Canineelectrophannacology of SC-36602, a new class I antiarrhythmicagent(abstract). FedProc 1985;44:899. 9. OOITLIEB SS, KUKIN ML, MEDINA N, YUSHAK M, PACKER M. Comparative hemodynamic effectsof procainamide, tocainide, andencainideinseverechronicheartfailure. Circulation 1990;81:860-4. 10. SCHWAR1Z M,COVINO B,DUCE B,et aI. Acutehemodynamic effectsof tocainide in patients undergoing cardiaccatheterization. J Clin Pharmaco1l979;19:100-7. II. TUCKER CR, WINKLE RA, PETERS FA, HARRISON DC. Acute hemodynamic effectsof intravenous encainide inpatients withheartdisease. AmHeartJI982;104:209-15. 12. BURTON JR, MATHEW MT, ARMSTRONG pw. Comparativeeffects of lidocaine and procainamide on acutelyimpaired hemodynamics. Am J MedI976;61:215-20.
EXTRACTO La farmacocineticay toleranciade actisomida fueron evaluadas despues de dosis intravenosasde 2.1, 4.2, y 8.4 mg/kg en una infusionsobre cinco horas. Las concentracionesen plasma obtenida en el grupo de dosis baja (2.1 mg/kg) estuvieron por debajo del limite de deteccion en el analisis y por esa razon no fueron incluidosen el analisis farrnacocinetico, Los parametros farmacocineticos obtenidos en el grupo de dosis media (4.2 mg/kg) y dosis alta (8.4 mg/kg) fueron: concentracionmaxima en plasma, 4.25 ± 0.26 ~g/mL y 7.81 ± 0.31 ug/ml.; area bajo la curva de concentraci6nen plasma contra tiempo, 19.79±2.96h·~g/mLy 39.81±7.05 h-ug/rnl.; constantede eliminacion en fase beta, 0.105 ± O.77h·' y 0.093 ± O.OO9h· l ; y vida media, 8.85 ± 4.61 h y 7.51 ± 0.69 h, respectivamente. La fraccion de contraccion ventricularizquierdadisminuyo en 10,11, y 16 por ciento en todos los grupos (dosis baja, media, yalta), respectivamente. La presion sanguineasistolica y diastolica no cambiaron significativamente en
ningun grupo. Los cambios en intervalosclectrocardiograficos para los tres grupos no fueron significativosexcepto en el grupo de dosis alta donde en un promediode 20 por ciento aumento el intervaloQRS. Los efectos adversos subjetivosmedios que necesitandescontinuar la infusion ocurrio en el grupo de dosis alta. Estos efectos incluyeron debilidad, perdida del sabor, y parestesiacircomural.Otros estudios son necesariospara garantizar un perfil farmacocinetico y el potencial terapeuticocompleto de actisomida. WILMA M. GUZMAN DE V ALlNES
RESUME Cette etude avait pour objectif de comparer Ie profil pharmacocinetique et l'innocuite de 2.1,4.2 et 8.4 mg/kg d'actisomide infuse sur une periode de cinq heures. Les concentrationsplasmatiquesobtenues chez Ie groupe recevant 2.1 mg/kg se trouverentsous la limitede detectionde l'analyse biochimiqueet consequemment ne furent pas indues dans l'analyse pharmacocinetique. Les parametrespharmacocinetiques de 4.2 et 8.4 mg/kg sont respectivement: concentrationsplasmatiques maximales de 4.25 ± 0.26 ug/ml, et 7.81 ± 0.31 ug/ml.; surfaces sous la courbe de 19.79± 2.96 h-ug/rnl, et 39.81 ± 7.05 h·~g/mL; constantes d'elimination (phase beta) de 0.105 ± 0.77 h-I et 0.093 ± 0.009 h-i; demivies de 8.85 ± 4.61 h et7.51 ± 0.69 h. La fraction d'ejection du ventriculegauche diminua de 10 pour cent, 11 pour cent et 16 pour cent apres infusionde 2.1,4.2 et 8.4 mg/kg respectivemenl. La frequence cardiaque au repos augmenta de 18 pour cent et 27 pour cent apres infusionde 4.2 et 8.4 mg/kg; 2.1 mg/kg d'actisornide n'affecta pas la frequence cardiaque au repos. Aucun effet n' a ete observe sur les pressions systoliqueet diastolique.Seule l'infusion de 8.4 mg/kg d'actisomide augmenta l'intervalle QRS de 20 pour cent. Des etourdissements, de la dysgueusieet de la parethesieont ete observes 11 la dose elevee, MICHELLE DEPOT
THE EFFECT OFPHENYLPROPANOLAMINE ON 24-HOUR BLOOD PRESSURE IN NORMOTENSIVE SUBJECTS ADMINISTERED INDOMETHACIN James M. McKenney, Jackson T. Wright, Jr., Gail M. Katz, and Robert P. Goodman
ABSTRACT: We evaluated the effect of phenylpropanolamine hydrochloride (PPA) in 14young, healthy, normotensive women who concurrently received indomethacin. Subjects received sustainedrelease (SR) indomethacin 75 mg bid and were randomly assigned to receive double-blind SR PPA75 mg/d or placebo for four days. After a six-day washout period, subjects were crossed over to the opposite four-daydouble-blind treatment. Following an additional six-day washout period, subjects received indomethacin placebo and PPA placebo during a final, single-blind four-day period. Twenty-four-hour
