Trapidil determines the fate of RHF rats through inhibition of ER stress.

Pulmonary arterial hypertension is a fatal disease, especially when it causes right heart failure (RHF). However, it is difficult to treat. It has been reported that trapidil (Tra) can improve the redox balance and cardiac conditions. In this study, we investigated the effect of Tra on RHF induced by monocrotaline (MCT) in rats. Male Wistar rats were treated with MCT or Tra. Treatment lasted 28 days, then rats were euthanized after echocardiography and catheterization. Subsequently, lungs and right ventricular myocardia were evaluated by hematoxylin and eosin, Masson, and TUNEL staining. Protein expression was detected by western blotting. We found remarkably expanded right ventricle end-diastolic volume, decreased partial pressure of oxygen (PaO2), increased partial pressure of carbon dioxide (PaCO2), right ventricular systolic pressure, mean pulmonary arterial pressure, lung/body weight, and liver/body weight in the RHF rat group, as well as increases in the apoptosis rate and the expression of endoplasmic reticulum stress (ERS)-related proteins. However, these changes were significantly inhibited by Tra. Our data suggested that inhibition of ERS is essential for improving RHF, and that therapeutic intervention of Tra in RHF rats works by reducing ERS.

Effect of trapidil in myocardial ischemia-reperfusion injury in rabbit.

OBJECTIVES: To evaluate the cardioprotective effects of trapidil on myocardial ischemia-reperfusion injury (MIRI) in rabbits. MATERIALS AND METHODS: Rabbits were subjected to 40 min of myocardial ischemia followed by 120 min of reperfusion. Blood for superoxide dismutase (SOD) and malondialdehyde (MDA) were estimated. At the end of reperfusion, the rabbits were sacrificed and the hearts were isolated for histological examination. An apoptotic index (AI) was determined using the terminal deoxynucleotidyl transferase (TdT)-mediated dUTP nick-end-labeling (TUNEL) method. The expression of apoptosis-related proteins Bax and Bcl-2 was analyzed using immunohistochemistry. Statistical analyses were performed by one-way analysis of variance (ANOVA), P < 0.05 considered statistically significant. RESULTS: Trapidil caused a significant (P < 0.05) increase in SOD activity, as decreased MDA levels and significantly (P < 0.05) reduced the expression of Bax as compared with the ischemia-reperfusion (IR) control group. CONCLUSION: Trapidil may attenuate the myocardial damage produced by IR injury and offer potential cardioprotective action.

Rationale and study design of the OISTER trial: optical coherence tomography evaluation of stent struts re-endothelialization in patients with non-ST-elevation acute coronary syndromes--a comparison of the intrEpide tRapidil eluting stent vs. taxus drug-eluting stent implantation.

BACKGROUND: Drug-eluting stents (DES) have been designed to prevent restenosis, but long-term clinical outcome may be offset by an increased risk of stent thrombosis, which is associated with suboptimal stent implantation or delayed re-endothelialization. DES implantation has also been associated with local persistent endothelial dysfunction. Conversely, Trapidil is a potent anti-inflammatory, vasodilatator and antiproliferative drug and several studies have shown anti-restenotic effects, suggesting substantial clinical benefits through the use of Trapidil-eluting DES. STUDY DESIGN: This is a longitudinal, single-blind, double-arm, randomized multicenter study. Forty patients with non-ST-elevation acute coronary syndromes who present at the index procedure with multivessel coronary disease in the major epicardial coronary arteries will be enrolled. Patients should present a culprit lesion with stenosis 70% or more associated with another stenosis 70% or more in another coronary artery. Patients will be randomized in a 1: 1 fashion to receive either an Intrepide trapidil-eluting stent or a Taxus paclitaxel-eluting stent on the culprit lesion. After 90 days, the nonculprit lesion will be treated with the stent of the opposite randomization arm and optical coherence tomography (OCT) analysis of the index stented segment will be performed. Follow-up angiography, combined with vasomotor analysis of endothelial function by rapid atrial pacing, will be done at 12 months after the index procedure on both stents. To further characterize the status of the endothelium, serum measurement of vascular endothelial growth factor gradient between the aorta and 15 mm distal to the implanted stent will be performed at 12 months. The primary endpoint of the study is to compare stent struts re-endothelialization at 90 days by OCT. The secondary endpoint is to compare angiographic outcome and coronary endothelial function 12 months after the index procedure and to compare clinical outcome at 1 and 2 years between trapidil-eluting DES versus paclitaxel-eluting DES. CONCLUSION: We hypothesize that the utilization of trapidil-eluting DES in the setting of acute coronary syndromes will be characterized by a greater early re-endothelialization associated with an antiproliferative effect offering a similar efficacy with a better safety profile compared with first-generation DES.

Clinical evidence for Japanese population based on prospective studies--linking clinical trials and clinical practice.

