Experimental study on phototoxicity and the photosensitization potential of ketoprofen, suprofen, tiaprofenic acid and benzophenone and the photocross-reactivity in guinea pigs.

BACKGROUND: Ketoprofen, suprofen and tiaprofenic acid are arylpropionic anti-inflammatories. Their chemical structures share the same elements as the benzoyl radical and the tiophene ring. We experienced nine cases of ketoprofen photoallergy, seven cases of suprofen photoallergy and three cases of tiaprofenic photoallergy. PURPOSE: To find the key structure of photosensitivity and photocross-reactivity to ketoprofen, suprofen and tiaprofenic acid. METHODS: : Three animals were tested for phototoxicity and six animals for the photosensitization potentials of ketoprofen, suprofen, tiaprofenic acid and benzophenone, and the photocross-reactivity of the above chemicals. Test substances were applied symmetrically on both sides of the animals' backs. The animals were irradiated with 180 mJ/cm2 UVB ((1/2) MED) and 10 J/cm2 UVA on the left side. The reactions were read on days 2, 3 and 4. The photosensitization potentials of ketoprofen, suprofen, tiaprofenic acid and benzophenone were determined using the Adjuvant-Strip method. Six animals were assigned to each test group and to a control group. RESULTS: Ketoprofen, suprofen, tiaprofenic acid and propionic acid showed negative reactions with the phototoxic test. Benzophenone showed phototoxic reactions to 40% acetone (ac.), 20% ac. and 10% ac. Therefore, we used 5% aq. benzophenone with the photosensitization test. Ketoprofen was the strongest photosensitizer (6/6) and showed photocross-reactivities to suprofen (2/6), tiaprofenic acid (3/6) and benzophenone (6/6). Suprofen was a strong photosensitizer (4/6) and showed photocross-reactivities to ketoprofen (1/4) and tiaprofenic acid (2/4), but not to benzophenone. Tiaprofenic acid was also a photosensitizer (2/6) but showed a photocross-reactivity only to benzophenone (2/2). Benzophenone was also the strongest photosensitizer (6/6), but did not photocross-react to the above three chemicals. CONCLUSION: From the test results, it appears that benzoyl radical is the key structure for photosensitivity and the photocross-reactivity of ketoprofen, suprofen and tiaprofenic acid. The whole structure of benzophenone was needed to induce photosensitization of benzophenone. The animals that were photosensitized from the entire structure of benzophenone did not photocross-react to ketoprofen, suprofen or tiaprofenic acid.

Antibodies directed to drug epitopes to investigate the structure of drug-protein photoadducts. Recognition of a common photobound substructure in tiaprofenic acid/ketoprofen cross-photoreactivity.

Drug-induced photoallergy is an immune adverse reaction to the combined effect of drugs and light. From the mechanistic point of view, it first involves covalent binding of drug to protein resulting in the formation of a photoantigen. Hence, determination of the structures of drug-protein photoadducts is of great relevance to understand the molecular basis of photoallergy and cross-immunoreactivity among drugs. Looking for new strategies to investigate the covalent photobinding of drugs to proteins, we generated highly specific antibodies to drug chemical substructures. The availability of such antibodies has allowed us to discriminate between the different modes by which tiaprofenic acid (TPA), suprofen (SUP), and ketoprofen (KTP) photobind to proteins. The finding that the vast majority of the TPA photoadduct can be accounted for by means of antibody anti-benzoyl strongly supports the view that the drug binds preferentially via the thiophene ring, leaving the benzene ring more accessible. By contrast, selective recognition of SUP-protein photoadducts by antibody anti-thenoyl evidences a preferential coupling via the benzene ring leaving the thiophene moiety more distant from the protein matrix. In the case of KTP, photoadducts are exclusively recognized by antibody anti-benzoyl, indicating that the benzene ring is again more accessible. As a result of this research, we have been able to identify a common substructure that is present in TPA-albumin and KTP-albumin photoadducts. This is remarkable since, at a first sight, the greatest structural similarities can be found between TPA and SUP as they share the same benzoylthiophene chromophore. These findings can explain the previously reported observations of cross-reactivity to KTP (or TPA) in patients photosensitized to TPA (or KTP).

Photocontact allergy due to suprofen.

