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Prostaglandins, Leukotrienes and Essential FattyAcids (1996) 54(5), 327-333 Pearson Professional Ltd 1996

T r e a t m e n t of p a t i e n t s with peripheral arterial occlusive disease Fontaine s t a g e III and IV with intravenous iloprost: an open study in 9 0 0 patients
Peter Staben, Manfred Albring
Schering AG, Gesch&ftsbereich Deutschland Medizin/Gesundheitswesen, Max-Dohrn-Str. 10, D-10589 Berlin, Germany.

Summary In an open study the clinical efficacy and tolerability of the stable prostacyclin (PGI2) analogue iloprost in the treatment of 900 patients with advanced peripheral arterial occlusive disease (Fontaine stage III and IV), enrolled by 169 centres, were investigated. Of these patients, treated with infusions over 6 h daily up to 42 days, 853 could be evaluated: four were excluded because of wrong diagnosis. The responder rates, defined as pain relief, no or reduced use of analgesics (stage III and IV), improvement of trophic lesions, i.e. complete or >_50% healing of ulcers, demarcation of necroses (stage IV), and global improvement, were 75.0% and 66.0% in stage III and 46.3% and 41.8% in stage IV patients in the valid case and intention-to-treat group, respectively. A complete healing of ulcers was observed in 12.3% of those patients (n = 375) presenting with ulcerations at the beginning of treatment. Diabetic and non-diabetic patients were comparable with regard to efficacy of iloprost. 71.4% and 66.2% (stage III and IV) of initial responders at 6 months follow-up were still free from rest pain and showing complete or partial healing of trophic lesions. 7.9% of stage III and 16.9% of stage IV patients underwent major amputation during the whole study period with a reduced amputation rate in responders compared to nonresponders in stage IV. 7.9% stage III and 13.2% stage IV patients died. 83.2% and 86.0% of stage III and IV patients presented with adverse events at any time of treatment, mainly headache, nausea and flush as well as gastrointestinal symptoms, occurring mostly during the titration phase. The investigators' judgement, however, revealed a very good and good tolerability in 74.8% of stage III and in 73.7% of stage IV patients.

INTRODUCTION

The treatment of patients with severe peripheral arterial disease (PAOD) presenting with rest pain and/or trophic lesions like ischaemic ulcers or gangrenes still remains a great problem. Invasive procedures such as percutaneous

Received 28 June 1995 Accepted21 August 1995 Correspondence to: Manfred Albring, Tel. 00 49-30-3 49 89-1 61 ; Fax. 00 4 9 30-3 49 89-3 65

catheter angioplasty or surgical bypass are the first options, if the patient is suited for these procedures. Mthough this management has become more and more improved, it is applicable in about 60% of these patients only. 1 Invasive techniques are limited by a small vessel diameter and/or by a very poor distal run-off due to an impaired microcirculation. Additionally, successful surgical and interventional treatment led to a varying one-year-patency rate between 40% and 9 0 % depending on the clinical status of the patient and the procedure
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employed.2 The remaining patients require further intervention. About 200/03 to 26% 4 of all revascularized patients have to undergo an amputation within one year, with a mortality rate of 25-30% after 2 and of 50-75% after 5 years. 2 Compared to the general population of comparable age the mortality of men presenting with chronic leg ischaemia is two times higher after 5 years. 5 Therefore, an efficacious pharmacological treatment of these patients is necessary. Controlled clinical trials of medical treatment of patients with PAOD stage III and IV, according to Fontaine, employed prostanoids: prostacyclin (PGI2), prostaglandin E1 (PGE1) and the first stable prostacyclin analogue, iloprost? Six published double-blind placebo-controlled trials with iloprost showed significant beneficial effects for this compound, z-12 One study running for 14 days only did not achieve statistical significance, although the reduction of symptoms was more pronounced with iloprost than after placebo. 12A recently conducted study comparing iloprost versus alprostadil revealed a similar therapeutic effect of both drugs. However, iloprost showed a comparable efficacy in diabetics whereas alprostadil showed a much less pronounced efficacy and a poorer outcome in diabetic patients. 13 To evaluate the efficacy and tolerability of iloprost on a broader basis, a multicentre open study was performed. Since there was sufficient evidence of the efficacy of floprost from the placebo-controlled studies and for ethical reasons we decided to omit a placebo group.