"Evidence-based medicine (EBM)" implies effective and high quality practice for patients based on well-grounded medical science. The success of clinical trials in Japan is essential to build original evidence specific for Japanese patients. Based on this concept, we have performed several large-scale clinical trials to provide EBM, including the Japanese Antiplatelets Myocardial Infarction Study [JAMIS; clinical improvement in acute myocardial infarction (AMI) patients with antiplatelet therapy], the Japanese beta-Blockers and Calcium Antagonists Myocardial Infarction (JBCMI; comparison of the effects of beta-blockers and calcium antagonists on cardiovascular events in post-AMI patients), a multicenter study for aggressive lipid-lowering strategy by HMG-CoA reductase inhibitors in patients with AMI (MUSASHI; effects of statin therapy on cardiovascular events in patients with AMI), and the Japanese Primary Prevention of Atherosclerosis with Aspirin for Diabetes (JPAD trial; efficacy of low-dose aspirin therapy for primary prevention of atherosclerotic events in type 2 diabetic patients). The results of these prospective studies were directly linked with clinical practice. We have acquired the know-how of large-scale clinical trials; an important point is to have passion for "buildup evidence specific for the Japanese" and to recruit subjects for enrollment after explaining the significance of "clinical trials for the Japanese".

The role of trapidil on neuronal apoptosis in neonatal rat model of hypoxic ischemic brain injury.

BACKGROUND: Hypoxic ischemic brain injury (HIBI) is a common cause of neonatal mortality and morbidity. Trapidil is an antiplatelet agent and several studies demonstrate the beneficial effect of trapidil in various forms of tissue injury. The effects of trapidil on neuronal apoptosis in HIBI have not been reported previously. AIMS: The aim of this study is to evaluate the effect of trapidil on neuronal apoptosis in neonatal rat model of HIBI. STUDY DESIGN: Seven-day-old Wistar rat pups were subjected to right common carotid artery ligation and hypoxia (92% nitrogen and 8% oxygen) for 2h. They were treated with trapidil or saline either immediately before or after hypoxia. In sham group animals, neither ligation, nor hypoxia were performed. Neuronal apoptosis was evaluated by the terminal deoxynucleotidyltransferase-mediated dUTP nick-end labeling (TUNEL) and caspase-3 staining methods. RESULTS: Trapidil treatment either before or after hypoxia results in significant reduction of the numbers of apoptotic cells in both hemispheres, when it is compared with saline treatment group. The numbers of apoptotic cells in right hemispheres in all groups are significantly higher than that in the left hemispheres. CONCLUSIONS: These results show that trapidil administration either before or after hypoxia reduces neuronal apoptosis and we propose that trapidil may be a novel approach for the therapy of HIBI.

Effects of low dose trapidil on electrical properties of a rat peripheral nerve after crush injury.

BACKGROUND: Trapidil has been shown to possess the protective effects in the treatment of ischemia and reperfusion injury in the peripheral nervous system. The purpose of this study was to determine the effects of low dose trapidil on peripheral nerve regeneration with electrophysiological method. METHODS: The sciatic nerve was compressed for 20 sec by using a jeweler's forceps. Trapidil treatment groups were administrated a single dose of trapidil (8 mg/kg) intraperitoneally just after the injury. Electrophysiological recordings were performed in crush and crush + trapidil treatment groups on the 2nd, 7th, 15th, 30th and 45th days following the nerve injury. RESULTS: EMG recordings on the second day following the crush injury showed low values of compound motor action potentials in the gastrocnemius muscle when compared to normal values obtained in intact animals; also, the values on the second day following the crush injury were significantly different between control and trapidil-treated groups. The action potential values for both groups did not yet reach baseline values at the end of the experiment. There was no difference in the action potential amplitude, area and distal latency values between rats with crush and crush+trapidil on all days. CONCLUSION: We could not prove a neuroprotective effect of a single low dose of trapidil in rat crush injury model using electrophysiological method.

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.

Effect of characteristics of compounds on maintenance of an amorphous state in solid dispersion with crospovidone.

Solid dispersion (SD) of indomethacin with crospovidone (CrosPVP) shows useful characteristics for preparation of dosage forms. This study aimed to determine the types of drugs that could adopt a stable amorphous form in SD. Twenty compounds with various melting points (70-218 degrees C), molecular weights (135-504) and functional groups (amide, amino, carbonyl, hydroxyl, ketone etc.) were prepared in SD with CrosPVP. The CrosPVP SDs were prepared using a mechanical mixing and heating method. Melting point and molecular weight were found to have no influence on the ability of a compound to maintain an amorphous state in SD. All compounds containing hydrogen-bond-donor functional groups existed in an amorphous state in SD for at least 6 months. Infrared spectra suggested an interaction between the functional groups of these compounds and amide carbonyl group of CrosPVP. Compounds without hydrogen-bond-donor groups could not maintain an amorphous state and underwent recrystallization within 1 month. It was suggested that the presence of a hydrogen-bond-donor functional group in a compound is an important factor affecting the stable formation of SD with CrosPVP, which contains a hydrogen-bond acceptor.

