August 26, 2008
Chloroquine: Novel Uses & Manifestations
By Cooper, R G Magwere, T
Chloroquine (CHQ) is a cheap, relatively well tolerated drug initially developed for the treatment of malaria in the 1930s. CHQ has, however, since accrued a plethora of uses in the treatment and amelioration of several other diseases and conditions because of its lysosomotropic properties. It also has characteristic physiological and systemic effects. This review gives an overview of the history and pharmacology of CHQ, and progresses to consider some of the mechanisms that may underlie its biochemical and physiological effects. Additionally, an overview of some of the novel uses of CHQ in the treatment of viral infections and cancer are presented. The antimalarial mechanisms of CHQ were not discussed in this review. The message is that CHQ, despite its welldocumented toxicity and adverse side effects may have important future uses that are associated with its lysosomotropic and immunomodulatory mechanisms. The possibility exists therefore that CHQ might be re-introduced into regular malaria treatment. Key words Anti-inflammatory - antimalarial - chloroquine - malaria - pharmacology - toxicologyIntroduction
The popularity of chloroquine [7-chloro-4-(4diethylamino-1- methylbutylamino) quinoline, CHQ] for malaria treatment in many Third World countries emanates from it being cheap, widely available, relatively well tolerated, and having a rapid onset of action15. CHQ is commonly sold as an over-the-counter medication and is also used as an anti-inflammatory drug in the treatment of rheumatoid arthritis6-8, discoid lupus erythematosus9-10 and amoebic hepatitis11. CHQ inhibits pro-inflammatory cytokine release into human whole blood and may be of therapeutic benefit not only during chronic inflammation, but also in diseases that are related to bacteria-induced inflammation12.
CHQ was first synthesised in Germany by Bayer Corporation in 1934 as a cheaper alternative to the costly naturally occurring quinine, but was then considered toxic for any significant biological use13. However, as the demand for cheaper, readily available antimalarial drugs escalated during World War II, CHQ received a new lease of life and was subsequently discovered to be more effective than the costly quinine or quinidine against intra-erythrocytic malarial parasites13. For the following two decades thereafter (1946-1966), CHQ emerged as the drug of choice for treatment and prophylaxis of malaria in most disease-endemic tropical countries14. The disadvantages of quinine/quinidine are that they are really toxic and have a short half-life15.
Properties of CHQ and its usage
CHQ is a bitter, colourless, dimorphic crystalline powder soluble in water at pH 4.5, but less so at more neutral or alkaline pH. It therefore dissolves rapidly in the stomach (pH 2.0). CHQ's bitter taste may be masked following administration in drug-loaded hydrogel beads enclosed in hard gelatin capsules16. CHQ has a quinoline ring like that of quinine and a side chain identical to that of quinacrine; and the chloride atom in the seventh position appears to be crucial to its antimalarial activity17. It specifically inhibits the malaria parasite's digestive pathway for haemoglobin9. There are two enantiomers, the (-)-chloroquine being less active than (+)- chloroquine enantiomer against chloroquineresistant strains of Plasmodium falciparum9. Comparative antimalarial drug trials in humans revealed that CHQ was a more effective antimalarial than quinidine and quinine13. Subsequently, it was developed as the first choice drug for prophylaxis and treatment of all types of malaria due to susceptible strains of P. falciparum, P. ovale, P. vivax and P. malariae17.
The major vector of malaria in Africa is the Anopheles gambiae complexl8. Malaria remains a major cause of mortality and morbidity in Africa, and there is a need to utilize effective prevention and intervention methods to combat the spread of the infection1920.
From 1966 onwards an emergence of CHQ resistence in malaria parasites was seen worldwide20-24. Indeed, four countries in Africa (Malawi, Kenya, Botswana and South Africa) now deploy pyrimethamine- sulphadoxine as their first-line antimalarial25. It is believed that factors such as inadequate dosing, incomplete courses of therapy, indiscriminate and inappropriate use, and reliance on less effective medications, have contributed to the emergence and spread of resistant parasites26,27. Even in the presence of CHQ resistance the drug may still be quite useful especially in areas with high communal immunity28. In a study from Ghana, a significantly higher proportion of inappropriateness of CHQ use was a factor influencing the lower sensitivity of P. falciparum29.
To ensure its efficacy, and when alternative drug combinations are inaccessible, CHQ may be coadministered with calcium channel blockers, tricyclic anti-depressants and anti-histamines resulting in maintenance of CHQ levels30. Other studies using cyproheptadine have shown it to reverse resistance to CHQ in strains of P. falciparum both in vivo and in vitro31. Significant protection against CHQ-resistant malaria in mice has been shown using Menhades- fish oil32. Bio (benzyl) polyamine analogues have also been shown to inhibit both CHQ-resistant and CHQ-sensitive strains of P. falciparum in vitro33. Other studies report the effectiveness of gold-CHQ complexes against resistant strains34. Antimalarial drug combinations of CHQ and primaquine have been reported to reduce therapeutic failure in CHQ-resistant P. vivax infection21, as has pyrimethamine-suIphadoxine-CHQ combinations25. The judicious use of such drug combinations with CHQ may help to avoid development of resistance and combat resistant infections35,36. Indeed, if the combined treatment translates into a 3-5 yr extension in the useful lifespan of CHQ, the overall cost would be less than that of developing the next, more expensive alternatives (mefloquine and quinine). As a response to increasing levels of resistance to antimalarial medicines, the WHO recommended that all countries experiencing resistance to conventional monotherapies, such as chloroquine, amodiaquine or sulphadoxine-pyrimethamine, should use combination therapies, preferably those containing artemisinin derivatives (ACTs - artemisinin-based combination therapies) for falciparum malaria37. Although combination therapies can be effective in reducing/ reversing incidences of CHQ resistance in parasites38, the WHO recommends that combination therapies be limited to: (i) artemether/lumefantrine; (ii) artesunate plus amodiaquine (in areas where the cure rate of amodiaquine monotherapy is greater than 80%); (iii) artesunate plus mefloquine (insufficient safety data to recommend its use in Africa); and (iv) artesunate plus sulphadoxine/pyrimethamine (in areas where the cure rate of sulphadoxine/pyrimethamine is greater than 80%).
Amodiaquine plus sulphadoxine/pyrimethamine may be considered as an interim option where ACTs cannot be made available, provided that efficacy of both is high.
Absorption, metabolism and excretion of CHQ
When administered orally, CHQ is rapidly and almost completely absorbed from the gastrointestinal tract with a bioavailability of 75-80 per cent39,40. Other routes of CHQ administration include subcutaneous, intramuscular and rectal41. Maximum plasma concentrations are reached in 1-2 h3,8,42 and remain up to 3.6 hours40 after administration. CHQ has a large apparent volume of distribution in the body (160-800 1/kg)25. It has a half-life ranging from 2-3 days in rats39,43,44 and up to 3-6 days in humans11. The elimination half-life of CHQ however varies greatly between plasma and tissue in humans, ranging from 2-3 days in plasma to over 300 h in tissues where the drug is more avidly bound45. Up to 70 per cent of an ingested dose of CHQ is excreted unchanged in the urine and the parent drug can still be detected in the urine up to 120 days following a single 300 mg dose in humans46. The total plasma clearance of CHQ is approximately 600 ml/min47 and the renal clearance is about 400-450 ml/min40. The distribution of CHQ within human blood is also important because the malaria parasite is intraerythrocytic during schizogony48. CHQ-induced redistribution of a neutral aminopeptidase may be the cause of haemoglobin accumulation in endocytic vesicles of malaria parasites49.
