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Parkinsonism, Tremor, and Depression Induced by Cinnarizine and Flunarizine

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Parkinsonism, Tremor, and Depression Induced by Cinnarizine and Flunarizine Age at diagnosis ofAIDS at this transbronchial biopsy did not show any pathogen. He patients will die without AIDS being diagnosed. In the hospital to October 1987 was treated with co-trimoxazole and hydrocortisone. United States 10% of patients with AIDS are over 50, After 14 days of co-trimoxazole he had improved 2-5% over 60, and 0 4% over 70. The table shows the Age (years) No of patients clinically and radiographically and was discharged age distribution of our patients with AIDS up to 0-19 2 receiving maintenance treatment. October 1987. Six of 235 (2 5%) patients were over 60. 20-24 19 P carinii pneumonia should be considered in all 25-29 26 30-34 48 patients with atypical chest infections, even when there 35-39 57 Comment are no apparent risk factors. 40-44 33 positive for HIV antibody 45-49 3 1 Both these patients were 50-54 7 and had a clinical and radiological presentation We thank Miss Linda Stannard for preparing the 55-59 6 suggestive of P carinni pneumonia that responded to manuscript and Dr D J R Morgan for his helpful comments. 60-64 2 65 4 treatment; thus the criteria fbr a diagnosis of AIDS were satisfied.' In case 2 the diagnosis was complicated I Anonymous. Revision of the CDC surveillance case definition for acquired imrmlunodeficiency syndrome. .7AMA 1987;258:1143-54. by the previous amiodarone treatment, though 2 Marchinski FE, Lansten TS, Waxman HL, Josephson ME. Amiodarone pneumonitis induced by amiodarone is unusual at a pulmonary toxicity. Ann Intern Med 1982;97:839-45. daily dosage less than 400 mg.23 Chest infections are 3 Suarez LD, Poderoso IJ, Elsner B, Bunster AM, Esteva H, Bellotti M. Subacute pneumopathy during amiodarone therapy. Chest 1983;83:566-8. common in the elderly. The increasing incidence of 4 Moss RJ, Miles SH. AIDS and the geriatrician.Am GeriatrSoc 1987;35:460-4. HIV infection and a reluctance ofolder homosexuals to admit to at risk behaviour may mean that elderly (Accepted 3 May 1988) Characteristics of 70 patients with parkinsonism or tremor induced Parkinsonism, tremor, and by cinnarizine. Unless otherwise stated, results are numbers (and depression induced by percentages) ofpatients cinnarizine and flunarizine Parkinsonism Tremor No of patients: 39 31 Women* 24 20 Dolors Capell, Joan-Ramon Laporte, Men* 13 11 Median age (range) (years) 78 (53-90) 68 (38-85) Josep-Maria Castel, Carmen Tristan, Dose (mg): Angeles Cos, Francisco Jose Morales-Olivas <150 3 (8) 12 (39) 150 28 (72) 14 (45) >150 6 (15) 5 (16) Unknown 2 (5) Department of Cinnarizine and flunarizine are piperazine derivatives Induction period: Pharmacology, Universitat calcium channel <l month 7(18) 6(19) with antihistamine properties and 1-6 months 6(15) 6 (19) Autonoma de Barcelona, blocking activity. Several recent reports have des- 6-12 months 6 (15) 10(32) CS Vall d'Hebron, cribed extrapyramidal reactions and depression 1-3 years 10(26) 5 (16) 08035-Barcelona, Spain >3 years 5(13) 0 Dolors Capella, MD, associate associated with their use. Unknown 5 (13) 4 (13) Recovered after withdrawal of drug: professor Within 1st 3 months 13 (33) 17 (55) Joan-Ramon Laporte, MD, In 3-6 months 9 (23) 0 professor Methods and results In 6-18 months 2 (5) 1 (3) of Unknown 4(10) 5 (16) Josep-Maria Castel, MD, In Spain a system of spontaneous reporting Not within 1st 3 months 4(10) 6 (19) research assistant adverse drug reactions has been operating since Not in 3-6 months .> 1 (3) 0 1983. Around 5000 reports have been received, of Not in 6-12 months 1 (3) 0 Service ofClinical Not in > I year 1 (3) 0 which 86 refer to cinnarizine as the suspected drug, Unknown 4 (10) 2 (7) Pharmacology, Clinica 25 to flunarizine, and five to both drugs taken Universitaria, Pamplona described Carmen Tristan, MD, simultaneously. Of these 116 reports 87 *The sex of two patients with parkinsonism was unknown. research assistant extrapyramidal symptoms or depression, or both: cinnarizine had been taken in 70 cases, flunarizine in improved when treatment stopped; three of them Service ofClinical 13, and both drugs in four. improved during the first month, but no exact Pharmacology, CMN Seventy patients developed tremor and parkin- information was available about the fourth. None of Marques de Valdecilla, sonism while being treated with cinnarizine (see table). these patients were taking any other drug which could Santander They were not taking other drugs likely to induce have contributed to their depression. Angeles Cos, MD, research parkinsonism, except for three patients, one of whom assistant was also taking sulpiride, one thiethylperazine sub- Comment Department of and dimenhydrinate, and one thioridazine (he Pharmacology, Universitat sequently recovered when cinnarizine was withdrawn In Spain cinnarizine is marketed in 10 pharma- de Valencia without stopping thioridazine). Eight