Chloroquine is a medication primarily used to prevent and treat malaria in areas where malaria remains sensitive to its effects. Certain types of malaria, resistant strains, and complicated cases typically require different or additional medication. Chloroquine is also occasionally used for amebiasis that is occurring outside the intestines, rheumatoid arthritis, and lupus erythematosus. While it has not been formally studied in pregnancy, it appears safe. It is also being studied to treat COVID-19 as of 2020. It is taken by mouth.
Common side effects include muscle problems, loss of appetite, diarrhea, and skin rash. Serious side effects include problems with vision, muscle damage, seizures, and low blood cell levels. Chloroquine is a member of the drug class 4-aminoquinoline. As an antimalarial, it works against the asexual form of the malaria parasite in the stage of its life cycle within the red blood cell. How it works in rheumatoid arthritis and lupus erythematosus is unclear.
Distribution of malaria in the world: ? Elevated occurrence of chloroquine- or multi-resistant malaria ? Occurrence of chloroquine-resistant malaria ? No Plasmodium falciparum or chloroquine-resistance ? No malaria
In treatment of amoebic liver abscess, chloroquine may be used instead of or in addition to other medications in the event of failure of improvement with metronidazole or another nitroimidazole within 5 days or intolerance to metronidazole or a nitroimidazole.
Chloroquine-induced itching is very common among black Africans (70%), but much less common in other races. It increases with age, and is so severe as to stop compliance with drug therapy. It is increased during malaria fever; its severity is correlated to the malaria parasite load in blood. Some evidence indicates it has a genetic basis and is related to chloroquine action with opiate receptors centrally or peripherally.
Unpleasant metallic taste
This could be avoided by "taste-masked and controlled release" formulations such as multiple emulsions.
This manifests itself as either conduction disturbances (bundle-branch block, atrioventricular block) or Cardiomyopathy - often with hypertrophy, restrictive physiology, and congestive heart failure. The changes may be irreversible. Only two cases have been reported requiring heart transplantation, suggesting this particular risk is very low. Electron microscopy of cardiac biopsies show pathognomonic cytoplasmic inclusion bodies.
Chloroquine has not been shown to have any harmful effects on the fetus when used in the recommended doses for malarial prophylaxis. Small amounts of chloroquine are excreted in the breast milk of lactating women. However, this drug can be safely prescribed to infants, the effects are not harmful. Studies with mice show that radioactively tagged chloroquine passed through the placenta rapidly and accumulated in the fetal eyes which remained present five months after the drug was cleared from the rest of the body. Women who are pregnant or planning on getting pregnant are still advised against traveling to malaria-risk regions.
There is not enough evidence to determine whether chloroquine is safe to be given to people aged 65 and older. Since it is cleared by the kidneys, toxicity should be monitored carefully in people with poor kidney functions.
While the usual dose of chloroquine used in treatment is 10 mg/kg, toxicity begins to occur at 20 mg/kg, and death may occur at 30 mg/kg. In children as little as a single tablet can cause problems.
Absorption of chloroquine is rapid and primarily happens in the gastrointestinal tract. It is widely distributed in body tissues. Protein binding in plasma ranges from 46% to 79%. Its metabolism is partially hepatic, giving rise to its main metabolite, desethylchloroquine. Its excretion is >=50% as unchanged drug in urine, where acidification of urine increases its elimination. It has a very high volume of distribution, as it diffuses into the body's adipose tissue.
Accumulation of the drug may result in deposits that can lead to blurred vision and blindness. It and related quinines have been associated with cases of retinal toxicity, particularly when provided at higher doses for longer times. With long-term doses, routine visits to an ophthalmologist are recommended.
Chloroquine is also a lysosomotropic agent, meaning it accumulates preferentially in the lysosomes of cells in the body. The pKa for the quinoline nitrogen of chloroquine is 8.5, meaning it is about 10% deprotonated at physiological pH (per the Henderson-Hasselbalch equation).[original research?] This decreases to about 0.2% at a lysosomal pH of 4.6.[original research?] Because the deprotonated form is more membrane-permeable than the protonated form, a quantitative "trapping" of the compound in lysosomes results.
Mechanism of action
Hemozoin formation in P. falciparum: many antimalarials are strong inhibitors of hemozoin crystal growth.
