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Lipids Mar 1992The effects of pyrimido-pyrimidine derivatives (dipyridamole, RA-642, and RA-233) on lipid peroxidation, using d-alpha-tocopherol as standard, were studied in enriched... (Comparative Study)
Comparative Study
The effects of pyrimido-pyrimidine derivatives (dipyridamole, RA-642, and RA-233) on lipid peroxidation, using d-alpha-tocopherol as standard, were studied in enriched membrane fractions from human and rat hepatocytes. Equimolar concentrations of ferrous sulfate and ascorbic acid were used to induce lipid peroxidation. The amount of peroxidized lipids observed in membrane fractions from human liver was smaller than in those from rat liver. In both species, however, pyrimido-pyrimidine derivatives, except for RA-233 in rat liver, inhibited lipid peroxidation dose-dependently in the following sequence: RA-642 greater than dipyridamole greater than d-alpha-tocopherol RA-233.
Topics: Animals; Ascorbic Acid; Cardiotonic Agents; Cell Membrane; Dipyridamole; Ferrous Compounds; Humans; Kinetics; Lipid Peroxidation; Liver; Malondialdehyde; Mopidamol; Pyrimidines; Rats; Species Specificity; Vitamin E
PubMed: 1522764
DOI: 10.1007/BF02536177 -
Thrombosis Research Aug 1991
Comparative Study
Topics: Adenosine; Cardiotonic Agents; Dipyridamole; Dose-Response Relationship, Drug; Humans; Male; Mopidamol; Platelet Aggregation Inhibitors; Pyrimidines; Theophylline
PubMed: 1754999
DOI: 10.1016/0049-3848(91)90233-m -
Methods and Findings in Experimental... 1991The effects of three pyrimido-pyrimidine derivatives (RA-642, dipyridamole and mopidamol) on hydroxyl anion-induced lipid peroxidation in cell membranes from liver,...
The effects of three pyrimido-pyrimidine derivatives (RA-642, dipyridamole and mopidamol) on hydroxyl anion-induced lipid peroxidation in cell membranes from liver, brain, kidney, lung and heart rat tissue were studied using d-alpha-tocopherol as standard for lipid peroxidation. Ferrous sulfate and ascorbic acid (FeAs) were used to induce lipid peroxidation via the formation of hydroxyl anions. The products resulting from the reaction with thiobarbituric acid were taken to be indicators of lipid peroxidation. Thiobarbituric acid reactive substances (TBARS) were produced by different rat tissues in the following sequence: brain greater than liver greater than kidney greater than heart greater than lung. Dose-response and time-response curves were plotted for all compounds. Inhibiting concentrations, 50% (IC50), ranged from 0.3-1.4 microM for RA-642, and 2.5 and 4.6 microM for dipyridamole. In liver mitochondrial membranes, IC50s of these compounds were 0.4 +/- 0.2 and 5.8 +/- 1.2 microM, respectively. At 15 min after beginning TBARS production, dipyridamole and RA-642 did not exert any inhibitory effect.
Topics: Animals; Cell Membrane; Dipyridamole; Dose-Response Relationship, Drug; Ferrous Compounds; In Vitro Techniques; Lipid Peroxidation; Male; Mopidamol; Pyrimidines; Rats; Rats, Inbred Strains
PubMed: 1881198
DOI: No ID Found -
Gynecologic Oncology Feb 1990This prospective double-blind, multicenter study was aimed at evaluating the clinical efficacy of RA 233 (a derivative of dipyridamole) in ovarian cancer. Following... (Clinical Trial)
Clinical Trial Randomized Controlled Trial
This prospective double-blind, multicenter study was aimed at evaluating the clinical efficacy of RA 233 (a derivative of dipyridamole) in ovarian cancer. Following primary surgery, 497 patients with ovarian cancer were treated with combination cytotoxic chemotherapy; those in clinical stage II were also treated with pelvic irradiation. The patients were randomly allocated to receive RA 233 (N = 251) or placebo (N = 246) for 2 years. The groups did not significantly differ from each other in any of the clinical, therapeutic, or histopathological variables evaluated. There were no significant differences between RA 233-treated patients and placebo-treated patients with respect to appearance of new metastases, progressive growth of malignancy, or survival of all patients, in any of the clinical stages of the disease, in radically operated patients or in nonradically operated patients, in different histopathological groups, or in different age groups. Hence, supplementation of carcinoma therapy with long-term administration of the antiplatelet drug RA 233 has no clinical benefit in this malignancy. Using Cox's multifactorial stepwise analysis, this study revealed that the clinical stage of the disease, the extent of surgery, and the histopathology of the tumor, but not the age of the patient or the use of RA 233, were significant and independent predictors of survival. With respect to the histopathology, the poor prognosis of serous and mesonephric carcinomas appeared to be independent of the other prognosis indicators.
