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Pharmacology & Toxicology Nov 1994We assessed the effect of dipyridamole, RA-642 and mopidamol, on lenticular opacities in a model of experimental diabetic cataracts in rats. All three...
We assessed the effect of dipyridamole, RA-642 and mopidamol, on lenticular opacities in a model of experimental diabetic cataracts in rats. All three pyrimido-pyrimidine derivatives caused a statistically significant reduction of opacification in crystalline lens as compared with untreated diabetic animals. The production of superoxide anions (phenazine methosulphate [PMS]-induced nitroblue tetrazolium [NBT] reduction) showed a decrease of 81.6%, 78.9% and 1.8% in lens tissue homogenates from rats treated with dipyridamole, RA-642 and mopidamol, respectively. Dipyridamole and RA-642 produced a statistically significant inhibition (50% and 64.8%, respectively) of lipid peroxidation (ferrous sulphate and ascorbic acid [FeAs]-induced malondialdehyde [MDA] production) as compared with the group of untreated diabetic rats. Mopidamol did not exert any inhibitory effect on lipid peroxidation. There was a statistically significant correlation between opacification of lens and PMS-induced NBT reduction and FeAs-induced MDA production. We conclude that the protective effect of dipyridamole and RA-642 from free radical damage to crystalline lens in the model of experimental diabetes used in this study, is the result of the antioxidant action of these compounds. The effect exerted by mopidamol, however, suggest a possible complementary effect of the pyrimido-pyrimidine derivatives through interaction with other mechanisms (e.g., the sorbitol pathway) implicated in the development of cataracts.
Topics: Animals; Blood Glucose; Cardiotonic Agents; Cataract; Diabetes Mellitus, Experimental; Dipyridamole; Lens, Crystalline; Lipid Peroxidation; Male; Malondialdehyde; Mopidamol; Pyrimidines; Rats; Rats, Wistar; Superoxides
PubMed: 7870694
DOI: 10.1111/j.1600-0773.1994.tb00356.x -
Annales Chirurgiae Et Gynaecologiae 1982
Review
Topics: Animals; Antineoplastic Agents; Blood Platelets; Carcinoma 256, Walker; Cyclic AMP; Head and Neck Neoplasms; Humans; Lung Neoplasms; Lymphoma; Male; Mice; Mopidamol; Neoplasm Metastasis; Neoplasm Recurrence, Local; Neoplasm Transplantation; Neuraminidase; Platelet Aggregation; Rabbits; Rats; Sarcoma; Vasodilator Agents
PubMed: 6287902
DOI: No ID Found -
American Journal of Clinical Oncology Dec 1982Considerable evidence has accumulated in recent years which implicates blood coagulation reactions in the growth and spread of malignancy. In particular, platelets may... (Clinical Trial)
Clinical Trial Review
Considerable evidence has accumulated in recent years which implicates blood coagulation reactions in the growth and spread of malignancy. In particular, platelets may accumulate on embolic tumor cells and facilitate their adhesion to the endothelium at distant sites perhaps by enhancing blood coagulation reactions. Alternatively, platelets may promote tumor cell proliferation by contributing a growth-promoting factor or through interactions mediated by prostaglandins. Inhibition of tumor growth and spread by platelet-inhibitory drugs has been demonstrated in several experimental tumor systems. Preliminary data suggest that similar effects may be seen in human malignancy. The purpose of this paper is to review relevant literature which provides the rationale for therapeutic trials of platelet-inhibitory drugs in human malignancy and to describe the experimental design for a trial involving one such drug, RA-233, in a recently established VA Cooperative Study.
Topics: Adenocarcinoma; Animals; Anticoagulants; Blood Platelets; Carcinoma, Small Cell; Clinical Trials as Topic; Colonic Neoplasms; Double-Blind Method; Humans; Lung Neoplasms; Mopidamol; Neoplasms; Neoplasms, Experimental; Pyrimidines; Random Allocation
PubMed: 6299092
DOI: 10.1097/00000421-198212000-00006 -
Biochimica Et Biophysica Acta Apr 1987A study has been made of the behaviour of the drugs dipyridamole and mopidamol (RA 233) attached to poly(N-vinylpyrrolidone). The inhibitory activities towards platelet...
