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B Yagen

Publications and source records attributed to B Yagen.

At least 37 records · Page 2Linked to original sources
PubMed1998

Low swelling, crosslinked guar and its potential use as colon-specific drug carrier.

PURPOSE: (a) To reduce the swelling properties of guar gum (GG) by crosslinking it with glutaraldehyde (GA), while maintaining its degradation properties in the presence of typical colonic enzymes, (b) to characterize the modified GG and to examine its degradation properties in vitro and in vivo, and (c) to assess, by drug probes with different water solubilities, the potential of the crosslinked GG to serve as a colon-specific drug carrier. METHODS: GG was crosslinked with increasing amounts of GA under acidic conditions to obtain different products with increasing crosslinking densities. These products were characterized by measuring (a) their swelling properties in simulated gastric and intestinal fluids, (b) their crosslinking densities, (c) the release kinetics of three different drugs: sodium salicylate (SS), indomethacin (Indo) and budesonide (Bud) from the crosslinked products into buffer solutions, with or without a mixture of galactomannanase and alpha-galactosidase, and (d) their in vivo degradation in the cecum of conscious rats with and without antibiotic treatment. RESULTS: Significant reduction in GG swelling properties, in both simulated gastric and intestinal fluids, was accomplished by its crosslinking with GA. The crosslinking density of the modified GG products was GA concentration-dependent. The release of SS from crosslinked GG discs was completed within 120 minutes. During the same period of time and for more than 10 hours the release of Indo and Bud was negligible. The release rate of the latter two drugs was enhanced when galactomannanase and alpha-galactosidase were added to the dissolution media. Discs made of the crosslinked GG were implanted in the cecum of rats and their degradation was assessed after 4 days. The extent of degradation was dependent on the amount of GA used for the crosslinking. After 4 days the same discs were recovered intact from rats exposed to antibiotic treatment and from simulated gastric and intestinal fluids. CONCLUSIONS: Reducing the enormous swelling of GG by crosslinking it with GA resulted in a biodegradable hydrogel which was able to retain poorly water soluble drugs, such as Indo and BUD, but not highly water soluble drugs, such as SS, in artificial gastrointestinal fluids. A variety of hydrogels with increasing crosslinking densities were produced and tested for their potential use as colon-specific drug platforms in vitro and in vivo. Their performance did not depend on creating physical barriers by means of compression.

Administration, Oral↗
PubMed1997

Isolation of N,N-dialkylated derivatives of valproylglycinamide from dog plasma by active charcoal adsorption and their quantification by high-performance liquid chromatography.

A selective assay for quantification of N,N-dimethylvalproylglycinamide (DM-VGD) and N,N-diethylvalproylglycinamide (DE-VGD) in dog plasma utilizing reversed-phase high-performance liquid chromatography and UV detection has been developed. These compounds are derivatives of the potential anticonvulsant drug, valproylglycinamide, which is currently undergoing clinical trials. The method is based on extraction of dog plasma with activated charcoal, separation of the charcoal pellet and extracting it with methanol, evaporation of the solvent and injecting the reconstituted residue onto the column. The active charcoal adsorption method is reliable and reproducible, and it provides a chromatogram free of interfering endogenous plasma compounds. The assay was validated and provided a limit of quantification of 2.3 mmol/l for DE-VGD and 5.3 mmol/l for DM-VGD. Mean recovery of these compounds from plasma averages 75%. This analytical method is suitable for the quantitative determination of DM-VGD and DE-VGD in plasma and it has been applied to a pharmacokinetic study of these compounds in a dog.

Animals↗
PubMed1997

Stereoselective pharmacokinetic analysis of valnoctamide in healthy subjects and in patients with epilepsy.

OBJECTIVE: To investigate the pharmacokinetics of the four stereoisomers of valnoctamide, a mild tranquilizer endowed with anticonvulsant properties. METHODS: Racemic valnoctamide, 400 mg, was administered orally to seven healthy subjects and to six patients with epilepsy stabilized with long-term carbamazepine therapy. In the patients with epilepsy, valnoctamide kinetics was also reassessed after 8-day oral dosing at a dosage of 600 mg daily. Plasma samples were assayed by gas chromatography-mass spectrometry with use of a capillary column coated with chiral stationary phase that enabled baseline resolution of the four stereoisomers, designated hereafter as A, B, C, and D (where A and C, together with B and D, represent enantiomeric pairs). RESULTS: In healthy subjects, stereoisomers A, C, and D showed similar kinetics, with an apparent oral clearance (CL/F) of about 4 1/2 L/hr, a half-life (t1/2) of about 10 hours, and an apparent volume of distribution (VSS/F) of about 65 L. However, stereoisomer B showed a much higher clearance (8.7 +/- 0.9 L/hr) and a shorter t1/2 (5.8 hours). For all stereoisomers, CL/F values in patients with epilepsy were about tenfold higher than those found in healthy subjects. Compared with healthy subjects, patients with epilepsy also showed shorter t1/2 values and higher VSS/F values for each of the stereoisomers. After 7-day dosing, CL/F values at steady state were lower than those determined in the same patients after a single dose. CONCLUSIONS: Valnoctamide exhibits enantioselectivity and diastereoselectivity, an observation that may have important practical implications if pharmacodynamic differences between stereoisomers are also found. The observed pharmacokinetic differences between healthy subjects and patients with epilepsy are likely to be related to induction of metabolism of valnoctamide stereoisomers by carbamazepine.

