iloprost and Diabetic-Angiopathies

Diabetic complications in the lower extremities, especially those secondary to diabetic macroangiopathy, have increasingly become a clinical emergency, given the high prevalence and progression of the disease. Until recently, the only approach to treating advanced stage disease was medical therapy and major amputation; however, the advent of revascularization procedures has radically improved the prognosis of patients with critical lower limb ischemia. In this setting, iloprost holds a dual position: as first-choice therapy in patients ineligible for revascularization and as complementary therapy in candidates for surgical or endovascular revascularization.

Topics: Diabetic Angiopathies; Drug Interactions; Humans; Iloprost; Peripheral Arterial Disease; Platelet Aggregation Inhibitors; Prostaglandins

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

In a randomized open controlled study the clinical effects and tolerability of prostaglandin E1 (PGE1) and the stable prostacyclin (PGI2) analogue, iloprost in the management of diabetic and non-diabetic patients with advanced peripheral arterial occlusive disease (PAOD Fontaine stage IV) were compared. 267 patients were enrolled in this multicentre study and treated for 21-28 days, either by daily infusions of 6 h with iloprost or 2 x 2 h with PGE1. At the end of treatment patients were assessed for evidence of improvement of trophic lesions, relief of rest pain and change of global clinical status. 228 patients were considered as evaluable for efficacy analysis, which revealed 52.7% responders in the iloprost group and 43.1% for PGE1 (p = 0.148). Whereas iloprost showed similar effects in diabetics and non-diabetics (53.3% and 51.4% response rates, respectively), the diabetics treated with PGE1 had a considerably poorer outcome (36.6% versus 53.3%). At 6 months follow-up 62.2% of patients in both groups were alive with a viable limb. Slightly more iloprost patients underwent major amputation (32.1% versus 27.2%), but the number of deaths was reduced by 50% in the iloprost group compared to the PGE1 group (7.5% versus 14.6%, p = 0.10). Side-effects such as headache, flushing and gastrointestinal symptoms were significantly more common in the iloprost group (73.9%) than in the PGE1 group (31.0%), particularly during the first 3 days of dose titration. No specific toxic or unexpected reactions were reported in either group.

Topics: Adult; Aged; Alprostadil; Arterial Occlusive Diseases; Arteriosclerosis Obliterans; Diabetic Angiopathies; Drug Tolerance; Female; Humans; Iloprost; Infusions, Intravenous; Male; Middle Aged; Peripheral Vascular Diseases

The efficacy of iloprost, a stable prostacyclin analog, was investigated in a placebo-controlled trial in 109 diabetics with ischemic lesions. 56 patients were randomly allocated to iloprost and 53 patients to placebo. Iloprost was intravenously applied for 6 hours daily on 28 consecutive days at an individually tolerated dose up to 2 ng/kg/min. The control group received identical solvent volumes. In addition all patients had an intensive basic, mainly local, therapy. At the end of the treatment in the iloprost group 31 of 50 patients (62%) showed partial (greater than 30%) or total healing of the lesion(s). In the placebo group this was the case in 12 of 51 patients (22.5%). The difference of 38.5% was statistically significant (p less than 0.05, chi 2-test, alpha = 0.05, beta = 0.1). The percentage of patients who were free of pain increased from 23% to 42% (+19%) in the iloprost group and from 38% to 48% (+10%) in the placebo group. After dose-titration iloprost was well tolerated. Flush, headache and abdominal complaints were the most frequent side effects. Heart rate and blood pressure were not influenced and the control of diabetes was not altered.

Topics: Adult; Aged; Diabetic Angiopathies; Female; Foot; Humans; Iloprost; Ischemia; Male; Middle Aged

Topics: Arterial Occlusive Diseases; Cardiovascular Agents; Clinical Trials as Topic; Diabetic Angiopathies; Epoprostenol; Humans; Iloprost; Multicenter Studies as Topic; Random Allocation

Topics: Adult; Aged; Arterial Occlusive Diseases; Blood Flow Velocity; Blood Viscosity; Clinical Trials as Topic; Diabetic Angiopathies; Double-Blind Method; Epoprostenol; Female; Humans; Iloprost; Infusions, Intravenous; Male; Middle Aged; Random Allocation

In 2 randomized, double-blind studies, 109 diabetic patients with trophic lesions and 101 non-diabetics suffering from peripheral vascular disease (PVD) stage IV (Fontaine) received daily 6-hour i.v. infusions of iloprost (less than or equal to 2ng/kg/min) or of placebo over 28 days. Iloprost treatment was superior to placebo, showing ulcer healing in more than 60% of patients compared to less than 25% in the control group. The beneficial effects were sustained during a 1 year follow-up period. Platelet activation, adhesion, aggregation and release reaction on atherosclerotic lesions, impaired microvascular perfusion, loss of microvascular barrier function, increased white blood cell - vessel wall interaction and hemorheological disturbances are all believed to play a role in PVD. Stable PGI2-mimetics inhibit platelet activation by all endogenous mediators as well as platelet release of mitogenic factors (PDGF).

