3 Antimalarials in rheumatic diseases SUSAN TETT DAVID CUTLER RICHARD DAY

Two drugs used for the treatment and prophylaxis of malaria--hydroxychloroquine and chloroquine--are also used to treat various rheumatic diseases, notably rheumatoid arthritis and systemic lupus erythematosus. Hydroxychloroquine and chloroquine have been used in the treatment of these connective-tissue disorders since the early 1950s. The antimalarials are sometimes termed slow-acting antirheumatic drugs, taking up to 6 months to achieve a maximal result in rheumatoid arthritis patients, and they are reported to improve the rheumatoid disease state in up to 60-80% of patients on long-term therapy. These results are not substantively different from those reported for other slow-acting antirheumatic agents. The mechanism of action of antimalarials in rheumatic diseases remains to be elucidated. There is no radiological evidence available to suggest that hydroxychloroquine or chloroquine can retard progression of joint damage in rheumatoid arthritis patients. However, these drugs have been subject to only limited study of their effects on the radiological abnormalities resulting from rheumatoid arthritis. A major advantage of hydroxychloroquine and chloroquine is the lack of potentially life-threatening toxicities, which is not the case with a number of other second-line antirheumatic medications available. These drugs are therefore an attractive alternative for use in the early stages of rheumatoid arthritis or in combination with other antiarthritic agents for more severe disease (see Chapter 11). This review focuses on the evidence for efficacy of antimalarials in the rheumatic diseases, new data concerning the pharmacokinetics and distribution of antimalarials and the implications of these findings for the clinical use of these drugs. EFFICACY

Hydroxychloroquine Mainland and Sutcliffe (1962) conducted a double-blind placebo-controlled clinical trial investigating the efficacy of hydroxychloroquine in adult patients with rheumatoid arthritis. The study was conducted over 6 months Baillibre' s Clinical Rheumatology--

Vol. 4, No. 3, December 1990 ISBN 0-7020-1484-2

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in a total of 113 patients, 60 randomized to receive placebo and 53 to receive hydroxychloroquine (800 mg of the sulphate salt daily). The rheumatoid parameters that improved and were ascribed to drug therapy included the change in functional class, the five-point score (one point each for improvement in morning stiffness, number of clinically active joints, grip strength, erythrocyte sedimentation rate (ESR), and 50-foot walking time) and the observers' overall assessment. In another double-blind crossover design trial 41 patients with rheumatoid arthritis were recruited (Hamilton and Scott, 1962). Each patient received, in a randomized order, 12 weeks of therapy with 600 mg of hydroxychloroquine sulphate and 3 mg of hydroxychloroquine (considered to be inactive, placebo therapy). In the patients' own estimation, improvement was greater on active therapy. A significant difference was noted in the number of extra analgesics required during the hydroxychloroquine and the placebo periods, less being required when the active drug dose was taken. Other parameters such as changes in joint tenderness, grip strength and ESR tended towards improvement with hydroxychloroquine, but did not achieve statistical significance. The study was only conducted over 3 months of therapy and greater differences may have been recorded had the study been extended over a longer period of time. Kersley and Palin (1959) gave alternating courses (about 3 months each) of hydroxychloroquine sulphate (400 or 800 mg per day), amodiaquine and placebo. The results showed much improvement (patients' evaluation and grip strength) in 50% of the patients taking 800mg hydroxychloroquine sulphate per day and some improvement in 100% of these patients. In 6% of the patients taking 400 mg per day much improvement was recorded and in 72% of these patients some improvement was noted. This compares with only 6% of patients showing some improvement on placebo therapy. Again this was a short study, but improvement was noted for the drug over placebo. Because of the variability in the rheumatoid disease state and the natural fluctuations of the disease with time, it was important initially to establish the efficacy of hydroxychloroquine by comparing it with placebo. As the therapy was shown to be effective, it becomes an ethical consideration whether therapy can be withheld. Later studies in rheumatoid arthritis are either open studies or they compare different doses of hydroxychloroquine, or compare efficacy against other established or experimental therapy. Placebo-controlled trials are no longer ethical after efficacy has been demonstrated. A retrospective study of 108 patients with rheumatoid arthritis receiving hydroxychloroquine was reported by Adams et al (1983). The patients were treated for longer than 6 months, most receiving 400 mg of the sulphate salt daily, but some receiving 200rag. Twelve per cent of the patients were reported to have achieved complete remission and 63% to show a 30% or greater response, assessed by measuring the active joint count, duration of morning stiffness, grip strength, proximal interphalangeal joint circumference, American Rheumatism Association (ARA) functional class, ESR and haemoglobin.

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Miller et al (1987) classified 37 rheumatoid arthritis patients as responders or non-responders to hydroxychloroquine, most patients receiving 400 mg of the sulphate salt daily. The response rate was 76%, with efficacy measured by changes in ESR, prednisone dose, duration of morning stiffness, joint count, global evaluation and grip strength. The authors found no correlation between response and plasma concentrations of hydroxychloroquine and metabolites. However, no indication was given of how the plasma was separated from cells, the variability of each measured plasma concentration, or whether silanized glass was used in the assay procedure. Thus, artefacts introduced in the assay procedure could have given misleading results (Tett et al, 1988). A controlled, double-blind study comparing 200mg and 400mg of hydroxychloroquine sulphate daily in the treatment of rheumatoid arthritis was reported by Pavelka et al (1989). Forty-three patients completed 1 year's therapy and both doses were reported to be effective, with a reduction in disease activity observed. Of the 9 laboratory and 11 clinical indices of efficacy monitored, no statistically significant differences between the two doses were reported, but the group of patients receiving 400mg of the sulphate salt daily reported more adverse effects. Recent studies reported by Nuver-Zwart et al (1989) and Van Der Heijde et al (1989) compare hydroxychloroquine therapy with sulphasalazine treatment in a double-blind, randomized comparative study in patients with definite or classical rheumatoid arthritis according to A R A criteria. The dosing regimen of hydroxychloroquine was an empirical one, with patients receiving 400 mg of hydroxychloroquine sulphate daily for 6 months, then decreasing to 200 mg daily. The rationale for this dosage regimen was not explained and does not appear to be based on pharmacokinetic considerations. Patients were found to respond more quickly to sulphasalazine but after 48 weeks a comparison of treatments showed no statistically significant differences in disease activity variables, including pain, general health, number of tender and swollen joints, ESR, CRP and haemoglobin. Clinical improvement in the hydroxychloroquine group reached a plateau and for some parameters worsened again after dosage reduction at 24 weeks. Nine out of 30 patients withdrew from the hydroxychloroquine group owing to inefficacy, indicating a response rate of approximately 70%. Sulphasalazine was found in this study to slow damage in the joints of hands and feet (assessed radiographically) compared with hydroxychloroquine. There is no comparison of hydroxychloroquine with placebo to establish whether hydroxychloroquine can prevent or slow progression of joint destruction in rheumatoid arthritis. A multicentre study conducted by American and Russian investigators (Brewer et al, 1986) assessed the response of patients with juvenile rheumatoid arthritis (JRA) to penicillamine and hydroxychloroquine compared with placebo in a double-blind trial. The 162 children enrolled in this 12-month study received hydroxychloroquine 6 mg of base per kg per day. The only index of articular disease that was alleviated significantly better by hydroxychloroquine than by placebo was pain on movement (the number of joints and the pain severity). In fact, even the placebo group improved

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markedly over the 12-month period. The parents' global assessment of the children's response favoured active therapy. The authors concluded that neither hydroxychloroquine nor penicillamine offered significant benefit over placebo therapy in the treatment of JRA. It should be noted that JRA comprises a heterogeneous group of diseases, unlike adult rheumatoid arthritis. In this study, the different manifestations of JRA were not analysed separately for response to active treatment. A number of short, uncontrolled trials have shown hydroxychloroquine therapy to be beneficial in lupus erythematosus. Mullins et al (1956) used doses up to 2400 mg of the sulphate salt per day to achieve impressive (94%) remission rates in lupus erythematosus. Cornbleet (1956) and Lewis and Frumess (1956) have documented a number of case histories of improvement of discoid lupus erythematosus with hydroxychloroquine therapy. Cornbleet used doses of 600 mg per day of hydroxychloroquine sulphate, while Lewis and Frumess used up to 1600 mg per day.

