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Central nervous system stimulants and anorectic agents
P. H. Connell
1
central nervous system stimulants and anorectic agents
The past year has not yielded any major developments in our knowledge of the adverse reactions to central .~timulants, but with the general development of consciousness of civil rights and of environmental and other possibly harmful features of modern society, there has been concern about the effects of caffeine though the numbers of ~ommunications have been small. The general impression of the author of this chapter is that political, environmental, economic and other factors have tended to slow down the communications concerning the CNS stimulants and that it would be advantageous ff research endeavours were based upon the mechanism of actions of drugs of these categories and on clinical evaluations which would bear in mind in the methodology the question of mechanisms of action when looking at side effects. ANALEPTICS THEOPHYLLINE AND RELATED SUBSTANCES
Tolerance and plasma concentrations Not every type of patient may have an equal tolerance to theophylline. A study of the paradoxical effect of adrenergic and methylxanthine drugs in cystic fibrosis involved administration of these drugs as aerosols to children and young adults with this disorder (lC). Theophylline was given in high dosage (10 mg/kg three times a day) and compared with placebo in 12 cases over a period of 3 - 4 weeks, with evaluation of plasma levels. Some children could tolerate high blood levels of theophylline but most experienced nausea and vomiting or headache even when the plasma level was appropriate. The fact that these patients seemed less able to tolerate theophylline than asthmatics suggested that a degree of tolerance comes with long-term usage. Liver dysfunc-
tion, which exists in 1 5 - 3 0 % of cystic fibrosis patients, might be another reason for the inability of some patients to tolerate usual dosages of theophylline. Responses to aerosolized bronchodilators were inconsistent from week to week and there was no concordance between response to isoproterenol and theophylline. The use of adrenergic and methylxanthine drugs in cystic fibrosis must be undertaken with caution. A study of 48 acutely ill hospitalized patients with chronic obstructive pulmonary disease (2 C) which, among other measurements, studied theophylline concentrations in the plasma, stressed that aminophylline administered i.e. according to the MitenkoOgilvie recommendations frequently produced excessive theophylline plasm a concentration~ and confirmed the relationship between toxiclty and plasma concentration (SEDA-1, p. 1). It identified tachycardia as a frequent toxic symptom and demonstrated that nausea and vomiting were not reliable harbingers of life-threatening toxicity. Such data as these, and continuing reports of convulsions and even death in both children and adults in whom serum theophylline levels have grossly exceeded the accepted range of some 1 0 - 2 0 flg/ml (3 e, 4 C) show that theophylline and aminophylline are still employed without due care, either when given orally or intravenously. It is especially important to ensure that children are only given these substances in appropriate dosage forms, that intravenous administration is slow, and that in cases with severe respiratory distress the special risk of ventricular fibrillation is taken into account; in many cases, a severely ill patient should be on cardiac monitoring during treatment with such a drug (5 R). Use in pregnancy A report, claimed to be the first, of transplacental arninophyUine toxicity in a
2 neonate (6 c) described symptoms of irritability, vomiting and jitteriness, possibly related to ingestion of aminophylline by the 36-year-old asthmatic mother who had taken aminophylline intermittently for episodes of wheezing during the pregnancy. One day before delivery she had been giw several drugs for her respiratory problem, including aminophylline (500 mg by suppository and 100 mg by mouth) frusemide and nitroglycerin. Aminophylline (100 mg) was subsequently given every 4 hours. The last dose was given 1 hour before delivery. At 6 hours the infant vomited and showed slight jitteriness. Blood-glucose ('Dextrostix' test) was more than 60 mg/dl. Similar symptoms were reported after the first and second feeding and he was transferred to the intensive care unit for observation. Various investigations were negative and without special treatment the infant improved and tolerated oral feeding well from the second day. The cord serum aminophylline concentration was 9.2 g/ml and serum aminophylline concentration at 52 hours was 5.8 g/ml. The authors rightly suggest that further observations are required to confirm the apparent assumption that aminophylline was responsible for the clinical findings.
Drug mixtures A double-blind trial in a general practice population of 36 patients of 'Nethaprin' expectorant syrup (7 C) which contained 10 mg etafedrine hydrochloride (a tertiary amine similar to ephedrine in its bronchodilator effect but which is said to cause less central nervous and cardiovascular system stimulation), 120 mg bufylline (theophylline aminoisobutanol which contains approximately 67% theophylline), 12 mg doxylamine succinate (an ethanolamine antihistamine), and 200 mg glyceryl gnalacolate (an expectorant), noted that five patients reported feeling slightly drowsy during treatment (1 on placebo and 4 on Nethaprin) and that no other side effects were recorded. CAFFEINE
Acute toxicity A recent report (8 c) notes tonic posturing and central nervous system irritability after concentrated tea ingestion in a sevenweek-old previously healthy infant; caffeine was the only xanthine found in the tea using a gas chromatographic analysis. As pointed out in SED VIII (p. 2), the evidence as to the lethal dose of caffeine is fragmentary. A report of a fatality after ingestion of caffeine in a 34-year-old female
P.H. Connell (9 r who, however, had a phenobarbital blood concentration of 0.4 mg/100 ml when found in a coma, stresses that a review of the literature yields few fatal cases and most of them as a result of doses erroneously administered by hospital personnel. The report states that it is generally accepted that the fatal dose of caffeine in humans is 10 g, although oral doses in reported fatalities range from 5 - 5 0 g. It is suggested that the infrequency of death as a result of ingestion of large amounts of caffeine is perhaps due in part to the emetic effect of the drug.
