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P D Williams

Publications and source records attributed to P D Williams.

At least 19 recordsLinked to original sources
PubMed1992

Development of a novel class of cyclic hexapeptide oxytocin antagonists based on a natural product.

A new structural class of cyclic hexapeptide oxytocin antagonists derived from Streptomyces silvensis and typified by L-365,209 (cyclo-[L-prolyl1-D-phenylalanyl2-L- isoleucyl3-D-dehydropiperazyl4-L-dehydroperazyl5-D-(N- methyl)phenylalanyl6]) was recently reported. In this paper we further delineate the structure-activity profile for this new class by systematic study of L-365,209 analogs obtained by total synthesis. The optimal combination of cyclic amino acid ring sizes at positions 1, 4, and 5 and the role of the N-alkyl substituent at position 6 was elucidated. The lipophilic amino acids at positions 2 and 3 and the unusual amino acid D-dehydropiperazic acid at position 4 were found to be the most critical residues for obtaining good oxytocin receptor affinity. Analogs containing a basic side chain at the less critical 5- and 6-positions maintained good receptor affinity and also had useful levels of water solubility for intravenous formulation. By combining potency- and solubility-enhancing substitutions, several analogs were identified that have the desired combination of properties in vitro (22, cyclo-[L-prolyl-D-tryptophanyl-L-isoleucyl-D-pipecolyl-L-pipeco lyl-D- histidyl]; 25, cyclo-[L-prolyl-D-2-naphthylalanyl-L-isoleucyl-D-pipecolyl-L -pipecolyl-D- histidyl]; 26, cyclo-[L-prolyl-D-tryptophanyl-L-isoleucyl-D-dehydropiperazyl-L-++ pipecolyl-D-histidyl]; 33, cyclo-[L-prolyl-D-tryptophanyl-L-isoleucyl-D-pipecolyl-L- piperazinylcarboxy-D-(N-methyl)phenylalanyl]; 34, cyclo-[L-prolyl-D-phenylalanyl-L-isoleucyl-D-dehydropiperazyl-L-or nithyl- D-(N-methyl)phenylalanyl]). In general, this class exhibited good selectivity for binding to the oxytocin receptor versus the arginine vasopressin V1a and V2 receptor subtypes, although increased V2 receptor affinity was observed in one case (32, cyclo[L-prolyl-D-2-naphthylalanyl-L-isoleucyl-D-pipecolyl-L- lysyl-D-(N- methyl)phenylalanyl]). Unexpectedly, compound 33 was found to stimulate contractions of the isolated rat uterus via activation of the uterine bradykinin receptor. Compounds 22, 25, 26, 33, and 34 were found to be potent antagonists of oxytocin-stimulated contraction of the rat uterus in vitro and in vivo. Compounds 22 and 25 were additionally characterized as potent antagonists of oxytocin-stimulated uterine contractions in the near-term pregnant rhesus monkey. These studies thus demonstrate the selectivity and efficacy of certain members of this novel class of antagonists and suggest their use as pharmacological tools in further defining the role of oxytocin in both term and preterm labor.

Amino Acid Sequence↗
PubMed1992

Radioligand binding studies reveal marked species differences in the vasopressin V1 receptor of rat, rhesus and human tissues.

The [3H]arginine-vasopressin ([3H]AVP) binding site in rat, rhesus and human liver and nonpregnant human uterus was characterized and contrasted. [3H]AVP bound with high affinity (Ki values, 0.2-0.6 nM) to preparations of all tissues studied. Competition binding studies using a series of compounds from three structural classes indicate a marked species difference between the rat and primate liver AVP-V1 site. This site in rhesus and human liver however, is essentially identical, indicating that the rhesus liver is an appropriate surrogate for human tissue. These studies also indicate that the AVP-V1 site of nonpregnant human uterus and human liver is equivalent.

