671

is probably concentrated in tissues rich in lipids. Thus, in some patients the parent drug nifedipine is very concentrated in gingiva.4 All lipophilic dihydropyridine calcium antagonists, including felodipine, could be susceptible to unpredictable sequestration, leading to the risk of local concentrations high enough to affect catecholamine stores. Compared with felodipine, amlodipine has

minor effects

on

catecholamine

stores,3 and

reduce

may

sympathetic activity in heart failure.5 Chronic heart failure is a progressive, highly lethal disease, most often treated at home by the family doctor. Treatment should therefore be safe and beneficial. Any activation of the adrenergic system is harmful, both directly and via amplification of the renin-angiotensin system. Felodipine activates the adrenergic systemand should therefore not be used in heart failure. If a calcium antagonist is strongly indicated because of, for example, severe myocardial ischaemia, amlodipine can be used, because it improves exercise capacity and reduces adrenergic stress in heart failure.5 Department of Biochemistry, University of Bergen, N-5009 Bergen, Norway

O. TERLAND

LB, Murray RG, Littler WA. Felodipine in patients with chronic heart failure. discrepant haemodynamic and clinical effects. Br Heart J 1987; 58: 122-28 2. Leenen FHH, Holliwell DL. Antihypertensive effects of felodipine associated with persistent sympathetic activation and minimal regression of left ventricular hypertrophy. Am J Cardiol 1992; 69: 639-45. 3. Terland O, Grønberg M, Flatmark T. The effect of calcium channel blockers on the H+-ATPase and bioenergetics of catecholamine storage vesicles. Eur JPharmacol 1 Tan

1991; 207: 37-41. 4. Ellis JS,

Seymour RA, Monkman SC, Idle JR. Gingival sequestration of nifedipine m nifedipine-induced gingival overgrowth. Lancet 1992; 339: 1382-83.

5 Packer

M, Nicod P, Khandhena BR,

placebo-controlled heart failure. J Am

al. Randomized, multicenter, double-blind, evaluation of amlodipine in patients with mild-to-moderate Coll Cardiol 1991; 17: 274A.

Clinical

SIR,-In Alzheimer’s disease (AD), mitochondrial cytochrome oxidase (complex IV) activity may be reduced.’ Moreover, point mutation in codon 331 of mitochondrial NADH dehydrogenase subunit 2 was found in AD brains.2 Our preliminary study in 27 AD patients demonstrated considerable effectiveness of mitochondrial activation therapy with coenzyme Q10 (COQ10)’ iron, and vitamin B6.3 Recently, among these patients, 2 in the same family were found to have mis-sense mutation of the amyloid p-protein precursor gene at codon 717 (Val Ile), which was reported in early onset-type familial AD patients.’-6 The therapy consisted of CoQ10 60 mg daily, sodium ferrous citrate 150 mg (Fe forming soluble chelates in a wide pH range), and vitamin B6 180 mg. Mental stage was evaluated with DSM-III-R criteria and Hasegawa’s dementia rating scale (HDS), a scale that is correlated with mini-mental state examination scores (r 0-93) .7 Daily activity was evaluated with functional assessment staging (FAST). Neither patient was given neuroleptics and neither had heart failure or anaemia. Serum iron concentrations were normal. Patient 1, a 49-year-old woman, had a 1-year history of progressive memory impairment (figure). Examination revealed disorientation for time and place, and impaired dialogue and behaviour. Brain computed tomography was normal. Her mental state improved to almost normal after 6 months of therapy. Her current IQ (Wechsler adult inventory scale) is 96. Daily activity improved from FAST stage 5 (moderate AD) to 1 (normal), and she can now ride a motorcycle and take care of patient 2. With the improved clinical dementia, increased blood flow of the cerebral cortex was revealed by single photon emission tomography. The power spectra of the electroencephalogram showed faster alpha wave activity. The symptoms progressed with cessation of the therapy and improved with its resumption (figure). Patient 2, the elder sister, was 58 years old, and had had progressive dementia for 4 years. After therapy, her mental state and daily activity improved gradually (HDS 12 to 22, FAST stage 6 to 3). However, she also had adult T-cell leukaemia, and at 18 months post-therapy her mental and physical condition deteriorated because of high fever and hypercalcaemia. =

of patient 1.

The patients’ mother had developed memory loss at age 65, followed by progressive global mental deterioration and death at age 70. Thus, her clinical course was different from that of her

daughters. The mean duration from onset of memory impairment to death 6-3 years (range 4-8) in 4 Japanese patients with the same mis-sense mutation. 1,6 Although our patient numbers are small, familial AD patients show dementia that progresses rapidly until death, and remission is not observed. Thus, we consider that treatment prevented the progression of dementia for 1-5-2 years in was

our

et

Coenzyme Q10, iron, and vitamin B6 in genetically-confirmed Alzheimer’s disease

course

patients.

