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Biomedical subjects

J Pitha

Publications and source records attributed to J Pitha.

At least 109 records · Page 6Linked to original sources
PubMed1983

Poly-L-methionine sulfoxide: a biologically inert analogue of dimethyl sulfoxide with solubilizing potency.

Poly-L-methionine sulfoxide is a water-soluble polymer containing the sulfoxide moiety. The preparation and radiolabeling of this polymer is described and its bioeffects are compared with those of dimethyl sulfoxide. Poly-L-methionine sulfoxide is similar to dimethyl sulfoxide in that it is a potent solubilizer of lipophilic compounds in water. Although the partition coefficient of poly-L-methionine sulfoxide in 1-octanol-water is only 20 times lower than that of dimethyl sulfoxide, it was found not to penetrate into intracellular spaces. In contrast to dimethyl sulfoxide, poly-L-methionine sulfoxide and L-methionine sulfoxide were found to be ineffective in inducing differentiation in murine erythroleukemia cells and inhibiting differentiation of avian neural crest cells, suggesting that compounds effective in these processes must have the ability to penetrate into cells or membrane proteins. Overall lack of bioactivity of poly-L-methionine sulfoxide, combined with low toxicity (2 g/kg, iv, in the mouse with no effect), makes this compound a suitable inert solubilizer and carrier for lipophilic drugs.

Animals↗
PubMed1983

Effect of a beta-adrenergic antagonist on blood pressure, heart rate and beta-adrenoceptors in turkey poults.

An irreversible beta-adrenergic blocker, bromoacetylalprenololmenthane (BAAM), was administered both peripherally and centrally to turkey poults, Meleagris gallopavo. Peripheral administration of BAAM (60 mg/kg body weight) effected a significant reduction in blood pressure and heart rate. Twenty minutes postinjection, mean blood pressure and heart rate were reduced 34.5 and 24.2%, respectively. Two days later, mean blood pressure values remained significantly depressed at 17.3% below preinjection determinations. Biochemical analysis of heart tissue following peripheral (intraperitoneal) injections of BAAM (60 mg/kg body weight) showed a significant decrease in beta-adrenergic receptors (BAR). Little or no change in the number of BAR in brain tissue was observed. Central (intraventricular) administration of BAAM (0.72 mg/g brain weight) resulted in no change in mean blood pressure or heart rate during a 20 min postinjection period. Biochemical analysis of heart tissue following central injections of BAAM showed little or no change in the number of BAR. There was, however, a significant decrease in the number of BAR in brain tissue.

Adrenergic beta-Antagonists↗
PubMed1983

beta-Adrenergic antagonists with multiple pharmacophores: persistent blockade of receptors.

beta-Adrenergic antagonists containing from one to four identical pharmacophores were prepared and studied. These compounds had the general structure R2NCH(CH3)CH2[-OCH2CH(CH3)-]2-8NR2, where R is either H or an aryl-OCH2CHOHCH2 group. Synthesis was achieved by reaction of aryl glycidyl ethers with Jeffamines, which are primary diamines used in the manufacture of plastics. The following aryl groups were used: 2-allyphenyl, 4-(2-methoxyethyl)phenyl, 1-naphthyl, and 4-methoxyphenyl. The first three correspond to moieties of the established drugs alprenolol, metoprolol, and propranolol, respectively. The affinities of these compounds for beta-adrenergic receptors of rat heart and lung were estimated by measuring their ability to compete with the specific binding of (-)-[3H]-dihydroalprenolol. Compounds containing one pharmacophore bound to the receptors with affinities comparable to those of the parent drugs and the blockade of receptors could be dissociated by successive washes as easily as were those of the parent drugs. Compounds containing two or three pharmacophores had somewhat lower affinities for receptors, but the resulting blockade was persistent even after successive washing.

Adrenergic beta-Antagonists↗
PubMed1983

Beta-adrenoreceptor antagonists with multiple pharmacophores: persistent inhibition of rat heart adenylate cyclase.

beta-Adrenoreceptor antagonists containing several pharmacophores, so called alprenolol-Jeffamines, were studied. These compounds are derived from Jeffamine NH2-CH-(CH3)-CH2-[-O-CH2-CH(CH3)-]n-NH2, n = 2.6 ave. by substitution of nitrogen with 3-(2-allylphenoxy)-2-hydroxypropyl groups, which are part of the Alprenolol pharmacophore. Alprenolol-Jeffamines inhibited (-)isoprenaline stimulated adenylate cyclase activity; the derivative with one pharmacophore was about 4-fold and the derivative with two pharmacophores was about 17-fold less potent than (+/-)alprenolol; the trisubstituted derivative which has one complete and two partial pharmacophores was ineffective. The ratio of Ki's for inhibition of (-)3H-DHA binding and for inhibition of adenylate cyclase were approximately one for each derivative. When (+/-)alprenolol and alprenolol-Jeffamine derivatives were injected intraperitoneally into rats and heart membranes or homogenates were prepared 18-20 h afterwards, the mono, di, and trisubstituted derivatives, but not (+/-)alprenolol, inhibited binding of (-)3H-DHA. This persistency pattern is different from that observed in vitro, where only di and trisubstituted derivatives are persistent. Slow metabolism/slow excretion of the monosubstituted derivative may be a source of the increased persistency in vivo. In similarly prepared animals, the dose-response curve for (-)isoprenaline stimulated adenylate cyclase was shifted to the right 3-to-4 fold for mono and disubstituted derivatives but was unaffected by (+/-)alprenolol and the trisubstituted derivative. The results suggest that these derivatives interact with physiologically important beta-adrenoreceptors in vitro, and that, in vivo, they persistently block beta-adrenoreceptors and inhibit isoprenaline stimulated adenylate cyclase.

