TREATMENT OF IDIOPATHIC ORTHOSTATIC HYPOTENSION WITH XAMOTEROL

1431

penicillin and the fever regressed Scarlet-fever-like peeling occurred after 15 days. Treatment with aspirin was started at 30 mg/kg daily. 2 months later the cervical lymph nodes had regressed and the only dermatological sign was a transverse groove crossing the nails. Two-dimensional echocardiography was normal. However, T4 and T8 lymphocytes were 15% and 56%, respectively. This patient met criteria for MLNS.3 A role for lymphotropic retrovirus infection in MLNS was suggested by Leung" on the basis of the immunological disturbances that accompany the acute phase of the disease. Shulman1 found reverse transcriptase activity in 8 of 18 children with Kawasaki disease. Human retroviruses include the lymphotropic viruses HTLV I and II and HIV-1 and HIV-2. Moynahan2 suggested a role for a flea-transmitted feline virus to explain the association of MLNS and the use of rug shampoo.s A lymphotropic virus inducing an immunodeficiency syndrome has been isolated in the cat. This virus is morphologically similar to HIV but antigenically different.6 Despite the epidemic spread of HIV infection no case associated with MLNS has hitherto been reported; the association in the above patient may be fortuitous or may indicate that the role of retroviruses in Kawasaki disease is limited to that of co-factor(s). She did not

respond

to

spontaneously after 8 days.

Department of Dermatology, Hôpital Purpan, 31059 Toulouse, France

ROLAND VIRABEN ANDRÉ DUPRE

Previous studies’ have indicated that convalescent-phase sera from Kawasaki syndrome patients do not react with antigens of HIV-1, so it seems that sera from such patients contain detectable antibodies to neither HIV-1 nor HTLV-1, HTLV-11, or SIV. We thank Mr William Switzer for expert technical assistance.

Epidemiology Office, Division of Viral Diseases, and AIDS Program, Center for Infectious Diseases, Centers for Disease Control, Atlanta, Georgia 30333, USA

ALAN M. RAUCH PATRICIA N. FULTZ V. S. KALYANARAMAN

1. Shulman S, Rowley A. Does Kawasaki disease have a retroviral aetiology? Lancet

1986;

ii: 545. 2. Bums J, Raif G, Schneeberger E, et al. Polymerase activity m lymphocyte culture supernatants from patients with Kawasaki disease. Nature 1986; 323: 814-16. 3. Rauch A, Hurwitz E. Centers for Disease Control (CDC) case definition for Kawasaki syndrome. Pediatr Infect Dis 1985; 4: 702-03. 4. Fultz P, McClure H, Anderson D, et al. Isolation of T-lymphotropic retrovirus from naturally infected sooty mangabey monkeys (Cercocebus atys). Proc Natl Acad Sci USA 1986; 93: 5286-90. 5. Newberger J, Takahashi M, Bums J, et al. The treatment of Kawasaki syndrome with intravenous gamma globulin N Engl J Med 1986; 315: 341-47.

TREATMENT OF IDIOPATHIC ORTHOSTATIC HYPOTENSION WITH XAMOTEROL

SIR,-Postural hypotension is an incapacitating manifestation of nervous system dysfunction and is difficult to treat in patients. Mehlsen and Trap-Jensen1 have reported that xamoterol, a &bgr;1-adrenoceptor partial agonist with 43% intrinsic sympathomimetic activity (ISA), produced beneficial effects in patients with postural hypotension who did not have central nervous system manifestations. We describe our experience with xamoterol in three male patients (aged 56, 60, and 61) with postural hypotension and central nervous system manifestations (ShyDrager syndrome). Before admission, the first patient was not on drug treatment while the other two cases were being treated with dihydroergotamine and etilefrine. In an initial two-week control period these drugs were continued while assessments were made in hospital. Supine heart rate and blood pressure were measured twice daily. During the next two weeks xamoterol, 200 mg twice a day, was given on an open basis and all other therapy stopped. In all three cases xamoterol increased supine heart rate and blood pressure (table). In two patients the frequencies of syncopal attack were reduced by xamoterol. The use of pindolol, a &bgr;-blocker with about 25 % I SA, in patients with postural hypotension has been reported. Man in’t Veld and Schalekamp2 suggested that pindolol was effective in patients with a post-ganglionic sympathetic lesion but ineffective in patients with multiple system atrophy. Robson3supported this view because pindolol was effective in patients with idiopathic peripheral

autonomic

1. Shulman

2.

ST, Rowley AH. Does Kawasaki disease have a retroviral aetiology? Lancet

1986; ii: 545. Moynahan EJ. Kawasaki disease: a

novel feline virus transmitted by fleas. Lancet 1987; i: 195. 3. Mas WR. Kawasaki disease—New York. MMWR 1980; 29: 61-63. 4. Leung DYM, Chu ET, Wood N. Immunoregulation T cell abnormalities in mucocutaneous lymph nodes syndrome. J Immunol 1983; 130: 2002-04. 5. Patriarca PA. Kawasaki’s syndrome: Association with the application of rug shampoo. Lancet 1982; ii: 578. 6. Pedersen NC, Ho EW, Brown ML, Yamamoto JK. Isolation of a T lymphotropic virus from domestic cats with an immunodeficiency-like syndrome. Science 1987; 235: 790-93.

