Joint Meeting of American Societyfor Biochemistry and Molecular Biology,

American Society for Pharmacologyand Experimental Therapeutics,French Pharmacological Society

and Pharmacological Society of Canada

Cardiovascular DrugsBoston, MA, USA

June 4–8, 2000

Alexander Scriabine

Yale University, School of Medicine New Haven, CT, USA

The joint meeting of four societies: American Society for Biochemistry and Molecular

Biology, The American Society for Pharmacology and Experimental Therapeutics, French

Pharmacological Society and Pharmacological Society of Canada, consisted of 190 ses-

sions (symposia or poster sessions) with a total of 1572 oral or poster presentations. The

symposium was held at Hynes Convention Center in Boston. It attracted ca 4000 partici-

pants (scientists, exhibitors and guests). This report summarizes only selected posters on

cardiovascular drugs presented at that meeting.

ANTITHROMBOTIC AND ANTICOAGULANT DRUGS

R. Potoczak et al. (Parke-Davis Pharmaceutical Research Division of Warner-Lambert

Company, Ann Arbor, MI, USA) described a new factor Xa inhibitor, PD-198961. Its

antithrombotic activity was demonstrated in vitro and in vivo. At 0.2 �M PD-198961 pro-

longed plasma prothrombin time (PT) in rabbits and at 0.16 �M in humans. At 0.3 to

3.0 �g�kg�min i.v. it prolonged time to occlusion of femoral artery in rabbits with ex-

250

Cardiovascular Drug ReviewsVol. 18, No. 3, pp. 250–253© 2000 Neva Press, Branford, Connecticut

Address correspondence to: Alexander Scriabine, M. D. Department of Pharmacology, Yale School of Med-

icine, 333 Cedar Street, New Haven, CT 06520. Fax: +1 (203) 458–8428.

perimental vessel injury; at these doses PD-198961 had minimal effects on coagulation

parameters.

Y. W. Peng et al. (Parke-Davis Pharmaceutical Research Division of Warner-Lambert

Company, Ann Arbor, MI, USA) used a new assay method to study factor Xa inhibitory

activity of PD-200022 (ZK-807834). The assay involved direct activation of factor X in

plasma by Russell’s viper venom and cleavage of a factor Xa specific chromogenic sub-

strate. In human plasma IC50 of PD-200022 was 0.01 �M. There was a good correlation

between plasma drug concentration and factor Xa activity in rabbit and dog thrombosis

models.

A. J. Chu et al. (Wayne State Univ., Detroit, MI, USA) found that histamine releaser,

48�80, depresses endotoxin-inducible tissue factor (TF) activity in human monocytes and

monocyte-like THP-1 cells. 48�80 blocked FVII binding to TF and, therefore, diminished

FVII activation and FVIIa formation. The authors suggested that 48�80 could be useful

therapeutically to antagonize TF-induced extrinsic hypercoagulation.

A. Z. Fernandez et al. (IVIC, Venezuela, and University of Maastricht, The Nether-

lands) purified draculin, an anticoagulant protein from vampire bat saliva. Draculin in-

hibits factor Xa with Ki = 14.8 nM. Glycosylation is required for the biological activity of

draculin. It appears that draculin forms a draculin-factor Xa complex in a two-step re-

action. The binding of draculin to factor Xa is tight and non-competitive.

Cardiovascular Drug Reviews, Vol. 18, No. 3, 2000

CARDIOVASCULAR DRUGS: JOINT MEETING 251

PD-198961

PD-200022 (ZK-807834)

PLATELET AGGREGATION INHIBITORS

K. Kounga et al. (Harvard Medical School, Charlestown, MA, USA) discovered that

chrysoptin, a 68 kDa protein from salivary glands of deerflies, is a glycoprotein IIb�IIIa

fibrinogen receptor antagonist. Chrysoptin’s cDNA has been cloned and expressed in ba-

calovirus. CDNA predicts a protein containing N-linked glycosylation sites. Glycosy-

lation appears to be important for the activity of chrysoptin. Identification of chrysoptin’s

functional domains may help in the development of novel platelet aggregation inhibitors.

