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Preparation and stability of organic nanocrystals. Experimental and molecular simulation studies.Khan, Shahzeb January 2012 (has links)
A major challenge affecting the likelihood of a new drug reaching the market is poor oral bioavailability derived from low aqueous solubility. Nanocrystals are rapidly becoming a platform technology to address poor solubility issues, although several challenges including stabilisation and control of particle size distribution for nanosuspensions still need to be addressed. The aim of this study was to revisit the simplest approach of re-precipitation and to identify the critical parameters, including the effect of different stabilisers as well as process conditions. We utilised a combined approach of both experiments and molecular modelling and simulation, not only to determine the optimum parameters but also to gain mechanistic insight. The experimental studies utilised three rather distinct, relatively insoluble drugs, the hypoglycaemic glibenclamide, the anti-inflammatory ibuprofen, and the anti-malarial artemisinin. The choice of crystal growth inhibitors/stabilizers was found to be critical and specific for each drug. The effect of the process variables, temperature, stirring rate, and the solute solution infusion rate into the anti-solvent, was rationalized in terms of how these factors influence the local supersaturation attained at the earliest stages of precipitation. Coarse grained simulation of antisolvent crystallisation confirmed the accepted two step mechanism of nucleation at high supersaturation which involves aggregation of solute particles followed by nucleation.
Recovery of nanocrystals from nanosuspensions is also a technical challenge. A novel approach involving the use of carrier particles to recovery the nanocrystals was developed and shown to be able to recover more than 90% of the drug nanocrystals. The phase stability of nanocrystals along with bulk crystals for the model compound glycine was explored using molecular dynamics simulation. The simulations were consistent with experimental data, a highlight being the ¿ phase transforming to the ¿ phase at temperature >400K and 20kbar respectively, as expected. Nanocrystals of ¿, ¿ and ¿ glycine, however did not show any phase transformation at high temperature.
In summary the study demonstrates that standard crystallization technology is effective in producing nanocrystals with the primary challenge being physico-chemical (rather than mechanical), involving the identification of molecule-specific crystal growth inhibitors and/or stabilizers. The developed nanocrystal recovery method should enable the production of nanocrystals-based solid dosage forms. The molecular simulation studies reveal that crystal-crystal phase transformations can be predicted for hydrogen-bonded systems. / HEC Pakistan and University of Malakand KP (Khyber Pakhtunkhwa)
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Development and evaluation of an oral fixed–dose triple combination dosage form for artesunate, dapsone and proguanil / van der Merwe, A.J.Van der Merwe, Adriana Johanna January 2011 (has links)
Malaria is a life–threatening disease caused by Plasmodium spp and causes over one million
deaths annually. The complex life cycle of the malaria parasite offers several points of attack
for the antimalarial drugs. The rapid spread of resistance against antimalarial drugs, especially
chloroquine and pyrimethamine–sulphadoxine, emphasises the need for new alternatives or
modification of existing drugs. Artemisinin–based combination therapies (ACT’s) with different
targets prevent or delay the development of drug resistance and therefore have been adopted
as first–line therapy by all endemic countries. Proguanil–dapsone, an antifolate combination is
more active than pyrimethamine–sulphadoxine and is being considered as an alternative to
pyrimethamine–sulphadoxine. Artesunate–proguanil–dapsone is a new ACT that has wellmatched
pharmacokinetics and is relatively rapidly eliminated; therefore there is a reduced risk
of exposure to any single compound and potentially a decreasing risk of resistance. A few
studies have been done on a triple fixed–dose combination therapy for malaria treatment and
such a combination for artesunate, proguanil and dapsone are not currently investigated,
manufactured or distributed. The aim of this study was to develop a triple fixed–dose
combination for artesunate, proguanil and dapsone.
