ABSTRACT
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 micrograms/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% suppression of PVCs of control for 8 hours) was met after the 300-mg dose in three patients. In three patients greater than 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 less than 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.
Subject(s)
Anti-Arrhythmia Agents/therapeutic use , Cardiac Complexes, Premature/drug therapy , Piperidines/therapeutic use , Administration, Oral , Anti-Arrhythmia Agents/administration & dosage , Anti-Arrhythmia Agents/pharmacokinetics , Blood Pressure/drug effects , Cardiac Complexes, Premature/physiopathology , Chromatography, High Pressure Liquid , Clinical Trials as Topic , Double-Blind Method , Female , Heart Conduction System/drug effects , Heart Rate/drug effects , Humans , Male , Middle Aged , Piperidines/administration & dosage , Piperidines/pharmacokinetics , Random AllocationABSTRACT
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 less than .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.(ABSTRACT TRUNCATED AT 250 WORDS)
Subject(s)
Tolmetin/analogs & derivatives , Tromethamine/pharmacokinetics , Administration, Oral , Adult , Aged , Aging/metabolism , Blood Proteins/metabolism , Drug Combinations/administration & dosage , Drug Combinations/pharmacokinetics , Female , Half-Life , Humans , Injections, Intramuscular , Ketorolac Tromethamine , Male , Protein Binding , Tolmetin/administration & dosage , Tolmetin/pharmacokinetics , Tromethamine/administration & dosageABSTRACT
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.
Subject(s)
Cerebrovascular Disorders/metabolism , Dexamethasone/pharmacology , Pentobarbital/metabolism , Animals , Blood Pressure/drug effects , Cats , Cerebrovascular Disorders/drug therapy , Kinetics , Metabolic Clearance RateABSTRACT
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 less than .0001). The tmax for LA 60 mg was significantly later (P less than .0001) than for conventional propranolol. Additionally, the apparent plasma half-life was significantly longer (P less than .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.
Subject(s)
Propranolol/pharmacokinetics , Administration, Oral , Adolescent , Adult , Biological Availability , Blood Pressure/drug effects , Delayed-Action Preparations , Double-Blind Method , Heart Rate/drug effects , Humans , Male , Physical Exertion , Propranolol/bloodABSTRACT
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 less than .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 less than .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.
Subject(s)
Propranolol/pharmacology , Adolescent , Adult , Blood Pressure/drug effects , Delayed-Action Preparations , Double-Blind Method , Heart Rate/drug effects , Humans , Male , Physical Exertion , Propranolol/administration & dosage , Propranolol/pharmacokinetics , Random AllocationABSTRACT
A low dose (1.25 mg) of indapamide (Lozol, Rhône-Poulenc Rorer Pharmaceuticals, Collegeville, PA) was evaluated in 222 elderly patients (> or = 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 < or = 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 > or = 10 mm Hg decrease or final value of < or = 90 mm Hg in sitting diastolic blood pressure) also showed superior (P < or = 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.(ABSTRACT TRUNCATED AT 250 WORDS)
Subject(s)
Hypertension/drug therapy , Indapamide/administration & dosage , Aged , Aged, 80 and over , Blood Pressure/drug effects , Double-Blind Method , Female , Humans , Indapamide/adverse effects , Indapamide/therapeutic use , Male , Middle Aged , Single-Blind MethodABSTRACT
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 less than .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.
Subject(s)
Kidney Failure, Chronic/blood , Ranitidine/blood , Aged , Biological Availability , Blood Urea Nitrogen , Creatinine/blood , Half-Life , Humans , Infusions, Parenteral , Kinetics , Male , Metabolic Clearance Rate , Middle AgedABSTRACT
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 high-dose 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 assignment 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 less than 0.01). Further, microbleeding was significantly greater for the piroxicam group during treatment than for either of the etodolac groups (p less than 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.