Chloroquine Freedman (1956) conducted the first double-blind, placebo-controlled trial with chloroquine. Sixty-six patients with rheumatoid arthritis were entered into the study comparing 4 months' therapy with either 200 or 300 mg of chloroquine diphosphate (34 patients) and placebo therapy. Chloroquine therapy was found to improve joint tenderness, grip strength and dexterity significantly over placebo therapy. Another double-blind placebo-controlled study by Rinehart et al (1957) concluded that chloroquine therapy (250 mg chloroquine diphosphate daily) led to an improvement in the disease state. A crossover design, double-blind placebo-controlled study was used to assess the efficacy of chloroquine diphosphate 500mg per day in 22 rheumatoid arthritis patients (Cohen and Calkins, 1958). Eighty per cent of the patients improved when receiving chloroquine therapy according to ARA criteria, and 70% according to clinical measurements including ESR, pain on motion, muscular weakness, duration of morning stiffness, fatiguability and anaemia, compared with only 6% of patients improving while receiving placebo therapy as judged by either criteria. In 1960 Freedman and Steinberg published results of a 1-year doubleblind placebo-controlled study of chloroquine sulphate 400 mg per day. Subjectively, 90% of the 42 patients on chloroquine therapy felt improved; however, only 30% showed objective improvement in the disease state. Deterioration occurred in 25% of the controls compared with only 5% of the patients receiving chloroquine. Popert et al (1961) administered 250 mg chloroquine diphosphate per day to 46 rheumatoid arthritis patients, with 47 patients as controls. This study was not completely blinded. One investigator, who conducted about onequarter of the follow-up assessments, knew the identity of the tablets. The treated patients showed significant improvements in clinical and laboratory features and significantly reduced rheumatoid factor titres. There was no influence on radiological progress of the disease over a 1-year period.

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One study has examined the effect of 6 months' chloroquine therapy in 28 patients with rheumatoid arthritis on bone and articular cartilage compared with 24 patients receiving placebo therapy (Julkunen et al, 1976). The heads of the metatarsal bones were excised because of destruction due to rheumatoid arthritis. In a blinded analysis of the removed joints, the degenerative changes in the articular cartilage in those patients given chloroquine were less marked. There was also a diminished tendency to pannus formation and more vigorous bone regeneration in the chloroquine group. A number of uncontrolled studies in rheumatoid arthritis and lupus erythematosus demonstrated an improvement in the disease state with chloroquine therapy. Haydu (1953) reported that 75 % of 28 patients showed considerable improvement of their rheumatoid arthritis over a 6-month period of chloroquine diphosphate therapy 500 mg three times per week. Pillsbury and Jacobson (1954) found that 15 out of 16 lupus erythematosus patients showed a good response to chloroquine diphosphate 250 mg per day. Bagnall (1957) colnpleted a 4-year study of chloroquine (250rag chloroquine diphosphate per day) in 125 rheumatoid arthritis patients. Seventy-one per cent of the patients showed either major improvement or remission. Included in Bagnall's report was a small double-blind study of 19 patients. Sixty-three per cent of these patients improved on active therapy; none improved on placebo. The study of Young (1959) used graded doses of chloroquine diphosphate, from 375 mg per week to 3000 mg per week in 50 rheumatoid arthritis patients for 18-36 months. Eighty-eight per cent of these had major improvement or complete remission. Dwosh et al (1977) compared 6 months of therapy with chloroquine diphosphate 250 mg per day with intramuscular gold and oral azathioprine. Articular index, grip strength and morning stiffness improved significantly with all three therapies, with no differences detected between the therapies. Wollheim et al (1978) administered chloroquine diphosphate 250 mg per day for 3 months, then divided the group of 15 patients into 9 responders and 6 non-responders, judged by subjective and objective criteria. ESR, Creactive protein, fibrinogen, orosomucoid, haptoglobin and ceru|oplasmin showed significant decreases with therapy in the responders compared with the non-responders. Plasma concentrations of chloroquine were reported to be similar in both groups, around 300-600 ng/ml.

Hydroxychloroquine compared with chloroquine Scherbel et al (1957) compared the effects of hydroxychloroquine sulphate (200-600 mg per day) and chloroquine diphosphate (250-500 mg per day) in patients with rheumatoid arthritis over 18 months of therapy. The authors showed the two drugs to be similarly effective, with about 70% of patients improving. They considered hydroxychloroquine to have an advantage over chloroquine because less gastrointestinal upset was noted with the former. A further study by Scherbel et al (1958) reported that 60% of a group of 60 patients receiving hydroxychloroquine sulphate (400-1000 mg per day) had

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major improvement or remission, with 93% obtaining minor improvement or greater. Of a group of 46 patients receiving chloroquine phosphate therapy (250-500 mg per day), 63% had major improvement or remission and 93% minor improvement or greater. Scull (1962) reported on 80 patients receiving chloroquine diphosphate 250 mg per day, 80 receiving hydroxychloroquine sulphate 400 mg per day and 36 receiving placebo. Scull reported a decrease in requirement for corticosteroids in 57% of the patients on active therapy and concluded that there was clinical improvement (measured by improvement in A R A classification) in a significant percentage of patients on these antimalarials, compared with a worsening of the disease state in those patients receiving placebo. Treatment with antimalarial drugs, hydroxychloroquine or chloroquine was reported to significantly reduce the number of disease flare-ups in a retrospective study of 43 systemic lupus erythematosus patients (Rothfield, 1988). The same study reported that general symptoms and skin manifestations of the disease were less when patients received 500 mg chloroquine diphosphate daily than when the same patients received no antimalarial therapy. The conclusion may be drawn from all these studies that hydroxychloroquine and chloroquine are effective in adult rheumatoid arthritis and lupus erythematosus, but possibly not in juvenile rheumatoid arthritis. The maximum antirheumatic effect may take up to 6 months, or more, to be achieved. Sixty to eighty per cent of patients improve using standard doses (200-400 mg hydroxychloroquine sulphate or 250 mg chloroquine diphosphate per day). Rheumatoid parameters that improve include joint function and tenderness, the number of joints involved with disease, morning stiffness, grip strength and ESR. Haemoglobin has been reported to improve in some studies, as has rheumatoid factor titre. Radiological evidence of improvement or slowing or joint destruction has not yet been demonstrated in any studies of chloroquine or hydroxychloroquine. TOXICITY The range of adverse effects appears to be similar for hydroxychloroquine and chloroquine. However, hydroxychloroquine in the usual doses employed appears to have an incidence of adverse effects about half that of chloroquine (Scherbel et al, 1957). The majority of these adverse effects are transient and insignificant, often resolving with continued therapy, only occasionally requiring decrease of the dose or termination of therapy. This contrasts with other second-line agents such as gold or penicillamine. Indeed, at the doses currently used it appears to be far more likely that patients will terminate therapy with antimalarials owing to inefficacy rather than toxicity (Richter et al, 1980), raising questions about whether adequate doses are being used. Mainland and Sutcliffe (1962) compared the incidence of adverse reactions reported in Patients receiving hydroxychloroquine sulphate

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(800mg per day) to that reported in the patients receiving placebo. The frequency of each reported effect, including pruritis, rash, headache, abdominal pain, tinnitus, nausea, dizziness, blurred vision, diarrhoea, anorexia, stomatitis, vomiting and photophobia was comparable between groups. For example 13% of the patients receiving hydroxychloroquine reported photophobia as an adverse effect, but so did 10% of the patients receiving placebo. Hamilton and Scott (1962) also found similar prevalences of adverse effects with placebo and hydroxychloroquine sulphate therapy (600 mg per day) and found no instance where the relationship of drug to adverse effects could be established. In an analysis of 805 rheumatoid patients receiving hydroxychloroquine or chloroquine therapy (Scherbel et al, 1958), adverse reactions involving the neurovascular system were reported (e.g. headache, difficulties in visual accommodation) and also adverse reactions involving the gastrointestinal tract (an 11% prevalence with hydroxychloroquine, a 19% prevalence with chloroquine), skin or endocrine system. These effects disappeared spontaneously in 67% of cases, and after dose reduction or temporary discontinuation in a further 26% of cases. In another study, Scull (1962) noted a prevalence of 9% for adverse effects associated with hydroxychloroquine. There was a greater than 20% prevalence associated with chloroquine therapy and an 11% prevalence associated with placebo therapy. Adverse effects noted in prisoners receiving a daily dose of chloroquine base 300 mg for 77 days (Alving et al, 1947) included minor visual difficulties (focusing from a near to a far object), hair bleaching in the blond subjects, decrease in the height of the 't' wave of the ECG in 12 out of the 20 men, skin eruptions and weight loss. Headaches were also reported; however, these were also reported during the placebo period and hence it was difficult to ascribe this effect to the drug. This group of subjects (volunteers?) could be a particularly difficult group to study and may perhaps be unreliable as sources of information. The toxicity reports involving chloroquine that most concern prescribers are those relating to the eye. A well-described 'bull's eye retinopathy', involving progressive decrease in theVisual fields may eventually lead to blindness. Many case reports of retinopathy following chloroquine therapy have been reported, mainly in the 1960s when higher doses were used than are currently employed, and a number of reviews on the subject have been published (for example, Bernstein, 1983). The first reports of chloroquine retinopathy were probably the 'eye changes' described as severe fundal changes with constriction of visual fields in two patients by Goldman and Preston in 1957. The retinopathy appears to be irreversible if not detected in the early stages and has been reported to progress after therapy has been ceased (Ogawa et al, 1979). Although there are very few literature reports of retinopathy due to hydroxychloroquine (Shearer and Dubois, 1967; Carr et al, 1968), most reviews of antimalarial therapy (for example, Baker and Rabinowitz, 1986) do not differentiate between hydroxychloroquine and chloroquine and ascribe the retinopathy reports to both drugs, rather than just to chloroquine. There may be a distortion in the apparently higher

