PubMed Health⌕ Search

Biomedical subjects

V S Murthy

Publications and source records attributed to V S Murthy.

At least 19 recordsLinked to original sources
PubMed1992

Use of intravenous esmolol to predict efficacy of oral beta-adrenergic blocker therapy in patients with neurocardiogenic syncope.

The usefulness of esmolol in predicting the efficacy of treatment with an oral beta-adrenergic blocking agent was evaluated in 27 consecutive patients with neurocardiogenic syncope. Seventeen patients had a positive head-up tilt test response at baseline and 10 patients required intravenous isoproterenol for provocation of hypotension. All patients were then given a continuous esmolol infusion (500 micrograms/kg per min loading dose for 3 min followed by 300 micrograms/kg per min maintenance dose) and rechallenged with a head-up tilt test at baseline or with isoproterenol. Of the 17 patients with a positive baseline tilt test response, 11 continued to have a positive response to esmolol challenge. Sixteen patients (including all 10 patients with a positive tilt test response with isoproterenol) exhibited a negative response to upright tilt during esmolol infusion. Irrespective of their response to esmolol infusion, all patients had a follow-up tilt test with oral metoprolol after an interval of greater than or equal to 5 half-lives of the drug. All 16 patients (100%) with a negative tilt test response during esmolol infusion had a negative tilt test response with oral metoprolol. Of the 11 patients with a positive tilt test response during esmolol infusion, 10 (90%) continued to have a positive response with oral metoprolol. It is concluded that in the electrophysiology laboratory, esmolol can accurately predict the outcome of a head-up tilt response to oral metoprolol. This information may be helpful in formulating a therapeutic strategy at the initial head-up tilt test in patients with neurocardiogenic syncope.

Administration, Oral↗
PubMed1991

Chronic verapamil treatment depresses automaticity and contractility in isolated cardiac tissues.

Chronically administered verapamil can accumulate in cardiac tissues and may depress cardiac function despite low plasma concentration. To examine this, two groups of rabbits were injected intraperitoneally twice a day with either 1 mg/kg verapamil or saline for 28 days. Fourteen hours after the last dose, right atrial tissue and right ventricular papillary muscle were isolated. Plasma and myocardial tissue concentrations of verapamil were determined. Plasma samples contained no detectable amounts of verapamil, but the myocardium contained 2.1 +/- 0.6 (mean +/- SE) ng of verapamil per gram of wet tissue. Spontaneous action potentials recorded from the sinoatrial node in the verapamil-treated group showed decreases in the phase 0 and phase 4 depolarization rates, a slower pacemaker rate, and an attenuated response to epinephrine compared with the saline-treated group. Papillary muscle in the verapamil-treated group exhibited a significantly lower force of contraction and a depressed contractile response to epinephrine compared with the control group. There were no differences in rate or contractile responses the day after single injection with 2 mg/kg verapamil or saline twice a day. Myocardial verapamil concentration increased with the duration of treatment and with the doses given; myocardial verapamil concentration was 3.0 +/- 0.6 ng/g wet tissue in the group treated for 28 days with 2 mg/kg verapamil. Our study shows that chronic treatment of rabbits with verapamil decreases cardiac chronotropic and inotropic responses to adrenergic stimuli despite no detectable verapamil in plasma, and that accumulation of verapamil in the myocardium is probably associated with these effects.

Action Potentials↗
PubMed1990

Plasma free and sulfoconjugated catecholamines during sustained exercise.

Previous research established a relationship between circulating sulfoconjugated norepinephrine (NE-SO4) and oxygen consumption at various exercise intensities. In this study, the stability of the NE-SO4 response was examined during sustained exercise at a constant relative intensity. Seven trained men bicycled at 78 +/- 3% of their maximal O2 consumption for 28 min and then rested on the ergometer for a comparable duration. After a 30-min rest, plasma samples were collected through an indwelling catheter at 7-min intervals during the exercise and recovery periods. Free NE and epinephrine increased sixfold during exercise. These changes were accompanied by increases in sulfoconjugated catecholamines, but only NE-SO4 achieved statistical significance (rest, 712 +/- 602; exercise, 1,329 +/- 1,163 pg/ml). This occurred at three collection periods (14, 21, and 28 min). Approximately 35, 52, and 95% of NE, epinephrine, and dopamine, respectively, existed as sulfoconjugated during exercise. Subject variation was present in the sulfoconjugated catecholamine response that could not be attributed to corresponding differences in circulating free catecholamine release. These findings implicate blood flow as a factor in the sulfoconjugation of NE, but not epinephrine or dopamine.