Animals↗
PubMed1992

Comparative pharmacological profile of muscarinic agonists in the isolated ileum, the pithed rat, and the mouse charcoal meal transit test.

1. Several reportedly selective (McN-A-343, M1; RS-86, M2; pilocarpine, M3) and non-selective (oxotremorine, acetylcholine, cis-dioxalone, arecoline, muscarine) muscarinic agonists were examined for comparative pharmacological potency in three diverse models: the guinea pig ileum, the pithed rat, and the mouse charcoal meal transit test. 2. In the guinea pig ileum, all of the compounds examined were associated with concentration-dependent contractions. 3. The apparent order of potency in the isolated ileum was cis-dioxalone greater than acetylcholine greater than oxotremorine greater than arecoline greater than RS-86 greater than pilocarpine greater than McN-A-343. 4. The pA2 values for atropine and pirenzepine in the ileum ranged from 8.4 to 9.4 and 6.1 to 7.7, respectively, indicative of a single receptor, most likely M3. 5. In the mouse charcoal meal transit test, non-selective muscarinic agonists produced dose-dependent increases in gastrointestinal transit, while selective agonists failed to produce any significant changes. 6. Scopolamine methylbromide, a peripherally acting non-selective muscarinic antagonist, significantly reduced the ability of muscarine to increase transit. 7. The compounds were further examined for dose-dependent pressor effects in the pithed rat, which are known to be mediated by stimulation of M1-receptors in sympathetic ganglia. 8. McN-A-343 produced the greatest pressor response, as measured by the percent increase in mean pressure, followed by pilocarpine. 9. Pirenzepine antagonized the pressor response of McN-A-343 and pilocarpine in a dose-dependent manner.

Animals↗
PubMed1992

Platelet cytosolic free calcium concentration, total plasma calcium concentration and blood pressure in human twins: a genetic analysis.

1. We used path analysis and maximum-likelihood model fitting to evaluate the relative contributions of genetic and environmental factors to the relationships observed between level of blood pressure and both total plasma calcium concentration and platelet cytosolic free calcium concentration in 109 twin pairs. 2. Total plasma calcium concentration was positively associated with systolic (r = 0.26, P less than 0.001) but not diastolic blood pressure, a relationship which remained significant after adjustment for albumin, age and body mass index. A relationship between platelet cytosolic free calcium concentration and both systolic and diastolic blood pressure (r = 0.17 and r = 0.13, respectively, P less than or equal to 0.05) was no longer significant after adjustment for age and body mass index. 3. Additive genetic influences, unique environmental effects and age contributed to 60%, 30% and 10% of the variance in systolic blood pressure, respectively. Additive genetic effects explained 78% of the variance in plasma total calcium concentration and at least 48% of the variance in platelet cytosolic free calcium concentration in females and 37% in males. 4. Bivariate factor models provided evidence of genetic, but not environmental, co-variation of total plasma calcium concentration and systolic blood pressure, suggesting that a common genetic factor (or factors) contributes to their univariate relationship. In contrast, there was evidence of environmental, but not genetic, covariation of platelet cytosolic free calcium concentration and systolic blood pressure, suggesting that some of the individual experiences specific to each twin may be causing these two traits to vary together. 5. The possible confounding effects of adiposity and environmental factors should be considered in future studies investigating the role of intracellular calcium levels in the pathogenesis of hypertension.

Adolescent↗
PubMed1992

Honors program participation and performance postgraduation.

Four groups of students were surveyed four to six years postgraduation regarding enrollment in graduate studies, research involvement, and occupancy of leadership positions in professional organizations. Group 1 (n = 20) consisted of honors graduates, Group 2 (n = 52) were high GPA non-honors graduates, Group 3 (n = 39) were low GPA graduates, and Group 4 (n = 16) were RN-to-BSN graduates with high GPAs but not in the honors program. Enrollment in graduate studies was the strongest outcome indicator of participation in the honors program. Honors graduates also held leadership roles in professional organizations significantly more than Groups 2 and 3, but were quite comparable to Group 4. Follow-up at 10 years postgraduation and replication of the study in other settings are recommended.

