FLUIDS FOR DIARRHŒA IN YOUNG CHILDREN

431 We have found that lithium in vitro strongly inhibits dopamine-sensitive adenylate cyclase in the striatum, olfactory tubercle, and cerebral cortex of the rat in a dose-related manner, leaving basal and fluoride-stimulated enzyme activities unaffected." Enzyme activities were measured by the method of Kababian et al. and cyclic A.M.P. by the method of Geisler et al. 10 Some of our recent experiments may contribute to the understanding of the observations described by Loudon and Waring. We have found that both lithium and the neuroleptic a-flupenthixol inhibit rat striatal adenylate cyclase activated maximally by dopamine, the inhibition being 29% for both agents. However, the inhibition by the combined addition of the two drugs was much higher (64%). Neither drug had any effect on basal adenylate cyclase activity (see table). A synergistic inhibitory effect by lithium and adrenaline on prostaglandin-induced cyclic A.M.P. synthesis in platelets has been reported by Wang et al.7 Thus, the adverse reactions during combined treatment with lithium and neuroleptics may be related to this combined inhibition on striatal adenylate cyclase. While neuroleptics block the effects of dopamine at the receptor level, lithium might operate at a distinct site beyond the receptor. The interaction of lithium with haloperidol could be explained by other mechanisms. However, an effect of lithium on striatal functions should be considered, since accumulation of lithium in the striatum has been observed in rat" and man. 12

study was supported by a grant from cc-flupenthixol was donated by H. Lundbeck & This

Department of Pharmacology, University of Copenhagen, DK-2100 Copenhagen Ø, Denmark

P. Carl Petersens Fond. Co. A/S, Copenhagen.

A. GEISLER R. KLYSNER

INTEGRATED CONCENTRATIONS OF CATECHOLAMINES IN PHÆOCHROMOCYTOMA

SIR,-Dr Atuk and Professor Westfall have provided an admirably clear and concise account of the well-known effects of adrenoceptor-blocking agents upon catecholamine metabolism (Jan. 29, p. 259). They are correct in stating that our results will have been modified by administration of phenoxybenzamine and propranolol, and we considered this during the preparation of our preliminary communication.13It is in the nature of this type of report that brevity may result in inadequate information being provided, and some elaboration may now be appropriate. During the study, a single oral dose of phenoxybenzamine 10 mg and propranolol 40 mg, was given one hour before blood-sampling began. Since no further medication was given, a steady decline in plasma levels, with half-lives of about 10 h14 (phenoxybenzamine) and 3 h’5 (propranolol), would be expected. Thus, although some modification of catecholamine metabolism would occur, periodic rises and falls in plasma adrenaline + noradrenaline levels (and in their relative proportions) cannot be explained by invoking pharmacological mechanisms. Active synthesis of catecholamines remains, therefore, a likely mechanism in phaeochromocytoma crises. As we indicated, data on peroperative integrated concentration studies will be published elsewhere. These studies were 8. Geisler,

A., Klysner, R., Thams, P. Acta physiol. scand. 1976, suppl. 440, p. 132. 9. Kebabian, J. W., Petzold, G. L., Greengard, P. Proc. natn. Acad. Sci., U.S.A, 1972, 69, 2145. 10. Geisler, A., Klysner, R., Thams, P., Christensen, S. Acta pharmac. toxicol. 1977, 40, 356. 11. Ebadi, M. S., Simmons, V. J., Hendrickson, M. J., Lacy, P. S. Eur. J. Pharmac. 1974, 27, 324. 12. Spirtes, M. A. Pharmac. Biochem. Behav. 1976, 5, 143. 13 Daggett, P., Carruthers, M. Lancet, 1976, ii, 830. 14 Nickerson, M., Collier, B. in The Pharmacological Basis of Therapeutics (edited by L. Goodman and A. Gilman); p. 539. New York, 1975. 15. Shand, D. G., Nuckolls, E. M., Oates, J. A. Clin. Pharmac. Ther. 1970, 11, 112.

