Prostacyclin Analogue Research Articles

Management and treatment of osteonecrosis in children and adolescents with acute lymphoblastic leukemia

There is no consensus regarding how to manage osteonecrosis in pediatric acute lymphoblastic leukemia patients. Therefore, we performed a quality assessment of the literature with the result of a search strategy using the MESH terms osteonecrosis, children, childhood cancer, surgery, bisphosphonates, 6 hydroxymethyl-glutaryl CoA reductase inhibitors, anticoagulants and hyperbaric oxygen, and terms related to these MESH terms. A randomized controlled trial showed that osteonecrosis can be prevented by intermittent, instead of continuous, corticosteroid administration. The studies on interventions after onset of osteonecrosis were of low-quality evidence. Seven pediatric acute lymphoblastic leukemia studies described non-surgical interventions; bisphosphonates (n=5), hyperbaric oxygen therapy (n=1), or prostacyclin analogs (n=1). Safety and efficacy studies are lacking. Five studies focused on surgical interventions; none was of sufficient quality to draw definite conclusions. In conclusion, preventing osteonecrosis is feasible in a proportion of the pediatric acute lymphoblastic leukemia patients by discontinuous, instead of continuous, steroid scheduling. The questions as to how to treat childhood acute lymphoblastic leukemia patients with osteonecrosis cannot be answered as good-quality studies are lacking.

Comments on the paper “Synergistic effects of prostacyclin analogs and phosphodiesterase inhibitors on cyclic adenosine 3′,5′ monophosphate accumulation and adenosine 3′5′ triphosphate release from human erythrocytes”

Comments on the paper “Synergistic effects of prostacyclin analogs and phosphodiesterase inhibitors on cyclic adenosine 3′,5′ monophosphate accumulation and adenosine 3′5′ triphosphate release from human erythrocytes”

Outcomes of Liver Transplantation for Porto-Pulmonary Hypertension in Model for End-Stage Liver Disease Era

Porto-pulmonary hypertension (POPH), once considered an absolute contraindication for liver transplantation (LT), has become a more accepted indication because of the evolution of treatment with prostacyclin analogues, phosphodiesterase inhibitors and endothelin receptor antagonists. An exception model for end stage liver disease (MELD) score of 22 is assigned to candidates with documentation of effective treatment. We examined the post-transplant outcomes of patients who received LT for POPH with exception. Scientific Registry of Transplant Recipients data on 34,318 adult (≥ 18 years) deceased donor LT recipients transplanted between March 1, 2002 and August 31, 2010 were reviewed. The diagnosis of POPH was ascertained from MELD exception forms. Patients were followed from the time of transplant until the earlier occurrence of death or end of the follow-up period. Cox regression was used to evaluate the predictors of post-LT mortality and graft failure. During the study period, 34,318 patients received deceased donor LT. Seventy eight out of 34,318 patients were transplanted for POPH with MELD exception. The 1-year adjusted risks of patient death and graft failure for patients transplanted under exception rules for POPH were significantly higher than with POPH adult recipients who did not receive exception points (death:hazard ratio [HR] = 2.25, p = 0.005 and graft failure HR = 1.96, p = 0.012). This study of national data suggests that treated POPH continues to be associated with inferior early post-transplant outcomes.

Effects of prostacyclin on the early inflammatory response in patients with traumatic brain injury-a randomised clinical study

