Topical Skin Application of Small-Molecule Antiplatelet Agent against Pressure Injury in Rat Models.

Due to prolonged forced positioning, the incidence of intraoperative pressure injuries is high. This study aimed to explore the impact of small-molecule antiplatelet drugs on pressure injuries by locally applying them before an injury occurs. In the first part of this study, water-soluble tracers with different molecular weights were applied to normal and early-stage pressure-injured skin. Through digital cameras, spectrophotometers, and histological observations, the penetration of tracers into the epidermis was clarified. In the second part of this study, a water-soluble antiplatelet drug called Trapidil (molecular weight = 205 Da) was applied to the left side of the back of a rat before, during, and after compression, and the contralateral side served as a non-intervention control group. The differences in pressure injuries between the two groups were observed through a digital camera, an ultraviolet camera, and temperature measurement, and skin circulation and perfusion were assessed via an intravenous injection of Evans Blue. The first part of this study found that water-soluble tracers did not easily penetrate normal skin but could more easily penetrate pressure-damaged skin. The smaller the molecular weight of the tracer, the easier it penetrated the skin. Therefore, in the next step of research, water-soluble drugs with smaller molecular weights should be selected. The second part of this study found that, compared with the control group, the occurrence rates and areas of ulcers were lower, the gray value was higher, and the skin temperature was lower in the Trapidil group (p < 0.05). After the intravenous Evans Blue injection, skin circulation and perfusion in the Trapidil group were found to be better. In conclusion, this study found that the topical skin application of a small-molecule antiplatelet agent may have significant effects against pressure injuries by improving post-decompression ischemia, providing new insights into the prevention and treatment of intraoperative pressure injuries.

Identification of potential biomarkers and pathogenesis in neutrophil-predominant severe asthma: A comprehensive bioinformatics analysis.

BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSION: This study identified potential biomarkers, pathogenesis, and therapeutic molecular targets for neutrophil-predominant severe asthma.

An Overview on Synthetic and Medicinal Perspectives of [1,2,4]Triazolo[1,5-a]pyrimidine Scaffold.

[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, CB2 cannabinoid agonists, feticide, and adenosine antagonists. Several clinical trials and marketed drugs such as Trapidil, Essramycin, Pyroxsulam, DSM-265, Flumetsulam, GNF-6702, and Cevipabulin indicate the potential of [1,2,4]triazolo[1,5-a]pyrimidine moiety with various functional groups in medicinal chemistry. Herein, we represent a concise report focusing on the synthetic strategies used for diversely substituted [1,2,4]triazolo[1,5-a]pyrimidine analogs and their pharmacological applications. To the best of our knowledge, since 1980, we are the first to write a review on this emerging scaffold, which reveals the synthetic strategies, and pharmacological activities of differently substituted [1,2,4]triazolo[1,5-a]pyrimidine with special emphasis on structure-activity relationship studies.

Endothelin-1 induces lysyl oxidase expression in pulmonary artery smooth muscle cells.

The increase in thickening of the arterial wall of pulmonary arterial hypertension (PAH) includes cellular proliferation as well as matrix deposition and interrupted internal elastic lamina (IEL) consisting of a thick homogeneous sheet of elastin. Little is, although, known about the detail of IEL formation in PAH. Endothelin-1 is overexpressed in pulmonary arterioles of PAH. We aimed to examine the expression of genes contributing to IEL formation in pulmonary artery smooth muscle cells (PASMCs) especially focused on lysyl oxidase (LOx), an exreacellular matrix enzyme that catalyzes the cross-linking of collagens or elastin. We quantified mRNA expressions of genes contributing to IEL formation including LOx in PASMCs using real-time quantitative polymerase chain reaction. We stimulated human PASMCs with endothelin-1 with prostacyclin or trapidil. Endothelin-1 significantly increased LOx expression. Prostacyclin and trapidil restored endothelin-1-induced LOx expression to the basal level. Endothelin-1 increased LOx expression strongly in PASMCs from PAH patients compared to those from controls. Trapidil reduced LOx expression only in PASMCs from PAH patients. Overexpressed endothelin-1 in PAH patients can increase expression of LOx and agitate cross-linking of elastin and collagen, resulting in ectopic deposition of these in the vascular media.

