Treadmill exercise-induced release of endothelin-1 in patients with peripheral arterial occlusive disease at Fontaine stage IIb.

BACKGROUND: Endothelin-1 (ET-1) is an endothelial vasoconstrictor mitogenic peptide which is thought to be a marker of endothelial damage and a potential participant in the pathophysiological processes of the development of atherosclerotic lesions and disease states associated with vasoconstriction and vasospasm. METHODS: To investigate the endothelin-1 release in response to dynamic exercise in patients with peripheral arterial occlusive disease (PAOD), plasma concentrations were determined by radioimmunoassay in 16 patients (14 men, 2 women, mean age 56.2 +/- 8.1 years) with peripheral arterial occlusive disease at Fontaine stage IIb and in 10 control subjects (8 men, 2 women, mean age 58.1 +/- 7.2 years) in normal health during treadmill testing (slope 5%, speed 3 km/hr). Blood samples were collected at rest from an antecubital vein, at the onset of claudication pain, and 10 minutes after exercise. RESULTS: Mean plasma endothelin-concentrations during the stress test increased significantly in the patients with arterial disease, rising from basal values of 4.4 +/- 0.6 pmol/L to values of 8.9 +/- 0.7 pmol/L at the end of the test (p < 0.0001), whereas it did not change significantly in control subjects (rising from 2.6 +/- 0.4 pmol/L to 2.7 +/- 0.5 pmol/L). Further, plasma endothelin- in the patients with arterial disease was at all times higher than in the control subjects (p < 0.0001). CONCLUSIONS: In conclusion, this study shows that in patients with peripheral arterial occlusive disease, plasma endothelin-1 increases after treadmill exercise performed until claudication pain supervenes. Raised endothelin-1 could be a marker of ischaemic acute endothelial damage and/or could contribute to increase the vascular resistance in ischaemic limbs of these patients during dynamic exercise by promoting arterial/arteriolar vasoconstriction or vasospasm.     

Comparison of the effectiveness of physical training with parenteral drug therapy in Fontaine stage IIb peripheral arterial occlusive disease]

In an open, randomized study in patients with peripheral arterial occlusive disease in state IIb according to Fontaine the clinical efficacy and tolerability of Actovegin upon intravenous and intraarterial application was examined compared to vascular training. 30 patients were included in each of the three therapy groups. Over a period of four weeks each patient received daily therapy--except for weekends. Patients of group I received a daily intravenous infusion of 250 ml Actovegin 20% p.i. the patients in group II received this medication by the intraarterial route. The third patient group received standardized vascular training. From a total of 90 patients 73 completed the study according to the study protocol. In all three groups the therapy resulted in the improvement of pain-free and pain-limited walking distances. Upon comparison of relative changes in the intraarterial and intravenous group significant differences turned out: whereas patients in the intravenous group achieved a mean increase in pain-free walking distance of 37.8%, a mean increase in walking distance of 44.9% in the intraarterial group was observed. With respect to maximum walking distances the relative improvements amounted to a mean of 44.0% in the intravenous group, and 64.3% in the intraarterial group. After training over four weeks in the vascular-training group the patients achieved a mean increase in pain-free walking distance of 69.6% and 53.5% in pain-limited walking distance. This meant a significantly greater improvement in pain-free walking distance compared to the intravenous group; the difference compared to the intraarterial group was not significant; however the mean values indicated that the vascular-training group showed greater improvements in pain-free walking distance, and more moderate improvements in maximum walking distance than the intraarterial group. However, these results were significantly modified, if a differentiation was made in the vascular-training group between patients with high and low compliance. In the patients' rating all three therapies were described as throughout beneficial, however, less positive for the intravenous therapy, which is in accordance to the results of changes in walking-distance. The results of the present study are discussed having in mind physical therapy being limited through contraindications and insufficient patient compliance.     

