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Biomedical subjects

E Bird

Publications and source records attributed to E Bird.

At least 19 recordsLinked to original sources
PubMed2000

Biphenylsulfonamide endothelin receptor antagonists. 2. Discovery of 4'-oxazolyl biphenylsulfonamides as a new class of potent, highly selective ET(A) antagonists.

The synthesis and structure-activity relationship (SAR) studies of a series of 4'-oxazolyl-N-(3,4-dimethyl-5-isoxazolyl)[1, 1'-biphenyl]-2-sulfonamide derivatives as endothelin-A (ET(A)) receptor antagonists are described. The data reveal a remarkable improvement in potency and metabolic stability when the 4'-position of the biphenylsulfonamide is substituted with an oxazole ring. Additional 2'-substitution of an acylaminomethyl group further increased the binding activity and provided one of the first subnanomolar ET(A)-selective antagonists in the biphenylsulfonamide series (17, ET(A) K(i) = 0.2 nM). Among the compounds described, 3 (N-(3,4-dimethyl-5-isoxazolyl)-4'-(2-oxazolyl)[1, 1'-biphenyl]-2-sulfonamide; BMS-193884) had the optimum pharmacological profile and was therefore selected as a clinical candidate for studies in congestive heart failure.

Administration, Oral↗
PubMed1998

Biphenylsulfonamide endothelin antagonists: structure-activity relationships of a series of mono- and disubstituted analogues and pharmacology of the orally active endothelin antagonist 2'-amino-N- (3,4-dimethyl-5-isoxazolyl)-4'-(2-methylpropyl)[1, 1'-biphenyl]-2-sulfonamide (BMS-187308).

Substitution at the ortho position of N-(3,4-dimethyl-5-isoxazolyl) benzenesulfonamide led to the identification of the biphenylsulfonamides as a novel series of endothelin-A (ETA) selective antagonists. Appropriate substitutions on the pendant phenyl ring led to improved binding as well as functional activity. A hydrophobic group such as isobutyl or isopropoxyl was found to be optimal at the 4'-position. Introduction of an amino group at the 2'-position also led to improved analogues. Combination of the optimal 4'-isobutyl substituent with the 2'-amino function afforded an analogue (20, BMS-187308) with improved ETA binding affinity and functional activity. Compound 20 also has good oral activity in inhibiting the pressor effect caused by an ET-1 infusion in rats. Doses of 10 and 30 micromol/kg iv 20 attenuated the pressor responses due to the administration of exogenous ET-1 to conscious monkeys, indicating that the compound inhibits the in vivo activity of endothelin-1 in nonhuman primates.

Administration, Oral↗
PubMed1997

Phallus preservation for urethral cancer: subcutaneous penectomy.

PURPOSE: We present a new alternative to amputating penectomy, subcutaneous penectomy, in the male patient with urethral cancer. MATERIALS AND METHODS: The surgical management and followup of 3 men with squamous cell cancers of the urethra are reviewed. RESULTS: At 22, 9 and 6 months postoperatively all patients were without evidence of local recurrence and were satisfied with phallic appearance. In 1 of 2 patients in whom the dorsal neurovascular bundle was not preserved there was distal glans necrosis and wound separation which resolved after conservative management. One of the 3 patients is contemplating phallus reconstruction. The patient who had pelvic lymph node metastases before penectomy died of metastatic complications without local failure 9 months postoperatively. CONCLUSIONS: Phallus preservation in men with urethral cancer can be accomplished successfully with this type of procedure. The dorsal neurovascular bundle should be preserved when feasible. We contend that the cosmetic and potential reconstructive outcomes are superior to amputation without sacrificing cancer therapy in the appropriately selected patient.

Adult↗
PubMed1995

Evidence for a preferential loss of enkephalin immunoreactivity in the external globus pallidus in low grade Huntington's disease using high resolution image analysis.

