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PubMed1994

Platelet and endothelial response with trapidil in patients with peripheral obliterative arteriopathy.

The activity of trapidil, an antiaggregating agent with PDGF antagonist properties, was investigated in order to verify its possible modulating effect in the endothelial and platelet activation. PDGF, t-PA, PAI-1 and ET-1 plasma levels were measured before and after a 2 month treatment period with trapidil 200 mg tablets bid or placebo in 30 patients affected by POA in Fontaine stage II. PDGF and PAI-1 significantly (p < 0.05) increased in the placebo group, and PDGF also in the comparison between treatments (p < 0.05). Aggregation data demonstrate an absence of Ca++ antagonist action of trapidil. The results of this study suggest that trapidil can interfere with the combined vascular and platelet response in atherogenesis.

Aged↗

PubMed1999

Platelet aggregation and platelet-derived growth factor inhibition for prevention of insufficiency of the transjugular intrahepatic portosystemic shunt: a randomized study comparing trapidil plus ticlopidine with heparin treatment.

Intimal proliferation at the interface between prosthetic material and tissue is an intrinsic phenomenon of stenting and the major cause of insufficiency of the transjugular intrahepatic portosystemic shunt (TIPS). For its prevention, a randomized study was performed comparing standard heparin treatment with a combination of trapidil, a drug with anti-platelet-derived growth factor (PDGF) activity, and ticlopidine, a platelet aggregation inhibitor. Ninety patients with cirrhosis who received a transjugular shunt were randomized, and 84 patients completed the trial. Group 1 (n = 42) received a bolus of heparin (12 to 24 U/kg) at shunt placement, followed by 1 week of intravenous and 4 weeks of subcutaneous heparin treatment. Group 2 (n = 42) received the same heparin bolus, followed by a 1-day intravenous heparin treatment and a 6-month treatment with trapidil (400 mg/d) and ticlopidine (250 mg/d). Shunt function was assessed by duplex-sonography and angiography. Stenoses were classified according to their location as type 1 (within the stent) and type 2 (in the draining hepatic vein). The estimated rate of overall stenoses (intention-to-treat analysis) at 1 year showed a significant reduction in patients receiving trapidil and ticlopidine (group 2) as compared with heparin (33 vs. 57%; P =.047). There was no difference in the estimated 1-year rate of type 1 stenoses between the two groups, but there was a significant reduction in type 2 stenoses (group 1: 58%, group 2: 19%; P =.016). The treatment effect continued after withdrawal of the drugs and was accompanied by a decreased incidence of rebleeding. The study demonstrates that the incidence of type 2 stenosis of the transjugular shunt can be reduced by combined inhibition of platelet aggregation and PDGF activity. The findings may be of relevance not only for the transjugular shunt, but also for other stent applications, e.g., vascular and biliary, as well as for bypass and shunt surgery.

Drug Therapy, Combination↗

PubMed1988

Effects of trapidil-derivatives on calcium channel currents in isolated ventricular cells from mice.

A single glass micropipette voltage clamp technique with intracellular dialysis was used to study the effects of the trapidil derivatives AR 12-456 and AR 12-463 on Ca channel currents carried by Ba2+ in isolated ventricular cells from mice hearts. Inspite of a more potent inhibition of the cAMP phosphodiesterase from heart (Bartel et al. 1985) a reversible Ca channel blocking action of both compounds could be observed. The concentration of half maximal block was calculated to about 50 mumol/l for both derivatives tested. Neither a shift in the current-voltage relationships nor a significant change in the potential for half maximal activation was found. The maximal Ba2+-conductance was reduced. The steady state inactivation was shifted towards more negative potentials by application of 100 mumol/l AR 12-463. The decay of the Ba currents was accelerated in the range of the applied test potentials between -20 and +20 mV. It is concluded that the new trapidil derivatives with more potent inhibitory action on cardiac phosphodiesterase than trapidil can block myocardial Ca channels.

Animals↗

PubMed2001

Effects of trapidil on ATPase, lipid peroxidation, and correlation with ultrastructure in experimental spinal cord injury.

