lloprost delivered via the BREELIBTM nebulizer: a review of the clinical evidence for efficacy and safety.

Inhaled iloprost is a well-established medication to treat pulmonary arterial hypertension (PAH), a serious and potentially fatal disease of the pulmonary resistance vessels. The therapeutic administration of iloprost requires six to nine inhalations per day, due to the short biological half-life of this prostacyclin analogue. The I-NebTM AADTM, introduced in 2006, is the most commonly used nebulizer for delivering iloprost, requiring at least 6.5 min for an inhaled dose of 5 µg. In order to reduce inhalation time, a portable nebulizer based on modern-device technology was developed. The acute safety and tolerability of rapid iloprost inhalation via the BREELIBTM nebulizer was assessed in a four-part clinical trial. In this review, I describe the rationale and features of the new nebulizer, with particular emphasis on the safety and tolerability profile of iloprost inhalation via BREELIBTM observed in the first clinical studies. Meanwhile, the BREELIBTM nebulizer is approved and available for inhaled iloprost therapy combining significantly reduced inhalation time with good tolerability. This new approach will certainly improve patient convenience and compliance, possibly resulting in broader acceptance and improved efficacy of iloprost aerosol therapy in PAH.

Rapid transition from inhaled iloprost to inhaled treprostinil in patients with pulmonary arterial hypertension.

BACKGROUND: Inhaled treprostinil is a prostacyclin analog approved for the treatment of pulmonary arterial hypertension (PAH) that may provide a more convenient treatment option for patients receiving inhaled iloprost while maintaining the clinical benefit of inhaled prostacyclin therapy. AIMS: In this open-label safety study, 73 PAH patients were enrolled with primarily World Health Organization Class II (56%) or III (42%) symptoms. At baseline, most patients (93%) were receiving 5 µg of iloprost per dose but 38% of patients reported a dosing frequency below the labeled rate of 6-9 times daily. Patients initiated inhaled treprostinil at 3 breaths four times daily (qid) at the immediate next scheduled iloprost dose. The primary objective was to assess the safety of rapid transition from iloprost to inhaled treprostinil; clinical status and quality of life were also assessed. RESULTS: Most patients (84%) achieved the target treprostinil dose of 9 breaths qid and remained on study until transition to commercial therapy (89%). The most frequent adverse events (AEs) were cough (74%), headache (44%), and nausea (30%), and five patients prematurely discontinued study drug due to AE (n = 3), disease progression (n = 1), or death (n = 1). At week 12, the time spent on daily treatment activities was reduced compared to baseline, with a mean total savings of 1.4 h per day. Improvements were also observed at week 12 for 6-min walk distance (+16.0; P < 0.001), N-terminal pro-B-type natriuretic peptide (-74 pg/mL; P = 0.001), and the Cambridge Pulmonary Hypertension Outcome Review (all domains P < 0.001). CONCLUSIONS: Pulmonary arterial hypertension patients can be safely transitioned from inhaled iloprost to inhaled treprostinil while maintaining clinical status.

Efecto de iloprost nebulizado combinado con óxido nítrico inhalado y sildenafilo oral en las presiones pulmonares de pacientes sometidos a trasplante pulmonar. Eficacia terapéutica en la hipertensión pulmonar intraoperatoria / Effect of nebulised iloprost combined with inhaled nitric oxide and oral sildenafil on lung transplant patients. Therapeutic efficacy in pulmonary hypertension during surgery