sympathectomy within the last 3 months, unsuccessful bypass procedure or unsuccessful prostanoid therapy of PAOD within the last 2 months, other diseases which could call in question the conduction of the study, other reasons (for example uncooperative behaviour of the patient), which excluded a participation in the study in the investigator's opinion. Patients with impaired renal function and/or a tendency to orthostatic hypotension could be included, but a special monitoring of these patients was then required. Patients with an osteomyelitis could participate in the study, but were to be treated additionally with antibiotics as a rule. An independent ethics committee, summoned by Schering AG, gave approval for the study prior to recruitment of patients, and the study was performed according to the Declaration of Helsinki.
Treatment

PATIENTS AND METHODS Patients

The diagnosis of severe limb ischaemia was based on rest pain, trophic lesions, localization of arterial occlusions or high grade stenosis by angiography and case history with regard to smoking, diabetes mellitus, disturbances of lipid metabolism and other concomitant diseases. Patients included in the study had to fulfil the following criteria: male and female above the age of 45 years with PAOD stage III and 1V according to Fontaine secondary to obliterating arterial sclerosis or diabetic angiopathy, requiring hospitalization, and a stable clinical status of PAOD for at least 14 days before inclusion into the study. The exclusion criteria were as follows: pregnancy or lactation (premenopausal women had to be tested for pregnancy), possibility for revascularization by surgical interventions, unstable coronary heart disease, heart failure NYHA III or IV despite treatment, myocardial infarction or stroke within the last 3 months, increased bleeding tendency or pathological platelet counts (<100 x 109 or >500 x 109/1), hematocrit of >0.48 I/l, hemoglobin of <100g/1, partial amputation within the last 4 weeks,

Each patient gave written or oral informed consent, the latter in the presence of a witness. All patients were free to withdraw on their own volition from the study at any time without giving any reason, and the supervising physician or investigator could withdraw a patient from the study, if he considered a further treatment was either not indicated or possibly harmful. Iloprost (0.1 mg/ml) was diluted 1:500 with normal saline or 5% dextrose solution before infusion. This infusion solution, freshly prepared every day, was then administered by a peripheral i.v. infusion or by a central catheter, using an infusion or syringe pump. On the first 3 days the infusion was started with a dose of 0.5 ng/kg/min and then increased every 30 min by a further 0.5 ng/kg/min up to a maximum tolerated dose of 2.0 ng/kg/min. If tolerated, this last dose was maintained up to the end of the daily 6 h infusion period. If side-effects occurred, which were intolerable to the patient, the dosage was reduced in steps of 0.5 ng/kg/min until the symptoms had disappeared or had become tolerable. The dose determined on the first 3 days was then infused daily over 6 h for the whole treatment period. In case of adverse events occurring again, the dose could be reduced again as described above. Blood pressure and heart rate were measured regularly during treatment. Infusions were given over 28 days. If the patient was considered by the investigator to have improved earlier, the therapy could be stopped before, but it was recommended that a duration of less than 21 days should be avoided. A prolongation of the therapy phase up to a maximum of 42 days was permitted. Side-effects reported by the patient or observed by the medical or nursing staff were documented. Effects on hematological, biochemical and cardiac parameters were assessed by performing appropriate laboratory tests at
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Prostaglandins, Leukotrienes and Essential Fatty Acids (1996) 54(5), 327-333

Treatment of patients with peripheral arterial occlusive disease Fontaine stage III and IV with intravenous iloprost 329

admission and at the end of the 2nd and 4th week of treatment, and in case of prolongation of the trial additionally in week 6. Treatment with other compounds for therapy of PAOD or with anticoagulants except heparin was not permitted during the entire course of the study. Antibiotics, as well as a local basic therapy if necessary, such as local hygiene care, wound dressing, removal of necrotic tissue and positioning of the leg, were permitted.
Assessments

