Search PubMed⌕ Search

Biomedical subjects

H Wilson

Publications and source records attributed to H Wilson.

At least 91 records · Page 5Linked to original sources
PubMed1988

Electrophysiologic and antiarrhythmic activities of 4-amino-N-[2-(diethylamino)ethyl]-3,5-dimethylbenzamide, a sterically hindered procainamide analogue.

Procainamide is a widely used antiarrhythmic that is fraught with therapeutic limitations such as a short half-life, production of autoimmune antibodies and a lupus-like syndrome, and complex pharmacokinetics. We synthesized the congeners of procainamide possessing one or two methyl substituents ortho to the 4-amino moiety (compounds 4 and 5, respectively), in order to sterically encumber the 4-amino substituent and prevent or diminish the rate of metabolic N-acetylation. Moreover, we anticipated that this structural alteration might eliminate the autoimmune toxicities associated with procainamide. Like procainamide, the two methylated analogues significantly reduced the rate of rise and amplitude of the action potential when studied in isolated canine Purkinje fibers. Whereas procainamide caused no significant change in action potential duration (APD), both methylated congeners significantly reduced APD at 70% and 95% repolarization. Moreover, the dimethylated congener was significantly more efficacious than procainamide in reducing ERP (effective refractory period) and increasing the ERP/APD70. The ability of these compounds to block ouabain-induced arrhythmias was studied in anesthetized dogs. Addition of two methyl groups ortho to the amine produced an increase in potency: The conversion doses for procainamide and the monomethyl and dimethyl congeners were 19.0, 18.3, and 14.3 mg/kg, respectively, following iv administration. After iv administration to rats, procainamide was extensively metabolized to N-acetylprocainamide and displayed a half-life of 0.4 h. In contrast, dimethylprocainamide was not metabolized by N-acetylation, had a half-life of 1.4 h, and provided greater peak plasma concentrations. Thus, addition of methyl substituents ortho to the 4-amino group of procainamide alters the electrophysiological characteristics of the compound, increases its potency against ouabain-induced arrhythmias in vivo, increases its plasma half-life, and prevents N-acetylation.

Acetylation↗
PubMed1987

Dihydropyridazinone cardiotonics: synthesis and inotropic activity of 5'-(1,4,5,6-tetrahydro-6-oxo-3-pyridazinyl)spiro[cycloalkane- 1,3'-[3H]indol]-2'(1'H)-ones.

In the 1,3-dihydro-5-(1,4,5,6-tetrahydro-6-oxo-3-pyridazinyl)-2H-indol-2-one series of cardiotonics, we found that a spirocycloalkyl ring may be annealed to the 3-position of the indolone moiety while retaining inotropic activity. An inverse relationship was found between spirocyloalkyl ring size and inotropic potency. ED50 values of the spirocyclopropane 10, spirocyclobutane 12, and spirocyclopentane 13 were 2.7, 35, and 133 micrograms/kg, respectively, following iv administration to pentobarbital-anesthetized dogs. The most potent compound prepared was 11 (5'-(1,4,5,6-tetrahydro-4-methyl-6-oxo-3-pyridazinyl)spiro[cyclopropane- 1,3'-[3H]indol]-2'(1'H)-one), the 4-methyl analogue of 10. This compound had an iv ED50 of 1.5 microgram/kg. Oral activity was evaluated by administering 50 micrograms/kg of 10 to conscious, chronically instrumented dogs. A 39% increase in LV dP/dt60 was observed, and an inotropic effect was demonstrable in excess of 7 h. Thus, the spirocyclic dihydropyridazinone inotropes are potent, long-acting, orally effective cardiotonics. Compound 11 was a potent inhibitor (IC50 = 13 nM) of cAMP phosphodiesterase derived from canine cardiac sarcoplasmic reticulum (SR-PDE). Importantly, -log IC50 values for inhibition of SR-PDE for this entire series of compounds were highly correlated (r = 0.949, p less than 0.02) with their inotropic -log ED50 values, supporting the hypothesis that inhibition of this enzyme contributes to the mechanism of action of the spirocyclic dihydropyridazinones.

3',5'-Cyclic-AMP Phosphodiesterases↗
PubMed1987

Pharmacology of LY195115, a potent, orally active cardiotonic with a long duration of action.

