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Biomedical subjects

J Pitha

Publications and source records attributed to J Pitha.

At least 19 recordsLinked to original sources
PubMed1992

The effect of ammonia and pH on brain gamma-glutamyl transpeptidase in young rats.

Acute hyperammonemia, induced by two consecutive injections of ammonium acetate (550 and 450 mg per kg b.wt.), decreased the activity of gamma-glutamyl transpeptidase (GGT) in most brain regions of 18- and 30-day-old rats. This decrease in the brain GGT activity was more pronounced in younger than in older rats. After the addition of NH4Cl to the incubation medium, the inhibitory action of NH4+ on this enzyme activity was also demonstrated in crude synaptosomal membranes at pH 7.4, but in a range of NH4+ concentrations many-times higher than those found in the plasma or brains of young hyperammonemic rats. Because similar concentrations of NH4+ stimulated the activity of the purified enzyme from rat kidney (mainly at pH 9.0), the inhibition of GGT activity in the young rat brain is probably mediated indirectly and not by a direct interaction of ammonia with the enzyme molecules.

Acetates↗
PubMed1992

Hydroxypropylcyclodextrins in parenteral use. I: Lipid dissolution and effects on lipid transfers in vitro.

Hydroxypropyl ethers of cyclodextrins form water-soluble inclusion complexes with lipids. Of the three hydroxypropylcyclodextrins examined, hydroxypropyl-alpha-cyclodextrin had limited specificity for phospholipids, and hydroxypropyl-beta-cyclodextrin had limited specificity for cholesterol, and hydroxypropyl-gamma-cyclodextrin was nonspecific. The formation of inclusion complexes was found to be a fast and reversible process in which complexation of cholesterol did not inhibit its oxidation by cholesterol oxidase, and cholesterol of the erythrocyte membrane could be exchanged within a minute for cholesteryl methyl ether which was in the inclusion complex. Thus, hydroxypropylcyclodextrin in the circulation may catalyze the transport of lipids in the direction of equilibrium distribution.

2-Hydroxypropyl-beta-cyclodextrin↗
PubMed1992

Hydroxypropylcyclodextrins in parenteral use. II: Effects on transport and disposition of lipids in rabbit and humans.

Hydroxypropyl ethers of cyclodextrins, after parenteral administration, come into contact with lipids in tissues and in circulation and form water-soluble inclusion complexes with these lipids. A single intravenous administration of hydroxypropyl-beta-cyclodextrin to a hereditary hyperlipidemic Watanabe rabbit slightly and temporarily decreased the level of total cholesterol in serum. Single injections of hydroxypropyl-alpha-cyclodextrin and of the corresponding gamma-homologue, both of which are less potent solubilizers of cholesterol, had lesser effects. Repeated administration of hydroxypropyl-beta-cyclodextrin to rabbits led to a gradual increase in total cholesterol in circulation and eventually to a slight relief of atherosclerotic lesions in the thoracic aorta. The only untoward effects of repeated treatments (total doses of up to 40 g/kg) were vacuoles in cells of proximal convoluted tubules in the kidneys. Repeated administration also strongly increased cholesterol in urine, probably because of excretion of the soluble cholesterol-hydroxypropyl-beta-cyclodextrin complex. Proteins in urine increased significantly, whereas triglycerides increased only moderately after repeated administrations. Intravenous infusion of hydroxypropyl-beta-cyclodextrin into a patient with hypervitaminosis A led to a release of liver-stored retinoids into serum in quantities much higher than those that could be directly solubilized by hydroxypropyl-beta-cyclodextrin. Levels of total cholesterol in the circulation of this patient decreased during the infusion. Thus, hydroxypropylcyclodextrins may serve as artificial lipid carriers in the circulation, and because the exchanges that involve inclusion complexation occur very quickly, the presence of hydroxypropylcyclodextrins in organisms may catalytically augment the establishment of equilibria in lipid distribution.

2-Hydroxypropyl-beta-cyclodextrin↗
PubMed1992

Distribution of substituents in O-(2-hydroxypropyl) derivatives of cyclomalto-oligosaccharides (cyclodextrins: influence of increasing substitution of the base used in the preparation, and of macrocyclic size.

