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Br. J. clin. Pharmac. (1982), 14 LETTERS TO THE EDITORS 565 EFFECT OF CIMETIDINE ON GONADAL FUNCTION IN MAN We were interested to read the paper by Wang et al. dine being an in man and this is sup- (1982) which showed that treatment of male patients ported by the finding that cimetidine competes with suffering from duodenal ulcer with cimetidine was for binding to receptors in associated with a significant rise in serum human skin fibroblasts (Sultan et al., 1980) as it also levels. We are aware of four other published studies does in mouse preparations (Funder & on this topic (including one cited by Wang et al., 1982 Mercer, 1979). (van Thiel et al., 1979)) in patients being treated for Since cimetidine but not has this effect acid peptic disorders with cimetidine (Carlson et al., then it is not a function of H2-receptor blockade 1981; Peden et al., 1981; Spona et al., 1981). (Peden et al., 1981). The clinical relevance of this All of these studies showed that treatment with recently became apparent to us when we were cimetidine was associated with a modest rise in basal referred a 50 year old man who had received testosterone levels although this rise was statistically cimetidine 1g/day continuously for 18 months for a significant in only two of the papers (Peden et al., stomal ulcer. He had gynaecomastia and complained 1981; van Thiel et al., 1979). Two of the studies were of impotence. Measurements of serum , prospective and comparative. That of Carlson et al. gonadotrophins, testosterone and oestradiol-17-,B (1981) found that treatment with cimetidine or ant- were all normal. His therapy was changed to acid was associated with a rise in testosterone while ranitidine. His gynaecomastia is regressing and he our own study comparing cimetidine and ranitidine in rapidly and fully recovered (and indeed has 15 patients showed that treatment with cimetidine but acquired non-specific urethritis). not ranitidine was associated with a rise in testo- sterone levels and also with a transient early rise in N.R. PEDEN & K.G WORMSLEY levels of luteinising hormone (Peden et al., 1981). On the basis of previous observations on changes on Department of Pharmacology and Therapeutics, gonadotrophins and testosterone during the use of Ninewells Hospital, Dundee DDJ 9SY antiandrogenic drugs in man (Kliman et al., 1974; Sizonenko et al., 1974) we concluded as have Wang et al. (1982) that our data were compatible with cimeti- Received and accepted June 30, 1982

References

CARLSON, H.E., IPPOLITI, A.F. & SWERDLOFF, R.S. Scand., 63,328. (1981). Endocrine effects of acute and chronic cime- SPONA, J., WEISZ, W., RUDIGER, E., HENTSCHEL, E., tidine administration. Dig. Dis and Sci., 26, 428-432. SCHUTZE, K., REICHEL, W., KERSTAN, E., FUNDER, J.W. & MERCER, J.E. (1979). Cimetidine occupies WEWALKA, F. & LOCHS, H. (1981). Hormone serum androgen receptors. J. clin. Endocrinol. Metab., 48, levels during oral cimetidine treatment of patients with 189-191. peptic ulcers. Hepato-Gastroenterol., 28, 165-168. KLIMAN, B., McLAUGHLIN, R., IRWIN, R. & PROUT, G.R. SULTAN, C., TERRAZA, A., DESCOMPS, B. & CRASTES DE (1974). Antiandrogen stimulation of plasma LH and PAULET, A. (1980). Cimetidine competition with testosterone. Clin. Res., 22, 342A. androgens for binding to human sex skin fibroblasts PEDEN, N.R., BOYD, E.J.S., BROWNING, M.C.K., androgen receptors. J. Biochem., 13, 839-840. SAUNDERS, J.H.B. & WORMSLEY, K.G. (1981). Effects VAN THIEL, D.H., GAVALER, J.S., SMITH, W.I. & PAUL, G. of two H2-receptor blocking drugs on basal (1979). Hypothalamic-pituitary-gonadal dysfunction in levels of gonadotrophins, prolactin, testosterone and men using cimetidine. New Engl. J. Med., 300, oestradiol-17,f during treatment of duodenal ulcer in 1012-1015. male patients. Acta Endocrinol., 96, 564-568. WANG, C., LAI, C.L., LAM, K.C. & YEUNG, K.K. (1982). SIZONENKO, P.C., PAUNIER, L. & CUENDET, A. (1974). Effect of cimetidine on gonadal function in man. Br. J. Evaluation of the hypothalamic pituitary gonadal axis by clin. Pharmac., 13, 791-794. a new antiandrogen (SCH 13521) in boys. Acta Paediatr.

