Chloroquine

Chloroquine is a 4-aminoquinoline drug long used in the treatment or prevention of malaria. As it also mildly suppresses the immune system, it is used in some autoimmune disorders, such as rheumatoid arthritis and lupus erythematosus. After the malaria parasite Plasmodium falciparum started to develop widespread resistance to chloroquine, new potential utilisations of this cheap and widely available drug have been investigated. For example, chloroquine is in clinical trials as an investigational antiretroviral in humans with HIV-1/AIDS and as a potential antiviral agent against chikungunya fever. Moreover, the radiosensitizing and chemosensitizing properties of chloroquine are beginning to be exploited in anticancer strategies in humans.

Pharmacology

Chloroquine has a very high volume of distribution, as it diffuses into the body's adipose tissue. Chloroquine and related quinines have been associated with cases of retinal toxicity, particularly when provided at higher doses for longer time frames. Accumulation of the drug may result in deposits that can lead to blurred vision and blindness. With long term doses, routine visits to an optometrist or ophthalmologist are recommended.

Chloroquine is also a lysosomotropic agent, meaning that it accumulates preferentially in the lysosomes of cells in the body. The pKa for the quinoline nitrogen of chloroquine is 8.5, meaning that it is ~10% deprotonated at physiological pH as calculated by the Henderson-Hasselbalch equation. This decreases to ~0.2% at a lysosomal pH of 4.6. Because the deprotonated form is more membrane permeable than the protonated form, this results in a quantitative "trapping" of the compound in lysosomes.

(Note that a quantitative treatment of this phenomenon involves the pKas of all nitrogens in the molecule; this treatment, however, suffices to show the principle)

The lysosomotropic character of chloroquine is believed to account for much of its anti-malarial activity; the drug concentrates in the acidic food vacuole of the parasite and interferes with essential processes.

Malaria prevention

Chloroquine can be used for preventing malaria from Plasmodium vivax, ovale and malariae. Many areas of the world have widespread strains of chloroquine-resistant P. falciparum, so other antimalarials like mefloquine or atovaquone may be advisable instead. Combining chloroquine with proguanil may be more effective against chloroquine-resistant Plasmodium falciparum than treatment with chloroquine alone, but is no longer recommended by the CDC due to the availability of more effective combinations.[1]

Doses

Per the Centers for Disease Control (CDC): Directions for Use The adult dosage is 500 mg chloroquine phosphate once a week. - Take the first dose of chloroquine 1 week before arrival in the malaria-risk area. - Take chloroquine once a week, on the same day of the week, while in the malaria-risk area. - Take chloroquine once a week for 4 weeks after leaving the malaria-risk area. Chloroquine should be taken on a full stomach to lessen nausea.

Chloroquine produced by Global Pharm is a white, round tablet with 7010 printed on one side. Don't chew the tablet, because it tastes horribly bitter.

Adverse effects

At the doses used for prevention of malaria, side effects include gastrointestinal problems such as stomach ache, itch, headache and blurred vision. When doses are extended over a number of months it is important to watch out for a slow onset of "changes in moods" (i.e.depression, anxiety). These may be more pronounced with higher doses used for treatment. Chloroquine tablets have an unpleasant metallic taste.

A serious side effect is also a rare toxicity in the eye (generally with chronic use), and requires regular monitoring even when symptom-free. The daily safe maximum doses for eye toxicity can be computed from one's height and weight using this calculator. The use of Chloroquine has also been associated with the development of Central Serous Retinopathy.

Chloroquine is very dangerous in overdose. It is rapidly absorbed from the gut and death often occurs within 2½ hours of taking the drug. The therapeutic index for chloroquine is small and just doubling the normal dose of chloroquine can be fatal.[2]

Mechanism of action

Inside the red blood cells, the malarial parasite must degrade the hemoglobin for the acquisition of essential amino acids, which the parasite requires to construct its own protein and for energy metabolism. This is essential for parasitic growth and division inside the red blood cell. It is carried out in the digestive vacuole of the parasite cell.

During this process, the parasite produces the toxic and soluble molecule heme. The heme moiety consists of a porphyrin ring called Fe(II)-protoporphyrin IX (FP). To avoid destruction by this molecule, the parasite polymerizes heme to form hemozoin, a non-toxic molecule. Hemozoin collects in the digestive vacuole as insoluble crystals.

Chloroquine enters the red blood cell, inhabiting parasite cell, and digestive vacuole by simple diffusion. Chloroquine then becomes protonated (to CQ2+) as the digestive vacuole is known to be acidic (pH 4.7), chloroquine then cannot leave by diffusion. Chloroquine caps hemozoin molecules to prevent further polymerization of heme, thus leading to heme build up. Chloroquine binds to heme (or FP) to form what is known as the FP-Chloroquine complex, this complex is highly toxic to the cell and disrupts membrane function. Action of the toxic FP-Chloroquine and FP results in cell lysis and ultimately parasite cell autodigestion. In essence, the parasite cell drowns in its own metabolic products.

