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PubMed2000

Two randomised and placebo-controlled studies of an oral prostacyclin analogue (Iloprost) in severe leg ischaemia. The Oral Iloprost in severe Leg Ischaemia Study Group.

UNLABELLED: Two separate studies are described using the same prostacyclin analogue in a similar group of patients. OBJECTIVES: to assess the tolerability and efficacy of two dose regimens of oral Iloprost compared with placebo in the treatment of patients with ischaemic ulcers, gangrene or rest pain due to severe arterial disease over a period of 4 weeks (Study A) and one year (Study B). DESIGN: multicentre, placebo controlled, double-blind, randomized prospective studies. SUBJECTS & METHODS: 178 (study A) and 624 (study B) patients with trophic skin lesions (ulcers or gangrene) or ischaemic rest pain due to severe arterial disease. To confirm severe arterial disease patients were required to have a systolic ankle Doppler pressure of 70 mmHg or less or a toe systolic Doppler pressure of 50 mmHg or less in one leg. In both studies patients were randomly allocated to three treatment groups: placebo, low dose Iloprost (50-100 microgram twice a day) or high dose (150-200 microgram twice a day) In Study A the main outcome measures were tolerability of different doses of Iloprost and death, major amputation, healing of trophic lesions and relief of rest pain at the end of the follow up, which was 5 months after the end of the treatment. In Study B the primary end point was time to major amputation and stroke or death up to 12 months. Secondary pre-defined end points included the combined end point of patients alive without amputation, no trophic skin changes, no rest pain and not on regular analgesics. RESULTS: the proportion of patients who completed the 4-week treatment period in Study A at the intended dose was 58%, 43%, 45% respectively in the placebo, low dose and high dose Iloprost groups. In an intention to treat analysis the proportion of patients who survived without major amputation, ulcers or gangrene and had no rest pain was 11% in the placebo group, 19% in the low dose iloprost group and 28% in the high dose Iloprost group. The pooled Iloprost groups showed a statistically significantly better result than the placebo group (p=0.04), as did the high dose Iloprost group compared to the placebo (p=0.014). In Study B there was no treatment benefit in terms of a primary end point of amputation and death. However the secondary combined end point of patients who survived without a major amputation, ulcers or gangrene and had no rest pain, nor a need for regular analgesia was favourable for Iloprost, with 18% of patients in the placebo group reaching this optimal secondary end point, compared to 23% in the low dose Iloprost group and 26% in the higher dose Iloprost group (p<0.05). CONCLUSIONS: oral Iloprost administered for a year showed no clear benefit in patients with advanced severe leg ischaemia (PAOD III and IV). The results obtained with 4 weeks' treatment in Study A and in previous trials of intravenous Iloprost could not be reproduced

Administration, Oral↗
PubMed2002

Intravenous iloprost for treatment failure of aerosolised iloprost in pulmonary arterial hypertension.

Treatment with aerosolised iloprost, a prostacyclin analogue, has beneficial effects in patients with pulmonary arterial hypertension (PAH). It is unclear if patients, whose clinical condition deteriorates under treatment with aerosolised iloprost, benefit from switching to continuous intravenous iloprost. The current authors report on 16 patients with severe PAH who received continuous intravenous iloprost after primary or secondary failure of treatment with aerosolised iloprost. Determinants of efficacy were survival, New York Heart Association (NYHA) class, and walking distance in the 6-min walk test. Of 93 patients with PAH treated with aerosolised iloprost, 16 required switching to intravenous iloprost for clinical deterioration. These patients had severe right heart failure with a cardiac index of 1.6+/-0.2 L x min(-1) x m(-2) and a mixed-venous oxygen saturation of 52+/-6%. Five of these patients showed no improvement and eventually died. Three patients had further deterioration in NYHA class and exercise capacity; two of them underwent lung transplantation; the third patient is still alive. Eight patients showed marked clinical improvement; one underwent lung transplantation and the others are currently alive and stable. In the latter group of patients, the walking distance in the 6-min walk test increased from 205+/-94 to 329+/-59 m. It was not possible to identify clinical or haemodynamic factors that would predict whether switching from inhaled to intravenous iloprost would have a beneficial effect. In patients with pulmonary arterial hypertension who deteriorated while being treated with aerosolised iloprost, switching to continuous intravenous iloprost caused substantial improvement in exercise capacity in eight of 16 patients but could not prevent progression of pulmonary hypertension in the remaining eight patients. Since it was impossible to predict the individual effects of this approach, intravenous prostaglandin treatment should be considered in pulmonary arterial hypertension patients who deteriorate while receiving iloprost aerosol.

