Prolonged release of iloprost enhances pulpal blood flow and dentin bridge formation in a rat model of mechanical tooth pulp exposure.

The aim of this study was to investigate the effect of prolonged release of iloprost, a prostacyclin analog, on angiogenesis and dental pulp healing in a rat model of mechanical pulp exposure. The profile of iloprost release from poly (lactic-co-glycolic) acid (PLGA) microspheres was evaluated, and expression of vascular endothelial growth factor (VEGF) mRNA was determined. The molars of rats were subjected to mechanical pulp exposure and 5 different forms of treatment: Ca(OH)2, PLGA (blank), iloprost, and iloprost/PLGA. Blood flow was determined at 0, 3, and 7 days using laser Doppler flowmetry. After 30 days, the tooth specimens were collected, and subjected to micro-CT and immunohistological analysis. The results showed that iloprost release from the microspheres was prolonged for 4 days, and that the treatment increased tooth blood flow for up to 7 days. At 30 days, an increase of mineralized tissue formation and dentin bridge formation was observed in the iloprost and iloprost/PLGA microsphere groups. VEGF expression was significantly increased in the iloprost/PLGA microsphere group relative to the other groups. In conclusion, this PLGA microsphere iloprost delivery system significantly increased dental pulp blood flow in a prolonged manner and increased tertiary dentin formation in this rat pulp injury model. Prolonged prostacyclin release could be a potentially useful approach for regeneration of dental pulp.

Iloprost infusion through elastomeric pump for the outpatient treatment of severe Raynaud's phenomenon and digital ulcers - a single centre experience.

Raynaud's phenomenon (RP) and digital ulcers (DU) are the main clinical features of vasculopathy that occurs in several systemic rheumatic diseases. Intravenous iloprost is recommended for the treatment of severe RP and DU in patients with systemic sclerosis and portable devices for iloprost infusion have been recently designed, allowing outpatient treatment. This new alternative for drug administration not only avoids absenteeism, with the patient having the opportunity to continue his own family and work life, but also reduces the costs associated with hospitalization. We describe our protocol and report our experience with 12 patients, for a total of 25 infusions, who have received domiciliary iloprost through elastomeric pump. Patients could easily manage the device and the treatment outcomes were promising, with all patients having DU healing, without any special safety concerns.

Inhibition of neointima formation after experimental coronary artery stenting: a new biodegradable stent coating releasing hirudin and the prostacyclin analogue iloprost.

BACKGROUND: To minimize acute stent thrombosis and development of restenosis, stents coated with biodegradable and nonbiodegradable polymers have been proposed to serve as sustained-release drug carriers. METHODS AND RESULTS: In both a sheep and a pig model, we examined the vascular response to standard and high-pressure implantation of coronary Palmaz-Schatz stents coated with a 10-microm layer of polylactic acid (MW 30 kDa) releasing recombinant polyethylene glycol (r-PEG)-hirudin and the prostacyclin analogue iloprost, both drugs with antithrombotic and potentially antiproliferative effects. Study observation time was 28 days. Between the corresponding stent groups, no differences were observed with regard to preplacement and postplacement implantation parameters. The morphometric analysis demonstrated that the coating was associated with a greater lumen diameter through a reduction in the mean restenosis area by 22.9% (P<0.02) in the standard-pressure model (sheep) and by 24.8% (P<0.02) in the overstretch pig model compared with uncoated control stents without inducing a local inflammatory response. CONCLUSIONS: The results from this study demonstrate beneficial effects of a polymeric stent coating with polylactic acid releasing r-PEG-hirudin and iloprost on the development of restenosis after coronary stent placement at 4 weeks, independent of the extent of vascular injury. Future studies are proposed to investigate the integration of other substances to further enhance the potential of the stent coating on reducing neointimal formation.

Iloprost up-regulates vascular endothelial growth factor expression in human dental pulp cells in vitro and enhances pulpal blood flow in vivo.

INTRODUCTION: Prostacyclin (PGI2) is a biomolecule capable of enhancing angiogenesis and cellular proliferation. METHODS: We investigated the influence of a PGI2 analogue (iloprost) on dental pulp revascularization in vitro and in vivo by using human dental pulp cells (HDPCs) and a rat tooth injury model, respectively. Iloprost stimulated the human dental pulp cell mRNA expression of vascular endothelial growth factor (VEGF), fibroblast growth factor-2 (FGF-2), and platelet-derived growth factor (PDGF) in a significant dose-dependent manner. This mRNA up-regulation was significantly inhibited by pretreatment with a PGI2 receptor antagonist and forskolin (a protein kinase A activator). In contrast, a protein kinase A inhibitor significantly enhanced the iloprost-induced mRNA expression of VEGF, FGF-2, and PDGF. Pretreatment with a fibroblast growth factor receptor inhibitor attenuated the VEGF, FGF-2, and PDGF mRNA expression, indicating opposing regulatory mechanisms. RESULTS: The effect of iloprost on the dental pulp was investigated in vivo by using a rat molar pulp injury model. The iloprost-treated group exhibited a significant increase in pulpal blood flow at 72 hours compared with control. CONCLUSIONS: The present study indicates that iloprost may be a candidate agent to promote neovascularization in dental pulp tissue, suggesting the potential clinical use of iloprost in vital pulp therapy.

