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Cardiovascular Journal of AfricaInsufficient oxygen supply to organs and tissues due to reduced arterial or venous blood flow results in ischaemia, during which, although ATP production stops, AMP and... (Comparative Study)
Comparative Study
AIM
Insufficient oxygen supply to organs and tissues due to reduced arterial or venous blood flow results in ischaemia, during which, although ATP production stops, AMP and adenosine continue to be produced from ATP. The fate of irisin, which causes the production of heat instead of ATP during ischaemia, is unknown. Iloprost and sildenafil are two pharmaceutical agents that mediate the resumption of reperfusion (blood supply) via vasodilatation during ischaemic conditions. Our study aimed to explore the effects of iloprost and sildenafil on irisin levels in the heart, liver and kidney tissues and whether these pharmaceutical agents had any impact on serum irisin and nitric oxide levels in rats with induced experimental myocardial ischaemia.
METHODS
The study included adult male Sprague-Dawley rats aged 10 months and weighing between 250 and 280 g. The animals were randomly allocated to eight groups, with five rats in each group. The groups were: sham (control), iloprost (ILO), sildenafil (SIL), ILO + SIL, myocardial ischaemia (MI), MI + ILO, MI + SIL and MI + ILO + SIL. The treatment protocols were implemented before inducing ischaemia, which was done by occluding the left coronary artery with a plastic ligature for 30 minutes. Following the reperfusion procedure, all rats were sacrificed after 24 hours, and their heart, liver and kidney tissues and blood samples were collected for analyses. An immunohistochemical method was used to measure the change in irisin levels, the ELISA method to quantify blood irisin levels, and Griess' assay to determine nitric oxide (NO) levels in the serum and tissue. Myocardial ischaemia was confirmed based on the results of Masson's trichrome staining, as well as levels of troponin and creatine kinase MB.
RESULTS
Irisin levels in biological tissue and serum dropped statistically significantly in the ischaemic group (MI), but were restored with ILO and SIL administration. Individual SIL administration was more potently restorative than individual ILO administration or the combined administration of the two agents. NO level, on the other hand, showed the opposite tendency, reaching the highest level in the MI group, and falling with the use of pharmaceutical agents.
CONCLUSIONS
Individual or combined administration of ILO and SIL reduced myocardial ischaemia and NO levels, and increased irisin levels. Elevated levels of irisin obtained by drug administration could possibly contribute to accelerated wound recovery by local heat production. Sildenafil was more effective than iloprost in eliminating ischaemia and may be the first choice in offsetting the effects of ischaemia in the future.
Topics: Adenosine Triphosphate; Animals; Disease Models, Animal; Energy Metabolism; Fibronectins; Iloprost; Kidney; Liver; Male; Myocardial Ischemia; Myocardial Reperfusion Injury; Myocardium; Nitric Oxide; Rats, Sprague-Dawley; Sildenafil Citrate; Vasodilation; Vasodilator Agents
PubMed: 28906529
DOI: 10.5830/CVJA-2017-025 -
European Respiratory Review : An... Mar 2009Prostacyclin and its analogues (prostanoids) are potent vasodilators, and exhibit antithrombotic, antiproliferative and anti-inflammatory properties. Pulmonary arterial... (Review)
Review
Prostacyclin and its analogues (prostanoids) are potent vasodilators, and exhibit antithrombotic, antiproliferative and anti-inflammatory properties. Pulmonary arterial hypertension (PAH) is characterised by vasoconstriction, thrombosis and proliferation, and is associated with reduced synthesis of endogenous prostacyclin. This provides a strong rationale for the use of prostanoids to treat PAH, a concept that is now supported by more than two decades of clinical research and experience. Intravenous and subcutaneous prostanoids have clearly demonstrated efficacy in severe PAH, but adverse events related to the drug delivery system, systemic side-effects and tachyphylaxis have driven research into alternative prostanoid treatments. Iloprost is administered by inhalation, and thus avoids most of the systemic side-effects associated with i.v. or subcutaneous prostanoid infusion. Two randomised controlled 12-week trials in patients with PAH have demonstrated efficacy and a favourable safety profile for iloprost as monotherapy (the AIR trial) and in combination with oral bosentan (STEP). Open-label uncontrolled long-term studies of inhaled iloprost therapy indicate that this treatment may improve long-term outcomes in PAH.