Adult↗
PubMed1990

Pharmacokinetics and safety of a phenytoin prodrug given i.v. or i.m. in patients.

ACC-9653, a prodrug of phenytoin synthesized to be water soluble, is converted to phenytoin by phosphatases. In this study, 43 patients received ACC-9653 IV or IM. Side effects were transient and minor. The conversion half-lives of ACC-9653 after intravenous and intramuscular administration averaged 8.4 and 32.7 minutes, respectively. Peak phenytoin concentrations occurred 42 minutes after IV and 151 minutes after IM administration.

Adult↗
PubMed1989

Phenytoin prodrug: preclinical and clinical studies.

The currently available phenytoin (PHT) solution has many disadvantages stemming from poor aqueous solubility of PHT. A novel approach to solve the problem has been the synthesis of a phosphate ester of PHT (PHT prodrug ACC-9653). This water-soluble compound is metabolized rapidly into PO4 and PHT. A four center open-label, baseline-controlled study of 43 patients with epilepsy maintained on oral twice-daily PHT monotherapy was performed to evaluate the safety and pharmacokinetic profile of the prodrug. Patients received an i.v. or i.m. dose of ACC-9653 at a dose equivalent to the patients' morning dose of PHT. Intravenous dosages were infused at a rate of 75 mg/min, and i.m. dosages were given as one or two injections. After a period of 6 days, during which patients were again maintained with oral PHT, they were given a dose of ACC-9653 via whichever route they had not yet received. The Tmax of the prodrug averaged 5.7 and 36 min (0.095 and 0.606 h) after i.v. and i.m. administrations, respectively. The elimination half-life of ACC-9653 (conversion from prodrug to PHT) after i.v. and i.m. administration was 8.4 and 32.7 min (0.140 and 0.545 h), respectively, and both were independent of the dose. The plasma clearance of ACC-9653 was not dependent on dose or route of administration and averaged 19.8 +/- 1.16 and 17.8 +/- 0.83 L/h after i.v. and i.m. administrations, respectively. The area under curve ratio of PHT after i.m. and i.v. ACC-9653 was 1.17 +/- 0.13 which was not significantly different from 1.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1989

Serum free levels and evaluation anticonvulsant drug interactions.

In clinical practice, serum level monitoring of anticonvulsant drugs is usually adequate. When there is an alteration in the binding of the anticonvulsant drug to the plasma proteins, however, the relationship between the serum concentration and therapeutic efficacy or toxicity becomes difficult to interpret. This can occur with combinations such as non-steroidal anti-inflammatory drugs (NSAIDs), phenytoin (Dilantin), carbamazepine (Tegretol), and valproic acid (Depakene) or when the albumin level is low. A failure to rely on serum free levels of the anti-convulsant under these circumstances can easily result in poor clinical decisions. The technique of serum free level measurement and illustrative examples of specific cases are provided to document the usefulness of this invaluable laboratory test.

Adult↗
PubMed1989

ICI 147,798: a slowly dissociable beta adrenoceptor antagonist that causes insurmountable beta-1 and surmountable beta-2 adrenoceptor antagonism in isolated tissues.