Objetivos: La presencia de hipertensión pulmonar tiene elevada incidencia durante el perioperatorio del trasplante pulmonar y puede condicionar deterioro hemodinámico que obligue a instaurar circulación extracorpórea. Nuestro objetivo es estudiar los efectos hemodinámicos en la circulación pulmonar y sistémica de la asociación de óxido nítrico e iloprost inhalados y sildenafilo por vía oral en pacientes con hipertensión pulmonar severa durante la cirugía de trasplante pulmonar. Pacientes y métodos: Durante el perioperatorio del trasplante pulmonar, 17 pacientes recibieron 10 mg de iloprost nebulizado cuando su presión arterial pulmonar media superó los 50 mmHg. Todos los pacientes recibieron 50 mg de sildenafilo por vía oral 30 min antes de la inducción anestésica y 20 ppm de NO inhalado tras la intubación traqueal. Se registraron las variables hemodinámicas y respiratorias en los tiempos basal (tras la inducción anestésica), previamente a la administración de iloprost, y a los 5 y 30 min de su administración. Resultados: La administración de iloprost redujo de forma significativa la presión arterial pulmonar e incrementó significativamente el índice cardiaco y la fracción de eyección del ventrículo derecho. No se produjeron modificaciones significativas de la presión arterial sistémica. Conclusiones: La triple asociación reduce significativamente las presiones pulmonares en el perioperatorio del trasplante pulmonar y debe considerarse en presencia de hipertensión pulmonar severa durante la intervención quirúrgica o el postoperatorio inmediato del trasplante pulmonar(AU)

Objectives: There is a high incidence of pulmonary hypertension during the lung transplant peri-operative period, and could lead to a haemodynamic deterioration that may require the need of extracorporeal circulation. Our aim was to study the haemodynamic effects on the pulmonary and systemic circulation of the combination of inhaled nitric oxide and iloprost and oral sildenafil in patients with severe pulmonary hypertension during lung transplant surgery. Patients and methods: Seventeen patients received 10mg of nebulised iloprost during the peri-operative period of the lung transplant when their mean pulmonary pressure exceeded 50 mmHg. All the patients received 50 mg of oral sildenafil 30 min before anaesthetic induction, 20 ppm of inhaled nitric oxide after tracheal intubation. The haemodynamic and respiratory variables were recorded at baseline (after anaesthetic induction), prior to the administering of iloprost, and at 5 and 30 min after it was given. Results: The administering of iloprost significantly reduced the pulmonary arterial pressure and significantly increases the cardiac index and the right ventricular ejection fraction. There were no significant changes occurred in the systemic arterial pressure. Conclusions: The triple combination significantly reduces the pulmonary pressures in the lung transplant peri-operative and should be considered when there is severe pulmonary hypertension during the surgery or during the immediate post-operative period of lung transplantation(AU)

Clinical pharmacology and efficacy of inhaled iloprost for the treatment of pulmonary arterial hypertension.

Similar to other prostanoids, iloprost is a potent vasodilator with considerable antiproliferative and anti-thrombotic properties, although the relevance of its ability to affect platelet aggregation in this subset of patients is unrecognized. The pathogenesis of pulmonary arterial hypertension (PAH) is a multifactorial and complex process secondary to an innate deficiency of substances that induce vasodilation and an overproduction of substances producing vasoconstriction. The production of endothelial vasoactive mediators such as nitric oxide, prostacyclin, endothelin-1, thromboxane and serotonin affect the growth of smooth muscle cells, which facilitate the development of structural remodeling changes that are characteristic of PAH. There have been remarkable advances in understanding the pathologic processes that are responsible for increasing pulmonary vascular resistance and that result in elevated pulmonary artery pressures in order to reverse and prevent progression of the disease process. The goals of treatment in these patients are to alleviate the patients' symptoms, to improve functional capacity and to prevent the progression of the disease. The prostacyclin analogs, such as iloprost, have given hope to these patients who struggle under the burdens of this complex disease.

Inhaled iloprost for therapy in pulmonary arterial hypertension.

Iloprost (Ventavis, Bayer Schering Pharma, Germany) is a synthetic prostacyclin that is used in its inhalative form for the therapy of pulmonary arterial hypertension. Long-term therapy can increase exercise capacity and quality of life. The use of modern nebulizers especially designed for the administration of iloprost guarantees the pulmonary deposition of the required doses and systematically minimizes side effects. Regarding existing data, inhalative iloprost acts in effective and safe combination with other classes of medication; indeed, such combination therapy is frequently necessary in pulmonary arterial hypertension.

Respuesta clínica al tratamiento con iloprost en paciente con enfermedad por ateroembolismo de colesterol / No disponible

No disponible

Iloprost inhalation redistributes pulmonary perfusion and decreases arterial oxygenation in healthy volunteers.

