Long-acting Prostacyclin Analogue Research Articles

Prostacyclins and pulmonary arterial hypertension in children.

Despite its low incidence, pulmonary hypertension in children places a substantial burden on families and society because survival can be shorter than 10 months and treatment options are limited and ineffective. Drugs to treat pulmonary hypertension include endothelin antagonists, phosphodiesterase type 5 inhibitors and prostacyclin, which is the most widely used to treat pediatric pulmonary hypertension. The main aim of this study was to provide a comprehensive overview of the advantages and disadvantages of prostacyclin and its analogs for treating pulmonary hypertension in children. To retrieve a thorough collection of studies, we performed a search in PubMed using the following combination of keywords: (Prostacyclins) or (Epoprostenol) or (Iloprost) or (Treprostinil) or (Beraprost), (children) and (pulmonary arterial hypertension). The time limits used for the search were December 1983 to May 2021. The search retrieved a total of 238 articles. Titles and abstracts of articles were screened for relevance, and all relevant articles published in English were included. Epoprostenol can be effective against severe pulmonary hypertension. Iloprost can treat severe persistent pulmonary hypertension in newborns and inhaled iloprost can be used in pulmonary vasoreactivity testing. Treprostinil is a long-acting prostacyclin analog, and it shows the highest antiproliferative activity among prostacyclins. Beraprost may be effective in premature infants, but available evidence comes from only one patient, so more clinical testing is needed.

Efficacy of oral triple upfront combination therapy (long-acting prostacyclin analogue, endothelin receptor antagonist, phosphodiesterase 5 inhibitor) in the patients with idiopathic/heritable pulmonary arterial hypertension

Efficacy of oral triple upfront combination therapy (long-acting prostacyclin analogue, endothelin receptor antagonist, phosphodiesterase 5 inhibitor) in the patients with idiopathic/heritable pulmonary arterial hypertension

The potential for inhaled treprostinil in the treatment of pulmonary arterial hypertension

Inhaled treprostinil is a safe and well-tolerated approved pharmaceutical for the treatment of pulmonary arterial hypertension. In a series of open-label studies and in the pivotal trial with 253 patients, this long-acting prostacyclin analogue demonstrated pronounced pulmonary selectivity of vasodilatory effects, improved physical capacity and excellent tolerability and safety following aerosol administration. For efficient treatment, only four daily inhalations of treprostinil are necessary compared with six to nine in iloprost aerosol therapy. This review describes in detail the development of inhaled treprostinil, starting with intravenous epoprostenol followed by inhaled iloprost and subcutaneous treprostinil, all three representing well-established and widely approved prostanoid therapies for pulmonary hypertension. In order to circumvent the drawbacks of intravenous epoprostenol, stable prostacyclin analogues with similar pharmacological properties have been investigated. In addition, alternative routes of administration have been proposed and evaluated, mainly inhaled and subcutaneous delivery. The concept of inhaled treprostinil was to combine the pulmonary selectivity of an aerosolized vasodilator with the long-acting effects of a stable prostacyclin analogue. Pulmonary arterial hypertension remains, however, a severe, life-threatening disease, in spite of the enormous progress in specific drug therapy over the last decade. Therefore, further improvement of drug therapy will be essential, with clear potential for inhaled treprostinil: a reduction of inhalation frequency and duration would markedly improve quality of life and compliance, and a longer-lasting local prostanoid effect might further enhance the efficacy of inhaled treprostinil. The advantageous pharmacological properties of treprostinil offer the opportunity to establish a convenient metered dose inhaler as a delivery system, to combine inhaled treprostinil with available or future drugs for pulmonary arterial hypertension, or to develop sustained release formulations of treprostinil suitable for inhalation based on liposomes or biodegradable nanoparticles.

Addition of Inhaled Treprostinil to Oral Therapy for Pulmonary Arterial Hypertension: A Randomized Controlled Clinical Trial