blood pressure (BP) monitoring every 30 minutes and a 24-hour urine collection for prostaglandin E, (POE,) were performed on the fourth day of each treatment period. Compliance with the medication regimen was confirmed by drug concentrations, pill counts, and urinary POE, concentrations. Compared with the indomethacin and placebo treatment periods, the combination of indomethacin and PPA had no significanteffect on mean systolic or diastolic BP during the 24-hour study period or during any four-hour interval. We conclude that the combination of SR PPA 75 mg/d and SR indomethacin 150mg/d for four days has no adverse effect on BP in normotensive women.
JAMES M. MCKENNEY, Phann.D., isa Professor, Department of Pharmacy and Pharmaceutics; JACKSON T.WRIGHT, Jr., M.D., Ph.D., isanAssociate Professor,
D1CPAnn Pharmacother1991;25:234-9.
Department ofIntemal Medicine; GAll.. M. KATZ, Phann.D., atthe time ofwriting, was a student, Department ofPharmacy and Pharmaceutics; and ROBERT P.GOOD· MAN, M.D., isanAssistant Professor, Department ofInternal Medicine, Medical College ofVirginia, Virginia Commonwealth University, Richmond, VA. Reprints: James M.McKenney, Phann.D., Virginia Commonwealth University, Box 533, MCV Station, Richmond, VA 23298. Supported inpart byThompson Medical Company, Inc., 919 Third Avenue, New York, NY 10022.
234 •
DICP, The Annals ofPharmacotherapy
•
PHENYLPROPANOLAMINEHYDROCHLORIDE (PPA) is a sympathomimetic amine widely used in prescription and overthe-counterdecongestants and anorexiants. In 1988, three PPAproductswereincludedin the top 200 mostcommonly prescribed drugs in the U.S} In spite of its widespread
1991 March, Volume 25
Research/Practice
use, PPA's unrestricted availability has been the topic of debate.v' Much of the debate concerns safety issues raisedby numerous case reportsthathave implicated it as a cause of hypertension.':" psychosis.v" cardiac arrhythmias,8.9.2O myocardial infarction, 21.22 seizures,23-25 cerebral hemorrhage.P-" stroke," acute tubular necrosis ,IS adultrespiratory distress syndrome," and cardiac arrest." These reports, however, are not in general agreement with the experimental literature, leading some to suggest that biasis evidentin the interpretation of the literature and that controlled evaluations of PPA are needed. 30 One of the areas of controversy is the effect of PPA on bloodpressure (BP). Structurally similarto ephedrine, amphetamine, and metaraminol, PPA is believed to act indirectly by causing release of norepinephrine from sympatheticstorage sites and to a lesserextent, by directstimulation of alpha- and beta-adrenergic receptors in vascular smooth muscle." This pharmacologic mechanism suggests that PPA could raise BP at therapeutic doses. Even through several case reportssuggestthatPPA can causehypertension, humanstudies, including a studyby us employing 24-hour ambulatory BP monitoring, have failed to demonstrate this effect when the drug is administered in recommended daily doses.32-35 It has been postulated that the absence of a hypertensive effectmayresultin part from the modulatinginfluence of compensatory mechanisms, especially prostaglandins.9 One case report has implicated indomethacin as the causeof the potentiation of the pressoreffects of PPA. This report describes a 27-year-old woman who received an appetite suppressant containing PPA for several monthsand developed a severe, throbbing, bifrontal headache and systolic BP of 210 mm Hg 30 minutes after ingesting one 25mg dose of indomethacin prescribed for tendonitis. These effects recurred upon rechallenge with the combination of PPA and indomethacin but not when indomethacin was given alone." This potential drug interaction has not been adequately evaluated in well-designed clinical trials. The objective ofthisstudywasto investigate theeffectof PPA on 24-hourBP in a group of ambulatory, normotensive, nonsmoking, healthy women who were administered indomethacin concurrently. Methods Fourteen healthy nonsmoking, female volunteers (aged 20-40 y, mean28.2±4.6) were recruited to participate in this study. The study wasreviewed and approved by the Human Research Committee and all subjects gave informed consent. A baseline history, physical examination, complete bloodcount, automated chemistry panel, urinalysis, and pregnancy test wereperformed on each subject.Qualifying subjects had a resting seateddiastolic BP
