Pharmacodynamics and pharmacokinetics of AM103, a novel inhibitor of 5-lipoxygenase-activating protein (FLAP).

The 5-lipoxygenase-activating protein (FLAP) gene and an increase in leukotriene (LT) production are linked to the risk of asthma, myocardial infarction, and stroke. We evaluated the pharmacodynamics, pharmacokinetics, and tolerability of 3-[3-tert-butylsulfanyl-1-[4-(6-methoxy-pyridin-3-yl)-benzyl]-5-(pyridin-2-ylmethoxy)-1H-indol-2-yl]-2,2-dimethyl-propionic acid (AM103), a novel FLAP inhibitor, in healthy subjects. Single and multiple doses of AM103 demonstrated dose-dependent inhibition of blood LTB(4) production and dose-related inhibition of urinary LTE(4). After a single oral dose (50-1,000 mg) of AM103, the maximum concentration (C(max)) and area under the curve (AUC) in plasma increased in a dose-dependent manner. After multiple-dose administration (50-1,000 mg once daily for 11 days), there were no significant differences in the pharmacokinetic parameters between the first and last days of treatment. AM103 was well tolerated at all doses in both the single- and multiple-dose cohorts. Further clinical trials with AM103 in inflammatory diseases are warranted.

Acute sensorineural hearing loss following intravenous ketoralac administration.

Ketoralac is an injectable nonsteroidal antiinflammatory drug (NSAID) widely used in both out-patient and in-patient settings. Side effects such as acute renal failure, hyperkalemia, gastritis, gastrointestinal bleeding, and asthmatic exacerbation, although rare, have been previously reported. We report the case of a 20-year-old female with polyarteritis nodosa (PAN) who developed bilateral sensorineural hearing loss 25 minutes after receiving 30 mg of intravenous ketoralac. The patient denied any previous medication sensitivities, and was taking oral methotrexate and prednisone at the time of emergency department admission. Both PAN and methotrexate have been independently demonstrated to cause sensorineural hearing loss. We postulate that the patient's hearing loss was the result of ketoralac's direct and indirect ototoxic effects that were potentiated as a result of her underlying illness and medications. We recommend the cautious use of ketorolac in patients with underlying illnesses where NSAID-induced ototoxicity could result in adverse otologic consequences.