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Airway neutrophilia has been associated with asthma severity and asthma exacerbations. This study attempted to identify biomarkers, pathogenesis, and therapeutic molecular targets for severe asthma in neutrophils using bioinformatics analysis.Fifteen healthy controls and 3 patients with neutrophilic severe asthma were screened from the Gene Expression Omnibus (GEO) database. Based on the analysis of differentially expressed genes (DEGs), functional and pathway enrichment analyses, gene set enrichment analysis, protein-protein interaction network construction, and analysis were performed. Moreover, small-molecule drug candidates have also been identified.Three hundred and three upregulated and 59 downregulated genes were identified. Gene ontology function enrichment analyses were primarily related to inflammatory response, immune response, leukocyte migration, neutrophil chemotaxis, mitogen-activated protein kinase cascade, Jun N-terminal kinase cascade, I-kappaB kinase/nuclear factor-κB, and MyD88-dependent toll-like receptor signaling pathway. Pathway enrichment analyses and gene set enrichment analysis were mainly involved in cytokine-cytokine receptor interaction, the TNF signaling pathway, leukocyte transendothelial migration, and the NOD-like receptor signaling pathway. Furthermore, 1 important module and 10 hub genes (CXCL8, TLR2, CXCL1, ICAM1, CXCR4, FPR2, SELL, PTEN, TREM1, and LEP) were identified in the protein-protein interaction network. Moreover, indoprofen, mimosine, STOCK1N-35874, trapidil, iloprost, aminoglutethimide, ajmaline, levobunolol, ethionamide, cefaclor, dimenhydrinate, and bethanechol are potential drugs for the treatment of neutrophil-predominant severe asthma.This study identified potential biomarkers, pathogenesis, and therapeutic molecular targets for neutrophil-predominant severe asthma.

[1,2,4]Triazolo[1,5-a]pyrimidine is an important heterocyclic scaffold known to have a wide range of pharmacological activities such as anticancer, antimicrobial, anti-tubercular, CB

The results on the in-stent restenosis in the mid-term period after successful coronary arteries chronic total occlusion (CTO) recanalization by the antegrade approach are assessed. The study included 117 patients who underwent coronary artery CTO recanalization for the period from 2009 to 2012. After 6.1 ± 0.9 months (stage К1) and 12.7 ± 1.6 months (stage К2), all patients were examined by coronary angiography, intravascular ultrasound and optical coherence tomography. During the frst half of the year after the CTO recanalization, there was a more frequent in-stent restenosis rate in the right coronary artery (in 25.6 %) as well as a predominance of focal types of restenosis (59.1 % of the total). The incidence of restenosis depending on the DES type varied over a wide range of values (from 0 to 52.4 % in the frst half of the year and from 0 to 41.2 % in the second half of the year). A signifcant increase in the incidence of restenosis was observed after the trapidil eluting stents implantation (52.4 % in the frst half of the year, 26.3 % in the second half of the year) and sirolimus eluting stents (38.9 % in the frst half, 41.2 % in the second half of the year). Our data show that different types of DES differently determine the changes in the vascular lumen during the medium term period after the successful CTO recanalization.

Background: Renal ischemia, followed by reperfusion (I/R) is one of the major causes of Acute Renal Failure (ARF) furthermore it resulted in distant organ dysfunctions. The pathogenesis of I/R is multifactorial.This study was designed to study the effect of trapidil treatment before renal I/R on hepatic and renal function,Material and Method: 30 male Sprague-Dawley rats were submitted to right nephrectomy and divided into three groups: Control group, renal I/R group, renal I/R group received trapidil 14mg/kg 7 days before I/R, 24 hours after reperfusion blood samples were collected for evaluation of: Serum Aspar-tate Aminotransferase (AST), serum alanine aminotransferase (ALT), blood urea nitrogen, serum creatinine, serum Nitric Oxide (NO), Tumor Necrosis Factor-a (TNF-a), Total Anti-oxidant Capacity (TAC), and serum Monocyte Chemoattractant Protein-1 (MCP-1). All animals were scarified, the liver and left kidney were removed to measure renal and hepatic Malond-idhyde (MDA), Glutathione Peroxidase (GPx) and Myeloper-oxidase (MPO), histopathological examination for the left kidneys was performed.Results: Treatment with trapidil (14mg/kg) for 7 days before renal I/R improved renal and hepatic dysfunction as evidenced by significant decrease in blood urea, serum creat-inine, and significant decrease in the activity of AST, ALT as compared to renal I/R group in addition trapidil supplemen-tation resulted in significant decrease in serum, TNF-a, MCP-1 as compared to renal I/R group on the other hand it resulted in significant increase in serum NO and total antioxidant capacity in addition it resulted in significant decrease in the level of renal and hepatic tissue MPO and MDA with signif-icant increase in tissue GPx as compared to renal I/R group these results are confirmed by histopathological findings.Conclusion: Trapidil supplementation before renal I/R can protect the kidney and liver and prevent its damage by increasing NO production with improvement of blood flow, anti-inflammatory and antioxidant effect.