Effects o f chronic use Recent concern as to the possible risks of chronic caffeine intake has been underlined by estimates of the large amounts of this substance which an average person may unwittingly ingest daily in the form of hot beverages, caffeinated soft drinks, chocolate bars, popular analgesics and prescribed medicines, e.g. for migraine (10 R, 1 It). Concern centres primarily on the cardiovascular effects, the influence on the central nervous system, and the possible repercussions for the stomach. However, one must also bear in mind the lack of exact knowledge as to the frequency of caffeinism in general or of coffee allergy, the older suspicion that caffeine might cause renal malignancy, and the ability of caffeine to catalyze the formation of N-nitrosamine in the digestive tract (12R). Cardiovascular effects A recent report of a case of paroxysmal atrial tachycardia (13 r) comments that caffeinism is a syndrome resulting from the excessive ingestion of caffeine and characterized primarily by cardiovascular and central nervous system manifestations. 'A variety of tachy-arrhythmias and extrasystoles are believed to reflect the toxic, cardiotonic effects of caffeine'. The importance of considering caffeinism as an underlying condition associated with paroxysmal atrial tachycardia is stressed. Comparisons of the mortality from ischaemic heart disease in Finland in North Karelia, where it is at its highest, and south west Finland, where it is at its lowest, set alongside consumption of coffee gives a positive correlation in terms of mortality, being highest in the area where coffee sales are higher (14c). Despite such reports, the doubt expressed earlier (SED VIII, p. 3; SEDA-I, p. 2) as to
CNS stimulants and anorectic agents
the existence of a link between caffeine and cardiac disease persists. When Yano et al. (15 c ) studied coronary disease over a sixyear period in 7705 Japanese men living in Hawaii, there did at first sight appear to be some correlation between the 294 new cases of coronary heart disease observed and the intake of coffee; however, it became statistically insignificant when cigarette smoking was taken into account. It is still true, as a recent and authoritative editorial reminds us, that 'in contrast to some retrospective studies, all prospective studies have failed to implicate coffee as an independent contributor to death from coronary heart disease or myocardial infarction' (16 R ). Central nervous system
Headaches and mental irritability are well-recognized complications of over-consumption of caffeine (SED VIII, p. 3; 12 r) and it has always been a curious fact that caffeine is present in analgesics which are commonly used habitually in the hope of relieving headache. A warning (17 r) that the presence of caffeine in these analgesics might be responsible for dependency and habituation to these products and thereby indirectly responsible for renal disease, has been published, based upon extensive (but unreported) enquiries among patients habituated to analgesics. Shorofsky and Lamm (18 R) have drawn attention to the severity of caffeine-withdrawal headache (SED VIII, p. 3), such as may be experienced by persons undergoing short-term fasting for religious reasons. Some individuals may indeed require caffeine suppositories during this period to prevent headache from occurring. Gastric effects
A review (19 r) refers to some literature and in particular to the work of Cohen and Booth (20 C) who examined the acidity of gastric juice after test solutions were administered consisting of a proprietary brand of instant coffee and one of decaffeinated coffee. Decaffeinated coffee was as potent as instant coffee in stimulating gastric acid secretion. 'To think of coffee in terms of caffeine may be excusable for the layman but certainly not for the scientist' is a view expressed in the review. DOXAPRAM Side effects of this central stimulant are
very frequent (SED VIII, p. 4; SEDA-1, p. 2) but they tend to be short-lived because of the brief half-life of the drug in plasma (21Cr). Of 20 patients aged 6 8 - 7 2 who were treated with doxapram infusion, 4 developed severe and violent restlessness, confusion or hallucinations at low doses. Three of these were known to have excessive alcohol intakes and 2 had abnormal liver function tests. It was felt that the effects were not due to alcohol withdrawal, as they were related to the onset and duration of doxapram infusion and persisted for a relatively short time after the infusion was stopped. A study of the use of doxapram for arousal from general anaesthesia in out-patients (22 C) using a double-blind method, noted that side effects in the first 10 minutes after anaesthesia were noted but none were serious. In the doxapram-treated group seven patients developed minor sequelae comprising excessive coughing (3), weeping (2), muscle tremor (1), and nausea together with a hysterical reaction to dreaming (1). However, minor problems were noted in 12 of the control patients: coughing (4), weeping (5), excessive sweating (1), excessive salivation (1), and vomiting (1). One patient in the doxapram-treated group developed nausea and vomiting after leaving the recovery area. ' A pleasant recovery with relative absence of side effects was a feature of the doxapram group'. ANORECTIC AGENTS AMPHETAMINES Though there have been few new scientific findings with respect to the amphetamines in the past year, the debate in the United States and elsewhere as to the desirability of further restrictions on theft use (23 R) has led to critical re-assessment of their usefulness as compared with their capacity for harm or misuse. Cardiovascular effects
Whilst the cardiodynamic effects of these drugs have received most emphasis (SED VIII, p. 12), they may also affect the vessel wall. A case report describes amphetamineinduced angiitis leading to renal failure in an intravenous user whose symptoms abated spontaneously, only to recur dramatically with renewed amphetamine usage and who,
4
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over a two-year period, developed malignant hypertension and terminal renal failure (24c).
will be presented later and can be anticipated with interest.
Central nervous system Despite the general opinion that amphetamines are not compatible with safe driving, a recent review (25 r) stresses the absence of hard data of any kind to enable the total contribution o f amphetamine abuse to traffic accidents to be assessed, and notes that the effect of amphetamines may enhance driving skills, though a prolonged 'spree' is widely recognized to result in abnormal psychological states that are incompatible with safe driving performance and that there is some evidence to suggest that amphetamines may induce overconfidence or increased risk acceptance. A longitudinal study (26 C) demonstrates the disruptive effects exerted by D-amphetamine on the neuroendocrine and sleeprelated organization of humans by using a double-blind method in 8 normal obese volunteers to assess effects on growth hormone, thyrotropin, cortisol, EEG changes etc., though the authors do not refer to earlier works such as Oswald's in the EEG discussion (SED VIII, p. 12).
Use in glaucoma A review of psychotropic medications and the glaucomas (29 R) includes a review of central nervous stimulants and concludes that although caution is advised, especially in patients over the age of 40, and the patient must be followed up, the evidence in the literature is that amphetamines (and other psychotropic drugs) are acceptably safe to prescribe even in patients with diagnosed glaucoma.
Misuse A study of five patients (27 C) who had injected intravenous phenmetrazine or methamphetamine showed rhabdomyolysis and shock with symptoms soon after injection, as well as chris, fever, sweats, nausea and abdominal cramps in four. Within hours vomiting, myalgias, paraesthesia, headache and orthostatism ensued. Cardiorespiratory arrest, accelerated bleeding and non-cardiac pulmonary oedema were observed in one patient. Treatment b y aggressive volume replacement after recognition of this syndrome led to recovery in all five patients. A study (28 C) of chronic cognitive, adaptive, m o t o r and sensory dysfunction associated with long-term use of volatile solvents and amphetamine presents in a Part I 'Group Profiles' report data on 160 subjects ineluding 77 drug abuse subjects and 83 sibling and peer controls. The data suggests that differences between the users and their siblings on certain tests, such as tests of memory function, rapid number letter manipulative skills and certain m o t o r function may be chronic-static sequelae of the drug abuse. A more detailed analysis of this and other data
Allergy Two cases are reported (30 c) of children aged 9 and 6 who were treated with methylphenidate for hyperkinetic behaviour disorders and who showed allergic manifestations (one developed angioneurotic oedema and the other showed urticaria). When the first patient was subsequently placed on dextroamphetamine he also developed urticaria.