The formulation was developed in three phases; basic formulation development, employing
factorial design to obtain two possible optimised formulations and evaluating the optimised
formulations. During the formulation development the most suitable manufacturing procedure
and excipients were selected. A full 24 factorial design (four factors at two levels) was used to
obtain the optimised formulations. As end–points to identify the optimised formulations, weight
variation, friability, crushing strength and disintegration of the tablets, were used. Statistical
analysis (one way ANOVA) was used to identify optimal formulations. To identify any
interaction between the active pharmaceutical ingredients (API’s) and the API’s and excipients,
differential scanning calorimetry was done. Flow properties of the powder mixtures (of the
optimised formulations) were characterised by means of angle of repose; critical orifice diameter
(COD); bulk density and tapped density; and flow rate. Tablets of the two optimised powder
formulations were compressed. The tablets were evaluated and characterised in terms of
weight variation, friability, crushing strength, disintegration and dissolution behaviour. Initial
formulation development indicated that wet granulation was the most suitable manufacturing method. The results from the factorial design indicated that different amounts (% w/w) of the
lubricant and binder as well as two different fillers influenced the weight variation, crushing
strength and disintegration statistically significant. Two formulations containing two different
fillers (microcrystalline cellulose or Avicel® PH 101, and lactose or Granulac® 200) were found to
be within specifications and ideal for manufacturing.
Tablets prepared from the FA formulation (formulation containing Avicel® PH 101) complied with
the standards and guidelines for weight variation, friability, crushing strength and disintegration
as set by the British Pharmacopoeia (BP). Tablets had an average crushing strength of 121.56
± 0.022 N. Tablets disintegrated within 52.00 seconds and a maximum weight loss of 0.68%
occurred during the friability test. Weight variation of the tablets prepared from the FG
formulation (formulation containing Granulac® 200) complied with the standards. Average
crushing strength was 91.99 ± 6.008 N and the tablets disintegrated within 140.00 seconds.
Percentage friability (1.024%) did not comply with the guideline of a percentage friability of less
than 1%, however, no cracked or broken tablets were seen.
Dissolution showed that 98, 93 and 94% of artesunate, proguanil and dapsone were
respectively released (of the label value) within 15 minutes for the FA formulations. Release of
artesunate, proguanil and dapsone for the FG formulation was 62, 85 and 92% for the same
time period. The release of the three API’s (the FG formulation) increased to 78, 89 and 92%, respectively, after 45 minutes. / Thesis (M.Sc. (Pharmaceutics))--North-West University, Potchefstroom Campus, 2012.
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Development and evaluation of an oral fixed–dose triple combination dosage form for artesunate, dapsone and proguanil / van der Merwe, A.J.Van der Merwe, Adriana Johanna January 2011 (has links)
Malaria is a life–threatening disease caused by Plasmodium spp and causes over one million
deaths annually. The complex life cycle of the malaria parasite offers several points of attack
for the antimalarial drugs. The rapid spread of resistance against antimalarial drugs, especially
chloroquine and pyrimethamine–sulphadoxine, emphasises the need for new alternatives or
modification of existing drugs. Artemisinin–based combination therapies (ACT’s) with different
targets prevent or delay the development of drug resistance and therefore have been adopted
as first–line therapy by all endemic countries. Proguanil–dapsone, an antifolate combination is
more active than pyrimethamine–sulphadoxine and is being considered as an alternative to
pyrimethamine–sulphadoxine. Artesunate–proguanil–dapsone is a new ACT that has wellmatched
pharmacokinetics and is relatively rapidly eliminated; therefore there is a reduced risk
of exposure to any single compound and potentially a decreasing risk of resistance. A few
studies have been done on a triple fixed–dose combination therapy for malaria treatment and
such a combination for artesunate, proguanil and dapsone are not currently investigated,
manufactured or distributed. The aim of this study was to develop a triple fixed–dose
combination for artesunate, proguanil and dapsone.
The formulation was developed in three phases; basic formulation development, employing
factorial design to obtain two possible optimised formulations and evaluating the optimised
formulations. During the formulation development the most suitable manufacturing procedure
and excipients were selected. A full 24 factorial design (four factors at two levels) was used to
obtain the optimised formulations. As end–points to identify the optimised formulations, weight
variation, friability, crushing strength and disintegration of the tablets, were used. Statistical
analysis (one way ANOVA) was used to identify optimal formulations. To identify any
interaction between the active pharmaceutical ingredients (API’s) and the API’s and excipients,
differential scanning calorimetry was done. Flow properties of the powder mixtures (of the
optimised formulations) were characterised by means of angle of repose; critical orifice diameter
(COD); bulk density and tapped density; and flow rate. Tablets of the two optimised powder
formulations were compressed. The tablets were evaluated and characterised in terms of
weight variation, friability, crushing strength, disintegration and dissolution behaviour. Initial
formulation development indicated that wet granulation was the most suitable manufacturing method. The results from the factorial design indicated that different amounts (% w/w) of the
lubricant and binder as well as two different fillers influenced the weight variation, crushing
strength and disintegration statistically significant. Two formulations containing two different
fillers (microcrystalline cellulose or Avicel® PH 101, and lactose or Granulac® 200) were found to
be within specifications and ideal for manufacturing.