Objective and designA prospective, randomised, double-blinded, clinical trial was performed at a level 1 trauma centre to determine if a prostacyclin analogue, epoprostenol (Flolan®), could attenuate systemic inflammatory response in patients with severe traumatic brain injury (TBI).Subjects46 patients with severe TBI, randomised to epoprostenol (n = 23) or placebo (n = 23).TreatmentEpoprostenol, 0.5 ng · kg-1 · min-1, or placebo (saline) was given intravenously for 72 hours and then tapered off over the next 24 hours.MethodsInterleukin-6 (IL-6), interleukin-8 (IL-8), soluble intracellular adhesion molecule-1 (sICAM-1), C-reactive protein (CRP), and asymmetric dimethylarginine (ADMA) levels were measured over five days. Measurements were made at 24 h intervals ≤24 h after TBI to 97–120 h after TBI.ResultsA significantly lower CRP level was detected in the epoprostenol group compared to the placebo group within 73–96 h (p = 0.04) and within 97–120 h (p = 0.008) after trauma. IL-6 within 73–96 h after TBI was significantly lower in the epoprostenol group compared to the placebo group (p = 0.04). ADMA was significantly increased within 49–72 h and remained elevated, but there was no effect of epoprostenol on ADMA levels. No significant differences between the epoprostenol and placebo groups were detected for IL-8 or sICAM-1.ConclusionsAdministration of the prostacyclin analogue epoprostenol significantly decreased CRP and, to some extent, IL-6 levels in patients with severe TBI compared to placebo. These findings indicate an interesting option for treatment of TBI and warrants future larger studies.Trial registrationClinicalTrials.gov Identifier, NCT01363583

Capsaicin 8% patch for treprostinil subcutaneous infusion site pain in pulmonary hypertension patients

BackgroundTreprostinil sodium improves haemodynamics and symptoms in pulmonary arterial hypertension (PAH) patients, but its subcutaneous (s.c.) administration can produce severe local site pain, and lead to discontinuation of vital treatment. Treprostinil is a prostacyclin analogue which stimulates prostacyclin receptors in skin nociceptor terminals, resulting in pain and cutaneous hypersensitivity, for which current pain remedies have limited effect. Capsaicin 8% patch relieves neuropathic pain for 3 months after a single 60 min cutaneous application; we investigated whether its pre-application can reduce s.c. trepostinil-induced pain. MethodsA single-centre, double-blind, randomized, placebo-controlled, crossover study was conducted to assess the safety and efficacy of a single capsaicin 8% patch pre-application for s.c. treprostinil pain in 11 PAH patients, relative to control patch with low-dose capsaicin 0.075% cream. ResultsThe primary efficacy endpoint, mean difference between the two treatment arms in an 11-point numerical pain rating scale from baseline to 2 weeks after patch applications, was significantly lower on the capsaicin 8% patch treatment arm [P=0.01, mean difference=−1.47 units, 95% credible interval (CI): −2. 59 to −0.38] in the patients who completed the study per protocol, although intention-to-treat analysis did not show significant difference (P=0.28). Heat pain thresholds were decreased (P=0.027, mean difference=5.43°C, 95% CI: 0.71–10.21) and laser Doppler flux increased (P=0.016, mean difference=370 units, 95% CI: 612 to 127.9) at the application site immediately after capsaicin 8% patch, confirming activity. ConclusionsFurther investigation of the efficacy of capsaicin 8% patch in this indication is warranted. Clinical trial registrationClinicalTrials.gov: NCT01393795.

Role of Vasodilation during Normothermic Machine Perfusion of DCD Porcine Livers

Normothermic machine perfusion (NMP) of the liver is a promising preservation modality that holds the potential to better preserve and even repair marginal grafts. In spite of several literature studies showing the benefits of NMP over cold storage, there is paucity of data regarding the mechanisms involved in the optimization of the microcirculation during preservation of these organs. We present our data on the impact of different vasodilators on DCD porcine livers preserved with NMP. Livers from 15 female Yorkshire pigs (30-40 kg) were subjected to 60 min of WIT followed by 10 h of NMP. Group PC (n = 5) received a prostacyclin analog (epoprostenol sodium) and the AD group (n = 5) received adenosine, whereas group WV (n = 5) was perfused without using any vasodilator. Liver function was assessed by measuring, liver enzyme levels, bile production rate, and histological analysis. At the end of perfusion, the PC group showed significantly lower AST (583 ± 62 vs. 2471 ± 745 and 2547 ± 690 IU/dl), ALT (41 ± 3 vs. 143 ± 28 and 111 ± 25 IU/dl) and LDH (840 ± 85 vs. 2756 ± 408 and 4153 ± 1569 IU/dl) levels compared to the AD and WV groups respectively (p<0.05). Bile production was significantly higher in the PC group compared to the AD group and WV, respectively (95 ± 9 vs. 37 ± 10 and 45 ± 18ml) (p<0.05). Histological samples of the PC group showed preserved hepatic architecture while those of the AD group and WV showed sinusoidal dilatation, architectural distortion, and profuse intraparenchymal hemorrhage. Maintenance of optimal microcirculatory homeostasis using proper vasodilators is a key factor in NMP of DCD livers.

