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

Quinine, an alkaloid derived from the bark of the cinchona tree was brought to Europe from Peru in the 17th century. Isolation of quinine and other cinchona alkaloids was achieved in France in the early part of the 19th century and uncertainties of supply of the bark stimulated efforts to synthesize quinine. While attempting synthesis, the young chemist, William H. Perkin, stumbled on mauve purple, the first aniline dye. Use of dyes in histopathology and the infant specialty of medical microbiology established the reputation of Paul Ehrlich, and partial success with the use of dyes in trypanosomiasis and malaria encouraged the German dye industry to pursue these substances as antimicrobial agents. By good fortune, this led to the discovery of the sulphonamides by Gerhard Domagk in the mid-1930s, an event that stimulated much other work and may have influenced the development of antibiotics.
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PMID:The quinine connection. 149 Sep 16

In searching for efficient, safe and radically curative agent and causal prophylactics for malaria, seven 2-methyl-5-substituted phenoxy-6-methoxy-8-(1-methyl-4-aminobutylamino)-quinolines (II1-7) were synthesized and their antimalarial activities were compared with the corresponding 4-methyl substituted derivatives of primaquine. The starting material, 2-nitro-4-methoxy-5-bromo-acetanilide (III), was prepared from p-methoxy aniline through acetylation, bromination and nitration. III was then condensed with substituted phenols in the presence of potassium carbonate. The condensed products were subsequently hydrolyzed with dilute alcoholic hydrochloric acid to yield 2-nitro-4-methoxy-5-substituted phenoxy-aniline (V) which underwent Skraup's reaction with 2-butenal to provide the key intermediates 2-methyl-5-substituted phenoxy-6-methoxy-8-nitroquinolines (VI). These 8-nitroquinoline derivatives were reduced to 8-aminoquinoline derivatives (VII). The latter were condensed with 4-bromo-1-phthalimido-pentane and then hydrolyzed with hydrazine hydrate, the final products were obtained as oxalate or succinate. The structure of the target compounds and unknown intermediates were confirmed by elementary and spectral analysis. Primary biological evaluation showed that all compounds II1-7 were much less active than the 4-methyl substituted derivatives and slightly less active than primaquine in both causal prophylactic test against Plasmodium yoelii and suppressive antimalarial test against P. berhei.
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PMID:[Synthesis of 2-methyl-5-substituted phenoxy-primaquine and antimalarials activity]. 223 31

The research efforts to identify the etiological agent of malarial fevers during the decade 1880-1890 are traced and the various factors which facilitated and retarded research are examined. Alphonse Laveran's original announcement of his observation of the malaria parasite was regarded with great skepticism. This was a result of a rival claim of a bacterial cause of malarial fevers, advanced by Edwin Klebs and Corrado Tommasi-Crudeli, and because of the failure of Laveran's germ to explain the clinical diversity and pathophysiology of malaria. Changes in research technology, particularly the effective use of aniline dye stains, made possible greater precision in the study of the blood of malaria patients and in the subsequent understanding of the asexual phase of the plasmodium life cycle by Ettore Marchiafava and Angelo Celli. Until 1886, however, the study of the plasmodium was confined to a small group of researchers whose work was regarded with considerable reserve by the medical profession. Early in 1886, when Camillo Golgi coordinated the life cycle of the organism with the clinical course of the different types of malarial fever, clinicians became interested in the work. By 1890 Laveran's germ was generally accepted but most of Laveran's initial ideas had been discarded in favor of the taxonomic work and clinical pathology of the Italian school.
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PMID:Laveran's germ: the reception and use of a medical discovery. 257 51

