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PubMed2000

Toxicity of anti-rheumatic drugs in a randomized clinical trial of early rheumatoid arthritis.

OBJECTIVE: To evaluate the toxicity of slow-acting anti-rheumatic drugs (SAARDs) and non-steroidal anti-inflammatory drugs (NSAIDs) in early rheumatoid arthritis. METHODS: Patients were randomized to receive a SAARD-hydroxychloroquine (HCQ; n=120), i.m. gold (n=114) or methotrexate (MTX; n=118)-or a NSAID only (n=67). Patients in the three SAARD groups were allowed to take NSAIDs. Follow-up included 545 patient-years (p-yr). Adverse effects were attributed to specific medications using the Naranjo scoring method. RESULTS: Fifty-five per cent of the patients suffered from adverse effect(s). Adverse effects were most common during i.m. gold therapy (87 per 100 p-yr), which led to permanent discontinuation of this treatment in 31 cases. The incidences of adverse effects that were probably attributable to NSAIDs in patients treated simultaneously with a SAARD were similar for the three SAARD groups. The mean period until the first adverse effect was longer in the MTX group (39 weeks) than in the HCQ group (27 weeks). Baseline clinical and sociodemographic parameters were not predictive of the occurrence of adverse effects. CONCLUSION: No adverse effect could be classified as definitely related to either SAARDs or NSAIDs by the Naranjo scoring method. The incidence of possible adverse effects of NSAIDs and SAARDs was 72 per 100 p-yr, and adverse effects led to permanent discontinuation of the therapy in 56 cases (13%) (31 patients receiving i.m. gold, 12 receiving MTX, 10 receiving HCQ and three receiving NSAID only).

Administration, Oral↗
PubMed2000

Meta-analysis of treatment termination rates among rheumatoid arthritis patients receiving disease-modifying anti-rheumatic drugs.

OBJECTIVE: To summarize the evidence on treatment withdrawal rates reported in observational studies and randomized controlled trials (RCTs) of methotrexate (MTX), parenteral gold (GST), sulphasalazine (SSZ) and hydroxychloroquine (HCQ) among patients with rheumatoid arthritis (RA). METHODS: Two independent Medline searches were used to retrieve relevant studies published between 1966 and 1997. Those which disclosed information on the number of patients withdrawing from the drug were retained. Cumulative probabilities of survival on treatment were then computed using actuarial survival estimates, and differences were tested using log-rank, Wilcoxon and Cox proportional hazards tests. RESULTS: A total of 159 studies provided withdrawal information, and the numbers of patients who withdrew, in general or because of inefficacy or toxicity, could be abstracted from 110 studies contributing 142 treatment arms (MTX, 48; GST, 56; SSZ, 22; HCQ, 16). Data for HCQ were available only up to 24 months, but combined percentages of patients estimated to have continued MTX, GST or SSZ, respectively, for 60 months were 36, 23 and 22% when all failures were considered, 75, 73 and 53% when withdrawals due to lack of efficacy alone were considered, and 65, 36 and 48% when only withdrawals due to toxicity were taken into account. The Cox proportional hazards test performed on all withdrawals, after adjusting for year of publication and type of study, revealed that patients remained on MTX significantly longer than they did on the other three agents; however, the patients stayed significantly longer on GST than MTX when withdrawals for inefficacy were analysed separately. No significant differences in withdrawal rates were noted between observational studies and RCTs. CONCLUSION: Patients with RA stay significantly longer on MTX than on other disease-modifying anti-rheumatic drugs. Higher withdrawal rates among those given GST are mainly due to high toxicity, whereas the majority of withdrawals from SSZ and HCQ result from lack of efficacy. Withdrawal rates in observational studies are similar to those reported in RCTs.

Antirheumatic Agents↗
PubMed1991

Disease-modifying antirheumatic drugs: gold, penicillamine, antimalarials, and sulfasalazine.

In the assessment of the effects of disease-modifying antirheumatic drugs, three or four clinical measurements supported by the erythrocyte sedimentation rate, and sometimes radiographs, are generally agreed to be correct. Some advocate functional assessments also, or even alternatively. Several studies compared gold, penicillamine, antimalarials, and sulfasalazine either with each other or with placebo, and occasionally with methotrexate. No important differences between the general performance of the four drugs were found. More work was reported on sulfasalazine than on the other three drugs; the data support that it has a place in our armamentarium. Several important contributions concerned strategies of treatment. It is considered that disease-modifying antirheumatic drugs should be used earlier and more aggressively in rheumatoid arthritis. This aspect was perhaps the key note of the 1990 literature on this topic. As part of the new strategies, combination therapy is urged by some rheumatologists, whereas others urge caution on the grounds that we do not yet know enough about the effects of combinations, or by how much the risks of adverse effects are increased in combination.

Anti-Inflammatory Agents, Non-Steroidal↗
PubMed1998

Disease-modifying antirheumatic drugs.