PYRIDOSTIGMINE IN HUMAN MILK

Cholinesterase inhibitors are still basic therapy for lactating mothers on maintenance therapy with myasthenia gravis and among these pyridostigmine is cholinesterase inhibitors the question often arises most commonly used. In the care of myasthenic whether breast feeding is riskful for the child due to 566 LETTERS TO THE EDITORS Br. J. clin. Pharnwc. (1982),14 transfer of these drugs via the milk. Skoglund et al. according to the method of Aquilonius et al. (1980). (1978), using a quantitative gas liquid chromato- The precision and sensitivity of the assay did not graphic method for pyridostigmine bromide (Chan et differ between plasma and milk. Control experiments al., 1976), were not able to detect this drug in breast were performed to ensure thatphenytoin, ingested by miLk from a treated mother. The development of a one of the mothers (case 1, daily dose 100 mg x 3) or more sensitive and selective analytical procedure has its did not interfere with the pyridostig- now enabled us to study the plasma and breast milk mine determination. concentrations of pyridostigmine in two nursing mothers.. Case 1 Both women, who gave informed consent, were suffering from myasthenia gravis and had been Plasma and milk samples were collected already 5 treated with oral pyridostigmine (Mestinon®, days after delivery (Table 1). The pyridostigmine Roche) for several years. Treatment was given during concentrations in maternal plasma ranged between 16 the whole pregnancy and lactation periods. Both and 31 ng/ml and similar concentrations were found women gave birth to normal infants, without signs of in the breast milk. Using the milk concentrations neonatal myasthenia. The infants were breast fed found and assuming a daily intake of 150 ml breast without addition of artificial formulas (see further milk per kg body weight, the amount of pyridosti- below). The gain of weight and the development of mine ingested by the nursing infant was calculated to the infants were normal, and there were no signs of about 3 ,ug/kg body weight per day. Since this cor- cholinergic drug effects (salivation, tear flow, gastro- responded to only 0.1% of the dose taken by the intestinal disturbances). mother, i.e. 3 mg/kg body weight, breast-feeding was Blood samples, collected by venipuncture in encouraged. heparinized tubes, were immediately cooled and Plasma and milk samples collected 35 days after plasma was separated by centrifugation and frozen. A delivery, when nursing was well established, showed 10 ml sample of breast milk was obtained by a breast pyridostigmine concentrations similar to those at 5 pump at the beginning of the nursing and immediate- days (Table 1). At 102 days after delivery the mother ly frozen. Plasma and milk samples were assayed for used a lower dose of pyridostigmine and somewhat pyridostigmine concentrations by gas comatography- lower concentrations were found both in plasma and mass spectrometry with deuterated internal standard milk.

Table 1 Individual pyridostigmine dosage, time of sample collection and the concentration of pyridostigmnine in maternal plasma, breast milk and infant plasma Sampling time Pyridostigmine concentration (nglml) Daily Days after h after Maternal Breast Milk/plasma Infant dose (a) delivery dose intake plasma milk ratio plasma Case 1 60mg x 3 5 0 16 18 1.13 2 20 4 31 24 0.77 60mg x 3 35 0 17 13 0.76 2 35 3.5 29 17 0.59 6 21 8 16 14 0.88 40mg x 3 102 0 6 x) 2 20 4 14 I 5 0.36 6 10 8 8 x) Case 2 60mg x 5 60 0 62 25 0.40 <2 0.5 100 1.3 85 2.6 60 22 0.37 <2 0.66 + 0.10

Mean + s.e. mean x) = denotes pyridostigmine concentrations of approximately 2-5 ng/ml (a) Only one dose was ingested during the study period. Br. J. clin. Pharmac. (1982), 14 LETTERS TO THE EDITORS 567

