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Atovaquone-Proguanil combination for malaria treatment: a systematic review with meta-analysisOduro, Abraham , Rexford January 2001 (has links)
A Research Report Submitted to the School of Public Health, 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 Tropical Diseases (Epidemiology and Biostatistics Option).
Johannesburg, January 2001 / Background: increasing spread of drug resistance among Plasmodium falciparum poses a serious threat to malaria treatment. The situation is complicated not only because new drugs are expensive and slow in development but also because they must be effective, preferably have a novel method of action, with an acceptable level of adverse effects, and be deployed in such a way as to prolong their use. / IT2018
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Bedeutung genetischer Polymorphismen im organischen Kationentransporter OCT1 für die Pharmakokinetik und Nebenwirkungen von Proguanil / Impact of genetic polymorphisms in organic cation transporter OCT1 on pharmacokinetics and side effects of ProguanilTann, Annabelle 23 January 2019 (has links)
No description available.
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Formulation, characterisation and in vivo efficacy of dapsone and proguanil in trimethylated chitosan microparticles / Jacobus van HeerdenVan Heerden, Jacobus January 2014 (has links)
Malaria is an infectious disease caused by various forms of the Plasmodium parasite. It is
responsible for thousands of deaths yearly with 90 % of those deaths being in sub-Saharan
Africa, thus making it a disease of global importance. The global burden of malaria is
worsened by resistance to current treatment, a lack in funding and limited research outputs.
More alternative ways of treatment must be explored and may include the co-formulation of
antimalarial drug substances as well as alternative ways of drug delivery.
Antifolates are drugs which interfere with an organism’s folate metabolism by inhibiting
dihydropteroate synthase (DHPS) or dihydrofolate reductase (DHFR). Dapsone is a synthetic
sulfone which has a mechanism of action that is very similar to that of sulphonamides. The
mechanism of action is characterised by the inhibition of folic acid synthesis through the
inhibition of dihydropteroate synthase (DHPS). Another antifolate drug, proguanil, is the
prodrug of cycloguanil. Its mechanism involves the inhibition of dihydrofolate reductase
(DHFR), thus inhibiting the malaria parasite to metabolise folates and therefore stunting its
growth. Unfortunately, dapsone has a serious side-effect in people with a deficiency of the
enzyme glucose-6-phosphate dehydrogenase (G6PD) causing oxidative stress on the red
blood cells leading to the rupturing of these cells.
The main objective of this study was to formulate and characterise TMC-TPP microparticles
loaded with the effective but toxic drug combination of dapsone and proguanil and to
determine if these drug-containing microparticles had in vivo efficacy against malaria.
N-trimethyl chitosan chloride (TMC), a partially quaternised chitosan derivative, shows good
water solubility across a wide pH range thus having mucoadhesive properties and excellent
absorption enhancing effects even at neutral pH. A faster, more efficient microwave
irradiation method was developed as an alternative to the conventional synthesising method
of TMC. TMC with the same degree of quaternisation (DQ), ± 60 %, was obtained in a quarter
of the reaction time (30 min) by using the newly developed method. The TMC synthesised
with the microwave irradiation method also exhibited less degradation of the polymer
structure, thus limiting the chance for the formation of any unwanted by-products (Omethylation,
N,N-dimethylation and N-monomethylation).
The formation of complexes by ionotropic gelation between TMC and oppositely charged
macromolecules, such as tripolyphosphate (TPP), has been utilised to prepare microparticles
which are a suitable drug delivery system for the dapsone-proguanil combination. Both these
drugs were successfully entrapped. These particles were characterised and the in vivo
efficacy against the malaria parasites was determined. The microparticles with both the
drugs, separately and in combination, displayed similar or better in vivo efficacy when
compared to the drugs without the TMC microparticles.
An in vitro dissolution study was also performed by subjecting the dapsone and proguanil
TMC formulations to 0.1N HCl dissolution medium. Samples were withdrawn after
predetermined time points and the drug concentration was determined with HPLC. It was
found that the TMC microparticles resulted in a sustained release profile since only 73.00 ±
1.70 % (dapsone) and 55.00 ± 1.90 % (proguanil) was released after 150 minutes. The in vivo
bioavailability of the dapsone and proguanil TMC formulations was evaluated in mice by
collecting blood samples at predetermined time points and analysing the samples with a
sensitive and accurate LC-MS/MS method. The in vivo bioavailability of the dapsone TMC
formulation relative to the normal dapsone formulation was found to be 244 % and 123 % for
the proguanil TMC formulation relative to the normal proguanil formulation.
These TMC-TPP microparticles formulations showed better in vivo efficacy and bioavailability
when compared to the normal formulation. Together with the sustained release, these
formulations may be a promising cheaper and more effective treatment against malaria. / PhD (Pharmaceutics), North-West University, Potchefstroom Campus, 2015
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Formulation, characterisation and in vivo efficacy of dapsone and proguanil in trimethylated chitosan microparticles / Jacobus van HeerdenVan Heerden, Jacobus January 2014 (has links)
Malaria is an infectious disease caused by various forms of the Plasmodium parasite. It is
responsible for thousands of deaths yearly with 90 % of those deaths being in sub-Saharan
Africa, thus making it a disease of global importance. The global burden of malaria is
worsened by resistance to current treatment, a lack in funding and limited research outputs.
