Psychosis in an adolescent patient with Wilson's disease: effects of chelation therapy.

Wilson's disease is a rare genetic disorder involving the liver and brain, with onset frequently in adolescence. Psychiatric symptoms are often the first manifestation of the disease and can obscure the diagnosis. Chelation therapy can reverse the fatal outcome of untreated patients, so early detection is critically important. This paper describes an adolescent with Wilson's disease who, after initiation of penicillamine therapy, developed florid psychosis that improved as copper levels were decreased and that did not require use of neuroleptic medication.

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.

Adverse drug effects attributed to phenylpropanolamine: a review of 142 case reports.

Phenylpropanolamine (PPA) is contained in about 106 products, over half of which are available over-the-counter (OTC). Most are cough/cold remedies; nine are OTC diet aids. More than nine million Americans were using OTC diet aids in 1981, making PPA the fifth most used drug in the United States, responsible for over $200 million in revenues. The safety of PPA remains controversial. Although most controlled studies indicate minimal pressor effects with recommended doses, adverse drug reactions (ADRs) continue to be documented. Since 1965, 142 ADRs have been reported in 85 studies, 69% of these in North America. Many such cases may go unrecognized. About two thirds of all ADRs occurred in females and in patients under 30. Of ADRs attributed to legitimately sold PPA products, 85% occurred after consumption of OTC products versus only 15% after prescription drugs. The PPA product often contained combination ingredients, or PPA was consumed along with additional drugs. An overdose of PPA was taken in about a third of the cases. After ingestion of non-overdose amounts, 82% of the ADRs were severe. The most frequent side effects involved symptoms compatible with acute hypertension, with severe headache the most common complaint. Twenty-four intracranial hemorrhages, eight seizures, and eight deaths (most due to stroke) were associated with PPA ingestion. We have summarized these data in an effort to alert clinicians to the prevalence of usage of PPA products and the potential for adverse effects. In patients who present with elevated blood pressure or signs of acute hypertension, especially hypertensive encephalopathy of undetermined origin, we recommend inquiry about recent ingestion of PPA-containing diet aids and cough/cold products and suggest having such patients remain upright rather than supine.

Phenylpropanolamine and caffeine use among diet center clients.

We surveyed phenylpropanolamine (PPA) use and overuse among 309 diet center clients. Fifty-one percent of all subjects surveyed reported using PPA drugs: 44 percent used cold medicines and 16 percent used diet aids. Twenty-two percent of diet aid users and 7 percent of cold medicine users reported that they deliberately used more than the dosage recommended to improve efficacy. Among diet aid users, 59 percent also regularly consumed caffeine. Despite package warnings, individuals who had been told by their doctors that they were hypertensive used PPA products as often as normotensive individuals. PPA, the fifth most frequently used drug in the USA, is contained in over-the-counter (OTC) diet aids as well as OTC and prescription cold medicines. Severe adverse drug reactions (ADRs) including hypertensive crisis, stroke and death have been attributed to PPA products. Clinical studies have shown that using greater than recommended doses of PPA and using PPA in combination with caffeine may increase the risk of ADRs. Overweight patients may be particularly at risk for ADRs to PPA because they are likely to be hypertensive and to use diet aids. We recommend informing diet center clients of the potential dangers of consuming PPA products, especially more than the recommended dose, in the presence of hypertension, and when other sympathomimetic drugs are being taken.

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.

Isoproterenol infusion test in anorexia nervosa: assessment of pre- and post-beta-noradrenergic receptor activity.

Anorexia nervosa is associated with alterations in sympathetic activity and metabolism that persist during and after weight recovery. This study assessed beta-adrenergic receptor activity, an important modulator of vascular and metabolic function, in anorexic patients studied when underweight and at intervals during recovery, in comparison with healthy volunteer women. An increase in heart rate, in response to increasing doses of isoproterenol, served as an index of postsynaptic activity. Anorexic patients, during refeeding and weight gain, needed a significantly higher dose of isoproterenol to increase basal heart rate by 25 beats/minute, compared with underweight anorexic patients. Down-regulated postsynaptic cardiac beta-adrenoceptors during weight gain may protect against refeeding-induced exaggerated sympathetic activity. Because presynaptic beta-adrenoceptors serve as a positive feedback loop for synaptic catecholamine secretion, the increase in plasma norepinephrine concentrations during the isoproterenol infusion served as an index of presynaptic activity. We found that increasing doses of isoproterenol were associated with a linear increase in plasma norepinephrine in each healthy volunteer. In contrast, anorexic patients at any state had a significantly more erratic secretion of plasma norepinephrine in response to increasing doses of isoproterenol. Altered regulation of presynaptic adrenoceptors may explain, in part, the large variance and little consensus between previous studies as to whether anorexic patients have reduced or normal plasma norepinephrine levels.

