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At least 19 recordsLinked to original sources
PubMed1991

Dose-dependent response to phenylpropanolamine: inhibition of orthostasis.

Phenylpropanolamine, a widely consumed over-the-counter drug, is known to elevate blood pressure, but the mechanism is unknown; it may be both a direct and indirect sympathomimetic. This study investigated the effects of 75-mg sustained-release phenylpropanolamine, 75-mg phenylpropanolamine plus 400-mg caffeine, and 150-mg phenylpropanolamine on blood pressure, plasma norepinephrine, and epinephrine levels in 16 normotensive subjects in a double-blind, placebo-controlled crossover design. Mean peak phenylpropanolamine levels of 317 +/- 26, 152 +/- 17, and 157 +/- 17 ng/mL for 150-mg phenylpropanolamine, 75-mg phenylpropanolamine, and 75-mg phenylpropanolamine plus 400-mg caffeine, respectively, were reached at about 3.6 hours after dosing. The maximal increases in supine diastolic blood pressures after all three phenylpropanolamine-containing drugs were almost three times that after placebo (P less than .05), but peak blood pressures occurred at about 2.3 hours earlier than peak phenylpropanolamine levels. Blood pressure increases correlated with phenylpropanolamine plasma levels (r = .49 for systolic blood pressure and r = .34 for diastolic blood pressure; P less than .0001 for both). Norepinephrine levels increased after the administration of 150-mg phenylpropanolamine and 75-mg phenylpropanolamine plus 400-mg caffeine; norepinephrine increases correlated with phenylpropanolamine levels (r = .34, P less than .0001). The expected increment in norepinephrine induced by standing was significantly decreased by phenylpropanolamine in a dose-dependent mode. The study supports the idea that phenylpropanolamine as both a direct (at alpha -1 and alpha-2 receptors) and an indirect sympathomimetic agent.

Blood Pressure↗
PubMed1988

A double dose of phenylpropanolamine causes transient hypertension.

PURPOSE: Phenylpropanolamine is widely used and freely available without a doctor's prescription in drug and grocery stores; it is the active ingredient in most diet aids and many cold preparations. Several cases of multiple cerebral hemorrhages associated with transient hypertension have recently been attributed to phenylpropanolamine in dosages equal to or less than that contained in two diet aids (i.e., 150 mg). Some evidence also exists on the additive effects of the co-ingestion of phenylpropanolamine and caffeine. We therefore undertook a study to demonstrate that a significant health risk can be caused by a double dose of a typical over-the-counter (OTC) diet aid (i.e., 150 mg phenylpropanolamine) and also when 75 mg phenylpropanolamine is taken with caffeine. SUBJECTS AND METHODS: Five men and one woman, ranging in age from 20 to 30, participated in this study. The drug preparations were administered to each subject on different study days in a double-blind, randomized-crossover design. Identical capsules contained 75 mg sustained-release phenylpropanolamine, 400 mg of sustained-release caffeine, or placebo. Subjects ingested three capsules at the beginning of each study day. For 150 mg, two phenylpropanolamine-containing capsules and one placebo were taken; for 75 mg, one phenylpropanolamine capsule and two placebos; and for phenylpropanolamine plus caffeine, one 75 mg phenylpropanolamine capsule, one 400 mg caffeine capsule, and one placebo. Blood pressure and heart rate were monitored throughout the study. RESULTS: Although 75 mg of phenylpropanolamine did not cause clinically relevant hypertension in our subjects, 150 mg of phenylpropanolamine and 75 mg of phenylpropanolamine plus 400 mg caffeine did result in significant blood pressure increases into the hypertensive range. CONCLUSION: We believe that consumers often assume that double the recommended dosage of an OTC drug is safe and more effective. We suggest that requiring a physician's prescription or an additional, stronger warning label on phenylpropanolamine-containing products may prevent substantial mortality and morbidity.

Adult↗
PubMed1994

Dispositional factors do not contribute to the enantiospecificity of the cardiovascular effects of phenylpropanolamine.

