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Population pharmacokinetics of pyronaridine in the treatment of malariaWattanavijitkul, Thitima 01 May 2010 (has links)
A novel pyronaridine-artesunate (PA) combination is being developed as a 3:1 fixed ratio oral combination against P. falciparum and P. vivax malaria. Pyronaridine (PYR) has been used on a limited basis as monotherapy to treat malaria in some provinces in China since 1970, and there are minimal published data on pharmacokinetics of PYR in humans.
In this thesis, the population pharmacokinetics (PPKs) of PYR is studied in different populations. In Chapter II, we develop a PPKs model in 91 healthy subjects participating in a Phase I study of PA. In addition, data from two Phase II and four Phase III studies of PA are pooled, and PPKs of PYR in 321 adult and 319 pediatric patients are investigated separately in Chapter III and IV, respectively. Chapter V provides comparisons of the results from each population.
PYR pharmacokinetics in each population is best described by a two-compartment model with first order absorption and elimination from the central compartment. Although the same structural model is used, pharmacokinetics of PYR differs among the three populations. PYR is absorbed faster and more variably in patients. The weight-normalized total apparent volumes of distribution (V/F) in adult and pediatric patients are approximately 5 and 3 times larger than in healthy subjects. Adult and pediatric patients have a mean weight-normalized oral clearance (CL/F) approximately 2 times higher than healthy subjects but the drug is eliminated more slowly in patient populations due to a much larger V/F. The average elimination half-lives are 8, 11 and 18 days in healthy, pediatric and adult patient populations, respectively. Pharmacokinetic modeling suggests that lean body weight is an important predictor of apparent central volume (V2/F) in adult patients while actual body weight is a significant covariate of V2/F and CL/F in children.
The parameters obtained from PPK modeling are plausible and estimated with acceptable precision. The final models are evaluated using a nonparametric bootstrap technique and visual predictive check. The final models are robust and adequately capture the overall pyronaridine pharmacokinetics. Further study in a broader patient population will be necessary to examine other covariates that influence pyronaridine pharmacokinetics.
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Chemical 'Fingerprinting' and Identification of Unknowns in Counterfeit Artesunate Antimalarial Tablets from Southeast Asia by Liquid Chromatography/Time-of-flight Mass SpectrometryHall, Krystyn Alter 12 1900 (has links)
The production and distribution of counterfeit drugs is a serious worldwide health problem. One recent example is the appearance of fake artesunate antimalarial tablets in Southeast Asia. Due to the malevolent circumstances in which these fakes are produced, concern over the presence of toxic tablet ingredients is very much a legitimate health issue. Therefore, quantification of the amount of active ingredient present in tablets marketed as artesunate, a drug used for the treatment of the multidrug-resistant Plasmodium falciparum malaria in Southeast Asia required liquid chromatography coupled to mass spectrometry (LC-MS). This quantification allows the classification of the tablets as genuine, sub-therapeutic or fake and the validation of field results using colorimetric tests. During the LC-MS experiments, there were the observations that several of the samples contained a “wrong” active ingredient (AI). This was identified via accurate mass measurements, chromatographic retention time and in-source collision-induced dissociation (CID)as erythromycin, a common antibiotic. Using multivariate unsupervised clustering algorithms, the LC-MS data was utilized for “chemically fingerprinting” the fake tablet samples and investigating the similarities between them. The results of this initial survey show a correlation between sample origin, the different types of fake authentication holograms found in the packaging and sample composition.
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Effects of novel chloroquine formulation on blood glucose concentration, renal and cardiovascular function in experimental animal paradigms.Murambiwa, Pretty. January 2011 (has links)
Malaria disease poses a serious global health burden as recent reports have indicated that nearly
half of the world’s population is at risk (WHO 2008). The World Health Organization (WHO)
Expert Consultative Team has reported that 90% of all malaria deaths occur in Sub Saharan
Africa. (WHO, 2008). Despite the numerous global efforts to control and manage the disease,
through various ways, use of chemotherapeutic agents continues to be the major intervention
strategy in the control of malaria. The WHO recommended use of Artermisinin combination
therapy (ACT) has been hampered by an imbalance between demand and supply in the poor
socioeconomically challenged rural populations of Sub Saharan Africa, the epicenter of malaria
infection. Chloroquine (CHQ), therefore, continues to be used in most malaria endemic areas in
developing countries despite development of P. falciparum resistance to the drug (WHO, 2006).