Tablets prepared from the FA formulation (formulation containing Avicel® PH 101) complied with
the standards and guidelines for weight variation, friability, crushing strength and disintegration
as set by the British Pharmacopoeia (BP). Tablets had an average crushing strength of 121.56
± 0.022 N. Tablets disintegrated within 52.00 seconds and a maximum weight loss of 0.68%
occurred during the friability test. Weight variation of the tablets prepared from the FG
formulation (formulation containing Granulac® 200) complied with the standards. Average
crushing strength was 91.99 ± 6.008 N and the tablets disintegrated within 140.00 seconds.
Percentage friability (1.024%) did not comply with the guideline of a percentage friability of less
than 1%, however, no cracked or broken tablets were seen.
Dissolution showed that 98, 93 and 94% of artesunate, proguanil and dapsone were
respectively released (of the label value) within 15 minutes for the FA formulations. Release of
artesunate, proguanil and dapsone for the FG formulation was 62, 85 and 92% for the same
time period. The release of the three API’s (the FG formulation) increased to 78, 89 and 92%, respectively, after 45 minutes. / Thesis (M.Sc. (Pharmaceutics))--North-West University, Potchefstroom Campus, 2012.
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PREPARATION AND APPLICATION OF CATALYSTS FOR THE STEREOSPECIFIC REDUCTION AND PHOTOOXYGENATION OF OLEFINS IN CONTINUOUS OPERATIONS: A NOVEL METHOD FOR THE PRODUCTION OF ARTEMISININFisher, Daniel C 01 January 2017 (has links)
Over the last two centuries, the discovery and application of catalysts has had a substantial impact on how and what chemicals are produced.Given their broad significance, our group has focused on developing new catalyst systems that are recoverable and reusable, in an attempt to reduce concomitant costs.
Our efforts have centered on constructing a recyclable chiral heterogeneous catalyst capable of effecting asymmetric hydrogenations of olefins with high stereoselectivity. A class of phosphinoimidazoline ligands, developed by researchers at Boehringer-Ingelheim, known as BIPI ligands, have proven efficacious in the asymmetric reduction of alkenes. However, these chiral ligands are homogeneous and coordinated to precious metals, rendering them irrecoverable and expensive. To address these issues, our group has derivatized the BIPI ligand-metal complex and immobilized it to the surface of graphene oxide as well as polystyrene. Their efficacy and recyclability toward the asymmetric hydrogenation of a functionalized olefin have been evaluated.
Another facet of our work has included developing a cost effective synthetic process to artemisinin, the gold standard drug in the treatment of malaria.As a natural product, artemisinin’s worldwide supply remains highly unpredictable, contributing to great price volatility.Combining the benefits of catalysis and the advantages of continuous flow chemistry, our research has sought to develop an economical approach to convert a biosynthetic precursor, artemisinic acid, to artemisinin in three chemical transformations.
High-throughput experimentation allowed us to screen a prodigious number of catalysts and identify those effective in the asymmetric hydrogenation artemisinic acid to dihydroartemisinic acid, the first step in the transformation. This screening directed us to an inexpensive, heterogeneous ruthenium catalyst. The second step of the process includes the photooxygenation of dihydroartemisinic acid, which involves photochemically generated singlet oxygen. We have evaluated a commercially available heterogeneous photocatalyst packed in a transparent bed, surrounded by light emitting diodes in the continuous photooxygenation of dihydroartemisinic acid to dihydroartemisinic acid hydroperoxide. The third and final step, an acid induced hock cleavage, initiates an intricate cascading reaction that installs an endoperoxide bridge to deliver artemisinin. Our process afforded a 57% yield from dihydroartemisinic acid to artemisinin.