Topics: Combined Modality Therapy; Female; Humans; Mopidamol; Neoplasm Metastasis; Neoplasm Staging; Ovarian Neoplasms; Placebos; Prognosis; Prospective Studies; Pyrimidines; Randomized Controlled Trials as Topic; Risk Factors; Statistics as Topic; Survival
PubMed: 2404838
DOI: 10.1016/0090-8258(90)90179-o -
The Journal of Neuroscience : the... Dec 1989Long-term facilitation (LTF), a form of synaptic plasticity demonstrated at the crayfish neuromuscular junction, is induced by tetanic stimulation and persists for...
Long-term facilitation (LTF), a form of synaptic plasticity demonstrated at the crayfish neuromuscular junction, is induced by tetanic stimulation and persists for hours. LTF can be divided into 2 phases: a tetanic phase, which occurs during stimulation, and a long-lasting phase, which persists after stimulation. Activators and potentiators of cAMP (forskolin and 3-isobutyl-methyl-xanthine) produce facilitation of excitatory postsynaptic potentials, which attain approximately the amplitude of the long-lasting phase of LTF but last for a shorter time. Localized presynaptic injection of a protein inhibitor ("Walsh inhibitor") specific for the cAMP-dependent protein kinase blocks the long-lasting phase of LTF at synapses near the injection site with no apparent effect on the tetanic phase. Normal LTF develops and persists at synapses of the same axon distant from the injection site. Localization of the injected inhibitor was confirmed by fluorescent tagging. Localized injection of SQ22,536, an adenylate cyclase inhibitor, also blocks the second phase of LTF near the injection site, but not at distant synapses. These experiments establish a role for adenylate cyclase activation in the long-lasting phase of LTF. The phosphatidylinositol second-messenger system is not important in LTF as inhibition of phospholipase C by injection of RA233, which blocks facilitatory effects of serotonin, does not affect any aspect of LTF.
Topics: 1-Methyl-3-isobutylxanthine; Adenine; Adenylyl Cyclase Inhibitors; Adenylyl Cyclases; Animals; Astacoidea; Bacterial Toxins; Colforsin; Cyclic AMP; GTP-Binding Proteins; Mopidamol; Neuromuscular Junction; Phospholipases; Protein Kinase Inhibitors; Time Factors
PubMed: 2480401
DOI: 10.1523/JNEUROSCI.09-12-04246.1989 -
Cancer Research Aug 1989The abilities of the Eli Lilly compounds LY150310, LY189332, and LY135305 to inhibit spontaneous metastasis and to increase animal survival were evaluated. These... (Comparative Study)
Comparative Study
The abilities of the Eli Lilly compounds LY150310, LY189332, and LY135305 to inhibit spontaneous metastasis and to increase animal survival were evaluated. These compounds represent widely varied structures and were evaluated because they have been found to inhibit thromboxane synthetase, cyclooxygenase, and thrombin activation, respectively. These biochemical processes have been proposed in the literature as targets for antimetastatic drugs. The purpose of this investigation was twofold: (a) to compare the antimetastatic activities of the Eli Lilly compounds to those of the reference antimetastatic compounds nafazatrom and RA233, and (b) to examine the correlation between inhibition of spontaneous lung metastasis and survival. Spontaneous metastasis of the Lewis lung carcinoma was used to evaluate the antimetastatic activity of the compounds. In this model 5 x 10(5) tumor cells were implanted into the gastrocnemius muscle, the primary tumor was resected on Day 14, and metastatic lung lesions were counted on Day 25. Compounds were administered every 12 h on Days 5 through 19. Nafazatrom, LY150310, LY189332, and LY135305 were found to inhibit spontaneous lung metastasis in a dose-dependent manner. The ED50 values for the respective inhibitions with these compounds were 50, 0.5, 2, and 0.35 mg/kg/day; the respective therapeutic indexes (LD50/ED50) were 7, 180, 255, and 511. To evaluate the effect of nafazatrom, LY150310, LY189332, and LY135305 on animal survival, the compounds were given at maximally antimetastatic doses of 200, 60, 20, and 6 mg/kg/day, respectively. Two dosing schedules were used: (a) on Days 5 through 19 and (b) on Day 5 until death. Neither the median survival times nor the numbers of long-term survivors were significantly changed with any of the compounds at any dosing schedule. RA233, given to a maximally tolerated dose of 200 mg/kg/day on Day 5 until death, did not inhibit lung metastasis and did not increase median survival time. Postmortem examination of animals dosed with nafazatrom, LY150310, LY189332, and LY135305 showed complete inhibition in lung lesions and the appearance of lesions in the liver, kidney, spleen, and brain. The results of this investigation show that the effect a compound has on the number of metastatic lesions in a target organ may not be predictive of its effect on survival. To successfully translate laboratory data into the clinic, survival should be considered as a predictor of a compound's potential clinical utility.