Interactions An excellent review (31 R) containing 111 references has discussed the interaction of stimulants with clinically relevant drugs and refers to clinical, biochemical, animal and other researches. It is stressed that when drug abuse is considered 'chronic drug abuse may result in an altered physiology that endures b e y o n d the cessation of drug administration, and subsequent administration of other drugs may thus result in an altered response'. There is so much data in this review that it is impossible to do justice to it in a brief summary, but some of the points stressed are that: alcohol increases blood level of amphetamine; tricyclic antidepressants increase brain levels of amphetamine; barbiturates and benzodiazepines enhance amphetamine hypermotility; in treating the amphetamine psychosis where tolerance has developed to the peripheral toxic effects, it is probably wiser to use a drug such as haloperidol, which does not increase the half-life of amphetamine as does chlorpromazine; laboratory experiments demonstrate that prior chronic narcotic treatment has a residual effect of enhancing subsequent behavioural response to stimulants.
CNS stimulants and anorectic agents DIETHYLPROPION (TENUATE, APISATE, AM FEPRAMONE)
The side effects of this mildly stimulant compound were very fully set out in earlier volumes (SED VIII, p. 16; SEDA-1, p. 2) and newer studies add nothing to the picture except as regards comparative findings and the possible usefulness of fixed combinations. One comparative study over an 11week period which compared diethylpropion and fenfluramine in 36 patients (32 c ) stressed that more persons had withdrawal side effects when they had been taking fenfluramine than when taking diethylpropion, and more persons withdrew in the first phase of the trial when on fenfluramine. However, the once-a-day dose of diethylpropion has not yet been compared with the sustained release form of fenfluramine and the author stresses the need for such comparative studies. A study (33 c) of a new anorectic pharmaceutical preparation containing 75 mg diethylpropion plus 10 mg diazepam noted that side effects were mild and less than those found with other anorexigenic preparations. However, side effects were observed in about 50% of the patients and constituted dry mouth, nervousness and mild depression. FENFLURAMINE (PONDERAX)
Interactions
In the full review of adverse reactions to this drug in SEDA-1 (pp. 4, 5) it was pointed out that cases of cardiovascular complications had occurred. A recent report (34 e) of a study in rabbits, carried out after the unfortunate anaesthetic death of a 23-year-old female who had been taking fenfluramine, gave data on ECG and phonocardiographical recordings on anaesthetized rabbits who received injections of adrenaline or fenfluramine. The changes seen with fenfluramine were greater in number and less readily reversed with beta-blockers and resuscitative drugs. These findings 'may support an interaction between halothane and fenfluramine in man, and it is suggested that the latter drug be discontinued a week prior to anaesthesia for elective surgery'. Slow-release forms
A comparison of form of fenfluramine 60 mg), fenfluramine mg t.i.d.) and placebo
an extended action (Pondimin Extentabe tablets (Pondimin 20 (35 c ) noted that the
side effects were similar in the two active preparations. The weight loss superiority of the sustained-release form was thought to be due to the greater reliability in taking one dose a day than three. If this is indeed the case, one is bound to wonder how meaningful the comparison of side effects between these two forms is, and the same may apply to the similar comparisons cited earlier (SEDA-1, p. 5). MAZINDOL (SANOREX, AN 448, TERONAC, SAH 42-548)
Studies cited earlier (SED VIII, p. 20; SEDA-1, pp. 5 - 7 ) h a v e established the general pattern of side effects. It is evident that dryness of the mouth, constipation and mild adrenergic effects can appear. Although it is generally considered that anorectic drugs can only usefully be given for brief periods, some newer work does provide evidence on longer-term treatment. One cross-over trial (36 C) was in 158 obese subjects (age 1 6 - 5 9 years) who were followed up as outpatients. The study examined the short-term evaluation of the effectiveness of the anorexiant in 102 patients; the long-term evaluation of the effectiveness of protracted discontinuous treatment with anorexiant in association with hypocaloric diet in 48 women (age 1 5 - 4 5 ) ; and the effectiveness of treatment with anorexiant in association with hypocaloric diets in refractory obesity in 9 patients. It was noted that nervousness, insomnia, dizziness, dry mouth, constipation, goose flesh and chills recur with a considera b l y higher frequency and intensity in the patients who started treatment with diet and active drug. These reactions receded upon suspension of the drug and were interpreted as drug-induced. However, these symptoms also appeared in patients treated with diet and placebo and seemed less frequent and less intense when the active drug is administered later on in treatment. The incidence of side effects, mostly of the sympathomimetic type, appeared to attenuate in long-term patients. It is suggested that after months of treatment the commitment needed to observe the diet may be less tolerated than the possible side effects of the drug which are reduced if the drug is given after a period of diet alone. Effect on libido
A short communication (37c), stating that about 5% of female patients treated
P. H. Connell
with mazindol had experienced an aphrodisiac effect, and quoting one patient aged 40 years who had such a strong craving for sexual intercourse that her husband, who had a good job over a hundred miles away, had to give it up to be home during the week should be treated with interest but with caution. If this effect were general and marked it is unlikely that prevous comprehensive studies would have failed to fiote it. METHYLPHENIDATE (R1TALIN) Variability o f response A report (38 c) stresses that in view of the variation in individual response of the hyperactive child with minimal brain dysfunction to methylphenidate it should be administered in an initial small divided dose of 10 mg daily and reference to a dosage schedule determined by b o d y weight seemed inadvisable except for research purposes. A patient previously reported by the author of the report in 1968 had shown difficulty in speaking and moving his lips and tongue, associated with twitching movement of the face. A lower dosage relieved these symptoms but a second attempt to raise the dose was accompanied by recurrence of the 'extrapyramidal and seizure-like signs and symptoms. The reaction in this patient appeared to be dose-related and not idiosyncratic'. Complications o f abuse As pointed out earlier (SED VIII, p. 22) parenteral abuse of methylphenidate, using injections home-made from tablets, may cause severe local and general reactions. A recent report of 5 patients suffering either from skin abscesses or cellulitis following parenteral methylphenidate abuse (39c), in which the injection paraphernalia of 100 heroin addicts were examined to determine the presence of organisms, failed to find Staphylococcus aureus and only four contained streptococcal species. The conclusion was that skin lesions observed in methylphenidate abusers may originate as sterile abscess or necrotic ulcers and arise because of local vasospasm and/or chemical irritation (due to materials used in tablet preparations such as lactose, sucrose, polyethylene glycol, magnesium stearate, tragacanth, cornstarch and talc). These lesions are then
susceptible to secondary infection by a hose of organisms normally present in the skin (such as Streptococcus viridans). NOREPHEDRINE (PHENYLPROPANOLAMINE) Though generally used as a nasal decongestant, this compound has in some countries been introduced as an anoreetie agent. A warning issued by the Swiss Pharmaceutical Association points out that the doses used for this purpose (e.g. 25 mg three times daily) can produce severe sympathicomimetic side effects, including hypertensive crises, arrhythmias and tachycardia (40 R ). DEANOL DERIVATIVES Esters and derivatives of deanol have been studied and sold under many different names. Among the better-known of them are Lucidril (also known as meclofenoxate, centrophonoxine and deanol p-chlorophenoxyacetate) and Debrumyl (a mixture of deanol pyroglutamate with heptaminol). The various substances are claimed to have central stimulant properties which are supposed to be of value in the aged, after cerebrovascular accidents and during the treatment of epilepsy. Despite the fact that they have existed for for many years, there is very little critical work in print t o throw light on their properties. A recent paper by Bornstein et al. (41 c ) relating to the use of Debrumyl in 146 cases concludes that there was spectacular improvement in a wide range of diagnoses, yet speaks of a complete absence of side effects, except in 7 cases who suffered some insomnia. There would seem every reason to examine these products critically. Lucidril is known to be an allergen (SED VIII, p. 382) and in one series it is known to have produced nausea, vomiting and stomach pain in 9 out of 25 cases (42c). SYDNOCARB This Soviet product was studied by Bach et al. in a series of 28 patients with various psychiatric diagnoses, but all considered to be in need of central stimulation. The dosage of 3 x 10 mg daily, which was considered effective, produced disturbances of sleep in 3 patients which could be overcome b y avoiding an evening dose. One other case complained of 'unrest', three of headache and one developed an allergic rash (43c).
