BRITISH MEDICAL JOURNAL VOLUME 282 2 MAY 1981 1433 urinary excretion rose to 2 17 1/24 h, with chloride 249 mmol/24 h and lymphocytic infiltration of the epidermis. Direct immunofluorescence tests potassium 178 mmol/24 h. Mean fall in body weight was 0-29 kg/day. The with labelled antihuman immunoglobulin A and G and C3 were negative. patient became oedema free over two weeks. Benoxaprofen was stopped on admission and the rash subsided over the Case 4-A 40-year-old man with severe ischaemic heart disease presented course of 14 days. Profuse desquamation occurred, particularly on the with congestive cardiac failure. Blood pressure was 170/90 mm Hg. palms of the hands. At no stage did the rash resemble a photoallergic or Piretanide was used in incremental doses up to 24 mg daily. On this dose phototoxic drug rash. urinary excretion was 1-0 1/24 h, with sodium 39 mmol/24 h, chloride 35 mmol/24 h, and potassium 35 mmol/24 h. Mean fall in body weight was 0-3 kg/day. As oedema persisted, 5 mg metolazone was added. Urinary Comment excretion rose to 2-48 1/24 h, with sodium 210 mmol/24 h, chloride 202 mmol/24 h, and potassium 73 mmol/24 h. Body weight fell by 0-6 kg/day. The Stevens-Johnson syndrome is a potentially lethal condition Oedema cleared over two weeks. Potassium supplements were necessary. that is often precipitated by drug treatment, sulphonamides being the drugs most commonly implicated.2 The association of this syndrome with treatment with benoxaprofen is important, especially Comment in view of the enthusiastic press reviews3 4 which greeted the launch of Adding relatively small doses of metolazone to high-dose "loop" the drug. diuretics significantly increased urine volume and excretion of sodium J and Mikulaschek Walter M. Long-term safety of benoxaprofen. Rheumatol chloride potassium, enabling body weight to fall and oedema to 1980;7, Suppl 6:100-7. clear. The response was immediate and sustained. An initial dose of 2 Bianchine JR, Macaraeg PUJ Jr, Lasagna L, et al. Drugs as etiological 2-5 mg metolazone is recommended. Profound natriuresis with factors in the Stevens-Johnson syndrome. Am3J Med 1969;44:390. associated kaliuresis may lead to hypovolaemia and hypokalaemia 3 Anonymous. Hope for arthritics. World Medicine 1980;16:4-7. respectively. These complications should be anticipated by gradual 4 The Times, Tucker A. Drug brings 'new era' in treatment of arthritis. The dose titration according to urine volume and changes in body weight Guardian 1980 October 15:2. and adequate potassium supplementation. Ideally the patient should be treated with caution in hospital, as dangerous, uncontrolled losses (Accepted 2 February 1981) of fluid and electrolytes may occur.4 The Royal Infirmary, Sunderland SR2 7JE We are grateful to Sisters M Morris and G Alcock for metabolic nursing, AILEEN E M TAYLOR, MRcp, registrar in dermatology and to Miss J E Davies for secretarial work. DAVID GOFF, MRCPATH, consultant haematologist T COLIN HINDSON, FRcp, consultant dermatologist IGunstone RF, Wing AJ, Shani HGP, Njemo D, Sabuka EMW. Clinical experience with metolazone in fifty-two African patients: synergy with frusemide. Postgrad MedJ 1971 ;47:789-93. 2 Epstein M, Lepp BA, Hoffman DS, Levinson R. Potentiation of furose- mide by metolazone in refractory oedema. Current Therapeutic Research 1977;21:656-67. 3 Asscher AW. Treatment of frusemide resistant oedema with metolazone. Failure of ejaculation with Clinical Trials Journal (London) 1974;4:134-9. 4 Black WD, Shiner PT, Roman J. Severe electrolyte disturbancesassociated indoramln with metolazone and furosemide. South MedJ 1978;71:380-1. (Accepted 12 February 1981) Indoramin (3-(2-(4 benzamidopiperid-1-yl)ethyl)indole) an alpha,- adrenergic-blocking agent is being investigated for the treatment of Singleton Hospital, Sketty, Swansea SA2 8QA hypertension, asthma, and migraine.1-3 While conducting a double- R R GHOSE, FRCPED, MRCP, consultant physician blind trial of indoramin in the prophylactic treatment of migraine S K GUPTA, MB, BS, medical registrar we found a high incidence of failure of ejaculation in male patients.

