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At least 19 recordsLinked to original sources
PubMed1992

Rapid chloroquine efflux phenotype in both chloroquine-sensitive and chloroquine-resistant Plasmodium falciparum. A correlation of chloroquine sensitivity with energy-dependent drug accumulation.

Recent reports suggest that lower levels of chloroquine accumulation in chloroquine-resistant isolates of Plasmodium falciparum are achieved by energy-dependent chloroquine efflux from resistant parasites. In support of this argument, a rapid chloroquine efflux phenotype has been observed in some chloroquine-resistant isolates of P. falciparum. In this study, no relationship was found between chloroquine sensitivity and the rate of [3H]chloroquine efflux from four isolates of P. falciparum with a greater than 10-fold range in sensitivity to chloroquine. All the isolates tested displayed the rapid efflux phenotype, irrespective of sensitivity. However, chloroquine sensitivity of these isolates was correlated with energy-dependent rate of drug accumulation into these parasites. Verapamil and a variety of other compounds reverse chloroquine resistance. The reversal mechanism is assumed to result from competition between verapamil and chloroquine for efflux protein translocation sites, thus causing an increase in steady-state accumulation of chloroquine and hence a return to sensitivity. Verapamil accumulation at a steady-state is increased by chloroquine, possibly indicating competition for efflux of the two substrates. Increases in steady-state verapamil concentrations caused by chloroquine were identical in sensitive and resistant strains, suggesting that similar capacity efflux pumps may exist in these isolates. These data suggest that differences in steady-state chloroquine accumulation seen in these isolates can be attributed to changes in the chloroquine concentrating mechanism rather than the efflux pump. It seems likely that chloroquine resistance generally in P. falciparum, results at least in part from a change in the drug concentrating mechanism and that changes in efflux rates per se are insufficient to explain chloroquine resistance.

Animals↗
PubMed1975

Chloroquine resistance in malaria: variations of substrate-stimulated chloroquine accumulation.

The response of [14C]chloroquine accumulation to the provision of substrate was evaluated using washed erythrocytes infected with Plasmodium berghei CS (chloroquine-susceptible), with P. berghei CR (chloroquine-resistant), with Plasmodium vinckei CS, with P. vinckei CR, or with a strain of P. berghei spontaneously resistant to chloroquine, Plasmodium berghei yoelii 17X. Erythrocytes infected with chloroquine-resistant parasites had a blunted response, particularly to low glucose concentrations. In the presence of 0.5 mM glucose in one set of experiments, for example, chloroquine accumulation increased by a factor of 8 in erythrocytes infected with P. berghei CS whereas there was no increase in erythrocytes infected with P. berghei CR or with P. berghei yoelii 17X; the difference between P. vinckei CS and P. vinckei CR was less dramatic. In every case except for P. berghei CR, the process of chloroquine accumulation in the presence of 5 mM glucose exhibited a component which became saturated at low concentrations of chloroquine in the medium. For P. berghei CR, plotting steady-state accumulation of chloroquine as a function of the concentration of chloroquine in the medium yielded a sigmoid curve, revealing that higher concentrations of chloroquine (above 100 mM) somehow relieve the blunted response to glucose and suggesting that the variation is in the process of accumulation rather than in substrate utilization.

Animals↗
PubMed1992

Energy dependence of chloroquine accumulation and chloroquine efflux in Plasmodium falciparum.

Chloroquine inhibits the growth of susceptible malaria parasites at low (nanomolar) concentrations because of an energy-requiring drug-concentrating mechanism in the parasite secondary lysosome (food vacuole) which is dependent on the acidification of that vesicle. Chloroquine resistance results from another energy-requiring process: efflux of chloroquine from the resistant parasite with a half-time of 2 min. Chloroquine efflux is inhibited reversibly by the removal of metabolizable substrate (glucose); it is also reduced by the ATPase inhibitor vanadate. These results suggest that chloroquine efflux is an energy-requiring process dependent on the generation and hydrolysis of ATP. Chloroquine efflux cannot be explained by differences in drug accumulation between chloroquine-susceptible and -resistant parasites because the 40-50-fold difference in initial efflux rates between -susceptible and -resistant parasites is unchanged when both parasites contain the same amount of chloroquine. Although chloroquine efflux is phenotypically similar to the efflux of anticancer drugs from multidrug-resistant (mdr) mammalian cells, it is not linked to either of the mdr-like genes of the parasite.