Statistics

The primary end-point was response to treatment, defined as pain relief, no or reduced use of analgesics (stage III), improvement of trophic lesions, i.e. complete or >50% healing of ulcers, demarcation of necroses (stage IV) and global improvement as assessed by the investigator. The assessment of trophic lesions was performed every two weeks by a semi-quantitative determination of the course of healing. Total healing, almost total healing and clinically relevant healing (at least 50%) of trophic lesions in terms of size and depth, good granulation and epithelialization of ulcers and in case of gangrenes/ mummifications healing or at least a status of demarcation were considered as improvement. The largest ulcer planimetric measurements and estimations of the total area as well as assessment of the degree of severity were performed every 2 weeks. The development of rest pain or pain due to trophic lesions was compared to the status at admission and assessed every week as follows: 'No pain during the last five days' before the next assessment, 'improved', 'unchanged', 'worsened'. Additionally, the patients assessed the severity of their pain using a visual analogue scale of I to 10 (1: no pain, 10: intolerable pain). The use of analgesics was assessed every week as follows: 'no analgesics during the last five days', 'decrease in use of analgesics by 50% or more', 'unchanged use of analgesics' or 'decrease of less than 50% or increased use' of analgesics. The global judgement by the investigator, based on size of ulcers, epithelialization, peri-ulcer-tissue, development of necroses, wound healing after removal of necrotic tissue, possibility for toe-amputation (distal shift of amputation level), development of pain, use of analgesics, thrombophlebitis and claudication was classified as: 'substantially improved', 'improved', 'unchanged' or 'deteriorated'. 3 and 6 months after admission to the study, besides an assessment of clinical status, trophic lesions, pain and use of analgesics, the number of patients with amputations and the number of deaths was recorded. There was an additional global and subjective judgement by the patient.
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Beside descriptive statistics (median, minimum, maximum, mean and standard error and frequency distributions) the following biostatistic methods were employed: chi-square-test for comparison of frequency distributions in subgroups, t-test for coupled values for comparison of quantitative pre- and post-treatment values and logrank-test for comparison of time points of amputations in subgroups (life table analysis). With regard to efficacy a valid case (VC) and an intention-to-treat (ITT) analysis were performed, both split into stage III and stage IV patients. The VC group included all patients treated for at least 2 l days with no interruption of treatment exceeding a total of 7 days, whereas the ITT group included all patients treated for at least 3 days.
RESULTS Baseline characteristics

The baseline characteristics are shown in Table 1. With regard to age, sex and smoking habits, the patients of stage III and stage IV were comparable, whereas more stage III patients presented with surgical interventions and more stage IV patients were diabetics and had previously undergone amputations. 900 patients were enrolled by 169 trial centres in Germany. 853 patients could be evaluated, while 4 of them had to be excluded because of wrong diagnosis (thromboangitis obliterans). The ITT analysis included
Table 1 Baseline characteristics of the patient population (n =
849) analysed on an intention-to-treat basis.

Stage III
Number of Patients Age (years) Mean + S.D. range Sex male female Diabetes mellitus Smoking habits in the medical history (positive) Ex-Smokers Smokers Disturbances of lipid metabolism Duration of PAOD (median) Previous amputations Other previous surgical procedures Rest pain Use of analgesics Number of patients with trophic lesions (ulceration and/or gangrene/mummification) 191 70.0 + 11,0 34-91 107 (56.0%) 84 (44.0%) 66 (34.6%) 75 (39.3%) 43 (22.5%) 75 (39.3%) 3 years 11.2% 40.1% 187 (97.9%) 143 (74,9%)

Stage IV
658 70.3 + 11.1 30-94 366 (55.7%) 291a (44.3%) 399 (60.6%) 238 (37.7%) 141 (21.5%) 199 (30.4%) 2 years 28.0% 20.7% 555 (84.3%) 526 (80%) 658 (100%)

a1 patient with missing data not taken into consideration.