This report outlines the long-term outcome after successful sealing of a coronary perforation with a covered stent in a patient with aspirin allergy.

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.

Platelet-derived growth factor receptor (PDGFR) signaling has been shown to inhibit osteogenesis. However, therapeutic efficacy of inhibiting PDGF signaling to bone regeneration in vivo and the specific mechanisms by which PDGFR signaling inhibits osteogenic differentiation remain unclear. In the present study, we examined the osteogenic effect of inhibiting PDGFR using trapidil, a PDGFR antagonist, in vivo and in vitro, and evaluated its mechanisms. A rat calvarial defect model was analyzed by micro-computed tomography and histology to determine the pro-osteogenic effect of trapidil in vivo. In addition, primary mouse calvarial osteoblast precursors were cultured in osteogenic differentiation medium with trapidil to study the mechanisms. Trapidil greatly promoted bone regeneration in a rat calvarial defect model and osteogenic differentiation of calvarial osteoblast precursors. For the mechanisms, trapidil induced phosphorylation of Smad1/5/9 and mitogen-activated protein kinase (MAPK) leading to enhance expression of Runx2, crucial transcription factor for osteogenesis. The pro-osteogenic effects of trapidil were inhibited by LDN193189, specific inhibitor of bone morphogenetic protein (BMP) receptor, ALK2 and ALK3, and by depletion of ALK3, and treatment with noggin, an antagonist of BMPs. Moreover, trapidil showed a synergistic effect with BMP2 on osteogenic differentiation. In conclusion, trapidil induced BMPR activity through upregulation of BMP signaling, leading to promoted osteogenesis in vitro and in vivo. Attenuated BMPR activity may be involved in the inhibition of osteogenesis by PDGFR signaling.

We previously demonstrated the cardio-protection mediated by the total flavonoid extracted from Dracocephalum moldavica L. (TFDM) following myocardial ischemia reperfusion injury (MIRI). The present study assessed the presence and mechanism of TFDM-related cardio-protection on MIRI-induced apoptosis in vivo. Male Sprague-Dawley rats experienced 45-min ischemia with 12 h of reperfusion. Rats pretreated with TFDM (3, 10 or 30 mg/kg/day) were compared with Sham (no MIRI and no TFDM), MIRI (no TFDM), and Positive (trapidil tablets, 13.5 mg/kg/day) groups. In MIRI-treated rats, high dose-TFDM (H-TFDM) pre-treatment with apparently reduced release of LDH, CK-MB and MDA, enhanced the concentration of SOD in plasma, and greatly reduced the infarct size, apoptotic index and mitochondrial injury. H-TFDM pretreatment markedly promoted the phosphorylation of PI3K, Akt, GSK-3β and ERK1/2 in comparison with the MIRI model group. Western blot analysis after reperfusion also showed that H-TFDM decreased release of Bax, cleaved caspase-3, caspase-7 and caspase-9, and increased expression of Bcl-2 as evident by the higher Bcl-2/Bax ratio. TFDM cardio-protection was influenced by LY294002 (PI3K inhibitor) and PD98059 (ERK1/2 inhibitor). Taken together, these results provide convincing evidence of the benefit of TFDM pretreatment due to inhibited myocardial apoptosis as mediated by the PI3K/Akt/GSK-3β and ERK1/2 signaling pathways.