RETROVIRUS SEROLOGY AND KAWASAKI SYNDROME

.

SIR,—The cause of Kawasaki syndrome has eluded investigators since the first cases were described in 1961. Investigators from two laboratories’.2 have detected reverse transcriptase (RT) activity in supernatant fluid of co-cultivated peripheral mononuclear cells from patients with this syndrome, raising the possibility that a retrovirus may be associated with Kawasaki disease. Burns et al,z using transmission electronmicroscopy, found particles resembling retroviruses in intracytoplasmic vacuoles of co-cultures from three patients with Kawasaki’s disease. The particles were 105-118 nm in diameter and had an electron-dense core. Known human retroviruses are the human T-lymphotropic virus types I and II and the human immunodeficiency viruses HIV-1and HIV-2. While HIV-1and HIV-2 share some antigenic epitopes, HIV-2 is more closely related to the simian immunodeficiency viruses (SIV), and antibodies to HIV-2 crossreact with all the major proteins of SIV (P. N. F., unpublished). We have tested sera from patients with Kawasaki disease for antibodies to HTLV-1 and SIV. Samples were collected during outbreaks of Kawasaki disease in Texas, Colorado, North Carolina, Ohio, and Nebraska between August, 1984, and July, 1985, and from age, race, and sex matched control infants and children. All cases met the Centers for Disease Control epidemiological case definition for Kawasaki syndrome.’ We tested convalescent-phase sera from 25 Kawasaki syndrome patients, paired acute and convalescent-phase sera from 3 Kawasaki syndrome patients, and sera from 11 randomly selected matched controls. We use immunoblotting with whole HTLV-1 from MT-2 cells as test antigen and indirect immunofluorescence for SIV antibodies 4 We randomly selected 9 convalescent-phase sera for additional testing for SIV antibodies by immunoblot. Laboratory personnel were blind to the case/control status of all samples tested. None of these sera was positive for either anti-HTLV-1 or anti-SIV. Positive control sera reacted appropriately.

most

MEAN

(SD) BLOOD PRESSURE AND HEART RATE AND FREQUENCY OF 2-WEEK CONTROL AND XAMOTEROL

SYNCOPAL ATTACKS DURING

TREATMENT PERIODS

*Dihydroergotamine 9 mg, etilefrine 60 mg per day; dihydroergotamine 12 mg, etilefrine 45 mg per day; SBP and DBP = systolic and diastolic blood pressure (mm Hg); HR heart rate (per min). =

1432 autonomic neuropathy but in patients with Shy-Drager syndrome, pindolol was ineffective and appeared to act as a &bgr;-antagonist. In the cases reported by Mehlsen and Trap-Jensen1 pindolol was ineffective or decreased mean blood pressure while xamoterol increased blood pressure and heart rate. In our patients with orthostatic hypotension and Shy-Drager syndrome, xamoterol increased blood pressure and heart rate. We therefore suggest that xamoterol may be useful for patients with postural hypotension whether or not central nervous system involvement is present.

First Department of Internal Medicine, Asahikawa Medical College,

Asahikawa, Hokkaido 078,

Japan

HIROHISA YAMASHITA OSAMU YAHARA NAOYUKI HASEBE YUICHIRO KAWAMURA ATSUSI OBARA HAJIME HONDA TAKASI KIMURA SOKICHI ONODERA

J, Trap-Jensen J. Xamoterol, a new selective beta-1-adrenoceptor partial agonist, in the treatment of postural hypotension Acta Med Scand 1986; 219:

1. Mehlsen

173-79. 2. Man in’t Veld AJ, Schalekamp MADH Pindolol acts as beta-adrenoceptor agonist in orthostatic hypotension: Therapeutic implications. Br Med J 1981; 282: 929-31. 3. Robson D. Pindolol in postural hypotension. Lancet 1981, ii: 1280.

involved in

a

serious accident.

Moreover, the

cost

of visits

to

the

emergency room and investigations may more than offset the savings made by switching formulations. There are several generic brands, and no way of predicting which a patient will receive. In disorders where small changes in drug levels may have serious consequences, switching from a branded to a generic product is not

always advisable. Any switch to a generic anticonvulsant drug should be accompanied by monitoring of blood levels for the first month, during which the patient should not drive. Once bioequivalence has been confirmed, the same generic product should be used every time the prescription is filled. We thank Dr Sudhansu

Chokroverty for his valuable suggestions.

Department of Neurology, UMDNJ-Robert Wood Johnson Medical School and University, New Brunswick, New Jersey 08903, USA

1.

RAJESH C. SACHDEO GEORGE BELENDIUK

Lamy PP. Generic equivalents: Issues and concerns. JClin Pharmacol 1986; 26:

309-16. 2. Colaizzi JL, Lowenthal DT Critical therapeutic categories: A contradiction to generic substitution? Clin Ther 1986; 8: 370-79.