A study has been made of the behaviour of the drugs dipyridamole and mopidamol (RA 233) attached to poly(N-vinylpyrrolidone). The inhibitory activities towards platelet aggregation induced by ADP or platelet activation factor (PAF) in sheep plasma have been examined and found to exceed the activities of the parent drugs, by factors up to 20. At the same time the abilities of the polymer-bound drugs in potentiating prostaglandin-type anti-aggregatory activities are much lower than those of the unattached drugs. The observations are explained in terms of polymer adsorption on to the platelet membranes, producing a high surface concentration of the drugs with consequent high inhibitory action. Intracellular action, such as the inhibition of phosphodiesterase, is reduced by the difficulty experienced by the polymeric drug in passing through the membrane, so that potentiation of prostaglandin activity, particularly against PAF, becomes small. A terpolymer containing units of dipyridamole and the prostaglandin analogue 5-(6-carboxyhexyl)-1-(3-cyclohexyl-3-hydroxypropyl)hydantoin (245C) shows a degree of 'self-potentiation'.
Topics: Adenosine Diphosphate; Dipyridamole; Humans; Kinetics; Mass Spectrometry; Mopidamol; Platelet Activating Factor; Platelet Aggregation; Polymers; Povidone; Structure-Activity Relationship
PubMed: 3828396
DOI: 10.1016/0304-4165(87)90068-7 -
Advances in Nephrology From the Necker... 1975
Review
Topics: Adenosine; Antidepressive Agents; Aspirin; Blood Platelets; Complement System Proteins; Endothelium; Glomerulonephritis; Hemostasis; Heparin; Histamine H1 Antagonists; Humans; Immunity; Immunoglobulins; Indomethacin; Kidney Diseases; Meclofenamic Acid; Mopidamol; Phagocytosis; Phenylbutazone; Platelet Aggregation; Prostaglandins; Pyrimidines; Sulfinpyrazone; Tranquilizing Agents; Warfarin
PubMed: 242207
DOI: No ID Found -
Blood Jun 1982Twenty dogs with naturally occurring metastatic tumors were treated with anticoagulants (Warfarin) or platelet enzyme inhibitor drugs (dipyridamole, dipyridamole plus...
Twenty dogs with naturally occurring metastatic tumors were treated with anticoagulants (Warfarin) or platelet enzyme inhibitor drugs (dipyridamole, dipyridamole plus aspirin, RA233, sulfinpyrazone, or a combination of RA233 and sulfinpyrazone) to determine if tumor-related reductions in platelet survival and concentration could be reversed. Anticoagulation was ineffective, while platelet enzyme inhibitors were able to produce improvements in platelet survival. Of the 18 dogs with metastatic tumor treated with platelet enzyme inhibitors, only 5 (28%) showed a reduction in platelet survival during the first week of observation on therapy compared to their baseline survivals. This is significantly different than the decreases in platelet survivals observed in 8 of 10 untreated dogs (80%) with metastatic tumor observed for the same interval. Furthermore, 8 of the 18 treated dogs (44%) had platelet survivals within 2 standard deviations of normal, compared to only 1 of 10 untreated dogs. Of the 8 dogs with normal platelet survivals, 6 were treated with a combination of a phosphodiesterase inhibitor (RA233 or dipyridamole) and a cyclooxygenase inhibitor (sulfinpyrazone or aspirin). The combination of RA233 and sulfinpyrazone was the best drug program tested and resulted in normal platelet survivals in 63% and improved platelet counts in 75% of the animals treated. Thus, platelet enzyme inhibitors with different mechanisms of action may have a synergistic effect in reversing the abnormal platelet hemostasis found in a variety of spontaneously occurring canine neoplasms.
