Platelet-derived growth factor-induced severe and chronic vasoconstriction of cerebral arteries: proposed growth factor explanation of cerebral vasospasm.

OBJECTIVE: After subarachnoid hemorrhage (SAH), platelet-derived growth factor-BB (PDGF-BB) is secreted in and around the cerebral arteries. To clarify the role of PDGF-BB in the development of vasospasm after SAH, we determined whether PDGF-BB alone can cause long-lasting vasoconstriction of a severity similar to that of vasospasm. In addition, the anti-vasospastic effect of trapidil, an antagonist of PDGF-BB function, was investigated. METHODS: We infused recombinant PDGF-BB (10 microg/mL saline as the vehicle) (n = 14) into the subarachnoid space of rabbits and analyzed alterations in the caliber of the basilar artery using repeated angiography. To study the role of PDGF-BB on the development of vasospasm, trapidil was administered continuously starting 1 hour after SAH, on day 0 (0.63-1.25 mg/kg /h or vehicle) for 47 hours (n = 24), or after the full development of cerebral vasospasm on day 2 (3.0 mg/kg/h or vehicle) for 0.5 hours (n = 17), and alterations in the caliber of the basilar artery were monitored. RESULTS: PDGF-BB caused long-lasting vasoconstriction, with maximum constriction of 56% (P < .001) of the control value (= 100%) on day 2, resembling vasospasm seen after SAH. Prolonged administration of intravenous trapidil, starting soon after SAH, prevented the development of vasospasm in a dose-dependent manner (P < .05, .01, or .001). Intravenous or intra-arterial administration of trapidil significantly dilated vasospasm (P < .01) on day 2, at least transiently. CONCLUSION: PDGF-BB, a growth factor synthesized in the subarachnoid space after SAH, can cause severe and long-lasting vasoconstriction. Significant prevention and resolution of vasospasm can be achieved by the PDGF-BB antagonist trapidil. We propose that excessive production of PDGF-BB, essentially aiming to repair injured arteries, causes cerebral vasospasm. Although the half-life of trapidil in serum may be shorter than that of PDGFG-BB-derived spasmogenic signaling, trapidil is a candidate drug for constructing a new therapeutic modality for preventing and resolving vasospasm.

Influence of systemically given placebo, trapidil and isosorbide dinitrate on norepinephrine-evoked hand vein constriction in healthy subjects.

Since trapidil (CAS 15421-84-8) is able to dilate human hand veins after local intravenous administration, four studies were carried out in healthy male volunteers using the dorsal hand vein compliance technique to test the influence of common systemic single doses of trapidil (200 mg orally, 100 mg intravenously) and isosorbide dinitrate (CAS 87-33-2, 20 mg orally) on norepinephrine (CAS 51-41-2)-evoked hand vein constriction in comparison with oral placebo. Oral placebo and oral trapidil were studied in a randomized double-blind cross-over design in 10 subjects aged 20 to 30 years, and oral isosorbide dinitrate and intravenous trapidil, in a randomized open cross-over design in 8 subjects aged 22 to 29 years. In the three similar studies with oral medications dose-response curves for venoconstriction by locally infused norepinephrine were established before and 1 h, 2 h and 3 h after oral medication and ED50 values of norepinephrine were calculated. The control dose-response curves and ED50 values of norepinephrine did not differ significantly. After oral placebo administration the dose-response curves of norepinephrine did not change significantly, but the ED50 of norepinephrine increased 3 h after placebo (from 12.1 to 31.7 ng/ min), indicating a lessening in norepinephrine effect at this time. After oral trapidil application the dose-response curves of norepinephrine shifted to the left compared with the pre-treatment curve (significantly 2 h after trapidil) and the corresponding curves after placebo with a significant decrease in the ED50 of norepinephrine 3 h after trapidil compared with placebo (from 31.7 to 12.6 ng/ min). After oral isosorbide dinitrate administration the dose-response curves of norepinephrine did not differ significantly from the pre-treatment curve, but they shifted to the left compared with the corresponding curves after placebo (significantly 3 h after isosorbide dinitrate). The ED50 of norephinephrine decreased significantly 2 h after isosorbide dinitrate compared with the pre-treatment value (from 9.4 to 3.3 ng/min) as well as 1 h, 2 h and 3 h after isosorbide dinitrate compared with placebo (from 32.4/21.3/31.7 to 7.3/3.3/6.0 ng/min). Therefore, oral trapidil and isosorbide dinitrate did not weaken norepinephrine-evoked hand vein constriction as expected but strengthened it slightly. Intravenously given trapidil led only to an insignificant short decrease followed by an insignificant increase in permanent venoconstriction due to local norepinephrine infusion. The data suggest that after systemic administration of trapidil or isosorbide dinitrate a hand vein constriction, which could be a reflex consequence of a drug-induced decrease in central venous pressure, exceeds an only discreet direct hand vein dilation.

