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Biomedical subjects

R Achari

Publications and source records attributed to R Achari.

At least 19 recordsLinked to original sources
PubMed2000

Effect of ritonavir on lipids and post-heparin lipase activities in normal subjects.

BACKGROUND: Intensive therapy of HIV infection with highly active antiretroviral therapy (HAART) dramatically reduces viral loads and improves immune status. Abnormalities of lipid levels, body fat distribution, and insulin resistance have been commonly reported after starting HAART. Whether the lipid abnormalities result from changes in metabolism after an improvement in HIV status or are partly attributable to the effects of protease inhibitor use is unknown. METHODS: Twenty-one healthy volunteers participated in a 2 week double-blind, placebo-controlled study on the effect of the protease inhibitor ritonavir on total lipids, apolipoproteins, and post-heparin plasma lipase activities. RESULTS: Those taking ritonavir (n = 11) had significantly higher levels of plasma triglyceride, VLDL cholesterol, IDL cholesterol, apolipoprotein B, and lipoprotein (a) compared with placebo (n = 8). HDL cholesterol was lower with therapy as a result of a reduction in HDL3 cholesterol. Post-heparin lipoprotein lipase (LpL) activity did not change but hepatic lipase activity decreased 20% (P < 0.01) in those taking ritonavir-compared with placebo. Although all lipoprotein subfractions became triglyceride enriched, most of the increase in triglyceride was in VLDL and not in IDL particles. CONCLUSION: Treatment with ritonavir in the absence of HIV infection or changes in body composition results in hypertriglyceridemia that is apparently not mediated by impaired LpL activity or the defective removal of remnant lipoproteins, but could be caused by enhanced formation of VLDL. Long-term studies of patients with HIV infection receiving HAART will be necessary to determine the impact of these drugs and associated dyslipidemia on the risk of coronary artery disease.

Adult↗
PubMed2000

Effect on bioavailability of admixing the contents of lansoprazole capsules with selected soft foods.

OBJECTIVE: This study was designed to compare the bioavailability of lansoprazole when administered as an intact capsule and when the contents are admixed with various soft foods. BACKGROUND: Patients sometimes cannot swallow or have difficulty swallowing intact capsules such as lansoprazole. To enable them to ingest the drug, the contents of the capsule can be admixed with small amounts of soft foods. METHODS: Twenty-four healthy adult volunteers participated in this single-dose, 4-period crossover study by ingesting the contents of a 30-mg lansoprazole capsule that had been emptied into either a tablespoon of yogurt (regimen A), Ensure pudding (regimen B), or cottage cheese (regimen C), or given as an intact capsule (regimen D) during the first study period. The regimen assignments were rotated at weekly intervals so that each subject received each regimen. Blood samples were obtained over the 12-hour period after administration of each regimen, and pharmacokinetic parameters were determined. RESULTS: Of the 23 subjects who completed all 4 periods of the study, 18 were male and 5 were female. Their mean (+/- SD) age was 33.3+/-11.6 years, and their ages ranged from 19 to 52 years. No statistically significant differences between regimens were detected in mean maximum concentration, area under the curve (AUC) from time zero to the last measurable concentration, and AUC from time zero to infinity (AUC0-infinity) using analysis of variance. A statistically significant difference was detected in the time to maximum concentration between regimens C and D at 2.1 and 1.5 hours, respectively (P < or = 0.05). Bioavailability was assessed by the two 1-sided tests procedure using a 90% CI for the AUC0-infinity ratio of test-to-reference regimens. The 90% CIs were all within an acceptable equivalence range of 0.80 to 1.25. CONCLUSION: These results indicate similar bioavailabilities between the regimen in which the lansoprazole capsule was emptied and administration of the intact capsule. However, they may have limitations in predicting the results in ill, elderly, or very young patients.

2-Pyridinylmethylsulfinylbenzimidazoles↗
PubMed2000

Lack of a clinically significant pharmacokinetic interaction between fenofibrate and pravastatin in healthy volunteers.