Oxidative stress injury and apoptosis are the main mechanisms of myocardial ischemia-reperfusion injury (MI/RI). Compounds with anti-oxidant properties can treat MI/RI. Therefore, identification of natural antioxidants such as herbs or botanical drugs is an ideal strategy to develop safe and effective anti-MI/RI drugs. Cardioprotective effects of Ginseng are well documented and are attributable to its anti-oxidant, anti-inflammatory, anti-tumorigenic, anti-arrhythmic, anti-ischemic properties. Ginseng monomer 20

The kidney is considered to be a structurally stable organ with limited baseline cellular turnover. Nevertheless, single cells must be constantly replaced to conserve the functional integrity of the organ. PDGF chain B (PDGF-BB) signaling through fibroblast PDGF receptor-In mice with fluorescent protein expression in renal tubular cells and PDGFRSingle-tubular cell ablation caused the migration and division of dedifferentiated tubular epithelial cells that preceded tubular regeneration. Moreover, tubular cell ablation caused immediate calcium responses in adjacent PDGFRAblated tubular cells are exclusively replaced by resident tubular cell proliferation in a process dependent on PDGFR

Short QT syndrome (SQTS) is a genetic arrhythmogenic disease that can cause malignant arrhythmia and sudden cardiac death. The current therapies for SQTS have application restrictions. We previously found that Mg· (NH(2)CH(2)CH(2)SO(3))2· H(2)O, a taurine-magnesium coordination compound (TMCC) exerted anti-arrhythmic effects with low toxicity. In this study we established 3 different models to assess the potential anti-arrhythmic effects of TMCC on type 2 short QT syndrome (SQT2). In Langendorff guinea pig-perfused hearts, perfusion of pinacidil (20 μmol/L) significantly shortened the QT interval and QTpeak and increased rTp-Te (P

Adenosine and related compounds have been shown to produce atrioventricular (AV) conduction block during acute myocardial ischemia. We investigated the effects of the antianginal drug trapidil, which has been shown to inhibit phosphodiesterase, on AV conduction disturbances in a canine model of acute myocardial ischemia. In 35 anesthetized dogs, the AV node artery was cannulated and perfused with arterial blood. Adenosine (300 µg, 650 µg, or 1000 µg) was injected into the AV node artery. With administration of adenosine at 300 µg, 650 µg, or 1000 µg, the atrio-His (AH) interval was increased by 14.6 ms, 22.3 ms, and 29.7 ms, respectively. The effects of adenosine were potentiated by pretreatment with intravenous dipyridamole (250 µg/kg), an inhibitor of adenosine uptake, but the effects of adenosine were attenuated with intravenous trapidil (3 mg/kg), an inhibitor of phosphodiesterase. AV node artery occlusion resulted in prolongation of the AH interval in 4 of 12 dogs. The ischemia-induced AH prolongation was potentiated with intravenous dipyridamole and attenuated with intravenous trapidil. AV conduction disturbances associated with inferior myocardial infarction may be related in part to endogenously released adenosine, and trapidil may be useful in treating AV block associated with acute AV node ischemia.

The use of drug-eluting stents (DES) allowed the reduction in the need for repeat revascularization. At the culprit site in acute myocardial infarction patients treated with first-generation DES, the interaction between the eluted drug and the underlying necrotic core may generate different patterns of pathologic vessel response and delayed healing. A new generation DES intrepide elutes trapidil. Its modes of action are neither cytotoxic nor cytostatic, and may promote normal re-endothelialization. Due to its high resolution, optical coherence tomography (OCT) allows accurate detection of thrombus deposition and stent strut coverage at follow-up. Intravascular ultrasound (IVUS) has enhanced tissue penetration and provides information on vessel remodeling. Using OCT and IVUS, we evaluated the intravascular morphology of the culprit vessel, the acute and intermediate result of novel DES implanted to treat an ST-segment elevation myocardial infarction.

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.

