Therapy and pharmacological properties of hydroxychloroquine and chloroquine in treatment of systemic lupus erythematosus, rheumatoid arthritis and related diseases.

OBJECTIVES: This review examines the pharmacokinetics, modes of action and therapeutic properties of the anti-malarial drugs, hydroxychloroquine (HCQ) and chloroquine (CQ), in the treatment of systemic lupus erythematosus (SLE), rheumatoid arthritis (RA) and related conditions, as well as osteoarthritis (OA). KEY FINDINGS: Both HCQ and CQ have historically been employed successfully for the treatment of SLE and RA for over 70 years. HCQ has been used extensively for SLE where it has a good reputation for controlling the dermatological complications in SLE. It has also been reported to effectively control the symptoms of Sjøgren's syndrome, as well as preventing thrombosis in phospholipid antibody (aPL) syndrome. In RA and SLE, HCQ is preferred because of the lower incidence of gastrointestinal adverse reactions compared with CQ and it might have a lower risk of ocular adverse reactions. There is increasing evidence that HCQ may reduce atherosclerosis and risks of cardiovascular disease in rheumatic patients. Both HCQ and CQ have been shown to improve glycaemia and reduce the risks of type II diabetes mellitus. Although both HCQ and CQ are effective in low-moderate RA, HCQ is now preferred as part of combination therapy for more severe disease. The advantages of combination therapy are that the doses of the individual drugs may be lowered so reducing adverse reactions. Both HCQ and CQ are diastereoisomers, have basic properties and are given as the sulphate and phosphate salts. While being relatively well absorbed orally and with good bioavailability, they have long and variable plasma terminal elimination half-lives (approximately 40-60 days). This reflects their high volume of distribution, V D (HCQ 44,000L; CQ 65,000L) which extends into aqueous compartments, long mean residence time (HCQ 1300 h; CQ 900 h) and with about half the drugs (metabolites) undergoing renal clearance. The strong binding to melanin reflects the ocular injury and dermatological properties of these drugs. The consensus is that the occurrence of ocular adverse reactions can be minimised by close attention to the dose (which should be set on a body weight basis) with regular (e.g. quarterly) retinal examination. Although HCQ and CQ can pass through the placenta, the use of these drugs during pregnancy does not appear to risk harm to the baby and might be beneficial to the mother with SLE and her child by controlling the SLE disease activity, which is known to be an important factor affecting pregnancy outcome. The modes of action of HCQ and CQ in these arthritides represent somewhat of an enigma. Undoubtedly, these drugs have multiple actions related, in part, their ability to accumulate in lysosomes and autophagosomes of phagocytic cells as well as affecting MHC Class II expression and antigen presentation; actions of the production of pro-inflammatory cytokines [e.g. interleukin-1 (IL-1) tumour necrosis factor-α (TNFα)]; control of toll-like receptor-9 activation; and leucocyte generation of reactive oxygen species (ROS); i.e. antioxidant activity. The actions of these drugs on T and B cells are less clear but may depend on these leucocyte-mediated actions. Anti-malarials also protect against cytokine-mediated cartilage resorption. This and other actions may underlie the potential benefits in treating OA. The exact relationships of these various actions, mostly determined in vitro, have not been specifically defined in vivo or ex vivo in relation to clinical efficacy. OUTCOMES: HCQ and CQ have a good reputation for being effective and relatively safe treatments in SLE, mild-moderate RA and Sjøgren's syndrome. There is need for (a) more information on their mode of action in relation to the control of these diseases, (b) scope for developing formulations that have improved pharmacokinetic and therapeutic properties and safety, and (c) further exploring their use in drug combinations not only with other disease modifying agents but also with biologics.

The biological activity of auranofin: implications for novel treatment of diseases.

More than 30 years ago, auranofin was developed for the treatment of rheumatoid arthritis as a substitution for the injectable gold compounds aurothiomalate and aurothioglucose. Both the ease of oral administration over intramuscular injections and more potent anti-inflammatory effects in vitro made auranofin seem like an excellent substitute for the traditional injectable gold compounds. Despite efficacy in the treatment of both rheumatoid arthritis and psoriasis, currently, auranofin is seldom used as a treatment for patients with rheumatoid arthritis as more novel anti-rheumatic medications have become available. Despite the decline in its clinical applications, research on auranofin has continued as it shows promise in the treatment of several different diseases. In recent years, advances in technology have allowed researchers to use molecular techniques to identify novel mechanisms of action of auranofin. Additionally, researchers are discovering potential new applications of auranofin. Dual inhibition of inflammatory pathways and thiol redox enzymes by auranofin makes it a new candidate for cancer therapy and treating microbial infections. This review will summarize recently obtained data on the mechanisms of action of auranofin, and potential new applications of auranofin in the treatment of various diseases, including several types of leukaemia, carcinomas, and parasitic, bacterial, and viral infections.