Administration, Inhalation↗
PubMed2006

Development of a common fully stereocontrolled access to the medicinally important and promising prostacyclin analogues iloprost, 3-oxa-iloprost and cicaprost.

We describe new fully stereocontrolled syntheses of the prostacyclin analogues iloprost (2), the most active component of the drugs Ilomedin and Ventavis, and 3-oxa-iloprost (3), a derivative that is expected to have a significantly higher metabolic stability than 2 perhaps allowing an oral application. The syntheses are based on the same strategy and chiral bicyclic building block as used in the synthesis of cicaprost (4), the third most potent analogue that exhibits, besides prostacyclin-like activities, antimetastatic activities. Reaction of the enantiopure C6-C13 bicyclic aldehyde 17 with Cl(3)CCOOH/Cl(3)CCOONa afforded trichlorocarbinol 24 which was converted via mesylate 25 to the C6-C14 bicyclic alkyne 9. The palladium-catalysed hydrostannylation of alkyne 9 gave with high regio- and stereoselectivity the alkenylstannane 26, Sn/Li exchange of which afforded the E-configured alkenyllithium derivative 8. Coupling of the C6-C14 building block 8 with the enantiopure C15-C20 building block, the N-methoxyamide 7, gave the C6-C20 bicyclic ketone 6 in high yield without epimerisation at C16. The configuration at C15 of iloprost (2) and 3-oxa-iloprost (3) was established through a highly diastereoselective reduction of ketone 6 with catecholborane and the chiral oxazaborolidine 28 which furnished alcohol (15S)-29. The highly stereoselective conversions of alcohol (15S)-29 to iloprost (2) and 3-oxa-iloprost (3), which include as key stereoselective steps an olefination with a chiral phosphonoacetate and a copper-mediated allylic alkylation, have already been described.

Epoprostenol↗
PubMed1986

[Effect of iloprost on aggregation behavior in kidney conditioning and changes in iloprost concentration in kidney preservation].

The conditioning of the donor by 1.0 microgram/kg X min Iloprost over 15 minutes leads to a considerable inhibition of the aggregation of thrombocytes in the domestic pig. 160% more ADP had to be added than before the application of Iloprost. When 0.5 microgram/ml Iloprost are added to the perfusion fluid and to the reperfusion fluid 0.22 microgram/ml and 0.27 microgram/ml, respectively, are to be proved in the venous efflux. Whether or not the difference is absorbed or metabolized must remain open. During the 72-hour storage of the kidney in a Euro-Collins-solution with 0.5 microgram/ml Iloprost after 24 hours a decrease of 0.34 microgram/ml, after 48 hours to 0.33 microgram/ml and after 72 hours to 0.20 microgram/ml takes place. Thus Iloprost is present in an effective concentration also after 72 hours. The decrease to one plateau rather speaks for a consumption by active metabolic effect or absorption than for a chemical decomposition.

Animals↗
PubMed1996

Effects of perioperative iloprost on patency of femorodistal bypass grafts. The Iloprost Bypass International Study Group.

