Academisch proefschrift - Amsterdam. / Summary in English, French, and German. Contains errata slip.

Quinine is an alkaloid natural product isolated from the bark of the cinchona tree. It has long served as a synthetic target due to its antimalarial properties. The total synthesis of quinine can be envisioned employing a recently developed catalytic enone cycloallylation methodology. This new process merges phosphine organocatalysis and transition metal catalysis. The pursuit of quinine details the first application of this novel method in organic synthesis. Herein, phosphine-catalyzed transformations of [alpha, beta]-unsaturated compounds as well as a historical overview of the alkaloid target are thoroughly reviewed. The following chapters discuss both racemic and asymmetric approaches toward quinine, including the completion of a formal synthesis. Not only has the cycloallylation proved successful in this synthetic application, but this body of work has seen the development of many highly selective transformations. / text

Thesis (Ph. D.)--University of Texas at Austin, 2008. / Vita. Includes bibliographical references.

Female Anopheles mosquitoes are the only known vectors of human malaria (1) so that eradication of the disease depends on either eliminating the Anopheles mosquito or controlling the Plasmodium organism. In the U.S., Fiji Islands, Hawaii, and Guam, the absence of malaria is due to the absence or elimination of the Anopheles (1). Where the mosquito is less easily eliminated, the Plasmodium parasite must be controlled, and so the quest for effective antiplasmodial drugs is a continuing effort. More than 20,000 drugs (1), 14,000 of which were investigated between 1941-1945 (2), have been studied in regard to their aniplasmodial effect. Although many have found to have some activity, quinine (I) (see Fig. 1) (obtained from the bark of the Cinchona tree) is still listed among the most effective (1, 3, 4). Consequently, there has been much study done on isomers and derivatives of quinine, where the vinyl group on C-3, various substituents or, and the stereochemistry of, C-9, and C-8 to N-1 bond are of major interest, as well as on compounds having structural similarities to quinine (3). The recent report of antimalarial activity of quinicine raises the question of whether or not the activity might be enhanced if the carbonyl group were reduced to the alcohol but the vinyl group left intact, resulting in a pair of diastereomeric quinicinls (XI) (see Fig. 1.) The diastereomeric quinicinls differ from quinicine at C-9 and from dihydroquinicinols at C-3. The presence of the hydroxyl group and the vinyl group, both of which have been mentioned as affecting the activity of Cinchona alkaloids, is expected to make the compounds more active than quinicine. This research was undertaken in an attempt to prepare, isolate, and characterize the diastereomeric quinicinols.

Hepatocyte transmembrane potential (V(m)) during osmotic stress responds as an osmometer, in part because of changes in membrane K+ conductance. This may contribute to the electromotive force that drives transmembrane Cl- fluxes. To test this, double-barreled ion-sensitive microelectrodes were used to measure changes in steady-state intracellular Cl- activity (a(Cl)/(i)) during osmotic stress applied to mouse liver slices. Hyperosmotic and hyposmotic conditions were created by rapidly switching to a solution in which sucrose concentrations were increased or reduced, respectively. Hyperosmotic stress [1.4 x control osmolality (280 mosmol/kgH2O)] decreased hepatocyte V(m) 46% from -39 ± 1 to -21 ± 1 mV (SE; n = 16 animals). Corresponding a(Cl)/(i) increased twofold from 19 ± 2 to 38 ± 3 mM. This shifted the Cl- equilibrium potential (E(Cl)) 19 mV, from -38 ± 0.3 to -19 ± 2 mV. Hyposmotic stress [0.71 x control osmolality (290 mosmol/kgH2O)] increased hepatocyte V(m) 64% from -28 ± 1 to -46 ± 1 mV (SE; n = 13 animals). Corresponding a(Cl)/(i) decreased 0.53-fold from 17 ± 1 to 8 ± 1 mM. This shifted the E(Cl) 20 mV from -26 ± 2 to -46 ± 3 mV. Thus hepatocyte a(Cl)/(i) is in electrochemical equilibrium with V(m). The paired measurements above were repeated after addition of K+-channel blockers quinine or Ba2+. Ba2+ (2 mM) had no effect on either V(m) or a(Cl)/(i) during hyperosmotic stress; however, Ba2+ significantly inhibited changes in V(m) and a(Cl)/(i) during hyposmotic stress. Effects of quinine (0.5 mM) on V(m) and a(Cl)/(i) during both hyperosmotic stress and hyposmotic stress were similar to those of Ba2+. A previous report shows that inhibition of hyposmotic stress-induced V(m) changes results in loss of hepatocyte volume regulation and greater swelling. Thus osmotic stress-induced changes in a(Cl)/(i) are nowhere near those predicted by cell water volume changes based on transmembrane osmotic pressure differences. We conclude that these larger changes in a(Cl)/(i) resulted from voltage-driven transmembrane Cl- fluxes.

No description available.

