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PubMed2004

Chloroquine resistance in Plasmodium chabaudi: are chloroquine-resistance transporter (crt) and multi-drug resistance (mdr1) orthologues involved?

We have identified in the rodent malaria parasite Plasmodium chabaudi orthologues of two Plasmodium falciparum genes, pfcrt and pfmdr1 which have been implicated as determinants of chloroquine resistance in the latter species. The sequences of the P. chabaudi genes, denoted, respectively, pccg10 and pcmdr1, were first determined in the chloroquine-sensitive clone AS, and found to be highly similar to those of P. falciparum. For pccg10, there was a nucleotide sequence identity of 68.6% and amino acid sequence identity of 75.1% within the predicted coding region. For pcmdr1, the sequence identities were 75.0% (nucleotide) and 78.1% (amino acid). The sequences of the genes were then determined in three P. chabaudi clones selected from clone AS which possessed three different levels of resistance to chloroquine. The sequences of both genes in all mutants were found to be identical to those of the sensitive AS from which they had been derived. Polymorphic sites were found in both genes between the AS clones and a genetically unrelated sensitive clone AJ. Analysis of genetic crosses between AJ and resistant AS clones showed no linkage between inherited parental alleles of pccrt and pcmdr1 and drug responses of the cloned progeny. This showed that neither of these genes, nor genes closely linked to them, were determinants of the chloroquine resistance in the P. chabaudi mutants.

Amino Acid Sequence↗
PubMedDate not supplied

The effect of artesunate combined with standard antimalarials against chloroquine-sensitive and chloroquine-resistant strains of Plasmodium falciparum in vitro.

The interactions of artesunate with chloroquine, mefloquine, quinine, doxycycline and pyrimethamine were tested in vitro against chloroquine-sensitive (D10) and chloroquine-resistant (RSA11) strains of Plasmodium falciparum. Mefloquine and quinine both showed synergism of artesunate activity against each of the strains, whilst doxycycline showed an additive interaction. Pyrimethamine combinations were antagonistic, and the combination of artesunate with chloroquine was antagonistic against RSA11, and additive against D10. Although weak antagonism in vitro might not indicate any clinical significance, synergism with artesunate may increase the clinical usefulness of either drug, and could potentially be of value in delaying the emergence of resistance.

Animals↗
PubMed1989

Open comparison of intramuscular chloroquine and quinine in children with severe chloroquine-sensitive falciparum malaria.

An open paired randomised comparison of intramuscular chloroquine (3.5 mg base/kg every 6 h) and intramuscular quinine (20 mg salt/kg followed by 10 mg/kg every 12 h) was carried out in 50 Gambian children with severe falciparum malaria. 8 children died, 6 from the quinine-treated and 2 from the chloroquine-treated group. Chloroquine reduced parasitaemia significantly more rapidly than did quinine, but other measures of the therapeutic response were similar in the two groups. Quinine injections were painful. These findings do not support the proposition that quinine is intrinsically superior to chloroquine in the treatment of severe drug-sensitive falciparum malaria.

Administration, Oral↗
PubMed1980

Sensitive method for the determination of chloroquine and its metabolite desethyl-chloroquine in human plasma and urine by high-performance liquid chromatography.

A method has been developed for the rapid quantitative analysis of chloroquine and its metabolite desethyl-chloroquine in plasma, blood and urine using high-performance liquid chromatography. An ethylene dichloride extract of the alkalinized biological samples was extracted with dilute acid and chromatographed on a reversed-phase column. Phosphate buffer in acetonitrile was used as the mobile phase with perchlorate as the counter-ion. Ultraviolet absorption at 254 or 340 nm or fluorescence detection was used. The fluorescence spectra and the fluorescence quantum yield of the substances were determined. Chloroquine and desethyl-chloroquine concentrations in the range of 10 nmol/l (UV-detection) and of 0.5 nmol/l (fluorescence detection) could be accurately measured with a relative standard deviation of 12%. The method should be adequate for therapeutic and pharmacokinetic studies.

Chloroquine↗
PubMed1993

Transcripts of the multidrug resistance genes in chloroquine-sensitive and chloroquine-resistant Plasmodium falciparum.