Effect of locally applied trapidil on norepinephrine- and dinoprost-evoked hand vein constriction in healthy men.

OBJECTIVE: In this study the effect of locally administered trapidil on human hand veins was examined. SUBJECTS: 10 healthy male volunteers aged 20 - 30 years were included. METHOD: The dorsal hand vein compliance technique was used. In a crossover design the influence of locally infused trapidil (mainly 5 - 400 microg/min) on hand veins preconstricted with either norepinephrine (adrenoceptor agonist) or dinoprost (prostaglandin F2alpha) was investigated. Preconstriction reduced the vein diameter by about 80% with continuous local infusion of individually determined doses of norepinephrine in the range 11 - 1,000 ng/min and dinoprost in the range 90 - 5,600 ng/min. Blood pressure, cardiac function (electrocardiogram) and skin temperature of the hand infused were monitored. RESULTS: Locally applied trapidil produced a dose-dependent dilation of hand veins preconstricted with norepinephrine and dinoprost. The corresponding ED50 values of trapidil did not differ significantly on an intraindividual comparison. Clinically important side effects with the drugs used were not observed. CONCLUSIONS: The results indicate that trapidil has a direct dilating action on superficial veins in humans. This effect is apparently achieved without involvement of adrenoceptors or prostanoid receptors in venous smooth muscle.

Trapidil is as effective as isosorbide-dinitrate for treating stable angina pectoris: a multinational, multicenter, double-blind, randomized study.

OBJECTIVE: Nitrates have long been used in the treatment of stable angina pectoris. We set out to show that trapidil, a triazolo-pyrimidine with a mode of action different from that of nitrates, is not inferior to isosorbide-dinitrate (ISDN) in the treatment of this clinical syndrome. PATIENTS AND METHODS: We studied the efficacy of 200 mg trapidil (t.i.d.) vs. ISDN (20 mg b.i.d.) in patients with chronic stable angina treated for 12 weeks. The therapeutic effect was measured in terms of responder rate as change in total exercise time (TET) by at least 60 seconds using the bicycle ergometer test. RESULTS: A total of 648 patients were included in the study. Responder rates in the Per- Protocol (PP) population (n = 529) were 50.4% (n = 133) in the trapidil group and 52.5% (n = 139) in the ISDN group (p = 0.233). As the lower non-inferiority limit (-15%) was clearly excluded from the 95% CI (pp: -10.6%, +6.4%; ITT -9.7%, 5.7%), non-inferiority of trapidil compared to ISDN can be concluded. Trapidil 200 mg t.i.d. combined with short-acting NTG prn as rescue medication over 12 weeks in subjects with chronic stable angina pectoris proved to have similar effects on TET and on other clinical endpoints as ISDN 20 mg b.i.d. The secondary efficacy analyses did not reveal any clinically relevant differences between treatment groups, and were not in conflict with the non-inferiority claim. Patients in the ISDN group had significantly more headache (34.1%; n = 110) compared to those taking trapidil (19.3%, n = 62; p <0.0001). CONCLUSIONS: Overall results of this study show that both drugs are equally effective and safe for the short-term treatment of patients with chronic stable angina pectoris and that trapidil can be considered as therapeutically equivalent to ISDN.

Double-blind randomized multicenter study on the efficacy of trapidil versus isosorbide dinitrate in stable angina pectoris.