EXTRACTO La farmacocineticay toleranciade actisomida fueron evaluadas despues de dosis intravenosasde 2.1, 4.2, y 8.4 mg/kg en una infusionsobre cinco horas. Las concentracionesen plasma obtenida en el grupo de dosis baja (2.1 mg/kg) estuvieron por debajo del limite de deteccion en el analisis y por esa razon no fueron incluidosen el analisis farrnacocinetico, Los parametros farmacocineticos obtenidos en el grupo de dosis media (4.2 mg/kg) y dosis alta (8.4 mg/kg) fueron: concentracionmaxima en plasma, 4.25 ± 0.26 ~g/mL y 7.81 ± 0.31 ug/ml.; area bajo la curva de concentraci6nen plasma contra tiempo, 19.79±2.96h·~g/mLy 39.81±7.05 h-ug/rnl.; constantede eliminacion en fase beta, 0.105 ± O.77h·' y 0.093 ± O.OO9h· l ; y vida media, 8.85 ± 4.61 h y 7.51 ± 0.69 h, respectivamente. La fraccion de contraccion ventricularizquierdadisminuyo en 10,11, y 16 por ciento en todos los grupos (dosis baja, media, yalta), respectivamente. La presion sanguineasistolica y diastolica no cambiaron significativamente en
ningun grupo. Los cambios en intervalosclectrocardiograficos para los tres grupos no fueron significativosexcepto en el grupo de dosis alta donde en un promediode 20 por ciento aumento el intervaloQRS. Los efectos adversos subjetivosmedios que necesitandescontinuar la infusion ocurrio en el grupo de dosis alta. Estos efectos incluyeron debilidad, perdida del sabor, y parestesiacircomural.Otros estudios son necesariospara garantizar un perfil farmacocinetico y el potencial terapeuticocompleto de actisomida. WILMA M. GUZMAN DE V ALlNES
RESUME Cette etude avait pour objectif de comparer Ie profil pharmacocinetique et l'innocuite de 2.1,4.2 et 8.4 mg/kg d'actisomide infuse sur une periode de cinq heures. Les concentrationsplasmatiquesobtenues chez Ie groupe recevant 2.1 mg/kg se trouverentsous la limitede detectionde l'analyse biochimiqueet consequemment ne furent pas indues dans l'analyse pharmacocinetique. Les parametrespharmacocinetiques de 4.2 et 8.4 mg/kg sont respectivement: concentrationsplasmatiques maximales de 4.25 ± 0.26 ug/ml, et 7.81 ± 0.31 ug/ml.; surfaces sous la courbe de 19.79± 2.96 h-ug/rnl, et 39.81 ± 7.05 h·~g/mL; constantes d'elimination (phase beta) de 0.105 ± 0.77 h-I et 0.093 ± 0.009 h-i; demivies de 8.85 ± 4.61 h et7.51 ± 0.69 h. La fraction d'ejection du ventriculegauche diminua de 10 pour cent, 11 pour cent et 16 pour cent apres infusionde 2.1,4.2 et 8.4 mg/kg respectivemenl. La frequence cardiaque au repos augmenta de 18 pour cent et 27 pour cent apres infusionde 4.2 et 8.4 mg/kg; 2.1 mg/kg d'actisornide n'affecta pas la frequence cardiaque au repos. Aucun effet n' a ete observe sur les pressions systoliqueet diastolique.Seule l'infusion de 8.4 mg/kg d'actisomide augmenta l'intervalle QRS de 20 pour cent. Des etourdissements, de la dysgueusieet de la parethesieont ete observes 11 la dose elevee, MICHELLE DEPOT
THE EFFECT OFPHENYLPROPANOLAMINE ON 24-HOUR BLOOD PRESSURE IN NORMOTENSIVE SUBJECTS ADMINISTERED INDOMETHACIN James M. McKenney, Jackson T. Wright, Jr., Gail M. Katz, and Robert P. Goodman
ABSTRACT: We evaluated the effect of phenylpropanolamine hydrochloride (PPA) in 14young, healthy, normotensive women who concurrently received indomethacin. Subjects received sustainedrelease (SR) indomethacin 75 mg bid and were randomly assigned to receive double-blind SR PPA75 mg/d or placebo for four days. After a six-day washout period, subjects were crossed over to the opposite four-daydouble-blind treatment. Following an additional six-day washout period, subjects received indomethacin placebo and PPA placebo during a final, single-blind four-day period. Twenty-four-hour
blood pressure (BP) monitoring every 30 minutes and a 24-hour urine collection for prostaglandin E, (POE,) were performed on the fourth day of each treatment period. Compliance with the medication regimen was confirmed by drug concentrations, pill counts, and urinary POE, concentrations. Compared with the indomethacin and placebo treatment periods, the combination of indomethacin and PPA had no significanteffect on mean systolic or diastolic BP during the 24-hour study period or during any four-hour interval. We conclude that the combination of SR PPA 75 mg/d and SR indomethacin 150mg/d for four days has no adverse effect on BP in normotensive women.