This study assessed the efficacy and safety of inhaled treprostinil in pulmonary arterial hypertension (PAH) patients receiving therapy with either bosentan or sildenafil.There is no cure for PAH, despite effective treatments, and outcomes remain suboptimal. The addition of inhaled treprostinil, a long-acting prostacyclin analog, might be a safe and effective treatment addition to other PAH-specific oral therapies.Two hundred thirty-five PAH patients with New York Heart Association (NYHA) functional class III (98%) or IV symptoms and a 6-min walk distance (6MWD) of 200 to 450 m while treated with bosentan (70%) or sildenafil were randomized to inhaled treprostinil (up to 54 mug) or inhaled placebo 4 times daily. The primary end point was peak 6MWD at 12 weeks. Secondary end points included time to clinical worsening, Borg Dyspnea Score, NYHA functional class, 12-week trough 6MWD, 6-week peak 6MWD, quality of life, and PAH signs and symptoms. The biomarker N-terminal pro-brain natriuretic peptide (NT-proBNP) was assessed.Twenty-three patients withdrew from the study prematurely (13 treprostinil, 10 placebo). The Hodges-Lehmann between-treatment median difference in change from baseline in peak 6MWD was 19 m at week 6 (p = 0.0001) and 20 m at week 12 (p = 0.0004). Hodges-Lehmann between-treatment median difference in change from baseline in trough 6MWD at week 12 was 14 m (p = 0.0066). Quality of life measures and NT-proBNP improved on active therapy. There were no improvements in other secondary end points, including time to clinical worsening, Borg Dyspnea Score, NYHA functional class, and PAH signs and symptoms. Inhaled treprostinil was safe and well-tolerated.This trial demonstrates that, among PAH patients who remain symptomatic on bosentan or sildenafil, inhaled treprostinil improves exercise capacity and quality of life and is safe and well-tolerated. (TRIUMPH I: Double Blind Placebo Controlled Clinical Investigation Into the Efficacy and Tolerability of Inhaled Treprostinil Sodium in Patients With Severe Pulmonary Arterial Hypertension; NCT00147199).

A Pediatric Case Study of Treprostinil Overdose

This case study reports the effects of a treprostinil accidental overdose in a patient with pulmonary hypertension. Treprostinil is labeled for treatment of pulmonary hypertension with New York Heart Association (NYHA) Class II, III and IV symptoms. It is characterized as a long-acting prostacyclin analog that can be delivered by intravenous or subcutaneous continuous infusions. This pediatric case report describes a massive overdose without significant side effects, thus suggesting a beneficial therapeutic index in pediatric patients.

Treprostinil-Based Therapy in the Treatment of Moderate-to-Severe Pulmonary Arterial Hypertension*: Long-term Efficacy and Combination With Bosentan

Treprostinil, a long-acting prostacyclin analog, diminished the symptoms of pulmonary arterial hypertension (PAH) in controlled 12-week clinical efficacy studies. This retrospective, single-center, open-label study was designed to assess the efficacy of long-term, subcutaneously administered, treprostinil-based therapy alone or in combination with bosentan for the treatment of moderate-to-severe PAH. Thirty-eight patients with pulmonary hypertension treated with subcutaneous treprostinil were followed up for a mean (+/-SD) duration of 984+/-468 days (range, 165 to 1,847 days). Oral bosentan was added to the treprostinil regimen if patients remained in New York Heart Association (NYHA) functional class III or II with intolerable prostacyclin side effects that limited therapy. Hemodynamic studies, Borg dyspnea score evaluations, 6-min walk (6MW) tests, and NYHA functional class determinations were performed at approximately 6-month intervals. Mean pulmonary artery pressure decreased from 59.7 to 50.5 mm Hg (p<0.001). Significant and sustained improvement in 6MW distance (p=0.022) and Borg dyspnea score (p=0.023) were observed. At the final observation, the mean dose of treprostinil was 37.8 ng/kg/min (range, 7.5 to 115 ng/kg/min). At baseline, 5% of patients were in NYHA functional class 2 or lower vs 58% at the last follow-up. Bosentan was added to the regimens of 19 patients. In those patients, significant additional improvement occurred in the pulmonary arterial pressure (p<0.001), 6MW distance (p=0.001), and Borg dyspnea scale (p=0.020) compared to baseline. Long-term treatment with subcutaneous treprostinil-based therapy improved functional parameters and hemodynamics in patients with moderate-to-severe PAH. In patients requiring combination therapy, the addition of oral bosentan to treprostinil-based therapy was safe, well-tolerated, and associated with further clinical improvements.