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Expression of Genes Encoding for Drug Metabolism in the Small IntestineLindell, Monica January 2003 (has links)
<p>This investigation focused on the mRNA expression of drug metabolising Cytochromes P-450 (CYP) and UDP-glucuronosyltransferases (UGT) and the transport protein P-glycoprotein (Pgp) in the small intestine of humans and rats.</p><p>The mRNA expression of the investigated genes in the human small intestine (duodenum) varies between individuals giving each one of us personal profile. In general, the most dominant forms are Pgp, CYPs 2C9, 2D6, 3A4, and UGTs 1A1, 1A10, 2B7. However, which of these is the highest expressed one varies between individuals.</p><p>The correlation in expression between some CYP forms and UGT forms respectively is relatively high, which indicates that they have some regulatory mechanisms in common. It was also shown that the mRNA expression of both CYPs and UGTs may be affected by endogenous and exogenous factors. Sex and ethnic background, affected the mRNA expression of CYP2A6 and 2E1 respectively. Commonly used drugs such as acetylsalicylicacid (ASA) and omeprazole (omep) affect CYP2A6, CYP2E1 (ASA) and CYP3A4, UGT1A4 (omep). The expression of UGT1A4 is also affected by smoking. All these factors are commonly used and can therefore lead to important drug-drug interactions.</p><p>It was also shown that the human small intestinal CYP mRNA expression pattern differs from that found in the rat. The rat CYP expression is rather constant between the different individuals, and the main rat intestinal forms are CYP1A1, CYP2C, CYP2D6 and CYP3A1. The expression is the same for females and males and no difference can be seen between the different segments of the rat small intestine. As metabolic studies have often been done with rat liver we compared the mRNA expression in the two organs. We found that the mRNA expression of 1A1 was absent in the liver and that the CYP2B1, CYP2Cs, CYP2D1 and Pgp all had a stronger mRNA expression in the small intestine compared to the liver. It is therefore important to realise that results from metabolic studies on liver may not be directly extrapolated to the small intestine.</p><p>Artemisinin is an orally used drug in multidrug treatment of malaria in Southeast Asia. It has been suggested that artemisinin can induce drug metabolism and therefore be involved in drug-drug interactions. This study shows that artemisinin induces mainly the CYP2B via nuclear receptor CAR.</p>
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Pharmacokinetic drug-drug interactions in the management of malaria, HIV and tuberculosisElsherbiny, Doaa January 2008 (has links)
<p> Malaria, Human Immunodeficiency Virus (HIV) and tuberculosis (TB) are global health problems having their worst situation in sub-Saharan Africa. Consequently, concomitant use of antimalarial, antiretroviral and antitubercular drugs may be needed, resulting in a potential risk of drug-drug interactions.</p><p>Cytochrome P-450 (CYP) enzyme induction/inhibition may lead to drug-drug interactions and can be detected by probe drugs. An analytical method was developed for the quantitation of mephenytoin, CYP2B6 and CYP2C19 probe, and its metabolites. </p><p>Induction/inhibition of principal CYP enzymes by the antimalarials; artemisinin, dihydroartemisinin, arteether, artemether and artesunate, was evaluated using the 4-hour plasma concentration ratios of probe drugs and their metabolites along with modelling the population pharmacokinetics of S-mephenytoin and its metabolites. The extent of change in enzymatic activities was different among the antimalarials, with artemisinin having strongest capacity for induction and inhibition, consequently, the strongest potential risk for drug-drug interactions. </p><p>Drug-drug interactions between the antitubercular rifampicin and the antiretrovirals nevirapine and lopinavir were assessed, in TB/HIV patients, by developing population pharmacokinetic models. Rifampicin increased nevirapine oral clearance. Simulations suggested that increasing the nevirapine dose to 300 mg twice daily when co-administered with rifampicin, would result in nevirapine concentrations above subtherapeutic levels, with minimum exposure above the recommended maximum concentration. Lopinavir is co-formulated with ritonavir in the ratio of 4:1. In children, increasing ritonavir dose four times did not completely compensate the enhancement of lopinavir oral clearance caused by rifampicin. However, the predicted lopinavir trough concentration was above the recommended minimum therapeutic concentration.</p><p>The work presented in this thesis followed an investigation line though not done for a particular drug. First the CYP enzymes involved in the interaction are identified. Afterwards, the expected drug-drug interaction is investigated where the potentially interacting drugs are concomitantly administered and an adjustment in the dose regimen is proposed that is subsequently evaluated.</p>
