Niemann-Pick type C1 (NPC) disease is a lysosomal storage disease caused by mutations in the NPC1 gene, leading to an increase in unesterified cholesterol and several sphingolipids, and resulting in hepatic disease and progressive neurological disease. Whereas subcutaneous administration of the pharmaceutical excipient 2-hydroxypropyl-beta-cyclodextrin (HPβCD) ameliorated hepatic disease, doses sufficient to reduce neurological disease resulted in pulmonary toxicity. In contrast, direct administration of HPβCD into the cisterna magna of presymptomatic cats with NPC disease prevented the onset of cerebellar dysfunction for greater than a year and resulted in a reduction in Purkinje cell loss and near normal concentrations of cholesterol and sphingolipids. Moreover, administration of intracisternal HPβCD to NPC cats with ongoing cerebellar dysfunction slowed disease progression, increased survival time, and decreased the accumulation of brain gangliosides. An increase in hearing threshold was identified as a potential adverse effect. Together, these studies in the feline animal model have provided critical data on efficacy and safety of drug administration directly into the CNS that will be important for advancing HPβCD into clinical trials.
Niemann-Pick disease type C (NPC disease) is an incurable cellular lipid trafficking disorder characterized by neurodegeneration and intralysosomal accumulation of cholesterol and glycosphingolipids. Treatment with miglustat, a small imino sugar that reversibly inhibits glucosylceramide synthase, which is necessary for glycosphingolipid synthesis, has been shown to benefit patients with NPC disease. The mechanism(s) and extent of brain cellular changes underlying this benefit are not understood. To investigate the basis of the efficacy of miglustat, cats with disease homologous to the juvenile-onset form of human NPC disease received daily miglustat orally beginning at 3 weeks of age. The plasma half-life of miglustat was 6.6 ± 1.1 hours, with a tmax, Cmax, and area under the plasma concentration-time curve of 1.7 ± 0.6 hours, 20.3 ± 4.6 μg/ml, and 104.1 ± 16.6 μg hours/ml, respectively. Miglustat delayed the onset of neurological signs and increased the lifespan of treated cats, and was associated with decreased GM2 ganglioside accumulation in the cerebellum and improved Purkinje cell survival. Ex vivo examination of microglia from the brains of treated cats revealed normalization of CD1c and class II major histocompatibility complex expression, as well as generation of reactive oxygen species. Together, these results suggest that prolonged Purkinje cell survival, reduced glycosphingolipid accumulation, and/or the modulation of microglial immunophenotype and function contribute to miglustat-induced neurological improvement in treated cats.
IntroductionHospital readmission following treatment for a life-threatening exacerbation of COPD with acute NIV is frequent and associated with an adverse impact in terms of lung function and health related quality of life. They have been identified as a priority area in the NHS with financial penalties for any patient readmitted within 28 days following discharge.MethodA multicentre open labelled randomised controlled trial recruited patients with persistent hypercapnia (PaCO2 > 7 kPa) 2–4 weeks following resolution of acute acidosis. Patients were randomised to either home oxygen therapy (HOT) or HOT and home mechanical ventilation (HOT-HMV). HMV was titrated overnight to control nocturnal hypercapnia. Follow up was for 12 months. The primary outcome, 12-month admission free survival, has been reported previously demonstrating a significant treatment effect (ERS 2016). Secondary outcome analysis included 28-day all-cause hospital readmission and 12 month exacerbation rate.Results116 patients were randomised (HOT = 59, HOT-HMV = 57), age 67 ± 10 years, FEV1 0.6 ± 0.2 L, PaCO2 7.9 ± 0.9 kPa. 28-day readmission was 22 (37%) in the HOT and 7 (12%) in the HOT-HMV arm (unadjusted HR 0.27, 0.12 to 0.63, p = 0.003; adjusted HR 0.26, 0.11 to 0.61, p = 0.002) (Figure 1). 12 month exacerbation rate was reduced from median 5 (1 to 9) per year in the HOT arm to 4 (2to 6) in the HOT-HMV arm (unadjusted HR 0.64 (0.44 to 0.94); p = 0.022; adjusted HR 0.66, 0.46 to 0.95, p = 0.026).ConclusionThe addition of HMV to HOT in patients with persistent hypercapnia following an acute life-threatening exacerbation of COPD reduces both 28-day readmission and 12 month exacerbation frequency. These data strongly support a change in clinical practice in the management of patients with severe COPD and persistent hypercapnia.Abstract S115 Figure 1Time to hospital re-admission by treatment arm
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