CNS stimulants and anorectic agents
7
REFERENCES 1. Shapiro, G.G., Bamman, J., Kanarek, P. and Bierman, C. W. (1976): The paradoxical effect of adrenergic and methylxanthine drugs in cystic fibrosis. Pediatrics, 58, 740. 2. Hendeles, L., Bighley, L., Richardson, R. H., Hepler, C.D. and Carmichael, J. (1977): Frequent toxicity from iv aminophylline infusions in critically ill patients. Drug lntelL clin. Pharmacol., 2, 12. 3. ZwiUich, C.W., Sutton, F.D., Neff, T. A., Cohn, W.M., Matthay, R.A. and Weinberger, M.M. (1975): Theophylline-induced seizures in adults: correlation with serum concentrations. Ann. intern. Med., 82, 784. 4. Matthay, R.A., Matthay, M.A. and Weinberg e l M. M. (1976): Grand mal seizures induced by oral theophylline. Thorax, 31,470. 5. Chaithiraphan, S. (1976): Fatal complication associated with intravenous use of aminophylline. J. med. Ass. Thailand, 59, 507. 6. Yeh, T.F. and Pildes, R.S. (1977): Transplacental aminophylline toxicity in a neonate. Lancet, 2, 910. 7. Vall~-Jones, J.C. (1976): A double-blind trial of Nethaprin expectorant syrup in patients with bronchospastic disease. Curt. Med. Res. Opin., 3, 624. 8. Brem, A. S., Martin, H. and Stern, L. (1977): Toxicity from tea ingestion in an infant: a computer simulation analysis. Pediat. Res. (Bait.), 11, 414. 9. Turner, J. E. and Cravey, R. H. (1977): A fatal ingestion of caffeine. Clin. ToxicoL, 10, 341. 10. Anonymous (1977): Coffeine in koffie. Ge-
neesmiddelenbulletin, 11, 6. 11. Kovan, C.D. (1977): More is high than the price. Med. J. Aust., 64, 866. 12. Editorial (1977): Headaches and coffee. Brit. reed. Z, 2, 284. 13. Josephson, G. W. and Stine, R. J. (1976): Caffeine intoxication: A case of paroxysmal atrial taehycardia. J. Amer. Coll. Emergency Phycns, 5, 776. 14. Hemminki, E. and Pesonen, T. (1977): Regional coffee consumption and mortality from ischemic heart disease in Finland. Acta reed.
scand., 201,127. 15. Yano, K., Rhoads, G.G. and Kagan, A. (1977): Coffee, alcohol and risk of coronary heart disease among Japanese men living in Hawaii. New Engl. J. Med., 297, 405. 16. Kannel, W. B. (1977): Coffee, cocktails and coronary candidates. New Engl. J. Med., 297, 443. 17. Bridges-Webb, C. and Grounds, M. (1976): Analgesic use and abuse: the role of caffeine. Med. J. Aust., 63, 805. 18. Shorofsky, M. A. and Lamm, N. (1977): Caffeine-withdrawal headache and fasting, iV. Y. St. Z Med., 77, 217. 19. Anonymous (1976): Coffee drinking and pep-
tic ulcer disease. Nutr. Rev., 34, 167. 20. Cohen, S. and Booth Jr., G. H. (1975): Gastric acid secretion and lower esophageal sphincter pressure in response to coffee and caffeine. New Engl. J. Med., 293, 897. 21. Baxter, A. D. (1976): Side effects of doxapram infusion. Europ. J. intens. CareMed., 2, 87. 22. Robertson, G.S., MacGregor, D.M. and Jones, C. J . (1977): Evaluation of doxapram for arousal from general anaesthesia in outpatients. Brit. J. Anaesth., 49, 133. 23. Holden, C. (1976): Amphetamines: tighter controls on the horizon. Science, 194, 1027. 24. Rifkin, S.I. (1977): Amphetamine-induced angiitis leading to renal failure. Sth. med..J. (Bgham, Ala.), 70, 108. 25. Hurst, P. M. (1976): Amphetamine and driving behaviour. Accid. Analys. Prevent., 8, 9. 26. Valverde, R.C., Pastrana, L.S., Ruiz, J. A., Solis, H., Jurado, J. L., Sordo, C. M., Fern~indezGuardiola, A. and Maisterrena, J.A. (1976): Neuroendocrine and electroencephalographic sleep changes due to acute amphetamine ingestion in human beings. Neuroendocrinology (Basel), 22, 57. 27. Kendrick, W. C., Hull, A. R. and Knochel, J. P. (1977): Rhabdomyolysis and shock after intravenous amphetamine administration. Ann. intern. Med., 86, 381. 28. Trites, R.L., Suh, M., Offord, D., Nielman, M. D. G. and Preston, D. (1976): Neuropsychologic and psychosocial antecedents and chronic effects of prolonged use of solvents and methamphetamine. Psychiat J. Univ. Ottawa, 111, 14. 29. Reid, W.H., Biouin, P. and Schermer, M. (1976): A review of psychotropic medications and the glaucomas. Int. Pharmacopsychiat., 11, 163. 30. Sverd, J., Hurwick, M. J., David, O. and Winsberg, B.G. (1977): Hypersensitivity to methylphenidate and dextroamphetamine; A report of two cases. Pediatrics, 59, 115. 31. Ellinwood Jr., E. H., Eibergen, R. D. and Kilbey, M. M. (1976): Stimulants; Interaction with clinically relevant drugs. Ann. N. Y. Acad. Sci.,
281,393. 32. Phillips, B. L.D. (1977): Treatment of obesity: comparison of diethylpropion and fenfluramine. Clin. TrialsJ., 14, 43. 33. Chiorboli, E., Da Rosa, J.C., BricareUo, S., Guerra, F.B., Lopes, M.A. and Colzani, R. (1976): Clinical trial with a new anorectic association in obesity. Folha Med., 72, 547. 34. Bennett, J. A. and Eltringham, R.J. (1977): ' Possible dangers of anaesthesia in patients receiving fenfluramine. Anaesthesia, 32, 8. 35. Tisdale Jr., S.A. and Ervin, D.K. (1976): Anorectic effectiveness of differing dosage forms of fenfluramine. Curt. ther. Res., 19, 589. 36. Enzi, G., Baritussio, A., Marchiori, E. and Crepaldi, G. (1976): Short-term and long-term
~ H . ConneH clinical evaluation of a non-amphetaminic anorexiant (Mazindol) in the treatment of obesity. J. int. med. Res., 4, 305. 37. Friesen, L. V.C. (1976): Aphrodisia with mazindol. Lancet, 4, 974. 38. Millichap, J.G. (1976): Methylphenidate dosage. Pediatrics, 58, 913. 39. Elenbaas, R. M., Waeckerie, J. F. and McNabhey, W. K. (1976): Abscess formation as a complication of parental methylphenidate abuse. s Amer. Coll. Emergency Phycns, 5, 977. 40. Anonymous (1977): Norephedrin (Phenylpropanolamin) statt Nor-d-pseudoephedrin als
