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M Bialer

Publications and source records attributed to M Bialer.

At least 73 records · Page 4Linked to original sources
PubMed1994

Effect of lactation on single-dose pharmacokinetics of norfloxacin nicotinate in ewes.

In a three-way crossover trial, six healthy Finnish-Merino-Awassi ewes were given a single intravenous injection of norfloxacin nicotinate (in a dose equivalent to 25 mg of norfloxacin base per kg of body weight) during nursing, 1 day after weaning, and 1 month after weaning. Blood and milk samples were collected at different time intervals following dosing, and norfloxacin concentrations were determined by a high-performance liquid chromatography assay. The serum drug concentration versus time data were analyzed by a noncompartmental approach which was based on the statistical-moment theory. The total body clearance values were 4.2 +/- 1.3 (injection during nursing), 1.6 +/- 0.3 (injection 1 day after weaning), and 3.1 +/- 0.8 ml/min/kg (injection 1 month after weaning). The mean residence times were 335 +/- 83, 797 +/- 129, and 481 +/- 102 min and terminal half-lives were 266 +/- 51, 603 +/- 94, and 372 +/- 68 min for the respective treatments. The estimated volumes of distribution at steady state were 1.3 +/- 0.1, 1.2 +/- 0.1, and 1.4 +/- 0.2 liter/kg for the respective treatments. Milk norfloxacin concentrations were up to 40 times higher than the corresponding concentrations in serum during lactation. Accordingly, in ewes with 1.5 liter of milk in the udder more than half of the drug in the animal appeared to be in the milk. Therapeutic concentrations of norfloxacin could be detected in the sera of suckling lambs, implicating that fluoroquinolone therapy should be discouraged during breast feeding. In lactating ewes and in ewes with full udders, moment analysis calculations did not show a significant difference between the system moment mean residence time and the system matrix mean residence time values. Thus, the pharmacokinetics of norfloxacin in the three groups could be described by the classical two-compartment open-body model with input and output occurring from the central compartment. The results did not support the existence of a distinguishable milk compartment. Milk secretion seemed to act as one of the clearance processes of the drug when milk was continuously removed.

Animals↗
PubMed1993

Pharmacokinetic analysis and anticonvulsant activity of two polyesteric prodrugs of valproic acid.

The pharmacokinetics of the following two polyesteric prodrugs of valproic acid (VPA) have been investigated: 1,4-butanediol divalproate (BDV) and glyceryl trivalproate (GTV). In addition, the anticonvulsant activity of these compounds has been evaluated and compared to that of VPA and valpromide (VPD). Valproic acid, and its two esteric derivatives were administered intravenously to six dogs at an equivalent dose (400 mg VPA) and their pharmacokinetics investigated. In the case of BDV, the biotransformation to VPA was complete, but in the case of GTV, it was only partial. Of the two investigated esteric prodrugs of VPA, only BDV demonstrated anticonvulsant activity and showed less neurotoxicity than VPA and VPD, and therefore had a better protective index. The anticonvulsant activity is explained on pharmacokinetic and pharmacodynamic grounds due to its complete conversion to VPA and the possible synergism in anticonvulsant activity between VPA and 1,4-butanediol.

Animals↗
PubMed1993

Prolongation of the circulation time of doxorubicin encapsulated in liposomes containing a polyethylene glycol-derivatized phospholipid: pharmacokinetic studies in rodents and dogs.

The pharmacokinetics of doxorubicin (DOX) encapsulated in liposomes containing polyethylene glycol-derivatized distearoylphosphatidylethanolamine (PEG/DSPE) were investigated in rodents and dogs. The plasma levels of DOX obtained with PEG/DSPE-containing liposomes were consistently higher than those without PEG/DSPE or when PEG/DSPE was replaced with hydrogenated phosphatidylinositol (HPI). Despite the inclusion of PEG/DSPE in liposomes, there was a significant drop in the plasma levels of DOX when the main phospholipid component, hydrogenated phosphatidylcholine, was replaced with lipids of lower phase transition temperature (dipalmitoylphosphatidylcholine, egg phosphatidylcholine), indicating that phase transition temperature affects the pharmacokinetics of liposome-encapsulated DOX. In beagle dogs, clearance was significantly slower for DOX encapsulated in PEG/DSPE-containing liposomes than in HPI-containing liposomes, with distribution half-lives of 29 and 13 hr, respectively. In both instances, almost 100% of the drug measured in plasma was liposome-associated. The apparent volume of distribution was only slightly above the estimated plasma volume of the dogs, indicating that drug leakage from circulating liposomes is insignificant and that the distribution of liposomal drug is limited mostly to the intravascular compartment in healthy animals.

