Antihypertensive effects of a new transdermal delivery system for clonidine (M-5041T) in spontaneously hypertensive rats.
The antihypertensive effects of a new transdermal delivery system for clonidine (clonidine tape; M-5041T) were investigated in spontaneously hypertensive rats and normotensive Wistar-Kyoto rats. In spontaneously hypertensive rats, M-5041T, at doses of 0.5-4.5 mg/kg (1.25-11.25 cm2/kg), produced a dose-dependent decrease of both systolic blood pressure and heart rate for 24 hr during transdermal application. These significant hypotensive effects lasted for 24 hr following the patching of M-5041T on the back of the animals at a dose of 4.5 mg/kg. In normotensive Wistar-Kyoto rats, the hypotensive and bradycardic effects of M-5041T were weak compared with those in spontaneously hypertensive rats. In both rat strains, M-5041T (4.5 mg/kg) caused behavioral changes such as sedation, piloerection and exophthalmos, accompanied by hypotensive effects. Both M-5041T (1.5 mg/kg) and clonidine (50 micrograms/kg, subcutaneously and 100 micrograms/kg, orally) induced similar hypotensive effects, accompanied by sedation. The hypotensive effects following transdermal M-5041T or systemic clonidine administrations were correlated with the time courses of the plasma clonidine concentration. In contrast to clonidine administered subcutaneously or orally, M-5041T produced a gradual increase in the plasma clonidine concentration, which persisted at a consistent level for at least 12 hr thereafter. Significant hypotensive effects lasted for 12 and 24 hr following M-5041T patching at 1.5 and 4.5 mg/kg, respectively. The present findings suggest that M-5041T can serve as an efficient and useful antihypertensive transdermal delivery system to achieve persistent blood pressure control.
Ishii
R
R
Central Research Laboratories, Maruho Co., Ltd., Osaka, Japan.
Naruse
T
T
Tagawa
T
T
Yamahata
T
T
Dote
S
S
Hamada
K
K
Ishida
T
T
Funabiki
K
K
Namba
K
K
D000279:Administration, Cutaneous; D000284:Administration, Oral; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D001794:Blood Pressure / Q000187:drug effects*; D001919:Bradycardia / Q000139:chemically induced; D003000:Clonidine / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use*; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D016503:Drug Delivery Systems; D008401:Gas Chromatography-Mass Spectrometry; D006207:Half-Life; D006339:Heart Rate / Q000187:drug effects*; D006973:Hypertension / Q000188:drug therapy*; D007279:Injections, Subcutaneous; D008297:Male; D051381:Rats; D011918:Rats, Inbred SHR; D011921:Rats, Inbred WKY
D003000:Clonidine