Compound LY195115 is a novel cardiotonic with both inotropic and vasodilator activities. In cat papillary muscles, LY195115 increased contractility in a concentration-dependent manner; its actions were not blocked by either prazosin or propranolol. An intravenous dose of 7.0 micrograms/kg LY195115 resulted in a 50% increase in contractility in anesthetized dogs; comparable inotropic responses were observed in anesthetized cats receiving 10 micrograms/kg i.v. These doses of LY195115 increased heart rates of both dogs and cats by less than 10%. Oral administration of 25 micrograms/kg to conscious dogs was associated with a selective inotropic response that was maximal at 3 h and maintained in excess of 23 h. This effect was not accompanied by gross behavioral changes or emesis. The hemodynamic profile of LY195115 was evaluated in anesthetized beagle dogs. A 60-min infusion of 1.0 microgram/kg/min LY195115 followed by a 5-min infusion of 10 micrograms/kg/min resulted in dose-dependent increases in contractility (LV dP/dt60) and heart rate; doses that increased LV dP/dt60 by 50% increased heart rate by less than 10%. Doses of greater than 5.0 micrograms/kg decreased left ventricular end-diastolic pressure and systemic vascular resistance; mean arterial blood pressure and cardiac output were unchanged. Estimated myocardial oxygen consumption (heart rate times either systolic or mean arterial blood pressure) was not altered by doses as high as 110 micrograms/kg. This balance of inotropic/vasodilator activities may provide a means of improving cardiac function while maintaining myocardial oxygen supply/demand.

Administration, Oral↗
PubMed1987

Severe pulmonary hypertension and arterial adventitial changes in newborn calves at 4,300 m.

Some human newborns have a syndrome characterized by irreversible pulmonary hypertension and severe hypoxemia and by medial hypertrophy and adventitial thickening of pulmonary arteries. We considered that newborn calves made severely hypoxic might reproduce features of the human disease. When 2-day-old calves were placed at 4,300 m simulated altitude, pulmonary arterial pressure was increased and could be reversed by 100% O2. However, after 2 wk at 4,300 m, pulmonary arterial pressures were suprasystemic and there was right-to-left shunting probably through the foramen ovale and a patent but restrictive ductus arteriosus. Suprasystemic pulmonary pressure and hypoxemia persisted with 100% O2 breathing. Morphometrical examination of the lung arteries showed a markedly thickened adventitia with cellular proliferation and collagen and elastin deposition. There was increased medial thickness and distal muscularization of the pulmonary arteries associated with decreased luminal diameter. The rapid development of severe pulmonary hypertension and poor responsiveness to O2 was associated with increased arterial wall thickness, particularly involving the adventitia. Thus the pulmonary arterial circulation in these calves, which were placed at high altitude for 2 wk, exhibited features resembling persistent pulmonary hypertension in newborn infants.

Altitude Sickness↗
PubMed1987

The pharmacokinetics and pharmacodynamics of newer inotropic agents.

In the past few years an intense effort has been directed toward the development of new inotropic agents for the treatment of chronic cardiac failure. Traditionally, therapy of this disease has included treatment with digitalis glycosides, diuretics, sodium restriction and vasodilators. While digitalis has proven to be an effective inotropic agent, it possesses a low therapeutic index and many patients remain symptomatic or 'refractory' despite its inotropic effects. This review focuses on the pharmacokinetics and pharmacodynamics of newer inotropic agents that have been developed or which are currently undergoing investigation. Amrinone and milrinone are two bipyridine derivatives which have been shown to be effective in the short term treatment of cardiac failure. Milrinone is currently being evaluated for its long term efficacy. The mechanism of action of amrinone and milrinone appears to be unrelated to the cardiac glycosides and sympathomimetic agents, and they are rapidly and well absorbed following oral administration. The bioavailability of milrinone appears to be somewhat reduced in patients with chronic cardiac failure. The distribution of these drugs to extravascular tissues is very rapid; the volume of distribution suggests that they are not extensively bound to tissues. While the volume of distribution of amrinone appears to be unaffected by the presence of heart failure, that of milrinone appears to be somewhat enhanced. The major route of elimination of both drugs appears to be excretion into urine as unchanged drug. A substantial fraction of the amrinone dose, however, undergoes hepatic metabolism to many metabolites, including an N-acetyl derivative. Clearance of amrinone and milrinone is dramatically reduced in patients with chronic cardiac failure compared with normal volunteers, resulting in proportionate increases in the serum half-lives of these drugs. Studies examining the acute and chronic disposition of these agents in cardiac failure patients have not demonstrated changes in their pharmacokinetics secondary to improvements in cardiocirculatory function. Both drugs show strong correlations between mean improvements in haemodynamics and drug serum concentrations, although considerable intrapatient variability may exist. It is currently unclear as to whether the site for the pharmacological action of amrinone is pharmacokinetically distinguishable from plasma. Enoximone and its sulphoxide metabolite, piroximone, are two compounds currently undergoing investigation for the treatment of chronic cardiac failure.(ABSTRACT TRUNCATED AT 400 WORDS)

Cardiotonic Agents↗
PubMed1987

The use of the Diagnostic Interview Schedule in drug-dependent patients.