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incidence due to chloroquine since chloroquine may have been used much more frequently in earlier years when much higher doses of antimalarials were used. The actual incidence of the adverse effect cannot be calculated because comparative usage figures for chloroquine and hydroxychloroquine have not been reported. In 1985 Finbloom et al addressed this question of the relative ocular toxicity of chloroquine and hydroxychloroquine, and the apparent discrepancyin the literature. They performed a retrospective study of their own patients, assessing the incidence of retinal toxicity with each drug. Of 31 patients taking chloroquine alone (mean dose of 329 mg of the diphosphate salt daily), 6 had developed retinopathy. None of the 66 patients taking hydroxychloroquine alone (mean dose of 280 mg of the sulphate salt daily) had developed retinal damage. The consensus of opinion appears to be that retinopathy is not associated with duration of therapy or the total cumulative dose, but rather with the daily dose of hydroxychloroquine or chloroquine, although the evidence for hydroxychloroquine is rather meagre. Blood concentrations have not been measured in these patients, so a concentration-effect relationship has not been established. Mackenzie and Scherbel (1980) reported that no case of retinopathy had been reported at a daily dose lower than 250mg of chloroquine diphosphate. Maximum recommended daily doses range from 4 mg kg-1 day- 1 (Mackenzie and Scherbel, 1980) to 5.1 mg kg-1 day- 1 (Mackenzie, 1983) for chloroquine diphosphate and from 6 mg kg -1 day -1 (Mackenzie and Scherbel, 1980) to 7.8 mg kg- 1 day- 1 (Mackenzie, 1983) for hydroxychloroquine sulphate. The authors report that permanent ocular damage is no longer detected at these lower doses. However, periodic ophthalmic examination (e.g. 3-6-monthly), with visual field assessment, is still recommended to detect any early macular changes. Less serious, reversible ocular changes have been reported following antimalarial therapy. Corneal opacities, reversible on discontinuation of therapy, have been reported in up to 20-40% of patients receiving chloroquine therapy (Rubin, 1968). They appear to be without serious visual consequence and may resolve even with continuing therapy. Acute toxicity has been reported following a number of poisoning episodes with chloroquine, including suicide attempts or accidental ingestion in children (Cann and Verhulst, 1961; DiMaio and Henry, 1974; Abu-Aisha et al, 1979; Frisk-Homberg et al, 1983). In the majority of cases, cardiorespiratory failure occurred within 3 hours of ingestion. In these cases the dose of chloroquine is very often not apparent. The lowest dose recorded for a successful suicide attempt in an adult is ten to twelve 250-mg chloroquine diphosphate tablets and death was reported after ingestion of three or four tablets of chloroquine in a 3-year-old child. Limited data are available on hydroxychloroquine overdose in humans, althoug h in animals the LOs0 and the maximum tolerated dose of hydroxychloroquine have been reported to be two to three times that of chloroquine (McChesney, 1983). In mice, for example, the LDs0 following oral dosing is reported to be 400mg of chloroquine base/kg compared with 1880 mg of hydroxychloroquine base/kg. Two studies have related serum concentrations of the antimalarials to the

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incidence of minor, reversible adverse effects (Frisk-Holmberg et al, 1979; Laaksonen et al, 1975). Frisk-Holmberg et al reported that 80% of rheumatoid arthritis patients in their study with serum concentrations of chloroquine base above 800 ng/ml had adverse effects. Laaksonen et al found a wide range of serum concentrations in 60 juveniles treated with chloroquine and 63 treated with hydroxychloroquine for juvenile rheumatoid arthritis. These authors proposed a maximum safe daily dose of chloroquine diphosphate (defined as below the dosage necessary for the appearance of corneal opacities) of 4 mg kg-1 day-~, or a serum concentration for chloroquine base of 250-280 ng/ml. The equivalent recommendations for hydroxychloroquine sulphate are a maximum daily dose of 5-7 mg kg -1 day -1, or a serum concentration of hydroxychloroquine base of 370-470 ng/ml.

Monitoring for toxicity Antimalarials are recognized as the least toxic of the disease-modifying antirheumatic drugs (Chapter 11). Baseline and 3-6-monthly formal ophthalmological examinations are mandatory. These should include fundoscopy and visual fields, charting. The Amsler grid has been advocated as a sensitive simple and inexpensive screen for early antimalarial-induced retinopathy (Easterbrook, 1988). There is no specific requirement for routine monitoring of blood or urine. A full blood count and urinalysis at about the time of retinal examinations is reasonable, however. PREGNANCY The use of antimalarials during pregnancy should be avoided if possible as these drugs cross the placenta and have been associated with fetal abnormalities. However, active disease, especially lupus, is hazardous for the fetus and this must be balanced against the hazards of treatment in individual cases. PHARMACOKINETICS The pharmacokinetics of both chloroquine and hydroxychloroquine are characterized by the same general features: extensive accumulation in tissues, moderate clearance and very long half-lives. A summary of the pharmacokinetic parameters in humans is presented in Table 1. Both drugs appear to be characterized by linear pharmacokinetics. The early suggestions that the disposition of chloroquine is non-linear are most likely artefacts of experimental design (Tett and Cutler, 1987).

Distribution The major reason for the extremely long half-lives of chloroquine and hydroxychloroquine is their unusually large volumes of distribution. On the

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s. TETT ET AL Table 1. Pharmacokinetic parameters of chloroquine (CQ) and hydroxychloroquine (HCQ). Parameter Elimination half-life (days) Total plasma clearance (ml/min) Total blood clearance (ml/min) Renal clearance (plasma) (ml/min) Renal clearance (blood) (ml/min) Non-renal clearance (plasma) (ml/min) Non-renal clearance (blood) (ml/min) V~,ss (plasma) (1) Va,ss (blood) (1) Mean residence time (h)

CQ*

HCQ?

45 1080 130 432 52 648 78 65 000 13 000 900

41 685 95 211 20 474 75 43 423 5 552 950

* Based on data reported by Frisk-Holmberg et al (1984) and Gustafsson et al (1987). t Based on data reported by Tett et al (1988).

basis of the values of Vd,ss reported in pharmacokinetic studies in human volunteers (Table 1), of the total amount of both drugs present in the body at steady-state, more than 99.9% is associated with tissues in some way. The mechanism of this extensive sequestration is still unclear, in spite of many studies (particularly with chloroquine) in both animals and humans. However, there is sufficient evidence to clearly reject certain possible explanations. Contrary to a recent claim (Birkett, 1988), evidence from animal studies shows unequivocally that accumulation in adipose tissue is not responsible for the large distribution volume of chloroquine, as the low levels detected in adipose tissue are much less than for most other tissues (McChesney et al, 1966, 1967). Chloroquine is known to bind avidly to melanin, but the suggestion that this is the cause of the very large distribution volume can also be rejected. While these interactions are very likely of considerable importance in accumulation in the retina, they do not provide a quantitative explanation of the large distribution volume. In particular, the half-life of chloroquine in Black subjects is not greater than for White subjects (Walker et al, 1987), contrary to expectations if melanin binding were quantitatively important in overall disposition. Tissue to plasma concentration ratios of chloroquine have been determined in many studies in animals, and a few post-mortem studies in humans, with consistently high ratios in lung, liver and spleen and low levels in muscle, adipose, brain tissue and bone. A study of chloroquine accumulation in isolated rat hepatocytes (Maclntyre and Cutler, 1988) has shown that, in this cell, accumulation of chloroquine is almost entirely the result of ion trapping in lysosomes. The basis for this accumulation is that, for diacidic bases such as chloroquine and hydroxychloroquine, the equilibrium distribution ratio for the ion trapping mechanism is given by (HIJHp) 2, where HE is the hydrogen ion concentration within the lysosome, and He is the hydrogen ion concentration in the reference phase, the free plasma concentration in this case. The predicted value of this term for distribution