CHQ is a weakly basic tertiary amine and is metabolized by oxidative deamination, elimination of the side chain, and N- oxidative pathways. It is oxidatively de-ethylated to give mono- desethylCHQ (30-40% of blood CHQ concentration) and then to bisdesethylCHQ (5-10% of blood CHQ concentration)50. Available data suggest that the enzymes responsible for CHQ metabolism in humans are the cytochrome P450 (CYP) isoforms CYP3A, CYP2C8, and CYP2D651- 53. The liver transforms approximately 30-50 per cent of the administered CHQ, although extrahepatic sites of microsomal metabolism could also be of clinical significance in view of the extensive tissue distribution of CHQ and the extrahepatic distribution of CYP3A isoenzymes51. Mono-desethylCHQ is the main metabolite of CHQ and it has been shown to have the same anti- malarial activity against CHQ-susceptible P. falciparum as the parent compound54. Bis-desethylCHQ is metabolized to a 4'-hydroxy- compound, which is further oxidised to its 4-carboxylic acid derivative. Further dealkylation of the CHQ side chain results in the production of 7-chloro-4-aminoquinoline55-56. In studies conducted on intravenous administration of CHQ at 2.5 mg/kg in rats, the excretion of monodesethylCHQ and bis-desethylCHQ was 25 and 64 per cent, respectively with maximum urinary excretion on the first day39. Renal clearance of mono-desethylCHQ accounts for 65 per cent of the apparent total clearance of CHQ57. Renal effects of CHQ
Current evidence suggests that CHQ may affect kidney function when taken either during treatment or prophylaxis of malaria or administered acutely or chronically in rats58-60 probably due to its accumulation in kidney cells56. The accumulation of CHQ in tissues may result from inhibition of anti-malarial microsomal metabolism in kidney cells and potentiate its uptake in lysosomes in the cytoplasm61. CHQ, which is also deposited in the adrenal glands62, may indirectly affect kidney function by modulating the secretory patterns of aldosterone to cause a reduction in tubular Na+ handling. The deposition of CHQ in the epithelial cells of the kidney may result in a possible interference with ion movements43,63. CHQ also causes vasodilatation and cardiac depression in rats64. This may alter perfusion pressure of the kidney and renal haemodynamics, and affect renal fluid and electrolyte handling. The lowering of Na+-K+-ATPase activity by CHQ is evidenced in the inhibition of renal brush border enzyme mediated carrier transport63. The influence of CHQ on renal fluid and electrolyte handling necessitates monitoring of kidney function in patients who consume the antimalarial in malaria endemic areas.
Chronic administration of CHQ has been reported to cause Na+ retention possibly via increase in plasma aldosterone concentrations59,66 and renal Na+-K+-ATPaSe activity67. It is not uncommon for people on CHQ prophylaxis to consume ethanol and/or analgesic drugs. The co-administration of CHQ with other drugs or substances that are substrates of the CYP enzymes (e.g., ethanol and paracetamol) can result in adverse effects to the kidney68-70. It was shown that concurrent administration of CHQ and ethanol induced extensive damage to the proximal tubules and collective duct cells of the kidney70. Recently it has also been proposed that the impairment of renal function by CHQ may be due to its modulatory effects on the renal tubular response to vasopressin, either directly by inhibiting cyclic AMP generation or indirectly via induction of nitric oxide (NO) production71. If NO is involved in the mediation of CHQ-improved insulin sensitivity, then the administration of inducible nitric oxide synthase (iNOS) blockers might halt or reverse glucose-induced insulin secretion in pancreatic beta-cells72. The critical role of nitric oxide in renal failure is underscored by findings that inhibition of iNOS in rats73 or iNOS knockout mice74 protects against acute renal failure.
Slow intravenous infusion of CHQ has been reported to alter kidney function by increasing urinary Na+ excretion58. Plasma arginine vasopressin (AVP) concentrations increase in rats following acute CHQ administration presumably to increase urinary Na+ excretion60,74-77. Natriuresis may also occur due to CHQ-induced synthesis of nitric oxide, which inhibits renal Na+-K+-ATPase activity78,79. Renal ion handling may be further potentiated by CHQ- induced, nitric oxide mediated inhibition of endothelial cell proliferation80.
Three consecutive days of oral CHQ administration has been reported to cause Na+ retention possibly via increases in plasma aldosterone concentrations59,66,69,70,76,81 and renal Na+-K+-ATPaSe activity67.
Pathomorphological influence of CHQ on the liver and kidney
CHQ is a potent autophagic drug that may lead to cellular degradation of hepatocytes in the liver with the concurrent production of vacuoles82-84. An initial decrease in the number and volume of mitochondria has also been reported83 due to their sequestration in autophagic vacuoles. Observed increases in the numbers of lysosomes suggest further cellular degradation. This is accompanied by fusion of lysosomes with autophagic vacuoles resulting in the biogenesis of new lysosomes84. CHQ accumulates especially in the Kupffer cells of the liver with resultant lysosomal damage including overloading of the liver lysosomes with non-digestible material, and an increase in their size and number85. The reported accumulation of CHQ in lysosomes86,87 has an apparent destabilising effect on lysosomal membranes88,89.
Colombo and Bertini90 argued that the biological and pharmacological actions of CHQ are directly related to its interaction with lysosomal membranes. CHQ, however, decreases the density of hepatocyte lysosomes, although it has no effect on sinusoidal cell lysosome density. Such a difference could result from the fact that sinusoidal cell lysosomes do not accumulate CHQ to the same extent as hepatocyte lysosomes, despite the former contributing to more than 40 per cent of the volume occupied by lysosomes in the liver91. The density decrease of lysosomes caused by CHQ has been reported to be due to their accumulation of the drug and their subsequent osmotic swelling92,93. Singh et al 94 reported additional effects of CHQ on organelles in rat hepatocytes as shown by increases in volume densities of mitochondria, lysosomes, rough and smooth endoplasmic reticula, and Golgi apparatus, and with a concomitant decrease in functional activity95.
Currently, there are only a few investigations on the effect of CHQ on kidney morphology70,96,97. CHQ may exert its renal effects indirectly via histopathological and ultrastructural cardiac damage98 through reductions in glomerular filtration rate (GFR). Given the importance of hepatic microsomal degradation of CHQ, an alteration in liver morphology by the antimalarial56 is likely to result in an impairment of its metabolism and an increase in its circulating levels. This is likely to result in an impairment of kidney function due to its reported accumulation in cells therein43,63. Investigating the effects of long-term oral CHQ administration on possible alterations of kidney structure may help to partially explain previously observed renal effects of CHQ on fluid and electrolyte balance58,59.
Effects of CHQ on cellular enzymes
The mechanisms underlying the physiological and systemic effects of CHQ are poorly understood. However, there is a growing body of literature to suggest that some of these effects may be exerted through interactions with cellular enzymes. Antimalarial drugs including CHQ were first documented to inhibit glucose 6-phosphate dehydrogenase activity in vitro99. Inhibition of drug metabolizing enzyme systems both in vivo and in vitro were described later67 and it was subsequently demonstrated that additional effects of CHQ included alterations in phospholipid compositions of microsomes100. Decreases in CYP-mediated microsomal aminopyrine-N-demethylase, aniline hydroxylase, and cytosolic glutathione S-transferase activities were also observed in rats following administration of CHQ. Other enzyme systems such as phospholipase A1 and A2 and lysophospholipase activities are also inhibited by CHQ and related drugs in vitro101. Mitochondrial NADH dehydrogenase, succinate dehydrogenase, and cytochrome C oxidase activities are reduced following CHQ treatment in rats95. Recent studies have shown that antimalarial drugs including CHQ decrease cytochrome aa3 and b content and adversely affect mitochondrial energy transduction in vivo by acting as uncouplers of oxidative phosphorylation102. The uncoupling effect of CHQ and other antimalarials was shown to be specific for sites II and III of phosphorylation but did not affect site I102. Modulation of drug metabolizing enzymes by CHQ can lead to significant drug-drug interactions in vivo that lead to the psychotic side effects of some antidepressants and neuroleptic drugs103.
