Cardiovascular Drugs and Therapy 1991; 5 Suppl. 3 © KI . . . . Academic Publishers, Boston. 3 4 3

Drug Therapy and

Adverse Drug Reactions II

76 COMPUTER DPUG DELIVERY SYSTEM FOR MODIFICATION OF ThE BLOOD PRESSURE IN ACUTE LEFT VENTRICULAR FAILDq~E

J . B l a c h o w i c z , G . O p o l s k i , M . G r a c z y ~ s k i , J . W 6 j c i c k i , J.Stanislawska, Dept. o f Cardiology & Anesthesiology M.A. and *) Inst. of Biocybernetics & Biomedical Eng. PAS, Warsaw, Poland.

A computer drug delivery system (DDS) was designed and developed for realization an automatic infusion of vasodilators (nitroglycerine - NTG) and catecholamines (dobutamine, dopamine - DA). The arterial blood pressure (BP) and heart rate has been chosen as a feedback parameters. In order to obtain the most effective drug infusion under condition of assumed patient haemodynamic parameters a threshold regulator has been used.

The computer DDS was applied in 20 patients (age: 60+/-11 y.) with acute myocardial infarction complicated by left ventricular failure. Preliminary clinical results indicate that it is possible to achieve higher (>30¢) doses of NTG than using standard realization of infusion (e.g. 52.3 ug/min for desired systolic BP in range of 105-120 mmHg versus 38 ug/min).

An application of the presented DDS allows to make a safe and effective infusion and leads to significant improvement of medical staff work.

77 BIOCHEMICAL AND HAEMODYNAMIC CONSEQUENCES OF PROLONGED ANGIOTENSIN II ANTAGONISM IN SHR B.BUNKENBURG, C.SCHNELL, H.P.BAUM AND J.M.WOOD. Cardiovascular Research Dept., Ciba-Geigy Ltd, Basle, Switzerland.

Conscious, freely-moving male SHR (11 weeks old) received a continuous infusion of vehicle (saline), an angiotensin converting enzyme inhibitor (ACEI) (benazeprilat), or a novel non-peptidic angiotensin II (ANGII) antagonist (ALIA) devoid of agonistic properties (free acid of DuP 753) for 7 days. The compounds were given by infusion to minimize any influence of their different pharmacokinetic properties. Mean arterial blood pressure (BP) and heart rate (HR) were recorded continuously. After 7 days, plasma concentrations of renin (PRC) and ANGII were measured.

n aP HR PRC ANGII (mmHg) (bls/min) (ngANGI/mltnr) (fmol/ml)

vehicle(9Oidlhour) 6 142¢ 9 300¢13 18.9¢ 4.4 6.8¢ 1.2 AIIA(lOmg/kg/day) 7 124¢12 322¢ 8 126.5:L14.0 67.0¢12.7 ACEI (3 mg/kg/day) 6 120¢11 313¢16 64.4+12.5 5.8.%.0.9

PRC and ANGII increased significantly in the AliA-treated rats, indicating that the negative feedback of ANGII on renin release was blocked. Despite the increase in ANGII, the AlIA lowered BP significantly in SHR and to a similar extent as the ACEI. BP remained lowered over the 7 days of treatment. Neither of the compounds had a significant effect on HR. These findings demonstrate that the AlIA and the ACEI have a similar antihypertensive efficacy in SHR. Although plasma concentrations of ANGII are not elevated above normal levels, ANGII appears to play an important role in the maintenance of the high BP in SHR.

78 THE POTENTIATING ACTIONS OF ENALAPRIL (E) AND CAPTOPRIL (C) ON SOME CARDIOVASCULAR EFFECTS QF BRADYKININ 08)

M. Prostran*, R. Samard~ , Z. Todorovi~, D. Mifid, N. Japnnd~M, B.D. Bcleslin, and D. Beleslin, Department of Pharmacology, Faculty of Medicine, P.O.Box 662, 11000 Belgrade, Yugoslavia

B (0.007 to 0.09 ug m1-1) produced a dose-related, but statistically insignificant depression of the isometric contraction (IC) of the isolated, spontaneously beating atria of the guinea-pig. B did not change the heart rate (HR), but a tendency to a slight decrease was observed. E (4.06 or 13.54 umol 1"1), produced a dose-related potentiation of the effect of the highest concentration of B on the I C C (in equhnollar concentrations with E) also potentiated the ef fea of the highest concentration of B on the IC. This effect of C was not a dose- related. Both E and C did not change the effect of B on the HR. B (0.001 to 1.0 ug/kg, i.v.) induced dose-related hypotcnsive responses in anaesthetized cats. Also, B did not produce significant change of the HR, but there was a tendency towards bradycardla. E (0.3 and 1.0 mg/kg, i.v.) significantly potentiated the depressor responses to B. However, the potentiating effect of E was not dose-dependent. C (0.3 mg/kg, i.v.) also signifitmatly potentiated both the hypotensive effect and the negative cbronotropic effect of B, but the potentiation was not dose-dependent. Our results indicate the presence of ACE in the heart tissue and involvement of ACE system in the negative chronotropic effect of B/n vivo conditions. The failure of ACE inhibitors to potentiate the depressor effect of B in a dose-depondent manner is explained with some other mechanism(s) independent of ACE inhibition.

