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PubMed1984

Actinic reticuloid. Response to combination treatment with azathioprine, hydroxychloroquine, and prednisone.

We treated an intractable case of actinic reticuloid with azathioprine, hydroxychloroquine, prednisone, and solar protection with E-Z film and obtained a clinically worthwhile effect. The patient was initially sensitive to less than 2 mjoules/cm2 ultraviolet B (UVB) and less than 1 joule/cm UVA, which caused erythematous and infiltrated scaly plaques that persisted for more than 6 weeks after testing. The case is also instructive in the difficulty presented in differentiating it from mycosis fungoides, and for the presence of Sézary-type cells in skin, blood, and lymph nodes.

Azathioprine↗
PubMed1987

Lupus profundus in children: treatment with hydroxychloroquine.

Discoid lupus erythematosus and lupus profundus, rare in children, are described in two young girls, one with onset at 3 1/2 years of age, the other at 8 years of age. Unusual nodules of the face that ultimately healed with atrophy and hyperpigmentation showed histologic and immunofluorescent confirmation of lupus erythematosus. These patients, the second and third in the English literature to be treated for childhood lupus profundus with antimalarials, responded successfully to hydroxychloroquine. No systemic involvement was found.

Child↗
PubMedDate not supplied

Delayed hypersensitivity to hydroxychloroquine manifested by two different types of cutaneous eruptions in the same patient.

Hydroxychloroquine (HXQ) sulphate is a synthetic antimalaria drug that is widely used in rheumatology due to its immunosuppressive properties. Delayed-type sensitization to this drug is rare. A 47-year-old woman diagnosed with HLA B27 ankylosing spondylitis was treated with HXQ for 22 days and had to discontinue the drug due to gastric intolerance. Five days later the patient developed erythema multiforme (EM) with an extensive and unusual distribution. Patch test with 10% HXQ in DMSO were positive at 48 hours. Eight days later a generalized pruriginous erythematous papular exanthema developed, and a skin biopsy was obtained. The first reaction was EM. Patch-testing elicited systemic eczematous contact dermatitis. We report two different clinical patterns of delayed hypersensitivity in the same patient and with the same drug.

Biopsy↗
PubMed1988

Analysis of blood and urine samples for hydroxychloroquine and three major metabolites by high-performance liquid chromatography with fluorescence detection.

A high-performance liquid chromatographic (HPLC) method using fluorescence detection is described for the quantification of hydroxychloroquine (HCQ) and three of its metabolites in blood and urine samples. The method is selective, permitting quantification of analytes without interferences from chloroquine or quinine in the sample. Detection limits for HCQ, desethylhydroxychloroquine, desethylchloroquine, and bisdesethylchloroquine are 10, 30, 5, and 5 ppb, respectively, for a 100-microliters blood or urine sample. The internally standardized method requires only one extraction step and utilizes normal-phase HPLC conditions including an amine modifier in the mobile phase. These conditions facilitate fluorescence detection, selective separation, and acceptable peak shapes. A mobile phase of 0.5% n-butylamine in methanol-hexane-methyl tert. butyl ether (1:1:1) is used in the analysis. Analysis of blood and urine samples from two healthy volunteers given 400 mg of Plaquenil (310 mg of HCQ base) weekly for four weeks provided data on HCQ metabolism for the two persons during the recommended chemoprophylactic regimen for malaria.

Chromatography, High Pressure Liquid↗
PubMed2003

Electrochemical study of hydroxychloroquine and its determination in plaquenil by differential pulse voltammetry.

