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Biomedical subjects

J Pitha

Publications and source records attributed to J Pitha.

At least 55 records · Page 3Linked to original sources
PubMed1987

A bromoacetylated analogue of cyanopindolol: an irreversible antagonist at rat beta-adrenoceptors.

A high affinity, chemically reactive cyanopindolol derivative. N8-bromoacetyl-N1-3'-(2-cyano-4-indolyloxy)-2'-hydroxypropyl-[Z]-1 ,8-diamino-p-menthane (Br-CYP) was synthesized and its interaction with beta-adrenoceptors characterized. Studies with rat heart, lung, brain, and red blood cell membranes indicated that the compound displaced 3H-dihydroalprenolol (3H-DHA) from beta-adrenoceptors with IC50 values in the nanomolar range. The concentration of functional beta-adrenoceptors in membranes was markedly reduced when membranes were preincubated with Br-CYP and then extensively washed prior to assay. (+/-)Alprenolol and (-)isoproterenol, but not (+)isoproterenol, when included in the preincubation prevented this reduction in binding sites by Br-CYP. Br-CYP was active in vivo when injected intraperitoneally into rats. A dose of 10 micrograms/kg reduced the concentration of binding sites in membranes from heart by 30%, lung by 36%, and RBC by 70%, but did not affect sites on brain membranes 16 hours after injection. Higher doses blocked virtually all the 3H-DHA binding sites in the peripheral organs studied. Br-CYP reduced the concentration of beta-adrenoceptors in membranes from these same tissues (but not brain tissue) as long as two weeks after injection with recovery of binding occurring more rapidly in heart tissue than lung and red blood cells. These results suggest that Br-CYP may be a useful compound for in vivo studies of the biochemistry and pharmacology of beta-adrenergic systems.

Adrenergic beta-Antagonists↗
PubMed1987

Inhibition of alpha 1-adrenergic responsiveness in intact cells by a new, irreversible receptor antagonist.

A novel alpha 1-adrenoreceptor antagonist, 1-(4-amino-6,7-dimethoxy-2-quinazolinyl)-4-(2-bicyclo [2.2.2] octa-2,5-dienylcarbonyl) piperazine, was synthesized and shown to potently block alpha 1-adrenoceptor-induced Ca2+ mobilization in intact rat parotid acinar cells. Irreversible inhibition was complete in less than 5 min. This alkylating prazosin derivative blocked Ca2+ release (IC50 approximately 5 X 10(-10)M) and [3H]-prazosin membrane binding (IC50 approximately 3 X 10(-10)M) in a concentration dependent fashion and increased the EC50 of epinephrine for Ca2+ efflux by approximately 35 fold. The agent however had no effect on muscarinic receptor-induced Ca2+ mobilization, or beta-adrenoreceptor-induced protein secretion, from cells. These findings suggest that this irreversible alpha 1-adrenoreceptor antagonist will be a valuable tool in probing alpha 1-adrenoreceptor function and metabolism in intact cells.

Adrenergic alpha-Antagonists↗
PubMed1987

Two beta-adrenergic pharmacophores on the same molecule. A set of agonist-antagonist combinations.

A series of compounds containing combinations of one or two pharmacophores of the agonist type (isoproterenol) or the antagonist type (propranolol or alprenolol) on the same molecule were prepared. The pharmacophores were connected by a derivative of polyethylene glycol with an average length of six atoms (carbon and oxygen). Furthermore, compounds containing two alprenolol residues, separated by chains of average lengths of 70 or 145 atoms, were synthesized. The abilities of these compounds to interact with beta-adrenoceptors of rat heart and lung tissues were examined by measuring the following parameters: competitive binding with [3H]dihydroalprenolol, activation of adenylate cyclase, and inhibition of isoproterenol-stimulated adenylate cyclase. The affinity of the compound with two isoproterenol pharmacophores for receptor was about the same as that with one isoproterenol pharmacophore and between 30 and 200 times weaker than that of (+/-)isoproterenol. Both mono- and bis-pharmacophore compounds partially stimulated catecholamine sensitive adenylate cyclase and at high concentrations inhibited the stimulation produced by (-)isoproterenol. The affinity of the compound with antagonist (propranolol) and agonist (isoproterenol) pharmacophores on the same molecule was intermediate between that of propranolol and isoproterenol. The compound was only able to inhibit adenylate cyclase activity. Compounds containing two antagonist (alprenolol) pharmacophores bound to receptors with affinities from an order of magnitude lower to about equal to that of the compound containing one pharmacophore. When membranes were preincubated with compounds containing two antagonist pharmacophores and then washed extensively, there were persistent effects of all of these compounds on the binding constants of [3H]dihydroalprenolol. All of these compounds were only able to inhibit adenylate cyclase activity and none exhibited any subtype selectivity at beta-adrenoceptors. The results suggest that, in the beta-adrenergic system, compounds with agonist and antagonist substituents on the same molecule exhibit properties of the substituent with the higher affinity for beta-adrenoceptor, and no agonist activity is evident when two antagonist pharmacophores are linked on the same molecule. All of the above results may be explained without recourse to cross-linking of beta-adrenoceptors with two pharmacophores, a phenomenon cited in similar studies of receptors for opiates and gonadotropin-releasing hormone.