Topics: Administration, Inhalation; Clinical Trials as Topic; Humans; Iloprost; Pulmonary Infarction; Vasodilator Agents
PubMed: 20956120
DOI: 10.1183/09059180.00011111 -
Health Technology Assessment... Oct 2009To investigate the clinical and cost-effectiveness of epoprostenol, iloprost, bosentan, sitaxentan and sildenafil for the treatment of adults with pulmonary arterial... (Review)
Review
Clinical and cost-effectiveness of epoprostenol, iloprost, bosentan, sitaxentan and sildenafil for pulmonary arterial hypertension within their licensed indications: a systematic review and economic evaluation.
OBJECTIVE(S)
To investigate the clinical and cost-effectiveness of epoprostenol, iloprost, bosentan, sitaxentan and sildenafil for the treatment of adults with pulmonary arterial hypertension (PAH) within their licensed indications.
DATA SOURCES
Major electronic databases (including the Cochrane Library, MEDLINE and EMBASE) were searched up to February 2007. Further data were obtained from dossiers submitted to NICE by the manufacturers of the technologies.
REVIEW METHODS
The systematic clinical and economic reviews were conducted according to accepted procedures. Model-based economic evaluations of the cost-effectiveness of the technologies from the perspective of the UK NHS and personal social services were carried out.
RESULTS
In total, 20 randomised controlled trials (RCTs) were included in this assessment, mostly of 12-18 weeks duration and comparing one of the technologies added to supportive treatment with supportive treatment alone. Four published economic evaluations were identified. None produced results generalisable to the NHS. There was no consensus in the industry submissions on the most appropriate model structure for the technology assessment. Improvement in 6-minute walk distance (6MWD) was seen with intravenous epoprostenol in primary pulmonary hypertension (PPH) patients with mixed functional class (FC) (mainly III and IV, licensed indication) compared with supportive care (58 metres; 95% CI 6-110). For bosentan compared with supportive care, the pooled result for improvement in 6MWD for FCIII patients with mixed PAH (licensed indication) was 59 metres (95% CI 20-99). For inhaled iloprost, sitaxentan and sildenafil no stratified data for improvement in 6MWD were available. The odds ratio (OR) for FC deterioration at 12 weeks was 0.40 (95% CI 0.13-1.20) for intravenous epoprostenol compared with supportive care. The corresponding values for inhaled iloprost (FCIII PPH patients; licensed indication), bosentan, sitaxentan (FCIII patients with mixed PAH; licensed indication) and sildenafil (FCIII patients with mixed PAH; licensed indication) were 0.29 (95% CI 0.07-1.18), 0.21 (95% CI 0.03-1.76), 0.18 (95% CI 0.02-1.64) and [Commercial-in-confidence information has been removed] respectively. The incremental cost-effectiveness ratios (ICERs) for the technologies plus supportive care compared with supportive care alone, determined by independent economic evaluation, were 277,000 pounds/quality-adjusted life-year (QALY) for FCIII and 343,000 pounds/QALY for FCIV patients for epoprostenol, 101,000 pounds/QALY for iloprost, 27,000 pounds/QALY for bosentan and 25,000 pounds/QALY for sitaxentan. For the most part sildenafil plus supportive care was more effective and less costly than supportive care alone and therefore dominated supportive care. In the case of epoprostenol the ICERs were sensitive to the price of epoprostenol and for bosentan and sitaxentan the ICERs were sensitive to running the model over a shorter time horizon and with a lower cost of epoprostenol. Two RCTs directly compared the technologies against each other with no significant differences observed between the technologies. Combinations of technologies were investigated in four RCTs, with some showing conflicting results.
CONCLUSION(S)
All five technologies when added to supportive treatment and used at licensed dose(s) were more effective than supportive treatment alone in RCTs that included patients of mixed FC and types of PAH. Current evidence does not allow adequate comparisons between the technologies nor for the use of combinations of the technologies. Independent economic evaluation suggests that bosentan, sitaxentan and sildenafil may be cost-effective by standard thresholds and that iloprost and epoprostenol may not. If confirmed, the use of the most cost-effective treatment would result in a reduction in costs for the NHS. Long-term, double-blind RCTs of sufficient sample size that directly compare bosentan, sitaxentan and sildenafil, and evaluate outcomes including survival, quality of life, maintenance on treatment and impact on the use of resources for NHS and personal social services are needed.
Topics: Antihypertensive Agents; Bosentan; Cost-Benefit Analysis; Endothelin Receptor Antagonists; Epoprostenol; Humans; Hypertension, Pulmonary; Iloprost; Isoxazoles; Phosphodiesterase Inhibitors; Piperazines; Purines; Sildenafil Citrate; Sulfonamides; Sulfones; Thiophenes; United States; Vasodilator Agents
PubMed: 19863849
DOI: 10.3310/hta13490 -
American Journal of Physiology. Lung... Oct 2018Cyclooxygenase-2 (COX-2/PTGS2) mediates hyperoxia-induced impairment of lung development in newborn animals and is increased in the lungs of human infants with...
