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PubMed2005

Effects of trapidil after crush injury in peripheral nerve.

In this study, we evaluated the effects of trapidil on crush injury by monitoring nitric oxide, malondialdehyde and transforming growth factor-Beta2 levels and by transmission electron microscopy in the rat sciatic nerve. The sciatic nerve was compressed for 20 sec by using a jewelers forceps. Trapidil treatment groups were administrated a single dose of trapidil (8 mg/kg) intraperitoneally just after the injury. The crush and crush + trapidil treatment groups were evaluated on the 2nd, 7th, 15th, 30th and 45th days of the post-crush period. On the 7th and 15th days, damage in thin and thick myelinated axons, endoneural edema and mitochondrial swelling were less severe in the trapidil group histopathologically. These findings supported the idea that trapidil prevented cell damage and edema at the injury site. Day/group interaction with regard to serum nitric oxide, malondialdehyde and transforming growth factor-Beta2 levels did not show significant changes.

Animals↗
PubMed1999

Trapidil inhibits monocyte chemoattractant protein-1 and macrophage accumulation after balloon arterial injury in rabbits.

Trapidil (triazolopyrimidine) is an antiplatelet agent that acts in part as a phosphodiesterase inhibitor and as a competitive inhibitor of the platelet-derived growth factor (PDGF) receptor. Trapidil has been shown to attenuate intimal hyperplasia in rat and hamster models of balloon arterial injury and to inhibit restenosis after percutaneous transluminal coronary angioplasty in several small clinical trials. Monocyte chemoattractant protein-1 (MCP-1) is a PDGF-inducible monocyte chemoattractant that is thought to play a particularly important role in recruiting monocyte/macrophages to sites of atherosclerosis and vessel injury. We hypothesized that, because of its ability to antagonize PDGF-mediated events, trapidil would inhibit the synthesis of MCP-1 and decrease macrophage accumulation in the injured arterial wall. Hypercholesterolemic rabbits were treated with trapidil (60 mg/kg/day subcutaneously) the day before and then daily for 6 days after balloon injury of the femoral artery; control rabbits received vehicle only. Trapidil resulted in a 75% reduction in MCP-1 expression and macrophage accumulation in the arterial wall 7 days after injury. This study suggests that trapidil has potent anti-inflammatory properties and that its activity in attenuating intimal hyperplasia may be in part attributed to its effects on macrophage accumulation.

Animals↗
PubMedDate not supplied

[Effect of trapidil and papaverine on thrombocyte aggregation and phosphodiesterase activity].

Trapidil effect on platelet aggregation in vitro and in vivo as well as on phosphodiesterase (PDE) activity was studied. Both ADP- and collagen-induced aggregation of human and rabbit platelets was inhibited by trapidil at concentrations of 60 mumol/l. The PDE activity of human platelet lysates was blocked at concentrations that were necessary to inhibit aggregation. Papaverine exerted 5 times higher inhibitory effects on aggregation and PDE activity as compared to trapidil. Infusion of trapidil to rabbits caused aggregation inhibition in vivo. Papaverine at equimolar doses was more effective than trapidil. At therapeutic doses trapidil is unlikely to produce adequate plasma levels for inhibition of platelet aggregation.

Adenosine Diphosphate↗
PubMed1980

Effects of trapidil on electrical activities of canine ventricular muscle.

The effects of N,N-diethyl-5-methyl[1,2,4]triazolo[1,5-alpha]pyrimidine-7-amine (trapidil) on the electrical activities of canine right ventricular muscle were studied using standard microelectrode techniques. Trapidil (10(-4) and 10(-3) mol/l) increased the plateau amplitude and shortened the duration of the action potential without changing the resting membrane potential and the maximum rate of rise of the action potential. Trapidil (10(-3) mol/l) restored regenerative action potentials (the slow response) in the ventricular muscle depolarized by elevation of extracellular K+ concentrations to 30 mmol/l. The slow response induced by trapidil was not affected by pindolol (10(-7) mol/l) which abolished that elicited by isoprenaline (10(-6) mol/l). These results indicate that the action of trapidil on the cardiac cell membrane is to increase the slow inward current during the action potential independently of stimulation of beta-adrenoceptors. Taken together with the results obtained by previous investigations the present results suggest that the increase in slow inward current during the action potential would be responsible for the positive inotropic effect of trapidil and would probably be related to its inhibitory action on cyclic AMP phosphodiesterase.