BACKGROUND: Trapidil is an inhibitor of phosphodiesterase I-IV with resulting positive lusitropic, vasodilating, and antiplatelet effects. HYPOTHESIS: This study was undertaken to compare the antianginal efficacy of trapidil with that of isosorbide dinitrate (ISDN) in patients with stable angina pectoris. METHODS: We studied 95 patients with stable angina pectoris who were randomized into a double-blind parallel group study with either oral trapidil or ISDN. After a 1-week run-in period and a 2-week wash-out phase, the patients received either trapidil 200 mg t.i.d. (n = 48) or ISDN 20 mg t.i.d. (n = 47) for 12 weeks. All antianginal medication, except sublingual glyceryl trinitrate (GTN), was discontinued during the study. Patients underwent an exercise electrocardiogram on an ergometer bicycle according to a modified Bruce protocol before and at 6 and 12 weeks during treatment. RESULTS: The workload capacity increased from 583 +/- 281 W.min before treatment to 833 +/- 444 W.min after 12 weeks of treatment in the trapidil group (p < 0.01) and from 555 +/- 276 W.min to 827 +/- 361 W.min in the ISDN group (p < 0.01). The anginal attacks per week as well as the use of GTN decreased significantly in both groups. After 12 weeks of therapy, the cumulative ST-segment depression during exercise decreased by 67% in the trapidil patients and by 23% in the ISDN patients. Compared with baseline, the double product at the 75 W level was reduced in both groups after 12 weeks of treatment. Blood pressure and heart rate at rest remained nearly unchanged. Overall, no statistical difference was found between the two study groups. The tolerability was good. CONCLUSION: Oral trapidil therapy is safe and effective in stable angina pectoris and is equivalent to standard therapy with ISDN.

Pharmacokinetics of trapidil, an antagonist of platelet derived growth factor, in healthy subjects and in patients with liver cirrhosis.

1. Pharmacokinetic parameters of trapidil (an antagonist of platelet derived growth factor) were evaluated in 12 healthy male subjects (study I) and in a group of 10 patients with liver cirrhosis (Child B) and five control subjects, respectively (study II). 2. Investigations were carried out after a single dose trapidil (200 mg) and at steady state after application of 200 mg trapidil three times daily for 5 days (study 1) or 4 days (study II). 3. Study I: The concentration-time curves of the terminal elimination phase of trapidil exhibited a slight convexity which might reflect nonlinear kinetics. The AUC of trapidil obtained after the first dose (20.5 [+/- 7.0 s.d.] micrograms ml-1 h) was markedly higher than the AUC determined at steady state (13.2 [+/- 3.8 s.d.] micrograms ml-1 h), the non-parametric 90% confidence intervals of the ratio day 5/day 1 was 0.58-0.73 (point estimator 0.64). 4. Study II: AUC averaged (21.4 [+/- 9.1 s.d.] micrograms ml-1 h) in controls and (34.4 [+/- 14.9 s.d.] micrograms ml-1 h) in cirrhotic patients. The 90% confidence intervals for the difference group 1 vs group 2 was 0.95-2.97 (point estimator 1.48, P = 0.066). At steady state, AUC averaged (13.7 [+/- 5.7 s.d.] micrograms ml-1 h) in controls and (20.8 [+/- 6.8 s.d.] micrograms ml-1 h) in cirrhotic patients (90% confidence intervals group 1 vs group 2: 0.88-2.20 [point estimator 1.45, P = 0.05]). As seen in study I, the AUC of trapidil obtained after the first dose was markedly higher than the AUC determined at steady state, the non-parametric 90% confidence intervals of the ratio day 5/day 1 was 0.48-0.84 (point estimator 0.66) in control subjects and 0.54-0.72 (point estimator 0.64) in cirrhotic patients, respectively. 5. An inverse correlation was seen between the results of the monoethylglycinxilidid (MEGX)-test and the AUC of trapidil (single dose: r = -0.516, P = 0.048; steady state: r = -0.548, P = 0.042). 6. Results of study I and study II indicate an autoinduction of trapidil metabolism after repeated oral doses. Although trapidil elimination is decreased in patients with liver cirrhosis (study II), the elimination half-life at steady state is relatively short (2.4 [+/- 1.1 s.d.] h) and therefore should prevent cumulation of trapidil even in cirrhotic patients.