Adenosine Triphosphatases↗
PubMedDate not supplied

Lack of effect of desipramine on the response to chloroquine of patients with chloroquine-resistant falciparum malaria.

The potential of desipramine to improve the efficacy of chloroquine against chloroquine-resistant Plasmodium falciparum in vivo in man was investigated. Fifty-three malaria patients were selected according to the criteria for the standard World Health Organization (WHO) in vivo test and were randomly divided in 2 groups. One group (n = 27) was given standard therapeutic doses of chloroquine (25 mg/kg body weight of base) and the other (n = 26) was given standard doses of chloroquine, as above, in combination with desipramine (1.3-2.8 mg/kg body weight) daily for 3 consecutive days. Standard WHO in vitro micro-tests were performed in parallel with the tests in vivo to provide chloroquine sensitivity patterns of the P. falciparum parasites. The results in vitro from both groups did not differ with regard to chloroquine sensitivity and the means of the pre-treatment parasite densities were similar. There was no apparent difference in parasite clearance in vivo between the 2 groups. This study provided no evidence for enhanced chloroquine efficacy in vivo through the use of desipramine in doses corresponding to the usual therapeutic range.

Animals↗
PubMed1992

[Alteration in resistance of Plasmodium falciparum to chloroquine after cessation of chloroquine medication for twelve years].

In view of the fact the resistance of Plasmodium falciparum to chloroquine occurred extensively in Hainan, a decision was made in 1979 that the use of chloroquine should be quit in the whole province. A longitudinal survey on chloroquine-sensitivity of P. falciparum was carried out during 1981-1991 to observe the variation in resistance of the parasite after the cessation of the chloroquine medication for every 2-3 years. A tendency of progressive decline of resistance was revealed. By using in vitro test, the rate of chloroquine-resistant P. falciparum dropped from 97.9% in 1981 to 60.9% in 1991 (P < 0.001). The mean dosage of chloroquine for complete inhibition of schizont formation declined from 10.46 pmol/microliters in 1981 to 3.02 pmol/microliters in 1991 (P < 0.001). The percentage of population requiring larger dosage (6.4 pmol/microliters to completely inhibit schizont formation declined from 83.3% in 1981 to 17.4% in 1991 (P < 0.001); whereas those requiring small dosage (1.6 pmol/microliters), increased from 4.2% in 1981 to 60.8% in 1991 (P < 0.001). In in vivo test, the rate of chloroquine-resistant P. falciparum decreased from 84.2% in 1981 to 40% in 1991 (P < 0.001). The proportion of RII plus RIII cases of the total resistant cases dropped from 59.4% in 1981 to 37.5% in 1991 (0.02 > P > 0.01).

Animals↗
PubMed1975

Evidence for a relationship between chloroquine and complement from studies with lymphocyte mitogens: possible implications for the mechanism of action of chloroquine in disease.

Chloroquine increases the inhibition of cultured lymphocytes by high concentrations of phytohemagglutinin (PHA) or concanavalin A (Con A). The inhibition is also increased by complement. Thus chloroquine and complement have similar effects. Time-course studies show that chloroquine increases the rate of onset of the complement-dependent inhibition. In serum preheated to inactivate complement, chloroquine can partially simulate the effect of complement. It is suggested that at certain stages in malaria or autoimmune disease the rate of clearance of parasitized erythrocytes or autoreactive lymphocytes is limited by the concentration of complement. Under these conditions a drug such as chloroquine, which could enhance or simulate the action of complement, might be of therapeutic value.