Cyclooxygenase-2 (COX-2/PTGS2) mediates hyperoxia-induced impairment of lung development in newborn animals and is increased in the lungs of human infants with bronchopulmonary dysplasia (BPD). COX-2 catalyzes the production of cytoprotective prostaglandins, such as prostacyclin (PGI), as well as proinflammatory mediators, such as thromboxane A2. Our objective was to determine whether iloprost, a synthetic analog of PGI, would attenuate hyperoxia effects in the newborn mouse lung. To test this hypothesis, newborn C57BL/6 mice along with their dams were exposed to normoxia (21% O) or hyperoxia (85% O) from 4 to 14 days of age in combination with daily intraperitoneal injections of either iloprost 200 µg·kg·day, nimesulide (selective COX-2 antagonist) 100 mg·kg·day, or vehicle. Alveolar development was estimated by radial alveolar counts and mean linear intercepts. Lung function was determined on a flexiVent, and multiple cytokines and myeloperoxidase (MPO) were quantitated in lung homogenates. Lung vascular and microvascular morphometry was performed, and right ventricle/left ventricle ratios were determined. We determined that iloprost (but not nimesulide) administration attenuated hyperoxia-induced inhibition of alveolar development and microvascular density in newborn mice. Iloprost and nimesulide both attenuated hyperoxia-induced, increased lung resistance but did not improve lung compliance that was reduced by hyperoxia. Iloprost and nimesulide reduced hyperoxia-induced increases in MPO and some cytokines (IL-1β and TNF-α) but not others (IL-6 and KC/Gro). There were no changes in pulmonary arterial wall thickness or right ventricle/left ventricle ratios. We conclude that iloprost improves lung development and reduces lung inflammation in a newborn mouse model of BPD.
Topics: Animals; Animals, Newborn; Bronchopulmonary Dysplasia; Disease Models, Animal; Female; Hyperoxia; Iloprost; Mice; Mice, Inbred C57BL; Pneumonia; Pregnancy; Pulmonary Alveoli; Vasodilator Agents
PubMed: 29952221
DOI: 10.1152/ajplung.00125.2017 -
Turkish Journal of Medical Sciences Oct 2021In this study, we aimed to investigate the effects of antioxidant iloprost (ILO) and ß3 adrenergic receptor agonist (BRL) on transient receptor potential ankyrin 1...
BACKGROUND
In this study, we aimed to investigate the effects of antioxidant iloprost (ILO) and ß3 adrenergic receptor agonist (BRL) on transient receptor potential ankyrin 1 (TRPA1) and transient receptor potential canonical 1 (TRPC1) ion channels on an experimental ischemia and reperfusion injury model in 30 male Wistar albino rats aged 8-10 weeks.
METHODS
Wistar Albino rats aged were divided into 5 equal groups. Group I Sham operation, Group II IR (ischemiareperfusion) procedure, Group III IR + intravenous ILO administration, Group IV IR + intraperitoneal BRL administration, and Group V IR + intravenous ILO + intraperitoneal BRL administration group. Two ng/kg/min ILO intravenous infusion was applied to the ILO group. A single dose of 5 mcg/kg BRL intraperitoneal was applied to BRL group. TOS (total oxidant status), TRPA1, and TRPC1 levels were measured with ELISA (enzyme linked immunosorbent assay) in serum, immunohistochemical staining in musculus quadriceps femoris tissue.
RESULTS
Compared with the sham group, the IR group had a statistically significant increase in serum levels of TOS (p = 0.004), TRPA1 (p = 0.002), and TRPC1 (p = 0.008) along with TRPA1- and TRPC1-immunoreactivity (p = 0.005, each) in the tissue. When compared with the IR group in terms of serum levels of TRPA1 and tissue TRPA1-immunoreactivity, although there was no statistically significant difference in the IR+Ilo (p = 0.257 and p = 0.429, respectively), IR+Brl (p = 0.024 and p = 0.177, respectively), and IR+Ilo+Brl (p = 0.024 and p = 0.329, respectively) groups, serum levels of TOS and TRPC1 along with tissue TRPC1-immunoreactivity were statistically significantly reduced in the IR+Ilo (p = 0.002, p = 0.008, and p = 0.004, respectively), IR+Brl (p = 0.004, p = 0.008, and p = 0.004, respectively), and IR+Ilo+Brl groups (p = 0.002, p = 0.008, and p = 0.004, respectively).
