830

antibiotic therapy for a septicaemia. Whilst on tobramycin and CyAthe serum creatinine rose and both drugs were discontinued. Renalfunction subsequently improved but hypertension developed andhe required hydralazine. 2 weeks after CyA had been stopped graftfailure developed. Intravenous HDMP was given at a dose of 20mg/kg/per day for 3 days and 10 mg/kg the next day. On steroidtherapy the hypertension became more difficult to control and thepatient complained of headache. On the fourth day of HDMPtherapy he had generalised convulsions which were controlled bydiazepam. At this time his blood pressure was 210/150 mm Hg.Computerised tomography and lumbar puncture were normal (CSFpressure not recorded). The platelet count was 26 x 109/1. Thepatient subsequently acquired temporal lobe epilepsy; his

haematological values are now normal.Case 3. -A 1 0-year-old male received HLA-matched bone marrow

from his sister in April, 1982. On day +30 he had biopsy-provengastrointestinal GVHD whilst on CyA. He received a course ofHDMP (as in case 2). Low-dose steroids were then continued untilGVHD recurred on day + 44. He was given intravenous HDMP at adose of 10 mg/kg for 2 days and 5 mg/kg on the third day. Hesubsequently had generalised convulsions which responded todiazepam. At this time his blood pressure was 180/160 mm Hg,platelet count 39 x 109/1, and his creatinine was 120 ptmol/1. SerumCyA levels were non-toxic. He made a full neurological recovery butsubsequently died of gastrointestinal GVHD.Case 4. -A 13-year-old girl was given bone marrow from her

HLA-matched brother in June, 1982. On day +8 she had acuteGVHD of the skin and received a course of intravenous HDMP (asin case 2). After the final dose of HDMP the patient had twogeneralised convulsions which were controlled by diazepam andphenytoin. At this time the blood pressure was 140/100 mm Hg, theserum creatinine was 238 J.lmol/l, and the serum CyA level was non-toxic. Complete neurological recovery ensued and a previoushistory of febrile convulsions was obtained. She is now

haematologically normal.We have not observed convulsions as a side-effect of CyA in

patients who have not also been receiving HDMP. Three of the fourpatients described were taking CyA at the time of the convulsionsand in the other (case 2) it had been recently withdrawn. Data on thepersistence of CyA in tissues after cessation of drug administrationare not available. HDMP has not been reported to cause

convulsions in children when used as an immunosuppressive agentin the absence of CyA. 3,4 However, we have seen convulsions in a65-year-old patient given HDMP alone. The combined use of CyAand methylprednisolone has not been reported to cause convulsionsin adults. 2, The previous report of CyA-related convulsions inchildren2 does not describe a temporal association with HDMPthough the report indicates that this combination of drugs wascommonly used. Other associated features include renal

impairment, thrombocytopenia, hypertension, and headache.

Royal Postgraduate Medical School,Hammersmith Hospital,London W12 0HS

S. DURRANTP. M. CHIPPINGS. PALMERE. C. GORDON-SMITH

TREATMENT OF WHOOPING COUGH

SIR,-Whooping cough is a treatable bacterial infection fromwhich no child need come to serious harm. This is borne out by thelow case fatality rate in the past thirty years. The organism is usuallysensitive to erythromycin, penicillin, ampicillin, co-trimoxazole,and tetracycline. Given early enough, antibiotics can be expected toreduce the bacterial population, the amount of endotoxin, theseverity and duration of symptoms, and the spread of the disease.

3. Orta-Sibu N, Chantler C, Bewick M, Haycock G. Comparison of high dose intravenousmethylprednisolone with low dose oral prednisolone in acute renal allograftrejection in children. Br Med J 1982; 285: 258—62.

4. Rose GM, Cole BR, Robson AM. The treatment of severe glomerulopathies in childrenusing high dose intravenous methylprednisolone pulses. Am J Kidney Dis 1981, 1:148-56

5. Starzl TE, Klintmalm GBG, Weil KR, Porter KA, Itwatsuki S, Schroter GPJ,Fernandez-Bueno C, MacHugh N. Cyclosporin A and steroid therapy in sixty sixcadaver kidney recipients. Surg Gynecol Obstet 1981; 153: 486-94.

TABLE I-WHOOPING COUGH IN ENGLAND AND WALES

I I

Sources: D.H.S.S. Report on Whooping Cough Vaccination by the Joint Committee onVaccination and Immunization (1977) and Office ofPopulanon Census and Survey returns1978-82.

*Until week ending Oct. 1 (provisional).

