Rheumatic diseases

Folic acid deficiency Hyperthermia Phenylketonuria Rheumatic disease Virilizing tumors Drugs and chemicals Androgenic chemicals Angiotensin-converting enzyme inhibitors Captopril, enalapril Antibiotics... 

Smiley, J.D. Hoffman, W.L. (1991). The role of infections in the rheumatic diseases molecular mimicry between bacterial and human stress proteins Am. J. Med. Sci. 301, 138-149. 

In general, treatment of the asthma underlying NSAlDs sensitivity should follow standard asthma guidelines. This type of asthma is often severe and frequently high doses of inhaled corticosteroids and daily doses of oral corticosteroids are necessary. A special treatment option is a chronic desensitization to aspirin [8]. Desensitization and aspirin maintenance is routinely used in some centers for treatment of chronic rhinusinusitis with nasal polyposis. It is the only available procedure which allows AIA patients with ischemic heart disease to use aspirin. During the state of desensitization to aspirin, not only aspirin but almost all strong NSAIDs are tolerated, so desensitization and NSAID maintenance could be used for treatment of rheumatic disease or chronic pain syndromes. 

Farrell, A.J., Blake, D.R., Palmer, R.J. and Moncada, S. (1992). Increased concentrations of nitrite in synovial fluid and serum samples surest increased nitric oxide synthesis in rheumatic diseases. Ann. Rheum. Dis. 51, 1219-1222. 

Traut, E. F. and E. W. Passarelli, Placebos in the Treatment of Rheumatoid Arthritis and Other Rheumatic Conditions , Annals of the Rheumatic Diseases 16 (1957) 18-22... 

MAK33 scFv rheumatic diseases, and other that create elevated or reduced levels of creatine kinase. N. tabacum SRI 35S No SP + 6-25 ng scFv/mg TSP 54... 

Due to the numerous possible reactions and related biological consequences, inappropriate overproduction of NO can cause a series of disease states such as a variety of neurodegeneration diseases including inflammation, rheumatic disease, septic shock, diabetes melhtus, and cerebral ischemia. Therefore development of isoform-specific NOS inhibitors to regulate NO synthesis has been an active research area. 

Applications. In the last decade a lot of research has been devoted to the development of catalytic routes to a series of asymmetric carboxylic acids that lack the acetamido ligand as additional functionality. In Figure 4.17 four are listed, which are important as anaesthetics for rheumatic diseases. Their sales in beat many bulk chemicals the turnover of Naproxen (retail) in 1990 was 700 million for 1000 tons. S-Naproxen is now being produced by Syntcx via resolution with a chiral auxiliary. The main patents from Syntex expired in the U.S. in 1993, the reason for a lot of activity to study alternative synthetic routes. Routes leading to an asymmetric centre are o asymmetric hydrogenation of an unsaturated acid, o asymmetric carbohydroxylation of a styrene precursor, o asymmetric hydroformylation of a styrene precursor and oxidation. 

There is also no compelling reason why the findings made in the somewhat popular models of type 1 diabetes should not be extended to other autoimmune diseases such as rheumatic diseases provided that there are clues about relevant antigens that are presented in local lymphoid tissue. 

Azathioprine is used in the treatment of several rheumatic diseases, including systemic lupus erythematosus (SLE) and RA. About 10-30% of RA patients discontinue AZA because of side effects (40). AZA is a prodrug that after oral intake is... 

In one study, 68 patients with rheumatic disease on AZA (2 to 3 mg/kg/d) were genotyped for TPMT and TPMT3A alleles. All patients were assessed for side effects from AZA, such as leukopenia, liver function abnormalities, and GI intolerance. Of these patients, 6 (9%) patients were heterozygous for TPMT3A, of whom 5 discontinued AZA within 4 weeks of starting the medication because of hematologic toxicity (48). In another study, 40 RA patients on AZA (0.7 to 1.4 mg/ kg/d) were genotyped for the TPMT alleles. Of the 40 patients, 6 discontinued... 

