iloprost and Hyperplasia

There are no established chemopreventive agents for lung cancer, the leading cause of cancer death in the United States. Prostacyclin levels are low in lung cancer and supplementation prevents lung cancer in preclinical models. We carried out a multicenter double-blind, randomized, phase II placebo-controlled trial of oral iloprost in current or former smokers with sputum cytologic atypia or endobronchial dysplasia. Bronchoscopy was performed at study entry and after completion of six months of therapy. Within each subject, the results were calculated by using the average score of all biopsies (Avg), the worst biopsy score (Max), and the dysplasia index (DI). Change in Avg was the primary end point, evaluated in all subjects, as well as in current and former smokers. The accrual goal of 152 subjects was reached and 125 completed both bronchoscopies (60/75 iloprost, 65/77 placebo). Treatment groups were well matched for age, tobacco exposure, and baseline histology. Baseline histology was significantly worse for current smokers (Avg 3.0) than former smokers (Avg 2.1). When compared with placebo, former smokers receiving oral iloprost exhibited a significantly greater improvement in Avg (0.41 units better, P = 0.010), in Max (1.10 units better, P = 0.002), and in DI (12.45%, P = 0.006). No histologic improvement occurred in current smokers. Oral iloprost significantly improves endobronchial histology in former smokers and deserves further study to determine if it can prevent the development of lung cancer.

Topics: Biopsy; Bronchi; Bronchoscopy; Double-Blind Method; Female; Follow-Up Studies; Humans; Hyperplasia; Iloprost; Lung Neoplasms; Male; Middle Aged; Smoking; Sputum; Treatment Outcome; United States; Vasodilator Agents

Acute allergic nasal inflammation is very common in the clinical allergic diseases, Prostaglandin I2 (PGI2) has been found to effective in combating inflammation. Iloprost, as an analog of PGI2, whose role and mechanisms in the acute allergic nasal inflammation remains unclear. It's necessary to elucidate the efficacy and potential mechanism of Iloprost in acute allergic nasal inflammation.. 36 female mice were randomly divided into DMSO group, IL 33 group, Iloprost group and IL 33+Iloprost intervention group. Mice were stimulated with IL 33 to construct an acute allergic nasal inflammation model. Hematoxylin and eosin (HE) and periodic acid Schiff reagent (PAS) staining, flow cytometry, Real time PCR and Enzyme linked immunosorbent assay (ELISA) was used to identify the role of Iloprost in acute allergic nasal inflammation. The comparison between multiplied groups was analyzed by ANOVA, and the Bonferroni method was used for further comparison of two groups.. Compared with IL 33 group, the inflammatory cell infiltration around the trachea and blood vessels of the lung tissue in the IL 33+ Iloprost group were reduced; goblet cell hyperplasia was observed in airway mucosa of IL 33 group, and the mucus secretion increased; the percentage of EOS and ILC2s in the BALF and lung single cell suspensions in IL 33+ Iloprost group were statistically lower than that of IL 33 group (p < 0.05); The mRNA expression levels of IL 5, IL 13, ST2 and GATA3 in the lung tissue of IL 33 group were higher than those in DMSO group (p < 0.05). After intervention with Iloprost, the mRNA expression levels of IL 5, IL 13, GATA3 and ST2 were lower than those in IL 33 group (p < 0.05) CONCLUSION: Iloprost may potentially inhibit the proliferation and activation of innate lymphoid cells 2 in mice with acute allergic inflammation, which maybe an effective option for the treatment of acute allergic inflammation related diseases.

Topics: Animals; Disease Models, Animal; Female; GATA3 Transcription Factor; Goblet Cells; Hyperplasia; Iloprost; Interleukin-1 Receptor-Like 1 Protein; Interleukin-13; Interleukin-33; Interleukin-5; Lung; Lymphocytes; Mice; Mucus; Nasal Mucosa; Random Allocation; Respiratory Mucosa; Rhinitis, Allergic; RNA, Messenger; Trachea

The history of lung cancer chemoprevention trials has been uniformly disappointing in that the large phase III studies showed no effect or harm in actively smoking participants, and smaller phase II studies have also been negative. In this issue of the journal (beginning on page 793), Keith and colleagues report their randomized, placebo-controlled trial of the oral prostacyclin analogue iloprost, the first trial to show an improvement in bronchial histology (i.e., regression), which occurred in former, but not current, smokers with sputum atypia. This Perspective discusses the strength of the clinical signal provided by this observation and its implications for further drug development.

Topics: Bronchi; Humans; Hyperplasia; Iloprost; Lung Neoplasms; Smoking; Vasodilator Agents