Homologues of the mammalian multidrug resistance gene have been identified in isolates and clones of Plasmodium falciparum and designated pfmdr1 and pfmdr2. Mutations in pfmdr1 have been associated with chloroquine resistance but confirmation could not be obtained in a genetic cross. We have examined the copy number and expression of pfmdr1 and pfmdr2 in chloroquine-sensitive and -resistant P. falciparum and have found no relationship between the copy number of either gene and chloroquine resistance. However, a marked correlation was seen between levels of mRNA transcribed for each gene and chloroquine resistance. Two transcripts of pfmdr1 were detected, and in the asexual blood cycle an 8 kb transcript appeared first, followed by the appearance of a 7 kb species.

Animals↗
PubMed1983

RII-RIII chloroquine resistant Plasmodium falciparum malaria from East Africa: studies of the in vivo and in vitro response to chloroquine.

A case is reported of Plasmodium falciparum malaria from East Africa resistant to chloroquine in the in vivo test at the RII level. Serum chloroquine concentrations and the in vitro test indicated RIII resistance. The need for further comparative studies of parasitaemia, serum chloroquine concentration and in vitro chloroquine sensitivity assessment is emphasized.

Adult↗
PubMed1987

Comparison of the relative in vitro activity of chloroquine and amodiaquine against chloroquine-sensitive strains of P. falciparum.

The activities of chloroquine and amodiaquine against a sensitive strain of Plasmodium falciparum found in children in Ibadan were compared using an in vitro technique. The criterion for drug activity was the inhibition of maturation of the parasites. Three sets of experiments were performed with each of the two drugs. The minimum concentration of chloroquine causing 90% inhibition of maturation was 25 nmol as compared with 12 nmol for amodiaquine. This suggests a two-fold increase in activity of amodiaquine when compared with chloroquine against sensitive strains of P. falciparum. The implication is that amodiaquine is a much more potent tool in malaria chemotherapy than the erstwhile overused chloroquine.

Amodiaquine↗
PubMed1999

Chloroquine-resistant Plasmodium falciparum cerebral malaria in a chloroquine-susceptible area.

Chloroquine-resistant Plasmodium falciparum is endemic in many areas. Saudi Arabia was considered to have chloroquine-susceptible P. falciparum. During the 1997-1998 season, an outbreak of malaria occurred in the southwestern region. Over a 4-month period, 32 cases (6.2%) of 520 malaria admissions met the World Health Organization criteria for cerebral malaria. The mean patient age was 28 years. Thirteen male and 19 female patients were admitted in coma. The mean duration of coma was 4.3 days; the case fatality rate was 41%. Compared with those who recovered, patients who died had a lower mean admission diastolic blood pressure and hemoglobin level, higher mean blood urea nitrogen and blood glucose levels, and thrombocytopenia. Logistic regression analysis identified treatment with quinine rather than chloroquine to be associated with survival. These findings show the potential of P. falciparum to emerge as chloroquine resistant in previously susceptible areas, resulting in significant morbidity and mortality in spite of sophisticated medical care.

Adolescent↗
PubMed1986

Enantioselective analysis of chloroquine and desethylchloroquine after oral administration of racemic chloroquine.

An enantioselective high-performance liquid chromatographic method for chloroquine and desethylchloroquine was developed using a chiral alpha 1-acid glycoprotein column. This method was used to determine concentrations of chloroquine and desethylchloroquine enantiomers in plasma and urine from volunteers given single oral doses of racemic chloroquine. The disposition of the enantiomers was different. The renal clearance of the chloroquine enantiomers was indicative of stereoselective renal secretion of the drug, and evidence for stereoselective metabolism also was found.

Adult↗
PubMed2003

Polymorphism in the Plasmodium falciparum chloroquine-resistance transporter protein links verapamil enhancement of chloroquine sensitivity with the clinical efficacy of amodiaquine.

BACKGROUND: Chloroquine accumulates in the acidic digestive vacuole of the intraerythrocytic malaria parasite, and prevents the detoxication of haematin released during haemoglobin digestion. Changes in protein PfCRT in the digestive vacuole membrane of growing intra-erythrocytic stages of Plasmodium falciparum are crucial for resistance. Expressed in yeast, PfCRT resembles an anion channel. Depressed anion channel function could increase intralysosomal pH to reduce entry of basic drug, or enhanced function could reduce drug interaction with target haematin. The most important resistance-associated change is from positively-charged lysine-76 to neutral threonine which could facilitate drug efflux through a putative channel. It has been proposed that the resistance-reversing effect of verapamil is due to hydrophobic binding to the mutated PfCRT protein, and replacement of the lost positive charge, which repels the access of 4-aminoquinoline cations, thus partially restoring sensitivity. Desethylamodiaquine, the active metabolite of amodiaquine, which has significant activity in chloroquine-resistance, may also act similarly on its own. METHODS: Changes in physicochemical parameters in different CQ-resistant PfCRT sequences are analysed, and correlations with drug activity on lines transfected with different alleles of the pfcrt gene are examined. RESULTS AND CONCLUSIONS: The results support the idea that PfCRT is a channel which, in resistant parasites, can allow efflux of chloroquine from the digestive vacuole. Activity of the chloroquine/verapamil combination and of desethylamodiaquine both correlate with the mean hydrophobicity of PfCRT residues 72-76. This may partly explain clinical-resistance to amodiaquine found in the first chloroquine-resistant malaria cases from South America and enables tentative prediction of amodiaquine's clinical activity against novel haplotypes of PfCRT.

