iloprost and Diabetes-Mellitus--Type-2

Revascularization by either bypass surgery or endovascular recanalization is considered the first-choice treatment in patients with critical limb ischemia (CLI). Only conservative options are left in CLI patients in whom successful revascularization strategies are not possible: in these patients, at present, prostanoids (iloprost and prostaglandin [PGE1]) represent the pharmacological treatment of choice. Iloprost resulted more effective than PGE1, in a 6 month follow-up, in both limb savage and in prevention of cardiovascolar death, either in diabetic or non diabetic patients with unreconstructable CLI. In our experience, in patients who have responded to a first cycle of therapy (early responders), performed for at least 2-3 weeks, cyclic annual further treatments with iloprost are usually able to stabilize arterial disease, with a regression to Fontaine II stage and, in absence of further arterial complications, with complete limb preservation for an unlimited period of time. In non-responder patients, who are not urgently supposed to undergo amputation, a second cycle of iloprost carried out within few months from the first one, is able to increase the percentage of responders to prostanoids (late responders). Vice versa, in non-responders to repeat prostanoid cycles, it is useful to verify the outcomes of further attempts at saving, the symptomatic limb by surgical or endovascular re-timing, spinal cord stimulation, gene or stem cell therapy. Our recent better outcomes are related to earlier microvascular diagnosis and to earlier, repeat, pharmacological treatments with iloprost. Transcutaneous oxygen and carbon dioxide monitoring improves the possibility of an earlier diagnosis of microvascular damages and categorizes CLI patients in responders and non-responders after prostanoid treatments.

Topics: Adolescent; Adult; Aged; Algorithms; Alprostadil; Amputation, Surgical; Diabetes Mellitus, Type 2; Diabetic Angiopathies; Female; Fibrinolytic Agents; Follow-Up Studies; Humans; Iloprost; Ischemia; Leg; Limb Salvage; Male; Meta-Analysis as Topic; Platelet Aggregation Inhibitors; Randomized Controlled Trials as Topic; Risk Factors; Time Factors; Vasodilator Agents

In type 2 diabetes impaired insulin-induced muscle perfusion is thought to contribute to reduced whole-body glucose uptake. In this study, we examined the effects of iloprost, a stable prostacyclin analogue, on insulin-induced muscle capillary recruitment and whole-body glucose uptake.. In a randomized cross-over design, 12 type 2 diabetes patients (age, 55 [46-69] years; BMI, 33.1 [31.0-39] kg/m. Our data suggest that acute improvement in insulin-stimulated muscle perfusion is not an attractive therapeutic approach to bypass cellular resistance to glucose uptake in type 2 diabetes. Whether long-term improvements in insulin-induced muscle perfusion may prove beneficial for glucose disposal remains to be determined.

Topics: Aged; Blood Glucose; Blood Volume; Cross-Over Studies; Diabetes Mellitus, Type 2; Diabetic Angiopathies; Down-Regulation; Female; Humans; Iloprost; Infusions, Intravenous; Insulin; Male; Microcirculation; Middle Aged; Muscle, Skeletal

Iloprost, a prostacyclin analogue, is used in the treatment of peripheral arterial occlusive disease at Leriche-Fontaine stages III-IV, through intravenous infusion for at least 21 days. Recently, iloprost has been shown to be safe and effective in critical limb ischemia patients when administered per 7 days. We investigated in patients at Leriche-Fontaine stages III-IV the effect of 1-week treatment with iloprost on plasma asymmetric dimethylarginine (ADMA), plasma and platelet serotonin, and on clinical response.. Twenty-four critical limb ischemia patients (16 men and 8 women, mean age 76+/-9.7 years) were included in the study and treated with intravenous iloprost (titrated from 0.5 up to 1.5 ng/kg/min) for 16 h a day for seven consecutive days. Blood samples were drawn before infusion on days 1, 4 and 8 of treatment, under the same conditions. Clinical assessment was performed by clinical evaluation, ankle/brachial pressure index and treadmill exercise test. During treatment with iloprost patients clinically improved and plasma levels of ADMA significantly decreased (p<0.001). We also observed a significant increase of serotonin (p<0.01) in platelets and a significant decrease of serotonin (p<0.001) in plasma. Similar variations of ADMA and serotonin were found in two subgroups of patients, diabetics and non-diabetics.. One-week treatment with iloprost in critical limb ischemia patients induced changes of peripheral markers of endothelial dysfunction and atherosclerosis, such as ADMA and serotonin, associated to a clinical improvement.

