Search

Prasugrel, a prodrug, is a novel and potent inhibitor of platelet aggregation in vivo. The metabolism of prasugrel and the elimination and pharmacokinetics of its active metabolite, 2-[1-[2-cyclopropyl-1-(2-fluorophenyl)-2-oxoethyl]-4-mercapto-3-piperidinylidene]acetic acid (R-138727), three inactive metabolites, and radioactivity were determined in five healthy male subjects after a single 15-mg (100 microCi) p.o. dose of [(14)C]prasugrel. Prasugrel was rapidly absorbed, and maximum plasma concentrations of radioactivity and R-138727 were achieved in 30 min, indicating rapid formation of R-138727. Prasugrel was extensively metabolized in humans, first by hydrolysis to a thiolactone, followed by ring opening to form R-138727, which was further metabolized by S-methylation and conjugation with cysteine. Total radioactivity was higher in plasma than in blood, suggesting limited penetration of prasugrel metabolites into red blood cells. Approximately 70% of the dose was excreted in the urine and 25% in the feces.

Objective To assess whether fluoxetine and its metabolite, norfluoxetine, are inhibitors of the metabolism of CYP3A substrates. Background Because inhibition of the first-pass metabolism of terfenadine may be associated with fatal arrhythmia, we assessed the possibility that fluoxetine inhibits this metabolism as a model for CYP3A drug interactions. Methods Male subjects (n = 12) were given two single doses of 60 mg terfenadine alone (treatment 1) and again after the eighth dose in a 9-day regimen of 60 mg fluoxetine once a day (treatment 2). Blood samples, collected up to 48 hours after each terfenadine dose, were assayed for terfenadine and terfenadine acid metabolite. The assay limits of quantification were 0.1 ng/ml and 5.0 ng/ml, respectively. Noncompartmental pharmacokinetic data for terfenadine and terfenadine acid metabolite were compared between treatments. Results Mean value ± SD plasma concentrations of fluoxetine (165 ± 45 ng/ml) and norfluoxetine (83 ± 23 ng/ml) achieved after the eighth dose did not cause a significant change in terfenadine acid metabolite pharmacokinetics. All terfenadine concentrations were less than 5 ng/ml and they were approximately 30% lower after fluoxetine pretreatment compared with terfenadine alone. The area under the concentration-time curve for terfenadine was lower after fluoxetine administration, a statistically significant difference, but the peak concentration of terfenadine was not significantly different. Because most antihistaminic activity after terfenadine administration is attributed to its acid metabolite, the small decrease in terfenadine concentration is not clinically significant. No subject discontinued the drugs because of an adverse event. Conclusion Fluoxetine did not inhibit the metabolism of terfenadine and is unlikely to affect the metabolism of terfenadine or other drugs that are CYP3A substrates. Clinical Pharmacology & Therapeutics (1997) 62, 643–651; doi

Objective To examine the pharmacokinetic interaction between the selective serotonin reuptake inhibitor sertraline and the tricyclic antidepressants desipramine or imipramine in 12 healthy male subjects. Methods Participants received a 50 mg single dose of either desipramine or imipramine under three conditions: alone, after a single 150 mg dose of sertraline, and after the eighth daily 150 mg dose of sertraline. Plasma samples were analyzed for desipramine or imipramine concentration by HPLC with electrochemical detection, and pharmacokinetics were determined with use of noncompartmental analysis of individual data. Results Multiple-dose, but not single-dose, treatment with sertraline significantly reduced apparent plasma clearance (CL/F) and prolonged the half-life of desipramine relative to baseline. These changes resulted in higher plasma desipramine concentrations, as indicated by a significant increase in maximum plasma concentration (Cmax) and area under the plasma concentration-time curve extrapolated to infinity [AUC(0-∞)] (22% and 54%, respectively). Both single- and multiple-dose treatment with sertraline significantly reduced the CL/F of imipramine. This effect was stronger after multiple predoses of sertraline, when imipramine Cmax and AUC(0-∞) were increased by 39% and 68%, respectively. These treatment effects were consistent between individuals. Conclusions This pharmacokinetic interaction is likely the result of an inhibition of CYP2D6 tricyclic metabolism by sertraline. When a tricyclic antidepressant, such as desipramine or imipramine, is coadministered with sertraline, lower dosages of the tricyclic agents may be necessary to prevent elevated tricyclic levels. Clinical Pharmacology & Therapeutics (1997) 62, 145–156; doi