3',5'-Cyclic-AMP Phosphodiesterases↗
PubMed1983

[The modification of the biosynthesis and effect of thromboxane A2 and prostacyclin by trapidil (Rocornal)].

The influence of the antianginal drug trapidil on the biosynthesis of thromboxane A2 (TXA2) and/or prostacyclin (PGI2), metabolites of arachidonic acid (AA), was investigated in rabbit and human platelet rich plasma (PRP), in homogenates of rabbit spleen and of rat lung and in aortic preparations of rats and rabbits, respectively. Trapidil showed a marked inhibition of the AA-induced aggregation and TXA2 biosynthesis in rabbit and human PRP. The TXA2 inhibition by trapidil was not demonstrable in damaged platelets and seems to require intact cells. In homogenates of rat lungs, trapidil remained without effect on the TXA2 and PGI2 synthesis. In rabbit spleen homogenates the drug induced an inhibition of the formation of both AA metabolites. In contrast to Japanese authors we could not observe any increase in PGI2 release in rat aortic preparation. The PGI2 release from isolated perfused guinea pigs hearts was enhanced; on the other hand, the PGI2 efflux from rabbit hearts remained unchanged. The antiaggregatory effect of PGI2 on the ADP-induced aggregation was strengthened by trapidil, showing an overadditive effect in rabbit PRP. The aggregation inducing effect of the prostaglandin endoperoxide analog U-46619 was inhibited by trapidil. A possible clinical significance of the inhibitions of the synthesis and effect of TXA2 for therapy of ischemic heart disease is discussed.

15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5↗
PubMed1984

Effects of trapidil and nitroglycerin on coronary circulation in conscious dogs.

Effects of trapidil and nitroglycerin (glyceryl trinitrate) on coronary blood flow or epicardial coronary diameter were studied in conscious dogs, instrumented with a Doppler flow probe or a pair of ultrasonic dimension crystals on the left circumflex coronary artery. Bolus intravenous injections of trapidil (0.5, 1.0 and 2.0 mg/kg i.v.) increased coronary blood flow, dose-dependently, such being comparable at the peak value seen with nitroglycerin (5, 10 and 20 micrograms/kg i.v.). Coronary blood flow following the intravenous administration of trapidil or nitroglycerin increased biphasically and returned to pre-drug levels in 1.4 +/- 0.2 min (trapidil 1 mg/kg i.v.) or 1.0 +/- 0.1 min (nitroglycerin 10 micrograms/kg i.v.), while the mean coronary diameter increased monophasically and approached the control level 5 min after drug administration. The first peak was observed before the maximal decrease in aortic pressure and the second peak was associated with concomitant increases in heart rate and myocardial contractility induced by a sudden hypotension. Propranolol, a beta-blocker, did not modify the initial peak but attenuated markedly the second peak (P less than 0.05) in case of trapidil (1.0 mg/kg i.v.) or nitroglycerin (10 micrograms/kg i.v.), which corresponded with reduced changes in reflex tachycardia and positive inotropism. Therefore, the direct effects of trapidil and nitroglycerin on coronary circulation of conscious dogs are an initial transient dilatation of the resistance vessels followed by a continuation of the dilatation of the conductance coronary vessels.

Animals↗
PubMed1980

[Effects of 5-methyl-7-diethylamino-s-triazolo-(1, 5-a) pyrimidine (trapidil) on various experimental hyperlipemias (author's transl)].

