Nader S. Jallad

Pharmacokinetics of Single‐Dose Oral and Intramuscular Ketorolac Tromethamine in the Young and Elderly

The elderly are likely candidates to receive analgesics for pain from a variety of etiologies. Ketorolac tromethamine is a nonsteroidal, analgesic, anti‐inflammatory, antipyretic investigational drug with anti‐prostaglandin synthetase activity. Sixteen healthy, young men (mean age 30 years and mean weight 75 kg) and 13 healthy, elderly subjects (11 men and two women; mean age 72 years and mean weight 75 kg) participated in an open‐label, parallel single‐dose study. On each day of ketorolac tromethamine administration the subjects fasted overnight and for 2 hours post‐dose. A single intramuscular (IM) dose of 30 mg of ketorolac tromethamine was administered followed by an oral dose (PO) of 10 mg after a 1 week washout period for the elderly subjects. Plasma samples were taken from 0 through 48 hours post‐dose and analyzed for ketorolac by HPLC. The elimination of ketorolac was decreased slightly in the elderly following both doses, as evidenced by a prolongation in half‐life (4.7 to 6.1 hours for PO and 4.5 to 7.0 hours for IM) and a reduced total plasma clearance compared to the young adult subjects. These differences were statistically significant (P < .001). Considerable overlap frequently was observed when comparing the range of values obtained for the young and elderly for plasma half‐life, clearance, AUC, Tmax and Cmax. The absorption of ketorolac tromethamine was not altered substantially in the elderly following either dose route. Ketorolac plasma protein binding was not altered substantially in the elderly. The present results show that the elderly may need slightly less frequent dosing of ketorolac than young adults to maintain similar plasma levels. In these studies there has been no evidence of drug accumulation in the elderly after long‐term ketorolac tromethamine administration when given in a tid or qid regimen.

Pharmacokinetics of ranitidine in patients with renal failure

The pharmacokinetics of ranitidine were studied in ten patients with renal failure (creatinine clearance, 6–54 mL/min) after intravenous (IV) (50 mg) and oral doses (150 mg). After oral administration, peak plasma concentrations of 378–808 ng/mL were obtained in two to six hours. Plasma concentrations declined very slowly and concentrations greater than 100 ng/mL were obtained for 16 to 20 hours after the dose. The elimination half‐life following oral administration was 8.5 ± 2.8 hours (standard deviation [SD]), and the bioavailability of ranitidine was 43.3% ± 10.5%. After IV administration, the elimination half‐life, plasma clearance, renal clearance, and volume of distribution were 7.0 ± 1.0 hours, 170 ± 38 mL/min, 36.0 ± 25.0 mL/min, and 1.3 ± 0.4 L/kg, respectively. About 20% of the IV dose and 9% of the oral dose were recovered unchanged in urine. There was a significant correlation between the renal clearance of ranitidine and creatinine clearance (r = .74, P < .05) after IV administration. The elimination half‐life in patients with renal insufficiency is about three times greater than that reported in the literature for healthy subjects. Similarly, the plasma clearance in these patients is about 20% of that reported in healthy subjects. The results indicate that ranitidine elimination is appreciably reduced in renal failure and that an adjustment of dose in patients with renal failure is warranted. A dose of 75 mg bid may be adequate in maintaining the therapeutic plasma concentrations that are required for adequate H2‐blocking activity.

Gastrointestinal blood loss in arthritic patients receiving chronic dosing with etodolac and piroxicam.

Etodolac, a new anti-inflammatory analgesic drug found to be effective in treating arthritis in a dose range of 100 to 300 mg bid, has been shown to induce significantly less gastrointestinal microbleeding in normal men than several other NSAIDs. In this study, the effect on gastrointestinal blood loss of highdose etodolac, 300 and 500 mg bid, versus piroxicam at its normal therapeutic dose of 20 mg qd, was investigated by the 51Cr method in 23 men with osteo- or rheumatoid arthritis. Placebo periods preceded and followed 28 days of active drug treatment. Blood and stool analyses were performed by an analyst not aware of drug assigment or study design. Patients receiving piroxicam, but not those receiving either dose of etodolac, had a significantly higher mean level of fecal blood loss in the active treatment phase compared with the pretreatment placebo level (p < 0.01). Further, microbleeding was significantly greater for the piroxicam group during treatment than for either of the etodolac groups (p < 0.01). There were no significant differences in fecal blood loss between the two groups receiving etodolac compared with pretreatment. Even at doses two to three times those found effective in the treatment of arthritis, etodolac produces no increase in fecal blood loss, in contrast to blood loss seen with the recommended dose of piroxicam. Fecal blood loss in osteoarthritic patients, not receiving an NSAID, was similar to normal subjects in previous studies.

