COMBINATION OF ROPINIROLE AND L-DOPA FOR USE IN THE TREATMENT OF PARKINSON'S DISEASE

Abstract: Novel combinations of ropinirole and L-DOPA for the treatment of Parkinson's Disease. The treatment is usually applied at an early stage of the disease and the L-DOPA is used at a low-dose in comparison to that which would be used at a corresponding stage of the disease, if L-DOPA was being used as monotherapy.

Description: COMBINATION OF ROPINIROLE AND L-DOPA FOR USE IN THE TREATMENT OF PARKIN¬ SON'S DISEASE This invention relates to a method of treatment of early stage Parkinson's Disease patients, in particular the use of a combination of ropinirole and L-DOPA. L-DOPA was first introduced over 25 years ago for the treatment of Parkinson's Disease and has since become the 'gold standard' for symptomatic therapy. Nevertheless, L- DOPA has disadvantages, primarily in terms of its long term motor complications. After several years treatment, patients experience a wearing off effect of L-DOPA at the end of dosing periods; these simple fluctuations may then develop into more complex on-off phenomenon where the patient may oscillate, sometimes rapidly and inconsistently, between being "on" (i.e. relatively free of Parkinsonian symptoms), and "off, or "frozen". Additionally, long term L-DOPA therapy is associated with the emergence of dyskinesias which may be as disabling as the disease itself, and often limit the L-DOPA dose. In an attempt to reduce these adverse effects of L-DOPA, dopamine agonists such as bromocriptine, pergolide and lisuride have traditionally been used as adjunct therapy. These drugs have longer half-lives than L-DOPA and so are able to prolong its dopaπrinergic effects and smooth out the wearing-off of doses. When used as adjunct therapy, dopamine agonists have been shown to improve the anti- Parkinsonian efficacy of L-DOPA. In addition, dopamine agonists have been used as monotherapy, to treat the early stages of the disease. There generally however comes a point in the treatment regimen when the addition of L-DOPA (so-called L-DOPA rescue) becomes necessary. Even so, the onset of L-DOPA associated complications is delayed in comparison with patients who are treated with L- DOPA from the outset. This earlier generation of dopamine agonists are ergoline derivatives and are non-specific dopamine agonists Ropinirole (4-(2-di-n-propylaminoethyl)-2(3H)-indolone) is the compound of formula (I): (I) This compound was first disclosed in EP 0 113 964-A1 (SmithKline Beckman Corp) as a peripheral, pre-synaptic D2-agonist, suitable for use in treating angina and hypertension. Subsequently, it was also shown to have central effects, as a post-synaptic D2-agonist in the brain (EP 0 299 602-A2, Smith Kline & French Laboratories). Furthermore, tolerance was developed to the peripheral effects. These central effects have led to the compound (as the hydrochloride salt) being developed for use in treating Parkinson's Disease. The different chemical class and receptor profile may lead to a different therapeutic and safety profile, in comparison with currently available dopamine agonists. A six month, multicentre, double blind, placebo controlled study on the efficacy and safety of ropinirole in patients with Parkinson's Disease who had not been previously treated with any anti-Parkinson therapy showed that the ropinirole- treated patients had a statistically significant difference in improved motor function over placebo-treated patients. In a second study, a six month planned interim analysis of a five year, double blind, L-DOPA controlled study showed that ropinirole was effective in early Parkinson's Disease, successfully maintained patients for six months and delayed the introduction of L-DOPA for that time period . There still remains the need however for developing further treatment regimens for Parkinson's Disease, which are more effective, especially in the early stages of the disease. Accordingly, the present invention provides a method of treatment for Parkinson's Disease which method comprises co-administering an effective amount of a combination of ropinirole and L-DOPA to a patient suffering from Parkinson's Disease. It will be appreciated that this method of treatment does not encompass the following therapies: 'rescue' therapy when L-DOPA may be used in addition to ropinirole, after an initial phase of ropinirole monotherapy; 'dopamine sparing' therapy when ropinirole may be used in addition to relatively high levels of L-DOPA, to reduce the amount of L-DOPA that is needed, so as to alleviate side effects associated with high levels/longer term usage of L-DOPA; and 'adjunct' therapy, when ropinirole may to administered to Parkinsonian patients not optimally controlled on L-DOPA alone. The present invention further provides:- a) ropinirole for use in the treatment of Parkinson's Disease in combination with L-DOPA in which L-DOPA is used at a low dose, in comparison to that which would be used at a corresponding stage of the disease, if L-DOPA was being used as monotherapy; b) use of ropinirole in the manufacture of a medicament for use in the treatment of Parkinson's Disease in combination with L-DOPA in which L-DOPA is used at a low dose, in comparison to that which would be used at a corresponding stage of the disease, if L-DOPA was being used as monotherapy;. c) L-DOPA for use in the treatment of Parkinson's Disease in combination with ropinirole in which L-DOPA is used at a low dose, in comparison to that which would be used at a corresponding stage of the disease, if L-DOPA was being used as monotherapy; d) use of L-DOPA in the manufacture of a medicament for use in the treatment of Parkinson's Disease in combination with ropinirole in which L-DOPA is used at a low dose, in comparison to that which would be used at a corresponding stage of the disease, if L-DOPA was being used as monotherapy.;. e) a therapeutic combination of ropinirole and L-DOPA for use in the treatment of Parkinson's Disease in which L-DOPA is used at a low dose, in comparison to that which would be used at a corresponding stage of the disease, if L-DOPA was being used as monotherapy. Suitably, treatment in accordance with the invention is used at an early stage of the development of Parkinson's Disease in a patient. Given the desirability of titrating either L-DOPA or ropinirole when taken separately, it is desirable to begin treatment in accordance with the invention using either ropinirole or L-DOPA alone, at a relatively low dosage. Suitably, a patient is initially titrated to an appropriate dosage of ropinirole, followed by the addtion of a low dosage of L-DOPA. The dosages of each may then be titrated according to an individual patients response, until an optimal therapeutic regimen is established. Suitably, L-DOPA is used at a low-dose, in comparison to that which would be used at a corresponding stage of the disease, if L-DOPA was being used as monotherapy. Suitable low dosages are in the range 25 to 200mg/day, preferably 25 to 150, more preferably 50 to lOOmg/day. In a suitable treatment regimen, the patient will be started on ropinirole at a low dosage, for instance 0.25mg tid and then titrated up towards 1.5mg tid, for instance over a three to six week period, in increments of 0.25mg, to allow for tolerance to develop to peripheral side effects such as vomitting and nausea. L-DOPA is then added in, at a dosage of 50mg tid, and after a suitable period, for instance two weeks, to allow for stabilisation and to check against any unforeseen drug interactions, the dosage of ropinirole is again increased, for instance to 2mg tid. The dosage of ropinirole may be increased further, for instance up to 8 mg tid, until no further beneficial therapeutic effect is seen, when the dosage of L-DOPA may be increased. It will however be appreciated that the response of individual patients varies and some may tolerate a more rapid rate of increase of dosage. The optimum daily dosage of ropinirole and L-DOPA must be determined by careful titration for each patient. An appropriate regimen will be at the discretion of the physician. In contrast, in conventional monotherapy, L-DOPA is used at an initial dosage of for instance 250mg/day and this is then titrated up towards a normal dosage range of from 2 to 8g/day. L-DOPA may be used alone or in combination with a peripheral decarboxylase inhibitor such as carbidopa ( for instance Sinemet (Du Pont) or benserazide (for instance, Madopar, Roche). A more rapid response at the initiation of therapy may be seen. Suitably, the separate dosages of L-DOPA and ropinirole will be taken by the patient at more or less the same time, and preferably three times a day. L-DOPA may be used in any of the pharmaceutical formulations in which it is normally provided, for instance tablets. Each dosage may be made up of a single tablet or a combination of different tablets which may be of the same or different strengths. Ropinirole may be used in any of the pharmaceutical formulations in which it is normally provided, for instance tablets. Each dosage may be made up of a single tablet or a combination of different tablets which may be of the same or different strengths. Ropinirole is preferably provided as the hydrochloride salt. In a further aspect, the present invention provides a kit comprising a first pharmaceutical formulation comprisng L-DOPA and a second pharmaceutical formulation comprising ropinirole.