Adult↗
PubMed1992

Behavioral characterization of the new potent nonselective dopamine agonist pergolide.

Pergolide (LY127809, CAS 66104-23-2), a non-selective dopamine agonist, was evaluated for broad behavioral properties in a wide range of pharmacological tests. The selective dopamine2(D2) agonist, bromocriptine, served as a reference standard for those tests where behavioral activity was noted with pergolide. Pergolide and bromocriptine were administered orally to mice at doses of 0.3-30 and 3-300 mg/kg, respectively. Both compounds produced biphasic effects on spontaneous activity, increased hexobarbital-induced sleep time, and lowered mouse body temperature. Qualitative changes with pergolide were observed with some mice showing hyporeactiveness, ptosis, slowed respiration and placing loss. Reserpine-induced hypothermia was reversed by pergolide with significant increases in the body temperature of reserpine-treated mice. However, a further reduction in the body temperature of reserpinized hypothermic mice was seen following bromocriptine administration. Acetic acid-induced writhing and performance on the rotarod were both impaired by higher doses of pergolide. Bromocriptine administration also reduced writhing at higher doses but did not alter performance on the rotarod. Pergolide had no effect on seizure activity as evaluated by electroshock, pentylenetetrazol (pentetrazol) or strychnine. Oxotremorine-induced tremors and salivation, grip strength, and tail-flick were not affected by pergolide. Neither pergolide nor bromocriptine altered established shuttle-avoidance behavior in rats at oral doses of 0.1 to 30 mg/kg. Behavioral assessment of pergolide in dogs was complicated by severe emetic responses at clinically relevant doses greater than 0.003 mg/kg. In summary, these data suggest that pergolide produces a behavioral profile which is characteristic of dopaminergics.(ABSTRACT TRUNCATED AT 250 WORDS)

Analgesics↗
PubMed1992

General pharmacology of pergolide in animals. 2nd communication: gastrointestinal, renal and miscellaneous studies.

Pergolide mesylate ((8 beta)-8-[(methylthio)methyl]-6-propylergoline monomethanesulfonate, LY 127809, CAS 66104-23-2) is a novel and potent dopamine agonist marketed for treating the symptoms of Parkinson's disease. The potential secondary pharmacological effects of this agent on the gastrointestinal and renal systems, as well as effects on local anesthesia, hemolysis, platelet aggregation, circulating blood glucose, primary antibody production, and the acute inflammatory response were examined. Pergolide exhibited significant pharmacological effects in gastrointestinal, renal and anti-inflammatory tests at high oral doses. Pergolide was essentially inactive in blood hemolysis, platelet aggregation, primary antibody production and local anesthesia testing. In summary, these studies confirm the pharmacological selectivity of pergolide, and indicate a low potential for secondary pharmacological side effects upon the functions tested at clinically relevant doses.

Anesthetics, Local↗
PubMed1991

Bradykinin agonist activity of a novel, potent oxytocin antagonist.

From a series of potent cyclic hexapeptide oxytocin (OT) antagonists, a compound that exhibited significant bradykinin (BK) agonist activity was identified. L-366,811 (cyclo[L-proline-D-tryptophan-L-isoleucine-D-pipecolic acid-L-piperazine-2-carboxylic acid-N-Me-D-phenylalanine]) stimulated phosphatidylinositol (PI) turnover in rat uterine slices in vitro (approximately EC50, 2 microM) with a maximal effect (15-fold increase over basal) greater than that obtained for either BK or OT. L-366,811 also elicited dose-related contractions of the isolated rat uterus, producing measurable effects at 100 nM. Several other equally potent OT antagonists from the cyclic hexapeptide structural class were either less potent or inactive as activators of uterine PI turnover or contractility. The stimulatory effects of L-366,811 on uterine PI turnover and contractions were blocked by BK antagonists but not by an arginine vasopressin (AVP)/OT antagonist. In radioligand binding studies, L-366,811 exhibited moderate affinity (IC50, 360 nM) for the [3H]BK binding site in rat uterus, consistent with its potency in the functional models. These results indicate that L-366,811 exhibits BK agonist activity in rat uterus in vitro.

