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The frequency of pancreatitis or hyperamylasaemia (serum amylasemore than 250 U/1; normal less than 100 U/1) was compared with thechi-squared test. 8 patients had pancreatitis (AZA 5, CSA 3), and 20patients had hyperamylasaemia (AZA 10, CSA 10). The differencewas not significant. Other causes of pancreatitis in the AZA groupwere hypercalcaemia (n = 3), cytomegalovirus (CMV) infection (1),and alcoholism (1). In the CSA group causes were hypercalcaemia(1), CMV infection (1), and unknown (1). These data show that thefrequency of acute pancreatitis and hyperamylasaemia is not
increased in renal transplant patients treated with AZA. Thus, AZAis at most a co-factor in inducing pancreatitis, since all these patientshad additional causative factors for the disease.
Department of Surgery,University of Zurich,8091 Zurich, Switrerland;and Department of Surgery,
University of Minneapolis, USA
T. W. FRICKD S. FRYDR. L. GOODALER. L. SIMMONSD. E. R. SUTHERLAND
J. S. NAJARIAN
1. Mallory A, Kern F. Drug-induced pancreatitis: a critical review. Gastroenlerology1980; 78: 813-20.
2. Mallory A, Kern F. Drug-induced pancreatitis. Baillieres Clin Gastroenterol 1988; 2:293-307.
3. Dobrilla G, Felder M, Chilovi F. Proven relationships between drugs and pancreatitis.Dtsch Med Wochenschr 1986; 111: 868-70.
4. Scarpelli DG. Toxicology of the pancreas. Toxicol Appl Pharmacol 1989; 101: 534-54.5. Banerjee AK, Patel KJ, Grainger SL. Drug induced acute pancrestitis—a critical
review. Med Toxicol Adverse Drug Exp 1989; 4: 186-98.6. Yoshimura N, Nakai I, Ohmori Y, et al. Effect of cyclosponne on the endocrine and
exocrine pancreas in kidney transplant recipients. Am J Kidney Dis 1988; 12: 11-17.7. Najarian JS, Fryd DS, Strand M, et al. A single institution, randomized, prospective
trial of cyclosporine versus azathiopnne-antilymphocyte globulin for
immunosuppression in renal allograft recipients Ann Surg 1985; 201: 142-57.
Cyclosporin and diclofenac interaction inrheumatoid arthritis
SIR,-We report a possible nephrotoxic drug interactionbetween cyclosporin (’Sandimmun’) and diclofenac (’Voltarol’) inpatients exposed to both drugs in a multicentre study of cyclosporinin severe rheumatoid arthritis. In this open study 104 patientsreceived cyclosporin for 12 months at a starting dose of 2-5 mg/kgper day titrated to a maximum of 5mg/kg per day according toresponse and toxicity. Of 20 patients on both cyclosporin anddiclofenac, 7 had a high probability of an interaction (ie, correctionof plasma creatinine, serum potassium, and blood pressure [BP] onwithdrawal of diclofenac alone); 9 had possible interaction (ie, drugdoses have not yet been altered or both agents were withdrawn orreduced simultaneously); and 3 had no interaction at 6 months orbeyond. 1 patient had no interaction at less than 1 month and waswithdrawn from the study due to headaches.
2 patients typify the response. Patient A had been on cyclosporinfor 16 weeks, starting at 200 mg per day and rising to 225 mg perday. Serum creatinine was stable at around 25% above baseline(102-109 umol/1) and diastolic BP was 95 mm Hg. Diclofenac wassubstituted for indomethacin at week 16 because of headache, andwithin 8 weeks serum creatinine had risen to 70% above baseline
(137 pmol/1) and BP to 200/115 mm Hg. Both agents werewithdrawn at week 24, and creatinine and BP fell to normal within 4weeks. After a further 3 weeks cyclosporin was reintroduced incombination with ketoprofen and serum creatinine remained stableat around 30% above baseline. However, BP again rose to 180/110mm Hg after 4 weeks which necessitated withdrawal of cyclosporinat 37 weeks. At 39 weeks, BP was 150/90 mm Hg and serumcreatinine was 91)miol/l. Patient B received cyclosporin anddiclofenac for 10 weeks, during which creatinine rose from 68 to 110umol/1 (65% rise, although still in normal range), and potassiumrose from 4-6 to 5-3 mmol/1 (upper limit of normal = 5 -0). Theselevels were maintained despite a reduction of cyclosporin from astarting dose of 175 mg per day to 100 mg per day over 4 months. At6 months diclofenac was withdrawn, and within 4 weeks creatininehad fallen to 84 nmol/1 and potassium to 4-5 mmol/1. Only whencyclosporin was subsequently increased to 250 mg per day didcreatinine again rise to 112 umol/1. By this time, 11 months into the
study, the patient was gaining substantial symptomatic relief andobjective measurements of arthritic activity had improved.Rheumatoid arthritis patients are often elderly, have reduced
renal function, and have received potentially nephrotoxic agents.However no link was apparent between prior exposure to otherpotentially nephrotoxic agents and the interaction described. Theaverage age of those with a probable interaction was 59-6 years(range 51-67), possible interaction 53-7 (38-65), and no interaction49-3 (40-60), suggesting that older patients may be at higher risk.