Administration, Oral↗
PubMed1997

Pharmacokinetics and antiepileptic activity of valproyl hydroxamic acid derivatives.

PURPOSE: To explore the utilization of seven novel hydroxamic acid derivatives of valproic acid (VPA) as new antiepileptics. METHODS: The study was carried out by investigating the pharmacokinetics of two active compounds in dogs and pharmacodynamics (anticonvulsant activity and neurotoxicity) of valproyl hydroxamic acid and six of its derivatives. RESULTS: Three valproyl hydroxamic acid derivatives: valproyl hydroxamic acid-VPA-HA, N-(1-hydroxyethyl)-valpromide-HEV and N-methoxy valpromide, showed better anticonvulsant activity than VPA at the maximal electroshock (MES) test. The remaining four compounds, O-valproyl-VPA-HA, N-valproyl-O-valproyl-VPA-HA, N-(1-methoxyethyl) valpromide and N-(1,2-dihydroxylpropyl)-valpromide were found to be inactive. Therefore, only the pharmacokinetics of the active compounds VPA-HA and HEV was studied. CONCLUSIONS: In contrast to valpromide (VPD) which is biotransformed to VPA, VPA-HA and HEV were found to be stable in vivo to the biotransformation of the amide to its corresponding acid. VPA-HA and HEV showed improved anticonvulsant activity over VPA because of their greater intrinsic activity and not due to better pharmacokinetic characteristics. This paper discusses the structural requirements for active anticonvulsant valproyl hydroxamic acid derivatives.

Animals↗
PubMed1996

Pharmacokinetic analysis and antiepileptic activity of tetra-methylcyclopropane analogues of valpromide.

PURPOSE: The described structure pharmacokinetic pharmacodynamic relationships (SPPR) study explored the utilization of tetramethylcyclopropane analogues of valpromide (VPD), or tetramethylcyclopropane carboxamide derivatives of valproic acid (VPA) as new antiepileptics. METHODS: The study was carried out by investigating the pharmacokinetics in dogs and pharmacodynamics (anticonvulsant activity and neurotoxicity) of the following three cyclopropane analogues of VPD: 2,2,3,3-tetramethylcyclopropane carboxamide (TMCD), N-methyl TMCD (M-TMCD) and N-[(2,2,3,3-tetramethylcyclopropyl)carbonyl]-glycinamide (TMC-GLD). RESULTS: The three investigated compounds showed a good anticonvulsant profile in mice and rats due to the fact that they were metabolically stable VPD analogues which were not biotransformed to their nonactive acid, 2,2,3,3-tetramethylcyclopropane carboxylic acid (TMCA). M-TMCD was metabolized to TMCD and TMC-GLD underwent partial biotransformation to its glycine analogue N-[(2,2,3,3-tetramethylcyclopropyl)carbonyl]-glycine (TMC-GLN). Unlike TMC-GLN, the above mentioned amides had low clearance and a relatively long half life. CONCLUSIONS: In contrast to VPD which is biotransformed to VPA, the aforementioned cyclopropane derivatives were found to be stable to amide-acid biotransformation. TMCD and M-TMCD show that cyclic analogues of VPD, like its aliphatic isomers, must have either two substitutions at the beta position to the carbonyl, such as in the case of TMCD, or a substitution in the alpha and in the beta positions like in the VPD isomer, valnoctamide (VCD). This paper discusses the antiepileptic potential of tetramethylcyclopropane analogues of VPD which are in animal models more potent than VPA and may be non-teratogenic and non-hepatotoxic.

Animals↗
PubMed1994

Pharmacokinetic profile of conjugated verrucarol urinary metabolites in dogs.