The clinical assessment of transitional vertebrae and back pain.

This study examines the relationship between radiological evidence of lumbar transitional vertebrae (LTV) and the clinical presentation of low back pain (LBP). A retrospective review of 232 consecutive patients presenting at a specialist musculo-skeletal clinic with LBP was conducted. The medical chart for each patient was reviewed for: gender, birth date, symptoms, physical findings, imaging results, and medications prescribed. Subjects were recognized as having a lumbar transitional vertebra if it was noted on their x-ray report. The prevalence of LTV was 9.5 %. This study is consistent with previous research, indicating that the prevalence of LTV is not significantly higher amongst patients with LBP. However, this study also provides further detail about the clinical presentation and management of patients with LTV. The information presented in this study will assist health care professionals in determining the clinical significance of a LTV seen on an x-ray film or noted in a radiologist's report.

Review of the pharmaceutical properties and clinical effects of the topical NSAID formulation, diclofenac epolamine.

BACKGROUND: Topical formulations of non-steroidal anti-inflammatory drugs (NSAIDs), in particular diclofenac (DI), have become popular for treating various acute and chronic painful inflammatory conditions. OBJECTIVE: To perform a literature review of (1) the use of topical NSAIDs; (2) the pharmaceutical, pharmacokinetic and pharmacodynamic properties of a medicated plaster (patch) containing diclofenac epolamine (DI-EP, Flector Tissugel, Flector patch) compared with other formulations of topical NSAIDs; and (3) evaluation of the clinical findings from studies with this novel DI-EP patch. OUTCOMES: (1) Pharmacokinetic studies involved determination of DI from DI-EP and separately epolamine (EP) and the epoxide metabolite (N-oxide-EP) in laboratory animals and humans; the latter being the major metabolite in humans. About 2% of DI is absorbed by the skin in humans and is excreted in the urine. Maximum plasma concentrations of 17.4 ng/mL DI are reached at 5.4 hours (approximate steady state conditions); the plasma elimination half-time (t(1/2)) being 26.4 hours. Low systemic levels of DI and EP are produced from DI-EP. Pronounced accumulation of DI occurs in the muscle layers and in synovial fluids of arthritic patients; (2) No significant toxicity occurs from EP nor N-oxide-EP, while that of oral DI-EP was similar to that from DI; and (3) In acute musculoskeletal conditions (sprains, tendonitis and sports injuries) and osteoarthritis DI-EP patches control pain and signs of joint or physical injury compared with placebo controls by 3-5 days with almost complete pain relief at 14 days. DI-EP was shown to have equivalent therapeutic effect to another DI diethylammonium gel formulation (Voltaren Emulgel). There were no reports of serious adverse events in the gastro-intestinal (GI) tract, kidneys or liver from DI-EP. Mild GI symptoms and skin reactions occur in 2 and 10% of patients, respectively. CONCLUSIONS: The patch delivery of DI in DI-EP affords controlled delivery of the active drug in contrast to that from application of gels or ointments of NSAIDs.

Clinical pharmacology of gold.

Since the dawn of civilization, elemental gold and gold compounds have been revered and utilized by Shamen and medical practitioners alike for many varied pathological problems. In the 20(th) century following the observations of Jacques Forestier, injectable gold compounds were successfully used for the treatment of rheumatoid arthritis. Of the many compounds developed, gold sodium thiomalate has been the most extensively studied by basic scientists and by clinicians. In the1980s, the oral gold compound auranofin showed promise as a therapeutic contender to injectable gold, but the clinical side effect profile and fear of long term effects of immune suppression by auranofin, resulted in gold sodium thiomalate continuing as the preferred gold compound for rheumatoid treatment. However, the increased use and demonstration of effectiveness of low dose Methotrexate (MTX) in rheumatoid treatment over the last 20 years has resulted in a significant decline in the use of injectable gold sodium thiomalate, this despite the claims and evidence that it remains a useful agent in the management of rheumatoid arthritis. Several authors still contend that the injectable gold compounds can still play a valuable role, and indeed may be the correct first choice in the management of rheumatoid arthritis.

