Relationship between the skin permeation movement of propranolol and skin inflammatory reactions.
We studied inflammatory reactions induced by dermal application of the beta-blocker propranolol (PRL) in ethanol to guinea pigs in order to elucidate the relation of the reactions with the cumulative PRL permeating amount through the stratum corneum or the PRL content in the stripped skin, and to investigate the chemical mediators responsible for the reactions. The cumulative PRL permeating amount through the stratum corneum increased rapidly up to 2 h after dermal application, then increased linearly with time up to 24 h after application. Visual observation revealed formation of erythema and edema at the applied site of PRL, and histopathological examination revealed infiltration of pseudoeosinophiles of dermis and epidermis and degeneration/necrosis of epidermis. In general, it was considered that the duration and the extent of these reactions were dependent on the PRL dosage and application time. It was expected that the cumulative PRL permeating amount through the stratum corneum could be used to predict possible inflammatory reactions during development of transdermal drug delivery systems. On the other hand, contact of PRL with guinea pig skin tissues released histamine, and intradermal injection of PRL caused an increase of capillary permeability at the site of application. Also, the inhibitory effects of anti-inflammatory agents (diphenhydramine, dexamethasone, indomethacin, cyproheptadine hydrochloride, CV3988 and AA-861) to PRL-induced erythema formation demonstrated that histamine and prostaglandins were responsible for the inflammatory reactions induced by PRL.
Toxicological Research Center, Nitto Denko Corporation, Ibaraki, Osaka, Japan.
I
I
Kobayashi
K
K
Hosaka
H
H
Maruo
Y
Y
Saeki
M
M
Kamiyama
C
C
Konno
M
M
Gemba
D000319:Adrenergic beta-Antagonists / Q000493:pharmacokinetics* / Q000633:toxicity*; D000818:Animals; D002199:Capillary Permeability / Q000187:drug effects / Q000502:physiology; D003875:Drug Eruptions / Q000209:etiology* / Q000378:metabolism*; D004890:Erythema / Q000139:chemically induced / Q000378:metabolism; D006168:Guinea Pigs; D006636:Histamine Release / Q000187:drug effects; D008297:Male; D011433:Propranolol / Q000493:pharmacokinetics* / Q000633:toxicity*; D012867:Skin / Q000187:drug effects / Q000378:metabolism; D012869:Skin Absorption / Q000187:drug effects / Q000502:physiology*
D000319:Adrenergic beta-Antagonists; D011433:Propranolol