Animals↗
PubMed1991

Chief resident training. Developing leadership skills for future medical leaders.

Most future medical leaders receive little or no formal exposure to management and leadership training activities. Industry invests considerable resources in such training for middle and senior level managers. With the increasing complexity of health care delivery systems and the increased involvement of diverse teams of individuals in the care of patients, it was believed that a training activity designed to enhance participant human interaction skills and teach about group behavior and team management might be valuable to pediatric chief residents. This article describes a 3-day workshop designed to develop such leadership skills. It has been conducted for 3 years with 117 participants. Results of end-of-course and 6-month follow-up evaluations show that participants enjoyed the training experience and believed it was valuable in helping them fulfill their leadership role as chief resident.

Curriculum↗
PubMed1991

Relationship between in vitro relaxation of the costo-uterine smooth muscle and mesovarial leiomyoma formation in vivo by beta-receptor agonists.

The three beta-agonists, salbutamol, ritodrine, and terbutaline have been shown to possess differing potentials to induce leiomyomas in rat costo-uterine muscle following chronic exposure (salbutamol greater than terbutaline greater than ritodrine). It has been suggested that the potential to induce leiomyomas is related to the relaxant properties of these agonists in the costo-uterine muscle. In order to test this hypothesis, the potencies of salbutamol, terbutaline, and ritodrine were compared to isoproterenol and norepinephrine in vitro in the rat costo-uterine smooth muscle, a beta 2-adrenergic receptor rich tissue. All compounds produced relaxation of potassium chloride (KCl) contracted costo-uterine smooth muscle. Significant differences in potency were observed, with isoproterenol being the most potent, followed in rank order by salbutamol, terbutaline and ritodrine. The relative potency of the non-selective beta-blocker propranolol in inhibiting the agonist mediated relaxant activity was similar for all agonists examined, indicative of interactions at the same receptor site (Tallarida and Jacob 1979). When tested for beta-agonist activity in the guinea pig atria, salbutamol and ritodrine were less potent in these tissues compared to the costo-uterine muscle. In summary, the in vitro pharmacological potency of salbutamol, terbutaline and ritodrine correlated with the potential to induce leiomyoma formation in rat costo-uterine muscle following chronic exposure to the respective beta-agonists. These results indicate that the isolated rat costo-uterine muscle is a sensitive model for comparing the potency of beta-agonists, and may assist in establishing the risk of costo-uterine leiomyoma formation in chronic rat studies relative to agents such as salbutamol.

Adrenergic beta-Agonists↗
PubMed1991

Vancomycin-induced release of histamine from rat peritoneal mast cells and a rat basophil cell line (RBL-1).

Rapid intravenous administration of the glycopeptide antibiotic, vancomycin, may cause a hypotensive reaction which can usually be prevented by infusing vancomycin in dilute solutions. The release of histamine from circulating cells such as basophils and tissue mast cells has been implicated in hypotensive reactions since the effects can be prevented by antihistamine pretreatment. The direct effects of vancomycin on histamine release were therefore investigated in rat peritoneal mast cells and rat leukemic basophils (RBL-1 cells). Suspension cultures of mast cells or RBL-1 cells were exposed to vancomycin for 30-60 minutes at concentrations comparable to those infused clinically (2.28 or 4.56 mg/ml). Vancomycin induced a time- and dose-dependent release of histamine into the culture media from both cell types. The reference degranulating agent, Compound 48/80 (CP 48/80), was also shown to induce histamine release from mast cells and RBL-1 cells. Mast cells were significantly more sensitive to vancomycin and CP 48/80 than RBL-1 cells and, unlike RBL-1 cells, were responsive to the inhibitory effects of cromolyn sodium on histamine release. Cromolyn sodium did not inhibit vancomycin-induced histamine release in RBL-1 or mast cells. Morphologically, mast cells exposed to either vancomycin or CP 48/80 exhibited dose-related degranulation. On the other hand, treatment-related degranulation effects of either vancomycin or CP 48/80 on RBL-1 cells could not be reliably distinguished from controls by qualitative evaluation. Based upon these findings it is concluded that mast cells may represent a more useful model to evaluate the potential of investigational agents to release histamine and to study mechanisms of histamine release than RBL-1 cells.