BACKGROUND: Previous studies have shown that ventilation-perfusion matching is improved in the prone as compared with that in the supine position. Regional differences in the regulation of vascular tone may explain this. We have recently demonstrated higher production of nitric oxide in dorsal compared with ventral human lung tissue. The purpose of the present study was to investigate regional differences in actions by another vasoactive mediator, namely prostacyclin. The effects on gas exchange and regional pulmonary perfusion in different body positions were investigated at increased prostacyclin levels by inhalation of a synthetic prostacyclin analogue and decreased prostacyclin levels by unselective cyclooxygenase (COX) inhibition. METHODS: In 19 volunteers, regional pulmonary perfusion in the prone and supine position was assessed by single photon emission computed tomography using (99m)Tc macro-aggregated albumin before and after inhalation of iloprost, a stable prostacyclin analogue, or an intravenous infusion of a non-selective COX inhibitor, diclofenac. In addition, gas distribution was assessed in seven subjects using (99m)Tc-labelled ultra-fine carbon particles before and after iloprost inhalation in the supine position. RESULTS: Iloprost inhalation decreased arterial PaO(2) in both prone (from 14.2+/-0.5 to 11.7+/-1.7 kPa, P<0.01) and supine (from 13.7+/-1.4 to 10.9+/-2.1 kPa, P<0.01) positions. Iloprost inhalation redistributed lung perfusion from non-dependent to dependent lung regions in both prone and supine positions, while ventilation in the supine position was distributed in the opposite direction. No significant effects of non-selective COX inhibition were found in this study. CONCLUSIONS: Iloprost inhalation decreases arterial oxygenation and results in a more gravity-dependent pulmonary perfusion in both supine and prone positions in healthy humans.

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.

Inhaled iloprost in pulmonary arterial hypertension.

OBJECTIVE: To review the pharmacology, pharmacodynamics, and clinical trials evaluating inhaled iloprost in pulmonary arterial hypertension (PAH). DATA SOURCES: A MEDLINE search (1996-February 2005) was performed using the key words pulmonary hypertension, iloprost, and epoprostenol. Information regarding Food and Drug Administration approval was obtained via the Internet. STUDY SELECTION AND DATA EXTRACTION: All clinical trials using inhaled iloprost in PAH published in English were identified. Additionally, references from the identified articles were reviewed. DATA SYNTHESIS: A stable analog of prostacyclin, inhaled iloprost is thought to promote benefit in PAH through vasodilation, antiproliferative effects, and inhibition of platelet aggregation. In a placebo-controlled trial of 203 patients, inhaled iloprost significantly improved the combined endpoint of change in New York Heart Association functional class and 10% improvement in 6-minute walk distance (p = 0.007). Small, short-term clinical trials demonstrated hemodynamic benefits for inhaled iloprost alone and in combination with other pulmonary vasodilating agents. The aerosolized delivery route and low incidence of adverse events are positive attributes for inhaled iloprost, while the frequency of administration and lack of comparative data limit its role in PAH. CONCLUSIONS: Currently, inhaled iloprost offers potential benefit for patients with contraindications to bosentan, preference for non-parenteral products, ineligibility for parenteral therapy, or as adjunctive therapy with other pulmonary vasodilators. Larger, long-term clinical trials are needed to solidify the role for inhaled iloprost in the management of PAH.

The effect of caffeine on peripheral vascular resistance in isolated perfused guinea pig hind limbs.