Terfenadine is metabolized by the cytochrome P-450 3A subfamily of enzymes (CYP3A). Certain macrolide antibiotic agents inhibit CYP3A and, when coadministered with terfenadine, result in a drug interaction. The authors compared the abilities of dirithromycin (a new macrolide antibiotic agent), its major metabolite erythromycylamine, and the known CYP3A substrate terfenadine to inhibit CYP3A in vitro. The hydroxylation of midazolam in human liver microsomes was used as a probe for CYP3A activity. Dirithromycin and erythromycylamine were low affinity inhibitors of CYP3A (inhibitory binding affinities of 493 mumol/L and 701 mumol/L, respectively); conversely, terfenadine was a moderate affinity inhibitor (inhibitory binding affinity of 28 mumol/L). Based on these data, the authors tested the hypothesis that dirithromycin would not interact with terfenadine in humans. Six healthy men received terfenadine alone (60 mg twice daily) for 8 days, after which dirithromycin (500 mg once daily) was added to the terfenadine regimen for an additional 10 days. The pharmacokinetics of terfenadine (and its acid metabolite) and the QTc interval were measured during both treatments, and it was found that neither parameter was affected. In this study, dirithromycin was found to have low affinity for human CYP3A in vitro, which is in accordance with the study's finding that in vivo dirithromycin has no major effect on the metabolism of the CYP3A substrate terfenadine in humans.

The dorsal hand vein distention technique has been used to study the effects of α-adrenergic receptor antagonists on α-agonist-induced venoconstriction. Using this technique, we investigated the dose-effect relationships between different intravenous routes of phentolamine (an α-antagonist) administration on norepinephrine (an α-agonist)-induced hand vein constriction. Hand vein studies were done on healthy men ; each man was studied on up to four occasions. On one occasion for each man, graded doses of phentolamine were infused into a hand vein preconstricted (submaximally) with norepinephrine. The dose of phentolamine producing a half maximal response (ED 50 ) for reversal of venoconstriction, and the maximal reversal were calculated. On the other three occasions (randomly allocated) for each man, graded doses of norepinephrine were infused into a hand vein before and during intravenous infusions of (1) control (vehicle solutions) ; (2) systemic (other arm vein) phentolamine ; and (3) local (hand vein) phentolamine. Systemic and local phentolamine dose ratios (ED 50 of norepinephrine during phentolamine, divided by ED 50 of norepinephrine before phentolamine ; divided by the control dose ratio) were calculated. These studies show that phentolamine (administered directly into a preconstricted hand vein) can completely reverse norepinephrine-induced venoconstriction. Phentolamine, administered by either local or systemic intravenous infusion, induces a significant rightward shift (approximately 10-fold) in responsiveness to norepinephrine-induced venoconstriction. To achieve comparable degrees of α-antagonism, however, systemic phentolamine must be administered intravenously at a dose approximately 3,000-fold higher than that of local phentolamine. Implications of these dose-effect relationships, and their possible application to the treatment of norepinephrine extravasation and to hand vein studies with other receptor agonist-antagonist combinations, are discussed.

Serotonin receptor (5-HT3) antagonists provide effective antiemetic therapy in cancer patients receiving emetogenic chemotherapy, such as cisplatin. Animal studies have shown that 5-HT3 receptor antagonists also have antiemetic activity in ipecac-induced emesis. The authors investigated the antiemetic activity of zatosetron maleate, a 5-HT3 receptor antagonist, on ipecac-induced emesis in dogs and healthy men. They also evaluated the effect of ipecac administration on serotonin release and metabolism by measuring urinary 5-hydroxyindoleacetic acid (5-HIAA) excretion in healthy men. In separate randomized, placebo-controlled trials, 20 dogs received zatosetron intravenously and eight healthy men received zatosetron (50 mg) orally, followed by ipecac syrup. In both trials, emetic response to ipecac was recorded, including the number and time of vomits and retches. Zatosetron treatment inhibited and delayed ipecac-induced emesis in both groups. In dogs, zatosetron inhibited ipecac-induced emesis in a dose-dependent manner with a 100-μg/kg dose producing complete inhibition. In men, zatosetron administration resulted in fewer emetic episodes after ipecac than had occurred with placebo administration (P = .03); vomiting was completely inhibited by zatosetron. In men, ipecac administration did not affect the urinary 5-HIAA/creatinine ratio (mg/g) or 5-HIAA excretion rate (μg/hour). Our study demonstrates that zatosetron has similar efficacy on ipecac-induced emesis in healthy men, as has been shown previously with other 5-HT3 receptor antagonists in chemotherapy-induced emesis in cancer patients. We did not observe the increase of urinary 5-HIAA in our study with ipecac-induced emesis, however, as has been described previously in cisplatin-induced emesis. Our study indicates that ipecac-induced emesis may be a useful model for testing 5-HT3 receptor antagonists for antiemetic activity in dogs and healthy men.