done after adrenoceptor blocking agents had been stopped, but a very similar pattern was observed. It thus seems that phenoxybenzamine + propranolol had relatively little effect in modifying plasma-catecholamine levels, in the patients studied. The graph presented by Dr Atuk and Professor Westfall indicates the usefulness of integrated concentrations of catecholamines since the kidney is an ideal (though inconvenient) integrator. Thus, the measurement of integrated concentrations of catecholamines has been shown to be an important new tool for studying patients with phaeochromocytoma. Middlesex Hospital, London W1

PETER DAGGETT

FLUIDS FOR DIARRHŒA IN YOUNG CHILDREN

SIR,-Dr Ware should have ended his letter (Jan. 29, p. 252): "Almost all infants with acute diarrhoea can be cured by replacing feeds with water. If diarrhoea persists ... the infant should be in hospital." The risk of dilutional hyponatraemia is surely less than the haphazard formulation of "glucose water" or "sugar and salt water." Derbyshire Children’s Hospital, Derby DE1 3BA

T. L. CHAMBERS

RIBONUCLEASE AS ANTIVIRAL AGENT IN MILK

SIR,-The finding by Matthews et at.’ of antiviral activity in milk is unquestionably important, but the factor(s) responsible must be identified before they can be tried as external supplements for disease prophylaxis in infants. Matthews et al. did not mention the fairly large amount of work which has .been done on inhibitors of mammary tumour virus (M.T.V.) reverse transcriptase in human milk. :.!-9 Significant quantities of ribonuclease (R.N.ase)-like activity exist in human milk, and this enzyme may be responsible for the anti-M.T.v. activity observed.6The heat-stable properties of the milk anti-R.N.A.viral activity reported by Matthews et al.’ are very similar to those of pancreatic-type R.N.ase. The absence of the antiR.N.A.-viral activity in dried milk’ may be due to the high-temperature, flash-drying procedure used to obtain the product. We suggest that the addition of R.N.ase (preferably at several different concentrations) to dried or heat-inactivated milk be carried out as a possible means of restoring the antiviral activity described by Matthews et al.’ As an additional control study, the milk of a certain fraction of Parsi women, which is known to be nearly devoid of all R.N.ase activity,9 might also be tested for antiviral activity in the presence and absence of exogenously added R.N.ase. We envisage that the target of R.N.ase action may be viral cores produced by the action of proteolytic and/or lipolytic enzymes (supplied by milk or an infant’s digestive tract) on viral envelopes. Should the experiments which we have suggested succeed in restoring antiviral activity to those milks lacking such activity, the addition of R.N.ase to commercial milks or infant formulae might be considered as a means of protecting individuals against infection by R.N.A. viruses. This procedure might then provide an excel1. Matthews, T. H. J., Lawrence, M. K., Nair, C. D. G., Tyrrell, D. A. J. Lancet, 1976, ii, 1387. 2. Sarkar, N. H., Charney, J., Dion, A. S., Moore, D. H. Cancer Res. 1973,

33, 626.

Spiegelman, S., Moore, D. H. Science, 1972, 175, 542. Feldman, S., Schlom, J., Spiegelman, S. Proc. nat. Acad. Sci. U.S.A. 1973, 70, 1976. 5. Schlom, J., Spiegelman, S., Moore, D. H. J. nat. Cancer Inst. 1972, 48, 3. Schlom, J.,

4.

1197. 6. 7.

McCormick, J. J., Larson, L. J., Rich, M. A. Nature, 1974, 251, 737. Gerard, G. F., Loewenstein, P. M., Green, M., Rottman, F. ibid. 1975, 256,

8. 9.

Sanner, J. Cancer Res. 1976, 36, 405. Das, M. R., Padhy, L. C., Koshy, R., Sirsat, S., Rich, M. Nature, 1976, 262,

140.

802.