Patients, methods, and results Patients diagnosed as suffering from either common or classical migraine as defined by the World Federation Neurology Research Group on Migraine and Headache were invited to participate in the trial. Those with coexistent Association between Stevens- medical or psychiatric complaints were excluded. A double-blind procedure was followed with patients receiving placebo, clonidine 0-05 mg three times Johnson syndrome and daily, or indoramin 20 mg three times daily for the first six months. Patients who had received clonidine during this time with no response were given benoxaprofen indoramin and those who had been taking placebo without improvement were randomly allocated to clonidine or indoramin for a subsequent six Benoxaprofen (Opren, Dista) is a non-steroidal anti-inflammatory months. Patients kept diary records and were reviewed monthly. agent related to naproxen and Eighteen men participated in the trial, of whom I1 received indoramin. ibuprofen. Reported side effects include Four men spontaneously complained of failure of ejaculation while receiving gastrointestinal ulceration and haemorrhage, photosensitivity, and indoramin. Of the remaining seven, five were available for review, the other onycholysis.' We report the development of severe erythema multi- two defaulting from follow-up. These five men were asked specifically forme with bullous lesions affecting the lips and buccal mucosa in a whether they had noted any change in sexual function, and two described patient who had recently started treatment with the drug. failure of ejaculation. The ages of the nine patients reviewed ranged from 19 to 47 years (mean 37 years). Most of those affected had taken indoramin for at least two weeks before noting the disturbance, although in one man it Case report had occurred on the day after starting treatment. All six affected patients described normal erections and had experienced orgasms despite total lack A 63-year-old woman was started on benoxaprofen 600 mgs daily to of ejaculation. None had noted this effect before starting indoramin, and it relieve osteoarthritic pain of the hands and left knee. She had been treated did not occur after the drug was stopped. No patients receiving placebo or with mefenamic acid and sulindac for several years, but these drugs were clonidine complained of change in sexual function. discontinued when benoxaprofen was started. Fourteen days later an erythematous papulopurpuric rash developed over the whole body surface, the thighs, forearms, and dorsum of hands being most severely affected. Comment Bullae were present in the mouth and on the lips. She complained of severe pruritus. No other abnormalities were found on examination. Ejaculation is a complex process affecting sympathetic, para- Erythrocyte sedimentation rate was 35 mm in the first hour; haemoglobin sympathetic, and somatic pathways. Sympathetic nerves stimulate the concentration 14-3 g/dl; and white cell count 7500 x 1091/ with a differential delivery of semen to the urethra by the vas deferens, seminal vesicles, count of neutrophils 74 %, lymphocytes 9 %, monocytes 11 % and eosinophils 6 %. A coagulation screen was normal, as were uric acid, urea, and electrolyte and prostate and prevent retrograde ejaculation by stimulating the concentrations, and results of liver function tests. Electrocardiography and internal urinary sphincter. Thoracolumbar sympathectomy from chest x-ray films were normal. A test for antinuclear factor was negative. T12 to L3 abolishes seminal emission without disturbing erectile Skin biopsy specimens were consistent with erythema multiforme, showing potency or the sensation of orgasm: the experience of "dry sex" as perivascular lymphocytic infiltrate in the dermis with spongiosis and described by Kedia and Markland.4 They also reported the same 1434 BRITISH MEDICAL JOURNAL VOLUME 282 2 mAY 1981 problem as a long-term effect of treatment with guanethidine or for a few hours. We were unable to obtain a fish from the same batch for thioridazine hydrochloride. A