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PubMed2004

Are evidence-based guidelines being followed for the monitoring of ocular toxicity of hydroxychloroquine? A nationwide survey of practice amongst consultant rheumatologists and implications for clinical governance.

OBJECTIVE: To determine whether consultant rheumatologists monitor the ocular toxicity of hydroxychloroquine according to standards set by national guidelines. METHOD: An observational cross-sectional questionnaire study of all consultant rheumatologists in the UK was undertaken. The main outcome measure was the proportion of rheumatologists who practise in compliance with nationally set standards. RESULTS: A wide variation in practice was found. Nearly half the respondents did not assess either baseline visual symptoms or visual acuity, and 3% undertook infrequent visual monitoring at intervals of longer than 1 yr. At least a quarter of rheumatologists within the survey routinely referred patients to ophthalmology, either for baseline visual screening or for regular visual monitoring. Such use of ophthalmology services was outside the recommendations of the guidelines and would suggest that these referrals were unnecessary. No differences in monitoring practices were ascertained between respondents from district general and teaching hospitals. CONCLUSION: The present study shows that nationally set guidelines for the monitoring of ocular toxicity of hydroxychloroquine are not consistently followed by rheumatologists with regard to baseline assessment, referral to ophthalmology and frequency of monitoring. Clinical guidelines aim to reduce variations in practice and to promote uniform and consistent best practice. The present study demonstrates a lack of conformity to national guidelines in respect of the monitoring of ocular toxicity of hydroxychloroquine. Clinical governance provides a framework for assuring quality in health care. The implications of this study for clinical governance would include understanding why barriers to the use of guidelines might occur and how they might be overcome, risk management, accounting for the reasonableness of a decision for positive divergence and audit.

Antirheumatic Agents↗

PubMed2003

Population pharmacokinetics of hydroxychloroquine in patients with rheumatoid arthritis.

SUMMARY: Hydroxychloroquine (HCQ) is an antimalarial drug that is also used as a second-line treatment of rheumatoid arthritis (RA). Clinically, the use of HCQ is characterized by a long delay in the onset of action, and withdrawal of treatment is often a result of inefficacy rather than from toxicity. The slow onset of action can be attributed to the pharmacokinetics (PK) of HCQ, and wide interpatient variability is evident. Tentative relationships between concentration and effect have been made, but to date, no population PK model has been developed for HCQ. This study aimed to develop a population PK model including an estimation of the oral bioavailability of HCQ. In addition, the effects of the coadministration of methotrexate on the PK of HCQ were examined. Hydroxychloroquine blood concentration data were combined from previous pharmacokinetic studies in patients with rheumatoid arthritis. A total of 123 patients were studied, giving the data cohort from four previously published studies. Two groups of patients were included: 74 received hydroxychloroquine (HCQ) alone, and 49 received HCQ and methotrexate (MTX). All data analyses were carried out using the NONMEM program. A one-compartment PK model was supported, rather than a three-compartment model as previously published, probably because of the clustering of concentrations taken at the end of a dosing interval. The population estimate of bioavailability of 0.75 (0.07), n = 9, was consistent with literature values. The parameter values from the final model were: Cl = 9.9 +/- 0.4 L/h, V = 605 +/- 91 L, ka = 0.77 +/- 0.22 hours(-1), t(tag) = 0.44 +/- 0.02 hours. Clearance was not affected by the presence of MTX, and, hence, steady-state drug concentrations and maintenance dosage requirements were similar. A population PK model was successfully developed for HCQ.

Adult↗

PubMed2004

Massive hydroxychloroquine overdose.

