708

HUMAN SERUM AND BILE CORRINOIDS: MEANS±SD (pg/ml) -

absorption mechanism poorly, while allowing reabsorption of intactcobalamin via that mechanism.Kalahari bushmen, who exist solely on natural diets, have serum

analogue levels similar to those of Americans, supporting theprobability that analogues were present in primitive man.9A preliminary abstract of this work appeared in Clin Res 1982; 30: 687A.

Hematology and Nutrition Laboratory,V.A. Medical Center,Bronx, N.Y. 10468, U.S.A.;and Department of Medicine,and Downstate Medical Center,

State University of New York,Brooklyn, N.Y.

SHOICHIRO KANAZAWAVICTOR HERBERTBARRY HERZLICHGEORGE DRIVASCATHY MANUSSELIS

LEGIONELLA MICDADEI (PITTSBURGH PNEUMONIAAGENT) MAY CAUSE NON-PNEUMONIC

LEGIONELLOSIS

SIR,-The Pittsburgh pneumonia agentl2 was later identified as abacterium belonging-to the genus Legionella and designated L.micdadei.3 3 It causes lung infection both in inpatients (especially inthose who are immunosuppressed4) and in the community.5,6 Wehave seen a case of protracted febrile illness without any signs orsymptoms from the respiratory tract in a previously healthy man.Serological tests pointed to L. micdadei infection.On Sept. 1, 1982, a 66-year-old man was admitted after a 10 day

history of fever (40-41°C) and severe muscle pain, mainly in thelegs. He had no cough, sputum, or any other focal symptoms. Hewas clear-minded and slightly dehydrated. Physical examinationrevealed no local signs of infection or other abnormalities. His chestX-ray suggested slight pulmonary fibrosis but not pneumonia orpleural effusion. The white blood ’cell count was 16 700/1 with amarked shift to the left, and Hb concentration was 8’ 0 mmol/l, theplatelet count 581 x 109/1, and the erythrocyte sedimentation rate(ESR) was 113 mm/h. Serum electrolytes, urea, and creatininevalues were normal. Bacteriological cultures from faeces, urine, andblood (14 times) were negative as were antibody tests for infectionwith Mycoplasma pneumoniae, ornithosis agent, Leptospira,cytomegalovirus, streptococci, Yersinia enterocolitica, Salmonellatyphl and S. paratyphi. The bone marrow showed plasma cellproliferation.Because of continuous high fever erythromycin 1 - 5 g daily was

started on day 3. However, the fever continued and the patient’sgeneral state deteriorated. The Hb concentration fell, and liverfunction became slightly impaired, with a moderate increase inserum lactate dehydrogenase and aspartate aminotransferaseactivities. The platelet count increased to 1034 x 109/1. On day 9 theantibiotic was changed to ampicillin 6 g, gentamicin 240 mg, andmetronidazole 1-5 5 daily. During the next 10 days the fever

9. Herbert V, Kanazawa S, Drivas G, et al. Evidence for presence of stable vitamin B12analogue in serum of bushmen on "natural" diets, and in liver of Americans, andanalogue absence in red cells of Americans and fruit bat serum (even after vitaminB12 supplementation). In: Proceedings of 19th Congress of the InternationalSociety of Haematology (Budapest, Aug. 1-7, 1982): 236.

1. Pasculle AW, Myerowitz RL, Rinaldo CR Jr. New bacterial agent of pneumoniaisolated from renal-transplant recipients. Lancet 1979; ii: 58-61.

2. Myerowitz RL, Pasculle AW, Dowling JN et al. Opportunistic lung infection due to"Pittsburgh pneumonia agent". N Engl J Med 1979; 301: 953-58.

3. Hébert GA, Steigerwalt AG, Brenner DJ. Legionella micdadei species nova:

Classification of a third species of Legionella associated with human pneumonia.Curr Microbiol 1980; 3: 225-57.

4. Yu VL, Zuravleff JJ, Elder EM, et al. Pittsburgh pneumonia agent may be a commoncause of nosocomial pneumonia: Seroepidemiological evidence Ann Intern Med1982, 97: 724-26.