Haagsma, C. J., Blom, H. J., van Riel, P. L., et al. (1999) Influence of sulphasalazine, methotrexate, and the combination of both on plasma homocysteine concentrations in patients with rheumatoid arthritis. Annals of the Rheumatic Diseases. 58, 79-84. 

Berkun, Y., Levartovsky, D., Rubinow, A., et al. (2004) Methotrexate related adverse effects in patients with rheumatoid arthritis are associated with the A1298C polymorphism of the MTHFR gene. Annals of the Rheumatic Diseases. 63, 227-231. 

Methotrexate is an antimetabolite of folic acid and has immunosuppressant properties. It inhibits the enzyme dihydrofolate reductase that is required for the synthesis of purines and pyrimidines. It is used in malignant disease, Crohn s disease, rheumatic disease and psoriasis. Folic acid is given with methotrexate to reduce the occurrence of side-effects particularly the risk of mucositis. 

Rheumatic disease is defined as disease of connective tissue and medical disorders of the musculoskeletal system . The medical discipline concerned with these diseases is referred to as rheumatology. The majority of rheumatic diseases are soft tissue rheumatism and nonspecific low back pain (LBP), autoimmune inflammatory rheumatic diseases, osteoarthritis (OA), osteoporosis, crystal-deposition disease and infectious arthritis. 

Therapeutic options in rheumatic disease consist of general, physical, and medical measures. General measures comprise general and local rest of the affected joints and local supports such as splints, corsets, and neck collars. Adjustment of life-style and protection against acute physical trauma and/or chronic overuse of affected joints are included in the... 

The autoimmune rheumatic diseases consists of Rheumatoid Arthritis (RA), Spondylarthritis (SpA), Systemic Lupus Erythematosus (SLE), Polymyositis, Dermatomyositis, Polymyalgia Rheumatica, Acute Temporal Arteritis, Giant Cell Arteritis, Behcet s Disease, Sjorgren s Syndrome, Felty s Syndrome and Mixed Connective Tissue Disease (MCTD). Spondylarthritis (SpA) can be subdivided in Reactive Arthritis (ReA), Ankylosing Spondylitis (AS), Psoriatic Arthritis (PsA), Arthritis associated with the inflammatory bowel diseases are Crohn s disease and Ulcerative Colitis (IBD), Undifferentiated SpA (UspA) and Sacro-ilitis, Juvenile SpA and Acute Anterior Uveitis (AAU). 

Chronic tuberculous arthritis is not at all rare in developing countries. Mycobacterial tuberculosis can directly or indirectly affect the musculoskeletal system. Most commonly there is a direct musculoskeletal involvement of M. tuberculosis which may lead to spondylitis, osteomyelitis, septic arthritis and tenosynovitis. M. tuberculosis has become an important pathogen in rheumatic diseases since the use of anti-TNF-a biopharmaceuticals was introduced. 

John Darmawan, MD, PhD WHO Expert on Rheumatic Disease, Geneva, Switzerland and Seroja Rheumatic Center, Jalan Seroja Dalam 7, Semarang 50136, Indonesia... 

E) The appearance of fever and malaise attributed to steroid withdrawal may be difficult to distinguish from reactivation of rheumatic disease. 

It is a NSAID with pronounced antirheumatic, antiinflammatory, analgesic and antipyretic properties. Inhibition of prostaglandin biosynthesis is fundamental mechanism of action. In rheumatic diseases, it leads to marked relief from pain at rest, pain on movement, morning stiffness and swelling of the joints, as well as by an improvement in function. 

It is indicated in suppression of inflammatory and allergic disorders, inflammatory bowel disease, asthma, immunosuppression and rheumatic disease. 