Hydroxychloroquine (HCQ) is a halogenated aminoquinoline that presents wide biological activity, often being used as an antimalarial drug. The electrochemical reduction of HCQ was investigated by cyclic voltammetry and chronoamperometry using glassy carbon electrodes. By cyclic voltammetry, in acid medium, only the cathodic peak was observed. The electrochemical behavior of this peak is dependent on pH and the electrodic process occurs through an E(r)C(i) mechanism. The electron number (1e) consumed in the reduction of HCQ was obtained by chronoamperometry. A method for the electrochemical determination of HCQ in pharmaceutical tablets was developed using differential pulse voltammetry. The detection limit reached was 11.2 microg ml(-1) of HCQ with a relative standard deviation of 0.46%. A spectrophotometric study of HCQ has been also carried out utilizing a band at 343 nm. The obtained detection limit and the relative standard deviation were 0.1 microg ml(-1) and 0.36%, respectively. The electrochemical methods are sufficiently accurate and precise to be applied for HCQ determination, in laboratorial routine, which can be used to determine the drug at low level.

Electrochemistry↗
PubMed2000

Hydroxychloroquine for the treatment of chronic graft-versus-host disease.

Chronic graft-versus-host disease (GVHD) is a major complication of allogeneic bone marrow transplantation. Both the disease and the medications used to treat it are associated with significant morbidity and mortality. The manifestations of chronic GVHD often resemble those of autoimmune disorders. Hydroxychloroquine (HCQ) is a 4-aminoquinoline antimalarial drug used for the treatment of autoimmune diseases. HCQ interferes with antigen processing and presentation, cytokine production, and cytotoxicity and is synergistic with cyclosporine and tacrolimus in vitro. Forty patients with steroid-resistant or steroid-dependent chronic GVHD were enrolled in a phase 2 trial of HCQ 800 mg (12 mg/kg) per day. Three complete responses and 14 partial responses were seen in 32 evaluable patients (53% response rate). All responders tolerated a >50% reduction in their steroid dose while receiving HCQ. Clinical response occurred at a median of 8 weeks (range, 4 to 24 weeks). No hematologic, hepatic, renal, or retinal toxicity was associated with HCQ. In light of its mechanisms of action, clinical activity for GVHD, and low toxicity profile, HCQ may be useful in a multiagent approach for the treatment of extensive chronic GVHD.

Adolescent↗
PubMed1998

Effect of experimental diabetes mellitus and arthritis on the pharmacokinetics of hydroxychloroquine enantiomers in rats.

PURPOSE: To study the effect of experimental diabetes and arthritis on the pharmacokinetics of hydroxychloroquine (HCQ) enantiomers in rats. METHODS: The pharmacokinetic studies were carried out following administration of 40 mg/kg of racemic HCQ to diabetic, insulin-treated diabetic, adjuvant arthritic and control rats. RESULTS: Renal (70% and 62% for R- and S-HCQ, respectively) and non-renal clearance (100% and 145% for R- and S-HCQ, respectively) of HCQ enantiomers were significantly increased in diabetic rats. Diabetes-induced alterations in the disposition of HCQ were reversed by insulin treatment. In arthritic rats, systemic clearance (CL) of HCQ enantiomers was significantly reduced (1.05 +/- 0.15 and 1.3 +/- 0.19 l/h/kg for R- and S-HCQ, respectively) compared to controls (1.69 +/- 0.32 and 1.93 +/- 0.34 l/h/kg for R- and S-HCQ, respectively). The fraction unbound of the R- and S-HCQ were 49.4% and 50.5% lower in platelet rich plasma of arthritic rats compared to healthy rats. Increased blood concentrations of HCQ enantiomers in arthritic rats were significantly related to the degree of inflammation. CONCLUSIONS: Diabetes significantly increased the CL of both R- and S-HCQ by increasing renal and non-renal clearance. Arthritis caused a significant decrease in CL of HCQ enantiomers through increased binding and a decreased intrinsic clearance. The effect of the diseases on the pharmacokinetics of HCQ, however, was not stereoselective.

Animals↗
PubMed2004

Assessing hydroxychloroquine toxicity by the multifocal ERG.