The present study was performed to investigate the effect of trapidil on ischemic damage of cells after spinal cord injury. The injury was produced by extradural clip compression of the exposed spinal cord in rats according to Rivlin and Tator. The ten rats in group 1 were used to determine normal findings without any surgery or medication. On the 15 rats in group 2, only six-level laminectomy was performed to determine the influence of the total laminectomy on the biochemical factors measured and the, light and ultrastructural findings. The 15 rats each in groups 3 and 4 were used as trauma and trapidil (40 mg/kg) treatment groups, respectively. The injury actually produced a significant decrease in Na+-K+/Mg+2 ATPase activity of the injured segments as early as 10 min after trauma. Trapidil attenuated Na+-K+/Mg+2 ATPase inactivation in the traumatized rats for 120 min after treatment (P<0.05) and significantly reduced the malone dialdehyde content below that in the traumatized group at all determined times (P<0.05). Light and electron microscopic findings supported the biochemical results.

Adenosine Triphosphatases↗

PubMed2005

Protective effects of trapidil in lung after abdominal aorta induced ischemia-reperfusion injury: an experimental study.

UNLABELLED: We aimed to investigate the protective effects of trapidil after the occlusion of abdominal aorta and the reperfusion injury in lung. Eighteen New Zealand albino rabbits were used in the study. In six animals [group 1, ischemia-reperfusion (IR) group], the abdominal aorta was exposed and a microvascular clamp was placed in the infrarenal abdominal aorta for 60 min. After the ischemic period, the microvascular clamp was removed and reperfusion was provided for 2 h. After the reperfusion period, the lungs were removed carefully and specimens were prepared for histopathological and biochemical studies in appropriate conditions. In group 2 (study group), trapidil (Rocarnal, Rentschler-UCB GmbH, Kerpen, Germany) was administered intraperitoneally as a single dose 1 h prior to trial, the IR procedure was performed and lung specimens were prepared similar to group 1. In group 3 (sham group), the infrarenal abdominal aorta was exposed and lung specimens were prepared for histopathological and biochemical studies at the end of the study. Histopathological changes, malondialdehyde (MDA), nitric oxide (NO) and total sulfhydryl group (T-SH) levels were evaluated. There was a statistical difference between the IR group and study group regarding NO and MDA levels (P < 0.05 and P < 0.01, respectively), but this was not detected between the IR group and the sham group (P > 0.05). There was no statistical difference among the three groups regarding T-SH levels (P > 0.05). While a statistical difference was found between the sham group and study group in the NO level (P < 0.05), no statistical difference was found in the MDA level (P > 0.05). There was a statistical difference in interstitial edema, PMN infiltration and hemorrhage scores among the groups (P < 0.05). There was a statistical difference between the IR group and study group in PMN infiltration (P < 0.05), but this was not detected between the groups in interstitial edema and hemorrhage scores (P > 0.05). There was a statistical difference between IR group and sham group in interstitial edema, PMN infiltration and hemorrhage scores (P < 0.05). Statistical difference was found between the sham group and study group in interstitial edema and hemorrhage scores (P < 0.05), but not in PMN infiltration (P > 0.05). CONCLUSIONS: Infrarenal abdominal aortic occlusion and reperfusion causes lung injury. We conclude that trapidil has preventive effects in the lung tissue after IR injury.

Animals↗

PubMed1995

Effects of trapidil on the PGI2 and TXA2 synthesis in human umbilical veins perfused in vitro.

Current therapeutical concepts for prophylactic treatment of preeclampsia are based on the hypothesis that this pathological state is mainly due to a functional imbalance between vascular prostacyclin (PGI2) and thromboxane A2 (TXA2) biosynthesis. The influence of Trapidil on PGI2 and TXA2 formation was studied by in vitro perfusion of human umbilical veins by measuring the production of the metabolites 6-keto-PGF1 alpha and TXB2, respectively, in the perfusates using Enzyme-Immunoassay. The basal production of 6-keto-PGF1 alpha was 90.6 pg/mL/cm of vessel wall, whereas TXB2 formation attained a rate of 7.5 pg/mL/cm. The addition of Trapidil to the perfusate resulted in a significant stimulation of PGI2 production but apparently does not exhibit any effect on TXB2 generation. These data support the suggestion that Trapidil may act by increasing the ratio of PGI2/TXA2 in favor of the antiaggregatory/vasodilatory PGI2.

6-Ketoprostaglandin F1 alpha↗

PubMed1976

[Modification of the isoprenaline-induced myocardial necrosis using trapidil].

Trapidil increases the isoprenalin-induced necrosis of the myocardium in the rat. In the paper is referred to the importance of the term of application in relation to the application of the infarcting noxa. Trapidil has a particularly unfavourable effect, if it is given after isoprenalin. The shift of the relation from the oxygen requirement to the oxygen supply by beta-adrenergic stimulation is regarded as an equivalent for the acute ischaemia. The authors see a connection between the phosphodiesterase-inhibiting activity of trapidil and the influence of the size of necrosis after the application of isoprenalin in the rat. These findings have also clinical importance, as the area of indication explicitly includes the application after fresh myocardial infarction and in acute pectanginous attack.