The functions of many of today's dual-chamber pacemakers are performed using custom microprocessors that are similar to those used in mainframe computers. The data storage and transmission capabilities of these microprocessor-controlled pacemakers can be used to record, process, and transmit information regarding the patient, pacemaker, or patient/pacemaker interaction. The limitations of such data processing systems depend upon (1) quantity and quality of incoming information, (2) software routines for data collection, and (3) the amount of available random access memory (RAM). Data obtained can be useful in patient management and follow-up, particularly in the areas of optimization of programming, monitoring of disease progression, assessment of pharmacologic therapy, and pacemaker troubleshooting. Anticipated advances in data collection capabilities will allow increasingly sophisticated analysis that will complement, and may in some cases, supplant the Holter monitor recording in evaluating some aspects of rhythm and/or pacemaker behavior in selected patients.

As in humans, theophylline intoxication in rabbits causes seizures and death. We studied whether the administration of phenobarbital or phenytoin following a toxic dose of theophylline would improve survival in rabbits. New Zealand white rabbits were infused intravenously with theophylline, 115 mg/kg over 50 minutes. Upon completion of the infusion, rabbits were randomized to receive either saline (control) (N = 60) or saline containing phenobarbital 20 mg/kg (N = 60), or phenytoin 12 mg/kg (N = 30), infused over 30 minutes. The number (and percentage) of rabbits surviving 24 hours in each group was: control 12 (20%), phenobarbital 30 (50%), and phenytoin 7 (23%) [X2; p less than 0.005; two-tailed]. In all fatal cases, death was preceded by a seizure; rabbits that survived did not seize. These results show that phenobarbital administered intravenously to theophylline-intoxicated rabbits prevented seizures and improved survival whereas phenytoin administration had no significant effect.

The use of intravenous xenon- 133 for determination of radionuclide first pass right ventricular ejection fraction is described. First pass determinations of right ventricular ejection fraction were made with both xenon- 133 and technetium-99m in 13 subjects (15 right ventricular ejection fraction determinations); results obtained with xenon- 133 show an excellent correlation (r = 0.98, p less than 0.002) with results obtained using technetium-99m. Because of rapid pulmonary elimination of xenon- 133 from the body, the use of this radioisotope allows multiple first pass right ventricular ejection fraction determinations within a short period of time, without significant radiation exposure for the patient.

Kinetics and sedative and psychomotor effects of diphenhydramine were investigated in elderly Caucasian women (greater than 64 yr. old). In a double-blind trial, each of 12 healthy subjects received on one of three occasions 50 mg/70 kg IV or oral diphenhydramine HCl or oral placebo. Plasma levels of diphenhydramine were measured in six subjects and tests of sedation and psychomotor performance were performed hourly for 8 hr in all subjects. Kinetic analysis showed that the volume of distribution (295 +/- 50 [SEM] l/70 kg), clearance (42 +/- 5 l/70 kg/hr), and plasma t1/2 (4.9 +/- 0.7 hr) were of the same order as in young adults. As in young adults, there was minimal psychomotor impairment after oral and after intravenous diphenhydramine. In contrast to young adults, however, elderly women did not report significant sedation after diphenhydramine. These results suggest that diphenhydramine may not be an effective sedative/hypnotic in elderly women.

A randomized crossover trial of the effect of oral activated charcoal on the kinetics of intravenous theophylline was carried out in six normal male subjects. After intravenous aminophylline (6 mg/kg), subjects received water or water with activated charcoal (140 gm) in divided doses over 12 hr. Serum theophylline concentrations were measured from 0 to 24 hr after the aminophylline infusion. Treatment with activated charcoal decreased the serum t 1/2 from 6.4 +/- 1.2 to 3.3 +/- 0.4 (SEM) hr and the serum AUC from 78 +/- 14 to 42 +/- 4 mg . hr/l. Percent decrease in AUC after treatment with charcoal correlated positively with the endogenous theophylline serum t 1/2 (r = 0.94). These results suggest that oral activated charcoal (1) enhanced the total body clearance of theophylline and (2) may be efficacious in the treatment of theophylline poisoning, especially in patients with prolonged serum t 1/2s of theophylline.