Adenylyl Cyclase Inhibitors↗
PubMed1983

Bromoacetylalprenololmenthane: a potent irreversible antagonist of beta adrenergic elicited protein exocytosis in rat parotid cells.

The interaction of bromoacetylalprenololmenthane (BrAlpM), an irreversible beta adrenergic receptor antagonist, with rat parotid acinar cells was studied in vitro. In the presence of BrAlpM, the rate of (-)-isoproterenol-induced exocrine secretion from cells, measured as percentage of amylase release, was markedly reduced. The concentration of (-)-isoproterenol required to elicit half-maximal protein secretion was about 100 times greater (5 microM) in the presence of 1 microM BrAlpM than in control incubations (0.05 microM). BrAlpM and propranolol were similar in their ability to inhibit parotid protein release (IC50 approximately 10(-7) M). To demonstrate that BrAlpM functioned as an irreversible beta adrenergic antagonist, cells were preincubated with BrAlpM for varying amounts of time and then washed three to six times before adding (-)-isoproterenol. At least 10 min preincubation was required to show irreversibility. Alprenolol, under the same preincubation conditions, was unable to inhibit amylase release. BrAlpM inhibited the binding of [3H]dihydroalprenolol to parotid beta adrenoreceptors over a concentration range similar to that required for inhibition of protein secretion. Cells incubated in the absence or presence of BrAlpM displayed a comparable morphologic appearance when viewed by light and electron microscopy. The degree of inhibition of isoproterenol-induced exocytosis of secretory granules by BrAlpM appeared to vary from cell to cell. These findings suggest that BrAlpM should be a useful probe to study beta adrenoreceptor function and metabolism in rat parotid acinar cells.

Adrenergic beta-Antagonists↗
PubMed1982

Mapping of mammalian beta-adrenoreceptors by use of macromolecular alprenolol derivatives. A comparison with amphibian erythrocyte receptors.

THe interaction of macromolecular alprenolol derivatives with beta-adrenoreceptors of rat heart, lung, and erythrocytes and frog erythrocytes has been studied. Macromolecular derivatives were prepared by covalently coupling alprenolol to dextrans containing a homologous series of spacer arms of various lengths. The affinity of these macromolecules for frog erythrocyte membranes increased with increasing length of spacer arm. In contrast, the affinity of these macromolecules for all mammalian membrane preparations was weak and insensitive to the length of the spacer arm. The inhibition of [3H]dihydroalprenolol binding to rat heart, lung, and erythrocyte membrane preparations by these macromolecular derivatives was more than 1000-fold less potent than inhibition by alprenolol. The results suggest different structural characteristics between mammalian and amphibian beta-adrenoreceptors; however, apparently only small differences between mammalian receptors could be distinguished with these probes.

Alprenolol↗
PubMed1982

Muir-Torre syndrome: report of a case and reevaluation of the dermatopathologic features.

Muir-Torre syndrome patients have multiple internal malignancies along with cutaneous sebaceous proliferations and keratoacanthomas. We describe a 62-year-old male with nine primarily internal malignancies who survived eight years after his initial tumor was identified. His sebaceous lesions ranged from innocuous adenomas to an anaplastic carcinoma of the chin which recurred and spread locally to involve the mandible and the right parotid region.

Humans↗
PubMed1982

Probe for polyanionic regions on the cell surface.

The binding of polyuridylate to cells in the presence of proflavine may be used as a probe to provide relative estimates of exposed polyanionic regions on the external surface of the cell. This probe binds preferably to hydrophilic, polyanionic regions, and soluble polysaccharides containing either carboxylate or sulfate groups compete with the binding of this probe. Binding of the probe to protein and lipid regions is considerably weaker. Virus-transformed human fibroblasts bind 10 times less of the probe than nontransformed cells when confluent monolayers are compared. However, as the cell density is decreased, the amount of probe bound per cell increases dramatically both for transformed as well as for normal cells. In fact, human fibroblasts (a) derived from normal donors, (b) from donors with different metabolic disorders, and (c) transformed by simian virus 40, all bind about the same amount of probe when compared at the same density. Populations of human fibroblasts aged in vitro, which contain high proportions of large cells and grow only to relatively low densities in monolayers, bind disproportionately large amounts of the complex.