ICI 147,798 has been shown to exhibit both diuretic and beta-antagonist properties in vivo. The present study investigated the nature and selectivity of the beta-antagonism in a variety of isolated tissues. ICI 147,798 produced a concentration-dependent suppression of the maximum chronotropic response of norepinephrine in guinea pig right atria (beta-1 adrenoceptor). ICI 147,798 caused a concentration-dependent shift to the right of the salbutamol concentration-response curve in the guinea pig trachea (beta-2 adrenoceptor), and Schild analysis suggested competitive inhibition. Propranolol produced parallel shifts to the right of the norepinephrine concentration-response curve in guinea pig right atria, except at relatively high concentrations. The inhibitory effects of propranolol in guinea pig right atria were reversed by greater than 95%, whereas the effects of ICI 147,798 were only slightly reversed after a 6-hr washout period. Preincubation of propranolol with ICI 147,798 in guinea pig right atria prevented completely the suppression of the norepinephrine maximum chronotropic response. Postincubation of propranolol with ICI 147,798 partially reversed the suppression of the maximum chronotropic response. ICI 147,798 had no effect on the maximum chronotropic responses of either histamine (H2-receptor) or forskolin (adenylate cyclase activation) in guinea pig right atria and had no effect on agonist responses in a variety of other receptor systems. The insurmountable beta-1 adrenoceptor antagonism was evaluated based on the assumptions of irreversible competitive antagonism, mixed competitive and noncompetitive antagonism and slowly dissociating competitive antagonism ("hemi-equilibrium" conditions). Concentration-dependent changes in norepinephrine KA values suggested the first three possibilities were unlikely.(ABSTRACT TRUNCATED AT 250 WORDS)

Adrenergic beta-Antagonists↗
PubMed1989

Insurmountable beta receptor blockade by ICI 147,798 in rabbits.

In rabbits, the characteristics of cardiac beta-1 receptor blockade produced by ICI 147,798, a novel beta receptor blocking agent with diuretic properties, were evaluated and compared with those of propranolol. In conscious rabbits, i.v. injections of 0.31, 1.0 and 3.1 mg/kg of ICI 147,798 and 1.0 mg/kg of propranolol caused significant bradycardia. ICI 147,798 produced a dose-dependent shift to the right of the dose-response (chronotropic) curve of isoproterenol with suppression of the maximal tachycardia, an effect characteristic of insurmountable beta receptor blockade. Propranolol also produced a shift to the right of the dose-response curve of isoproterenol without affecting the maximal tachycardia. ICI 147,798-induced antagonism was specific for beta adrenoceptors as it failed to modify the effects of acetylcholine, angiotensin II, phenylephrine, adenosine, histamine and prostaglandin E2 on mean arterial pressure and heart rate. In rabbits with prior autonomic blockade, ICI 147,798, like propranolol, failed to inhibit the positive chronotropic effects of theophylline which are mediated by postreceptor mechanisms. In reserpinized rabbits, ICI 147,798 was found to have no intrinsic sympathomimetic activity. Unlike the effects of propranolol, which were attenuated by first-pass through the hepatic vascular bed, the effects of ICI 147,798 were unaffected suggesting an absence of first-pass metabolism. The effects of propranolol (1.0 mg/kg i.v.) were not detectable at 24 hr after injection, whereas significant beta receptor blocking activity was still present at 24 hr after ICI 147,798 (1.0 mg/kg i.v.). The results suggest that ICI 147,798 is a specific, long-acting, insurmountable beta-1 receptor blocking agent without intrinsic sympathomimetic activity.(ABSTRACT TRUNCATED AT 250 WORDS)

Adrenergic beta-Antagonists↗
PubMed1988

Controlled beta-receptor blockade with esmolol and flestolol.

Beta-receptor-blocking agents are commonly used in the management of various cardiovascular diseases. Recently, esmolol, a pharmacokinetically novel cardioselective beta-receptor-blocking agent, has been introduced for use in the treatment of critically ill patients. It is devoid of intrinsic sympathomimetic activity and in doses used clinically, it has no direct depressant effect on the heart. Esmolol is an ester and is metabolized by choline-esterase to ASL 8123, an inactive molecule. Esmolol has an elimination half-life of nine minutes which accounts for its ultrashort duration of action. This unique pharmacokinetic property provides two advantages over other longer-acting beta-receptor-blocking agents. First, the magnitude of beta-receptor blockade can be titrated to a desired level. Second, if adverse effects are experienced, reducing the dosage or terminating the infusion results in rapid reversal of its pharmacological effects. Another ultrashort-acting, non-cardioselective beta-receptor blocking agent, flestolol is undergoing clinical evaluation. Esmolol has been approved for the management of supraventricular tachycardia. The clinical safety of these novel drugs will expand the use of beta-receptor-blocking agents in the management of cardiovascular diseases in critically ill patients.

Adrenergic beta-Antagonists↗
PubMed1987

Esmolol: a titratable short-acting intravenous beta blocker for acute critical care settings.

