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Biomedical subjects

M Bialer

Publications and source records attributed to M Bialer.

At least 109 records · Page 6Linked to original sources
PubMed1984

Disposition of progabide and valproic acid following intraperitoneal administration in rhesus monkey.

The pharmacokinetic characteristics of progabide, a new gamma-aminobutyric acid-mimetic drug, were evaluated following single- and multiple-dose administration of a progabide suspension through a chronic intraperitoneal catheter. Several issues pertaining to the bioavailability of progabide were addressed: first-pass effect, incomplete dissolution, and dose and time dependency. Four male monkeys received five treatments: three intraperitoneal doses (50, 100, and 150 mg), one oral dose (50 mg), and one intravenous bolus dose (150 mg). Bioavailability following intraperitoneal administration was incomplete, consistent with a first-pass effect predicted from intravenous data. There were no significant differences between the absolute bioavailabilities of the three intraperitoneal doses, which ranged between 40 and 49%. The apparent half-life (t 1/2) observed after intraperitoneal administration was significantly longer than the elimination half-life by the intravenous route and tended to increase with dose. This behavior is consistent with dissolution rate-limited absorption. The bioavailability of the suspension administered orally was compared with that of the intraperitoneal route, and no difference was found. However, the apparent t 1/2 by the oral route was significantly longer than that of the intraperitoneal route. In multiple-dosing studies, four different dosing regimens (all intraperitoneal) were examined, including 50 mg every 2 or every 6 h, 20 mg every 2 h, and 40 mg every 4 h. In all these regimens, plasma levels exhibited an accumulation compared with single-dose predictions. Large oscillations in plasma levels were observed when the dosing interval was 6 h and side effects were observed when the dosing interval was 2 h.(ABSTRACT TRUNCATED AT 250 WORDS)

Absorption↗
PubMed1984

Pharmacokinetics of valproic acid obtained after administration of three oral formulations to humans.

The pharmacokinetics and bioavailability of valproic acid (VPA) were compared in six healthy volunteers after oral administration of the drug as follows: 1 g in standard tablet form, 1 g in enteric-coated tablet form, and 0.8 g in gelatin-capsule form. Following the administration of standard tablets, VPA concentrations reached a peak mean +/- SD of 105.4 +/- 9.0 micrograms/ml at 1 h and declined monoexponentially, with a terminal half-life of 14.9 +/- 2.4 h. Following the administration of the capsule, the serum concentration reached a peak of 82.1 +/- 14.8 micrograms/ml at 4 h. Following the administration of an enteric-coated tablet, there was an average time lag of 2 h with a delayed peak serum concentration of 93.5 +/- 13.1 micrograms/ml at 6 h. An identical terminal half-life of VPA was obtained for the three oral formulations. The bioavailability of the three VPA formulations was not significantly different, and it may be concluded that these formulations are bioequivalent.

Administration, Oral↗
PubMed1981

Antiparasitic structure-activity relationships of congocidine derivatives.

Several congocidine analogs were synthesized and tested for in vivo activity against Trypanosoma congolense and in vitro activity against amastigotes of Leishmania tropica. The tripyrrole derivative, beta-([N-methyl-4-[N-methyl-4-(guanidinoacetamido)pyrrole-2-carboxamido]pyrrole -2-carboxamido]pyrrole-2-carboxamido)butyroamidine dihydrochloride, was less toxic and more active than congocidine. The guanidinoacetyl moiety appears to be a structural requirement for antiparasitic activity in the congocidine series.

Animals↗
PubMed1981

Disposition of sulfadimethoxine in cattle: inclusion of protein binding factors in a pharmacokinetic model.

Sulfadimethoxine was administered intravenously and orally to four cattle, and plasma and urine samples were collected at various times postdose. Modeling these data with a linear pharmacokinetic model gave unsatisfactory fits, and the data were subsequently fitted to a one-compartment model with saturable protein binding. The saturable protein binding model included the usual linear excretion and elimination processes as well as protein binding parameters. The values obtained in vivo for the binding constant, 5.01 x 10(4) M-1, and the total protein concentration, 7.89 x 10(-4) M, compared favorably with previously reported in vitro values. These results indicate that protein binding can be successfully included in a pharmacokinetic model.

Administration, Oral↗
PubMed1980

Structure-activity relationships of pyrrole amidine antiviral antibiotics III: preparation of distamycin and congocidine derivatives based on 2,5-disubstituted pyrroles.