Previous studies have shown that in advanced cases of Huntington's disease, enkephalin-immunoreactive striatal projections to the external globus pallidus may be more affected than substance P-containing striatal projections to the inner segment of the pallidum [Reiner A. et al. (1988) Proc. natn. Acad. Sci. U.S.A. 85, 5733-5737]. Other immunohistochemical [Ferrante R. J. et al. (1990) Soc. Neurosci. Abstr. 16, 1120] and neurochemical observations [Storey E. and Beal M.F. (1993) Brain 116, 1201-1222] suggest no difference in the loss of these peptide-containing pathways in Huntington's disease. In view of the potential significance of this issue for understanding the neuropathological process in Huntington's disease, we examined the globus pallidus in control and Huntington's disease brains, using a quantitative approach which involved high resolution image analysis of 7 microns frozen sections to determine the overall density of peptide-immunoreactive terminals. Results showed that in the controls there was no significant difference between the density of enkephalin- and substance P-immunoreactive terminals in the external and internal globus pallidus, respectively. In all Huntington's disease brains, including grade 1 cases, enkephalin-immunoreactive terminals in the external globus pallidus were significantly reduced compared to substance P-positive boutons in the internal segment of the adjacent section. In comparison to controls, enkephalin immunoreactivity in all Huntington's disease cases was significantly lower; substance P-immunoreactive terminals in the internal globus pallidus were significantly lower than controls in some of the grade 2 cases and in the grade 3 cases.(ABSTRACT TRUNCATED AT 250 WORDS)

Aged↗
PubMed1995

CAG expansion affects the expression of mutant Huntingtin in the Huntington's disease brain.

A trinucleotide repeat (CAG) expansion in the huntingtin gene causes Huntington's disease (HD). In brain tissue from HD heterozygotes with adult onset and more clinically severe juvenile onset, where the largest expansions occur, a mutant protein of equivalent intensity to wild-type huntingtin was detected in cortical synaptosomes, indicating that a mutant species is synthesized and transported with the normal protein to nerve endings. The increased size of mutant huntingtin relative to the wild type was highly correlated with CAG repeat expansion, thereby linking an altered electrophoretic mobility of the mutant protein to its abnormal function. Mutant huntingtin appeared in gray and white matter with no difference in expression in affected regions. The mutant protein was broader than the wild type and in 6 of 11 juvenile cases resolved as a complex of bands, consistent with evidence at the DNA level for somatic mosaicism. Thus, HD pathogenesis results from a gain of function by an aberrant protein that is widely expressed in brain and is harmful only to some neurons.

Adult↗
PubMed1990

Analysis of expression of cholecystokinin in dopamine cells in the ventral mesencephalon of several species and in humans with schizophrenia.

The ventral mesencephalons of hamster, guinea pig, cat, monkey, and several humans with and without the diagnosis of schizophrenia were analyzed with in situ hybridization and immunohistochemistry. Extensive codistribution of cholecystokinin mRNA and tyrosine hydroxylase [L-tyrosine, tetrahydropteridine: oxygen oxidoreductase (3-hydroxylating), EC 1.14.16.2] mRNA was observed in cats and monkeys as well as in all five human subjects with the diagnosis of schizophrenia and in two out of five control brains. Double labeling revealed coexistence of the two markers in cat, monkey, and human. No cholecystokinin mRNA or cholecystokinin peptide was detected in the substantia nigra/ventral tegmental area of the hamster or guinea pig, even after acute and chronic neuroleptic treatment.

Animals↗
PubMed1988

Organization of dopamine D1 and D2 receptors in human striatum: receptor autoradiographic studies in Huntington's disease and schizophrenia.

The technique of quantitative autoradiography was used to examine the effects of Huntington's disease (HD) and schizophrenia on the organization of striatal dopamine (DA) D1 and D2 receptors. Whereas the striatum of HD cases showed a reduction in the density of D1 ([3H]SCH 23390) and D2 ([3H]spiroperidol) receptors, the patterning of D2 receptor loss did not match that of the D1 receptor loss. The HD loss of D1 D1 receptors (65%) is far greater than the loss of D2 receptors (28%). Whereas there was a dorsal-ventral gradient of effect on both receptor subtypes, the effects of HD on D2 receptors in the ventral putamen (PUT) and nucleus accumben septi (NAS) were minimal. Similarly, muscarinic M1 and M2 receptors demonstrate different patterns of alteration in HD. The M2 subtype, labeled with [3H]N-methylscopolamine (in the presence of excess pirenzepine to occlude M1 sites), was depleted far more than the M1 receptor subtype, labeled with [3H]pirenzepine. Although the effects of HD on [3H]mazindol labeling of DA terminals were more heterogeneous, there appeared to be a relative preservation of this afferent input to the striatum of the HD cases. In the schizophrenic cases, our autoradiographic studies confirm previous reports of an elevation of D2 receptor density in the striata of many schizophrenics. This increase was evident even though two of the three cases were known to have not been treated with neuroleptics, and the third case may also have been drug naive. However, the increase was far greater in the NAS (164%) and ventral PUT (173%) than more dorsally in the striatum (68%). The density of D1 receptors and DA terminals labeled with [3H]mazindol in the striatum of schizophrenics was not significantly different from that of control cases. Thus in both HD and schizophrenia, the ratio of D2/D1 receptors is altered in favor of the D2 population, particularly in the NAS.