Disturbances of noradrenergic systems in normal weight bulimia: relationship to diet and menses.

Several lines of evidence suggest that noradrenergic (NE) disturbances occur in normal-weight bulimic patients. The purpose of this study was to investigate factors that may be related to noradrenergic disturbances. First, we measured plasma NE during bingeing and vomiting. We found that this behavior activated the sympathetic nervous system. Bingeing produced a significant increase in the duration and the peak increase of plasma NE when compared with normal controls eating a large meal. Second, we assessed basal peripheral and central NE levels near in time (within several days of hospital admission) to chronic bingeing and vomiting. At this time, bulimics had normal basal plasma and CSF NE levels. Finally, we restudied the same patients after 30 days of inpatient hospitalization and observed abstinence from bingeing and vomiting. In this last state, bulimics had a reduction of basal plasma and cerebrospinal fluid (CSF) NE levels compared with themselves on admission and compared with healthy controls. This study confirms that reduced noradrenergic activity occurs in normal-weight bulimic women and suggests that this abnormality may emerge during abstinence from bingeing. We hypothesize that dietary intake is related to noradrenergic activity, but cause and effect remain uncertain. Noradrenergic disturbances did not appear to be related to weight, depression, physical activity, or amino acid precursors. Lower CSF NE levels were found in amenorrheic bulimic women in both states, suggesting that a noradrenergic disturbance may be associated with the frequent incidence of amenorrhea in bulimic women.

Calcium attenuates epinephrine's beta-adrenergic effects in postoperative heart surgery patients.

Epinephrine and calcium possess both cardiac inotropic and vasopressor activity. In addition, epinephrine's cardiovascular effects are mediated via increases in intracellular calcium. As a result, many clinicians administer the two agents together in an attempt to augment their effects. Although this approach seems rational, it has never been proven effective. We evaluated the cardiovascular and hyperglycemic actions of epinephrine (10 and 30 ng/kg/min), with and without calcium chloride administration (10 mg/kg bolus followed by 2 mg/kg/hr infusion), in a prospective, randomized, blinded, crossover designed study. Twelve adult patients were studied 1 day after aortocoronary bypass surgery. Calcium chloride raised ionized calcium levels from 1.06 +/- 0.03 (mean +/- SEM) to 1.44 +/- 0.05 mM (p less than 0.05). Calcium raised mean arterial pressure from 85 +/- 1 to 94 +/- 2 mm Hg (p less than 0.05) but had no significant effect on cardiac index. Epinephrine alone at 10 and 30 ng/kg/min significantly raised cardiac index from 2.7 +/- 0.2 to 3.0 +/- 0.2 (p less than 0.05) and 3.6 +/- 0.3 (p less than 0.05) l/min/m2. After calcium, epinephrine failed to significantly increase cardiac index. Epinephrine at 30 ng/kg/min significantly increased mean arterial pressure from 87 +/- 1 to 95 +/- 2 mm Hg (p less than 0.05). After calcium, epinephrine had no significant effect on blood pressure. In addition, epinephrine's hyperglycemic effect was blunted by calcium. Plasma epinephrine levels were similar during control and calcium infusions. We conclude that calcium blunts epinephrine's beta-adrenergic actions in postoperative cardiac surgery patients.

Catecholamines: study of interspecies variation.

In the last three decades, numerous articles on plasma catecholamine concentrations in various settings have been published in the medical literature. Despite this abundance of information, no summary article has analyzed the species variations in circulating catecholamine concentrations. In this paper, the plasma catecholamine responses to various stresses in 31 animal groups have been compiled from greater than 200 publications (with greater than 5000 animal subjects). Primitive cartilaginous fish such as the shark and the lamprey have the highest reported basal plasma catecholamine concentrations. Birds, mammals, and teleost fish have the lowest concentrations. The lower circulating catecholamine concentrations parallel anatomical changes in the development of the adrenal medulla and the development of the nervous system. Decapitation, hypoxia, hemorrhage, and hypothermia are the experimental conditions associated with the greatest stress-induced changes in plasma catecholamine concentrations. The differences in experimental design are tabulated to afford the reader an opportunity to compare catecholamine levels among species. The table provides a detailed guide to normal concentrations and normal responses in 31 species. This report gives a dynamic overview of catecholamine concentrations in human and animal physiology and may be particularly helpful to investigators involved in catecholamine research.

Clinical, psychophysiological, and neurological characteristics of volunteers with impaired smooth pursuit eye movements.

