Microcirculation and tolerability following i.v. infusion of PGE1 and iloprost: a randomized cross-over study in patients with critical limb ischemia.

In a randomized cross-over study, the effect of PGE(1) and iloprost on microcirculation as well as the tolerability was investigated in 36 patients with peripheral arterial occlusive disease stage III and IV according to Fontaine. Patients received PGE(1) and iloprost by single 3-h i.v. infusions on two different days at doses recommended by the manufacturers or in previous studies (PGE(1): first hour 20 microg, next 2h 30 microg each. Iloprost: first hour 0.5 ng/kg/min, next 2h 1.0 ng/kg/min). Transcutaneous oxygen pressure (tcPO(2)) values increased much more with PGE(1). Median tcPO(2) increase over baseline 30 min after the end of infusion was 9 and 2 mmHg for PGE(1) and iloprost, respectively, corresponding to median AUC differences from baseline of 1050 and 210 min mmHg. Because of its exploratory character, the study was not powered to test for significance. Adverse effects occurred in 19.4% (PGE(1)) and 30.6% (iloprost) of patients. Dose reduction was required in 3 patients receiving iloprost (hypotension, nausea, irritation of the infused vein), and in none receiving PGE(1).

[DRG-based cost analysis of inpatient conservative treatment of stage III/IV peripheral arterial occlusive disease]. / DRG-basierte Kostenanalyse zur stationären konservativen Behandlung der PAVK Stadium III/IV.

UNLABELLED: DRG-based cost analysis of inpatient conservative treatment of PAD stage III/IV BACKGROUND: In a prospective study carried out by the German Society of Angiology and the DRG Competence Center, Munich, the question was investigated whether the costs of conservative treatment of patients with PAOD stage III/IV (DRG F65) are adequately represented within the current G-DRG system. METHODS UND PATIENTS: Between September 1 and December 16, 2002, a total of 704 patients with DRG F65 (peripheral vascular diseases) were evaluated at 8 angiologic centers in Germany. Apart from the length of hospital stay, the total costs (cost equivalents) were calculated using a method developed by the DRG Research Group at the University of Münster. Moreover, the study population was compared with a German calculation sample for the DRGs F65A/B, as published by InEK. RESULTS: As it turned out, conservatively treated patients with PAOD stage III or IV (DRGs F65A/B) cause significantly (p < 0.001) higher costs and have significantly (p < 0.001) greater lengths of hospital stay than patients who were also assigned to DRG F65 because of other vascular diseases. At the same time it became clear that angiologic centers treat twice as many patients with critical limb ischemia in comparison with the German average. The reimbursement hitherto estimated by InEK covers not even half the cost actually produced by conservative treatment of PAD stage III/IV. CONCLUSION: To ensure a performance-related reimbursement, a new basis DRG for patients with PAD stage III/IV has to be created, as has ben proposed by the German Society of Angiology. Otherwise, adequate conservative therapy in accordance with existing guidelines, of patients who cannot be treated surgically or interventionally will not be possible any more in the future.

Improvement of peripheral and cardiopulmonary performance after a short-term exercise program with additive prostaglandin E1.

In patients with intermittent claudication, the walking distance can be increased, both by means of several months of intensive training and administration of IV prostaglandin E1 (PGE1) for 4 weeks. The aim of this study was, therefore, to investigate whether the combination of intensive training and PGE1 infusions during pedalergometry can increase peripheral and cardiopulmonary performance after 2 weeks. Ten patients with intermittent claudication received a once-daily intravenous infusion of 60 microg PGE1 over 2 hours during pedalergometry. In addition, a physical training program was carried out mornings and afternoons, as well as progressive treadmill training. Walking distance (3 km/h, 12%) and cardiopulmonary performance were determined at the beginning and end of the 2-week treatment. Results were compared with those of a historical control group having received a similar training program without PGE1. The initial walking distance increased from 71 to 166 m (134%). At the same time, peak work load increased by 108%, and the physical work capacity by 100%. Cardiopulmonary function improvement was reflected in all the parameters investigated (peak VO2; peak VO2/peak work load ratio; slope of deltaVO2/deltat; RER). Compared with the historical control group, the difference between the two groups with regard to the increase in walking distance was significant in favor of the combined training program with PGE1. The combination of short-term intensive training and PGE1 infusions during pedal ergometry significantly improves both the peripheral as well as the highly restricted functional capacity in patients with intermittent claudication.

