Abstracts of Papers Clinical Pharmacological Meeting

s of papers V A . ~ V2-mmUmqum-~ H Y P ~ ~ 1~ ~ . H. I~,F. DBrkx,H. Y~lst~e=P. Mmlo~s,J Smits,A.Msn in 't Veld, M. s Vl-agcnist desa~D-~EJnine vaso~sain (I][I%VP),40 p~ ~_n iv, towered systauc ~ fro~ ~56 (5), ~ ( ~ ) , to 145 (6) mmHg, diastolic I~ from 94(5) to 81(4) mm~ and incree~d heszt rote n ~ 66 (5) to 92 (5) b~ in nine mtients wtt~ ~ t i a l hypm~m~on. 1~-~=~ n o ~ ro~ t'z~m 282 (37) to 584 (64) I~Jml. We have ~ev i~3.v su~estsd t rot the h~otensive effect of X~VP might be due to antsg~sm of the Vl-mEL~tsd imessor eCs oi" AVP. In in vitro systa~s, i.e. AVP-induced plstelet aggregation and st~m~ssinn of renin release from kidmey slices, the pA2 os IX~VP is about 7. In the pithed rat doses of [DAVP ~p to 540 ng/kg per m~_n. had no demmst~ antagonistic eiT~t on the Iressor res~ to AVP. RIA meesLa.sments of I~VP in plato d ~ DDAVP inlbalcn in 7 nanml veltmtoers showed peak levels of 3.1 (0.3) nM. ~hese levels are Im~bahly too low to cause V1-an~. Patients with X-link~ nephrogm~c d~betes ins~ are resistant to the V2-,~i~tsd antidiuretic action of AVs and ~VP. ~ fe~md that these ~atients (n=3) are also resistant to ~be Stlm,latory effect os []DAVP on ~he release of factor VIII:C and VIIIR:Ag and tlsmm~type p1,-m~nogen activator ~M vascular endothelium, sug~slng a more ga~ral V2-receptor defect. ~ese patients also showed no changes in 8P, heart rate and plasma norsdrerallne altar ~AVP.Tne ca~rler ~ normal responses to C~AVP. ~he dose of D[]AVP we used ~as high but in our im-avio~s studies pstlents with a non-f~ctioning temoreflex due to autoncmic neurops~/V showed a ;%~otensive response to doses as low as 1-2 ng/kg per rain. ~us vesodilatatinn and bsroreflex-induc~ increased s'y~cethatic act3vi~ in z~sTonse to D~V'P a~e~s to d e p m d o n V2-reeepior activation.IX~VP ca~mot be used in idau~ carriers in f.m~l~es at risk. Dept. of Int~Tml Medicine I, ~.*,Universlt~ Rott~, Dept.of Pharmacology, Universit~ os Maastricht, Stichting Cr%w~burah, NooMorp, Netherlm*~ RENAL ARTERY OCCLUSION DURING TREATMENT WITH ACEINHIBITORS IN HYPERTENSIVE PATIENTS WITH UNILATERAL ARTERY STENOSIS: A SIDE EFFECT? C.T. Postma, W.H.L. Hoefnagels, Th. Thlen After our e a r l i e r repor t on renal a r te ry ooc}uslon during ACE i n h l b l t l o n (BMJ 1986; 292: 2425), we saw 6 more pa t ien ts wlth t h i s compl ica t ion . Pat ients : i nd i v i dua l data: see tab le . 4x the c c c l u s i d 6 ~ s found by planned angioplasty and 4x i t was detected by ''mTo-DTPA renal scan showin E unilateral decline in rensl function, followed by arterioEraphy, I x at operation. No distinct chanEes in oreatinine level were found. Blood pressure levels Esve no clues os an occlusion while in all patients blood pressure was controlled sufficiently. Treatment: 8x captopril, Ix enalapril, A Arteriose-e-~r-68Ts? F Fibromuscular dysplasia. ~ e interval t~ (weeks) o ~ (~u~m ~e sex EraSe(%) type a~lo-stsrt ~F,~eks ACE di~. ~-block. start ~E coel~i~ teeatment 6q m 50--75 A 52 54 54 ' + q? f > 90 A O 11 11 + . 53 m 50--75 A 251 3q ~ + "23 f 50-75 F 2 25 22 + q3 s > 90 A 8 8 6 * 62 m 75-@0 A I 63 63 + 51 m > 90 A 19 22 22 + -62 m 75-@0 A 12 14 14 + -49 f > 90 A I 19 19 + Conclusion: several reports describe the decline YE--~E~a-~-~netion on the affected side in unilateral renal artery stenosis durinE treatment with ACE-inhibition. In these 9 patients an occlusion developed, and because in former anti-hypertensive treatment we very rarely observed this complication, we consider it to be a side effect 0s ACE-inhibitors. Department of Medicine, Division of General Internal Medicine, St. Radboud University Hospital, P.O. Box 9101, 6500 HB NijmeEen, The Netherlands z88 Vol. 9 I987 