The pharmacokinetics and blood pressure response of the phenylpropanolamine enantiomers (i.e., d- and l-phenylpropanolamine) were determined after the separate oral administration of racemic dl-phenylpropanolamine (75 mg), l-phenylpropanolamine (37.5 mg), and d-phenylpropanolamine (37.5 mg) to six healthy volunteers. No significant differences were observed between any of the pharmacokinetic parameters of d- and l-phenylpropanolamine when the enantiomers were administered individually or as the racemate. There was also no difference in the ex vivo plasma protein binding of d- and l-phenylpropanolamine, determined individually or as the racemate. Significant increases from baseline in systolic and diastolic blood pressure (supine and standing) were observed for dl- and l-phenylpropanolamine, whereas d-phenylpropanolamine had no effect on blood pressure. The effects of dl- and l-phenylpropanolamine on blood pressure were not significantly different. The data from this study show that pharmacokinetic factors do not contribute to the stereospecificity of the cardiovascular effects of phenylpropanolamine or to the interindividual variability in the blood pressure response to phenylpropanolamine.

Adolescent↗
PubMed2000

Phenylpropanolamine and the risk of hemorrhagic stroke.

BACKGROUND: Phenylpropanolamine is commonly found in appetite suppressants and cough or cold remedies. Case reports have linked the use of products containing phenylpropanolamine to hemorrhagic stroke, often after the first use of these products. To study the association, we designed a case-control study. METHODS: Men and women 18 to 49 years of age were recruited from 43 U.S. hospitals. Eligibility criteria included the occurrence of a subarachnoid or intracerebral hemorrhage within 30 days before enrollment and the absence of a previously diagnosed brain lesion. Random-digit dialing identified two matched control subjects per patient. RESULTS: There were 702 patients and 1376 control subjects. For women, the adjusted odds ratio was 16.58 (95 percent confidence interval, 1.51 to 182.21; P=0.02) for the association between the use of appetite suppressants containing phenylpropanolamine and the risk of a hemorrhagic stroke and 3.13 (95 percent confidence interval, 0.86 to 11.46; P=0.08) for the association with the first use of a product containing phenylpropanolamine. All first uses of phenylpropanolamine involved cough or cold remedies. For men and women combined, the adjusted odds ratio was 1.49 (95 percent confidence interval, 0.84 to 2.64; P=0.17) for the association between the use of a product containing phenylpropanolamine and the risk of a hemorrhagic stroke, 1.23 (95 percent confidence interval, 0.68 to 2.24; P=0.49) for the association with the use of cough or cold remedies that contained phenylpropanolamine, and 15.92 (95 percent confidence interval, 1.38 to 184.13; P=0.03) for the association with the use of appetite suppressants that contained phenylpropanolamine. An analysis in men showed no increased risk of a hemorrhagic stroke in association with the use of cough or cold remedies containing phenylpropanolamine. No men reported the use of appetite suppressants. CONCLUSIONS: The results suggest that phenylpropanolamine in appetite suppressants, and possibly in cough and cold remedies, is an independent risk factor for hemorrhagic stroke in women.

Adolescent↗
PubMedDate not supplied

Cardiovascular studies of phenylpropanolamine.

Phenylpropanolamine is found in a number of over-the-counter preparations commonly used for appetite control or as a cold remedy. Even though widely used, some questions still exist as to its effect on the cardiovascular system of man. Both anesthetized and unanesthetized adult beagle dogs were used in this study. In the unanesthetized conditioned dog, blood pressure and heart rate were measured using an inflatable tail cuff. In the first group, consisting of 12 dogs, phenylpropanolamine was given (0.0, 3.1, 6.25 and 12.5 mg/kg) via a stomach tube and the animals were followed for 300 minutes. Each dose of phenylpropanolamine was given to 4 groups made up of 3 dogs each. It produced dose-dependent increases in blood pressure and decreases of heart rate. Maximum changes were noted at 30 to 60 minutes, lasting for 3 to 5 hours. A second group of 9 unanesthetized dogs was given repeated oral doses of phenylpropanolamine (3 groups of 3 animals each). Doses of 3 mg/kg and 6 mg/kg, given orally, produced approximately the same increase in blood pressure and decrease of heart rate as previously observed. At 6 hours, these same doses of phenylpropanolamine produced little or no change in either parameter. At 24 hours after the first dose, however, the dogs responded in much the same manner as with the first administration of phenylpropanolamine. Control dogs given water did not exhibit any degree of tachyphylaxis. Dogs anesthetized with Na pentobarbital were given oral and intravenous doses of phenylpropanolamine (0.0-25 mg/kg). The overall response was like that observed in the unanesthetized preparation with the important exception that low doses (0.1-3 mg/kg) produced significant increases in both heart rate and blood pressure, while higher doses (6-25 mg/kg) resulted in a lesser overall effect. Six anesthetized animals were used to study the effects of phenylpropanolamine and norepinephrine on the cardiovascular function. Both the increase in blood pressure and left ventricular force of contraction, produced by the first dose of phenylpropanolamine, were markedly reduced or absent with the second administration of the drug. In addition, the classic blood pressure response to norepinephrine was likewise increased by prior administration of phenylpropanolamine.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed2004

