Apomorphine

Apomorphine (APO) is an aporphine derivative used in human and veterinary medicine. APO activates D₁, D(2S), D(2L), D₃, D₄, and D₅ receptors (and is thus classified as a non-selective dopamine agonist), serotonin receptors (5HT(1A), 5HT(2A), 5HT(2B), and 5HT(2C)), and α-adrenergic receptors (α(1B), α(1D), α(2A), α(2B), and α(2C)). In veterinary medicine, APO is used to induce vomiting in dogs, an important early treatment for some common orally ingested poisons (e.g., anti-freeze or insecticides). In human medicine, it has been used in a variety of treatments ranging from the treatment of addiction (i.e., to heroin, alcohol or cigarettes), for treatment of erectile dysfunction in males and hypoactive sexual desire disorder in females to the treatment of patients with Parkinson's disease (PD). Currently, APO is used in patients with advanced PD, for the treatment of persistent and disabling motor fluctuations which do not respond to levodopa or other dopamine agonists, either on its own or in combination with deep brain stimulation. Recently, a new and potentially important therapeutic role for APO in the treatment of Alzheimer's disease has been suggested; APO seems to stimulate Aβ catabolism in an animal model and cell culture, thus reducing the rate of Aβ oligomerisation and consequent neural cell death.

Dopaminergic function has a key role in normal brain function, dopaminergic dysfunction being implicated in numerous neuropsychiatric disorders. Animal studies show that dopaminergic stimulation regulates dopaminergic function, but it is not known whether this exists in humans. In the first study (study 1), we measured dopamine synthesis capacity (indexed as Kicer) to identify the relationship between baseline and change in Kicer under resting conditions for comparison with effects of dopaminergic stimulation. In the second study (study 2), we used a within-subjects design to test effects of dopaminergic stimulation on dopamine synthesis capacity. In study 1, eight volunteers received two 18F-DOPA scans on separate days, both at rest. In study 2, 12 healthy male volunteers received two 18F-DOPA positron emission tomographic (PET) scans after treatment with either the dopamine partial agonist apomorphine (0.03 or 0.005 mg kg-1) or placebo. In study 1, no significant correlation was found between baseline and change in dopamine synthesis capacity between scans (r=-0.57, n=8, P=0.17, two-tailed). In study 2, a significant negative correlation was found between baseline dopamine synthesis capacity and percentage change in dopamine synthesis capacity after apomorphine challenge (r=-0.71, n=12, P=0.01, two-tailed). This correlation was significantly different (P<0.01) from the correlation between baseline and change in dopamine synthesis capacity under unstimulated conditions. One-way repeated-measures analysis of variance showed a significant group (study 1/study 2) × time interaction (F(1,18)=11.5, P=0.003). Our findings suggest that regulation of dopamine synthesis capacity by apomorphine depends on baseline dopamine function, consistent with dopamine stimulation stabilizing dopaminergic function. Loss of this autoregulation may contribute to dopaminergic dysfunction in brain disorders such as schizophrenia, substance dependence, and Parkinson's disease.

Despite much research, it remains unclear if dopamine is directly involved in novelty detection or plays a role in orchestrating the subsequent cognitive response. This ambiguity stems in part from a reliance on experimental designs where novelty is manipulated and dopaminergic activity is subsequently observed. Here we adopt the alternative approach: we manipulate dopamine activity using apomorphine (D1/D2 agonist) and measure the change in neurological indices of novelty processing. In separate drug and placebo sessions, participants completed a von Restorff task. Apomorphine speeded and potentiated the novelty-elicited N2, an Event-Related Potential (ERP) component thought to index early aspects of novelty detection, and caused novel-font words to be better recalled. Apomorphine also decreased the amplitude of the novelty-P3a. An increase in D1/D2 receptor activation thus appears to potentiate neural sensitivity to novel stimuli, causing this content to be better encoded.

Conventional delivery of apomorphine hydrochloride (APO) for management of 'OFF' periods in Parkinson's disease is limited to subcutaneous or sublingual delivery, and would substantially benefit from a transdermal drug delivery system (TDDS). Minimal progression has been made thus far in this area, with current literature presenting debatably flawed or inconsistent experimental design for ex vivo percutaneous permeation and deposition studies, a crucial step in understanding TDDS performance. Provided here is an improved, robust, versatile and easily-transferred analytical methodology, fully validated in accordance with guidelines provided by the International Council for Harmonization of Technical Requirements for Pharmaceuticals for Human Use (ICH). Reversed-phase high performance liquid chromatography (RP-HPLC) is employed with ultraviolet-visible (UV) light or fluorescence intensity (FID) detection in conjunction with a Franz diffusion-cell setup that ensures stability of APO and uses physiologically relevant neonatal porcine skin. Thus, this methodology may be reliably employed by future researchers developing an APO TDDS. To demonstrate application, a superficial investigation into model pressure-sensitive adhesive (PSA) patch systems provided sustained percutaneous delivery of up to 4.015 ± 2.361 µg/cm2/hr APO over a 24-hour period. These offer brief insight into a system that has yet to be studied in-depth for percutaneous delivery of APO, and highlight the importance of alternative penetration enhancers or enhancement techniques in developing a TDDS with clinical potential.