We report a case presenting with massive overdose of hydroxychloroquine who survived without any sequelae. A 17-year-old girl presented to the Emergency Department 45 min after the ingestion of 22 g of hydroxychloroquine in a suicide attempt. We believe this is highest dose yet reported in the medical literature. The patient developed hypotension, life-threatening ventricular arrhythmias and mild hypokalemia. She was managed with saline infusion and dopamine for hypotension, gastric lavage and activated charcoal for decontamination, lidocain, magnesium sulfate and defibrillation for pulseless ventricular tachycardia. Potassium replacement and bicarbonate administration were performed. Quick treatment of hypotension, gastric decontamination, continuous long-term cardiac monitoring, and treatment of arrhythmias are the cornerstones of hydroxychloroquine overdose management.

Adolescent↗

PubMed1996

Hydroxychloroquine relative bioavailability: within subject reproducibility.

Six healthy volunteers received hydroxychloroquine sulphate 200 mg orally on four occasions (three tablets, one solution). Maximum hydroxychloroquine blood concentration (Cmax; range 135-422 ng ml-1) and time to maximum (tmax; range 1.5-7.0 h) for the three tablet doses showed significant differences between subjects (P < 0.009; between subject coefficients of variation (CVs) 34% and 27%, respectively). There were no within subject differences in Cmax (P = 0.32; mean within subject CV 11%), Cmax corrected for weight (P = 0.28) or tmax (P = 0.35; mean within subject CV 16%). Truncated areas under the hydroxychloroquine blood concentration-time curve of the three tablets were different between (P = 0.0001) but not within subjects (P = 0.13). Again, between subject CV (38%) was more than three times the mean within subject CV (12%). Bioavailability was not limited by tablet formulation. The significant variability in relative bioavailability between but not within individuals indicated that individualising dosing to target concentrations associated with optimal outcomes may minimise variability in response.

Adolescent↗

PubMed1989

A double blind comparative study of sulphasalazine and hydroxychloroquine in rheumatoid arthritis: evidence of an earlier effect of sulphasalazine.

In a double blind, single observer, 48 week study the effects of sulphasalazine (2 g daily) and hydroxychloroquine (400 mg daily months 0-6, thereafter 200 mg daily) were compared in 60 patients with definite or classical rheumatoid arthritis. They had not been treated previously with second line drugs. The onset of response with sulphasalazine was earlier than with hydroxychloroquine. After 48 weeks a comparison of the treatments showed no statistically significant differences in disease activity variables. Adverse reaction was the main reason for withdrawal in the sulphasalazine group and lack of efficacy in the hydroxychloroquine group. All adverse reactions, one being agranulocytosis after eight weeks of sulphasalazine treatment, appeared in the first three months of treatment and were completely reversible.

Adolescent↗

PubMed1982

Inhibition of leucocyte motility and prevention of immune-complex experimental colitis by hydroxychloroquine.

The inhibitory effects of hydroxychloroquine on leucocyte motility have been compared with those of prednisolone. It has been shown to have similar potency to prednisolone as an inhibitor of human neutrophil and monocyte motility. Hydroxychloroquine has then been compared with placebo in the prevention of an immune-complex experimental colitis in rabbits. Rectal biopsies were taken from rabbits 24 hours after initiation of colitis, coded, and graded histologically. The summated gradings for acute inflammation and goblet cell depletion had worsened more in the control rabbits (mean grade +6.7) than in the treated rabbits (mean grade +1.8) P less than 0.05. There was no difference in the mononuclear cell infiltrate between the two groups. Hydroxychloroquine, which is a potent inhibitor of leucocyte motility, effectively prevents the acute inflammatory infiltrate in this experimental colitis model and therefore merits trial in human ulcerative colitis.

Animals↗

PubMed1994

Fulminant hepatic failure secondary to hydroxychloroquine.

Hydroxychloroquine is widely used in rheumatological disease but hepatic side effects have not been reported previously. Two cases are described of fulminant hepatic failure developing after the start of hydroxychloroquine treatment for a chronic rheumatological disorder. In both cases the symptoms of liver disease developed within two weeks of starting hydroxychloroquine and rapidly progressed to fulminant hepatic failure and in neither case was there any pre-existing liver disease. One patient had emergency orthotopic liver transplantation and the other died before a donor organ became available.