Treprostinil for pulmonary hypertension

Treprostinil is a stable, long-acting prostacyclin analogue which can be administered as a continuous subcutaneous infusion using a portable miniature delivery system. Subcutaneous treprostinil has been shown in a large multicenter randomized controlled trial to improve exercise capacity, clinical state, functional class, pulmonary hemodynamics, and quality of life in patients with pulmonary arterial hypertension, an uncommon disease of poor prognosis. Side effects include facial flush, headache, jaw pain, abdominal cramping, and diarrhea, all typical of prostacyclin, and manageable by symptom-directed dose adjustments, and infusion site pain which may make further treatment impossible in 7%-10% of the patients. Long-term survival in pulmonary arterial hypertension patients treated with subcutaneous treprostinil is similar to that reported with intravenous epoprostenol. There are uncontrolled data suggesting efficacy of subcutaneous treprostinil in chronic thromboembolic pulmonary hypertension. Treprostinil can also be administered intravenously, although increased doses, up to 2-3 times those given subcutaneously, appear to be needed to obtain the same efficacy. Preliminary results of a randomized controlled trial of inhaled treprostinil on top of bosentan and sildenafil therapies have shown significance on the primary endpoint, which was exercise capacity as assessed by the distance walked in 6 minutes. Trials of oral formulations of treprostinil have been initiated.

Safety and Efficacy of Inhaled Treprostinil as Add-On Therapy to Bosentan in Pulmonary Arterial Hypertension

This study evaluated the safety and efficacy of inhaled treprostinil as add-on therapy to oral bosentan in patients with pulmonary arterial hypertension (PAH). The addition of a long-acting prostacyclin analogue via the inhaled route might be a safe and effective strategy to optimize therapy in PAH patients on bosentan. Twelve patients with symptomatic PAH despite bosentan received either 30 microg of inhaled treprostinil 4 times daily (n = 6) or 45 microg 4 times daily (n = 6), via an ultrasonic nebulizer. Six-min walk distance (6MWD), functional class, and hemodynamics were assessed at baseline and 12 weeks. One patient was excluded from analysis due to the subsequent finding of pulmonary capillary hemangiomatosis. In the remaining 11 patients, inhaled treprostinil was safe and well tolerated. Inhaled treprostinil was associated with an increase in 6MWD at 12 weeks (baseline 339 +/- 86, 12 week, 1 h post-inhalation 406 +/- 121 m, 67-m change, p = 0.01). An improvement in 6MWD of 49 m from baseline was noted during the trough period, just before inhalation of treprostinil (p = 0.009). The 6MWD improvement of at least 10% was noted in 1 of 6 patients receiving 30 microg versus 5 of 6 receiving 45 microg. Over 12 weeks, significant decreases were noted in mean pulmonary arterial pressure (-10%) and in pulmonary vascular resistance (-26%). Functional class improved from III to II in 9 of 11 patients. This trial suggests that inhaled treprostinil is safe, well tolerated, and associated with significant improvements in exercise capacity, functional class, and pulmonary hemodynamics in symptomatic patients with PAH on bosentan.

Sildenafil Improves Dynamic Vascular Function in the Brain: Studies in Patients with Pulmonary Hypertension

Background: Prostaglandins and nitric oxide play a pivotal role in the regulation of macro- and microcirculatory blood flow distribution. Interference with both mediator systems have been implicated in cerebrovascular dysfunction. Inhaled iloprost (long-acting prostacyclin analogue) and the phosphodiesterase-5 inhibitor sildenafil have recently shown efficacy in the treatment of chronic pulmonary hypertension. We investigated the impact of these agents on cerebral microcirculatory regulation in patients suffering from this disease. Methods: In 11 patients suffering from severe pulmonary hypertension, a functional transcranial Doppler test utilizing a visual stimulation paradigm was undertaken to measure the evoked flow velocity in the posterior cerebral artery. Measurements were performed in parallel to right heart catheterization and pharmacological testing of the pulmonary vasoreactivity. After assessment of baseline measurements, inhaled iloprost and oral sildenafil were given consecutively for testing of cerebral and pulmonary vascular function. The data gained from the Doppler measurements were compared to data from 22 healthy volunteers. Results: Both substances provoked a significant reduction of pulmonary arterial pressure and vascular resistance, accompanied by minor changes in systemic vascular resistance. In contrast to these superimposable hemodynamic profiles opposite effects were observed regarding cerebral vascular tone: cerebral microvascular reactivity, as assessed by attenuation and time rate parameters, was significantly improved by sildenafil, but slightly worsened by iloprost. Conclusions: Sildenafil has beneficial effects on cerebral vascular reactivity indicative of an improvement in neurovascular coupling in patients with pulmonary hypertension. These results warrant further investigations of the influence of sildenafil on dynamic vascular function in the brain independent of the underlying disease.