Animals↗

PubMed1992

Pharmacokinetics of trapidil (Rocornal) in patients with chronic liver disease.

The pharmacokinetics of trapidil (Rocornal, Deutsches Hydrierwerk Rodleben GmbH) were studied in 15 patients with chronic liver disease (12 patients with hepatic cirrhosis, 2 patients with alcoholic fatty liver, one patient with liver fibrosis). Trapidil was given orally (200 mg, Rocornal dragees 100 mg) as well as intravenously (100 mg) in random order. Serum samples were analyzed for trapidil by HPLC. The pharmacokinetic parameters were compared with the parameters of 12 healthy volunteers, investigated by Weiss [1991]. Total plasma clearance was decreased significantly in patients with hepatic cirrhosis (99.6 ml/min vs 273.1 ml/min in controls and 255.3 ml/min in patients with non cirrhotic liver disease). However, there was no difference in clearance between patients with compensated and patients with decompensated cirrhosis. Clearance and aspartate aminotransferase activity correlated inversely. In addition, in some of the patients suffering from portal hypertension delayed absorption was observed, but the difference did not reach statistical significance. The volumes of distribution were significantly lower in patients with non alcoholic cirrhosis (19.9 l vs 36.8 l in controls and 41.0 l in patients with alcoholic cirrhosis). It might be concluded from this study, that dosage adjustments are necessary in treatment of patients with cirrhosis. In patients suffering from portal hypertension an intravenous administration should be prefered.

Chromatography, High Pressure Liquid↗

PubMedDate not supplied

The trapidil derivative AR 12456 protects against serum hyperlipidemia in guinea pigs.

The administration of the trapidil derivative AR 12465 (5 mg/kg body weight) intraperitoneally to hypercholesterolemic guinea pigs caused a stronger reduction in serum total cholesterol (TC) than trapidil (20 mg/kg, i.p.) or a vehicle injection (saline with 5% ethanol i.p.). The stronger reduction of TC is caused by a lower level in the sum of all beta-migrating lipoproteins and an enhanced level of high-density lipoprotein. The levels of free and esterified cholesterol were not changed in kidney and left cardiac ventricle, but significantly enhanced (P less than 0.05) in the liver of all groups fed a cholesterol-rich diet. The elevation in liver cholesterol was higher in the group treated with AR 12456 than in the group treated with trapidil or with vehicle. The treatment with AR 12456 diminished the ratio TXB2/6-keto-PGF1 alpha for the capacity of aorta to form these prostanoids. In conclusion, our data show that AR 12456 has a strong antilipidemic action in guinea pigs fed a cholesterol-rich diet.

3',5'-Cyclic-AMP Phosphodiesterases↗

PubMed1991

[Modification of pulmonary hypertension in patients with chronic obstructive lung diseases by trapidil (Rocornal) in an acute trial].

Acute effects of Trapidil (Rocornal, Deutsches Hydrierwerk Rodleben) on pulmonary hemodynamics were studied in 47 patients. A marked decrease of pulmonary artery pressure, pulmonary vascular resistance and of right ventricular stroke work at rest and during exercise in different degrees of severity of pulmonary hypertension was shown. Especially the influence on stable pulmonary hypertension is of interest, but there was no statistical significance during exercise because of the small number of patients. Considerable objective or/and subjective side effects were not noticed. Possible multifactorial mechanisms of these effects including the left ventricular function and the role of prostaglandins are discussed. The effect of trapidil is compared with other investigated pulmonary vasodilators, such as nitrates and nifedipine. Because of hitherto there are no other studies with Rocornal in patients with COPD, further acute studies and placebo controlled long term studies with monitoring of pulmonary hemodynamic are necessary. Than it will be possible to clarify the role of trapidil in therapeutical concepts of pulmonary hypertension.

Adult↗

PubMed1990

[Clinical utility of long-term administration of trapidil (MDR-1865) in the treatment of diabetic retinopathy].

