Side-Effects of Anti-Inflammatory Drugs: are they Essential or can they be Circumvented?

Mw, Whitehouse; Kd, Rainsford

doi:10.1007/978-3-0348-7290-4_17

Cited by 9 publications

(5 citation statements)

References 76 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…15 A successful dermal prodrug of ketoprofen and/or naproxen should exhibit optimum lipophilicity (partition coefficient) and should be stable toward chemical degradation prior to hydrolysis within the skin by enzymes. The temporary masking of the carboxylic group of ketoprofen and naproxen via simple esterification has been proposed as a promising means of reducing GI irritation 16 and it is also a useful means of modifying the lipophilicity of parent molecules to optimize partitioning into the skin and to maximize percutaneous penetration. 17,18 Simple naproxen esters release naproxen very slowly in human serum and skin-serum homogenate, but a few prodrug esters penetrate the skin markedly better than naproxen.…”

Section: Introductionmentioning

confidence: 99%

In vitro evaluation of acyloxyalkyl esters as dermal prodrugs of ketoprofen and naproxen

Rautio

Taipale

Gynther

et al. 1998

Journal of Pharmaceutical Sciences

View full text Add to dashboard Cite

A series of acyloxyalkyl esters of ketoprofen and naproxen were synthesized and investigated as topical prodrugs with the aim of improving the dermal delivery of the drugs. In addition, some hydroxyalkyl esters of ketoprofen and naproxen were synthesized as possible intermediates of acyloxyalkyl prodrugs. All of the prodrugs were more lipophilic than their parent molecules, as evaluated by drug partitioning between 1-octanol and phosphate buffer at pH 7.4 (log Papp). However, their solubilities in aqueous solutions decreased markedly compared with the parent molecules. The prodrugs were stable toward chemical hydrolysis in aqueous solutions (pH 7.4), but were hydrolyzed to the parent drug both in 80% human serum and in human skin homogenate, with half-lives ranging from 4 to 137 min and from 13 to 403 min, respectively. The abilities of the selected naproxen acyloxyalkyl prodrugs to deliver naproxen through excised human skin were evaluated. Generally, the prodrugs showed similar dermal delivery as the parent drug through cadaver skin. In the present series of lipophilic prodrugs of naproxen, the prodrug with the highest aqueous solubility was the most effective prodrug to deliver naproxen through the skin.

show abstract

Section: Introductionmentioning

confidence: 99%

In vitro evaluation of acyloxyalkyl esters as dermal prodrugs of ketoprofen and naproxen

Rautio

Taipale

Gynther

et al. 1998

Journal of Pharmaceutical Sciences

View full text Add to dashboard Cite

show abstract

“…The data from the early studies by Riker, from patients who received nimesulide for the treatment of rheumatoid arthritis, are of interest since they indicate that high doses of nimesulide (1000-1200 mg daily) may cause elevation of liver enzymes in this disease. This aspect is important in relation to the effects of the drug in rheumatoid arthritis since hepatic changes are evident in this disease [23], possibly involving subnormal rates of drug detoxification [24]. The main arthritic indication for nimesulide is the treatment of osteoarthritis and not rheumatoid arthritis.…”

Section: Discussionmentioning

confidence: 99%

An analysis from clinico-epidemiological data of the principal adverse events from the COX-2 selective NSAID, nimesulide, with particular reference to hepatic injury

1998

Inflammopharmacol

Self Cite

View full text Add to dashboard Cite

The safety of the cyclo-oxygenase-2 (COX-2) selective NSAID, nimesulide, has been evaluated from information (a) in clinical trials in osteoarthritis that have been performed in Europe as well as in earlier pilot studies that were performed in patients with rheumatoid arthritis in the USA, and (b) in post-marketing studies (PMS) that have been performed by the manufacturer since the introduction of the drug in Europe and some South American countries. Upon analysis there have been clear indications of elevation of liver enzymes being related to the drug in 3/753 patients who were investigated in clinical trials in osteoarthritis. The results of the analysis of adverse drug reactions (ADRs) in patients with osteoarthritis (which is the principal indication for the drug) in PMS showed that the greatest number of these were in the skin and appendages, digestive system and organs wherein metabolic effects were manifest. There was a relatively low number of reports of gastrointestinal ulceration and haemorrhage, and these observations are in agreement with published experimental studies in humans and laboratory animals. Recent reports of ADRs in the liver in 25 patients were analysed in detail. In many of the cases there was evidence of confounding disease (e.g. cancer, prior liver damage) or prior or concurrent intake of known hepatotoxic NSAIDs (diclofenac, aspirin). Often elevations of liver enzymes above the laboratory norms are the only indication of liver injury and this in many cases is variable. The major cases of elevated liver enzymes and other liver changes have been in elderly patients.This first extensive analysis of ADRs from a COX-2 selective NSAID, nimesulide, indicates that there is a relatively low incidence of ADRs especially in the gastrointestinal tract, while those in the liver are within or below the general incidence with other NSAIDs.

show abstract

“…These new derivatives would appear to offer considerable therapeutic potential since, as a group, the salicylates have generally fewer side-effects when compared with other nonsteroid anti-inflammatory (NSAI) drugs [5,6]; gastrointestinal irritancy/ulcerogenicity being the principal untoward effects. 'Correspondence to Dr K.D.…”

Section: Introductionmentioning

confidence: 99%

Bio-distribution in rats of some salicylates with low gastric ulcerogenicity

et al. 1980

Self Cite

View full text Add to dashboard Cite

The distribution of three radioactively labelled salicylate derivatives with low ulcerogenic activity was compared with that of acetylsalicylic acid (ASA) and salicylic acid using whole body autoradiography and liquid scintillation counting techniques in rats. The methyl ester of ASA (AME) was distributed in vivo very similarly to that observed with ASA and salicylic acid. AME is rapidly demethylated following absorption from the stomach and is subsequently converted to ASA and salicylate. Salicylate is the main metabolite produced from both AME and ASA, which specifically accumulates in inflamed tissues. The 3-methyl- and 6-methyl-substituted salicylic acids are not as rapidly absorbed as either ASA or salicylic acid and do not pass readily into the brain or bone marrow. These results show that the methyl (ester) group of AME (which adequately protects the gastric mucosa from damage caused by ASA itself) does not impair the quantity of pharmacologically active form of drug (salicylate and ASA) generated in vivo. However, insertion of the methyl group at the 3- and 6-position of salicylic acid markedly affects both absorption, distribution and pharmaco-activity of these acids.

show abstract

Side-Effects of Anti-Inflammatory Drugs: are they Essential or can they be Circumvented?

Cited by 9 publications

References 76 publications

In vitro evaluation of acyloxyalkyl esters as dermal prodrugs of ketoprofen and naproxen

In vitro evaluation of acyloxyalkyl esters as dermal prodrugs of ketoprofen and naproxen

An analysis from clinico-epidemiological data of the principal adverse events from the COX-2 selective NSAID, nimesulide, with particular reference to hepatic injury

Bio-distribution in rats of some salicylates with low gastric ulcerogenicity

Contact Info

Product

Resources

About