Appetitziigler? Schweiz. Apoth. Ztg., 115, 430a. 41. Bornstein, S., Dantlo, C. B., Fai, R., Kaufman, E., Pigeon, R. and Teulieres, J. (1976): Utilisation d'un psychostimulant: D6brumyl. Psychol. m~d., 8, 1121. 42. Schilter, R. (1974): Zur Wirkung yon Cerutil (Centrophenoxin) bei zerebralsklerotischen Patienten. Z. Alternsforsch., 28, 231. 43. Bach, O., Petermann, H. and Heber, I. (1976): Erfahrungen mit einem neuen psychostimulierenden Medikament: Sydnocarb. Psychiat. Neurol. meal. Psychol. (Lpz.), 28, 609.
1
central nervous system stimulants and anorectic agents
The past year has not yielded any major developments in our knowledge of the adverse reactions to central .~timulants, but with the general development of consciousness of civil rights and of environmental and other possibly harmful features of modern society, there has been concern about the effects of caffeine though the numbers of ~ommunications have been small. The general impression of the author of this chapter is that political, environmental, economic and other factors have tended to slow down the communications concerning the CNS stimulants and that it would be advantageous ff research endeavours were based upon the mechanism of actions of drugs of these categories and on clinical evaluations which would bear in mind in the methodology the question of mechanisms of action when looking at side effects. ANALEPTICS THEOPHYLLINE AND RELATED SUBSTANCES
Tolerance and plasma concentrations Not every type of patient may have an equal tolerance to theophylline. A study of the paradoxical effect of adrenergic and methylxanthine drugs in cystic fibrosis involved administration of these drugs as aerosols to children and young adults with this disorder (lC). Theophylline was given in high dosage (10 mg/kg three times a day) and compared with placebo in 12 cases over a period of 3 - 4 weeks, with evaluation of plasma levels. Some children could tolerate high blood levels of theophylline but most experienced nausea and vomiting or headache even when the plasma level was appropriate. The fact that these patients seemed less able to tolerate theophylline than asthmatics suggested that a degree of tolerance comes with long-term usage. Liver dysfunc-
tion, which exists in 1 5 - 3 0 % of cystic fibrosis patients, might be another reason for the inability of some patients to tolerate usual dosages of theophylline. Responses to aerosolized bronchodilators were inconsistent from week to week and there was no concordance between response to isoproterenol and theophylline. The use of adrenergic and methylxanthine drugs in cystic fibrosis must be undertaken with caution. A study of 48 acutely ill hospitalized patients with chronic obstructive pulmonary disease (2 C) which, among other measurements, studied theophylline concentrations in the plasma, stressed that aminophylline administered i.e. according to the MitenkoOgilvie recommendations frequently produced excessive theophylline plasm a concentration~ and confirmed the relationship between toxiclty and plasma concentration (SEDA-1, p. 1). It identified tachycardia as a frequent toxic symptom and demonstrated that nausea and vomiting were not reliable harbingers of life-threatening toxicity. Such data as these, and continuing reports of convulsions and even death in both children and adults in whom serum theophylline levels have grossly exceeded the accepted range of some 1 0 - 2 0 flg/ml (3 e, 4 C) show that theophylline and aminophylline are still employed without due care, either when given orally or intravenously. It is especially important to ensure that children are only given these substances in appropriate dosage forms, that intravenous administration is slow, and that in cases with severe respiratory distress the special risk of ventricular fibrillation is taken into account; in many cases, a severely ill patient should be on cardiac monitoring during treatment with such a drug (5 R). Use in pregnancy A report, claimed to be the first, of transplacental arninophyUine toxicity in a
2 neonate (6 c) described symptoms of irritability, vomiting and jitteriness, possibly related to ingestion of aminophylline by the 36-year-old asthmatic mother who had taken aminophylline intermittently for episodes of wheezing during the pregnancy. One day before delivery she had been giw several drugs for her respiratory problem, including aminophylline (500 mg by suppository and 100 mg by mouth) frusemide and nitroglycerin. Aminophylline (100 mg) was subsequently given every 4 hours. The last dose was given 1 hour before delivery. At 6 hours the infant vomited and showed slight jitteriness. Blood-glucose ('Dextrostix' test) was more than 60 mg/dl. Similar symptoms were reported after the first and second feeding and he was transferred to the intensive care unit for observation. Various investigations were negative and without special treatment the infant improved and tolerated oral feeding well from the second day. The cord serum aminophylline concentration was 9.2 g/ml and serum aminophylline concentration at 52 hours was 5.8 g/ml. The authors rightly suggest that further observations are required to confirm the apparent assumption that aminophylline was responsible for the clinical findings.
