1136

BONE-MARROW DEPRESSION BY LONG-ACTINGDIAMINOPYRIMIDINES

SIR,—Dr Douglas and his colleagues (Sept. 17, p. 607)report on treatment with D.D.M.P. (2,4-diamino-5-[3’,4’-dich-loroephenyl]-6-methyl pyrimidine) and protection with single-dose folinic acid (calcium leucovorin).

D.D.M.P. is an antitumour drug of great interest. It may,however, as Douglas et al. state, cause severe bone-marrowtoxicity which can be abolished by folinic-acid protection(simultaneous administration) or folinic-acid rescue. Althoughthe drug was used clinically in 1952 the ideal schedule in manhas not yet been defined. In our experience bone-marrow toxi-city is unpredictable. Thus in a phase-I trial where D.D.M.P.was administered orally in doses of 25 mg/m2 weekly fivepatients had life-threatening thrombocytopenia and leuco-penia. Toxicity occurred after one or two doses, despite folinic-acid rescue at the first sign of haematological toxicity. Fourother patients tolerated the same regimen for weeks withoutsigns of serious haematological toxicity.

Participating in an investigation with the early clinical trialgroups of E.O.R.T.C. and using weekly doses of 50 mg/m2orally simultaneously with low-dose leucovorin 3 or 9 mg/tn2we found the same highly unpredictable individual tolerance toD.D.M.P.

We would advise caution on the general use of D.D.M.P. untilfurther research on the combined use of D.D.M.P. and folinicacid has been done.

MOGENS HANSENHEINE H. HANSEN

Finsen Institute,DK-2100 Copenhagen, Denmark

DICHLOROACETATE IN BIGUANIDE-INDUCEDLACTICACIDOSIS

SIR,—We read with great interest the report by ProfessorIrsigler and his colleagues on the attempted treatment ofsevere buformin-induced lacticacidosis with dichloroacetate(D.C.A.) (Nov. 12, p. 1026). We regard as premature, however,their conclusion that "in man severe biguanide-induced lactic-acidosis is too far advanced to be influenced by D.C.A." Themechanism of action of D.C.A. and the physiology of lactateclearance show that D.C.A. on its own is not appropriate ther-apy for severe cases.

Early work showed that D.C.A. had a mild hypoglycæmicand hypolactatxmic effect in normal and diabetic animalsl-4and that its main action was through activation of pyruvatedehydrogenase.5 This appeared to be primarily an extrahepaticeffect so that in hepatectomised animals D.C.A. prevented therelease of lactate, pyruvate, and alanine from extrahepatic tis-sues.3 We and other workers then showed that D.C.A. could pre-vent phenformin from causing lacticacidosis in animals andcould reverse moderately severe lacticacidosis secondary to

biguanide or fructose administration or mild liver damage.**’*In contrast D.C.A. did not reverse type-A lacticacidosis-that

is, the anaerobic form.8 We also noted that severe biguanidelacticacidosis could not be reversed by D.C.A. alone.9 Thismakes physiological sense in that the body depends largely onthe liver for lactate clearance. Cohen and his colleaguesshowed that the liver produced rather than cleared lactatewhen the pH fell below 7.9,10 Thus in severe lacticacidosis even

1. Lorini, M., Ciman, M. Biochem. Pharmac. 1962, 11, 823.2. McAllister, A., Allison, S. P., Randle, P. J. Biochem J. 1973, 134, 1067.3. Blackshear, P. J., Holloway, P. A. H., Alberti, K. G. M. M. ibid. 1974, 142,

279.4. Blackshear, P. J., Holloway, P. A. H., Alberti, K. G. M. M. ibid, 1975, 146,

447.5. Whitehouse, S., Randle, P. J. ibid. 1973, 134, 651.6. Alberti, K. G. M. M., Holloway, P. A. H. Diabetes, 1977, 26, 377.7. Johnson, G. A., Man, K. C., Alberti, K. G. M. M. Biochem. Soc. Trans.