In an attempt to diagnose other psychiatric disorders in substance abusers, some clinicians and investigators have utilized the NIMH Diagnostic Interview Schedule (DIS). This study assessed the validity of the DIS in a drug-dependent population by comparing DIS diagnoses with clinical diagnoses in 124 hospitalized drug abusers. Every attempt was made to establish the validity of the clinical diagnoses; these represented a consensus of two independent psychiatrists, based on repeated clinical interviews, observation of ward behavior, and information obtained from relatives regarding patient and family history. Concordance between clinical and DIS diagnoses (represented by the kappa statistic and percent agreement) was only moderate for DSM-III Axis I disorders other than substance abuse. In addition, the DIS diagnosed alcoholism less often and antisocial personality disorder more often than the clinicians. Factors contributing to the discrepancy between clinical and DIS diagnoses in this specific population include (a) drug abuse effects, whereby distinguishing between drug effects and primary psychiatric symptoms may be difficult; and (b) the effect of the treatment process itself, whereby patients are encouraged to rethink the role drugs have played in causing some of their difficulties. Patients' reports of the chronology of their symptoms may thus change according to what they have learned in treatment. The authors conclude that the DIS, like any single diagnostic interview, may have limited utility early in the treatment of drug-dependent patients, since their recollection of their previous symptoms may change dramatically as a result of treatment efforts.

Adult↗
PubMed1987

Pharmacokinetics and hemodynamics of amrinone in patients with chronic cardiac failure of diverse etiology.

The pharmacokinetics of amrinone and its relationship to ventricular function were assessed in 15 patients with chronic cardiac failure following the administration of a single 100 mg oral dose. Patients examined had Class II (1 patient), Class III (13 patients) and Class IV (1 patient) heart failure as characterized by the New York Heart Association classification. Blood samples were obtained following amrinone administration at selected times for 8 hours following the dose. Cardiac output was assessed serially for 5 hours following amrinone dosing. Mean (SD) peak plasma concentrations of amrinone (2.1 (1.1) mcg/ml) were obtained 0.5 to 2 hours after drug administration. The mean (SD) apparent oral clearance, apparent volume of distribution at steady state and half-life of amrinone were 0.23 (0.13) L/hr/kg, 1.2 (0.4) L/kg, and 4.8 (3.0) hr. Peak increases in cardiac index averaged 50% of baseline values and improvement was maintained at least 5 hours following amrinone dosing when compared to baseline cardiac index (p less than 0.05). Examination of the relationship between cardiac index corrected for baseline and amrinone plasma concentrations within individuals yielded strong and highly significant relationships (r greater than 0.90; p less than 0.025) in five patients, while in the remaining patients, either no relationship existed or insufficient data was available for analysis. When the data from all patients were pooled, a modest though significant relationship (r = 0.67; p less than 0.01) existed between cardiac index corrected for baseline and the post-absorptive, post-distributive amrinone plasma concentration. No difference in response to amrinone as a function of failure etiology or functional aerobic capacity was evident. Evaluation of the relationships between the mean improvement in cardiac index versus amrinone plasma concentration, as well as the time courses of these parameters indicate that the site of action of amrinone may be pharmacokinetically distinguishable from plasma and the tissues in instantaneous equilibrium with plasma.

Acetylation↗
PubMed1986

Effects of exposure of DNA to methyl mercury on its activity as a template-primer for DNA polymerases.

A previous publication [Frenkel, Cain, and Chao, Biochem. Biophys. Res. Commun. 127, 849-856 (1985)] described the observation that double-stranded DNA which was briefly exposed to methyl mercury (MeHg) and purified to remove free methyl mercury was transcribed at a higher rate by RNA polymerase II from wheat germ. The specificity of this phenomenon has now been investigated by examining the activity of this MeHg-exposed DNA as a template-primer for DNA polymerases. DNA synthesis by the bacteriophage T4-induced DNA polymerase was higher with the MeHg-exposed DNA as a template-primer than with control DNA. In contrast, the rate of DNA synthesis by E. coli DNA polymerase I was lower with the MeHg-exposed DNA as template-primer. With both enzymes (as well as with RNA polymerase II), after denaturation of the MeHg-exposed and control DNAs the differences in template activity were either eliminated or markedly reduced. The enzymes are thus able to detect a MeHg-induced alteration in DNA. In contrast, circular dichroism, a physical method that is sensitive to conformational changes in DNA, did not detect any difference between the MeHg-exposed and control DNAs.