Animals↗
PubMed1991

The proconvulsive activity of quinolone antibiotics in an animal model.

The side-effect profile of quinolone antibiotics in man includes CNS disturbances such as dizziness, insomnia and convulsions. Although it has been suggested that the proconvulsive liability of quinolones involves an interaction with GABA receptors in the central nervous system, no animal model has been described to evaluate or confirm the mechanism of this effect. The proconvulsive activity of the quinolone antibiotics, nalidixic (NAL) and oxolinic (OXO) acid were tested in male mice following oral doses of 10-100 mg/kg utilizing the convulsive stimuli pentylenetetrazole (PTZ), picrotoxin, strychnine or electroshock. While NAL and OXO did not alter the threshold for convulsions induced by PTZ, strychnine or picrotoxin, both agents lowered the threshold for electroshock-induced seizures. Furthermore, the proconvulsive actions of NAL and OXO were completely blocked by the excitatory amino acid receptor antagonists, MK-801 and 2-amino-4-phosphonobutyric acid (AP-4). These data indicate that the mechanism of convulsive liability of quinolone antibiotics does not involve GABA receptor interactions as previously thought, but appears to involve activation of excitatory amino acid (EAA) receptors, possibly located in the optic region of the central nervous system.

Animals↗
PubMed1991

Renin inhibitors containing conformationally restricted P1-P1' dipeptide mimetics.

A series of renin inhibitors containing lactam-bridged P1-P1' dipeptide mimetics based on the ACHPA (4(S)-amino-5-cyclohexyl-3(S)-hydroxypentanoic acid) design was studied. The inhibitors were obtained by aldol addition of various lactams with N alpha-Boc-L-cyclohexylalaninal, followed by Boc group removal and acylation with Boc-Phe-His. The aldol diastereomer having the S configuration at the two newly generated stereogenic centers gave optimal enzyme inhibition. Potency was further enhanced in the gamma-lactam ring series by substitution with small hydrophobic groups to mimic the P1' side chain of the renin substrate. Thus, 2(S)-[(Boc-L-phenylalanyl-L-histidyl)amino]-3-cyclohexyl-1(S)-hydroxyl-1 - (1,5,5-trimethyl-2-oxopyrrolidin-3(S)-yl)propane (34) has an IC50 of 1.3 nM in the human plasma renin assay. A variety of substituents on the lactam nitrogen are tolerated and can be used to vary the physical properties of the inhibitor. By using a model of the human renin active site, the conformation of 34 in the enzyme-inhibitor complex is proposed. This modeled conformation is very similar to the solid-state conformation of 2(S)-[(Boc-L-phenylalanyl-L-histidyl)amino]-3-cyclohexyl-1(S)-hydroxyl- 1-(1-methyl-2-oxopyrrolidin-3(S)-yl)propane (36), the structure of which was determined by single-crystal X-ray diffraction analysis. The most potent ACH-PA-lactam renin inhibitors show good selectivity when assayed against other types of aspartic proteinases. By varying the lactam ring substituents, potent and selective inhibitors of cathepsin D and cathepsin E can be obtained.

