Treatment of Parkinson's Disease with Aporphines

Cotzias, George C.; Papavasiliou, Paul S.; Tolosa, Eduardo; Mendez, Jorge S.; Bell-Midura, Margaret

doi:10.1056/nejm197603112941101

Cited by 170 publications

(51 citation statements)

References 24 publications

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“…The inhibition of the cyclase by high concentrations of ac- tivator and the reversal of this inhibition by dopamine are compatible with the concomitant antagonism and synergism encountered between some aporphines and L-dopa in patients with Parkinson's disease (15,16). This phenomenon consisted of an increase in the antiparkinsonism effects of L-dopa by apomorphine (15) or N-propylnoraporphine (16) and the blocking of the dyskinesia produced by L-dopa.…”

Section: Resultsmentioning

confidence: 65%

“…Such a stimulation was indeed restricted to the active forms of dopaminergic drugs because metabolites and precursors were as inactive in stimulating the cyclase in vitro as they have been in stimulating mammalian or human brain experimentally in vivo (2). The one exception-the inhibition of the action of apomorphine on the enzyme by O-methylated apomorphines-duplicated experiments in animals (17) and perhaps simulated the loss of potency of aporphines with time encountered in the treatment of parkinsonism (16).…”

Section: Resultsmentioning

confidence: 99%

“…This phenomenon consisted of an increase in the antiparkinsonism effects of L-dopa by apomorphine (15) or N-propylnoraporphine (16) and the blocking of the dyskinesia produced by L-dopa.…”

Section: Resultsmentioning

confidence: 99%

“…Concomitantly, dopamine at 10 MM lessened the inhibition caused by excess.activator. As we discuss below, these trends might explain the paradoxical synergism and antagonism between some aporphines and Ldopa encountered by us while investigating the treatment of Parkinson's disease in man (15,16).…”

mentioning

confidence: 99%

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Opposing effects of dopaminergic to cholinergic compounds on a cerebral dopamine-activated adenylate cyclase.

Tang¹,

Cotzias²

1977

Proc. Natl. Acad. Sci. U.S.A.

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We have studied these possibilities in the hope of advancing the treatments of Parkinson's disease and of psychosis. To this end we used adenylate cyclase from mouse caudate to screen agents that can affect the symptoms of Parkinson's disease. These included drugs that stimulate the dopaminergic system in man or animals and inactive metabolites and precursors thereof and compounds that activate or inhibit the cholinergic system, which counterbalances the dopaminergic one in the brain (7,8).MATERIALS AND METHODS Animals. These were 5-to 6-week-old male Swiss albino mice, weighing 23-27 g, maintained on Purina Chow and water ad lib., and kept in an air-conditioned room on a 12-hr lightto-darkness cycle. The experiments were started in midday by decapitating the animals in a cold room. The brains were removed within 30 sec and placed on a cold watch glass. The lateral ventricles were entered by removing their roofs. The exposed heads of the caudates were scooped out with forceps.Determination of Dopamine-Stimulated Adenylate Cyclase Activity. The methods are essentially those developed in Greengard's laboratory (9). All fragments of both caudates (about 30 mg) were placed in Krebs-Ringer bicarbonate solution, pH 7.4, which had been gassed for 2 min with 5% CO2/ 95% 02. They were homogenized in 0.5 ml of 50 mM Trismaleate buffer, pH 7.4, containing 12.5 mM theophylline, 0.25 mM ethylene glycol-bis(Q-aminoethyl ether)-NN'-tetraacetic acid, and 2.5 mM MgSO4. Aliquots (0.4 ml) of the homogenates were placed in 5-ml Pyrex tubes that had previously been equilibrated to 30°in an orbital water bath. The control tubes received 50 gl of H20. The experimental tubes received different additives in different series of experiments, the concentrations of which are given below. In one series, 50 ,ul containing either dopamine or a dopaminergic substance was added. In another series, the tubesi received 25 ,ul containing one of the above substances plus 25 jul containing-an inhibitor, a metabolite, or a precursor thereof. In another series, the precursors and metabolites were tested in various concentrations for activation of the cyclase. In still another series, the metabolites were screened for inhibition of the dopamine-dependent activation. Finally, some cholinergic and anticholinergic agents were screened for activation or inhibition of the cyclase.The reaction was started by adding 50 jul of a 0.5 mM solution of ATP with mixing and then incubating in a 30°orbital water bath. After 2.5 min, the reaction was terminated by immersion of the tubes into a boiling water bath for 2 min. The homogenates were centrifuged at 1500 X g for 5 min. The supernatant solutions were quick-frozen until analyzed for adenosine 3': 5'-cyclic monophosphate (cyclic AMP) according to Gilman (10).The results of the cyclic AMP determinations were used as follows. We first computed the mean ±SEM of both nonstimulated and stimulated samples. From these we calculated the net dopamine-stimulated cyclic AMP produced by subtracting the mean nonstimulated acti...

