PubMed Health⌕ Search

Biomedical subjects

V K Piotrovskii

Publications and source records attributed to V K Piotrovskii.

18 recordsLinked to original sources
PubMed1991

An initial slope method for model structure: independent estimation of the elimination rate constant of a metabolite.

A model structure-independent method for calculating the true elimination rate constant of a primary metabolite is presented. It does not require direct metabolite administration and uses data on drug and metabolite blood (plasma) concentrations after a bolus drug input. The method has been tested and compared with the moment method and the area function method using errorless and errant data simulated on the basis of one- and two-compartment models of the metabolite kinetics. In contrast to known methods the proposed method provided exact estimates of the elimination rate constant in the case of errorless data of both one- and two-compartment models. However the estimates are sensitive to random errors in the concentration data.

Mathematical Computing↗
PubMed1990

Development of tolerance to nifedipine in patients with stable angina pectoris.

1. The possibility of development of tolerance to the anti-ischaemic and anti-anginal effects of nifedipine during sustained administration for 2 months was studied in 15 patients with stable angina pectoris by means of repeated exercise tests on a treadmill. 2. After acute administration of nifedipine (20-30 mg) substantial anti-ischaemic and anti-anginal effects lasted for at least 4 h in all patients. 3. During sustained nifedipine treatment with a dose schedule which provided continuous anti-ischaemic effect during a day (mean daily dose 82.7 +/- 6.0 mg, range 60-120 mg) a substantial attenuation of this effect was registered. The duration of the anti-ischaemic effect was 5.4 +/- 0.3 h after acute administration, decreasing significantly to 3.6 +/- 0.4 h during sustained administration. 4. The attenuation of the nifedipine effect was not associated with worsening of the patients' condition. 5. Plasma concentrations of nifedipine and its metabolite were similar after acute administration and during sustained treatment. Protein binding of nifedipine also remained constant during the study. 6. There was marked interindividual variation in the degree of attenuation of the nifedipine effect during sustained administration. In five patients nearly complete loss of nifedipine efficacy was registered. Eight to ten days after stopping regular administration of nifedipine only partial restoration of nifedipine effect was observed. 7. We conclude that during sustained nifedipine administration tolerance to its anti-ischaemic, anti-anginal and circulatory effects develops in a substantial number of patients with stable angina pectoris.

Angina Pectoris↗
PubMed1989

Serum binding of nifedipine and verapamil in patients with ischaemic heart disease on monotherapy.

Serum free fractions of nifedipine, verapamil and some of their metabolites were measured in patients with ischaemic heart disease receiving single oral dose and chronic monotherapy and were compared with those obtained in vitro. The percentages of unbound nifedipine and verapamil in vitro (concentration range 50-200 and 150-400 ng ml-1, respectively) were 2.51 and 7.23%, respectively, and did not differ from those found on monotherapy with these drugs (2.05 and 8.08%, respectively), and after single dosing. It is suggested that, during treatment with nifedipine or verapamil, their serum metabolites do not affect binding of the parent drugs to serum proteins.

Adult↗
PubMed1987

New transdermal and transmucosal nitroglycerin delivery systems in patients with ischaemic heart disease.

The efficacy of a transdermal (Nitroderm-TTS) and a transmucosal (Trinitrolong) nitroglycerin (NG) formulation has been compared with sublingual NG in 9 patients with ischaemic heart disease and stable angina pectoris. The duration and the degree of anti-ischaemic effect were assessed in terms of similar, individually adjusted work loads performed prior to and repeatedly after drug application in comparison with placebo. The anti-ischaemic effect of nitroderm appeared in 0.5-3 h after administration, reached a maximum in about 3.8 h and persisted for 7.9 h. The maximal nitroderm effect was significantly lower than that of sublingual NG or Trinitrolong. The effect of Trinitrolong was less variable and lasted for 4.6 h. It was evident in all patients 0.5 h after drug administration. Plasma NG levels were monitored in 9 patients after sublingual NG and trinitrolong and in 4 following Nitroderm. The relative bioavailability of Nitroderm and Trinitrolong according to the pharmacokinetic data was 29% and 256%, respectively, of sublingual NG tablets. A therapeutic NG level in blood (0.5 ng/ml) after Trinitrolong appeared much earlier (2 min) than after Nitroderm (1 h). A significant reduction in the effect of sublingual NG was observed during Nitroderm application. Thus, the transdermal NG formulation did not exhibit an antianginal effect lasting for 24 h; transmucosal NG had a relatively short, but more pronounced and stable antianginal effect.

Administration, Cutaneous↗
PubMed1987

Pharmacokinetic stochastic model with Weibull-distributed residence times of drug molecules in the body.

The use of a function to fit blood concentration-time data points is equivalent, under certain assumptions, to specifying a model of the distribution of residence times of the drug molecules in the body (stochastic pharmacokinetic model). An empirical density function of the Weibull type is offered to describe this distribution. The model gives the following disposition function describing the time course of the drug concentrations in blood after an intravenous bolus input: C delta (t) = D/CLs lambda ts-1exp(-lambda ts). It contains only three parameters: lambda is like an 'elimination rate constant' in the single-exponential model into which the Weibull function reduces when the shape parameters becomes equal to unity; CL is the conventional systemic drug clearance, and, D is the dose injected. The Weibull function gives an analytical solution of the convolution integral for zero-order input, thereby permitting use of the model for intravenous infusion data and for extravascular administration, when the absorption may be considered to be zero-order. Using examples from the literature it is shown that in some cases the Weibull function gives a better fit than may be obtained with two- and three-exponential or gamma functions.

Animals↗
PubMed1987

The use of Weibull distribution to describe the in vivo absorption kinetics.