Pharmacokinetics of Ranitidine after Intravenous Administration in Hemodialysis Patients

The pharmacokinetics of ranitidine and its removal by hemodialysis were determined in 9 patients with chronic renal failure requiring hemodialysis. Ranitidine (50 mg) was administered as an intravenous bolus at the beginning of the dialysis procedure, which lasted for 4 h. The elimination half-life, plasma clearance and volume of distribution (VD area) of ranitidine in these patients were 9.0 +/- 2.6 h (mean +/- SD), 305 +/- 152 ml/min and 3.5 +/- 1.9 liters/kg, respectively. About 8% of the administered dose was removed during a single dialysis procedure. The elimination of ranitidine is appreciably reduced in these patients. These results suggest that the dose of ranitidine should be adjusted in patients with severe renal failure who are undergoing hemodialysis, and a suitable schedule for dosing such patients is suggested.

Pharmacokinetics and pharmacodynamics of long-acting propranolol 60-mg capsules: a comparative evaluation.

This double‐blind, placebo‐controlled, four‐period cross‐over study was undertaken to evaluate the sustained‐release characteristics of long‐acting propranolol hydrochloride (Inderal LA, Ayerst Laboratories, New York, NY) 60 mg qd, to compare the pharmacokinetic and pharmacodynamic properties of this formulation with conventional propranolol 20 mg tid, and to evaluate the proportionality of long‐acting propranolol 60 mg (LA 60 mg) and long‐acting propranolol 80 mg (LA 80 mg). Pharmacodynamic effects were evaluated in 34 healthy subjects by assessing heart rate, systolic blood pressure, and the product of heart rate and systolic blood pressure (double product) after exercise‐induced tachycardia following both acute (day 1) and steady state (day 4) drug administration. The Cmax following administration of LA 60 mg was 9.5 and 11.4 ng/mL on days 1 and 4, respectively, compared with 18.8 and 20.0 ng/mL with 20 mg tid (P < .0001). The tmax for LA 60 mg was significantly later (P < .0001) than for conventional propranolol. Additionally, the apparent plasma half‐life was significantly longer (P < .0001) than with conventional propranolol. The LA 60‐mg formulation was dose proportional to the LA 80‐mg formulation. Pharmacodynamic evaluations showed no significant differences between LA 60 mg and 20 mg tid at any times tested with either acute or steady state dosing. This study demonstrates that LA 60 mg displays characteristics of a sustained‐release formulation, is proportional with LA 80 mg, and produces pharmacodynamic effects that are similar to 20‐mg tid dosing.

Efficacy and pharmacokinetics of oral pirmenol, a new antiarrhythmic drug

Pirmenol is a new orally effective antiarrhythmic agent. Reported are the results of oral administration of pirmenol to six patients (age 48.5 ± 8.6 years, weight 83 ± 15 kg) with stable ventricular extrasystoles (PVCs)—average ectopy rate 1040 ± 630/hr (mean ± SD). Patients received oral doses of placebo or 200 mg of pirmenol in a double‐blind cross‐over fashion followed by a single‐blind rising‐dose administration of 250 mg and 300 mg of pirmenol. The time period between doses was 48 hours. Pirmenol was rapidly absorbed (time to peak plasma levels 1 to 1.5 hours) and the mean maximum plasma concentrations were 1.8, 2.7 and 3.4 μg/mL with 200‐mg, 250‐mg and 300‐mg doses, respectively. The elimination half‐life was 9.3 ± 3.0 hours and 31 ± 14% of the dose was recovered in urine. The response criterion (80% suppresion of PVCs of control for 8 hours) was met after the 300‐mg dose in three patients. In three patients >80% reduction occurred for up to 8 hours after the 200‐mg dose. Pirmenol administration was not associated with any significant changes in blood pressure, heart rate, hepatic and renal function, PR interval or QRS duration. LV ejection fraction determined echocardiographically decreased from 63.0 ± 6.9% predose to 59.7 ± 5.0% about 2 hours after the 300‐mg dose and QT interval increased by <10%. Two patients complained of transient bad taste sensation. Our results suggest that 250 mg to 300 mg of pirmenol, administered twice a day will suppress the PVCs effectively.

Comparative Pharmacodynamics and Pharmacokinetics of Conventional and Long-Acting Propranolol

This investigation was conducted to compare the pharmacokinetic and pharmacodynamic effects of single and multiple doses of conventional propranolol and long‐acting propranolol in healthy human volunteers. Two double‐blind, randomized, double‐crossover, Latin square studies were carried out. One study evaluated long‐acting propranolol 160 mg/d, conventional propranolol 40 mg qid, or placebo for seven days in 24 men. The other study compared long‐acting propranolol 80 mg/d, conventional propranolol 20 mg qid, or placebo for seven days in 27 men. At specific times after the administration, blood samples were obtained, and heart rate and blood pressure were measured; exercise tests were done both on the first day and at steady state (day 7). In both studies, the area under the plasma propranolol concentration‐time curve and the peak concentration were significantly less (P < .0001) after the administration of long‐acting propranolol compared with conventional propranolol on both day 1 and day 7; in addition, the elimination half‐life was longer after administration of the long‐acting preparation (9 hr) compared with that following the conventional dosage form (4 hr). Both conventional and long‐acting propranolol significantly decreased the exercise heart rate at each of the selected time points (P < .05) compared with placebo. Reduction in exercise heart rate was greater with conventional propranolol than with the long‐acting formulation, but the differences were not statistically significant, when exercise was performed only at trough levels of the conventional drug. The decreases in exercise heart rate were correlated with plasma propranolol concentrations.