Prostacyclin Agonist (L165041) Enhances Embryos Survival after Vitrification and Warming

We have reported that the addition of a prostacyclin analogue to culture media enhances mouse embryo complete hatching, implantation and delivery rates (Huang et al, 2003, 2004). Recently we also have seen that prostacyclin enhances human embryo implantation and clinical pregnancy rate (Wun et al, 2013). Can these beneficial effect also be seen after vitrification and warming? Prostacyclin action is mediated through its nuclear receptor, peroxisome-proliferator-activated receptor δ (PPARδ ) (Kang et al, 2011).

Incremental Burden of Disease in Patients Diagnosed with Pulmonary Arterial Hypertension Receiving Monotherapy and Combination Vasodilator Therapy

Pulmonary arterial hypertension (PAH) is a rare, severely debilitating disease with high mortality. There are limited data available on treatment patterns and burden of disease from conditions of actual care. This analysis assesses the burden of disease for patients with PAH treated with monotherapy and combination therapies excluding and including intravenous (IV) prostacyclin analogues (PGI2). Data were drawn from the Adelphi PAH Disease Specific Programme, a cross sectional survey of consulting patients undertaken in the US, Germany, Italy and the UK in 2010. Outcomes included demographics, clinical characteristics, health-care resource utilization, and quality of life measured by the Cambridge Pulmonary Hypertension Outcome Review (CAMPHOR). Data were analyzed from 446 patients receiving ≥1 of 3 PAH-specific treatment classes. Physicians comprised mainly pulmonologists and cardiologists. The symptoms, functioning and quality of life scales of the CAMPHOR instrument were completed by 218, 229, and 214 patients, respectively. Although 46.2% of patients were classified as World Health Organization (WHO) functional class III or IV, only 24.4% of the population received combination therapy. Combination therapy including IV PGI2 was used in 4.7% of all patients. Patients on monotherapy had the lowest pulmonary vascular resistance values, the highest recorded 6-min walk distance and the lowest recorded levels of dyspnea. Patients on combination therapy including IV PGI2 scored worse on all three variables and had more hospitalizations than patients on less aggressive combination therapy. With increasing therapeutic regimens, the CAMPHOR scores were higher, indicating worse states of health. Combination treatment and particularly the use of prostacyclins remain underused in an unselected population of PAH patients surveyed under conditions of actual care. The disease burden is substantial and increases with greater severity of disease and more aggressive treatments. This necessitates improvement in optimizing current therapy, as well as novel and innovative combination options.

Retrospective analysis of the frequency of centrofacial telangiectasia in systemic sclerosis patients treated with bosentan or ilomedin

BackgroundBosentan is a dual endothelin receptor antagonist initially introduced for the treatment of pulmonary arterial hypertension and recently approved for the treatment of digital ulcers in patients with systemic sclerosis (SSc). Our clinical observations indicate that bosentan therapy may be associated with an increased frequency of centrofacial telangiectasia (TAE). Here, we sought to analyze the frequency of TAE in patients with SSc who were treated with either bosentan or the prostacyclin analog iloprost.MethodsWe conducted a retrospective analysis in 27 patients with SSc undergoing therapy with either bosentan (n = 11) or iloprost (n = 16). Standardized photodocumentations of all patients (n = 27) were obtained at a time point ten months after therapy initiation and analyzed. A subgroup of patients (bosentan: n = 6; iloprost: n = 6) was additionally photodocumented prior to therapy initiation, enabling an intraindividual analysis over the course of therapy.ResultsAfter ten months of therapy patients with SSc receiving bosentan showed a significantly (P = 0.0028) higher frequency of centrofacial TAE (41.6 ± 27.8) as compared to patients with SSc receiving iloprost (14.3 ± 13.1). Detailed subgroup analysis revealed that the frequency of TAE in the bosentan group (n = 6 patients) increased markedly and significantly (P = 0.027) by 44.4 after ten months of therapy (TAE at therapy initiation: 10.8 ± 5.1; TAE after ten months of therapy: 55.2 ± 29.8), whereas an only minor increase of 1.9 was observed in the iloprost group (n = 6 patients; TAE at therapy initiation: 18.3 ± 14.5; TAE after ten months of therapy: 20.2 ± 15.5), yet without reaching statistical significance (P = 0.420).ConclusionsThe use of bosentan may be associated with an increased frequency of TAE in patients with SSc. Patients should be informed about this potential adverse effect prior to therapy. Treatment options may include camouflage or laser therapy.