The pharmacokinetics and renal excretion of a trichothecene mycotoxin, verrucarol, were studied in six mongrel dogs following IV administration (0.4 mg kg-1). The fraction of verrucarol excreted intact in the urine ranged from 0.9% to 2.7% of the administered dose. The fraction of verrucarol metabolites excreted in the urine was 32-60% for verrucaryl glucuronides and 32-47% for verrucaryl sulphates. These urinary conjugated metabolites were analysed quantitatively following their enzymatic hydrolysis. The half-life of verrucarol calculated from the urinary data of its conjugated metabolites was not significantly different from the half-life calculated from the plasma data of the parent compound.

Animals↗
PubMed1992

The toxicity of macrocyclic trichothecenes administered directly into the rat brain.

The tested macrocyclic trichothecenes are produced by Myrothecium fungi and by the plant Baccharis megapotamica. The toxicity of five macrocyclic trichothecenes has been measured by intracerebral and subcutaneous injection into rats. It is assumed that the toxic effects are based on inhibition of protein synthesis. Intoxication of rats by these compounds finds expression in slowly progressing respiratory depression and paralysis of skeletal muscles. The macrocyclics are derived from verrucarol, which lacks ring D and exhibits only low toxicity. The high toxicity of the macrocyclics, established by intracerebral and subcutaneous applications, may thus be attributed to the presence of the large ring D.

Animals↗
PubMed1992

Trichothecene mycotoxins inhibit phosphoinositide hydrolysis in bovine platelets stimulated with platelet activating factor.

The effects of the trichothecene mycotoxins, acetyl T-2 toxin, T-2 toxin, HT-2 toxin, diacetoxyscirpenol (DAS), deoxynivalenol (DON) and T-2 tetraol on phospholipid turnover were determined in bovine platelets prelabelled with [1-14C]arachidonic acid (AA). In resting, non-stimulated platelets exposed to acetyl T-2 toxin, a marked decrease in [1-14C]phosphatidylinositol (PI) along with a marked increase in [1-14C]phosphatidic acid (PA) were observed, whereas T-2 toxin, and HT-2 toxin only induced a significant increase in [1-14C]PA. In contrast, in platelet activating factor (PAF)-stimulated platelets, the mycotoxins were found to suppress both the agonist-induced loss of [1-14C]PI and the appearance of [1-14C]PA with acetyl T-2 toxin being the most effective and T-2 toxin, HT-2 toxin, and DAS essentially equally effective. T-2 tetraol and DON did not affect phospholipid metabolism either in unstimulated or PAF stimulated platelets. The alterations in [1-14C]PI and [1-14C]PA suggest that the inhibitory toxins may activate a specific phospholipase C (PLC) in the unstimulated platelets and then impede further PLC activation in PAF-stimulated platelets.

Animals↗
PubMed1991

Metabolism of T-2 toxin by rat brain homogenate.

HT-2 toxin was the sole metabolite formed when T-2 toxin was treated with homogenate from brain without its blood content. Homogenate from brain with its full blood content produced--besides HT-2 toxin--T-2 triol, neosolaniol, 4-deacetylneosolaniol and T-2 tetraol, i.e. the same metabolites formed by incubation of T-2 toxin with whole rat blood.

Animals↗
PubMed1991

Central effects of cycloheximide alone and of its combination with T-2 toxin.

The antibiotic cycloheximide inhibits protein synthesis in eukaryotic cells. This overall effect is similar to that of T-2 toxin, but the mechanism of intoxication by these two inhibitors are different. This is shown here by intracerebral injections of mixtures of T-2 toxin and cycloheximide, leading to potentiation of their toxic effects. The histopathology of cerebral intoxication by the two compounds is similar, but after cycloheximide the lesions appear earlier, and repair is faster.

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↗
PubMed1989

The cytotoxicity of T-2 toxin and related 12,13-epoxytrichothecenes to Adriamycin-sensitive and -resistant P388 leukemia cells.

The cytotoxicity of T-2 toxin and related trichothecenes was studied in Adriamycin-sensitive and -resistant P388 leukemia cells in vitro. The structure-activity relationship indicated that a free hydroxyl in the C-3 position contributed to the activity. Free hydroxyls at the 4, 8, and 15 positions interfered with the activity, and their estrification resulted in improved cytotoxicity. The cytotoxic activity of these trichothecenes did not seem to be related to their degree of lipophilicity. Adriamycin-resistant P388 cells were cross-resistant to the trichothecenes, and this resistance could be circumvented by verapamil.

Animals↗
PubMed1989

Structure-activity relationships for the direct toxic action of trichothecenes on rat brain.

Three classes of 12,13-epoxytrichothecenes, differing in the number of hydroxy or acetoxy substituents, were implanted or injected into rat brain to establish structure-toxicity relationships. A free 3 alpha-hydroxy group increases toxicity more than 10-fold, when compared to trichothecenes lacking this substituent. The 8 alpha-hydroxy group enhances toxicity about 4-fold.