Adrenergic beta-Agonists↗
PubMed1987

gamma-Cyclodextrin:testosterone complex suitable for sublingual administration.

A crystalline complex of testosterone with gamma-cyclodextrin was evaluated for solubility and dissolution rate. Whereas these parameters were at least an order of magnitude lower than those of testosterone complexes with amorphous derivatives of cyclodextrins, the properties of the crystalline complex enabled the preparation of a suitable pharmaceutical form for the sublingual administration of hormone to humans. This is in contrast to the situation with similar beta-cyclodextrin complexes, in which such administration was ineffective. Sublingual administration of the gamma-cyclodextrin complex, as shown in previous work using amorphous complexes, avoided rapid first-pass loss of hormone and directed it effectively into the circulation; administration of the complex into the stomach resulted in much lower circulatory hormone levels.

Administration, Sublingual↗
PubMed1987

Severe hypervitaminosis A in siblings: evidence of variable tolerance to retinol intake.

A 2-year-old boy had signs and symptoms of chronic hypervitaminosis A. A course of increasing severity led to eventual death. A younger brother later had similar clinical features. Chicken liver spread containing up to 420 IU/g vitamin A was the likely source of intoxication. Markedly elevated circulating retinyl ester levels have persisted in the surviving sibling for 3 subsequent years despite severe restriction of vitamin A intake. A therapeutic trial of the carbohydrate-derived complexing agent 2-hydroxypropyl-beta-cyclodextrin was initiated. Circulating retinyl esters transiently increased during the infusion (from 407 to 4791 micrograms/dL), and urinary total vitamin A excretion, undetectable before infusion, increased to 23 micrograms/dL after infusion. The frequency of hypervitaminotic episodes has decreased somewhat in the 2 years since the infusion, probably related to dietary vitamin A restriction. The occurrence of this syndrome in two brothers, while a sister ingesting the same diet remains completely healthy, suggests an inherited variance in tolerance to vitamin A intake.

2-Hydroxypropyl-beta-cyclodextrin↗
PubMed1987

Affinity labels for beta-adrenoceptors: preparation and properties of alkylating beta-blockers derived from indole.

New alkylating ligands derived from indole with high affinity for beta-adrenoceptors were synthesized and their properties examined. N8-(Bromoacetyl)-N1-[3-(4-indolyloxy)-2-hydroxypropyl]-(Z)-1,8-dia mino-p- menthane (8) and its N1,N8 isomer (9) were prepared by the reaction of bromoacetyl bromide with a product of the condensation of 4-indolyl glycidyl ether with (Z)-1,8-diamino-p-menthane. A similar reaction employing 2-cyano-4-indolyl glycidyl ether yielded the respective cyano derivatives 10 and 11. Apparent affinities (Ki, M) for beta-adrenoceptors on membrane preparations from rat heart and lung were 4.6 X 10(-10) and 1.34 X 10(-9) for 8, 2.3 X 10(-8) and 4.5 X 10(-9) for 9, 6.1 X 10(-10) and 1.49 X 10(-9) for 10, and 1.83 X 10(-9) and 2.78 X 10(-9) for 11, respectively. When membranes were preincubated with the above ligands (1 X 10(-8) M, 30 min, 30 degrees C) and then washed extensively, reduction in the concentration of specific binding sites of [3H]dihydroalprenolol ranged from 7% to 76% and there was no change in KD of the remaining binding sites. (+/-)-Alprenolol and (-)-isoproterenol, but not (+)-isoproterenol, when included with the alkylating ligands in the preincubation mixtures, prevented the reduction in concentration of [3H]dihydroalprenolol binding sites. Compounds 8-11 alone did not stimulate adenylate cyclase activity in rat heart homogenates. However, these compounds inhibited (-)-isoproterenol-stimulated adenylate cyclase activity with Ki values ranging between 5 X 10(-9) and 60 X 10(-9) M. These results suggest that high-affinity irreversible beta-adrenergic antagonists were obtained that may be useful for in vivo studies of beta-adrenoceptors.

