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Biomedical subjects

G B Phillips

Publications and source records attributed to G B Phillips.

At least 19 recordsLinked to original sources
PubMed1992

Synthesis, cardiac electrophysiology, and beta-blocking activity of novel arylpiperazines with potential as class II/III antiarrhythmic agents.

A series of novel arylpiperazines have been prepared in an attempt to incorporate both class II (beta-receptor blocking) and class III antiarrhythmic properties in a single molecule. The key step in the preparation of the new compounds involves a regioselective heterocyclic ring formation. All but four compounds significantly prolonged action potential duration in canine cardiac Purkinje fibers (class III activity). All but one of the compounds demonstrated beta-receptor affinity in a competitive binding assay and three had beta 1-receptor selectivity. Compared to sotalol, a reference class II/III agent, arylpiperazine 7a (4-[(methylsulfonyl)amino]-N-[(4- phenylpiperazin-2-yl)methyl]benzamide) demonstrated beta 1-selectivity and was 1 order of magnitude more potent in the in vitro class III and the beta 1-receptor screens. Compound 7a was evaluated further and found to be effective in preventing programmed electrical stimulation-induced arrhythmias in conscious dogs (class III activity) and against epinephrine-induced arrhythmias in halothane anesthetized dogs (class II activity).

Action Potentials↗
PubMed1992

The variability of the serum estradiol level in men: effect of stress (college examinations), cigarette smoking, and coffee drinking on the serum sex hormone and other hormone levels.

The results of studies carried out to evaluate the relationship of estradiol to coronary heart disease and its risk factors in men have been conflicting. Three possible causes of these conflicting results are (a) an inherent variability of the estradiol level within individual men; (b) the confounding effects on the estradiol level of certain common exogenous factors such as psychological stress, cigarette smoking, and coffee drinking; and (c) methodology and study design. The present study was conducted to test in men the inherent variability of the serum estradiol level and the effects of psychological stress (college examinations), cigarette smoking, and coffee drinking on the serum estradiol level. Subsets of 41 men, 19-57 years of age, were studied. A highly significant correlation in the estradiol levels was found between two fasting samples taken 30 minutes, 19.1 (mean) days, 2-6 months, and 10-89 months apart. Neither the stress of college examinations nor 30 minutes of cigarette smoking or coffee drinking had any apparent effect on the serum estradiol level, even in the presence of a two- to fivefold increase in the level of other hormones in four subjects with an autonomic reaction (three to smoking and one to venipuncture). It appears that the serum estradiol level is remarkably stable in men when taken under controlled conditions and that neither inherent fluctuation in this level nor the effects of the exogenous factors as studied are responsible for the conflicting results.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1990

Synthesis and cardiac electrophysiological activity of aryl-substituted derivatives of the class III antiarrhythmic agent sematilide. Potential class I/III agents.

Twelve novel derivatives of the selective class III antiarrhythmic agent sematilide were prepared in an attempt to incorporate both class I and class III electrophysiological properties into a single molecule. Electrophysiological activity was determined by standard microelectrode techniques in canine cardiac Purkinje fibers. Initial assessment of class I efficacy was carried out in a ouabain-induced arrhythmia model in guinea pigs. All of the compounds prolonged action potential duration in Purkinje fibers (class III activity), and three were active against ouabain-induced arrhythmias (class I activity). Selected compounds were evaluated further in dogs for efficacy against arrhythmias occurring 24 h following coronary ligation (automatic arrhythmias) and induced by using programmed electrical stimulation techniques (reentrant arrhythmias). The most effective compounds from the series are 3g and -j, which were effective in both canine models. Molecular modeling and structure-activity relationships are discussed.

Action Potentials↗
PubMed1990

Synthesis and cardiac electrophysiological activity of N-substituted-4-(1H-imidazol-1-yl)benzamides--new selective class III agents.

The synthesis and cardiac electrophysiological activity of 18 N-substituted imidazolylbenzamides or benzene-sulfonamides are described. Compounds 6a,d,f-k and 11 exhibited potency in the in vitro Purkinje fiber assay comparable to that of N-[2-(diethylamino)ethyl]-4- [(methylsulfonyl)amino]benzamide (1, sematilide), a potent selective class III agent which is undergoing clinical trials. These data indicate that the 1H-imidazol-1-yl moiety is a viable replacement for the methylsulfonylamino group for producing class III electrophysiological activity in the N-substituted benzamide series. N-[2-(Diethylamino)ethyl]-4-(1H-imidazol-1-yl)benzamide dihydrochloride (6a) was further studied in two in vivo models of reentrant arrhythmias and showed potency and efficacy comparable to those of 1.

Animals↗
PubMed1990

Synthesis of novel (aryloxy)propanolamines and related compounds possessing both class II and class III antiarrhythmic activity.

Several (aryloxy)propanolamines and related compounds (i.e. 5-13, 16-18, 20-24, 27-33, 35, 37-39, 41, and 42) were synthesized and investigated for their class III electrophysiological activity and class II (beta-blocking) effects with use of in vitro and in vivo models. Structure-activity relationships are discussed for a series of 30 compounds. A number of these compounds prolonged the action potential duration at 95% repolarization of isolated canine cardiac Purkinje fibers by 20% (C20APD95) at concentrations of less than 1.0 microM, with no significant effects on cardiac conduction. beta-Adrenergic receptor binding studies showed that some of these compounds were 2-20 times more potent for cardiac beta 1 receptors than for beta 2 receptors. In particular, compounds 32, 41, 1, and especially (S)-1 were found to be orally active class III agents in anesthetized mongrel dogs (1 or 3 mg/kg, id) and efficacious at suppressing programmed electrical stimulation induced arrhythmias in halothane-anesthetized dogs. The profile of these compounds was similar to that found for sotalol. Compound (S)-1, which was more potent than sotalol in the PES study and equieffective in the halothane/epinephrine dog model, is being investigated further as a combined class III/II antiarrhythmic agent.