Aged↗
PubMed1987

Maternal dietary NaCl intake influences weanling rats' salt preferences without affecting taste nerve responsiveness.

The present study examined the relationship between maternal dietary NaCl intake during the period from conception through weaning and weanling rats' elective consumption of salt; the study asked whether or not changes in offsprings' salt intake was mediated by altered taste responsiveness. The subjects were the 21-day-old offspring of 24 adult female rats fed diets containing .08% (low), 1% (mid), or 4% (high) NaCl from conception through weaning. Maternal dietary salt levels influenced offsprings' salt intake. In long-term food choice tests, the mid and high salt rats ate more salted food and had higher salt preferences than the low salt animals; in long-term solution choice tests, the mid and high salt rats drank more saline and less water and had higher saline preferences than the low salt rats. Nevertheless, the group differences in salt preference were not due to changes in taste responsiveness. There were no differences between the groups in saline preferences in short-term tests or in the amplitudes of chorda tympani nerve responses to concentration series of several salts. The implications of these data for understanding the physiological basis for group differences in salt preference are discussed.

Animals↗
PubMed1987

The neuronal growth-associated protein GAP-43 (B-50, F1): neuronal specificity, developmental regulation and regional distribution of the human and rat mRNAs.

The protein that has been designated as GAP-43, B-50, F1 or pp46 is associated with the growth and modulation of neuronal connections. cDNA clones for the rat and human genes were isolated and used to demonstrate that the messenger RNA for the protein is expressed only in neurons, that its overall level is highest in the developing brain, and that in the adult human brain levels of the mRNA are highest in the associative neocortex.

Animals↗
PubMed1986

Maternal dietary sodium chloride levels affect the sex ratio in rat litters.

Eighty-eight adult female rats were fed diets containing either 0.08, 0.12, 1, 3, or 4% NaCl for at least one week prior to breeding and throughout gestation. Within 24 hours of birth, all pups were sexed based on anogenital distance, and the number of males and females were recorded. The amount of sodium chloride in mother rats' diets was inversely related to the proportion of phenotypic males in the litter. As dietary salt increased, the proportion of males decreased. These alterations in dietary NaCl affected the sex ratio without disrupting litter size or the general health of the offspring. Dietary mineral content may affect the phenotypic sex ratio through changes in the genotypic sex ratio, or alternatively, via changes in the environment in which the genes are expressed. These findings are important for basic research concerning maternal nutrition and development.

Animals↗
PubMed1986

Dietary salt affects fluid intake and output patterns of pregnant rats.

This study was done to determine how differences in dietary NaCl influence water and electrolyte balance during gestation. Eighteen adult female rats were fed diets containing either 0.12 (low), 1.0 (mid, control), or 3.0% (high) NaCl throughout gestation. On gestation days 1-19, body weight, water and food intakes, urine volume and electrolyte levels were measured. On gestation day 20, amniotic fluid electrolyte levels were determined; litter sizes were assessed 24-hr after birth. Because food intakes were similar throughout gestation, the dams of the three groups ingested different amounts of NaCl. Differences in dietary NaCl were accompanied by large differences in the daily patterns of urine sodium, urine sodium/potassium ratios, water intake, and urine volume. Despite these differences in intake and output, water and electrolyte balance (intake minus output) was the same for the three groups. There were no differences in the dams' body weights, amniotic fluid electrolyte levels, or litter sizes. The long-term consequences of perinatal dietary NaCl for the developing pups are discussed.