Oral administration is the major delivery route for CHQ. However, CHQ is a bitter drug, with an
inconvenient dosing schedule leading to incomplete courses of therapy by most malaria patients.
Oral CHQ administration is also associated with adverse effects in various organ systems
resulting from deposition of CHQ in these organs to elicit impairment of glucose homeostasis,
renal and cardiovascular function. Alternative methods of CHQ administration such as
transdermal delivery have, therefore, been suggested, in an effort not only to avoid the bitter
taste, but also to modify the dosing schedule, which may improve patient comfort and
compliance. Transdermal delivery of CHQ via an amidated matrix patch, which is envisaged to
ensure a slow, controlled and sustained release of therapeutic concentrations of CHQ, may
circumvent the previously reported adverse effects of oral CHQ. It is against this background
that the current study compared the effects of transdermal CHQ patch and oral chloroquine in the
management of malaria as assessed by the ability to clear parasites of P. berghei infected rats.
The other aims were to investigate and distinguish between the patho physiological effects of
malaria and CHQ treatments on blood glucose and plasma insulin concentration, renal and
cardiovascular function in male Sprague-Dawley rats.
To investigate and distinguish between the pathophysiological effects malaria infection and CHQ
treatments on blood glucose homeostasis, renal and cardiovascular function markers, separate
groups of non infected and P. berghei infected male Sprague Dawley rats (90g-150g) were used.
The animals were treated twice daily with oral CHQ (60mg/kg) and a once off transdermal
delivery of CHQ via topical application of pectin CHQ matrix patch (53mg/kg) in a 21 day study
divided into pre treatment, (days 0-7) treatment (days 8-12) and post treatment (days 13-21)
periods. The animals were housed individually in metabolic cages for the duration of the study.
Treatment was for 5 consecutive days. Measurements of body weight, food and water intake,
mean arterial pressure (MAP), blood glucose concentration, % parasitaemia, haematocrit, and 24
hour urine volume, Na+, K+, urea and creatinine outputs were done every day during the
treatment period, and every third day during the pre and post treatment periods. Separate groups
of non fasted conscious animals (n=6) were sacrificed on days 0, 7, 8, 9, 10, 12, 14 and 21, at 24
hours after the last treatment for oral CHQ administration and after a once off patch application
on the first day of treatment. The plasma obtained was assayed for plasma insulin, lipid profile
parameters and plasma Na+, K+, urea and creatinine. The harvested liver and gastrocnemius
muscle were used for determination of glycogen concentration.
The current study has demonstrated the sustained controlled release of CHQ from the pectin
matrix patch, demonstrating the therapeutic ability to clear P. berghei malaria parasites from
systemic circulation. Malaria infection and oral CHQ treatment exhibited blood glucose lowering
effects which were circumvented by topical application of the pectin CHQ matrix patch.
Oral CHQ elevated hepatic glycogen concentration through mechanisms that are still to be
elucidated. Topical application of CHQ via pectin matrix patch did not alter hepatic and
gastrocnemius muscle glycogen concentrations. Malaria infection and oral CHQ delivery
reduced food intake, water intake and % body weight changes of the animals as well as inducing
natriuresis, reduced urine output and increased urinary creatinine outputs. Malaria infection was
also shown to elicit hyperkalaemia and kaliuresis in experimental animals. Hypotensive effects
of malaria infection and oral CHQ delivery were also demonstrated in the current study. Malaria
infection and oral CHQ delivery elevated plasma total cholesterol and LDL-c as well as
reduction in the cardio protective particle, plasma HDL-c, concentrations. Topically delivered
CHQ via pectin CHQ matrix patch did not evoke any such alterations, suggestive of its ability to
circumvent the observed adverse effects of oral CHQ delivery due to sustained, controlled
release of therapeutic concentrations of CHQ from the transdermal formulation.