Case 2 (Rane & Wilson, 1976). However, in both our cases the amount of pyridostignine per kg body weight Plasma and milk concentrations of pyridostigmine at ingested by the nursing infant was only 0.1% or less of 60 days after delivery are shown in Table 1. The that taken by the mother. It is therefore not astonish- concentrations of pyridostigmine in maternal plasma ing that pyridostigmine was not detectable in infant varied between 60 and 100 ng/ml, and the milk con- plasma, and that there were no signs ofdrug effects in centrations were about 40% of the plasma concentra- the infants. tions. The mother's daily dose was about 5 mg/kg These data indicate that maternal with body weight and the calculated daily pyridostigmine pyridostigmine normally is no obstacle to breast- intake of the infant was about 3.5 ,ug/kg body weight. feeding, at least with doses in the range used here The plasma of the infant did not contain detectable (180-300 mg/day). In infants with severely impaired amounts of pyridostigmine, i.e. < 2 ng/ml. renal function caution is recommended. In a previous study ofa nursing woman treated with pyridostigmine, the drug was not detectable in breast The authors are indebted to Mrs Susanne Floberg for milk (Skoglund et al., 1978). The method used, how- skilful technical assistance. ever, was considerably less sensitive than the present one. Despite the relatively low doses and plasma LARS-IVAR HARDELL', BJORN concentrations in the mothers, we were able to detect LINDSTROM;, GUDMAR LONNERHOLMI & pyridostigmine in all breast milk samples. The con- PER OLOF OSTERMAN2 centration of pyridostigmine in breast milk was 36113% of that in maternal plasma, a surprisingly The Departments of Pediatrics' and Neurology, high value considering the fact that pyridostigmine is University Hospital, Uppsala, Sweden and the an ionized quaternary amine. :'Department ofDrugs, National Board ofHealth and Pyridostigmine is predominantly eliminated un- Welfare, Uppsala, Sweden changed in the (Chan & Calvey, 1976). Since renal function is not fully developed in the newborn infant, one should expect a somewhat slower renal Received April 24, 1982, elimination of the drug during the first months of age accepted June 30, 1982

References

AQUILONIUS, S.-M., ECKERNAS, S.-A., HARTVIG, P., method for the determination of neostigmine and LINDSTROM, B. & OSTERMAN, P.O. (1980). Phar- pyridostigmine in human plasma. J. Chromatogr., 120, macokinetics and oral of pyridostigmine 349-358. in man. Eur. J. clin. Pharmac., 18, 423-428. RANE, A. & WILSON, J.T. (1976). Clinical CHAN, K. & CALVEY, T.N. (1976). Renal clearance of in children. Clin. Pharmacokin., 1, 2-24. pyridostigmine in patients with myasthenia gravis. Eur. SKOGLUND, R.R., ROBERTS, C.C. & HUDDLESTONE, J. Neurol., 16,69-72. (1978). The role of anti-acetylcholine receptor antibody CHAN, K., WILLLAMS, N.E., BATY, J.D. & CALVEY, T.N. in neonatal myasthenia gravis. Bull. Los Angeles (1976). A quantitative gas-liquid chromatographic Neurol. Soc., 43, 66-69.

AZATHIOPRINE DOSAGE SCHEDULE AND REJECTION EPISODES IN RENAL TRANSPLANT RECIPIENTS

Although azathioprine, in conjunction with , 1975). Cell killing is not only related to drug concen- is used universally to prevent rejection of kidney tration but also duration of cellular exposure to the transplants its precise mode of action as an immuno- drug. After a massive dose (7.5 g) the toxicity of supressive drug is unknown. As it is cytotoxic, one azathioprine is very low (Carney et al., 1974) whereas possible mechanism is by killing lymphocytes that are with chronic administration in doses above 2-3 mg/kg stimulated to divide by foreign graft antigens so that toxicity frequently occurs (Bach, 1975). clones of immunocompetent cells are deleted In the light of these observations we have investi- (Berenbaum, 1969). Like its parent drug, 6- gated, in a pilot study, the effect ofdosage schedule of mercaptopurine, its cytotoxicity is probably depen- azathioprine on the severity and frequency of dent on the phase of the cell cycle (Hill & Baserga, rejection episodes in patients with cadaver kidney