OBJECTIVE: To investigate the effect of a 3 day perioperative iloprost regimen on the patency of femorodistal bypass grafts. DESIGN: Prospective, randomised, placebo-controlled study. SETTING: Twenty-one specialised vascular surgical centres in Northern Europe. SUBJECTS AND TREATMENTS: Preoperatively 528 patients undergoing femorodistal bypass surgery were randomised to receive either iloprost or placebo intravenously at the beginning of the operation and in three daily 6 h infusions postoperatively with an intragraft injection given on completion of the bypass procedure. CHIEF OUTCOME MEASURES: Patency, surgical interventions and clinical outcome were recorded in all cases for 12 months after bypass. RESULTS: Five hundred and seventeen patients received a bypass as planned and were evaluable. The graft material was vein in 424 cases (82%) and prosthetic or partly prosthetic in 92 (18%). Overall primary patency rates at 12 months were 52.0% for vein grafts and 45.1% for prosthetic grafts (p = 0.25). The effect of iloprost on primary patency was not statistically significant at 12 months in either vein or prosthetic grafts, but an early effect of improved patency in prosthetic grafts was seen over the first 3 days. Other results at the end of follow-up were similar in both treatments groups: 105 patients (20.3%) had been amputated, a further 85 (16.4%) had died and 78 (15.1%) were still suffering from rest pain or trophic lesions. Two hundred and thirty-eight patients (46.0%) were alive with both legs and either no symptoms or only intermittent claudication after 12 months. CONCLUSIONS: In the setting of this multicentre trial no long-term benefits from the use of a 3 day iloprost regimen were demonstrated. Surprisingly small differences were found between the outcomes of vein and prosthetic femorodistal bypass grafts.

Aged↗
PubMed2005

Fully stereocontrolled total syntheses of the prostacyclin analogues 16S-iloprost and 16S-3-oxa-iloprost by a common route, using alkenylcopper-azoalkene conjugate addition, asymmetric olefination, and allylic alkylation.

In this article we describe fully stereocontrolled total syntheses of 16S-iloprost (16S-2), the most active component of the drugs Ilomedin and Ventavis, and of 16S-3-oxa-iloprost (16S-3), a close analogue of 16S-2 having the potential for a high oral activity, by a new and common route. The key steps of this route are (1) the establishment of the complete C13-C20 omega side chain of the target molecules through a stereoselective conjugate addition of the alkenylcopper derivative 9 to the bicyclic C6-C12 azoalkene 10 with formation of hydrazone 8, (2) the diastereoselective olefination of ketone 7 with the chiral phosphoryl acetate 39, and (3) the regio- and stereoselective alkylation of the allylic acetate 43 with cuprate 42. These measures allowed the 5E,15S,16S-stereoselective synthesis of 16S-2 and 16S-3, a goal which had previously not been achieved. Azoalkene 10 was obtained from the achiral bicyclic C6-C12 ketone 11 as previously described by using as key step an enantioselective deprotonation. The configuration at C16 of omega-side chain building block 9 has been installed with high stereoselectivity by the oxazolidinone method and that at C15 by a diastereoselective oxazaborolidine-catalyzed reduction of the C13-C20 ketone 23 with catecholborane. Surprisingly, a high diastereoselectivity in the reduction of 23 was only obtained by using 2 equiv of oxazaborolidine 24. Application of substoichiometric amounts of 24 resulted in irreproducible diastereoselectivities ranging from very high to nil.

Alkenes↗
PubMed2004

[Iloprost and selective pulmonary vasodilation. Clinical results of intraoperative and postoperative inhalation of iloprost].

Pulmonary hypertension is a major risk factor in cardiac surgery and has significant impact on morbidity and mortality in the perioperative period. Nitric oxide (NO) is considered to be the gold standard for treatment of pulmonary hypertension in the perioperative setting. The aerosolized administration of the prostacyclin analogue iloprost is a new alternative with similar pulmonary-selective vasodilation and virtually no systemic side-effects. Relevant complications including increased postoperative bleeding have not been observed.

Administration, Inhalation↗
PubMed1998

Oral iloprost in Raynaud's phenomenon secondary to systemic sclerosis: a multicentre, placebo-controlled, dose-comparison study.

