Details
Stereochemistry | RACEMIC |
Molecular Formula | C18H26ClN3.H3O4P |
Molecular Weight | 417.867 |
Optical Activity | ( + / - ) |
Defined Stereocenters | 0 / 1 |
E/Z Centers | 0 |
Charge | 0 |
SHOW SMILES / InChI
SMILES
OP(O)(O)=O.CCN(CC)CCCC(C)NC1=CC=NC2=C1C=CC(Cl)=C2
InChI
InChIKey=AEUAEICGCMSYCQ-UHFFFAOYSA-N
InChI=1S/C18H26ClN3.H3O4P/c1-4-22(5-2)12-6-7-14(3)21-17-10-11-20-18-13-15(19)8-9-16(17)18;1-5(2,3)4/h8-11,13-14H,4-7,12H2,1-3H3,(H,20,21);(H3,1,2,3,4)
Chloroquine (brand name Aralen) is indicated for the suppressive treatment and for acute attacks of malaria due to P. vivax, P.malariae, P. ovale, and susceptible strains of P. falciparum. The drug is also indicated for the treatment of extraintestinal amebiasis. In addition, chloroquine is in clinical trials as an investigational antiretroviral in humans with HIV-1/AIDS and as a potential antiviral agent against chikungunya fever. The mechanism of plasmodicidal action of chloroquine is not completely certain. However, is existed theory, that like other quinoline derivatives, it is thought to inhibit heme polymerase activity. 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 non-toxic molecule. 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 biocrystallization of heme, thus leading to heme buildup. 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.
CNS Activity
Sources: https://www.ncbi.nlm.nih.gov/pubmed/6129306
Curator's Comment: Known to be CNS penetrant in rat. Human data not available.
Originator
Sources: https://www.ncbi.nlm.nih.gov/pubmed/22411634
Curator's Comment: # Hans Andersag and coworkers at the Bayer laboratories
Approval Year
Targets
Primary Target | Pharmacology | Condition | Potency |
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Target ID: CHEMBL613897 Sources: https://www.ncbi.nlm.nih.gov/pubmed/14967191 |
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Target ID: P13774 Gene ID: NA Gene Symbol: NA Target Organism: Plasmodium falciparum Sources: https://www.ncbi.nlm.nih.gov/pubmed/10187806 |
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Target ID: CHEMBL364 |
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Target ID: CHEMBL613897 Sources: https://www.ncbi.nlm.nih.gov/pubmed/14967191 |
Conditions
Condition | Modality | Targets | Highest Phase | Product |
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Curative | ARALEN Approved UseARALEN is indicated for the suppressive treatment and for acute attacks of malaria due to P. vivax, P.malariae, P. ovale, and susceptible strains of P. falciparum. The drug is also indicated for the treatment of extraintestinal amebiasis. ARALEN does not prevent relapses in patients with vivax or malariae malaria because it is not effective against exoerythrocytic forms of the parasite, nor will it prevent vivax or malariae infection when administered as a prophylactic. It is highly effective as a suppressive agent in patients with vivax or malariae malaria, in terminating acute attacks, and significantly lengthening the interval between treatment and relapse. In patients with falciparum malaria it abolishes the acute attack and effects complete cure of the infection, unless due to a resistant strain of P. falciparum. Launch Date1949 |
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Curative | ARALEN Approved UseARALEN is indicated for the suppressive treatment and for acute attacks of malaria due to P. vivax, P.malariae, P. ovale, and susceptible strains of P. falciparum. The drug is also indicated for the treatment of extraintestinal amebiasis. ARALEN does not prevent relapses in patients with vivax or malariae malaria because it is not effective against exoerythrocytic forms of the parasite, nor will it prevent vivax or malariae infection when administered as a prophylactic. It is highly effective as a suppressive agent in patients with vivax or malariae malaria, in terminating acute attacks, and significantly lengthening the interval between treatment and relapse. In patients with falciparum malaria it abolishes the acute attack and effects complete cure of the infection, unless due to a resistant strain of P. falciparum. Launch Date1949 |
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Primary | Unknown Approved UseUnknown |
Cmax
Value | Dose | Co-administered | Analyte | Population |
---|---|---|---|---|
700 ng/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/18594802/ |