Administration of CHQ to rats was shown to also cause alterations in several hepatic and renal antioxidant enzymes thereby inducing an oxidative stress in these organs104,105. When given to rats orally at 20 mg/kg once a week for 4 wk, CHQ caused an oxidative stress in rat liver as shown by elevated activity of superoxide dismutase and decreases in H^sub 2^O^sub 2^-decomposing enzymes such as catalase and glutathione peroxidase. Increased markers of lipid peroxidation were increased in these organs confirming the extent of oxidative damage following the CHQ administration104. CHQ thus increased the intracellular levels of H^sub 2^O^sub 2^, a condition that exacerbated the susceptibility of rat organs to lipoxidative damage from subsequent oxidative challenges with menadione (30 mg/kg) or CCl^sub 4^ (1.25 ml/kg)105. In recent studies, it has been proposed that the retinopathy106 and genotoxicity107 exhibited by CHQ is due to its ability to induce intracellular and intraorgan oxidative stress/damage; and it is plausible that CHQ-induced organ failure could be exerted through such mechanisms.
CHQ induces the expression of iNOS108, a property that is responsible for many of its physiological effects in organs such as the kidneys. It was shown that CHQ at non toxic concentrations (10- 100 [mu]M) could activate tyrosine kinase and protein kinase C to induce p38MAPK activation resulting in induction of iNOS expression and increased NO production in glioma C6 cells108. The stimulatory effects of CHQ on NO production were also demonstrated in mouse, pig, and human endothelial cells in vitro80 and are thought to be mediated via a CHQ-induced impairment of iron metabolism. In patients with rheumatoid arthritis, CHQ has hormone-like effects in that NO production stimulates glucose-induced insulin secretion as well as preventing degradation of insulin109. The effects of CHQ on NO production, however, seem to be cell type-dependent. In murine peritoneal macrophages that have been stimulated with either interferon-gamma (IFN-gamma) or bacterial lipopolysaccharide (LPS), CHQ inhibited iNOS activity and NO synthesis in a dose-dependent manner110. The inhibition of NO production by CHQ in macrophages occurred at both mRNA110 and protein111 levels where decreases in these cellular components were observed following exposure to the drug. Effects of CHQ on cytokines and the immune system
The lysosomotropic effects of CHQ are widely believed to be responsible for its anti-inflammatory properties and effectiveness in the treatment of some autoimmune diseases112. CHQ was shown to decrease the production of the pro-inflammatory cytokines IFN- gamma, tumour necrosis factor-alpha (TNF-alpha), and interleukin-6 (IL-6) in LPS- or phytohemagglutininstimulated peripheral blood mononuclear cells113, and also augmented LPS-induced expression of TNF-alpha, IL1alpha, IL-1beta and IL-6 in monocytic and microglial cells114. When administered alone however, CHQ induced, rather that inhibited, the production of pro-inflammatory cytokines in astroglial cells through activation of the transcription factor NF- kappaB114. Park and colleagues114 concluded that CHQ could induce either anti-inflammatory or pro-inflammatory responses in the CNS depending on the cellular context.
CHQ also exerts anti-inflammatory effects via non-lysosomotropic mechanisms115. CHQ was shown to inhibit TNF-alpha release in macrophages through inhibition of TNF-alpha mRNA synthesis, thereby showing it can also disrupt gene transcription115-117 but does so without interfering with posttranslational modification or release of the cytokine from macrophages118. Jang and colleagues showed that CHQ also interfered with macrophage function by blocking the conversion of cell-associated TNF-alpha to mature protein, and reduced the levels of IL1beta and IL-6 mRNA by altering their stability in a pH-dependent manner118. In human histiocytic U-937 cells, CHQ was shown to decrease cell surface expression of TNF- alpha receptors by retarding their transport to the cell surface119. The blocking of pro-inflammatory cytokines by CHQ was shown to be protective against LPS- and Escherichia coli DNA-induced inflammatory responses and/or sepsis in mice120. CHQ also inhibits cytokine release into human whole blood, an effect that could be beneficial in diseases that are related to bacterial-induced inflammation12. These anti-inflammatory properties of CHQ could have photoprotective effects in conditions such as lupus erythematosus121 and could be exploited in the amelioration of conditions such as post-transfusion graft-versus-host disease122.
The immunomodulatory effects of CHQ could theoretically have deleterious implications for diseases whose pathogenicity relies on suppression of the immune system. Seth and colleagues123 showed that CHQ administration exacerbated the severity of Semliki Forest virus infections in mice by upregulating the mRNA levels of pro- inflammatory cytokines such as IL-1, IL-6, and IFN-gamma -inducing factor, among others. However, this is the only incidence in the literature to date that has shown induction of pro-inflammatory cytokines by CHQ. As such, it is not known how CHQ treatment could affect the course of viral infections such as HIV in humans. However, the evolution of AIDS-causing HIV strains has recently been postulated to be related to CHQ use in humans124,126.
A new lease of life for CHQ
The forgone discussion has shown that the physiological, cellular, and biochemical effects of CHQ are exerted through pleiotropic mechanisms involving both lysosomotropic-dependent and independent effects. This cornucopia of mechanisms of action has seen CHQ persist on therapeutic regimens for several diseases and conditions despite its systemic toxicity and the emergence of drug resistance in malaria parasites.
CHQ for treatment of viral infections?
CHQ is currently under clinical trials as a potential, antiretroviral drug in humans. Malariotherapy is basically safe for HIV infection and it improves some immunological parameters of HIV positive patients127 resulting in an increased CD4 count128. Therapeutically induced acute vivax malaria was shown to be well tolerated in 20 HIV-positive subjects who represented a range of CD4 cell lines from 15-1868 per microlitre127. Paton et al129 argued that drug combinations of HCHQ and/or hydroxycarbamide and didanosine may be suitable for poorer countries. HCHQ has been shown to suppress HIV-1 replication in T cells and monocytes in vitro by inhibiting post-transcriptional modification of the virus130-132. Early in 1995, Sperber et al131 reported that administration of CHQ for 8 wk to HIV-1 positive patients resulted in decreases in copy number of HIV-1 mRNA as well as reductions in plasma levels of the pro-inflammatory cytokine IL-6 compared to placebo. In 1998, Pardridge et al132 reported that CHQ could inhibit replication of HIV-1 in human peripheral lymphocytes at concentrations similar to those achievable in humans in vivo, with minimal effects on host cell DNA replication. The mechanism of action of CHQ on HIV-1 and - 2 was later shown by Savarino and colleagues133,134 to include structural alterations in newly formed viral envelope glycoproteins (gp120) which led to impairment of the infectivity and ability to form syncytia by the newly formed viruses.
