We investigated the natural history of cholelithiasis in 59 samples of stones from the gallbladder or common bile duct in 15 patients, using as a tracer for the timing of stone formation the 14C released into the environment during nuclear weapons testing. The ages of the stones were correlated with the dates of onset of symptoms and with other clinical data. None of 11 symptomatic patients had symptoms or complications until at least two years (mean +/- SD, 8.0 +/- 5.1 years) after stone formation began. There was a lag time of 11.7 +/- 4.6 years between initial stone formation and cholecystectomy. The growth rates of stones from 11 symptomatic patients and 4 asymptomatic patients were similar (2.6 +/- 1.4 and 2.6 +/- 1.1 mm per year). Studies of two stones retrieved from the common bile duct showed that one had the same age as a cholecystic stone; the other, removed two years after cholecystectomy, apparently grew in the common bile duct. The long latency period between the formation of gallstones and the onset of symptoms indicates that interruption of the natural progression of gallstone disease is potentially possible with medical therapy.

Alpha-terthienyl (alpha-T), a phototoxic thiophene compound isolated from marigolds (Tagetes species), affects cell membranes and does not appear to induce cytogenetic damage. This study was undertaken to investigate topical delivery of alpha-T and characterize its cutaneous phototoxicity in combination with long-wave UV radiation (UVA) in comparison with locally (intradermal) administered alpha-T. Percutaneous penetration (PC) of 0.1% and 1% alpha-T in a 3% Azone gel vehicle was studied in guinea pig skin in vitro and quantitated by UV fluorescence microscopy. Dose-dependent PC of epidermis, adnexae, and superficial dermis was demonstrated in vitro. Alpha-terthienyl (0.1% and 1%) in this vehicle was applied topically in vivo and irradiated with 30 J/cm2 UVA at intervals of 10 min-24 h. Maximum sensitization was achieved with irradiation 1 h following drug application. The clinical response was dose-dependent consisting of erythema, edema, crusting, erosion, and inhibition of hair growth and was observed 72 h to 7 days postirradiation. A comparable dose-dependent phototoxic response was observed when 5-500 micrograms alpha-T were injected intradermally and irradiated with UVA. These results indicated that low-dose topical alpha-T in a nonirritating vehicle can rapidly produce cutaneous photosensitization. Topical alpha-T/UVA may provide a selective and safer alternative approach for the photochemotherapy of psoriasis and other cutaneous diseases.