Identification of Patient Needs and Preferences in Pigmented Villonodular Synovitis (PVNS) Using a Qualitative Online Bulletin Board Study.

INTRODUCTION: Pigmented villonodular synovitis (PVNS), also known as giant-cell tumour of the tendon sheath (GCTT), is a rare, benign proliferative tumour affecting the inner lining of synovial joints and tendon sheets. Information on treatment needs of PVNS patients to inform drug development is currently scarce. We conducted an exploratory qualitative study with PVNS patients to generate insights into the objective and emotional aspects related to their medical journey and experiences of living with this disease. METHODS: A 4-day study using an online bulletin board (OBB), an asynchronous, online qualitative research platform, was conducted with patients recruited via physician referral who underwent screening questions to ensure eligibility for the study and willingness to participate. The discussion was moderated, was structured and allowed open answers in response to other participants' posts. RESULTS: Eleven patients (4 from the USA, 4 from the UK and 3 from Canada; 45% female), aged 28-57 years, suffering from PVNS for 2-27 years participated in the study. Key patient insights from the study were: (1) pain was the topmost, spontaneous thought that the participants associated with PVNS, constituting a significant emotional and psychological burden; (2) surgery (arthroscopy) did not completely ameliorate symptoms associated with PVNS, as the relapse rate was high in these patients; (3) PVNS has a substantial negative financial impact on patients, their families and the healthcare system; (4) orthopaedic specialists/surgeons predominantly managed PVNS, as surgery is currently the only therapeutic option. CONCLUSION: PVNS patients expressed an urgent need for a medical drug treatment, which can reduce pain, avoid relapses and provide an alternative to surgery, the current standard of care.

Comparison of Macitentan and Bosentan on Right Ventricular Remodeling in a Rat Model of Non-vasoreactive Pulmonary Hypertension.

AIMS: We compared the efficacy of macitentan, a novel dual endothelin A/endothelin B receptor antagonist, with that of another dual endothelin receptor antagonist, bosentan, in a rat model of non-vasoreactive pulmonary hypertension (PH) with particular emphasis on right ventricular (RV) remodeling. METHODS AND RESULTS: Unlike monocrotaline or hypoxic/sugen rats, bleomycin-treated rats presented a non-vasoreactive PH characterized by the absence of pulmonary dilatation to adenosine. We therefore chose the bleomycin rat model to compare the effects of the maximally effective doses of macitentan and bosentan on pulmonary vascular and RV remodeling. Macitentan (100 mg·kg(-1)·d(-1)), but not bosentan (300 mg·kg(-1)·d(-1)), significantly prevented pulmonary vascular remodeling, RV hypertrophy, and cardiomyocyte diameter increase. Cardiac protection by macitentan was associated with a significant attenuation of genes related to cell hypertrophy and extracellular matrix remodeling. Microautoradiography and high performance liquid chromatography analysis showed greater distribution of macitentan than bosentan in the RV and pulmonary tissue. CONCLUSIONS: Macitentan was more efficacious than bosentan in preventing the development of pulmonary and RV hypertrophies in a model of non-vasoreactive PH. Greater ability to distribute into the tissue could contribute to the greater structural improvement by macitentan compared with bosentan.

Effect of cyclosporine and rifampin on the pharmacokinetics of macitentan, a tissue-targeting dual endothelin receptor antagonist.

Macitentan is a dual endothelin receptor antagonist under phase 3 investigation in pulmonary arterial hypertension. We investigated the effect of cyclosporine (Cs) and rifampin on the pharmacokinetics of macitentan and its metabolites ACT-132577 and ACT-373898 in healthy male subjects. In addition, in vitro studies were performed to investigate interactions between macitentan and its active metabolite ACT-132577 with human organic anion-transporting polypeptides (OATPs). The clinical study (AC-055-111) was conducted as a two-part, one-sequence, crossover study. Ten subjects in each part received multiple-dose macitentan followed by multiple-dose co-administration of Cs (part A) or rifampin (part B). In the presence of Cs, steady-state area under the plasma concentration-time profiles during a dose interval (AUC(τ)) for macitentan and ACT-373898 increased 10% and 7%, respectively, and decreased 3% for ACT-132577. Steady-state AUC(τ) of macitentan and ACT-373898 in the presence of rifampin decreased 79% and 64%, respectively. For ACT-132577, no relevant difference in AUC(τ) between the two treatments was observed. Macitentan co-administered with Cs or rifampin was well tolerated. The complementary in vitro studies demonstrated no marked differences in uptake rates of macitentan and ACT-132577 between the wild-type and OATP over-expressing cells over the concentration range tested. Concomitant treatment with Cs did not have any clinically relevant effect on the exposure to macitentan or its metabolites, at steady-state. Concomitant treatment with rifampin reduced significantly the exposure to macitentan and its metabolite ACT-373898 at steady-state but did not affect the exposure to the active metabolite ACT-132577 to a clinically relevant extent.

Cross-species pharmacologic evaluation of plasmin as a direct-acting thrombolytic agent: ex vivo evaluation for large animal model development.

PURPOSE: Human plasma-derived plasmin has been developed for the treatment of thrombosed hemodialysis arteriovenous grafts and vascular occlusive diseases. To further investigate this drug in large animal models and derive preliminary dosing estimates, the authors compared plasmin's relative lytic potential in four species, including man. The goal was to find which species' whole blood clots best compared to human clots in terms of lysis with plasmin. The results from these studies will serve to guide species selection for large animal experimentation. MATERIALS AND METHODS: Clotted blood from human, pig, sheep, and bovine subjects were treated with saline solution control, plasmin, or tissue plasminogen activator. Electron microscopy (EM) techniques were used to investigate the effects of clot size and fragmentation on plasmin lysis, the effects of intrathrombic infusion by injection of plasmin directly into whole blood clots, and species fibrin structural differences. RESULTS: Under static conditions, plasmin efficiently lysed clots from all species studied at an optimal dose of 4-5 mg per 4-5 g of clot. With fragmented human clots, plasmin (5 mg)-induced lysis was 80% +/- 2% at 60 minutes. Porcine clots were more resistant to plasmin lysis compared with human, ovine, and bovine clots. Percent lysis at 60 minutes with plasmin for ovine clots was 72% +/- 3% (4-mg dose), compared with 50% +/- 4% for porcine clots (5-mg dose; P < .05). EM of porcine clots showed a compact fibrin network that appeared more dense than that in human or sheep clots, which may account for the decreased lytic rate. CONCLUSIONS: Human plasmin is an effective direct-acting thrombolytic agent that is capable of lysing fibrin from several species. Ex vivo lysis studies were used to investigate the most appropriate large animal model that best approximates plasmin lysis with human clots under certain conditions. It was determined that ovine clots treated with plasmin most closely resemble the lysis observed with human clots.

Locally delivered plasmin: why should it be superior to plasminogen activators for direct thrombolysis?

With advances in the field of thrombolytic therapy, whereby clots are routinely treated locally via a catheter, traditional systemic thrombolytics such as plasminogen activators might not be the best drugs for this task. Plasmin represents a new class of thrombolytic agents that exhibit direct fibrinolytic activity, without the need for either plasminogen or a plasminogen activator. In contrast to plasminogen activators, this independence from plasminogen allows plasmin to efficiently dissolve long, retracted blood clots that are inherently deficient in plasminogen. Preclinical safety studies in rabbits demonstrate that plasmin, in contrast to tissue-type plasminogen activator, does not cause re-bleeding from preformed hemostatic plugs. These results predict that plasmin will prove to be both superior to, and safer than, plasminogen activators in the dissolution of long, retracted blood clots in humans.