Topics: Aged; Aged, 80 and over; Arginine; Arterial Occlusive Diseases; Blood Platelets; Blood Pressure; Diabetes Mellitus, Type 2; Drug Administration Schedule; Exercise Test; Female; Humans; Iloprost; Infusions, Intravenous; Male; Peripheral Vascular Diseases; Platelet Aggregation Inhibitors; Serotonin; Treatment Outcome

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

Erythrocytes release both O(2) and a vasodilator, ATP, when exposed to reduced O(2) tension. We investigated the hypothesis that ATP release is impaired in erythrocytes of humans with type 2 diabetes (DM2) and that this defect compromises the ability of these cells to stimulate dilation of resistance vessels. We also determined whether a general vasodilator, the prostacyclin analog iloprost (ILO), stimulates ATP release from healthy human (HH) and DM2 erythrocytes. Finally, we used a computational model to compare the effect on tissue O(2) levels of increases in blood flow directed to areas of increased O(2) demand (erythrocyte ATP release) with nondirected increases in flow (ILO). HH erythrocytes, but not DM2 cells, released increased amounts of ATP when exposed to reduced O(2) tension (Po(2) < 30 mmHg). In addition, isolated hamster skeletal muscle arterioles dilated in response to similar decreases in extraluminal O(2) when perfused with HH erythrocytes, but not when perfused with DM2 erythrocytes. In contrast, both HH and DM2 erythrocytes released ATP in response to ILO. In the case of DM2 erythrocytes, amounts of ATP released correlated inversely with glycemic control. Modeling revealed that a functional regulatory system that directs blood flow to areas of need (low O(2)-induced ATP release) provides appropriate levels of tissue oxygenation and that this level of the matching of O(2) delivery with demand in skeletal muscle cannot be achieved with a general vasodilator. These results suggest that the inability of erythrocytes to release ATP in response to exposure to low-O(2) tension could contribute to the peripheral vascular disease of DM2.

Topics: Adenosine Triphosphate; Adult; Aged; Animals; Case-Control Studies; Cell Hypoxia; Computer Simulation; Cricetinae; Diabetes Mellitus, Type 2; Diabetic Angiopathies; Erythrocytes; Female; Humans; Iloprost; Male; Mesocricetus; Microcirculation; Middle Aged; Models, Cardiovascular; Muscle, Skeletal; Oxygen; Regional Blood Flow; Vasodilation; Vasodilator Agents; Young Adult

The association of vasoplegic shock and myocardial infarction in a patient under iloprost treatment for critical ischemia of the lower limbs has not previously been reported.. A 56 year-old man suffering from type 2 diabetes, hypertension and dyslipidemia developed critical ischemia of the right leg and was treated with iloprost. On the 19th day of infusion, he developed a vasoplegic shock with myocardial infarction. The shock resolved and he recovered from the infarction.. This case report indicates the need for reinforced blood pressure and electrocardiographic monitoring in diabetes patients treated with iloprost.

Topics: Diabetes Mellitus, Type 2; Follow-Up Studies; Humans; Iloprost; Ischemia; Leg; Male; Middle Aged; Myocardial Infarction; Shock, Cardiogenic; Time Factors; Vasodilator Agents

Topics: Diabetes Mellitus, Type 2; Diabetic Angiopathies; Gases; Humans; Iloprost; Ischemia; Leg; Platelet Aggregation Inhibitors; Treatment Failure; Treatment Outcome

The prognosis of cholesterol embolism is often poor, and no treatment is presently available. We report the use of a stable prostacyclin analogue in treating cholesterol embolism in a diabetic patient with arteriopathy. As a sole therapy, it improved cutaneous manifestations and pain, in parallel with an increased transcutaneous oxymetry. We think that prostacyclin analogues are novel candidates for the treatment of cholesterol embolism.