Randomized reliability study evaluating constant-load and graded-exercise treadmill test for intermittent claudication.

The aim of this randomized study was to compare the reliability of the treadmill test at constant-load (C-test, 3 km/hr; fixed grade of 12%) recommended in Germany with that of the graded-exercise test (G-test, 3 km/hr; increase in grade of 3.5% every 3 minutes) propagated in the United States. In 50 patients with an absolute claudication distance (ACD) in the C-test of between 50 and 400 m, the two treadmill tests were carried out in randomized order on one and the same day, and repeated on 3 days within 1 week. For the initial claudication distance (ICD), the intraclass correlation was 0.88 in the C-test and 0.87 in the G-test. For the ACD the coefficients were identical at 0.91. The within-subject variation (CVwithin) in the C-test and G-test was 25% and 27% for the ICD and for the ACD 24% and 21%, respectively. The between-subject variation was very similar with 72% and 73% (ICD) and with 78% and 68% (ACD). However, in ACDs below 100 m and between 100 to 150 m, the C-test showed significantly smaller coefficients of variation than the G-test: 13% vs 81% and 14% vs 50%, respectively. In conclusion, the results showed that both C-test and G-test are equally well reproducible.

Effects of prostaglandin E1 metabolites on the induction of arterial thromboresistance.

Prostaglandin (PG) E1 has been shown to induce arterial thromboresistance in experimental animals and in man. It is known to be degraded in vivo to metabolites which have comparable (13,14-dihydro-PGE1) or no (15-keto-PGE1, 15-keto-13,14-dihydro-PGE1) biological activity. It was the goal of this study to examine whether 13,14-dihydro-PGE1 and its derivatives might share biological activity in rendering the arterial wall less thrombogenic. Using a cross-perfusion technique the aorta and iliac artery surface were exposed to a donor rabbits' blood. We examined the intact endothelial lining and a surface which had been deendothelialized before by means of a Fogarty catheter. Donor animals and/or receiver animals were treated daily for 1 week with 13,14-dihydro-PGE1, PGE1, 15-keto-PGE1, 15-keto-13,14-dihydro-PGE1, or the vehicle only, respectively. From the group of the receiver animals, a subgroup of 6 animals each was treated for the same period of time with either 13,14-dihydro-PGE1, PGE1, 15-keto-PGE1, 15-keto-13,14-dihydro-PGE1, or the vehicle. Immediately after the last administration of the respective PG or solvent, native blood from a donor rabbit was circulated [30 mL/min. under in vivo flow conditions (60 Hz)] over an arterial segment of a receiver animal. Deposition of 111Indium-oxine labeled autologous platelets per surface unit was quantitatively assessed. In vitro perfusion data were morphometrically analysed. In animals pretreated with 13,14-dihydro-PGE1 the thromboresistance was almost comparable to that achieved with PGE1. In contrast, pretreatment of the donor animals (platelet) had only minor effects on the thromboresistance. The other compounds showed no effects. In vitro perfusion of human saphenous vein segments revealed PGE1 and 13,14-dihydro-PGE1 again to be of comparable potency, while 15-keto-PGE1 and 15-keto-13,14-dihydro-PGE1 were only active at concentrations being several orders of magnitude higher. Not only PGE1 but also its in vivo formed metabolite PGE0 may play an important role in inducing improvement of haemostatic balance via the vascular wall rather than the platelets. The other metabolites, however, are unlikely to exhibit an effect at biologically relevant concentrations.

Treadmill testing for evaluation of claudication: comparison of constant-load and graded-exercise tests.