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.

Trapidil induces osteogenesis by upregulating the signaling of bone morphogenetic proteins.

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.

Trapidil improves hemodynamic, echocardiographic and redox state parameters of right ventricle in monocrotaline-induced pulmonary arterial hypertension model.

BACKGROUND: Pulmonary arterial hypertension is a disease characterized by increased pulmonary vascular resistance and redox imbalance, leading to failure of right ventricle. Trapidil has been described to improve the redox balance and cardiac conditions. HYPOTHESIS: Trapidil can improve the redox balance and contribute to functional improvements of the RV in PAH. METHODS AND RESULTS: Male, 5week-old Wistar rats were divided into four groups: Control, Control + Trapidil, Monocrotaline and Monocrotaline + Trapidil. PAH was induced by an intraperitoneal injection of monocrotaline 60 mg/kg at day 0. Treatment started at day 7 (5 or 8 mg/kg/day) until day 14, when animals were euthanized after echocardiography and catheterism. Right ventricular systolic pressure and pressure/time derivatives were increased in monocrotaline animals. The increased right ventricular diameters in monocrotaline groups were reduced with trapidil. Monocrotaline groups showed higher lipid peroxidation and glutathione peroxidase activity. Trapidil reduced NADPH oxidases activities and increased the reduced glutathiones/total glutathiones ratio. Protein expression of phospholamban in RV was diminished in monocrotaline groups, whereas expression of RyR and SERCA was enhanced in the groups treated with trapidil. CONCLUSION: Our data suggest that trapidil induces an improvement in RV remodeling in PAH model, mitigating the progression of the disease.

Renal Interstitial Platelet-Derived Growth Factor Receptor-ß Cells Support Proximal Tubular Regeneration.

BACKGROUND: 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-ß (PDGFRß) contributes to interstitial-epithelial cell communication and facilitates regenerative functions in several organs. However, the potential role of interstitial cells in renal tubular regeneration has not been examined. METHODS: In mice with fluorescent protein expression in renal tubular cells and PDGFRß-positive interstitial cells, we ablated single tubular cells by high laser exposure. We then used serial intravital multiphoton microscopy with subsequent three-dimensional reconstruction and ex vivo histology to evaluate the cellular and molecular processes involved in tubular regeneration. RESULTS: Single-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 PDGFRß-positive interstitial cells and the rapid migration thereof toward the injury. These PDGFRß-positive cells enclosed the injured epithelium before the onset of tubular cell dedifferentiation, and the later withdrawal of these PDGFRß-positive cells correlated with signs of tubular cell redifferentiation. Intraperitoneal administration of trapidil to block PDGFRß impeded PDGFRß-positive cell migration to the tubular injury site and compromised the recovery of tubular function. CONCLUSIONS: Ablated tubular cells are exclusively replaced by resident tubular cell proliferation in a process dependent on PDGFRß-mediated communication between the renal interstitium and the tubular system.

25-Hydroxyl-protopanaxatriol protects against H2O2-induced H9c2 cardiomyocytes injury via PI3K/Akt pathway and apoptotic protein down-regulation.