DISCUSSION
In IR group serum TOS, TRPA1 and TRPC1 levels ,and tissue TRPA1 and TRPC1 immunoreactivity were statistically significant increase when compared to the sham group. In IR+ILO, IR+BRL and IR+ILO+BRL groups serum TRPA1 and tissue TRPA1 immunoreactivity did not change when compared to IR group. Serum TOS and TRPC1 levels, tissue TRPC1 immunoreactivty were statistically significant decreased when compared to IR group. More detailed and expanded population studies are needed to discuss our results.
Topics: Male; Rats; Animals; Iloprost; Cytoskeletal Proteins; Reperfusion Injury; Administration, Intravenous; Antioxidants; Rats, Wistar; TRPA1 Cation Channel
PubMed: 34174803
DOI: 10.3906/sag-2104-68 -
BMC Pulmonary Medicine Jan 2016Combination therapy is frequently used to treat patients with pulmonary hypertension but few studies have compared treatment regimens. This study examined the long-term... (Observational Study)
Observational Study
BACKGROUND
Combination therapy is frequently used to treat patients with pulmonary hypertension but few studies have compared treatment regimens. This study examined the long-term effect of different combination regimens of inhaled iloprost and oral sildenafil on survival and disease progression.
METHODS
This was a retrospective study of patients in the Giessen Pulmonary Hypertension Registry who received iloprost monotherapy followed by addition of sildenafil (iloprost/sildenafil), sildenafil monotherapy followed by addition of iloprost (sildenafil/iloprost), or upfront combination therapy (iloprost + sildenafil). The primary outcome was transplant-free survival (Kaplan-Meier analysis). When available, haemodynamic parameters and 6-minute-walk distance were evaluated.
RESULTS
Overall, 148 patients were included. Baseline characteristics were similar across treatment groups; however, the iloprost + sildenafil cohort had higher mean pulmonary vascular resistance and pulmonary arterial pressure than the others. Transplant-free survival differed significantly between groups (P = 0.007, log-rank test). Cumulative transplant-free survival was highest for patients who received iloprost/sildenafil (1 year survival: iloprost/sildenafil, 95.1%; sildenafil/iloprost, 91.8%; iloprost + sildenafil, 62.9%); this group also remained on monotherapy significantly longer than the sildenafil/iloprost group (median 17.0 months vs 7.0 months, respectively; P = 0.004). Compared with pre-treatment values, mean 6-minute-walk distance increased significantly for all groups 3 months after beginning combination therapy.
CONCLUSIONS
In this observational study of patients with pulmonary hypertension receiving combination therapy with iloprost and sildenafil, cumulative transplant-free survival was highest in those who received iloprost monotherapy initially. However, owing to the size and retrospective design of this study, further research is needed before making firm treatment recommendations.
Topics: Administration, Inhalation; Administration, Oral; Adult; Aged; Cohort Studies; Disease Progression; Drug Therapy, Combination; Female; Humans; Hypertension, Pulmonary; Iloprost; Kaplan-Meier Estimate; Lung Transplantation; Male; Middle Aged; Registries; Retrospective Studies; Sildenafil Citrate; Survival Rate; Vasodilator Agents
PubMed: 26753921
DOI: 10.1186/s12890-015-0164-2 -
Acta Bio-medica : Atenei Parmensis Aug 2023Iloprost is recommend worldwide for the treatment of RP and the healing of DUs. The aim of this study is to report the regimens of Iloprost administered in different... (Review)
Review
BACKGROUND AND AIM
Iloprost is recommend worldwide for the treatment of RP and the healing of DUs. The aim of this study is to report the regimens of Iloprost administered in different rheumatological centers within the same regional Health System Methods: A questionnaire exploring different items related to the use of Iloprost was developed and reviewed by three expert rheumatologists. The questionnaire was distributed as an online survey to all local SSc referral centers in Emilia-Romagna (Italy). Data are reported as percentage or median with interquartile range (IQR), as appropriate. An updated review of world literature on this topic was also carried out.
RESULTS
All the invited centers completed the survey. There were both local (8) and university hospitals (4). The majority (58%) had a rheumatologist as head physician. All centers used Iloprost: a single monthly administration was the most common treatment (75%). The cycle lasted 1 [IQR 1-2] days with a 0.5-2.0 ng/Kg/min dose according to the drug tolerance of the patients. There were overall 68 spots (beds, reclining armchair, or simple armchair); 2.0 [1.5-4.0] patients were able to receive Iloprost at the same time. University Hospitals had more physicians at their disposal than local hospitals but less paramedic personnel (respectively: 1.8 vs 1.2 physicians, 1.5 vs 2.1 nurses).