It is now believed that CHQ, through its lysosomotropic effects of increasing intra-organellar pH, could impair the catalytic function of the glucosyltransferases involved in processing of HIV glycoproteins135. Thus CHQ has potential for use as an adjunct in standard antiretroviral drug therapy. Some research groups have since demonstrated that CHQ has synergistic effects with zidovudine, didanosine, and hydroxyurea133,134,136 as well as with protease inhibitors such as indinavir, ritonavir, and saquinavir136. The presence of CHQ in breast milk137 and in blood138 has been postulated to be related to a reduction in the risk of vertical transmission of HIV in humans. CHQ is associated with low levels of HIV RNA in breast milk137. To date, CHQ is among several drugs that have been shown to have in vitro activity against the replication of SARS or coronavirus infections139.
CHQ - a part in anticancer strategies?
In 1992, Djordevic and colleagues140 reported that treatment of mouse melanoma cells with CHQ potentiated the effectiveness of radiation-induced cell killing. Human MDA-MB231 cancer cells were influenced by CHQ via radiosensitizing effects through a destabilisation of lysosomes and plasma membranes89. They showed that treatment of MDA-MB231 cells with CHQ resulted in the latter accumulating into lysosomes thereby causing their volume to increase; the swelling of the lysosomes was associated with translocation of ceramide to the lysosomal surface thus inducing massive necrotic cell death when the cells were exposed to radiation89. Other research groups have also demonstrated, using a wide range of concentrations (0.25-128 [mu]M) for 24-72 h, that low doses of CHQ inhibited growth of A549 human lung cancer cells in culture and that higher doses of CHQ induced A549 cell death by necrosis141.
CHQ also has potential for use as a chemosensitizer in cancer in conjunction with some conventional antineoplastic agents. CHQ has recently been shown to inhibit the function of membrane-associated proteins belonging to the p-glycoprotein and multi-drug resistance (MDR) protein families89,142,143. These proteins are at the forefront as mediators of chemotherapy resistance in a wide range of cancers because they pump drugs out of cells and are usually overexpressed in most chemoresistant cell phenotypes144. The inhibition of drug efflux from the cell by CHQ and related antimalarials could help in sensitizing resistant cells to the cytotoxic effects of anticancer drugs by maintaining high intracellular concentrations of the chemotherapeutic agent. Indeed, some research groups have shown that CHQ enhances the toxicity of doxorubicin in some resistant cancer cell lines143 as well as augment the antiviral effects of some agents136. However, the use of CHQ in vivo is not without its attendant problems. Radiotherapy given after a course of CHQ treatment led to unexpected skin reactions145, and this has prompted other workers to suggest a rigorous revaluation and delineation of all undesirable side effects before CHQ can be used safely in any new treatments146.
A comeback for the malaria miracle drug?
In 1993 Malawi, an African country, withdrew CHQ from use as a treatment for malaria in favour of the sulphadoxine-pyrimethamine combinations. A decade later, there was a return of CHQ-sensitive P. falciparum malaria in Malawi147. In Uganda, a study demonstrated that there were no pharmacokinetic interactions between CHQ, sulphadoxine and pyrimethamine when given together148.
In their study Kublin and colleagues147 measured the prevalence of the pfcrt 76T genotype (a molecular marker for CHQ-resistance) and observed that after 10 yr of CHQ withdrawal, the prevalence of this genotype decreased from a peak of 85 per cent in 1992 to only 13 per cent in 2000. A subsequent trial in 2001 showed that CHQ was able to clear 100 per cent of infections in a group of asymptomatic P. falciparum infections and no incidence of the pfcrt genotype was detected147. These findings were later corroborated by the another group who showed that CHQ cured 99 per cent of 80 malaria cases in Blantyre (Malawi) and the cure rate was even superior to that of the sulphadoxinepyrimethamine combination149. However, the authors urged a cautious return to the use of CHQ in malaria endemic areas and suggest that it be used in combination with other drugs to prevent the recurrence of drug resistance in parasites.
CHQ is one of the most successful and widely used medications and with obvious health precautions, saving countless lives from the scourge of malaria. Its relatively simple manufacturing methods mean that it is affordable in many countries of the world. It has numerous other uses that could prove significant as measures are sought desperately to combat the spread of some viral diseases and cancer. Indeed, there is the real potential for CHQ to be restored to the antimalarial armamentarium; and, efforts must focus on understanding the mode of action of antimalarial agents and on the mechanism by which the P. falciparum impedes the action of these drugs150. References
1. Salomone S, Godfraind T. Drugs that reverse chloroquine resistance in malaria. Trends Pharmacol Sci 1990; 11 : 475-6.
2. Veignie E, Moreau S. The mode of action of chloroquine. Non- weak base properties of 4-aminoquinolines and antimalarial effects on strains of Plasmodium. Ann Trop Med Parasitol 1991; 85 : 229-37.
3. de Vries PJ, Oosterhuis B, van Boxtel CJ. Single-dose pharmacokinetics of chloroquine and its main metabolite in healthy volunteers. Drug Invest 1994; 8 : 143-9.
4. Wetsteyn JCFM, de Vries PJ, Oosterhuis B, van Boxtel CJ. The pharmacokinetics of three multiple dose regimens of chloroquine: implications for malaria chemoprophylaxis. Br J Clin Pharmacol 1995; 39 : 696-9.
5. Verhoef H, Hodgins E, Eggelte TA, Carter JY, Lema O, West CE, et al. Anti-malarial drug use among pre-school children in an area of seasonal malaria transmission in Kenya. Am J Trop Med Hyg 1999; 61 : 770-5.
6. Titus EO. Recent developments in the understanding of the pharmacokinetics and mechanism of action of chloroquine. Ther Drug Monit 1989; 11 : 369-79.
7. Augustijns P, Geusens P, Verbeke N. Chloroquine levels in blood during chronic treatment of patient with rheumatoid arthritis. Eur J Clin Pharmacol 1992; 42 : 429-33.
8. Augustijns P. Verbeke N. Stereoselective pharmacokinetic properties of chloroquine and de-ethyl-chloroquine in humans. Clin Pharmacokinet 1993; 24 : 259-69.
9. Krishna S, White NJ. Pharmacokinetics of quinine, chloroquine and amodiaquine. Clinical implications. Clin Pharmacokinet 1996; 30 : 263-99.
10. Meinao IM, Sato EI, Andrade LEC, Fenaz MB, Atra E. Controlled trial with chloroquine diphosphate in systemic lupus erythematosus. Lupus 1996; 5 : 237-41.
11. Abdi AY, Gustafsson LL, Ericsson O, Hellgren U. Handbook of drugs for tropical parasitic infections. 2nd ed. London: Taylor & Francis Ltd; 1995.
12. Karres I, Kremer JP, Dietl I, Steckholzer U, Jochum M, Ertel W. Chloroquine inhibits proinflammatory cytokine release into human whole blood. Am J Physiol 1998; 274 : R1058-64.
13. Bruce-Chwatt LJ, editor. Chemotherapy of malaria. 2nd ed. WHO Monograph Series 27. Geneva: World Health Organization; 1981.
14. Radl S. From chloroquine to antineoplastic drugs? The story of antibacterial quinolones. Arch Pharm Med Chem Res 1996; 329: 115- 9.
15. Sowunmi A. Disposition of oral quinine in African patients suffering from acute uncomplicated falciparum malaria. East Afr Med J 1996; 73 : 519-23.
16. Munjeri O, Hodza P, Osim EE, Musabayane CT. An investigation into the suitability of amidated pectin hydrogel beads as a delivery matrix for chloroquine. J Pharm Sci 1998; 87 : 905-8.