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®-dammarane -3 beta,6 alpha,12 beta,20,25-pentol(25-hydroxyl-Protopanaxatriol,25-OH-PPT), a novel compound, which belongs to panaxatriol category, is extracted from the leaves and stem of ginseng. It was first investigated for its anti-tumorigenic properties. In this study, we explored whether 25-OH-PTT plays a role in antioxidant stress injury and anti-apoptosis in cardiomyocytes. We also explored the mechanisms in order to provide a theoretical basis to develop 25-OH-PPT as a new drug for treatment of MI/RI. First, we used H2O2 to induce H9c2 cardiomyocytes in vitro resulting in an oxidative stress injury model and pretreated with 25-OH-PPT. Secondly, we examined the viability of H9c2 cells by MTT assay, the reactive oxygen species (ROS) content and mitochondrial membrane potential by flow cytometry as well as cell apoptosis by flow cytometry Annexin-FITC/PI and Hoechst 33258 staining. Furthermore, we pretreated H9c2 cells with PI3K inhibitor, LY294002, and observed the above phenomenon. Lastly, we examined the expressions of proteins related to the PI3K/Akt signaling pathway and the apoptotic proteins. We found that 25-OH-PPT can protect H9c2 cells against H2O2-induced injury, decrease apoptosis of H9c2 cells and ROS generation, and increase the mitochondrial membrane potential. It can also upregulate the protein expressions of p-Akt, p-eNOS, and Bcl-2 and down-regulate apoptotic proteins Bax and Caspase-3. Our results indicate that 25-OH-PPT inhibits H2O2-induced H9c2 cardiomyocytes injury through PI3K/Akt pathway. It may become a potential safe and effective traditional Chinese medicine monomer for treatment of MI/RI.

Therapeutic effects of a taurine-magnesium coordination compound on experimental models of type 2 short QT syndrome.

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· (NH2CH2CH2SO3)2· H2O, 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<0.05 vs control). Subsequently, perfusion of TMCC (1-4 mmol/L) dose-dependently increased the QT interval and QTpeak (P<0.01 vs pinacidil). TMCC perfusion also reversed the rTp-Te value to the normal range. In guinea pig ventricular myocytes, perfusion of trapidil (1 mmol/L) significantly shortened the action potential duration at 50% (APD50) and 90% repolarization (APD90), which was significantly reversed by TMCC (0.01-1 mmol/L, P<0.05 vs trapidil). In HEK293 cells that stably expressed the outward delayed rectifier potassium channels (IKs), perfusion of TMCC (0.01-1 mmol/L) dose-dependently inhibited the IKs current with an IC50 value of 201.1 µmol/L. The present study provides evidence that TMCC can extend the repolarization period and inhibit the repolarizing current, IKs, thereby representing a therapeutic candidate for ventricular arrhythmia in SQT2.

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.

Trapidil, a platelet-derived growth factor antagonist, inhibits osteoclastogenesis by down-regulating NFATc1 and suppresses bone loss in mice.

Trapidil, a platelet-derived growth factor antagonist, was originally developed as a vasodilator and anti-platelet agent and has been used to treat patients with ischemic coronary heart, liver, and kidney disease. In this study, we investigated the effects of trapidil on osteoclastogenesis and elucidated the possible mechanism of action of trapidil. Trapidil strongly inhibited osteoclast formation in co-cultures of bone marrow cells and osteoblasts without affecting receptor activator of NF-κB ligand (RANKL) or osteoprotegerin expression in osteoblasts. In addition, trapidil suppressed RANKL-induced osteoclast formation from osteoclast precursors. Trapidil reduced RANKL-induced expression of nuclear factor of activated T cells, cytoplasmic 1 (NFATc1), a master transcription factor for osteoclastogenesis, without affecting the expression of c-Fos that functions as a key upstream activator of NFATc1 during osteoclastogenesis. Ectopic expression of a constitutively active form of NFATc1 reversed the anti-osteoclastogenic effect of trapidil, indicating that NFATc1 is a critical target of the anti-osteoclastogenic action of trapidil. RANKL-induced calcium oscillation and Pim-1 expression, which are required for NFATc1 induction and osteoclastogenesis, were abrogated by trapidil. Consistent with the in vitro results, trapidil had a potent inhibitory effect on osteoclast formation and bone resorption induced by interleukin-1 in an animal model. Taken together, our data demonstrate that trapidil abrogates RANKL-induced calcium oscillation and Pim-1 expression required for NFATc1 induction, thereby inhibiting osteoclastogenesis.

Antithrombotic therapy for improving maternal or infant health outcomes in women considered at risk of placental dysfunction.

