Safety, Tolerability and Clinical Effects of a Rapid Dose Titration of Subcutaneous Treprostinil Therapy in Pulmonary Arterial Hypertension: A Prospective Multi-Centre Trial.

BACKGROUND: Subcutaneous treprostinil has dose-dependent beneficial effects in patients with severe pulmonary arterial hypertension, but adverse effects like infusion site pain can lead to treatment discontinuation. OBJECTIVES: The objective of this study was to evaluate safety, tolerability and clinical effects of a rapid up-titration dosing regimen of subcutaneous treprostinil using proactive infusion site pain management. METHODS: Effects of rapid up-titration dosing regimen on tolerability and clinical parameters were evaluated in this 16-week, open-label multi-centre study. RESULTS: Thirty-nine patients with idiopathic or heritable pulmonary arterial hypertension on stable treatment with oral pulmonary arterial hypertension-approved drugs (90% on dual combination therapy) were included. Patients achieved a median treprostinil dosage of 35.7 ng/kg/min after 16 weeks. A good overall safety profile was demonstrated with 3 patients (8%) withdrawing due to infusion site pain, which occurred in 97% of patients. After 16 weeks, median 6-min walking distance, cardiac index, pulmonary vascular resistance, and tricuspid annular plane systolic excursion improved. CONCLUSIONS: Rapid up-titration of subcutaneous treprostinil was well tolerated, achieving a clinically effective dose associated with improvement of exercise capacity and haemodynamics after 16 weeks. A rapid dose titration regimen and proactive infusion site pain management may improve the handling of this therapy and contribute to better treatment outcome.

Systemic inflammation after aortic cross clamping is influenced by Toll-like receptor 2 preconditioning and deficiency.

BACKGROUND: The perioperative morbidity and mortality of abdominal aortic aneurysm repair is linked to systemic inflammation. Important triggers of the latter are Toll-like receptors (TLRs), which play a central role in innate immunity. Ischemia/reperfusion (I/R) injury can be influenced by either TLR stimulation before I/R (preconditioning) or TLR dysfunction (deficiency or polymorphism). The influence of TLR2 stimulation or deficiency on systemic cytokine release and organ damage after aortic cross clamping has not been evaluated yet. METHODS: Wild type (WT) and TLR2-deficient mice were subjected to 1 h ischemia and 2 or 4 h reperfusion of the infrarenal aorta. One group of WT mice was preconditioned with the synthetic TLR2 agonist Pam(3)Cys-Ser-Lys(4) (Pam(3)CSK(4)). Sham-operated animals without I/R served as controls. Plasma levels of interleukin (IL)-1ß, IL-2, IL-4, IL-5, IL-6, IL-10, IL-12, granulocyte macrophage-colony stimulating factor, tumor necrosis factor-α, alanine transaminase (ALT), aspartate transaminase (AST), lactate dehydrogenase (LDH), and creatinine were measured. RESULTS: I/R injury caused by transient clamping of the infrarenal aorta led to a time-dependent increase of all measured cytokines except IL-4, IL-5, and granulocyte macrophage-colony stimulating factor. This was accompanied by elevated markers of organ damage (ALT, AST, and LDH) except creatinine. Preconditioning with Pam(3)CSK(4) led to lower plasma concentrations of all cytokines, with the exception of anti-inflammatory IL-10 which was significantly upregulated. Furthermore, ALT, AST, and LDH plasma concentrations were lower in the preconditioning group. TLR2-deficient mice similarly showed reduced signs of systemic inflammation and organ damage, although less distinctive. IL-2, IL-6, IL-12, ALT, and LDH were time dependently lower compared with WT mice. IL-10 concentration was higher in TLR2-deficient mice compared with WT. CONCLUSIONS: Both, preconditioning via TLR2 and TLR2 deficiency, ameliorate systemic inflammation and organ damage during I/R injury caused by clamping of the infrarenal aorta. Compared with untreated WT animals, Pam(3)CSK(4) preconditioned and TLR2-deficient mice showed lower concentrations of pro-inflammatory cytokines, whereas anti-inflammatory IL-10 was elevated in both groups. This was accompanied by reduced organ dysfunction parameters.