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between a lysosome (pH = 4.8) and plasma (pH = 7.4) for chloroquine and hydroxychloroquine is about 160000. Thus, although lysosomes occupy only a small fraction of the cell volume, their extremely high capacity to accumulate a diacidic weak base allows them to overwhelm other mechanisms of accumulation. This mechanism, scaled up to the level of the intact liver (in rats), predicts a liver: plasma accumulation ratio in good agreement with in vivo data. Since those tissues with high accumulation ratios tend to be lysosome-rich tissues, and those with low accumulation ratios tend to be deficient in lysosomes, it is possible that the pattern of accumulation in vivo is largely due to differences in the lysosomal content of different tissues. Consistent with this idea is the observation that muscle tissue, with a low accumulation ratio and a low lysosomal content, shows only minor changes in binding with tissue homogenization (MacIntyre and Cutler, 1986). For liver tissue, homogenization (which also disrupts lysosomes) results in a large reduction of uptake to approximately the level of muscle (MacIntvre and Cutler, 1988). Although animal tissue binding data appears to be reasonably well explained by the hypothesis that accumulation is largely a result of lysosomal ion trapping, a major discrepancy remains when an attempt is made to scale up the animal data to describe disposition in humans. Predicted volumes of distribution in humans, using animal tissue : plasma binding data, results in estimates at least an order of magnitude smaller than those calculated from pharmacokinetic studies in human subjects. The reason for this discrepancy is at present unclear. It indicates that in spite of extensive investigation much remains to be learned about the pharmacokinetics of chloroquine. There is much less information available on tissue distribution of hydroxychloroquine than for chloroquine, but the same general features are apparent. Like chloroquine, hydroxychloroquine has a very large distribution volume (Tett et al, 1988) and a similar pattern of distribution between tissues. If lysosomal trapping were the sole explanation for the large volume of distribution of these compounds they would be expected to have the same distribution volumes. Although the distribution volumes of both drugs are large, that for hydroxychloroquine is less than that for chloroquine (Table 1). However, the permeability coefficient for hydroxychloroquine is substantially less than that for chloroquine (by a factor of 1/50 for the human erythrocyte membrane (Ferrari and Cutler, 1990)), suggesting that the smaller value for hydroxychloroquine may be due to a reduced rate of uptake by tissue cells compared with chloroquine. The distribution of both chloroquine and hydroxychloroquine within blood is characterized by extensive accumulation within blood cells. Equilibrium distribution in blood is shown in Table 2. Binding to plasma proteins is modest (Tett et al, 1988). Both drugs accumulate in red cells by a combination of binding to intracellular materials, presumably haemoglobin, and iontrapping due to the slightly acidic interior of the red cell relative to plasma. However, for both drugs, accumulation is much greater in white cells (Bergquist and Domeij-Nyberg, 1983). This appears to be due to the high lysosomal content of white cells. As noted above, the accumulation ratio in

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:S. TETT ET AL Table 2. Distribution of chloroquine (CQ) and hydroxychloro-

qnine (HCQ) within blood. Percentage in fraction at equilibrium

Total plasma Plasma water Plasma protein bound Erythrocytes Other cells Blood: plasma ratio

CQ

HCQ

13 6.5 6.5 24 63

14 7.7 6.3 31 55

7.6

7.2

lysosomes of diacidic weak bases like chloroquine and hydroxychloroquine is of the order of 160 000. This high level of accumulation poses a problem in pharmacokinetic studies. Bergquist and Domeij-Nyberg (1983) showed that during separation of cells and plasma, lysis of cells and release of chloroquine occurs unless special precautions are taken. The result is that variable and unreproducible plasma concentrations are reported. A similar problem occurs with hydroxychloroquine (Tett et al, 1988), In view of these difficulties it has been recommended that pharmacokinetic studies be based on the measurement of blood concentrations rather than plasma concentrations. Several reports in the literature suggest that chloroquine may have stereoselective disposition. Chloroquine enantiomers undergo stereoselective binding to human serum albumin and a!-acid glycoprotein (Ofori-Adjei et al, 1986a). One study has reported that the renal clearance of chloroquine is stereoselective (Ofori-Adjei et al, 1986b); another has shown that (+)chloroquine has a higher renal clearance than (-)chloroquine in rheumatoid arthritis patients (Gustafsson et al, 1990). It is not possible at present to assess the likely clinical significance of these observations. There is no information on stereoselectivity of either efficacy or toxicity of chloroquine or hydroxychloroquine in rheumatoid patients. No studies have been conducted on stereoselectivity of hydroxychloroquine disposition. Elimination

Both chloroquine and hydroxychloroquine have large total plasma clearances (Table 1), amounting to about 40% of plasma cardiac output for chloroquine and about 30% of cardiac output for hydroxychloroquine. These clearances are similar in magnitude to the plasma flow rate to the eliminating organs and suggest unusually efficient elimination processes. However, there are grounds for thinking that plasma clearances are misleading for these compounds. The total blood clearances of both chloroquine and hydroxychloroquine (Table 1) are much smaller than the plasma clearances, and represent a relatively small proportion of the expected blood flow to the eliminating organs. These differences between plasma and blood clearances are due to the high accumulation of both drugs in blood ceils. The large blood: plasma ratios (Table 2) indicate that the total rate of delivery of drug to eliminating

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organs via blood is much greater than via plasma alone, If only a small proportion of drug cont~iiiaed within blood cells is released during passage through an eliminating organ, this naa3tbe very significant compared with the rate of supply in plasma and lead to a marked overestimate of the significance of plasma clearances. Regardless of the intrinsic efficiency of the eliminating processes (which may be high) the extensive accumulation of these drugs in blood cells results in clearances with respect to blood that are only modest. It is, however, clear that the renal processing of both chloroquine and hydroxychloroquine involves tubular secretion. For both drugs, the renal clearance is substantially greater than can be accounted for by glomerular filtration (which is not influenced by cellular uptake). Chloroquine is metabolized primarily via the N-dealkylation pathway, first to N-desethylchloroquine (CQM; Figure 1), which is subsequently metabolized to bisdesethylchloroquine (CQMM). Both of these metabolites ~ire excreted in urine, with high renal clearances. The N-dealkylation pathway for hydroxychloroquine is capable of producing two mono-dealkylated products, CQM and N-desethylhydroxychloroquine (HCQM). HCQM is excreted in the uri~te and is also dealkylated further to produce bisdesethylchloroquine (CQMM), A number of other minor metabolites have been proposed by Koppel et at (1987), Little is known about the subsequent fate of CQMM. This is found at low concentrations in human studies following either chloroquine or hydroxychloroquine dosage. Following injection of CQMM in monkeys it disappears rapidiy (McChesney et al, 1967), and, except for a small amount of a carboxylic acid metabolite, no subsequent breakdown products have been detected. There is evidence that CQM and CQMM are active antimalarial agents (Aderounmu, 1984) but no evidence is available on the antirheumatic activity of any of the metabolites of chloroquine or hydroxychloroquine.

CI

H3 . ./R1 HN-CH-CH2-CH2-CH2-N \R 2

Hydroxychloroquine (HCQ) Chloroquine (CQ) Desethylchloroquine (CQM)

Desethylhydroxychloroquine(HCQM) Bisdesethylchloroquine(CQMM)

R1 -CH2CH3 -CH2CH3 -CH2CH3 -H - H

R2

--CH2CH20H -CH2CH3 -H -CH2CH20H --H

Figure 1, Structures of chloroquine, hydroxychloroquine and their major metabolites.

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Absorption Both chloroquine and hydroxychloroquine are incompletely and fairly slowly absorbed following oral administration to fasting volunteers. Chloroquine is reported to be absorbed to the extent of 89 + 16% in fasting volunteers (Gustafsson et al, 1983). Absorption of hydroxychloroquine from an oral tablet in healthy fasting volunteers was estimated to be 74 + 13% and the absorption half-time was estimated to be 3.6 + 2.1 h (Tett et al, 1989). Three studies have reported the influence of food on chloroquine absorption following an oral tablet. These studies have reported conflicting results. Tulpule and Krishnaswamy (1982) showed a variable but significant increase in peak levels after food. Lagrave et al (1985) found no effect on the extent of absorption with a low-fat-low-protein meal, but a small increase in levels was observed following dosing with a high-fat-high-protein meal. Harron et al (1986) found no change in the area under the plasma concentration-time curve for the first 24 hours after dosing with a carbohydrate meal, compared with fasting controls, but noted some differences at later times. The same study reported an absence of effect on chloroquine absorption of aspirin or paracetamol. On balance it appears that administration of chloroquine with food is advisable to minimize possible adverse gastrointestinal effects. Unpublished results from our laboratory indicate that the only effect of a high-fat-high-protein meal on absorption of hydroxychloroquine was an increase in the lag-time before absorption commences. This increase is unlikely to be of clinical significance, with chronic dosing, suggesting that hydroxychloroquine should also be administered with food. It is unclear whether chloroquine and hydroxychloroquine experience a significant first-pass effect, or whether the incomplete absorption is due to a failure of orally administered doses of drug to reach the liver. If the kinetics of uptake by blood cells is rapid enough that near-equilibrium conditions exist with respect to distribution within blood, the hepatic extraction ratio for both chloroquine and hydroxychloroquine indicates only a very small first-pass effect. However, as noted above, the kinetics of uptake do not appear to be rapid enough to justify this interpretation. Further work is needed to clarify this point. It is of potential clinical significance as this may be a source of variability in plasma concentrations between patients.