Disease-modifying antirheumatic drug (DMARD) therapy is now clearly accepted as the primary treatment for rheumatoid arthritis, with an increasing emphasis on use of combination therapy. Data on combination therapy have highlighted the difficulties in performing these studies and the large number of patients required to produce meaningful results. Combination studies have focused on use of rapidly decreasing high-dose steroids as a part of the combination and emphasize the importance of using patients with early rheumatoid arthritis. Even with relatively aggressive use of DMARDs, the majority of patients develop erosions. Adverse reactions to DMARDs continue to concern clinicians, although evaluation of the frequency of these events has led to a reappraisal of previously accepted monitoring strategies in some cases. For example, it may not be cost-effective to subject patients on antimalarials to regular review by an ophthalmologist because of the low frequency of serious eye defects. Studies have also identified risk factors for the development of pulmonary toxicity in association with methotrexate. That DMARDs are effective in treating rheumatoid arthritis is beyond question-just how effective they are and what combinations of DMARDs will show improved efficacy will provide data for the next annual review.

Antimalarials↗
PubMed2003

Is there still a role for traditional disease-modifying antirheumatic drugs (DMARDs) in rheumatoid arthritis?

Rheumatoid arthritis is a chronic and debilitating disease, affecting an estimated 1% of the population worldwide. The past decade has witnessed an explosion in our understanding of the pathophysiology of rheumatoid arthritis and therefore in our ability to more effectively target the disease process. Although a cure remains elusive, remission is an approachable goal. There has been a complete remodeling of the traditional "pyramid" by rheumatologists, who now treat rheumatoid arthritis earlier and more aggressively than ever before. Standard single therapy with disease-modifying antirheumatic drugs, which was previously the final step in treating rheumatoid arthritis, is now practically bypassed in the deluge of information suggesting that combinations of disease-modifying antirheumatic drugs or newer biologic therapy is more effective. It is difficult to assimilate all the data and develop a rational approach; however, the bottom line is often the deciding factor: the newer agents are tremendously expensive. The intent of this article is to review recent and relevant trials in the treatment of rheumatoid arthritis, suggest a treatment algorithm, and argue that traditional disease-modifying antirheumatic drugs continue to play a pivotal role.

Anti-Inflammatory Agents↗
PubMed1992

Diseases of the intestine mimicking Crohn's disease.

We describe five patients who were initially thought to have Crohn's disease and were treated accordingly. The original diagnosis was based upon clinical presentation, roentgenograms, and histological examination, but subsequent follow-up showed that diagnosis to be in error. The following diagnoses were established instead: tuberculosis, Actinomyces Israeli infection, reaction to gold therapy, metastatic cancer, and linitis plastica. We stress the importance of considering conditions that can mimic Crohn's disease.

Actinomycosis↗
PubMed1991

Drug-induced pulmonary disease: an update.

The review provides an update of drug-induced pulmonary disorders, focusing on newer agents whose effects on the lung have been studied recently. Included among these drugs are cyclosporine, cytosine arabinoside (Ara-C), amiodarone, interleukin-2 (IL-2), OKT3, tricyclic antidepressants, and bromocriptine. A brief review of the most common cytotoxic and noncytotoxic agents causing pulmonary toxicity is also included.

Antibodies, Monoclonal↗
PubMed1997

Alternative treatments in the patient with intractable asthma.

Various medications have been suggested as alternative therapy for oral corticosteroids in the treatment of asthma, due to the known adverse effects of oral corticosteroids. Examples of such medications include methotrexate, gold, cyclosporin A, hydroxychloroquine, and dapsone, all of which have a significant side-effect profile. Intravenous gammaglobulin therapy used as an immuno-modulator has little if any side-effects, but it is very costly. The antileukotrienes represent a safe class of medications that may be of particular benefit to certain subgroups of asthmatic patients. Antileukotrienes have become commercially available in other countries.

Adrenal Cortex Hormones↗
PubMed1988

Structure of chlorobis(dicyclohexylphenylphosphine)gold(I).

[AuCl[C6H11)2(C6H5)P]2], Mr = 781.2, monoclinic, P2(1), a = 11.117 (4), b = 13.606 (5), c = 12.284 (4) A, beta = 109.59 (3) degrees, V = 1753 (2) A3, Z = 2, D chi = 1.48 g cm-3, lambda(Mo K alpha) = 0.71073 A, mu = 43.8 cm-1, F(000) = 792, T = 296 K, final R = 0.024 for 3239 unique observed reflections. The formation of complexes of the type LnAuX, where L is a phosphine, and X is halide or pseudohalide, shows considerable dependence on the nature of the phosphine. When L = Ph3P, three- and four-coordinated complexes are very easily prepared. However, for L = Cy3P, only linearly coordinated complexes could be isolated. The geometry of the title complex, with L = CyPhP, is best described as distorted trigonal planar. The P-Au-P angle is 158.24 (5) degrees while the P-Au-Cl angles are 92.63 (6) and 108.71 (6) degrees. Au-P distances are 2.300 (1) and 2.324 (1) A while Au-Cl is 2.744 (2) A.