DNA↗
PubMed1986

Clinical spectrum of Kawasaki disease in infants younger than 6 months of age.

We report an unselected series of eight patients younger than 6 months of age with Kawasaki disease evaluated between January 1982 and May 1984. The incidence of coronary artery aneurysms (six patients) and the mortality (two patients) were unusually high in this small series. Because of the confusing clinical presentation in three patients, diagnosis was delayed until pathologic or echocardiographic evidence of coronary vasculitis or aneurysm was discovered. The currently accepted clinical criteria for Kawasaki disease may not always identify patients with the pathologic findings of the syndrome who are younger than 6 months of age. The diagnosis of Kawasaki disease and echocardiographic evaluation of the coronary arteries should be considered in young infants with prolonged fever of unknown origin.

Aspirin↗
PubMed1986

Bipyridine cardiotonics: the three-dimensional structures of amrinone and milrinone.

The cardiotonic drug milrinone (1,6-dihydro-2-methyl-6-oxo-[3,4'-bipyridine]-5-carbonitrile) is superior to its analogue amrinone (5-amino-[3,4'-bipyridin]-6(1H)-one) by virtue of its greater potency and reduced side effect profile. We confirmed initial reports on the potencies of milrinone and amrinone and found that after intravenous administration to phenobarbital anesthetized dogs, the drugs had cumulative inotropic ED50's of 37 and 1891 micrograms/kg, respectively; relative effects on heart rate and blood pressure were comparable. There are two structural differences between amrinone and milrinone: (1) milrinone has a pyridone 2-methyl substituent and (2) the pyridone 5-amino substituent of amrinone is replaced with a nitrile in milrinone. We confirmed structure-activity studies that indicated that the 2-methyl substituent appears to be primarily responsible for the dramatic difference in the potencies of amrinone and milrinone. A plausible explanation for the effect of the methyl substituent is an altered molecular topology resulting from its steric interaction with the 3',5'-hydrogen atoms. Consequently, we probed the three-dimensional structures of these two compounds by X-ray crystallography. The dihedral angle between the planes formed by the two aromatic rings of amrinone was 1.3 degrees. In marked contrast, the corresponding angle for milrinone was 52.2 degrees. Moreover, 1H NMR studies revealed conformational differences in solution. Whereas the 2-methyl substituent undoubtedly produces some electronic and hydrophobic perturbations in the bipyridine cardiotonic series, the most significant effect, from a global viewpoint, is the altered molecular topology.

Aminopyridines↗
PubMed1986

Dihydropyridazinone cardiotonics: the discovery and inotropic activity of 1,3-dihydro-3,3-dimethyl-5-(1,4,5,6-tetrahydro-6-oxo-3-pyridazinyl)-2H -indol-2- one.

We discovered that 6 (N-[4-(1,4,5,6-tetrahydro-6-oxo-3-pyridazinyl)phenyl]acetamide) is a potent positive inotrope in dogs, and we have prepared several lactam analogues of this agent. These included 16 (1,3-dihydro-5-(1,4,5,6-tetrahydro-6-oxo-3-pyridazinyl)-2H-indol-2-one), 32 (the analogous quinolin-2-one), and 37 (the analogous benzazepin-2-one). The inotropic ED50's of these compounds were 24, 3.3, and 5.2 micrograms/kg, respectively, after iv administration to pentobarbital-anesthetized dogs. Compound 20 (LY195115, 1,3-dihydro-3,3-dimethyl-5-(1,4,5,6-tetrahydro-6-oxo-3-pyridazinyl)-2H-i ndol-2- one), the geminal dimethyl analogue of 16, was 3.5-fold more potent than 16 when administered iv (ED50 = 6.8 micrograms/kg). However, the most profound effect of the geminal alkyl substitution was on oral activity. The approximate ED50's of 20 and 16 after oral administration to conscious dogs were 25 and 400 micrograms/kg, respectively. The increase in contractility produced by 25 micrograms/kg of 20 was maximally sustained in excess of 8 h. Thus, 20 is one of the most potent and long-acting oral inotropes described to date.

Administration, Oral↗
PubMed1986

The effects of alfentanil and selected narcotic analgesics on the rate of action potential discharge of medullary respiratory neurones in anaesthetized rats.

