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Query: UMLS:C0024530 (malaria)
 44,886 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Several reports suggest that the antimalarial mode of action of quinoline drugs may differ in their mechanistic details. The malaria parasite Plasmodium falciparum was treated in culture with chloroquine, amodiaquine, quinine and mefloquine in a dose- and time-dependent fashion. After removal of the drug, the viability of the parasites and their hemoglobin content were determined. Whereas in the presence of chloroquine and amodiaquine, there was a correlation between parasite killing and accumulation of hemoglobin, with quinine and mefloquine parasite killing was not associated with the accumulation of hemoglobin. Mefloquine inhibited the chloroquine-dependent accumulation of hemoglobin. It is suggested that whereas chloroquine and amodiaquine inhibit the digestion of hemoglobin, mefloquine and possibly quinine inhibit the ingestion of host cell hemoglobin by interfering with the ingestion process. These results may explain the demonstrable antagonism between chloroquine and mefloquine and their antipodal sensitivity to these drugs.
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PMID:Differential effects of 4-aminoquinoline-containing antimalarial drugs on hemoglobin digestion in Plasmodium falciparum-infected erythrocytes. 1185 90

The isolation in 1972 of artemisinin by Chinese scientists, and their development of all the derivatives now used in the treatment of malaria today, were of outstanding importance. The results which have accumulated both from the Chinese work and from that subsequently conducted on a worldwide basis provide for a relatively comprehensive understanding of the chemistry, pharmacological profiles, toxicology, metabolism, and effects on the malaria parasite. The optimal regimens for use in the field are also apparent, particularly in combinations with longer half-life quinoline antimalarials. Thus the future use of the artemisinin class of drug appears assured. However, the mechanism of action needs to be clarified. More importantly from a clinical viewpoint, problems inherent in the current derivatives must be addressed, particularly that of neurotoxicity, if new artemisinin derivatives are to be introduced in a normal drug regulatory environment. The application of established principles of modern drug design should indeed allow for the first truly rationally designed, in so far as the target is still unknown, derivatives to come to hand.
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PMID:Artemisinin and derivatives: the future for malaria treatment? 1196 90

Malaria pigment (haemozoin, HZ) is the detoxification product of haemoglobin-derived haem of intraerythrocytic malaria parasites. At schizont rupture, haemozoin accumulates inside host phagocytic cells. The chemical structure and the spectroscopic characteristics of haemozoin are identical to those of beta-haematin (BH), a synthetic pigment obtained from Ferriprotoporphyrin IX (Fe (III) PPIX) in acidic conditions. The process of BH formation is the target of quinoline antimalarials. Here, we summarise the results of our studies on the ultrastructural characteristics, biological and pharmacological relevance of synthetic vs. native haemozoin. 1) By electron microscopy, native HZ and synthetic BH appear as dark brown crystals, morphologically indistinguishable and are internalised by phagocytes at the same extent. 2) Both HZ and BH modulate the production of cytokines (TNF and NO) and increase the susceptibility to lipid peroxidation of mouse or human phagocytes. The antioxidant status of the phagocytes regulates the susceptibility to BH/HZ-mediated effects. 3) The process of BH formation from Fe(III)PPIX, hence haem detoxification, can be inhibited by electrochemically-reduced, Fe(II)PPIX molecules. Maintaining iron in the reduced state can thus be considered a new pharmacological target. This was confirmed by the observation that thiol-reducing agents (NAC, cystein) were able to inhibit BH formation and were toxic to parasites in vitro.
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PMID:Ultrastructural characteristics, biological activity and pharmacological relevance of synthetic malaria pigment (beta-haematin). 1207 77

Intraerythrocytic malaria parasites produce large amounts of toxic ferriprotoporphyrin IX (FP) during their digestion of host cell haemoglobin. The inhibition of biomineralisation of FP to haemozoin (or beta-haematin) by antimalarial drugs underlies their mode of action. We have developed an in vitro microassay for testing the inhibition of biomineralisation by drugs. It is based on the detection by optical density measurement of solubilised beta-haematin remaining after contact with drugs. The assay uses a 192-microM haemin chloride solution in dimethyl sulfoxide, 96-well filtration microplates as well as normal microplates; it lasts 18-24h and requires a spectrophotometer. We determined by this assay the IC(50) of chloroquine phosphate (28microM) and quinine base (324microM) and showed that unlike previous methods it is insensitive to inorganic anions. We also determined the activity of synthetic dyes and plant extract to determinate the interference of coloured compounds on the accuracy of the test. We found that methylene blue, thionine (IC(50) 38 and 87microM, respectively), and an extract of plants that contains quinoline derivatives, inhibited the biomineralisation of FP regardless of their intrinsic colour.
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PMID:A non-radiolabelled ferriprotoporphyrin IX biomineralisation inhibition test for the high throughput screening of antimalarial compounds. 1212 52