This study was conducted to evaluate the potential pharmacokinetic interaction between fenofibrate and pravastatin. A total of 23 healthy adult volunteers received single-dose 201 mg fenofibrate alone, 201 mg fenofibrate + 40 mg pravastatin, and 40 mg pravastatin alone in a three-period crossover experiment. Plasma samples were collected at predetermined times and were analyzed with validated methods for the quantitation of fenofibric acid, pravastatin, and 3 alpha-hydroxy-isopravastatin (3 alpha-iso-PV). Pharmacokinetic parameters of these three compounds were calculated using noncompartmental methods and compared by analyses of variance and bioavailability assessments. Concomitant administration of fenofibrate and pravastatin did not affect the pharmacokinetics of either fenofibric acid or pravastatin. However, the AUC0-infinity and Cmax of 3 alpha-iso-PV were increased by 26% and 29%, respectively. The moderate increase in the formation of this pravastatin metabolite should not raise any clinical concerns due to its much lower pharmacological potency compared to pravastatin and lack of toxicity.

Adult↗
PubMed2000

The relationship between terazosin dose and blood pressure response in hypertensive patients.

A double-blind, randomized, placebo-controlled, multicenter study was conducted to describe the dose-response curve for terazosin on blood pressure. A total of 128 patients with mild to moderate essential hypertension (supine diastolic blood pressure, 100 to 114 mmHg) participated in the study. The study consisted of a 4-week single-blind placebo lead-in period and a 14-week double-blind treatment period. Patients were randomized in equal numbers to four parallel treatment groups: terazosin 1, 2, and 5 mg; terazosin 2, 5, and 10 mg; terazosin 20, 40, and 80 mg; and placebo. The 24-hour ambulatory blood pressure measurements were performed at the end of the placebo lead-in period and at the end of each 4-week fixed-dose period. The nonlinear, mixed-effect model computer program was used to analyze the dose-response relationship. There was a strong dose-response relationship between fall in blood pressure and the 1 to 10 mg terazosin dose, as well as a plateauing of response for terazosin doses above 10 mg. The maximum antihypertensive response (Emax) to terazosin was 10.7 mmHg for systolic blood pressure and 8.0 mmHg for diastolic blood pressure. The daily dose of terazosin, which produced 50% of the maximum response (ED50), was 3.0 mg for systolic blood pressure and 1.5 mg for diastolic blood pressure. The results of this study suggest that although some patients may benefit from terazosin doses of greater than 10 mg, doses up to 10 mg will maximize therapeutic benefit for most patients, with acceptable side effects.

Adrenergic alpha-Antagonists↗
PubMed1998

Effects of oral and intravenous terazosin and head-up tilt on blood pressure responses in patients with hypertension.

Terazosin is a selective alpha1-adrenoceptor antagonist. A double-blind, randomized, placebo-controlled, two-period study evaluated the effects of posture and of oral and intravenous administration of terazosin on blood pressure and heart rate in patients with hypertension. At least one week after withdrawal of all antihypertensive medications, 31 patients with sitting diastolic blood pressure of 95 to 114 mmHg were enrolled in the study. After a 24-hour, single-blind, placebo lead-in phase, the patients were randomized to receive either oral terazosin (1 mg on day 1, 2 mg on day 2, and 5 mg on days 3 and 4), a 12-hour intravenous infusion of terazosin (2.5 mg, 5 mg, or 7.5 mg), or placebo for 4 consecutive days. Head-up tilt (60 degrees for 20 minutes) evaluations were performed before and 0.5, 1.5, 2.5, 6, 12, and 16 hours after start of administration during the placebo lead-in phase and on each of the 4 days of the double-blind treatment phase. Blood pressure and heart rate were monitored every 2 minutes during the 20-minute tilt. Statistically significantly larger mean changes in blood pressure and heart rate were observed with the 7.5-mg intravenous dose of terazosin compared with those after oral terazosin or placebo. With respect to intravenous terazosin, the orthostatic changes were maximal on the first day of the 4-day treatment and increased with increasing doses of terazosin. Maximum orthostatic changes in blood pressure after oral administration of terazosin were not significantly different from those observed with placebo. The most common treatment-emergent adverse events during tilt were dizziness and nausea. Dizziness occurred more frequently with intravenous terazosin than with oral terazosin. The results of this study indicate that oral dose titration of terazosin rather than a slower rate of terazosin infusion minimized the postural effects on blood pressure and associated symptoms during head-up tilt.

Administration, Oral↗
PubMed1992

Terazosin: a new alpha adrenoceptor blocking drug.