Subject(s)
Acetates/adverse effects , Anti-Inflammatory Agents, Non-Steroidal/adverse effects , Arthritis, Rheumatoid/drug therapy , Gastrointestinal Hemorrhage/chemically induced , Osteoarthritis/drug therapy , Piroxicam/adverse effects , Adult , Aged , Dose-Response Relationship, Drug , Etodolac , Gastrointestinal Hemorrhage/diagnosis , Humans , Male , Middle Aged , Occult BloodABSTRACT
The discipline of Clinical Pharmacology serves many purposes and plays a critical role in therapeutic education, especially in a medical school. An effective program bridges the gap between basic pharmacology and clinical practice. A clinical pharmacology program must provide the student with the necessary information to employ the basic pharmacology knowledge gained in formatting a successful therapeutic plan. The program is built around the student and brings together the best to be offered in 2 or more disciplines; it requires diverse disciplines to work together in a variety of departments and centers which cut across disciplinary lines. In order to facilitate this interaction, the Division of Clinical Pharmacology at the University of Miami embarked on establishing a Ph.D. program with an emphasis on Clinical Pharmacology utilizing an already established unique program referred to as "Interdepartmental Graduate Studies". To enter the structured Ph.D. program the students must be among the fellowship awardees of the Interdepartment Graduate Studies Program, which is administered by social committees with specific roles, directions and guidelines. The students follow the general requirements of the Ph.D. degree set forth by the graduate school. Students attend formal classes tailored to their program of interest based on the committee's recommendations in the respective departments involved. The significance of this program is that it can be tailored to fit individual areas of interest leading to a well-developed researcher who is neither overspecialized nor undereducated and able to make rational decisions in an age of multiple therapies.
Subject(s)
Curriculum , Pharmacology, Clinical/education , Academic Dissertations as Topic , Fellowships and Scholarships , Financing, Organized , Florida , Humans , Interdepartmental Relations , Pharmacology, Clinical/economics , TherapeuticsABSTRACT
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.
Subject(s)
Guanabenz/therapeutic use , Guanidines/therapeutic use , Hypertension/drug therapy , Administration, Oral , Adult , Aged , Blood Pressure/drug effects , Dose-Response Relationship, Drug , Female , Guanabenz/administration & dosage , Guanabenz/adverse effects , Humans , Male , Middle Aged , Pulse/drug effectsABSTRACT
Indomethacin, a nonsteroidal anti-inflammatory drug, may cause gastric mucosal damage as shown by fecal blood loss. A randomized, double-blind, placebo-controlled, parallel group study was conducted to determine the effects of 400 mcg b.i.d. misoprostol, a synthetic prostaglandin E1 analog, on intestinal blood loss caused by 50 mg t.i.d. indomethacin. Forty-two arthritic patients, mean age 59 years, received indomethacin for 14 days. Those with baseline blood loss of at least 1.5 ml/day during the first 7 days were randomized to 400 mcg of misoprostol or placebo (days 8 to 14). Fecal blood loss was measured using 51Cr labelled red blood cell technique. Success was defined as a reduction in mean daily blood loss of at least 50% during the treatment period compared to mean daily blood loss during the baseline (pre-treatment) phase. The mean daily blood loss on treatment days 9-15 was not significantly reduced from baseline in either group. These data neither confirm nor deny the effectiveness of misoprostol in reducing fecal blood loss caused by indomethacin. The results may have been confounded by the administration of misoprostol twice daily while indomethacin was administered three times daily. In addition, fecal blood loss as an indicator of gastrointestinal mucosal damage is not a sensitive measure; it is characterized by poor reproducibility and wide fluctuations within individual responses. Inappropriate laboratory techniques may have further reduced the sensitivity and reliability of this procedure.