OBJECTIVE: To identify the optimal dose of oral iloprost on the basis of efficacy and tolerability in patients with Raynaud's phenomenon secondary to systemic sclerosis. DESIGN: Multicentre, randomized, parallel-group comparison of two different doses of oral iloprost and placebo. SETTING: European university hospitals. PATIENTS: A total of 103 patients with Raynaud's phenomenon secondary to systemic sclerosis. INTERVENTION: Patients received one of three treatments for 6 weeks: placebo, oral iloprost 50 microg or oral iloprost 100 microg. Each treatment was taken twice daily, giving total daily doses of iloprost of 100 and 200 microg. MEASUREMENTS: The frequency, total daily duration and severity of Raynaud's attacks were recorded in a specially designed patient diary; physician's global assessment and adverse events were recorded at visits to the clinic. Analysis was performed on an intention-to-treat population. RESULTS: A total of 103 patients were recruited, 89 completed the assessments throughout the treatment period and 82 completed an additional 6 weeks of follow-up after treatment. Thirty-five patients received placebo, 33 received iloprost 50 microg and 35 received iloprost 100 microg. The mean percentage reductions in the frequency, total daily duration and severity of Raynaud's attacks were numerically greater in the iloprost groups at the end of treatment and at the end of follow-up. At the end of treatment (6 weeks), there were significant treatment differences in the total daily duration of attacks (P = 0.03), but not in the severity (P = 0.07) or the frequency of attacks (P = 0.37). At the end of follow-up (12 weeks), there were significant treatment differences in the total daily duration of attacks (P = 0.001) and in the severity of attacks (P = 0.007), but not in the frequency of attacks (P = 0.07). Percentages of patients improved at the end of treatment as assessed by the physician were 44% placebo, 57% iloprost 50 microg and 64% iloprost 100 microg (not significant). Side-effects were reported by 80% of patients on placebo, 85% on oral iloprost 50 microg and 97% on oral iloprost 100 microg. Premature discontinuations of treatment in each group were 9, 30 and 51%, respectively, with 6, 27 and 51% being due to adverse events. CONCLUSION: The results on the daily duration of Raynaud's attacks suggest that both 50 and 100 microg oral iloprost twice daily may be effective in the treatment of Raynaud's phenomenon secondary to systemic sclerosis. The 50 microg iloprost dose was better tolerated in this patient group.

Administration, Oral↗
PubMed2006

Comparison of pharmacokinetics and vasodilatory effect of nebulized and infused iloprost in experimental pulmonary hypertension: rapid tolerance development.

Aerosolized iloprost has been suggested for selective pulmonary vasodilatation in severe pulmonary hypertension, but its pharmacokinetic profile is largely unknown. In perfused rabbit lungs, continuous infusion of the thromboxane mimetic U46619 was employed for establishing stable pulmonary hypertension. Delivery of a total amount of 75, 300, and 900 ng of iloprost to the bronchoalveolar space by a 10 min-aerosolization maneuver caused a dose-dependent pulmonary vasodilatation. Similarly, dose-dependent appearance of iloprost in the recirculating perfusate was noted, with maximum intravascular concentrations of iloprost ranging at 140, 510, and 1163 pg/mL at the same time period. Comparing pharmacokinetics and pharmacodynamics in a more detailed fashion, the following aspects were of interest. (i) The bioavailability (i.e., the percentage of aerosolized iloprost appearing intravascularly) decreased from 76% at the lowest to 33% at the highest iloprost dosage. (ii) The pulmonary vasodilatory response commenced already during the nebulization maneuver and preceded the perfusate entry of iloprost. (iii) After 3-3.5 h, the pulmonary vasodilatory response to aerosolized iloprost had virtually completely leveled off, whereas approximately two-thirds of the maximum iloprost perfusate levels were still detectable. A corresponding loss of vasodilatory response was also noted in experiments with continuous iloprost perfusion for clamping of the intravascular concentration of this prostanoid. We conclude that aerosolized iloprost causes dose-dependent vasodilatation and iloprost entry into the vascular space in a pulmonary hypertension model. Limited bioavailability in the higher dose range may suggest active prostanoid transport processes, and the early pulmonary vasodilatory response appears to be independent of prostanoid entry into the vessel lumen. Surprisingly, rapid tolerance development to the vasodilatory effect of iloprost is noted, occurring even with fully maintained perfusate levels of this agent.

