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.

Antithrombin activity of gold sodium thiomalate.

Gold sodium thiomalate has been shown to inhibit serine esterase enzymes isolated from the lysosomes of white cells. We demonstrate for the first time to our knowledge that gold sodium thiomalate is inhibitory to the serine esterase thrombin in its interaction with washed human platelets, human platelet-rich plasma, and human platelet-poor plasma. Since thrombin is a serine esterase phylogenetically related to the serine esterases elastase and cathepsin G, the most likely mechanism of action is an interaction of the gold thiol complex with one or all of the four cysteine-cysteine disulfide bridges of the thrombin molecule.

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.

D-penicillamine: chemistry and clinical use in rheumatic disease.

The discovery of D-penicillamine and its uses in medicine are reviewed. Chemical-physical properties are discussed, and the molecular structure of D-penicillamine and several of its reaction products are illustrated. Examples of its three main types of biochemical reactions--sulfhydryl-disulfide exchange, thiazolidine formation, and metal chelation are included. Trials of D-penicillamine in RA patients are reviewed critically. The administration of the drug is discussed in detail, including dosages, clinical and laboratory responses, patterns of adverse side effects or toxicity, drug-induced autoimmune diseases, indications and contraindications, and the monitoring and management of patients.

Gold induced thrombocytopenia: 12 cases and a review of the literature.

Gold induced thrombocytopenia is immune mediated, with the production of platelet associated IgG leading to peripheral platelet destruction. An association with HLA-DR3 has been demonstrated. Corticosteroid therapy is effective in treatment, although other modes of therapy may be as efficacious.

Problems of antiarthritic therapy in the elderly.

Rheumatic diseases are prevalent in the elderly population, resulting in high morbidity caused mainly by lack of mobility. Consequently, the use of antirheumatic drugs in older persons is extensive. This review outlines some of the hazards encountered in the use of antirheumatic drugs in the elderly. Analgesics such as propoxyphene and acetaminophen are useful adjuncts to the treatment of arthritic pain, but propoxyphene has been associated with respiratory depression, and renal clearance of acetaminophen is reduced in elderly subjects. Salicylates may cause deafness, and like the other nonsteroidal anti-inflammatory drugs, may cause salt and water retention resulting in congestive cardiac failure. Phenylbutazone should not be used because of the risk of blood dyscrasia, and indomethacin has been reported as interfering with the antihypertensive effect of beta-blockers. Chloroquine levels may be raised in patients with impaired renal function, and there is increased risk of retinal damage with the drug in elderly subjects. Injectable gold compounds and penicillamine are not contraindicated in the elderly, because they are just as efficacious as in younger persons for the treatment of rheumatoid arthritis. Toxicity due to gold compound is not increased in the elderly, but skin rashes and abnormalities of taste do occur more commonly in elderly patients treated with penicillamine. Corticosteroids do not affect disease progression and therefore should be used only in acute severe disease for short periods of time. As in the younger population, treatment of gout in the elderly is dependent on renal function.(ABSTRACT TRUNCATED AT 250 WORDS)

Efficacy and toxicity of D-penicillamine for rheumatoid disease in the elderly.

The efficacy and the toxicity pattern of D-penicillamine were studied in patients with rheumatoid disease followed up between April 1975 and March 1979. The population of patients was divided into an elderly group (greater than or equal to 60 years old, mean = 65 years) and a younger group (less than 60 years old, mean = 41 years). Patients with classic or definite rheumatoid disease not responsive to nonsteroidal drugs were eligible. The mean durations of disease prior to D-penicillamine therapy were five years in the elderly and seven years in the younger group. Overall, the mean follow-up time was 11 months. The average dosages of D-penicillamine were 461 mg/day in the elderly and 520 mg/day in the younger patients. Results indicated that D-penicillamine was efficacious in 75 per cent of the elderly during all time periods after three months, and in 75 per cent of the younger patients after three months until at least two years. Prior gold-salt therapy did not influence efficacy. Toxicity was significantly greater in the elderly for overall skin rash (P less than 0.01), severe skin rash (P less than 0.01), and marked abnormalities in the ability to taste (P less than 0.05). The incidence of hematologic toxicity was not increased in the elderly compared with the younger patients. Toxicity in either group was not influenced by prior gold-salt therapy. It is concluded that D-penicillamine was equally efficacious in both elderly and younger groups, and that the toxicity patterns were similar except for increased tendencies toward rashes and taste abnormalities in the elderly.

Maternal and neonatal implications of congenital complete heart block in the fetus.