Animals↗
PubMed1993

Comparative pharmacokinetics of the newer antiepileptic drugs.

During the past few years a major increase has taken place in the number of drugs which have become available in the antiepileptic arsenal. In fact, 3 new antiepileptic drugs, vigabatrin, oxcarbazepine and lamotrigine, were recently approved in several European countries. Two other drugs, felbamate and gabapentin, are expected to be approved in the US in the near future. This review comparatively evaluates the pharmacokinetics of the following 10 new antiepileptic drugs: felbamate, flunarizine, gabapentin, lamotrigine, oxcarbazepine, remacemide, stiripentol, tiagabine, topiramate and vigabatrin. Three of the new drugs, gabapentin, topiramate and vigabatrin, are more promising on the basis of their pharmacokinetic features. They are well absorbed, excreted mainly unchanged in the urine, and are not susceptible to enzyme induction or inhibition. Their drug interaction potential appears to be minimal. About 50% of felbamate is excreted unchanged, with the rest eliminated by metabolism. The remaining drugs are eliminated by metabolic processes such as glucuronidation (lamotrigine), deglycine formation (remacemide) or oxidative metabolism (flunarizine and stiripentol). Oxcarbazepine and remacemide have high hepatic clearance and are biotransformed to hydroxy and deglycine metabolites, respectively, with the activity of their metabolites contributing to the antiepileptic activity of the parent drug after oral administration, despite high first-pass effect metabolism. Gabapentin and oxcarbazepine do not behave pharmacokinetically as their original design intended. Gabapentin is not effective as a chemical drug delivery system for gamma-aminobutyric acid (GABA), and oxcarbazepine serves as a prodrug to its hydroxy metabolite, but does not act as a drug on its own. Nevertheless, these 2 agents demonstrate efficacy in extensive preclinical and clinical trials. Although the pharmacokinetics features of these drugs are important, these features are secondary to their pharmacodynamic properties--i.e. to the requirement that new antiepileptic drugs have to have proven clinical efficacy and safety in epileptic patients.

Acetamides↗
PubMed1992

Pharmacokinetic analysis of ester prodrugs of valproic acid.

The pharmacokinetics of five monoester prodrugs of valproic acid (VPA) were investigated: propyl valproate (P-VPA), butyl valproate (B-VPA), isobutyl valproate (IB-VPA), isoamyl valproate (IA-VPA), and hexyl valproate (H-VPA). In addition, the anticonvulsant activity of these compounds was evaluated and compared with that of VPA and valpromide (VPD). The pharmacokinetics of VPA and its five ester derivatives were determined after intravenous administration of equivalent doses (400 mg of VPA) to six dogs. The five ester prodrugs of VPA were biotransformed to VPA; the biotransformation was complete for P-VPA, B-VPA, and H-VPA but was only partial for IB-VPA and IA-VPA. Because of the rapid conversion of the prodrugs to the parent drug, levels of VPA in plasma after administration of the prodrugs peaked at 6-26 min after dosing and did not yield an in vivo sustained-release dosage profile. Of the five ester prodrugs of VPA, only P-VPA demonstrated anticonvulsant activity. P-VPA also was less neurotoxic than VPA and VPD; therefore, it has a better protective index.

Animals↗
PubMed1992

Pharmacokinetic analysis of the structural requirements for forming "stable" analogues of valpromide.