Animals↗
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↗
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↗
PubMed1977

Effects of chloroquine on the adrenocortical function. III. Sex differences in concentrations of cholesterol and ascorbic acid in the suprarenal gland after a single administration of chloroquine in the rat.

Effects of single doses of 4-(4-diethylamino-1-methylbutylamino)-7-chloroquinoline (chloroquine diphosphate, Delagil Egyt) given orally (40, 80, 160 and 320 mg of base/kg) or s.c. (40, 80 and 120 mg of base/kg) upon cholesterol and ascorbic acid concentrations in the white rat suprarenal glands were followed up. The occurrence of signs of adrenocortical activation was found to be dependent on the route of application and sex of animals. Chloroquine given s.c. caused a decrease in ascorbic acid level only in doses close to LD50. The oral administration of chloroquine in doses of 80 mg/kg and more produced a significant decrease in cholesterol and ascorbic acid concentrations in the suprarenal glands of female rats, while in males chloroquine in any of the dose levels tested was without effect.

Administration, Oral↗
PubMed1975

Increased frequency of chloroquine resistant P. falciparum on a rubber estate in Peninsular Malaysia during two years of systematic chloroquine treatment.

Chloroquine pressure was applied over a 22 month period on a somewhat isolated, malarious rubber estate by examination of residents at 4-week intervals and treatment of parasitaemias with chloroquine. During this time the monthly attack rate for P. falciparum rose four-fold to an average of nearly 18% per month, while that of P. vivax remained relatively constant at about 8%. Eight in vivo chloroquine resistance studies, which allowed both detection of late recrudescing R-I resistance and estimation of the risk of reinfection, showed an apparent rise in the drug resistance rate, from 12% to 20% prior to the study to the range of 40-50%. Virtually all resistance encountered was R-I in nature. There was no convincing evidence of chloroquine resistance among 148 tested P. vivax infections.

Blood↗
PubMed1976

Studies on the resistance of malaria to chloroquine and to a combination of chloroquine and pyrimethamine in Peninsular Malaysia.

In vivo chloroquine resistance surveys, which allowed for detection of late recrudescing RI resistance, were conducted in three regions of Peninsular Malaysia, which were previously not recognized as having appreciable drug resistance. Among the 485 Plasmodium falciparum infections tested resistance rates ranged locally from 20% to 67% in those with parasitaemias over 1,000 per mm3, and 5% to 59% in all parasitaemias. The region found to have the most serious resistance was western Pahang. In one study a combination of chloroquine and pyrimethamine proved no more efficacious than chloroquine alone. Most of the resistance encountered was the late recrudescing RI type. There was no apparent correlation between drug resistance and Anopheles balabacensis as this species was not found despite intensive collections in two of the three main regions. There was no evidence of resistance among the 222 P. vivax and 35 P. malariae infections also tested.

Child↗
PubMedDate not supplied

Chloroquine-resistant Plasmodium falciparum isolates from the Sudan lack two mutations in the pfmdr1 gene thought to be associated with chloroquine resistance.

Isolates of Plasmodium falciparum from 3 areas of the Sudan were recovered from cryopreservation in London and their chloroquine sensitivity was determined in vitro. Chloroquine resistance was detected in 6/6 isolates from Khartoum, 1/4 from Sennar and 3/3 from Gadarif, indicating that resistance is spreading. All the isolates were sensitive to mefloquine. Studies using blood spots on glass fibre discs and the polymerase chain reaction did not detect two mutations in the pfmdr1 gene, thought to be correlated with chloroquine-resistance, in any of the isolates studied.

Amino Acid Sequence↗
PubMed1976

Uptake of 14C-labelled chloroquine and an 125I-labelled chloroquine analogue in some polypeptide hormone producing cell systems.