Topics: Aniline Compounds; Animals; Antineoplastic Agents; Carcinoma; Chemical Phenomena; Chemistry; Dose-Response Relationship, Drug; Drug Evaluation, Preclinical; Female; Fibrinolytic Agents; Imidazoles; Lung Neoplasms; Mice; Mopidamol; Naphthalenes; Neoplasm Metastasis; Propylamines; Pyrazoles; Pyrazolones; Random Allocation; Tetrahydronaphthalenes
PubMed: 2743339
DOI: No ID Found -
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 -
European Journal of Cancer & Clinical... Jun 1989The pyrimido-pyrimidine derivatives RA233 and RX-RA85, which are potent inhibitors of platelet and tumour phosphodiesterases, were developed as antitumour agents....
The pyrimido-pyrimidine derivatives RA233 and RX-RA85, which are potent inhibitors of platelet and tumour phosphodiesterases, were developed as antitumour agents. Clinical as well as animal studies suggest a tumour type specific, although moderate, antitumour activity for RA233. In our search for more potent congeners of RA233, we found that RX-RA85 was cytotoxic for cultured B16 melanoma and Lewis lung carcinoma cells at drug concentrations above 4 micrograms/ml whereas RA233 concentrations up to 400 micrograms/ml were tolerated. When tested for their effects on cell cycle distribution, RX-RA85 was 100-fold more potent than RA233 in producing an increase in the proportion of cells in S and G2 + M phase in 3LL cells. Progression of 3LL cells through the cell cycle was delayed for 5 h by RA233 treatment, whereas RX-RA85 was ineffective. In contrast, B16 cells responded poorly to either drug. The effects of both compounds were not only tumour cell specific but also dependent on the stage of tumour cell growth (drugs added to synchronously vs. asynchronously growing cultures). In the case of RX-RA85, the potency to affect tumour cell cycle distribution was highly dependent on tumour cell number, making the potential of this drug as an antitumour agent somewhat limited.
Topics: Animals; Cell Cycle; Cell Line; Flow Cytometry; Lung Neoplasms; Melanoma, Experimental; Mice; Mopidamol; Phosphodiesterase Inhibitors; Pyrimidines; Tumor Cells, Cultured
PubMed: 2753057
DOI: 10.1016/0277-5379(89)90152-1 -
Pneumologie (Stuttgart, Germany) Jun 1989Between January 1982 and April 1986 a double-blind randomized placebo controlled study of mopidamol, employed as adjunct therapy to surgery in patients with non-small... (Clinical Trial)
Clinical Trial Randomized Controlled Trial
Between January 1982 and April 1986 a double-blind randomized placebo controlled study of mopidamol, employed as adjunct therapy to surgery in patients with non-small cell bronchial carcinoma, was performed at 7 hospitals. The main criteria were occurrence of metastases and survival. Mopidamol was given perioperatively at a dose of 2 x mg i.v. daily, and postoperatively orally at a dose of 3 x 500 mg daily. The treatment period was scheduled to at least 2 years and in some of the patients was prolonged to 3 years. The standard therapy of each individual center was given as basic therapy. A total of 270 patients were included in the study, 147 in the placebo and 123 in the mopidamol group. By the end of the study 52 deaths from metastases had occurred in the placebo group (35%) compared with only 32 (26%) in the mopidamol group. This difference is statistically significant at p less than 0.05 with the one-sided test. A comparison of life-tables according to Kaplan-Meier shows a statistically significant difference in favour of the group treated with mopidamol (savage p less than 0.05). Cox's multivariate analysis confirmed the statistically significant difference in favour of the group treated with mopidamol, the inclusion of the risk factors tumour stage and histology in the evaluation results in a p-value of 0.02. With respect to the incidence of metastases there were no appreciable differences between the treatment groups. The incidence of side effects or undesired events was equal in both groups.(ABSTRACT TRUNCATED AT 250 WORDS)
Topics: Aged; Carcinoma, Non-Small-Cell Lung; Clinical Trials as Topic; Combined Modality Therapy; Dose-Response Relationship, Drug; Double-Blind Method; Drug Administration Schedule; Female; Humans; Lung Neoplasms; Male; Middle Aged; Mopidamol; Prospective Studies; Pyrimidines; Random Allocation
PubMed: 2547216
DOI: No ID Found -
American Journal of Clinical Oncology Jun 1989One hundred and one patients with oat (small) cell lung cancer have been treated with CAVE [Cytoxan, Adriamycin, Vincristine, and etoposide (VP-16)] chemotherapy +/-... (Clinical Trial)
Clinical Trial Comparative Study
One hundred and one patients with oat (small) cell lung cancer have been treated with CAVE [Cytoxan, Adriamycin, Vincristine, and etoposide (VP-16)] chemotherapy +/- RA233 (a platelet-inhibiting agent). There was no difference in disease-free interval, pattern of relapse, or survival between groups.
Topics: Actuarial Analysis; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Small Cell; Cyclophosphamide; Double-Blind Method; Doxorubicin; Female; Humans; Lung Neoplasms; Male; Middle Aged; Mopidamol; Podophyllotoxin; Prospective Studies; Pyrimidines; Random Allocation; Vincristine
PubMed: 2543207
DOI: 10.1097/00000421-198906000-00016