Chronic hyperparathyroidism (HPT) is a common cause of metabolic bone disease. These studies investigated the underlying cellular and molecular mechanisms responsible for the detrimental actions of elevated parathyroid hormone (PTH) on the skeleton. Bone biopsies from hyperparathyroid patients revealed an association between parathyroid bone disease and increased numbers of bone marrow mast cells. We therefore evaluated the role of mast cells in the etiology of parathyroid bone disease in a rat model for chronic HPT. In rats, mature mast cells were preferentially located at sites undergoing bone turnover, and the number of mast cells at the bone–bone marrow interface was greatly increased following treatment with PTH. Time-course studies and studies employing parathyroid hormone–related peptide (PTHrP), as well as inhibitors of platelet-derived growth factor-A (PDGF-A, trapidil), kit (gleevec), and PI3K (wortmannin) signaling revealed that mature mast cell redistribution from bone marrow to bone surfaces precedes and is associated with osteitis fibrosa, a hallmark of parathyroid bone disease. Importantly, mature mast cells were not observed in the bone marrow of mice. Mice, in turn, were resistant to the development of PTH-induced bone marrow fibrosis. These findings suggest that the mast cell may be a novel target for treatment of metabolic bone disease. © 2010 American Society for Bone and Mineral Research.

BACKGROUND: Trapidil, an antianginal drug with inhibitory effects on platelet-derived growth factor (PDGF), has been shown to reduce reactive fibrosis in models of central nervous system injury. Therefore, we evaluated trapidil's effects on fibroblast activity, Schwann cell proliferation, and PDGF receptor levels in rats after transection and anastomosis of the sciatic nerve. We also evaluated the effect of Schwann cell proliferation on regeneration of anastomosed sciatic nerves. METHODS: Wistar rats were randomly divided into 3 groups. Group 1 (N?10) was used to determine normal peripheral nerve morphology (via light and electron microscopy) and PDGF receptor levels. Group 2 (N?20) underwent sciatic nerve anastomosis after nerve transection to examine the influence of the surgical procedure on PDGF receptor levels and the microscopic findings. Group 3 (20 rats) received a single intraperitoneal dose of trapidil (40 mg/kg) immediately after the surgical procedure to investigate its effects on fibroblast activity, Schwann cell proliferation, and PDGF levels. RESULTS: PDGF-A and PDGF-B receptor levels were lower in group 3, the trapidil-treated group, than group 2 on all posttransection days examined. Ultrastructural analysis revealed that group 3 also had lower levels of fibroblast activity and Schwann cell proliferation than group 2. However, the peripheral nerve ultrastructure and degree of axonal regeneration were similar between groups 2 and 3 at 14 days posttransection. CONCLUSIONS: Trapidil treatment significantly decreased reactive fibrosis and PDGF receptor expression after peripheral nerve injury, and thus, may be useful therapeutically. These results also suggest that Schwann cells alone are not effective in promoting neurite formation. © 2008 by Lippincott Williams & Wilkins.

Because conventional absorption models often fail to describe plasma concentration-time profiles following oral administration, empirical input functions such as the inverse Gaussian function have been successfully used. The purpose of this note is to extend this model by adding a first-order absorption process and to demonstrate the application of population analysis using maximum likelihood estimation via the EM algorithm (implemented in ADAPT 5). In one example, the analysis of bioavailability data of an extended-release formulation, as well as the mean dissolution times estimated in vivo and in vitro with the use of the inverse Gaussian function, is well in accordance, suggesting that the inverse Gaussian function indeed accounts for the in vivo dissolution process. In the other example, the kinetics of trapidil in patients with liver disease, the absorption/dissolution parameters are characterized by a high interindividual variability. Adding a first-order absorption process to the inverse Gaussian function improved the fit in both cases.

Azolopyrimidines are biologically interesting molecules as indicated by the large number of recent papers dealing with synthesis, chemistry, and pharmacology of these molecules [1 – 9]. For example, zaleplon (1), a pyrazolopyrimidine, is a hypnotic agent licensed for treatment of insomnia [10], and allopurine (2), a 4-hydroxypyrazolopyrimidine used in the treatment of hyperuricemia and gout, inhibits de novo purine biosynthesis and xanthine oxidase [11] (Fig. 1). The triazolopyrimidine trapidil and its derivatives are coronary vasodilating and potential antiatherosclerotic drugs [12 – 14]. Also, pyrimidobenzimidazoles have been found to be of pharmacological interest; for example, pyrimido[1,2-a]benzimidazoles have been described as anti-hypertensive [15], anti-diabetic [16] and anti-inflammatory [17].