Administration, Topical↗
PubMed1989

Comparison of the toxicity of two trichothecenes applied topically to brain and liver of rats.

T-2 toxin has been found previously to be markedly more toxic upon intracerebral than upon systemic administration. In order to study the generality of this difference, we have applied to brain and liver of albino rats two different types of trichothecenes: T-2 toxin as a representative of 'simple' and myrotoxin B as a representative of 'macrocyclic' members of this series. Myrotoxin B, when applied intracerebrally, was about 100 times more poisonous than T-2 toxin. In contrast, upon intrahepatic injection both compounds exhibited similar degrees of toxicity. The different behavior of the two trichothecenes in the organs tested may be due to local metabolic factors.

Animals↗
PubMed1988

Pharmacokinetics and protein binding of trichothecene mycotoxins, T-2 toxin and HT-2 toxin, in dogs.

The pharmacokinetics of T-2 toxin, following i.m. and i.v. administration (0.4 mg/kg), were investigated in five dogs. Following i.m. administration, the mean pharmacokinetic parameters for T-2 and HT-2 toxins were, respectively: apparent half-life 21 +/- 5 and 73 +/- 7 min; peak plasma concentration 182 +/- 42 and 74 +/- 16 ng/ml; time to reach peak plasma concentration 9.4 +/- 6.4 and 49 +/- 11 min. Mean residence time calculation, using moment analysis, showed that the terminal slope of T-2 toxin plasma levels following i.m. administration corresponds to the absorption rate constant of the toxin due to the flip-flop phenomenon. T-2 toxin was completely absorbed following i.m. administration and its absolute bioavailability was 1.17 +/- 0.25. A plasma protein binding study showed that in a concentration range of 70-500 ng/ml, T-2 and HT-2 toxins have a mean free fraction of 30.6 +/- 3.1% and 32.6 +/- 3.6% with no concentration dependency. At physiological conditions (temperature and pH), both T-2 and HT-2 toxins were unstable in whole blood and their in vitro stability half-lives were 6.9 and 0.84 hr, respectively. However, under similar conditions, these toxins were stable in plasma for 7 hr. Their instability in whole blood, therefore, may be related to enzymes present in the blood cells.

Animals↗
PubMed1988

Cerebral toxicity of the trichothecene toxin T-2, of the products of its hydrolysis and of some related toxins.

T-2 toxin and its metabolites (resulting from enzymatic hydrolysis by rat brain homogenate) were applied to the midbrain of albino rats, either in solid form or dissolved in dimethyl sulfoxide (DMSO). Solid implants of HT-2 toxin and of T-2 triol were lethal in the range of 10-20 micrograms per rat, i.e. similar to the effect of T-2 toxin itself. For four further trichothecenes, the following decreasing order of toxicities was found: T-2 tetraol = iso-T-2 toxin greater than T-2 tetraol tetraacetate greater than T-2 toxin acetate. Implants of the last compound were the least toxic in the present series of trichothecenes; its LD50 value was nearly ten times higher than that of T-2 toxin. A similar gradation of toxicity was observed upon intracerebral injection of the compounds dissolved in DMSO. Here the only exception was the markedly reduced toxicity of T-2 toxin itself. From these data, the role of free 3 alpha- and 4 beta-hydroxyl groups has been evaluated. For subcutaneous applications, the largest ratio of LD50 values was 5, i.e. for the pair T-2 triol-T-2 tetraol tetraacetate. Among the signs of central intoxication, convulsions, adipsia and aphagia were marked. Pathological changes in the brain tissue, mainly involving necrotic, hemorrhagic and inflammatory lesions at the sites of application, were similar for all trichothecenes tested in this study.

Animals↗
PubMed1988

Metabolism of canthaxanthin, a red diketocarotenoid, by chickens.

Canthaxanthin, (4,4'-diketo-beta,beta-carotene), a red carotenoid used to extend the dominant wavelength of the yellow pigments in the skin and egg yolk of chickens, was fed (70 micrograms/g diet) to chicks depleted of normal tissue oxycarotenoids. High performance liquid chromatography analysis of tissues from such chicks revealed that a portion of canthaxanthin was reduced to 4-hydroxyechinenone (4-hydroxy-4'-keto-beta,beta-carotene) that in turn was reduced in part to isozeaxanthin (4,4'-dihydroxy-beta,beta-carotene). The alcohols thus formed were acylated in part to 4-hydroxyechinenone monoester and isozeaxanthin monoester and diester. Individual metabolites were identified by retention times, ratios A470/A430, and stopped-flow spectral analyses, which were identical in each case to authentic standards. Ratios of canthaxanthin to metabolites varied with the tissue, but in general metabolites were concentrated in the integument.

Animals↗