Inhaled iloprost as a bridge to heart transplantation in a patient with endomyocardial fibroelastosis and severe pulmonary hypertension

Background: Endomyocardial fibrosis (EMF) is an endemic disease which can lead to partial obliteration of one or both ventricles with decreased ventricular distensibility and impaired diastolic filling. Results: We describe the intra- and postoperative course of an 18-year-old female patient undergoing orthotopic heart transplantation (HTx) because of EMF. Her body surface area was 1.18 m2. Blood pressure was 106/63mmHg during paroxysmal atrial fibrillation. She continously received an i.v. medication of 5µg/kg/min dopamine and 0.75µg/kg/min milrinone. Pulmonalis catheter examination revealed a PA of 83/39mmHg; mean pulmonary artery pressure (PAP) was 53mmHg; post-capillary wedge pressure was 15mmHg; trans-pulmonary gradient was 38mmHg; pulmonary vascular resistance (PVR) was 1113 dyn, systemic vascular resistance (SVR) was 2051 dyn. She received 50µg/day inhaled iloprost (Ilomedin®). This therapy was able to keep the preoperative PVR/SVR ratio below 30%. On day 33 of her hospitalisation, HTx was performed. Postoperative hemodynamics and respiratory conditions were stable without inhaled iloprost or nitric oxide. On postoperative day 3, however, iloprost therapy had to be restarted because of an increase in PAP levels. On postoperative day 24, the patient was discharged. Iloprost therapy was continued for additional 2 months then stopped since right heart catheter examination revealed hemodynamics within normal ranges and routine biopsy was grade 0. Conclusion: Inhaled iloprost, a long-acting prostacyclin analogue, can ameliorate pulmonary hypertension very successfully. In this case inhaled iloprost therapy was able to avoid the previously considered combined heart-lung transplantation. The 1-year follow data demonstrate the complete disappearance of pulmonary hypertension.

Iloprost

Iloprost is a long-acting prostacyclin analogue with potent vasodilating properties. When applied per inhalation, iloprost rapidly and remarkably reduces pulmonary vascular resistance and thereby pulmonary artery pressure for approximately 60-120 min. In addition, if iloprost is inhaled and not infused, major systemic side-effects such as a significant reduction of the systemic arterial pressure can mostly be circumvented. Inhaled iloprost can be applied by means of ultrasound or by oxygen flow with both techniques being available for intensive care ventilators. For use in the anaesthesia circuit a special construction was built.

Antiremodeling effects of iloprost and the dual-selective phosphodiesterase 3/4 inhibitor tolafentrine in chronic experimental pulmonary hypertension.

Severe pulmonary hypertension is a disabling disease with high mortality. We investigated acute and chronic effects of iloprost, a long-acting prostacyclin analogue, and the dual-selective phosphodiesterase 3/4 inhibitor tolafentrine in monocrotaline-induced pulmonary hypertension in rats. Twenty-eight and 42 days after administration of the alkaloid, right ventricular systolic pressure increased from 25.8+/-2.0 to 62.9+/-3.4 and 70.5+/-7.4 mm Hg, with concomitant decline in cardiac index, central venous oxygen saturation, and arterial oxygenation. Marked right heart hypertrophy was demonstrated by the strongly elevated ratio of right ventricle/left ventricle plus septum weight, and massive thickening of the precapillary artery smooth muscle layer was shown histologically. Western blot analysis demonstrated increased levels of matrix metalloproteinases (MMPs) -2 and -9 and increased gelatinolytic activities in isolated pulmonary arteries. In these animals, both intravenous iloprost and tolafentrine displayed characteristic features of pulmonary vasodilators. When chronically infused from days 14 to 28, both agents significantly attenuated all monocrotaline-induced hemodynamic and gas exchange abnormalities as well as right heart hypertrophy. Full normalization of all variables including right ventricle size was achieved on combined administration of both agents during this period. This was also true for MMP-2 and MMP-9 expression and activity. Moreover, when iloprost plus tolafentrine was used for late therapeutic intervention, with infusion from days 28 to 42 after full establishment of severe pulmonary hypertension and cor pulmonale, hemodynamic, gas exchange, and cardiac and pulmonary vascular remodeling changes were significantly reversed. We conclude that the combined administration of iloprost and a dual-selective phosphodiesterase 3/4 inhibitor prevents and reverses the development of pulmonary hypertension and cor pulmonale in response to monocrotaline in rats. This regimen may therefore offer a possible antiremodeling therapy in severe pulmonary hypertension.