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Expression of Genes Encoding for Drug Metabolism in the Small IntestineLindell, Monica January 2003 (has links)
This investigation focused on the mRNA expression of drug metabolising Cytochromes P-450 (CYP) and UDP-glucuronosyltransferases (UGT) and the transport protein P-glycoprotein (Pgp) in the small intestine of humans and rats. The mRNA expression of the investigated genes in the human small intestine (duodenum) varies between individuals giving each one of us personal profile. In general, the most dominant forms are Pgp, CYPs 2C9, 2D6, 3A4, and UGTs 1A1, 1A10, 2B7. However, which of these is the highest expressed one varies between individuals. The correlation in expression between some CYP forms and UGT forms respectively is relatively high, which indicates that they have some regulatory mechanisms in common. It was also shown that the mRNA expression of both CYPs and UGTs may be affected by endogenous and exogenous factors. Sex and ethnic background, affected the mRNA expression of CYP2A6 and 2E1 respectively. Commonly used drugs such as acetylsalicylicacid (ASA) and omeprazole (omep) affect CYP2A6, CYP2E1 (ASA) and CYP3A4, UGT1A4 (omep). The expression of UGT1A4 is also affected by smoking. All these factors are commonly used and can therefore lead to important drug-drug interactions. It was also shown that the human small intestinal CYP mRNA expression pattern differs from that found in the rat. The rat CYP expression is rather constant between the different individuals, and the main rat intestinal forms are CYP1A1, CYP2C, CYP2D6 and CYP3A1. The expression is the same for females and males and no difference can be seen between the different segments of the rat small intestine. As metabolic studies have often been done with rat liver we compared the mRNA expression in the two organs. We found that the mRNA expression of 1A1 was absent in the liver and that the CYP2B1, CYP2Cs, CYP2D1 and Pgp all had a stronger mRNA expression in the small intestine compared to the liver. It is therefore important to realise that results from metabolic studies on liver may not be directly extrapolated to the small intestine. Artemisinin is an orally used drug in multidrug treatment of malaria in Southeast Asia. It has been suggested that artemisinin can induce drug metabolism and therefore be involved in drug-drug interactions. This study shows that artemisinin induces mainly the CYP2B via nuclear receptor CAR.
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Pharmacokinetic drug-drug interactions in the management of malaria, HIV and tuberculosisElsherbiny, Doaa January 2008 (has links)
Malaria, Human Immunodeficiency Virus (HIV) and tuberculosis (TB) are global health problems having their worst situation in sub-Saharan Africa. Consequently, concomitant use of antimalarial, antiretroviral and antitubercular drugs may be needed, resulting in a potential risk of drug-drug interactions. Cytochrome P-450 (CYP) enzyme induction/inhibition may lead to drug-drug interactions and can be detected by probe drugs. An analytical method was developed for the quantitation of mephenytoin, CYP2B6 and CYP2C19 probe, and its metabolites. Induction/inhibition of principal CYP enzymes by the antimalarials; artemisinin, dihydroartemisinin, arteether, artemether and artesunate, was evaluated using the 4-hour plasma concentration ratios of probe drugs and their metabolites along with modelling the population pharmacokinetics of S-mephenytoin and its metabolites. The extent of change in enzymatic activities was different among the antimalarials, with artemisinin having strongest capacity for induction and inhibition, consequently, the strongest potential risk for drug-drug interactions. Drug-drug interactions between the antitubercular rifampicin and the antiretrovirals nevirapine and lopinavir were assessed, in TB/HIV patients, by developing population pharmacokinetic models. Rifampicin increased nevirapine oral clearance. Simulations suggested that increasing the nevirapine dose to 300 mg twice daily when co-administered with rifampicin, would result in nevirapine concentrations above subtherapeutic levels, with minimum exposure above the recommended maximum concentration. Lopinavir is co-formulated with ritonavir in the ratio of 4:1. In children, increasing ritonavir dose four times did not completely compensate the enhancement of lopinavir oral clearance caused by rifampicin. However, the predicted lopinavir trough concentration was above the recommended minimum therapeutic concentration. The work presented in this thesis followed an investigation line though not done for a particular drug. First the CYP enzymes involved in the interaction are identified. Afterwards, the expected drug-drug interaction is investigated where the potentially interacting drugs are concomitantly administered and an adjustment in the dose regimen is proposed that is subsequently evaluated.