additional ceutical preparations, eight of which are fixed dose Francisco Jose patients (two men, six women) presented with combinations with other drugs. The most common Morales-Olivas, associate parkinsonism and three men presented with tremor indications are cerebral and peripheral arterial professor while being treated with flunarizine (5 mg/day in one insufficiency. The top selling preparations contain patient and 10 mg/day in 10). Four other patients 75 mg per tablet, and the recommended dose is 75 mg Correspondence to: developed parkinsonism (two men) or tremor (one twice a day. Approved indications for flunarizine are Professor Laporte. man, one woman) while treated simultaneously with the same as for cinnarizine. In the United Kingdom both drugs. cinnarizine is marketed as 15 mg tablets for vestibular Four patients (two men, two women, aged 24 to 67) disorders and motion sickness, with a maximum presented with depression while taking flunarizine recommended dose of 30 mg three times a day.4 In (three patients, one of them also with tremor) or Spain 5-7% of the population over the age of 60 may be cinnarizine (one patient, who also presented with receiving long term cinnarizine.5 The consumption of parkinsonism). The daily dose offlunarizine was 10 mg flunarizine is also high: in 1986, 1-2 million units were and of cinnarizine 150 mg. The intervals between dispensed. Not surprisingly therefore a large number starting drug treatment and the appearance of the first of cases of extrapyramidal symptoms and depression symptoms ranged from two days (in this patient tremor attributed to these drugs have been assembled by our was also noted) to 10 months. The four patients national scheme. 722 BMJ VOLUME 297 17 SEPTEMBER 1988 As the table shows, parkinsonism can be induced to this effect. We have started a case-control study with even by daily doses of cinnarizine of less than 150 mg. the aim of quantifying the risk of extrapyramidal Patients with tremor tended to be younger (Mann- disorders associated with these drugs. Whitney U test, p=0O0043), however, and seemed to have taken lower cumulative doses than those with 1 Marti Mass6 JF, Carrera N, de la Puente E. Posible parkinsonismo por cinaricina. Med Clin (Barc) 1985;85:614-6. parkinsonism (Mann-Whitney U test, p=0O0417). 2 Chouza C, Scaramelli A, Caamauio JL, De Medina 0, Alianati R, Romero S. Patients with flunarizine induced parkinsonism Parkinsonism, tardive dyskinesia, akathisia, and depression induced by younger affected by flunarizine. Lancet 1986;i: 1303-4. (median age 63) were than those 3 Meyboom RHB, Ferrari MD, Dieleman BP. Parkinsonism, tardive dyskinesia, cinnarizine (median age 78) (Mann-Whitney U test, akathisia, and depression induced by flunarizine. Lancet 1986;ii:292. p=00059), and these differences were apparently not 4 Joint Formulary Committee. British national formulary number 14. London: British Medical Association and The Pharmaceutical Society ofGreat Britain, related to different indications for the use ofeach drug. 1987:160. Cinnarizine and flunarizine are piperazine deriva- S Laporte JR, Capella D. Useless drugs are not placebos: lessons from flunarizine tives structurally related to some phenothiazines, and and cinnarizine. Lancet 1986;ii:853-4. this may explain their extrapyramidal effects. Their calcium channel blocking activity may also contribute (Accepted 9 May 1988) Dangerous oronasal obstruction Several days before her death she became cyanotic with tightly closed toothless mouth and pinched in nostrils. in weak senile patients Nasal catarrh and a deviated nasal septum were found. A nasal catheter was introduced but was removed by the patient. The nose was taped so that the nostrils A M M Berkhout, H J M Cools could not be pulled inwards by suction; the patient did not protest. de Bieslandhof Nursing and During routine surveillance in this 320 bed nursing Case 5-An 88 year old woman who had suffered a Rehabilitation Centre, 2612 centre patients are sometimes found in a dangerous complete stroke was receiving digoxine and dytaurese. VC Delft, The Netherlands condition of dyspnoea and cyanosis. We describe five In the past she had broken her nose. She had neither A M M Berkhout, MD, cases in which was caused by oronasal teeth nor dentures. One week before her death she physician this condition H J M Cools, MD, adjunct obstruction. developed a respiratory tract infection. She ate and director drank little and became bedridden. The next day she suffered an episode similar to those experienced by the Correspondence to: Dr Case reports patients in case 1-4. There was no recurrence. She died Cools. Case I-An 85 year old woman with severe of aspiration pneumonia. Alzheimer's disease was emaciated, drank little, and remained bedridden; she was receiving no drugs. She was found in a dangerous dyspnoeic and cyanotic state; Comment the nostrils were sucked in during inspiration but a Since 1984 five women in this centre have been certain degree of inspiration was audible.
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