Terazosin (Hytrin; Abbott Laboratories, North Chicago, IL) is a new, selective alpha 1-adrenoceptor blocking agent used on once-a-day basis for therapy of mild-to-moderate hypertension. Its pharmacologic properties are similar to those of prazosin. Terazosin however, differs from prazosin in that its water solubility is 25 times greater than that of prazosin and its elimination half-life is about three times that of prazosin. Greater water solubility facilitates intravenous formulation, and longer half-life allows once-daily administration of terazosin. Terazosin is effective in lowering blood pressure and has a beneficial effect on plasma lipid profile. The major advantage of terazosin compared with prazosin, however, is its long duration of action. Terazosin is safe and effective when used in combination with diuretics and other antihypertensive agents, and in the long-term treatment of patients with mild to moderate essential hypertension.

Adrenergic alpha-Antagonists↗
PubMed1991

Terazosin: pharmacokinetics and the effect of age and dose on the incidence of adverse events.

Terazosin is a new, long-acting, selective, postsynaptic alpha 1-adrenergic receptor antagonist with a chemical structure similar to that of prazosin. In this article the pharmacokinetics of terazosin are reviewed, and the incidence of adverse events in a dose-response study and a meta-analysis of 20 placebo-controlled trials involving a total of 1814 patients is presented. Peak plasma concentrations of terazosin are achieved 1 to 2 hours after oral administration. The relatively long half-life of terazosin (12 hours) enables it to be administered in a once-a-day regimen. Dose and plasma levels of terazosin show a linear relationship. Terazosin is rapidly and completely absorbed after oral administration. The pharmacokinetics of terazosin are not significantly affected by food, age, hypertension, or renal impairment. Adverse events after the administration of terazosin are usually minor and not age related. The incidence of syncope after therapeutic dosages of terazosin is minimal. Terazosin's effectiveness, combined with its pharmacokinetics, safety profile, and potentially favorable lipid effect, makes it a highly appropriate choice for antihypertensive therapy.

Adrenergic alpha-Antagonists↗
PubMed1990

Efficacy of terazosin in the treatment of essential hypertension in blacks.

The antihypertensive effects of the selective alpha 1-adrenoceptor antagonist, terazosin, in black patients with uncomplicated, mild to moderate essential hypertension were examined retrospectively in seven randomized, double-blind, placebo-controlled trials conducted in the United States. Following 4 to 13 weeks of treatment with terazosin (2-40 mg, once daily), supine and standing systolic and diastolic blood pressures were decreased significantly from baseline, and these decreases were significantly greater than those observed in the placebo group (P less than 0.05). Blood pressure changes in the black and white patient subgroups were comparable. Terazosin was generally well tolerated with a low incidence of serious side effects. We conclude that terazosin is a safe and effective antihypertensive agent in black patients with essential hypertension.

Adolescent↗
PubMed1990

Effects of terazosin on serum lipid levels in hypertensive blacks.

The effects of terazosin, a new, selective, alpha 1-adrenoceptor antagonist, on the serum lipid levels were examined in 103 black patients with uncomplicated, mild to moderate essential hypertension in six randomized, double-blind, placebo-controlled trials conducted in the United States. Terazosin produced statistically significant (P less than 0.05) reductions in total serum cholesterol and triglyceride levels and a marginally significant (P = 0.080) reduction in the combined low-density lipoprotein (LDL-C) and very-low-density lipoprotein (VLDL-C) cholesterol fraction when compared with placebo. We conclude that terazosin, unlike thiazide diuretics, has a favourable effect on the serum lipid profiles of hypertensive blacks.

Adolescent↗
PubMed1989

Phenytoin prodrug 3-phosphoryloxymethyl phenytoin (ACC-9653): pharmacokinetics in patients following intravenous and intramuscular administration.