More alternative ways of treatment must be explored and may include the co-formulation of
antimalarial drug substances as well as alternative ways of drug delivery.
Antifolates are drugs which interfere with an organism’s folate metabolism by inhibiting
dihydropteroate synthase (DHPS) or dihydrofolate reductase (DHFR). Dapsone is a synthetic
sulfone which has a mechanism of action that is very similar to that of sulphonamides. The
mechanism of action is characterised by the inhibition of folic acid synthesis through the
inhibition of dihydropteroate synthase (DHPS). Another antifolate drug, proguanil, is the
prodrug of cycloguanil. Its mechanism involves the inhibition of dihydrofolate reductase
(DHFR), thus inhibiting the malaria parasite to metabolise folates and therefore stunting its
growth. Unfortunately, dapsone has a serious side-effect in people with a deficiency of the
enzyme glucose-6-phosphate dehydrogenase (G6PD) causing oxidative stress on the red
blood cells leading to the rupturing of these cells.
The main objective of this study was to formulate and characterise TMC-TPP microparticles
loaded with the effective but toxic drug combination of dapsone and proguanil and to
determine if these drug-containing microparticles had in vivo efficacy against malaria.
N-trimethyl chitosan chloride (TMC), a partially quaternised chitosan derivative, shows good
water solubility across a wide pH range thus having mucoadhesive properties and excellent
absorption enhancing effects even at neutral pH. A faster, more efficient microwave
irradiation method was developed as an alternative to the conventional synthesising method
of TMC. TMC with the same degree of quaternisation (DQ), ± 60 %, was obtained in a quarter
of the reaction time (30 min) by using the newly developed method. The TMC synthesised
with the microwave irradiation method also exhibited less degradation of the polymer
structure, thus limiting the chance for the formation of any unwanted by-products (Omethylation,
N,N-dimethylation and N-monomethylation).
The formation of complexes by ionotropic gelation between TMC and oppositely charged
macromolecules, such as tripolyphosphate (TPP), has been utilised to prepare microparticles
which are a suitable drug delivery system for the dapsone-proguanil combination. Both these
drugs were successfully entrapped. These particles were characterised and the in vivo
efficacy against the malaria parasites was determined. The microparticles with both the
drugs, separately and in combination, displayed similar or better in vivo efficacy when
compared to the drugs without the TMC microparticles.
An in vitro dissolution study was also performed by subjecting the dapsone and proguanil
TMC formulations to 0.1N HCl dissolution medium. Samples were withdrawn after
predetermined time points and the drug concentration was determined with HPLC. It was
found that the TMC microparticles resulted in a sustained release profile since only 73.00 ±
1.70 % (dapsone) and 55.00 ± 1.90 % (proguanil) was released after 150 minutes. The in vivo
bioavailability of the dapsone and proguanil TMC formulations was evaluated in mice by
collecting blood samples at predetermined time points and analysing the samples with a
sensitive and accurate LC-MS/MS method. The in vivo bioavailability of the dapsone TMC
formulation relative to the normal dapsone formulation was found to be 244 % and 123 % for
the proguanil TMC formulation relative to the normal proguanil formulation.
These TMC-TPP microparticles formulations showed better in vivo efficacy and bioavailability
when compared to the normal formulation. Together with the sustained release, these
formulations may be a promising cheaper and more effective treatment against malaria. / PhD (Pharmaceutics), North-West University, Potchefstroom Campus, 2015
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Contribution à l'étude de la résistance<br />de Plasmodium falciparum à l'atovaquone-proguanilMusset, Lise 14 June 2006 (has links) (PDF)
L'apparition récurrente de Plasmodium falciparum résistant aux antipaludiques est un obstacle majeur au contrôle du paludisme. Introduite en 2000, une nouvelle association très bien tolérée, l'atovaquone-proguanil est rapidement devenue le traitement de choix des accès palustres simples dans certains hôpitaux français. Ce travail de recherche avait pour objectif d'approfondir les connaissances sur la résistance à cette association. Nous n'avons détecté aucune résistance naturelle à l'atovaquone-proguanil en Afrique de l'Ouest et dans l'Océan Indien parmi 477 isolats. La majorité des rechutes précoces sont liées à une malabsorption des principes actifs alors que les échecs tardifs sont liés à la présence de parasites hautement résistants in vitro présentant, au moment de la rechute, une mutation au niveau du codon 268 du cytochrome b (Y268S ou Y268C) sans augmentation du nombre de copies de ce gène, évalué par PCR en temps réel à 16 ± 9 copies par parasite. Le séquençage du génome mitochondrial et l'analyse de marqueurs microsatellites chromosomiques des parasites isolés avant et après la rechute parasitaire montrent que la mutation associée à cette résistance est apparue indépendamment chez chacun des six patients en échec étudiés. L'atovaquone-proguanil est efficace pour le traitement des voyageurs avec moins de 0,1% de résistance. Le risque actuel de dispersion des résistances est négligeable puisqu'elles émergent chez des patients traités hors de zone de transmission. Par contre, si cette association devait être déployée en zone d'endémie, il serait indispensable de la combiner avec d'autres molécules.
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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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