Adenylyl Cyclases↗
PubMed1987

Carbostyril derivatives having potent beta-adrenergic agonist properties.

Derivatives carrying a substituent in the para position of the phenyl group of 8-hydroxy-5-[2-[(1-phenyl-2-methylprop-2-yl)amino]-1-hydroxyethyl] carbostyril (10) were prepared and their effects on beta-adrenoceptors evaluated in vitro. Unsubstituted compound 10, iodo 11, amino 12, and bromoacetamido 13 derivatives (all racemic) bound to the receptor with 15-100-fold lower dissociation constants than that of (-)-isoproterenol. All the above compounds stimulated adenylate cyclase more potently than (-)-isoproterenol. The intrinsic activities of compounds 10 and 12 were equal to that of (-)-isoproterenol. The intrinsic activities of compounds 11 and 13 were 1.3 and 1.2 times that of (-)-isoproterenol, respectively. Treatment of membrane preparations with bromoacetamido derivative 13 resulted in an irreversible loss of binding sites, and thus, 13 seems to be an alkylating affinity label for beta-adrenoceptors.

Adenylyl Cyclases↗
PubMed1986

A new photoaffinity probe, 4-amino-2-[4-(4-azidocinnamoyl)piperazino]-6,7-dimethoxyqu inazoline, for alpha 1-adrenoceptors.

A photoaffinity probe for alpha 1-adrenoceptors was synthesized and its properties examined on rat brain membrane preparations. The binding of 4-amino-2-[4-(4-azidocinnamoyl)piperazino]-6,7-dimethoxyquin azoline (ACP) to these receptors was of high affinity (KD = 1.05 nM) and reversible in the dark. A dose-dependent decrease in the concentration of [3H]prazosin binding sites without a change in KD was observed when membranes were preincubated with ACP, photolyzed, and then extensively washed prior to assay. This reduction in receptor concentration was prevented by alpha 1-adrenergic ligands. The specificity of ACP for alpha 1-receptors was further demonstrated by its inability to compete with [3H]dihydroalprenolol and [3H]yohimbine binding in these same membranes. Also, the concentrations and affinity constants of beta-adrenoceptors and alpha 2-adrenoceptors were unaffected in membranes which had been photolyzed after preincubation with ACP. No reduction in concentration of alpha 1-adrenoceptors was detected if ACP was photolyzed prior to incubation with receptors or if ACP was maintained in darkness throughout the experiment. The results suggest that ACP is a specific and sensitive photoprobe that may be useful for further studies on alpha 1-adrenoceptor coupled systems and that may be particularly suited for use in cell culture work.

Affinity Labels↗
PubMed1986

Hydrophilic cyclodextrin derivatives enable effective oral administration of steroidal hormones.

Condensation products of beta-cyclodextrin with propylene oxide or epichlorohydrin, which are amorphous and thus very soluble in water, were used to form complexes with testosterone, progesterone, and estradiol. Sublingual/buccal administration of tablets of these complexes led to effective absorption and entry of the hormones into the systemic circulation, followed by gradual elimination; rapid first-pass loss was avoided. beta-Cyclodextrin itself, its 2,6-dimethyl derivative, and a nonionic detergent did not enable effective buccal absorption. Absorption from the GI tract of hormones complexed with hydrophilic cyclodextrins was also less effective. Effective absorption of drugs from the oral cavity requires (a) that the drug and solubilizer form a complex of the inclusion type which dissolves completely and rapidly and (b) that the solubilizer neither enters nor damages oral tissue.

Administration, Oral↗
PubMed1986

Muir-Torre syndrome. Histologic spectrum of sebaceous proliferations.

The sebaceous proliferations seen in patients with Muir-Torre syndrome are unique and difficult to classify. Having reviewed over 50 skin biopsies from five patients with Muir-Torre syndrome, we conclude that the primary proliferation involves the hair follicle and most often resembles either a keratoacanthoma or a sebaceous proliferation, but may have histologic features of both lesions. Unusual patterns seen in the sebaceous components may include solid basaloid sheets, mucinous areas, and convoluted glands.