Pharmaceutisch Weekblad Sciennfic Edition PLASMA LEVELS OF VERAPAMIL AND AGE L.M.A.B. van BoEtel, R.O.B. B~hm, J.M.V. Mooy*, P.M.H. Schiffers, and K.H. Rahn* There are data suggesting that verapamil (v) more effectively lowers blood pressure in elderly than in young patients with hypertension. It is not clear whether these differences are due to altered V pharmacokinetics with aging. Ten young subjects (u (age 21-31, mean 23 years) and 10 elderly (age 55-75, mean 66 years) volunteers (ES) were given 40 mg V orally. All subjects had normal liver and kidney function tests. After drug intake, blood was drawn repeatedly for determination of V plasma levels by HPLC with fluorometric detection. V terminal phase halflife was longer (p40.05) in ES (398• min) than in YS (270• min). Oral clearance of the calcium antagonist was lower (p~0.Ol) in the ES (3585• ml/min) than in YS (9005• nl/min). V peak concentration was higher (p< 0.02) in ES (51.9• ng/ml) than in YS (31.0• ng/ml). Time to peak concentration of V was 102• min io YS and 75• mio in ES. The difference is not statistically significant (p)0.4). These results show that age strongly influences the pharmacokinetics of V. This could be the cause of an enhanced antihypertensive effect of V in elderly patients with hypertension. Depts. of Pharmacology and Medicine*, University of Limburg, P.O. Box 616, 6200 MD Maastrieht, The Netherlands. -S~CTIVITY OF BISO~ROLOL COMP/~ WIT~ AT~OLOL P.~C. Chan~r S. van Veen~ P. Verlle~ and P. van Brum~elen In t roduc t ios : B x p e r ~ e n t a l evidence suggnsts t h a t the new drug b t sopro lo l (BPL) e x h i b i t s g r e a t e r ~ l ' a d r e n ~ 1 7 6 s e l e c t i v i t y than other 6 t s e l e c t i v e he tab lcckers . We co.pored the hmomodyna~c and hormonal p~oper t ies of B~L v i t h a t e s o l o l (kTL} and placebo (PLC) in 8 hea l thy subjects. Methods: In a double-blind randomized order e i t h e r an ora l dose of PLC, BPL 20 mg or &TL 100 eg was given v l t h a t l e a s t a 5 days vashout period in between. 2 Hours after drug administration tsoproterenol (ISO) was infused int ravenously: 4, 8, 16 and 30 ng/kqleln a f t e r PLC and 30, 60, 130 and 300 nq/kg/eis a f t e r ATL or BPL. Each dose ISO for 20 s in . 4 Hours a f t e r drug admin i s t ra t ion a b i c y c l e e x e r c i s e t e s t IBIS) yes c a r r i ed out . Blood samples were taken for determinat ion of plasma ren t s a c t i v i t y (PRA), n o r a d e n a l i u e , a d r e n a l i n e (ADR), K , g lscose , l a c t a t e and serum l e v e l s of ATL or BPL. Dur ing the ISO i n f u s i o n b lood p ressure and hear t r a t e were measured v l t h an automated device (Dyna~ap) and during the BiRx a sphyqmomanometer and a one-lead ~CG was used. In the same sub , ac t s , on 2 other occasions# ISO, 0.02~ O.10, 0.40 and 1.20 ng/kg/mln for 3 rain per dose, and ~DR, 0.08 and 2.0 nq/kq/mln for 6 rain per dose, were infused in to the b rach i s l a r t e r y ( i s ) , before and 2 hours a f t e r e i t h e r BPL 20 mg or ATL 100 mq. Forearm blood f lo~ was measured by venous-occlusion plethysmography. Blood pressure was measured i . e . . Teo-vay ana lys i s of Variance was ased. Resul t s : Both during I S ~ i v and the BiEx the bae~odynamie and hormonal ehan~es +were sear i d e n t i c a l a f t e r BPL asd ATL. Mean values of changes in plssan g during I S ~ l . v . and in PRA durin~ BIEx in 8 heal th~ sub , ac t s t a f t e r PLCt ATL and BPL. ISOPR~ALINE1. v. BICYCI~~ R C I SE Plasaa P o t a s s l ~ Plasma Renio Act hasa l dose I dose I I dose I I I dose IV basa l 150 Watt P ~ 4.1 4 .2 4.2 4 .0 3 .9 3.2 8 .6 A ~ 4 .3 4.4 4 .4 4 .2 3 .9 1.3 4 .9 4.3 4.3 6 .3 3 .9 3 . 6 * 1 .5 4 . 2 * * Statist/eel s/gnl6icance between ATL and BPL: *pMore