15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5↗
PubMed1990

Iloprost inhibits neutrophil-induced lung injury and neutrophil adherence to endothelial monolayers.

We hypothesized that Iloprost, a long-acting prostacyclin analog, would inhibit neutrophil (PMN)-induced lung injury and decrease PMN adherence to vascular endothelium. Human PMNs infused into isolated buffer-perfused rat lungs subsequently stimulated with phorbol myristate acetate (PMA) resulted in lung injury as assessed by the accumulation of [125I]bovine serum albumin (125I-BSA) in lung parenchyma and alveolar lavage fluid. Addition of Iloprost to the lung perfusate, prior to activation of the PMNs, reduced lung injury as assessed by a decrease in the accumulation of 125I-BSA in the lung. This protective effect was not due to the vasodilatory effect of Iloprost. Protection by Iloprost was not linked to a reduction in PMA-induced PMN superoxide production since Iloprost did not reduce the amount of superoxide released into lung perfusate. In vitro, Iloprost caused a dose-dependent inhibition of PMA-stimulated PMN adherence to endothelial cells. Iloprost did not affect the number of Mo1 adhesion molecules constitutively expressed or the number of receptors expressed on the PMNs following PMA. Addition of cAMP or dibutyryl cAMP to the endothelial cells mimicked the effects of Iloprost, diminishing PMA-stimulated PMN adhesion. In separate experiments, addition of the phosphodiesterase inhibitor IBMX to Iloprost resulted in a greater inhibition of PMA-stimulated PMN adherence, while addition of an adenylate cyclase inhibitor, SQ 22,536, or cAMP antibodies with the Iloprost abolished Iloprost's inhibitory effect on PMN adhesion. Thus, Iloprost inhibits PMA-activated PMN-induced lung injury despite continued superoxide production. Iloprost inhibition of PMN adhesion is dependent on cAMP.

1-Methyl-3-isobutylxanthine↗
PubMed2006

Successful switch from long-term intravenous iloprost to non-invasive combination therapy in idiopathic pulmonary arterial hypertension.

In Europe intravenous (IV) iloprost, an alternative to epoprostenol, is an accepted treatment option for severely compromised patients with idiopathic pulmonary arterial hypertension (IPAH). Once initiated, this therapy usually has to be continued lifelong or as bridging to transplantation. In our paper we describe two patients with IPAH in World Health Organisation (WHO) functional classes II and III while on treatment with continuous IV iloprost monotherapy or combination therapy with continuous IV iloprost plus oral bosentan, respectively. The duration of IV iloprost therapy was 4.5 and 2.5 years, respectively. Because of life-threatening or recurring catheter-related complications during long-term IV iloprost therapy, these patients were switched to non-invasive combination therapy consisting of oral bosentan plus aerosolized iloprost (patient 1) and oral bosentan plus aerosolized iloprost plus oral sildenafil (patient 2), respectively. After four weeks of additional bosentan therapy, stepwise reduction and discontinuation of IV iloprost were performed within eight hours in the patient in WHO class II, and within five days in the patient in WHO class III. Simultaneously, therapy with aerosolized iloprost was started in the first patient and with aerosolized iloprost plus sildenafil in the second patient. Both patients were safely switched from IV iloprost to non-invasive combination therapy while WHO classification of functional status remained unchanged for at least 12 and 14 months, respectively. These data suggest that selected patients with complications due to IV iloprost treatment can be safely switched to non-IV combination therapies.

Antihypertensive Agents↗
PubMed1989

Characterization of the interaction between prostacyclin and human serum albumin using a fluorescent analogue, 2,6-dichloro-4-aminophenol iloprost.