Topics: Animals; Blood Platelets; Cell Survival; Cyclooxygenase Inhibitors; Dogs; Enzyme Inhibitors; Fibrinogen; Fibrinolytic Agents; Kinetics; Mopidamol; Neoplasms; Phosphodiesterase Inhibitors; Platelet Count; Sulfinpyrazone; Warfarin
PubMed: 6805531
DOI: No ID Found -
Cancer Mar 1979Various known and presumed characteristics of malignant cells that permit metastasis and factors that contribute to the establishment of secondary tumor foci are... (Review)
Review
Various known and presumed characteristics of malignant cells that permit metastasis and factors that contribute to the establishment of secondary tumor foci are reviewed. The potential for therapeutic control with and the limitations of chemotherapy are discussed briefly.
Topics: Animals; Antigens, Neoplasm; Antineoplastic Agents; Cell Adhesion; Cell Membrane; Cell Transformation, Neoplastic; Humans; Macrophages; Mopidamol; Neoplasm Metastasis; Neoplasms; Neoplastic Cells, Circulating; Platelet Aggregation
PubMed: 371787
DOI: 10.1002/1097-0142(197903)43:3<790::aid-cncr2820430303>3.0.co;2-f -
Laryngologie, Rhinologie, Otologie Dec 1983Our clinical study to prevent relapse and metastases in several sarcomas and malignant lymphomas of the head and neck region with a long-term treatment with mopidamole... (Review)
Review
Our clinical study to prevent relapse and metastases in several sarcomas and malignant lymphomas of the head and neck region with a long-term treatment with mopidamole was initiated in 1972 because the pyrimido-pyrimidine derivative was shown to inhibit platelet aggregation in vivo and to increase significantly the circulation time of intravenously injected, 32P-labelled Ehrlich ascites tumour cells in mouse blood. The aggregation of platelets to circulating tumour cells and their subsequent adhesion to vascular endothelium in turn appeared to be part of the early stages of the metastatic process. It seems, however, that other related mechanisms are also involved in the clinical results obtained. Mopidamole, as other related derivatives, probably inhibits platelet aggregation by inhibition of PDE-induced decomposition of cAMP and may stimulate the synthesis and/or release of prostacyclin from the vessel wall which in turn activates adenylate cyclase involved in cAMP synthesis. The latter mechanism was definitely shown only for the related pyrimido-pyrimidine derivative dipyridamole, the methyl-xanthine derivative pentoxifylline and the methyl-pyrazoline derivative nafazatrom. The increase of cAMP levels by mopidamole results in an inhibition of 3H-thymidine incorporation into human neoplastic cells and a direct inhibition of its mitotic rate. The adding of mopidamole to a culture of a human promyelocytic leukemic cell line promotes a reverse transformation of the malignant cells to normal which appears to be a permanent phenotypic change. Furthermore, mopidamole was shown to diminish significantly spontaneous lung metastases in syngenic Wilms' tumor (nephroblastoma) of the rat, the C1300-neuroblastoma of the mouse and the HM-Kim mammary carcinoma of the rat.(ABSTRACT TRUNCATED AT 250 WORDS)
Topics: Animals; Bencyclane; Cell Adhesion; Cells, Cultured; Dipyridamole; Humans; Lymphocytes; Mice; Mopidamol; Neoplasm Metastasis; Pentoxifylline; Phosphorus Radioisotopes; Platelet Aggregation; Pyrazoles; Pyrazolones; Pyrimidines; Rats
PubMed: 6369051
DOI: No ID Found -
British Journal of Haematology May 1976Adenosine inhibits the aggregation of human but not of rat platelets whereas both are inhibited by prostaglandin E1 or by the pyrimido-pyrimidine compound RA233. In... (Comparative Study)
Comparative Study