The effects of intravenous injections of alfentanil, fentanyl, phenoperidine or morphine on respiratory and peak inspiratory air flow rate, the diaphragm electromyogram (EMG), the activity recorded extracellularly from respiratory neurones located in the ventral respiratory group and the cardiovascular system were examined in anaesthetized rats. Alfentanil produced dose-dependent changes in peripheral and central respiratory parameters, which were prevented by naloxone pretreatment. Minimal effects were produced on the cardiovascular system. The bradypnoea was principally due to a prolongation of the inspiratory phase and was accompanied by a comparable decrease in the peak inspiratory air flow rate. Alfentanil prolonged the discharge duration of inspiratory neurones such that it still maintained a strict phase correlation with the diaphragm EMG, but changes in firing frequency were inconsistent and negligible. The action on expiratory neuronal discharge was analogous to that on inspiratory neuronal discharge but delayed in onset. Hypotension produced by morphine limited the dose used but the respiratory responses to morphine and other selected narcotic analgesics were otherwise similar to that of alfentanil, differing mainly in time-course and magnitude. From the respiratory parameters assessed, the order of duration of effect was morphine greater than phenoperidine greater than fentanyl greater than alfentanil and the relative potencies were 0.1, 0.5, 2.5 and 1 respectively. The selective prolongation of inspiration and the immediate action on inspiratory neurones suggests that systemically administered narcotic analgesics may alter the mechanisms within the central respiratory rhythm generator which determine the cessation of inspiration.

Action Potentials↗
PubMed1986

Effect of insulin and oral glutathione on glutathione levels and superoxide dismutase activities in organs of rats with streptozocin-induced diabetes.

The effect of insulin or glutathione treatment on glutathione content of liver and jejunal mucosa and on superoxide dismutase (SOD) activity of liver, kidney, and erythrocytes was investigated in pair-fed animals with streptozocin (STZ)-induced diabetes. Diabetes lowered hepatic glutathione concentration, but glutathione concentration of the jejunal mucosa was not affected. Insulin, but not oral glutathione, restored hepatic glutathione concentration to normal levels. Diabetes depressed activity of the cytosolic form of SOD in liver, kidney, and erythrocyte. Treatment of diabetic rats with oral glutathione or intramuscular insulin increased cytosolic SOD activity of renal cortex and liver (but not erythrocytes) to control levels. These results suggest a link between glutathione metabolism and cytosolic SOD activity in diabetes.

Animals↗
PubMed1985

Biochemical studies on rabbits with aluminium induced neurofilament accumulations.

The activities of acid phosphatase, hexosaminidase, beta-galactosidase, Mg2+-stimulated Na+K+ATPase, fumarase and ATP:citrate lyase were measured in grey matter of rabbit spinal cord 7-8 days after intra-ventricular or intra-cisternal injection of aluminium. RNA, DNA, and water content were measured in whole spinal cords. Choline acetyltransferase (CAT) and acetylcholinesterase were assayed in dorsal grey matter of the cord, which contained no aluminium-induced neurofilament accumulations (NFAs), and ventral grey matter, which had large numbers of such NFAs. CAT was also assayed in the hypoglossal nerve. None of these measures were consistently altered in the aluminium treated rabbits, although the activity of beta-galactosidase was increased in the NFA-free caudate nucleus of rabbits given aluminium intra-ventricularly, possibly due to the presence of phagocytes on the ventricular surface of the caudate. It is concluded that neither aluminium nor its induced NFAs has a gross effect on neuronal metabolism within 7-8 days.

ATP Citrate (pro-S)-Lyase↗
PubMed1985

Milrinone in the treatment of chronic cardiac failure: a controlled trial.

This study examines the acute hemodynamic response to intravenous and oral milrinone in 12 patients with moderate to moderately severe heart failure. The patients received milrinone or placebo at random in an 8-week double-blind trial. Dosing level and schedule were determined by the hemodynamic results. Acute and chronic plasma samples for milrinone concentration were drawn from patients throughout the study. Milrinone was administered intravenously in successive doses of 25, 50, and 75 micrograms/kg. This resulted in a 16.5%, 12.5%, and 28.4% peak increase in cardiac index, with a concomitant 24%, 29%, and 38% decrease in pulmonary capillary wedge pressure. There were no significant relationships between any of the mean maximal hemodynamic values and milrinone plasma concentration. Six patients received milrinone and six patients received placebo; only five patients completed the blinded phase. There was no significant difference between the groups in exercise capacity, but the conditions of five of the six patients who received placebo deteriorated. In two of the patients who received milrinone the aerobic capacity improved greater than 2 cc/min/kg over baseline, and an additional two patients reported a marked subjective improvement. The results of this study indicate that oral milrinone in the management of patients with chronic cardiac failure would justify larger controlled studies.

Administration, Oral↗