OBJECTIVES: To compare the correlation and practicability of single-stage vs. graded treadmill protocols in the assessment of the absolute claudication distance (ACD). DESIGN: Randomized open study. MATERIAL AND METHODS: In 52 patients with peripheral arterial occlusive disease, the ACD on treadmill at 3 km/h and 12% grade (constant-load test = C-test) ranged form 50 to 400 m. The C-test and the graded-exercise test (walking on the treadmill at 3 km/h and 0% gradient for 3 min, with subsequent increase in gradient of 3.5% every 3 min = G-test) were carried out at random on the same day under standardized conditions. RESULTS: The ACD was higher in the G-test than in the C-test (360.4 +/- 208.8m vs. 166.5 +/- 93.6m; p < 0.001). The coefficients of variation were very similar (57.9% and 56.2%, respectively). In the subgroup of patients with an ACD of between 100 m and 150 m, a large difference was found both for the coefficient of variation (58.6% G-test, 9.6% C-test) and for the standard deviation (339.8 +/- 199.0m and 133.1 +/- 12.8m, respectively). CONCLUSIONS: For the assessment of the ACD in patients with severe claudication the C-test would seem to be more suitable than the G-test.

Improvement in the quality of life after i.v. PGE1 therapy for intermittent claudication.

BACKGROUND: Increasingly and justifiably, clinical studies are now being expected to investigate the influence of therapeutic measures also on the quality of life of the patient. PATIENTS AND METHODS: Since no data on the variability of changes in the quality of life of the patient following PGE1 treatment are so far available, the initial investigation was designed as an uncontrolled pilot study. 104 patients (median age 64.5 years) with a maximum of walking distance on the treadmill (3 km/12%) of 50-250 m were included and given a daily intravenous infusion of 60 micrograms PGE1 (Prostavasin) over a period of 4 weeks excluding weekends. This was followed by a treatment-free follow-up period of 3 months. Changes in the quality of life were recorded with both the newly developed disease-specific questionnaire PAVK-86, and the generic questionnaire SF 36; in addition, the pain-free and maximum walking distances on the treadmill were also established prior to and immediately following treatment, as also at the end of the follow-up period. RESULTS: The quality of life was significantly improved in all dimensions (functional status, complaints, pain, mood, anxiety, social life, treatment expectations) in addition to a marked increase in the median pain-free walking distance from 77 to 108 m (p < 0.001) and the maximum walking distance from 118 to 171 m (p < 0.001). At the end of the 3-month observation period, the improvement was essentially still demonstrable. CONCLUSION: The study has shown for the first time that treatment with intravenous PGE1 brings about not only the already known increase in the walking distance, but also a clinically relevant and significant improvement in the patient's quality of life.

PGE1-induced arterial thromboresistance is a vascular property as identified by cross-perfusion technique.

Prostaglandin (PG) E1 has been shown to improve thromboresistance. This experiment was designed to examine whether an effect on the arterial wall or the platelets is responsible for this phenomenon. Using a cross-perfusion model, the aortic and iliac artery endothelium of rabbits was removed by a balloon catheter before being perfused with blood of donor rabbits. Donor and/or receiver animals were treated with 20 microg PGE1 or vehicle (cyclodextrin) intravenously daily for 1 week. After the last administration of PGE1 or its vehicle, the animals were killed and native blood from a donor rabbit was recirculated (30 ml/min) via a deendothelialized segment of a receiver rabbit. The contact (C) and spread (S) platelets as well as the denuded surface covered with platelet aggregates (> 5 microm in height) were quantified by morphometry. Deposition of (111)In-oxine labeled autologous platelets was quantitatively determined per surface unit. In addition, PGI(2)- and TXB2-formation by the denuded aortic and iliac artery segments was determined. Pretreatment of receiver rabbits with PGE1 resulted in morphometrically assessed decreased platelet adhesion and aggregation, even when the donor rabbit was vehicle-treated. A vehicle-treated receiver rabbit, in contrast, shows platelet deposition comparable to controls, even if the donor rabbit was PGE1-pretreated. Treatment of donor animals with PGE1 did not result in a reduction in thrombogenicity. The beneficial in vivo PGE1 action of decreased arterial thrombogenicity is thus mediated by an effect on the vascular wall rather than on circulating platelets.