17. Pandey AV, Bisht H, Babbarwal VK, Srivastava J, Pandey KC, Chauhan VS. Mechanism of malarial haem detoxification inhibition by chloroquine. Biochem J 2001; 355 : 333-8.
18. Snow RW. Craig M, Deichmann U, Marsh K. Estimating mortality, morbidity and disability due to malaria among Africa's non-pregnant population. Bull World Health Organ 1999; 77 : 624-40.
19. Snow RW, Omumbo JA, Lowe B, Molyneux CS, Obiero JO. Palmer A, et al. Relation between severe malaria morbidity in children and level of Plasmodium falciparum transmission in Africa. Lancet 1997; 349 : 1650-4.
20. Baird JK. Resurgent malaria at the millennium: control strategies in crisis. Drugs 2000; 59 : 719-43.
21. Baird JK, Basri H, Subianto B, Fryauff DJ, McElroy PD, Leksana B, et al. Treatment of chloroquine-resistant Plasmodium vivax with chloroquine and primaquine or halofantrine. J Infec Dis 1995; 171 : 1678-82.
22. Frappier F, Jossang A, Soudon J, Calvo F, Rasoanaivo P, Ratsimamanga-Urverg S, et al. Bisbenzylisoquinolines as modulators of chloroquine resistance in Plasmodium falciparum and multidrug resistance in tumor cells. Antimicrob Agents Chemother 1996; 40 : 1476-81.
23. Phillips-Howard PA Confronting the challenge of antimalarial drug resistance in Africa. Managing the introduction of new antimalarial drugs to Africa: theory and practice. PPH Antimal Drug Policy 1998; 27 : 1-24.
24. Molyneux DH, Floyd K, Barnish G, Fevre EM. Transmission control and drug resistance in malaria: a crucial interaction. Parasitol Today 1999; 15 : 238-40.
25. White NJ, Nosten F, Looareesuwan S, Watkins WM, Marsh K, Snow RW, et al. Averting a malaria disaster. Lancet 1999; 353 : 1965-7.
26. Shapira A.. The resistance of falciparum malaria in Africa to 4-aminoquinolines and antifolates. Scand J Infect Dis 1990; 75(Suppl) : 1-64.
27. Bloland PB, Lackritz EM, Kazembe PN, Were JBO, Steketee R, Campbell CC. Beyond chloroquine: implications of drug resistance for evaluating malaria therapy efficacy and treatment policy in Africa. J Infect Dis 1993; 767 : 932-7.
28. Karbwang J, Harinasuta T. Overview: clinical pharmacology of antimalarials. Southeast Asian J Trop Med Public Health 1992; 23 (Suppl 4): 95-109.
29. Abuaku BK, Koram KA, Binka FN. Antimalarial drug use among caregivers in Ghana. Afr tilth Sci 2004; 4 : 171-7.
30. Basco LK, Ringwald P, Le Bras J. In vivo-in vitro test for chloroquine potentiation by cyproheptadine against Plasmodium falciparum. Trans R Soc Trop Med Hyg 1991; 85 : 206-7.
31. Peters W, Ekong R, Robinson BL, Warhurst DC, Pan X-Q. Antihistaminic drugs that reverse chloroquine resistance in Plasmodium falciparum. Lancet 1989; 2 : 334-5.
32. Levander OA, Ager AL Jr, Morris VC, May RG. Menhadenfish oil in a vitamin E-deficient diet: protection against chloroquine- resistant malaria in mice. Am J Clin Nutr 1989; 50 : 1237-9.
33. Bitonti AJ, Dumont JA, Bush TL, Edwards ML, Stemerick DM, McCann PP, et al. Bis(benzyl)polyamine analogs inhibit the growth of chloroquine-resistant human malaria parasites (Plasmodium falciparum) in vitro and in combination with alpha- difluoromethylornithine cure murine malaria. Proc Natl Acad Sci USA 1989; 86: 651-5.
34. Dadachova E. Preparation of ^sup 198^Au(I)-labelled gold- chloroquine complex [^sup 198^Au(PPh^sub 3^)(CQ)]PF^sub 6^ as a potential antimalarial agent. J Label Compd Radiopharm 1999; 42 : 287-92.
35. McIntosh HM, Greenwood BM. Chloroquine or amodiaquine combined with sulfadoxine-pyrimethamine as a treatment for uncomplicated malaria - a systematic review. Ann Trop Med Parasitol 1998; 92 : 265-70.
36. Warhurst DC. Drug resistance in Plasmodium falciparum malaria. Infection 1999; 27 (Suppl. 2) : S55-8.
37. WHO Antimalarial drug combination therapy: Report of WHO technical consultation, 4-5 April. World Health Organization (WHO/ CDS/RBM/2001.35), Geneva, Switzerland; 2001.
38. Facts on ACTs (Artemisinin-based combination therapies). January update. World Health Organization, Geneva, Switzerland; 2006. Available at: http://www.rbm.who.int/ cmc_upload/0/000/015/ 364/RBMlnfosheet_9.htm
39. Adelusi SA, Salako LA. Tissue and blood concentrations of chloroquine following chronic administration in the rat. J Pharm Pharmacol 1982; 34 : 733-5.
40. Gustafsson LL, Walker O, Alvan G, Beermann B, Estevez F, Gleisner L, et al. Disposition of chloroquine in man after single intravenous and oral doses. Br J Pharmacol 1983; 15 : 471-9.
41. Minker E, Ivan J. Experimental and clinicopharmacological study of rectal absorption of chloroquine. Acta Phys Academiae Sci Hung 1991; 77 : 237-48.
42. Walker O, Dawodu AH, Adeyokunnu AA, Salako LA, Alvan G. Plasma chloroquine and desethylchloroquine concentrations in children during and after chloroquine treatment for malaria. Br J Pharmacol 1983; 16 : 701-5.
43. McChesney EW, Banks WF Jr., Fabian RJ. Tissue distribution of chloroquine, hydroxychloroquine, and desethylchloroquine in the rat. Toxicol Appl Pharmacol 1967; 10 : 501-13.
44. White NJ. Antimalarial pharmacokinetics and treatment regimens. Br J Clin Pharmacol 1992; 34 : 1-10.
45. Desjardins RE, Doberstyn EB, Wernsdorfer WH. The treatment and prophylaxis of Malaria. In: Wernsdorfer WH, McGregor I, editors. Malaria: Principles and practice of malariology. Vol. I. London: Churchill Livingstone; 1988 p. 827-59.
46. Pussard E, Verdier F. Antimalarial 4-aminoquinolines: mode of action and pharmacokinetics. Fund CHn Pharmacol 1994; 8: 1-17.
47. Walker O, Alvan G, Beerman B, Gustafsson LL, Lindstom BL, Sjoqvist F. The pharmacokinetics of chloroquine in healthy volunteers. Br J Clin Pharmacol 1982; 14 (Suppl) : 624.
48. Frisk-Holmberg M, Bergkvist Y, Domeij-Nyberg B, Hellstrom L, Jasson F. Chloroquine serum concentration and side-effects: evidence for dose-dependent kinetics. Clin Pharmacol Ther 1979; 25 : 345-50.
49. Fitch CD, Cai GZ, Chen YF, Ryerse JS. Relationship of chloroquine-induced redistribution of a neutral aminopeptidase to hemoglobin accumulation in malaria parasites. Arch Biochem Biophys 2003; 410 : 296-306.
50. Houze P, de Reynies A, Baud FJ, Benatar MF, Pays M. Simultaneous determination of chloroquine and its three metabolites in human plasma, whole blood and urine by ion-pair high-performance liquid chromatography. J Chromatogr 1992; 574 : 305-12.
