Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0018681 (headache)
 56,091 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Nabumetone, a nonsteroidal anti-inflammatory drug of the naphthylalkanone class, was studied in an open-label fashion to compare the relative single-dose and steady-state kinetics in young healthy male volunteers and in elderly patients with degenerative joint disease. Seventeen healthy male volunteers 21 to 30 years of age and 17 patients 60 to 75 years of age were studied. After a single oral dose of 1,000 mg nabumetone, blood and urine samples were collected over a five-day period. Plasma was assayed for nabumetone and the active metabolite, 6-methoxynaphthylacetic acid, and the urine was assayed for five metabolites. Following this phase, they received daily oral doses of 1,000 mg nabumetone for 14 days. After the final dose, blood and urine samples were again collected for five days for the same assays. These data were fitted to a single compartment model and the derived data are as follows: mean maximal plasma concentration, maximal time concentration, area under the plasma-time curve, elimination rate constant, and elimination half-life in the young group after single dose were 22.9, 8.4, 838, 0.032, and 21.2, respectively, whereas on steady-state, values were 33.6, 4.1, 666, 0.031, and 22.1, respectively. In the elderly group after single dose, these values were 30.2, 10.8, 1,538, 0.024, and 29.2, whereas on steady-state, they were 50.0, 7.2, 1,092, 0.027, and 25.6. The accumulation ratio was 1.6 in the young and 1.8 in the elderly. Side effects in the young were mild and consistent of headaches, epigastric discomfort, nausea, and vomiting, whereas in the elderly they consisted mainly of headaches. No significant changes in complete blood cell count, blood chemistries, or urinalysis were noted. We concluded from these data that the drug does not accumulate if given every 24 hours; therefore, a single daily dose should provide sufficient therapy and that due to a difference in elimination, elderly patients may require a lower dose.
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PMID:Nabumetone kinetics in the young and elderly. 368 2

Nabumetone is a nonsteroidal anti-inflammatory prodrug, which exerts its pharmacological effects via the metabolite 6-methoxy-2-naphthylacetic acid (6-MNA). Nabumetone itself is non-acidic and, following absorption, it undergoes extensive first-pass metabolism to form the main circulating active metabolite (6-MNA) which is a much more potent inhibitor of preferentially cyclo-oxygenase (COX)-2. The three major metabolic pathways of nabumetone are O-demethylation, reduction of the ketone to an alcohol, and an oxidative cleavage of the side-chain occurs to yield acetic acid derivatives. Essentially no unchanged nabumetone and < 1% of the major 6-MNA metabolite are excreted unchanged in the urine from which 80% of the dose can be recovered and another 10% in faeces. Nabumetone is clinically used mainly for the management of patients with osteoarthritis (OA) or rheumatoid arthritis (RA) to reduce pain and inflammation. The clinical efficacy of nabumetone has also been evaluated in patients with ankylosing spondylitis, soft tissue injuries and juvenile RA. The optimum oral dosage of nabumetone for OA patients is 1 g once daily, which is well tolerated. The therapeutic response is superior to placebo and similar to nonselective COX inhibitors. In RA patients, nabumetone 1 g at bedtime is optimal, but an additional 0.5-1 g can be administered in the morning for patients with persistent symptoms. In RA, nabumetone has shown a comparable clinical efficacy to aspirin (acetylsalicylic acid), diclofenac, piroxicam, ibuprofen and naproxen. Clinical trials and a decade of worldwide safety data and long-term postmarketing surveillance studies show that nabumetone is generally well tolerated. The most frequent adverse effects are those commonly seen with COX inhibitors, which include diarrhoea, dyspepsia, headache, abdominal pain and nausea. In common with other COX inhibitors, nabumetone may increase the risk of GI perforations, ulcerations and bleedings (PUBs). However, several studies show a low incidence of PUBs, and on a par with the numbers reported from studies with COX-2 selective inhibitors and considerably lower than for nonselective COX inhibitors. This has been attributed mainly to the non-acidic chemical properties of nabumetone but also to its COX-1/COX-2 inhibitor profile. Through its metabolite 6-MNA, nabumetone has a dose-related effect on platelet aggregation, but no effect on bleeding time in clinical studies. Furthermore, several short-term studies have shown little to no effect on renal function. Compared with COX-2 selective inhibitors, nabumetone exhibits similar anti-inflammatory and analgesic properties in patients with arthritis and there is no evidence of excess GI or other forms of complications to date.
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PMID:Nabumetone: therapeutic use and safety profile in the management of osteoarthritis and rheumatoid arthritis. 1545 29