A phenytoin prodrug, 3-phosphoryloxymethyl phenytoin (ACC-9653; 1), has been developed with more favorable physicochemical properties than phenytoin for parenteral administration. The purpose of this study was to evaluate the pharmacokinetic profile of 1 following iv and im administration in adult patients receiving chronic oral phenytoin monotherapy. Each patient (9 males, 1 female) received a single iv dose of undiluted 1 equivalent to their twice daily phenytoin dose (100-200 mg). An equivalent dose of im 1 was administered in the gluteus maximus muscle one week later. Serial blood samples were obtained after each dose. Phenytoin and 1 concentrations were measured using HPLC. Compartmental analysis using weighted nonlinear least squares, and noncompartmental pharmacokinetic analysis were performed on each patient's concentration-time data. Data following iv 1 in eight of ten patients were best described using a two-compartment model. Mean pharmacokinetic parameter estimates for iv 1 in these patients were central volume of distribution (Vdc) of 0.040 +/- 0.0084 L/kg and plasma disappearance half-life (t1/2 alpha) of 8.0 +/- 2.9 min ("conversion" t1/2). Overall mean clearance (CL) was 0.24 +/- 0.080 L/kg/h in the 10 patients. Mean pharmacokinetic parameter estimates for im 1 were a rate constant (ka) of 2.47 +/- 1.41 h-1 and an absolute bioavailability (F) of 100.5 +/- 20.3%. Mean observed tmax values for phenytoin were 0.57 +/- 0.26 and 1.46 +/- 0.76 h following iv and im 1, respectively. Model-independent estimates of clearance agreed well with the compartmental analyses. Steady-state predose phenytoin concentrations did not significantly vary from the comparable concentrations following iv 1 administration (p = 0.22).(ABSTRACT TRUNCATED AT 250 WORDS)

Chromatography, High Pressure Liquid↗
PubMed1988

Determination of a novel antiarrhythmic agent ACC-9358 in human plasma by high-performance liquid chromatography.

A liquid chromatographic method for the determination of ACC-9358, an antiarrhythmic agent, in human plasma is described. ACC-9358 was extracted from plasma into chloroform and back extracted into 0.01 N hydrochloric acid. ACC-9358 in the acidic extract was eluted from a Novapak C18 column using a 87:13:0.1 (by volume) mixture of phosphate buffer (pH 3.0), acetonitrile, and triethylamine as the mobile phase and measured at 280 nm. The average extraction recoveries were 78.4 and 85.4% at the 0.5- and 5-micrograms/ml level, respectively. Standard curves were linear and reproducible over the concentration range of 0.01-10 micrograms/ml, with coefficients of determination better than 0.999. Coefficients of variation for both within-day and day-to-day analysis were less than 11%. The assay method is sensitive, reproducible, and suitable for disposition studies of ACC-9358 in humans.

Anti-Arrhythmia Agents↗
PubMed1987

Esmolol-digoxin drug interaction.

An open-label baseline-controlled study was conducted in 11 healthy male subjects to study the possible interaction between the cardioselective, short-acting beta blocker esmolol and digoxin when administered concurrently under steady-state conditions. Steady-state concentration, elimination half-life, and the total body clearance of esmolol were not changed significantly (P greater than .05) by digoxin. Digoxin peak concentration and the time to reach the peak concentration were not affected by esmolol. However, the digoxin AUC during the six-hour esmolol infusion increased from 2.60 +/- 0.59 to 2.88 +/- 0.75 ng.hr/mL (P less than .05). There were no clinically significant changes in the heart rate and blood pressure during this drug interaction study. The PR intervals were similar between digoxin monotherapy and esmolol plus digoxin combined treatment. Although digoxin did not influence the kinetics of esmolol, the small increase seen in digoxin serum concentration during the combination therapy warrants that caution be exercised during concurrent administration of esmolol and digoxin to patients.

Adolescent↗
PubMed1987

Pharmacokinetics of esmolol in hepatic disease.

Esmolol is an intravenous beta blocker with a short duration of action. The pharmacokinetics of esmolol and its acid metabolite, ASL-8123, were studied in nine patients who had stable, biopsy-proved Laennec's cirrhosis and in three normal volunteer controls. Kinetics were determined after a four-hour continuous infusion of esmolol at a rate of 200 micrograms/kg/min. Blood samples were collected during the infusions and at frequent intervals thereafter. The parameters studied were the steady state concentration, the total body clearance, the elimination half-life, the area under the curve, and the volume of distribution. No significant differences in any of these parameters were detected between control subjects and those with hepatic disease, for either esmolol or its acid metabolite. It is concluded from this study that Laennec's cirrhosis does not cause any change in the pharmacokinetics of esmolol or its major metabolite. Therefore, adjustments in dosage of esmolol are not required for patients with Laennec's cirrhosis.

Adult↗
PubMed1987

Pharmacokinetics and pharmacodynamics of flestolol, a new short-acting, beta-adrenergic receptor antagonist.

