Naproxen Subject

The hydrolysis of racemic non-natural amides has led to useful products and intermediates for the fine chemical industry. Thus hydrolysis of the racemic amide (2) with an acylase in Rhodococcus erythrolpolis furnished the (S)-acid (the anti-inflammatory agent Naproxen) in 42 % yield and > 99 % enantiomeric excess1201. Obtaining the 7-lactam (—)-(3) has been the subject of much research and development effort, since the compound is a very versatile synthon for the production of carbocyclic nucleosides. An acylase from Comamonas acidovor-ans has been isolated, cloned and overexpressed. The acylase tolerates a 500 g/ litre input of racemic lactam, hydrolyses only the (+)-enantiomer leaving the desired intermediate essentially optically pure (E > 400)[211. 

There were no differences in the incidence of middle and distal duodenum lesions (14). Esophageal ulceration with bleeding was reported in an elderly woman with esophageal dysmotility (SEDA-17, 112). Esophageal symptoms and esophageal ulcers were reported with naproxen sodium tablets (as opposed to capsules) for over-the-counter use (SEDA-22, 111). Naproxen did not cause reflux and had no significant effect on motility in healthy subjects (15). 

In an analysis of nine double-blind, controlled studies, adverse reactions to naproxen in older and in younger subjects had similar incidences (29). 

Anttila M, Haataja M, Kasanen A. Pharmacokinetics of naproxen in subjects with normal and impaired renal function. Eur J Clin Pharmacol 1980 18(3) 263-8. 

The ability of the gastroduodenal mucosa to adapt to repeated exposure to NSAIDs and aspirin is well documented, and some reports have shown the possible involvement of H. pylori in this process (76,81). In one endoscopic study in volunteers, mucosal adaptation to naproxen after 4 weeks of treatment occurred in 53% of H. py/on-positive subjects and in 81% in H. py/on-negative subjects (82). 

Johnsen and coworkers [160] conducted another observational population-based case-control study to identify the risk of AMI in patients who used nonaspirin non-selective and COX-2 specific NSAIDs. Information for the study was collected from hospital discharge databases in Denmark and included 10, 280 cases of first-time hospitalization for AMI and 102, 797 matched controls without a history of AMI. Data was obtained for patients with a mean age of 69.6 years. There was a significantly higher incidence of serious cardiovascular events (AMI) in those whom were taking rofecoxib in comparison to subjects not taking NSAIDs (nonusers). Same observation was noted in the celecoxib, other COX-2 selective inhibitors, naproxen, and other non-selective NSAIDs groups, although to a lesser extent than for rofecoxib. In this study, celecoxib was associated with the lowest risk of AMI when compared to rofecoxib and the other non-selective NSAIDs. The authors concluded that caution should... 

Rodriguez, Varas-Lorenzo etat.[188]2004 Nested case- Ml associated with 404183 subjects 50- control cohort NSAIDuse 84years old. 20000 Controls were randomly sampled and frequency was matched to cases by age, sex, and calendaryear. Multivariate Adjusted Odds ratio Current NSAID use vs nonuse 1.07 (0.95-1.20) Previous CHD History 1.12 (0.91-1.38) Incidence rate of Ml was slightly higher among people with history of CHD. Estimates for Naproxen, ibuprofen, and diclofenac were comparable with no major effects on the risk of Ml. 

COX-2 inhibitors demonstrate similar analgesic benefits when compared to traditional NSAIDs. For example, 748 subjects randomized to rofecoxib (12.5 or 25 mg daily) or diclofenac (50 mg three times daily) showed similar improvements in pain, stiffness, physical function, and other measures of efficacy. In a 12-week trial of 1003 subjects with knee OA, celecoxib at 100 or 200 mg twice daily was more effective than placebo and comparable to naproxen 500 mg twice daily for relief of pain, stiffness, and limitation of physical function. ... 

Ester hydrolysis, performed under basic conditions, proceeded without affecting the d.r. The resulting diacid 20 was subjected to hydrolysis at controlled pH and high temperature to afford acid (5)-21 in 99% e.e. This crucial step involves a 1,2-aryl shift that occurs in a completely stereocontrolled fashion. Debromination of (5)-21 gave naproxen 22 in high overall yield. 

Acetyl-6-methoxy-naphthalene may be prepared by the acylation of 6-methoxynaphthalene. The resulting product is then subjected to a series of reactions, namely Wilgerodt-Kindler reaction, esterification, alkylation and hydrolysis ultimately yields /)Z-Naproxen. Resolution of the resulting racemic mixture is caused through precipitation of the more potent /)-enantiomer as the cinchonidine salt. 

Consistent with in vitro observations, plasma from subjects who had taken ibuprofen 400 mg exhibited significant Cox-1 selectivity with a ratio of 1.50 over 9 hours, a result comparable to the reported ex vivo selectivity ratio of 1.58 over 8 hours for the unselective Cox inhibitor Naproxen 500 mg. ... 

A study in healthy subjects found that diclofenac increased the clearance of amoxicillin. An isolated report describes acute interstitial nephritis with nephrotic syndrome associated with the use of naproxen and amoxicillin. 

Sodium bicarbonate 700 mg or 1.4 g increased the rate of absorption of a single 300-mg dose of naproxen in 14 healthy fasted subjects, whereas magnesium oxide or aluminium hydroxide 700 mg had the opposite effect, and reduced the rate of absorption. Magnesium carbonate had little effect. On the other hand when 15 or 60 mL of aluminium/magnesium hydroxide (Maalox) was given, the rate and extent of absorption of naproxen were slightly increased. ... 

Capone ML, Sciulli MG, Tacconelli S, Grana M, Ricciotti E, Renda G, Di Gregorio P, Mer-ciaro G, Patrignani P. Pharmacocfynamic interaction of naproxen wiA low-dose aspirin in healthy subjects. JAm Coll Cardiol(2005) 45,1295-1301. 

The absorption of a single 250-mg dose of naproxen was delayed but not reduced in 8 healthy fasting subjects by the simultaneous use of colestyramine 4 g in 100 mL of orange juice. The amount absorbed after 2 hours was reduced from 96% to 51%, but was complete after 5 hours. ... 

Probenecid 500 mg twice daily increased the plasma levels of naproxen 250 mg twice daily by 50% in 12 healthy subjects. ... 

Naproxen 250 mg twice daily given to healthy subjects with omeprazole 20 mg daily, pantoprazole 40 mg daily, or esomeprazole 40 mg daily for one week had no effeet on the pharmacokinetics of either naproxen or the proton pump inhibitor. 

Hassan-Alin M, Naesdal J, Nilsson-Pieschl C, Langstrom G, Andersson T. Lack of pharmacokinetic interaction between esomeprazole and the nonsteroidal anti-inflammatory drugs naproxen and rofecoxib in healthy subjects. Clin Drug Invest (2005) 25, 731-40. 

Diphenhydramine hydrochloride 50 mg had no clinically significant effects on the pharmacokinetics of a single 220-mg dose of naproxen sodium in 27 healthy subjects. The pharmacokinetics of diphenhydramine were similarly unaffected by naproxen. No special precautions appear to be... 

---