The treatment of theophylline intoxication is reviewed. Efforts should be made to decrease the absorption of theophylline from the gastrointestinal tract by the oral administration of activated charcoal and sorbitol; stomach emptying procedures are recommended only in limited circumstances. Patients should receive intensive supportive care and appropriate treatment for complications of intoxication, including metabolic and cardiovascular abnormalities and seizures. Despite these treatments, morbidity (including residual neurological deficits) and mortality may occur. Therefore, efforts to actively remove theophylline from the body before complications occur should be considered in an attempt to reduce morbidity and mortality. The oral administration of multiple doses of activated charcoal (which increases theophylline clearance) is recommended for nearly all patients with theophylline intoxication. Although controversial, hemoperfusion--an efficient but invasive active removal procedure--is recommended in severely intoxicated patients who satisfy specific indications; the prophylactic administration of phenobarbital to prevent seizures should also be considered in these patients. Although these recommendations are rationally based on the extant evidence, controlled clinical trials in patients with theophylline intoxication are needed to prove their utility.

The pharmacokinetics of lidocaine were investigated in 17 healthy young adult volunteers seven Caucasians, five Orientals, and five Blacks). With the assumption of a one-compartment open model and linear pharmacokinetics, analysis of the data determined that there were no significant differences in the volume of distribution, clearance, elimination half-life, and serum protein binding of lidocaine among these racial groups. Our finding that lidocaine clearance and protein binding are not significantly different in young adult Caucasians and Orientals is consistent with our previous hypothesis that drugs metabolized in the body by N-dealkylation (lidocaine and diphenhydramine) area cleared at similar rates in young adult Caucasians and Orientals when protein binding is taken into account.

Procainamide is probably the most common offending drug responsible for the drug-induced lupus erythematosus syndrome today. Pericarditis has been reported to occur in from 14 to 18 per cent of the cases of procainamide-induced lupus erythematosus, and occasional reports of massive pericardial effusion, pericardial tamponade and constrictive pericarditis have appeared in the literature. We describe a patient who presented with features of procainamide induced lupus erythematosus without any clinical evidence of pericarditis. He underwent coronary bypass surgery 12 days after administration of the drug was stopped and was found to have a significant pericardial effusion at the time of surgery; histologic examination of pericardial tissue and pericardial fluid confirmed that the pericardial effusion was related to the procainamide-induced lupus syndrome. The incidence of pericarditis in procainamideinduced lupus erythematosus may be higher than presently accepted figures would indicate. Symptoms and signs related to procainamide-induced lupus pericarditis may cause diagnostic confusion with common postoperative bypass complications; the full implications of this disease entity to the patient undergoing coronary bypass are unknown.

The effect of repeated oral doses of activated charcoal on theophylline kinetics was studied in six subjects with hepatic cirrhosis and five patients with moderate theophylline poisoning to determine whether an activated charcoal regimen would be a useful strategy in patients with theophylline poisoning who did not require hemoperfusion. Six subjects with cirrhosis were injected IV with 6 mg/kg aminophylline followed by either water or water with activated charcoal (140 gm) in divided doses over 12 hr. In these subjects, treatment with activated charcoal decreased the mean (+/- SE) serum theophylline t1/2 from 12.7 +/- 4.0 hr to 4.0 +/- 0.7 hr. Subjects with the longest control t1/2s demonstrated the greatest charcoal effect. We developed a mathematical model that predicts that treatment with repeated oral doses of activated charcoal would result in an average serum theophylline t1/2 of 7.1 hr or less even if the subject's endogenous theophylline t1/2 is very long. In a pilot study of five patients with moderate theophylline poisoning, treatment with repeated oral doses of activated charcoal was well tolerated and led to a mean (+/- SE) t1/2 that was shorter than expected (4.9 +/- 0.8 hr, range 3.1 to 7.1 hr). We conclude that repeated oral doses of activated charcoal are relatively more effective in decreasing the serum theophylline t1/2 in persons with long endogenous t1/2s and that this may be useful for certain patients with mild or moderate theophylline poisoning.