Twenty patients on Plaquenil treatment were evaluated for retinal toxicity using the (EOG) and the mfERG. Group 1 comprises 15 patients (30 eyes) with normal EOG. From these patients 11 (22 eyes) showed normal RRD of mfERG in area 1 and area 2. The rest four patients (8 eyes) the RRD were reduced. Six months after interruption of HC, the mfERG improved in three cases. Group 2 comprises 5 patients (10 eyes) with subnormal EOG. Four (8 eyes) of these showed a decrease of RRD of the mfERG in area 1 and 2. In the rest one (2 eyes) the RRD were normal. Six months after interruption of HC the mfERG and the EOG improved in 2 cases. These results postulate that the mfERG may be used as an alternative method, perhaps more sensitive, for the detection of the HC retinopathy and the follow up of the patients on hydroxychloroquine.

Adult↗
PubMed2002

Different effects of chloroquine and hydroxychloroquine on lysosomal function in cultured retinal pigment epithelial cells.

Although relatively rare, retinopathy based on a disturbed metabolism of the retinal pigment epithelium (RPE), with ensuing degeneration of photoreceptors, is a known complication of treatment with the 4-aminoquinolones, chloroquine (CQ) and hydroxychloroquine (HCQ), in autoimmune diseases. The reported frequency of retinopathy, however, is much lower for HCQ than for CQ (less than 0.08% versus 1-2%). To test whether the difference in toxicity between the two lysosomotropic drugs is related to different lysosomal influence, we exposed confluent RPE cell cultures to CQ or HCQ for 2 weeks. To induce lipofuscin (LF) formation, known to be accelerated by increased lysosomal pH and intra-lysosomal oxidation during degradation of auto-/heterophagocytosed material, such treatment was combined with feeding of cells with photoreceptor outer segments (POS) and hyperoxia (40% ambient oxygen). HCQ was found to be a less potent enhancer of lipofuscinogenesis compared to CQ, apparently due to its less effective inhibition of lysosomal degradative capacity (evaluated by vital staining of lysosomes with Lyso Tracker Red, and periodic acid-Schiff reaction). This conclusion is supported by the fact that NH4Cl, a non-fluorescent substance which acts similarly to 4-aminoquinolones, induced an increase in LF fluorescence paralleled by increased periodic acid-Schiff reactivity of RPE cells.

Animals↗
PubMed1999

Ocular toxicity and hydroxychloroquine: guidelines for screening.

Chloroquine and hydroxychloroquine (4-aminoquinolones) are used by dermatologists for the treatment of a wide range of disorders. It is widely recognized that their use may lead to ocular complications, but policies for ophthalmological screening and follow-up vary widely. In this article, the current literature on the ocular complications of antimalarials is reviewed, together with the results of a recent survey of dermatological practice on screening. New recommendations for ophthalmological screening recently produced by the Royal College of Ophthalmologists, the British Association of Dermatologists and the British Association of Rheumatologists are presented. It is recommended that baseline screening should include an assessment of renal and liver function, an enquiry about visual impairment and the recording of near visual acuity. Follow-up should comprise an enquiry about visual problems at each clinic visit and assessment of visual acuity once yearly. The multidisciplinary nature of the committee producing the new guidelines will hopefully mean that they will be acceptable to and usable by all those who routinely prescribe antimalarial drugs.

Antimalarials↗
PubMed2001

Early induction of apoptosis in B-chronic lymphocytic leukaemia cells by hydroxychloroquine: activation of caspase-3 and no protection by survival factors.

We have investigated the effect of hydroxychloroquine (HCQ), an anti-rheumatic drug, on malignant B cells from 20 patients with B-chronic lymphocytic leukaemia (B-CLL). HCQ induced a decrease in cell viability in a dose- and time-dependent manner. The mean IC50 was 32 +/- 7 microg/ml (range, 10-75 microg/ml) for 24 h of exposure. This cytotoxic effect was owing to apoptosis, as demonstrated by morphological changes, annexin V binding capacity and DNA fragmentation (28 +/- 4% of apoptotic cells as early as 5 h post incubation, increasing to 82 +/- 4% at 18 h post treatment). The apoptosis was associated with caspase-3 activation because the cleavage and activity of caspase-3 were increased by HCQ. The amount of bcl-2 protein was reduced during apoptosis, evidenced using quantitative flow cytometry. As early as 1 h post-HCQ treatment, a reduction of the mitochondrial transmembrane potential was measured by 3,3'-dihexyloxacarbocyanine iodide. Interestingly, the HCQ effect was not affected by exposure to interleukin-4 or co-culture with bone marrow stromal cells. Our observations suggest that HCQ may offer a new therapeutic tool in the treatment of B-CLL patients.