Phenylpropanolamine constricts mouse and human blood vessels by preferentially activating alpha2-adrenoceptors.

Phenylpropanolamine (dl-norephedrine) was one of the most widely used therapeutic agents to act on the sympathetic nervous system. Because of concerns regarding incidents of stroke, its use as a nasal decongestant was discontinued. Although considered an alpha1-adrenergic agonist, the vascular adrenergic pharmacology of phenylpropanolamine was not fully characterized. Unlike most other circulations, the vasculature of the nasal mucosa is highly enriched with constrictor alpha2-adrenoceptors. Therefore, experiments were performed to determine whether phenylpropanolamine activates vascular alpha2-adrenoceptors. Mouse tail and mesenteric small arteries and human small dermal veins were isolated and analyzed in a perfusion myograph. The selective alpha1-adrenergic agonist phenylephrine caused constriction of tail and mesenteric arteries and human veins. The selective alpha2-adrenergic agonist UK14,304 [5-bromo-N-(4,5-dihydro-1H-imidazol-2-yl)-6-quinoxalinamine] caused constriction in tail arteries and in human veins, but not mesenteric arteries. The lack of constriction to UK14,304 was also observed in endothelium-denuded mesenteric arteries. Phenylpropanolamine constricted both types of artery but was 62-fold more potent in tail arteries. In mesenteric arteries, constriction to phenylpropanolamine was not affected by the selective alpha2-adrenergic antagonist, rauwolscine (10(-7) M) but was abolished by the selective alpha1-adrenergic antagonist, prazosin (3 x 10(-7) M). In contrast, constriction to phenylpropanolamine in tail arteries and in human veins was inhibited by rauwolscine but not prazosin. Therefore, phenylpropanolamine is a preferential alpha2-adrenergic agonist. At low concentrations, it constricts blood vessels that express functional alpha2-adrenoceptors, whereas at much higher concentrations, phenylpropanolamine also activates vascular alpha1-adrenoceptors. This action likely contributed to phenylpropanolamine's therapeutic activity, namely constriction of the nasal vasculature.

Adrenergic alpha-1 Receptor Agonists↗
PubMed1990

The effects of urine pH modification on the pharmacokinetics and pharmacodynamics of phenylpropanolamine.

To determine whether urinary alkalinization had an effect on the plasma pharmacokinetics and pharmacodynamics of phenylpropanolamine, a double-blind crossover study was conducted in four healthy, normotensive male volunteers. The subjects received 25 mg immediate-release phenylpropanolamine and either placebo or sodium bicarbonate in a balanced randomized order. The bicarbonate treatment consisted of 6 g sodium bicarbonate 30 min prior to the phenylpropanolamine and then 3 g sodium bicarbonate every 4 hr for the next 16 hr. During the control treatment, phenylpropanolamine and a placebo for bicarbonate (lactose) were given on the same schedule. Blood and urine samples were collected over 24 hr and analyzed by HPLC. A supine blood pressure and pulse were obtained before each blood sample. The bicarbonate treatment significantly increased the urine pH throughout the study period and decreased phenylpropanolamine renal clearance by 33.5%. The apparent total-body clearance was also decreased by 31.5% and resulted in higher postabsorptive plasma phenylpropanolamine concentrations in each subject as compared to the control treatment. Both systolic and diastolic blood pressures changed significantly from baseline in both treatments. The bicarbonate treatment was accompanied by significantly higher diastolic blood pressures than in the control treatment, but there was no effect on systolic blood pressures. Generally, when the blood pressure-concentration pairs were plotted chronologically, clockwise hysteresis curves resulted. Heart rates did not change significantly from baseline values for either treatment. In this small group of normotensive healthy male volunteers, urinary alkalinization significantly depressed the renal clearance of phenylpropanolamine, producing higher postabsorptive phenylpropanolamine plasma concentrations and a small but significant increase in the diastolic blood pressure.