Subcutaneous to Intravenous Prostacyclin Analog Transition in Pulmonary Hypertension

Prostacyclin analogs are Food and Drug Administration-approved therapies for the treatment of pulmonary arterial hypertension and can be administered by inhalational, intravenous (IV), or subcutaneous (SQ) routes. Because there are limited data to guide the transition between SQ to IV prostacyclin analogs, we describe our experience. We performed a retrospective review of patients with pulmonary hypertension diagnosed by right heart catheterization, who underwent transition from SQ to IV prostacyclin analogs. We included 7 patients with pulmonary arterial hypertension and 2 with chronic thromboembolic pulmonary hypertension in this retrospective study. Median (interquartile range) age was 54 (39-63) years, and 67% were women. The reasons for the SQ to IV switch were site pain (n = 6, 67%), major surgery (n = 2, 22%), and septic shock (n = 1, 11%). SQ treprostinil was converted to IV treprostinil (n = 5, 56%) or IV epoprostenol (n = 4, 44%). When SQ treprostinil was converted to IV treprostinil, the initial mean (range) dose decreased from 84.9 (36.5-167) to 70.8 (24-114) ng·kg⁻¹·min⁻¹. When SQ treprostinil was converted to IV epoprostenol, the dose decreased from 24.5 (17.5-30) to 13.3 (9-20) ng·kg⁻¹·min⁻¹. The patient transitioned from SQ to IV treprostinil in the context of septic shock died a month after hospitalization. No deteriorations were observed in the remaining patients during the first year. Under careful monitoring, SQ treprostinil was transitioned to IV treprostinil or epoprostenol without complications. Dosing downadjustment was needed in some patients who were switched over from SQ to IV prostacyclin analogs.

Pulmonary arterial hypertension related to human immunodeficiency virus infection: A case series.

To present 18 new cases of human immunodeficiency virus (HIV)-related pulmonary arterial hypertension (PAH) with presenting features, treatment options and follow-up data. This is a single-centre, retrospective, observational study that used prospectively collected data, conducted during a 14-year period on HIV-related PAH patients who were referred to a pulmonary hypertension unit. All patients infected with HIV were consecutively admitted for an initial evaluation of PAH during the study period and included in our study. Right heart catheterisation was used for the diagnosis of PAH. Specific PAH treatment was started according to the physician's judgment and the recommendations for idiopathic PAH. The data collected included demographic characteristics, parameters related to both HIV infection and PAH and disease follow-up. Eighteen patients were included. Intravenous drug use was the major risk factor for HIV infection. Risk factors for PAH, other than HIV infection, were present in 55.5% patients. The elapsed time between HIV infection and PAH diagnoses was 12.2 ± 6.9 years. At PAH diagnosis, 94.1% patients had a CD4 cell count > 200 cells/μL. Highly active antiretroviral therapy (present in 47.1% patients) was associated with an accelerated onset of PAH. Survival rates were 93.8%, 92.9% and 85.7% at one, two and three years, respectively. Concerning specific therapy, 33.3% of the patients were started on a prostacyclin analogue, and the rest were on oral drugs, mainly phosphodiesterase-5 inhibitors. During the follow-up period, specific therapy was de-escalated to oral drugs in all of the living patients. The survival rates of HIV-related PAH patients were higher, most likely due to new aggressive specific therapy. The majority of patients were on oral specific therapy and clinically stable. Moreover, sildenafil appears to be a safe therapy for less severe HIV-related PAH.