Isomers of distamycin A and tripyrrole congocidine containing 2,5-disubstituted pyrroles were synthesized along with distamycin and congocidine homologs containing a single pyrrole ring. Selected compounds were evaluated for their cytotoxicity and antiviral activity. All of the tripyrrole derivatives tested in this series were nontoxic but were less active than distamycin A. The monopyrrole derivative, N-methyl-5-nitropyrrole-2-carboxamido-beta-propionamidine hydrochloride, was nontoxic and was almost as active antivirally as distamycin A.

Antiviral Agents↗
PubMed1980

Structure-activity relationships of pyrrole amidine antiviral antibiotics. 2. Preparation of mono- and tripyrrole derivatives of congocidine.

Representatives of three types of congocidine (1) analogues were synthesized. These were tested for cytotoxicity, inhibition of herpes simplex virus (HSV) replication in cultured cells, and effects on the synthesis of HS DNA in isolated nuclei in vitro, as well as on DNA synthesis by purified HSV DNA polymerase. All synthesized tripyrrole derivatives of congocidine were less cytotoxic and more active than the parent drug in all the three ant iviral tests.

Antiviral Agents↗
PubMed1979

Structure--activity relationships of pyrrole amidine antiviral antibiotics. 1. Modifications of the alkylamidine side chain.

Representatives of three types of side-chain analogues of distamycin A (1) were synthesized. These were tested for cytotoxicity, inhibition of herpes simplex virus (HSV) replication in cultured cells, effects on the synthesis of HSV DNA in isolated nuclei in vitro, as well as on DNA synthesis by purified HSV DNA polymerase. Distamycin A was the most active compound in all three antiviral tests, as well as the most toxic. However, several compounds, in particular the aromatic analogues 15 and 16, showed no toxicity under the experimental conditions used but were still very active in the three antiviral tests.

Animals↗
PubMedDate not supplied

Bretylium pharmacokinetics and bioavailabilities in man with various doses and modes of administration.

The pharmacokinetics and bioavailabilities of bretylium tosylate were studied in 9 male normal volunteers by 60 min constant rate intravenous infusions of 200, 300, and 400 mg, by intramuscular injection of 300 and 400 mg, by oral administration of 100, 200, and 400 mg in solution, and by oral administration of 200 mg tablets. The latter studies were repeated in the same 5 volunteers which were also studied by all modes of administration and at several doses. Intravenous studies showed a sum of 3 exponentials to characterize plasma level-time studies with a terminal half-life of 535 +/- 32 (S.E.M.) min (n = 12). The urinary recovery of unchanged drug was 77 +/- 4(S.E.M.)(n = 14). Half-lives within a subject were correlated and independent of dose. Intramuscular administration showed an apparent half-life of first-order invasion of 79 +/- 13 (S.E.M.) min (n = 6) with no apparent dose dependency and a urinary recovery of unchanged drug of 95.4 +/- 3.2 (S.E.M.) per cent with a terminal half-life similar to the intravenous studies. Oral solutions had smaller lag times of absorption [17 +/- 4(S.E.M.) min] than tablets [56 +/- 9 (S.E.M.) min] and longer apparent half-lives of first-order absorption [231 +/- 23 (S.E.M.) min] than tablets [87 +/- 15 (S.E.M.) min]. The tablets had slightly greater bioavailabilities [27 +/- 2.3 (S.E.M.) per cent] than the oral solutions [22.1 +/- 2.2 (S.E.M.) per cent] but with no apparent dose dependencies. Renal clearances were the same for all modes of administration. Means +/- S.E.M. were 735 +/- 32, i.v., 686 +/- 38, i.m., and 623 +/- 57 ml min-1, p.o. Apparent overall volumes of distribution were 589 +/- 401, i.v. and 450 +/- 671 (S.E.M.), i.m. The i.v. studies in three dogs confirmed the three-compartment body model and the high overall volumes of distribution, had terminal half-lives similar to humans and had renal clearances of 84, 164, and 207 ml min-1 that were in excess of glomerular filtration. There were no significant changes of cardiovascular parameters with the time course of the drug in the body and no significant drug-affected clinical parameters. The only consistent side effect was a generally transient nasal congestion at plasma peak time on intravenous administration.

Administration, Oral↗
PubMedDate not supplied

Comparative pharmacokinetic analysis of a novel sustained release dosage form of valproic acid in dogs.

