iloprost and Cardiovascular-Diseases

The therapy of systemic sclerosis (SSc) remains a challenge for dermatology, rheumatology, internal medicine, and other disciplines. Organ involvement, above all kidney and lungs, is a key therapeutic issue. The current developments in organ-specific therapy are the main topic of the article. Finally, possibilities of disease-modifying drugs and value of HSCT are discussed.

Topics: Angiotensin-Converting Enzyme Inhibitors; Cardiovascular Diseases; Fibrosis; Fingers; Gastrointestinal Agents; Hematopoietic Stem Cell Transplantation; Humans; Hypertension, Pulmonary; Iloprost; Kidney Transplantation; Piperazines; Purines; PUVA Therapy; Raynaud Disease; Recurrence; Scleroderma, Systemic; Sildenafil Citrate; Skin Ulcer; Sulfones; Ultraviolet Therapy; Vasodilator Agents

Iloprost, an analogue of prostacyclin, is often utilised in subjects with diabetes mellitus complicated by macroangiopathy.. The effects of iloprost infusion on plasminogen activator inhibitor type-1 (PAI-1), glucometabolic control and cardiovascular equilibrium in patients with type-2 diabetes mellitus and peripheral arterial occlusive disease were investigated. Thirteen (7 men/6 women) normal-weight, normotensive and non-smoker type-2 diabetic patients (63.8 +/- 3.4 years, mean +/- SD) with peripheral arterial occlusive disease, stage-II according to Fontaine classification, were enrolled. Eight (four men/four women) patients underwent three study designs, each separated by a 1-week interval: study I, infusion of iloprost (3 ng kg(-1) min(-1) for 5 h) for 1 day alone (short-term treatment); study II, infusion of saline (for 5 h) for 1 day (control treatment); study III, infusion of iloprost (3 ng kg(-1) min(-1) for 5 h) over a period of 28 days (long-term treatment). The remaining five (three men/two women) patients underwent study IV only, infusion of saline over a period of 28 days (placebo treatment). Plasma levels of glucose, plasminogen, PAI-1 activity and fibrinogen, blood pressure and heart rate were determined in all studies, while plasma insulin levels, blood HbA(1c), walking distance and Winsor index only in studies III and IV.. Both short- and long-term treatments with iloprost significantly reduced PAI-1 activity (baseline vs end: 17.4 +/- 1.9 AU/ml vs 15.0 +/- 1.6 AU/ml, P < 0.02; 20.5 +/- 7.6 AU/ml vs 7.9 +/- 2.1 AU/ml, P < 0.002, respectively). Long-term treatment with iloprost significantly increased walking distance (baseline vs end: 325 +/- 41 m vs 496 +/- 52 m, P < 0.0001), but not Winsor index. Neither glucometabolic control nor cardiovascular equilibrium were affected by short- and long-term treatments with iloprost. Control and placebo treatments did not cause any significant modifications in the parameters evaluated.. If confirmed by further investigations, the results of this pilot study suggest that iloprost, infused for both brief and long periods, is able to reduce the cardiovascular risk factor PAI-1, increases free walking capacity and does not affect glucometabolic control and blood pressure in type-2 diabetic patients complicated by macroangiopathy.

Topics: Aged; Blood Glucose; Blood Pressure; Cardiovascular Diseases; Diabetes Mellitus, Type 2; Fasting; Female; Fibrinogen; Glycated Hemoglobin; Humans; Iloprost; Insulin; Male; Middle Aged; Peripheral Vascular Diseases; Pilot Projects; Plasminogen; Plasminogen Activator Inhibitor 1; Platelet Aggregation Inhibitors; Risk Factors; Time Factors; Treatment Outcome; Walking

Platelets are critical for haemostasis and blood clotting. However, since under normal circumstances blood should flow without clotting, its function is regulated via a complex interplay of activating and inhibiting signal transduction pathways. Understanding this network is crucial for treatment of cardiovascular and bleeding diseases. Detailed protein interaction and phosphorylation data are explored to establish a simplified Boolean model of the central platelet cascades. We implemented the model by means of CellNetAnalyzer and showed how different signalling events coalesce into a fully activated system state. Furthermore, we examined the networks' inherent threshold behaviour using the semi-quantitative modelling software SQUAD. Finally, predictions are verified monitoring phosphorylations which mark different activation phases as modelled. The model can also be applied to simulate different pharmacological conditions as they modify node activity (aspirin, clopidogrel, milrinon, iloprost, combination) and is available for further studies. It agrees well with observations. Activatory pathways are diversified to cope with complex environmental conditions. Platelet activation needs several activation steps to integrate over different network subsets, as they are formed by the interplay of activating kinases, calcium mobilization, and the inhibiting cAMP-PKA system. System stability analysis shows two phases: a sub-threshold behaviour, characterized by integration over different activatory and inhibitory conditions, and a beyond threshold phase, represented by competition and shutting down of counter-regulatory pathways. The integrin network and Akt-protein are critical for stable effector response. Dynamic threshold-analysis reveals a dependency of the relative activating input strength necessary to irreversibly engage the system from the absolute inhibitory signal strength.

Topics: Aspirin; Blood Platelets; Cardiovascular Diseases; Clopidogrel; Hemorrhage; Humans; Iloprost; Integrins; Milrinone; Models, Biological; Molecular Dynamics Simulation; Phosphorylation; Platelet Activation; Platelet Aggregation; Platelet Aggregation Inhibitors; Proto-Oncogene Proteins c-akt; Signal Transduction; Ticlopidine

Prostacyclin (PGI(2)) and its analogues protect from cardiovascular disease through pleiotropic effects such as vasodilation, inhibition of platelet aggregation, leukocyte adhesion, and vascular smooth muscle cell (VSMC) proliferation. Additionally, prostacyclin synthase (PGIS) and PGI(2) also possess anti-cancer properties. As of late (2009-2010), numerous studies have identified the deleterious side-effects of chemotherapy on the cardiovascular system, which have been deemed as a serious clinical issue. Cardiomyocyte damage, induced by oxidative stress, is one of the clinical consequences caused by routine cancer chemotherapy. Previous studies indicate iloprost, a PGI(2) analogue, can protect against doxorubicin-induced (DOX) cardiomyocyte injury in vitro and in vivo without compromising tumor suppression. Therefore, we hypothesize PGI(2) can be used as a cardioprotective supplement to attenuate the damaging cardiac effects caused by the traditional cancer chemotherapy regimen.

Topics: Angiography; Animals; Antineoplastic Agents; Cardiovascular Diseases; Doxorubicin; Drug Therapy, Combination; Epoprostenol; Humans; Iloprost; Mice; Myocytes, Cardiac; Neoplasms; Oxidative Stress; Platelet Aggregation Inhibitors; Treatment Outcome