Discovery of 13-oxa prostaglandin analogs as antiglaucoma agents: synthesis and biological activity.

FP-Class prostaglandin analogs have demonstrated utility for the treatment of glaucoma and ocular hypertension. A series of novel FP prostaglandin analogs was designed to optimize topical ocular activity and reduce ocular side-effects by replacing 13-carbon with oxygen. A facile synthesis was successfully developed for synthesis of the 13-oxa prostaglandins from the commercially available Corey aldehyde benzoate. Among the compounds synthesized, AL-16082 was the most potent prostaglandin FP agonist in vitro. In a prostaglandin FP receptor-linked second-messenger assay, phosphoinositide (PI) turnover, it exhibited a potency value (EC(50)) of 1.9 nM (78% max. response relative to fluprostenol). The isopropyl ester of AL-16082, compound AL-16049, significantly lowered intraocular pressure (IOP) in the ocular hypertensive monkey eyes by 30%. In the study of acute ocular irritation response in New Zealand albino rabbits, AL-16049 produced lower incidence of hyperemia, swelling, and discharge than PGF(2alpha) (1 microg), and a similar incidence of hyperemia, swelling, and discharge to latanoprost (1.8 microg). AL-16049 also produced no signs of ocular irritation or discomfort in the cat at the doses evaluated.

Tin in canned food: a review and understanding of occurrence and effect.

Tinplate is light gauge, steel sheet or strip, coated on both sides with commercially pure tin and has been used for well over a hundred years as a robust form of food packaging. Altogether, about 25,000 million food cans are produced and filled in Europe per annum, about 20% of these having plain internal (unlacquered) tin-coated steel bodies. Worldwide, the total for food packaging is approximately 80,000 million cans. Tinplate is also extensively used for the production of beverage cans. Europe produces and fills over 15,000 million tinplate beverage cans per annum all of which are internally lacquered. The use of tinplate for food and beverage packaging, will result in some tin dissolving into the food content, particularly when plain uncoated internal surfaces are used. The Provisional Tolerable Weekly Intake for tin is 14 mg/kg body weight and recommended maximum permissible levels of tin in food are typically 250 mg/kg (200 mg/kg UK) for solid foods and 150 mg/kg for beverages. However, the question arises as to whether evidence exists that such elevated levels of tin in food in any way constitute a risk to human health. This review considers the factors affecting the dissolution of tin, the reported measurements/surveys of actual levels of tin in canned foods and the studies and reports of acute (short term) toxicity relating to the ingestion of elevated levels of tin in food products. Chronic studies are mentioned, but are not covered in detail, since the review is mainly concerned with possible effects from the ingestion of single high doses. From published data, there appears to be a small amount of evidence suggesting that consumption of food or beverages containing tin at concentrations at or below 200 ppm has caused adverse gastrointestinal effects in an unknown but possibly small proportion of those exposed. However, the evidence supporting this assertion is derived from reports of adverse effects which offer data that are limited, incomplete or of uncertain veracity. Clinical studies provide greater confidence regarding the effects of exposure concentration and dose, but few relevant studies have been made. Adverse gastrointestinal effects were observed in limited clinical studies at concentrations of 700 ppm or above, although no adverse gastrointestinal effects were also reported in two studies at higher concentrations. Overall, therefore, the published data do not present a particularly comprehensive profile on the toxic hazard to man of acute exposure to divalent inorganic tin. A food survey suggested that the contents of almost 4% of plain internal tinplate food cans contain over 150 mg/kg of tin and over 2.5 million such cans are consumed every year in the UK alone. Despite this, in the last 25 years, there have been no reports of acute effects attributable to tin contamination in the range 100-200 ppm. These facts strongly suggest that there is little evidence for an association between the consumption of food containing tin at concentrations up to 200 ppm and significant acute adverse gastrointestinal effects. Clearly though, only further clinical studies will generate unequivocal evidence that current legislative limits provide safe levels for adults in the general population.