Esmolol (Brevibloc) is an intravenous, short-acting, titratable, cardioselective beta blocker with a very rapid onset and offset of action (t1/2 = 9.2 minutes). Esmolol-induced beta blockade can be maintained as long as infusion is continued. It exhibits neither intrinsic sympathomimetic activity nor significant membrane-stabilizing activity. It is rapidly metabolized by an esterase in the erythrocyte cytosol to an inactive acid metabolite. Its hemodynamic and electrophysiologic effects are similar to those of other beta blockers. Unlike the effects of other beta blockers, however, the effects of esmolol dissipate rapidly to baseline within 30 minutes after its discontinuation. Evidence obtained from clinical studies indicates that esmolol is effective and safe in reducing the ventricular rate in patients with supraventricular tachyarrhythmias, and in reducing the heart rate in patients with acute myocardial infarction and/or unstable angina. Esmolol has also been shown to be effective and safe in attenuating the tachycardia and hypertension seen during the intraoperative period. Data from postoperative patients indicate that esmolol is ideal as sole-agent therapy for the treatment of moderate postoperative hypertension associated with a hyperdynamic state. The short duration of action and titratability of esmolol make it an ideal drug for use in patients in whom the clinical need for beta blockade is limited in duration, and it offers additional safety in patients in whom beta blockade is beneficial; however, it might be precluded because of coexisting contraindications. To date, experience with esmolol in over 1200 patients has been gathered, and the adverse effect profile is basically similar to that reported here.

Adrenergic beta-Antagonists↗
PubMed1987

Controlled beta-receptor blockade with flestolol: a novel ultrashort-acting beta-blocker.

The pharmacological properties of an ultrashort-acting beta-receptor blocking agent, flestolol, were evaluated in rabbits. Infusion of graded doses (1-100 micrograms/kg/min, i.v.) into conscious rabbits produced dose-dependent bradycardia without any significant effect on mean arterial pressure. A desired level of heart rate could be obtained by either increasing or decreasing the dose infused. Such titration could be done by changing the dose of flestolol at 20-min intervals. Infusion of 31 micrograms/kg/min of flestolol into reserpinized, conscious rabbits had no effect on mean arterial pressure or heart rate but produced significant inhibition of isoproterenol-induced hypotension and tachycardia. This dose had no effect on the chronotropic and vascular effects of norepinephrine (NE), angiotensin II, adenosine, or acetylcholine. In these rabbits, flestolol was greater than 10-fold as active as esmolol, another ultrashort-acting beta-blocking agent, in inhibiting the responses to isoproterenol. In rabbits under pentobarbital anesthesia, infusion of flestolol (3.1, 10, and 31 micrograms/kg/min) produced dose-dependent beta-receptor blockade. On termination of a 70-min infusion, recovery of the responses to isoproterenol occurred within 30 min. In a separate series of experiments, the effects of infusion of flestolol (10 micrograms/kg/min) into the portal vein were compared with the effects of infusion of the same dose of flestolol into the femoral vein of anesthetized rabbits. Infusion into the femoral vein produced bradycardia and inhibited the hypotensive as well as cardioaccelerator effects of isoproterenol. Infusion into the portal vein was devoid of either effect, suggesting extensive inactivation by the liver.(ABSTRACT TRUNCATED AT 250 WORDS)

Adrenergic beta-Antagonists↗
PubMed1987

Transient pulmonary platelet sequestration during endotoxemia in dogs.

We evaluated the time-course of regional platelet sequestration, following a bolus dose of endotoxin in anesthetized dogs. Autologous indium 111 labeled platelets, representing less than 1% of the circulating platelets, were injected 35-60 min prior to administering endotoxin intravenously to dogs. A gamma camera was used to monitor the distribution of these platelets within the thorax and abdomen. Alterations in the circulating blood platelet count paralleled the changes in blood radioactivity, enabling us to use external imaging to evaluate platelet kinetics. Marked hypotension and thrombocytopenia occurred within 6 min after administering endotoxin. The platelet pool in the lungs peaked at 9 min and was temporally related to the decrease in circulating platelet count, hypotension and increase in liver size. Translocation of platelets from the lungs to the circulating platelet pool occurred during the subsequent hour with sequestration occurring in the liver and possibly other organs. During this phase there was a recovery in platelet count to 35% of baseline levels but without significant recovery in mean arterial pressure. Based on these results we propose that endotoxin-induced thrombocytopenia results from pulmonary and hepatic sequestration of platelets, but that sequestration of platelets in the lungs is only transient. The mechanism and significance of subsequent translocation of platelets from the lungs to other sites, particularly the liver and the circulating platelet pool, remain to be investigated.