Departments of Neuropsychiatry and Neurology, Hyogo Prefectural Amagasaki Hospital, Hyogo 660, Japan, Department of Neurology, Brain Research Institute,

Niigata University, and College of Medical Care and Techology, Gunma University

MASAKI IMAGAWA SATOSHI NARUSE

SHOJI TSUJI AKIHIRO FUJIOKA HARUYASU YAMAGUCHI

DW, Filley CM, Parks JK. Cytochrome oxidase deficiency m Alzheimer’s disease. Neurology 1990; 40: 1302-03. 2. Lin F-H, Lin R, Wisniewski HM, et al. Detection of point mutations in codon 331 in mitochondrial NADH dehydrogenase subunit 2 in Alzheimer’s brains Biochem Biophys Res Commun 1992; 182: 238-46 3. Imagawa M. Therapy with a combination of coenzyme Q10, vitamin-B6 and iron for Alzheimer’s disease and senile dementia of Alzheimer type. In: Iqbal K, et al, eds. Alzheimer’s disease: basic mechanisms, diagnosis and strategies. New York: Wiley, 1. Parker

4.

1991; 649-51. Goate A, Chartier-Harlin M-C, Mullan M, et al. Segregation of a missense mutation in the amyloid precursor protein gene with familial Alzheimer’s disease. Nature 1991;

349: 704-06. 5. Naruse S, Igarashi S, Kobayashi H, et al. Mis-sense mutation Val→Ile in exon 17 of amyloid precursor protein gene in Japanese familial Alzheimer’s disease. Lancet

1991; 337: 978-97. 6. Yoshioka K, Miki T, Katsuya T, et al. The 717Vat→Ile substitution in amyloid precursor protein is associated with familial Alzheimer’s disease regardless of ethnic groups. Biochem Biophys Res Commun 1991; 178: 1141-46. 7. Hasegawa K. The clinical assessment of dementia in the aged. a dementia screening scale for psychogeriatric patients. In. Bergener M, et al, eds Aging in the eighties and beyond. New York. Springer, 1983: 207-18

Age-related increase of Helicobacter pylori frequency in symptom-free and in dyspeptic children SiR,—Dr Bateson (May 2, p 1121) suggests that the age-related increase in Helicobacter pylori frequency shown by Dr Mendall and colleagues (April 11, p 896) may be a serological artifact and that if H pylori status was measured more directly, such an age-related increase may not be seen. Dr Blecker and Dr Vandenplas (June 20, p 1537), on the other hand, demonstrate an age-related increase in H pylori colonisation assessed serologically in symptom-free children. We report 207 symptom-free children aged 4-15, who have been assessed serologically (in-house ELISA, specificity and sensitivity 93%)1 and 594 children who underwent endoscopy between January, 1988, and December, 1991, for dyspeptic symptoms and who have been assessed histologically (Giemsa) and with a rapid urease test (CP--test, Gist-Brocades).

672

FREQUENCY OF H PYLORI POSITIVE CHILDREN BY AGE

I

*p < 05, X2 test

vs

I

symtpom-free children

m same

age group

age-related increase in H pylori occurrence both in and in dyspeptic children, and a significantly higher symptom-free frequency of the infection in dyspeptic children aged 8-15 compared with symptom-free children of the same age (table). Bateson, using the CLO-test, also showed an age-related increase in H pylori frequency up to age 70. With continuous, long-term colonisation by H pylori, atrophic gastritis could develop and colonisation might be lost. Bateson’s results may reflect the known high false-negative rate for H pylori in patients aged over 702 in whom, although seropositive (reflecting past infection), the organism cannot be cultured because of gastric mucosal atrophy with associated loss of cellular binding sites and thus loss of H pylori. We found

an

Paediatric Gastroenterology, University of Turin, 10126 Turin, Italy, 1st Medical Clinic, University of Bologna; and Department of Microbiology, University College and Middlesex School of Medicine. London

GIUSEPPINA ODERDA DINO VAIRA JOHN HOLTON

1. Oderda

2.

G, Vaira D, Holton J, Dowsett JF, Ansaldi N. Serum pepsinogen I and IgG antibody to Campylobacter pylori in non-specific abdominal pain in childhood. Gut 1989; 30: 912-16. Karnes WE, Samloff IM, Siurala M, et al. Positive antibody and negative tissue staining for Helicobacter pylori in subjects with atrophic body gastritis. Gastroenterology 1991, 101: 167-74.