GENERIC VERSUS BRANDED CARBAMAZEPINE

CERVICAL CANCER SCREENING

SIR,-A generic drug is defmed as a compound with the same structure and pharmacological properties as that in a proprietary brand, but costing less. US Food and Drug Administration guidelines on bioequivalence allow for some variation in different formulations, and this can be important clinically if there is a very sharp threshold for therapeutic efficacy. The area under the

SIR,—Dr Laara and colleagues (May 30, p 1247) paint an impressionistic picture of the benefits of screening without any attempt to disentangle the effects of a spontaneous decline in incidence and mortality. Norway, with no nationwide screening, has always been presented as a black sheep among the Nordic countries, and virtually every article on the subject contains a graph showing a falling incidence of cervical cancer in Denmark, Sweden, Iceland, and Finland, while in Norway the incidence rises relentlessly. Laara and colleagues now show that from 1955 the cumulative mortality in Norway was decreasing at a slope similar to that in Sweden. While the increasing incidence in Norway has been blamed on the lack of nationwide screening, the decreasing mortality is now explained by the existence of unorganised screening. One cannot have it both

chemical

curve and maximum drug concentration have to be within 25 % of the values for the reference parent compound in 75 % of the patients tested in a crossover bioequivalence study.For example, in a bioequivalence study of 200 mg branded carbamazepine (’Tegretol’) 75 % of patients on generic carbamazepine would have to fall into a 150 to 250 mg dose equivalence window. We have seen breakthrough seizures in three patients who were well controlled on tegretol and were switched to a generic preparation. A 51-year-old man who had had partial complex seizures since childhood had been clinically stable and seizure-free for 9 months on phenytoin 200 mg and tegretol 1200 mg daily. At one clinic visit he was given a new prescription which was filled with generic carbamazepine. Within 5 days he had generalised tonic-clonic and partial complex seizures. After six seizures in 3 weeks he was referred for neurological evaluation. His medication was altered to tegretol and he has remained seizure-free for 6 months. A 46-year-old woman with a history of partial complex generalised tonic-clonic convulsions had been seizure-free for 3 months while on 1600 mg tegretol daily. After one routine clinic generic carbamazepine was dispensed. Some days later she had severe generalised tonic-clonic seizures and had to be taken to hospital by ambulance. Her seizures were controlled by intravenous diazepam. Back on tegretol she has been seizure-free for almost a year. A 22-year-old woman with a history of partial seizures lost her job and health insurance cover because of her seizure disorder. She joined a health maintenance organisation and had to switch to generic carbamazepine. Before that she had been seizure-free on 800 mg tegretol daily for a year. After experiencing four generalised seizures in 4 days, accompanied by a rash on her face, arms, and hands, she was seen in the hospital emergency room. Back on tegretol her rash cleared and she has been seizure-free for 6 months. A patient who is clinically stable on 1000 mg tegretol may, when switched to a generic product, be taking a preparation that is equivalent only to 900 mg or even 800 mg of tegretol.2 This effective reduction in dosage is enough, in some cases, to cause breakthrough seizures. This is not to say that the generic medicine is ineffective: if patients take enough of the generic medication to attain the blood carbamazepine levels they had with tegretol their seizures would be controlled. However, for a saving in costs of 4 cents a tablet the patient runs the risk of losing his driving licence for a year or being

ways.

Laara

et

al do

not comment on

the

only organised Norwegian

programme, in Østfold County. This started in 1960 and covered ages 25-59, with about 70% attendance rates. After round 4, in 1974, reduction in the incidence of invasive cancer, expressed as a ratio of observed to expected cases, was from 0-96 to 0-90 (6%).

While there was a 44 % reduction in mortality from cervical cancer in 0stfold in the 5-year period immediately before the onset of screening, there was no change in mortality during the 14 years of the programme.’ Perhaps it was this disappointing experience which made the Norwegians reluctant to embark on a nationwide programme.

The Icelandic data are striking but difficult to relate to screening. The annual mortality in the most screened group (ages 25-59) before screening was 11.7/105 (1955-59); a decade after screening it was 12.2/105 (1970-74).z What is the explanation? Advocates of screening believe that screening every 2-5 years can reduce the incidence of cervical cancer by 80%.3 Such estimates ignore the fact that in many countries (eg, Japan, France, and Italy), mortality from cervical cancer is much lower than it is in Sweden and has been falling for the past 20 years at rates similar to the rate seen in Sweden; yet these falls are not explainable by nationwide programmes.’ The lack of correlation between screening activity and cervical cancer mortality is supported by a large volume of evidence. Just one example, from Sweden: in Malmö, with a wider screening net than usual (ages 20-69), 92 % women were screened by 1979, but the numbers of invasive carcinomas seen between 1970 and 1979 were the same every year.’ Moreover, in Sweden, over 80% of invasive cancers in women targeted for screening (age 30-49) occurred within 5 years of the last smear.6 We all remember the enthusiasm generated by the British Columbia results in the 1960s; these are now rarely mentioned since the data failed to demonstrate clearly any effect of screening on