Drug mixtures A double-blind trial in a general practice population of 36 patients of 'Nethaprin' expectorant syrup (7 C) which contained 10 mg etafedrine hydrochloride (a tertiary amine similar to ephedrine in its bronchodilator effect but which is said to cause less central nervous and cardiovascular system stimulation), 120 mg bufylline (theophylline aminoisobutanol which contains approximately 67% theophylline), 12 mg doxylamine succinate (an ethanolamine antihistamine), and 200 mg glyceryl gnalacolate (an expectorant), noted that five patients reported feeling slightly drowsy during treatment (1 on placebo and 4 on Nethaprin) and that no other side effects were recorded. CAFFEINE
Acute toxicity A recent report (8 c) notes tonic posturing and central nervous system irritability after concentrated tea ingestion in a sevenweek-old previously healthy infant; caffeine was the only xanthine found in the tea using a gas chromatographic analysis. As pointed out in SED VIII (p. 2), the evidence as to the lethal dose of caffeine is fragmentary. A report of a fatality after ingestion of caffeine in a 34-year-old female
P.H. Connell (9 r who, however, had a phenobarbital blood concentration of 0.4 mg/100 ml when found in a coma, stresses that a review of the literature yields few fatal cases and most of them as a result of doses erroneously administered by hospital personnel. The report states that it is generally accepted that the fatal dose of caffeine in humans is 10 g, although oral doses in reported fatalities range from 5 - 5 0 g. It is suggested that the infrequency of death as a result of ingestion of large amounts of caffeine is perhaps due in part to the emetic effect of the drug.
Effects o f chronic use Recent concern as to the possible risks of chronic caffeine intake has been underlined by estimates of the large amounts of this substance which an average person may unwittingly ingest daily in the form of hot beverages, caffeinated soft drinks, chocolate bars, popular analgesics and prescribed medicines, e.g. for migraine (10 R, 1 It). Concern centres primarily on the cardiovascular effects, the influence on the central nervous system, and the possible repercussions for the stomach. However, one must also bear in mind the lack of exact knowledge as to the frequency of caffeinism in general or of coffee allergy, the older suspicion that caffeine might cause renal malignancy, and the ability of caffeine to catalyze the formation of N-nitrosamine in the digestive tract (12R). Cardiovascular effects A recent report of a case of paroxysmal atrial tachycardia (13 r) comments that caffeinism is a syndrome resulting from the excessive ingestion of caffeine and characterized primarily by cardiovascular and central nervous system manifestations. 'A variety of tachy-arrhythmias and extrasystoles are believed to reflect the toxic, cardiotonic effects of caffeine'. The importance of considering caffeinism as an underlying condition associated with paroxysmal atrial tachycardia is stressed. Comparisons of the mortality from ischaemic heart disease in Finland in North Karelia, where it is at its highest, and south west Finland, where it is at its lowest, set alongside consumption of coffee gives a positive correlation in terms of mortality, being highest in the area where coffee sales are higher (14c). Despite such reports, the doubt expressed earlier (SED VIII, p. 3; SEDA-I, p. 2) as to
CNS stimulants and anorectic agents
the existence of a link between caffeine and cardiac disease persists. When Yano et al. (15 c ) studied coronary disease over a sixyear period in 7705 Japanese men living in Hawaii, there did at first sight appear to be some correlation between the 294 new cases of coronary heart disease observed and the intake of coffee; however, it became statistically insignificant when cigarette smoking was taken into account. It is still true, as a recent and authoritative editorial reminds us, that 'in contrast to some retrospective studies, all prospective studies have failed to implicate coffee as an independent contributor to death from coronary heart disease or myocardial infarction' (16 R ). Central nervous system
Headaches and mental irritability are well-recognized complications of over-consumption of caffeine (SED VIII, p. 3; 12 r) and it has always been a curious fact that caffeine is present in analgesics which are commonly used habitually in the hope of relieving headache. A warning (17 r) that the presence of caffeine in these analgesics might be responsible for dependency and habituation to these products and thereby indirectly responsible for renal disease, has been published, based upon extensive (but unreported) enquiries among patients habituated to analgesics. Shorofsky and Lamm (18 R) have drawn attention to the severity of caffeine-withdrawal headache (SED VIII, p. 3), such as may be experienced by persons undergoing short-term fasting for religious reasons. Some individuals may indeed require caffeine suppositories during this period to prevent headache from occurring. Gastric effects
A review (19 r) refers to some literature and in particular to the work of Cohen and Booth (20 C) who examined the acidity of gastric juice after test solutions were administered consisting of a proprietary brand of instant coffee and one of decaffeinated coffee. Decaffeinated coffee was as potent as instant coffee in stimulating gastric acid secretion. 'To think of coffee in terms of caffeine may be excusable for the layman but certainly not for the scientist' is a view expressed in the review. DOXAPRAM Side effects of this central stimulant are
very frequent (SED VIII, p. 4; SEDA-1, p. 2) but they tend to be short-lived because of the brief half-life of the drug in plasma (21Cr). Of 20 patients aged 6 8 - 7 2 who were treated with doxapram infusion, 4 developed severe and violent restlessness, confusion or hallucinations at low doses. Three of these were known to have excessive alcohol intakes and 2 had abnormal liver function tests. It was felt that the effects were not due to alcohol withdrawal, as they were related to the onset and duration of doxapram infusion and persisted for a relatively short time after the infusion was stopped. A study of the use of doxapram for arousal from general anaesthesia in out-patients (22 C) using a double-blind method, noted that side effects in the first 10 minutes after anaesthesia were noted but none were serious. In the doxapram-treated group seven patients developed minor sequelae comprising excessive coughing (3), weeping (2), muscle tremor (1), and nausea together with a hysterical reaction to dreaming (1). However, minor problems were noted in 12 of the control patients: coughing (4), weeping (5), excessive sweating (1), excessive salivation (1), and vomiting (1). One patient in the doxapram-treated group developed nausea and vomiting after leaving the recovery area. ' A pleasant recovery with relative absence of side effects was a feature of the doxapram group'. ANORECTIC AGENTS AMPHETAMINES Though there have been few new scientific findings with respect to the amphetamines in the past year, the debate in the United States and elsewhere as to the desirability of further restrictions on theft use (23 R) has led to critical re-assessment of their usefulness as compared with their capacity for harm or misuse. Cardiovascular effects
Whilst the cardiodynamic effects of these drugs have received most emphasis (SED VIII, p. 12), they may also affect the vessel wall. A case report describes amphetamineinduced angiitis leading to renal failure in an intravenous user whose symptoms abated spontaneously, only to recur dramatically with renewed amphetamine usage and who,
4
~ H . ConneH
over a two-year period, developed malignant hypertension and terminal renal failure (24c).
will be presented later and can be anticipated with interest.