Amodiaquine↗
PubMed1978

Chloroquine treatment in rheumatoid arthritis. Correlation of clinical response to plasma protein changes and chloroquine levels.

15 patients with active RA were observed over a 3-month period after starting chloroquine treatment. Clinical condition, plasma levels of chloroquine and levels of 15 individual plasma proteins were checked monthly. Nine patients responded favourably to therapy, 6 failed to respond. The responders had lower initial CRP, orosomucoid and ceruloplasmin levels, whereas their IgA and IgM levels were slightly elevated. Significant reductions in the levels of CRP, haptoglobin, orosomucoid, fibrinogen and ceruloplasmin occurred in the responder group of patients. Alfa1-antitrypsin, antichymotrypsin C3 and C4 levels within the normal range were frequently encountered despite other clear-cut signs of activity. The chloroquine levels did not differ between responders and non-responders, the mean concentrations being 1.04 and 1.6 micromol/l respectively. This study has also demonstrated that in selected cases, despite active joint disease, all acute phase proteins may be normal. Finally, it was obvious that chloroquine, even when inducing remission, only brought about a partial normalization of the plasma protein pattern.

Adult↗
PubMed1992

Activity of azithromycin (CP-62,993) and erythromycin against chloroquine-sensitive and chloroquine-resistant strains of Plasmodium falciparum in vitro.

Several antibiotics, including the macrolide erythromycin and the azalides azithromycin (CP-62,993) and CP-63,956, that inhibit protein synthesis on 70S ribosomes demonstrated antimalarial effects in vitro against two strains of Plasmodium falciparum, one sensitive to chloroquine and the other resistant. In 48-hr incubations, erythromycin was 10-fold less potent than the azalides against the chloroquine-resistant strain. Erythromycin and the azalides were essentially equipotent against the chloroquine-sensitive strain. An additive effect occurred with the azalides in combination with chloroquine against both strains, but this was not seen with erythromycin.

Animals↗
PubMed1993

Hemoglobin catabolism and host-parasite heme balance in chloroquine-sensitive and chloroquine-resistant Plasmodium berghei infections.

Catabolism of host hemoglobin by the malaria parasite liberates required amino acid precursors, but is also releases large amounts of potentially toxic heme that accumulates in parasite food vacuoles during intra-erythrocytic development. The schizonticidal drug chloroquine binds to free heme with high affinity and is concentrated in parasite food vacuoles. To better understand the disposition of heme within the host-parasite complex, we studied the balance of hemoglobin and heme in Plasmodium berghei-infected reticulocytes in the rat and compared this process in chloroquine-sensitive (CS) and chloroquine-resistant (CR) parasites. We found that CS P. berghei parasites have 1.5-fold more heme than CR parasites isolated from rats, and that CS P. berghei-infected reticulocytes accumulate more chloroquine than CR P. berghei-infected reticulocytes. Despite these differences in parasite heme content, the decrease in host cell hemoglobin content and the rate of free amino acid generation within the host-parasite complex is similar in CS and CR P. berghei-infected rat reticulocytes. The heme content of the infected reticulocyte-parasite complex decreases with increasing parasitemia but to a lesser extent than expected for the decrease in hemoglobin. Furthermore, the decrease in host-parasite heme is accelerated in the CR P. berghei infection compared with the CS P. berghei infection. Therefore, hemoglobin catabolism by malaria parasites is associated with the overall loss of heme from the host-parasite complex and with variable deposition of heme within parasites.(ABSTRACT TRUNCATED AT 250 WORDS)

Analysis of Variance↗
PubMed1976

Effects of chloroquine on the adrenocortical function. II. Histological, histochemical and biochemical changes in the suprarenal gland of rats on long-term administration of chloroquine.