5. Macfarlane JT, Finch RG, Laverick A, et al. Pittsburgh pneumonia agent andlegionellosis in Nottingham. Br Med J 1981, 283: 1222.

6. Ackley AM. Community-acquired Legionella micdadei pneumonia. Lancet 1981; i: 221.

gradually subsided, and the patient improved despite a further fallin Hb concentration to 6 - 2 mmol/1. He was discharged on day 27.3 3weeks later he had completely recovered. His ESR was 22 mm/h andall other laboratory test values were back to normal.Antibody titres to L. micdadei (indirect fluorescent antibody test)

were 64 on day 1 (Sept. 2) and 256 on Sept. 15; on Dec. 20 the titrewas 128. Antibodies to L. pneumophila serogroups 1-6, L.

bozemanii, L. dumoffii, L. gormanii, L. jordanis, and L. longbeachaeserogroups 1 and 2 were all <64. Attempts were not made to isolateLegionella from the environment or from the patient, who had notbeen abroad. No other cases were seen among his contacts.All previous reports of L. micdadei infection have involved

pneumonia, 1,2,4-7 most of them being in patients on immuno-suppressive therapy. Our patient did not have respiratory tractdisease. The remarkable thrombocytosis does not seem to have beendescribed in earlier cases of L. micdadei infection.The dose and duration of erythromycin treatment was probably

insufficient. Success has ,been reported with 2-4 g erythromycindaily for 12-27 days in L. micdadei pneumonia, and erythromycinis bactericidal against L. micdadei at concentrations readily achievedin vivo.8 8Since July 1, 1981, L. micdadei has been included in our battery of

antigens in the IFA test for Legionella antibodies. Nine patients,including the present case, have had serological indication of a L,micdadei infection with a rise in titre of 128 or more. The other eightpatients had pneumonia, and three died. Another eleven patientshad single or static L. micdadei antibody titres of 256 or more-i.e.,presumptive evidence of infection with this agent at some time.Between July 1, 1978, and July 1, 1982, sera from 1090 Danishpatients have been tested for Legionella antibodies. In more than halfthe cases the first ten of the thirteen antigens mentioned above wereused in the IFA test. Ninety-nine had diagnostic or presumptivetitres: thus one-fifth of the Legionella positive cases were probablycaused by L. micdadei indicating that L. micdadei infection may bequite common, and the spectrum of the clinical picture seems toextend beyond pneumonia.

Department of Medicine C,Aalborg Hospital,DK-9100 Aalborg, Denmark

FLEMMING KNUDSENARNE H&Oslash;J NIELSENKJELD BO HANSEN

KLAUS LIND

Mycoplasma Laboratory,Blood Bank and Blood

Grouping Department,Statens Seruminstitut, Copenhagen

BETA-BLOCKERS FOR PREGNANCY HYPERTENSION

SIR,-Dr Rubin and colleagues’ paper (Feb 26, p 431) is surely amilestone in the management of hypertension in pregnancy. Thebeta-adrenergic blocking drug atenolol, when given to patients withpregnancy associated hypertension in the last trimester, lowered’blood pressure, prevented proteinuria, and reduced the number ofhospital readmissions; the incidence of respiratory distress

syndrome in the newborn fell while neonatal bradycardia was of noclinical significance. If there is a criticism of this study it might bethat pregnancy associated hypertension must be a mixed bag ofconditions, including gestational hypertension, genuine pre-eclampsia, and the return of the blood pressure to the level thatpreceded the mid-trimester drop. Unfortunately, the diagnosisdepended on a sign unsupported by histological evidence of

pathological change in the kidney or placental site.The next step must be to compare a beta-blocker such as atenolol

with the alpha and beta blocker labetolol, which may be moresuitable in pregnancy because it is short-acting. Another step, I

suggest, is to attempt to prevent the rise in blood pressure in the first

7. Wing EJ, Schafer FJ, Pasculle AW. Successful treatment of Legionella micdadei(Pittsburgh pneumonia agent) pneumonia with erythromycin. Am J Med 1981; 71:836-40.

8. Dowling JN, Weyant RS, Pasculle AW. Bactericidal activity of antibiotics againstLegionella micdadei (Pittsburgh pneumonia agent). Antimicrob Ag Chemother 1982,22: 272-76.