The drug in vivo absorption rate reflects the distribution of drug molecules absorption times. For the latter the Weibull distribution is suggested and some examples taken from the literature are used to support the proposal. Cumulative absorption data for theophylline in man and pantothenic acid in rats are linearized in the double log coordinates, and the Weibull absorption model parameters are estimated by linear regression. The mean absorption time values calculated from these parameters are in close agreement with those assessed by the model-independent method.

Absorption↗
PubMed1986

The effect of oral verapamil therapy on antipyrine clearance.

The influence of chronic verapamil treatment on antipyrine elimination was studied in eight angina patients. Antipyrine half-life (mean +/- s.d.) was 13.1 +/- 1.15 h at the start of therapy and 16.6 +/- 3.05 h (P less than 0.05) during chronic oral administration of verapamil (80-120 mg four or three times daily for 4 to 7 months). There was a significant decrease in antipyrine clearance (mean +/- s.d, 43.2 +/- 16.8 ml min-1 vs 28.7 +/- 16.6 ml min-1, P less than 0.01) while the change of distribution volume was insignificant. Verapamil elimination was also found to be impaired after chronic dosing as compared to single administration. Half-lives measured from the concentration vs time and urinary excretion rate vs time curves were both prolonged and oral clearance was decreased. Our results suggest that the inhibition of drug-metabolizing enzymes accounts for the impairment of verapamil elimination on chronic administration.

Administration, Oral↗
PubMed1986

Model-independent definition of the initial volume of distribution of drugs in the body.

Model-independent definition of the initial volume of distribution of drugs in the body as a limit of the ratio of the drug content in the body to its blood concentration with time from the start of drug administration tending towards zero is given. This definition makes it possible to calculate the initial volume of distribution as the ratio of the initial rate of drug administration to the value of the first derivative of the blood-concentration-time curve at the start of administration. The definition proposed enables one to overcome difficulties of the conventional definition of the initial volume of distribution (as the ratio of the dose administered to the initial blood concentration of a drug). Two methods for estimating the first derivative of the concentration-time curve are compared. The first one requires a single measurement of the drug concentration in blood at the time point as close as possible to the start of administration. The value of the derivative is calculated as the ratio of the drug concentration to the time of blood sampling. The second method requires at least two measurements of drug concentration during administration at various time points and consists in approximating the time dependence of the derivative by an exponential function. The value of the derivative at the start of administration can be found by extrapolation of the function to zero. The application of the methods proposed is illustrated by examples of calculating the initial volume of distribution from the data simulated by a computer on the basis of a two-compartment model.(ABSTRACT TRUNCATED AT 250 WORDS)

Humans↗
PubMed1986

Disposition kinetics and urinary excretion of verapamil and some of its primary metabolites after oral administration in patients with angina pectoris.

Pharmacokinetics of verapamil and of its three primary metabolites [norverapamil, 2-(3,4-dimethoxyphenyl)-2-isopropyl-6-azaheptanitrile (D-617) and 2-(3,4-dimethoxyphenyl)-2-propylamino-3-methylbutyronitrile (D-260)] was studied after oral administration in 7 patients with stable angina pectoris. Serum levels of metabolites were found to be in the same range as that of the intact drug. Areas under the serum concentration time curves of each metabolite were higher and serum half-lives were significantly longer than those of verapamil. Half-life values obtained from urinary excretion data and from serum levels did not differ for the metabolites, but for the unchanged drug, the half-life from urinary excretion data was longer. Cumulative urinary excretion of verapamil, norverapamil, D-617 and D-620 up to 48 h postdose was averaged to 1%, 2.2%, 11.4%, and 6.7% of the dose administered, respectively. The extent of verapamil bioavailability was directly measured in one patient receiving an intravenous dose as well as an oral one and was found to be 42.3%. In other patients, bioavailability was assessed by means of a regression equation relating the reciprocal of bioavailability and oral clearance of the drug, and was averaged at 35.1%. The possibilities of contribution of the metabolites to verapamil effects in patients were discussed.

Administration, Oral↗
PubMed1984

Identification of a prazosin metabolite and some preliminary data on its kinetics in hypertensive patients.

A metabolite of prazosin was detected in serum from hypertensive patients treated with prazosin. Its structure as 2-(1-piperazinyl)-4-amino-6,7-dimethoxyquinazoline was established by UV, IR, and mass-spectrometry. An assay method for simultaneous determination of prazosin and its metabolite in serum, urine and saliva is described. Preliminary data about the kinetics of prazosin and the metabolite after a single oral dose of prazosin 1 mg, and after multiple doses of 1 to 5 mg t.i.d. for 6-82 days in 7 patients with hypertension, are presented. After the single dose the metabolite level was much lower than that of intact drug, even though the former was eliminated much more slowly than the latter. The slow elimination of the metabolite led to its eventual accumulation in serum during multiple administration. The mean accumulation ratio of the metabolite was estimated to be at least 5.5 (from 3.0 to 7.9). Prazosin itself had a low accumulation ratio, so the mean steady-state level of the intact drug on multiple administration was several times lower than that of metabolite. As this metabolite has some hypotensive effect in animals, it may account for part of the therapeutic activity of parzosin in patients. The mean steady-state concentration of intact prazosin during the course of treatment were found to be significantly lower than that predicted from a single dose study.

Adult↗
PubMed1984

On the usefulness of ultrafiltration in drug-protein binding studies.

Severe non-specific adsorption of verapamil, nifedipine, prazosin and nadolol was observed during ultrafiltration of the drug solutions through the Centriflo CF 50A, YMT, YMB and Visking membranes. The results question the adequacy of the ultrafiltration procedure for the protein binding assay of the tested drugs.

Nadolol↗