Specific Inhibition of Platelet Agglutination and Aggregation by Aromatic Amidino Compounds

Geratz, J. D.; Tidwell, R. R.; Brinkhous, K. M.; Mohammad, Sameer; Dann, Otto; Loewe, H

doi:10.1055/s-0038-1646701

Cited by 13 publications

(5 citation statements)

References 20 publications

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“…In the present study, this was shown by a dose-related inhibitory effect of ASA. This is contrary to the idea that collagen induces a nearly complete ADP-mediated sequence of reactions as has been claimed by Geratz et al (33), but not supported by Nunn (34). The importance of either of these pathways is most probably species-specific since Mallarkey et al (35) concluded that in rats, one third of the aggregatory response to collagen was mediated by products of cyclooxygenase activity, whereas in guinea-pigs, about 60% of the response was due to products of the cyclooxygenase pathway.…”

Section: O-o: Dihydralazine + Adp; A---a: Adpcontrasting

confidence: 95%

Evaluation of Pulmonary Accumulation of 51Chromium-Labelled Rat Platelets following Intravenous Application of ADP and Collagen

Klee

Seiffge²

1991

Thromb Haemost

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SummaryWe examined the effects of ADP- and collagen-induced pulmonary platelet embolism in the rat. Homologous 51Chromium-labelled platelets were used to monitor extracorporally the distribution of platelets in the circulation. For that purpose, collimated iodide scintillation detectors were placed above thorax (C1) and abdomen (C2). A dose-dependent increase in thoracic radioactivity, paralleled by a decrease in the abdomen, was observed after intravenous injection of ADP and collagen. This resulted in a shift of C1/C2, so that the effect of collagen was more pronounced (maximal increase of C1/C2 = 134%) than ADP (maximal increase of C1/C2 = 79%). The increase in thoracic radioactivity was caused by the uptake of platelets in the lung as was shown after administration of collagen (6-fold enrichment of labelled platelets). Lung platelet sequestration resulted in a dose-dependent thrombocytopenia. The ADP-and collagen-induced pulmonary platelet embolism reversibly provoked cardiovascular symptoms of shock: hypotension and bradycardia. Impaired gas exchange during platelet accumulation manifested itself in a reversible arterial hypoxaemia and hyper-capnia, followed by a weak acidosis. We were able to inhibit ADP-dependent thoracic platelet accumulation by ticlopidine in a dose-related manner as well as collagen-induced thoracic platelet accumulation by acetylsalicylic acid. The results indicate that behaviour of homologous labelled rat platelets in vivo can easily be monitored, thus offering the opportunity to investigate the effects of antiaggregatory drugs on platelets in their natural environment.

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Section: O-o: Dihydralazine + Adp; A---a: Adpcontrasting

confidence: 95%

Evaluation of Pulmonary Accumulation of 51Chromium-Labelled Rat Platelets following Intravenous Application of ADP and Collagen

Klee

Seiffge²

1991

Thromb Haemost

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“…Pentamidine also inhibited the binding of 125 I-fibrinogen to platelets. Pen tamidine does not inhibit ristocetin-induced aggregation (25). This inhibition could be due to a direct action of pentamidine on fibrinogen binding or indirectly by acting on signal transduction or other cellular events.…”

Section: Discussionmentioning

confidence: 75%

Pentamidine: A Non-Peptide GPIIb/IIIa Antagonist – In Vitro Studies on Platelets from Humans and Other Species

et al. 1992

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SummaryIn this paper we show that the non-peptide anti-parasite agent pentamidine is a broad spectrum anti-platelet agent with an IC50 of 1.1 µM in ADP-induced platelet aggregation in human platelet rich plasma (PRP). It had similar activity when collagen, arachidonic acid, platelet activating factor, thrombin and epinephrine were used. It had no effect on platelet intracellular cAMP levels. It inhibited 125I-fibrinogen, 125I-fibronectin and 125I-von Willebrand factor binding to ADP-activated fixed platelets with IC50 values of 160, 160 and 60 nM respectively. Pentamidine showed a high degree of species selectivity with slightly less activity in monkey and dog PRP and little activity in guinea pig, rabbit, rat and mouse PRP compared with human. This was similar to the other RGD analogues tested. This species specificity was shown to be dependent on the species of platelets and independent of the species of fibrinogen. Thus, pentamidine is a potent non-peptide inhibitor of fibrinogen binding to GPIIb/IIIa.

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“…Aromatic dicationic compounds, including bisbenzamidines and dicationically substituted bisbenzimidazoles and carbazoles, have excellent experimental anti-Pneumocystis activities (14,40,46,48,50,51) and are also active against other microbial pathogens, including protozoan parasites (2-5, 10, 38, 41, 43, 44), fungi (45), and some viruses (25-27, 49, 53). Aromatic dications also possess other pharmacological properties, including antiinflammatory and anticoagulant activities (29)(30)(31)(32)(33)(34)(35)(36)(37). Two problems hindering development of these compounds as new drugs, however, are limited oral bioavailability and toxicity (24,38,48,51).…”

mentioning

confidence: 99%

Anti- Pneumocystis Activities of Aromatic Diamidoxime Prodrugs

Hall¹,

Kerrigan²,

Ramachandran³

et al. 1998

Antimicrob Agents Chemother

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Aromatic dicationic compounds, such as pentamidine, have potent antimicrobial activities. Clinical use of these compounds has been restricted, however, by their toxicity and limited oral activity. A novel approach, using amidoxime derivatives as prodrugs, has recently been proposed to overcome these limitations. Although results were presented for amidoxime derivatives of only one diamidine, pentamidine, the authors in the original proposal claimed that amidoxime derivatives would work as effective prodrugs for all pharmacologically active diamidines. Nine novel amidoxime derivatives were synthesized and tested in the present study for activity against Pneumocystis carinii in corticosteroid-suppressed rats. Only three of the nine compounds had significant oral anti-Pneumocystis activity. The bisbenzamidoxime derivatives of three direct pentamidine analogs had excellent oral and intravenous activities and reduced acute host toxicity. These compounds are not likely candidates for future drug development, however, because they have chronic toxic effects and the active amidine compounds have multiple sites susceptible to oxidative metabolism, which complicates their pharmacology and toxicology. Novel diamidoximes from three other structural classes, containing different groups linking the cationic moieties, lacked significant oral or intravenous anti-Pneumocystis activity, even though the corresponding diamidines were very active intravenously. Both active and inactive amidoximes were readily metabolized to the corresponding amidines by cell-free liver homogenates. Thus, the amidoxime prodrug approach may provide a strategy to exploit the potent antimicrobial and other pharmacological activities of selected, but certainly not all, aromatic diamidines.

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Specific Inhibition of Platelet Agglutination and Aggregation by Aromatic Amidino Compounds

Cited by 13 publications

References 20 publications

Evaluation of Pulmonary Accumulation of 51Chromium-Labelled Rat Platelets following Intravenous Application of ADP and Collagen

Evaluation of Pulmonary Accumulation of 51Chromium-Labelled Rat Platelets following Intravenous Application of ADP and Collagen

Pentamidine: A Non-Peptide GPIIb/IIIa Antagonist – In Vitro Studies on Platelets from Humans and Other Species

Anti- Pneumocystis Activities of Aromatic Diamidoxime Prodrugs

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