Adolescent↗

PubMed1981

Clinical and experimental evaluation of the thromboprophylactic effect of hydroxychloroquine sulfate after total hip replacement.

The rate of postoperative deep vein thrombosis was studied by the 125I-fibrinogen method in 35 patients after total hip replacement. 12 out of 18 patients treated prophylactically with hydroxychloroquine sulfate developed deep vein thrombosis compared with 11 out of 17 patients in the control group. Platelet aggregability was inhibited in vitro by high concentrations of hydroxychloroquine sulfate, but these concentrations were not obtained in vivo and platelet aggregation was not limited in patients treated with hydroxychloroquine sulfate (Plaquenil).

Adult↗

PubMed1993

Hydroxychloroquine, dosage parameters and retinopathy.

In a study designed to determine the presence of retinopathy in patients taking hydroxychloroquine we compared 82 patients attending a rheumatology clinic who had taken hydroxychloroquine for over 1 year with controls. Outcome measurements included fundoscopy, fundus photography and automated computerized visual fields of the macular area. No patient was found to have retinopathy. No correlation could be found between indices of visual field function and total drug usage, average daily dose, dosage in mg/kg body weight or duration of treatment. Retinopathy is unlikely to occur at dosages of hydroxychloroquine of less than 6.5 mg/kg body weight with under 10 years of treatment. Present guidelines for ophthalmic screening of patients on antimalarial therapy are too rigorous and visual field testing if not of benefit. Further recommendations are made for ophthalmic supervision.

Adolescent↗

PubMed2000

The benefit of combining hydroxychloroquine with quinacrine in the treatment of SLE patients.

BACKGROUND: Although the benefit of antimalarials in the treatment of cutaneous LE is well established, the effect of combined hydroxychloroquine and quinacrine treatment in systemic lupus erythematosus with major organ involvement remains underappreciated. PATIENTS: Six active SLE patients (SLEDAI score > 5 points), with a mean duration of illness 9.1 yr (range 2-17 yr) were started on quinacrine (100 mg/d) following failure to achieve clinical remission on a therapeutic regimen which included a maintenance dose of hydroxychloroquine (400 mg/d) together with prednisone (either 10-20 mg/d or higher daily doses of this agent for short periods) and azathioprine (150 mg/d) or methotrexate (7.5 mg/week). OUTCOME: In 5/6 of the patients the addition of quinacrine to the previous treatment resulted in complete remission (SLEDAI 0-2 points), which persisted over the follow-up period [mean +/- 2.2 yr (range 0.5-3.5)]. During this period hydroxychloroquine and azathioprine were reduced to 200 mg/d and 100 mg/d respectively, whereas prednisone was modified as follows: in 2 patients daily administration was discontinued; in one the dose was reduced to 2.5 mg/d (from that of > or = 20 mg/d); in 2 others the previous need for an intermittent course was avoided. However, in one out of the six patients the addition for 3 months of quinacrine to the therapeutic protocol did not result in clinical improvement and was therefore discontinued. CONCLUSIONS: The promising results of this preliminary investigation encourages the combined use of the two antimalarial drugs in appropriate candidates. This modality may induce remission, seems to be safe and possesses a steroid sparing effect.

Adult↗

PubMed2006

Hydroxychloroquine use predicts complete renal remission within 12 months among patients treated with mycophenolate mofetil therapy for membranous lupus nephritis.