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Efeito da infusão de Artemisia annua cultivada em solo com aplicação de silicato de cálcio e magnésio sobre o controle de Toxoplasma gondii in vitroRostkowska, Cristina 24 August 2012 (has links)
Fundação de Amparo a Pesquisa do Estado de Minas Gerais / Toxoplasmosis is an important zoonotic disease due to ability of its causal agent,
Toxoplasma gondii, to infect large number of vertebrates and to be associated with congenital
infection or opportunistic disease in immunosuppressed patients. As the traditional treatment
has shown adverse effects, low-toxicity compounds including artemisinin and its derivatives
have been researched, as well Artemisina annua tea infusion. The use of silicon in the soil of
A. annua crops and its role on artemisinin content has not been studied yet. This study aimed
to investigate the effects of silicon on A. annua plant physiology and the role of the tea
infusion obtained from these plants in the control of T. gondii infection in cell culture. The
experimental design was a completely randomized design (CRD), in which A. annua was
planted in the soil with five different doses of calcium/magnesium silicate (0, 200, 400, 800
and 1600 kg ha-1) and five replications, and maintained in a greenhouse. Analysis of foliar
macronutrients showed a significant increase only for nitrogen, in the presence of the highest
dose of silicate in the soil. The foliar micronutrient and Si concentrations as well the plant
height were not significantly changed with any silicate doses in the soil. The use of 400 kg
ha-1 of silicate induced the highest total glandular trichome area that was also associated with
the intact glandular trichomes, as observed by scanning electron microscopy, and with the
highest artemisinin content in plant leaves and tea infusion, as determined by thin layer
chromatography (TLC) and high performance liquid chromatography (HPLC), respectively.
HeLa cell treatments along with or after T. gondii infection, with infusion of A. annua grown
in the soil without or with silicate (400 kg ha-1), induced a decrease of parasite proliferation in
a dose-dependent manner, as also seen for cell treatment with pure artemisinin. In conclusion,
the use of silicon had positive effect on the glandular trichome areas and artemisinin contents,
but this outcome was not associated with a better efficacy of A. annua tea infusion on T.
gondii replication. These findings suggest that other components rather than artemisinin could
be contributing to this effect, such as flavonoids present in its leaves, which may act in
synergism with the artemisinin and improve its efficacy. / A toxoplasmose é uma zoonose importante devido à capacidade de seu agente causal,
Toxoplasma gondii, de infectar um grande número de vertebrados e ser associada com
infecção congênita ou doença oportunista em pacientes imunocomprometidos. O tratamento
tradicional mostra efeitos adversos levando à pesquisa de compostos de baixa toxicidade
como a artemisinina, seus derivados e a infusão da planta Artemisia annua. A utilização de
silício no solo de culturas de A. annua e seu papel no conteúdo de artemisinina ainda não
foram estudados. O objetivo deste estudo foi investigar os efeitos do silício sobre a fisiologia
da planta A. annua e o papel da infusão destas plantas sobre o controle da infecção de T.
gondii em cultura celular. Foi utilizado o delineamento inteiramente ao acaso (DIC), no qual
A. annua foi plantada em solo com aplicação de cinco diferentes dosagens de silicato de
cálcio/magnésio (0, 200, 400, 800 e 1600 kg ha-1), em cinco repetições e mantida em casa de
vegetação. A análise de macronutrientes foliares mostrou um aumento significativo apenas
para o nitrogênio, na presença da maior dosagem de silicato no solo. As quantidades de
micronutrientes e silício foliares bem como a altura da planta não foram significativamente
alteradas em quaisquer dosagens de silicato no solo. A aplicação de 400 kg ha-1 de silicato
induziu a maior área de tricomas glandulares totais que foi associada com os tricomas
glandulares intactos, como observado por microscopia eletrônica de varredura, e com o mais
alto conteúdo de artemisinina nas folhas e na infusão da planta, como determinado por
cromatografia em camada fina (TLC) e cromatografia líquida de alta eficiência (HPLC),
respectivamente. Os tratamentos de células HeLa, simultaneamente ou após a infecção por T.