The effectiveness of chloroquine against the parasite has declined as resistant strains of the parasite evolved which effectively neutralized the drug via mechanism that drains chloroquine away from the digestive vacuole. CQ-Resistant cells efflux chloroquine at 40 times the rate of CQ-Sensitive cells, this is related to a number of mutations that trace back to transmembrane proteins of the digestive vacuole, including an essential mutation in the PfCRT gene (Plasmodium falciparum Chloroquine Resistance Transporter). This mutated protein may actively pump chloroquine from the cell. Resistant parasites frequently have mutated products or amplified expression of ABC transporters that pump out the chloroquine, typically PfMDR1 and PfMDR2 (Plasmodium falciparum Multi-Drug Resistance genes). Resistance has also been conferred by reducing the lower transport activity of the intake mechanism, so less chloroquine is imported into the parasite[1].

Research on the mechanism of chloroquine and how the parasite has acquired chloroquine resistance is still ongoing, and this article is not by any means fact. Other theories of chloroquine's mechanism of action suggest DNA intercalation or a combination of the disrupted membrane function of the lysosome.

Against rheumatoid arthritis, it operates by inhibiting lymphocyte proliferation, phospholipase A, release of enzymes from lysosomes, release of reactive oxygen species from macrophages, and production of IL-1.

As an antiviral agent, it impedes the completion of the viral life cycle by inhibiting some processes occurring within intracellular organelles and requiring a low pH. As for HIV-1, chloroquine inhibits the glycosylation of the viral envelope glycoprotein gp120, which occurs within the Golgi apparatus.

The mechanisms behind the effects of chloroquine on cancer are currently being investigated. The best know effects (investigated in clinical and pre-clinical studies) include radiosensitising effects through lysosome permeabilisation, and chemosensitising effects through inhibition of drug efflux pumps (ATP-binding cassette transporters)or other mechanisms (reviewed in the second-to-last reference below).

Notes

1. ^ CDC. Health information for international travel 2001--2002. Atlanta, Georgia: U.S. Department of Health and Human Services, Public Health Service, 2001.
2. ^ Cann HM, Verhulst HL (1961). "Fatal acute chloroquine poisoning in children". Pediatrics 27 (1): 95–102. 

References

  • Plowe CV. Antimalarial drug resistance in Africa: strategies for monitoring and deterrence. Curr Top Microbiol Immunol. 2005;295:55-79.
  • Uhlemann AC, Krishna S. Antimalarial multi-drug resistance in Asia: mechanisms and assessment. Curr Top Microbiol Immunol. 2005;295:39-53.
  • Identification of a chloroquine importer in Plasmodium falciparum. Differences in import kinetics are genetically linked with the chloroquine-resistant phenotype. J Biol Chem. 1997 Jan 31;272(5):2652-8.
  • Yam JC, Kwok AK. Ocular toxicity of hydroxychloroquine. Hong Kong Med J. 2006 Aug;12(4):294-304.
  • 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 Nov;3(11):722-7.
  • Savarino A, Lucia MB, Giordano F, Cauda R. Risks and benefits of chloroquine use in anticancer strategies. Lancet Oncol. 2006 Oct;7(10):792-3.
  • Sotelo J, Briceno E, Lopez-Gonzalez MA. Adding chloroquine to conventional treatment for glioblastoma multiforme: a randomized, double-blind, placebo-controlled trial. Ann Intern Med. 2006 Mar 7;144(5):337-43. Summary for patients in: Ann Intern Med. 2006 Mar 7;144(5):I31.

External links

Malaria
Classification & external resources

Plasmodium falciparum ring-forms and gametocytes in human blood.
ICD-10 B 50.
ICD-9 084

OMIM 248310
DiseasesDB 7728
MedlinePlus 000621
eMedicine med/1385   emerg/305 ped/1357
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immune system is a collection of mechanisms within an organism that protects against disease by identifying and killing pathogens and tumor cells. It detects a wide variety of agents, from viruses to parasitic worms, and needs to distinguish them from the organism's own healthy
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MeSH D001327 Autoimmunity is the failure of an organism to recognize its own constituent parts (down to the sub-molecular levels) as "self", which results in an immune response against its own cells and tissues.
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Rheumatoid arthritis
Classification & external resources

ICD-10 M 05. -M 06.
ICD-9 714

OMIM 180300
DiseasesDB 11506
MedlinePlus 000431
eMedicine med/2024   emerg/48 pmr/124
MeSH D001172

Rheumatoid arthritis (
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Lupus Erythematosus
Classification & external resources