The detection of congenital complete heart block (CCHB) in a fetus should alert the obstetrician that the welfare of both the mother and the newborn infant may be in jeopardy. An awareness of this uncommon cause of fetal bradycardia and judicious intrapartum monitoring can avert hasty and unnecessary cesarean section for suspected fetal asphyxia. Neonatal consequences may range from no effect to life-threatening congestive heart failure. The apparently healthy mothers of these infants may be at increased risk for the subsequent development of collagen vascular disease. Three recent case reports demonstrate the spectrum of neonatal and maternal disease that may accompany CCHB. The significance of abnormal serology suggesting a propensity for collagen vascular disease in an otherwise healthy parturient is discussed, and a program for follow-up is proposed.

The pharmacokinetics of flurbiprofen in younger and elderly patients with rheumatoid arthritis.

The pharmacokinetics of flurbiprofen (Ansaid Tablets, Upjohn Company of Canada, Don Mills, Ontario) were evaluated in both younger (40 to 60 years) and elderly (65 to 83 years) rheumatoid arthritic patients after both a 100-mg single-dose administration and at steady state during a 100-mg twice-a-day dosage regimen. Both flurbiprofen plasma concentration-time profiles and the urinary excretion of flurbiprofen and its major metabolites were evaluated. The results indicate that the pharmacokinetics of flurbiprofen are linear in both age groups based on only minor changes between single-dose and steady-state parameter determinations and the agreement between calculated and predicted accumulation values in plasma concentrations. Only minor differences in the pharmacokinetic parameters were observed between the younger and elderly patients. Only free flurbiprofen clearance was found to have a significant but variable correlation to patient age. The effect of flurbiprofen on the urinary excretion of two prostaglandins were also evaluated throughout this study. In both age groups, the maximum decrease in urinary excretion was observed after the first dose, and this effect was maintained throughout the remainder of the study. Percent decreases from baseline in urinary excretion during drug administration were similar for both age groups. Similar side-effect profiles were observed between age groups.

Clinical therapeutic trial of aspirin and azapropazone in rheumatoid arthritis when prescribed singly and in combination.

A double-blind, crossover trial was carried out to assess the clinical efficacy of 3.6 g aspirin, 1200 mg azapropazone and the two drugs together in 24 adult patients with classical or definite rheumatoid disease. Pain score, morning stiffness and patients' assessment of pain were significantly improved for each drug regimen when compared to placebo. There was no significant difference among the individual drug regimens. Azapropazone was the best drug regimen in terms of improving pain score, morning stiffness and patient assessment of pain, but this was not statistically significant. It is concluded that there is no justification for prescribing aspirin with azapropazone in patients with rheumatoid disease.

A biological effect on platelets by the minor component of gold sodium thiomalate--a by-product of heat sterilization and exposure to light.

Gold sodium thiomalate as currently used is a mixture probably consisting of small polymers of different structures. The colourless and yellow solutions have been studied in platelets, which had been known to show biological effects of the yellow solution. Only the yellow solution causes ADP dependent platelet aggregation. Platelets treated with the yellow solution contain larger particles (100-700 nm in diameter) compared to a maximal particle size of 40 nm from the colourless solution. The biological differences observed may be due to phagocytosis of the larger components with resultant ADP release and aggregation.

Biological action of colorless and yellow solutions of gold sodium thiomalate on thrombin activity and the mixed lymphocyte reaction.

Gold sodium thiomalate is a pale yellow powder which forms a colorless solution when added to sterile water. The marketed form of gold sodium thiomalate is a pale yellow solution. The yellow color develops as a result of the sterilization process. This study demonstrates that the physical change induced in the drug by the sterilization process has no effect on the action of gold sodium thiomalate on the serine esterase thrombin, nor on the inhibition of the mixed lymphocyte response. Thus it is unlikely that the yellow component is responsible for benefit in rheumatoid arthritis. If the components creating the yellow color cause toxicity, the preparation and/or formulation of the drug should be changed.

Effect of R and S enantiomers of naproxen on aggregation and thromboxane production in human platelets.

The effects of R and S enantiomers of naproxen [(+)-6-methoxy-alpha-methyl- 2-naphthaleneacetic acid] were studied on platelet aggregation and on the production of thromboxane B2 from collagen-stimulated human platelets in order to determine the effect of each enantiomer in terms of cyclooxygenase inhibition. S-Naproxen caused inhibition of platelet aggregation in platelet-rich plasma and washed human platelets in a concentration-related fashion in the range 1-80 micrograms/L. A similar concentration-related suppression was noted for R-naproxen, but this inhibition was significantly less than that induced by S-naproxen for all concentrations except 1 micrograms/L. Similarly, both R- and S-naproxen (1-80 micrograms/L) caused a concentration-dependent suppression of thromboxane B2 production from platelet-rich plasma. These values were significant at all concentrations of drug (10-80 micrograms/L) except at 1 micrograms/L. Significant differences in thromboxane B2 production from washed human platelets were noted at concentrations of 10 and 25 micrograms/L. The findings support previous studies reported in the literature that S-naproxen is more active than R-naproxen. Our findings that S-naproxen is more active than R-naproxen on collagen-stimulated platelet aggregation and prostaglandin production suggest that the findings of greater activity of S isomer over the R isomer in animal models of inflammation may be a direct expression of the differential action on prostaglandin synthesis.