Adult↗
PubMed1989

Individual variability in the blood pressure response to intravenous phenylpropanolamine: a pharmacokinetic and pharmacodynamic investigation.

The intersubject variability in blood pressure response to 0.44 mg/kg intravenous phenylpropanolamine (d,l-norephedrine) was studied in 10 normal subjects. A phenylpropanolamine or placebo infusion was administered over 45 minutes on separate days according to a double-blind, balanced protocol. Blood pressure increased by 24 +/- 13/16 +/- 7 mm Hg (systolic/diastolic, mean +/- SD) after the phenylpropanolamine infusion and was statistically different from the placebo infusion response (7 +/- 5/8 +/- 3 mm Hg). Phenylpropanolamine infusions were terminated early in two subjects (hyperresponders) after 0.31 and 0.23 mg/kg because of excessive increases in blood pressure (52/30 and 34/21 mm Hg, respectively). The hyperresponders had the lowest peak serum phenylpropanolamine concentrations. These data suggest that considerable intersubject variability exists in the blood pressure response to intravenous phenylpropanolamine. A pharmacokinetic basis for the variability in response to racemic phenylpropanolamine was not observed. A relationship did not exist within the group between blood pressure effect and serum concentration but did exist within each subject. Therefore phenylpropanolamine's blood pressure effect in an individual cannot be predicted solely from a serum concentration of racemic drug.

Adult↗
PubMed1991

A pharmacodynamic interaction between caffeine and phenylpropanolamine.

The pharmacokinetic and pharmacodynamic interaction between caffeine and phenylpropanolamine has been investigated in six normal subjects in a double-blind, placebo-controlled, Latin-square design study. After 3 days on a 100 mEq sodium, xanthine-free diet, fasting subjects were placed in a supine position and were given 25 mg phenylpropanolamine and placebo, 250 mg caffeine and placebo, or 25 mg phenylpropanolamine and 250 mg caffeine in random order. Blood pressure, pulse, plasma renin activity, and plasma catecholamine levels were measured before and for 3 hours after drug administration. Plasma and urinary phenylpropanolamine, caffeine, and caffeine metabolite levels were measured serially for 48 hours. Coadministration of caffeine and phenylpropanolamine produced an additive increase in blood pressure. This effect could not be explained by any pharmacokinetic interaction between the two drugs and occurred even though phenylpropanolamine attenuated the epinephrine and renin response to caffeine. These data suggest that a clinically relevant interaction between caffeine and phenylpropanolamine does occur in drug-free subjects and that this interaction cannot be explained by a mechanism involving the sympathetic or renin-angiotensin systems.

Adult↗
PubMed2001

Phentolamine reduces myocardial injury and mortality in a rat model of phenylpropanolamine poisoning.

BACKGROUND: Phenylpropanolamine produces dose-related, life-threatening cardiovascular, and central nervous toxicity from alpha-adrenergic overstimulation. Although some recommend the alpha-adrenergic antagonist, phentolamine, as treatment for such toxicity, its therapeutic efficacy has not been previously studied. We sought to determine if pretreatment with phentolamine could reduce acute myocardial injury and mortality in rats administered an overdose of phenylpropanolamine. METHODS: In the mortality arm of the study, 28 unanesthetized, male Wistar rats (14 animals per group) were randomized to receive an intraperitoneal injection of phentolamine (3 mg/kg) or an equal volume of normal saline diluent (control group). Twenty-five minutes later, all rats received an intraperitoneal injection of phenylpropanolamine (150 mg/kg). Mortality was compared at 24 hours. In the myocardial injury arm of the study, 20 unanesthetized rats (10 per group) were randomized to receive an intraperitoneal injection of phentolamine (3 mg/kg) or normal saline (control group). Twenty-five minutes later, all rats received an intraperitoneal injection of phenylpropanolamine (75 mg/kg). Seventy-two hours after phenylpropanolamine administration, all surviving animals were sacrificed and transverse sections of their hearts were graded histologically for injury by a blinded cardiac pathologist. RESULTS: Twelve rats died within 6 hours of phenylpropanolamine administration. Mortality was significantly lower in the phentolamine-pretreated rats (2/14; 14%) as compared to the control group (10/14; 71%; p = 0.006). The degree of myocardial injury was significantly lower in the phentolamine-pretreated rats (0) as compared to the control group (1.4 +/- 1.6; p = 0.012). CONCLUSION: In this rat model, phentolamine pretreatment prevented acute myocardial injury and significantly reduced lethality from an intraperitoneal phenylpropanolamine overdose.