Clinical pharmacokinetics The most significant feature of the pharmacokinetics of chloroquine and hydroxychloroquine is the long half-life of both drugs. Following initiation of maintenance dosing with either drug, 3 or 4 months' delay is expected before steady-state levels are reached. Similarly, on stopping dosing, at least 3 or 4 months' delay will be experienced before concentrations fall to insignificant levels. Indeed, the metabolites appear to have even longer half-lives and would take even longer to reach steady-state or be eliminated after dosing ceases. The reason for the long half-lives for chloroquine and hydroxychloroquine is extensive uptake by tissues, rather than poor

481

ANTIMALARIALS IN RHEUMATIC DISEASES Table 3. The approach to steady-state blood concentrations of hydroxychloroquine with daily dosing (from Tett et al, 1989). Time (days) 14 30 60 120 180

Fraction of steady state

Blood concentration (ng/ml) 155 mg/day

Blood concentration (ng/ml) 310 mg/day

0.45 0.63 0.78 0.91 0.96

444 622 770 898 948

888 1244 1540 1796 1895

clearance. A consequence is that haemodialysis is unlikely to be of value in the treatment of overdose cases (Tett et al, 1989). From our studies of the pharmacokinetics of hydroxychloroquine we have estimated the expected average steady-state concentrations of this drug at any time during the approach to steady-state concentrations (Tett et al, 1989; Table 3). Although a therapeutic concentration range is not yet determined, the data from Table 3 indicate that concentrations in blood achieved after 4 months' dosing with 155 mg/day could be achieved after 2 weeks' dosing with 310 mg/day. Thus, it might be reasonable to employ a higher dosing rate in the first 2 weeks of therapy in order to reach steadystate concentrations more rapidly. Frisk-Holmberg et al (1979) have proposed (but not established) a therapeutic concentration range for chloroquine in rheumatoid arthritis of 700-2100 ng/ml in blood. Preliminary results from our own cross-sectional study of rheumatoid arthritics taking hydroxychloroquine indicates that only one-third have steady-state concentrations within the proposed therapeutic range for chloroquine (Tett et al, 1990). In general, it is likely that doses of antimalarials used to treat rheumatoid arthritis are too low. The establishment of a safe therapeutic concentration range for antimalarial drugs in the treatment of rheumatic diseases is urgently needed so that safe and effective dosing regimens can be established. The oral absorption of both drugs appears to be relatively insensitive to the presence of food, with the possibility of a slight increase in levels after high-fat-high-protein meals with chloroquine. To minimize the possibility of gastrointestinal side-effects, both drugs should be administered with food. Our own studies reveal moderate intersubject variability in the bioavailability of hydroxychloroquine (Tett et al, 1989), so that poor response may relate to poor bioavailability in some instances. About 40% of a dose of chloroquine is excreted unchanged in the urine (Gustafsson et al, 1987); for hydroxychloroquine about 20-25% of a dose is excreted in urine unchanged (Tett et al, 1988). This suggests possible complications in patients with renal failure. In an anuric patient, levels of chloroquine about 70%, and levels of hydroxychloroquine about 25-30% above normal are expected with the normal dosage regimen. In either case a significant consideration is whether changes occur in the metabolism of these drugs in renal failure. There have been no studies to investigate this matter.

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MECHANISM OF ACTION Although the mode of action of antimalarials in rheumatoid arthritis and systemic lupus erythematosus remains unknown, it is strongly suspected that antimalarials influence the course of these diseases by perturbing the aberrant immune responses integral to both rheumatoid arthritis and systemic lupus erythematosus (Paulus, 1982). As discussed elsewhere in this article, the massive accumulation of chloroquine and hydroxychloroquine in the acid-vesicle system, notably the lysosomes of cells that contain these organelles, such as polymorphs, lymphocytes and macrophages, is most likely to be responsible for the antirheumatic and immunosuppressive actions of antimalarials, as many important cell functions depend upon these subcellular organelles. A general criticism of much of the work devoted to elucidating the mode of action of antimalarials is that concentrations employed in in vitro experiments far exceed those measured in vivo. Thus, our own studies on patients with rheumatoid arthritis taking an average of 224rag/day of hydroxychloroquine indicate that average blood concentrations of hydroxychloroquine are 631ng/ml (2 IXM) and plasma concentrations are 80 ng/ml (0.25 tXM) (Tett et al, 1990). The therapeutic concentration range for serum chloroquine in rheumatoid arthritis that has been proposed is 200--600 ng/ml (Frisk-Holmberg et al, 1979).

Lysosomotropic actions As noted previously, chloroquine and hydroxychloroquine accumulate avidly in the cellular acid-vesicle system (transport vesicles, endosomes, lysosomes, Golgi complex, phagolysosomes, see Krogstad and Schlesinger, 1987) in a variety of cells and concentrations in these organelles can approach millimolar levels (MacIntyre and Cutler, 1988). It is now known that the acid-vesicle system is an intracellular network responsible for the movement of macromolecules intracellularly and for communication within the cell and with the extracellular environment (Krogstad and Schlesinger, 1987). Important functions such as receptor recycling, digestion and metabolism of membrane lipid and glycosylation of proteins occur in the various components of the acid-vesicle system. The pH of these organelles shifts towards neutral as a result of the accumulation of the basic antimalarial drugs and this new pH is outside the optimal range for the many acid protease enzymes contained in these organelles (Okhuma and Poole, 1978; De Duve et al, 1974). However, at least with respect to the malarial parasite, chloroquine can kill even without significant alteration in vacuolar pH, suggesting alternative or additional mechanisms of action (see Ginsburg and Geary, 1987; Ginsburg et al, 1989). Inhibition of an acid protease in Plasrnodiurnfalciparum that increases with increasing pH suggests two complementary mechanisms for the antimalarial actions of chloroquine (Levy et al, 1974). Other lysosomal enzymes are also inhibited by chloroquine, e.g. proteases in fibroblasts, cathepsin B and various phospholipases, the latter as a result of antimalarials forming stable

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complexes with acidic phospholipids, thereby limiting the access of phospholipases to these phospholipids (see Ginsburg and Geary, 1987). Specifically, the lysosomal enzyme phospholipase A2, which is important in the production of arachidonate and its metabolites, is inhibited by chloroquine (Matsuzawa and Hostetler, 1980). Serum chloroquine and hydroxychloroquine concentrations achieved in the treatment of rheumatoid arthritis raise the acid-vesicle pH very quickly when mammalian cells are exposed to similar concentrations in vitro and from these and other studies it is reasonable to surmise that vesicle pH rises during chloroquine or hydroxychloroquine therapy for rheumatoid arthritis (see Ohkuma and Poole, 1978; Krogstad and Schlesinger, 1987). Also, antimalarials (chloroquine 30-300p~g/ml; 0.1-1 mra) have been shown to stabilize lysosomal membranes and to inhibit release of lysosomal enzymes (Allison and Young, 1964; Weismann, 1964; Zvaifter, 1964) and this may be an important mechanism for reducing lysosomal enzyme-induced damage in inflammation. Leukocytes and lymphocytes removed from subjects taking antimalarials show 'autophagic vacuoles' where primary lysosomes are fused with other intracellular membrane structures such as endoplasmic reticulum. These vacuoles, or myeloid bodies, appeared to contain tightly packed whorls of membrane, suggesting a failure to digest the membranes perhaps due to a failure to deliver active lysosomal enzyme to the vacuole (Fedorko, 1967; Abraham et al, 1968; Sando et al, 1979; Jones et al, 1984), again in keeping with antimalarial-induced interference with acid vesicle function. Phagocytes