BACKGROUND: The role of caffeine in cardiovascular disease is controversial. Most of its pharmacologic actions are attributed to its role as an adenosine antagonist. Adenosine is one of the most important endogenous vasodilatative substances and is released under ischemic conditions, for example, in the skeletal muscle of patients with peripheral arterial occlusive disease. We aimed to investigate the influence of caffeine on peripheral vascular resistance and on the beneficial vasodilatory effect of adenosine in isolated perfused guinea pig hind limbs. MATERIALS AND METHODS: (1) Caffeine was administered at 0.5, 5, and 50 micromol/L under normoxic conditions. (2) The vasculature of the perfused guinea pig hind limb was precontracted with noradrenaline (3 micromol/L), followed by adenosine (10 micromol/L) under normoxic conditions. When vascular resistance (VR) had reached a steady state, caffeine was administered additionally at dosages of 0.5, 5, and 50 micromol/L. (3) This protocol was repeated using iloprost 0.1 micromol/L instead of adenosine as vasodilatory substance. (4) Under hypoxia, caffeine was again administered at the above dosages. (5) Under hypoxia, experiments with adenosine A2-receptor antagonists (alloxazine 10 micromol/L and ZM 241385 100 nmol/L) were done. RESULTS: Under normoxic conditions, 0.5 and 5 micromol/L caffeine had nearly no effect on vascular resistance compared with baseline conditions. A slight, but statistically not significant decrease in VR was achieved with 50 micromol/L caffeine. In the presence of noradrenaline, the vasodilatory effect of adenosine was reduced by 7.6 +/- 1.6% after the addition of 0.5 micromol/L caffeine, and by 37.3 +/- 3.8% at a dosage of 5 micromol/L caffeine. A dosage of 50 micromol/L caffeine completely abolished the vasodilatative effect of adenosine. In the presence of iloprost, only a slight but statistically insignificant inhibitory influence (0.9%) of caffeine at a dosage of 50 micromol/L could be seen. Hypoxia significantly reduced VR. Caffeine at 0.5 micromol/L diminished this effect by about 53.2 +/- 4.6% and abolished it at 5 and 50 micromol/L. The hypoxia-induced adenosine-mediated vasodilatation seems to be an adenosine A2A-receptor-mediated effect. CONCLUSIONS: The observed effect of hypoxia-induced vasodilatation in peripheral arteries may be the result of the vasodilatory effect of elevated endogenous adenosine during hypoxia. For patients with peripheral arterial disease, drinking of caffeine-containing beverages may reduce the beneficial vasodilatory effect of elevated endogenous adenosine levels.

Pharmacokinetics and metabolism of infused versus inhaled iloprost in isolated rabbit lungs.

Iloprost is a potent prostacyclin analog, which has been shown to exert beneficial effects in several vascular disorders. Inhalation of aerosolized iloprost was found to cause selective pulmonary vasodilatation, and this approach is under current investigation for treatment of chronic pulmonary hypertension. The present study investigated pharmacokinetics and metabolism of aerosolized iloprost in isolated buffer-perfused rabbit lungs, compared with intravascular administration of the prostanoid. After buffer admixture of iloprost, a steady decline of perfusate concentrations of the intact prostanoid was noted (half-life approximately 3.5 h), mostly attributable to progressive metabolism to dinor- and tetranoriloprost. Inhaled iloprost rapidly entered the intravascular compartment, with peak buffer concentrations being noted after 30 min (bioavailability approximately 63%). Compared with infused iloprost, significantly more rapid metabolism to dinor- and tetranoriloprost was noted for iloprost administered via the inhalative route of application. However, the percentage of the nebulized agent that enters the intravascular space as intact iloprost displays the same clearance rate as directly perfusate-admixed prostanoid. We conclude that a high percentage of inhaled iloprost rapidly enters the intravascular compartment in intact rabbit lungs. The lung is capable of metabolizing iloprost via beta-oxidation, and more rapid appearance of dinor- and tetranoriloprost is noted for the inhalative as compared with the intravascular route of iloprost administration.

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.

Pharmacokinetics of oral iloprost in patients with Raynaud's phenomenon secondary to systemic sclerosis.