Subject(s)
Arthritis, Rheumatoid/drug therapy , Gastrointestinal Hemorrhage/prevention & control , Indomethacin/adverse effects , Misoprostol/therapeutic use , Osteoarthritis/drug therapy , Double-Blind Method , Female , Gastrointestinal Hemorrhage/chemically induced , Humans , Indomethacin/therapeutic use , Male , Middle Aged , Misoprostol/adverse effects , Occult Blood , Treatment OutcomeABSTRACT
The antihypertensive effect of doxazosin 1-16 mg once-daily was compared with that of atenolol 50-100 mg once-daily, and placebo, utilizing a double-blind parallel group (12 patients each) design. Blood pressure (BP) and pulse rate were determined in out-patients who returned for clinic visits every 2 weeks for 14 weeks. During the first 4 weeks, all patients received single-blind placebo therapy. During the subsequent 10 weeks, patients were randomized to placebo, atenolol or doxazosin treatment. After 2 weeks of doxazosin therapy 16 mg daily, there was a significant decrease from baseline (single-blind placebo period) in supine diastolic BP (P less than 0.01) and standing diastolic BP (P less than 0.001). The decreases in supine and standing diastolic BPs in the doxazosin 16 mg daily group were significantly (P less than 0.01) different from the corresponding BPs of the placebo group. At weeks 12 and 14, heart rates in the doxazosin group were not significantly different from baseline or from those in the placebo group. After 4 and 6 weeks of atenolol 100 mg daily, there was a significant decrease from baseline in both supine (P less than 0.001 and P less than 0.05) and standing (P less than 0.05) diastolic BPs and heart rates (P less than 0.05). However, when the atenolol group was compared with the placebo group, a significant decrease occurred only with supine diastolic BP at week 12 (P less than 0.01) and not at week 14; but significant decreases occurred in supine and standing heart rates at weeks 12 and 14 (P less than 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)
Subject(s)
Antihypertensive Agents/therapeutic use , Atenolol/therapeutic use , Hypertension/drug therapy , Prazosin/analogs & derivatives , Adult , Aged , Antihypertensive Agents/adverse effects , Blood Pressure/drug effects , Clinical Trials as Topic , Double-Blind Method , Doxazosin , Female , Heart Rate/drug effects , Humans , Hypertension/physiopathology , Male , Middle Aged , Prazosin/adverse effects , Prazosin/therapeutic use , Random AllocationABSTRACT
Digoxin doses of 14.3, 5.72 or 1.43 mcg/kg were administered to 8 cats and the plasma digoxin concentrations (concns) were measured as a function of time for 96 hr. Pharmacokinetic linearity was evidenced by: (1) mean plasma clearance (Clp) of 4.05 ml/(kg x min) with a coefficient of variation of 34.6% and a range of 2.69-6.71; (2) linear relationship between total area under the plasma concn-time curve and the administered dose. Further evidence for linearity was the lack of dose-dependence of apparent elimination half-life (beta). The volume of distribution and beta for cats were respectively (mean +/- s.d.) 20.4 +/- 5.35 L/kg and 0.0120 +/- 0.0030 hr-1. Results from cats were compared with literature data for dogs and man. The order of Clp in units of ml/(kg x min) were: infant greater than dog greater than cat greater than adult man.
Subject(s)
Digoxin/blood , Adult , Animals , Cats , Dogs , Humans , Infant , Kinetics , Species SpecificityABSTRACT
The aims of this study were to describe the pharmacokinetics of propranolol in the cat, to compare pharmacokinetic parameters for propranolol in the cat with those of four other species and to apply the two-step infusion method of Wagner (Clin. Pharmacol. Ther. 16, 691-700, 1974) in order to attain a rapid steady-state level for propranolol in plasma. Seven healthy adult cats received propranolol either as an I.V. bolus or by the two-step I.V. infusion method. The latter method was very effective in rapidly attaining and maintaining steady-state plasma propranolol levels. Pharmacokinetic parameters for propranolol in the cat are as follows: plasma clearance, 31.3 ml/(kg x min); volume of distribution, 1.57 L/kg; elimination half-life, 35 min. When compared with other species, the order of plasma clearances for propranolol were: rat greater than dog greater than cat greater than man greater than monkey. A plot of total area under the plasma propranolol concentration-time curve versus dose was not linear at the lower doses, but was linear at doses greater than 0.242 mg/kg.