To the best of our knowledge, the results of the present study provides the first evidence of the
release of therapeautic CHQ concentrations from pectin CHQ matrix patch that cleared the
malaria parasites from systemic circulation as well as demonstrating the ability of the
transdermal formulation to circumvent the adverse effects of oral CHQ delivery in glucose
homeostasis, renal and cardiovascular function markers. This is clinically relevant as it provides
a feasible and novel alternative method of CHQ delivery that could play a major role in the
effective management of malaria. / Thesis (Ph.D.)-University of KwaZulu-Natal, Westville, 2011.
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The efficacy and safety of artemisinin-based combination therapy for the treatment of uncomplicated Plasmodium falciparum malaria in non-pregnant adults and children : a systematic review.Zani, Babalwa. 15 November 2013 (has links)
Effective case management of malaria is hampered by the spread of parasite resistance to nonartemisinin
antimalarials. To counteract the impact of drug resistance, the World Health
Organization (WHO) has endorsed artemisinin-based combination therapy (ACT) as the first-line
treatment for uncomplicated Plasmodium falciparum malaria. Currently recommended
ACTs are artemether-lumefantrine, artesunate plus amodiaquine, artesunate plus mefloquine,
artesunate plus sulfadoxine-pyrimethamine and dihydroartemisinin-piperaquine.
This study sought to review evidence of the efficacy and safety of different non-artemisinin
antimalarials in combination with artesunate, artemether or dihydroartemisinin for the
treatment of uncomplicated P. falciparum malaria in non-pregnant adults and children. The
search for randomized controlled trials (RCTs) was conducted in the Cochrane Central
Register for Controlled Trials (CENTRAL), MEDLINE, EMBASE and in ClinicalTrials.gov
in January 2009. The eligibility and the methodological quality of trials were assessed and
data were extracted, using standard forms. Data were captured and analyzed in Review
Manager Software, versions 4.2 and 5.0. The outcomes assessed were: treatment failure, fever
and parasite clearance time, calculating the relative risk (RR) and a weighted mean difference
(WMD) with a 95% confidence interval and p-values, indicating statistical significance at
0.05.
Thirty-seven trials with 6862 participants were included. Artesunate combined with
amodiaquine had a statistically significant lower risk of treatment failure compared to the
combination of artesunate with sulfadoxine-pyrimethamine (RR=0.57, 95% CI [0.33, 0.97],
p=0.04, seven trials, N=1341). In addition, treatment with artesunate plus mefloquine was
significantly associated with a lower risk of treatment failure compared to artesunate plus
azithromycin (RR=0.04, 95% CI [0.00, 0.64], p=0.02, one trial, N=54). There was no
significant difference when either mefloquine or atovaquone-proguanil were combination
partners with artesunate (RR=2.6, 95% CI [0.93; 7.24], p=0.07, one trial, N=1066). When
artesunate was combined with chloroquine, primaquine or azithromycin and compared with
artesunate monotherapy, there was no statistically significant difference in the risk of
unadjusted treatment failure. Each of these comparisons had one trial each. Artesunate plus
chloroquine was quicker at clearing fever compared to artesunate plus sulfadoxinepyrimethamine
(WMD= -7.20, 95% CI [-12.53, -1.87], one trial, N=132).
Few trials adequately reported adverse events. There was no significant difference observed in
the risk of adverse events between artesunate plus amodiaquine compared with artesunate
monotherapy, however, adverse events were significantly less in artesunate plus amodiaquine
compared to artesunate plus methylene-blue. Artesunate plus amodiaquine on the other hand
had significantly more adverse events reported compared to artesunate plus sulfadoxine-pyrimethamine.
The findings of this study support the implementation of artemisinin-based combination
therapy for the treatment of uncomplicated malaria. Most crucially, this review found a greater
advantage of combining amodiaquine with artesunate compared to sulfadoxine-pyrimethamine.