Among 22 patients with isolated mitral regurgitation of various origins, systolic time intervals (preejection period [PEP] index, left ventricular ejection time [LVET] index and PEP/LVET) and echocardiographic measures of left ventricular performance (end-diastolic diameter [Dd], end-systolic diameter [Ds], and the percent change in minor axis diameter [% delta D]) were calculated. The patients were classified into two groups, those with a normal or supernormal % delta D (group I, 15 patients) and those with a decreased % delta D (group II, 7 patients). On group analysis, prolongation of the preejection period, shortening of the left ventricular ejection time and an increase in PEP/LVET was generally characteristic of patients with mitral regurgitation. These changes were accentuated when mitral regurgitation was complicated by echocardiographic evidence of diminished left ventricular contractile performance (% delta D less than 30 percent). An increase in PEP/LVET to greater than 0.05 was consistently associated with abnormal left ventricular performance, whereas a normal PEP/LVET ratio reflected normal or supernormal left ventricular performance. An inverse linear relation was found between PEP/LVET and % delta D. When compared with previous data on the relation of these variables among patients without valve insufficiency, PEP/LVET proved to be increased for any level of % delta D in mitral regurgitation. The state of digitalization did not appear to influence the relation between PEP/LVET and % delta D. The use of echocardiographic measurements augments the determination of systolic time intervals in the analysis of left ventricular performance in patients with mitral regurgitation.

Simultaneous hemodynamic and radionuclide angiographic assessment was made at rest and during exercise in nine patients with severe chronic congestive heart failure to determine the value of radionuclide left ventricular ejection fraction measurement in predicting the hemodynamic response to short-term treatment with oral hydralazine. Hydralazine, 50 to 100 mg orally every 6 hours, produced significant increases in cardiac index and stroke volume index at rest and during exercise (p < 0.01) and in left ventricular stroke work index at rest (p < 0.01) and during exercise (p < 0.05), significant decreases in systemic vascular resistance at rest and during exercise (p < 0.01) and significant increases in radionuclide angiographic left ventricular ejection fraction at rest (control 0.21 ± 0.06 vs. hydralazine 0.26 ± 0.07, p < 0.01) and during exercise (control 0.21 ± 0.08 vs. hydralazine 0.24 ± 0.09, p < 0.05). However, there were no statistically significant correlations between changes in radionuclide ejection fraction with hydralazine and changes in hemodynamic variables with hydralazine, either at rest or during exercise. Patients responding hemodynamically to hydralazine could not be separated from those not responding on the basis of the radionuclide ejection fraction at rest or changes in ejection fraction with hydralazine.It is concluded that: 1) hydralazine exerts beneficial effects on cardiac index, stroke volume index, left ventricular stroke work index and systemic vascular resistance both at rest and during exercise; 2) hydralazine therapy is associated with improvement in the radionuclide left ventricular ejection fraction both at rest and during exercise; but 3) the radionuclide ejection fraction response to hydralazine does not correlate with and cannot be used to predict the hemodynamic response to hydralazine in patients with severe chronic congestive heart failure.

Patients with mitral valve disease and extreme enlargement of the left atrium usually exhibit significant decrease in chamber size following corrective mitral valve surgery. We describe a patient in whom extreme right and left atrial enlargement developed, and progressed following mitral valve replacement, with no evidence of prosthetic valve malfunction or tricuspid valve disease.

In vitro, the transport of [14C]nicotine into the isolated choroid plexus, the anatomical locus of the blood–CSF barrier, was studied. The isolated rabbit choroid plexus accumulated [14C]nicotine by two processes: an active saturable transport process and a nonsaturable process. The [14C]nicotine accumulation process by choroid plexus was not due to binding or intracellular metabolism of the [14C]nicotine. The [14C]nicotine accumulation process in isolated choroid plexus was inhibited by weak bases, including tolazoline and lidocaine, but not by the weak acid probenecid. The accumulation process was decreased 60% by iodoacetate and dinitrophenol and by low temperatures. These results are consistent with previous autoradiographic evidence showing the choroid plexus concentrated [14C]nicotine in vivo, and suggest that the choroid plexus may transfer nicotine between blood and CSF in vivo.

A retrospective study of the clinical course and outcome of patients with serum digoxin concentrations (SDCs) greater than 3 ng/mL was conducted to determine the probability of a patient without initial signs or symptoms of digoxin toxicity subsequently developing signs or symptoms. Of 123 patients with SDCs greater than 3 ng/mL, 54 had no apparent signs or symptoms of toxicity at the time the index SDC was determined (group 1). Of these 54, two patients developed definite digoxin toxicity, although neither suffered significant morbidity. Digoxin administration was reduced or discontinued in all patients but one in group 1. There were no significant differences between the patients who had no signs or symptoms of digoxin toxicity (group 1) and those who did have signs or symptoms (group 2) in the mean SDC (3.9 +/- 0.1 vs 4.2 +/- 0.2 ng/mL, respectively), the serum creatinine (2.9 +/- 0.2 vs 3.4 +/- 0.4 mg/dL), or the incidence of atrial fibrillation (29/54 vs. 35/69) and coronary artery disease (21/54 vs. 18/69). The authors conclude that clinically stable patients receiving digoxin who have elevated SDCs but are without signs or symptoms of digoxin toxicity are at low risk of developing serious digoxin toxicity and do not generally require treatment beyond the discontinuation of digoxin therapy.