Y. Dobrydenva et al. (East Virginia Med. School, Norfolk, VA, USA; Old Dominion

Univ., Norfolk, VA, USA; and School of Chemical Sciences, Urbana, IL, USA) studied

the effects of a series of tetrahydrochrysenes (THCs) on calcium influx into thrombin-

stimulated human platelets. The authors measured calcium concentration in human plate-

lets in a suspension. THCs (unsubstituted THC-diol, trans-diethyl THC, and racemic cis-

diethyl THC inhibited calcium elevation with an IC50 � 0–5 �M. Trans-diethylTHC dime-

thyl ether was inactive. The effects of some THCs were inhibited by thapsigargin, sug-

gesting that their mechanism of action may involve inhibition of store-operated calcium

channels.

F. Burslem and Peter Ellis (Pfizer Central Research, Sandwich, UK) reported that

sildenafil, at 10 nM to 1 �M enhanced platelet antiaggregatory activity of sodium nitro-

prusside in human or rabbit platelets. Sildenafil alone had no effect on platelet aggre-

gation. In vivo, in rabbits, sildenafil, at 0.01 or 0.03 mg�kg i.v., improved blood flow and

reduced thrombus formation. In humans, sildenafil, 50 mg p.o., potentiated the antiaggre-

gatory activity of sodium nitroprusside without any effect on bleeding time.

MISCELLANEOUS CARDIOVASCULAR DRUGS

D. Lerni-Barbaz et al. (Universities of Montreal and Sherbrooke, Quebec, Canada)

antagonized pressor responses to angiotensin II in rats by L 163,017. At 7 mg�kg i.p. the

drug blocked pressor responses to angiotensin II. When microencapsulated formulation of

L 163,017 was used, the duration of action of the drug was increased to 8 h.

Subodh Verna et al. (University of Calgary, Canada) found that tetrahydrobiopterin

augments acetylcholine-induced relaxation of strips of human saphenous vein from pa-

tients undergoing bypass graft surgery.

Cardiovascular Drug Reviews, Vol. 18, No. 3, 2000

252 A. SCRIABINE

L 163,017

A. J. Cayatte et al. (Boston University Medical Center, Boston, MA, USA, and Institut

de Recherche Servier, France) reported that a new TxA2 receptor antagonist, S18886

(15-hydroxy-11 alpha, 9 alpha (epoxy methano) prosta-5,13-dienoic acid) inhibits athero-

genesis in ApoE deficient mice. S18886, at 5 mg�kg�day for 11 weeks, decreased aortic

root lesions and ICAM-1 levels. Aspirin at 20 mg�kg�day was ineffective. The results

suggested that blockade of TxA2 receptors has an antiatherogenic effect by a mechanism

independent from platelet derived TxA2.

M. Y. K. Lee and R. Y. K. Man (University of Hong Kong) studied coronary

vasodilator effects of genistein, a phytoestrogen from soybeans. It was previously reported

to have hypocholesterolemic and antioxidant activities. The authors found that in vitro, in

porcine coronary artery, genistein enhanced vasodilator effects of sodium nitroprusside or

cromakalim. The vasodilator effect of genistein appears to be direct and not endothelium-

dependent.

D. M. Kopustinskiene et al. (Kaunas University, Kaunas, Lithuania) studied the ef-

fects of diazoxide on isolated rat heart mitochondria and concluded that at 250 �M diazo-

xide uncouples mitochondrial respiration by inhibiting complex II of mitochondrial respi-

ratory chain. Since this effect of diazoxide was not antagonized by 5-hydroxydecanoate,

the authors concluded that it is not due to KATP channel opening.

D. L. Anderson et al. (Glaxo Wellcome Inc. Research Triangle Park, NC, USA)

studied the effects of the �1A-adrenoceptor selective agonist, NS-49 on hemodynamics

and intraurethral pressure in conscious dogs. At 3 to 100 �g�kg i.v. or 200 �g�kg p.o.

NS-49 increased intraurethral and arterial blood pressure and lowered heart rate. In con-

scious animals NS-49 appears to have less urethral selectivity than in anesthetized

animals.

Cardiovascular Drug Reviews, Vol. 18, No. 3, 2000

CARDIOVASCULAR DRUGS: JOINT MEETING 253

NS-49