Intraoperative inhalation of the long-acting prostacyclin analog iloprost for pulmonary hypertension

Pulmonary hypertension (PHT) contributes significantly to morbidity and mortality in cardiac surgery—especially in patients with long-standing mitral valve disease. Vasodilators administered intravenously can reduce pulmonary vascular resistance but also have an effect on the systemic circulation. Arterial hypotension must be expected, which results in reduction of right coronary blood flow and may lead to further deterioration of right ventricular performance. Inhaled nitric oxide (NO) is a more selective pulmonary vasodilator with virtually no systemic side effects. Recently, the inhalational use of the long-acting prostacyclin analog iloprost has been reported to offer superior selective pulmonary vasodilating properties relative to NO inhalation in primary PHT. We report our initial experience with the intraoperative use of iloprost inhalation in a case series of cardiac surgical patients.

Treatment of a case of acute right heart failure by inhalation of iloprost, a long-acting prostacyclin analogue

Perioperative acute right heart failure after orthotopic heart transplantation contributes significantly to morbidity and mortality. Vasodilators administered intravenously may decrease pulmonary vascular resistance, but also affect systemic circulation. A decrease of mean arterial pressure will result in reduced right coronary blood flow and deterioration of right ventricular performance. Vasodilators administered by inhalation, i.e. nitric oxide and prostacyclin, are attractive due to a more selective effect on the pulmonary circulation. This is the first report on the use of aerosolized iloprost, a long-acting prostacyclin analogue, applied for treatment of postoperative right heart failure in cardiac transplantation. After uneventful surgery, a heart transplant recipient was extubated on the first postoperative day and exhibited right heart failure on the following day. Standard treatment did not resolve this clinical problem sufficiently. A trial with inhalation of iloprost (16 μg per inhalation cycle, applied six times per day) was initiated. Iloprost inhalation resulted in a sufficient decrease of pulmonary vascular resistance (–23.5%), while cardiac index (+24.0%) and mixed venous saturation (+9.0%) increased. No profound effect on the systemic vascular resistance was observed (–2.8%). Iloprost inhalation may be an effective alternative to nitric oxide in the intensive care management of acute right heart failure after orthotopic heart transplantation. Due to the prolonged effect on the pulmonary vascular resistance, iloprost is especially useful for extubated patients.

Protection against gas exchange abnormalities by pre-aerosolized PGE1, iloprost and nitroprusside in lung ischemia-reperfusion.

Development of severe gas exchange abnormalities and respiratory failure is a major threat in lung transplantation. We used a model of ischemia-reperfusion injury in buffer-perfused rabbit lungs, with gas exchange conditions being analyzed in detail by the multiple inert gas elimination technique. A total of 150 min of warm ischemia was performed, and anoxic ventilation and a positive intravascular pressure were maintained throughout the ischemic period. Reperfusion provoked a transient, mostly precapillary pulmonary artery pressure elevation and progressive lung edema formation attributable to increased capillary permeability. Severe ventilation-perfusion mismatch with predominance of shunt flow became apparent within minutes after onset of reperfusion. 5 min-aerosolization maneuvers for alveolar deposition of prostaglandin E1, the long-acting prostacyclin analogue iloprost or the nitric oxide donor agent sodium nitroprusside were undertaken at the onset of ischemia. All preaerosolized vasodilator agents markedly reduced the pulmonary artery pressure elevation and the leakage response upon reperfusion. Most impressively, maintenance of physiological ventilation-perfusion matching was achieved by these maneuvers, and the development of shunt flow was largely suppressed. Preischemic alveolar deposition of PGE1, iloprost, and sodium nitroprusside by aerosol technique is highly effective in conserving normal pulmonary hemodynamics, microvascular integrity, and physiological gas exchange conditions upon reperfusion. This approach may offer as new strategy for maintenace of pulmonary function in lung transplantation.

Trial of a novel prostacyclin analog, UT-15, in patients with severe intermittent claudication