Efficacy of a new prostaglandin E1 regimen in outpatients with severe intermittent claudication: results of a multicenter placebo-controlled double-blind trial.

For the first time efficacy and safety of a new prostaglandin E1 (PGE1) regimen in the treatment of intermittent claudication were evaluated in a randomized, double-blind, placebo-controlled multicenter clinical trial. The study involved 213 outpatients with a maximum walking distance of 50 to 200 m measured on the treadmill (3 km/hr, 12% grade). After a 2-week run-in phase they received a 2-hour intravenous infusion of 60 micrograms PGE1 or placebo 5 days a week for 4 weeks. It was followed by a 4-week interval treatment with the same medication administered only twice a week. Patients were monitored for 3 months when they received no study medication. In the PGE1 group the intention-to-treat analysis (n = 208) revealed an increase in walking distance after 4 weeks of 75% (placebo, 43%). At the end of the interval treatment the walking distance had improved to 101% (placebo, 60%). The results remained virtually constant during follow-up (PGE1, 104%, placebo, 63%). Between-group comparisons showed significant differences in favor of PGE1 for all three time points of measurement (p < 0.05, p < 0.01, and p < 0.05). PGE1 was well tolerated; the rate of adverse reactions related to the treatment was 12.8% (placebo, 7.7%). In summary, these results show that the new PGE1 regimen is effective and safe in the treatment of outpatients with intermittent claudication.

Prostaglandin E1 decreases circulating endothelial cells.

Prostaglandin E1 (PGE1) has been claimed to have cytoprotective effects and also to decrease thrombogenicity. The effect of intraarterial (i.a.) and intravenous (i.v.) administration of PGE1 on the number of circulating endothelial cells (CEC) was investigated in patients with peripheral vascular disease (PVD). Patients with hyperlipoproteinemia and also smokers exhibited higher numbers of CEC. PGE1 significantly (p < 0.01) decreased CEC. In parallel, plate let survival was prolonged (r = 0.82). This effect lasted for more than a month after stopping PGE1-therapy. The observed decrease in CEC reflects the decreased thrombogenicity and improved haemostasis achieved after PGE1.

[Development of an illness-specific instrument for assessment of quality of life in patients with arterial occlusive disease (Peripheral Arterial Occlusive Disease 86 Questionnaire)]. / Entwicklung eines krankheitsspezifischen Instruments zur Erfassung der Lebensqualität von Patienten mit arterieller Verschlusskrankheit (PAVK-86 Fragebogen.

Impairment in health-related quality of life in patients with peripheral arterial occlusive disease (PAOD) are well-known to clinicians, but due to the lack of disease specific assessment instruments, have not been systematically investigated. We describe the development and psychometric testing of a 86-items patient-based questionnaire for the assessment of the quality of life in PAOD containing 7 dimensions: functional status, pain, symptoms, mood, disease related anxiety, social life and treatment evaluation. The questionnaire was included along with standard questionnaires in a prospective study with 308 patients suffering from PAOD in Fontaine stages I to IV before and one week into treatment. Psychometric testing pertained to reliability (internal consistency, retest), validity (convergent, discriminant) and sensitivity (treatment-related change over time). In addition patient acceptance of the questionnaire was assessed. Psychometric testing yield exellent results regarding scale structure and reliability of the newly developed questionnaire. Validity was reflected in high correlations with standard generic questionnaires and in discriminating in quality of life between patients according to disease severity. The sensitivity was reflected in improved quality of life ratings in patients with improved treadmill performance. Patients needed 20 minutes for responding and rated the questionnaire to be easily understandable and not exhausting. These results show that the newly developed PAVK-86 questionnaire is a reliable, valid and sensitive instrument for the assessment of quality of life in patients with arterial occlusive disease which can be used in clinical studies, epidemiological research and quality assurance programs.

Prostaglandin E1 increases binding of 123I-low-density lipoprotein to the human liver in vivo.