Adenoma↗
PubMed1986

Characteristics of the beta-adrenoreceptor from neuronal and glial cells in primary cultures of rat brain.

The cellular characteristics of the beta-adrenoreceptor in glial and neuronal cells from the newborn rat brain were determined by (-)-[125I]iodocyanopindolol binding. In membranes from both cell types, the binding was saturable and from competition assays the potency series of (-)-isoproterenol greater than (-)-epinephrine = (-)-norepinephrine greater than (+)-isoproterenol was observed. 5'-Guanylyl-imidodiphosphate reduced the affinity of (-)-isoproterenol for the beta-adrenoreceptor from glial cells but had no effect on agonist affinity in neuronal cells. Chronic treatment of both cell types with (-)-isoproterenol reduced the receptor content and the capacity of the agonist to increase the cellular cyclic AMP content. However, the receptor recovery after chronic agonist treatment was faster in glial cells (72 h) than neuronal cells (120 h) and was blocked by cycloheximide. Treatment of both types with the irreversible beta-blocker bromoacetylalprenololmentane (2 microM) reduced the receptor content by 78% but no receptor recovery was observed for 120 h after the initial receptor loss. The data indicated that the majority of beta-adrenoreceptors in both cell types are the beta-1 subtype, but show some differences in receptor-agonist interactions. Furthermore, these CNS cells may be useful models for regulatory studies on the beta-adrenoreceptor.

Adrenergic beta-Agonists↗
PubMed1986

Lung beta-adrenoreceptor blockade affects perinatal surfactant release but not lung water.

We induced beta-adrenergic receptor blockade at 28 days gestation in the fetal rabbit with an irreversible beta-antagonist, bromace-tylalprenolomenthane (BrAlp). There was a marked decrease in concentration of available receptors in lung with increasing doses of BrAlp. BrAlp treatment decreased isoproterenol, but not prostaglandin, stimulated adenosine 3',5'-cyclic monophosphate (cAMP) generation in lung minces, and had no effect on activation of adenylate cyclase through non-beta-receptor-mediated components of the cyclase system in particulate preparations. Phospholipid recovery via lung lavage was significantly less from treated fetuses than from controls in groups delivered by cesarean section at 30 days (-31%) or vaginally at 31 days (-34%) and not allowed to air breathe. However, if fetuses from either group were allowed to air breathe, the difference was abolished. BrAlp treatment did not affect the phospholipid composition in lavage fluid, the rate of phosphatidylcholine synthesis, or tissue content of total or saturated phosphatidylcholine. Beta-adrenergic receptor blockade did not produce a significant change in lung water content either at or after birth regardless of the route of delivery. These data indicate that endogenous catecholamines play a role in surfactant secretion in both the fetal and newborn rabbit. We found no effects of BrAlp treatment on lung water, suggesting perhaps a less important role of endogenous catecholamines or that fewer receptors are required for this response than remained after treatment.

Alprenolol↗
PubMed1986

Differential recovery of beta adrenoreceptor antagonist and agonist high affinity binding sites in the guinea-pig lung after irreversible blockade.

The recovery of guinea-pig lung beta adrenoreceptors and beta adrenergic-mediated airway responsiveness was studied after irreversible receptor blockade with bromoacetylalprenololmentane (BAAM). The antagonist receptor concentration and those receptors able to form the agonist high affinity binding state were determined by (-)-[3H]dihydroalprenolol (DHA) and [3H]hydroxybenzylisoproterenol (HBI) binding, respectively. Airway responsiveness was measured by the ability of isoproterenol infusions to shift the histamine dose-response curve for airway constriction. Twenty-four hours after a single i.p. injection of BAAM (20 mg/kg), both [3H]DHA and [3H]HBI binding were reduced by 48 to 51% without changing the KD value for either ligand. In addition, there was a complete block of airway responsiveness to isoproterenol infusion at 1 microgram/kg/min although responsiveness similar to control values was observed at a higher infusion rate (10 micrograms/kg/min). Ninety-six hours after BAAM treatment, [3H]DHA binding had recovered to the control value whereas no recovery of [3H]HBI binding or of airway responsiveness was observed. By 144 hr after injection, both [3H]HBI binding and airway responsiveness had recovered to control values. The data indicate that after irreversible blockade, the total receptor population as measured by antagonists recovers relatively quickly followed by a slower recovery of those receptors able to form the agonist high affinity binding state that parallels the recovery of airway responsiveness.