Samples of O-(2-hydroxypropyl)derivatives of cyclomaltoheptaose (beta-cyclodextrin) with increasing substitution were prepared by withdrawing aliquots at different times from a reaction mixture containing cyclomaltoheptaose and an excess of (S)-propylene oxide in 0.39 M aqueous sodium hydroxide. The distributions of substituents between the different molecules and between the different alpha-D-glucopyranosyl residues in these samples were determined by mass spectrometry and methylation analysis, respectively. The solubilities of the samples and their association constants with phenolphthalein were also determined. The relative reactivities at O-2 and O-3 versus O-6, calculated using Spurlin's equations, decreased with increasing degree of substitution, probably because of steric hindrance. No significant differences were observed when different strong bases were used as promoters of the hydroxypropylation of cyclomaltoheptaose. The hydroxypropylation of cyclomaltohexaose (alpha-cyclodextrin) and cyclomalto-octaose (gamma-cyclodextrin) was briefly investigated.

Carbohydrate Conformation↗
PubMed1991

Crystal structure of 2-O-[(S)-2-hydroxypropyl]cyclomaltoheptaose.

2-O-[(S)-2-Hydroxypropyl]cyclomaltoheptaose crystallises in the monoclinic space group P2(1) with unit-cell dimensions a = 15.072(1), b = 10.409(1), c = 20.623(2) A, and beta = 108.52(1) degrees. The structure was solved by X-ray diffraction and refined to an R-value of 0.096. The macrocyclic ring of the cyclomaltoheptaose moiety is less symmetrical than that in cyclomaltoheptaose. The glucose residue that carries the hydroxypropyl group inclines much more with its primary hydroxyl side towards the inside of the macrocycle than the other glucose residues. The molecules are arranged in a herring-bone fashion to form a cage-type packing structure. The hydroxypropyl group is inserted into the cavity of an adjacent molecule related by a two-fold screw axis, and the hydroxyl group is linked to an HO-6 via OH...water...OH hydrogen bonds. The crystal contains 8.5 water molecules which occupy 11 sites. Two water molecules are included at the primary hydroxyl side of the cyclomaltoheptaose cavity.

Carbohydrate Conformation↗
PubMed1991

Synthesis of some 2-O-(2-hydroxyalkyl) and 2-O-(2,3-dihydroxyalkyl) derivatives of cyclomaltoheptaose.

On alkylation of cyclomaltoheptaose with oxiranes, promoted by alkali of low concentration, substitution at secondary positions, particularly at O-2, is favoured. The reaction has been used to prepare the 2-O-[(R)- and (S)-2-hydroxypropyl], 2-O-(2-hydroxy-2-methylpropyl), 2-O-[(R)- and (S)-2,3-dihydroxypropyl], and 2-O-[(R)- and (S)-2,3-dihydroxy-2-methylpropyl] derivatives. Each of these derivatives is less soluble in water than cyclomaltoheptaose, and their complexes with toluene, in contrast to that of cyclomaltoheptaose, are well soluble in water.

Carbohydrate Conformation↗
PubMed1991

Structural determinants of 5-HT1A versus 5-HT1D receptor binding site selectivity.

A structure-activity analysis was used to identify selective 5-HT1A versus 5-HT1D receptor agents. An analysis of published data identified 13 drugs which display nanomolar affinity for the 5-HT1A receptor and that have been analyzed at 5-HT1D receptor binding sites. Four agents display greater than or equal to 100-fold selectivity for the 5-HT1A receptor. Two structural features were identified which hypothetically result in selectivity for 5-HT1A versus 5-HT1D binding sites. The linkage of an indole ring to a basic nitrogen atom via the 4 position on the indole ring or the absence of an indole ring are two features which lower the affinity for the 5-HT1D receptor, but do not necessarily lower the affinity for the 5-HT1A receptor. A series of 7 agents (5 indoles, 2 quinolines) was identified which met these hypothetical selectivity criteria. These compounds were then analyzed in radioligand binding studies. These 7 agents display affinities of 1.3-170 nM for the 5-HT1A receptor binding site, and 1,800-13,000 nM for the 5-HT1D receptor binding site. All 7 agents display greater than or equal to 47-fold selectivity for the 5-HT1A versus 5-HT1D site and 4 of the agents are greater than 100-fold selective. Compound No. 1 (N,N'-bis[3-(4-indolyloxy)-2-hydroxypropyl]-(Z)-1,8-diamino-p-meth ane) and compound No. 2 (N8-[3-(4-indolyloxy)-2-hydroxypropyl]-N1-(propioloyl)-(Z)-1 ,8-diamino-p-methane) are the most selective agents yet described for 5-HT1A versus 5-HT1D receptor binding sites.(ABSTRACT TRUNCATED AT 250 WORDS)

Adenylyl Cyclases↗
PubMed1991

Oversaturated solutions of drug in hydroxypropylcyclodextrins: parenteral preparation of pancratistatin.