Effects of 5-methyl-7-diethylamino-s-triazolo-1, 5-a) pyrimidine (trapidil, Rocornal), a therapeutic agent for ischemic heart disease, on various types of experimental hyperlipemias were studied. With administration of trapidil, elevation of serum high density lipoprotein cholesterol (HDL-C) levels and reduction in serum total cholesterol (TC), low density lipoprotein and very low density lipoprotein cholesterol (LDL-C) and the ratio of HDL-C to LDL-C (LDL-C/HDL-c) were observed in most disease models. Changes in HDL-C levels and LDL-C/HDL-C in the hyperlipemia induced by lipid-enriched diet in mice and in the hyperlipemia induced by high cholesterol diet in Japanese quails were of statistical significance. Also, amelioration of reduction in HDL-C induced by high fat emulsion plus 6-n-propyl-2-thiouracil in rats was observed to be significant. Moreover, trapidil significantly reduced TC, LDL-C levels and LDL-C/HDL-C in the hyperlipemia in hamsters. To investigate possible mechanisms of therapeutic effects of trapidil, blood enzyme activities in Japanese quails with hyperlipemia were assayed. Trapidil showed increases in plasma lipoprotein lipase and serum lecithin-cholesterol acyltransferase activities. These results suggest that trapidil may be an effective chemotherapeutic agent for treating ischemic heart disease.

Animals↗
PubMed1995

[Effect of trapidil in prevention of pre-eclampsia and fetal retardation].

Pre-eclampsia is suggested to be characterized by a functional imbalance between vascular prostacyclin and thromboxane A2 production. On the basis of this hypothesis it is attempted to correct this pathologic conditions by pharmacological manipulation with Trapidil, a triazolo pyrimidin derivative, because of its effects on the prostanoid metabolism. A prospective, randomized, double blind, placebo-controlled study was carried out to investigate Trapidil in the prevention of pregnancy-induced hypertension or pre-eclampsia. A total of 160 pregnant women with the risk to develop pre-eclampsia received Trapidil or placebo between week 24 and 38 of gestation. The number of patients in whom pregnancy-induced hypertension or pre-eclampsia developed was significantly lower in the Trapidil-treated (5.5%) compared with the placebo-treated group (14.1%). Additionally, a reduced risk of preterm deliveries and severe fetal growth retardation could be observed. In 7 patients with manifest pre-eclampsia or pregnancy-induced hypertension the circulating eicosanoid concentrations were determined before and during Trapidil medication. Trapidil was associated with an about twofold increase of 6-keto PGF1 alpha concentration in the peripheral venous blood, while the concentration of thromboxane A2 revealed no changes.

6-Ketoprostaglandin F1 alpha↗
PubMed1997

Pharmacokinetics of the PDGF-antagonist trapidil in patients with and without renal impairment.

The pharmacokinetics of the PDGF-antagonist trapidil and its major metabolite desethyl-trapidil (M 1) were studied in patients with and without renal failure after a single dose of 200 mg and following 4-day treatment with 200 mg t.i.d. Twenty patients were classified according to their renal function as assessed by creatinine clearance (C(Cr)) in group A: 133.7 +/- 30.3 ml/min (n = 8), group B: 63.6 +/- 15.4 ml/min (n = 6) and group C: 17.9 +/- 6.1 ml/min (n = 6), patients on hemodialysis were not enrolled. After the first dose maximal plasma concentrations of trapidil with 5.99 +/- 1.60 (A), 5.76 +/- 1.46 (B) and 5.63 +/- 1.53 micrograms/ml (C) were not different between groups, but somewhat lower on day 4 with 4.96 +/- 0.78 (A), 5.78 +/- 1.78 (B) and 5.47 +/- 1.42 micrograms/ml (C). Similarly, AUC0-infinity-values on day 1 with 16.9 +/- 4.8 (A), 20.2 +/- 6.7 (B) and 22.2 +/- 11.2 micrograms/ml x h (C) showed only modest (NS) differences between groups, but decreased markedly on day 4 to 10.8 +/- 1.8 (A), 13.6 +/- 5.8 (B) and 14.4 +/- 4.3 micrograms/ml x h (C). Linear regression analysis between AUC and C(Cr) demonstrated no relationship between these parameters. For plasma concentrations of M 1 no significant differences were seen between groups. At steady state maximal plasma concentrations of M 1 occurred earlier and were slightly increased. In one patient (group B) receiving tamoxifen comedication markedly elevated plasma concentrations of trapidil and desethyltrapidil occurred, suggesting a pharmacokinetic interaction. Trapidil may be safely given to patients with impaired renal function, the apparent decrease of trapidil plasma concentrations may suggest autoinduction of metabolizing enzymes.

