Chloroquine: Mode of Action

Ciak, Jennie; Hahn, Fred E.

doi:10.1126/science.151.3708.347

Cited by 102 publications

(42 citation statements)

References 18 publications

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“…This concentration is in the range of 0.5 to 5 ,ug/ml of plasma which is commonly attained in CQ-treated patients with rheumatoid arthritis (12). At 1 mM or higher, CQ can inhibit some species of bacteria by directly impairing DNA and RNA synthesis (2). TB apparently are among these susceptible species of bacteria, because they were inhibited by CQ in 7H9 broth at 500 ,ug/ml (1 mM) and were killed by concentrations of 2,000 jig/ml or more (Fig.…”

Section: Resultsmentioning

confidence: 99%

Inhibition of tubercle bacilli in cultured human macrophages by chloroquine used alone and in combination with streptomycin, isoniazid, pyrazinamide, and two metabolites of vitamin D3

Crowle

May

1990

Antimicrob Agents Chemother

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Intracellular tubercle bacilli (TB) reside in vacuoles in infected human macrophages (MPs). The Tubercle bacilli (TB) in infected human macrophages (MPs) reside in vacuoles (4). These vacuoles might be phagolysosomes, which would be acidic and have several acid-dependent enzymes and activities (18). The presumed vacuolar acidity is thought to affect the activities of certain anti-TB drugs. It is supposed to decrease that of streptomycin (SM) (7) and increase that of pyrazinamide (PZA) (21,22,27).Chloroquine (CQ) is a drug which is widely used against malaria and certain kinds of chronic inflammatory diseases (3, 28). It is also used experimentally to study the acidic vacuoles of animal cells (16,24), because it is a lysosomotropic base (13, 28) which can increase the pH of these vacuoles and inhibit their acid-dependent activities (16,24). Thus, it inhibits malaria parasites by concentrating in the parasite's food vacuoles (lysosomes), raising their pH, and interfering with their digestive functions. This deprives the parasites of critical nutrients (13). Similarly, CQ can raise the pH of phagolysosomes in mammalian cells and affect their digestive functions (16,18,24). If TB do live in acid phagolysosomes in MPs and CQ can raise the pH of these vacuoles, then this drug should increase the anti-TB effectiveness of SM and lower that of PZA. This was tested in the experiments described here. While CQ enhanced the effectiveness of SM, as expected, it did not suppress that of PZA. Also, unexpectedly, it was itself able to inhibit TB in MPs, and it enhanced the anti-TB activity of another drug, isoniazid (INH), whose activity is not pH sensitive.(

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Section: Resultsmentioning

confidence: 99%

Inhibition of tubercle bacilli in cultured human macrophages by chloroquine used alone and in combination with streptomycin, isoniazid, pyrazinamide, and two metabolites of vitamin D3

Crowle

May

1990

Antimicrob Agents Chemother

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“…It is striking that a reduction in schizont nuclei is now also defined to be a result of CQ toxicity, and that this occurs regardless whether CQ is administered at R, T or S. As CQ disturbs Hz formation primarily by acting on heme and heme-related compounds, reactive oxygen species created as a result of this chemistry might be damaging DNA or DNA replication machinery, and therefore indirectly decrease the amount of the DNA formed during S. This explanation also requires early Hb catabolism in R. Alternatively the explanation could be more complicated, and involve yet undescribed interactions between CQ (or CQ -heme conjugates) and cyclins or other molecules that regulate the poorly understood nuclear division during S, or perhaps even direct interaction between DNA and CQ or CQ -heme adducts [2][3][4][5][6][7][8][9].…”

Section: Discussionmentioning

confidence: 99%

“…Cohen and Yielding further proposed that DNA synthesis is inhibited through an effect on DNA and RNA polymerase, due to the binding of CQ to DNA primer [4]. Hahn et al investigated aminoquinoline action vs. nucleic acids and proposed that CQ stabilizes double stranded DNA [5,6]. Meshnick and colleagues have also proposed that a portion of the CQ mechanism comes from binding to DNA, possibly by preventing formation of Z-DNA [7,8].…”

Section: Introductionmentioning

confidence: 99%

Stage independent chloroquine resistance and chloroquine toxicity revealed via spinning disk confocal microscopy