The effect of 15 cyclodextrin derivatives (polar-electroneutral, cationic, anionic, and lipophilic) and of three 2-hydroxypropyldigitonins on the solubility of pancratistatin, an anticancer drug, was evaluated. The direct solubilizations into aqueous solutions were invariably low (0.1-1.2 mg/mL compared with 50 micrograms/mL in water). Complexes of pancratistatin with hydroxypropyl-beta-cyclodextrin were more stable (Kapp 153 M-1) than those with hydroxypropyl-gamma-cyclodextrin (Kapp 108 M-1). Acceptable preparations were made by dissolution of pancratistatin in a large excess (50x) of hydroxypropylcyclodextrin by ammonia and then freeze drying to ammonia-free preparations. In these preparations, both the inclusion and interdispersion phenomena were operative, and the preparations dissolved rapidly forming clear solutions of pancratistatin of concentrations up to 9 mg/mL. These solutions were oversaturated and while those based on hydroxypropyl-beta-cyclodextrin precipitated within 1 h; those based on hydroxypropyl-gamma-cyclodextrin were stable for at least 4 h when kept in a plastic container (i.e., time sufficient for potential use in parenteral preparations).

Amaryllidaceae Alkaloids↗
PubMed1991

Characterization of a novel and potent 5-hydroxytryptamine1A receptor antagonist.

A series of pindolol derivatives (n = 7) was analyzed in radioligand binding, biochemical and behavioral studies. Three of these drugs (Compounds A, B, and C) are extremely potent (i.e., Ki values less than 1.0 nM) at 5-hydroxytryptamine1A (5-HT1A) sites labeled by [3H] 8-hydroxy-2-(di-n-propylamino) tetralin (8-OH-DPAT). Moreover, these drugs are selective in that they are approximately an order of magnitude less potent at beta-adrenergic receptors labeled by 3H-dihydroalprenolol (DHA). Compound A (N1-(bromoacetyl)-N8-[3-(4-indolyloxy)-2-hydroxypropyl]-(Z)-1,8-di amino-p- methane) is also significantly less potent at 10 other neurotransmitter receptor sites analyzed. In addition, Compound A (10(-10) M to 10(-3) M) has no effect on baseline forskolin-stimulated adenylate cycalse activity in rat hippocampus. By contrast, nanomolar concentrations of the drug significantly (p less than 0.01) reverse 8-OH-DPAT-induced inhibition of forskolin-stimulated activity. In behavioral studies. Compound A (0.5 mg/kg) alone has no effect on baseline measures of reciprocal forepaw treading in the rat. Pretreatment with Compound A, however, significantly (p less than 0.05) inhibits the reciprocal forepaw treading induced by 8-OH-DPAT. These data suggest that Compound A is a potent and selective antagonist of 5-HT1A receptors in the CNS.

8-Hydroxy-2-(di-n-propylamino)tetralin↗
PubMed1991

Cyclodextrin sulfates: characterization as polydisperse and amorphous mixtures.

Alpha- and beta-cyclodextrins and their hydroxypropyl derivatives were converted by the reaction with chlorosulfonic acid in pyridine to the corresponding sulfates. Cyclodextrin sulfates were shown by fast-atom bombardment mass spectrometry (negative ion mode, triethanolamine matrix) to be mixtures with nearly symmetrical distributions of degree of substitution by sulfate groups and by powder X-ray diffraction to be amorphous. Thus, in these aspects, cyclodextrin sulfates are similar to the potent drug solubilizers hydroxypropylcyclodextrins.

Cyclodextrins↗
PubMed1990

(S)-2-hydroxypropyl-beta-cyclodextrin, a new chiral stationary phase for reversed-phase liquid chromatography.