Small diameter PTFE grafts are prone to thrombosis and intimal hyperplasia development. Heparin graft coating has beneficial effects but also potential drawbacks. The purpose of this study was to evaluate the experimental efficacy of PEG-hirudin/iloprost coated small caliber PTFE grafts.. Thirty-six femoro-popliteal ePTFE grafts (expanded polytetrafluoroethylene, diameter 4 mm) were inserted into 18 pigs. Grafts were randomised individually for each leg and grouped for 3 groups. Group I consisted of native ePTFE grafts, group II were grafts coated with a polylactide polymer (PLA) without drugs and group III grafts were coated with PLA containing a polyethylene glycol (PEG)-hirudin/iloprost combination. The follow-up period was 6 weeks. Patency rates were calculated and development of pseudointima inside the grafts was noted. Thickness of intimal hyperplasia at the distal anastomoses was measured using light microscopy.. Patency rates for group I were 6/9 (67%), for group II 9/10 (90%) and 12/12 (100%) for group III. In groups I and II there was a significant reduction of blood flow proximal to the graft at graft harvest, to 29+/-12 and 28+/-20 ml/min respectively (both p<0.01 versus preoperative value), whilst in group III blood flow, 99+/-21 ml/min, remained at the preoperative level. Subtotal stenosis due to development of pseudointima was noted in each of the native and PLA coated grafts but not in group III grafts. Intimal hyperplasia at the distal anastomosis was lowest in group III.. The PEG-hirudin/iloprost coating of ePTFE prostheses effectively reduced pseudointima and intimal hyperplasia development and led to superior graft patency.

Topics: Anastomosis, Surgical; Animals; Blood Flow Velocity; Blood Vessel Prosthesis; Coated Materials, Biocompatible; Femoral Artery; Fibrinolytic Agents; Hirudins; Hyperplasia; Iloprost; Polyesters; Polytetrafluoroethylene; Popliteal Artery; Sus scrofa; Tunica Intima; Vascular Patency

1. The present experiments were designed to investigate the mechanisms causing intimal hyperplasia in connection with the impaired synergism between prostaglandin I2 (PGI2) and nitric oxide (NO) in human uterine arteries (UAs). 2. In order to assess the magnitude of intimal hyperplasia, the intima:media ratio (%) was estimated with the aid of an image analyser. Human UAs were classified into two groups, I and II on the basis of the ratio and the degree of elastin deposition of histologically normal specimens. The intima:media ratio in group II was determined to be 38.9 +/- 7.7% (n = 6), which was significantly (P < 0.01) higher than that in group I (16.5 +/- 1.5%, n = 7). Less deposition of elastin was found in group I than in group II. 3. The relaxation activities of iloprost (IP) as a stable analogue of PGI2 and sodium nitroprusside (SNP) as a NO donor were not different between the two groups. When the minimum concentrations (Cmin) of IP and SNP in producing relaxation were applied together to the UA strips, these compounds interacted synergistically in group I. The observed relaxation (48.7 +/- 8.8%, n = 7) in this group was significantly (P < 0.01) greater than the predicted value of 18.8 +/- 3.1% (n = 7) (the mathematical sum of the relaxations caused by IP and SNP alone). By contrast, these agents interacted in an additive manner in group II. The observed relaxation (20.8 +/- 9.5%, n = 6) was not significantly different from the predicted value (18.6 +/- 2.4%, n = 6) in this group. 4. During the relaxation produced by the addition of IP and SNP alone or in combination, the changes in cyclic nucleotides (cyclic AMP and cyclic GMP) contents (pmol mg-1 protein) were assayed. When IP and SNP at Cmin were applied together to the UA strips, these compounds interacted synergistically in increasing cyclic nucleotides in group I. The observed net increase in the content was determined to be 1.46 +/- 0.30 (P < 0.05 vs. the predicted value of 0.67 +/- 0.12) in this group (n = 7). By contrast, the observed net increase (0.40 +/- 0.07, n = 6) did not exceed the predicted value (0.65 +/- 0.07, n = 6) in group II. 5. These results suggest that the formation of intimal hyperplasia in group II may be closely related to the impaired synergism between PGI2 and NO in the human UAs.

Topics: Adult; Arteries; Cyclic AMP; Cyclic GMP; Epoprostenol; Female; Humans; Hyperplasia; Iloprost; In Vitro Techniques; Middle Aged; Nitric Oxide; Nitroprusside; Uterus

This study evaluated the efficacy of a prostacyclin analog, iloprost, and a thromboxane A2 receptor antagonist, daltroban, as inhibitors of experimental intimal hyperplasia. The vascular injury model used is based on an endothelial injury induced by a brief infusion of air into an isolated segment of the common carotid artery in the rat. Iloprost and daltroban were administered by continuous IV infusion for two weeks. The infusion rates were 0.1 micrograms/kg/min for iloprost and 0.1 mg/kg/hr for daltroban; these dosing rates are associated with significant alterations in eicosanoid-related pharmacologic effects. The animals were sacrificed at two weeks and the carotid arteries fixed in situ for light microscopy. The myointimal thickening was measured as the intima to media area (I/M) ratio. The control animals developed marked intimal thickening, with an I/M ratio of 0.76 +/- 0.12 (mean +/- SEM; N = 7). There was no inhibition of intimal hyperplasia (P greater than 0.05) after either iloprost (I/M ratio: 1.04 +/- 0.13; N = 8) or daltroban (I/M ratio: 0.70 +/- 0.04; N = 6). It is concluded that neither of these two modulators of eicosanoid activity, iloprost and daltroban, inhibit intimal hyperplasia following experimental endothelial injury.

Topics: Animals; Carotid Arteries; Carotid Artery Injuries; Endothelium, Vascular; Hyperplasia; Iloprost; In Vitro Techniques; Infusions, Intravenous; Male; Phenylacetates; Rats; Rats, Inbred Strains; Receptors, Prostaglandin; Receptors, Thromboxane; Sulfonamides; Thromboxane A2