709

place-i.e., to prevent admissions due to hypertension just as we dothose due to anaemia and poorly controlled diabetes. If the bloodpressure is unusually high in the first trimester or if the diastolic isas high as 80 mm Hg at the twentieth week then a subsequent rise inblood pressure, sometimes with proteinuria, may occur.

1

In an uncontrolled trial over the past two years at this hospitallabetolol has been given to 329 patients considered to have an’abnormally high blood pressure after allowance for age, race, andstate of the pregnancy. This has been a continuing experience sincethe results of treating the first 60 or so cases was reported.2 Nopatient is admitted to hospital unless non-infective proteinuriaensues, there is significant growth retardation of the fetus (the newCardiff fundal heights charts seem as helpful as serial scanning3), orblood pressure escapes control. A diastolic pressure of 110 mm Hg,despite an increasing dosage of labetolol, associated with fetalgrowth retardation, usually warrants admission. Exceptionally,labetolol may be combined with drugs such as hydralazine,bendrofluazide, and methyldopa when control of the pressure seemsessential and termination inappropriate. Labetolol does not

adversely affect the fetus although it may not reduce the incidence ofgrowth retardation. Neonatal bradycardia and hypoglycaemia areinsignificant, as is respiratory distress syndrome.In the puerperium the drug should be continued until the third

day test the return of blood pressure to its pretreatment level alarmsthe inexperienced. Maybe it should be continued to the next

pregnancy in a few patients.Our experience, unlike that of Rubin et al, is that in the third

trimester moderate degrees of proteinuria may clear duringtreatment when this begins late in pregnancy. Perhaps these are nottrue cases of pre-eclampsia. Obstetricians are uncriticallydependent on the sphygmomanometer.New Cross Hospital,Wolverhampton ALAN M. SMITH

DIFFERENCE IN BIOACTIVITY BETWEEN TWOPREPARATIONS OF CYCLOPHOSPHAMIDE

SIR,-There is interest in very high dose cyclophosphamide (50mglkg daily for 4 days) for the treatment of small cell carcinoma ofthe bronchus4 and in allogeneic bone marrow transplantation.Haemorrhagic cystitis is a major complication at these dose levels;this can be avoided by the use of mesna.4

4

During a 4 week recent period our normal preparation ofcyclophosphamide (Farmitalia Carlo Erba) was not available andinstead we used ’Endoxana’ (WB Pharmaceuticals) in four patients.All these patients had haemorrhagic cystitis of mild or moderateseverity while on the same dose of cyclophosphamide and mesna asused in the previous series of twenty-five patients.While the two cyclophosphamide preparations had the same

nuclear magnetic resonance spectra, optical activities (bypolarimetry), and gas-liquid chromatographic properties, their

mass spectral properties were quantitatively different. This

suggests minor structural differences between the molecules in thetwo preparations. In rats on doses of 50 mg/kg daily the WB .Pharmaceutical preparation was more active than the Farmitaliaproduct, as judged by depression of spleen weights and bladdertoxicity (oedema). 5

It is possible that in the chemical synthesis of the two preparationsisomeric forms of cyclophosphamide may be made, or that in asterioisomeric mixture of the drug there are different

proportions of the two enantiomers. One of these enantiomers maybe more bioactive than the other. Differences in the metabolic

profiles of the enantiomers of cyclophosphamide have been

1 MacGillivray I. Hypertension in pregnancy. J Maternal Child Health 1977; 2: 245-522 Riley A, Symonds EM. The investigation of labetolol in the management of

hypertension in pregnancy Amsterdam: Excerpta Medica, 1982.3 Calvert JP, Crean EE, Newcombe RG, Pearson JF. Antenatal screening by

measurement of symphysis-fundus height. Br Med J 1982; 285: 846-494 Souhami RL, Harper PG, Linch D, et al High dose cyclophosphamide with

autologous marrow transplantation as initial treatment of small cell carcinoma of thebronchus Cancer Chemother Pharmacol 1982; 8: 31.