Aged↗
PubMed1997

The in vitro effect of hydroxychloroquine on skin morphology and transglutaminase.

BACKGROUND: Antimalarials are some of the most notorious drugs which may induce psoriasis, with 25% of all reported cases being associated with them. Antimalarials do not induce psoriasis de novo, but trigger subclinical psoriasis. In a previous report, we suggested that antimalarials exert their effect by interfering with the epidermal transglutaminase (TGase) activity. OBJECTIVE: To verify this hypothesis by examining the effect of hydroxychloroquine sulfate (HCQS) on cultured human skin and on TGase activity in vitro. MATERIALS AND METHODS: Skin samples from normal donors were cultured in the presence of HCQS for 4 days, and then processed for microscopic examination. TGase activity was assayed in the presence of HCQS and compared with blanks. RESULTS: Significant changes in epidermal morphology were seen in all explants cultured in the presence of HCQS at all concentrations employed. Areas of enhanced and irregular keratinization were observed in the upper epidermis, while a loss of cell polarity, with keratinocyte crowding and disarray, was seen in the lower epidermis. In addition, we observed intraepidermal splitting at different levels and dermo-epidermal detachments. HCQS showed a concentration-dependent inhibition of TGase activity. CONCLUSIONS: We suggest that HCQS causes an initial break in the barrier function of the epidermis by inhibiting TGase activity; this is followed by a physiologic response of the epidermis aimed at barrier restoration. This rather nonspecific stimulus to epidermal proliferation is probably sufficient to trigger psoriasis in predisposed individuals or aggravate it in psoriatic patients.

Antimalarials↗
PubMed1999

The in vitro effect of hydroxychloroquine on skin morphology in psoriasis.

BACKGROUND: In earlier papers, we suggested that the aggravation of psoriasis by antimalarial drugs (analogous to hypolipidemic drugs) could be initiated by a break in the epidermal barrier. We suggested that these drugs exerted their effect by inhibiting epidermal transglutaminase activity, and supported this hypothesis by demonstrating the effect of hydroxychloroquine sulfate (HCQS) on the morphology of cultured skin and on liver transglutaminase activity. In the present article, we describe, for the first time, the morphologic changes induced by HCQS on cultured skin of psoriatic patients. METHODS: Uninvolved (apparently normal) skin explanted from the back of two psoriatic patients was cultured in the presence of 9.2 and 13.8 mM of HCQS for 3 days. The morphologic changes were evaluated in a blind manner. The experiment was repeated twice. RESULTS: Significant changes in the epidermal morphology of psoriatic skin cultured in the presence of HCQS, compared with skin cultured without the presence of the drug, were observed. The most striking changes were enhanced and irregular keratinization and dermo-epidermal detachment and cleft formation. No parakeratosis or other characteristics of psoriasis were observed. CONCLUSIONS: The first changes caused by HCQS on the cultured skin of psoriatic patients are not characteristic of psoriasis, and include hyperproliferation and enhanced and irregular keratinization. The present experimental study gives further support to the hypothesis that HCQS causes an initial break in the barrier function of the epidermis (probably by inhibiting transglutaminase activity), which is followed by a physiologic response of the epidermis aimed at barrier restoration. This rather nonspecific stimulus to epidermal proliferation is probably sufficient to trigger psoriasis, in vivo, among genetically predisposed patients.

Antimalarials↗
PubMed2002

Hydroxychloroquine-induced apoptosis of chronic lymphocytic leukemia involves activation of caspase-3 and modulation of Bcl-2/bax/ratio.

