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General Pharmacology Jul 19961. The in vitro production of ferrous-induced lipid peroxidation was 5.71 times higher in rat lung tissue than in human lung membranes. 2. The pyrimido-pyrimidine...
1. The in vitro production of ferrous-induced lipid peroxidation was 5.71 times higher in rat lung tissue than in human lung membranes. 2. The pyrimido-pyrimidine derivative RA-642 shows a more potent inhibition of ferrous-induced lipid peroxidation than dipyridamole; mopidamol had no effect. All the compounds showed higher anti-peroxidative effect in rat than in human lung tissue.
Topics: Adult; Aged; Animals; Antioxidants; Dipyridamole; Female; Ferrous Compounds; Humans; In Vitro Techniques; Lipid Peroxidation; Lung; Male; Malondialdehyde; Middle Aged; Mopidamol; Pyrimidines; Rats; Rats, Wistar; Thiobarbituric Acid Reactive Substances; Vitamin E
PubMed: 8842690
DOI: 10.1016/0306-3623(95)02098-5 -
Thrombosis Research Feb 1996We compared the effects of dipyridamole, RA-642, and mopidamol on platelet activity and thromboxane/prostacyclin balance in relation to the degree of retinal... (Comparative Study)
Comparative Study
We compared the effects of dipyridamole, RA-642, and mopidamol on platelet activity and thromboxane/prostacyclin balance in relation to the degree of retinal vascularization in a model of experimental streptozotocin-induced diabetes in rats. After 3 months, collagen-induced platelet aggregation in whole blood was 25% higher in diabetic animals than in nondiabetics. Dipyridamole inhibited 43% platelet aggregation, mopidamol 39%, and RA-642 36%. Platelet production of thromboxane B2 was 87% higher in untreated diabetic rats. Mopidamol and RA-642 produced a 46% and 41% inhibition of thromboxane B2. Dipyridamole did not inhibited thromboxane B2 synthesis. Aortic production of 6-keto-PGF1 alpha was 43% lower in untreated diabetic animals and showed no change after treatment with either mopidamol or RA-642. In contrast, dipyridamole caused a 90% increase in aortic production of prostacyclin. Computerized analysis of retinal vascularization showed that untreated diabetic rats had a 81% decrease in the area occupied by peroxidase-labelled vessels as compared with nondiabetics. Treatment with dipyridamole, mopidamol, and RA-642 caused 2.5-fold, 2.8-fold and four-fold increases, respectively, in the percentage of retinal surface occupied by peroxidase-labelled vessels. Differences in retinal vascularization between diabetic animals given RA-642 and nondiabetic controls were negligible.
Topics: Animals; Blood Glucose; Diabetes Mellitus, Experimental; Diabetic Retinopathy; Dipyridamole; Epoprostenol; Male; Mopidamol; Neovascularization, Pathologic; Platelet Aggregation Inhibitors; Pyrimidines; Rats; Rats, Wistar; Thromboxanes
PubMed: 8928090
DOI: 10.1016/0049-3848(96)00004-7 -
Journal of Medicine 1996A series of pyrimido-pyrimidine derivatives were tested for their effect on membrane fluidity-deformability of human red blood cells and on human platelet aggregation....
A series of pyrimido-pyrimidine derivatives were tested for their effect on membrane fluidity-deformability of human red blood cells and on human platelet aggregation. These agents were also tested for their intracellular cAMP increasing activity and proliferation inhibitory activity in neoplastic cells. The order of activity was established and clinical implications discussed. Several derivatives are under study as antineoplastic agents.
Topics: 3',5'-Cyclic-AMP Phosphodiesterases; Adenosine Diphosphate; Antineoplastic Agents; Cell Division; Cyclic AMP; Erythrocyte Deformability; Hemorheology; Humans; Melanoma; Molecular Structure; Mopidamol; Platelet Aggregation; Platelet Aggregation Inhibitors; Pyrimidines; Tumor Cells, Cultured
PubMed: 8863175
DOI: No ID Found -
American Journal of Hematology Jun 1995Small cell carcinoma of the lung (SCCL) responds commonly to combination chemotherapy but resistance to therapy follows. Prior reports have suggested that a relationship...
Pretreatment fibrinogen levels are associated with response to chemotherapy in patients with small cell carcinoma of the lung: Department of Veterans Affairs Cooperative Study 188.