Cell Line↗
PubMed1982

Regeneration of beta-adrenergic receptors in senescent rats: a study using an irreversible binding antagonist.

The drug used in this study, bromoacetylalprenololmenthane, has the ability to bind and block irreversibly beta-adrenergic receptors. The drug was bound to membranes prepared from hearts, lungs, and brains of both senescent and young rats with a similar affinity. When this drug was injected into rats in nontoxic doses (up to 70 mg/kg), up to 90% of beta-adrenergic receptors were irreversibly blocked 4 hr after injection, whereas the injection of similar amounts of (+/-)-alprenolol was without effect on receptor number. In senescent animals this blockade lasted considerably longer than in young animals; receptor numbers in hearts and lungs of senescent rats returned to control levels only 1 month after injection. The number of beta-adrenergic receptors in brains of senescent rats was unaffected by this drug. Thus, based upon the long-lasting blockade of beta-adrenergic receptors in therapeutically important organs, it appears that irreversible binding blockers may have potential in the treatments of senescent organisms.

Adrenergic beta-Antagonists↗
PubMed1982

Irreversible blockade of beta adrenoreceptors and their recovery in the rat heart and lung in vivo.

The interaction of a bromoacetylated derivative of alprenolol (Alm-CO-CH2Br) with cardiac and lung beta adrenoreceptors was partially characterized. After a short incubation period, the concentration of Alm-CO-CH2Br that inhibited specific [3H]dihydroalprenolol binding by 50% in cardiac and lung membranes was 0.5 and 0.11 microM, respectively. The blockade was time-dependent and Scatchard analysis showed no change in the KD value for specific (-)-[3H]dihydroalprenolol binding but a loss of beta adrenoreceptor content after membrane pretreatment with Alm-CO-CH2Br. The blockade was not reversed by extensive membrane washing, although concurrent treatment with alprenolol fully protected whereas phentolamine had no protective effect. Alm-CO-CH2Br produced a dose-dependent blockade of heart and lung beta adrenoreceptors in vivo and the compound had little or no effect on the growth rate of the rat. Four hours after a single i.p. injection of Alm-CO-CH2Br at 35 mg/kg, the heart and lung beta adrenoreceptor content was decreased by 88 and 90%, respectively. The time required for complete recovery from irreversible beta adrenoreceptor blockade was about 200 hr in the heart and 650 hr in the lung. These results suggest that Alm-CO-CH2Br may be a useful probe for the beta adrenoreceptor both in vitro and for recovery studies in vivo.

Adrenergic beta-Antagonists↗
PubMed1981

Progressive nodular histiocytoma.

Progressive nodular histiocytoma is a clinically distinct variant in the general group of normolipemic histiocytic proliferations. Its cardinal feature is the presence of two different lesions--a superficial yellow-brown papule and a deep nodule. We describe herein a 29-year-old man with such lesions. Histologically, a variety of fibrous and cellular patterns were seen, mimicking the wide spectrum of findings in ordinary dermatofibromas. On ultrastructural examination, the most striking feature of the preponderant cell was lipid phagocytosis.

Adult↗
PubMed1980

Age-related decrease in repair of oxidative damage to surface sulfhydryl groups on rat adipocytes.

Adipocytes were isolated from the Wistar and Sprague-Dawley strains of rats of different ages. An impermeable reagent, mercury-[3H] dextran, was used to quantitate the sulfhydryl groups on the surface of these cells. The application of this reagent after the pre-reduction of cells with 2-mercaptoethanol yielded a measure of the total sulfhydryl and disulfide groups located there. Aging was found to significantly decrease the ratio of the number of exofacial sulfhydryl groups to the total number of exofacial sulfhydryl and disulfide groups.

Adipose Tissue↗
PubMed1980

Macromolecular beta-adrenergic antagonists discriminating between receptor and antibody.

The beta-adrenergic antagonist, alprenolol, was attached in an irreversible manner to macromolecular dextran via side arms that differed in length. The ability of these macromolecules to bind to the beta-adrenergic receptor of frog erythrocytes and to catecholamine-binding antibodies raised against partially purified receptors was studied. Compared to the parent drug the potency of binding of macromolecular alprenolol to the receptor decreased about 1/10, 1/600, and 1/8000 when the length of the arm separating alprenolol from the dextran moiety was 13, 8, and 4 atoms, respectively. In contrast, the binding potencies of the parent drug and of all its macromolecular derivatives for the antibody were within the same order of magnitude. Thus, conversion of a drug to a macromolecular form may not only sustain its binding activity but may also lead in a higher selectivity. The macromolecular derivatives described here may be suitable probes for investigation of the location and of the molecular properties of the binding sites for beta-adrenergic drugs.

Alprenolol↗