Subject rheumatoid arthritis

The first two selective COX-2 inhibitors to be marketed and subjected to in depth clinical trials were celecoxib and rofecoxib. Both compounds are as effective as standard NSAIDs in rheumatoid arthritis, osteoarthritis and for pain following orthopaedic or dental surgery. Gastrointestinal side effects were far fewer than with comparator diugs and in fact were no... 

Selley et al. (1992) have recently employed gas chromatography combined with mass spectrometric detection to determine levels of the cytotoxic monounsaturated aldehyde 4-hydroxy-/7 t-2-nonenal in the blood plasma of healthy human subjects, and patients with rheumatoid and osteoarthritis. Intriguingly, this lipid peroxidation end-product is present at a concentration ofc. lx 10 mol/dm in healthy and osteoarthritic human plasma samples (but significantly elevated in those collected from rheumatoid arthritis patients). Although at least some of this could originate from the oxidative degradation of PUFAs invm, there may be a relationship existing between these levels and the frequency of thermally/... 

A number of studies in humans show that PUFAs can generate significant immunomodulatory effects. Generally, these studies have utilized considerably lower amounts of fish oil to treat subjects than found in most animal studies. Numerous clinical trials have examined the effects of fish oil on rheumatoid arthritis and many have reported statistically significant benefits such as decreased morning stiffness and numbers of tender joints [57]. Several other studies have reported that PUFAs can provide therapeutic benefits for patients with IgA nephropathy, the most common primary human glomerulonephritis... 

In the course of studies on aminoaciduria in Fanconi s syndrome, Dent (Dl) isolated from the urine of the subject investigated a simple peptide identified as serylglycylglycine. Carsten (Cl) found in normal urine several peptides containing in every case one of the dicarboxylic amino acids. He discovered also two tetrapeptides, one of them consisting of equimolar amounts of aspartic acid and glycine, and the second composed of glycine, alanine, and glutamic acid in the ratio 2 1 1. The first of these tetrapeptides was also found in the urine of a patient with rheumatoid arthritis. 

Ranganathan, P., Culverhouse, R., Marsh, S., et al. (2004) Single nucleotide polymorphism profiling across the methotrexate pathway in normal subjects and patients with rheumatoid arthritis. Pharmacogenomics. 5, 559-569. 

Two forms of gold provide medical treatments. The radioactive isotope Au-198, with a short half-life of 2.7 days, is used to treat cancer and is produced by subjecting pure gold to neutrons within a nuclear reactor. A gold salt, a solution called sodium thiosulfate (AuNa O Cl ), is injected as an internal treatment for rheumatoid arthritis. However, since gold and some of its compounds are toxic when ingested, this treatment may cause complications such as skin rashes and kidney failure. It is a less popular treatment, particularly with the development of newer and more effective medications. 

The degree of study subject tolerability to a drug should be assessed in conjimction with the laboratory safety and efficacy data, so that an overall risk to benefit assessment can be made. Poorly tolerated drugs, however efficacious for use in self-limiting non-serious diseases, are unlikely to become successful medicines. On the other hand, study subjects with serious illnesses, such as active rheumatoid arthritis, are frequently quite prepared to put up with poorly tolerated drugs (e.g. intramuscular gold injections or intra-articular steroid injections) if efficacy is good and the alternatives are no more attractive. 

Pharmacokinetics The absolute bioavailability after a 70 mg subcutaneous dose of Kineret in healthy subjects is 95%. In subjects with rheumatoid arthritis, maximum plasma concentrations of anakinra occurred 3 to 7 hours after subcutaneous administration. The terminal half-life ranged from 4 to 6 hours. No unusual pharmacokinetics was observed on repeated daily dosing. 

Ten years ago monoclonal antibodies (MAb) were of considerable interest but faded after clinical and commercial failures. Further clinical and laboratory testing revealed that only humanized MAb were likely to be of any benefit in a human patient. From a practical standpoint this research developed, and humanized MAb were launched onto the market, with success in the treatment of several diseases including rheumatoid arthritis. These developments justify a chapter on the subject in this book. 

Haqqi et al. (1999) investigated the impact of polyphenols present in green tea on rheumatoid arthritis (RA). The study used mice as test subjects and showed that although 92% of ordinary mice developed RA when injected with a compound that induced RA, less than half of the mice that consumed the green tea polyphenols developed RA after a similar injection. 

Inflammation is associated with various diseases such as rheumatoid arthritis, cancer, myocarditis, arteriosclerosis, bowel diseases, multiple sclerosis, asthma, and many others. While several inflammatory markers are commonly expressed during any inflammatory disorder, some are symptom specific. Therefore, the gene array data will be particularly helpful in indicating the appropriate disease model for subsequent preclinical and clinical tests. Only functional, active extracts with potentially safe and novel modes of actions may then be subjected to labor-intensive large-scale extraction, fractionation, characterization, and isolation of novel bioactive components. We believe that the strategy as described schematically in Figure 4.1 will allow efficient use of plant extracts and other natural resources toward identification of novel drug leads for human health care. 

Etodolac distributes well into synovial fluid, the proposed primary site of action of NSAID s. Following multiple doses of 200 mg twice daily for 7 days, the Cmax in synovial fluid was 2.6 pg /mL and the tmax was 3.2 hours [44]. The synovial fluid AUC of total etodolac was about 67% of the serum values [44]. The AUC of the unbound etodolac was 172% of the serum values. After a single 200 mg dose of etodolac, the ratio of (S)-etodolac to (i )-etodolac in six subjects with rheumatoid arthritis was 0.074 in plasma and 0.17 in synovial fluid [45]. 

C6. Catalano, M. A., Carson, D. A., Slovin, S. F., Rich man, D. D., and Vaughan, J. H., Antibodies to Epstein-Barr virus-determined antigens in normal subjects and in patients with seropositive rheumatoid arthritis Proc. Natl. Acad. Sci. U.S.A. 76, 5825-5826 (1979). 

Slaughter, L., Carson, D. A., Jensen, F. C., Holbrook, T. L., and Vaughan, J. H., In vitro effects of Epstein-Barr virus on peripheral blood mononuclear cells from patients with rheumatoid arthritis and normal subjects. ]. Exp. Med. 148, 1429-1434 (1978). 

The maintenance of the normal, anomalous viscosity index of synovial fluid is essential for its proper function as a lubricant between joint surfaces. The concentration and the degree of polymerization of hyaluronic acid in synovial fluids of patients with rheumatoid arthritis and other degenerative joint diseases have been the subjects of widespread investigation. Ragan and Meyer (R1) ascribed the changes in synovial fluid in... 

Joint symptoms in patients taking penicillamine vary from creaking and subjective discomfort and worsening of joint pain to severe arthralgia (327-329). Paradoxical acute severe exacerbation of rheumatoid arthritis has been reported in three patients, probably induced by penicillamine (330). Arthritis can also be a manifestation of peniciUamme-mduced systemic lupus erythematosus. 

In another study, a 16-week, randomized, double-blind, placebo-controlled trial, eligible subjects with active seropositive or erosive rheumatoid arthritis were randomly allocated to three treatment groups doxycycline 200 mg intravenously, azithromycin 250 mg orally, or placebo (24). The primary end-points were changes between baseline and week 4 in the tender joint count, erythrocyte sedimentation rate, and urinary excretion of pyridinoline. The trial was stopped prematurely after 31 patients had been enrolled. Three subjects were withdrawn because of worsening arthritis. There were no significant differences across the groups in any of the three primary clinical endpoints. The authors concluded that doxycycline did not reduce disease activity or collagen cross-link production. 

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