Adrenergic beta-Agonists↗
PubMed1985

Irreversible inactivation of the beta-adrenoreceptor by a partial agonist. Evidence for selective loss of the agonist high affinity binding sites.

The catecholamine derivatives aminomenthylnorepinephrine (compound 1) and bromoacetylaminomenthylnorepinephrine (compound 2) were synthesized and their interaction with the rat lung beta-adrenoreceptor was characterized. Compared to (-)-isoproterenol, compounds 1 and 2 were 10 and 280 times less potent, respectively, at inhibiting (-)-[3H]dihydroalprenolol binding. At pH 7.4, all 3 compounds induced a loss of receptors (40-60%) which could be recovered by treatment with guanyl-5'-yl imidodiphosphate (Gpp(NH)p). However, at pH 8.1 Gpp(NH)p treatment did not recover those receptors lost by compound 2 only. The compound 2-induced receptor loss at pH 8.1 was time-dependent, prevented by propranolol but unaffected by Gpp(NH)p or after membrane heating at 50 degrees C which prevented the formation of the agonist high affinity binding state. Although, the maximal receptor loss as measured by [3H]dihydroalprenolol was 40-60%, more than 80% of the receptors were lost when measured by direct agonist binding, and the receptors left showed little agonist high affinity binding state formation. In rat reticulocyte membranes, compounds 1 and 2 stimulated adenylate cyclase activity with intrinsic activities of 0.55 and 0.31, respectively. However, at pH 8.1, compound 2 initially stimulated the enzyme followed by a blockade. These data indicated that both compounds 1 and 2 were partial beta-adrenoreceptor agonists and, at pH 8.1, compound 2 appeared to bind irreversibly only to those lung receptors able to form the agonist high affinity binding state. Furthermore, after irreversible binding, compound 2 appeared to act as an antagonist.

Adenylyl Cyclases↗
PubMed1985

Amorphous water-soluble derivatives of cyclodextrins: nontoxic dissolution enhancing excipients.

Dissolution properties of drugs may be improved by their conversion to an amorphous state or by complexation with cyclodextrins. The present report describes the preparation of cyclodextrin derivatives which are intrinsically amorphous, and water-soluble, and their use as complexation agents. Such derivatives were prepared by condensation of alpha-, beta-, or gamma-cyclodextrins with epoxides (propylene oxide, isobutylene oxide, epichlorohydrin, 1,4-butanediol diglycidyl ether). The condensation products effectively solubilized estradiol, progesterone, or testosterone in water; these solutions, upon freeze-drying, yielded solids which could be directly compressed to tablets which dissolve completely within minutes. Condensation products of cyclodextrins did not have any untoward or toxic effects when administered chronically to mice per os for a 16-week period.

Animals↗
PubMed1985

Alkylating beta-blockers: activity of isomeric bromoacetyl alprenolol menthanes.

An affinity label for beta-adrenoceptors, N-(bromoacetyl)-N'-[3-(o-allylphenoxy)-2-hydroxypropyl]-1,8-dia min o-p-menthane, has been extensively used in the form of a mixture of four isomers. In the present study, all four isomers were isolated, their structures elucidated, and their interactions with beta-adrenoceptors characterized. The isomer with the aromatic (pharmacophore) group on carbon 1 of p-menthane and with the Z configuration (Z-1) predominates in the mixture and has the highest affinity for beta-adrenoceptors of rat heart (KD = 3 X 10(-8) M) and lungs (KD = 2 X 10(-8) M). This isomer acts as a ligand that binds irreversibly at the drug binding site of the receptor (i.e., after treatment and extensive washing of the membrane preparation, the concentration of the receptors is decreased in a dose-dependent manner), while binding characteristics of the remaining receptors are not changed. The corresponding E diastereomer (E-1) also binds irreversibly to the drug binding site of the receptor. The isomer with the aromatic group on carbon 8 and the Z configuration (Z-8) modifies the receptor noticeably only at higher concentrations and then on a site apparently different from the drug-binding site, i.e., affinity of receptors after the treatment and washing is changed. The corresponding E diastereomer (E-8) modified both the drug-binding and alternative binding site. The results suggest that there is some flexibility in the conformation of the beta-adrenoceptor that enables pairs of ligands, differing by axial or equatorial positions of critical groups, to alkylate the receptor in an analogous manner.

Adrenergic beta-Antagonists↗