Administration, Oral↗
PubMed1992

Effects of trapidil (triazolopyrimidine), a platelet-derived growth factor antagonist, in preventing restenosis after percutaneous transluminal coronary angioplasty.

Trapidil (triazolopyrimidine), a platelet-derived growth factor antagonist, is a potential inhibitor of intimal proliferation after percutaneous transluminal coronary angioplasty (PTCA). To study its efficacy, 72 patients were randomized to receive Trapidil (600 mg/day orally for 1 week before PTCA and for 4 to 6 months after PTCA; n = 36) or aspirin and dipyridamole (aspirin, 300 mg/day, and dipyridamole, 150 mg/day; n = 36). At entry, both groups were comparable with regard to age, sex, dilated vessels, severity of pre-PTCA stenosis, residual stenosis after PTCA, and prevalence of coronary risk factors. Repeat coronary angiography was performed 6 months after PTCA. Restenosis, defined as the loss of at least 50% of the gain in luminal diameter accomplished by dilation, was present in seven patients (19.4%) in the trapidil group and 15 patients (41.7%) in the aspirin-dipyridamole group (p less than 0.05). The progression of stenosis in patients with less than 30% residual stenosis was significant in both groups. Furthermore, in the patients with residual stenosis of more than 30%, progression of stenosis was less in the trapidil group than in the aspirin-dipyridamole group. Thus trapidil was useful in preventing intimal proliferation after PTCA, especially in patients with more than 30% residual stenosis after PTCA.

Angioplasty, Balloon, Coronary↗
PubMed1980

Effect of trapidil on prostacyclin generation of arterial wall.

Prostacyclin (PGI2) has been reported to be a labile but potent inhibitor of platelet aggregation and a powerful vasodilator. This paper reports the effect of trapidil on PGI2 generation in rat aorta by means of bioassay system. The aortic ring was incubated in 0.05 M Tris HCl buffer (pH 7.5) for 10 min. This incubation medium was added into human PRP, and then incubated at 37 degrees C for 2 min., and ADP was added. PGI2 activity was assayed by the inhibitory percentage of ADP induced platelet aggregation. When the aortic ring was incubated in a medium containing trapidil, PGI2 generation was accelerated. This acceleration was inhibited by pretreatment with indomethacin. Moreover, the aortas of rats intravenously injected with 30 mg/kg of trapidil were incubated in the same way, and PGI2 activity in the medium was estimated. More potent PGI2 activity was observed in the aortas of rat treated with trapidil compared with the controls. These results indicate that acceleration of PGI2 generation from aorta by trapidil is involved in the mode of action of this drug of thrombus formation.

Animals↗
PubMed2005

Protective effect of trapidil against oxidative organ damage in burn injury.