In order to investigate the usefulness of prolonged administration of trapidil in the treatment of diabetic retinopathy, a follow-up study was carried out after the end of a placebo-controlled, double-blind study of the drug in case of the trapidil-treated group who continued to be treated with 300 mg/day of trapidil (Rocornal) (TT group) and those of the placebo group who were not given any treatment after the end of the study (PP group). The TT group was significantly superior or tended to be superior to the PP group in improvement of hard exudates, retinal hemorrhages and soft exudates, and also in improvement of capillary microaneurysms on fluorescein fundus angiography. In the course of diabetic retinopathy by the global evaluation of findings in individual cases, the TT group was significantly superior or tended to be superior to the PP group. Photocoagulation was performed on 20 (28%) of 72 eyes of the PP group and 13 (19%) of 68 eyes of the TT group, with the mean interval to photocoagulation being 7.2 months for the PP group and 14.0 months for the TT group. There was a significant difference between the 2 groups in terms of the interval to photocoagulation. Randomized fundus photographic evaluation of the findings by the central evaluation committee showed that the TT group was significantly superior or tended to be superior in improving retinal hemorrhages, soft exudates and leakage of fluorescein dye, and was also significantly superior or tended to be superior in relation to the course of the retinopathy, which was consistent with the evaluation by the attending ophthalmologists.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗

PubMed1985

Trapidil and other 5-triazolo-(1, 5-alpha)-pyrimidine derivatives as calcium channel blockers in 108CC5 cells.

The action of trapidil (RocornalR) and its derivatives AR 12-456 and AR 12-160 on the inward calcium current (ICa) was studied in mouse neuroblastoma x rat glioma hybrid cells of the line 108CC5 under voltage clamp conditions by means of a suction pipette method. A dissociation constant of the calcium channel-trapidil complex of 277 microM was estimated for the initial inhibition of ICa by trapidil. Half maximal block of ICa was produced by 80 +/- 20 microM AR 12-456 and 500 +/- 150 microM AR 12-160.

Animals↗

PubMed1988

Influence of the antianginal drug trapidil and its derivative AR 12463 on arachidonic acid liberation and thromboxane formation in thrombin-stimulated platelets.

The 5,7-disubstituted s-triazolo(1,5-a)pyrimidines (TPs) trapidil and AR 12463 inhibited the thrombin-induced Thromboxane (TX) formation in washed human platelets in a concentration-dependent manner (Ic50:trapidil 410 mumol/l and AR 12463 9 mumol/l). The arachidonic acid (AA) liberation measured in parallel was unchanged or only reduced to a small extent. The present study shows that the inhibition of TX formation by trapidil and AR 12463 is independent of AA liberation of platelets.

Antihypertensive Agents↗

PubMed1987

Gas chromatographic evaluation of trapidil and its desethyl metabolite in biological fluids for pharmacokinetic and bioavailability investigations.

This paper describes a suitable and cost-saving method for quantitative analysis of trapidil (5-methyl-7-diethylamino-s-triazolo [1,5-a]pyrimidine) and its desethyl metabolite in plasma and urine for pharmacokinetic and bioavailability investigations. Trapidil and desethyl-trapidil were extracted from plasma, concentrated and injected into the gas chromatography without any derivatization process. The authors suggest a series of internal standards. A thermoionic specific detector enables high sensitivity to be achieved, i.e. 20 ng/ml, and good specificity. The method is cost-saving in that it allows about 30 analyses a day to be performed without automatic integrators, and about 50 analyses a day with these integrators.

Biological Availability↗

PubMed1986

[Protective effect of thromboxane A2 synthetase inhibitor (trapidil) on acutely-induced cerebral ischemia].

The experimental study presented was undertaken to evaluate the role of thromboxane A2 contributing to aggravating cerebral ischemia, and to examine the effect of a thromboxane A2 synthetase inhibitor, trapidil on cerebral ischemia. Cerebral ischemia model was induced in 16 week old spontaneously hypertensive rats (SHR) by bilateral common carotid artery ligation (BLCL). Two doses of trapidil 15 mg/kg was intraperitoneally administered one dose 2 hr before and one dose 15 min after BLCL in SHR. While control animals only underwent BLCL. Brain tissue metabolites such as ATP, lactate and pyruvate, brain water content and plasma thromboxane B2 and 6 Keto PGF1 alpha were determined 3 hr after BLCL. Scanning electron microscopic observations were also recorded. ATP concentrations were 1.36 +/- 0.23 n moles/mg wet tissue in the trapidil treated group, 0.61 +/- 0.26 n moles/mg wet tissue in the control group, the difference between the treated and the control being significant (P less than 0.001). Lactate concentrations were 4.70 +/- 1.20 n moles/mg wet tissue in the treated group, 12.17 +/- 8.53 n moles/mg wet tissue in the control group, the difference between the treated and the control being significant (P less than 0.02). Pyruvate concentrations were 0.59 +/- 0.11 n moles/mg wet tissue in the treated group, 0.43 +/- 0.16 n moles/mg wet tissue in the control, the difference was also significant (P less than 0.05). Average water content was 78.87 +/- 0.59% in the treated group, 79.82 +/- 0.33% in the control.(ABSTRACT TRUNCATED AT 250 WORDS)

Adenosine Triphosphate↗

PubMed1982

[Effect of trapidil on prostacyclin formation by rabbit heart tissue].