The lysosomotropic character of chloroquine is believed to account for much of its antimalarial activity; the drug concentrates in the acidic food vacuole of the parasite and interferes with essential processes. Its lysosomotropic properties further allow for its use for in vitro experiments pertaining to intracellular lipid related diseases, autophagy, and apoptosis.
Inside red blood cells, the malarial parasite, which is then in its asexual lifecycle stage, must degrade hemoglobin to acquire essential amino acids, which the parasite requires to construct its own protein and for energy metabolism. Digestion is carried out in a vacuole of the parasitic cell.
Hemoglobin is composed of a protein unit (digested by the parasite) and a heme unit (not used by the parasite). During this process, the parasite releases 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 biocrystallizes heme to form hemozoin, a nontoxic molecule. Hemozoin collects in the digestive vacuole as insoluble crystals.
Chloroquine enters the red blood cell by simple diffusion, inhibiting the parasite cell and digestive vacuole. 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 biocrystallization of heme, thus leading to heme buildup. Chloroquine binds to heme (or FP) to form 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. Parasites that do not form hemozoin are therefore resistant to chloroquine.
Resistance in malaria
Since the first documentation of P. falciparum chloroquine resistance in the 1950s, resistant strains have appeared throughout East and West Africa, Southeast Asia, and South America. The effectiveness of chloroquine against P. falciparum has declined as resistant strains of the parasite evolved.
Resistant parasites are able to rapidly remove chloroquine from the digestive vacuole using a transmembrane pump. Chloroquine-resistant parasites pump chloroquine out at 40 times the rate of chloroquine-sensitive parasites; the pump is coded by the P. falciparum chloroquine resistance transporter (PfCRT) gene. The natural function of the chloroquine pump is to transport peptides: mutations to the pump that allow it to pump chloroquine out impairs its function as a peptide pump and comes at a cost to the parasite, making it less fit.
Resistant parasites also frequently have mutation in the ABC transporterP. falciparum multidrug resistance (PfMDR1) gene, although these mutations are thought to be of secondary importance compared to PfCRT. An altered chloroquine-transporter protein, CG2 has been associated with chloroquine resistance, but other mechanisms of resistance also appear to be involved.
Chloroquine has antiviral effects against some viruses. It increases late endosomal and lysosomal pH, resulting in impaired release of the virus from the endosome or lysosome - release of the virus requires a low pH. The virus is therefore unable to release its genetic material into the cell and replicate.
In Peru, the indigenous people extracted the bark of the Cinchona tree (Cinchona officinalis) and used the extract to fight chills and fever in the seventeenth century. In 1633 this herbal medicine was introduced in Europe, where it was given the same use and also began to be used against malaria. The quinoline antimalarial drug quinine was isolated from the extract in 1820, and chloroquine is an analogue of this.
Chloroquine was discovered in 1934, by Hans Andersag and coworkers at the Bayer laboratories, who named it Resochin. It was ignored for a decade, because it was considered too toxic for human use. Instead, the DAK used the chloroquine analogue 3-methyl-chloroquine, known as Sontochin. After Allied forces arrived in Tunis, Sontochin fell into the hands of Americans, who sent the material back to the United States for analysis, leading to renewed interest in chloroquine. United States government-sponsored clinical trials for antimalarial drug development showed unequivocally that chloroquine has a significant therapeutic value as an antimalarial drug. It was introduced into clinical practice in 1947 for the prophylactic treatment of malaria.
Society and culture
Resochin tablet package
Chloroquine comes in tablet form as the phosphate, sulfate, and hydrochloride salts. Chloroquine is usually dispensed as the phosphate.
Brand names include Chloroquine FNA, Resochin, Dawaquin, and Lariago.
Chloroquine, in various chemical forms, is used to treat and control surface growth of anemones and algae, and many protozoan infections in aquariums, e.g. the fish parasite Amyloodinium ocellatum.
Chloroquine and COVID-19
There is limited evidence on the use of chloroquine in people with COVID-19. Chloroquine has been approved by Chinese, South Korean and Italian health authorities for the experimental treatment of COVID-19. These agencies noted contraindications for people with heart disease or diabetes. However, use of chloroquine is only recommended in the setting of an approved trial or under the details outlined by Monitored Emergency Use of Unregistered Interventions. On 1 April 2020, the European Medicines Agency (EMA) issued guidance that chloroquine and hydroxychloroquine are only to be used in clinical trials or emergency use programs. On 29 May 2020, the EMA stated that patients already taking chloroquine for unrelated conditions, should continue to do so, always under the supervision of their doctor.