JAMES M. MCKENNEY, Phann.D., isa Professor, Department of Pharmacy and Pharmaceutics; JACKSON T.WRIGHT, Jr., M.D., Ph.D., isanAssociate Professor,
D1CPAnn Pharmacother1991;25:234-9.
Department ofIntemal Medicine; GAll.. M. KATZ, Phann.D., atthe time ofwriting, was a student, Department ofPharmacy and Pharmaceutics; and ROBERT P.GOOD· MAN, M.D., isanAssistant Professor, Department ofInternal Medicine, Medical College ofVirginia, Virginia Commonwealth University, Richmond, VA. Reprints: James M.McKenney, Phann.D., Virginia Commonwealth University, Box 533, MCV Station, Richmond, VA 23298. Supported inpart byThompson Medical Company, Inc., 919 Third Avenue, New York, NY 10022.
234 •
DICP, The Annals ofPharmacotherapy
•
PHENYLPROPANOLAMINEHYDROCHLORIDE (PPA) is a sympathomimetic amine widely used in prescription and overthe-counterdecongestants and anorexiants. In 1988, three PPAproductswereincludedin the top 200 mostcommonly prescribed drugs in the U.S} In spite of its widespread
1991 March, Volume 25
Research/Practice
use, PPA's unrestricted availability has been the topic of debate.v' Much of the debate concerns safety issues raisedby numerous case reportsthathave implicated it as a cause of hypertension.':" psychosis.v" cardiac arrhythmias,8.9.2O myocardial infarction, 21.22 seizures,23-25 cerebral hemorrhage.P-" stroke," acute tubular necrosis ,IS adultrespiratory distress syndrome," and cardiac arrest." These reports, however, are not in general agreement with the experimental literature, leading some to suggest that biasis evidentin the interpretation of the literature and that controlled evaluations of PPA are needed. 30 One of the areas of controversy is the effect of PPA on bloodpressure (BP). Structurally similarto ephedrine, amphetamine, and metaraminol, PPA is believed to act indirectly by causing release of norepinephrine from sympatheticstorage sites and to a lesserextent, by directstimulation of alpha- and beta-adrenergic receptors in vascular smooth muscle." This pharmacologic mechanism suggests that PPA could raise BP at therapeutic doses. Even through several case reportssuggestthatPPA can causehypertension, humanstudies, including a studyby us employing 24-hour ambulatory BP monitoring, have failed to demonstrate this effect when the drug is administered in recommended daily doses.32-35 It has been postulated that the absence of a hypertensive effectmayresultin part from the modulatinginfluence of compensatory mechanisms, especially prostaglandins.9 One case report has implicated indomethacin as the causeof the potentiation of the pressoreffects of PPA. This report describes a 27-year-old woman who received an appetite suppressant containing PPA for several monthsand developed a severe, throbbing, bifrontal headache and systolic BP of 210 mm Hg 30 minutes after ingesting one 25mg dose of indomethacin prescribed for tendonitis. These effects recurred upon rechallenge with the combination of PPA and indomethacin but not when indomethacin was given alone." This potential drug interaction has not been adequately evaluated in well-designed clinical trials. The objective ofthisstudywasto investigate theeffectof PPA on 24-hourBP in a group of ambulatory, normotensive, nonsmoking, healthy women who were administered indomethacin concurrently. Methods Fourteen healthy nonsmoking, female volunteers (aged 20-40 y, mean28.2±4.6) were recruited to participate in this study. The study wasreviewed and approved by the Human Research Committee and all subjects gave informed consent. A baseline history, physical examination, complete bloodcount, automated chemistry panel, urinalysis, and pregnancy test wereperformed on each subject.Qualifying subjects had a resting seateddiastolic BP