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849 patients: 191 of stage III, 658 of stage IV according to Fontaine. The VC group included 660 patients: 159 stage III and 501 stage IV patients. The mean duration of PAOD was 3 years in stage III and 2 years in stage IV patients.
Course of trial

Table 3 Response rates of VC groups after stratification of the


parameters with regard to prognostic data.

Parameter
Diabetes mellitus Smokers Disturbances of lipid metabolism Obesity no yes no yes no yes no yes

Stage III
77.5% 75.9% 77.0% 80.6% 74.7% 80.0% 76.8% 77.1%

Stage IV
50.7% 44.6% 46.3% 44.7% 47.0% 46.8% 45.8% 50,7%

The treatment was terminated regularly or prematurely because of early improvement in 76.4% of stage III and 65.0% of stage IV patients. A discontinuation of therapy was necessary in 23.6% of stage III and in 35.0% of stage IV patients for the following reasons: insufficient efficacy, adverse events and other reasons, for example withdrawal of consent or poor compIiance of the patient. The duration of treatment was <28 days in 34.0% and 38.9%, 28 days in 60.7% and 51.1%, and >28 days in 5.2% and 10.0% of stage III and IV patients, respectively. The mean daily dose of iloprost from day 4 onwards was about 1.6 ng/kg body weight/rain.
Efficacy at the end of treatment

sults were obtained with hypertension as concomitant disease and in case of little consumption of analgesics. Stage IV patients showed less pronounced response rates if they were older than 70 years and if they were suffering from coronary heart disease.
Amputations and deaths

The VC analysis showed a response rate of 75.0% in stage III and 46.3% in stage IV patients after 4 weeks treatment. The response rate in ITT analysis was 66.0% in stage III and 41.8% in stage IV patients, as shown in Table 2. A complete healing of ulcers was observed in 12.3% of those patients presenting with ulcerations at the beginning of treatment. Pain relief, including patients with no pain at the end of the study, was achieved in 81.9% stage III and in 62.6% stage IV patients presenting with pain at the onset of the study. The following risk factors, evaluated by VC analysis only, did not influence the results significantly, in that 80.6% and 44.7% of smokers, 80.0% and 46.8% of patients with disturbances of lipid metabolism and 77.1% and 50.7% patients with obesity (stage III and IV, respectively) were assessed as responders showing nearly identical results like patients without the above-mentioned risk factors. Patients presenting with diabetes mellitus (34.6% stage III and 60.6% stage IV) showed a response to iloprost in 75.9% and 44.6%, respectively, as shown in Table 3. The outcome of stage III patients was negatively influenced by amputation in medical history, and better reTable 2 Response rates of stage III and stage stage IV patients
evaluated by VC and I'IT analysis.

During the entire course of the study, including therapy phase and follow-up, amputations, assessed on the highest individual level, were performed in 234 cases (Table 4). The amputation rate was 9.4% and 32.8%, revealing major amputations in 7.9% and 16.9% in stage III and stage IV patients, respectively (Table 5). In the follow-up period, the amputation rate was higher, but fewer amputations occurred in stage IV responders than in non-responders, as shown in Table 4. 15 stage III and 87 stage IV patients (7.9% and 13.2%) died during the treatment phase and follow-up period. A differentiation of responders and non-responders showed a higher mortality in non-responders (Table 6).
Assessment of improvement

A 3 months follow-up could be performed in 159 stage III and 567 stage IV patients and a 6 months follow-up

Table 4 Number of responders and impact of response on


amputations during therapy phase and follow-up period, analysed on an intention-to-treat basis. For each patient the highest amputation level was included only.