Reprint requests: Mark J. Goldberg, M.D., Dept. of Medicine, Section of Cardiovascular Diseases, Sinai Hospital of Detroit, 6767 West Outer Dr., Detroit, MI 48235. vein graft. Thrombolysis was “late,” both in the sense that graft occlusion occurred several weeks after surgery, and that treatment was administered several days after the onset of symptoms. We believe this represents a promising new application for streptokinase therapy. JP, a 53-year-old male with unstabie angina and a history of previous myocardial infarction, underwent coronary angiography on July 27, 1982. The study revealed a 70 % stenotic lesion in the proximal left anterior descending artery, a 90 % stenotic lesion in the proximal portion of a relatively large intermediate branch, and total proximal occlusion of the right coronary artery. Left ventriculography showed normal segmental wall motion, with the left ventricular ejection fraction being 58%. Coronary artery bypass graft surgery was performed on August 4, 1982. Saphenous vein grafts were fashioned for the left anterior descending artery, the intermediate branch, and the posterior descending branch of the right coronary artery. The early postoperative course was uneventful. The patient was discharged in excellent condition 7 days after surgery.

The effect of multiple oral doses of activated charcoal on digitalis glycoside kinetics was studied to determine whether an activated charcoal regimen might have utility in treating patients with digitalis toxicity. Normal subjects were given intravenous infusions of digoxin 0.75 mg/70 kg or digitoxin 1 mg/70 kg iv followed by either water alone or water with activated charcoal in divided doses in a randomized crossover design. A subject with chronic renal failure was also given digoxin 0.5 mg/70 kg iv followed by water alone or water with activated charcoal. In six normal subjects, treatment with activated charcoal did not increase digoxin clearance (Cl) significantly (16.79 ± 1.70 vs. 22.68 ± 3.51 L/h). However, digitoxin Cl did increase significantly, from 0.24 ± 0.01 to 0.47 ± 0.04 L/h. In the renal failure subject, digoxin Cl increased from 3.6 L/h to 10.1 L/h. We conclude that the activated charcoal regimen is probably useful in patients with digitoxin toxicity. Although similar benefit is limited in patients with normal renal function who develop digoxin toxicity, it is possible that activated charcoal will be useful in patients with prolonged digoxin elimination due to renal dysfunction.

The effect of size and frequency of oral doses of activated charcoal on theophylline kinetics was studied. Six fasting, healthy men received intravenous infusions of aminophylline (6 mg/kg) over 1 hr, followed by either no activated charcoal as a control, 5 gm activated charcoal every 2 hr for 6 doses, 10 gm every 2 hr for 6 doses, 10 gm every hr for 12 doses, 20 gm every 2 hr for 6 doses, or 40 gm every 4 hr for 3 doses. Five grams every 2 hr decreased serum theophylline t 1/2 from the control of 9.1 +/- 0.7 to 5.6 +/- 0.4 (SE) hr and decreased the AUC from the control of 123 +/- 11 to 79 +/- 6 mg X hr/l. The regimen of 20 gm every 2 hr further decreased theophylline t 1/2 to 4.3 +/- 0.4 hr and decreased AUC to 62 +/- 6 mg X hr/l. When a 120-gm dose of activated charcoal was given as a regimen of 40 gm every 4 hr or as a regimen of 10 gm every hr, there were small differences in serum theophylline t 1/2 (5.4 +/- 0.3 and 4.3 +/- 0.2 hr) and in AUC (73 +/- 5 and 60 +/- 4 mg X hr/l). Repeated small doses of oral activated charcoal enhanced the total body clearance of theophylline, and larger doses induced a relatively small further increase. There was little difference between the effects of the same total dose every 4 hr vs every hour.