Small cell carcinoma of the lung (SCCL) responds commonly to combination chemotherapy but resistance to therapy follows. Prior reports have suggested that a relationship may exist between plasma fibrinogen levels and response to therapy in SCCL. This study was designed to determine the possible predictive value of the fibrinogen level for tumor response (chemoresistance) in SCCL. Pretreatment fibrinogen levels were correlated with outcome and response to therapy in a cohort of 119 previously untreated patients with SCCL who were admitted to VA Cooperative Study 188. Higher pretreatment fibrinogen levels at diagnosis correlated significantly with more advanced stage of disease at entry (P < 0.001) and with reduced overall survival (P = 0.030). In addition, higher pretreatment fibrinogen levels were correlated significantly with a reduced likelihood of achieving subsequent disease regression with combination chemotherapy (P = 0.005). Because several clinical trials have shown that anticoagulant therapy improves tumor response rates and survival of SCCL, we postulate that tumor cell thrombin generation not only promotes SCCL growth but may also be primarily responsible for both increased fibrinogen levels and for resistance to chemotherapy. These findings provide incentive for studies of thrombin effects on the development of multidrug resistance, and for new clinical trials of more potent and specific inhibitors of thrombin that may further improve tumor response and survival in SCCL.
Topics: Carcinoma, Small Cell; Cohort Studies; Drug Resistance; Fibrinogen; Fibrinolysin; Fibrinopeptide A; Fibrinopeptide B; Humans; Lung Neoplasms; Mopidamol; Randomized Controlled Trials as Topic; Regression Analysis; Thrombin
PubMed: 7771466
DOI: 10.1002/ajh.2830490208 -
Thrombosis Research Jan 1995
Topics: Adult; Cell Communication; Dipyridamole; Endothelium, Vascular; Humans; In Vitro Techniques; Male; Mopidamol; Perfusion; Platelet Aggregation; Platelet Aggregation Inhibitors
PubMed: 7701482
DOI: 10.1016/0049-3848(95)90869-h -
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 -
Biochemical Pharmacology Jan 1994The chronic administration of 10 mg/kg/day of dipyridamole to rats produced 33.7% inhibition of platelet aggregation induced with ADP and a 93% increase in... (Comparative Study)
Comparative Study
The chronic administration of 10 mg/kg/day of dipyridamole to rats produced 33.7% inhibition of platelet aggregation induced with ADP and a 93% increase in 6-keto-prostaglandin F1 alpha (6-keto-PGF1 alpha) in vascular samples, versus saline-treated rats. Mopidamol, 8.3 mg/kg/day, caused 50.6% inhibition of ADP-induced platelet aggregation, 37.6% inhibition of aggregation induced with arachidonic acid, a 47.6% decrease in serum levels of thromboxane B2 and a 23.7% increase in the vascular production of 6-keto-PGF1 alpha, versus saline-treated rats. Dipyridamole showed a higher in vitro anti-aggregating effect in whole blood (IC50 6.6 microM) than in platelet-rich plasma (PRP) (IC50 210 microM), when ADP was used as inducer, and had no effect in the presence of arachidonic acid. Mopidamol exerted a similar effect in whole blood (IC50 3.7-20 microM, depending on the inducer) and PRP (IC50 11-17.3 microM), and showed a dose-dependent inhibition of platelet aggregation and thromboxane B2 synthesis induced with arachidonic acid (IC50 16.8-22.3 microM). Mopidamol also inhibited enzymatically induced lipid peroxidation) (IC50 89 +/- 5.9 mumol/L) and had no effect on free radical-induced lipid peroxidation. The dose-dependent increase in 6-keto-PGF1 alpha in vascular samples after incubation with dipyridamole showed a negative linear correlation with inhibition of lipid peroxidation (r2 = 0.77). It is concluded that the phosphodiesterase inhibitors, dipyridamole and mopidamol, interfere in a different manner with platelet function. It seems that mopidamol may also exert a selective effect on platelet thromboxane synthesis.
Topics: Animals; Blood Platelets; Blood Vessels; Cyclooxygenase Inhibitors; Dipyridamole; Enzyme Activation; Epoprostenol; Humans; Lipid Peroxidation; Male; Mopidamol; Platelet Aggregation; Prostaglandin-Endoperoxide Synthases; Rats; Rats, Wistar; Thromboxane A2
PubMed: 8304965
DOI: 10.1016/0006-2952(94)90008-6 -
Clinical & Experimental Metastasis Jan 1994Prostacyclin and its stable analogues have been shown to interfere specifically with certain steps of the metastatic cascade. The antimetastatic activity of the stable...
Prostacyclin and its stable analogues have been shown to interfere specifically with certain steps of the metastatic cascade. The antimetastatic activity of the stable prostacyclin analogue Cicaprost (Schering AG) on haematogenous metastasis in a series of tumours in rats and mice has been well established. In order to test the effect of Cicaprost on lymphogenous metastasis we chose the metastatic cell clone MTLn3 derived from the 13762NF rat mammary carcinoma. The effect of Cicaprost on prevention of lung metastasis, lymph node metastasis and primary tumour growth was investigated. Cicaprost given in daily doses of 0.01, 0.03 and 0.1 mg/kg orally, reduced the number of lung metastases in a dose-dependent manner. Whereas the median number of lung metastases in the controls was greater than 1000, Cicaprost at a dose of 0.1 mg/kg reduced the number of lung metastases to between 11 and 100. The weight of the ipsilateral axillary lymph nodes was diminished by Cicaprost to 30-50% of controls. Moreover, metastasis to the contralateral axillary lymph node was completely inhibited by Cicaprost at all three doses tested. Cicaprost did not influence the growth rate of the MTLn3 cell clone implanted into the mammary fat pad or the weight of the primary tumour at the end of treatment. In conclusion, in addition to its dose-dependent effect on haematogenous metastasis, Cicaprost strongly inhibits lymph node metastasis.