51. Ducharme J, Farinotti R. Clinical pharmacokinetics and metabolism of chloroquine. Focus on recent advancements. Clin Pharmacokinet 1996; 31 : 257-74.
52. Kim KA, Park JY, Lee JS, Lim, S. Cytochrome P450 2C8 and CYP3A4/5 are involved in chloroquine metabolism in human liver microsomes. Arch Pharm Res 2003; 26 : 631-7.
53. Projean D, Baune B, Farinotti R, Flinois JP, Beaune P, Taburet AM, et al. In vitro metabolism of chloroquine: identification of CYP2C8, CYP3A4, and CYP2D6 as the main isoforms catalyzing N-desethylchloroquine formation. Drug Metab Disposition 2003; 31 : 748-54. 54. Aderounmu AF. In vitro assessment of the antimalarial activity of chloroquine and its major metabolites. Am J Trop Med Parasitai 1984; 78 : 581-5.
55. Kuroda K. Detection and distribution of chloroquine metabolites in human tissues. J Pharmacol Exp Ther 1962; 137: 156- 61.
56. McChesney EW, Conway WD, Banks WF, Rogers JE, Shekosky JM. Studies of the metabolism of some compounds of the 4-amino-7- chloroquinoline series. J Pharmacol Exp Ther 1966; 151 : 482-93.
57. Adjepon-Yamoah KK, Ofori-Adjei D, Woolhouse NM, Lindstrom B. Whole-blood single-dose kinetics of chloroquine and desethylchloroquine in Africans. Ther Drug Monit 1986; 8 : 195-9.
58. Musabayane CT, Ndhlovu CE, Mamutse G, Bwititi P, Balment RJ. Acute chloroquine administration increases renal sodium excretion. J Trop Med Hyg 1993; 96 : 305-10.
59. Musabayane CT, Ndhlovu CE, Balment RJ. The effects of oral chloroquine administration on kidney function. Renal Fail 1994; 16 : 221-8.
60. Musabayane CT, Windle RJ, Forling ML, Balment RJ. Arginine vasopressin mediates the chloroquine induced increase in renal sodium excretion. Trop Med Int Health 1996; 1 : 542-50.
61. Back DJ, Purba HS, Park BK, Ward SA, Orme ML. Effect of chloroquine and primaquine on antipyrine metabolism. Br J Clin Pharmacol 1983; 16 : 497-502.
62. Gustafsson LL, Lindstrom B, Grahnen A, Alvan G. Chloroquine excretion following malaria prophylaxis. Br J Clin Chem 1987; 24 : 221-4.
63. Knox JM, Owens DW. The chloroquine mystery. Arch Dermatol 1966; 94 : 205-14.
64. Sofola OA, Olude IO, Adegoke F. The effects of chronic chloroquine toxicity on blood pressure of rats. J Trop Med Hyg 1981; 84: 249-52.
65. Chesney RW, Budreau AM. Chloroquine, a novel inhibitor of amino acid transport by rat renal brush border membrane vesicles. Amino Acids 1995; 8 : 141-58.
66. Ogilvie KM, Lee S, Weiss B, Rivier C. Mechanisms mediating the influence of alcohol on the hypothalamic-pituitary-adrenal axis responses to immune and non-immune signals. Alcohol Clin Exp Res 1998; 22 : 2435-75.
67. Novoa E, Rodrigo R. Renal handling of electrolytes and (Na+K)- ATPase activity after unilateral nephrectomy during long-term ethanol feeding. Acta Physiol Pharmacol Ther Latinoamer 1989; 39 : 15-26.
68. Ahmed MH, Ashton N, Balment RJ. Renal function in a rat model of analgesic nephropathy: effect of chloroquine. J Pharmacol Exp Ther 2003; 305 : 123-30.
69. Musabayane CT, Cooper RG, Osim E, Balment RJ. Renal electrolyte and fluid handling in the rat following chloroquine and/ or ethanol administration. Gen Pharmacol - Vasc Syst 2000; 34 : 43- 51.
70. Musabayane CT, Cooper RG, Prasada Rao PVV, Balment RJ. Effects of ethanol on the changes in renal fluid and electrolyte handling and kidney morphology induced by long-term chloroquine administration to rats. Alcohol 2000; 22 : 129-38.
71. Ahmed MH, Osman MM. Why does chloroquine impair renal function? Chloroquine may modulate the renal tubular response to vasopressin either directly by inhibiting cyclic AMP generation, or indirectly via nitric oxide. Med Hypotheses 2007; 68 : 140-3.
72. Ahmed MH. Insulin resistance and nitric oxide and associated renal injury: innocent bystanders or accessories to the crime? NZ Med J 2006; 119 : U2112.
73. Noiri E, Peresleni T, Miller F, Goligorsky MS. In vivo targeting of inducible NO synthase with oligodeoxynucleotides protects rat kidney against ischemia. J Clin Invest 1996; 97 : 2377- 83.
74. Ling H, Edelstein C, Gengaro P, Meng X, Lucia S, Knotek M, et al. Attenuation of renal ischemia-reperfusion injury in inducible nitric oxide synthase knockout mice. Am J Physiol 1999; 277 : F383- 90.
75. Cooper RG, Musabayane CT. The acute effects of combined chloroquine and ethanol on renal electrolyte handling. Proceedings of the 2nd International MIM African Malaria Conference; 1999, March 14-19; Durban, South Africa; 1999. p. C-42-3.
76. Cooper RG, Musabayane CT. Effects of ethanol on plasma chloroquine, arginine vasopressin (AVP) concentrations and renal hydro-electrolyte handling in the rat. Renal Fail 2000; 22 : 785- 98.
77. Musabayane CT, Mus vibe A, Wenyika J, Munjeri O, Osim EE. Chloroquine influences renal function in rural Zimbabweans with acute transient fever. Renal Fail 1999; 21 : 189-97.
78. Liang MY, Knox FG. Nitric oxide activates PKC alpha and inhibits Na+-K+-ATPase in opossum kidney cells. Am J Physiol-Renal Physiol 1999; 277 : F859-65.
79. Kang DG, Kim JW, Lee J. Effects of nitric oxide synthesis inhibition on the Na, K-ATPase activity in the kidney. Pharmacol Res 2000; 41 : 121-5.
80. Ghigo D, Aldieri E, Todde R, Costamagna C, Garbarino G, Pescarmona G, et al. Chloroquine stimulates nitric oxide synthesis in murine, porcine, and human endothelial cells. J Clin Invest 1998; 702 : 595-605.
81. Cooper RG, Osim E, Musabayane CT. Ethanol reduces the natriuretic effect of chloroquine. In: Samkange C, editor. Proceedings of the 1997 Annual Medical Research Day, 1997 October 25; Harare, Zimbabwe; 1997. p. 9.
82. Abraham R, Hendy R, Grasso P. Formation of myeloid bodies in rat liver lysosomes after chloroquine administration. Exp Mol Path 1968; 9: 212-29.
83. Wisner-Gebhart AM, Brabec RK, Gray RH. Morphometric studies of chloroquine-induced changes in hepatocytic organelles in the rat. Exp Mol Path 1980; 33 : 144-52.
84. Ericsson JL. Mechanism of cellular autophagy. In: Dingle JT, Fells HB, editors. Lysosomes in biology and pathology, Vol. 2. New York: Wiley; 1969. p. 345-94.