The antimalarial herb, Azadirachta indica, acts by redox perturbation in the form of the imposition of substantial oxidant stress during malarial infection. The aqueous leaf extract substantially inhibited NADPH cytochrome C(P-450) reductase activity in rats with a significant increase in the microsomal protein. The aniline hydroxylase activity and the phenobarbitone metabolism were also enhanced. The flavonoids quercetin-3-rhamnoside and quercetin-3-rutinoside (rutin) were isolated as the major constituents of the extract. The significance of these findings in clinical malaria chemotherapy is discussed.
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PMID:Biochemical mechanism of the antimalarial activity of Azadirachta indica leaf extract. 308 17

Therapeutic erythrocytapheresis (TEA) has been used in different diseases such as polycythemia vera (PV), secondary erythrocytosis or hemochromatosis as a process of the less cumbersome but more expensive phlebotomy. TEA is preferred in emergency conditions such as thrombocytosis or in conditions such as porphyria cutanea tarda (PCT) or erythropoietic porphyria when plasma exchange (PEX) is often combined with TEA to reduce extracellular levels of uroporphyrin which contribute to plasma hyperviscosity. TEA is often combined with drug therapy that varies from etoposide in PV to EPO and desferoxamine which are used to mobilize and reduce iron stores in hemochromatosis. Benefits from this combination may be more long lasting than expected. Nonetheless for TEA, there is no standard protocol and, clinical experience with this therapy remains highly anecdotal. Therapeutic red cell-exchange (TREX) has been used with much interest over the years, starting with the management of hemolytic disease of the newborn and later used to correct severe anemia in thalassemia patients thereby preventing iron overload. It has also been used for the management of complications of sickle cell disease such as priapism, chest syndrome, stroke, retinal, bone, splenic and hepatic infarction or in preparation for surgery by reducing HbS to less than 30%. Automated apheresis has also favored the use of TREX in conditions such as paroxysmal nocturnal hemoglobinuria and aniline poisoning, arsenic poisoning, Na chlorate intoxications and CO intoxications, hemoglobinopathies, autoimmune hemolytic anemia, reactions due to ABO incompatibility, in preparation for ABO incompatible bone marrow transplantation or for preventing anti-D immunization after the transfusion of D(+) cells to D(-) recipients. Another field of application has been in the emergency management of intraerythrocytic parasite infections such as malaria and babesiosis. Application of TREX may be wide but its real use remains limited. In our personal experience, in 16 years, only 167 TREX procedures have been carried out in a total of 13,747 therapeutic procedures. This represents only 1.21% of the total.
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PMID:Clinical application of therapeutic erythrocytapheresis (TEA). 1083 21

Human cerebral malaria is caused by a protozoan parasitic with no cure till date. The isolation of brain capillaries i.e. microvessels has permitted the in vitro study related to cerebral function. Microvessels were isolated from normal and P. yoelii infected mice brain cortex and subjected to biochemical characterization by the following enzyme markers viz alkaline phosphatase, gamma-glutamyI transpeptidase and monoamine oxidase and electron microscopically. Limited studies have been carried out in relation to drug metabolizing enzymes in cerebral microvessels of rodents. The present studies have been carried out in relation to status of drug metabolizing enzymes during P. yoelii infection in cerebral microvessels of mice. The data obtained depicted a clear cut impairment of cytochrome P450 (a terminal monooxygenase) and related indices viz b5, benzopyrene hydroxylase, aminopyrene-n-demethylase, aniline hydroxylase except NADH cytochrome e reductase which increased during P. yoelii infection in mice as compared to normal. Further the oral drug administration (arteether) treatment brought back the altered MFO system normal a week alter cessation of drug treatment.
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PMID:Studies on drug metabolizing enzymes during arteether treatment of Plasmodium yoelii nigeriensis infected mice cerebral microvessels. 1663

