Combination therapy in the management of pulmonary arterial hypertension.

BACKGROUND: Pulmonary arterial hypertension (PAH) is a progressive disease without a cure, which can lead to right heart failure and death. Over the past decades, several therapeutic advances have been developed for the management of PAH. Although these agents have demonstrated clinical safety and efficacy, some patients may require additional drug therapy due to a lack of response or disease progression. AIMS: The purpose of this review was to evaluate the safety and efficacy of various combination PAH therapies. MATERIALS & METHODS: A systematic search was conducted using the MEDLINE database (1966 and June 2012) for relevant clinical studies. Searches were limited to English, human and clinical trial using the terms sildenafil, tadalafil, vardenafil, phosphodiesterase inhibitor, prostacyclin, prostaglandin, epoprostenol, treprostinil, iloprost, beraprost, endothelin receptor antagonist, bosentan, ambrisentan, sitaxsentan and pulmonary hypertension. RESULTS: Overall, 22 studies met inclusion criteria. Overall, the majority of trials demonstrated clinical efficacy in improving functional class, reducing pulmonary pressure, or increasing exercise capacity. Most trials were uncontrolled with small sample sizes investigating the acute effects of combination therapy and lacking long-term clinical outcomes. Adjunctive therapy was well tolerated by most patients. DISCUSSION: Overall, combination therapy is relatively safe and well tolerated. Published guidelines provide evidence-based recommendations for monotherapy. However, suggestions for combination therapy in refractory PAH patients are lacking. Several studies evaluating several combination therapies have been published. The preferred combination treatment among several PAH drug therapies remain controversial. Therefore, clinicians should consider ease of administration, cost, and tolerability when choosing specific combination therapies. CONCLUSION: Combination therapy appears promising for patients who are refractory to treatment or whose disease progression is not well controlled with monotherapy. An optimal combination drug therapy regimen remains debatable and should be customized for individual PAH patients. Further studies are needed to determine the optimal combination therapy in PAH based upon efficacy, safety and cost.

Characterization of the rabbit homolog of human MUC1 glycoprotein isolated from bladder by affinity chromatography on immobilized jacalin.

The urinary bladder is lined by transitional epithelium, the glycocalyx on the luminal surface has interesting properties and is implicated in protective functions. Glycoconjugates are major components of the glycocalyx, but their biochemical nature is not well understood. Previous studies on rabbit bladder indicated the presence of significant levels of sialoglycoproteins compared to glycosaminoglycans in the epithelium. In this study, rabbit explant cultures were radiolabeled by precursor sugars or amino acids and a major lectin-reactive glycoprotein of rabbit bladder mucosa was isolated by affinity chromatography on jacalin-agarose. The radiolabeled glycoprotein was purified to homogeneity by a second cycle on the lectin column, followed by gel filtration and density gradient centrifugation. The average molecular mass of the glycoprotein was estimated to be 245 kDa and 210 kDa by gel filtration and SDS-PAGE, respectively. Its buoyant density was 1.40 g/ml, suggesting a carbohydrate content of approximately 50%. The percent distribution of glucosamine-derived tritium label in sialic acid, galactosamine, and glucosamine was 30, 52, and 18, respectively. The glycoprotein consisted entirely of small sialylated and neutral oligosaccharides O-glycosidically linked to serine and threonine residues. The same glycoprotein could be immunoprecipitated with an antibody against the carboxy terminal 17 amino acid peptide of human MUC1 mucin glycoprotein. This suggests that this mucin glycoprotein is the rabbit homolog of MUC1 glycoprotein, which has been previously established to be a component of human bladder urothelium and has been purified from human urine and biochemically characterized.

Characterization and immunohistochemical localization of the glycoconjugates of the rabbit bladder mucosa.

An impairment of the mucosal glycoconjugates could be an important factor in the development of bladder disorders such as interstitial cystitis. However, very little definitive biochemical information is available on the glycoco-jugate components of the mammalian bladder mucosa. In this-study, the mucosa from metabolically radiolabeled rabbit bladder was separated, delipidated, and digested with protease, and the released glycosaminoglycans and glycopeptides were fractionated. About 80 and 36% of the nondialyzable tritium and 35S activities, respectively, was associated with the sialoglycopeptide fractions. The balance of the total tritium activity in the protease digest was in glycosaminoglycans identified as hyaluronan, chondroitin sulfates, and heparan sulfate. Immunohistochemical examination using anti-heparan sulfate antibodies, including one against mouse syndecan-1, indicated the presence of heparan sulfate proteoglycan in the epithelium. In contrast, there was no significant staining of the bladder epithelium with anti-chondroitin-4- and 6-sulfate antibodies or hyaluronan-binding protein. The lamina propria and muscle layers showed strong staining with anti-chondroitin-4-sulfate antibody and hyaluronan-binding protein and weak staining with anti-chondroitin-6-sulfate antibody. The insignificant levels of glycosaminoglycans in the glycocalyx of bladder mucosa epithelium suggest that glycosaminoglycans may be less important than other glycoconjugates in maintaining normal epithelial function and in bladder disorders such as interstitial cystitis.