85. Schneider P, Korolenko TA, Busch U. A review of drug-induced lysosomal disorders of the liver in man and laboratory animals. Microsc Res Tech 1997; 36 : 253-75.
86. Allison AC, Young MR. Uptake of dyes and drugs by living cells in culture. Life Sci 1964; 3 : 1407-14.
87. MacIntyre AC, Cutler DJ. Kinetics of chloroquine uptake into isolated rat hepatocytes. J Pharm Sci 1993; 82 : 592-600.
88. Weissmann G. Lysosomes and joint disease. Arthritis Rheum 1966; 9: 834-40.
89. Zhao H, Cai Y, Santi S, Lafrenie R, Lee H. Chloroquine- mediated radiosensitization is due to the destabilization of the lysosomal membrane and subsequent induction of cell death by necrosis. Radiat Res 2005; 164 : 250-7.
90. Colombo MI, Bertini F. Properties of binding sites for chloroquine in liver lysosomal membranes. J Cell Physiol 1988; 137 : 598-602.
91. Blouin A, Bollender RP, Weibel ER. Distribution of organelles and membranes between hepatocytes and nonhepatocytes in the rat liver parenchyma. A stereological study. J Cell Biol 1977; 72 : 441- 55.
92. Wibo M, Poole B. Protein degradation in cultured cells. II. The uptake of chloroquine by rat fibroblasts and the inhibition of cellular protein degradation and cathepsin B1. J Cell Biol 1974; 63 : 430-40.
93. Limet JN, Quintart J, Schneider YJ, Courtoy PJ. Receptor- mediated endocytosis of polymeric IgA and galactosylated serum albumin in rat liver. Evidence for intracellular ligand sorting and identification of distinct endosomal compartments. Eur J Biochem 1985; 146 : 539-48.
94. Singh KP, Krause W, David H, von Zglinicki J. Effects of chloroquine on hepatocyte organelles in rat. Exp Pathol 1985; 28: 119-24.
95. Deepalakshmi PD, Parasakthy K, Shanthi S, Devaraj NS. Effect of chloroquine on rat liver mitochondria. Indian J Exp Biol 1994; 32 : 797-9.
96. Hosteller KY, Richman DD. Studies on the mechanism of phospholipid storage induced by amantadine and chloroquine in Madin Darby canine kidney cells. Bio hem Pharmacol 1982; 31 : 3795-9.
97. Prasada Rao PVV, Cooper RG, Musabayane C. Histopathological changes in kidneys of rats exposed to chloroquine and ethanol in combination. In: Sharp B, editor. Proceedings of the 2nd International MIM African Malaria Conference; 1999. March 14-19; Durban, South Africa; 1999. p. C-140-1.
98. Teixeira RA, Filho MM, Benvenuti LA, Costa R, Pedrosa AA, Nishioka SAD. Cardiac damage from chronic use of chloroquine. A case report and review of the literature. Arq Bras Cardiol 2002; 79 : 85- 8.
99. Cotton DW, Sutorius AH. Inhibiting effect of some antimalarial substances on glucose-6-phosphate dehydrogenase. Nature 1971; 233 : 197.
100. Emerole GO, Thabrew MI. Changes in some rat hepatic microsomal components induced by prolonged administration of chloroquine. Biochem Pharmacol 1983; 32 : 3005-9.
101. Loffler BM, Bohn E, Hesse B, Kunze H. Effects of antimalarial drugs on phospholipase A and lysophospholipase activities in plasma membrane, mitochondrial, microsomal and cytosolic subcellular fractions of rat liver. Biochim Biophys Acta 1985; 835 : 448-55.
102. Katewa SD, Katyare SS. Treatment with antimalarials adversely affects the oxidative energy metabolism in rat liver mitochondria. Drug Chem Toxicol 2004; 27 : 41-53.
103. Alisky JM, Chertkova EL, Iczkowski KA. Drug interactions and pharmacogenetic reactions are the basis for chloroquine and mefloquine-induced psychosis. Med Hypotheses 2006; 67 : 1090-94.
104. Magwere T, Naik YS, Hasler JA. Effects of chloroquine treatment on antioxidant enzymes in rat liver and kidney. Free Radical Biol Med 1997; 22 : 321-7.
105. Magwere T, Hasler JA. The role of xenobiotics in the modulation of antioxidant status and susceptibility to oxidative damage. In: Bahorun T, Gurib-Fakim A, editors. Molecular and therapeutic aspects of Redox biochemistry, London: OICA International (UK) Limited; 2003. p. 78-86.
106. Toler SM. Oxidative stress plays an important role in the pathogenesis of drug-induced retinopathy. Exp Biol Med (Maywood) 2004; 229 : 607-15.
107. Farombi EO. Genotoxicity of chloroquine in rat liver cells: protective role of free radical scavengers. Cell Biol Toxicol 2006; 22 : 159-67.
108. Chen TH, Chang PC, Chang MC, Lin YF, Lee HM. Chloroquine induces the expression of inducible nitric oxide synthase in C6 glioma cells. Pharmacol Res 2005; 57 : 329-36.
109. Ahmed MH. Nitric oxide might be involved in the pathogenesis of chloroquine-induced lipidosis. Clin Ther 2005; 27 : 509-10.
110. Park YC, Pae HO, Yoo JC, Choi BM, Jue DM, Chung HT. Chloroquine inhibits inducible nitric oxide synthase expression in murine peritoneal macrophages. Pharmacol Toxicol 1999; 85 : 188-91. 111. Hrabak A, Sefrioui H, Vercruysse V, Temesi A, Bajor T, Vray B. Action of chloroquine on nitric oxide production and parasite killing by macrophages. Eur J Pharmacol 1998; 354 : 83-90.
112. Wozniacka A, Lesiak A, Narbutt J, Kobos J, Pavel S, Sysa- Jedrzejowska A. Chloroquine treatment reduces the number of cutaneous HLA-DR+ and CD1a+ cells in patients with systemic lupus erythematosus. Lupus 2007; 16 : 89-94.
113. van den Borne BE, Dijkmans BA, de Rooij HH, le Cessie S, Verweij CL. Chloroquine and hydroxychloroquine equally affect tumor necrosis factor-alpha, interleukin 6, and interferon-gamma production by peripheral blood mononuclear cells. J Rheumatol 1997; 24 : 55-60.
114. Park J, Kwon D, Choi C, Oh JW, Benveniste EN. Chloroquine induces activation of nuclear factor-kappaB and subsequent expression of pro-inflammatory cytokines by human astroglial cells. J Neurochem 2003; 84 : 1266-74.
115. Weber SM, Levitz SM. Chloroquine interferes with lipopolysaccharide-induced TNF-alpha gene expression by a nonlysosomotropic mechanism. J Immunol 2000; 165 : 1534-40.
116. Zhu X, Ertel W, Ayala A, Morrison MH, Perrin MM, Chaudry IH. Chloroquine inhibits macrophage tumour necrosis factor-alpha mRNA transcription. Immunology 1993; 80: 122-6.
117. Weber SM, Chen JM, Levitz SM. Inhibition of mitogenactivated protein kinase signalling by chloroquine. J Immunol 2002; 168 : 5303- 9.
118. Jang CH, Choi JH, Byun MS, Jue DM. Chloroquine inhibits production of TNF-alpha, IL-1beta and IL-6 from lipopolysaccharide- stimulated human monocytes/macrophages by different modes. Rheumatology 2006; 45 : 703-10.