A new sustained release dosage form of valproic acid (VPA) was developed. The new sustained release dosage form was administered (twice, with and without food) to five dogs in comparison to a standard tablet (Depakine, Labaz) and an i.v. preparation of the drug. Drug level monitoring in the plasma was performed by a GLC assay. Results indicate that the sustained release formulation exhibited a more prolonged and uniform absorption rate, yielded more sustained plasma levels after ingestion, and showed an overall bioavailability of 0.84 (95 per cent C.I. = 0.72, 0.96) relative to an equivalent dose of a conventional tablet.

Animals↗
PubMedDate not supplied

Pharmacokinetics of valpromide in dogs after various modes of administration.

Valpromide-Dipropylacetamide was administered to five dogs via five modes: Three oral formulations (solution, capsule, and enteric-coated tablet), intravenous and intramuscular injections. No significant change in the terminal half-life of valpromide could be observed after the various modes of administration in each dog. Valpromide was more rapidly absorbed after the administration of an oral solution than after i.m. injection. Similar data also were obtained for its metabolite--valproic acid. It was shown that valpromide in the dogs was partly biotransformed to valproic acid. The average fraction of valpromide that was transformed to valproic acid (fm) ranged from 30-55 per cent after all the oral and parenteral administrations, except for the enteric-coated tablet, which showed a very low bioavailability of valpromide.

Administration, Oral↗
PubMedDate not supplied

Pharmacokinetics of valproic acid in volunteers after a single dose study.

The pharmacokinetics of valproic acid (VPA) was investigated in six healthy volunteers. This was done by monitoring total and free (unbound) valproic acid levels in the serum, and the amount of one of its metabolites, VPA glucuronide, in the urine as a function of time, after a single dose administration of the parent drug. VPA half-life calculated from the urine data of the metabolite was shorter than the half-life calculated from the blood data. About 15 to 20 per cent of the administered oral dose of VPA was excreted in the urine as VPA glucuronide. The average free fraction of VPA obtained in this study, by using the EMIT technique, ranged from 1.5 to 11.5 per cent with a mean value of 4.9 per cent.

Adult↗
PubMedDate not supplied

Pharmacokinetic evaluation of novel sustained-release dosage forms of valproic acid in humans.

Five new sustained-release dosage forms of valproic acid (VPA) were developed. The new sustained-release formulations were administered to six healthy subjects for comparison with a standard tablet and an i.v. preparation of the drug. Three of the formulations exhibited a more prolonged and uniform absorption rate and yielded more sustained serum levels after ingestion. These three formulations maintained serum therapeutic levels of VPA for 24 h after a single oral administration of 1 g, and were bioequivalent to a marketed standard tablet of VPA. The absorption profile of the various oral formulations was analysed pharmacokinetically, using the Loo-Riegelman procedure.

Administration, Oral↗
PubMedDate not supplied

Effects of phenobarbital steady state levels on antipyrine clearance and distribution in the rat.

A group of 15 rats received two intravenous bolus doses of antipyrine (15 mg/kg) separated by a 57 hour infusion (with bolus dose) of phenobarbital. Phenobarbital bolus doses and infusion rates were based on a preliminary pharmacokinetic study (7 rats) and were varied to achieve a broad range of steady state levels. Antipyrine and phenobarbital blood levels were measured by high pressure liquid chromatography. Antipyrine kinetics obeyed first order monoexponential decay, and the parameters (clearance, volume, half-life) were determined. Antipyrine clearance increased in all animals during phenobarbital infusions with a per cent increase ranging between 54.6 and 269 per cent. However, no significant correlation was found between the per cent increase in antipyrine clearance and phenobarbital concentration (r = 0.19). The volume of distribution of antipyrine increased in 14 of 15 animals with increases ranging between 7.7 and 45.8 per cent.

Animals↗
PubMedDate not supplied

The relationship between drug input and mean residence time in the body.

The relationship between the mean residence time after oral dosing or any other non-instantaneous mode of administration (MRTni) was explored by a series of computer simulations. MRTni was calculated from the ratio of AUMC to AUC (where AUC and AUMC are the zeroth and first statistical moments, respectively, of the drug concentration-time curve). A continuous linear relationship between MRTni and 1/ka or 1/k0 was observed. In the 'flip-flop' case where ka less than K (where K is the last elimination rate constant), the extrapolation from t* to infinity (where t* is the last observed plasma concentration) should be done using ka instead of K. If K is used, underestimated values of MRTni will be obtained. The findings from this investigation have practical application in the design and pharmacokinetic evaluation of novel sustained-release dosage forms.

Administration, Oral↗