The objective of this study was to identify clinical predictors of response to initial mycophenolate mofetil (MMF) therapy for membranous lupus nephritis (MLN). We observed the clinical outcomes of patients in the Hopkins Lupus Cohort within the first year of initiation of treatment with MMF therapy for newly diagnosed MLN, classified according to the new International Society of Nephrology/Renal Pathology Society (ISN/RPS) 2003 classification. Complete renal remission was defined as proteinuria less than 500 mg/24 hours. Demographic, clinical, treatment and laboratory data were examined for their association with renal remission. Twenty-nine MLN patients treated with MMF were identified. Eleven (38%) patients achieved complete renal remission by 12 months. Of those taking hydroxychloroquine, 7/11 (64%) were in remission within 12 months compared to only 4/18 (22%) of those not on hyroxychloroquine (P = 0.036 based on a log-rank test). This association persisted after controlling for the presence of anti-ds-DNA (P = 0.026). Our results provide evidence that hydroxychloroquine has a benefit for renal remission when MMF is used as the initial therapy for MLN. Although hydroxychloroquine is frequently stopped in patients with lupus nephritis, this study suggests it should be started or maintained.

Adolescent↗

PubMed2004

Chloroquine and hydroxychloroquine as inhibitors of human immunodeficiency virus (HIV-1) activity.

Recent advances in the development of antiretrovirals have significantly extended life-spans and positively impacted morbidity of HIV-seropositive patients. While effective, antiretrovirals are associated with complex medication regimens, large pill burdens, and significant side effects which may impact quality of life. Researchers continue to examine various chemical entities in their search for agents with anti-HIV activity. Ideal agents would be efficacious, easily dosed and administered, inexpensive, and with few adverse effects. Chloroquine and its analog hydroxychloroquine are two inexpensive agents that are widely used for the treatment of malaria and have been shown to achieve some level of anti-HIV activity. The exact mechanism of chloroquine and hydroxychloroquine's anti-HIV activity has not yet been discerned but may be related to effects on HIV's surface envelope glycoprotein 120. If found efficacious, both drugs would offer significant advantages to current therapy including a unique mechanism of action, lack of cross-resistance with other antiretrovirals, and low cost. Early and limited in vitro and in vivo data have demonstrated modest anti-HIV efficacy as indicated by measures of viral burden. Effects on CD4+ cell counts have not been as pronounced. It is premature to advocate the use of either of these agents in the management of routine HIV disease; however; the drugs should be further studied to determine their benefit in the treatment of patients who have exhausted all standard treatments. Larger, well-controlled trials are needed to discern the potential role of chloroquine and hydroxychloroquine in the management of HIV.

Animals↗

PubMed1997

The lysosomotropic amines, chloroquine and hydroxychloroquine: a potentially novel therapy for graft-versus-host disease.

We have recently shown that the lysosomotropic amine, chloroquine, can inhibit the development of graft-versus-host disease (GVHD) secondary to minor histocompatibility (MiHC) differences in mice. In addition, we have shown that both chloroquine and hydroxychloroquine can inhibit T cell responses in vitro to minor and major histocompatibility (MHC) antigens. We review the rationale for the use of lysosomotropic amines, whose primary mechanism of action appears to be inhibition of MHC class II antigen presentation, as therapy for GVHD in humans. Used in low concentrations, these agents appear to have no direct effect on T cells either in vitro or in vivo although they may have a direct effect at higher concentrations. The lysosomotropic amines, at low concentrations, in combination with the T cell-specific agent, cyclosporin A, synergistically suppresses the T cell response to MiHC and MHC in mouse and in human. We present the initial data from the human clinical trials using hydroxychloroquine. We hypothesize that the lysosomotropic amines may have unique beneficial effects on immune reconstitution following bone marrow transplantation. The lysosomotropic amines, hydroxychloroquine and chloroquine, represent agents with unique mechanisms of action that may be used to control GVHD in humans.

Animals↗

PubMed2001

Hydroxychloroquine sulphate inhibits in vitro apoptosis of circulating lymphocytes in patients with systemic lupus erythematosus.

