BETA-BLOCKERS FOR PREGNANCY HYPERTENSION
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HUMAN SERUM AND BILE CORRINOIDS: MEANSSD (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
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 (40-41C) 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 patientsgeneral 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. Hbert 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
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.
In an uncontrolled trial over the past two years at this hospitallabetolol has been given to 329 patients considered to have anabnormally 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 notadversely 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 nextpregnancy 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
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, theirmass spectral properties were quantitatively different. Thissuggests 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 differentproportions 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 atconventional dosage, with very high doses differences intherapeutic 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
SiR,-As stressed in your note (Nov. 27, p. 123) Ciba-Geigysdecision 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 bilateralangiographic papilloedema, and colour vision disturbance. Twocomputed tomographic scans of the brain and a cerebralangiogram 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 notrestricted 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,Hpital de lHtel-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.