Steve Austin

BACKGROUND: Current hemophilia treatment involves frequent intravenous infusions of clotting factors, which is associated with variable hemostatic protection, a high treatment burden, and a risk of the development of inhibitory alloantibodies. Fitusiran, an investigational RNA interference (RNAi) therapy that targets antithrombin (encoded by SERPINC1), is in development to address these and other limitations. METHODS: In this phase 1 dose-escalation study, we enrolled 4 healthy volunteers and 25 participants with moderate or severe hemophilia A or B who did not have inhibitory alloantibodies. Healthy volunteers received a single subcutaneous injection of fitusiran (at a dose of 0.03 mg per kilogram of body weight) or placebo. The participants with hemophilia received three injections of fitusiran administered either once weekly (at a dose of 0.015, 0.045, or 0.075 mg per kilogram) or once monthly (at a dose of 0.225, 0.45, 0.9, or 1.8 mg per kilogram or a fixed dose of 80 mg). The study objectives were to assess the pharmacokinetic and pharmacodynamic characteristics and safety of fitusiran. RESULTS: No thromboembolic events were observed during the study. The most common adverse events were mild injection-site reactions. Plasma levels of fitusiran increased in a dose-dependent manner and showed no accumulation with repeated administration. The monthly regimen induced a dose-dependent mean maximum antithrombin reduction of 70 to 89% from baseline. A reduction in the antithrombin level of more than 75% from baseline resulted in median peak thrombin values at the lower end of the range observed in healthy participants. CONCLUSIONS: Once-monthly subcutaneous administration of fitusiran resulted in dose-dependent lowering of the antithrombin level and increased thrombin generation in participants with hemophilia A or B who did not have inhibitory alloantibodies. (Funded by Alnylam Pharmaceuticals; ClinicalTrials.gov number, NCT02035605 .).

Changes in small intestinal structure, cytokinetics, and function are dynamic ways in which the gut adapts to diet, disease, and damage. Adequate length provides a static 'reserve' permitting an immediate response to pathophysiological changes. The length of the small intestine from conception to adulthood using data taken from eight published reports of necropsy measurement of 1010 guts is described. Mean length at 20 weeks' gestation was 125 cm, at 30 weeks' 200 cm, at term 275 cm, at 1 year 380 cm, at 5 years 450 cm, at 10 years 500 cm, and at 20 years 575 cm. Prenatal small intestinal growth exceeded that of body length according to the law: small intestinal length alpha body length to the power 4/3. After birth there was a noticeable deceleration: small intestinal length alpha body length to the power 1/2. The coefficient of variation of small intestinal length postnatally was 24%, sixfold greater than for body length. The rapid prenatal small intestinal growth rate ensures that the mature newborn has adequate small intestine to meet postnatal nutritional demands, but handicaps the preterm infant who undergoes intestinal resection. The wide variation in lengths suggests a 'surplus' surface area that is immediately available to respond, independent of dynamic mucosal changes, to fluctuations in food availability, local intestinal disease, damage, rapid transit, and resection.

OBJECTIVES: To determine the degree of dopaminergic response of swallowing dysfunction in Parkinson's disease. METHODS: Fifteen patients with idiopathic Parkinson's disease and symptomatic dysphagia were studied. All had motor fluctuations in response to long term levodopa therapy. On two separate days, after overnight withdrawal of all antiparkinsonian medication, a modified barium swallow using cinefluoroscopy and different food consistencies was performed before and after administration of oral levodopa and subcutaneous apomorphine. RESULTS: Despite all patients having an unequivocal motor response to both agents, there were few significant responses in any of the quantitative or qualitative criteria of swallowing dysfunction assessed. The oral preparatory phase, generally considered a more voluntary component of swallowing, showed a response, but not with all consistencies. In a subgroup of patients the pharyngeal phase time also improved. CONCLUSIONS: These findings suggest that parkinsonian swallowing dysfunction is not solely related to nigrostriatal dopamine deficiency and may be due to an additional non-dopamine related disturbance of the central pattern generator for swallowing in the pedunculopontine nucleus or related structures in the medulla.