Clinical efficacy of IV prostaglandin E1 and IV pentoxifylline in patients with arterial occlusive disease of fontaine stage IIb: A multicenter,randomized comparative study

The IV infusions of both prostaglandin E₁ (PGE₁) and pentoxifylline showed good efficacy in prolonging the claudication distance and maximum walking range of patients with intermittent claudication, and the Doppler pressures were used as parameters of efficacy. IV PGE₁ was significantly superior after 4 weeks' therapy as to both claudication distance and maximum walking range. The ankle pressure indices were significantly elevated in both groups at the end of therapy. The therapeutic effect proved to persist in both groups after a 12 month follow-up, with adverse reactions occurring in two patients treated with PGE₁ and in six patients treated with pentoxifylline. The study supports the view that the intravenous infusion of PGE₁ is an efficacious and well-tolerated therapy for intermittent claudication.     

Haemodilution with medium molecular weight hydroxyethyl starch in patients with peripheral arterial occlusive disease stage IIb.

The basic therapy of peripheral arterial occlusive disease stage IIb, according to Fontaine, is exercise. It should be determined whether a mild hypervolaemic haemodilution with hydroxyethyl starch or Ringer lactate can produce a further increase in walking distance. For this purpose, three groups of 25 patients each were formed. One group exercised three times weekly and the second group, in addition to exercise, underwent a mild hypervolaemic to isovolaemic dilution therapy with HES for a period of 6 weeks. In the final group the haematocrit was reduced to the same extent by venesections and volume substitution using Ringer lactate. The walking distance in the HES group increased from 216 m to 311 m (44%), in the Ringer lactate group from 214 m to 258 m (20%), and in the exercise group from 213 m to 242 m (14%). On comparison of the groups, the increase in pain-free walking distance in the HES group differs significantly (P less than 0.05) from that achieved in the other groups. It was demonstrated that haemodilution with HES in combination with exercise brings about a clinical effect three times that achieved by exercise alone. Venesection with subsequent administration of Ringer lactate and exercise is superior to exercise alone but markedly inferior to the combination therapy with HES.     

Meta-analysis of randomised controlled prostaglandin E1 studies in peripheral arterial occlusive disease stages III and IV

BACKGROUND: The relevance of Prostaglandin El (PGE,) in the treatment of peripheral arterial occlusive disease stage III and IV was to be evaluated for the first time by a meta-analysis. PATIENTS AND METHODS:Altogether, 643 patients were analyzed from seven randomized, controlled PGE1 studies that were comparable with regard to patient selection, study design and endpoints. Of these, only placebo-controlled studies (n = 254) were included in the formal meta-analysis using the method of DerSimonian and Laird. Additionally, the response rate and the rate of adverse events were determined for the pooled groups of all studies. RESULTS: At the end of treatment, PGE1 showed a significantly better response (ulcer healing and/or pain reduction) as compared to placebo (47.8% for PGE1, vs. 25.2% for placebo, p = 0.0294). A significant difference in favor of PGE1 was also seen for the combined endpoint "major amputation or death" after 6-month follow-up (22.6% for PGE1 vs. 36.2% for placebo, p = 0.0150). The response rate (ulcer healing and/or pain relief) of the pooled treatment groups was 60.2% for PGE1, 25.2% for placebo, and 53.6% for iloprost. The adverse events rate of the pooled treatment groups showed good tolerability for PGE, with a rate of 39.6% in comparison to 73.9% for iloprost and 15.4% for placebo. CONCLUSION: For patients with peripheral arterial occlusive disease stage III or IV not eligible for arterial reconstruction, PGE1 therapy not only has significant beneficial effects over placebo on ulcer healing and pain relief but also increases the rate of patients surviving with both legs after 6-months follow-up.     

Mechanisms of action of prostaglandin E1 in therapy of peripheral arterial occlusive diseases

Mode of action of prostaglandin E1 in the treatment of peripheral arterial disease. Prostaglandin E1 has been used for the first time in the treatment of peripheral arterial occlusive disease 30 years ago. Although widely used, the exact mechanism of the known beneficial effects is not completely understood. A strong vasodilation is induced after intra-arterial administration of PGE1, but is not seen, when PGE1 is intravenously infused. Because of the clinical efficacy of intravenously given PGE1, vasodilation is not considered as important mode of action. Many effects of PGE1 has been described on cellular factors in the blood, hemostasis and fibrinolysis and endothelium. Some of these effects are discussed.     