The processes of chemotaxis, phagocytosis and superoxide production by polymorphs and monocytes activated by multiple agents is inhibited by chloroquine and hydroxychloroquine (Ward, 1966; Rhodes et al, 1982; Hurst et al, 1986, 1988; Miyachi et al, 1986). Interestingly, the polymorph may accumulate chloroquine more avidly than mononuclear leukocytes do (Raghoebar et al, 1986). Antimalarials, because of their accumulation in lysosomes and their interference with lysosomal function, inhibit the dissociation of phagocytosed receptor ligand complexes in the phagolysosome and reduce receptor recirculation and receptor affinity for ligands such as antigens and lysosomal enzymes (Krogstad and Schlesinger, 1987). Interactions with DNA

Studies in the 1960s demonstrated that chloroquine would bind strongly to double-stranded DNA, probably intercalating between base pairs of the DNA (Kurnick and Radcliffe, 1962; Stollar and Levine, 1962; Allison et al, 1965; Cohen and Yielding, 1965), thereby stabilizing the double helix of the molecule. The binding site for antimalarials on DNA suggested that the actions of the DNAase enzyme could be interfered with by antimalarials (Kurnick and Radcliffe, 1962). This interaction with DNA was felt to be responsible for the antiplasmodial effects of chloroquine but this view is no longer accepted because other antimalarials such as mefloquine do not

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interact with DNA, concentrations necessary are not achieved in the nucleus of the malarial parasite, and chloroquine does not selectively exert this effect on parasite but not host cells (see Ginsburg and Geary, 1987; Krogstad and Schlesinger, 1987). These considerations may not apply to the action of antimalarials in rheumatic diseases, however. Chloroquine also inhibits DNA polymerase and, to a lesser extent, RNA polymerase at high drug concentrations. Thus, as a result of the effects on DNA, chloroquine inhibits cell growth at reasonably low concentrations (10 p,M) (Gabourel, 1963). It is of interest that patients treated with chloroquine show evidence of more chromosomal damage in cultured lymphocytes than control patients (Neill et al, 1973).

Immunological actions of potential relevance Immunosuppressive actions of antimalarials have been demonstrated. Chloroquine inhibits lymphocyte responsiveness to mit0gens in vitro (Hurvitz and Hirschhorn, 1965 (10 ~Lg/ml; 31 ~M); Trist and Weatherall, 1981 (10-30 ~M); Djiksman, 1988) and ex vivo in patients with rheumatoid arthritis treated with chloroquine (Panayi et al, 1973). During the process of transformation, lymphocytes develop lysosome-like structures (Weissmann, 1965) and Trist and Weatherall (1981) postulated that antimalarials inhibit lymphocyte transformation by interfering with the release of essential RNAases from these lysosomes. Production of antibodies against rabies virus was inhibited by chloroquine in volunteers undergoing immunization against rabies but antibodies after typhoid vaccine were not reduced (Thompson and Bartholomew, 1964). Antimalarials might exert their effects on lymphocyte function in humans by inhibiting the accessory, antigen-processing functions of monocytes/ macrophages (Salmeron and Lipsky, 1983). In addition, antimalarials inhibit the release of interleukin I from monocytes at achievable concentrations in vivo and this may have widespread effects on the inflammatory and immunological processes operative in rheumatoid arthritis and systemic lupus erythematosus (Salmeron and Lipsky, 1983; Allison and Lee, 1987). Allison and Lee (1987) have proposed that slow-acting antirheumatic drugs, including the antimalarials, act by inhibiting proliferation of cells of the mononuclear lineage but accelerating the differentiation of these cells, cells of this lineage being major producers of interleukin 1 and other inflammatory mediators. The significant reduction of circulating immune complexes in patients with rheumatoid arthritis taking chloroquine (SegalEiras et al, 1985) may be due to the inhibition of interleukin 1 release by monocytes.

Cartilage Animal studies suggest that antimalarials can protect and heal damaged cartilage (Volastro et al, 1973) and this may be achieved by inhibiting the cartilage-damaging actions of prostaglandins (Manku et al, 1976). This supports the interesting observations of Julkunen et al (1976) that chloro-

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q u i n e is a s s o c i a t e d w i t h less c a r t i l a g e d e g e n e r a t i o n t h a n s e e n with p l a c e b o in excised human cartilage.

SUMMARY The antimalarials hydroxychloroquine and chloroquine remain established a n d effective a g e n t s for t h e t r e a t m e n t o f r h e u m a t o i d arthritis a n d s y s t e m i c lupus erythematosus. Although the mechanisms of action remain uncertain, e v i d e n c e is a c c u m u l a t i n g t h a t t h e a n t i r h e u m a t i c a n d i m m u n o l o g i c a l effects o f t h e a n t i m a l a r i a l s a r e r e l a t e d to t h e i r m a s s i v e d i s t r i b u t i o n into t h e c e l l u l a r acid-vesicle system. T h e s e d r u g s a r e a t t r a c t i n g n e w i n t e r e s t b e c a u s e t h e i r r e l a t i v e safety r e c o m m e n d s t h e i r use in e a r l y r h e u m a t o i d arthritis a n d as a component of second-line antirheumatic drug combinations. The absence of d a t a e x a m i n i n g t h e effect o f a n t i m a l a r i a l s u p o n r a d i o l o g i c a l p r o g r e s s i o n o f r h e u m a t o i d a r t h r i t i s n e e d s to b e rectified. R e c e n t u n d e r s t a n d i n g o f t h e pharmacokinetics of these drugs reveals that steady-state concentrations are n o t a c h i e v e d for at l e a s t 3 - 4 m o n t h s . P r e l i m i n a r y i n f o r m a t i o n also suggests a r e l a t i o n s h i p b e t w e e n b l o o d c o n c e n t r a t i o n s a n d effect. T a k e n t o g e t h e r , t h e s e d a t a suggest t h a t m o r e e f f e c t i v e d o s a g e r e g i m e n s will b e p o s s i b l e w h e n therapeutic concentration ranges are properly established.

REFERENCES Abraham R, Hendy R & Grasso P (1968) Formation of myeloid bodies in rat liver lysosomes after chloroquine administration. Experimental Molecular Pathology 9: 212-229. Abu-Aisha H, Abu-Sabaa HMA & Nur T (1979) Cardiac arrest after intravenous chloroquine injection. Journal of Tropical Medicine and Hygiene 82: 36--37. Adams EM, Yocum DE & Bell CL (1983) Hydroxychloroquine in the treatment of rheumatoid arthritis. American Journal of Medicine 75: 321-326. Aderounmu AF (1984) In vitro assessment of the antimalarial activity of chloroquine and its major metabolites. Annals of Tropical Medicine and Parasitology 78: 581-585. Allison AC & Lee SW (1987) Pro-inflammatory and catabolic effects of interleukin-1 and their antagonism by glucocorticoids. In Brooks PM, Day RO, Williams K & Graham G (eds) Basis for variability of response to anti-rheumatic drugs, pp 207-225. Agents and Actions supplement 24. Basel: Birkhauser Verlag. Allison AC & Young MR (1964) Uptake of dyes and drugs by living cells in culture. Life Sciences 3: 1407-1414. Allison JL, O'Brien RL & Hahn FE (1965) DNA: Reaction with chloroquine. Science 149: 1111-1113. Alving AS, Eichelberger L, Craige Bet al (1947) Studies on the chronic toxicity of chloroquine (SN-7618). Journal of Clinical Investigation 27: 60-65. Bagnall AW (1957) The value of chloroquine in rheumatoid disease. A four year study of continuous therapy. Canadian Medical Association Journal 77: 182-194. Baker DG & Rabinowitz JL (1986) Current concepts in the treatment of rheumatoid arthritis. Journal of Clinical Pharmacology 26: 2-21. Bergquist Y & Domeij-Nyberg B (1983) Distribution of chloroquine and its metabolite desethylchloroquine in human blood cells and its implication for the quantitative determination of these compounds in serum and plasma. Journal of Chromatography 272: 137148. Bernstein HN (1983) Opthalmologic considerations and testing in patients receiving long-term antimalarial therapy. American Journal of Medicine 75: 25-34. Birkett DJ (1988) Pharmacokinetics made easy (III). Half-life. Australian Prescriber 11: 57-59.

