The relationship between development of ultraviolet erythema and release of prostaglandins in guinea pig skin.

Ultraviolet erythema in the guinea pid has been in use for many years as a model for assessing the anti-inflammatory potency of non-steroidal anti-inflammatory agents, the degree of erythema usually being estimated about 2 h after u.v. exposure. Using a suction blister technique for obtaining tissue fluid from erythemic and normal skin of the guinea pig we have shown that prostaglandin output in ultraviolet-irradiated skin increases rapidly during the first 2 h after irradiation, at which time the erythema reaches near-maximal development. Flurbiprofen, a potent non-steroidal anti-inflammatory agent, almost totally prevents the appearance of prostaglandins in the blister fluid and significantly reduces the degree of erythema in the skin during this early period. However, in flurbiprofen-treated animals, although prostaglandin synthesis is also suppressed at 4 to 5 h after exposure and is still partially suppressed at 17 h, a well developed erythema nevertheless appears by 4 h. This indicates the appearance of one or more non-prostaglandin mediators in the later stages of the reaction.

Ocular accumulation and toxicity of certain systemically administered drugs.

Certain polycyclic compounds with a coplanar ring structure (phenothiazines, thioxanthenes, 4-aminoquinolines, and amitriptyline), monocyclic sympathomimetic amines, and other drugs become concentrated in the eyes of animals following acute or chronic systemic administration. Some are known to cross the placental barrier and accumulate in the fetal eye. Following drug withdrawal, these substances disappear relatively slowly from ocular tissues compared with other tissues. The main reason for the accumulation of these compounds seem to be their affinity for the melanin of the uveal tract and pigment epithelium and they therefore do not accumulate in the eyes of albino animals. The mechanism of uptake by melanin probably involves a "charge transfer" reaction involving the transfer of an electron from drug to melanin, which acts as an "electron trap" and in consequence binds the donor compound firmly. The accumulation of a nontoxic drug in the eye is not necessarily of clinical significance, but ocular damage can occur in patients on long-term tricyclic agents when the amount, duration, and frequency of dosage are sufficiently high. The most serious form of ocular damage is pigmentary retinopathy, which, if caused by chloroquine, is irreversible. In contrast, phenothiazine retinopathy is reversible. Lesions may also be produced in anterior structures of the eye, usually the cornea and lens, by both chloroquine and the phenothiazines, but they are of a relatively minor nature. Possible mechanisms for the oculotoxicity of the phenothiazines and antimalarials are discussed, particularly in relation to melanin.