We synthesized a fluorescent probe, 2,6-dichloro-4-aminophenol iloprost or dichlorohydroxyphenylamide of iloprost (DCHPA-iloprost) by reacting the stable prostacyclin analog, iloprost (ZK 35 374), with 2,6-dichloro-4-aminophenol with a yield of 60%. This probe exhibited an optical spectrum which overlapped with the emission spectrum of the sole tryptophan of human serum albumin (HSA). Energy transfer from the tryptophan residue to the phenol moiety of DCHPA-iloprost was observed. We utilized this donor-quenching phenomenon to quantitate the binding stoichiometry and affinity as well as the association rate of DCHPA-iloprost binding to HSA. As DCHPA-iloprost showed similar binding characteristics similar to those of iloprost and prostacyclin and competed with iloprost for HSA binding sites, we used DCHPA-iloprost as a probe to locate the binding domain of prostacyclin (PGI2) in HSA. The distance between the tryptophan indole and the phenol group of DCHPA-iloprost was estimated to be 15-18 A. Because iloprost binding to HSA was competitive with warfarin and not with free fatty acid, we propose that PGI2 binds to the 'domain 2' of HSA was competitive with warfarin and not with free fatty acid, we propose that PGI2 binds to the 'domain 2' of HSA molecules. A possible molecular mechanism by which HSA reduces the chemical degradation of PGI2 and stabilizes its activity could be derived from this model.

Binding Sites↗
PubMed2002

Combination therapy with oral sildenafil and inhaled iloprost for severe pulmonary hypertension.

BACKGROUND: Inhalation of the stable prostacyclin analogue iloprost is being studied for treatment of pulmonary hypertension. The selective phosphodiesterase-5 inhibitor sildenafil has been reported to cause pulmonary vasodilatation. OBJECTIVE: To evaluate the safety and effectiveness of oral sildenafil, alone and in combination with inhaled iloprost, for treatment of pulmonary hypertension. DESIGN: Randomized, controlled, open-label trial. SETTING: Intensive care unit. PATIENTS: 30 patients with severe pulmonary arterial hypertension (n = 16), chronic thromboembolic pulmonary hypertension (n = 13), or pulmonary hypertension due to aplasia of the left pulmonary artery (n = 1), all classified as New York Heart Association class III or IV. INTERVENTION: All patients received inhaled nitric oxide and aerosolized iloprost (inhaled dose, 2.8 microg). They were then randomly assigned to receive 12.5 mg of oral sildenafil, 50 mg of sildenafil, 12.5 mg of sildenafil plus inhaled iloprost, or 50 mg of sildenafil plus inhaled iloprost. MEASUREMENTS: Systemic and pulmonary arterial pressure, pulmonary arterial occlusion pressure, cardiac output, central venous pressure, peripheral arterial oxygen saturation, and arterial and mixed venous blood gases were measured during right-heart catheterization by using a Swan-Ganz catheter. RESULTS: In rank order of pulmonary vasodilatory potency (maximum reduction of pulmonary vascular resistance and increase in cardiac index), 50 mg of sildenafil plus iloprost was most effective, followed by 12.5 mg of sildenafil plus iloprost. Iloprost alone and 50 mg of sildenafil were almost equally effective but were less potent than the combination regimens, and the least potent treatments were 12.5 mg of sildenafil and nitric oxide. In patients who received 50 mg of sildenafil plus iloprost, the maximum change in pulmonary vasodilatory potency was -44.2% (95% CI, -49.5% to -38.8%), compared with -14.1% (CI, -19.1% to -9.2%) in response to nitric oxide. With administration of 50 mg of sildenafil plus iloprost, the area under the curve for reduction in pulmonary vasodilatory resistance surpassed that of administration of 50 mg of sildenafil alone and iloprost alone combined, the vasodilatory effect lasted longer than 3 hours, and systemic arterial pressure and arterial oxygenation were maintained. No serious adverse events occurred. CONCLUSION: Although limited by the small sample and lack of long-term observations, the study shows that oral sildenafil is a potent pulmonary vasodilator that acts synergistically with inhaled iloprost to cause strong pulmonary vasodilatation in both severe pulmonary arterial hypertension and chronic thromboembolic pulmonary hypertension.

3',5'-Cyclic-GMP Phosphodiesterases↗
PubMed2000

Beneficial effects of iloprost during experimentally induced hemorrhagic shock.