The serological hallmark of systemic lupus erythematosus (SLE) is the presence of antibodies against double-stranded DNA. However, several studies have suggested that it is not DNA itself, but nucleosomes that are the immunogenic particles involved both in the induction of anti-DNA antibodies, and in the pathophysiology of SLE. Meanwhile, It has been demonstrated that there is an accelerated in vitro apoptosis of lymphocytes from patients with SLE. Therefore, one can postulate that the process of apoptosis may provide a source of nuclear antigens to drive the autoantibody response seen in SLE. Our study has demonstrated that hydroxychloroquine exhibits an anti-apoptotic action and this anti-apoptotic effect is dependent on monocyte coexistence. We used both morphology assessment and fluorescent antibody cell sorter (FACS) analysis to measure the apoptotic percentage of lymphocytes from 25 SLE patients in medium alone (control) or with the addition of different concentrations of hydroxychloroquine. Our results have shown that there is a significant decrease in the percentage of apoptosis at the therapeutic concentration (10(-6) M) as compared with the control (p < 0.05). It has been reported that the anti-rheumatic properties of hydroxychloroquine result from its interference with antigen processing in macrophages and other antigen-presenting cells. We propose that this results in decreased stimulation of autoreactive lymphocytes reactive with self-peptides, and consequently diminution of activation-induced cell death (apoptosis) of mature peripheral lymphocytes.

Acridine Orange↗

PubMed1975

Hydroxychloroquine sulfate in prevention of thromboembolic phenomena in surgical patients.

Hydroxychloroquine sulfate appears to be a safe drug with no apparent hemorrhagic or other complications when used pre- and postoperatively in the manner described. With the criteria for thromboembolism of abnormal impedance plethysmography and confirmatory clinical signs, protection seems to have been afforded by hydroxychloroquine sulfate. Since these studies support prior extremely favorable results, further clinical trial with parenteral hydroxychloroquine sulfate seems indicated.

Hematocrit↗

PubMed1989

Adjunctive use of hydroxychloroquine in childhood dermatomyositis.

We examined retrospectively the use of hydroxychloroquine in 9 patients with childhood dermatomyositis (DM). These patients had an incomplete response to corticosteroid therapy or had disease exacerbation when attempting to taper corticosteroids. They received hydroxychloroquine in a mean dosage of 3.6 mg/kg (range 2-5 mg/kg) while maintaining corticosteroid therapy. Significant improvement was noted at 3 months of therapy in rash (p less than 0.0001), proximal (p = 0.0004) and abdominal muscle strength (p = 0.0001) and at 6 months of therapy in reduced prednisone dosage (p less than 0.02). These data suggest hydroxychloroquine may be helpful in some patients with childhood DM, particularly those with prominent cutaneous disease or significant corticosteroid toxicity.

Adolescent↗

PubMed1985

Comparison of hydroxychloroquine and chloroquine use and the development of retinal toxicity.

We assessed the frequency of retinal toxicity in patients receiving either chloroquine or hydroxychloroquine and factors which may predict patient susceptibility to toxicity. The overall frequency of retinopathy was 6% (7 of 110 patients). Of the 31 patients receiving chloroquine alone, 6 developed toxicity (19%). In contrast, of the 66 patients receiving hydroxychloroquine, none developed retinopathy. Retinopathy was associated with greater age and with greater accumulative doses of chloroquine. Thus, hydroxychloroquine can be used safely with minimal risk of toxicity.

Adult↗

PubMed1984

Modification of transoperative changes in blood fluidity by hydroxychloroquine: a possible explanation for the drug's antithrombotic effect.

A study was carried out in 40 patients undergoing minor surgery to investigate the effect of hydroxychloroquine on haemorrheological parameters which might explain its reported anti-thrombotic action. Twenty patients received 600 mg to 1400 mg hydroxychloroquine sulphate in the 48-hour period before operation and the control group of 20 patients received placebo. Blood samples were taken during the 24 hours before and on the day after operation. The results showed that in the hydroxychloroquine-treated group the transoperative increase in fibrinogen was associated with a reduction in plasma viscosity compared with an increase in the control group. Furthermore, the mean value for whole blood viscosity at middle shear rate decreased post-operatively in the drug-treated group whereas it increased in patients who had received placebo.

Blood Sedimentation↗