The following valpromide (VPD) analogues were synthesized and their structure-pharmacokinetic relationships explored: 3-ethyl pentanamide (EPD), methylneopentylacetamide (MND), 1-methyl cyclohexanecarboxamide (MCD), cycloheptanecarboxamide (CHD), and t-butylacetamide (TBD). Two aliphatic (EPD and MND) and two cyclic amides (MCD and CHD) underwent complete or partial conversion to their corresponding acids. The only amide found in this study to be "stable" to the amide-acid biotransformation was TBD. It also had the lowest clearance and the longest half-life and mean residence time. Unlike the other investigated amides, TBD contained two substitutions of two methyl moieties at the beta position of its chemical structure. A "stable" valpromide analogue must have either two substitutions at the beta position, such as in the case of TBD, or a substitution in the alpha and beta positions, such as in the case of the VPD isomer valnoctamide (VCD). This paper discusses the antiepileptic potential of stable VPD analogues which may be more potent and less teratogenic than their biotransformed isomers.

Animals↗
PubMed1992

Pharmacokinetic evaluation of sustained release formulations of antiepileptic drugs. Clinical implications.

Epilepsy is a chronic disease that requires long term therapy, and most of the established antiepileptic drugs (the exception is phenobarbital) must be administered several times daily. This results in compliance problems and fluctuations in plasma concentrations which may lead to subtherapeutic and potentially toxic levels. Development of sustained release formulations of the existing antiepileptic agents may improve antiepileptic therapy. At present, only the following 4 major drugs are used for the treatment of epilepsy: phenobarbital, phenytoin, carbamazepine and valproic acid. Of these, only the latter 2 are suitable candidates for sustained release formulations. This review, therefore, focuses on the evaluation and clinical implications of sustained release formulations of valproic acid and carbamazepine.

Absorption↗
PubMed1991

Stability of diltiazem in different biological fluids.

The hydrolysis of diltiazem in biological fluids: whole blood, plasma, and gastric fluid was investigated under conditions considered close to the physiological situation. The most significant rate of hydrolytic degradation was found in whole blood (half-life of 27 h), followed by plasma (half-life of 88 h), while the least significant degradation rate was observed in gastric fluid (half-life 153 h). The kinetic profiles of diltiazem hydrolysis indicate that hydrolytic degradation in the biological fluids makes a minimal contribution to the clearance and disposition of the drug.

Biotransformation↗
PubMed1991

The effect of raising gastric pH with ranitidine on the absorption and elimination of theophylline from a sustained-release theophylline tablet.

Prior to evaluating the effect of ranitidine on theophylline absorption from a sustained-release theophylline tablet, the effect of ranitidine on the time course of gastric pH in 12 healthy subjects was evaluated with an encapsulated radio-telemetry device (Heidelberg capsule). Gastric pH was measured hourly from 7 AM to 1 PM prior to beginning ranitidine treatment at 2 PM (150 mg every 4 hr for eight doses). The next day, pH was again measured hourly from 7 AM to 7 PM. Subjects fasted overnight and remained fasted until lunch at 11 AM. Prior to ranitidine treatment, the mean morning gastric pH remained between 1.5 and 2.2. After lunch, the pH increased to 2.2-2.3. During ranitidine treatment the mean morning gastric pH measurements were 5.5 to 5.8, decreasing after lunch to 3.1 by 4 PM and increasing to 3.9 at 7 PM. One week later the subjects participated in a three-way crossover theophylline bioavailability study receiving at weekly intervals, single doses at 7 AM of (a) 5 x 100-mg immediate-release tablets, (b) 2 x 300-mg sustained-release theophylline tablets, and (c) 2 x 300-mg sustained-release theophylline tablets after ranitidine pretreatment of 150 mg every 4 hr beginning at 2 PM the previous day. The increase in gastric pH with ranitidine had no effect (P greater than 0.05) on the rate and extent of absorption or on the elimination rate of theophylline.

Adult↗
PubMed1991

Pharmacokinetics and anticonvulsant activity of three monoesteric prodrugs of valproic acid.

The pharmacokinetics of valproic acid (VPA) were compared in dogs with those of the prodrugs ethyl valproate (E-VPA), trichloroethyl valproate (T-VPA), and valproyl valproate (V-VPA). Valproic acid, E-VPA, T-VPA, and V-VPA were administered intravenously and orally to six dogs at equimolar doses. The three VPA prodrugs were rapidly converted to VPA. The biotransformation was complete in the case of E-VPA and T-VPA but was only partial in the case of V-VPA. Because of the rapid conversion to the parent drug, after administration of the prodrugs, VPA plasma levels did not yield a sustained-release profile. Further, the anticonvulsant activity of prodrugs was compared in mice to that of VPA and valpromide (VPD). The anticonvulsant activity of E-VPA, T-VPA, and V-VPA was less than that of VPA.