White female Wistar rats were used in order to study the influence of long-term oral application of 7-chloro-4-(4-diethylamino-1-methylbutylamino) quinoline (chloroquine) in doses of 30, 40 and 80 mg of base/kg upon the suprarenal gland. Histological, histochemical and biochemical findings give evidence of adrenocortical activation induced by chloroquine at all dose levels tested. The differences between the signs of adrenocortical activation as observed after the various doses were only those of quantity and time onset. The results indicate that the stimulation of the suprarenal cortex produced by repeated administration of chloroquine is not solely a manifestation of toxic action of chloroquine.

Adrenal Glands↗
PubMedDate not supplied

In-vitro antimalarial activity of azithromycin against chloroquine sensitive and chloroquine resistant Plasmodium falciparum.

BACKGROUND: [corrected] The spread of drug resistance in Plasmodium falciparum has made the situation essential to look into new effective therapeutic agents like antibiotics. Azithromycin is a potential, chemotherapeutic agent which possesses antimalarial activity and favourable pharmacokinetic properties. It is an azalide microbiocide derived semi-synthetically from macrolide erythromycin. Like other antibiotics, the azalide azithromycin has ability to inhibit protein synthesis on 70S ribosomes. SETTINGS: Experimental study. SUBJECTS AND METHODS: The parasiticidal profile was studied in five chloroquine sensitive and five chloroquine resistant P. falciparum isolates obtained from various places of India. The antimalarial activity was evaluated in P. falciparum schizont maturation by short term culture for 24 hours and by exposing the parasites to the drug for 96 hours. Parasites synchronized at ring stage were put for culture with various concentrations of azithromycin dihydrate (0.01-40 micro/ml). RESULTS: At highest concentration (40 micro/ml), parasite growth was inhibited totally in all 10 isolates. Antimalarial activity at 96 hours was greater than at 24 hours in both chloroquine sensitive and resistant parasites, which may indicate that the inhibition of parasite growth may occur at clinically achievable concentration of the drug when parasites were exposed for several asexual cycles. CONCLUSION: Azithromycin shows a potential for eventual use alone or in combination in the treatment of chloroquine sensitive and resistant P. falciparum malaria.

Animals↗
PubMed1999

[Differences in haemozoin production and pathogenicity between chloroquine-sensitive and chloroquine-resistant strains of Plasmodium berghei].

AIM: To better understand the differences in haemozoin formation and pathogenicity between chloroquine-sensitive(N) and chloroquine-resistant(RC) strains of Plasmodium berghei. METHODS: IRC mice were grouped as follows: group Xba I (Normal control, NC), group II (control treated with chloroquine alone, CC), group III (mice infected with N strain), group IV (mice infected with RC strain, RC) and group V (mice infected with RC strain and treated with chloroquine, RCC). Morphologic features of the parasites, parasitaemia, histological and ultrastructural changes of livers among the groups were compared. RESULTS: Severe damages of the hepatic cells of the N group including increased lysosomes and swollen and fused mitochondria were detected. On the contrary, the prominent features in liver section of the RC group were inflammatory cell (notably mononuclear) infiltration and Kupffer cell activation. Numerous trophozoites and schizonts were sequestrated in hepatic sinusoids and less degeneration of parenchymal cells was found except for some swollen and vacuolated mitochondria. Internal food vacuoles containing haemozoin were found in the parasites of the N group, whereas external food vacuoles without haemozoin granules were arranged in foamy appearance within the parasitized cell of the RC group. CONCLUSION: P. berghei RC strain may modify the mode of ingestion and degradation of hemoglobin in the parasites, resulting in impeding haemozoin formation. The difference in virulence between the N and RC strain of P. berghei is probably attributed to the significant differences in the induction of immune response of the host.

Animals↗
PubMedDate not supplied

[Chloroquine as a poison in murder. Report of fatalities after criminal or suicidal chloroquine administration].

Presented is a case of murder by means of chloroquine, committed on a 36-year-old male. The wife of the deceased had confessed to have secretely administered chloroquine-containing tablets to her husband. She was lawfully sentenced to life-imprisonment. The toxicological findings of this case are compared to the results of two chloroquine suicide cases and discussed in the context of the referring literature. An additional case where chloroquine intoxication was doubtful is introduced because of the unusual circumstances under which it occurred.

Adult↗