Anesthetic management of pediatric with congenital heart disease with pulmonary hypertension.

Sir, The presence of congenital heart disease (CHD) increases the morbidity and mortality of children undergoing noncardiac surgery. Certain patients have been identified as high risk group of patients among them one is CHD with pulmonary hypertension. A 5-year-old child with 8 kg weight had atrial septal defect (ASD), ventricular septal defect (VSD), left to right shunt with severe pulmonary hypertension (PHT) and was posted for open ureterolithotomy. During preanesthetic checkup, he was having cough and tachypnea. Pulse rate was 108/min, noninvasive blood pressure (NIBP) 100/60 mm of Hg and SPO2 100% on air. His routine blood investigations were within normal limits. X-ray chest showed severe cardiomegaly. electrocardiogram (ECG) showed sinus tachycardia, biventricular hypertrophy with left axis deviation. His 2D echo showed small ostium secundum ASD with left to right shunt, large inlet VSD with bidirectional shunt (11-12 mm) and severe pulmonary arterial hypertension (PAH). Pediatric cardiologist advised surgery with very high risk. On the day of surgery, patient was premedicated with oral midazolam 0.5 mg/kg with SPO2 monitoring before 45 min. After taking him in the operation theater, ECG, pulse oxymetry, and NIBP applied. Patient was induced with injection-glycopyrrolate 0.04 mg, injection- fentanyl 2 μg/kg and injection- propofol 20 mg. Patient's airway was secured with laryngeal mask airway no. 1.5 and anesthesia was maintained with oxygen, sevoflurane with spontaneous respiration. At the end of surgery patient was extubated uneventfully and shifted to high dependency unit with standard monitoring. Postoperatively analgesic injection diclofenac sodium was given 8 hourly. Congenital heart disease is the most common birth defect, occurring in approximately one in 125 live births. Due to advances in modern medicine, mean 90% of these children now survive to adulthood; they pose a challenge for anesthesia because perioperative morbidity and mortality is greater compared with other children.[1] Left to right shunts is the most common lesions representing over 50% of children with CHD. Most children do not manifest heart failure unless their shunt produces a pulmonary to systemic fraction of 3-1.[2] Four major complications of CHD are arrhythmias, cardiac failure, PHT and cyanosis. The anesthetic goals in managing such a patient are to prevent an increase in pulmonary vascular resistance and depression of myocardial function. PHT crisis intervention measures such as 100% oxygen, inhaled nitric oxide, phosphodiesterase inhibitors, prostacyclin analogues, inotropes and other measures to maintain cardiac output and pulmonary blood flow must be prepared and administered accordingly as the need arises.[3] Retrospective analysis of children with PAH who had undergone noncardiac surgery or cardiac catheterization demonstrated incidences of major complications (cardiac arrest or pulmonary hypertensive crisis) and death that are many times greater than those reported in all children undergoing surgical procedures.[4] A complete history and physical examination, focusing on cardiac signs and symptoms previous surgical and catheterization procedures are essential. Echocardiography is noninvasive and the mainstay of diagnostic testing. Midazolam, fentanyl, a small dose of propofol or a low concentration of sevoflurane may be used for induction of anesthesia. When paralysis is required, neuromuscular blocking agents with minimal hemodynamic effects are preferable. (e.g. rocuronium and vecuronium)[3,4] Good intraoperative and postoperative analgesia is associated with improved surgical outcome.[5] Hence, these types of children require knowing about the disease, to make an efficient management plan and always to be prepared to treat complications.