Animals↗
PubMed1991

Clinical pharmacology of valpromide.

Valpromide has been used as an antiepileptic and antipsychotic drug for the past 25 years in several European countries. Unlike its corresponding acid, valproic acid, whose pharmacokinetics have been quite extensively reviewed, and despite years of clinical use, it appears that no reviews have been written on the pharmacokinetics of valpromide. This article summarises and analyses its pharmacokinetics from various aspects, with a special emphasis on the differences between valpromide and valproic acid. In humans, valpromide is a prodrug of valproic acid. Despite their chemical similarity, the pharmacokinetics of the 2 drugs in humans are quite distinct. Compared with valproic acid. valpromide has a very short half-life (mean +/- SD: 0.84 +/- 0.33h; n = 6), a high clearance value (70 +/- 31 L/h) and a large volume of distribution (75 +/- 13L). Despite its rapid biotransformation to valproic acid, valpromide has some special characteristics, such as its inhibition of the enzyme epoxide hydrolase which is responsible for the metabolism of carbamazepine-10, 11-epoxide. This review discusses the pharmacokinetics of valpromide, the interactions between it and other drugs such as carbamazepine and amitriptyline, and its antiepileptic and antipsychotic activities.

Amitriptyline↗
PubMed1990

Pharmacokinetics of urinary metabolites of cannabidiol in the dog.

The pharmacokinetics of cannabidiol (CBD) and six of its urinary metabolites was investigated in dogs. CBD was administered intravenously to three dogs, and urine was collected at specified time intervals over a period of 30 h. The apparent terminal half-life of CBD calculated from the slope of the sigma minus plot was significantly shorter (2 h) than the half-life of CBD calculated from plasma data (8 h), and the apparent terminal half-life of the metabolites was similar to that of the CBD calculated from plasma data, indicating that the elimination of these metabolites was formation rate limited. The time course of the metabolite excretion could be divided into two phases: the first phase contained mainly monohydroxy metabolites, and the second phase contained mainly metabolites with a carboxylic acid moiety in their side-chain.

Animals↗
PubMed1990

Pharmacokinetics of the trichothecene mycotoxin verrucarol in dogs.

Verrucarol is a simple trichothecene which is structurally related to T-2 and HT-2 toxins. Several macrocyclic trichothecenes which are ester derivatives of verrucarol possess antitumor activity. The pharmacokinetics of verrucarol has been studied in eight dogs following iv and oral administrations (0.4 and 0.8 mg/kg, respectively). The iv study showed that verrucarol has a mean (+/- SD) clearance of 11 +/- 5.5 mL/min/kg, a volume of distribution of 1.2 +/- 0.6 L/kg, and a terminal half-life of 1.6 +/- 0.5 h. Following oral administration, the absolute bioavailability of verrucarol was 44 +/- 33%, and its terminal half-life was similar to that obtained after iv administration. In comparison with T-2 and HT-2 toxins, verrucarol has a longer half-life and a lower clearance, and its liver extraction ratio is about one third of that of T-2 and HT-2 toxins. Therefore, verrucarol is less susceptible to a liver first-pass effect and its partially absorbed after oral administration. These characteristics make verrucarol the first partially absorbed trichothecene whose pharmacokinetics was investigated following oral administration.

Administration, Oral↗
PubMed1990

Structure-pharmacokinetic relationships in a series of short fatty acid amides that possess anticonvulsant activity.