Subject(s)
Propranolol/metabolism , Animals , Cats , Dogs , Haplorhini , Humans , Kinetics , Propranolol/blood , Rats , Species Specificity , Time FactorsABSTRACT
1. The disposition of nalmefene was evaluated in young and elderly normal healthy volunteers. Subjects received either a single 1 mg (n = 18 young; n = 11 elderly) or 2 mg (n = 8 young; n = 15 elderly) intravenous bolus dose of nalmefene. 2. Following the administration of nalmefene, the initial plasma concentrations were significantly higher in elderly vs young subjects. The higher concentrations were the result of the 30 to 40% smaller central compartment apparent volume of distribution that was observed in the elderly subjects as compared with the young volunteers (2.8 +/- 1.1 vs 3.9 +/- 1.11 kg-1 for 1 mg dose). The elderly volunteers also had a significantly shorter distributional half-life (t1/2 lambda 1) than young volunteers (0.7 +/- 0.7 vs 1.3 +/- 0.8 h for 1 mg dose). No significant differences between groups were observed for the elimination half-life, clearance or steady-state apparent volume of distribution. 3. Although transiently higher nalmefene plasma concentrations were observed in the elderly immediately following drug administration, there was no association between this observation and adverse events. We conclude that no dosage alteration is warranted in elderly patients.
Subject(s)
Naltrexone/analogs & derivatives , Narcotic Antagonists/pharmacokinetics , Adult , Age Factors , Aged , Aged, 80 and over , Humans , Middle Aged , Naltrexone/pharmacokineticsABSTRACT
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.
Subject(s)
Ranitidine/metabolism , Renal Dialysis , Adult , Half-Life , Humans , Injections, Intravenous , Kidney Failure, Chronic/metabolism , Kinetics , Middle Aged , Ranitidine/administration & dosage , Ranitidine/bloodABSTRACT
24 h after ligation of the left middle cerebral artery in cats (sham operation in the control group), a constant intravenous infusion of digoxin was begun and continued to toxicity (ventricular rhythm) and death. We found that the lethal dose of digoxin was significantly less in the stroke group than in the control group, but the lethal plasma digoxin concentration was significantly greater in the stroke group than in the control group. In a subsequent study, we demonstrated that ischemic stroke caused a significant prolongation in the elimination half-life of digoxin and an increase in the volume of distribution. The mean plasma clearance of the stroke group was approximately three fourths of that of the control group. We concluded that the decreased tolerance to digoxin after ischemic stroke was due to the prolonged half-life and decreased clearance of digoxin.
Subject(s)
Digoxin/toxicity , Ischemic Attack, Transient/physiopathology , Animals , Blood Gas Analysis , Blood Pressure , Cats , Cerebrovascular Disorders/physiopathology , Digoxin/blood , Digoxin/metabolism , Electrocardiography , Hematocrit , Ischemic Attack, Transient/metabolism , KineticsABSTRACT
The efficacy of pentobarbital in the delayed treatment of acute cerebral ischemia was investigated in cats. Cerebral ischemia was produced by left middle cerebral artery (LMCA) ligation. Ten cats received 50 mg/kg of pentobarbital prior to ligation; a second group of 10 cats received the same dose of pentobarbital 2 hrs after ligation, and the control group of 7 cats received no pentobarbital. Brains were removed after spontaneous or induced death and the volume infarction was determined histologically. It was found that the volume of brain infarction in the group receiving pentobarbital 2 hrs after ligation was significantly less than that of the control group, which received no pentobarbital; but the volume of infarction in the former group was significantly greater than that found in the experimental group, which received pentobarbital prior to ligation. However, the mortality after LMCA ligation was higher in the 2 experimental groups, which received pentobarbital therapy, than in the control group, which did not receive pentobarbital. An hypothesis was advanced, which speculated that secondary adrenal insufficiency and altered cardiovascular function accounted for the increased mortality after pentobarbital treatment of patients with ischemic stroke.