Central nervous system Despite the general opinion that amphetamines are not compatible with safe driving, a recent review (25 r) stresses the absence of hard data of any kind to enable the total contribution o f amphetamine abuse to traffic accidents to be assessed, and notes that the effect of amphetamines may enhance driving skills, though a prolonged 'spree' is widely recognized to result in abnormal psychological states that are incompatible with safe driving performance and that there is some evidence to suggest that amphetamines may induce overconfidence or increased risk acceptance. A longitudinal study (26 C) demonstrates the disruptive effects exerted by D-amphetamine on the neuroendocrine and sleeprelated organization of humans by using a double-blind method in 8 normal obese volunteers to assess effects on growth hormone, thyrotropin, cortisol, EEG changes etc., though the authors do not refer to earlier works such as Oswald's in the EEG discussion (SED VIII, p. 12).
Use in glaucoma A review of psychotropic medications and the glaucomas (29 R) includes a review of central nervous stimulants and concludes that although caution is advised, especially in patients over the age of 40, and the patient must be followed up, the evidence in the literature is that amphetamines (and other psychotropic drugs) are acceptably safe to prescribe even in patients with diagnosed glaucoma.
Misuse A study of five patients (27 C) who had injected intravenous phenmetrazine or methamphetamine showed rhabdomyolysis and shock with symptoms soon after injection, as well as chris, fever, sweats, nausea and abdominal cramps in four. Within hours vomiting, myalgias, paraesthesia, headache and orthostatism ensued. Cardiorespiratory arrest, accelerated bleeding and non-cardiac pulmonary oedema were observed in one patient. Treatment b y aggressive volume replacement after recognition of this syndrome led to recovery in all five patients. A study (28 C) of chronic cognitive, adaptive, m o t o r and sensory dysfunction associated with long-term use of volatile solvents and amphetamine presents in a Part I 'Group Profiles' report data on 160 subjects ineluding 77 drug abuse subjects and 83 sibling and peer controls. The data suggests that differences between the users and their siblings on certain tests, such as tests of memory function, rapid number letter manipulative skills and certain m o t o r function may be chronic-static sequelae of the drug abuse. A more detailed analysis of this and other data
Allergy Two cases are reported (30 c) of children aged 9 and 6 who were treated with methylphenidate for hyperkinetic behaviour disorders and who showed allergic manifestations (one developed angioneurotic oedema and the other showed urticaria). When the first patient was subsequently placed on dextroamphetamine he also developed urticaria.
Interactions An excellent review (31 R) containing 111 references has discussed the interaction of stimulants with clinically relevant drugs and refers to clinical, biochemical, animal and other researches. It is stressed that when drug abuse is considered 'chronic drug abuse may result in an altered physiology that endures b e y o n d the cessation of drug administration, and subsequent administration of other drugs may thus result in an altered response'. There is so much data in this review that it is impossible to do justice to it in a brief summary, but some of the points stressed are that: alcohol increases blood level of amphetamine; tricyclic antidepressants increase brain levels of amphetamine; barbiturates and benzodiazepines enhance amphetamine hypermotility; in treating the amphetamine psychosis where tolerance has developed to the peripheral toxic effects, it is probably wiser to use a drug such as haloperidol, which does not increase the half-life of amphetamine as does chlorpromazine; laboratory experiments demonstrate that prior chronic narcotic treatment has a residual effect of enhancing subsequent behavioural response to stimulants.
CNS stimulants and anorectic agents DIETHYLPROPION (TENUATE, APISATE, AM FEPRAMONE)
The side effects of this mildly stimulant compound were very fully set out in earlier volumes (SED VIII, p. 16; SEDA-1, p. 2) and newer studies add nothing to the picture except as regards comparative findings and the possible usefulness of fixed combinations. One comparative study over an 11week period which compared diethylpropion and fenfluramine in 36 patients (32 c ) stressed that more persons had withdrawal side effects when they had been taking fenfluramine than when taking diethylpropion, and more persons withdrew in the first phase of the trial when on fenfluramine. However, the once-a-day dose of diethylpropion has not yet been compared with the sustained release form of fenfluramine and the author stresses the need for such comparative studies. A study (33 c) of a new anorectic pharmaceutical preparation containing 75 mg diethylpropion plus 10 mg diazepam noted that side effects were mild and less than those found with other anorexigenic preparations. However, side effects were observed in about 50% of the patients and constituted dry mouth, nervousness and mild depression. FENFLURAMINE (PONDERAX)
Interactions
In the full review of adverse reactions to this drug in SEDA-1 (pp. 4, 5) it was pointed out that cases of cardiovascular complications had occurred. A recent report (34 e) of a study in rabbits, carried out after the unfortunate anaesthetic death of a 23-year-old female who had been taking fenfluramine, gave data on ECG and phonocardiographical recordings on anaesthetized rabbits who received injections of adrenaline or fenfluramine. The changes seen with fenfluramine were greater in number and less readily reversed with beta-blockers and resuscitative drugs. These findings 'may support an interaction between halothane and fenfluramine in man, and it is suggested that the latter drug be discontinued a week prior to anaesthesia for elective surgery'. Slow-release forms
A comparison of form of fenfluramine 60 mg), fenfluramine mg t.i.d.) and placebo
an extended action (Pondimin Extentabe tablets (Pondimin 20 (35 c ) noted that the
side effects were similar in the two active preparations. The weight loss superiority of the sustained-release form was thought to be due to the greater reliability in taking one dose a day than three. If this is indeed the case, one is bound to wonder how meaningful the comparison of side effects between these two forms is, and the same may apply to the similar comparisons cited earlier (SEDA-1, p. 5). MAZINDOL (SANOREX, AN 448, TERONAC, SAH 42-548)