We tested the effects of hydroxychloroquine (HCQ), an anti-rheumatic drug, on the viability of chronic lymphocytic leukemia (CLL) cells. HCQ induced a decrease in cell viability in a dose- and time-dependent manner. The mean LC50 calculated for the cells of 20 patients was 32 +/- 7 microg/ml (range, 10-75 microg/ml). We observed a large increase in apoptotic cell number after 24 h of incubation with 50 microg/ml HCQ (55 +/- 6 vs. 23 +/- 3% in medium alone, p < 0.001). Indeed, HCQ in leukemic cells induced the features of apoptosis (cell shrinkage, decrease in mitochondrial transmembrane potential, phosphatidylserine externalization, chromatin condensation and DNA fragmentation). HCQ had marked selective cytotoxicity when compared with normal blood mononuclear cells, in which the LC50 was >100 microg/ml at 24 h. HCQ induced the proteolytic cleavage of poly(ADP(adenosine 5'-diphosphate)ribose) polymerase (PARP) and increased the activity of caspase-3. The expression of bcl-2 and bax proteins was significantly modified after incubation with the drug and HCQ activity against CLL cells occurred independently of the presence of IL-4, sCD40L and bone marrow stromal cells.

Apoptosis↗
PubMed2006

Chronic hydroxychloroquine use associated with QT prolongation and refractory ventricular arrhythmia.

BACKGROUND: Hydroxychloroquine (HCQ) is used for treatment of lupus erythematosus. The cardiac toxicity of HCQ has focused primarily on acute intoxication. We report a case of chronic use of HCQ associated with torsade de pointes. CASE REPORT: A 67-year-old female presented with acquired long QT interval syndrome with a refractory ventricular arrhythmia. She was receiving chronic therapeutic doses of HCQ for the treatment of lupus erythematosus. Torsades de pointes was diagnosed in the Emergency Department (ED). After excluding other causes of long QT syndrome, the HCQ was suspected as the cause of her ventricular tachycardia. After discontinuing the HCQ, the QT interval was shorter and the patient recovered after treatment with lidocaine and isoproterenol. CONCLUSION: The chronic use of HCQ for rheumatic diseases, or as an anti-malarial drug, should be balanced against the risk of developing potentially lethal cardiac arrhythmias.

Aged↗
PubMed2001

Hydroxychloroquine enhances the endocrine secretion of adenovirus-directed growth hormone from rat submandibular glands in vivo.

Use of gene transfer technology for treating single protein deficiency disorders requires delivery of therapeutic levels of the transgene product. We have suggested that salivary glands may provide a potentially valuable target site for certain systemic applications of gene therapeutics (He et al., Gene Ther. 1998;5:537-541). However, the ability of salivary glands to deliver therapeutic proteins to either the upper gastrointestinal tract via saliva or to the bloodstream, as required, must be carefully evaluated. In the anterior pituitary gland, human growth hormone (hGH) is secreted into the bloodstream via the regulated secretory pathway. However, when expressed from an adenoviral vector delivered to salivary glands, most hGH follows the regulated, tissue-specific, exocrine secretory pathway into saliva, where it is not therapeutically useful. We tested the hypothesis that the commonly used, FDA-approved drug hydroxychloroquine (HCQ) can divert adenovirus-directed hGH from this regulated secretory pathway in rat submandibular glands and enhance delivery into the bloodstream. In untreated rats, there was approximately 20-fold more vector-directed hGH in saliva than in serum. Administration of HCQ led to a shift of hGH secretion into the bloodstream. When delivered at doses of 1 or 10 mg/kg body weight, via intraperitoneal injection plus intraductal infusion, the saliva:serum hGH ratio was approximately 2:1. Such HCQ delivery did not significantly alter the total amount of hGH measured, but increased the serum level of hGH 5- to 6-fold. Also, HCQ had no significant effects on serum chemistries or hematological parameters. We conclude that HCQ is able to significantly enhance hGH secretion from salivary glands into the bloodstream and may be useful to facilitate clinical applications of gene therapeutics via salivary glands.

Adenoviridae↗