Stage III
Number of patients Number of responders Amputations in all patients Amputations during active therapy: Responders Non-responders Amputations in follow-up-period: Responders Non-responders 191 126 (66.0%) 18/191 (9.4%) 0/126 5/65 (7.7%) 7/126 (5.6%) 6/65 (9.2%)

Stage IV
658 275 (41.8%) 216/658 (32.8%) 4/275 (1.5%) 69/383 (18.0%) 40/275 (14.5%) 103/383 (26.9%)

Stage III
VC groups ITT groups 75.0% 66.0%

Stage IV
46,3% 41.8%

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Treatment of patients with peripheral arterial occlusive disease Fontaine stage III and IV with intravenous iloprost 331

Table 5 Differentiation of amputations (rate at 6 months) with regard to amputation level including therapy phase and follow-up period, analysed on an intention-to-treat basis Stage III
Number of patients Minor amputations Major amputations All amputations 191 1.5% 7.9% 9.4%

Stage IV
658 15.9% 16.9% 32.8%

Table 6 Deaths, including therapy phase and follow-up period, analysed on an intention-to-treat basis. Stage III All patients Responders Non-responders
15/191 (= 7.9%) 8/128 (= 6.3%) 7/63 (= 11.1%)

Stage IV
87/658 (= 13.2%) 26/278 (_=9.4%) 61/380 (-- 16.1%)

The good judgement of tolerability may be explained by the investigators relating the side-effects mainly to the pharmacological actions of iloprost. Of the severe adverse events reported in 6 patients including 5 deaths none could be attributed to iloprost. However, the pulmonary edema reported here had a definite relation to the iloprost treatment as judged by the investigator; the patient recovered completely by adequate counter measures. By comparing pre- and post-treatment values, a decrease in erythrocyte and leukocyte counts as well as in hemoglobin and hematocrit, a slight increase in platelet counts, in GPT and in PPT and a slight decrease in Quick-values were observed. These findings can be considered as clinically not relevant. The changes observed in red blood cell parameters and leukocyte counts might have been due to a hemodilution effect caused by the infusions.
DISCUSSION

in 156 stage III and 547 stage iV patients. As far as assessable, the numbers and percentages of the initial responders still substantially improved or improved at the end of follow-up period were 75 (71.40/0) stage III and 155 (66.2%) stage iV patients. Further more, there was an improvement of non-responders who became responders at the end of follow-up period in 12 stage III and in 51 stage iV patients. In any case an amputation was assessed as deterioration.
Drug tolerance and safety

If any adverse event at any time of treatment was considered, 83.2% stage III and 86.0% stage IV patients showed adverse events, with an overall result of 85.4%, occurring mainly during titration phase. The most common adverse events observed are contained in Table 7. A temporary infusion stop or a dose reduction alleviated the side-effects or made them tolerable to the patient with a decrease of symptoms from 68.60/0 (day 1 to 3) to 21.1% (day 22 to 28). Despite the high percentage of side-effects the global assessment of tolerability by the investigator basing on systemic and local tolerance revealed the following judgement: very good in 23.0%, good in 50 4%, moderate in 17.6% and poor in 9.0% (stage III and iV patients).
Table 7 Adverse events reported during therapy phase in all patients group, analysed on an intention-to-treat basis.
Headache Flush Nausea Vomiting Pain other than rest pain Hypertension Hypotension Vertigo 492 (57.95%) 269 (31.68%) 266 (31.33%) 143 (16.84%) 141 (16.61%) 90 (10.60%) 77 (9.07%) 52 (6.12%)

This multicentre study was performed to assess the clinical efficacy and tolerabflity of the stable prostacyclin analogue iloprost on a broader basis. Stage III and stage iV patients, according to Fontaine, were included in this study. The primary end-points of this trial were alleviation of rest pain in stage III patients and total or partial healing of trophic lesions in stage iV patients. An elimination or alleviation of rest pain was achieved in 75.0% of the VC group and in 66.0% of patients in the ITT group, which was within the range of 19-87% as reported in former studies.7-]0,~2,13 Responder rates of 46.3% in stage iV patients in the VC group analysis were within the reported range of 17-62% responders after iloprost. 7-13 The results reported here were clearly above the therapeutic effects of placebo with 10-49/0 (pain relief 7-~2 and 8-400/0 (improvement of trophic lesions), s-~2 The response rates in diabetic stage III and stage iV patients (75.9% and 44.6%, respectively) were comparable to those in non-diabetic patients (77.5% and 50.7% respectively) and also were comparable to former studies with response rates of 61% in stage III 7 and of 53.30/013 and 620/09in stage IV patients with diabetes. The response rate for the ITT analysis with 41.8% was also in the range of reported results. A rate of 85.4% of the patients presenting with sideeffects was within the range of 73.9-90% as observed in other iloprost studies. 7-~3 The most common side-effects were headache in about 58%, nausea in 31.3% and facial flushing in 31.7% of all patients. The severity and frequency of these adverse events were more pronounced during the titration phase, as reported earlier. 7-H,~3 These adverse events were due