BACKGROUND: The aim of the study was to evaluate the efficacy of iloprost on myocardial insufficiency associated with hypovolemic shock in dogs. We designed the study as a controlled randomized study. METHODS: Sixteen mixed-breed dogs were included into the study and divided into two equal groups as the control and iloprost groups. Mean arterial pressure was reduced to 45 mmHg by withdrawing the arterial blood into citrated bags. The control group did not receive any drug but the other group received iloprost at a rate of 20 ng/kg/min by an infusion pump. Iloprost infusion was started 30 min after the blood pressure was reduced to 45 mmHg. All measurements were made before removal of blood, 45 min after exsanguination and at 1 hour intervals for 3 hours. Left ventricular stroke work index was measured 72 hours after the study. The hemodynamic and biochemical parameters and blood gas analysis were obtained. RESULTS: After hemorrhage, cardiac index (CI) decreased significantly from 132 +/- 14 to 51 +/- 8 ml/kg/min in the control group and from 128 +/- 11 ml/kg/min to 47 +/- 13 ml/kg/min in the iloprost group, respectively but at the end of the third hour it was 81 +/- 8 ml/kg/min in the control group and 105 +/- 6 ml/kg/min in the iloprost group (p < 0.05). Tumor necrosis factor-alpha (TNF alpha) was 41 +/- 8 pg/ml in the control group and 18 +/- 6 in the iloprost group 3 hours after bleeding (p < 0.05). Tumor necrosis factor-alpha concentration was significantly higher in the control group than in the iloprost group. There was no significant difference in pH between the groups but actual bicarbonate concentrations were different between the groups (p < 0.05). At the end of the third hour total body oxygen consumption was 105 +/- 11 ml/min in the control group and 132 +/- 12 ml/min in the iloprost group (p < 0.05). Oxygen delivery 3 hours after hemorrhage was 201 +/- 19 ml/min in the control group and 252 +/- 24 ml/min in the iloprost group (p > 0.05). Left ventricular stroke work index was higher in the iloprost group (p < 0.05). CONCLUSIONS: Hemorrhagic shock causes tumor necrosis factor-alpha release which may lead to multiple organ failure. Organ dysfunction still persists even after the appropriate treatment. Iloprost attenuates the release of tumor necrosis factor-alpha which may improve the adverse effects of hemorrhagic shock.

Animals↗
PubMed2004

The evaluation of the no-independent vasodilatative effect of iloprost in isolated perfused Guinea pig hind limbs.

AIM: In critical limb ischemia vasodilatators play an important role in the treatment of the disease. Considering that the endothelium is seriously damaged in these patients, we wanted to evaluate if the vasodilatative effect of iloprost does or does not depend on the endothelium by using the model of the isolated perfused guinea pig hind limb. METHODS: A catheter was inserted via the distal aorta and common iliac artery. After stabilization, iloprost was administered at a dosage of 0.1 microM. In a subsequent series of experiments precontraction of the peripheral vascular bed was achieved with 40 mM KCl followed by 0.1 microM iloprost. In a 3rd series of experiments L-NAME (100 microM) was administered after the equilibration period for 30 minutes, followed by 0.1 microM iloprost. In the 4th series of experiments, after the administration of L-NAME (100 microM), KCl (40 mM) was administered to precontract the vascular bed and iloprost 0.1 microM was added. RESULTS: The administration of iloprost alone and after addition of KCL induced a significant decrease in vascular resistance(-49.6+/-14.1% [x+/-SEM, n=7]). The addition of L-NAME did not affect vascular resistance. The consecutive addition of iloprost reduced vascular resistance significantly (-4.2+/-0.7% [x+/-SEM, n=7]). After addition of L-NAME 100 microM and precontraction with KCl 40 mM, iloprost once again significantly reduced peripheral vascular resistance (-51.5+/-14.4% [x+/-SEM, n=6]). Reduction of peripheral vascular resistance by iloprost was comparable to that without L-NAME. CONCLUSION: Our data show that iloprost at a dosage of 0.1 microM achieves a significant reduction in peripheral vascular resistance and that the vasodilatative effect of iloprost is independent of NO. Iloprost therefore seems to be an ideal vasodilatative drug for the treatment of patients with impaired endothelial function.

