1387

does not give comprehensive answers, there is in our opiniongood evidence for its usefulness in resource allocation andhealth planning.!National Public Health Institute,00280 Helsinki, Finland

KARI POIKOLAINEN

JUHANI ESKOLA

1. Charlton JRH, Hartley RM, Silver R, Holland WW. Geographical variation inmortality from conditions amenable to medical intervention in England andWales. Lancet 1983; i: 691-96.

DEMARCATION OF THE ABSURD

SIR,-Dr Skrabanek concludes (April 26, p 960) that

Popper’s criterion of falsifiability allows non-metaphysicalnonsense. I doubt if the example chosen disproves the validityof the epistemological principle of falsification. The statement"In Azerbaijan there lives a man who was born in 1500" impliesa special contradiction to the general statement that "There isno human being more than 150 years old". This generalstatement has never been falsified by a single exception.According to Popper, it is justifiable statement as "virtuallytrue" if it never has been falsified despite nearly infinite

opportunities for doing so. Once a general statement has beenaccepted as virtually true, any special statement incontradiction to it is not reasonable because of its falsifiabilitybut simply false. What remains is the unsurmountable gapbetween empirical and logical truth. It is logically impossible towin three times in two games, but it is empirically impossible("virtually impossible") to win 1000 times in a row if thea-priori likelihood of winning is 0 1.

Stellmacherweg 43,D - 4400 Munster, West Germany HARALD FIEDLER

INFLUENCE OF DILTIAZEM ON CYCLOSPORINCLEARANCE

SIR,—Dr Pochet and Dr Pirson (April 26, p 979) report thatdiltiazem affects cyclosporin metabolism in a kidney transplantrecipient. We have observed a similar case.A 40-year-old woman with chronic renal insufficiency

secondary to polycystic kidney disease received a transplant inFebruary, 1986. She was treated with oral cyclosporin 15 mg/kgdaily and low-dose prednisone. 7 days after the transplantationher serum creatinine was 180 mol/1 and the trough cyclosporinwhole blood level (radioimmunoassay) was 290 ng/ml.Diltiazem 240 mg per day was started for angina pectoris. 4 dayslater cyclosporin levels rose to 1000 ng/ml and remained highdespite reductions in cyclosporin doses (table). Although thepatient had probably not achieved a steady state for cyclosporinan interaction with diltiazem was suspected, and on the 21 st dayafter transplant the cyclosporin dose was changed to 50 mg byintravenous infusion over 2 h every 12 h (1 -5 mg/kg daily), forcyclosporin blood clearance studies.

3 days later seven blood samples with EDTA were collectedover a dosing interval (12 h). The area under the curve (AUC)for cyclosporin blood concentration versus time was calculated

CSA DOSES, CSA LEVELS, AND SERUM CREATININE AFTER RENAL

TRANSPLANTATION

by the trapezoidal method. Drug clearance was calculated as theintravenous dose divided by the AUC. Under diltiazem theAUC was 11 090 ng.h.ml-1 and the clearance was 1- 18 ml min-1 I

kg-1. Diltiazem was discontinued and these studies were

repeated 4 days later, with the same intravenous cyclosporindose. Without diltiazem the AUC was 3410 ng.h.ml-1 and theclearance was 3-8 ml.min -1 kg-1. Subsequently cyclosporin wasgiven orally again and diltiazem 240 mg per day was

reintroduced. 2 months after the transplant the cyclosporindose was 4-9 mg/kg daily and the blood level was 580 ng/ml, forthe same diltiazem dose. No rejection episode was noted duringthis period.

In this patient cyclosporin clearance increased after diltiazemwithdrawal. As suggested by Pochet and Pirson, increasedcyclosporin blood concentrations were due to interference fromdiltiazem in cyclosporin clearance, probably because bothdrugs are predominantly eliminated by the liver1,2 via

cytochrome P-450 hepatic enzymes.1,3 The inhibition of

cyclosporin metabolism should be taken into account whenthese two drugs are administered together.

Department of Nephrologyand Pharmacokinetics Unit,

Hospital de Bellvitge,Barcelona, Spain

J. M. GRIÑOI. SABATEA. M. CASTELAO

J. ALSINA

1. Kahan BD. Individualization of cyclosporine therapy using pharmacokinetic andpharmacodynamic parameters. Transplantation 1985; 40: 457-76.

2. Needleman P, Corr PB, Johnson EM Jr. Drugs used for the treatment of angina:Organic nitrates, calcium channel blockers, and &bgr;-adrenergic antagonists. In:Goodman A, Goodman LS, Rall TW, Murad T, eds. The pharmacologicalbasis of therapeutics. New York: Macmillan, 1985: 806-26.

3. Renton KW. Inhibition of hepatic microsomal drug metabolism by the calciumchannel blockers diltiazem and verapamil. Biochem Pharmacol 1985; 34:2549-53.

SAFETY OF ORAL ANTICOAGULATION

SIR,-Dr Sandercock and his colleagues rightly emphasise(April 5, p 788) the increase in "definite" intracranial

haemorrhage due to anticoagulants used in conventional doses.However, many intracranial events in the Sixty Plus trial,twhich Sandercock et al cite in making their point, were"non-definite" in that, for one reason or another, it was notpossible to distinguish with certainty between infarction andhaemorrhage. In total, there were 20 intracranial events inpatients on placebo compared with 12 in those on

anticoagulants. From the Sixty Plus and other trials2 it seemspossible that after myocardial infarction the increase in cerebralhaemorrhage due to anticoagulants is more than offset by thedecrease in intracranial events that either are or may be due tothrombosis. Until recently, it has been generally assumed thatoral anticoagulants will be effective only if used in doses

producing a coagulation defect of an intensity at which the riskof bleeding is just being avoided. There is, however, increasingreason to believe that lower than conventional doses may beeffective in preventing thrombosis while, at the same time,carrying lower risks of bleeding.3-5MRC Epidemiology and Medical Care Unit,Northwick Park Hospital,Harrow, Middlesex HA1 3UJ T. W. MEADE

1. Sixty-Plus Reinfarction Study Research Group. A double-blind trial to assesslong-term oral anticoagulant therapy in elderly patients after myocardialinfarction. Lancet 1980; ii: 989-94.

2. Medical Research Council. Assessment of short-term anticoagulantadministration after cardiac infarction. Br Med J 1969; i: 335-42.

3. Hull R, Hirsh J, Jay R, et al. Different intensities of oral anticoagulant therapy inthe treatment of proximal-vein thrombosis. N Engl J Med 1982; 307:1676-81.

4. Smith JR, White AM. Fibrin, red cell and platelet interactions in an experimentalmodel of thrombosis. Br J Pharmacol 1982; 77: 29-38.

5. Francis CW, Marder VJ, McCollister Evarts C, Youkoolbodi S. Two-stepwarfarin therapy. Prevention of postoperative venous thrombosis withoutexcessive bleeding. JAMA 1983; 249: 374-78.