5 mg/kg 1 times / day multiple, oral dose: 5 mg/kg route of administration: Oral experiment type: MULTIPLE co-administered: |
CHLOROQUINE plasma | Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE food status: UNKNOWN |
AUC
Value | Dose | Co-administered | Analyte | Population |
---|---|---|---|---|
134087 ng × h/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/18594802/ |
5 mg/kg 1 times / day multiple, oral dose: 5 mg/kg route of administration: Oral experiment type: MULTIPLE co-administered: |
CHLOROQUINE plasma | Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE food status: UNKNOWN |
T1/2
Value | Dose | Co-administered | Analyte | Population |
---|---|---|---|---|
209 h EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/18594802/ |
5 mg/kg 1 times / day multiple, oral dose: 5 mg/kg route of administration: Oral experiment type: MULTIPLE co-administered: |
CHLOROQUINE plasma | Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE food status: UNKNOWN |
Funbound
Value | Dose | Co-administered | Analyte | Population |
---|---|---|---|---|
45% EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/18594802/ |
5 mg/kg 1 times / day multiple, oral dose: 5 mg/kg route of administration: Oral experiment type: MULTIPLE co-administered: |
CHLOROQUINE plasma | Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE food status: UNKNOWN |
Doses
Dose | Population | Adverse events |
---|---|---|
3 g single, oral Overdose |
unknown, 14 years n = 1 Health Status: unknown Age Group: 14 years Sex: F Population Size: 1 Sources: |
Other AEs: Cardiac arrest... |
600 mg 2 times / day multiple, oral (starting) Highest studied dose Dose: 600 mg, 2 times / day Route: oral Route: multiple Dose: 600 mg, 2 times / day Sources: |
pregnant, 20.7 years n = 300 Health Status: pregnant Condition: malaria Age Group: 20.7 years Sex: F Population Size: 300 Sources: |
Other AEs: Dizziness, Vomiting... Other AEs: Dizziness (19%) Sources: Vomiting (17%) Palpitations (5%) Headache (6%) Nausea (5%) Abdominal pain (2%) |
AEs
AE | Significance | Dose | Population |
---|---|---|---|
Cardiac arrest | 3 g single, oral Overdose |
unknown, 14 years n = 1 Health Status: unknown Age Group: 14 years Sex: F Population Size: 1 Sources: |
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Vomiting | 17% | 600 mg 2 times / day multiple, oral (starting) Highest studied dose Dose: 600 mg, 2 times / day Route: oral Route: multiple Dose: 600 mg, 2 times / day Sources: |
pregnant, 20.7 years n = 300 Health Status: pregnant Condition: malaria Age Group: 20.7 years Sex: F Population Size: 300 Sources: |
Dizziness | 19% | 600 mg 2 times / day multiple, oral (starting) Highest studied dose Dose: 600 mg, 2 times / day Route: oral Route: multiple Dose: 600 mg, 2 times / day Sources: |
pregnant, 20.7 years n = 300 Health Status: pregnant Condition: malaria Age Group: 20.7 years Sex: F Population Size: 300 Sources: |
Abdominal pain | 2% | 600 mg 2 times / day multiple, oral (starting) Highest studied dose Dose: 600 mg, 2 times / day Route: oral Route: multiple Dose: 600 mg, 2 times / day Sources: |
pregnant, 20.7 years n = 300 Health Status: pregnant Condition: malaria Age Group: 20.7 years Sex: F Population Size: 300 Sources: |
Nausea | 5% | 600 mg 2 times / day multiple, oral (starting) Highest studied dose Dose: 600 mg, 2 times / day Route: oral Route: multiple Dose: 600 mg, 2 times / day Sources: |
pregnant, 20.7 years n = 300 Health Status: pregnant Condition: malaria Age Group: 20.7 years Sex: F Population Size: 300 Sources: |
Palpitations | 5% | 600 mg 2 times / day multiple, oral (starting) Highest studied dose Dose: 600 mg, 2 times / day Route: oral Route: multiple Dose: 600 mg, 2 times / day Sources: |
pregnant, 20.7 years n = 300 Health Status: pregnant Condition: malaria Age Group: 20.7 years Sex: F Population Size: 300 Sources: |
Headache | 6% | 600 mg 2 times / day multiple, oral (starting) Highest studied dose Dose: 600 mg, 2 times / day Route: oral Route: multiple Dose: 600 mg, 2 times / day Sources: |
pregnant, 20.7 years n = 300 Health Status: pregnant Condition: malaria Age Group: 20.7 years Sex: F Population Size: 300 Sources: |
Overview
CYP3A4 | CYP2C9 | CYP2D6 | hERG |
---|---|---|---|
OverviewOther
Other Inhibitor | Other Substrate | Other Inducer |
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Drug as perpetrator
Target | Modality | Activity | Metabolite | Clinical evidence |