Management of chronic musculoskeletal pain in the elderly: opinions on oral medication use.

The use of oral medication in the treatment of chronic musculoskeletal pain in the elderly requires careful selection of drugs to control pain with consideration for both the physiological state and the presence of disease(s). Recent advances have improved the understanding of biomolecular mechanisms of chronic pain. These include the production of powerful pro-inflammatory cytokines by glial and microglial cells, which then lead to activation of major pain pathways from the periphery through the dorsal horn and supra-spinal pathways to the somatosensory and other higher cortical centres. This has allowed better recognition for intervention with anti-inflammatory agents to control cytokine production (e. g. prednisolone, triamcinolone and other brain-penetrating corticosteroids). Advances in understanding of chronic pain have lead to recognition of neuronal PX2 puringergic receptors as potential sites for drugs to control pain by more selective actions. Pain control in the elderly involves extensive use of analgesics, among them the non-steroidal anti-inflammatory drugs (NSAIDs), paracetamol (acetaminophen), and various narcotics. Each of these has its drawbacks, mostly related to potential toxicities. Attempts to reduce the serious gastro-intestinal (GI) adverse effects of the NSAIDs by the introduction of the highly selective COX-2 inhibitors (coxibs) have only had limited benefit in reducing these untoward actions. Moreover, the risks of serious cardiovascular (CV) and renal side-effects, though statistically infrequent, are none the less of major concern. Cardio-renal effects have been attributed to some (e. g. diclofenac), but not all (e. g. naproxen) conventional NSAIDs. Here we make recommendations for a selection of certain NSAIDs to be used for pain therapy in the elderly in consideration of their relative safety and pharmacokinetics. While newer formulations of narcotics have given some advance in pain control, the application of this group of drugs requires close supervision in the elderly, especially those with cognitive decline, since drug actions on the central and peripheral nervous systems (CNS, PNS) can result in significant adverse effects of these agents (e. g. constipation, drowsiness, respiratory and cardiovascular decline). Improvements in the safety and effectiveness of musculoskeletal pain therapy in the elderly can only be achieved by identification and frequent re evaluation of the cause of the chronic pain and the impact on the patient's general medical state.

Osteoarthritis: symptoms, signs and source of pain.

Osteoarthritis is the most common form of arthritis. The condition is characterised by loss or failure of the functional and/or biochemical integrity of the joint. The clinical symptoms include joint stiffness, pain and dysfunction, but the principal problem for the majority of patients is the pain. Although there are no pain receptors in the cartilage, the origin of the pain is thought to be due to stimulation of the A delta mechanoreceptors and the C polymodal nerve endings in the synovium and surrounding tissues. However, some of the pain experienced in and around the joints is referred pain or sympathetic efferent pain. In addition, there is a poor correlation of clinical symptoms with radiological or imaging appearance. This lack of correlation of clinical evaluation and imaging makes attempts at treatment difficult and compromises attempts to design studies and to evaluate the outcome of osteoarthritis in clinical trials.

Nonsteroidal anti-inflammatory drugs: overused or underused in osteoarthritis?

Arthritis and musculoskeletal disorders are common. Arthritis currently accounts for 2% to 3% of all cases of disability, and the numbers are rising. Nonsteroidal anti-inflammatory drugs (NSAIDs) are widely used, with 75 million prescriptions annually in the United States and 25 million in the United Kingdom. The volume of side effects noted, most of which are gastrointestinal and can be serious, imply the overuse of these drugs, especially in relation to the estimated prevalence of osteoarthritis (OA), where pain relief may be considered more important than an anti-inflammatory effect. There are conflicting data about the efficacy of NSAIDs compared with analgesics alone for pain relief. However, the interpretation of data comparing the two drug classes is limited by shortcomings in research methodologies and by difficulties in incorporating the anti-inflammatory effect of NSAIDs into the outcomes. The efficacy of paracetamol for some patients has been underestimated; however, although those with mild disease may find paracetamol adequate, most patients with OA are likely to gain more benefit from NSAIDs.

A comparative study of signal versus aggregate methods of outcome measurement based on the WOMAC Osteoarthritis Index. Western Ontario and McMaster Universities Osteoarthritis Index.

