Classical dopamine agonists.

The pioneering work of Arvid Carlsson has laid the foundation for a number of innovative therapies for severe central nervous system (CNS) diseases. He was awarded the Nobel Price for the discovery of the crucial role of dopamine (DA) as a neurotransmitter in the CNS, thereby forming the basis for the symptomatic therapy of Parkinson's disease (PD) with L-DOPA and subsequently dopaminergic drugs. Parenteral apomorphine has a short lasting effect in PD, bromocriptine can be administered orally and has a long-lasting effects but is poorly tolerated. Lisuride on the other hand has a high affinity to DA receptors and can be administered orally, parenterally or via the transdermal route of administration. Last but not least Carlsson developed the concepts of presynaptic effects of DA agonists as well as DA partial agonism potentially innovative mechanisms for treatment of PD and schizophrenia.

ANNIVERSARY REVIEW: 50 years since the discovery of bromocriptine.

Ergotism is the long-term ergot poisoning by ingestion of rye or other grains infected with the fungus Claviceps purpurea and more recently by excessive intake of ergot drugs. It has either neuropsychiatric or vascular manifestations. In the Middle Ages, the gangrenous poisoning was known as St. Anthony's fire, after the order of the Monks of St. Anthony who were particularly skilled at treating the condition. In 1917, Prof. Arthur Stoll returned home to Switzerland from Germany, to lead the development of a new pharmaceutical department at Sandoz Chemical Company. Stoll, using the special methods of extraction learned from his work with his mentor Willstetter, started his industrial research work with ergot. He succeeded in isolating, from the ergot of rye, ergotamine as an active principle of an old popular remedy for excessive post-partum bleeding. The success of this discovery occurred in 1918 and was translated into a pharmaceutical product in 1921 under the trade name Gynergen. In subsequent work, Stoll and his team were leaders in identifying the structure of the many other alkaloids and amines produced by Claviceps purpurea This was the cultural background and scientific foundation on which bromocriptine was discovered.

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.

History of levodopa and dopamine agonists in Parkinson's disease treatment.

Striatal dopamine deficiency in Parkinson's disease (PD), first described in 1960, was a key event that led to the era of levodopa therapy. In 1961, levodopa was first tried in PD patients, but throughout most of the 1960s the results were inconsistent. In 1967, questions about the effectiveness of levodopa in PD were finally set aside when Cotzias and colleagues reported dramatic improvement in PD patients with oral administration of levodopa in increasing amounts over long periods. The major side effects of levodopa administration, i.e., dyskinesias and motor fluctuations, also became apparent at this time. In the early 1970s, the advantages of adding a dopa decarboxylase inhibitor to treatment were discovered--reducing side effects and gaining better symptom control--and the first levodopa combination, carbidopa/levodopa, became commercially available in 1975. Since then, PD researchers have attempted to overcome complications with such techniques as continuous levodopa infusion and, most recently, long-acting levodopa combinations. A dopamine agonist, apomorphine, was used in 1970 as a means to overcome side effects and loss of levodopa efficacy. However, side effects and difficulty of administration limited its use. Dopamine agonists began to find a place in routine treatment of PD after the discovery of bromocriptine's benefits in PD in 1974. Since then, new approaches have been tried, such as dopamine agonist monotherapy and early therapy in combination with levodopa. The development of new dopamine agonists has led to characterization of dopamine receptor subtypes and agonists targeted to stimulation of specific receptors.