---|---|---|---|---|
no | no (co-administration study) Comment: chloroquine did not affect the activities of CYP1A2, CYP2C19, CYP2E1, CYP3A4 |
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no | no (co-administration study) Comment: chloroquine did not affect the activities of CYP1A2, CYP2C19, CYP2E1, CYP3A4 |
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no | no (co-administration study) Comment: chloroquine did not affect the activities of CYP1A2, CYP2C19, CYP2E1, CYP3A4 |
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no | no (co-administration study) Comment: chloroquine did not affect the activities of CYP1A2, CYP2C19, CYP2E1, CYP3A4 |
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yes [IC50 1096 uM] | ||||
yes [IC50 2.5 uM] | ||||
yes [Ki 12 uM] | weak (co-administration study) Comment: selective inhibiton; Chloroquine produced a reduction in the metabolism of debrisoquine as evaluated by the debrisoquine recovery ratio, a measure of CYP2D6 activity. This reduction was progressive from the first to the seventh dose. This decrease in metabolism was modest (about 7% after the first dose and about 18% after seven doses) but statistically significant |
Drug as victim
Target | Modality | Activity | Metabolite | Clinical evidence |
---|---|---|---|---|
yes | ||||
yes | ||||
yes | yes (co-administration study) Comment: Concomitant administration of a single dose of chloroquine and cimetidine daily starting 4 days prior to chloroquine, resulted in a 50% increase in chloroquine half-life, associated with a 50% decrease in its clearance.Since the AUC of desethylchloroquine decreased by 47%, cimetidine probably decreased chloroquine clearance by inhibiting its hepatic desethylation. |
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yes | yes (co-administration study) Comment: Concomitant administration of a single dose of chloroquine and cimetidine daily starting 4 days prior to chloroquine, resulted in a 50% increase in chloroquine half-life, associated with a 50% decrease in its clearance.Since the AUC of desethylchloroquine decreased by 47%, cimetidine probably decreased chloroquine clearance by inhibiting its hepatic desethylation. |
Tox targets
Target | Modality | Activity | Metabolite | Clinical evidence |
---|---|---|---|---|
Sources: https://pubmed.ncbi.nlm.nih.gov/14729380/ Page: 44.0 |
PubMed
Title | Date | PubMed |
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A Comparative Study of Hymenolepicides in Hymenolepis Mana Infestation of Rats. | 1962 Jul |
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Amrinone for refractory cardiogenic shock following chloroquine poisoning. | 1991 |
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Occurrence of chloroquine-induced psychotic manifestations in children with malaria. | 1992 |
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Seizures associated with chloroquine therapy. | 1992 Aug |
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Chloroquine related complete heart block with blindness: case report. | 1992 Jan |
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Involvement of GABAergic mechanisms in chloroquine-induced seizures in mice. | 1992 Mar |
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[Heart conduction disorders in long-term treatment with chloroquine. Two new cases]. | 1992 May 2-9 |
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Cardiac damage from chronic use of chloroquine: a case report and review of the literature. | 2002 Jul |
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Side effects of and compliance with malaria prophylaxis in children. | 2002 Nov-Dec |
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[Chloroquine cardiomyopathy revealed by complete atrio-ventricular block. A case report]. | 2002 Sep |
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EGb 761 is a neuroprotective agent against beta-amyloid toxicity. | 2002 Sep |
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Control of mammary tumor cell growth in vitro by novel cell differentiation and apoptosis agents. | 2002 Sep |
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Chloroquine cardiotoxicity: clinicopathologic features in three patients and comparison with three patients with Fabry disease. | 2002 Sep-Oct |
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Severe mucocutaneous necrotizing vasculitis associated with the combination of chloroquine and proguanil. | 2003 |