[Effect of trapidil in prevention of pre-eclampsia and fetal retardation]. / Untersuchungen über den Einfluss von Trapidil zur Prävention von Präeklampsie und fetaler Retardierung.

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.

Trapidil (triazolopyrimidine), a platelet-derived growth factor antagonist, reduces restenosis after percutaneous transluminal coronary angioplasty. Results of the randomized, double-blind STARC study. Studio Trapidil versus Aspirin nella Restenosi Coronarica.

BACKGROUND: Trapidil is an antiplatelet drug with specific platelet-derived growth factor antagonism and antiproliferative effects in the rat and rabbit models after balloon angioplasty. METHODS AND RESULTS: The Studio Trapidil versus Aspirin nella Restenosi Coronarica (STARC) is a multicentric, randomized, double-blind trial to assess the effects of trapidil in angiographic restenosis prevention after percutaneous transluminal coronary angioplasty (PTCA). Patients received either trapidil 100 mg TID or aspirin at the same dosage at least 3 days before angioplasty and for 6 months thereafter. Coronary angiograms before PTCA, after PTCA, and at 6-month follow-up were quantitatively analyzed with manual calipers. Of the initial 384 patients recruited, 254 were evaluable for restenosis analysis (128 trapidil, 126 aspirin). Restenosis, defined as a loss of initial percent gain after PTCA of at least 50% (primary end point), occurred in 24.2% of the trapidil group and 39.7% of the aspirin group (P < .01). A similar result was obtained when restenosis per vessel was considered (trapidil, 23.3%; aspirin, 36.9%; P = .018). Clinical events at follow-up were similar in the two groups except that recurrent angina was significantly more frequent in the aspirin group, 43.7% versus 25.8% in the trapidil group (P < .01). Trapidil was well tolerated: only 6 patients had to discontinue the drug because of side effects, which was not different from the aspirin group. CONCLUSIONS: Trapidil reduces restenosis after PTCA at the dosage of 100 mg TID and favorably influences the clinical outcome thereafter.

[Therapy of ischemic heart disease with Trapidil. Observations with 4,014 patients in medical practice]. / Therapie der ischämischen Herzkrankheit mit Trapidil. Anwendungsbeobachtung an 4,014 Patienten in der ärztlichen Praxis.

METHOD: Within the framework of a user observations study, 4,014 patients with ischemic heart disease were treated with Trapidil and kept under observation for 12 weeks. RESULTS: During the course of therapy, a decrease in the incidence and intensity of attacks of angina pectoris and in the number of weekly short-term nitrate applications was observed. Side effects, most commonly nausea, headache, GI complaints and giddiness, were reported by only 3.8% of the patients. The efficacy of the preparation was assessed to be good or very good in more than 89%, tolerability in more than 90%, of the cases. These results are in accord with the assessment in reports in the international literature to the effect that Trapidil has a good therapeutic action.

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.

[Oral trapidil treatment of Fontaine stage II arteriosclerotic circulatory disorders of the legs--a double-blind study]. / Orale Trapidiltherapie bei arteriosklerotischen Durchblutungsstörungen der Beine im Stadium II nach Fontaine--eine Doppelblindstudie.

In a double blind study altogether 41 patients with obliterating arteriosclerosis at stage II after Fontaine have been treated for 26 weeks either with 3 X 100 mg Trapidil (Rocornal) daily or placebo. In the second half of the study under Trapidil in contrast to placebo a clinically relevant additional increase of the distance of the intermitent claudication was the result. On the other hand, the plethysmographically measured reserve of the arterial blood supply did not show any changes in the two groups. A specific influence of Trapidil on the lipoprotein metabolism is apparently not present, since there appeared favourable influence on the hyperlipoproteinaemia diagnosed in 37 out of 41 patients both under placebo and under Trapidil.