Valpromide (VPD) and valnoctamide (VCD) are two isomers which are aliphatic amides derived from short fatty acids that possess anticonvulsant activity. Our previous studies with VPD, VCD, and other related compounds showed that the biotransformation of these amides to their respective homologous acids is the key issue in their possessing pharmacological activity. In this study, we explored the structure--pharmacokinetic relationships of the following five isomers or analogues of VPD: diisproprylacetamide (DID), diallylacetamide (DAD), octanamide (OAD), ethylisobutylacetamide (EID), and dimethylbutylacetamide (DBD). In addition, the anticonvulsant activity of these compounds was evaluated and compared with that of VPD and VCD. No plasma levels of OAD could be detected after its iv administration. Octanamide (OAD) was very rapidly metabolized to its homologous acid, octanoic acid (OAA). Octanamide (OAD) was different from the other four amides investigated, having a high clearance (due to metabolic processes in the blood) and possessing the least anticonvulsant activity. All of the other amides were stable in blood and showed similar pharmacokinetic parameters. Unlike the other amides, DID and VCD did not metabolize to their respective homologous acids due to the fact that they had a substituted beta position in their aliphatic side chain. Our study showed that, despite similarities in the chemical structures of the amides investigated, significant differences were observed in their pharmacokinetics and in the fraction of the amide (fm) biotransformed to its homologous acid. These differences in fm values may, therefore, account for the observed differences in the respective pharmacological activities, in general, and in the extent of the anticonvulsant activity, in particular, of the amides.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1990

Application of a variance-stabilizing transformation approach to linear regression of calibration lines.

A variance-stabilizing transformation (VST) was applied to the linear regression of calibration standards of different drugs in plasma. This transformation involved the normalization of the dependent variable peak height or peak area ratio (Y), and the independent variable, plasma drug concentration (C). This transformation led to a constant variance in the regression error term across the measured concentration range and allowed the evaluation of the unbiased slope and y intercept with minimum variance. The utility of the VST procedure in comparison with the ordinary least squares (OLS) approach, routinely used in pharmaceutical studies for constructing calibration lines, is described. The principal advantage of the VST approach is allowing a lower minimum level of drug quantification while using a single calibration line over a wide range of drug concentrations. The VST method is especially useful to quantify drug plasma levels in pharmacokinetic evaluation of sustained-release dosage forms, where the precise quantification of low levels of drug is critical. The application of the VST method was explored and evaluated in comparison with the OLS method for pharmacokinetic assays of diltiazem, gallopamil, nitroglycerin, and nicotine.

Calibration↗
PubMed1990

Pharmacokinetics of a valpromide isomer, valnoctamide, in healthy subjects.

The pharmacokinetics of a single 400 mg oral dose of valnoctamide (VCD) has been investigated in seven healthy, adult, male volunteers. VCD was not biotransformed rapidly to its corresponding acid valnoctic acid (VCA), unlike its isomer valpromide (VPD). It had a mean residence time of 13.2 h and a terminal half-life of 9.3 h. Throughout the study, only low plasma levels of VCA could be detected. Thus, unlike VPD, which is a pro-drug of the corresponding acid, (valproic acid, VPA). VCD appears to act as a drug in its own right, and it does not undergo similar hydrolysis. The pharmacokinetic difference may account for the different pharmacological activities of the two isomers.

Adult↗
PubMed1990

Identification of metabolites of the 1",1"-dimethylheptyl analogue of cannabidiol in rat and dog in vivo.

1. Metabolism of the 1",1"-dimethylheptyl analogue of cannabidiol (DMH-CBD) was studied using an isolated perfused rat liver preparation and in rat and dog urine. 2. Metabolites were identified using g.l.c.-mass spectrometry of the trimethylsilyl (TMS), methyl ester/TMS and [2H9]TMS derivatives. 3. In contrast with the metabolism of cannabidiol, the dimethylheptyl analogue gave low concentrations of metabolites in all media examined. 4. Four metabolites were found in the perfusion fluid. Two were identified as 6- and 7-hydroxy-DMH-CBD and the other two were found to be hydroxylated in the dimethylheptyl chain but at undetermined positions. 5. Five metabolites were identified in dog urine; these were the 6- and 7-mono-hydroxy and 6,7-dihydroxy derivatives of acids formed by one stage of beta-oxidation of the dimethylheptyl chain, and the 6- and 7-hydroxy derivatives of corresponding acids formed by loss of three carbon atoms from the chain. 6. Metabolic routes were very similar to those found earlier for cannabidiol.

Animals↗