Animal models of thermal injury indicate reactive oxygen species and inflammatory cytokines as causative agents in tissue injury on various organs distant from the original wound. Trapidil has various properties, such as inhibition of platelet aggregation and lipid peroxidation as well as reduction of the inflammatory response to injury. This study was designed to determine the possible protective effect of trapidil treatment against oxidative organ damage in lung, intestine and kidney induced by cutaneous thermal injury. Thirty Wistar rats were randomly divided into five groups. Sham group (n=6) was exposed to 21 degrees C water while burn-3 h group (n=6) and burn+trap-3h group (n=6), burn-24 h (n=6) and burn+trap-24 h groups were exposed to boiling water for 12s to produce a full thickness burn in 35-40% of total body surface area. In both burn+trap-3 h and burn-trap-24 h group, 8 mg/kg trapidil was given intravenously immediately after thermal injury. Three and 24 h later, tissue samples were taken for biochemical analysis from lung, intestine and kidney and blood samples were obtained to determinate serum TNF-alpha levels. Cutaneous thermal injury caused a significant increase in myeloperoxidase (MPO) activity and malondialdehyde (MDA) and 3-nitrotyrozine (3-NT) levels in all tissues and elevated serum TNF-alpha levels at post-burn 3 and 24 h. Trapidil treatment significantly reduced in biochemical parameters, as well as serum TNF-alpha levels. These data suggest that trapidil has a protective effect against oxidative organ damage in burn injury.

Animals↗
PubMed1994

Trapidil inhibits human mesangial cell proliferation: effect on PDGF beta-receptor binding and expression.

Mesangial cell (MC) proliferation, a histopathologic feature common to many human glomerular diseases, is regulated by several growth factors through their binding to specific cell surface receptors. Platelet-derived growth factor (PDGF) is a peptide exerting a potent mitogenic activity on MC. Recently, an increased expression of both PDGF protein and its receptor has been localized in the mesangial areas of several experimental as well as human proliferative glomerulonephritides (GN). Thus, it may be postulated that the inhibition of PDGF action could prevent MC proliferation during mesangial proliferative GN. Trapidil, an antiplatelet drug, has been shown to inhibit the growth of several cell types both in vitro and in vivo. The present study was aimed at evaluating the effect of Trapidil on human MC in vitro. The addition of 100 to 400 micrograms/ml Trapidil significantly reduced cell proliferation induced by different growth factors (FCS, PDGF-BB, bFGF, EGF), the highest inhibitory effect being on PDGF-BB stimulated MC growth. The effect of the drug was dose-dependent and seemingly specific: aspirin was devoid of any anti-proliferative action, while dypiridamole proved to be toxic. Receptor binding experiments showed that Trapidil competitively inhibited 125I-PDGF-BB binding to its cell surface receptors, without inducing receptor internalization, at least after short-term (2 hr) incubation. In contrast, long-term (48 hr) exposure to 400 micrograms/ml Trapidil caused a sharp increase of PDGF-BB binding. Similar effects on cell proliferation and 125I-PDGF-BB binding were observed when NIH-3T3 fibroblasts were exposed to the test substance.(ABSTRACT TRUNCATED AT 250 WORDS)

3T3 Cells↗
PubMed1999

Effect of the platelet-derived growth factor antagonist trapidil on mesangial cell proliferation in rats.

Platelet-derived growth factor (PDGF) is known as a potent mediator in the proliferation of mesangial cells in culture and in mesangial proliferative nephritis. The present study was undertaken to evaluate the effect of trapidil, an antagonist of PDGF, on mesangial cell proliferation in culture and in anti-Thy-1.1 nephritis in rats. Trapidil significantly inhibited 3H-thymidine incorporation in the mesangial cells stimulated by PDGF BB and suppressed mesangial cell proliferation in culture in a dose-dependent manner. In anti-Thy-1.1 nephritis, a significant reduction in the number of total glomerular cells and also proliferating (proliferating cell nuclear antigen positive) cells was demonstrated on day 7 in the rats treated with trapidil as compared with controls. Although renal function expressed as blood urea nitrogen and creatinine levels did not differ between rats with and without trapidil treatment, the present results suggest a salutary effect of trapidil on mesangial cell proliferation. PDGF, therefore, could play an important role in mediating mesangial cell proliferation.