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Therapy of glioblastoma multiforme improved by the antimutagenic chloroquine. | 2003 Feb 15 |
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[Toxic lesions of the organ of vision caused by chloroquine derivatives]. | 2003 Jan-Feb |
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Chloroquine-induced phospholipidosis of the kidney mimicking Fabry's disease: case report and review of the literature. | 2003 Mar |
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[Chloroquine-induced myopathy and neuropathy: progressive tetraparesis with areflexia that simulates a polyradiculoneuropathy. Two case reports]. | 2003 Mar 16-31 |
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Differential diagnosis of high serum creatine kinase levels in systemic lupus erythematosus. | 2003 Nov |
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Increased CSF protein in chloroquine-induced axonal polyneuropathy and myopathy. | 2003 Sep |
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Identification of human cytochrome P(450)s that metabolise anti-parasitic drugs and predictions of in vivo drug hepatic clearance from in vitro data. | 2003 Sep |
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[Infectious diseases in 2003]. | 2004 |
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Heart transplantation in a patient with chloroquine-induced cardiomyopathy. | 2004 Feb |
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The antimalarial potential of 4-quinolinecarbinolamines may be limited due to neurotoxicity and cross-resistance in mefloquine-resistant Plasmodium falciparum strains. | 2004 Jul |
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Survival and surface adherence ability of bacterial pathogens in oral liquid pharmaceuticals and their containers. | 2004 Jun |
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Inhibition of human P450 enzymes by multiple constituents of the Ginkgo biloba extract. | 2004 Jun 11 |
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The multifocal pattern electroretinogram in chloroquine retinopathy. | 2004 Mar-Apr |
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The ability of chloroquine to prevent tat-induced cytokine secretion by monocytes is implicated in its in vivo anti-human immunodeficiency virus type 1 activity. | 2004 Nov |
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Seizure associated with chloroquine therapy in a patient with systemic lupus erythematosus. | 2004 Sep |
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Chloroquine-induced cardiomyopathy-echocardiographic features. | 2005 Apr |
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Skeletal muscle expression of clathrin and mannose 6-phosphate receptor in experimental chloroquine-induced myopathy. | 2005 Apr |
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Enhanced anticryptococcal activity of chloroquine in phosphatidylserine-containing liposomes in a murine model. | 2005 Feb |
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[Malaria chemoprophylaxis in traveling children]. | 2005 Jan |
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[Acute hydroxychloroquine poisoning. The danger of rapid or excessive correction of initial hypokalemia]. | 2005 Jul 23 |
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Chloroquine-induced lipidosis mimicking Fabry disease. | 2005 May |
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Protective effects of different antioxidants and amrinone on vancomycin-induced nephrotoxicity. | 2005 Nov |
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Selective enhancement of cellular oxidative stress by chloroquine: implications for the treatment of glioblastoma multiforme. | 2006 Dec 15 |
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CpG-B oligodeoxynucleotide promotes cell survival via up-regulation of Hsp70 to increase Bcl-xL and to decrease apoptosis-inducing factor translocation. | 2006 Dec 15 |
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[Cytochrome P-450 and the response to antimalarial drugs]. | 2006 Jan |
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Plasmodium berghei: development of an irreversible experimental malaria model in Wistar rats. | 2006 Jul |
