soluble sodium salt of hydralazine pyruvic acid hydrazone (2) was synthesized, its chemical purity and stability was checked, and an intravenous formulation was prepared. Isomeric forms were identified. Doses of 0.3, 0.6, and 1.1 mumol/kg of 2 were administered intravenously to one slow and one heterozygous fast acetylator of sulfamethazine. The slow acetylator received two additional doses of 0.06 and 0.14 mumol/kg. Peak plasma levels of 1 of 18 mumol/L were attained without tachycardia or hypotension in either subject. There was no evidence of nonlinearity in kinetics over the dose range studied and clearance remained constant in both subjects (0.517 +/- 0.033 mL/min/kg in the slow acetylator and 0.744 +/- 0.058 mL/min/kg in the fast acetylator). The distribution of 1 varied unpredictably with dose, and changes were reflected in the terminal half-life (3.47-5.97 h in the slow acetylator and 2.06-5.33 h in the fast acetylator). Only traces of the acetylated metabolite of hydralazine, 3-methyl-s-triazolo[3,4-a]phthalazine (3), were detected in the plasma of the subjects, suggesting that significant metabolism via this route was unlikely. An established and specific assay for hydralazine was further modified to allow measurement of levels as low as 1 nmol/L (0.2 ng/mL).(ABSTRACT TRUNCATED AT 250 WORDS)

Acetylation↗
PubMed1983

Endralazine - a new hydralazine-like antihypertensive with high systemic bioavailability.

Endralazine (E), a new hydralazine-like antihypertensive was given intravenously (0.05 mg/kg) to 10 normal volunteers (5 slow and 5 fast acetylators). Plasma levels were fitted to a 3 compartment model and pharmacokinetic parameters (area under curve [AUC infinity 0], clearance, volume of distribution, half-lives) obtained in the usual way. Bioavailabilities of 5 and 10 mg oral doses of E were determined from the AUC infinity 0 generated in a previous study of oral E given to the same subjects. E had high system bioavailability (73.5-99.1%) suggesting that it was almost completely absorbed without undergoing appreciable first-pass metabolism. Furthermore, dose size and acetylator phenotype did not significantly affect the bioavailability of E. This behavior contrasts with that of hydralazine where systemic bioavailability was less than 40%, and 2 to 3 times higher in slow acetylators than in fast acetylators. It is concluded that the bioavailability of E is high and not influenced by acetylator phenotype; these properties suggest some clinical advantages for the drug.

Absorption↗
PubMed1982

Influence of acetylator phenotype on the pharmacokinetics of a new vasodilator antihypertensive, endralazine.

Five and 10 mg single oral doses of a new vasodilator antihypertensive, endralazine (E) were given on separate occasions to 17 normal male volunteers (8 slow, 7 heterozygous fast and 2 homozygous fast acetylators). The homozygous fast acetylators were excluded from statistical comparisons. Only small differences were observed in the pharmacokinetics of E between the phenotypes and there was no evidence of non-linearity at the 2 dose levels studied. Terminal half-lives ranged from 2.59 to 7.14 h with a mean of 4.30 +/- 1.08 h for the 5 mg dose and 4.25 +/- 1.09 h for the 10 mg dose. There was no significant difference in half-lives between slow and heterozygous fast acetylators. The mean area under the plasma level-time curve (AUC0 infinity) was 18.2% lower (p less than 0.05) in the heterozygous fast acetylators than in the slow acetylators following the 5 mg dose and 11.0% lower (p greater than 0.05) following the 10 mg dose. Extremely rapid absorption of the drug precluded accurate estimation of absorption rates. The AUC0 infinity of the acetylation metabolite (methyltriazolo-endralazine) was small compared to that of E although higher in the heterozygous fast acetylators than in the slow acetylators (p less than 0.01).

Acetylation↗
PubMed1981

Sensitive high-performance liquid chromatographic assay for endralazine and two of its metabolites in human plasma.

Endralazine (I) is a new antihypertensive which is chemically and pharmacologically related to hydralazine and dihydralazine. A sensitive high-performance liquid chromatographic-fluorescence assay for the drug and two of its metabolites [methyltriazoloendralazine (VII) and hydroxymethyltriazoloendralazine (VIII)] in human plasma was developed. After conversion of I and its internal standard to triazolopyridopyridazine derivatives the latter and metabolites were separated by high-performance liquid chromatography and detected using their fluorescence. The limits of detection of the assay were 1 nmol/l for I and VII and 0.1 nmol/l for VIII. Intra-assay coefficients of variation were 2.5-5.1% for I (range 1000-10 nmol/l), 4.2-4.5% for VII (range 100-5 nmol/l) and 3.4-5.7% for VIII (range 100-1 nmol/l). Following oral administration of 5 and 10 mg of I to two normal volunteers (slow acetylators) peak plasma levels of I occurred between 0.75 and 1 h after the dose, and declined in a biexponential fashion. The terminal half-life ranged from 2.8-3.7 h. These results contrast with those obtained for hydralazine in plasma where in vitro and in vivo half-lives were less than 30 min.