Topics: Animals; Blood Platelets; Cardiovascular Agents; Clinical Trials as Topic; Diabetic Angiopathies; Disease Models, Animal; Double-Blind Method; Epoprostenol; Humans; Iloprost; Infusions, Intravenous; Microcirculation; Random Allocation; Rats; Thrombosis; Ulcer; Vascular Diseases

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

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

The aim of this study was to assess the tolerance and report obtained results with a stable prostacyclin analogue (iloprost) in diabetic patients with severe forms of permanent lower limb ischaemia.. Sixty-four consecutive unselected patients, in stage III and IV of Leriche and Fontaine, turned down for vascular surgery after angiography and treated with iloprost during 28 days, were enrolled in this study. Patients were followed-up clinically (ischemic pain, trophic change, walking distance) and with transcutaneous oxymetry (D28). Long-term assessment (6 and 12 months) was expressed as rate of death, major amputation and of live patients with viable limbs and walking. There was no manifestation of intolerance to iloprost. Were considered as responders patients offering a lack or significant decrease in pain, a reduction of trophic lesions and improvement or recovery of walking.. Response at two months is lasting: 29 responders (45.3%) and 35 non-responders (54.7%). At 6 months and one year, we observed that 8 (12.5%) and 15 (24.1%) patients respectively had died; 19 (29.6%) and 22 (34.3%) patients underwent major amputation, but 41 (64%) and 34 (53.1%) patients were still alive with their limb and conservative walking. In responder group, at 6 months, 28 (96.5%) patients were alive without amputation for only 13 (37.1%) among non-responders. At one year, 79.3% of the responders and 31.4% of the non-responders were alive without amputation. A total loss of walking, a segmental amputation and a previous amputation of opposite limb were more often noted in no responder group. But no predictive factor was referred to TcPO(2) in particular. Results ware similar in the group of 136 non diabetic patients treated during the same period (67.9% alive with limb at 6 months).. This retrospective study, despite its limitations, underlines the clinical particularities of critical ischaemia in diabetics and the good tolerance to iloprost. This point allowed patients, in non-surgical chronic critical ischaemia, to avoid being confined to bed and to access to benefits of a early physiotherapy, in association with local treatment. However, no predictive criterion of long-term results could be established, except initial clinical severity and clinical change one month after treatment.

Topics: Aged; Aged, 80 and over; Amputation, Surgical; Diabetic Angiopathies; Female; Humans; Iloprost; Ischemia; Leg; Male; Middle Aged; Predictive Value of Tests; Retrospective Studies; Treatment Outcome; Vasodilator Agents

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

The authors, after examination of pharmacologic profile of Iloprost, prostacyclin synthetic analogue, report their clinical experience from January 1992 to June 1997 on 105 patients with severe ischaemia of inferior limbs. They utilize two protocols: 0.5-2 ng/kg/min x 6 hs once a day x 28 days and 1-1.5 ng/kg/min x 6 hs twice a day x 12 days. The first protocol were practise along the first 2 years; the second on following period as long as today. The results, evaluated on clinical criteria, are referred entity and time of pain remission and decrease of analgesic use, performance status improvement, increase of gear autonomy and, if present, wound healing. The incidence of amputation was 4.76% (5 pts). The authors issue that Iloprost is a conservative treatment, often alternative with amputation, giving sometimes to patients a longtime functional "restitutio ad integrum".

Topics: Arterial Occlusive Diseases; Critical Illness; Diabetic Angiopathies; Follow-Up Studies; Humans; Iloprost; Infusion Pumps; Ischemia; Leg; Treatment Outcome; Vasodilator Agents

Topics: Adult; Cardiovascular Agents; Diabetic Angiopathies; Epoprostenol; Humans; Iloprost; Ischemia; Leg; Male