Claims: Claims 1. A method of treatment for Parkinson's Disease which method comprises co- administering an effective amount of a combination of ropinirole and L-DOPA to a patient suffering from Parkinson's Disease. 2. A method as claimed in claim 1 in which the Parkinson's Disease is at an early stage. 3. A method as claimed in claim 1 or 2 in which a patient is initially titrated to an appropriate dosage of ropinirole, followed by the addition of L-DOPA 4. A method as claimed in any one of claims 1 to 3 in which L-DOPA is used at a low- dose, in comparison to that which would be used at a corresponding stage of the disease, if L-DOPA was being used as monotherapy. 5. A method as claimed in claim 4 in which L-DOPA is used in dosage of 25 to 150 mg per day. 6. A method as claimed in claim 5 in which L-DOPA is used in dosage of 50 to 100 mg per day. 7. Ropinirole for use in the treatment of Parkinson's Disease in combination with L- DOPA in which L-DOPA is used at a low dose, in comparison to that which would be used at a corresponding stage of the disease, if L-DOPA was being used as monotherapy. 8. Use of ropinirole in the manufacture of a medicament for use in the treatment of Parkinson's Disease in combination with L-DOPA in which L-DOPA is used at a low dose, in comparison to that which would be used at a corresponding stage of the disease, if L-DOPA was being used as monotherapy. 9. L-DOPA for use in the treatment of Parkinson's Disease in combination with ropinirole in which L-DOPA is used at a low dose, in comparison to that which would be used at a corresponding stage of the disease, if L-DOPA was being used as monotherapy. 10. Use of L-DOPA in the manufacture of a medicament for use in the treatment of Parkinson's Disease in combination with ropinirole in which L-DOPA is used at a low dose, in comparison to that which would be used at a corresponding stage of the disease, if L-DOPA was being used as monotherapy. 11 A therapeutic combination of ropinirole and L-DOPA for use in the treatment of Parkinson's Disease in which L-DOPA is used at a low dose, in comparison to that which would be used at a corresponding stage of the disease, if L-DOPA was being used as monotherapy.

Inventors: FUELL DIANE, FUELL, DIANE
Applicants: FUELL DIANE, SMITHKLINE BEECHAM PLC, FUELL, DIANE
Application year: 1997
Main classification: A61K31
IPC codes: A61K31