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S. TETT ET AL

Brewer EJ, Giannini EH, Kuzmina N & Alekseev L (1986) Penicillamine and hydroxychloroquine in the treatment of severe juvenile rheumatoid arthritis. New England Journal of Medicine 314: 1269-1276. Cann HM & Verhulst HL (1961) Fatal acute chloroquine poisoning in children. Paediatrics 27: 95-102. Carr RE, Henkind P, Rothfield N & Siegel IM (1968) Ocular toxicity of antimalarial drugs. American Journal of Opthalmology 66: 738-744. Cohen AS & Calkins E (1958) A controlled study of chloroquine as an antirheumatic agent. Arthritis and Rheumatism 1: 297-312. Cohen SN & Yielding JL (1965) Spectrophotometric studies of the interaction of chloroquine with deoxyribonucleic acid. Journal of Biological Chemistry 240: 3123-3131. Cornbleet T (1956) Discoid lupus erythematosus treated with Plaquenil. Archives of Dermatology and Syphilology 73: 572-575. De Duve C, De Barsy T, Poote Bet al (1974) Lysosomotropic agents. BiochemicalPharmacology 23: 2495-2531. Dijkmans BA, de Vries E, de Vreede TM & Cats A (1988) Effects of anti-rheumatic drugs on in vitro mitogenic stimulation of peripheral blood mononuclear cells. TransplantProceedings 20 (supplement 2): 253-258. DiMaio VJM & Henry LD (1974) Chtoroquine poisoning. Southern Medicine Journal 67: 1031-1935. Dwosh IL, Stein HB, Urowitz MB et al (1977) Azathioprine in early rheumatoid arthritis. Comparison with gold and chloroquine. Arthritis and Rheumatism 20: 685-692. Easterbrook M (1988) Ocular effects and safety of antimalarial agents. American Journal of Medicine 85(supplement 4A): 23-29. Fedorko M (1967) Effect of chloroquine on morphology of cytoplasmic granules in maturing human leukocytes--an ultrastructural study. Journal of Clinical Investigation 12: 19321942. Ferrari V & Cutler DJ (1990) Kinetics and thermodynamics of chloroquine and hydroxychloroquine transport across the human erythrocyte membrane. Biochemical Pharmacology 39: 753-762. Finbloom DS, Silver K, Newsome DA & Gunkel R (1985) Comparison of hydroxychloroquine and chloroquine use and the development of retinal toxicity. Journal of Rheumatology 12: 692-694. Freedman A (1956) Chloroquine and rheumatoid arthritis. A short-term controlled trial. Annals of the Rheumatic Diseases 15: 241-256. Freedman A & Steinberg VL (1960) Chloroquine in rheumatoid arthritis. A double blindfold trial of treatment for one year. Annals of the Rheumatic D&eases 19: 243-250. Frisk-Holmberg M, Bergquist Y, Domeij-Nyberg B et al (1979) Chloroquine serum concentration and side effects: Evidence for dose-dependent kinetics. Clinical Pharmacology and Therapet4tics 25: 345-350. Frisk-Holmberg M, Bergquist Y & England U (1983) Chloroquine intoxication. BritishJournal of Clinical Pharmacology 15: 502-503. Frisk-Holmberg M, Bergquist Y, Termond E & Domeij-Nyberg B (1984) The single dose kinetics of chloroquine and its major metabolite desethylchloroquine in healthy subjects. European Journal of Clinical Pharmacology 26: 521-530. Gabourel JD (1963) Effects of hydroxychloroquine on the growth of mammalian cells in vitro. Journal of Pharmacology Experimental Therapeutics 141: 122-130. Ginsburg H & Geary TG (1987) Current concepts and new ideas on the mechanisms of action of quinoline-containing antimalarials. Biochemical Pharmacology 36: 1567-1576. Ginsburg H, Nissani E & Kurgliak M (1989) Alkalinization of the food vacuole of malaria parasites by quinoline drugs and alkylamines is not correlated with their antimalarial activity. Biochemical Pharmacology 38(16): 2645-2654. Goldman L & Preston RH (1957) Reactions to chloroquine observed during treatment of various dermatologic disorders. American Journal of Tropical Medicine and Hygiene 6: 654-657. Gustafsson LL, Walker D, Alvan G e t al (1983) Disposition of chloroquine in man after single intravenous and oral doses. British Journal of Clinical Pharmacology 15: 471-479. Gustafsson LL, Lindstrom B, Grahen A & Alvan G (1987) Chloroquine excretion following malaria prophylaxis. British Journal of Clinical Pharmacology 24: 221-224.

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Gustafsson LL, Nordmark B, Ericsson O & Hermansson J (1990) The pharmacokinetics of (+)- and (-)-chloroquine in patients with rheumatoid arthritis. British Journal of Clinical Pharmacology (in press). Hamilton EBD & Scott JT (1962) Hydroxychloroquine sulfate (Plaquenil) in treatment of rheumatoid arthritis. Arthritis and Rheumatism 5: 502-515. Harron DWG, Ali AA, Mohmed SS & Collier PS (1986) Chloroqulne interactions with food and analgesics in Sudanese men. Acta Pharmacologica et Toxicologica (Supplement V) Abstracts 11: 219. Haydu GG (1953) Rheumatoid arthritis therapy: A rationale and the use of chloroquine diphosphate. American Journal of Medicine Science 225: 71-75. Hurvitz D & Hirschhorn K (1965) Suppression of in vitro lymphocyte responses by chloroqulne. New England Journal of Medicine 273: 23-26. Hurst NP, French JK & Bell AL (1986) Differential effects of mepacrine, chloroquine and hydroxychloroquine on superoxide anion generation, phospholipid methylation and arachidonic acid release by human blood monocytes. Biochemical Pharmacology 35: 3083-3089. Hurst NP, French JK, Gorjatschko L & Betts WH (1988) Chloroquine and hydroxychloroquine inhibit multiple sites in metabolic pathways leading to neutrophil superoxide release. Journal of Rheumatology 15: 23-27. Jones CJP, Salisbury RS & Jayson MIV (1984) The presence of abnormal lysosomes in lymphocytes and neutrophils during chloroquine therapy: a quantitative ultrastructural study. Annals of the Rheumatic Diseases 43: 710-715. Julkunen H, Rokkanen P & Laine H (1976) Chloroquine treatment and bone changes in rheumatoid arthritis. Scandinavian Journal of Rheumatology 5: 36-38. Kersley GD & Palin AG (1959) Amodiaquine and hydroxychloroquine in rheumatoid arthritis. Lancet 2: 886-888. Koppel C, Tenczer J & Ibe K (1987) Urinary metabolism of chloroquine. ArzneimittelForschung 37: 208-211. Krogstad DJ & Schlesinger MD (1987) Acid-vesicle function, intracellular pathogens, and the action of chloroquine against Plasmodium falciparum. New England Journal of Medicine 317: 542-559. Kurnick NB & Radcliffe IE (1962) Reaction between DNA and quinacrine and other antimalarials. Journal of Laboratory and Clinical Medicine 60: 669-688. Laaksonen AL, Koskiahde V & Juva K (1975) Dosage of antimalarial drugs for children with juvenile rheumatoid arthritis and systemic lupus erythematosus. Scandinavian Journal of Rheumatology 3: 103-108. Lagrave M, Stahel E & Betschart B (1985) The influence of various types of breakfast on chloroquine levels. Transactions of the Royal Society of Tropical Medicine and Hygiene 79: 559. Levy MR, Siddiqui WA & Chou SC (1974) Acid protease activity in Plasmodium falciparum and P. knowlesi and ghosts of their respective host red cells. Nature 247: 546-549. Lewis HM & Frumess GM (1956) Plaquenil in the treatment of discoid lupus erythematosus. Archives of Dermatology and Syphilology 73: 576-581. McChesney EW (1983) Animal toxicity and pharmacokinetics of hydroxychloroquine sulfate. American Journal of Medicine 75: 11-18. McChesney EW, Conway WD, Banks WF et al (1966) Studies of the metabolism of some compounds of the 4-amino-7-chloroquinoline series. Journal of Pharmacology and Experimental Therapeutics 151: 482-493. McChesney EW, Shekosky JM & Hernandez PH (1967) Metabolism of chloroquine-3-14C in the rhesus monkey. Biochemical Pharmacology 16: 2444-2447. Maclntyre AC & Cutler DJ (1986) In vitro binding of chloroquine to rat muscle preparations. Journal of Pharmaceutical Sciences 75: 1068-1070. Maclntyre AC & Cutler DJ (1988) Role of lysosomes in hepatic accumulation of chloroquine. Journal of Pharmaceutical Sciences 77: 196-199. MacKenzie AH (1983) Dose refinements in long-term therapy of rheumatoid arthritis with antimalarials. American Journal of Medicine 75: 40-45. MacKenzie AH & Scherbel AL (1980) Chloroquine and hydroxychloroquine in rheumatological therapy. Clinics of the Rheumatic Diseases 6: 545-565. Mainland D & Sutcliffe MI (1962) Hydroxychloroquine sulfate in rheumatoid arthritis, a six month, double-blind trial. Bulletin of the Rheumatic Diseases 13: 287-290.