Oral treprostinil for the treatment of pulmonary hypertension

Pulmonary arterial hypertension (PAH) is a rare yet progressive and life-threatening condition that, despite the availability of FDA-approved therapies, remains incurable. Prostacyclin analogues are a mainstay of therapy for patients with PAH, but in spite of demonstrated improvements in survival, exercise capacity and hemodynamics, these agents have been limited by poor pharmacokinetics and complex administration requirements. Treprostinil diolamine (Orenitram™; United Therapeutics) is a novel oral formulation that joins the approved parenteral and inhaled formulations (Remodulin® and Tyvaso®; United Therapeutics). It displays similar pharmacokinetic properties, while offering the potential for improved patient compliance through the convenience of oral dosing. Following the demonstration of improved exercise capacity as monotherapy in patients with de novo PAH (FREEDOM-M), treprostinil diolamine was recently approved by the FDA for the treatment of patients with WHO group 1 PAH and continues to be evaluated in a number of clinical trials in this patient population.

Pharmacological management of pulmonary arterial hypertension.

Pharmacological management of pulmonary arterial hypertension.

New Oral Drugs for Pulmonary Arterial Hypertension: Macitentan, Riociguat, and Treprostinil

In 2013, the US Food and Drug Administration (FDA) approved 3 new oral drugs for the treatment of pulmonary arterial hypertension (PAH; World Health Organization [WHO] Group 1 pulmonary hypertension [PH]). These include the endothelin receptor antagonist macitentan, the soluble guanylate cyclase stimulator riociguat, and the prostacyclin analogue treprostinil. In addition, riociguat was approved for the treatment of patients with inoperable or postsurgery recurrent or persistent chronic thromboembolic PH (CTEPH; WHO Group 4 PH). The approval of these drugs has several important clinical implications: first, in a disease where many of the currently available treatments are complicated by significant side effects and/or complex administration regimens, the availability of new oral drugs clearly represents a valuable addition to the armamentarium. Second, the macitentan study was the first long-term, event-driven trial to be published in the PAH field, making the results more robust and paving the way for improved clinical trial design in the future. Third, riociguat is the first FDA-approved medical treatment regimen for selected CTEPH patients, thus providing a critical treatment option for patients with inoperable or recurrent/persistent CTEPH. Lastly, the approval of oral treprostinil made this drug the first oral prostacyclin analogue to be available in the United States. In this article, the authors will discuss the mechanisms of action of macitentan, riociguat, and oral treprostinil; review the landmark trials that led to the FDA approval of these drugs, and discuss their clinical use.

Long-term survival of Japanese patients with pulmonary arterial hypertension treated with beraprost sodium, an oral prostacyclin analogue.

Beraprost was developed as the first oral prostacyclin analog to treat patients with pulmonary arterial hypertension (PAH). Although this drug demonstrates improvements in the patient's exercise capacity and symptoms, it carries a weak recommendation in the PAH evidence-based treatment algorithm due to a lack of durability of effects. However, this therapy remains a major treatment method in Japan due to its availability and inexpensive cost. The purpose of this study was to elucidate whether this drug exhibits durable effects on sustained overall survival. A comparison of survival benefits was completed among patients undergoing treatment with beraprost (n=35) or conventional therapy (n=44). In addition, the estimated survival calculated using the equation developed by the National Institutes of Health Registry was used for the analysis. Although no significant differences were observed between the two groups using the Kaplan-Meier survival curve, a statistical difference was observed between the patients receiving high-dose beraprost therapy (>120 μg) and those receiving conventional therapy (5- and 10-year survival: 71.1% and 49.4% vs. 37.7% and 21.2%, respectively; p=0.0466). Moreover, the cumulative survival rates in the patients receiving beraprost were slightly better than the estimated survival rates. In the PAH patients with connective tissue diseases, a tendency towards better survival outcomes was observed in the group treated with beraprost. This study suggests the survival benefits of high-dose beraprost therapy for patients with PAH. The retrospective nature of this study, however, makes it difficult to conclude definitively that beraprost exerts significant beneficial effects on survival.

Pharmacological interventions for improved colonic anastomotic healing: a meta-analysis.