BACKGROUND: Pregnancy complications such as pre-eclampsia and eclampsia, intrauterine growth restriction and placental abruption are thought to have a common origin related to abnormalities in the development and function of the placenta. OBJECTIVES: To compare, using the best available evidence, the benefits and harms of antenatal antithrombotic therapy to improve maternal or infant health outcomes in women considered at risk of placental dysfunction, when compared with other treatments, placebo or no treatment. SEARCH METHODS: We searched the Cochrane Pregnancy and Childbirth Group's Trials Register (17 July 2012). SELECTION CRITERIA: Randomised controlled trials comparing antenatal antithrombotic therapy (either alone or in combination with other agents) with placebo or no treatment, or any other treatment in the antenatal period to improve maternal or infant health outcomes in women considered at risk of placental dysfunction. DATA COLLECTION AND ANALYSIS: Two review authors evaluated trials under consideration for appropriateness for inclusion and methodological quality without consideration of their results according to the prestated eligibility criteria. We used a fixed-effect meta-analysis for combining study data if the trials were judged to be sufficiently similar. We investigated heterogeneity by calculating I² statistic, and if this indicated a high level of heterogeneity among the trials included, we used a random-effects model. MAIN RESULTS: Our search strategy identified 18 reports of 14 studies for consideration. The original review included five studies (484 women) which met the inclusion criteria, with a further five studies included in the updated review, involving an additional 655 women. The overall quality of the included trials was considered fair to good.Nine studies compared heparin (alone or in combination with dipyridamole or low-dose aspirin) with no treatment; and one compared trapidil (triazolopyrimidine).While this review identified the use of heparin to be associated with a statistically significant reduction in risk of perinatal mortality (six studies; 653 women; risk ratio (RR) 0.40; 95% confidence intervals (CI) 0.20 to 0.78), preterm birth before 34 (three studies; 494 women; RR 0.46; 95% CI 0.29 to 0.73) and 37 (five studies; 621 women; RR 0.72; 95% CI 0.58 to 0.90) weeks' gestation, and infant birthweight below the 10th centile for gestational age (seven studies; 710 infants; RR 0.41; 95% CI 0.27 to 0.61), there is a lack of reliable information available related to clinically relevant, serious adverse infant health outcomes, which have not been reported to date. AUTHORS' CONCLUSIONS: While treatment with heparin for women considered to be at particularly high risk of adverse pregnancy complications secondary to placental insufficiency was associated with a statistically significant reduction in risk of perinatal mortality, preterm birth before 34 and 37 weeks' gestation, and infant birthweight below the 10th centile for gestational age when compared with no treatment for women considered at increased risk of placental dysfunction, to date, important information about serious adverse infant and long-term childhood outcomes is unavailable.

Effects of the antianginal drug trapidil on atrioventricular conduction disturbances during acute myocardial ischemia.

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.

Optical coherence tomography in ST-elevation myocardial infarction treated with novel drug-eluting stent: preprocedural, postimplant and 2-month follow-up findings.

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.

Protective effect of trapidil and l-arginine against renal and hepatic toxicity induced by cyclosporine in rats.

RATIONALE: Cyclosporine A (CsA) leads to renal and liver injury, production of free radicals and nitric oxide (NO) deficiency. This study investigates the possible protective effects of trapidil and L-arginine against CsA-induced tissue injury. OBJECTIVES: Forty adult male Wistar rats (180 +/- 20 g) were divided into five groups, eight animals in each. The first group served as control, second group served as CsA group, third group served as CsA + trapidil group, fourth group served as CsA + L-arginine group, and fifth group served as CsA + trapidil + L-arginine group. Kidney and liver functions, inflammatory mediators, cytokines, oxidant and antioxidant parameters as well as histopathological studies of renal and liver tissue were assessed in all groups. MAIN FINDINGS: CsA induced renal and hepatic dysfunction, which was confirmed by laboratory and histopathological examination. Administration of trapidil diminished the renal and liver injury and significantly attenuated the levels of serum creatinine, urea, aspartate aminotransferase (AST), alanine aminotransferase (ALT), interleukin-1beta (IL-1beta), tumor necrosis factor alpha (TNF-alpha), monocyte chemoattractant protein-1 (MCP-1), and oxidative stress, while it significantly elevated the level of serum nitric oxide and the activity of antioxidative stress. L-Arginine gave the same trend as trapidil, but trapidil effect was more pronounced. Coadministration of trapidil + L-arginine significantly ameliorated the toxic effect of CsA, but did not differ significantly from the effect of trapidil alone. CONCLUSIONS: Treatment with trapidil or L-arginine diminished the renal and hepatic CsA-induced toxicity. However, the effect of trapidil was more pronounced. Therefore, treatment with trapidil alone may be the most economic and effective as a potential therapeutic agent in CsA injury.