TABLE II-MINIMUM INHIBITORY CONCENTRATIONS (iaglnil)

Sources Garrod et al. and *Bushby.’ 3

Also, it is still not generally known that the paroxysmal cough issusceptible to the action of steroids. A short course of oralprednisolone will much reduce the severity and number of coughingspasms in a few days.Case 1. -A 9-week-old baby was admitted with severe spasms of

coughing, vomiting, and cyanosis for 2 days. Her older sister hadhad a cough for a month. The clinical diagnosis of whooping coughwas confirmed by isolation of Bordetella pertussis, sensitive to

erythromycin and penicillin, from a pernasal swab. She was nursedin oxygen in a head box and given erythromycin, and all spasmswere recorded. She had 33 spasms on the second day and 30 on thethird. Oral prednisolone, 5 mg three times daily, was then added. 18spasms were recorded during the next day, then 9, and, after 5 daysof treatment, only 3, at which point steroids were discontinued. Thecough returned a few days later but in a much milder form andHaemophilus influenzae was isolated from a pharyngeal aspirate. Sheimproved rapidly after a course of amoxycillin and was dischargedhome fully recovered 3 weeks from the start of the illness.Case 2.-This 8-week-old baby was admitted with a severe

paroxysmal cough which had started 1 month previously and forwhich she had already been given a short course of erythromycin.Her older brother had had whooping cough when she was born. Theclinical diagnosis of whooping cough was confirmed by the findingof B. pertussis in a pernasal swab, with a concomitant finding of H.influenzae. She was treated symptomatically at first but continued tohave between 8 and 16 spasms a day, and then bilateral X-raychanges of pneumonitis developed despite ampicillin andflucloxacillin. Oral prednisolone, 5 mg four times daily, was thenadded with immediate improvement. Only 1 spasm was recorded onthe third day of treatment and the X-ray changes had cleared. Thedose was reduced slowly over the next 12 days and she wasdischarged home fully recovered.Case 3.-This 13-week-old boy was admitted with numerous

severe spasms of coughing with cyanosis. He was born 6 weekspremature and both his older siblings had had a paroxysmal cough.He had been given co-trimoxazole shortly before admission and,although the clinical features were consistent with whoopingcough, B. pertussis could not be isolated from a pernasal swab but H.influenzae, resistant to co-trimoxazole, was obtained. He was givenampicillin and flucloxacillin but continued to have from 26 to 56spasms daily and intravenous feeding became necessary. Oral

prednisolone, 5 mg three times daily, was started after 9 days, withdramatic improvement. Only 4 spasms were recorded on the second

1. Zoumboulakis D, Anagnostakis D, Albanis V, Matsaniotis N Steroids in treatment ofpertussis: a controlled clinical trial. Arch Dis Child 1973; 48: 51-54

2. Garrod LP, Lambert HP, O’Grady F. Antibiotic and chemotherapy, 5th ed.

Edinburgh: Churchill Livingstone, 1981.3. Bushby SRM. Trimethoprim-sulfamethoxazole: in vitro microbiological aspects J

Infect Dis 1973; 128 (suppl.): 442-62.

831

day of treatment and he was discharged home fully recovered a fewdays later.All three infants were too young to have had any immunisations

and of an age when the risks of whooping cough are generallyconsidered greatest. None had been given prophylactic antibiotics;nor had antibiotics been used to reduce the infectivity of the affectedsiblings, despite the presence of a new baby in the home.Discussions of whooping cough epidemics have tended to

concentrate on vaccination to the exclusion of the proper use ofantibiotics in cases and contacts, a policy that is much more likely toachieve an immediate impact on an epidemic. The three case-reports show that, properly treated, whooping cough is neither alife-threatening nor prolonged illness, even in very young infants.They were the only inpatients with more than mild pertussis undermy care in the past twelve months and there has been one sinceJune. In contrast to the reported recent increase, there seems to beno epidemic in this part of London.

I have been deluged with inquiries by alarmed parents, mostlywith babies too young to be vaccinated, or with infants who had, forsound medical reasons, not been given pertussis vaccine or withmuch older children for whom the benefits of primary pertussisvaccination are questionable. Unfortunately, the campaign to

vaccinate has been pursued in such a way as to make parents fearfulof the consequences if the pertussis component is, quite properly,withheld. Family doctors and paediatricians must expect heavy callson their time to provide the necessary reassurance. They should alsobe prepared to prescribe antibiotics readily in suspected cases and allcontacts, including adults, and to add a short course of oralprednisolone if severe and distressing spasms of coughing develop.Charing Cross Hospital,London W68RF HERBERT BARRIE

WHITHER THE LATEST INSULINS?

