Pharmacological properties : תכונות פרמקולוגיות

Pharmacodynamic Properties

5.1   Pharmacodynamic properties

'Sinemet CR' is a combination of carbidopa, an aromatic amino acid decarboxylase inhibitor, and levodopa, the metabolic precursor of dopamine, in a polymer-based controlled-release tablet formulation, for use in the treatment of Parkinson’s disease. 'Sinemet CR' is particularly useful to reduce ‘off’ time in patients treated previously with a conventional levodopa/decarboxylase inhibitor combination who have had dyskinesias and motor fluctuations.


Patients with Parkinson’s disease treated with preparations containing levodopa may develop motor fluctuations characterised by end-of-dose failure, peak dose dyskinesia, and akinesia. The advanced form of motor fluctuations (‘on-off’ phenomenon) is characterised by unpredictable swings from mobility to immobility. Although the causes of the motor fluctuations are not completely understood, it has been demonstrated that they can be attenuated by treatment regimens that produce steady plasma levels of levodopa.


Levodopa relieves the symptoms of Parkinson’s disease by being decarboxylated to dopamine in the brain. Carbidopa, which does not cross the blood-brain barrier, inhibits only the extracerebral decarboxylation of levodopa, making more levodopa available for transport to the brain and subsequent conversion to dopamine. This normally obviates the necessity for large doses of levodopa at frequent intervals. The lower dosage reduces or may help eliminate gastro-intestinal and cardiovascular side-effects, especially those which are attributed to dopamine being formed in extracerebral tissues.

'Sinemet CR' is designed to release the active ingredients over a four-six hour period. With this formulation there is less variation in plasma levodopa levels and the peak plasma level is 60% lower than with conventional 'Sinemet', as established in healthy volunteers.

In clinical trials, patients with motor fluctuations experienced reduced ‘off’-time with 'Sinemet CR' when compared with 'Sinemet'. The reduction of the ‘off’-time is rather small (about 10%) and the incidence of dyskinesias increases slightly after administration of 'Sinemet CR' compared to standard 'Sinemet'. Global ratings of improvement and activities of daily living in the ‘on’ and ‘off’ state, as assessed by both patient and physician, were better during therapy with 'Sinemet CR' than with 'Sinemet'. Patients considered 'Sinemet CR' to be more helpful for their clinical fluctuations, and preferred it over 'Sinemet'. In patients without motor fluctuations, 'Sinemet CR' under controlled conditions, provided the same therapeutic benefit with less frequent dosing than with 'Sinemet'. Generally, there was no further improvement of other symptoms of Parkinson’s disease.

Pharmacokinetic Properties

5.2   Pharmacokinetic properties

The pharmacokinetics of levodopa following administration of 'Sinemet CR' were studied in young and elderly healthy volunteers. The mean time to peak plasma levodopa level after 'Sinemet CR' was approximately two hours compared to 0.75 hours with 'Sinemet'. The mean peak plasma levodopa levels were 60% lower with 'Sinemet CR' than with 'Sinemet'.
The in vivo absorption of levodopa following administration of 'Sinemet CR' was continuous for 4 to 6 hours. In these studies, as with patients, plasma levodopa concentrations fluctuated in a narrower range than with 'Sinemet'. Because the bioavailability of levodopa from 'Sinemet CR' relative to 'Sinemet' is approximately 70%, the daily dosage of levodopa in the controlled release formulation will usually be higher than with conventional formulations.
There was no evidence that 'Sinemet CR' released its ingredients in a rapid or uncontrolled fashion.

It is not known whether or not or to what extent the absorption is influenced by a protein rich diet. The bioavailability may be influenced by drugs which affect the gastro-intestinal propulsion.