A research report submitted to the Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, in partial fulfilment of the requirements for the degree of Master of Science in Medicine in Pharmaceutical Affairs. Johannesburg, 2003 / Quinine is a naturally occurring alkaloid found in the bark of the South American cinchona tree. It is used to treat malaria, to relieve nocturnal leg cramps and is used as an antipyretic. Anecdotal evidence, especially from community pharmacists, suggests widespread misuse of quinine sulphate. It has been taken for a range of non-indicated uses ranging from a single dose monthly contraceptive to a post coital “morning after” contraceptive. A self-administered questionnaire, together with a confidentiality and anonymity declaration, was offered to all females requesting quinine sulphate at a pharmacy in Hillbrow, Johannesburg. After completing the questionnaire, the participants were counselled on the proper indications, as well as the consequences of misuse of quinine. / IT2018

Submitted by Marcos Anselmo (marcos.anselmo@unipampa.edu.br) on 2016-04-04T14:38:17Z No. of bitstreams: 1 Alessandra Melise Golke.pdf: 1584787 bytes, checksum: c4cea85302181139401e8596c156ca0a (MD5) / Made available in DSpace on 2016-04-04T14:38:18Z (GMT). No. of bitstreams: 1 Alessandra Melise Golke.pdf: 1584787 bytes, checksum: c4cea85302181139401e8596c156ca0a (MD5) Previous issue date: 2015-07-27 / A malária é causada por protozoários do gênero Plasmodium, sendo que o P. falciparum é responsável pela maioria das mortes. O quadro clínico dessa parasitose inclui febre, calafrios, cefaleia, vômito, diarreia, anemia, coma e morte. O mais antigo antimalárico é a quinina, um alcaloide obtido a partir da casca da árvore de espécies de Cinchona. Devido a sua toxicidade e ao surgimento de novos fármacos, seu uso foi limitado, porém voltou a ter maior importância em virtude da resistência do plasmódio a outros medicamentos. Uma alternativa para minimizar a toxicidade é o desenvolvimento de uma forma farmacêutica capaz de tornar esse fármaco menos tóxico, como os sistemas nanoencapsulados. O presente trabalho teve como objetivo verificar parâmetros hematológicos, bioquímicos e de estresse oxidativo em ratos Wistar tratados com nanocápsulas contendo quinina. Os animais foram divididos em quatro grupos, os quais receberam os seguintes tratamentos: controle (solução salina - NaCl 0,9%); quinina livre (75mg/Kg/dia); nanocápsulas brancas; nanocápsulas contendo quinina (75mg/Kg/dia). As formulações foram administradas três vezes ao dia por via intraperitoneal durante sete dias consecutivos. No oitavo dia os ratos foram eutanasiados e o sangue venoso foi coletado para análises posteriores. O tratamento com nanocápsulas contendo quinina foi capaz de manter os níveis hematológicos dentro dos limites normais. Os marcadores das funções cardíaca, hepática e renal apresentaram níveis sanguíneos significativamente diminuídos no grupo tratado com nanocápsulas contendo quinina em relação ao grupo tratado com quinina livre. As enzimas antioxidantes catalase, superóxido dismutase e glutationa peroxidase apresentaram uma atividade significativamente mais elevada no grupo tratado com nanocápsulas contendo quinina comparado ao grupo quinina livre, assim como o nível de glutationa reduzida. A quinina foi capaz de induzir dano lipídico, proteico e genético, e sua nanoencapsulação atenuou o dano. Assim, estes resultados demonstraram que a nanoencapsulação pode ser eficaz na redução dos efeitos adversos causados pela quinina, tornando este medicamento mais seguro para o tratamento da malária. / Malaria is caused by protozoa of the genus Plasmodium, which P. falciparum is responsible for the most deaths. The clinical picture this parasitosis include fever, chills, headache, vomit, diarrhea, anaemia, coma and death. The oldest antimalarial is quinine, an alkaloid obtained bark species Cinchona. Due to their toxicity and the appearance of new drugs, its use was limited, but again had greater importance because to Plasmodium resistance to other drugs. An alternative to minimize toxicity is the development of a pharmaceutical form capable of less toxic drug, as nanoencapsulated systems. This present work had objective to verify hematological, biochemical and oxidative stress parameters in rats Wistar treated with nanocapsules containing quinine. The animals were divided into four groups which received the following treatments: control (solution saline - 0.9% NaCl); free quinine (75mg/kg/day); blank nanocapsules; quinine-loaded nanocapsules (75 mg/kg/day). The formulations were administered three times a day intraperitoneally during seven consecutive days. On the eighth day the rats were euthanized and venous blood was collected for followed analysis. Treatment with quinine-loaded nanocapsules was able to maintain the blood levels with normal limits. The markers of cardiac, hepatic and renal function showed blood levels significantly decreased in the group treated with quinine-loaded nanocapsules compared to the group treated with free quinine. The antioxidant enzymes catalase, superoxide dismutase and glutathione peroxidase were significantly higher activity in the group treated with quinine-loaded nanocapsules compared to free quinine group, as well as the level of reduced glutathione. Quinine was able to induce lipid, protein and genetic damage, and its nanoencapsulation attenuate the damage. Then, these results demonstrate that nanoencapsulation can be effective in reducing the adverse effects caused by quinine, making this a safer medicament for treatment malaria.

Proefschrift--Rijksuniversiteit te Leiden, 1994.

Thesis (Ph. D.)--University of Washington, 2007. / Vita. Includes bibliographical references (leaves 99-100).