Efficacious Response with Lower Dose Indapamide Therapy in the Treatment of Elderly Patients with Mild to Moderate Hypertension

A low dose (1.25 mg) of indapamide (Lozol®, Rhône‐Poulenc Rorer Pharmaceuticals, Collegeville, PA) was evaluated in 222 elderly patients (≥50 years) with mild to moderate essential hypertension in a multicenter, randomized, double‐blind, parallel‐group clinical trial. A 4‐week single‐blind placebo washout period was followed by an 8‐week double‐blind treatment period. Patients were randomized to receive indapamide 1.25 mg/day or to receive placebo. The primary efficacy variable was the mean change in sitting diastolic blood pressure from baseline to week 8. Eighty‐one patients in the indapamide group (73%) and 87 patients in the placebo group (78%) completed the 8 weeks of double‐blind therapy. Therapy with 1.25 mg of indapamide produced greater reductions compared with placebo in sitting diastolic blood pressure after 8 weeks of therapy, with statistical significance (P ≤ 0.0015) seen after only 2 weeks of therapy and continuing throughout the 8 weeks. All secondary efficacy measures (sitting systolic blood pressure, standing systolic and diastolic blood pressures, and ≥ 10 mm Hg decrease or final value of ≤ 90 mm Hg in sitting diastolic blood pressure) also showed superior (P ≤ 0.0014) improvement in the indapamide group compared with placebo after 8 weeks of double‐blind treatment. During the 8‐week double‐blind treatment period, incidence rates for all adverse events and for drug‐related adverse events were similar between the two treatment groups. Among patients who received indapamide, the only drug‐related adverse events that occurred with an incidence of ≥ 2% were headache (4%), dizziness (4%), asthenia (2%), pain (2%), abnormal vision (2%), and impotence (2%). Similar incidence rates for these adverse events were seen in the placebo group. Among indapamide patients, mean changes in potassium (–0.27 mEq/L), uric acid (0.76 mg/dL), and BUN (1.42 mg/dL) were noted but not clinically significant.

Dose-Response Relationship of Single Oral Doses of Guanabenz in Hypertensive Patients

A single-blind, placebo-controlled study was conducted to determine the dose-response relationship of guanabenz, administered as single oral doses to patients with mild or moderate hypertension. Twelve hypertensive patients received ascending oral doses of 2, 4, 8, 16, 24, and 32 mg of guanabenz. Dose-response relationships were evaluated for the nine patients who received placebo and all six guanabenz doses. The greatest maximum response (40/24 mm Hg) was seen for the 16 mg guanabenz dose. Since eight of the nine patients had mild hypertension, they may have responded maximally to the lower guanabenz doses, precluding larger decreases with the 24 and 32 mg doses. The mean onset of satisfactory blood pressure reduction decreased from 4 to 2 h and the mean duration increased from 6 to 22 h as the oral dose was increased from 2 to 32 mg. In eight patients, the responses to 16 mg of guanabenz administered sublingually and orally were compared. The sublingual and oral routes produced similar mean (20/13 mm Hg) and maximum (33/24 mm Hg) blood pressure decreases as well as mean onset (2 h) and duration (16.5 h) of satisfactory response. Additional studies involving patients with more severe hypertension are needed to further characterize the dose-response relationship of oral guanabenz and to establish a dose-response relationship for sublingual guanabenz.

Alteration of Pharmacokinetic Parameters for Pentobarbital by Ischemic Stroke and Reversion to Normal by Dexamethasone Treatment

The values of the pharmacokinetic parameters for pentobarbital were determined in 18 cats, 12 of which were subjected to acute ischemic stroke by ligation of the left middle cerebral artery (LMCA). All 18 ats received 50 mg/kg sodium pentobarbital during operation. The following three experimental groups were formed: control (sham-operated); ischemic stroke plus administration of 4 mg/kg dexamethasone; and ischemic stroke without dexamethasone administration. Ischemic stroke significantly prolonged the plasma half-life of pentobarbital, but concurrent administration of dexamethasone prevented this effect. Ischemic stroke significantly reduced the plasma clearance of pentobarbital, but dexamethasone prevented this reduction. Ischemic stroke significantly increased the area under the plasma pentobarbital concentration-time curve, but dexamethasone prevented this increase. Ischemic stroke significantly reduced the volume of distribution, but dexamethasone did not prevent this reduction. The alterations of the value of these pharmacokinetic parameters for pentobarbital by ischemic stroke and reversion to normal by dexamethasone treatment are discussed in the light of certain known circulatory changes which occur secondary to ischemic stroke and dexamethasone treatment.