ICD-10 L 93. , M 32.
ICD-9 710.0

OMIM 152700
DiseasesDB 12782
MedlinePlus 000435
eMedicine med/2228   emerg/564
MeSH D008180

Systemic Lupus Erythematosus (
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Malaria
Classification & external resources

Plasmodium falciparum ring-forms and gametocytes in human blood.
ICD-10 B 50.
ICD-9 084

OMIM 248310
DiseasesDB 7728
MedlinePlus 000621
eMedicine med/1385   emerg/305 ped/1357
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P. falciparum

Binomial name
Plasmodium falciparum
Welch, 1897

Plasmodium falciparum is a protozoan parasite, one of the species of Plasmodium that cause malaria in humans.
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Antiretroviral drugs are medications for the treatment of infection by retroviruses, primarily HIV. Different classes of antiretroviral drugs act at different stages of the HIV life cycle.
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Acquired immunodeficiency syndrome (AIDS)
Classification & external resources

The Red ribbon is a symbol for solidarity with HIV-positive people and those living with AIDS.
ICD-10 B 24.
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Antiviral may refer to:
  • Antiviral drug
  • Antiviral Therapy, an academic journal
  • List of antiviral drugs
  • Antivirus software

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The volume of distribution (VD) , also known as apparent volume of distribution, is a pharmacological term used to quantify the distribution of a medication throughout the body after oral or parenteral dosing.
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adipose tissue or fat is loose connective tissue composed of adipocytes. Its main role is to store energy in the form of fat, although it also cushions and insulates the body.
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For the moth genus, see Retina (moth).


The retina is a thin layer of neural cells that lines the back of the eyeball of vertebrates and some cephalopods. It is comparable to the film in a camera.
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Blindness is the condition of lacking visual perception due to physiological or neurological factors.

Various scales have been developed to describe the extent of vision loss and define "blindness.
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Optometry (Greek: optos meaning seen or visible and metria meaning measurement) is a health care profession concerned with eyes and related structures, vision, visual system and vision information processing in humans.
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Ophthalmology is the branch of medicine which deals with the diseases and surgery of the visual pathways, including the eye, brain, and areas surrounding the eye, such as the lacrimal system and eyelids.
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Lysosomes are organelles that contain digestive enzymes (acid hydrolases). They digest excess or worn out organelles, food particles, and engulfed viruses or bacteria. The membrane surrounding a lysosome prevents the digestive enzymes inside from destroying the cell.
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In chemistry, the Henderson-Hasselbalch (frequently misspelled Henderson-Hasselbach) equation describes the derivation of pH as a measure of acidity (using pKa, the acid dissociation constant) in biological and chemical systems.
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A plasmodium is also the macroscopic form of the protist known as a slime mould.

Plasmodium



Scientific classification

Domain: Eukaryota
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P. vivax

Binomial name
Plasmodium vivax
Grassi & Feletti 1890

The parasite Plasmodium vivax is the most frequent and widely distributed cause of benign, but recurring (tertian), malaria.
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P. ovale

Binomial name
Plasmodium ovale
Stephens 1922

Plasmodium ovale is a species of parasitic protozoa that causes tertian malaria in humans.
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P. malariae

Binomial name
Plasmodium malariae
Feletti & Grassi, 1889

Plasmodium malariae is a parasitic protozoa that causes malaria in both humans and dogs.
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Antimalarial drugs are designed to prevent or cure malaria. Some antimalarial agents, particularly chloroquine and hydroxychloroquine, are also used in the treatment of rheumatoid arthritis and lupus associated arthritis. There are many of these drugs currently on the market.
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Mefloquine is an orally administered antimalarial drug used as a prophylaxis against and treatment for malaria. It also goes by the trade name Lariam® (manufactured by Roche Pharmaceuticals) and chemical name mefloquine hydrochloride (formulated with HCl).
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Atovaquone (alternative spelling: atavaquone) is a chemical compound that belongs to the class of naphthalenes. Atovaquone is a hydroxy-1,4-naphthoquinone, an analog of ubiquinone, with antipneumocystic activity. Its average wholesale price is about $2.13 per standard 250 mg.
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Proguanil (proguanil hydrochloride) is a prophylactic antimalarial drug, which works by stopping the malaria parasite, Plasmodium falciparum and Plasmodium vivax, from reproducing once it is in the red blood cells.
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P. falciparum

Binomial name
Plasmodium falciparum
Welch, 1897

Plasmodium falciparum is a protozoan parasite, one of the species of Plasmodium that cause malaria in humans.
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The Centers for Disease Control and Prevention (or CDC) is an agency of the United States Department of Health and Human Services based in unincorporated DeKalb County, Georgia adjacent to the campus of Emory University and east of the city of Atlanta.
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An adverse drug reaction (abbreviated ADR) is an expression that describes the unwanted, negative consequences associated with the use of given medications. An ADR is a particular type of adverse effect.
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