Animals↗
PubMed1991

Patterns of coping in black working women.

This study examined the replicability of the factor patterns of the Lazarus Revised Ways of Coping Scale on a sample of 191 black working women aged 22 to 64 years (M = 37.8, SD = 10.8) in a community in the southeastern United States. The majority of the women worked as clerks and service workers in one agency. The scale was administered individually and the items analyzed using alpha and confirmatory principal components analysis with oblique rotation. Two of the 8 scales derived by Lazarus's group, seeking social support and positive reappraisal, emerged as significant in the current analysis.

Adaptation, Psychological↗
PubMed1991

Beta-adrenoceptor profile of ractopamine HCl in isolated smooth and cardiac muscle tissues of rat and guinea-pig.

The investigational sympathomimetic amine, ractopamine hydrochloride, has been profiled for adrenergic activity in selected smooth and cardiac muscle preparations. There was no significant interaction of ractopamine with alpha-adrenergic receptors in the rat vas deferens at concentrations up to 10(-5) M. However, ractopamine produced a concentration-dependent increase in the force and rate of contractions of atria isolated from normal and reserpinized guinea-pigs (EC50 = 1 x 10(-7) M). These increases were submaximal compared with isoprenaline (70-85%), suggesting partial agonist activity at the beta 1-receptor site. Ractopamine completely relaxed the KCl-contracted guinea-pig trachea and rat costo-uterine smooth muscle to their resting tensions (EC50 = 3 x 10(-7) and 5.5 x 10(-8) M, respectively), indicative of full beta 2-agonist properties. Propranolol blocked the response of ractopamine in isolated tracheal and atrial tissues (pA2 = 7.70), demonstrating a beta-adrenergic mechanism of activity. Ractopamine also exhibited antagonism of the response of the guinea-pig trachea to the beta-agonist, isoprenaline. Relative to other beta-agonists, ractopamine was 100-fold more potent than the phenethanolamines, salbutamol and ritodrine, at the beta 1-adrenoceptor, and approximately 7- to 11-fold more potent than ritodrine, but only one-sixth to one-tenth as potent as salbutamol at the beta 2-adrenoceptor. Thus, ractopamine possesses significant beta 1- and beta 2-agonist properties. The submaximal stimulation of the force and rate of atrial contractions is indicative of a partial beta 1-agonist, while the maximal relaxation of the tracheal and costo-uterine smooth muscle is characteristic of a full beta 2-agonist.

Adrenergic beta-Agonists↗
PubMed1991

Cardiovascular and autonomic pharmacology of the macrolide antibiotic LY281389 in anesthetized beagles and in isolated smooth and cardiac muscles.

As part of the preclinical safety evaluation process, an investigational macrolide antibiotic, LY281389, was examined for autonomic activity in isolated smooth and cardiac muscle preparations and for cardiovascular effects by intravenous infusion in anesthetized beagles. Concentration-dependent antagonism of acetylcholine and angiotensin I (guinea pig ileum), norepinephrine (rat vas deferens), and isoproterenol (guinea pig atria) was observed at LY281389 concentrations of greater than or equal to 10(-5) M. At LY281389 concentrations of greater than or equal to 10(-4) M, the response of the guinea pig ileum to electrical stimulation was also inhibited approximately 65 to 100%, indicative of potential anticholinergic or alpha-adrenergic activity. In anesthetized dogs, the predominant effect of LY281389 was an increase in heart rate at doses of greater than or equal to 200 micrograms/kg of body weight. LY281389 also produced slight increases in mean arterial pressure and shortening of the P-R interval of the electrocardiogram. In summary, LY281389 possesses nonselective receptor antagonist activity in vitro and produces cardiovascular stimulation in anesthetized dogs. These results indicate that, in addition to potent antimicrobial activity, the macrolide antibiotic LY281389 may exert unexpected actions on cardiovascular function.

Acetylcholine↗