Two hundred eighty-five volunteers from a community college were screened on campus for accuracy of their smooth pursuit eye movements (SPEM) by electrooculograph (EOG). Those volunteers with the least and the most accurate SPEM were recalled to the laboratory for a comprehensive evaluation of clinical and demographic characteristics, family history, neurological status, and psychophysiological and biological measures, including SPEM [repeat EOG test and infrared (IR) test], an electroencephalogram, auditory and visual evoked potentials, reaction time (RT), the continuous performance task (CPT), platelet monoamine oxidase (MAO), plasma amine oxidase, and dopamine-beta-hydroxylase (DBH). Low-accuracy SPEM was associated with social isolation, inadequate rapport, eccentricity, and a variety of related schizotypal or schizophrenia-like characteristics, but not with generalized psychopathology or other demographic/medical/clinical history variables. Low-accuracy SPEM also was associated with neurological and psychophysiological abnormalities frequently observed in schizophrenic patients. These results suggest that impaired SPEM may reflect an underlying central nervous system dysfunction that is specifically associated with clinical and biological characteristics related to schizophrenia, even in the absence of overt schizophrenia.

Transient hypertension after two phenylpropanolamine diet aids and the effects of caffeine: a placebo-controlled follow-up study.

PURPOSE AND PATIENTS AND METHODS: Reports of severe adverse reactions following the ingestion of single (75 mg) or double doses of the sympathomimetic drug phenylpropanolamine (PPA), with and without caffeine, prompted us to undertake a study of the effects of five drug preparations (75 mg PPA, 150 mg PPA, 75 mg PPA plus 400 mg caffeine, 400 mg caffeine, and placebo) in 16 resting, normotensive subjects. The study was of a double-blind, randomized, crossover design. Each subject consented to take the five drug preparations on different study days, which were separated by at least 48 hours. RESULTS: Compared with blood pressure (BP) values obtained after placebo ingestion, significant BP increases occurred over several hours following 150 mg PPA and after 75 mg PPA plus 400 mg caffeine. Significant BP increases after ingestion of 75 mg PPA and after 400 mg caffeine were less frequent. The mean peak BP following 150 mg PPA was 173 +/- 9/103 +/- 4 mm Hg, compared with 148 +/- 4/97 +/- 3 mm Hg after the other three active preparations; after placebo, peak BP reached 137 +/- 8/85 +/- 5 mm Hg. CONCLUSION: These results indicate that 150 mg PPA (the amount in two diet aids) substantially elevates BP. Our findings may explain some of the recent case reports of nontraumatic intracranial hemorrhage in young, healthy persons ingesting PPA at recommended or minimally greater dosages. We suggest physicians inform patients who are likely consumers of PPA (i.e., those with allergies, those with eating disorders, overweight persons, women during the postpartum period) and patients at risk for stroke (i.e., the elderly and hypertensive patients) of the risks of taking more than the recommended amounts of PPA and of combining caffeine with PPA.

Alterations in sympathetic nervous system activity with intraoperative hypothermia during coronary artery bypass surgery.

To determine how intraoperative hypothermia associated with coronary bypass surgery (CABS) alters sympathetic nervous system (SNS) activity, we prospectively studied 21 adult CABS patients and measured preoperative, intraoperative, and postoperative circulating catecholamine concentrations. Because thyroid hormone levels change rapidly following CABS, we also serially measured these hormone levels. The measured plasma concentrations for each of the above variables were corrected for hemodilution during CABS by using serum albumin changes as a reference. It was concluded that important alterations in SNS activity and thyroid hormone homeostasis occur in humans during CABS and deep hypothermia, and that changes in core temperature may contribute to these findings. We speculate that these hormonal changes may influence the response to adrenergic receptor therapy in hypothermic patients and may contribute to arrhythmias during rewarming and the immediate postoperative period.

Disulfiram-induced fulminating hepatitis: guidelines for liver-panel monitoring.

Although psychiatrists have medical responsibility for many alcoholic patients, the psychiatric literature, in contrast with the general medical literature, contains few reports of disulfiram-induced hepatotoxicity. For that reason, the authors review the literature on disulfiram hepatitis and report a case of severe fulminating hepatitis associated with disulfiram use, despite careful and currently accepted standard-of-care clinical and biochemical monitoring. All but two of the 17 disulfiram-associated hepatotoxic cases reviewed developed symptoms after 2 weeks to 2 months of use. Six patients died. This article discusses strategies for avoiding that rare but life-threatening side effect. The strategies include more frequent initial measurements of liver enzymes than is now accepted. Currently, only two reports recommend liver-function studies on a regular schedule for patients taking disulfiram. The authors believe that liver-function tests should be administered before treatment, at 2-week intervals for 2 months, and at 3- to 6-month intervals thereafter. The authors emphasize that the hepatotoxicity reaction is rare and do not discourage the use of disulfiram in appropriate patients; rather, they wish to heighten the index of suspicion to disulfiram-induced hepatotoxicity.