Topics: Animals; Antineoplastic Agents; Dose-Response Relationship, Drug; Epoprostenol; Female; Lung Neoplasms; Lymphatic Metastasis; Mammary Neoplasms, Experimental; Mopidamol; Rats; Rats, Inbred F344
PubMed: 8287616
DOI: 10.1007/BF01784330 -
Cancer Apr 1993Several studies have provided evidence suggesting that platelets play a key role in tumor metastasis. A number of antiplatelet agents have been used to prevent tumor...
BACKGROUND
Several studies have provided evidence suggesting that platelets play a key role in tumor metastasis. A number of antiplatelet agents have been used to prevent tumor metastasis in animal models and humans. Antiplatelet agents, dipyridamole (adenosine transport inhibitor), and RA-233 (inhibitor of cAMP PDE) were used to prevent tumor-cell-platelet interactions both in in vitro and in vivo systems; however, the data were not very conclusive.
METHODS
Our studies used dipyridamole and RA-233 alone and in combination to investigate their effects on human pancreatic tumor cells (RWP-2)-induced platelet aggregation in human blood and on hepatic metastasis in nude mice. To examine effects of dipyridamole and RA-233 on liver metastasis, the tumor cells (RWP-2) were injected intrasplenically in nude mice grouped into control, dipyridamole (8 mg/kg), RA-233 (8 mg/kg), and dipyridamole plus RA-233 (8 mg/kg each). The agents were administered intraperitoneally 1 hour before and 24 hours after the tumor cell injection.
RESULTS
When dipyridamole and RA-233 were used alone, only weak to moderate effects were seen on RWP-2 tumor cell-induced platelet aggregation. However, these agents, when combined, strongly inhibited the tumor cell-induced aggregation in human platelet-rich plasma. In tumor metastasis experiments, reductions of approximately 70% in hepatic nodules and 90% in surface area occupied by the tumor were seen with the combination treatment (dipyridamole plus RA-233) as compared with the control group of mice.
CONCLUSIONS
This study suggests that the combination of dipyridamole and RA-233 provides an effective intervention for the antithrombotic approach to the treatment of cancer metastases.
Topics: Adenosine; Animals; Dipyridamole; Drug Screening Assays, Antitumor; Drug Synergism; Humans; Liver Neoplasms; Mice; Mice, Nude; Mopidamol; Pancreatic Neoplasms; Platelet Aggregation; Tumor Cells, Cultured
PubMed: 8453569
DOI: 10.1002/1097-0142(19930415)71:8<2466::aid-cncr2820710807>3.0.co;2-q -
Brain Research Dec 1992The effects of pyrimido-pyrimidine derivatives (dipyridamole, RA-642 and mopydamole) on lipid peroxidation (inhibition of the production of malondialdehyde, MDA) in...
The effects of pyrimido-pyrimidine derivatives (dipyridamole, RA-642 and mopydamole) on lipid peroxidation (inhibition of the production of malondialdehyde, MDA) in different regions of the rat brain were studied. Ferrous sulfate and ascorbic acid (FeAs) were used to induce lipid peroxidation via the formation of hydroxyl anions. The antiperoxidative effect of RA-642 (in the microM range) was 10 times more potent than that of dipyridamole. Mopydamole did not exert any inhibitory effect on MDA production. In a model of ischemia reperfusion with bilateral occlusion of the common carotid arteries for 1 h and restoration of circulation for a period of 2 h, dipyridamole inhibited FeAs-induced MDA production but did not protect from postischemic brain tissue damage (measured by mitochondrial reduction of tetraphenyl tetrazolium). RA-642 inhibited FeAs-induced MDA production and showed 50-67% protection from tissue damage as compared with untreated animals, while mopydamole did not inhibit MDA production and showed 30-48% protection. No correlation was found between inhibition of lipid peroxidation and protection from brain tissue damage.
Topics: Animals; Brain; Dipyridamole; Disease Models, Animal; Ischemic Attack, Transient; Lipid Peroxidation; Male; Mitochondria; Mopidamol; Oxidation-Reduction; Pyrimidines; Rats; Rats, Wistar; Reperfusion Injury; Tetrazolium Salts
PubMed: 1472997
DOI: 10.1016/0006-8993(92)91481-s