A 79-year-old Japanese woman developed edematous erythema on sun-exposed areas 3 months after applying Sulprotin ointment, which contains 1% suprofen (SP), a phenylacetic acid derivative. A patch test with Sulprotin ointment as it was negative, but a photopatch test with Sulprotein ointment as is was positive. A photopatch test with 10-3% SP was positive, as was that obtained with an SP analogue, 3% ketoprofen, but that with the ointment base of Sulprotin was negative. Photopatch tests with other SP analogues such as flurbiprofen, ibuprofen, and pranoprofen were negative. She developed abnormal erythema with monochromatic irradiation in the range from 320 to 380 nm on the uninvolved abdominal skin where 1% SP had been applied 24 hours (h) before irradiation. The action spectrum for this erythema agreed with the absorption spectrum of SP in the range of UVA. The MED after applying SP was below that after applying w. pet. in the range from 250 to 290 nm and from 300 to 320 nm. Positive intracutaneous test results were obtained with an irradiated mixture of human serum albumin (HSA) and SP at 48 and 72 h after injection and negative ones with a mixture of HSA and irradiated SP.

Allergic photocontact dermatitis due to suprofen. Photopatch testing and cross-reaction study.

We report 5 cases of photocontact dermatitis due to suprofen, a nonsteroidal anti-inflammatory drug introduced to the Japanese market in 1989, and available as a 1% ointment. The patients developed pruritic eczematous lesions after applying the ointment for from 2 weeks to 3 months. All 5 patients reacted positively to photopatch testing with ultraviolet A (UVA) and suprofen down to 0.1-0.01% pet., and 3 patients showed positive reactions with ultraviolet B (UVB) and suprofen down to 1.0-0.1%. Moreover, all patients showed a cross-reaction with tiaprofenic acid, which has a very similar chemical structure to suprofen. However, there was no cross-reaction between suprofen and ketoprofen. Prescribers should be aware of the existence of photocontact sensitivity due to these drugs.

The epidemiology of the acute flank pain syndrome from suprofen.

Suprofen, a new nonsteroidal anti-inflammatory drug, was marketed in early 1986 as an analgesic agent. Until physicians began reporting an unusual acute flank pain syndrome to the spontaneous reporting system, 700,000 persons used the drug in the United States. Through August 1986, a total of 163 cases of this syndrome were reported. To elucidate the epidemiology of the syndrome, a case-control study was performed, comparing 62 of the case patients who had been reported to the spontaneous reporting system to 185 suprofen-exposed control subjects who did not have the syndrome. Case patients were more likely to be men (odds ratio, 3.8; 95% confidence interval, 1.2-12.1), suffer from hay fever and asthma (odds ratio, 3.4; 95% confidence interval, 1.0-11.9); to participate in regular exercise (odds ratio, 5.9; 95% confidence interval, 1.1-30.7), especially in the use of Nautilus equipment (p = 0.02); and to use alcohol (odds ratio, 4.4; 95% confidence interval, 1.1-17.5). Possible risk factors included young age, concurrent use of other analgesic agents (especially ibuprofen), preexisting renal disease, a history of kidney stones, a history of gout, a recent increase in activity, a recent increase in sun exposure, and residence in the Sunbelt. These were findings that were suggestive but did not reach conventional statistical significance. These findings are consistent with the postulated mechanism for this unusual syndrome: acute diffuse crystallization of uric acid in renal tubules.

Immune hemolytic anemia associated with tolmetin and suprofen.

This article reports the first case of immune hemolytic anemia possibly associated with the ingestion of suprofen. The patient suffered from massive hemoglobinuria and acute renal failure. Serologic studies of the patient's serum revealed suprofen-dependent red cell antibodies. However, tolmetin-dependent antibodies were also found in the serum, showing the same properties as the suprofen antibodies and an even higher titer. The patient not only had drug-dependent antibodies in the serum, but also had developed autoantibodies, a phenomenon that has been described for several other drugs. The working mechanism by which suprofen and tolmetin caused immune hemolysis had properties of both the immune complex model and the induction of autoimmunity. Although it was unclear whether the immune hemolytic anemia was the result of suprofen, tolmetin, or cross-reacting antibodies, we feel that suprofen should be added to the list of nonsteroidal anti-inflammatory drugs associated with a positive direct antiglobulin test.

Suprofen treatment of contact lens-associated giant papillary conjunctivitis.