A hipertensão arterial pulmonar (HAP) é uma doença progressiva caracterizada por aumento da resistência vascular pulmonar e consequente aumento da pós-carga do ventrículo direito, levando à insuficiência ventricular direita e morte. Distúrbios entre vasodilatadores e vasoconstritores são consequências agravadas por desequilíbrios redox presentes na HAP. O Trapidil é uma droga antiplaquetária, antimitogênica e inibidora de fosfodiesterase usada atualmente na clínica para prevenir a restenose. Estudos recentes também descrevem a capacidade do fármaco de melhorar o equilíbrio redox, diminuindo a peroxidação lipídica e formação de superóxido. Nesse sentido, o objetivo desse trabalho foi verificar os efeitos do Trapidil no modelo de hipertensão arterial pulmonar induzida por monocrotalina, avaliando o estado redox e o remodelamento cardíaco. Para isso, foram utilizados ratos Wistar com 5 semanas de idade divididos em quatro grupos: Controle, Controle + Trapidil, Monocrotalina e Monocrotalina + Trapidil. A HAP foi induzida com uma injeção intraperitoneal de monocrotalina 60 mg/kg no dia 0. O tratamento com o Trapidil começou no dia 7 (5 mg/kg/dia – Experimento 1 ou 8 mg/kg/dia – Experimento 2) até o dia 14, quando os animais foram sacrificados logo após ecocardiografia e cateterismo do ventrículo direito. O coração foi isolado, separado em ventrículo direito e esquerdo (VD e VE), pesado e armazenado para análises de expressão proteica (SERCA, Fosfolambam, p-Fosfolambam e RyR) e bioquímica do estado redox. Observamos aumento da congestão hepática e da hipertrofia do VD nos animais que receberam monocrotalina. O Trapidil (5 mg/kg/dia) foi capaz de reduzir a congestão hepática, entretanto não reduziu a hipertrofia do VD. A pressão sistólica e as derivadas pressão/tempo positiva e negativa se mostraram aumentadas nos animais com indução da HAP, enquanto que os animais que receberam o fármaco (8 mg/kg/dia) apresentaram derivadas pressão/volume positivas com valores não diferentes do grupo Controle. Houve aumento dos diâmetros diastólico e sistólico do VD nos grupos que receberam monocrotalina, indicando dilatação da câmara. Já o tratamento com Trapidil (5 mg/kg/dia) reduziu esses diâmetros. Funcionalmente, observamos diminuição da fração de encurtamento, razão pico E/A e TAPSE nos grupos que receberam monocrotalina, sendo que o fármaco não modificou esses parâmetros. A análise do estado redox demonstrou maior lipoperoxidação e atividade da glutationa peroxidase nos grupos monocrotalina, já o tratamento com Trapidil (8 mg/kg/dia) reduziu a atividade de NADPH oxidases e aumentou a razão GSH/glutationas totais. A expressão proteica de Fosfolambam no VD aparece diminuída nos grupos monocrotalina; a expressão proteica de SERCA e RyR aparece aumentada nos grupos que receberam Trapidil (8 mg/kg/dia). Os dados observados sugerem que o Trapidil induz uma melhora do remodelamento cardíaco direito em modelo de HAP induzida por monocrotalina. A melhora do balanço redox e maior expressão de SERCA e RyR sem aumento da derivada pressão/volume positiva indica que os animais tratados com o fármaco podem estar mais preparados para enfrentar a progressão da doença. Pulmonary arterial hypertension (PAH) is a progressive disease characterized by increased pulmonary vascular resistance and consequent increased afterload of the right ventricle, leading to right ventricular failure and death. PAH disorders between vasodilators and vasoconstrictors are consequences aggravated by redox imbalances present in the disease. Trapidil is an antiplatelet, phosphodiesterase’s inhibitory and antimitogenic drug currently used in the clinic to prevent restenosis. Recent studies also describe the ability of Trapidil to enhance the redox balance by decreasing lipid peroxidation and superoxide formation. In this way, the objective of this study was to assess the effects of Trapidil in pulmonary arterial hypertension model induced by monocrotaline, evaluating the redox state and cardiac remodeling. Male Wistar rats (5 weeks old) were divided into four groups: Control; Control + Trapidil; Monocrotaline; Monocrotaline + Trapidil. PAH was induced with an intraperitoneal injection of monocrotaline 60mg/kg on day 0. Treatment with Trapidil started on day 7 (5 mg / kg / day - Experiment 1 or 8 mg / kg / day - Experiment 2) until day 14, when the animals were sacrificed after echocardiography and catheterization of the right ventricle. The heart was isolated, separated into right and left ventricle (RV and LV), weighed and stored for protein expression analysis (SERCA, phospholamban, p-phospholamban and RyR) and biochemistry analysis of redox balance. We observed increased hepatic congestion and RV hypertrophy in animals that received monocrotaline. Trapidil (5 mg/kg/day) was able to reduce the hepatic congestion, though not reduced RV’s hypertrophy. The systolic pressure and positive and negative pressure/time derivatives have shown increased in animals with induced PAH, whereas animals given the drug (8 mg/kg/day) positive pressure/time derivative values were not different compared to Control group. We also observed an increase of RV’s diastolic and systolic diameters in the groups that received monocrotaline, indicating dilatation of the chamber, as treatment with Trapidil (5mg/ kg/day) reduced these diameters. Functionally, we observed a decrease of fractional shortening, peak E/A ratio and TAPSE in the groups that received monocrotaline, whereas Trapidil did not modify these parameters. The analysis of the redox state showed higher lipid peroxidation and glutathione peroxidase activity in groups with induced PAH. Treatment with Trapidil (8 mg/kg/day) reduced the activity of NADPH oxidases and increased the GSH/total glutathiones ratio. Protein expression of phospholamban in RV appears diminished in monocrotaline groups; protein expression of RyR and SERCA appears enhanced in the groups treated with Trapidil (8 mg/kg/day). The observed data suggest that the Trapidil induces an improvement in right ventricle remodeling in the model of PAH induced by monocrotaline. The improvement in the redox balance and increased expression of RyR and SERCA without increasing the positive pressure/volume derivative indicates that animals treated with the Trapidil may be more prepared to face the progression of the disease.