Adrenergic alpha-Agonists↗
PubMed1982

Stability of phenylpropanolamine hydrochloride in liquid formulations containing sugars.

Stability studies with a decongestant syrup formulation containing phenylpropanolamine hydrochloride in a sugar vehicle indicated a loss of phenylpropanolamine hydrochloride. To ascertain the biological significance of this indicated chemical loss, the degraded formulation was administered to human volunteers and the urinary excretion of phenylpropanolamine hydrochloride was determined. The excretion and chemical assay patterns were in good agreement, indicating that the sugar vehicle was both chemically and biologically incompatible with phenlypropanolamine hydrochloride. A control formulation made with phenylpropanolamine hydrochloride in a sorbitol vehicle showed good chemical stability and urinary excretion patterns. Further studies showed chemical losses with phenylpropanolamine hydrochloride in the presence of fructose, dextrose, and 5-(hydroxymethyl)-2-furaldehyde but not with levulinic acid. Possible mechanisms for the sugar-phenylpropanolamine hydrochloride interaction are discussed.

Carbohydrates↗
PubMed1993

Phenylpropanolamine potentiation of acetaminophen-induced hepatotoxicity: evidence for a glutathione-dependent mechanism.

Pretreatment of male ICR mice with the adrenergic agonist phenylpropanolamine (200 mg/kg, ip) resulted in a marked potentiation of hepatotoxicity produced by acetaminophen (400 mg/kg, ip). Enhanced liver necrosis with phenylpropanolamine pretreatment was evident both by measurement of serum aminotransferase activity and by histopathologic examination. Several lines of experimental evidence suggest this interaction is a result of the hepatic glutathione depression produced by alpha-adrenergic compounds, which adds to the glutathione depression caused by toxic, or nearly toxic, doses of acetaminophen. First, the potentiation of acetaminophen hepatotoxicity was time-dependent, being observed only when phenylpropanolamine was administered as a 3-hr pretreatment and not when given 1 hr before, with, or 3 hr after acetaminophen. The 3-hr interval between phenylpropanolamine and acetaminophen doses corresponds to the characteristic lag period required for alpha-adrenergic agents (including phenylpropanolamine) to produce significant and maximal effects on hepatic glutathione content. Second, dose-response relationships for phenylpropanolamine and acetaminophen were such that increased toxicity was observed only when the interaction was sufficient to lower hepatic glutathione concentrations below a level regarded as critical in preventing acetaminophen-induced hepatotoxicity. Third, when animals were pretreated with two nonadrenergic depletors of hepatic glutathione, diethylmaleate (125 mg/kg, ip) or the glutathione synthesis inhibitor buthionine sulfoximine (222 mg/kg, ip), at doses producing glutathione depletion approximating that observed with the adrenergic agents, acetaminophen hepatotoxicity was potentiated to the same extent. From these observations it is postulated that a variety of adrenergic compounds known to deplete hepatic glutathione by a moderate 30-50% may potentiate the hepatotoxicity of acetaminophen and possibly other hepatotoxic compounds for which glutathione conjugation is an important detoxification pathway.

Acetaminophen↗
PubMed1990

Phenylpropanolamine increases plasma caffeine levels.