Previous in vitro radioligand binding data have shown that prostaglandin E1 (PGE1) increases the number and the binding affinity of low-density lipoprotein (LDL) receptors of the human liver. Experimental data in normo- and hypercholesterolaemic rabbits have confirmed these findings, showing a significant increase in LDL-binding to the liver in vivo after prolonged PGE1 therapy. METHODS. This study aimed to confirm the experimental and animal data in human in vivo. 123I-LDL binding to the liver was quantified in vivo in patients suffering from peripheral vascular disease, seven of them with heterozygous familial hypercholesterolaemia (HC) and five with normal total plasma cholesterol, after PGE1 administration (5 ng.kg-1.min-1; 6 h daily for 5 days/week for 5 weeks). LDL uptake by the liver was quantified by single photon emission computer tomography (SPECT). RESULTS. The amount of LDL trapped by the liver in normocholesterolaemics (45.6%) was significantly higher than in hypercholesterolaemics (22.0%). PGE1 induced an increase in liver LDL binding, which was more pronounced in HC (+38.2%) than in normocholesterolaemic patients (+8.11%).

[Quality of life in peripheral arterial occlusive disease. Multicenter study of quality of life characteristics with a newly developed disease-specific questionnaire]. / Lebensqualität bei peripher-arterieller Verschlusskrankheit. Multizentrische Untersuchung zur Lebensqualitätscharakteristik mit einem neu entwickelten krankheitsspezifischen Fragebogen (PAVK 86).

AIM: Owing to a lack of disease-specific measuring instruments, no systematic investigations of the impairment of the quality of life in patients with peripheral arterial occlusive disease (PAOD) have so far been possible. The aim of the present study, therefore, was to develop an appropriate questionnaire and to submit it to a psychometric test in a sufficiently large number of patients. PATIENTS AND METHOD: A disease-specific questionnaire comprising 86 individual items was developed (PAVK 86) and was tested in a longitudinal study involving 308 patients with confirmed peripheral arterial occlusive disease, Fontaines's stages I to IV. At the same time, three established generic questionnaires were also employed (SF 36, NHP, Every Day Life). RESULTS: Analysis showed that, in comparison with a normal population, the quality of life in patients with PAOD is considerably impaired, in particular by pain, anxiety, general complaints and reduced physical mobility and performance, and is comparable with that of patients suffering from renal carcinoma. In Fontaine's stage III and IV, the quality of life is significantly more greatly impaired than in patients with stage II disease. No differences in quality of life were to be found between Fontaine's stages III and IV. The psychometric test revealed that the PAVK 86 questionnaire is a sensitive, reliable, valid and practicable measuring instrument. CONCLUSION: The PAVK 86 questionnaire is suitable for determining the course and outcome of therapeutic measures on the quality of life of PAOD patients, and can therefore be included in clinical studies. In addition, its use in combination with established generic questionnaires also permits a comparison with age-matched healthy control groups, and is thus also of importance for the assessment of aspects of health economics.

PGE0 inhibits collagen and glycosaminoglycan-synthesis in the rabbit arterial wall.

The influence of 13,14-dihydro-PGE1 (PGE0), a biologically active metabolite of PGE1, on collagen and glycosaminoglycan synthesis by the rabbit arterial wall was assessed and compared with the effect of PGE1. Collagen (COL) and glycosaminoglycan (GAG) synthesis was measured using 14C proline- and 35S-incorporation respectively and both were subsequently quantified by autoradiography. PGE1 decreased GAG-synthesis by 40%, while PGE0 caused a 25% decrease. COL-synthesis after PGE1 treatment was diminished by 35%, while the biologically active metabolite caused a drop of 30%. Five and 15 micrograms/kg doses of both compounds were almost equally effective, 1 microgram was without effect. These findings indicate that PGE0 shares the inhibitory effect of PGE1 on COL and GAG biosynthesis. This metabolite has about 60 to 70% of the biological activity of its parent compound PGE1. These results suggest that part of the effects of PGE1 in inhibiting extracellular matrix production could be due to its metabolite PGE0.

Prostaglandins and arterial wall lipid metabolism--in vitro, ex-vivo and in-vivo radioisotopic studies.