(S)-2- and (R,S)-2-hydroxypropyl-beta-cyclodextrin have been bonded to silica gel and evaluated as stationary phases for reversed-phase liquid chromatography. Stationary phases also were prepared on two silicas having different pore sizes and surface areas. Dissimilarities were observed in enantiomeric selectivities between these columns and also between these and the native beta-cyclodextrin columns. With the exception of compounds 5 and 10, all other racemates reported here which have been successfully resolved on the new phases are enantiomers which have not been previously reported as separated on the beta-cyclodextrin stationary phase. In some cases, there were also differences in enantioselectivities observed between the (S)- and the (R,S)-hydroxypropyl-beta-cyclodextrin phases on the same silica. The results are discussed in terms of the retention mechanism and compared to results reported earlier for beta-cyclodextrin columns.

Chemical Phenomena↗
PubMed1990

Distribution of substituents in 2-hydroxypropyl ethers of cyclomaltoheptaose.

The distribution of substituents in 2-hydroxypropyl ethers of cyclomaltoheptaose, prepared by alkylation of the carbohydrate with propylene oxide in aqueous sodium hydroxide, was investigated. The samples were fully methylated and hydrolyzed, and the resulting mixture of alkylated sugars analyzed as their alditol acetates by g.l.c.-m.s. High and low alkali concentration favored the formation of 2-hydroxypropyl ethers at O-6 and O-2, respectively; substitution at O-2 increased the reactivity of O-3. The overall extent of substitution had only secondary effects on the relative reactivities of O-6 and O-2, and the 2-hydroxypropyl groups remained unevenly distributed among the glucose residues, even when the overall substitution increased. Only small proportions of the isomeric 2-(1-hydroxypropyl) ethers were formed, and the percentage of oligopropylene glycol ethers was also low.

1-Propanol↗
PubMed1990

Behavior and physiological effects of supplemental episodes of testosterone, its precursors and metabolite in rats.

Androgen-sensitive behavior and physiology were examined in gonadally intact male rats receiving daily injections of steroids (0.4 mg/kg) in two pharmaceutical forms for one month. When steroids were injected as aqueous solutions of hydroxypropyl-beta-cyclodextrin complexes, a form which insures a rapid distribution through the organism, testerosterone strongly increased behavioral parameters, while testosterone precursors (dehydroepiandrosterone and 4-androstene-3, 17-dione) and metabolite (5-alpha-dihydrotestosterone) decreased them. These results suggest that it is not possible to produce an effective testosterone pulse by metabolic conversion through supplemental pulses of precursors. The treatments did not affect sperm counts in epididymis. The size of ventral prostate was increased only after the administration of 4-androstene-3,17-dione or 5-alpha-dihydrotestosterone, not after testosterone or dehydroepiandrosterone. When steroids were injected in oil, a pharmaceutical form which distributes steroids slowly and in a protracted manner, testosterone led to an enlargement of the prostate in addition to the increase in behavioral parameters seen with the complexed form. The suppression in behavior and prostate enlargement by other steroids were more pronounced than when these were administered in complexed forms. Obviously, some of the adverse effects of the presently used depot steroid preparations are of pharmacokinetic origin.

Androstenedione↗
PubMed1990

Pharmaceutical usefulness of hydroxypropylcyclodextrins: "e pluribus unum" is an essential feature.

A series of hydroxypropyl-beta-cyclodextrins was prepared by a method that leads to a preferential substitution on the secondary hydroxyls, mainly O-2, of beta-cyclodextrin with (S)-2-hydroxypropyl groups. The series consisted of mixtures of compounds with average degrees of substitution of 8, 3, and 1.6 and of a specially isolated monosubstituted compound; thus, the number of components progressively decreased in this series. The crystallinity in the series increased progressively, the first member being fully amorphous and the last one fully crystalline. All members of the series formed clear aqueous solutions at concentrations of greater than 50.0, 2.0, 0.6, and 0.3%, respectively. Therefore, pharmaceutically useful hydroxypropylcyclodextrin preparations are those containing a large number of chemically individual compounds--a feature resulting in an amorphous state and high water solubility.

Chemical Phenomena↗
PubMed1990

Enhancement of the antiinflammatory effect of ethyl 4-biphenylyl acetate in ointment by beta-cyclodextrin derivatives: increased absorption and localized activation of the prodrug in rats.