The effects of the widely consumed drugs caffeine and phenylpropanolamine are mediated through activation of the central and sympathetic nervous systems. Severe, life-threatening, and occasionally fatal hypertensive reactions have been reported after their combined use. This study examined the possible pharmacokinetic interaction of phenylpropanolamine and caffeine. Sixteen normal subjects received combinations of caffeine, phenylpropanolamine, and placebo. In subjects receiving 400 mg caffeine plus 75 mg phenylpropanolamine, the mean (+/- SEM) peak plasma caffeine concentration of 8.0 +/- 2.2 micrograms/ml was significantly greater than after 400 mg caffeine alone (2.1 +/- 0.3 micrograms/ml; t[24] = 2.4; p less than 0.01). Physical side effects were more frequent after the phenylpropanolamine-caffeine combination than after either drug alone or after placebo. Greater increases in both systolic and diastolic blood pressures occurred after the combination than after either drug alone. Because caffeine levels can be increased greatly when certain other drugs are coconsumed, these data indicate that phenylpropanolamine may enhance absorption or inhibit elimination of caffeine and may explain increased side effects reported after their combined use.

Adult↗
PubMed2003

The effects of phenylpropanolamine on Zucker rats selected for fat food preference.

Treatments of human and rodent obesity frequently involve administration of amphetamine derivatives, much like phenylpropanolamine, which suppress food intake. The Zucker rat is a commonly employed model of youth-onset obesity in which the homozygous genotype manifests hyperphagia as well as other characteristics that parallel human obesity. Using a macronutrient selection procedure, we examined phenylpropanolamine's differential actions in controlling dietary intake, spontaneous open-field activity, and regional hypothalamic neurotransmitter levels in obese female Zucker rats of varying fat food preference. We hypothesized that phenylpropanolamine would alter hypothalamic monoamine levels differently in low-fat preferring and high-fat preferring Zucker rats, and hence affect feeding behavior and activity differently in these two groups. It was found that in high-fat preferring animals, phenylpropanolamine significantly decreased spontaneous open-field activity, decreased only carbohydrate caloric intake, and increased serotonin and 5-HIAA levels in the paraventricular nucleus (PVN). In low-fat preferring animals, phenylpropanolamine decreased carbohydrate, protein, and total caloric intake, had no significant effect of spontaneous activity, and increased serotonin and 5-hydroxyindole acetic acid levels in the PVN. Inherent and induced physiological differences of low-fat and high-fat preferring animals are discussed as well as phenylpropanolamine's potential in combination drug therapy for the treatment of human hyperphagic obesity.

Animals↗
PubMed1989

Terfenadine with or without phenylpropanolamine in the treatment of seasonal allergic rhinitis.

The efficacy of terfenadine in combination with phenylpropanolamine was assessed by comparison with terfenadine alone in a double-blind, parallel group study of 66 patients with nasal birch pollen allergy. The patients were allocated randomly into two groups; 34 patients received terfenadine (60 mg) twice daily and 32 patients a combination tablet containing terfenadine (60 mg) and phenylpropanolamine (50 mg) twice daily for 17 days during the birch pollen season. Nasal symptoms (sneezing, discharge, itching and blockage) were relieved significantly by both drugs, but control of symptoms was more rapid and better with the terfenadine-phenylpropanolamine combination. Rhinoscopic evaluation of nasal secretion and mucosal swelling showed no differences between the treatment groups. Compared with pre-season values, nasal peak expiratory flow (PEF)-values worsened significantly during the season in the terfenadine, but not in the terfenadine-phenylpropanolamine, group. The general condition of the patients was significantly better in the terfenadine-phenylpropanolamine group. There were no marked side-effects in either group. At the end of the trial some of the patients in both treatment groups still had symptoms; this is apparently due to the long-lasting and severe pollen season. It is concluded that terfenadine combined with phenylpropanolamine gives better control of seasonal allergic rhinitis than terfenadine alone.

Benzhydryl Compounds↗
PubMed1996

The pharmacokinetics and bioavailability of clemastine and phenylpropanolamine in single-component and combination formulations.