Aspirin (acetylsalicylic acid, Figure 7.9) is a derivative of salicyclic acid, which was first used in 1875 as an antipyretic and antirheumatic. The usual dose for mild pain is 300-600 mg orally. In the treatment of rheumatic diseases, larger doses, 5-8 g daily, are often required. Aspirin is rapidly hydrolysed in the plasma, liver and eiythrocytes to salicylate, which is responsible for some, but not all, of the analgesic activity. Both aspirin and salicylate are excreted in the urine. Excretion is facilitated by alkalinisation of the urine. Metabolism is normally very rapid, but the liver enzymes responsible for metabolism are easily saturated and after multiple doses the terminal half-life may increase from the normal 2-3 h to 10 h. A soluble salt, lysine acetylsalicylic acid, with similar pharmacological properties to aspirin, has been used by parenteral administration for postoperative pain. Aspirin in low doses (80-160 mg daily) is widely used in patients with cardiovascular disease to reduce the incidence of myocardial infarction and strokes. The prophylaxis against thromboembolic disease by low-dose aspirin is due to inhibition of COX-1-generated thromboxane A2 production. Because platelets do not form new enzymes, and COX-1 is irreversibly inhibited by aspirin, inhibition of platelet function lasts for the lifetime of a platelet (8-10 days). 

Frequently, the constant release of a drug from pharmaceutical dosage forms enables one to obtain a suitable pharmacological and therapeutic response. However, for therapy of certain pathologies, i.e. some heart and rheumatic diseases, or in the utilization of some drags such as contraceptive steroids and antibiotics, it would be more useful to obtain different plasma levels of the active principle at different times related to painful symptoms or circadian rhythms, etc. In these cases the desired therapeutic results can usually be obtained with frequent administration of conventional dosage forms which lead to a prompt absorption of the active principle. This kind of drag treatment is often compromised by a lack of full compliance by the patient. Until now there have been few systems that allow the release of the active principle in successive pulses at precise and well-controlled time periods [11,12]. 

Salicylates and other similar agents used to treat rheumatic disease share the capacity to suppress the signs and symptoms of inflammation. These drugs also exert antipyretic and analgesic effects, but it is their anti-inflammatory properties that make them most useful in the management of disorders in which pain is related to the intensity of the inflammatory process. 

The NSAIDs have a number of commonalities. Although not all NSAIDs are approved by the FDA for the whole range of rheumatic diseases, most are probably effective in rheumatoid arthritis, seronegative spondyloarthropathies (eg, psoriatic arthritis and arthritis associated with inflammatory bowel disease), osteoarthritis, localized musculoskeletal syndromes (eg, sprains and strains, low back pain), and gout (except tolmetin, which appears to be ineffective in gout). 

Meloxicam is an enolcarboxamide related to piroxicam that preferentially inhibits COX-2 over COX-1, particularly at its lowest therapeutic dose of 7.5 mg/d. It is not as selective as celecoxib and may be considered "preferentially" selective rather than "highly" selective. The drug is popular in Europe and many other countries for the treatment of most rheumatic diseases and approved for treatment of osteoarthritis in the USA. It is associated with fewer clinical gastrointestinal symptoms and complications than piroxicam, diclofenac, and naproxen. Similarly, while meloxicam is known to inhibit synthesis of thromboxane A2, even at supratherapeutic doses its blockade of thromboxane A2 does not reach levels that result in decreased in vivo platelet function (see common adverse effects above). 

In addition to its rheumatic disease indications, sulindac suppresses familial intestinal polyposis and it may inhibit the development of colon, breast, and prostate cancer in humans. It appears to inhibit the occurrence of gastrointestinal cancer in rats. The latter effect may be caused by the sulfone rather than the sulfide. 

Chloroquine and hydroxychloroquine are used mainly in malaria (see Chapter 52) and in the rheumatic diseases. The mechanism of the antiinflammatory action of these drugs in rheumatic diseases is unclear. The following mechanisms have been proposed suppression of T-lymphocyte responses to mitogens, decreased leukocyte chemotaxis, stabilization of lysosomal enzymes, inhibition of DNA and RNA synthesis, and the trapping of free radicals. 

Cyclophosphamide s major active metabolite is phosphoramide mustard, which cross-links DNA to prevent cell replication. It suppresses T-cell and -cell function by 30-40% T-cell suppression correlates with clinical response in the rheumatic diseases. Its pharmacokinetics and toxicities are discussed in Chapter 54. 

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