The release of prostacycline-like compound (PGI2) from the rabbit myocardium was estimated from its ability to inhibit platelet aggregation. Pieces of cardiac tissue were incubated in 0.05% M Tris buffer (pH 8) with arachidonic acid for 10 minutes. The aliquot of incubation medium was added to the rabbit platelet-rich plasma, and PGI2 generation was estimated from the ADP-induced aggregation as compared with antiaggregation activity produced by a known amount of synthetic PGI2. Trapidil (0.7 mM) increased PGI2 generation in the rabbit myocardium from 0.22 +/- 0.03 to 0.41 +/- 0.07 ng/mg wet weight of tissue (n = 7), p less than 0.01), but had no influence on the radioimmunologically assayed content of prostaglandins E and F2 in the incubation medium. Activation effect of trapidil on PGI2 generation in the rat aorta (Kawamura et al, 1980) and rabbit heart (our data), and its inhibitory effect both on the biosynthesis and thromboxan A2 action (Ohnishi et al, 1981) suggest that antiaggregation and coronarolytic actions, positive inotropic and chronotropic effects of trapidil on the myocardium are mediated via local generation of PGI2 and thromboxan A2.

Animals↗

PubMed1995

Fast and reproducible vascular neointima formation in the hamster carotid artery: effects of trapidil and captopril.

Neointima formation was induced in the hamster carotid artery by mechanical intraluminal injury with a catheter covered with roughened dental cement, Neointimal thickening occurred as early as 7 days after denudation and further increased during the next 1 to 2 weeks. Proliferation indices of smooth muscle cells (SMCs) showed the highest proportion of proliferating cells in the media and neointima respectively 1 and 5 days after the vascular injury. Transmission and scanning electron microscopy of damaged carotid artery sections as well as immuno-histochemical stainings of von Willebrand factor (vWF) confirmed that reendothelialization was progressive and already complete on day 14, at which time the neointima formation was almost complete. In order to pharmacologically characterize this model further, the effects on neointima formation of trapidil (triazolopyrimidine), a platelet-derived growth factor (PDGF) antagonist, and captopril, an angiotensin converting enzyme inhibitor, were investigated. Trapidil administered orally twice daily at total doses of 25, 50 and 100 mg/kg/day, started 3 days prior to infliction of injury and up to 7 or 14 days after the catheterization, significantly reduced neointima formation. Captopril administered orally three times daily at a total dose of 100 mg/kg/day, equally reduced neointima formation, with 100 mg/kg/day trapidil being more effective than 100 mg/kg/day captopril 7 days after injury. When the treatment by either one of these drugs was arrested on day 7, neointima formation resumed quickly. The hamster appears to be a small, reproducible and fast model for the study of SMC proliferation, requiring only relatively small amounts of experimental drugs. The model furthermore is sensitive to substances known to reduce neointima formation in other animal models.

Angiotensin-Converting Enzyme Inhibitors↗

PubMed1981

Effects of trapidil on thromboxane A2-induced aggregation of platelets, ischemic changes in heart and biosynthesis of thromboxane A2.

Trapidil inhibited the aggregation of rat platelets and the contraction of the isolated aortic strip of rabbit mainly caused by thromboxane A2, and the thromboxane A2 biosynthesis in rabbit platelets. The drug also reduced ischemic changes in ECG, the incidence of myocardial infarction, histopathological changes and a decrease in serum high density lipoprotein cholesterol, and inhibited an increase in plasma thromboxane B2 and a decrease in plasma 6-keto-prostaglandin F1 alpha content in the animals with an experimental ischemic heart injury caused by the injection of thromboxane A2 into the coronary artery. These findings suggest that trapidil is a new type of a therapeutic agent for ischemic heart disease which not only dilates the coronary artery but also inhibits the actions and biosynthesis of thromboxane A2 and may promote the biosynthesis of prostaglandin I2.

6-Ketoprostaglandin F1 alpha↗