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 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.

Modulation of the dissolution profiles from Geomatrix multi-layer matrix tablets containing drugs of different solubility.

A new multi-layer tablet design has recently been proposed for constant drug release: Geomatrix Technology (Jago Pharma, Muttenz, Switzerland). It consists in the application of a drug-free barrier layer on one or both bases of an active core (hydrophilic matrix). The partial coating modulates the core hydration process and reduces the surface area available for drug release. The result is an extended release that draws close to a linear profile. The device was mainly intended for soluble drugs, while an excessive reduction of the release rate may be obtained with drugs of low solubility. In this study a new time-dependent polymeric barrier is proposed to control the release of sparingly soluble drugs. Two different barrier compositions (one swellable and one erodible) are applied on active cores containing drugs of different water solubility, Trapidil, Ketoprofen and Nicardipine hydrochlorides, and the drug dissolution patterns of the different multi-layer devices are compared. During dissolution, the swellable barrier swells and gels, but is not eroded, thus acting as a modulating membrane during the release process. The erodible barrier, instead, is progressively removed by the dissolution medium, exposing in time an increasing extent of the planar surface(s) of the core to interaction with the outer environment and to drug release. Both types of coatings are able to control drug release from the devices: the swellable barrier shows a stronger modulation efficiency and is more suitable to modify the delivery pattern of highly soluble drugs; the erodible barrier shows a time-dependent coating effect that provides better control of the dissolution profile of sparingly soluble drugs.

[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.

The trapidil restenosis trial (STARC study): background, methods and clinical characteristics of the patient population.

Restenosis remains the principal drawback of percutaneous transluminal coronary angioplasty (PTCA) since 30-35% of patients still experience it 6 months after the intervention. Several studies have clearly demonstrated that restenosis is a complex multifactorial process that involves smooth muscle cell (SMC) migration and proliferation in the intimal layer of the coronary artery. Among others, the platelet-derived growth factor (PDGF) seems to play an important role in this process. That is why researches have been made in finding and developing new agents able to inhibit PDGF. Trapidil (triazolopyrimidine) (T), is a potent PDGF inhibitor that has been efficacious in preventing restenosis after balloon angioplasty in the experimental animal and after PTCA in a limited clinical trial. The Trapidil Restenosis Trial (STARC study) is a double blind randomized trial of T 100 mg t.i.d. vs. Aspirin (ASA) 100 mg t.i.d. 360 patients have been enrolled from April 1990 until May 1992, excluding recent myocardial infarctions, thrombolysis, restenotic and venous graft lesions and 302 have terminated follow-up. This paper describes the clinical background, the protocol and baseline data of the patient population including data regarding initial stenosis and type of vessel treated.

New oral system for timing-release of drugs.

Polymeric barriers applied by compression have already been used to control drug release rate from matrix tablets. In this paper, polymeric barrier layers, used to prepare and develop a new device able to release the drug after a programmable period of time, are described. Some matrix core formulations, containing Trapidil or Sodium Diclofenac as a model drug, were dry-coated using either a swellable or an erodible shell. This coating prevents drug release from the core until the polymeric layer is not completely eroded or swollen. The time-lag can be modified by changing the barrier formulation and/or the coating thickness. Also drug release profiles (release rate and kinetics), can be widely modified changing the barrier layer characteristics.

[Modification of pulmonary hypertension in patients with chronic obstructive lung diseases by trapidil (Rocornal) in an acute trial]. / Die Beeinflussung der pulmonalen Hypertension bei Patienten mit chronisch obstruktiven Lungenkrankheiten (COLD) durch Trapidil (Rocornal) im Akutversuch.

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.

Effect of the combination of antiplatelet agents in man: combination of aspirin, trapidil, ticlopidine and dipyridamole.

An in vitro study of how platelet aggregation would be inhibited by the combination of aspirin or ticlopidine irreversibly inhibitory to platelet aggregation and trapidil or dipyridamole reversibly inhibitory, was carried out. The measured 50% inhibition concentrations indicated that aspirin was most inhibitory to collagen-induced platelet aggregation, followed by trapidil, ticlopidine and dipyridamole in decreasing sequence of inhibition. The combination of either aspirin or ticlopidine with trapidil inhibited platelet aggregation more intensely than the combination of either agent with dipyridamole. Thus, in clinical use of aspirin or ticlopidine, it may be expected that the lower dosage of aspirin or ticlopidine with lower frequencies of side effects inhibits platelet aggregation effectively with the combination of trapidil rather than dipyridamole.