Hemoglobin digestion in the intraerythrocytic trophozoite stages of the malaria parasite releases large quantities of heme, which is then detoxified by crystallization into regular crystallites, which are subsequently secreted into the host vascular network as malaria pigment. This crystalline product is isostructural with the synthetic phase b-hematin, and its structure, solved from its powder diffraction pattern, (Pagola et al., 2000), corresponds to a hydrogen bonded chain of propionate linked dimers, Figure 1. This is an example where the crystalline phase is the macromolecule of direct biological interest, particularly in light of the currently accepted hypothesis for the quinoline antimalarial drug action being the inhibition of b-hematin formation and biosynthesis. A surprisingly array of spectroscopically similar closely related phases can also form during the reactions which are used to synthesize b-hematin. Scanning electron microscopy and X-ray powder diffraction have been used to characterize these materials. Taken together these results indicate that infrared spectroscopy, in itself, is insufficient to identify synthetic analogs to malaria pigment and that a combination of electronmicroscopy and powder diffraction are required to unambiguously characterize these heme aggregates.
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PMID:Phase homogeneity and crystal morphology of the malaria pigment beta-hematin. 1235

Haeme metabolism remains a vulnerable problem for the intraerythrocytic Plasmodium which catabolises haemoglobin as a source of amino acids in an acidic, oxygen-rich lysosome-like digestive vacuole. Haeme monomer, capable of generating oxygen radicals, transforms into an inert crystal named malarial pigment or haemozoin by forming unique dimers that then crystalise. Laveran first described pigmented bodies in humans to define a protozoan as the aetiologic agent of malaria. The trail of malaria pigment enabled Ross to implicate the mosquito in the life cycle of Plasmodium. In 1991, Slater and Cerami postulated a unique iron-carboxylate bond between two haemes in haemozoin crystals based on infrared and X-ray spectroscopy data. Additionally, parasite extracts were shown to possess a 'haeme polymerase' enzymatic activity as the process of crystal formation was then termed. Importantly, the quinolines, such as choloroquine, inhibit haemozoin formation. A Plasmodium falciparum derived histidine-rich protein II, which binds haeme and initiates haemozoin formation, is present in the digestive vacuole. Pfhistidine-rich protein II and Pfhistidine-rich protein III are sufficient, but not necessary for haemozoin formation as a laboratory clone lacking both still makes the haeme crystals. The reduvid bug, and the Schistosoma and Haemoproteus genera also make haemozoin. Recently, Bohle and coworkers used X-ray diffraction to document the iron-carboxylate bond in intact desiccated parasites and to show that a Fe1-O41 head to tail haeme dimer is the unit building block of haemozoin. The role of the Plasmodium histidine-rich protein family members, lipids or potential novel proteins in the exact molecular assembly of the large molecular weight haeme crystals in the protein rich digestive vacuole needs to be solved. Accurate experimental determination of the role of haemozoin formation and inhibition as the target of chloroquine is fundamental to determination of the mechanism of quinoline drug action and resistance. The enhanced understanding of the biosynthetic pathway leading to haemozoin formation using functional proteomic tools and the mechanisms through which existing antimalarial drugs affect Plasmodium haeme chemistry will help design improved chaemotherapeutic agents.
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PMID:Theories on malarial pigment formation and quinoline action. 1243 49