Both cyclosporin and diclofenac are known to cause renal
dysfunction,l.2 but we can only speculate on the interactive toxicitydescribed. In the patients reported here, concentrations of cyclo-sporin in (whole blood trough levels measured by Sandozmonoclonal RIA) did not show marked changes when diclofenacwas withdrawn or introduced; thus there is no evidence of a
pharmacokinetic interaction. Cyclosporin nephrotoxicity may in-volve prostaglandins/thromboxane.3 The known effects of di-clofenac on cyclo-oxygenase2 suggests an additive effect in thekidney itself. We believe the combination of diclofenac and
cyclosporin should be avoided. If, however, they are used together,more frequent monitoring of renal function will be necessary andone or other may have to be withdrawn if renal functiondeteriorates. As yet, we have not seen a similar frequency ofinteractive nephrotoxicity with other non-steroidal anti-
inflammatory drugs used concomitantly with cyclosporin.Sandoz Pharmaceuticals,Frimley Business Park,Camberley, Surrey GU16 5SG, UK J. P. BRANTHWAITEWest Suffolk Hospital,Bury St Edmunds, Suffolk A. NICHOLLS
1. Mihatsch MJ, Thiel G, Ryffel B. Cyclosporin nephrotoxicity. Adv Nephrol 1988, 17:303-20.
2. Todd PA, Sorkin EM. Diclofenac sodium: reappraisal of its pharmacodynamic andpharmacokynetic properties and therapeutic efficacy Drugs 1988, 35: 244-85
3. Neild G. Postaglandins Leukot. Essent Fatty Acids 1988; 33: 207-12.
Seasonal overeating and fetal movementsSIR,—One hallmark of the Christmas season is overeating, often
marked by sluggishness the day after. The effects of such excess onthe consumer are well known, but what happens to the fetus?Nine healthy women of gestational age 12-21 weeks with
singleton uncomplicated pregnancies had 30 min ultrasound scansdone on Dec 27. All reported having had a good Christmas andhaving eaten over the previous two days at least three times the usualamount. All had abstained from alcohol and none smoked. Thenumber and duration of fetal movements were recorded. Ascontrols we used scans done 2 weeks before Christmas on ninewomen matched for gestational age, time of day, parity, age,socioeconomic status, previous 2 h activity, alcohol, and smokinghabits.The number of movements in 30 min averaged 54 (SD 5) in the
pre-Christmas group but only 6-5 (3) in the post-Christmas group(p < 0005). The duration of movements was 21 (8) min and 3 (4)min, respectively (p < 0-001).Thus the fetus too may suffer from that extra helping of
Christmas pudding. These data support evidence that the normalactivities of the mother can influence the behaviour of the fetus.’
School of Psychology,Queen’s University of Belfast,Belfast BT71NN, UK,and Royal Maternity Hospital, Belfast
P. G. HEPPERS. SHAHIDULLAH
1. Hepper PG, Shahidullah S. Fetal response to maternal shock. Lancet 1990, 336: 1068
CORRECTION
Non-A, non-B hepatitis specific antibodies directed to host-derivedepitope.-In this article by Dr S. Michiro and colleagues (Dec 8, p 1400) thereference for the method of testing for genomic RNA of HCV should not benumber 14, but should be ref 20: Okamato H, Okado S, Sugiyama Y, et alDetection of hepatitis C virus RNA by two-stage polymerase chain reactionwith two pairs of primers deduced from the 5’-non coding region. Jpn J ExpMed 1990; 60: 215-22.