Subacute myopathy during omeprazole

therapy SIR,-Side-effects associated with omeprazole have described." We report effect.

an

omeprazole-associated

been muscular side-

A 78-year-old woman was given omeprazole 40 mg daily because haemorrhage from duodenal ulcer. After 14 days, omeprazole was reduced to 20 mg daily. Hepatic and renal function was normal. She began to develop slowly progressive muscular weakness and after 4 weeks of treatment needed help in walking and rising from squatting. Pain, fever, and sensory and constitutional symptoms were absent. Examination showed moderate weakness in the neck and proximal limb muscles, without atrophy, and with reflexes slightly reduced but not absent. The most relevant laboratory findings were: normal creatine phosphokinase, aldolase, and sedimentation rate. haemoglobin, erythrocyte Electromyograph of the femoris and tibialis anterior muscles revealed normal interference pattern with maximum effort, without fibrillations nor fasciculations at rest. A few motor-unit potentials were polyphasic with short duration and amplitude. Motor and sensory nerve conduction were normal in peroneal and sural nerves. Biopsy of quadriceps muscle revealed slight atrophy of type II fibres. A side-effect of omeprazole was suspected and the drug was discontinued after 31 days. The weakness resolved slowly and the patient returned to her baseline state. After 13 weeks, omeprazole 20 mg daily was reinstituted with the patient’s informed consent. 2 weeks later muscular weakness was again observed. Clinical electromyographic, and histological findings were similar to those of the first episode but muscle enzymes were higher than normal: creatine phosphokinase 759 IU/1 (normal < 165), aldolase 20 IU/1 (normal < 8). After withdrawal of omeprazole, the weakness and enzyme abnormalities resolved in 30

of

days.

The proximal weakness of our patient, with normal stretch reflexes and without muscle atrophy or sensory abnormalities, must The histological and be attributed to a myopathy. electromyographic findings are unspecific but accord with a myopathy. The close relation of symptoms and laboratory findings with omeprazole treatment and the positive rechallenge suggest a causal link.

Internal Medicine, Neurology and Pharmacy Services, Hospital Severo Ochoa, 28911 Madrid, Spain

F. J. GARROTE C. LACAMBRA T. DEL SER B. GARCÍA DÍAZ G. OBESO J. SOLÍS

1. Covens

C, Verhelst J, Mahler C. Painful gynaecomastia during omeprazole therapy 1991; 338: 1153 2. Dutertre JP, Soutif D, Jouville AP, Cadenne M, Valat JP, Autret E Sexual disturbances during omeprazole therapy Lancet 1991; 388: 1022. 3. Sellaph S. An unusual effect of omeprazole. case report Br J Gen Pract 1990, 40: 389 4. Markes DR, Joy JV, Bonhein NA Hemolytic anemia associated with the use of omeprazole. Am J Gastroenterol 1991; 86: 217-18. Lancet

Clozapine and hyponatraemia SiR,—We report hyponatraemia related to treatment with clozapine in a 39-year-old woman with schizophrenia who had been started on the drug 7 weeks earlier and was on 350 mg per day. She presented with a grand mal seizure. Sodium 113 mmol/l, reverted to normal by the next day after stopping clozapine and restricting fluid. No other cause for the hyponatraemia was identified. Hyponatraemia and inappropriate antidiuretic hormone secretion secondary to therapy with other neuroleptics and water intoxication in psychotic patients has been reported.1 We know of no other case of hyponatraemia associated with clozapine. The Sandoz Clozapine Monitoring Service told us that they had two reports. Both were outside the UK and few details are available. The first was a 28-year-old man who was also taking captopril and who presented with seizures on clozapine 350 mg daily. The second was a 49-year-old man who had been on clozapine 500 mg daily for 5 months and who presented with epilepsy and coma; the coma was attributed to acute hyponatraemia (sodium 113 mmol/1 for 1 day) due "to potomania and not due to clozapine" (we presume this implies water intoxication). Thus clozapine should be added to the list of psychotropic drugs that may contribute to hyponatraemia. Because up to 14% of patients on higher doses of clozapine (over 600 mg per day) report seizures,2 it is important that hyponatraemia is both considered and excluded as a possible epileptogenic trigger in such patients. ALAN D. OGILVIE Royal Edinburgh Hospital, MELANIE F. CROY Edinburgh EH10 5HF, UK 1. Crammer JL Drinking, thirst and water intoxication., Br J Psychiatry 1991, 159: 83-89 2. Alphs LD, Metzler HY, Bastani B, Ramirez LF Side effects of clozapine and their management. Pharmacopsychiatry 1991, 24: 46.

Secondary leukaemias after epipodophyllotoxins SIR,-Dr Zeimet and colleagues (Aug 8, p 379) describe two developed secondary leukaemia after treatment, and for serous carboplatin etoposide, including cystadenocarcinoma. One of these patients had CDl9 + /CD 10 B-lineage leukaemia, suggesting that etoposide, a topoisomerase II inhibitor, can induce leukaemias of lymphoid as well as myeloid lineage. In children, secondary acute lymphoblastic leukaemia (ALL) is rare. Of 3445 children treated for solid tumours at our institution from 1962 to 1991, this complication was seen in only 2 patients, neither of whom had received chemotherapy for their primary disease (neuroblastoma and retinoblastoma).1 By contrast, 13 of these patients have developed secondary acute myeloid leukaemia (AML), which was attributed to the use of adults who

epipodophyllotoxins in 2.2 Treatment-related leukaemias

are more common

among

our

patients treated initially for ALL, especially since the introduction of intensive epipodophyllotoxin therapy. Among 980 patients