high proportion ofour patients receiving analysis. the alpha,-blocking agent indoramin described a similar phenomenon. Failure of ejaculation with indoramin is probably due to its action on transmission at the short adrenergic neurones of the male reproductive Comment tract, although further studies are indicated, including studies of Our patient developed classical symptoms of scombrotoxicity urine obtained before and after masturbation, to determine whether immediately after eating smoked mackerel. Many of the features of retrograde ejaculation occurs. this condition are similar to those encountered in histamine poisoning Although a few reports' 5 have mentioned sexual dysfunction in a and may be relieved by antihistamine drugs (H,-receptor blockers).' small number of patients, the high incidence of failure of ejaculation Though histamine concentrations in affected fish often exceed without disturbance of erection and with the sensation of orgasm has 100 mg/100 g,' well-documented episodes of scombrotoxicity have not been emphasised. Two-thirds of our patients suffered from failure been reported where no excess of histamine was found, and non- ofejaculation while taking the fairly low daily dose of 60 mg indoramin, scombroid fish, such as herring, may have high histamine concen- and this emphasises the need to question patients about sexual trations without producing symptoms. Thus the toxin is probably a performance when they are being treated with this or other alpha- more stable histamine-like compound.' adrenergic-blocking agents. This finding may also support the In scombrotoxicity the clinical presentation often includes a rapid hypothesis that this group of drugs may be developed for use as weak pulse and palpitation; Gilbert et all found six episodes of reversible male contraceptives.4 palpitation among 30 incidents of poisoning, but electrocardiograms We thank Dr C Mawdsley for allowing us to study his patients. The drugs were not recorded. Histamine is released in large quantities in were supplied by Wyeth Laboratories. anaphylactic reactions, and its toxic effects2 on the myocardium may Requests for reprints should be addressed to Dr B Pentland, University cause some of the deaths associated with this condition. In severely Department of Medical Neurology, Royal Infirmary, Lauriston Place, affected cases electrocardiograms have occasionally been recorded and Edinburgh. have disclosed arrhythmias, which may be supraventricular-for example, atrial fibrillation.3 In our patient the histamine-like toxin ' Lewis PJ, George CF, Dollery CT. Clinical evaluation of indoramin, a may have induced atrial flutter, which persisted after the other effects new antihypertensive agent. Eur J Clin Pharmacol 1973;6:211-6. of the toxin had disappeared. 2 Bianco S, Griffin JP, Kamburoff PL, Prime FJ. Prevention of exercise- induced asthma by indoramin. Br MedJ 1974;iv:18-20. In most cases of scombrotoxicity palpitation may be sympathetically 3 Wainscott G, Volans GN, Wilkinson M, Faux GA. Indoramin in preven- mediated, as a result of the peripheral effects of the histamine-like tion of migraine. Lancet 1975 ;ii :32-3. compound, and hence readily abolished by Hl-antagonists. Direct 'Kedia KR, Markland C. The ejaculatory process. In: Hafez ESE, ed. stimulation of the heart via H2-receptors, however, may activate a Human semen andfertility regulation in men. St Louis: C V Mosby, 1976: magnesium-dependent channel,4 which may give rise to arrhythmia, 497-503. as in this patient. In view of the potentially serious complications of 6 Faerchtein I, Roque AF, Kastansky I, Campos JC, Puppin S. A placebo histamine-receptor stimulation, the cardiac rhythm of patients with controlled trial of the alpha-blocker, indoramin, in the treatment of scombroid poisoning should be observed before treatment with arterial hypertension. Curr Med Res Opin 1976;3:675-84. histamine antagonists is started. (Accepted 9 February 1981) Nearly 30 years ago atrial flutter was observed after a "heavy sea- food meal."5 Perhaps closer scrutiny of