The kinetics and psychomotor effects of diphenhydramine were investigated in Orientals and Caucasians. Each of 5 Oriental and 5 Caucasian young adults received on 1 of 3 occasions diphenhydramine 50 mg/70 kg body weight either intravenously or orally, or placebo. Plasma levels of diphenhydramine were measured hourly for 8 hr at each session. Tests of subjective sedation and psychomotor performance were performed at hourly intervals. The results showed that after both intravenous and oral diphenhydramine, at all times Orientals had plasma levels approximately half those of Caucasians. With the assumption of linear kinetics and a 1-compartment open model, analysis of the data showed that the volume of distribution (VD) and plasma clearance (Cl) but not plasma half-life (t 1/2) were higher in Orientals than Caucasians: [VD = 480 +/- 24 (SEM) and 292 +/- 36 1/70 kg; Cl = 79 +/- 7 and 51 +/- 7 1/70 kg/hr; t 1/2 = 4.1 +/- 0.4 and 4.3 +/- 0.4 hr]. Unbound diphenhydramine in fresh plasma was higher in Orientals than Caucasians [24.0 +/- 1.9% (SEM) and 14.8 +/- 1.5%] and probably explains the increased VD in Orientals. Orientals had significantly less sedation and deterioration in psychomotor performance.

We investigated the effect of multiple oral doses of activated charcoal on the pharmacokinetics of intravenously administered phenobarbital in a randomized crossover trial. Six healthy men volunteered to take 200 mg of phenobarbital sodium per 70 kg of body weight intravenously on two separate occasions. On one occasion, each subject received oral activated charcoal (180 g) in divided doses over three days after the infusion of phenobarbital. Serum levels of phenobarbital were measured in all subjects up to 96 hours after the infusion, and urinary excretion of phenobarbital was measured in two subjects 24 to 96 hours after the infusion. A pharmacokinetic analysis showed that the charcoal decreased the serum half-life of phenobarbital form 110 +/- 8 to 45 +/- 6 hours (S.E.M.) (P less than 0.01), increased the total body clearance of phenobarbital from 4.4 +/- 0.2 to 12.0 +/- 1.6 ml per kilogram per hour (P less than 0.01), and increased the nonrenal clearance from 52 to 80 per cent of the total body clearance. We conclude that oral administration of activated charcoal enhances the nonrenal clearance of phenobarbital.

We review our experience in the management of patients with plasma theophylline concentrations of 30 micrograms/ml or greater. Over a two-and-a-half-year period, 22 patients (Group 1) had plasma theophylline concentrations of 37 +/- 1 micrograms/ml (mean +/- SE) and experienced no severe toxicity (i.e., ventricular extrasystoles or tachycardia, seizures, cardiovascular collapse, or death). Six patients (Group 2) took overdoses of theophylline (92 +/- 12 micrograms/ml) and one died. Eight patients (Group 3) were iatrogenically intoxicated (48 +/- 6 micrograms/ml) and three died. Six patients from Groups 2 and 3 underwent hemoperfusion and did well, except for one patient, in whom seizures developed before hemoperfusion was initiated. We conclude from this experience that charcoal hemoperfusion is a useful procedure for the treatment of theophylline intoxication because of: (1) the serious morbidity and mortality of theophylline intoxication, (2) the prevention of complications with hemoperfusion, and (3) the relative safety of the procedure. We provide tentative guidelines for the initiation of hemoperfusion for the treatment of theophylline intoxication.

The effect of the surface area of activated charcoal on theophylline clearance was studied. Eight fasting, healthy men received intravenous infusions of either aminophylline (6 mg/kg, N = 3) or theophylline (5 mg/kg, N = 5) over 1 hour followed by either 5 Gm standard activated charcoal every 2 hours, 20 Gm every 2 hours, or 5 Gm PX-21 activated charcoal (with 3.6 times the surface area) every 2 hours. Theophylline t 1/2 and AUC with each regimen were respectively 6.3 +/- 0.5 (S.E.) hours and 88.9 +/- 8.4 mg/liter X hr with 5 Gm standard activated charcoal, 5.3 +/- 0.3 hours and 75.4 +/- 4.9 mg/liter X hr with 5 Gm PX-21, and 4.9 +/- 0.2 hours and 67.7 +/- 3.6 mg/liter X hr with 20 Gm standard activated charcoal. There was a relationship between the activated charcoal surface area and the reduction in theophylline t 1/2 and AUC. We conclude that the clearance of theophylline is related to the surface area of activated charcoal administered and that PX-21 may be a more potent activated charcoal product for enhancing theophylline removal.