Health experts warned against the misuse of the non-pharmaceutical versions of chloroquine phosphate after a husband and wife consumed a fish tank antiparasitic containing chloroquine phosphate on 24 March, with the intention of it being prophylaxis against COVID-19. One of them died and the other was hospitalized. Chloroquine has a relatively narrow therapeutic index and it can be toxic at levels not much higher than those used for treatment--which raises the risk of inadvertent overdose. On 27 March 2020, the US Food and Drug Administration (FDA) issued guidance, "do not use chloroquine phosphate intended for fish as treatment for COVID-19 in humans".
The FDA has cautioned against using the drug outside a hospital setting or clinical trial after reviewing adverse events including ventricular tachycardia, ventricular fibrillation, and deaths. On 28 March 2020 the FDA authorized the use of hydroxychloroquine and chloroquine under an emergency use authorization (EUA). The treatment has not been approved by the FDA. The experimental treatment is authorized only for emergency use for people who are hospitalized but not able to receive treatment in a clinical trial. In anticipation of product shortages, the FDA issued product-specific guidance for chloroquine phosphate and for hydroxychloroquine sulfate for generic drug manufacturers. On 15 June 2020, the FDA revoked the emergency use authorization for chloroquine and hydroxychloroquine.
A study of chloroquine in 81 people hospitalized before confirmation of COVID-19, compared high dose chloroquine to low-dose chloroquine. People were also treated with ceftriaxone and azithromycin. By the sixth day of treatment, seven people in the high-dose group and four people in the low-dose group had died, leading to an immediate end to the trial.
On 29 May 2020, the EMA issued a public health statement reminding healthcare professionals to closely monitor people with COVID-19 who are receiving chloroquine. It also published a list of references of observational studies of chloroquine and hydroxychloroquine in people with COVID-19.
On 4 June 2020, there was a retraction of a major multinational analysis that clearly stated having found no clinical benefit while administrating chloroquine, hydroxychloroquine, alone or accompanied by a macrolide and in contrast did raise the percentages of high risk side effects, most prominently cardiac dysrrythmias.
On 15 June 2020, the FDA updated the fact sheets for the emergency use authorization of remdesivir to warn that using chloroquine or hydroxychloroquine with remdesivir may reduce the antiviral activity of remdesivir.
Chloroquine in COVID-19 research
Chloroquine has been under rigorous investigation for its purposed role of a potential COVID-19 therapeutic regimen. One of the biggest trials currently going on is the Solidarity Trial, organised and performed by WHO. On 23 May 2020, the Trial's directors decided to temporarily pause hydroxychloroquine administration, due to safety concerns.
Chloroquine had been also proposed as a treatment for SARS, with in vitro tests inhibiting the SARS-CoV virus. In October 2004, a group of researchers at the Rega Institute for Medical Research published a report on chloroquine, stating that chloroquine acts as an effective inhibitor of the replication of the severe acute respiratory syndrome coronavirus (SARS-CoV) in vitro.
Chloroquine was being considered in 2003, in pre-clinical models as a potential agent against chikungunya fever.
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^"EUA Archive". U.S. Food and Drug Administration (FDA). 15 June 2020. Retrieved 2020. On June 15, 2020, based on FDA's continued review of the scientific evidence available for hydroxychloroquine sulfate (HCQ) and chloroquine phosphate (CQ) to treat COVID-19, FDA has determined that the statutory criteria for EUA as outlined in Section 564(c)(2) of the Food, Drug, and Cosmetic Act are no longer met. Specifically, FDA has determined that CQ and HCQ are unlikely to be effective in treating COVID-19 for the authorized uses in the EUA. Additionally, in light of ongoing serious cardiac adverse events and other serious side effects, the known and potential benefits of CQ and HCQ no longer outweigh the known and potential risks for the authorized use. This warrants revocation of the EUA for HCQ and CQ for the treatment of COVID-19.This article incorporates text from this source, which is in the public domain.