Ethyl 4-biphenylyl acetate (EBA) is a prodrug of the antiinflammatory 4-biphenylyl acetic acid (BPAA). The inclusion complexes of EBA with beta-cyclodextrin (beta-CyD), heptakis(2,6-di-O-methyl)-beta-cyclodextrin (DM-beta-CyD), and 2-hydroxypropyl-beta-cyclodextrin (HP-beta-CyD) at a molar ratio of 1:2 (EBA:cyclodextrin) were prepared and used to make hydrophilic antiinflammatory ointments. The in vitro release of EBA from the ointments was enhanced by complexation in the order of beta-CyD less than DM-beta-CyD less than or equal to HP-beta-CyD. The improvement correlated with the improved solubility and not with the decreased diffusibility observed to occur upon the complexation of EBA. In vivo the complexation with cyclodextrin derivatives increased both the release of EBA from the vehicle and its conversion in the underlying tissue to BPAA, but the total of EBA and BPAA in the tissue was decreased. In vitro studies confirmed that the effects of cyclodextrin derivatives on the conversion were exerted indirectly. The combination of the enhanced release and of the enhanced prodrug hydrolysis by esterases in the site where the antiinflammatory action is required resulted in increased therapeutic effects. In the model of carrageenan-induced acute edema in rat paw, the complexation improved the therapeutic effects over those of EBA alone in the order of beta-CyD less than DM-beta-CyD less than HP-beta-CyD. HP-beta-CyD may be a particularly useful cyclodextrin derivative since it improves the topical availability and does not irritate tissues.

Animals↗
PubMed1989

Differential effects of alpha-, beta- and gamma-cyclodextrins on human erythrocytes.

Alpha-, beta- and gamma-cyclodextrins are cyclic hexamers, heptamers, and octamers of glucose, respectively, and thus are hydrophilic; nevertheless, they have the ability to solubilize lipids through the formation of molecular inclusion complexes. The volume of lipophilic space involved in the solubilization process increases with the number of glucose units in the cyclodextrin molecule and, consequently, cyclodextrins were found to have different effects on human erythrocytes: (a) in the induction of shape change from discocyte to spherocyte the potency was observed to be alpha greater than gamma, but with beta-cyclodextrin hemolysis occurred before the change was complete; (b) in the increase of fluorescence intensity of 1-anilinonaphthalene-8-sulfonate in cyclodextrin-pretreated membranes, the observed potency was beta much greater than gamma greater than alpha; (c) in the release of potassium and hemoglobin, the potency was beta greater than alpha greater than gamma. The potencies of cyclodextrin for solubilizing various components of erythrocytes were alpha greater than beta much greater than gamma for phospholipids, beta much greater than gamma greater than alpha for cholesterol and beta much greater than gamma greater than alpha for proteins. The solubilization potencies were derived from concentration/final-effect curves. The above processes occurred without entry of solubilizer into the membrane, since (a) beta-[14C]cyclodextrin did not bind to erythrocytes and (b) cyclodextrins did not enter the cholesterol monolayer. A study of the [3H]cholesterol in erythrocytes indicated that beta-cyclodextrin extracted this lipid from membrane into a new compartment located in the aqueous phase which could equilibrate rapidly with additional erythrocytes. Therefore, the effects of cyclodextrins differ from those of detergents which first incorporate themselves into membranes then extract membrane components into supramolecular micelles.

Cyclodextrins↗
PubMed1989

Alkylation of cyclomalto-oligosaccharides (cyclodextrins) with dialkyl sulfate-barium hydroxide: heterogeneity of products and the marked effect of the size of the macrocycle.

The alkylation of cyclomalto-oligosaccharides (cyclodextrins, CDs) with dialkyl sulfate-barium hydroxide has been claimed to yield 2,6-di-O-alkyl derivatives. Re-investigation by plasma desorption-m.s. of the products of laboratory methylation of alpha CD, beta CD, or gamma CD and ethylation of beta CD and several commercial preparations revealed them to be mixtures with broad and roughly symmetrical distributions of the degree of substitution. Recrystallization separated the components only partially. Analysis of the product of methylation of a mixture of CDs established the order of reactivity gamma much greater than alpha greater than or equal to beta. The reactivity of gamma CD thus resembles that of amylose.

Alkylation↗