Gligorijevic

Purdy

Elliott

et al. 2008

Molecular and Biochemical Parasitology

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We previously customized a Nipkow spinning disk confocal microscope (SDCM) to acquire 4D data for live, intraerythrocytic malarial parasites (Gligorijevic, B. et al., Biochemistry 45, 12400). We reported that chloroquine (CQ) treatment did not appear to affect progress through the cell cycle, and suggested that toxicity may be manifested post-schizogony. We now use SDCM, synchronized cell culture and continuous vs. bolus drug dosing to investigate stage specific CQ effects in detail. We develop a novel, extremely rapid method for counting schizont nuclei in 3D. We then quantify schizont nuclei and hemozoin (Hz) production for live parasite cultures pulsed with CQ at different stages in the cell cycle and find that bolus treatment of rings affects the multiplicity of nuclear division. We quantify parasitemia and merozoite development in subsequent cycles following bolus CQ exposure and find that a portion of CQ toxicity is manifested post schizogony as "delayed death". Using these methods and others we compare CQ sensitive (CQS) vs. resistant (CQR) strains as well as transfectants that are CQR via introduction of mutant PfCRT. Surprisingly, we find that PfCRT confers resistance to CQ administered at the very early ring stage of development, wherein a digestive vacuole is not yet formed, as well as at the schizont stage, wherein Hz production is thought to plateau. Taken together, these data force a rethinking of CQ pharmacology and the mechanism of CQR.

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“…Al ser la CQ altamente permeable a membranas lipídicas, es capaz de distribuirse en varios organelos y en el núcleo celular originando cambios a varios niveles (DNA, RNA, RedOx, acidificación, impacto directo en moléculas de membrana) [20,21]. En virtud de esta acumulación no específica en organelos intracelulares, provoca la liberación de especies reactivas, algunas como grupos Hemo en glóbulos rojos con lísis celular y muerte de los plasmodios infectantes.…”

Section: Discussionunclassified

Cardiomiopatías químicas: Repercusión funcional de la cloroquina en corazón aislado

Costa¹,

Torres²,

Hartmann³

et al. 2014

An Facultad Med

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ResumenLa cloroquina, es un fármaco utilizado en tratamiento y profilaxis de enfermedades producidas por plasmodios como malaria. También es usada en el tratamiento de algunas neoplasias, artritis reumatoide y lupus eritematoso crónico. La intoxicación por cloroquina puede resultar en cuadros clínicos de extrema gravedad, pudiendo ocasionar la muerte de los pacientes. Entre los órganos de impacto de toxicidad de la cloroquina se encuentra el corazón. Las características fisiopatológicas de las fallas cardíacas que origina la exposición aguda a cloroquina están pobremente caracterizadas.Este trabajo estudia los efectos de exposición aguda a cloroquina en corazón, identificando algunas funciones y moléculas afectadas en dicho órgano. Nuestros hallazgos indican que cloroquina produce inotropismo negativo (dosis de efecto medio, IC50 ~ 5 μM), siendo totalmente reversible a bajas dosis. Las cinéticas de promoción y de lavado del efecto, son sumamente rápidas (segundos). Cloroquina es también cronotrópica negativa y arritmogenética, con IC50 levemente mayor. Dosis superiores a 100 μM eliminan contracciones con persistencia de actividad eléctrica. Canales de Ca 2+ tipo L se bloquean a partir de estas concentraciones.Los resultados sugieren que la exposición extracelular aguda a cloroquina en el rango μM, en corazones aislados, afectan la función cardíaca contráctil y eléctrica, con diferente sensibilidad para ambas. El bloqueo a canales de Ca 2+ tipo L, sugiere que éstos pueden estar involucrados en el desacople excitocontráctil que produce la droga, mediante inhibición de la liberación de Ca 2+ inducida por Ca 2+, pudiendo relacionarse con su capacidad de producir cardiomiopatías químicas.Palabras Claves: Cloroquina, antimaláricos, corazón aislado, cardiomiopatías químicas, canales de Ca 2+ tipo L, calcio intracelular cardíaco.Title: Chemical cardiomyopathies: Functional consequences of the application of chloroquine to guineapig isolated hearts. AbstractChloroquine, is a drug used in the treatment and prophylaxis of plasmodium related diseases, such as malaria. It is also used in the treatment of rheumatoid arthritis, chronic lupus erythematosus or neoplasms. It has a toxic collateral effect and deaths have been reported in patients who have used it. One of the targets of CQ toxicity is the heart. The pathophysiological features of heart failure caused by acute exposure to chloroquine are poorly characterized.This paper characterizes the effects of acute exposure to chloroquine at the cardiac level, trying to understand how this drug may impair heart function. Our findings indicate that cholorquine has a negative inotropic effect (mean effect dose, IC50 ~ 5 μM), being reversible at low concentrations. The kinetics of promotion and wash-out are extremely fast (seconds). Chloroquine has also an arrhythmogenic and a

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Chloroquine: Mode of Action

Cited by 102 publications

References 18 publications

Inhibition of tubercle bacilli in cultured human macrophages by chloroquine used alone and in combination with streptomycin, isoniazid, pyrazinamide, and two metabolites of vitamin D3

Inhibition of tubercle bacilli in cultured human macrophages by chloroquine used alone and in combination with streptomycin, isoniazid, pyrazinamide, and two metabolites of vitamin D3

Stage independent chloroquine resistance and chloroquine toxicity revealed via spinning disk confocal microscopy

Cardiomiopatías químicas: Repercusión funcional de la cloroquina en corazón aislado

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