A critical review of apomorphine hydrochloride sublingual film for the treatment of Parkinson's disease 'OFF' episodes.

Introduction: Parkinson's disease (PD) is a neurodegenerative disorder defined by its motor features. Levodopa therapy is the gold standard therapy, but over time, response is impeded by the development of motor fluctuations, including 'off' episodes where PD symptoms reemerge. Sublingual apomorphine offers a new, novel, and effective therapy developed for treatment of 'off' episodes. Areas covered: Apomorphine is an old dopamine agonist developed as a subcutaneous injectable rescue therapy for 'off' periods in PD that was approved in the United States in 2004. We will discuss its history, chemistry and clinical use. We will also cover the recent development and approval of sublingual apomorphine film that offers a novel formulation and provides effective treatment for 'off' episodes including results of the phase 3 randomized, double-blinded, placebo-controlled study. Oral mucosal side effects, which were mild to moderate and reversible in most patients experiencing them, will be discussed. Expert opinion: The new sublingual apomorphine is safe and effective for relief of 'off' periods that impact quality of life. Its ease of use will be beneficial to those with needle phobia and device challenges with currently available injectable and inhaled therapeutics. Side effect profile is an improvement from previous attempts at sublingual formulation.

Signaling dependent and independent mechanisms in pemphigus vulgaris blister formation.

Pemphigus vulgaris (PV) is an autoimmune epidermal blistering disease caused by autoantibodies directed against the desmosomal cadherin desmoglein-3 (Dsg3). Significant advances in our understanding of pemphigus pathomechanisms have been derived from the generation of pathogenic monoclonal Dsg3 antibodies. However, conflicting models for pemphigus pathogenicity have arisen from studies using either polyclonal PV patient IgG or monoclonal Dsg3 antibodies. In the present study, the pathogenic mechanisms of polyclonal PV IgG and monoclonal Dsg3 antibodies were directly compared. Polyclonal PV IgG cause extensive clustering and endocytosis of keratinocyte cell surface Dsg3, whereas pathogenic mouse monoclonal antibodies compromise cell-cell adhesion strength without causing these alterations in Dsg3 trafficking. Furthermore, tyrosine kinase or p38 MAPK inhibition prevents loss of keratinocyte adhesion in response to polyclonal PV IgG. In contrast, disruption of adhesion by pathogenic monoclonal antibodies is not prevented by these inhibitors either in vitro or in human skin explants. Our results reveal that the pathogenic activity of polyclonal PV IgG can be attributed to p38 MAPK-dependent clustering and endocytosis of Dsg3, whereas pathogenic monoclonal Dsg3 antibodies can function independently of this pathway. These findings have important implications for understanding pemphigus pathophysiology, and for the design of pemphigus model systems and therapeutic interventions.