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Section: Resultsmentioning

confidence: 65%

Section: Resultsmentioning

confidence: 99%

“…This phenomenon consisted of an increase in the antiparkinsonism effects of L-dopa by apomorphine (15) or N-propylnoraporphine (16) and the blocking of the dyskinesia produced by L-dopa.…”

Section: Resultsmentioning

confidence: 99%

mentioning

confidence: 99%

See 2 more Smart Citations

Opposing effects of dopaminergic to cholinergic compounds on a cerebral dopamine-activated adenylate cyclase.

Tang¹,

Cotzias²

1977

Proc. Natl. Acad. Sci. U.S.A.

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“…Todos os pacientes submetidos a estas altas doses de apomorfina (600 a 1400 mg ao dia) apresentaram uremia que, embora reversível, limitava o seu uso 6 . A ministração parenteral necessitava de doses muito menores para serem efetivas (a partir de 1 mg ao dia), não produzindo uremia, mas com potente efeito emético 5 .…”

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Apomorfina: uma alternativa no controle das flutuações motoras na doença de Parkinson

Ferraz¹,

Azevedo-Silva²,

Borges³

et al. 1995

Arq. Neuro-Psiquiatr.

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RESUMO -As flutuações motoras (FM) decorrentes do uso prolongado de levodopa são uma das principais complicações do tratamento da doença de Parkinson (DP). A utilização da apomorfina, um potente agonista de receptores dopaminérgicos, associada ao domperidone para bloquear seus efeitos eméticos, surge como uma alternativa para contornar as FM dos parkinsonianos. Para adquirirmos experiência inicial com essa droga, decidimos estudar a ação e os efeitos adversos da apomorfina em um grupo de quatro pacientes do nosso ambulatório com o diagnóstico de DP e com flutuaçãoes de rendimento da levodopa. A apomorfina foi administrada por via subcutânea, sendo obtido o estado "on" em todos os pacientes com doses entre 1,5 e 3 mg por aplicação. A latência para o início do efeito variou de 7 a 30 minutos e a duração da ação de 60 a 85 minutos. O estado "on" produzido com a apomorfina foi indistinguível do observado com a levodopa, inclusive com a ocorrência de discinesias. Não foram observados efeitos colaterais significativos. Nossa experiência inicial mostra que a apomorfina, em doses relativamente baixas, é uma alternativa eficaz para as FM da DP, com poucos efeitos colaterais. PALAVRAS-CHAVE: doença de Parkinson, tratamento; apomorfina, uso terapêutico; levodopa, efeitos adversos.Apomorphine: an alternative in the management of motor fluctuations of Parkinson's disease SUMMARY -Levodopa-induced motor fluctuations (MF) is a disabling complication of Parkinson's disease (PD) and is usually refractory to conventional treatment. Apomorphine, a dopamine agonist with affinity for both Dl and D2 receptors, has been emerged as an useful alternative in the management of MF of PD. The frequency of nausea and vomiting prevented its use in the past, but the simultaneous administration of domperidone has proved to be able to control these side effects. Although apomorphine has been successfully used to control levodopa-induced MF in other countries, it has not been considered in the management of PD in Brazil. We report here our initial experience with subcutaneous injections of apomorphine combined to oral domperidone. We administered apomorphine in doses ranging from 1.5 to 3 mg in four PD patients with MF of our outpatient clinic. All the doses administered switched the "off state to a motor response qualitatively similar to what is seen in the "on" phase induced by levodopa, including the occurence of dyskinesia. The latency to turn "on" after apomorphine ranged from 7 to 30 minutes and the duration of the response ranged from 60 to 85 minutes. We observed yawning in all four patients, labial paresthesia in one patient and an inespecific unpleasent sensation in another patient. These side effects were not significant in our four patients.Our data show that the use of apomorphine adds a reliable and effective strategy in the management of MF of PD patients.

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Modification of Tardive Dyskinesia and Spasmodic Torticollis by Apomorphine

Tolosa¹

1978

Arch Neurol

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Treatment of Parkinson's Disease with Aporphines

Cited by 170 publications

References 24 publications

Opposing effects of dopaminergic to cholinergic compounds on a cerebral dopamine-activated adenylate cyclase.

Opposing effects of dopaminergic to cholinergic compounds on a cerebral dopamine-activated adenylate cyclase.

Apomorfina: uma alternativa no controle das flutuações motoras na doença de Parkinson

Modification of Tardive Dyskinesia and Spasmodic Torticollis by Apomorphine

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