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to the m o d e of action of iloprost 12 and can be judged as tolerable and acceptable c o m p a r e d to the severity of the critical limb ischaemia. 8 As k n o w n from other studies with iloprost, 8,9,H,12 a dose reduction or a t e m p o r a r y stop of infusion can alleviate the side-effects. It should be stressed again that the iloprost titration r e g i m e n allowed for tolerable side-effects to occur and did not request dose reduction for mild and m o d e r a t e side-effects. The overall a m p u t a t i o n rate of 9.4% (stage III) and 32.8% (stage W patients) and in particular the rate of major amputations (Z9% and 16.90/0) was at the lower m a r g i n of 16-33/0 reported in other iloprost studies2 -13 The death rate, including t r e a t m e n t phase and followup period, reported in Z9% stage III and 13.2% stage IV patients was slightly above the death rate of 3 - 1 0 % reported in former trials) ,~2,~3 In conclusion, this study with 849 patients in 169 centres supports the results of placebo-controlled studies with respect to efficacy and safety of iloprost.
ACKNOWLEDGEMENTS

Manfred Albring contributed on behalf of the floprost team, consisting of Mr Oentrich, Dr Staben, Dr Steyrer, Dr Taschke and Dr Thoma. We are grateful to the following trialists participating in the study for their successful engagement: Horst Ahlbrecht (Hamburg), Arhanase Andriopoulos (Ffirth), Bernhard Angelkort (Dortmund), Wemer Bachmann (Kronach), Uwe Baer (Berlin), Viktor-J. Balan (Borken), Karl Bauer (Ruhpolding), Uwe Becker (Malente), Wolfgang Beischer (Stuttgart), Kurt Benz (Lichtenfels), Baron Peter yon Bilderling (Mfinchen), Thomas Binz (Trier), Horst Bisler (Essen), W. Bobbert (Koblenz), W. H. Boesken (Trier), Hans B6hme (Wolfsburg), Roll B6ke (Lfibbecke), Gerd Bonnet (K61n), D. Borm (Hildesheim), Okke Bouwman (Albstadt), E. Braganza (Olpe), Thomas Brecht (Bonn), Joachim Breuning (Nfirtingen), Bemd Burow (Celle), C. Classen (Bad Nauheim), Hans-Dietmar Clevert (Berlin), Faisal Daoud (Osterholz-Scharmbeck), Jfirgen C. Dembski (Koblenz), Henry Dienst (Detmold), Volker D6rnberger (Tfibingen), Riad E1-Kassar (Waltrop), Franz-Norbert Fischer (Bremerhaven), Michael Fleischer (Marktredwitz), Helmut Frank (Pfarrkirchen), Wolfgang Frank (Lfidinghausen), Hans-J. Frob6se (K6sching), Arnold Gaitzsch (K61n), G. Gamst~itter (Wiesbaden), Otto Giersberg (Arnsberg), Bhanji Gohfl (Albstadt-Ebingen), Brigitte Gorgla (Sulzbach), Werner Goring (Mfinchen), Wolfgang Grafen (Naila), Friedrich Gr6gler (Ravensburg), Konrad Hahn (Alt6tfing), Horst Hamaam (Bochum), M. Happerger (Schongau), Karl-Eugen Hauptmann (Trier), Wolfgang Heger (Bretten), D. Heinrich (Wetzlar), Jfirgen Hengstmann (Berlin), Wolfgang Hepp (Berlin), Walter Hojdis (Wuppertal), Johannes Horn (Mfinchen), Svante Horsch (K61n), H. M. Hulten (Hattingen), Yousef Ibrahim (Hebertsfelden), Hansheiner Illig (Bad Reichenhall), Heinrich Ilse (Bad Mergentheim), Olaf Jacobsen (Neumfinster), Jost Jenkner (Tuttlingen), Klaus Josefiak (Krefeld), Helmut Kaiser (Kaiserslautem), Walter Kilchenstein (Mfinchen), Folker Klinke (Ibbenbfiren), Hans-Jfirgen Krabb (Dortmund), Wolfgang Kroh (Bad Nauheim), Christoph Krfiger (Lfidenscheid), Marianne Krfiger (Mfinchen), Bernd Ktineth (Neumarkt), Hans-Werner Kuhlmann (Dinslaken), Klaus Landendinger (Vilsbiburg), Heinz