488

s. TEIT ET AL

Manku MS & Horrobio IF (1976) Chloroquine, quinine, procaine, quinidine, tricyclic antidepressants, and methylxanthines as prostaglandin agonists and antagonists. Lancet 2: 1115--1117. Matsuzawa Y & Hostetler KY (1980) Inhibition of lysosomal phospholipase A and phospholipase C by chloroquine and 4,4'-bis(diethylaminoethoxy) a,13-diethl-diphenylethane. Journal of Biological Chemistry 255: 5190-5194. Miller DR, Fiechtner J J, Carpenter JR et al (1987) Plasma hydroxychloroquine concentrations and efficacy in rheumatoid arthritis. Arthritis and Rheumatism 30: 567-571. Miyachi Y, Yoshioka A, Imamura S & Niwa Y (1986) Antioxidant action of antimalarials. Annals of the Rheumatic Diseases 45: 244-248, Mullins JF, Watts FL & Wilson CJ (1956) Plaquenil in the treatment of lupus erythematosus. Journal of the American Medical Association 30: 567-571. Neill WA, Panayi GS, Duthie JJR & Prescott RJ (1973) Action of Chloroquine phosphate in rheumatoid arthritis. Annals of the Rheumatic Diseases 32: 547-550. Nuver-Zwart IH, Van Riel PLCM, Van De Putte LBA & Gribnau FWJ (1989) A double blind comparative study of sulphasalazine and hydroxychloroquine in rheumatoid arthritis: evidence of an earlier effect of sulphasalazine. Annals of the Rheumatic Diseases 48: 389--395. Ofori-Adjei D, Ericsson O, Lindstrom B & Sjoqvist F (1986a) Protein binding of chloroquine enantiomers and desethylchloroquine. British Journal of Clinical Pharmacology 22: 356358. Ofori-Adjei D, Ericsson O, Lindstrom B e t al (1986b) Enantioselective analysis of chloroquine and desethylchloroquine after oral administration of racemic chloroquine. Therapeutic Drug Monitoring 8: 457-461. Ohkuma H & Poole B (1978) Fluorescence probe measurement of the intralysosomal pH in living cells and the perturbation of pH by various agents. Proceedings of the National Academy of Sciences of the USA 75- 3327-3331. Ogawa S, Kurumatani N, Shibaike N & Yamazoe S (1979) Progression of retinopathy long after cessation of chloroquine therapy. Lancet i: 1408. Panayi GS, Neill WA, Duthie J JR & McCormick JN (1973) Action of chloroquine phosphate in rheumatoid arthritis. I. Immunosuppressive effect. Annals of the Rheumatic Diseases 32: 316-318. Parke A (1988) Antimalarial drugs and pregnancy. American Journal of Medicine 85(supplement 4A): 30-33. Paulus HE (1982) An overview of benefit/risk of disease modifying treatment of rheumatoid arthritis as of today. Annals of the Rheumatic Diseases 41 (supplement): 26-29. Pavelka K, Pavelka K, Peliskova Z et al (1989) Hydroxychloroquine sulphate in the treatment of rheumatoid arthritis: A double blind comparison of two dose regimens. Annals of the Rheumatic Diseases 48: 542-546. Pillsbury DM & Jacobson C (1954) Treatment of chronic discoid lupus erythematosus with chloroquine (Aralen). Journal of the American Medical Association 154: 1330-1333. Popert AJ, Meijers KAE, Sharp J & Bier F (1961) Chloroquine diphosphate in rheumatoid arthritis. A controlled trial. Annals of the Rheumatic Diseases 20: 18-35. Raghoebar M, Peeters PAM, Van Den Berg WB & Van Ginneken CAM (1986) Mechanisms of cell association of chloroquine to leucocytes. Journal of Pharmacology and Experimental Therapeutics 238: 302. Rhodes JM, McLaughlin JE, Brown DJ et al (1982) Inhibition of leukocyte motility and prevention of immune-complex experimental colitis by hydroxychloroquine. Gut 23:181-187. Richter JA, Runge LA, Pinals RS & Oates RP (1980) Analysis of treatment terminations with gold and antimalarial compounds in rheumatoid arthritis. Journal of Rheumatology 7: 153--159. Rinehart RE, Rosenbaum EE & Hopkins CE (1957) Chloroquine therapy in rheumatoid arthritis. Northwest Medicine 56: 703-805. Rothfield N (1988) Efficacy of antimalarials in systemic lupus erythematosus. American Journal of Medicine 85 (supplement 4A): 53-56. Rubin M (1968) The antimalarials and the tranquilizers. Diseases of the Nervous System 29: 67-76. Salmeron G & Lipsky P (1983) Immunosuppressive potential of antimalarials. American Journal of Medicine 75 (supplement 1A): 19-24.

ANTIMALARIALS IN RHEUMATIC DISEASES

489

Sando GN, Titus-Dillon P, Hall CW & Neufeld EF (1979) Inhibition of receptor-mediated uptake of a lysosomal enzyme into fibroblasts by chloroquine, procaine and ammonia. Experimental Cellular Research 119: 359-364. Scherbel AL, Schuter SL & Harrison JW (1957) Comparison of effects of two antimalarial agents, hydroxychloroquine sulfate and chloroquine phosphate, in patients with rheumatoid arthritis. Cleveland Clinics Quarterly 24: 98-104. Scherbel AL, Harrison JW & Atdjian M (1958) Further observations on the use of 4aminoquinoline compounds in patients with rheumatoid arthritis or related diseases. Cleveland Clinics Quarterly 25: 95-111. Scull E (1962) Chloroquine and hydroxychloroquine therapy in rheumatoid arthritis. Arthritis and Rheumatism 5: 30-36. Segal-Eiras A, Segura GM, Babini JC et al (1985) Effect of antimalarial treatment on circulating immune complexes in rheumatoid arthritis. Journal of Rheumatology 12: 87-89. Shearer RV & Dubois EL (1967) Ocular changes induced by long-term hydroxychloroquine (Plaquenil) therapy. American Journal of Ophthalmology 64: 245-252. Stollar D & Levine L (1962) Antibodies to denatured deoxyribonucleic acid in lupus erythematosus serum. V. Mechanism of DNA-anti-DNA inhibition by chloroquine. Archives of Biochemical Biophysics 101: 335-341. Tett SE & Cutler DJ (1987) Apparent dose-dependence of chloroquine pharmacokinetics due to limited assay sensitivity and short sampling times. European Journal of Clinical Pharmacokinetics 31: 729-731. Tett SE, Cutler D J, Day RO & Brown KF (1988) A dose-ranging study of the pharmacokinetics of hydroxychloroquine following intravenous administration to healthy volunteers. British Journal of Clinical Pharmacology 26: 303-313. Tett SE, Cutler D J, Day RO & Brown KF (1989) Bioavailability of hydroxychloroquine tablets in healthy volunteers. British Journal of Clinical Pharmacology 27" 771-779. Tett SE, Cutler DJ & Day RO (1990) Hydroxychloroquine concentrations and clinical effects in rheumatoid arthritis patients. European Journal of Pharmacology 183: 1035. Thompson G R & Bartholomew L (1964) The effect of chloroquine on antibody production. University of Michigan Medical Center Journal 30: 227-230. Trist D G & Weatherall M (1981) Inhibition of lymphocyte transformation by mepacrine and chloroquine. Journal of Pharmacy and Pharmacology 33: 434-438. Tulpule A & Krishnaswamy K (1982) Chloroquine kinetics in the undernourished. European Journal of Clinical Pharmacology 24: 271-273. Van Der Heijde DM, Van Riel PL, Nuver-Zwart IH et al (1989) Effects of hydroxychloroquine and sulphasalazine on progression of joint damage in rheumatoid arthritis. Lancet i: 1036-1038. Volastro PS, Malawista SE & Chrisman OD (1973) Chloroquine: protective and destructive effects on injured rabbit cartilage in vivo. Clinical Orthopaedics 91: 243-248. Walker O, Salako LA, Alvan G et al (1987) The disposition of chloroquine in healthy Nigerians after single IV and oral doses. British Journal of Clinical Pharmacology 23: 295-301. Ward PA (1966) The chemosuppression of chemotaxis. Journal of Experimental Medicine 124: 209-248. Weissmann G (1964) Labilization and stabilization of lysosomes. Federation Proceedings 23: 1038-1044. Weissmann G (1965) Lysosomes. New England Journal of Medicine 273: 1143-1149. Wollheim FA, Hanson A & Laurell CB (1978) Chloroquine treatment in rheumatoid arthritis. Scandinavian Journal of Rheumatology 7: 171-176. Young JP (1959) Chloroquine phosphate (Aralen) in the long-term treatment of rheumatoid arthritis. Annals of Internal Medicine 51: 1159-1178. Zvaifler NJ (1964) The subcellular localisation of chloroquine and its effect on lysosomal disruption. Arthritis and Rheumatism 7: 760-761.