5 Shaw IC, Earl LK, McLean AEM, Souhami RL. Differences in the activity of twocommercially available preparations of cyclophosphamide. Human Toxicol (inpress)

described.6 While these differences may be unimportant at

conventional dosage, with very high doses differences in

therapeutic activity and toxicity between one preparation andanother may become vitally important.When prescribing high doses it is important to adhere to one

commercial preparation of cyclophosphamide or to regulate thedosage of the drug and mesna according to the preparation.Cyclophosphamide appears to be one of those few examples of drugsfor.which generic prescribing is not applicable.Departments of Clinical Pharmacologyand Chemistry,

University College London,London WC1F 6JJ;and Department of Radiotherapyand Oncology,

University College Hospital, London

I. C. SHAWL. K. EARLM. N. MRUZEKP. G. HARPERA. E. M. MCLEANR. L. SOUHAMI

OXYQUINOUNE TOXICITY

SiR,-As stressed in your note (Nov. 27, p. 123) Ciba-Geigy’sdecision gradually to phase out clioquinol containing preparationsis the logical consequence of much evidence linking clioquinol withSMON (subacute myelo-optic neuropathy), mainly in Japan. Theneurotoxicity of other oxyquinolines has been much less welldocumented.2 We have seen SMON in a patient using a combinationof tilbroquinol and tiliquinol (’Intetrix’), two oxyquinolines slightlydifferent from clioquinol. This is, to our knowledge, the first reportof neurotoxicity with this compound that is prescribed worldwide.A 60-year-old man was admitted in October, 1982, for visual

impairment, tiredness, and weight loss (9 kg in 5 months). He had along history of constipation and diarrhoea, and a barium enema haddemonstrated sigmoid diverticulosis, for which the patient had beentaking tiliquinol and tilbroquinol continuously for four years at anaverage daily dose of 80 mg and 200 mg, respectively.The neurological symptoms consisted of a 2 year history of pain,

dysaesthesiae, and paraesthesiae of the arms and legs inducinginsomnia for 3 months; impairment of thermic sensibility in thedistal parts of the legs; cerebellar ataxia; anxiety; and poor memory.He had no muscular weakness, pyramidal signs, or impairmentof deep sensation. Laboratory findings in blood and CSF (includinggamma-globulins) were normal. Eye symptoms appeared in July,1982, consisting of right scotoma, asymmetric bilateral

angiographic papilloedema, and colour vision disturbance. Twocomputed tomographic scans of the brain and a cerebral

angiogram were normal.Thus, this case fulfilled the two cardinal and most of the major

signs required for diagnosis by the Japanese SMON ResearchCommission.3 Furthermore, 3 months after withdrawal of intetrixwe observed a dramatic improvement in neurological symptoms, arelief of abdominal pain, and a 9 kg weight gain; there was no changein the ophthalmological picture.We suggest that oxyquinolines other than clioquinol may cause

neuro-ophthalinoldgical damage, and that the problem is not

restricted to Japanese people. This is the first case of such toxicityreported with tilbrbquinol/tiliquinol, a drug combination with largesales worldwide. Furthermore the treatment was about 50 timeslonger than the period recommended by the manufacturers,suggesting that the neurotoxicity is a cumulative effect of thiscompound and the result of obvious overdosage. Physicians shouldrestrict the prescription of all hydroxyquinolines to short-termcourses.

Internal Medicine and Nutrition Service

and Ophthalmology Service,H&ocirc;pital de l’H&ocirc;tel-Dieu,75181 Paris, France

MICHEL SOFFERARNAUD BASDEVANT

JEAN-JACQUES SARRAGOUSSIJOCELYNE RAISONBERNARD GUY-GRAND

6. Jarman M, Milsted RAV, Smyth JF, Kinas RW, Pankiewicz K, Stec WJ. Comparativemetabolism of cyclophosphamide and its enantiomers in humans. Cancer Res 1979;39: 2726

1. SMON Research Commission. Reviews on SMON. Jap J Med Sci Biol 1975; suppl 28:1.

2. Hansson O Toxicity of oxyquinolines Lancet 1977; i 1152.3 Nakae K, Yamamoto SI, Igata A. Subacute myelo optic neuropathy (SMON) in Japan

Lancet 1971; ii: 510-12.