Studies were conducted in healthy male volunteers (n = 171; age range, 19-49 years; 22-27 subjects per study) to examine the following: pharmacokinetics and dose proportionality of the antihistamine clemastine; the effect of coadministration of phenylpropanolamine and clemastine on the pharmacokinetics of the two drugs; and the bioavailability of clemastine tablets and combination tablets of clemastine and sustained-release phenyl-propanolamine under fasted and fed conditions after single-dose administration and at steady state. All studies used crossover designs, with randomized drug treatments separated by a 7-day washout period for the single-dose studies, and with administration every 6 or 12 hours for 7 days per treatment for the steady-state studies. After single oral doses of clemastine solution (1,2, and 4 mg), the area under the concentration-time curve (AUC) and maximum concentration (Cmax) were dose proportional. Clemastine showed a first-pass reduction in the extent of absorption, with oral bioavailability calculated as 39.2 +/- 12.4%. Extravascular distribution of drug was suggested by the high volume of distribution (799 +/- 315 L) and low Cmax (0.577 +/- 0.252 ng/mL/mg) observed at 4.77 +/- 2.26 hours after administration, and by the biphasic decline in plasma concentration. The terminal elimination half-life (t1/2) of clemastine was 21.3 +/- 11.6 hours. Steady-state concentrations of clemastine were consistent with linear pharmacokinetic processes, and clearance was unaffected by age in the range studied, or by race. Clemastine solution and tablets were bioequivalent, and food had no significant effect on rate and extent of absorption of clemastine. The 1- and 2-mg clemastine tablets showed proportional bioavailability. Coadministration of clemastine with phenylpropanolamine did not significantly influence the pharmacokinetics of clemastine or the AUC and elimination t1/2 of phenylpropanolamine, but reduced the rate of absorption of phenylpropanolamine. Combination tablets containing 1 mg or 2 mg of immediate-release clemastine plus 75 mg of sustained-release phenylpropanolamine for twice daily administration were bioequivalent to the separate components and showed no significant interaction with food.

Adult↗
PubMed1991

Potentiation of carbon tetrachloride hepatotoxicity by phenylpropanolamine.

Hepatic necrosis produced by carbon tetrachloride (0.02, 0.06, or 0.20 ml/kg, ip) in mice was found to be potentiated by simultaneous cotreatment with phenylpropanolamine (200 mg/kg, ip), a drug with catecholamine-like pharmacologic effects. The ability to potentiate carbon tetrachloride-induced hepatic necrosis was shared by a compound with agonist effects relatively selective for alpha 2-adrenoreceptors (clonidine, 5 mg/kg, ip), but not by specific alpha 1-adrenoreceptor agonists (phenylephrine, up to 100 mg/kg, ip and methoxamine, up to 50 mg/kg, ip) or by the beta-adrenoreceptor agonist isoproterenol (up to 100 mg/kg, ip). Yohimbine (5 mg/kg, ip), a selective alpha 2-adrenoreceptor antagonist, completely blocked the potentiating effect of phenylpropanolamine on carbon tetrachloride hepatotoxicity, providing further evidence that the increased hepatotoxic response with phenylpropanolamine cotreatment was mediated through alpha 2-adrenoreceptor stimulation. Four potential mechanisms for phenylpropanolamine potentiation of liver injury from carbon tetrachloride were examined: (1) increased concentrations of carbon tetrachloride in the liver from greater absorption or altered distribution; (2) diminished food consumption leading to a starvation-like increase in responsiveness to carbon tetrachloride; (3) impaired detoxification through a depletion of hepatic glutathione content; and (4) enhanced toxicity produced by elevated core body temperature. None of these potential mechanisms was supported by the experimental results. It is concluded that phenylpropanolamine and related compounds potentiate carbon tetrachloride hepatotoxicity through a mechanism involving alpha 2-adrenoreceptor stimulation that has yet to be identified.

Animals↗
PubMed1987

An examination of the intravenous self-administration of phenylpropanolamine using a cocaine substitution procedure in the baboon.

Intravenous self-administration of phenylpropanolamine HCl (0.10 to 10.0 mg/kg/injection) was examined in baboons under conditions in which baseline responding was maintained by intravenous injections of cocaine HCl (0.32 mg/kg/injection). Drug was available under a FR 160-response schedule of intravenous injection. Each drug injection was followed by a 3-hr time-out allowing a maximum of eight injections per day. Phenylpropanolamine or phenylpropanolamine vehicle (saline) was substituted for cocaine for a period of 15 days followed by a return to the cocaine baseline. Response rates after phenylpropanolamine substitution were similar to those maintained by saline substitution, and lower than those maintained under cocaine baseline conditions. At the two highest doses of phenylpropanolamine tested (3.2 and 10.0 mg/kg/injection) concurrent food maintained behavior was suppressed.

Animals↗