Continuous dopaminergic stimulation by pramipexole is effective to treat early morning akinesia in animal models of Parkinson's disease: A pharmacokinetic-pharmacodynamic study using in vivo microdialysis in rats.
Short-acting dopamine (DA) agonists are usually administered several times a day resulting in fluctuating plasma and brain levels. DA agonists providing continuous dopaminergic stimulation may achieve higher therapeutic benefit for example by alleviating nocturnal disturbances as well as early morning akinesia. In the present study continuous release (CR) of pramipexole (PPX) was maintained by subcutaneous implantation of Alzet minipumps, whereas subcutaneous PPX injections were used to mimic PPX immediate release (IR) in male Wistar rats. In the catalepsy bar test, PPX-CR (1 mg/kg/day) reversed the haloperidol-induced motor impairment in the morning and over the whole observation period of 12h. In contrast, PPX-IR (tid 1 mg/kg, pre-treatment the day before) was not effective in the morning but catalepsy was reduced for 6 h after PPX-IR (1 mg/kg) injection. In the reserpine model, early morning akinesia indicated by the first motor activity measurement in the morning was significantly reversed by PPX-CR (2 mg/kg/day). Again, PPX-IR (tid 0.3 mg/kg, pre-treatment the day before) was not able to antagonise early morning akinesia. These results are in agreement with in vivo microdialysis measurements showing a continuous decrease of extracellular DA levels and a continuous PPX exposure in the PPX-CR (1 mg/kg/day) group. In contrast, PPX-IR (0.3 mg/kg) produced a transient decrease of extracellular DA levels over 6 h and showed maximum PPX levels 2 h after dosing which decreased over the following 6-8 h. The present study demonstrates that PPX-CR may offer a higher therapeutic benefit than PPX-IR on early morning akinesia and confirms earlier reports that PPX-IR reverses motor impairment for several hours.
Ferger
Boris
B
CNS Diseases Research, Boehringer Ingelheim Pharma GmbH & Co. KG, Birkendorfer Strasse 65, 88397 Biberach, Germany. boris.ferger@boehringer-ingelheim.com
Buck
Kerstin
K
Shimasaki
Makoto
M
Koros
Eliza
E
Voehringer
Patrizia
P
Buerger
Erich
E
D000818:Animals; D052160:Benzothiazoles / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*; D002375:Catalepsy / Q000139:chemically induced / Q000188:drug therapy / Q000378:metabolism; D003692:Delayed-Action Preparations / Q000378:metabolism; D004195:Disease Models, Animal; D004298:Dopamine / Q000378:metabolism; D018491:Dopamine Agonists / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*; D004409:Dyskinesia, Drug-Induced / Q000188:drug therapy* / Q000378:metabolism; D005110:Extracellular Space / Q000187:drug effects / Q000378:metabolism; D006220:Haloperidol; D015918:Infusion Pumps, Implantable; D007279:Injections, Subcutaneous; D008297:Male; D010300:Parkinson Disease / Q000188:drug therapy / Q000378:metabolism; D020734:Parkinsonian Disorders / Q000188:drug therapy* / Q000378:metabolism; D017440:Photoperiod; D000077487:Pramipexole; D051381:Rats; D017208:Rats, Wistar; D012110:Reserpine; D013997:Time Factors
D052160:Benzothiazoles; D003692:Delayed-Action Preparations; D018491:Dopamine Agonists; D000077487:Pramipexole; D012110:Reserpine; D006220:Haloperidol; D004298:Dopamine