Gold↗
PubMed1988

[N,N-bis(2-hydroxyethyl)dithiocarbamato-S,S']dichlorogold( II).

[Au(C5H10NO2S2)Cl2], Mr = 448.1, space group P212121 (No. 19), a = 7.446 (2), b = 11.434 (4), c = 13.110 (3) A, V = 1116.2 (5) A3, Z = 4, Dm = 2.74 (5), Dx = 2.67 g cm 3, graphite-monochromatized Mo Ka radiation, lambda = 0.71069 A, mu = 144.0 cm-1, F(000) = 832.2, T = 298 K, R = 0.0432, wR = 0.0397 for 1974 unique reflections and 118 parameters. The gold atom is in a roughly squareplanar environment, distorted as a result of the small bite distance of the chelating dithiocarbamate ligand. Molecules pack in the crystal lattice such that there are linear...S...Au...S... chains parallel to the a axis.

Hydrogen Bonding↗
PubMed1989

Structure of (2-benzoxazolethiolato)(triphenylphosphine)gold(I).

[Au(C7H4NOS)(C18H15P)], Mr = 609.7, monoclinic, P2(1)/n, a = 12.709 (3), b = 12.871 (4), c = 13.462 (6) A, beta = 94.64 (3) degrees, V = 2195 (2) A3, Z = 4, Dx = 1.84 g cm-3, lambda(Mo K alpha) = 0.71073 A, mu = 68.7 cm-1, F(000) = 1176, T = 296 K, final R = 0.033 for 2823 unique observed reflections. The 2-benzoxazolethiolate ligand (Sboz), which contains three potential coordination sites (N, O and S), forms a linear complex with a P-Au-S angle of 176.43 (8). The Au-P and Au-S distances are 2.258 (2) and 2.299 (2) A, respectively. This angle and these bond distances are similar to those of other phosphorous-gold-sulfur complexes such as the antiarthritic drug auranofin.

Chemical Phenomena↗
PubMed1991

Structure of chloro(dicyclohexylphenylphosphine)gold(I).

[AuCl(P(C6H5)(C6H11)2)), Mr = 506.8, orthorhombic, P2(1)2(1)2(1), a = 8.476 (5), b = 13.747 (2), c = 15.951 (3) A, V = 1858.8 (3) A3, Z = 4, Dx = 1.81 g cm-3, lambda (Mo K alpha) = 0.71073 A, mu = 81.24 cm-1, F(000) = 984, T = 296 K, final R = 0.031 for 1860 unique observed reflections. The complex Cy2PhPAuCl adopts the two-coordinate linear geometry typical of AuI complexes. The P-Au-Cl angle is 178.3 (1) degrees while Au-P and Au-Cl distances are 2.234 (2) and 2.281 (3) A, respectively. The geometry of the P atom is tetrahedral with an average Au-P-C angle of 112.1 (3) degrees and an average P-C distance of 1.827 (8) A.

Models, Molecular↗
PubMed1992

Structure of tris(dicyclohexylphenylphosphine)gold(I) perchlorate.

[Au(P(C6H11)2(C6H5))3][ClO4], M(r) = 1119.59, trigonal, R3c, a = 13.192(5), c = 52.83 (2) A, V = 7962 (9) A3, Z = 6, Dx = 1.401 g cm-3, lambda(Mo K alpha) = 0.71073 A, mu = 29.5 cm-1, F(000) = 3468, T = 296 K, final R = 0.047 for 1321 unique observed reflections. The Au atom in the anion and the perchlorate ion in [Au(Cy2PhP)3][ClO4] lie on a threefold axis. The complex has an almost ideal trigonal-planar geometry, with an Au--P distance of 2.421 (3) A, P--Au--P angles of 119.9 (3) degrees, and the Au atom only 0.08 (2) A out of the plane defined by the three P atoms.

Chemical Phenomena↗
PubMed1995

Chrysiasis revisited: a clinical and pathological study.

Chrysiasis is a distinctive and permanent pigmentation of light-exposed skin resulting from the administration of parenteral gold salts. We report a study of 40 Caucasian patients with rheumatoid arthritis, treated with intramuscular sodium aurothiomalate, of whom 31 had chrysiasis. Visible changes develop above a threshold, equivalent to 20 mg/kg gold content, and their severity depends upon cumulative dose. Focal aggregates of particulate gold are deposited in the reticular and papillary dermis in amounts that correlate with the degree of pigmentation. Characteristically, initially the periorbital region is affected by a mauve discoloration, which intensifies and deepens into a blue/slate-grey colour, while extending to involve the face, neck and upper limbs. Although chrysiasis develops insidiously and patients may be unaware of the changes, positive identification is important in order to avoid misdiagnosis and medical mismanagement, and afford appropriate reassurance. Prevention is difficult, but measures to reduce sunlight exposure may be helpful.

Antirheumatic Agents↗