Animals↗
PubMed1983

Trapidil, a coronary vasodilator, inhibits IgE-mediated histamine release from human basophils.

The effect of trapidil, a coronary vasodilator, on histamine release from human basophils was studied. Trapidil inhibited IgE-mediated, anti-IgE-induced histamine release in a dose-dependent fashion (ID50 : 5.8 x 10(-4) M). In contrast, histamine release induced by calcium ionophore A23187, formyl-L-methionyl-L-leucyl-L-phenylalanine and polymyxin B was not affected by this agent. Two-stage experiments suggested that the effect of trapidil was exerted not only on the first Ca2+-independent activation stage, but also on the second Ca2+-dependent stage. These results, together with recent reports that trapidil has a bronchodilator action, suggest that trapidil could be used in the treatment of asthmatic patients.

Asthma↗
PubMed1983

Acute effects of intravenous trapidil on hemodynamics, coronary circulation and myocardial metabolism in man.

The acute effects of intravenous trapidil on hemodynamics, coronary circulation and myocardial metabolism were evaluated in 19 patients (Group I: 10 patients of chest pain syndrome; Group II: 9 patients of coronary heart disease). The heart rate increased (p less than 0.05) and aortic pressure decreased (p less than 0.01) during a 6-min study period. Pulmonary arterial end-diastolic pressure decreased slightly in both groups and cardiac output increased prominently in Group II. Myocardial oxygen consumption did not change significantly 3 and 6 min after trapidil injection. Coronary sinus flow increased slightly (statistically not significant) despite a decrease in aortic pressure, and thus, coronary vascular resistance decreased significantly in both groups. Coronary A-V O2 difference decreased 3 min after trapidil injection and no significant change in the lactate extraction ratio was observed. The diameter of the left main coronary artery increased by about 6% after an administration of trapidil. These results suggest that trapidil has the beneficial effect of coronary vasodilation and it increases cardiac output, despite a decrease in the preload, without a significant increase in myocardial oxygen consumption. The latter may be due to an afterload reduction effect of this drug.

Aged↗
PubMed1981

Depressant effect of trapidil on dog coronary arterial contraction induced by ergonovine.

Effects of trapidil on ergonovine-induced contractions of isolated dog coronary arteries were investigated in vitro. Ergonovine produced dose-dependent contractions of helical strips cut from the left circumflex branches of coronary arteries. Trapidil significantly depressed these-contractions. 5-HT also produced dose-dependent contractions of the strips, which were depressed by trapidil. In isolated rabbit femoral arterial preparations, norepinephrine dose-dependently contracted the strips. Phentolamine significantly depressed these contractions, and trapidil depressed them when relatively high doses were applied previously. Results indicate that trapidil has a depressant effect on coronary arterial contractions induced by ergonovine, partly through antagonism to 5-HT receptor and/or adrenergic alpha receptor.

Animals↗
PubMed1991

Antiproliferative effect of trapidil on PDGF-associated growth of human glioma cell lines in vitro.

The effects of trapidil on platelet-derived growth factor (PDGF)-associated growth of glioblastoma cells were studied. The assessment using PDGF-dependent rat lung endothelium cells revealed secretion of a PDGF-like factor from SF-126 cell line but not from SF-188. Human recombinant PDGF stimulated proliferation of both these glioblastoma cell lines. The anti-PDGF monoclonal antibody inhibited the growth of SF-126 more than SF-188. The results suggest the presence of an autocrine growth mechanism in SF-126 cells mediated by PDGF. The growth of both SF-126 and SF-188 cells was suppressed by trapidil, a specific PDGF antagonist, at 10 and 50 micrograms/ml, respectively. The proliferative response to exogenous PDGF and the antagonistic effect of trapidil were greater in the SF-126 cell line. In addition, trapidil markedly reduced production of prostaglandin E2 in both glioblastoma cell lines. This anti-proliferative effect on malignant glioma cells suggests that trapidil might be a new therapeutic agent for malignant gliomas.

Animals↗