dietary factors may help explain some paroxysmal arrhythmias. Royal Infirmary, Edinburgh BRIAN PENTLAND, MRCP, lecturer in medical neurology IGilbert RJ, Hobbs G, Murray CK, Cruikshank JG, Young SEJ. Scombro- DOROTHY A ANDERSON, MSc, MPs, principal pharmacist, Lothian toxic fish poisoning: features of the first 50 incidents to be reported in drug information centre Britain (1976-9). Br MedJ3 1980;281:71-2. JULIAN A J H CRITCHLEY, MRcp, lecturer in therapeutics and clinical 2 Peters GA, Horton BT. Continuous intravenous administration of pharmacology histamine: effect on the electrocardiogram and serum potassium. Am Heart Jf 1944;27:845-58. 3 Booth BH, Patterson R. Electrocardiographic changes during human anaphylaxis. JAMA 1970;211:627-31. 4 Spah F, Fleckenstein A. Evidence of a new, preferentially Mg-carrying, transport system besides the fast Na and the slow Ca channels in the excited myocardial sarcolemma membrane. J Mol Cell Cardiol 1979; Scombrotoxic atrial flutter 11:1109-27. 5 Hejtmancik MR, Herrmann GR, Bradfield JY. Atrial flutter. I. Clinical aspects. Am HeartJ' 1950;40:884-90. Scombrotoxic fish poisoning has been recognised as a major form of ichthyosarcotoxism in many parts of the world.' Scombridae include (Accepted 12 February 1981) tuna, bonito, and mackerel, and poisoning occurs after ingestion of fish that have formed a histamine-like toxin. Once produced this toxin is remarkably resistant to further preparation; to prevent its Ealing Hospital, Southall, Middlesex UBi 3HW formation immediate packing at 0°C is essential as soon as possible registrar after the fish have been caught. If fish are allowed to remain at room LESZEK BORYSIEWICZ, mB, MRCP, medical temperature tissue concentrations of histamine rise rapidly, possibly Royal Postgraduate Medical School, London W12 OHS due to the action of bacteria on available histidine residues. DENNIS KRIKLER, MD, FRCP, consultant cardiologist

Case report A 60-year-old man was admitted with a four-day history of palpitation ALEXANDER. It is called Alisander, Horse-parsley, and Wild-parsley, that had started after a large meal that had included smoked mackerel. and the Black Pot-herb; the seed of it is that which is usually sold in Within two hours he had developed flatulence, upper abdominal pain, and It is usually sown nausea, followed by weakness, pulsating headache, a sensation of fear, apothecaries' shops for Macedonian Parsley-seed. itching of the scalp, increased frequency of micturition, and rapid regular in all the gardens in Europe, and so well known, that it needs no palpitation. After 48 hours he had sought advice and was referred to us. He farther description. It flowers in June and July; the seed is ripe in was in atrial flutter with a ventricular rate of 150/minute; blood pressure August. was 160/90 mm Hg, with no evidence of cardiac failure. Heart sounds were It is an herb of Jupiter, and therefore friendly to nature, for it normal. Routine blood investigations, including blood count, erythrocyte warms a cold stomach, and opens a stoppage of the liver and spleen; sedimentation rate, cardiac enzymes, urea, electrolytes, and thyroid function it is good to move women's courses, to expel the afterbirth, to break tests, were all normal. Chest radiography showed normal heart size and no wind, to provoke urine, and helps the stranguary; and these things pulmonary congestion. He reverted spontaneously to sinus rhythm the next will do likewise. If either of them be boiled in wine, or day. Arrhythmia did not recur during follow-up of 18 months, which the seeds included four 24-hour ambulatory electrocardiograms taken in relation to being bruised and taken in wine, is also effectual against the biting similar meals. of serpents. And you know what Alexander pottage is good for, that Of 10 people who had also eaten the mackerel at the dinner, three had you may no longer eat it out of ignorance but out of knowledge. developed headache and itching of the scalp and six had felt generally unwell (Nicholas Culpeper (1616-54) The Complete Herbal, 1850.)