Four of the most disabling human diseases are syphilis, malaria, schizophrenia, and manic-depressive illness. The history of the development of treatments for these seemingly unrelated disorders intersects at several points. Treatment of tertiary cerebral syphilis (general paresis) by inducing fever with malaria led to a Nobel Prize. Although attempts to synthesize quinine, a plant product effective against malaria, failed, these efforts encouraged industrial organic chemists to synthesize many useful substances, including dyes, antibiotics, and antihistamines. The aniline-derived dye methylene blue was a member of a new class of polycyclic chemicals, the phenothiazines. Efforts to modify phenothiazines to find an antimalarial agent also failed but led to novel antiemetic-sedative antihistamines, including promethazine, promazine, and eventually chlorpromazine--the first effective treatment for schizophrenia and mania. Chlorpromazine has antipsychotic and antimanic properties, and it revolutionized the therapeutics of psychotic illnesses.
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PMID:Neurosyphilis, malaria, and the discovery of antipsychotic agents. 1880 5

Trypanothione reductase (TR) is an essential enzyme of trypanosomatids and therefore a promising target for the development of new drugs against African sleeping sickness and Chagas' disease. Diaryl sulfides with a central anilino moiety, decorated with a flexible N-alkyl side chain bearing a terminal ammonium ion, are a known class of inhibitors. Using computer modelling, we revised the binding model for this class of TR inhibitors predicting simultaneous interactions of the ammonium ion-terminated N-alkyl chain with Glu18 as well as Glu465'/Glu466' of the second subunit of the homodimer, whereas the hydrophobic substituent of the aniline ring occupies the "mepacrine binding site" near Trp21 and Met113. Systematic alteration of the carboxylate-binding fragments and the diaryl sulfide core of the inhibitor scaffold provided evidence for the proposed binding mode. In vitro studies showed IC(50) values in the low micromolar to submicromolar range against Trypanosoma brucei rhodesiense as well as the malaria parasite Plasmodium falciparum.
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PMID:Diaryl sulfide-based inhibitors of trypanothione reductase: inhibition potency, revised binding mode and antiprotozoal activities. 1893

Malaria is one of the leading causes of severe infectious disease worldwide; yet, our ability to maintain effective therapy to combat the illness is continually challenged by the emergence of drug resistance. We previously reported identification of a new class of triazolopyrimidine-based Plasmodium falciparum dihydroorotate dehydrogenase (PfDHODH) inhibitors with antimalarial activity, leading to the discovery of a new lead series and novel target for drug development. Active compounds from the series contained a triazolopyrimidine ring attached to an aromatic group through a bridging nitrogen atom. Herein, we describe systematic efforts to optimize the aromatic functionality with the goal of improving potency and in vivo properties of compounds from the series. These studies led to the identification of two new substituted aniline moieties (4-SF(5)-Ph and 3,5-Di-F-4-CF(3)-Ph), which, when coupled to the triazolopyrimidine ring, showed good plasma exposure and better efficacy in the Plasmodium berghei mouse model of the disease than previously reported compounds from the series.
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PMID:Lead optimization of aryl and aralkyl amine-based triazolopyrimidine inhibitors of Plasmodium falciparum dihydroorotate dehydrogenase with antimalarial activity in mice. 2151 59

A 16-year-old girl working in a paint and dye-casting factory of aniline dyes presented to the emergency with cyanosis, fever and altered sensorium. She had been diagnosed as a case of malaria and treated with chloroquine elsewhere. At admission, her saturation was 79%, which did not improve despite mechanical ventilation with 100% oxygen. Her PaO2 levels, however, remained high-140 mmHg. The observed difference in PaO2 and SpO2 prompted us to investigate her for methemoglobinemia, which was confirmatory. Despite symptomatic and specific treatment, she succumbed to her illness possibly due to late presentation and prolonged cerebral anoxia. Though the girl's raised methemoglobin levels may be explained by her history of exposure to aniline dyes, the temporal association of her methemoglobinemia related symptoms with chloroquine administration cannot be ignored. We believe that this rare complication of chloroquine therapy should be kept in mind before prescribing it to any child with malaria.
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PMID:Death in an adolescent girl with methemoglobinemia and malaria. 2157 86


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