Action Potentials↗
PubMed1988

Serum sex hormone levels and myocardial infarction in the Honolulu Heart Program. Pitfalls in prospective studies on sex hormones.

It has been hypothesized that hyperestrogenemia may underlie myocardial infarction. As a test of this hypothesis, the serum estradiol and testosterone levels were estimated in samples collected prospectively from 96 male patients aged 52-74 years [mean age 60.8 +/- 6.3 (SD)] who had had a myocardial infarction and from 96 matched control subjects in the Honolulu Heart Program. Established risk factors for myocardial infarction were measured prospectively. No significant difference between patients and control subjects in mean estradiol or testosterone level was observed. The only established risk factor that was significantly different was blood pressure, which was higher in the patients. Thus, the data did not confirm the hypothesis. However, two major pitfalls for prospective studies of estradiol in myocardial infarction, which might have affected the validity of the results, were observed, namely, deterioration of estradiol values with prolonged storage (8.5-12 years in this study) and intervention. The value of this study, therefore, may lie in pointing out difficulties in carrying out prospective studies on sex hormones.

Aged↗
PubMed1985

Levels of serum sex hormones and risk factors for coronary heart disease in exercise-trained men.

On the basis of previous findings, it has been hypothesized that hyperestrogenemia may be the major predisposing factor for coronary heart disease and that an elevation in the estradiol-to-testosterone ratio, or a closely related hormonal alteration, may cause the expression of risk factors for coronary heart disease. The present study was carried out to investigate whether exercise training, which has been reported to reduce risk factors for coronary heart disease, affects the serum sex hormone levels. The serum sex hormone levels, established risk factors for coronary heart disease, and physical fitness were measured in 10 men who had undergone at least six months of intensive exercise training and in 10 sedentary men of similar age. Despite evidence for a strikingly higher level of physical fitness and a lower level of risk factors in the trained group, no significant difference in mean serum estradiol level was found. Nor did three subjects from the sedentary group show a decrease in estradiol level after three to four months of exercise training. The mean estradiol-to-testosterone ratio, however, was significantly lower in the trained group and might account for the lower level of risk factors in that group. If the hypothesis is correct, exercise training may decrease established risk factors for coronary heart disease without decreasing the risk of coronary heart disease.

Adult↗
PubMed1981

Gastric cytomegalovirus infection in bone marrow transplant patients: an indication of generalized disease.

Cytomegalovirus infection in immunosuppressed patients is well known. It usually appears as an interstitial pneumonitis that may progress to a disseminated viral infection. The authors report on two patients who, after bone marrow transplantation, had signs and symptoms of gastric ulceration as the initial manifestation of cytomegalovirus infection. Both died with disseminated cytomegalovirus infection. Though gastric presentation is unusual for cytomegalovirus infection, epigastric pain and gastrointestinal hemorrhage in a bone marrow transplant patient may herald a potentially lethal viral infection.

Acute Disease↗
PubMed1978

Radical scavenging as the mechanism for stimulation of prostaglandin cyclooxygenase and depression of inflammation by lipoic acid and sodium iodide.

Certain radical-trapping reducing agents have been shown to stimulate prostaglandin biosynthesis in vitro (1--6) and to depress phorbol myristate acetate-induced mouse ear edema (16). The increased prostaglandin synthesis resulted from influences on the cyclooxygenase. To ascertain whether these alterations were due to direct interaction with the enzyme or to indirect scavenging of the oxidant released during PGG2 reduction, we report the effects of lipoic acid and sodium iodide. Both of these agents stimulated the enzymatic oxygenation of arachidonic acid, increased the reduction of PGG2 to PGH2, quenched the EPR signal induced by arachidonic acid and depressed mouse ear edema. In addition to discovering two unusual antiinflammatory agents, we have confirmed that materials with entirely different structures can have identical effects on the cyclooxygenase, suggesting indirect stimulation of this enzyme due to trapping of the oxidant.

Animals↗
PubMed1977

Relationship between serum sex hormones and glucose, insulin and lipid abnormalities in men with myocardial infarction.

Fifteen patients who had had a myocardial infarction before the age of 43 were compared with thirteen age-matched normal subjects. Twelve of the patients and three of the controls had a delayed glucose and insulin peak in the glucose and insulin areas than normal curves. When the measurements of the four patients with the largest areas under the glucose tolerance curve were separated, significant correlations were observed in the remaining patients and controls. The ratio in serum of the concentrations of estradiol-17beta to testosterone (E/T) correlated with serum glucose area (r equals + 0.69, P is less than 0.001), insulin area (r equals + 0.80, P is less than 0.001), and the ratio of insulin area to glucose area (I/G) (r equals + 0.64, P is less than 0.005) in the glucose tolerance test. Serum cholesterol concentration correlated with E/T, insulin area, and I/G, and serum triglyceride concentration correlated with glucose area, I/G, and serum cholesterol concentration. The hypothesis is presented (i) that in men who have had a myocardial infarction, an abnormality in glucose tolerance and insulin response and elevation in serum cholesterol and triglyceride concentrations are all part of the same defect (glucose-insulin-lipid defect), (ii) that this glucose-insulin-lipid defect when glucose intolerance is present is the "mild diabetes" commonly associated with myocardial infarction but is based on a mechanism different from that of classical diabetes, (iii) that this glucose-insulin-lipid defect is secondary to an elevation in E/T, and (iv) that an alteration in the sex hormone milieu is the major predisposing factor for myocardial infarction.

Adult↗