Discontinuing long-term Iloprost treatment for Raynaud's Phenomenon and systemic sclerosis: a single-center, randomized, placebo-controlled, double-blind study.

BACKGROUND: Iloprost has been reported to reduce Raynaud`s phenomenon (RP) and to inhibit progression of systemic sclerosis (SSc). OBJECTIVE: The aim of our study was to compare monthly iloprost infusions with placebo in patients treated long-term. METHODS: Seventeen patients, six with RP and 11 with SSc on monthly treatment with iloprost, received either a 3-hour intravenous infusion of iloprost or an equal volume of placebo once per month for 4 months in a monocentric, randomized, placebo-controlled, double-blind study. Raynaud attacks as measured by diary entries, skin temperature, skin sclerosis, fist closure, mouth opening, and digital ulcers were recorded during the observation period. RESULTS: Whereas mouth opening improved significantly (p = 0.043) in the iloprost-treated group, RS improved in both patient groups. However, no significant differences were found in the outcome measures. CONCLUSION: Although iloprost influences the inflammatory cascade in SSc, no statistical differences were seen in our study, indicating that treatment strategies with iloprost should be modified.

Iloprost-containing liposomes for aerosol application in pulmonary arterial hypertension: formulation aspects and stability.

PURPOSE: Pulmonary arterial hypertension (PAH) is a severe and progressive disease. The prostacyclin analogue iloprost is effective against PAH, but requires six to nine inhalations per day. The feasibility of liposomes to provide a sustained release formulation to reduce inhalation frequency is evaluated from a technological point of view. METHODS: Liposomal formulations consisting of di-palmitoyl-phosphatidyl-choline (DPPC), cholesterol (CH) and polyethyleneglycol-di-palmitoyl-phosphatidyl-ethanolamine (DPPE-PEG) were prepared. Their physico-chemical properties were investigated using dynamic light scattering, atomic force microscopy and differential scanning calorimetry. Stability of liposomes during aerosolization using three different nebulizers (air-jet, ultrasonic and vibrating mesh) was investigated with respect to drug loading and liposome size, pre- and post-nebulization. RESULTS: The phospholipid composition affected the diameters of liposomes only slightly in the range of 200-400 nm. The highest iloprost loading (12 microg/ml) and sufficient liposome stability (70% drug encapsulation post-nebulization) was observed for the DPPC/CH (70:30 molar ratio) liposomes. The formulation's stability was confirmed by the relatively high phase transition temperature (53 degrees C) and unchanged particle sizes. The incorporation of DPPE-PEG in the liposomes (DPPC/CH/DPPE-PEG, 50:45:5 molar ratio) resulted in decreased stability (20-50% drug encapsulation post-nebulization) and a phase transition temperature of 35 degrees C. The vibrating mesh nebulizer offered a number of significant advantages over the other nebulizers, including the production of small aerosol droplets, high output, and the lowest deleterious physical influence upon all investigated liposomes. CONCLUSION: Iloprost-loaded liposomes containing DPPC and CH components yield formulations which are well suited to aerosolization by the vibrating mesh nebulizer. The investigation of sustained release effects for the treatment of PAH in ex vivo and in vivo models is under way.

Intravenous iloprost treatment of Raynaud's phenomenon and ischemic ulcers secondary to systemic sclerosis.