The effect of oral activated charcoal on the pharmacokinetics of intravenous imipramine was studied in a randomized, crossover trial. Four normal men received intravenous imipramine (12.5 mg/70 kg) on two separate occasions, followed by either water or water plus high-surface-area activated charcoal (180 gm) in divided doses over 24 hours. Serum imipramine concentrations were measured from 0 to 24 hours after the imipramine infusion. There was no difference in the mean (+/- SE) t1/2 (9.0 +/- 0.8 vs. 10.9 +/- 1.6 hours), apparent volume of distribution (11.2 +/- 2.1 vs. 12.4 +/- 2.1 L/kg), or systemic clearance (992.2 +/- 138.3 vs. 930.3 +/- 101.9 ml/min/70 kg) of imipramine after dosing without and with oral activated charcoal, respectively (P greater than 0.05; paired t test). These results suggest that multiple oral doses of activated charcoal do not increase the clearance of imipramine in man.

Patients with phenobarbital overdose who are treated only with supportive care may remain comatose for several days because of the long elimination half-life of phenobarbital. We treated two patients with phenobarbital overdoses with the nasogastric administration of multiple doses of activated charcoal. This safe therapy markedly shortened both the elimination half-life of phenobarbital and the duration of coma in these patients. If all such patients respond similarly, we believe that the nasogastric administration of multiple doses of activated charcoal is the method of choice to accelerate the elimination of phenobarbital from the body.

Activated charcoal is widely used as an adsorbent for the management of patients with drug overdoses and poisonings. Activated charcoal can be used orally to prevent drug and poison absorption in cases of overdose and poisoning. Multiple oral doses of charcoal increase the elimination of several, but not all, drugs and poisons. The effectiveness of multiple oral doses of charcoal in accelerating drug clearance is dependent primarily on the endogenous clearance of the drug or poison and its volume of distribution. Multiple doses of charcoal are used to shorten the period of supportive care in certain patients or to more rapidly remove drugs or poisons that may cause tissue damage, eg, theophylline. Charcoal is a safe, effective, and inexpensive alternative to more invasive treatments for some cases of drug overdose and poisoning.

Excerpt Amoxapine (Asendin, Lederle Laboratories, Pearl River, New York), a tricyclic dibenzoxazepine antidepressant, has been recently marketed in the United States. Development of new tricyclic a...

• Our systematic approach to the evaluation and treatment of the acutely poisoned patient involves establishing an accurate diagnosis and prognosis that often may be based on quantitation of the blood concentration of the toxic substance. The major feature of this approach is the proper selection of treatment(s) for the poisoned patient, ie, decontamination and supportive care and, in some cases, antidotal therapy and/or active removal of the toxic substance. Invasive, expensive methods of active removal (eg, hemodialysis or hemoperfusion) are generally recommended only if specific criteria are satisfied. Noninvasive, inexpensive methods of active removal (eg, manipulation of urinary pH or the oral administration of multiple doses of activated charcoal) may have significant utility in the treatment of poisoned patients not requiring invasive methods. This systematic approach to the poisoned patient should lead to an effective use of treatment modalities with minimal risks and optimal clinical results. ( Arch Intern Med 1986;146:1381-1385)

To the Editor.— Previous studies have shown that the administration of multiple oral doses of activated charcoal will decrease the elimination half-life of phenobarbital. 1,2 An uncontrolled trial in patients with phenobarbital overdose treated with this regimen suggested that coma time and duration of mechanical ventilation were decreased consistent with the decrease in phenobarbital halflife. 3 However, the obvious thesis that decreasing the half-life of phenobarbital by administering multiple doses of activated charcoal would result in a decrease in coma time and duration of mechanical ventilation in patients with phenobarbital overdose requires final proof. Pond et al 4 have tested this thesis. In a small randomized controlled trial, they have confirmed that repeated doses of activated charcoal, compared with single doses, decrease the serum half-life of phenobarbital in patients with phenobarbital overdose. But, it is surprising that the duration of mechanical ventilation was not different in the two groups. However

• Sulindac is a nonsteroidal anti-inflammatory agent that has been associated with serious adverse reactions. We saw four patients with reactions associated with sulindac. Our patients, one of whom died, had high temperatures and involvement of one or more organs, including the skin, liver, CNS, lymph nodes, bone marrow, and lungs. Eight similar previously reported cases also are summarized. In view of these cases of sulindac-induced toxicity, six of which were proved unequivocally by drug rechallenge, we suggest that physicians be cautious in prescribing this agent. ( Arch Intern Med 1982;142:1292-1294)