We examined the electrophysiological effects of trapidil on the ionic currents influencing the repolarization and on the transient inward current (IT;) that can cause triggered arrhythmia using the whole-cell patch-clamp technique in guinea pig ventricular myocytes. Trapidil shortened the action potential duration (APD) and increased the delayed rectifier potassium current (I K ) in a concentration-dependent manner. The effect of trapidil on the rapidly and slowly activating components of I K (I K r and I K s , respectively) was studied by the envelope of tails test. Trapidil failed to affect I K r and selectively enhanced I K s . Trapidil increased the amplitude of the L-type Ca 2 + current (I C a , L ), with an acceleration of its inactivation, whereas isoproterenol, a β-adrenoceptor agonist, increased the amplitude of the I C a , L in a different manner. Isoproterenol activated I T i ; however, trapidil not only failed to facilitate I T i but also suppressed isoproterenol-induced IT;. The inhibitory effect of trapidil on isoproterenol-induced I T i is at least partly via a reduction of Ca 2 + overload through an acceleration of I C a , L inactivation and/or a sarcoplasmic reticulum (SR) Ca 2 + channel modulation. These results suggest that trapidil does not prolong the QT interval and has an antiarrhythmic effect on arrhythmias elicited by triggered activity secondary to Ca 2 + overload at much higher concentrations than clinical concentration.

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.

The objective of this study was to investigate the effect of trapidil 200 mg t.i.d. in preventing the occurrence of death, of myocardial infarction and the need for repeat revascularization at 12 months after balloon PTCA with or without stenting. Coronary restenosis after stenting is still a major drawback of percutaneous coronary interventions (PCI) for 30-40% of patients. Trapidil has been shown to prevent restenosis after PTCA. Eligible patients were randomized to placebo or oral trapidil 200 mg t.i.d. at least 48 hr before PCI and continuing 6 months after a successful balloon angioplasty or stent implantation. Aspirin was given to all patients, and ticlopidine 250 mg b.i.d. to those who received a stent for 4 weeks. In a randomized subgroup of 216 patients, quantitative coronary angiography was performed also at 6-month follow-up. Out of the 933 patients enrolled, primary endpoint incidence was 20.3% in trapidil and 18.0% in placebo (P = 0.37). When recurrence or deterioration of angina was added to the combined endpoint, incidence was 27.4% in trapidil and 23.0% in placebo (P = 0.12). Restenosis rate in patients with 6-month angiography was 25.0% in trapidil arm vs. 30.1% in placebo (P = 0.43). Stent restenosis rate was similar in patients randomized to trapidil or placebo (30.2% vs. 23.8%, respectively; P = 0.44), while in patients treated with balloon angioplasty, it was lower in trapidil (17.1%) than in placebo (40.0%; P = 0.03). Oral trapidil 200 mg t.i.d. for 6 months in addition to aspirin did not influence the occurrence of major cardiac events after coronary angioplasty with or without stenting. In a prespecified subgroup of 191 patients treated with balloon angioplasty only, trapidil reduced angiographic restenosis.