Iloprost is a chemically stable, pharmacologically highly potent prostacyclin-minietic. The therapeutic efficacy of the intravenous preparation was proven in patients with peripheral arterial occlusive disease or with Raynaud's phenomenon (RP). Recently, a sustained release oral preparation was developed for outpatient therapy. The purpose of the current study was to investigate whether the oral drug has a different pharmacokinetic profile in patients with RP secondary to systemic sclerosis (SSc) in comparison with healthy volunteers. Ten patients with RP secondary to SSc and 10 healthy volunteers (matched for age and sex) participated. Oral iloprost 50 microg was given twice daily for 8 days with dosing intervals of 5 h and plasma levels were taken over 10 h on Day 1 and 8. Plasma levels of iloprost were determined by a validated specific and sensitive radio-immunoassay. Compared with healthy volunteers, patients with SSc exhibited higher AUC values (by mean factors of 2. 1 and 2.0 on Day 1 and 8) and maximum plasma levels (by mean factors of 1.6 and 1.8 on Day 1 and 8). The increased systemic iloprost exposure was observed after both daily doses and on both monitored study days. Mean AUC values did not show accumulation over the 8 days. These findings are in agreement with a reduced total clearance of iloprost given by i.v. route in SSc patients compared to healthy volunteers, although no participant with severe renal impairment was included. A weak but significant correlation was found between individual creatinine clearance and AUC values. In conclusion, RP secondary to SSc is associated with an increased systemic iloprost exposure which is probably caused by changes of the metabolic clearance of iloprost. These effects cannot be explained by changes of renal function alone.

Clinical pharmacokinetics of vasodilators. Part II.

Stimulating cardiac beta 1-adrenoceptors with oxyfedrine causes dilatation of coronary vessels and positive inotropic effects on the myocardium. beta 1-adrenergic agonists increase coronary blood flow in nonstenotic and stenotic vessels. The main indication for the use of the phosphodiesterase inhibitors pamrinone, mirinone, enoximone and piroximone is acute treatment of severe congestive heart failure. Theophylline is indicated for the treatment of asthma, chronic obstructive pulmonary disease, apnea in preterm infants ans sleep apnea syndrome. Severe arterial occlusive disease associated with atherosclerosis can be beneficially affected by elcosanoids. These drugs must be administered parenterally and have a half-life of only a few minutes. Sublingual or buccal preparations of nitrates are the only prompt method (within 1 or 2 min) of terminating anginal pain, except for biting nifedipine capsules. The short half-life (about 2.5 min) of nitroglycerin (glyceryl trinitrate) makes long term therapy impossible. Tolerance is a problem encountered with longer-acting nitric oxide donors. Knowledge of the pharmacokinetic properties of vasodilating drugs can prevent a too sudden and severe blood pressure decrease in patients with chronic hypertension. In considering the administration of a second dose, or another drug, the time necessary for the initially administered drug to reach maximal efficacy should be taken into account. In hypertensive emergencies urapidil, sodium nitroprusside, nitroglycerin, hydralazine and phentolamine are the drugs of choice, with the addition of beta-blockers during catecholamine crisis or dissecting aortic aneurysm. Childhood hypertension is most often treated with angiotensin-converting enzyme (ACE) inhibitors or calcium antagonists, primarily nifedipine. Because of the teratogenic risk involved with ACE inhibitors, extreme caution must be exercised when prescribing for adolescent females. The propagation of health benefits to breast-fed infants, combined with more women delaying pregnancy until their fourth decade, has entailed an increase in the need for hypertension management during lactation. Low dose hydrochlorothiazide, propranolol, nifedipine and enalapril or captopril do not pose enough of a risk of preclude breastfeeding in this group. The most frequently used antihypertensive agents during pregnancy are methyldopa, labetalol and calcium channel antagonists. Methyldopa and beta-blockers are the drugs of choice for treating mild to moderate hypertension. Prazosin and hydralazine are used to treat moderate to severe hypertension and hydralazine, urapidil or labetalol are used to treat hypertensive emergencies. The use of overly aggressive antihypertensive therapy during pregnancy should be avoided so that adequate uteroplacental blood flow is maintained. Methyldopa is the only drug accepted for use during the first trimester of pregnancy.

Pharmacokinetics and pharmacodynamics of intra-graft iloprost in femorodistal bypass surgery.

Intra-graft injection of the prostacyclin analogue, iloprost, was performed at the end of femorodistal bypass procedures in 12 patients with severe peripheral arterial occlusive disease. Iloprost plasma levels were measured and compared with changes in haemodynamics. There was a high initial iloprost plasma level (mean 625 pg/ml) which dropped to a mean of 50 pg/ml after 15 min. This correlated with an immediate reduction in systolic blood pressure which had returned to pretreatment levels after 15 min. In contrast, the vascular resistance distal to the graft showed a reduction after 5 min which was maintained for at least 20 min after iloprost injection and the mean blood flow through the graft increased steadily throughout the same period of measurement. The study showed an effect of iloprost on blood pressure which correlated with plasma levels, but the time course of the changes in distal vascular resistance and graft blood flow demonstrated an effect more prolonged than the half-life of iloprost.