Prostacyclin is an endothelially derived vasodilator and inhibitor of platelet aggregation. Despite its therapeutic potential for peripheral arterial disease, the short half-life and chemical instability are barriers to routine therapy. Accordingly, prostacyclin analogs are being evaluated in patients with peripheral arterial disease. State-of-the-art non-invasive ultrasonography allows for serial testing of the hemodynamic effects of vasoactive drugs. The safety, efficacy and hemodynamic effects of UT-15, a novel, long-acting prostacyclin analog, were studied in patients with severe intermittent claudication. A total of eight patients with stable severe intermittent claudication, Fontaine classes IIb-III, were admitted to the hospital for intravenous infusion of UT-15. A symptom-limited, dose-escalation protocol was instituted, beginning with placebo and then with increasing dosage at 60-min intervals, followed by a 2-h period of maintenance dose at the maximum well-tolerated infusion rate. The hemodynamic response in the lower limbs was assessed with serial ultrasonography, segmental arterial pressures and pulse volumes. Blood flow in the common femoral artery increased 29% (p = 0.003) by the end of the maintenance period and remained above baseline throughout the washout period (p = 0.044). Blood velocity in the lower limb increased in most of the peripheral arteries. These increases achieved statistical significance in the common femoral artery (p = 0.025) and anterior tibial artery (p = 0.019), and approached significance in the popliteal artery (p = 0.062). In two of four patients in whom blood flow was undetectable before the infusion, arterial blood flow at the ankle level became apparent on ultrasonography during maintenance infusion. UT-15 infusion improved the pulse volume recording (p = 0.016) but the ankle/brachial index did not change significantly. Common side effects at peak dose included headache and nausea. There were no serious adverse events attributable to UT-15 treatment. In most patients, the optimal infusion rate was 10-20 ng/kg per min. In conclusion, ultrasonography is a novel approach for assessing the hemodynamic response to vasoactive agents. UT-15 is well tolerated when given for up to 2 h and increases arterial blood flow and velocity in patients with severe intermittent claudication.

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.

Iloprost infusion decreases skeletal muscle ischemia-reperfusion injury

Iloprost (a long-acting prostacyclin analog) has been demonstrated to decrease cardiac muscle infarct size after ischemia-reperfusion injury. We investigated the ability of iloprost to decrease skeletal muscle injury and platelet sequestration after ischemia-reperfusion injury in a canine bilateral isolated gracilis muscle model. Anesthesized animals (n = 13) were subjected to 6 hours of gracilis muscle ischemia and 1 hour of reperfusion. Fifteen minutes before muscle reperfusion, the animals were infused with radium 111-labeled autogenous platelets. Experimental animals (n = 7) received a continuous preischemic intravenous infusion of iloprost (0.45 microgram/kg/hr) and two 0.45 microgram/kg intravenous injections of iloprost (10 minutes before the ischemic interval and 10 minutes before reperfusion). Muscle injury was measured with triphenyltetrazolium chloride histochemical staining. Platelet sequestration within ischemic muscle specimens was determined by measuring indium 111 activity in a gamma counter. Iloprost infusion decreased muscle infarct size from 57.0% +/- 12.6% in control animals to 15.8% +/- 4.4% in experimental animals (p less than 0.05). Platelet uptake in experimental and control muscle was 1.2 +/- 0.21 x 10(7) and 2.17 +/- 0.48 x 10(7) platelets/gm ischemic muscle, respectively (p = 0.1). Although platelet sequestration was not altered significantly in this experiment, a reduction in skeletal muscle injury was confirmed. Further investigation on the mechanisms of action of iloprost in chronic and acute skeletal muscle ischemia is warranted.

Iloprost infusion decreases skeletal muscle ischemia-reperfusion injury

Iloprost (a long-acting prostacyclin analog) has been demonstrated to decrease cardiac muscle infarct size after ischemia-reperfusion injury. We investigated the ability of iloprost to decrease skeletal muscle injury and platelet sequestration after ischemia-reperfusion injury in a canine bilateral isolated gracilis muscle model. Anesthetized animals (n = 13) were subjected to 6 hours of gracilis muscle ischemia and 1 hour of reperfusion. Fifteen minutes before muscle reperfusion, the animals were infused with radium 111-labeled autogenous platelets. Experimental animals (n = 7) received a continuous preischemic intravenous infusion of iloprost (0.45 μg/kg/hr) and two 0.45 μg/kg intravenous injections of iloprost (10 minutes before the ischemic interval and 10 minutes before reperfusion). Muscle injury was measured with triphenyltetrazolium chloride histochemical staining. Platelet sequestration within ischemic muscle specimens was determined by measuring indium 111 activity in a gamma counter. Iloprost infusion decreased muscle infarct size from 57.0% ± 12.6% in control animals to 15.8% ± 4.4% in experimental animals (p < 0.05). Platelet uptake in experimental and control muscle was 1.2 ± 0.21 × 107 and 2.17 ± 0.48 × 107 platelets/gm ischemic muscle, respectively (p = 0.1). Although platelet sequestration was not altered significantly in this experiment, a reduction in skeletal muscle injury was confirmed. Further investigation on the mechanisms of action of iloprost in chronic and acute skeletal muscle ischemia is warranted.