gondii, com infusão de A. annua cultivada sem ou com silicato (400 kg ha-1) aplicado ao solo,
induziram decréscimo dependente da dose na proliferação parasitária, como também
verificado para o tratamento das células com artemisinina pura. Em conclusão, o uso de silício
teve efeito positivo sobre as áreas de tricomas glandulares e seu conteúdo de artemisinina,
mas este resultado não foi associado com melhor eficácia da infusão de A. annua sobre a
replicação intracelular de T. gondii. Estes resultados sugerem que outros componentes além
da artemisinina poderiam contribuir para este efeito, como os flavonóides presentes nas folhas
de A. annua que podem atuar em sinergismo com a artemisinina e melhorar a sua eficácia. / Doutor em Imunologia e Parasitologia Aplicadas
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Etude des déterminants du paludisme chez les militaires français déployés en Guyane dans le cadre de la lutte contre l’orpaillage illégal / Determinants of malaria among French armed forces involved in military operation to control and reduce illegal gold mining in French GuianaPommier de Santi, Vincent 27 June 2017 (has links)
Les militaires français sont engagés depuis 2002 dans des opérations de lutte contre l’orpaillage illégal en Guyane. Malgré un programme de prévention du paludisme dimensionné et organisé, ces opérations se sont accompagnées d’une augmentation de l’incidence du paludisme. Cette thèse a pour objectif d’identifier les déterminants humains, vectoriels et parasitaires du paludisme en Guyane. La première partie de cette thèse permet de mieux décrire le faciès épidémiologique du paludisme en forêt guyanaise. Nous avons clairement établi le lien entre paludisme et orpaillage illégal. Une étude, menée en milieu orpailleur a démontré l’existence de foyers de paludisme hyperendémiques, avec une prédominance de P. falciparum et un risque d’émergence de résistance aux traitements combinés à base d’artémisinine. Les investigations entomologiques ont permis de confirmer le rôle d’Anopheles darlingi comme vecteur majeur du paludisme en forêt mais aussi l’existence d’une activité de piqûre diurne sous la canopée. Elles ont permis en outre de mieux identifier les autres vecteurs secondaires en forêt : An. nuneztovari et An. triannulatus, mais surtout An. ininii et An. marajoara. En seconde partie, une étude de cohorte en population militaire a permis d’estimer l’exposition au paludisme par l’utilisation d’outils sérologiques. La distribution des preuves sérologiques d’une infection palustre était en faveur d’une exposition plus fréquente à P. falciparum. Les taux d’incidence des infections étaient de 40 pour 100 personnes années que ce soit pour P. falciparum ou P. vivax. Le seul facteur protecteur était l’observance parfaite de la chimioprophylaxie par doxycycline. / Since 2002, French armed forces are involved in operations against illegal gold mining in French Guiana. Despite a properly dimensioned prevention program against malaria conducted, a drastic increase of malaria incidence has been observed among military personnel. The first part of this thesis aimed to describe the determinants of malaria in French Guiana forest, including human, vector and parasite features. We have established the link between malaria among military personnel and illegal gold mining sites. A study conducted among gold miners’ population has shown hyperendemic malaria foci in the rain forest, mainly due to P. falciparum, and highlighted a real risk for emergence of artemisinin resistance. Entomologic investigations supported that Anopheles darlingi is the main vector for malaria in rain forest. In addition, we have demonstrated the existence of daytime biting activity by An. darlingi in the forest, which might play a key role in malaria epidemic outbreaks among military personnel. Other sylvatic vectors were identified, as An. nuneztovari and An. triannulatus, but especially An. ininii and An. marajoara. The second part of the thesis, focused on a prospective cohort study conducted among French military population, highlighted real malaria exposure using serological tools. Serological evidences of Plasmodium infection (SEI) were more frequent for P. falciparum than P. vivax, in agreement with our findings in illegal gold miners’ population. SEI incidence rates were high, around 40 per 100 person-years for P. falciparum and P. vivax. Only complete compliance to malaria chemoprophylaxis using daily 100 mg doxycycline protected against malaria infection.
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