After the injection of 14C-labelled chloroquine and the 125I-labelled chloroquine analogue 4-(31-dimethylaminopropylamino)-7-iodoquinoline [125I]DAPQ into mice, rats and a monkey the distribution of the radioactivity was studied by autoradiographical methods. A high and persistent uptake occurred in some endocrine cell systems, such as the pancreatic islets, the hypophysis, the adrenal medulla and the thyroid (in cells that were probably identical with the parafollicular cells). The melanin-containing tissues were the only ones which showed a higher uptake and retention of radioactivity. The above mentioned endocrine cells and the melanocytes have a common embryological origin and common morphological and cytochemical characteristics. They have been called the APUD (Amine Precursor Uptake and Decarboxylation)-cell series. It is proposed that the polypeptide hormone producing cells and the melanocytes may use a similar mechanism for accumulating chloroquine and (as shown earlier) also some other drugs such as nicotine, alprenolol, local anesthetics and atropine. These drugs however, accumulate stronger within the melanocytes and become bound to the melanin for a long time. The ability to accumulate these drugs may be considered another characteristic of the APUD-cell series.

Adrenal Medulla↗
PubMed1992

New trends in chloroquine efficacy in the treatment of malaria: significance of low (scanty) parasitaemia in an endemic area, with emerging chloroquine-resistant P. falciparum.

In a continuous malaria therapy surveillance, using in vivo (WHO) seven-day-test, extended to 14 days follow up, we evaluated the significance of low (scanty) parasitaemia, in an area with chloroquine resistance P. falciparum (CRPF), where self-medication is widely practised. We found that 30.9 pc of the patients screened had Plasmodium species, and 71.4 pc of these had low parasite counts of less than 500 parasites/mm3, whole blood. Eight pc of these were febrile and 41.7 pc of the parasite strains were not susceptible to chloroquine. Parasite strains from four of the patients were also resistant to other antimalarials. These patients gave psychosomatic symptoms, and were seen by a psychiatrist. We conclude that 41 pc of the patients with low parasite counts consist of patients with CRPF and/or multiple-drug resistant P. falciparum in this area. These do not only cause chronic anaemia, but also may be responsible for moderate psychosomatic symptoms in all ages.

Adult↗
PubMed1992

Plasmodium chabaudi: association of reversal of chloroquine resistance with increased accumulation of chloroquine in resistant parasites.

The effects of tricyclic antidepressants, desipramine and imipramine, and phenothiazines, chlorpromazine and trifluoperazine, on chloroquine (CQ)-resistant and CQ-sensitive lines of P. chabaudi were examined in vivo. In mice that received daily injections of these drugs the growth of CQ-resistant and CQ-sensitive parasites was unaffected or affected very slightly, if at all. A combination of CQ and each drug suppressed the growth of CQ-resistant parasites in a dose-dependent manner. In addition, in CQ-sensitive parasites each drug also increased the susceptibility to CQ. Measurements of CQ levels by high-performance liquid chromatography showed that CQ accumulated in sensitive parasites to more than twice the level in resistant parasites at 2 to 4 hr after an injection of CQ. Verapamil and desipramine substantially increased CQ levels in both CQ-resistant and CQ-sensitive parasites. These results suggest that not only Ca2+ antagonists but tricyclic antidepressants reverse CQ resistance in CQ-resistant parasites and enhance the inhibitory effect in sensitive parasites by increasing CQ levels in those parasites. The effects of Ca2+ antagonists, tricyclic antidepressants, and phenothiazines on a pyrimethamine-resistant line of P. chabaudi were also studied. None of the Ca2+ antagonists (verapamil, nicardipine, and diltiazem) affected the growth of the parasite in combination with 20 mg/kg pyrimethamine. Tricyclic antidepressants and phenothiazines suppressed pyrimethamine-resistant parasites to some extent. However, the extent of this suppression was less pronounced as compared with that of suppression of CQ resistance by the same drugs.

Animals↗