The pharmacokinetics and pharmacodynamics of flestolol, a new short-acting, beta-adrenergic receptor antagonist, were examined in nine healthy subjects after a constant intravenous infusion of 5 micrograms/kg/min for 72 hours. Flestolol blood levels were determined by high-performance liquid chromatography. In all subjects, flestolol blood concentration attained steady state 30 minutes after initiation of infusion. The mean +/- standard deviation steady-state concentration of flestolol was 31.1 +/- 12.0 ng/mL. The elimination half-life averaged 7.2 minutes. The mean +/- standard deviation total body clearance was 181 +/- 66 mL/min/kg. The apparent volume of distribution and the area under the curve averaged 1.89 L/kg and 2.23 micrograms-hr/mL, respectively. Flestolol did not cause any significant change (P greater than .05) in the heart rate or systolic or diastolic blood pressure from the baseline. Flestolol significantly (P less than .05) attenuated the isoproterenol-induced increase in heart rate and systolic blood pressure and decrease in diastolic blood pressure in comparison with baseline. The average maximum reduction in isoproterenol tachycardia was in the range of 63% to 79% during flestolol infusion. There was a rapid recovery from beta blockade after termination of flestolol infusion; the recovery averaged 96% 20 minutes after the infusion was stopped. We conclude that flestolol exhibits a very short half-life and is cleared mainly by extrahepatic routes. It is an effective beta blocker and possesses a short duration of action.

Adrenergic beta-Antagonists↗
PubMed1986

Metabolism and urinary excretion of esmolol in humans.

The urinary excretion patterns of esmolol, a short-acting beta blocker, and its major metabolite were investigated in eight healthy men after intravenous infusion of 50, 100, 200, and 300 micrograms/kg/min of esmolol for six hours and 150 micrograms/kg/min for 24 hours. Esmolol and the metabolite concentrations in urine were determined by high-performance liquid chromatography. The mean urinary recoveries of the unchanged drug were 0.64%, 0.67%, 0.69%, 0.77%, and 0.98% after the 50, 100, 150, 200, and 300 micrograms/kg/min dose, respectively. Recovery of the metabolite was independent of dose, and the overall mean recovery accounted for 73% of administered dose. The results of this study indicate that esmolol is extensively metabolized, and the extent of the metabolism is not dose related in the dosage range used. The renal route plays a very minor role in the elimination of the drug but is important for the elimination of the metabolite.

Adrenergic beta-Antagonists↗
PubMed1986

Tolerance and beta-adrenergic blocking activity of flestolol, a short-acting beta blocker.

The tolerance and beta-adrenergic blocking activity of flestolol, a short-acting beta-blocker, was investigated in 30 subjects. Flestolol infused intravenously at doses up to 100 micrograms/kg/min was found to be well tolerated. A dose-dependent attenuation of isoproterenol-induced tachycardia and increase in systolic blood pressure occurred with flestolol at doses ranging from 0.5 to 15.0 micrograms/kg/min. The average percent reduction in isoproterenol-induced tachycardia (beta-blockade) at each dose of flestolol, 0.5, 2.5, 5.0, 15.0, and 50.0 micrograms/kg/min, was 15.1%, 45.9%, 67.0%, 85.9%, and 90.3%, respectively. The onset of beta-blockade occurred within 30 minutes. After the end of flestolol infusion there was a marked reduction in beta-blockade within 6 minutes, with complete recovery from beta-blockade within 30 to 45 minutes. There was a statistically significant (P less than 0.01) positive correlation between flestolol dosage and its blood levels (r = 0.91) as well as between the flestolol-induced beta-blockade and its dosage (r = 0.62).

Adult↗
PubMed1986

Liquid-chromatographic analysis for esmolol and its major metabolite in urine.

We describe a simple, reproducible liquid-chromatographic method for determination of esmolol (a short-acting beta blocker) and its major metabolite in human urine. Esmolol is extracted from urine at a pH of 8.4 into methylene chloride; the more polar metabolite remains in the aqueous phase. We then measure esmolol with a muBondapak C18 column and measure ultraviolet absorbance at 229 nm; the metabolite is analyzed with a Spherisorb phenyl column, with absorbance measured at 280 nm. The average extraction recoveries of esmolol and the metabolite were 95 and 92%, respectively. Standard curves were linear and reproducible for esmolol from 0.025 to 5 mg/L and for the metabolite from 1 to 250 mg/L. Within-day CVs for both compounds were less than 6%.

Chromatography, High Pressure Liquid↗