The Many Faces of Apomorphine: Lessons from the Past and Challenges for the Future.

Apomorphine is now recognized as the oldest antiparkinsonian drug on the market. Though still underused, it is increasingly prescribed in Europe for patients with advanced Parkinson's disease (PD) with motor fluctuations. However, its history is far from being limited to movement disorders. This paper traces the history of apomorphine, from its earliest empirical use, to its synthesis, pharmacological development, and numerous indications in human and veterinary medicine, in light of its most recent uses and newest challenges. From shamanic rituals in ancient Egypt and Mesoamerica, to the treatment of erectile dysfunction, from being discarded as a pharmacological tool to becoming an essential antiparkinsonian drug, the path of apomorphine in the therapeutic armamentarium has been tortuous and punctuated by setbacks and groundbreaking discoveries. Throughout history, three main clinical indications stood out: emetic (gastric emptying, respiratory disorders, aversive conditioning), sedative (mental disorders, clinical anesthesia, alcoholism), and antiparkinsonian (fluctuations). New indications may arise in the future, both in PD (palliative care, nonmotor symptoms, withdrawal of oral dopaminergic medication), and outside PD, with promising work in neuroprotection or addiction.

Apomorphine and levodopa in Parkinson's disease: Two revolutionary drugs from the 1950's.

This article reviews the history of apomorphine and levodopa, which were both discovered in the 1950's and have revolutionized treatment paradigms of Parkinson's disease. Although the discovery of levodopa is a prime example of successful translation of basic neuroscience into clinical routine, the history of apomorphine was based on less solid evidence. Despite this, both drugs are, more than 6 decades after the first clinical experiments, still the two most efficacious medications to treat patients with Parkinson's disease. New and promising delivery strategies for both levodopa and apomorphine are currently under investigation to further improve clinical responses.

The role of subcutaneous infusion of apomorphine in Parkinson's disease.

Continuous subcutaneous apomorphine infusion therapy (CSAI) has proved to be effective in advanced Parkinson's Disease patients with motor fluctuations not controlled by oral or transdermal medication. In this clinical setting it competes directly with intrajejunal levodopa and deep brain stimulation (DBS), however randomised controlled comparative studies are lacking. The advantages of CSAI is that it is the least invasive of these three therapeutic options, is reversible, practical to use and has shown significant efficacy for the management of both peak-effect dyskinesias and off-period nonmotor-symptoms. Contraindications to the use of CSAI are severe dementia or neuropsychiatric symptoms and severe biphasic dyskinesias, however unlike DBS, advanced age is not a contraindication. This review summarises the evidence regarding efficacy, safety and tolerability of CSAI, provides guidance on the selection of suitable patients and gives practical instructions on how to initiate CSAI and manage possible adverse events.

Erich Harnack (1852-1915) and a short history of apomorphine.

Apomorphine, now established as an efficacious therapy for refractory motor fluctuations in levodopa-treated Parkinson's disease, has a long and chequered history in medical and veterinary therapeutics. The preclinical in vivo pharmacological effects of apomorphine were first studied about 150 years ago following which the drug was introduced for the treatment of behavioural vices in domesticated animals. Erich Harnack's early pharmacological studies in Dorpat (now Tartu, Estonia), where he belonged to the pharmacological dynasty of Buchheim and Schmiedeberg, are of particular historical significance as he emphasised that while apomorphine had potent emetic effects, the drug also had complex effects on the central nervous system.

Apomorphine in dopaminergic therapy.

Apomorphine is a potent molecule for the treatment of Parkinson's disease (PD). It can be obtained in both the R and S forms, and it is the former that is the therapeutically active form. Due to its structural similarity with 3,4-dihydroxyphenethylamine, dopamine, apomorphine can function as an agonist in the treatment of PD as it can stimulate both the D1 and D2 receptors of the striatum. The clinical efficacy of apomorphine is similar to that of 3,4-dihydroxyphenylalanine, levodopa (L-dopa), the cornerstone drug in dopaminergic therapy. (R)-Apomorphine is efficacious for one of the most challenging aspects in the management of PD, namely, managing the unpredictable "on-off" period as a rescue medication after oral administration of a therapeutic drug such as L-dopa. The effectiveness is due to its rapid control of the wearing-off period of the orally administered medicine. This short review will trace the progress of apomorphine use starting with its initial discovery and the first indications for which it was used, discovery of its "cure" for PD, and the studies that led to demonstrating its therapeutic efficacy. The key structural features of apomorphine responsible for its activity are illustrated along with major issues of chemical stability. From a drug delivery point of view, the current form of administration of apomorphine and some of the potential alternate methods of delivery are reviewed.

Apomorphine to Uprima: the development of a practical erectogenic drug: a personal perspective.

The development process for apomorphine SL as an effective treatment for patients with erectile dysfunction has been somewhat unusual. As often is the case, much of the impetus for the basic research originated in academia. However, somewhat unusually, the impetus for early stage clinical research also lay in the hands of the academics. This article represents a historical perspective from one of those involved throughout.

Apomorphine revived: fortified, prolonged, and improved therapeutical effect.

An historical review is presented of the evolution of the clinical apomorphine treatment. Some of the results from the last 10 years of psychopharmacological research have led us to the hypothesis that there exists a close relationship between abstinence and craving symptoms in drug and alcohol addicts, and that anxiety, depression, and tremor symptoms in Parkinsonism (and dementia senilis), are due to disturbances of the same, mainly dopaminergic, pathways in the CNS. In such cases, by means of effective preparations for oral use, we have utilized the synergistic effect of small amounts of apomorphine, L-dopa, and decarboxylase inhibitor with considerable therapeutic effect.