Animals↗
PubMed1988

Desensitization of platelets to iloprost. Loss of specific binding sites and heterologous desensitization of adenylate cyclase.

The binding characteristics of [3H]prostacyclin and [3H]iloprost ([3H]5-[(E)-(1S,5S,6R,7R)-7-hydroxy-6-[(E)-(3S,4RS) -3-hydroxy-4-methyl-1-octen-6-inyl]-bicyclo[3.3.0]octan-3-yl idene] -pentanoic acid) and platelet adenylate cyclase activities were investigated in platelet-rich plasma preincubated with iloprost. The exposure of platelets to 0.1 microM iloprost (12 h, 20 degrees C) caused a significant loss of iloprost binding sites (P less than 0.01) without causing changes in binding affinity. This loss of specific [3H]iloprost binding was time- and dose-dependent. The reduction of iloprost receptor density was accompanied by an impaired responsiveness of platelet adenylate cyclase to iloprost, prostaglandin D2 and forskolin. In contrast, basal adenylate cyclase activity was not affected by iloprost pretreatment. The diminished response of the enzyme to GTP and NaF pointed to an involvement of the stimulatory guanyl nucleotide-binding protein (Gs) in iloprost-induced heterologous desensitization. Consequently, [32P]NAD+ and cholera toxin were used for the direct labelling of Gs. Platelet membranes desensitized to iloprost incorporated less label into the 45 kD subunit of Gs. These data suggest that the site of action of iloprost for heterologous desensitization of human platelet adenylate cyclase is located on Gs.

Adenosine Diphosphate↗
PubMed1995

Prostacyclin receptor in the brain and central terminals of the primary sensory neurons: an autoradiographic study using a stable prostacyclin analogue [3H]iloprost.

Presence and localization of the prostacyclin receptor in the rat brain and spinal cord were examined by in vitro autoradiography using [3H]iloprost, a highly specific and stable agonist for this receptor. Density of specific binding sites for iloprost was generally high in four regions of the lower brain stem, that is, the medial and commissural subnuclei of the nucleus tractus solitarius, the area postrema, superficial layers of the spinal trigeminal nucleus caudalis and dorsal horn. Moderate density was found in the thalamus, cerebral cortex, hippocampus, striatum and dorsal cochlear nucleus. The distribution pattern was distinct from those of other prostanoid binding sites previously studied except that prostaglandin E2 binding sites were also abundant in the nucleus tractus solitarius, spinal trigeminal nucleus caudalis and dorsal horn. Even in these regions, binding sites for iloprost had several features clearly different from those for prostaglandin E2. First, within the medial and commissural subnuclei of the nucleus tractus solitarius, iloprost binding sites were distributed preferentially in the dorsal part, while those for prostaglandin E2 were located more ventrolaterally. Second, on postnatal day 0, iloprost binding sites have already been expressed in large amounts in the nucleus tractus solitarius, spinal trigeminal nucleus caudalis and dorsal horn of rats, while prostaglandin E2 binding sites are negligible at this stage. Thirdly, the binding of 10 nM [3H]iloprost in these three regions was almost completely displaced by 10 microM unlabelled iloprost but only slightly by 10 microM unlabelled prostaglandin E2. Unilateral nodose ganglionectomy or dorsal rhizotomy decreased the density of iloprost binding sites in the nucleus tractus solitarius or dorsal horn, respectively, with a greater decrease in the operated side. Ligation of the vagus either central or peripheral to the nodose ganglion resulted in an accumulation of iloprost binding sites proximal to the ligation. These results suggest that specific binding sites for iloprost, presumably prostacyclin receptor, are present in the nervous system and, in particular, that the iloprost binding sites in the nucleus tractus solitarius, dorsal horn and possibly in the superficial layers of the spinal trigeminal nucleus caudalis are produced in their sensory ganglia and transported to central terminals of the primary sensory afferents as well as to their peripheral terminals.

Animals↗