Lang (Nordenham), Volker Lauff (Minden), Peter Leins (Erbendorf), Volker Lenner (Schw~ibisch Hall), Martin Leugner (Bremen), Achim Leyhe (Bochum), Hubertus Lindner (Pregnitz), P. Lippers (Neuss), F.-W. Lohmann (Berlin), Maria-Regina Lohmfiller (Mfinster), A. Lfidtke-Handjery (Berlin), Hans Mackrodt (Dfisseldor0, H. F. K. MAnnl (Straubing), Wolfgang M~iurer (Bayreuth), Josef Meentken (Osnabrfick), P. Meier zu Eissen (Moers), Andreas Mietaschk (Mfinchen), Carmine Minale (Wuppertal), Ulrich M6sseler (Harem), Gudrun Nagel (Hannover), Joachim Neitzel (Witten), Karl Neufeldt (Mfinchen), Klaus-Jfirgen Nordmann (Malente), H. R. Ochs (Soest), Anneliese Ott (Berlin), W. P~ffgen (Leverkusen), Karl-Heinz Peter (Ahlen), F.-J. PevelingOberhag (Kevelaer), Renate Plathow (Heide), Michael Probst (Herrsching), Hans-Jfirgen Radtke (Ebensfeld), Otto Reck (Ebermannstadt), F.-J. Riedhammer (Burglengenfeld), Volkart Rfippell (Zweibrficken), Gunter Schimmel (Hamburg), Gabriele Schlosser (Siegen), D. Schmidt-Dannert (Leer), U. Schneider-May (Dortmund), Adalbert Scholz (Konstanz), Jochen Schopohl (Bad Oeynhausen), Wemer Schraa 0Nesel), Michael Schreiber (Berlin), J. Schulze-Buschoff (Berlin), G. Schuster (Wittlich), Harry Schfitz (Viersen), Peter Schwandt (Miinchen), Ulrich Schwedes (Hamburg), Hartmut Schweikert (Mfinchberg), Erich-Dieter Schwilden (Esslingen), Wolfgang Seitz (Recklinghausen), Peter Semler (Berlin), Joachim Siegmund (Gifhorn), E. Spaeker (Duisburg), Wilhelm Spitzer (Neustadt a. d. Aisch), C.-D. Stahlknecht (Starnberg), Ulf Stockmann (Berlin), Heinz-Gfinther Straaten (Trier), E. Strunk (Siegen), Otto Symann (Steinfilrt), L. H. Tan (Hamburg), Walter Thimme (Berlin), Mahmood Tokhi (Selb), Bernhard Unkel (Gelsenkirchen-Buer), Hildegard Uptmoor (Quakenbrfick), E. van den Berg (Krefeld), H. Vargas-Montano (Lemgo), Akos Varszegi (Hamburg), Horst Vogel (Wfirselen-Bardenberg), Dierk V61ker (Bad Oeynhausen), Gebhard yon Haehling (Zwiesel), E. Ulrich ross (Karlsruhe), Hans Otto Wack (Ludwigsburg), Klaus Wette (Hof), Klaus Wiek (Berlin), Edlef Wischh6fer (K6sching), Horst Wunsch (Konstanz).
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Prostaglandins, Leukotrienes and Essential Fatty Acids (1996) 54(5), 327-333