Action of gold sodium thiomalate on experimental thrombosis in vivo.

In order to study the effect of gold compounds on the action of thrombin in vivo, experiments were performed to measure platelet survival and the weight of thrombus formation in experimental models of intra-aortic thrombosis by two indwelling aortic catheter methods. We have called these the long and short catheter methods. Platelet survival was reduced in all gold-treated and control animals which had indwelling aortic catheters. In the long catheter model, New Zealand White male rabbits were treated with one of the following: gold sodium thiomalate, sterile water, gold thioglucose, gold sodium thiosulfate, disodium thiomalate. Gold sodium thiomalate-treated rabbits had a reduced weight of experimentally induced intra-aortic thrombi compared with animals treated with sterile water or equimolar concentrations of gold thioglucose, gold sodium thiosulfate, or disodium thiomalate. This reduction in thrombus weight in the animals treated with gold sodium thiomalate was not reflected by changes in platelet survival or fibrinolysis. The serum gold levels achieved in these in vivo experiments was in the range of 5.0 X 10(-5) to 1.0 X 10(-4) M. These values are comparable to levels which can be achieved in human subjects immediately after a gold injection. In the short catheter model, New Zealand White male rabbits were treated with either gold sodium thiomalate, gold thioglucose, disodium thiomalate, or auranofin. Controls were given either water or 0.05% chlorocresol. Water-treated and gold sodium thiomalate-treated animals were also given 51Cr-labeled platelets and 125I-fibrinogen before insertion of the catheter.(ABSTRACT TRUNCATED AT 250 WORDS)

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.

The contribution of William Hunter (1718-1783) to the study of bone and joint disease.

William Hunter (1718-1783), the elder of the two famous Hunter brothers, is best known for his remarkable book The Anatomy to the Human Gravid Uterus, and for his contributions to the art of midwifery. However, Hunter also made significant observations in cardiovascular disease, in comparative anatomy, and paleopathology. It is perhaps not sufficiently known that he also made significant contributions in rheumatic disease, and in particular, the anatomy and physiology of cartilage.

Measurement of pain threshold in patients with rheumatoid arthritis, osteoarthritis, ankylosing spondylitis, and healthy controls.

Pain threshold was measured using a pressure algometer in 126 subjects, of whom 54 were females and 72 males. These subjects included 18 males and 18 females with rheumatoid arthritis, 18 males and 18 females with osteoarthritis, 18 males with ankylosing spondylitis, and 18 male and 18 female healthy control volunteers. Six points were studied on each side of the body: 2 cm above the eyebrow on the forehead, lateral aspect of the arm at the insertion of the deltoid muscle, midpoint of the ulna, hypothenar eminence in the palm, midpoint of the quadriceps muscle, and midpoint of the antero-medial aspect of the tibia. None of these points corresponded to the "trigger" points in fibromyalgia. The pain threshold was statistically significantly higher in patients with ankylosing spondylitis than in patients with osteoarthritis, and these in turn were statistically higher than in the normal subjects. Patients with rheumatoid arthritis had significantly lower pain thresholds than the normal subjects. No laterality in pain threshold was identified, but females had in general a lower pain threshold.

A controlled comparison of piroxicam and diclofenac in patients with osteoarthritis.

Eighty patients with osteoarthritis were randomly assigned to either piroxicam (20 mg daily) or diclofenac (75-150 mg daily) in a 12-week double-blind, parallel groups study. In the 70 patients who completed the study, both medications were effective; statistically significant improvement was observed on all assessments of efficacy. However, no statistically significant differences between the two drugs were seen on any of the efficacy parameters measured. There was a trend towards better tolerance in the piroxicam treated patients, although this was not statistically significant; 3 of the 40 piroxicam treated patients versus 6 of the 40 patients on diclofenac were discontinued from the trial due to intolerable adverse events.

Robert Burns's illness revisited.

A careful review of Robert Burns's terminal illness, especially as documented in his correspondence, supports the widely held contention that death may have been due to subacute bacterial endocarditis secondary to chronic rheumatic heart disease. However, it is also possible that death have been caused by brucellosis or some non-infectious process such as malignant lymphoma. There is no evidence that Robert Burns suffered from either chronic alcoholism or venereal disease. The evidence that he may have died a doctor's martyr as a result of treatment with a mercury ointment is critically examined.