Pharmacokinetics and tolerability of oral iloprost in thromboangiitis obliterans patients.

OBJECTIVE: Iloprost is a potent PGI2 mimetic, which has been shown to be therapeutically effective in several vascular disorders. Due to its rapid clearance from the central compartment, iloprost is administered mainly by i.v. infusion, which limits its use to hospitalized patients. In order to improve pharmacotherapeutic use of this PGI2 mimetic, an oral extended-release (ER) dosage form has been developed, which should mimic plasma level profiles as observed after i.v. infusion and serve as a therapeutic equivalent. METHODS: This trial was performed to investigate the tolerability and pharmacokinetics of iloprost administered perorally, compared with i.v. infusion, in 12 patients suffering from thromboangiitis obliterans (TAO). A dose titration was carried out for 1 week with i.v. iloprost, followed by a p.o. titration and treatment phase of 3 weeks' duration. Pharmacokinetics was investigated at the individually tolerated dose levels; i.e., on days 5-7 (i.v. infusion at 2, 2.5 and 3 ng.kg-1.min-1), and twice during p.o. treatment after b.i.d. administration of 50, 100, 150, 200 or 300 micrograms. RESULTS: Individual tolerability of iloprost varied: 7 patients out of 12 tolerated the maximum i.v. dose of 3 ng.kg-1.min-1; six tolerated the maximum oral dose of 600 micrograms. No patients withdrew from the study due to adverse events. Flush and headache were the most common adverse events and seemed to be related to the study drug. After i.v. infusion of iloprost, dose-normalized (3 ng.kg-1.min-1), steady-state plasma levels were 260 pg.ml-1. Terminal half-life was 0.57 h. Total clearance ranged from 8 to 17 ml.min-1.kg-1. Peroral administration of the ER formulation resulted in dose-dependent Cmax and AUC values. AUC values of the first and second daily dose interval, i.e., 0-5 h and 5-11 h after first dosing, were almost identical. Absolute bioavailability was 24%, with the exception of two patients who tolerated only 50 micrograms b.i.d. and exhibited a bioavailability of approx. 60%. The AUC values observed in weeks 2 and 4 were identical, demonstrating low day-to-day variability of iloprost plasma level profiles in TAO patients. CONCLUSION: Based upon pharmacokinetic data, the ER formulation provides an equivalent to the i.v. infusion of iloprost and broadens the range of therapy to nonhospitalized patients. The availability of capsules with 50 and 100 micrograms iloprost enables individual dose titration and pharmacotherapy. Beneficial effects, as observed with i.v. iloprost in TAO patients, should therefore be achievable by peroral pharmacotherapy using the new ER formulation.

[Thrombocyte prostacyclin receptors in gestational hypertension and pre-eclampsia]. / Thrombozytäre Prostacyclin-Rezeptoren bei Gestationshypertonie und Präeklampsie.

OBJECTIVE: To determine prostacyclin (PGI2) receptor characteristics in pregnancies complicated by hypertension and to assess any relation to the clinical outcome. METHODS: Radioligand binding studies with [3H]-Iloprost were performed to measure receptor capacity (Bmax) and affinity (Kd-1) using platelet membranes from patients with preeclampsia, gestational hypertension or normal pregnancy. RESULTS: PGI2 receptor capacity did not differ between the patient groups. In contrast, PGI2 receptor affinity was diminished in gestational hypertension and considerably reduced in preeclampsia compared to normal pregnancy. A similar pattern was found in fetal growth (normal pregnancy > gestational hypertension > preeclampsia). Furthermore, the rate of low Apgar scores and acidosis was increased in preeclampsia. CONCLUSIONS: In preeclampsia reduced platelet PGI2 receptor affinity was found as well as poor pregnancy outcome in comparison with normal pregnancy, whereas these differences were less pronounced in gestational hypertension. This suggests a role of PGI2 and its receptor in gestational hypertension and in particular in preeclampsia.