Studies cited earlier (SED VIII, p. 20; SEDA-1, pp. 5 - 7 ) h a v e established the general pattern of side effects. It is evident that dryness of the mouth, constipation and mild adrenergic effects can appear. Although it is generally considered that anorectic drugs can only usefully be given for brief periods, some newer work does provide evidence on longer-term treatment. One cross-over trial (36 C) was in 158 obese subjects (age 1 6 - 5 9 years) who were followed up as outpatients. The study examined the short-term evaluation of the effectiveness of the anorexiant in 102 patients; the long-term evaluation of the effectiveness of protracted discontinuous treatment with anorexiant in association with hypocaloric diet in 48 women (age 1 5 - 4 5 ) ; and the effectiveness of treatment with anorexiant in association with hypocaloric diets in refractory obesity in 9 patients. It was noted that nervousness, insomnia, dizziness, dry mouth, constipation, goose flesh and chills recur with a considera b l y higher frequency and intensity in the patients who started treatment with diet and active drug. These reactions receded upon suspension of the drug and were interpreted as drug-induced. However, these symptoms also appeared in patients treated with diet and placebo and seemed less frequent and less intense when the active drug is administered later on in treatment. The incidence of side effects, mostly of the sympathomimetic type, appeared to attenuate in long-term patients. It is suggested that after months of treatment the commitment needed to observe the diet may be less tolerated than the possible side effects of the drug which are reduced if the drug is given after a period of diet alone. Effect on libido
A short communication (37c), stating that about 5% of female patients treated
P. H. Connell
with mazindol had experienced an aphrodisiac effect, and quoting one patient aged 40 years who had such a strong craving for sexual intercourse that her husband, who had a good job over a hundred miles away, had to give it up to be home during the week should be treated with interest but with caution. If this effect were general and marked it is unlikely that prevous comprehensive studies would have failed to fiote it. METHYLPHENIDATE (R1TALIN) Variability o f response A report (38 c) stresses that in view of the variation in individual response of the hyperactive child with minimal brain dysfunction to methylphenidate it should be administered in an initial small divided dose of 10 mg daily and reference to a dosage schedule determined by b o d y weight seemed inadvisable except for research purposes. A patient previously reported by the author of the report in 1968 had shown difficulty in speaking and moving his lips and tongue, associated with twitching movement of the face. A lower dosage relieved these symptoms but a second attempt to raise the dose was accompanied by recurrence of the 'extrapyramidal and seizure-like signs and symptoms. The reaction in this patient appeared to be dose-related and not idiosyncratic'. Complications o f abuse As pointed out earlier (SED VIII, p. 22) parenteral abuse of methylphenidate, using injections home-made from tablets, may cause severe local and general reactions. A recent report of 5 patients suffering either from skin abscesses or cellulitis following parenteral methylphenidate abuse (39c), in which the injection paraphernalia of 100 heroin addicts were examined to determine the presence of organisms, failed to find Staphylococcus aureus and only four contained streptococcal species. The conclusion was that skin lesions observed in methylphenidate abusers may originate as sterile abscess or necrotic ulcers and arise because of local vasospasm and/or chemical irritation (due to materials used in tablet preparations such as lactose, sucrose, polyethylene glycol, magnesium stearate, tragacanth, cornstarch and talc). These lesions are then
susceptible to secondary infection by a hose of organisms normally present in the skin (such as Streptococcus viridans). NOREPHEDRINE (PHENYLPROPANOLAMINE) Though generally used as a nasal decongestant, this compound has in some countries been introduced as an anoreetie agent. A warning issued by the Swiss Pharmaceutical Association points out that the doses used for this purpose (e.g. 25 mg three times daily) can produce severe sympathicomimetic side effects, including hypertensive crises, arrhythmias and tachycardia (40 R ). DEANOL DERIVATIVES Esters and derivatives of deanol have been studied and sold under many different names. Among the better-known of them are Lucidril (also known as meclofenoxate, centrophonoxine and deanol p-chlorophenoxyacetate) and Debrumyl (a mixture of deanol pyroglutamate with heptaminol). The various substances are claimed to have central stimulant properties which are supposed to be of value in the aged, after cerebrovascular accidents and during the treatment of epilepsy. Despite the fact that they have existed for for many years, there is very little critical work in print t o throw light on their properties. A recent paper by Bornstein et al. (41 c ) relating to the use of Debrumyl in 146 cases concludes that there was spectacular improvement in a wide range of diagnoses, yet speaks of a complete absence of side effects, except in 7 cases who suffered some insomnia. There would seem every reason to examine these products critically. Lucidril is known to be an allergen (SED VIII, p. 382) and in one series it is known to have produced nausea, vomiting and stomach pain in 9 out of 25 cases (42c). SYDNOCARB This Soviet product was studied by Bach et al. in a series of 28 patients with various psychiatric diagnoses, but all considered to be in need of central stimulation. The dosage of 3 x 10 mg daily, which was considered effective, produced disturbances of sleep in 3 patients which could be overcome b y avoiding an evening dose. One other case complained of 'unrest', three of headache and one developed an allergic rash (43c).
CNS stimulants and anorectic agents
7
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281,393. 32. Phillips, B. L.D. (1977): Treatment of obesity: comparison of diethylpropion and fenfluramine. Clin. TrialsJ., 14, 43. 33. Chiorboli, E., Da Rosa, J.C., BricareUo, S., Guerra, F.B., Lopes, M.A. and Colzani, R. (1976): Clinical trial with a new anorectic association in obesity. Folha Med., 72, 547. 34. Bennett, J. A. and Eltringham, R.J. (1977): ' Possible dangers of anaesthesia in patients receiving fenfluramine. Anaesthesia, 32, 8. 35. Tisdale Jr., S.A. and Ervin, D.K. (1976): Anorectic effectiveness of differing dosage forms of fenfluramine. Curt. ther. Res., 19, 589. 36. Enzi, G., Baritussio, A., Marchiori, E. and Crepaldi, G. (1976): Short-term and long-term
~ H . ConneH clinical evaluation of a non-amphetaminic anorexiant (Mazindol) in the treatment of obesity. J. int. med. Res., 4, 305. 37. Friesen, L. V.C. (1976): Aphrodisia with mazindol. Lancet, 4, 974. 38. Millichap, J.G. (1976): Methylphenidate dosage. Pediatrics, 58, 913. 39. Elenbaas, R. M., Waeckerie, J. F. and McNabhey, W. K. (1976): Abscess formation as a complication of parental methylphenidate abuse. s Amer. Coll. Emergency Phycns, 5, 977. 40. Anonymous (1977): Norephedrin (Phenylpropanolamin) statt Nor-d-pseudoephedrin als
Appetitziigler? Schweiz. Apoth. Ztg., 115, 430a. 41. Bornstein, S., Dantlo, C. B., Fai, R., Kaufman, E., Pigeon, R. and Teulieres, J. (1976): Utilisation d'un psychostimulant: D6brumyl. Psychol. m~d., 8, 1121. 42. Schilter, R. (1974): Zur Wirkung yon Cerutil (Centrophenoxin) bei zerebralsklerotischen Patienten. Z. Alternsforsch., 28, 231. 43. Bach, O., Petermann, H. and Heber, I. (1976): Erfahrungen mit einem neuen psychostimulierenden Medikament: Sydnocarb. Psychiat. Neurol. meal. Psychol. (Lpz.), 28, 609.