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.

Psychiatric side effects attributed to phenylpropanolamine.

Phenylpropanolamine (PPA) is a sympathomimetic drug similar in structure to amphetamine which, in the United States, is present in over 130 medications, primarily decongestants, cough/cold remedies, and anorectic agents. We have reviewed 37 cases (published in North America and Europe since 1960) that received diagnoses of acute mania, paranoid schizophrenia, and organic psychosis and that were attributed to PPA product ingestion. Of the 27 North American case reports, more reactions followed the ingestion of combination products than preparations containing PPA alone; more occurred after ingestion of over-the-counter products than those obtained by prescription or on-the-street; and more of the cases followed ingestion of recommended doses than overdoses. Groups at particular risk appear to be those with a past or family psychiatric history, children under the age of 6 and post-partum women. Failure to recognize PPA as an etiological agent in the onset of symptoms usually led to a diagnosis of schizophrenia or mania, lengthy hospitalization, and treatment with substantial doses of neuroleptics or lithium. While generally safe at recommended doses, PPA can be hazardous to susceptible individuals and we urge physicians to be alert to the potential for PPA related psychiatric reactions. We have compiled an alphabetized table (Table 1: Prescription and Over-the-Counter Products Containing Phenylpropanolamine) allowing busy clinicians quick access to those drugs containing PPA.

The effects of phenylpropanolamine on human sympathetic nervous system function.

Phenylpropanolamine (PPA) is a sympathomimetic agent, very similar in structure to amphetamine. In the United States, it is present in over 130 medications, primarily anorectic agents and cough and cold remedies, many available without a prescription. The effects of PPA on blood pressure (BP) remain controversial and its mechanisms of action unknown. We studied acute (1 and 2 hours) and 2-week effects of a daily dose of 75 mg of sustained release PPA administered to 14 normal volunteers. Measurements of heart rate, BP, and plasma catecholamines (CA) were made with the subject in the supine and standing positions, and upon gripping a hand dynamometer for 5 minutes. Although systolic BP across all postures and sampling times was significantly higher when subjects were taking PPA in comparison to placebo (F = 5.95, p = 0.03), in no subject did the increase in BP reach hypertensive or clinically significant levels and no substantial changes in CA levels were found. Our study population was relatively young and normotensive; even such a small BP increase may pose greater problems for hypertensive, obese subjects likely to be users of diet aids. Strenuous isometric exercise did not cause any greater increase in BP or CA after subjects took PPA versus placebo. PPA blood levels 24 hours after the last of 14 daily doses were similar to levels 1 and 2 hours after an initial dose. We conclude from these data that recommended doses of PPA have only minimal sympathetic nervous system (SNS) and cardiovascular effects in young, healthy, normotensive populations at the times and dose studied.

Plasma and urinary catecholamines in salt-sensitive idiopathic hypertension.

Nineteen patients with normal renin idiopathic hypertension were arbitrarily classified as salt-sensitive or salt-resistant depending on whether their mean arterial pressure did or did not increase by 8% or more when sodium intake was increased. The responses of the two subsets and of five normal subjects to sodium intakes of 9, 109, and 249 mEq/day given for 7 days were as follows: The salt-sensitive subjects retained more sodium than normal and plasma or urinary norepinephrine did not decrease when they were given a high sodium intake; urinary dopamine was normal but did not increase normally when sodium intake was increased. The salt-resistant subjects excreted sodium normally and plasma and urinary norepinephrine was decreased by 30 and 37%, respectively, when they were given a high sodium intake; urinary dopamine was supernormal and did not increase further when sodium intake was increased. Cumulative sodium retention during the high sodium intake was directly related to the percentage of change in plasma norepinephrine in the hypertensive subjects, suggesting that renal adrenergic activity was a factor in the impaired sodium excretion in the salt-sensitive patients. Cumulative sodium retention and the percentage of change in plasma norepinephrine were inversely related to urinary dopamine in the hypertensive subjects, suggesting that increased formation of dopamine in renal and neural tissue in the salt-resistant subjects may have been responsible for the differences between the subsets in renal and adrenergic responses to a high sodium intake.(ABSTRACT TRUNCATED AT 250 WORDS)

Is topical application of epinephrine at skin graft donor sites during halothane anesthesia safe?

Topical epinephrine is useful in controlling the bleeding of skin graft donor sites. However, the use of exogenous epinephrine during halothane anesthetization increases the risk of cardiac arrhythmias. This study shows that there is no significant increase in plasma epinephrine levels after topical administration of up to 80 cc of 1:500,000 epinephrine, suggesting that the use of this dose in conjunction with halothane anesthesia is safe.