119. Jeong JY, Choi JW, Jeon KI. Jue DM. Chloroquine decreases cell-surface expression of tumour necrosis factor receptors in human histiocytic U-937 cells. Immunology 2002; 105 : 83-91.
120. Hong Z, Jiang Z. Liangxi W, Guofu D, Ping L, Yongling L, et al. Chloroquine protects mice from challenge with CpG ODN and LPS by decreasing proinflammatory cytokine release. Int Immunopharmacol 2004; 4 : 223-34.
121. Wozniacka A, Lesiak A, Narbutt J, McCauliffe DP, SysaJedrzejowska A. Chloroquine treatment influences proinflammatory cytokine levels in systemic lupus erythematosus patients. Lupus 2006; 15 : 268-75.
122. Nishimura M, Hidaka N, Akaza T, Tadokoro K, Juji T. Immunosuppressive effects of chloroquine: potential effectiveness for treatment of post-transfusion graft-versus-host disease. Transfusion Medicine 1998; 8 : 209-14.
123. Seth P, Mani H, Singh AK, Banaudha KK, Madhavan S, Sidhu GS, et al. Acceleration of viral replication and up-regulation of cytokine levels by antimalarials: implications in malaria-endemic areas. Am J Trop Med Hyg 1999; 61 : 180-6.
124. Parris GE. The timing is right: Evolution of AIDS-causing HIV strains are consistent with history of chloroquine use. Med Hypotheses 2006; 67 : 1258-9.
125. Parris GE. Update on hypothesis linking chloroquine- resistant malaria to disease-causing HIV. Med Hypotheses 2006; 67 : 670-1.
126. Parris GE. AIDS: caused by development of resistance to drugs in a non-target intracellular parasite. Med Hypotheses 2007- 68: 151-7.
127. Chen X, Xiao B, Xu H, Shi W, Gao K, Rao J. Procedure and clinical assessments of malariotherapy: recent experience in 20 HIV patients. Chin Med J (Engl.) 2003; 116 : 1016-21.
128. Heimlich HJ, Chen XP, Xiao BQ, Liu SG, Lu YH, Spletzer EG, et al. Malariotherapy for HIV patients. Mech Ageing Dev 1997; 93 : 79-85.
129. Paton NI, Aboulhab J, Karin F. Hydroxychloroquine, hydroxycarbamide, and didanosine as economic treatment for HIV-1. Lancet 2002; 359 : 1667-8.
130. Ornstein MH, Sperber K. The anti-inflammatory and antiviral effects of hydroxychloroquine in two patients with acquired immunodeficiency syndrome and active inflammatory arthritis. Arthritis Rheum 1996; 39 : 157-61.
131. Sperber K, Louie M, Kraus T, Proner J, Sapira E, Lin S, et al. Hydroxychloroquine treatment of patients with human immunodeficiency virus type 1. Clin Ther 1995; 17 : 622-36.
132. Pardridge WM, Yang J, Diagne A. Chloroquine inhibits HIV-1 replication in human peripheral blood lymphocytes. Immunol Lett 1998; 64 : 45-7.
133. Savarino A, Gennero L, Chen HC, Serrano D, Malavasi F, Boelaert JR, et al. Anti-HIV effects of chloroquine: mechanisms of inhibition and spectrum of activity. AIDS 2001; 15 : 2221-9.
134. Savarino A, Gennero L, Sperber K, Boelaert JR. The antiHIV- 1 activity of chloroquine. J Clin Virol 2001; 20 : 131-5.
135. Savarino A, Boelaert JR, Cassone A, Majori G, Cauda R. Effects of chloroquine on viral infections: an old drug against today's diseases? Lancet Infect Dis 2003; 3 : 722-7.
136. Boelaert JR, Sperber K, Piette J. Chloroquine exerts an additive in vitro anti-HIV type 1 effect when associated with didanosine and hydroxyurea. AIDS Res Hum Retrovirus 1999; 15 : 1241- 7.
137. Semrau K, Kuhn L, Kasonde P, Sinkala M, Kankasa C, Shutes E, et al. Impact of chloroquine on viral load in breast milk. Trop Med Int Health 2006; 11 ; 800-3.
138. Neely M, Kalyesubula I, Bagenda D, Myers C, Olness K. Effect of chloroquine on human immunodeficiency virus (HIV) vertical transmission. Afr Health Sci 2003; 3 : 61-7.
139. de Clercq E. Potential antivirals and antiviral strategies against SARS coronavirus infections. Expert Rev Anti Infect Ther 2006-4 : 291-302.
140. Djordevic B, Lange CS, Rotman M. Potentiation of radiation lethality in mouse melanoma cells by mild hyperthermia and chloroquine. Melanoma Res 1992; 2 : 321-6.
141. Fan C, Wang W, Zhao B, Zhang S, Miao J. Chloroquine inhibits cell growth and induces cell death in A549 lung cancer cells. Bioorg Med Chem 2006; 14 : 3218-22.
142. Vezmar M, Georges E. Direct binding of chloroquine to the multidrug resistance protein (MRP): possible role for MRP in chloroquine drug transport and resistance in tumor cells. Biochem Pharmacol 1998; 56 : 733-42.
143. Vezmar M, Georges E. Reversal of MRP-mediated doxorubicin resistance with quinoline-based drugs. Biochem Pharmacol 2000; 59 : 1245-52.
144. Kvackajova-Kisucka J, Barancik M, Breier A. Drug transporters and their role in multidrug resistance of neoplastic cells. Gen Physiol Biophys 2001; 20 : 215-37.
145. Rustogi A, Munshi A, Jalali R. Unexpected skin reaction induced by radiotherapy after chloroquine use. Lancet Oncol 2006; 7 : 608-9.
146. Savarino A, Lucia MB, Giordano F, Cauda R. Risks and benefits of chloroquine use in anticancer strategies. Lancet Oncol 2006; 7 : 792-3.
147. Kublin JG, Cortese JF, Njunju EM, Mukadam RA, Wirima JJ, Kazembe PN, et al. Re-emergence of chloroquine-sensitive Plasmodium falciparum malaria after cessation of chloroquine use in Malawi. J Infect Dis 2003; 187 : 1870-5.
148. Obua C, Ntale M, Lundblad MS, Mahindi M, Gustafsson LL, Ogwal-Okeng JW, et al. Pharmacokinetic interactions between chloroquine, sulfadoxine and pyrimethamine and their bioequivalence in a generic fixed-dose combination in healthy volunteers in Uganda. Afr Health Sci 2006; 6 : 86-92.
149. Laufer MK, Thesing PC, Eddington ND, Masonga R, Dzinjalamala FK, Takala SL, et al. Return of chloroquine antimalarial efficacy in Malawi. N Engl J Med 2006; 355 : 1959-66.
150. Lelievre J, Berry A, Benoit-Vical F. Artemisinin and chloroquine: do mode of action and mechanism of resistance involve the same protagonists? Curr Opin Investig Drugs 2007; 8: 117-24.
R.G. Cooper & T. Magwere*
Division of Physiology, Faculty of Health, Birmingham City University & * University of Leeds, Faculty of Medicine & Health, St. James University Hospital, Cancer Research Building, Leeds, UK
Received March 13, 2007
Reprint requests: Dr R.G. Cooper, Senior Lecturer, Division of Physiology, Faculty of Health, Birmingham City University,
704 Baker Building, Franchise Street, Perry Barr, Birmingham B42 2SU, UK
e-mail: [email protected]
Copyright Indian Council of Medical Research Apr 2008
(c) 2008 Indian Journal of Medical Research. Provided by ProQuest LLC. All rights Reserved.