OBJECTIVE: We conducted this study to assess the clinical usefulness and physiologic effects of intravenous iloprost in patients with Raynaud's phenomenon secondary to systemic sclerosis. METHODS: Thirty-five patients with Raynaud's phenomenon secondary to systemic sclerosis, including 11 with digital ischemic ulcerations, were enrolled in a double blind placebo controlled parallel study in 2 centers. Following a 2 week washout, subjects received intravenous iloprost (0.5-2.0 ng/kg/min) or saline by continuous infusion for 6 h on 5 consecutive days. Clinical assessments, status of digital ulcers, measures of in vivo platelet activation and detailed studies of peripheral vascular response to cold challenge, were performed at entry, at 5 days of therapy and at biweekly intervals for 10 weeks. RESULTS: Complete healing of all cutaneous lesions (ulcers, fissures, and paronychia) was observed 10 weeks after treatment in 6 of 7 patients receiving iloprost versus none of 4 receiving placebo (p = 0.015). Ischemic digital tip ulcers completely healed in all 4 patients with ulcers in the iloprost group, but none in the placebo group (p = 0.029). Patient diaries of frequency, duration and symptoms of Raynaud's phenomenon showed improvement in both groups. Critical ischemic temperature (finger temperature during controlled cold challenge at which Raynaud's or loss of detectable digital blood flow occurred) progressively decreased in the iloprost group from 21.3 +/- 7.3 degrees C at baseline to a minimum of 16.1 +/- 3.2 degrees C at 8 weeks after treatment (p = 0.076), whereas no consistent changes were observed in the placebo group. Treatment was associated with improvement in the rate of skin temperature recovery following cold challenge. No changes were noted in ambient digital skin temperature, total digital blood flow, finger systolic pressure or in measures of in vivo platelet activation. One subject dropped out with chest pain, but adverse effects of nausea, vomiting, headache and jaw pain were otherwise limited to the 5 days of drug infusion. CONCLUSION: Iloprost appears useful for the treatment of digital ulcers in systemic sclerosis and is associated with evidence of prolonged physiologic improvement although the mechanism of this effect remains unclear.

[Long-term treatment of primary pulmonary hypertension with inhaled iloprost]. / Langfristige Behandlung der primären pulmonalen Hypertonie mit inhalativem Iloprost.

BACKGROUND: Continuous intravenous infusion of prostacyclin is an effective treatment for primary pulmonary hypertension. This approach, however, requires the insertion of a permanent central venous catheter with the potential risk of serious complications. Recently, administration of aerosolized iloprost, a stable prostacyclin analogue, has been introduced as an alternative therapy for severe pulmonary hypertension. METHODS: We evaluated the effects of treatment with aerosolized iloprost over a one-year period on exercise capacity and hemodynamic variables in patients with primary pulmonary hypertension. RESULTS: Twenty-four patients with primary pulmonary hypertension received aerosolized iloprost at a cumulative daily dose of 100 to 150 micrograms for at least one year. The mean (+/- SD) walking distance in the 6-min-walk test increased from 278 +/- 96 meters at base line to 363 +/- 135 meters after 12 months (P < 0.0001). During the same period, the mean pulmonary artery pressure declined from 59 +/- 10 mmHg to 52 +/- 15 mmHg (P = 0.006), the cardiac output increased from 3.8 +/- 1.4 l/min to 4.4 +/- 1.3 l/min (P = 0.02), and the pulmonary vascular resistance declined from 1.205 +/- 467 dynes.s.cm-5 to 925 +/- 469 dynes.s.cm-5 (P = 0.0003). Treatment was generally well tolerated and except for mild coughing, minor headache and jaw pain in some patients, no side effects occurred. CONCLUSIONS: Long-term treatment with aerosolized iloprost is safe and has sustained effects on exercise capacity and pulmonary hemodynamics in patients with primary pulmonary hypertension.

Long-term treatment of primary pulmonary hypertension with aerosolized iloprost, a prostacyclin analogue.

BACKGROUND: Continuous intravenous infusion of epoprostenol (prostacyclin) is an effective treatment for primary pulmonary hypertension. This approach requires the insertion of a permanent central venous catheter, with the associated risk of serious complications. Recently, aerosolized iloprost, a stable prostacyclin analogue, has been introduced as an alternative therapy for severe pulmonary hypertension. METHODS: We evaluated the effects of aerosolized iloprost on exercise capacity and hemodynamic variables over a one-year period in patients with primary pulmonary hypertension. RESULTS: Twenty-four patients with primary pulmonary hypertension received aerosolized iloprost at a daily dose of 100 or 150 microg for at least one year. The mean (+/-SD) distance covered in the six-minute walk test increased from 278+/-96 m at base line to 363+/-135 m after 12 months (P<0.001). During the same period, the mean pulmonary arterial pressure before the inhalation of iloprost declined from 59+/-10 mm Hg to 52+/-15 mm Hg (P=0.006), cardiac output increased from 3.8+/-1.4 liters per minute to 4.4+/-1.3 liters per minute (P=0.02), and pulmonary vascular resistance declined from 1205+/-467 dyn x sec x cm(-5) to 925+/-469 dyn x sec x cm(-5) (P<0.001). The treatment was generally well tolerated, except for mild coughing, minor headache, and jaw pain in some patients. CONCLUSIONS: Long-term treatment with aerosolized iloprost is safe and has sustained effects on exercise capacity and pulmonary hemodynamics in patients with primary pulmonary hypertension.