Tissue concentrations of ofloxacin in necrotic foot lesions of diabetic and non-diabetic patients with peripheral arterial occlusive disease

Six diabetic patients with infected foot lesions (mean age 64 years) and six male patients (mean age 71 years) with ischemic acral ulceration due to advanced peripheral arterial occlusive disease were treated with 200 mg ofloxacin b.i.d. The necrotic margin tissue concentrations of ofloxacin determined by HPLC and confirmed by microbiological assay were in the same range (1.6 to 6.4 mg/kg) as plasma levels (1.6 to 5.9 mg/l). No difference of plasma and tissue concentrations was found between patients with peripheral vascular disease and diabetics, respectively. After three weeks treatment bacterial wound pathogens disappeared in 7 subjects, changed in 4 patients and were resistant in one patient. Clinical improvement appeared in 9 of 12 patients after three weeks of therapy. Satisfactory tissue levels of orally administered ofloxacin were achieved in the infected necrotic tissue area of diabetic and non-diabetic patients with impaired peripheral arterial circulation.     

Hemostatic and fibrinolytic effects of systemic prostaglandin E1 therapy in patients with peripheral arterial disease

BACKGROUND: The study was designed to evaluate if there is any evidence of a hyperfibrinolytic bleeding-risk under systemic treatment with prostaglandin E1 (PGE1) of patients with peripheral arterial disease (PAD). PATIENTS AND METHODS: The in vivo effect of PGE1 on the fibrinolytic and hemostatic process was tested on 15 patients before and after treatment with Alprostadil for 21 days using D-dimers (DD), fibrinogen, prothrombin time (PT), partial thromboplastin time (PTT), antithrombin (AT), ProC-Global, plasminogen, plasminogen activator inhibitor activity (PAI), alpha 2-antiplasmin, coagulation factor XII, basal and activated fibrinolytic capacity (fib. cap.). RESULTS: There was no significant difference in DD, fibrinogen, PT, PTT, AT, ProC-Global, plasminogen, PAI, alpha 2-antiplasmin, coagulation factor XII, basal and activated fibrinolytic capacity observed after the treatment. CONCLUSION: Summarizing this study there is no hyperfibrinolytic bleeding-risk after the systemic therapy with Alprostadil to be expected.     

前列腺素E1对先心病重度肺动脉高压患者肺组织结构的影响

选择 2 8例先心病重度肺动脉高压患者 ,在应用前列腺素 E1 (PGE1 )前后行肺组织活检术 ,光镜下观察肺小动脉组织结构及其变化特点。用法 :PGE1 15～ 2 5 ng/ (kg·min)持续静滴 ,每天用药 10～ 12 h,14 d为 1疗程。结果示有 2 6例患者的肺组织结构明显改善 ,病理损害减轻 ,其他 2例无变化。认为应用 PGE1 治疗能够改善肺组织结构 ,使病情减轻 ,且能提高手术治愈率     

前列腺素E_1治疗周围动脉硬化闭塞症的临床观察

目的　总结 1984～ 2 0 0 0年应用前列腺素E1 (PGE1 )治疗周围动脉硬化性闭塞症 (PAOD)的临床效果。方法　回顾研究 4 4 8例PAOD患者应用PGE1 治疗的效果 ,其中男性 383例 ,女性 6 5例 ,年龄 4 3～ 89(6 1.4 )岁。应用PGE1 10 0～2 0 0 μg静点一日一次。结果　效果优良者 30 2例 (6 7.4 % )、差者 35例 (7.8% )、无效 30例 (6 .7% )、截肢 6 8例 (15 .2 % )和死亡 13例 (2 .9% )。结论　PGE1 是治疗PAOD效果良好的药物     

