History of the Molecule Across the Centuries We review the pharmacology and clinical studies of the efficacy and safety of subcutaneous apomorphine administration in treating motor fluctuations in PD and give a brief overview of alternative apomorphine formulations currently in clinical development. The current role of apomorphine in the treatment of PD is in the management of levodopa-related motor complications-as either intermittent subcutaneous pen injections or continuous subcutaneous mini-pump delivery. The response to levodopa is maintained in the long term, but many patients develop challenging motor complications such as motor fluctuations and dyskinesia as the disease progresses. Dopamine replacement with oral levodopa is still the gold standard of symptomatic therapy, matched only by apomorphine in its effect size on motor symptoms. PD was the first neurodegenerative disease for which highly efficacious treatments became available. In addition, most patients with PD also experience non-motor symptoms (NMS), adding to the overall burden of parkinsonian morbidity. PD is clinically defined by the presence of bradykinesia and at least one additional cardinal motor feature (rigidity or rest tremor). Neuropathological hallmarks are progressive loss of dopaminergic neurons in the pars compacta of the substantia nigra, causing striatal dopamine deficiency, and intracellular inclusions containing aggregates of alpha-synuclein. Parkinson’s disease (PD) is the second most frequent neurodegenerative disease, affecting 1% of the population aged > 60 years and reaching 3% in the highest age groups. We then summarize the evidence regarding the efficacy and tolerability of apomorphine, both in its established formulations (subcutaneous intermittent injection and continuous infusion) and in the new preparations currently under investigation.
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We provide an overview of the pharmacological mechanism of action of the drug in light of its effects on Parkinson’s disease symptoms.
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Dopaminergic side effects such as nausea, somnolence and hypotonia, as well as administration site reactions, are often mild or treatable, but somnolence and skin reactions in particular can sometimes be reasons for premature discontinuation. Continuous apomorphine infusion reduced around 50% of the daily “off” time in several studies.
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Clinical trials have shown that intermittent apomorphine injections provide rapid and effective relief from unpredictable “off” periods. Apomorphine, a short-acting D 1- and D 2-like receptor agonist, is the only drug proven to have an efficacy equal to that of levodopa, albeit with a shorter time to onset and effect duration. In the advanced phase of the disease, patients may experience motor complications despite optimized pharmacological therapy. Satisfactory management of Parkinson’s disease is a challenge that requires a tailored approach for each individual.