Regulating the cancer-inducing potential of non-steroidal anti-inflammatory drugs: some lessons from the 1970s and 1980s.

This article systematically examines government regulation of medicines in the U.K. and the U.S. with specific reference to carcinogenic risk assessment. By taking four non-steroidal anti-inflammatory drugs (NSAIDs) as case studies, it is argued that there have been inconsistencies between regulatory practice and the scientific standards supposed to have been upheld by drug regulatory agencies. Moreover, those inconsistencies are shown to form a trend over time which suggests an erosion and neglect of regulatory rigour during the 1980s. This takes the form of awarding the benefit of the many scientific doubts in carcinogenicity testing to manufacturers rather than to patients.

Photodynamic lipid peroxidation by the photosensitizing nonsteroidal antiinflammatory drugs suprofen and tiaprofenic acid.

The photochemistry of the photosensitizing nonsteroidal antiinflammatory drugs tiaprofenic acid and suprofen involves the intermediacy of short-lived species (i.e. radicals). The data obtained in the present work strongly suggest that such intermediates may be responsible for the phototoxicity of 2-arylpropionic acids by inducing photodynamic lipid peroxidation at drug concentrations likely to be reached in the skin. This has been investigated using linoleic acid as a model lipid and determining the amount of hydroperoxides by measuring the spectrophotometric absorption at 233 nm, associated with the formation of dienic hydroperoxides. The major photoproducts of tiaprofenic acid and suprofen are derivatives bearing an ethyl side chain. Photoproducts of this type, due to the lack of polar moieties, are highly lipophilic and likely to accumulate in the lipid bilayer of cell membranes. Taking into account their ability to induce photodynamic lipid peroxidation and their marked photostability, it is conceivable that such photoproducts can participate in many catalytic cycles, playing a significant role in the mechanism of photosensitization by tiaprofenic acid and suprofen.

Effects of suprofen on the isolated perfused rat kidney.

Although suprofen has been associated with the development of acute renal failure in greater than 100 subjects, the mechanism of damage remains unclear. The direct nephrotoxic effects of a single dose of 15 mg of suprofen were compared in the recirculating isolated rat kidney perfused with cell-free buffer with or without the addition of 5 mg/dL of uric acid. There were no significant differences in renal sodium excretion, oxygen consumption, or urinary flow rates in kidneys perfused with suprofen compared with the drug-free control groups. In contrast, a significant decline in glomerular filtration rate was found after the introduction of suprofen to the kidney perfused with uric acid; no changes were found with suprofen in the absence of uric acid. A significant decrease in the baseline excretion rate of uric acid was found in rats given suprofen, compared with drug-free controls. However, the fractional excretion of uric acid was unchanged between the groups over the experimental period. In summary, suprofen causes acute declines in renal function, most likely by directly altering the intrarenal distribution of uric acid.

Suprofen-induced uricosuria. A potential mechanism for acute nephropathy and flank pain.

Suprofen, a nonsteroidal anti-inflammatory drug, has been associated with the onset of acute flank pain, hematuria, and transient renal dysfunction after the ingestion of one or two doses, particularly in young males. Potential mechanisms of this nephropathy were evaluated in normal males following ingestion of suprofen (200 mg) on two occasions: the first with ad libitum fluid intake and the second during forced water diuresis. On the first study occasion, creatinine clearance, the fractional excretions of uric acid (FEUA) and sodium (FENa), the urinary concentration of undissociated uric acid, and the urinary excretions of prostaglandins and glomerular and tubular proteins were assessed. On the second occasion, inulin and PAH clearances and FEUA and FENa were determined. Within 90 min after suprofen administration, the FEUA increased from 8.8 +/- 2.6 to 35.5 +/- 9.6% (p less than 0.05). Urine became supersaturated for uric acid during ad libitum fluid intake. Glomerular filtration rate, renal plasma flow, and FENa decreased significantly, while prostaglandin and protein excretions did not change. The findings are consistent with acute uric acid nephropathy as a mechanism of suprofen-induced renal dysfunction.