It is the aim of this paper to review our findings in vitro, in experimental animals and in human on arterial wall lipid metabolism. Radiolabelling of LDL indicates that experimentally induced lesions in hypercholesterolemic rabbits do show less lipid accumulation if treated with prostaglandins (PGI2, PGE1, 13,14-dihydro-PGE1) or stimulators of prostaglandin synthesis (isradipine, a calcium channel blocker of the dihydropyridine family). Endogenous blockade of cyclooxygenase by ASA-pretreatment results in a complete abolishing of this apparently PG-mediated benefit. In-vivo studies using autologous 123I-labeled LDL without therapeutic intervention exhibit a quite good reproducibility of the imaging technique. While PGE1 (at 2 different therapeutic regimens) is inducing lipid lesion regression, the comparable benefit induced by isradipine again disappears with concomitant ASA-therapy. Quantitative estimation of arterial wall lipid metabolism in patients undergoing vascular surgery demonstrates that PGI1- (and cAMP-) increase are paralleled by a several-fold increase of acid and neutral cholesterol ester hydrolase and a decrease in net arterial cholesterol ester content. This benefit again disappears with concomitant ASA-therapy. These findings are allowing to conclude that (exogenously added or endogenously stimulated) prostaglandins do significantly improve arterial wall lipid metabolism.

[The effectiveness of standardized exercise training in intermittent claudication]. / Wirksamkeit eines standardisierten Bewegungstrainings bei Claudicatio intermittens.

In stage II peripheral arterial occlusive disease (PAOD) physical training is generally the therapy of choice if no reopening procedures are indicated. The aim of this pilot study was to ascertain the increase in claudication distance due to the exclusive implementation of an intensive exercise programme under standardized conditions, for a planned double blind placebo controlled study regarding the efficacy of pharmacotherapy in addition to physical training. 23 in-patients (median age 62 years) with an absolute claudication distance on treadmill of between 50 m and 200 m (12% inclination, 3 km/h walking speed) participated 5 days a week in the following intensive standardized physical training programme: in the morning and afternoon supervised gymnastics for about 30 minutes, followed by 2 cycles of treadmill exercise each amounting to 66% of the absolute claudication distance. After a training programme of 4 weeks the mean initial claudication distance rose significantly from 83 m to 134 m (61%), as did the mean absolute claudication distance from 127 m to 222 m (75%). If an increase in claudication distance of at least 60% is taken as criterion of efficacy, 48% of the patients can be defined as responders. After completion of personal inquiries 62% of the patients were willing to participate in a similar training programme again.

Synergism between PGE1-metabolites(13,14-dihydro-prostaglandin E1, 15-keto prostaglandin E1, 15-keto-13,14-dihydro-prostaglandin E1) and nitric oxide (NO) on platelet aggregation.

A synergistic antiplatelet effect between prostaglandins (PG), cAMP-stimulators and nitric oxide (NO), a cGMP-stimulator, has already been described. Data on a synergism between NO and the metabolites of PGE1, however, are lacking so far. We therefore tested the antiplatelet activity of the metabolites of PGE1 alone and their synergism with NO on human platelets of 8 healthy volunteers in vitro. 13,14-DH-PGE1 (ID 50 = 10.8 ng/ml platelet rich plasma (PRP)) was the only PGE1 metabolite inhibiting the ADP-induced platelet aggregation, its efficacy being 76.4% of the parent compound PGE1 (ID 50 = 8.25 ng/ml PRP). NO (ID 50 = 0.52 microM) also inhibited platelet aggregation. The combined addition of 13,14-dihydro-prostaglandin E1 (13,14-DH-PGE1) and NO caused an additive effect. The other PGE1-metabolites tested, 15-keto prostaglandin (15-K-PGE1) (ID 50 = 16.2. micrograms/ml PRP) and 15-keto-13,14-dihydro-prostaglandin(15-K-13,14-DH-PGE1) (ID 50 = 14.8 micrograms/ml PRP), neither had any relevant antiaggregatory capacity themselves nor a synergistic effect with NO. These findings could be of clinical relevance as a NO-synergism may occur not only with therapeutically administered PGE1 but also with its biologically active metabolite 13,14-DH-PGE1.