Chromatography, High Pressure Liquid↗
PubMed1981

Relationship of psychological factors to failure of antihypertensive drug treatment.

Personality traits and pretreatment symptoms of 69 hypertensive patients were documented with self-administered questionnaires. Thirteen patients (19%) dropped out during 12 months of treatment. Five of these were lost from follow up and eight failed to tolerate their allotted medication. In this series treatment failure did not seem dependent on the type of drug used, but was linked with a high suspiciousness level and a high pretreatment symptom score. Both measures varied independently of one another and a select group of 10 patients who scored highly on both, had a failure rate of 60%. Our results suggest that hypertensives with an increased predisposition to drug treatment failure can be identified at the pretreatment stage. Recognition of such individuals should assist in their routine clinical management and in the design of antihypertensive drug trials.

Adult↗
PubMed1980

Selective high-performance liquid chromatographic assays for hydralazine and its metabolites in plasma of man.

Selective high-performance liquid chromatographic assays for hydralazine (I), hydralazine pyruvic acid hydrazone (II) and the acetylation metabolites, namely s-triazolo[3,4-alpha]-phthalazine (V) and 3-hydroxymethyl (VI) and 3-methyl-s-triazolo[3,4-alpha]phthalazine (VII) in human plasma were developed. Utilizing the fluorescence of these compounds or their derivatives the limits of detection could be extended down to 5 nmole/l (1 ng/ml) for I, 1 nmole/l (0.2 ng/ml) for II and 0.5 nmole/l (0.1 ng/ml) for V--VII. The intra-assay coefficients of variation for the assays ranged from 2 to 7% over the concentration range 5.0 to 0.05 micromole/l and the inter-assay variability in the slope of the standard curves ranged rom 4 to 8%. An improved method for measuring the sum of I plus all its hydrazones (apparent I) was also developed. On addition of I to fresh plasma at 37 degrees, half the added I was converted to II within 15 min and there was no detectable level of I, 2 h after the addition. The plasma level--time course of I, and its metabolites in a healthy volunteer (slow acetylator) following separate oral and intravenous administrations of I indicated that I contributed only a small fraction (4.3 and 4.7% respectively) to the area under the plasma level--time curve of apparent hydralazine.

Chromatography, High Pressure Liquid↗
PubMed1978

Interference in assays for hydralazine in humans by a major plasma metabolite, hydralazine pyruvic acid hydrazone.

The present study showed that published spectrophotometric and GLC methods for hydralazine in plasma do not distinguish between the drug and a major plasma metabolite, hydralazine pyruvic acid hydrazone. These methods involve the acid treatment of the sample, which hydrolyzes that hydrazone back to hydralazine. A specific GLC assay for the hydrazone was developed and involves its selective extraction from plasma and transformation to 3-trifluoromethyl-s-triazolo[3,4-a]phthalazine. This derivative could be sensitively measured by GLC using an electron-capture detector. With this procedure, it was shown that most "apparent hydralazine" in plasma is the hydrazone, which forms rapidly from hydralazine and endogenous pyruvic acid. Previous work indicated that the hydrazone was inactive when administered intravenously to rabbits.

Chromatography, Gas↗
PubMed1977

The ambiguity of adverse drug reactions.

Three clinical pharmacologists independently evaluated 500 untoward clinical events reported by physicians as adverse drug reactions (ADRs). They often disagreed with the reporting physicians and with each other. They judged 14.4-28.2% of the events to be definite, 26.4-38.0% probable, 21.4-31.0% possible and 15.8-28.2% of the events to be definite, 26.4-38.0% probable, 21.4-31.0% possible and 15.8-28.2% unlikely ADRs. In their opinion 19.1-32.4% of the drugs blamed were definitely, 29.8-34.4% probably, 24.9-36.7% possibly and 8.4-14.5% not responsible for the adverse reactions. Evaluators disagreed among themselves about the drug most likely to have been responsible in 36.4% of the events, about ADRs causing hospital admission in 56.8%, about severe ADR morbidity in 55.8%, about ADR prolongation of hospitalization in 67.3% and ADR prolongation of hospitalization in 67.3% and about ADR contribution to death in 71.0%. The divergence of judgements suggests that suspected ADRs are usually ambiguous clinical events, and that incidence, severity, medical consequences and cost of ADRs can only be estimated.

Drug-Related Side Effects and Adverse Reactions↗
PubMed1976

The vasodilator--beta-blocker interaction--some determinants of its clinical success.

A number of structurally dissimilar compounds, sharing the ability to induce vasodilatation have come into clinical usefulness as antihypertensive drugs. Their successful utilisation often depends critically on an appropriate combination with diuretics and beta-blockers. Beta-blockers can specifically inhibit the reflex cardiac stimulation which otherwise may limit the tolerability and haemodynamic value of these drugs. A synergistic antihypertensive effect has been demonstrated with hydrallazine and propranolol and possibly exists with other combinations. Generally, vasodilators are not first-line drugs in chronic therapy but are best added to beta-blockers. Variations of the dose-response and the time-course of effect are stressed as being important determinants of a successful interaction.

Adrenergic beta-Antagonists↗