This multicenter study of patients with contact lens-associated giant papillary conjunctivitis (GPC) was a randomized, double-masked comparison of a 1.0% suprofen solution versus the suprofen vehicle solution (placebo). Patients were given two drops of medication four times daily for up to 28 days and were clinically examined on days 0, 2, 7, 14, 21, and 28. The physicians' clinical judgments of the patients' responses to therapy significantly favored suprofen over placebo at day 21 (P = 0.02), while strongly favoring suprofen at day 14 (P = 0.057) and at day 28 (P = 0.067). The patients' opinions of their response to therapy significantly favored suprofen on day 14 (P = 0.03); a trend for suprofen was evident on day 28 (P = 0.1). Treatment with suprofen led to a greater overall reduction in ocular signs and symptoms than with placebo. Strong trends approaching statistically significant levels were found for reductions in the principal ocular sign, papillae, at day 28 (P = 0.068) and in mucus strands at days 14 and 28 (P = 0.09), which also favored suprofen.

The importance of adverse reaction reporting by physicians. Suprofen and the flank pain syndrome.

The role of spontaneous reporting in detecting the suprofen-associated flank pain syndrome was examined, including the specific effect of the "Dear Doctor" letter in accelerating the information-gathering process once the initial signal was generated. We believe this to be a noteworthy example of the ability of spontaneous reporting to produce a timely and unequivocal signal of drug-related risk. It also serves to demonstrate the need for vigilant postmarketing surveillance for all newly marketed drugs in the United States, even though considerable premarketing and postmarketing drug experience may exist from use in countries outside of the United States.

Renal effects of nonsteroidal anti-inflammatory drugs.

All nonsteroidal anti-inflammatory drugs (NSAIDs) inhibit cyclooxygenase, and consequently renal functions dependent upon prostaglandin synthesis can be affected. Fortunately, renal function in normal individuals is relatively independent of the PG system, and thus the NSAIDs don't usually produce any renal dysfunction. However, in some circumstances, inhibition of PG dependent renal functions can produce clinically significant effects. When the kidney is in a salt retaining state or when there is renal vascular damage, NSAIDs can reduce renal blood flow and glomerular filtration rate producing acute renal failure that is reversible upon discontinuation of the drug. NSAIDs can also: 1) reduce sodium excretion and blunt the diuretic effect of loop diuretics, thus producing or exacerbating edema, 2) inhibit PG dependent renin secretion occasionally resulting in hyperkalemia, 3) enhance the antidiuretic effects of vasopressin and 4) reduce the antihypertensive efficacy of several drugs. Evidence that any NSAID "spares" renal cyclooxygenase is controversial, and no NSAID is devoid of clinical problems. Syndromes that are less obviously related to inhibition of renal PG synthesis are acute interstitial nephritis with or without the nephrotic syndrome, renal papillary necrosis, and chronic interstitial nephritis. Recently a unique syndrome of flank pain and mild reversible renal dysfunction has been described in healthy individuals receiving suprofen, a uricosuric NSAID. This syndrome may be due to uric acid crystal deposition in the renal tubules and has resulted in the removal of suprofen from the US market.

Suprofen-related nephrotoxicity. A distinct clinical syndrome.

We describe a unique clinical syndrome of flank pain and acute renal failure that is associated with suprofen, a nonsteroidal anti-inflammatory drug that has recently been made available in the United States. In the initial 6 months of the drug's distribution in this country, at least 16 patients developed this syndrome. All 16 had acute flank pain and 13 developed mild reversible renal failure within 12 hours of ingestion of one to three suprofen capsules. This syndrome is unlike other nephrotoxic syndromes related to nonsteroidal anti-inflammatory drugs. The mechanism is not known.

Effects of suprofen on renal function in patients with rheumatoid arthritis.

Suprofen is a new potent analgesic with antiinflammatory properties that appears to inhibit prostaglandin synthetase in a tissue-selective manner, having relatively little effect on the kidneys of experimental animals. The effects were studied of one week of treatment of rheumatoid arthritis patients with suprofen or ibuprofen on Na+ and K+ excretion, creatinine clearance, urinary enzymes that are markers for tubular damage, and urinary prostaglandins such as PGE2 and 6-keto PGF1 alpha (a stable metabolite of prostacyclin). Neither compound caused changes in renal function related to the week of treatment, but significant decreases in prostaglandins were observed: this change was fully reversible after discontinuation of the drug.

Suprofen-induced acute renal failure.

A case report of acute flank pain with reversible renal failure in a young adult after taking three doses of suprofen is presented. Blood urea nitrogen and serum creatinine values returned to normal from significantly elevated levels on admission.