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Mefloquine toxicity presenting with polyneuropathy - a report of two cases in India. | 2006 Jun |
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Frequency of high-risk use of QT-prolonging medications. | 2006 Jun |
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Antimalarial myopathy: an underdiagnosed complication? Prospective longitudinal study of 119 patients. | 2006 Mar |
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Tetrahydrocurcumin: effect on chloroquine-mediated oxidative damage in rat kidney. | 2006 Nov |
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Cardiomyopathy related to antimalarial therapy with illustrative case report. | 2007 |
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Crystal structure of an FIV/HIV chimeric protease complexed with the broad-based inhibitor, TL-3. | 2007 Jan 9 |
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Chloroquine-induced recurrent psychosis. | 2007 Jul-Aug |
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[Reversible restrictive cardiomyopathy secondary to chloroquine]. | 2007 Jun 23 |
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Heart conduction disorders related to antimalarials toxicity: an analysis of electrocardiograms in 85 patients treated with hydroxychloroquine for connective tissue diseases. | 2007 May |
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Effects of CpG-B ODN on the protein expression profile of swine PBMC. | 2007 Nov-Dec |
Sample Use Guides
The dosage of chloroquine phosphate is often expressed in terms of equivalent
chloroquine base. Each 500 mg tablet of ARALEN (chloroquine phosphate) contains the equivalent of 300 mg chloroquine base. In infants and children the dosage is preferably calculated by body weight.
Malaria: Suppression—Adult Dose: 500 mg (= 300 mg base) on exactly the same day of each week. Pediatric Dose: The weekly suppressive dosage is 5 mg calculated as base, per kg of body weight, but should not exceed the adult dose regardless of weight. If circumstances permit, suppressive therapy should begin two weeks prior to exposure. However, failing this in adults, an initial double (loading) dose of 1 g (= 600 mg base), or in children 10 mg base/kg may be taken in two divided doses, six hours apart. The suppressive therapy should be continued for eight weeks after leaving the endemic area.
For Treatment of Acute Attack. Adults: An initial dose of 1 g (=600 mg base) followed by an additional 500 mg (= 300 mg base) after six to eight hours and a single dose of 500 mg (= 300 mg base) on each of two consecutive days. This represents a total dose of 2.5 g chloroquine phosphate or 1.5 g base in three days. The dosage for adults of low body weight and for infants and children should be determined as follows: First dose: 10 mg base per kg (but not exceeding a single dose of 600 mg base) Second dose: (6 hours after first dose) 5 mg base per kg (but not exceeding a single dose of 300 mg base) Third dose: (24 hours after first dose) 5mg base per kg Fourth dose: (36 hours after first dose) 5 mg base per kg For radical cure of vivax and malariae malaria concomitant therapy with an 8-aminoquinoline compound is necessary. Extraintestinal Amebiasis: Adults, 1 g (600 mg base) daily for two days, followed by 500 mg (300 mg base) daily for at least two to three weeks. Treatment is usually combined with an effective intestinal amebicide.
Route of Administration:
Oral
In Vitro Use Guide
Sources: https://www.ncbi.nlm.nih.gov/pubmed/19194831
Chloroquine inhibited mouse colon cancer cell line CT26 cells proliferation by concentration- and time-dependent manner. This effect was associated with apoptosis induction and decreased level of phosphorylated p42/44 mitogen-activated protein kinase and phosphorylated Akt. The cytotoxicity of chloroquine on CT26 cells was determined by the MTT assay. Cells were seeded in 96-well plates at the density of 2000/well and cultured for 24 hr, followed by chloroquine treatment (100, 50, 25, 12.5, 6.25, and 3.125 μ mol/L) for 24, 48, and 72 hr, respectively.
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1446-17-9
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83818
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7FY24HE2G3
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DTXSID10932343
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ACTIVE MOIETY
SUBSTANCE RECORD