The quinolines have been used in the treatment of malaria, arthritis, and lupus for many years, yet the precise mechanism of their action remains unclear. In this study, we used a functional proteomics approach that exploited the structural similarities between the quinoline compounds and the purine ring of ATP to identify quinoline-binding proteins. Several quinoline drugs were screened by displacement affinity chromatography against the purine binding proteome captured with gamma-phosphate-linked ATP-Sepharose. Screening of the human red blood cell purine binding proteome identified two human proteins, aldehyde dehydrogenase 1 (ALDH1) and quinone reductase 2 (QR2). In contrast, no proteins were detected upon screening of the Plasmodium falciparum purine binding proteome with the quinolines. In a complementary approach, we passed cell lysates from mice, red blood cells, or P. falciparum over hydroxychloroquine- or primaquine-Sepharose. Consistent with the displacement affinity chromatography screen, ALDH and QR2 were the only proteins recovered from mice and human red blood cell lysate and no proteins were recovered from P. falciparum. Furthermore, the activity of QR2 was potently inhibited by several of the quinolines in vitro. Our results show that ALDH1 and QR2 are selective targets of the quinolines and may provide new insights into the mechanism of action of these drugs.
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PMID:Discovery of novel targets of quinoline drugs in the human purine binding proteome. 1243 4

The quinolines, hydroxychloroquine (Plaquenil) and chloroquine are used primarily for their anti-inflammatory effects in the treatment of auto-immune conditions such as rheumatoid arthritis. Another common use of these drugs is the prophylaxis and suppression of malaria. The use of quinolines may cause several ocular side-effects. The most significant complication is irreversible macular damage resulting in both visual acuity and visual field loss. However, the Royal College of Ophthalmologists, UK (RCO) recently recommended against the monitoring of patients receiving quinoline therapy as it was deemed to be too costly, given the low incidence of retinal complications. In this article, we present a case of hydroxychloroquine retinopathy, describe the ocular changes associated with quinoline therapy and recommend an optometric review schedule for patients who are currently taking these drugs. Furthermore, we recommend a proactive approach toward medical practitioners prescribing these drugs for optometric-based monitoring of these patients.
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PMID:Management of patients undergoing hydroxychloroquine (Plaquenil) therapy. 1247 64

Antimalarial chemotherapy has become more complex and challenging because of multidrug resistant strains of Plasmodium falciparum. Due to resistance of malarial parasite against well known drugs, the chemotherapy of malaria has become complicated. In this review we have discussed brief introduction followed by life cycle of malaria parasite. The list of commercially available antimalarial drugs along with there action on different stages of parasite have been discussed. A brief description of their mechanism of action and advantages and disadvantages were reported. The natural products as antimalarial have been discussed in the review. On the basis of chemical classes the natural products were divided in the following categories; Quinoline alkaloids, Iso-quinoline alkaloids, Indoloquinoline alkaloids, Carbolines, Bis-isoquinoline, 4-Quinazole derivatives, Trioxanes, Terpenes, Naphthoquinone, Anthraquinones, Chalcones, Hydroxy flavanones, Coumarins and phenolic glycoside. The combination chemotherapy has been highlighted in the review. The Biochemical and Immunological changes in malarial infection are discussed along with complications of malarial chemotherapy due to resistance. In the conclusion section, the future strategies for the chemotherapy of malaria have been discussed.
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PMID:Perspective in antimalarial chemotherapy. 1267 7

Chloroquine has been used in Madagascar since 1945 and remains the first-line treatment for uncomplicated cases of malaria. Low-grades of resistance type R1 and R2 have been reported. Thus, in vitro tests were performed in order to monitor the drug sensitivity of Plasmodium falciparum from different study sites, with the aim of identifying alternatives to chloroquine. Chloroquine IC50 values ranged from 0.2 nM to 283.4 nM (n = 190, mean IC50 = 52.6 nM; 95% CI = 46.1-59.1 nM). Fifteen isolates (7.9%) were chloroquine-resistant. One mefloquine-resistant isolate was detected (1/139). The test isolates were sensitive to amodiaquine (n = 118), quinine (n = 212), pyrimethamine (n = 86) and cycloguanil (n = 79). The median IC50 for amodiaquine was 12.3 nM (mean IC50 = 15.3 nM, 95% CI = 13.3-17.3 nM). Amodiaquine was 3.4 times as active as chloroquine in vitro and 7 times as active as quinine against P. falciparum. These results indicate that amodiaquine may be a potent alternative to chloroquine in Madagascar. There was positive correlation between tested quinoline-containing drugs activities, which suggests in vitro cross-susceptibility.
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PMID:In vitro sensitivity of Plasmodium falciparum to amodiaquine compared with other major antimalarials in Madagascar. 1270 75


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