1977, 5, 1387.8. Loubatieres, A. L., Ribes, G., Valette, G. Br. J. Pharmac. 1976, 58, 429P.9. Holloway, P. A. H., Alberti, K. G. M. M. Diabetologia, 1977, 13, 402

10. Lloyd, M. H., Iles, R. A., Simpson, B. R., Strunin, J. M., Layton, J. M.,Cohen, R. D. Clin. Sci. mol. Med. 1973, 45, 543.

if D.C.A. stops further production of lactate and pyruvate, anylactate in the circulation will remain and pH status will notimprove until pH has been at least in part corrected.

This may explain the apparent failure of D.C.A. in ProfessorIrsigler’s case. His results show that D.C.A. was probably hav-ing an effect in that pyruvate decreased while lactate and pHremained stable when they might have been expected to

worsen. Presumably the liver was not metabolising lactatebecause of the low pH. We would suggest that D.C.A. is worthyof further trial in the treatment of even severe biguanide andother type-B lacticacidoses but that other measures are alsonecessary. Thus pH must be corrected and circulatory supportand tissue oxygenation must be provided. One could draw theanalogy with treating diabetic coma with insulin alone, whichis rarely successful; other measures, such as rehydration, areessential.

.

We look forward to further reports of the treatment of lac-ticacidosis in which D.C.A. has been used in conjunction withother appropriate measures.

Chemical Pathologyand Human Metabolism,

Faculty of Medicine,University of Southampton,Southampton General Hospital,Southampton SO9 4XY

K. G. M. M. ALBERTIMALCOLM NATTRASSP. A. H. HOLLOWAY

DISCONTINUATION OF MAINTENANCE DIGOXIN

SIR,—We fully support the conclusions of Dr Hull and DrMackintosh (Nov. 19, p. 1054) of the absence of any deterio-ration in signs and symptoms after discontinuation of long-term digoxin therapy in patients with heart-failure in sinusrhythm.

In an attempt to find out if digoxin is of any benefit to thepatient in sinus rhythm with congestive heart-failure due tomyocardial disease we measured the response to exercise of sixpatients, comparing their submaximal exercise performance ondiuretic treatment alone with that when they were takingdigoxin plus diuretics.’ An essential pre-requisite of the studywas that all patients were given optimal doses of diure-

tics-i.e., a sufficient dose of frusemide to reduce body weightto a basal level where each patient was free of oedema andwithout clinical evidence of raised central venous pressures.For five of the six patients who completed three pairs of exer-cise tests over the course of 3 months, there was no objectivechange in the physical signs at rest, no change in the workloads achieved, and no significant changes in the heart-rate,respiratory-rate, ventilation, or respiratory quotient at eachwork load when digoxin was either added to or subtractedfrom the treatment regimen. The sixth patient had more fre-quent supraventricular ectopic beats and angina when digoxinwas withdrawn and was unable to complete the study.We would suggest that in the management of heart-failure

with normal rhythm, diuretics should be used first and the res-ponse of the patient should be monitored in terms of body-weight and evidence of vascular and interstitial space conges-tion. Where these drugs produce a stable "dry" weight with noevidence of venous-pressure elevation, it is unlikely that

digoxin will result in any further improvement in exercisetolerance. Nevertheless this could, and perhaps should, betested in each patient seen.The role of digoxin in yielding long-term benefit to patients

with heart-failure caused by myocardial disease refractory todiuretic management, and also where angina and frequentectopic beats complicate the clinical problem, remains to bedefined.

D. McH. is a Medical Research Council of New Zealand overseastravelling fellow.Department of Medicine,Charing Cross Hospital Medical School,London W6 8RF

D. MCHAFFIE

A. GUZ

1. McHaffie, D. J., Purcell, H., Mitchell-Heggs, P., Guz, A. Q. Jl. Med. 1977,46, 557.