Animals↗
PubMed1985

Behavioral and neural gustatory responses in rabbit.

To provide more information on a potentially valuable preparation for studies in taste and appetite, we have examined the taste preferences (and aversions) and chorda tympani sensitivity of the rabbit. Adult male New Zealand rabbits were given a two-bottle preference test between water and various molar concentrations of NaCl, KCl, sucrose, sodium saccharin, quinine hydrochloride and HCl. The rabbits exhibited the expected preferences for sucrose and aversions for quinine and HCl. Unexpectedly, however, the rabbits exhibited only a mild preference for NaCl, a stronger preference for KCl, and an aversion to sodium saccharin. Multiunit discharges of the chorda tympani nerve to the same taste stimuli indicated that the anterior tongue receptors are acutely sensitive to KCl, NaCl and quinine, but not to sucrose, HCl and saccharin. The chorda tympani was more responsive to KCl than to NaCl. Dilute concentrations of both NaCl and sodium saccharin elicited a two-component response consisting of an immediate excitatory phase followed by a tonic inhibitory phase. This complex response pattern of the whole nerve to NaCl and sodium saccharin is discussed in relation to the impulse frequencies in hypothesized water-sensitive and salt-sensitive fibers. Both the behavioral and neural data are discussed in relation to similar data obtained in rat and hamster.

Animals↗
PubMed1984

n-Electrode three-dimensional liquid chromatography with electrochemical detection for determination of neurotransmitters.

Coulometric electrodes in series have been used with liquid chromatography with electrochemical detection to increase selectivity and resolution for the direct analysis of tissue neurotransmitters. Use of three coulometric sensors for electrochemical modification, selectivity, and peak identification has been expanded into "gate" cells of three or four coulometric electrodes that allow elimination of all electrochemically irreversible substances, and "array" cells of up to 15 coulometric electrodes for separation of co-eluting compounds by their current/voltage characteristics. On-column sensitivity of the sensor arrays is 0.4 to 4 pg. Gate cell selectivity favors electrochemically reversible compounds over irreversible ones, e.g., 3-methoxy-4-hydroxyphenylglycol vs ascorbate, by a factor of up to 10(4). Resolution across the multi-electrode array cells allows separation of co-eluting compounds with half-wave potentials differing by as little as 30 to 40 mV. Cells with three to 15 electrodes have been used to measure monoamines and metabolites in brain; monoamines directly in serum filtrate; and the state of oxidation of 5-hydroxytryptamine and 5-hydroxytryptophan in cerebrospinal fluid of patients with Alzheimer's disease.

5-Hydroxytryptophan↗
PubMed1984

Area postrema: part of the autonomic circuitry of caloric homeostasis.

Investigations in which lesion techniques are used suggest a role for the area postrema (AP) in caloric homeostasis. Ablations of the AP in rat are associated with temporary hypophagia, hypodipsia, and rapid body weight loss. This is followed by a steady period of relatively normal eating and drinking and body weight gain. This steady period is characterized specifically by lowered body weight maintenance levels, overingestion of palatable foods, and attenuated taste aversion learning and glucoprivic feeding. These effects cannot be attributed simply to lesions of central terminations of gustatory and visceral afferents. The AP may be involved in feeding behaviors that are triggered by chemical signals in the blood or cerebrospinal fluid. In addition, the AP along with the adjacent nucleus tractus solitarii (NTS) seems to be part of the central autonomic system subserving caloric homeostasis; this system includes the lateral hypothalamus, which has a well-documented role in energy balance. The contribution of the AP along with the NTS must be considered with respect to their relationship to other structures within this system.

Animals↗
PubMed1983

Area postrema lesions disrupt food intake induced by cerebroventricular infusions of 5-thioglucose in the rat.

The present experiment assesses the contribution of the area postrema (AP) to glucoprivic feeding in the rat. Lateral ventricular infusions of 5-thioglucose increased pelleted food intake in sham animals but not in animals with AP lesions. Drinking in response to infusion of angiotensin II into the lateral ventricle was not reduced by AP lesions. The data suggest that the AP is part of the brainstem circuitry underlying glucoprivic feeding.

Animals↗