79 ANTIHYPERTENSIVE AND HAEMODYNAMIC EFFECTS OF LISINOPRIL AND DYAZIDE IN THE ELDERLY

W R MCNABB, M A VELLA, T S PADAYACHES AND R R LEWIS, D e p a r t m e n t o f G e r i a t r i c end G e n e r a l M e d i c i n e , G u y ' s H o s p i t a l , London g e l

In e l d e r l y hyper tens ive p a t i e n t s (mean nee 75 years) t h l s double b l i nd study compared acute and e igh t weak e f f e c t s of l l s l n o p r l l (LSP) (n=6) and Dyazide (n=7) on blood p r e s s u r e (BP), r e n a l p l a s m a f l o w i n m11mtn (RPF), glomerulnr filtrstlon rate In mllmln (OFR) and mlddle c e r e b r a l a r t e r y b lood f l o ~ - v e l o c l t l e s (CBFV).

BP F e l l ~r l th tn one h o u r on LSP w i t h a mean f a l l o v e r O-8h of 29±8 ran Hg s y s t o l i c and 13±5 mm Hg d i a s t o l i c . RPF was unchanged (154±48 placebo: 170±34 LSP). GFR f e l l from 63~t8 to 5 l± t3 p<O.05) over O-ah0 mainly due to a 6-8h f a l l from 69±11 to 45~9. On LSP at atEht weeks RPF (218±60) and GFR (69±20) were unchanged from placebo.

In con t ras t , the BP d id not change a f t e r the f i r s t dose of D y a z i d e bu t RPF f e l l o v e r O-8h f r o m 178±47 ( p l a c e b o ) t o 156±45 (p<0.051. GFR f e l l between 4-6h from 65±13 to 46±16 but over O-ah was not d i f f e r e n t (58±12) f rom placebo (64±12). At e ight weeks on Dyazide the BP had f a l l e n by 17±6 mm Hg s y s t o H c end 11±4 mm Hg d i n a t o l l c compared to placebo, w i th no f u r t h e r chanse in RPF (154±69) or GFR (55±22), CBFV were unchanged at fou r hours and e igh t weeks w i th both drugs.

Cardiovascular Drugs and Therapy 1991; 5 Suppl. 3 © Kluwer Academic Publishers, Boston.

80 THE EFFECT OF FELODIPINE ON HEPATIC BLOOD FLOW AND ANTIPYRINE CLEARANCE.

J. Aberg, R. Bergstrand, and B. Edgar, Astra Cardiovascular, Hfisels, S-431 83, Sweden.

Drugs that can alter hepatic blood flow or hepatic enzyme activity have a potential of changing the hepatic elimination of other drugs. Antipydne (AP) and indocyanine green (ICG) clearance are used as markers for changes in hepatic enzyme activity and hepatic blood flow, respectively. Felodipine (F) is a second generation calcium antagonist of the dihydropyddine class. The plain tablet of F (P'l') is rapidly absorbed resulting in high plasma peaks while the formulation used in the clinic is an extended release dosage form (ER) with slow and sustained absorbtion. Methods: PT 10 mg and ER 10 mg were administered in a placebo controlled, randomisad cross-over study to 12 healthy males. Each cross-ovar period lasted for 14 days separated by 14 days of wash-out AP and ICG clearance and BP, HR and plasma F concentrations were assessed the last treatment day. Results: Plasma F concentrations were higher with higher fluctuations on PT com- pared to ER. Cma x was 15.8 + 6.6 nM and 9.1 + 7.3 nM; Cmi n 0.7 ± 0.4 nM and 1.5 ± 1.1 nM on PT and ER, respectively. F did not affect AP dearance but increased ICG ciearafice. This increase was more pronounced on PT. At Cma x ICG clearance was increased by 55 % compared to placebo. No increase was seen on ER. Conclusion: F does not influence hepatic enzyme activity. The plain tablet causes a greater variation in plasma concentrations of F and hepatic blood flow, compared to the ER formulation. Drug interactions seem less likely with the ER formulation F, than with a plain tablet.

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81 B R O N C H O C O N S T R I C T I O N F O L L O W I N G INTRAVENOUS DIPYRIDAMOLE FOR MYOCARDIAL THALLIUM STUDIES

A. Keech. J. McCarthy, L. B. Arkles, and A. Hamer , Repatr iat ion General Hospital, Heidelberg, Melbourne, 3081, Austral ia

In order to assess the effect on respiratory function of dipyridamole used in myocardial stress thallium studies, we studied 22 consecutive adults referred for thall ium imaging with serial spirometry.

Forced expiratory volume over 1 second (FEV1) fell significantly in 12 individuals following intravenous dipyridamole, including 5 with no history of respiratory disease, in most cases asymptomatic. However in 2 subjects, both with chronic airflow obstruction [CAO], clinical as thma developed, with falls in FEV1 of 123ml and 197m1 respectively. Breathlessness and FEV1 change abated spontaneously in one by 35 minutes, and promptly following in t ravenous aminophylline in the other. In those with CAO, resting FEV1 fell by 58±11ml (4.5%, p<0.0001) a t 10 minutes, and by 6 1 ! l l m l (4.7%, p<0.0001) a t 25 minutes, compared to falls of 2~-15ml (1.0%, p=NS) and 33±15ml (1.4%, p<0.05) a t 10 and 25 minutes in those without respiratory disease. Changes in FEV1 were unrelated to occurrence of reversible myocardial thall ium defect.

C o n c l u s i o n s In t r avenous d ipyr idamole can adverse ly affect respiratory function and cause bronchospasm. Significant declines in FEV1 can occur even in the absence of a history of respiratory disease, but appear likely to be clinically important where a history of CAO is present. Aminophylline appears to rapidly reverse these effects and should be available for immediate intravenous use.