Antithrombotic therapy for improving maternal or infant health outcomes in women considered at risk of placental dysfunction.

BACKGROUND: Pregnancy complications such as pre-eclampsia and eclampsia, intrauterine growth restriction and placental abruption are thought to have a common origin related to abnormalities in the development and function of the placenta. OBJECTIVES: To compare, using the best available evidence, the benefits and harms of antenatal antithrombotic therapy to improve maternal or infant health outcomes in women considered at risk of placental dysfunction, when compared with other treatments, placebo or no treatment. SEARCH STRATEGY: We searched the Cochrane Pregnancy and Childbirth Group's Trials Register (March 2010). SELECTION CRITERIA: Randomised controlled trials comparing antenatal antithrombotic therapy (either alone or in combination with other agents) with placebo or no treatment, or any other treatment in the antenatal period to improve maternal or infant health outcomes in women considered at risk of placental dysfunction. DATA COLLECTION AND ANALYSIS: Two review authors evaluated trials under consideration for appropriateness for inclusion and methodological quality without consideration of their results according to the prestated eligibility criteria. We used a fixed-effect meta-analysis for combining study data if the trials were judged to be sufficiently similar. We investigated heterogeneity by calculating I(2) statistic, and if this indicated a high level of heterogeneity among the trials included we used a random-effects model. MAIN RESULTS: Our search strategy identified 14 reports of 10 studies for consideration, of which five met the inclusion criteria, involving 484 women. Four studies compared heparin (alone or in combination with dipyridamole) with no treatment; and one compared trapidil (triazolopyrimidine). While there were no statistically significant differences identified for the primary outcomes following heparin treatment, it was associated with a reduction in the risk of pre-eclampsia, eclampsia, and infant birthweight less than the 10th centile for gestational age. AUTHORS' CONCLUSIONS: The review identified no significant differences for the primary outcomes perinatal mortality, preterm birth less than 34 weeks' gestation, and childhood neurodevelopmental handicap, although the number of studies and participants was small. While treatment with heparin appears promising with a reduction in pre-eclampsia, eclampsia, and infant birthweight less than the 10th centile for gestational age, the number of studies and participants included was small, and to date important information about serious adverse infant and long-term childhood outcomes is unavailable. Further research is required.

[Investigation of the effects of low dose aspirin therapy on primary and secondary prevention of cardiovascular disease].

We examined the efficacy of low-dose aspirin for the primary prevention of atherosclerotic events in patients with type 2 diabetes. Multicenter, prospective, randomized, open -label, blinded end-point trial enrolled 2,539 patients with type 2 diabetes. A total of 154 atherosclerotic events occurred: 68 in the aspirin group and 86 in the nonaspirin group (log -rank test, p = 0.16). The multicenter study was performed to find out whether aspirin or trapidil would improve clinical outcome. The study was a multicenter, open-label, randomized controlled trial of aspirin 81 mg/day, trapidil 300 mg/day, and no antiplatelets in patients with acute myocardial infarction (AMI) admitted within 1 month from the onset of symptoms. Long-term use of aspirin reduced the incidence of recurrent AMI (p = 0.0045).

The role of mast cells in parathyroid bone disease.

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.

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.