To identify pharmaceuticals for the prophylaxis of anastomotic leakage (AL), we systematically reviewed studies on anastomosis repair after colorectal surgery. We searched PubMed and EMBASE for articles published between January 1975 and December 2012. We included studies in English with the primary purpose of promoting healing of anastomoses made in the colon or rectum under uncomplicated conditions. We excluded studies on adverse events from interventions, nutritional interventions or in situ physical supporting biomaterials. The primary outcome was biomechanical strength or AL. We performed meta-analyses on therapeutic agents investigated by three or more independent research groups using the same outcome. The DerSimonian-Laird method for random effects was applied with P < 0.05. Of the 56 different therapeutic agents assessed, 7 met our inclusion criteria for the meta-analysis. The prostacyclin analog iloprost increased the weighted mean of the early bursting pressure of colonic anastomoses in male rats by 60 mmHg (95%CI: 30-89) vs the controls, and the immunosuppressant tacrolimus increased this value by 29 mmHg (95%CI: 4-53) vs the controls. Erythropoietin showed an enhancement of bursting pressure by 45 mmHg (95%CI: 14-76). The anabolic compound growth hormone augmented the anastomotic strength by 21 mmHg (95%CI: 7-35), possibly via the up-regulation of insulin-like growth factor-1, as this growth factor increased the bursting pressure by 61 mmHg (95%CI: 43-79) via increased collagen deposition. Hyperbaric oxygen therapy increased the bursting pressure by 24 mmHg (95%CI: 13-34). Broad-spectrum matrix metalloproteinase inhibitors increased the bursting pressure by 48 mmHg (95%CI: 31-66) on postoperative days 3-4. In the only human study, the AL incidence was not significantly reduced in the 103 colorectal patients treated with aprotinin (11.7%) compared with the 113 placebo-treated patients (9.7%). This systematic review identified only one randomized clinical trial and seven therapeutic agents from pre-clinical models that could be explored further for the prophylaxis of AL after colorectal surgery.

Inhaled iloprost for the treatment of patient with Fontan circulation.

Decreased exercise capacity after Fontan surgery is relatively common and the failure of the Fontan state gradually increases with age. However, there is no further treatment for patients with Fontan circulation. Pulmonary vasodilation therapy is an effective method to solve this problem because pulmonary vascular resistance is a major factor of the Fontan problem. Inhaled iloprost is a chemically stable prostacyclin analogue and a potent pulmonary vasodilator. We experienced two cases of Fontan patients treated with inhaled iloprost for 12 weeks. The first patient was an 18-year-old female with pulmonary atresia with an intact ventricular septum, and the second patient was a 22-year-old male with a double outlet right ventricle. Fifteen years have passed since both patients received Fontan surgery. While the pulmonary pressure was not decreased significantly, improved exercise capacity and cardiac output were observed without any major side effects in both patients. The iloprost inhalation therapy was well tolerated and effective for the symptomatic treatment of Fontan patients.

Transition from prostacyclin analogue infusion to oral therapy in patients with pulmonary arterial hypertension: a 5-year follow-up.

Transition from prostacyclin analogue infusion to oral therapy in patients with pulmonary arterial hypertension (PAH) is possible with acceptable short- and midterm results. However, there is a paucity of data on long-term outcomes after successful transition. Using a predefined protocol, transition to oral therapy was attempted in 22 patients with clinically stable PAH. Clinical and hemodynamic data were retrospectively collected at baseline as well as during and after transition. Parameters for successful versus nonsuccessful transition were also evaluated. All patients had severe PAH at baseline and showed clinical and hemodynamic improvement with prostacyclin analogue infusion. Initial oral agents used for transition were bosentan (63.6%), sildenafil (31.8%), and tadalafil (4.5%). Combination therapy was used in 68% of the patients. Successful transition was achieved in 11 patients (50%) with a mean transition duration of 16 months. After successful transition, clinical and hemodynamic parameters remained stable at midterm (mean, 18 months) and long-term (mean, 60 months) follow-up. Compared with the successful transition group, patients who experienced failure were older, had a higher frequency of idiopathic PAH, and had worse hemodynamic parameters during treatment with prostacyclin analogue alone, as well as during the transition period. In conclusion, successful transition from prostacyclin analogue infusion to oral therapy can be achieved in a significant proportion of patients with clinically stable PAH. After an initial successful transition, patients were able to maintain clinical and hemodynamic stability at the mid- and long-term follow-up.

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