Topics: Aged; Crystallization; Diabetes Mellitus, Type 2; Diabetic Angiopathies; Embolism, Cholesterol; Humans; Iloprost; Male

We previously showed the correlation between the extent of vascular complications and erythrocyte adherence to endothelium in diabetes mellitus. The accumulation of advanced glycation end products (AGEs) on the erythrocyte surface in diabetes mediates their interaction with endothelial cells through a specific endothelial receptor for AGEs (RAGE). Binding of diabetic erythrocytes to endothelial cells resulted in evidence of oxidant stress responsible for a range of cellular perturbations. In the present study, we have investigated the effect of iloprost, a prostacyclin analog, on several activities modified by diabetic erythrocyte-endothelium interaction: 1) generation of oxidant stress based on production of thiobarbituric acid reactive substances (TBARS: control: 2.37 +/- 0.32 versus iloprost: 1.39 +/- 0.005 mumol/10(11) cells), 2) alteration of the endothelial barrier function as measured by an increase permeability to 125I-albumin (control: 13.31 +/- 0.85 versus iloprost: 9.45 +/- 0.7 10(-7) cm/s) of the endothelial cell monolayer, 3) modification of the endothelial cell function showed by an increase in interleukin-6 release (control: 21.66 +/- 3.11 versus iloprost 15.45 +/- 0.76 ng/10(6) cells). The increase in permeability to albumin as well ass TBARS production and interleukin-6 release were inhibited by iloprost (10(-8)-10(-6) mol/l) treatment in a dose-dependent fashion. These results indicate that erythrocyte associated AGEs might alter endothelial cell function. The perturbations can be limited in vitro by iloprost.

Topics: Adult; Cell Adhesion; Cell Membrane Permeability; Diabetes Mellitus, Type 2; Endothelium, Vascular; Erythrocytes; Female; Humans; Iloprost; Interleukin-6; Male; Middle Aged; Oxidative Stress; Platelet Aggregation Inhibitors

To investigate the effect of iloprost infusion on insulin action.. Thirteen healthy subjects and 13 non-insulin-dependent diabetes mellitus (NIDDM) patients matched for age (68.2 +/- 0.5 vs. 67.9 +/- 0.5 years, NS), gender ratio (7 men:6 women vs. 6 men:7 women), body weight, body fat distribution, arterial blood pressure, and plasma triglyceride levels (1.89 +/- 0.09 vs. 1.87 +/- 0.08 mmol/l, NS) were studied. In eight healthy subjects and eight NIDDM patients, we studied insulin action by euglycemic glucose clamp (insulin infusion rate 2 mU.kg-1.min-1) along with saline and iloprost delivery (0.7 ng.kg-1.min-1). In the other five subjects of each group, forearm blood flow and insulin-mediated glucose uptake during saline and iloprost infusion (0.7 ng.kg-1.min-1) were investigated.. Iloprost infusion improved insulin-stimulated whole-body glucose uptake and oxidative and nonoxidative glucose metabolism in both study groups. Forearm blood flow under basal conditions and with insulin infusion (2 mU.kg-1.min-1) did not show any significant difference from that during saline and iloprost infusion (0.7 ng.kg-1.min-1) in healthy subjects and diabetic patients.. Iloprost infusion improves insulin action in healthy subjects and NIDDM patients.

Topics: Aged; Blood Glucose; Blood Pressure; Case-Control Studies; Diabetes Mellitus, Type 2; Diastole; Drug Interactions; Female; Heart Rate; Humans; Iloprost; Infusions, Intravenous; Insulin; Kinetics; Male; Muscle, Skeletal; Reference Values; Regional Blood Flow; Systole