Naproxen toxicity

Naproxen toxicity can occur at very high doses (150-500 mg/kg). Naproxen toxicity is relatively uncommon compared to other NSAIDs such as aspirin and ibuprofen. See below for description of signs and symptoms of naproxen toxicity. 

Bombardier C, Laine L, Reicin A et al (2000) Comparison of upper gastrointestinal toxicity of rofecoxib and naproxen in patients with rheumatoid arthritis. VIGOR Study Group. N Engl JMed 343 1520-1528... 

Nonsteroidal antiinflammatory drugs (NSAIDs) are the mainstay of therapy because of their excellent efficacy and minimal toxicity with shortterm use. There is little evidence to support one NSAID as more efficacious than another, and three drugs (indomethacin, naproxen, and sulindac) have FDA approval for this indication (Table 1-1). 

In Sect. 8.2.3, we have discussed 1-alkyl-l-azacycloalkan-2-ones (8.32, n = 1 or 2 m = 3, 4, 5 or 6) as a group of amidoalkyl esters, taking prodrugs of indomethacin (8.9, R = OH) and naproxen (8.26) as examples [43a,b]. For both compounds, the prodrugs in the series n = 1 were rapidly hydrolyzed (tm ca. 0.5-1 h in pH 7.4 buffer at 32°). Furthermore, the carbinolamides liberated were not fully stable and broke down by hydrolysis to produce the toxic formaldehyde (Fig. 8.3) [62], Thus, the half-life of decomposition of A-(hydroxymethyl)benzamide (HOCH2-NH-CO-C6H5), a pro-moiety of 8.56 discussed below, was 160 h at pH 7.4 and 37° [69]. This means that a small amount of formaldehyde may be formed in vivo. 

Acetyls alley lie acid was shown to prevent cirrhosis under certain experimental conditions [125]. Naproxen and indomethacin partially protected against LPS and D-galactosamine-in-duced hepatotoxicity [126] Acetylsalicylic acid and ibuprofen were also protective in endo-toxic shock [127]. Endotoxaemia is one of the complications in cirrhotic patients [128] and is probably caused by an impaired ability of the liver to take up and detoxify gut-derived LPS [116]. The presence of portosystemic shunts in cirrhotic patients may also contribute to this spill-over of LPS into the systemic circulation [129]. NSAIDs, however, are also reported to provoke deleterious effects on renal function in cirrhosis [130], and can therefore not be used in cirrhotic patients. Cell-specific delivery of NSAIDs to SECs and/or KCs may make application of these drugs in cirrhosis feasible by circumventing the renal side-effects. 

Apart from the salicylates NSAIDs include several classes of weak acids like propionic acid derivatives such as ibuprofen, carprofen, fenbufen, fenoprofen, flurbiprofen, ketorolac, loxoprofen, naproxen, oxaprozin, tiaprofenic acid and suprofen. Phenylbutazone is the most important representative of the pyrazolon derivatives which have a bad reputation for their risk of potentially fatal bone-marrow toxicity. To the acetic acid derivatives belong in-domethacin, diclofenac and sulindac. Sulindac is a pro-drug with less toxicity than indomethacin. The enolic acids include piroxicam, droxicam and tenoxicam. Meloxicam is an analog of piroxicam and has a high selectivity for COX-2. 

Cleuvers M. (2(X)4). Mixture toxicity of the anti-inflammatory drugs diclofenac, ibuprofen, naproxen, and acetylsahcyhc acid. Ecotoxicology and Environmental Safety 59 309-315. 

Claire Bombardier, Loren Laine, et al., Comparison of Upper Gastrointestinal Toxicity of Rofecoxib and Naproxen in Patients with Rheumatoid Arthritis. VIGOR Study Group, New England Journal of Medicine 343, no. 21, November 23, 2000, pp. 1,520-1,528. Also available online. URL http //content.nejm.org/ cgi/content/full/343/21/1520. Downloaded April 15, 2009. 

Rofecoxib shows significantly less gastrointestinal toxicity compared to ibuprofen in studies with osteoarthritis patients (Laine et al., 1999) and compared to naproxen in patients with rheumatoid arthritis (Bombardier et al., 2000). 

Shanbhag, V. R., Crider, A. M., Gokhale, R., et al. Ester and amide prodrugs of ibuprofen and naproxen Synthesis, anti-inflammatory activity, and gastrointestinal toxicity. J. Pharm. Sci. 81 149—154, 1992. 

The highly water-soluble 2-hydroxypropyl-/i-cyclodextrin (2-HP-/1-CD) is a commercially useful general complexing agent. Inclusion complexes of poorly water-soluble Naproxen with 2-HP-/1-CD were useful to increase its solubility and dissolution rate, and resulted in an enhancement of bio-availability and minimized the gastrointestinal toxicity of the drug [69]. The water solubility of melatonin, which is an indole amide neurohormone, was also enhanced in a complex with 2-HP-/J-CD [70]. 

BETA-BLOCKERS NSAIDS - INDOMETACIN, PIROXICAM, POSSIBLY IBUPROFEN, NAPROXEN 1 hypotensive efficacy of beta-blockers. There does not seem to be this effect with other NSAIDs Additive toxic effects on kidney, and sodium and water, retention by NSAIDs. NSAIDs can raise BP by inhibiting renal synthesis of vasodilating prostaglandins. It is uncertain why this effect is specific to these NSAIDs Watch for 1 response to beta-blockers... 

METHOTREXATE ANALGESICS-NSAIDs t methotrexate levels, with reports of toxicity, with ibuprofen, indome-tacin and possibly diclofenac, flurbiprofen, ketoprofen and naproxen Uncertain postulated that an NSAID-induced 1 in renal perfusion may have an effect Consider using an alternative NSAID... 

NS AIDs ANTIGOUT DRUGS-PROBENECID T levels of indometacin, ketorolac and possibly dexketoprolien, ketoprofen, naproxen, tenoxicam and tiaprofenic acid Probenecid competitively inhibits renal metabolism of these NSAIDs Watch for signs of toxicity of these NSAIDs. Consider using an alternative NSAID. The manufacturers of ketorolac advise avoiding co-adminis-tration of ketorolac and probenecid... 

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