SIR,-The initial clinical trial of biosynthetic human insulin(BHI) reported by Dr Clark and colleagues (Aug. 14, p. 354) hasshown that its action is not superior to that of either bovine orporcine insulins. Indeed, in terms of the more rapid onset andshorter duration of action leading to morning and eveningpreprandial hyperglycaemia, BHI may have disadvantages in themanagement of some patients. We shall nevertheless witness a trendtowards the transfer of patients to human insulin, a situation notunlike the introduction of purified porcine insulins which havemade a marginal difference to the management of most patients. IThis trend will be hastened by the decision of one pharmaceuticalcompany (Novo) to replace part of its monocomponent range withhuman insulin, and by the ultimate withdrawal of non-purifiedbovine insulins.We are studying 60 patients on highly purified bovine insulins,

many of whom have previously received non-purified bovine orpurified porcine insulins. Our preliminary findings suggest thatthere is no significant difference in diabetic control in our patientson highly purified bovine insulin, as judged by total daily insulindosage and serial haemoglobin Ale estimations (table), whencompared with control achieved on their former therapy. Wesuggest that the only indication at present for transferring patients

1. Editorial. Highly purified insulins. Lancet 1979; i: 363-64.

HAEMOGLOBIN A Ic LEVELS AND DAILY INSULIN REQUIREMENTS INDIABETICS DURING A FIFTEEN MONTH PERIOD OF STUDY

Paired Student’s t-tests were done, comparing times - 3 to 0 with + 3 to + 6, + 6 to +9, and+ 9 to + 12; all differences were non-significant.

from purified bovine insulin to BHI is the rarely encounteredallergic manifestation.Of further concern are the financial implications for the

introduction of BHI. Both purified porcine insulin and BHI aremore expensive than either purified or non-purified bovine insulins.The contract price for 10 ml U40 soluble/neutral insulins for

hospital prescription, which is the source for most diabetics in theU.K., is as follows: soluble 0.32p, ’Neusulin’ purified bovineinsulin (Wellcome) 0.62p, ’Actrapid’ (Novo) ;C2.45, ’Velosulin’(Nordisk) 2.45, ’Human Actrapid’ (Novo) 3.00—i.e., virtually atenfold range in price. Although a reduction in the cost of BHI isforecast with improvements in DNA recombinant and enzymesubstitution technology, we are sceptical that BHI will eventuallybe cheaper than the bovine insulins, which could remain a majorsource of insulin, despite previously reported doubts.2 Thesecostings have financial implications for the budget of the NationalHealth Service, and also for Third World countries where the costof purified or human insulins may be prohibitive and unnecessary.

Alexander Simpson Laboratoryfor Metabolic Research,

Saint Mary’s Hospital Medical School,London W2

J. H. PARRR. R. ABRAHAMM. W. J. DAVIEA. DORNHORSTV. WYNN

SUBARACHNOID CALCITONIN FOR INTOLERABLEPAIN

SIR,-Noting our paper in the European_7ournal of PharmacologlDr Shaw (Aug. 14, p. 390) warns against the administration ofsalmon calcitonin via subarachnoid injection. In our terminalcancer patients we did not use the Armour calcitonin that is

commercially available in Italy and which contains preservativesand gelatin but calcitonin (batch E19/Cl) given to us by Armourwith the specification that it was "in aqueous solution and free ofadditives".This calcitonin preparation did not cause any of the side-effects

Shaw reports in dogs and baboons. Moreover the intracisternalinjection of calcitonin in mice4 and rabbits5 did not lead to

respiratory distress, toxicity, or death.Furthermore terminal cancer patients with unbearable pain have

now been given calcitonin by subarachnoid injection at a dose of 100IU per 70 kg, one-third the dose used in our previous series. Thistime we used commercially available Sandoz salmon calcitonin,which is in aqueous solution, contains only a trace of acetic acid aspreservative, and has no gelatin. While a strong analgesic effect wasobserved in these patients, no important side-effects developed,apart from those already described (i.e., short lasting vomiting insome patients and increased diuresis). In different species the samedrug given via the same route can cause completely different effectsand/or side-effects.6 All the same we agree with Shaw that morethorough animal studies should be done to reveal any side-effectsdue, for example, to chronic use of the drug.

Istituto di V Clinica Medica,Policlinico Umberto I,University of Rome,00100 Rome, Italy

Ospedale S Giuseppe,Marino, Rome

FRANCO FRAIOLIANDREA FABBRILUCIO GNESSICOSTANZO MORETTICLAUDIA SANTORO

MAURIZIO FELICI

2. WHO Expert Committee on Diabetes Mellitus. Second report. Tech Rep Ser WHO1980; no 646: 63.

3. Fraioli F, Fabbri A, Gnessi L, Moretti C, Santoro C, Felici M. Subarachnoid injectionof salmon calcitonin induces analgesia in man. Europ J Pharmacol 1982; 78:381-82.

4. Yamamoto M, Kumagai F, Tachikawa S, Maeno H Lack of effect of levallorphan onanalgesia induced by intraventricular application of porcine calcitonin in mice.Europ J Pharmacol 1979; 55: 211-13.

5. Pecile A, Ferri S, Braga PC, Olgiati VR. Effects of intracerebroventricular calcitonin inthe conscious rabbit. Experientia 1975; 31: 332—33.

6. Jacob J. The influence of variations in species and strains of experimental animals ondrug responses. In: Tedeschi DH, Tedeschi RE, eds. Importance of fundamentalprinciples in drug evaluation: New York: Raven Press, 1968: 53-68.