Animals↗
PubMed1987

Evaluation of myocardial perfusion and coronary vascular resistance following withdrawal of chronic nitroglycerin treatment in rabbits.

This investigation was performed to determine whether the abrupt withdrawal of chronically administered nitroglycerin (NTG) alters coronary vascular resistance and myocardial perfusion in an experimental rabbit model. New Zealand white rabbits received 2 inches of topical NTG (2%) applied 3 times daily over a 6 week period. Forty hours after abrupt withdrawal of NTG left ventricular blood flow was assessed by the radioactive microsphere technique. Coronary resistance was significantly increased in NTG-withdrawal rabbits at the baseline (21.5 +/- 3.1) compared to controls (13.5 +/- 1.2) and remained elevated after ergonovine administration at both the early (NTG-withdrawal: 20.9 +/- 3.5 vs controls 12.6 +/- 1.5) and late (NTG-withdrawal: 17.1 +/- 3.1 vs controls: 11.6 +/- 0.9) sampling periods. Neither ergonovine nor indomethacin significantly altered blood flow compared to earlier values. However, the NTG-withdrawal rabbits exhibited significantly lower blood flow to the left ventricle compared to controls after ergonovine administration at both early (NTG-withdrawal: 4.80 +/- 0.72 ml/min/gram vs controls: 6.98 +/- 0.79 ml/min/gram) and late (NTG-withdrawal: 5.30 +/- 0.80 ml/min/gram vs controls: 7/52 +/- 0.66 ml/min/gram) sampling periods and also following indomethacin administration (NTG-withdrawal: 4.24 +/- 0.46 ml/min/gram vs controls: 7.52 +/- 1.26 ml/min/gram). Electrocardiographic evidence of myocardial ischemia was noted in the NTG-withdrawal rabbits following intracardiac injection of microspheres. These studies show that increased sensitivity of NTG-withdrawal rabbits to ergonovine or microsphere injection is associated with increased coronary vascular resistance. However, severe myocardial ischemia was not observed.

Animals↗
PubMed1986

Esmolol and the adrenergic response to perioperative stimuli.

Esmolol, an ultra-short-acting, cardioselective, beta-receptor blocking agent, has been developed for use in clinical conditions requiring controlled beta-receptor blockade. Its esterase-induced rapid metabolic inactivation and resulting brief pharmacologic effect provides control over the magnitude and duration of beta-receptor blockade. In placebo-controlled clinical trials, the effects of infusion of esmolol on the sympathetically mediated hemodynamic responses to stressful events during the perioperative period were evaluated in patients scheduled for surgical procedures under general anesthesia. In patients undergoing either noncardiac or cardiac surgical procedures, esmolol was effective in attenuating tachycardia that is normally seen during induction of anesthesia, laryngoscopy and endotracheal intubation, or sternotomy and aortic dissection by reducing the hemodynamic stress on the heart with negligible adverse effects. This much-desired cardioprotective effect of esmolol will be of special value to patients with coronary artery disease and patients with an unstable cardiovascular status who are undergoing major surgical procedures with general anesthesia.

Adrenergic beta-Antagonists↗
PubMed1986

Mechanism of counteraction of aflatoxin toxicity by thymine and folic acid in Bacillus megaterium.

Thymine and cytosine as well as the intermediates in pyrimidine biosynthetic pathway dihydroorotic acid, orotic acid, carbamyl aspartate and 5'-uridine monophosphate and folic acid, was synergistic. 2-14C-Thymine, 6-14C-orotic acid and 14C-formate but not 2-14C-uracil, were incorporated into DNA more in the presence of aflatoxin. These findings indicated that aflatoxin inhibited the pyrimidine base synthesis which could be overcome to a great extent by the addition of thymine and folic acid to aflatoxin-treated cells.

Aflatoxin B1↗