Umeclidinium bromide (GSK573719; UMEC), a new long-acting muscarinic receptor antagonist (LAMA), is in development with vilanterol (GW642444; VI), a selective long-acting β2 agonist (LABA), as a once-daily inhaled combination therapy for the treatment of chronic obstructive pulmonary disease (COPD). A single dose healthy volunteer study was conducted to assess the safety and tolerability, pharmacodynamics (PD) and pharmacokinetics (PK) of inhaled umeclidinium (500 µg) and vilanterol (50 µg) when administered separately and in combination using a novel dry powder inhaler (NDPI). Co-administration of single inhaled doses of umeclidinium and vilanterol to healthy Japanese subjects was well tolerated and not associated with meaningful changes in systemic exposure or PD effects compared with administration of either compound individually. Pharmacokinetic assessments showed rapid absorption for both drugs (Tmax = 5 min for both umeclidinium and vilanterol) followed by rapid elimination with median tlast of 4–5 h for umeclidinium and median tlast of 1.5–2.0 h for vilanterol. Assessments of pharmacokinetic interaction were inconclusive since for umeclidinium, Cmax following combination was higher than umeclidinium alone but not AUC whereas for vilanterol, AUC following combination was higher than vilanterol alone but not Cmax. There were no obvious trends observed between individual maximum supine heart rate and umeclidinium Cmax or vilanterol Cmax when delivered as umeclidinium 500 µg and vilanterol 50 µg combination or when delivered as umeclidinium or vilanterol alone.Trial RegistrationClinicaltrials.gov NCT00976144

Detailed biochemical and molecular investigations in a patient with Kearns-Sayre syndrome are presented. Polarographic studies in isolated mitochondria revealed a global impairment in respiratory capacity consistent with an admixture of functional and non-functional mitochondria. Cytochrome difference spectra revealed a selective deficiency in cytochrome aa3. Western immunoblot studies revealed normal subunit content of Complexes I, III and IV. Southern blot studies of mtDNA showed a deletion of approximately 5 Kb coexisting with wild type DNA. PCR analysis confirmed that this deletion lies between the ATPase8 and NAD coenzyme Q oxidoreductase subunit 5 (ND5) genes. Breakpoint sequencing revealed a 13 nucleotide direct repeat flanking sequence (ACCTCCCTCACCA) consistent with slippage in mtDNA during replication as the mechanism of deletion. Histochemical studies of skeletal muscle revealed many cytochrome oxidase negative fibres and immunocytochemical studies showed cytochrome oxidase negative areas with abundant respiratory complex protein suggesting upregulation. The value of a multifaceted approach in unravelling the pathophysiology of mitochondrial diseases is emphasised.

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