OBJECTIVE: To compare signal versus aggregate measurement strategies using the VA3.0S version of the Western Ontario and McMaster Universities (WOMAC) Osteoarthritis (OA) Index. METHODS: Seventy patients with OA of the knee were asked to identify a signal item for each of the 3 dimensions of the WOMAC OA Index at baseline and termination of a 12-week, double blind, randomized, controlled trial. RESULTS: The signal method detected statistically significant alterations in health status at relatively small sample sizes and with a relative efficiency close to or at unity. In addition to a low prevalence of deterioration in nonsignal items, we observed some inconsistency in signal selection. CONCLUSION: Signal methods of measurement may provide an alternative approach to outcome measurement provided issues of nonsignal deterioration and the consistency of signal selection can be addressed.

A multicenter study of tenoxicam and diclofenac in patients with osteoarthritis of the knee.

OBJECTIVE: To conduct the first Canadian study of the comparative efficacy and safety of tenoxicam and diclofenac in patients with primary osteoarthritis (OA) of the knee. METHODS: Tenoxicam 20 mg per os once daily (po od) was compared to diclofenac (Voltaren) 50 mg per os 3 times a day (po tid) in a 12-week, double blind, randomized, controlled, multicenter, parallel trial. The primary outcome measure was the pain dimension of the WOMAC OA Index. Following an initial screening visit and a 3 to 7 day NSAID-free washout period (i.e., baseline), patients were assessed at Weeks 2, 4 and 12; assessments including some 15 efficacy variables and safety variables. RESULTS: Ninety-eight patients [tenoxicam (n = 48), diclofenac (n = 50)] participated in the trial. Statistically significant (p < or = 0.05) improvements in all 3 dimensions of the WOMAC OA Index and six efficacy variables were noted in both treatment groups. No significant between drug differences were noted on any efficacy variable. Significantly fewer patients reported adverse events in the tenoxicam group (21 vs 33, p = 0.03). CONCLUSION: Tenoxicam is efficacious and well tolerated in patients with OA of the knee. In this group of patients it was similar in efficacy and superior in tolerability to diclofenac 150 mg/day (50 mg tid). Thus the benefit/risk ratio of tenoxicam was superior to that of diclofenac in this study.

Site of action for the inhibition by gold sodium thiomalate of rabbit platelet activation.

The inhibitory action of the gold-based drug gold sodium thiomalate was investigated in rabbit platelets. Gold sodium thiomalate at concentrations of 0.25-13 x 10(-4) M inhibits collagen-, ADP-, and 9,11,dideoxy-11 alpha,9 alpha-epoxymethanoprostaglandin F2 alpha (U46619)-induced aggregation as well as collagen- and U46619-induced serotonin release. This inhibition occurs in both Tyrodes-albumin or Tyrodes-gelatin buffer systems. Preincubation of gold sodium thiomalate with platelets resulted in less inhibition as the time of preincubation increased. The inhibitory effect of gold sodium thiomalate could be removed by washing the platelets. Other sulfhydryl-reacting compounds, such as D-penicillamine, thiomalic acid, 5,5'-dithiobis-2-nitrobenzoic acid, and 6,6'-dithiodinicotinic acid, were all capable of inhibiting collagen-induced aggregation and serotonin release. Evidence is presented that gold sodium thiomalate interferes with the activation of rabbit platelets by several activators, that this action of gold sodium thiomalate is similar to the action of other sulfhydryl-reacting agents, that this inhibition is likely occurring at the membrane, and that the action of the drug is not dependent on the presence of albumin.

Osteoarthritis antirheumatic drug trials. I. Effects of standardization procedures on observer dependent outcome measures.

We designed a study to assess the effects of standardization procedures on reducing interobserver variability for outcome measures given in the current Food and Drug Administration and European League Against Rheumatism guidelines and others selected from the rheumatology literature. Over 2 days, 6 rheumatologists independently examined 6 patients with osteoarthritis (OA) in predetermined order before and after standardizing their examination techniques. An important and beneficial effect of the standardization procedure was observed on the majority of outcome variables. Such reductions in observer variability have the potential to diminish sample size requirements for OA antirheumatic drug studies.

Osteoarthritis antirheumatic drug trials. II. Tables for calculating sample size for clinical trials.

The calculation of sample size for clinical trials requires knowledge of the standard deviation (SD) of index variables. There are no published lists of SD and it is difficult to locate variance estimates based on relevant populations. In this study we used standardized procedures to determine in 60 patients with osteoarthritis (OA) of the knee the standard deviation of key outcome measures recommended in current Food and Drug Administration and European League Against Rheumatism guidelines for OA clinical trials. These tables will be useful to clinical researchers in selecting outcome measures as well as for calculating sample size requirements for future clinical studies in OA.