Treatment of complications of peripheral obstructive arterial disease with prostaglandin E1

Forty-one subjects diagnosed with complications of peripheral obstructive arterial disease were treated with continuous infusions of Prostaglandin E1 (PGE1) over a three-week period during 1981-1982 in an open-label, uncontrolled study under ward conditions. Ischemic rest pain and ulcers were treated with intravenous infusions of PGE1 at dose rates of 14-21 ng kg-1 min-1 for seventy hours, once a week. Symptomatic relief of rest pain and spontaneous healing of stable ulcers occurred. Whereas classically dependable noninvasive circulation evaluations were not prognostic of the treatment's success, they did suggest local and rheological changes rather than a generalized vasodilation. The PGE1 infusion is efficacious for an unknown length of time, which may somehow be related to inhibition of platelet aggregation. Since transient ischemic attack (TIA) and cerebrovascular accident (CVA) were found to be associated with PGE1 infusion, cerebrovascular evaluation must be conducted prior to considering PGE1 replacement therapy for the individual patient.     

Pentoxifylline treatment in patients with occlusive peripheral arterial disease. Circulatory changes and effects on prostaglandin synthesis

Pentoxifylline has recently been reported to stimulate in vitro the synthesis of prostacyclin. However it is not known so far whether the drug is able to stimulate prostacyclin synthesis in man also in vivo. In the present study the effects of pentoxifylline on prostaglandin synthesis and several circulatory parameters were studied in 10 controls and 10 patients with occlusive arterial disease after acute i.v. and medium term oral treatment. Prostacyclin (as 6-keto-PGF1 alpha) and PGE2 plasma concentrations have been measured together with arterial blood flow, peripheral vascular resistance, platelet aggregation and red blood cell deformability. Pentoxifylline was found both in healthy subjects and patients to significantly increase prostacyclin plasma concentration after i.v. treatment. In medium term oral treatment prostacyclin concentration was found to increase only two hours after administration and not 8 hours after. No significant variations in PGE2 plasma concentration were found at any time in both groups. Pentoxifylline significantly enhanced resting and post-ischemic blood flow of the lower limbs and simultaneously decreased peripheral vascular resistance both in healthy subjects and patients. Different grades of delayed platelet aggregation and increased red blood cell deformability were also observed. In conclusion results of the present placebo controlled study show that pentoxifylline increases arterial blood flow in patients with occlusive arterial disease. Moreover pentoxifylline induces a temporary stimulation of prostacyclin synthesis which can be suggested to contribute to the clinical activity of the drug as far as an antithrombotic effect in terms of inhibition of platelet aggregation is concerned.     

Preliminary evaluation of AS-013 (prodrug of prostaglandin E1) administration for chronic peripheral arterial occlusive disease

Prostaglandin E₁ (PGE₁) and one of its prodrugs, AS-013, were formulated in lipid microspheres (lipo-PGE₁ and lipo-AS, respectively), and their acute clinical efficacy and safety were compared in a randomized, placebo-controlled, single-blind test. Lipo-PGE₁ (10 µg), lipo-AS (5 µg), or an inactive placebo was intravenously administered to human subjects once daily for 3 days. The acute efficacy of lipo-PGE₁ and lipo-AS was each quantitatively assessed in male patients with chronic peripheral arterial occlusive diseases (PAOD) by measuring ankle brachial pressure, skin temperature, transcutaneous oxygen pressure (tcPO₂), transcutaneous carbonic dioxide pressure, and cutaneous blood flow (BF) with a laser Doppler flowmeter during and after administration of each drug. Informed consent was obtained from all patients. Laboratory data did not suggest any adverse effect of lipo-AS administration, which significantly improved tcPO₂ and BF, suggesting that the microhemorrheological effects of lipo-AS are of potential therapeutic value in the treatment of PAOD.Presented at the 37^th Annual World Congress, International College of Angiology, Helsinki, Finland, July 1995.