CONCLUSIONS
These observations were in line with the majority of previous studies reporting different regimens, comparing similar (but not identical) dose and schedule administration, however, despite differences being at times substantial, no standard infusion method is yet available.
Topics: Humans; Iloprost; Epoprostenol; Prostaglandins I; Wound Healing; Surveys and Questionnaires; Scleroderma, Systemic
PubMed: 37539603
DOI: 10.23750/abm.v94i4.14317 -
Turkish Journal of Medical Sciences Jun 2017The protective effects of prostaglandin (PG) analogs on ischemia-reperfusion (I/R) have been well documented; however, comparative studies are lacking. The aim of the...
BACKGROUND/AIM
The protective effects of prostaglandin (PG) analogs on ischemia-reperfusion (I/R) have been well documented; however, comparative studies are lacking. The aim of the present study was to determine whether iloprost or alprostadil is more effective in preventing muscle I/R injury.
MATERIALS AND METHODS
Thirty-two rats were divided into four groups (n = 8): sham, control, IL (I/R + iloprost), and AL (I/R + alprostadil). I/R was induced by a tourniquet in the hindlimb for 3 h/3 h. The IL and AL groups received iloprost (0.5 ng kg min) and alprostadil (0.05 µg kg min) during reperfusion, respectively. After 6 h, blood and muscles were collected for analyses.
RESULTS
Serum TNF-α and IL-1β levels were decreased in the IL and AL groups compared with the control group (P < 0.05), whereas IL-6 levels did not change significantly. Tissue malondialdehyde levels were significantly lower in the IL and AL groups (P < 0.05). Tissue catalase levels showed no difference. The histological damage scores and apoptosis scores were both significantly decreased in the IL and AL groups compared with the control group (P< 0.05).
CONCLUSION
The present study indicated that iloprost and alprostadil attenuated I/R injury in skeletal muscle. However, no comparable difference was evident regarding the efficacies of either PG analog.
Topics: Alprostadil; Animals; Apoptosis; Female; Iloprost; Inflammation; Interleukin-1beta; Muscle, Skeletal; Oxidoreductases; Protective Agents; Rats; Rats, Sprague-Dawley; Reperfusion Injury; Tumor Necrosis Factor-alpha
PubMed: 28618761
DOI: 10.3906/sag-1604-59 -
Therapeutic Advances in Respiratory... 2019Inhaled iloprost is a well-established medication to treat pulmonary arterial hypertension (PAH), a serious and potentially fatal disease of the pulmonary resistance... (Review)
Review
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-Neb AAD, 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 BREELIB 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 BREELIB observed in the first clinical studies. Meanwhile, the BREELIB 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.
Topics: Administration, Inhalation; Drug Administration Schedule; Half-Life; Humans; Hypertension, Pulmonary; Iloprost; Nebulizers and Vaporizers; Time Factors; Vascular Resistance; Vasodilator Agents
PubMed: 30874487
DOI: 10.1177/1753466619835497 -
Vascular Health and Risk Management 2009In the pediatric population, pulmonary hypertension may present as an acute event in the setting of lung or cardiac pathology or as a chronic disease, mainly as... (Review)
Review
In the pediatric population, pulmonary hypertension may present as an acute event in the setting of lung or cardiac pathology or as a chronic disease, mainly as idiopathic pulmonary hypertension or associated with congenital heart disease. Recently, new pharmacologic approaches have demonstrated significant efficacy in the management of adults with pulmonary arterial hypertension; these include intravenous epoprostenol, prostacyclin analogs, endothelin receptor antagonists and phosphodiesterase type 5 inhibitors. The same treatment strategies are currently used in children. There are only few reports of the use of inhaled iloprost in pediatrics, only one of which reported the use of chronic inhaled iloprost in a significant number of children. This report showed that 1) the acute pulmonary vasodilator response to inhaled iloprost is equivalent to that of inhaled nitric oxide; 2) acute inhalation of iloprost can induce bronchoconstriction 3) the addition of inhaled iloprost can reduce the need for intravenous prostanoid therapy in some patients; 4) most children tolerated the combination of inhaled iloprost and endothelin receptor antagonist or phosphodiesterase inhibitors; 5) Several patients had clinical deterioration during chronic inhaled iloprost therapy and required rescue therapy with intravenous prostanoids. In this review we will discuss the role of inhaled iloprost in acute and chronic pulmonary hypertension in children.
Topics: Acute Disease; Administration, Inhalation; Adult; Antihypertensive Agents; Child; Chronic Disease; Drug Therapy, Combination; Humans; Hypertension, Pulmonary; Iloprost; Treatment Outcome; Vasodilator Agents
PubMed: 19436672
DOI: 10.2147/vhrm.s3222