Adenosine inhibits the aggregation of human but not of rat platelets whereas both are inhibited by prostaglandin E1 or by the pyrimido-pyrimidine compound RA233. In human platelets all three agents increase adenosine-3'-5'-cyclic monophosphate (cAMP). If the inhibition of aggregation depended on this increase, adenosine might be expected not to increase cAMP in rat platelets. Under conditions in which adenosine inhibited aggregation and increased cAMP in human platelets, adenosine caused a similar increase in cAMP in rat platelets without inhibiting their aggregation. The aggregation of rat platelets was inhibited as effectively as that of human platelets by PGE1 or RA233 at concentrations which caused greater increases in cAMP than did the highest concentrations (2.8 X 10(-4) M) of adenosine it was possible to use. When the increase of cAMP in rat platelets by PGE1 was limited to that produced by adenosine, PGE1 like adenosine failed to inhibit aggregation. Therefore, the difference in the inhibitory effectiveness of adenosine on rat and human platelets was quantitative rather than qualitative and apparently depended on the inability of adenosine to increase cAMP sufficiently in rat platelets. When cAMP had been increased by adenosine, PGE1 or RA233, the addition of ADP caused cAMP to decrease rapidly in both human and rat platelets to between +22 and -18% of control values, except that the decrease in rat platelets was to +40% after RA233 had been present for 0.5 min before ADP. The increase in cAMP produced in rat platelets by adenosine at 5 X 10(-6) to 2.8 X 10(-4) M for 3 min was associated with a small increase in aggregation velocity. It is suggested that the comparative ineffectiveness of adenosine as an inhibitor of platelet aggregation, particularly with rat but less so also with human platelets, is because, unlike PGE1 or RA233, adenosine has two opposing actions on aggregation; one being inhibition by activating adenylate cyclase and increasing cAMP, and the other being potentiation by uptake. This hypothesis accounts for the present results as well as for the earlier observation that dipyridamole which prevents the uptake of adenosine potentiates its inhibitory effect on the aggregation of human platelets.
Topics: Adenosine; Adenosine Diphosphate; Animals; Blood Platelets; Cyclic AMP; Humans; In Vitro Techniques; Mopidamol; Platelet Aggregation; Prostaglandins E; Rats
PubMed: 178342
DOI: 10.1111/j.1365-2141.1976.tb00969.x -
Journal of Neurophysiology Jul 19891. In a crustacean neuromuscular preparation, the walking leg opener muscle of the freshwater crayfish Procambarus clarkii, application of serotonin (1 microM) produces...
1. In a crustacean neuromuscular preparation, the walking leg opener muscle of the freshwater crayfish Procambarus clarkii, application of serotonin (1 microM) produces presynaptic depolarization and long-lasting facilitation of excitatory postsynaptic potentials (EPSPs). The frequency of spontaneously released transmitter quanta also increases. Facilitation of evoked EPSPs declines after serotonin application in two phases. 2. Serotonin-induced facilitation was examined using simultaneous pre- and postsynaptic intracellular microelectrode recording. A presynaptic microelectrode recorded action potentials and membrane potential of a presynaptic axonal branch, and one or more postsynaptic microelectrodes recorded EPSPs in muscle fibers innervated by the excitatory motor axon. Components of the phosphatidylinositol second messenger system and pharmacologic agents affecting this system were injected through the presynaptic electrode, and changes in synaptic transmission were measured. 3. Presynaptic injection of inositol 1,4,5-triphosphate (IP3) causes presynaptic depolarization, increases the frequency of spontaneously released transmitter quanta, and promotes a relatively short-lasting facilitation of evoked EPSPs. These actions are consistent with elevation of intracellular Ca2+ and resemble the early phase of serotonin-induced facilitation. 4. Application of a phorbol ester, 12-O-tetradecanoyl-phorbol-13-acetate (TPA), that activates protein kinase C (C-kinase), produces a long-lasting, low-level facilitation of evoked EPSPs. Application of another phorbol ester, phorbol-12-monoacetate (PTMA), which does not activate C-kinase has no effect. 5. Presynaptic injection of RA 233, a phospholipase C (PLP-C) inhibitor, blocks all aspects of serotonin-induced facilitation. This compound was found to have no general deleterious effects on synaptic transmission and does not block other forms of synaptic facilitation in this preparation.(ABSTRACT TRUNCATED AT 250 WORDS)
Topics: Animals; Astacoidea; Membrane Potentials; Mopidamol; Neuromuscular Junction; Phorbol Esters; Phosphatidylinositols; Serotonin; Time Factors; Type C Phospholipases
PubMed: 2754475
DOI: 10.1152/jn.1989.62.1.239