Corticosteroids are used to reduce the oedema and prevent scar tissue formation of the upper airways by their ability to inhibit influx of inflammatory cells, limit capillary permeability and block collagen synthesis in the early stages of wound healing. Triazolopyrimidine (Trapidil) 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, with its vasodilator and NO releasing effect may have some potential to diminish the tissue injury. This study was carried out to evaluate the effects of trapidil (triazolopyrimidine) on lipid peroxidation and nitric oxide in the corticosteroid-impaired healing of tracheal anastomoses. Thirty-four adult Wistar rats were divided into five groups. The animals underwent tracheal transection and primary anastomoses. The groups were assigned as follows: group I, control, (GI, n = 6); group II, sham, (GII, n = 6); group III, dexamethasone, 0.1 mg kg−1 twice daily intramuscularly, (GIII, n = 8); group IV, trapidil, 6 mg kg−1 twice daily intraperitoneally (GIV, n = 7); group V, dexamethasone, 0.1 mg kg−1 plus trapidil, 6 mg kg−1 twice daily (GV, n = 7), for 1 week. After 1 week, anastomotic healing was assessed by measurement of bursting pressure, evaluation of histopathology, measurement of MDA and nitrite/nitrate levels. In GIII, GIV and GV bursting pressures resulted in significantly reduced anastomotic strength compared to the controls (p

Despite its nephrotoxic potential, the aminoglycoside antibiotic gentamicin (GM) is still considered to be an important agent against life-threatening infections. The goal of reducing or protecting against its nephrotoxicity has attracted much effort and attention during the last decade. This article reviews some of the literature published during the last decade on the effects of agents that ameliorate or augment GM nephrotoxicity. Notable among the ameliorating agents are antioxidant agents. These include different classes of compounds that include beta blockers (e.g. carvedilol), superoxide dismutase mimetic agents (e.g. M40403), hormones (e.g. melatonin), iron chelators (e.g. deferrioxamine), vitamins (vitamin C and E) and medicinal plants (e.g. garlic). Other ameliorating agents include antibiotics (e.g. ceftriaxone), antiplatelet drugs (e.g. trapidil) and Ca++ agents that may augment GM nephrotoxicity include cyclosporin and the Ca++-channel blocker verapamil.

Background: Trapidil has various properties including vasodilatation, inhibition of lipid peroxidation and platelet aggregation as well as, and reduction of, the inflammatory response to injury. The aim of the present study was to investigate the effects of trapidil on dexamethasone-impaired colonic anastomotic healing in an experimental rat model. Methods: Twenty-four Wistar rats underwent colonic transsection and primary anastomosis. Rats were divided into four groups of six: group 1 (G1), control; group 2 (G2) trapidil, 8 mg/kg per day intravenously; group 3 (G3) dexamethasone, 0.1 mg/kg per day intramuscularly; and group 4 (G4) dexamethasone 0.1 mg/kg intramuscularly and trapidil 8 mg/kg intravenously per day, for 1 week. Anastomotic bursting pressure, hydroxyproline level, histopathological grading, malondialdehyde and nitrite/nitrate levels were determined. Results: Dexamethasone-impaired anastomotic healing was found to be improved by trapidil administration in terms of anastomotic bursting pressure and hydroxyproline content (P = 0.026, and P = 0.017). In addition, histopathological examination revealed an increase in fibroblast proliferation and collagen deposition (P = 0.004, and P = 0.015) and a decrease in leucocyte infiltration (P = 0.004). Moreover, serum nitrite/nitrate and malondialdehyde levels decreased when G3 was compared to G4 (P