The efficacy of artesunate plus mefloquine was superior to that of artesunate
plus azithromycin. Furthermore, the combination of artemisinins with chloroquine, primaquine
and azithromycin has shown very low efficacy and these combination therapies should not be
recommended. The reporting of efficacy was not standardized as many trials did not
differentiate between re-infections and recrudescences. Adverse events were also not
adequately reported. / Thesis (M.Sc.)-University of KwaZulu-Natal, Pietermaritzburg, 2011.
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Effect of pyrimethamine on gametocytogenesis, exflagellation and asexual growth in southern African isolates of Plasmodium Falciparum.Tsoka, Joyce Mahlako. January 1995 (has links)
Pyrimethamine efficacy was investigated in vitro on the blood asexual stages, the sexual stages
and exflagellation in Plasmodium falciparum. Gametocytogenesis was stimulated following the
standard methods on five isolates of Plasmodium falciparum. From these five isolates, RSA
2, 3 and 5 produced gametocytes which reached maturity within seven days and the
gametocytes were able to exflagellate. Isolate MW2 produced young gametocytes which
disappeared within ten days. NF54 produced mature gametocytes which lasted for 24 hours
only.
There were no statistically significant differences between the static and the synchronization
methods of gametocyte stimulation for any of the isolates. The effect of pyrimethamine was
investigated by adding a known concentration of the drug (For RSA 2, MW2 and NF54,
l00nmol/ℓ; RSA 3 and 5, 3000nmol/ℓ pyrimethamine) to the culture medium for seven days
during gametocyte stimulation. The results of this investigation show that there was
gametocytocidal activity on the isolates that were used and pyrimethamine also had a
schizontocidal action on NF54 and the young gametocytes of this isolate were destroyed by
the drug. At concentrations which were inhibitory to asexual parasites, the drug had a
sporontocidal effect on isolate RSA 2 but not on isolate RSA 5. The pyrimethamine MIC
values for asexual parasites ranged from 300nmol/ℓ to > 3000nmol/ℓ (RSA 2 and 5 were not
inhibited at 3000nmol/ℓ ). These results are consistent with those found in previous studies
when pyrimethamine resistance was first detected in South Africa. The chloroquine MICs indicate a good correlation with the results obtained from previous drug
sensitivity tests for all the isolates examined using both the 48-hour in vitro test and isotope
incorporation for growth assessment. The isobolograms constructed to determine relationship
between chloroquine and pyrimethamine indicated no synergism for isolates RSA 2 and 5, but
the Σ relative IC[50]s indicated a weak synergism. Both the isobolograms and the Σ relative IC[50]s
for the isolates RSA 6, 9 and 14 indicated an antagonistic action between chloroquine and
pyrimethamine. The results obtained from this study have important implications for malaria
control in South Africa. / Thesis (M.Sc.)-University of Natal, Pietermaritzburg, 1995.
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Exploring malaria case management of underfive children in households and public primary health care facilities in the Kibaha district, Tanzania /Nsimba, Stephen E. D., January 2003 (has links)
Diss. (sammanfattning) Stockholm : Karol. inst., 2003. / Härtill 5 uppsatser.
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Pharmacodynamic interactions of quinolines with other antimalarial compounds in vitro /Mariga, Shelton Tendai, January 2005 (has links)
Diss. (sammanfattning) Stockholm : Karolinska institutet, 2005. / Härtill 4 uppsatser.
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Characterisation and evaluation of novel potential target (tubulin) for antimalarial chemotherapy /Low, Chee Kin Andrew. January 2004 (has links)
Thesis (Ph.D.)--Murdoch University, 2004. / Thesis submitted to the Division of Health Sciences. Bibliography: leaves 214-249.
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Mechanism of antimalarial action of tetracycline /Phisit Prapunwattana, Yongyuth Yuthavong, January 1986 (has links) (PDF)
Thesis (M.Sc. (Biochemistry))--Mahidol University, 1986.
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Analysis of dihydrofolate reductase variations in relation to antifolate resistance in Plasmodium vivax /Hastings, Michele Dawn. January 2004 (has links)
Thesis (Ph. D.)--University of Washington, 2004. / Vita. Includes bibliographical references (leaves 101-112).
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