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1.
Trans R Soc Trop Med Hyg ; 102(11): 1095-101, 2008 Nov.
Article in English | MEDLINE | ID: mdl-18541280

ABSTRACT

Tafenoquine is being developed for radical cure and post-exposure prophylaxis of Plasmodium vivax malaria. In an open-label study, 1512 Australian Defence Force personnel received one of three tafenoquine 3 d regimens [400 mg once daily (od), 200 mg twice daily (bid), 200 mg od] or daily primaquine (22.5 mg) plus doxycycline (100 mg) over 14 d in Bougainville and in Timor-Leste for post-exposure prophylaxis. The relapse rate of subjects treated in Bougainville with tafenoquine (n=173) was 1.2% (200 mg bid x 3 d) and 2.3% (400 mg od x 3 d), while primaquine plus doxycycline (n=175) was 3.4%. For subjects treated in Timor-Leste with tafenoquine (n=636), the relapse rate was 4.9% (200 mg od x 3 d), 5.3% (200 mg bid x 3 d) and 11.0% (400 mg od x 3d), while primaquine plus doxycycline (n=289) was 10.0%. The most frequent adverse events reported across all groups were nausea, abdominal distress and diarrhoea. There was a dose-dependent reduction in adverse events with a reduced dose of tafenoquine, with the lowest dose (total 600 mg over 3 d) producing rates of adverse events equivalent to that of primaquine plus doxycycline. The much shorter dosing regimen of tafenoquine should increase compliance, which is often suboptimal with primaquine after leaving an endemic area. [Australian New Zealand Clinical Trials Registry Number 12607000588493].


Subject(s)
Aminoquinolines/administration & dosage , Antimalarials/administration & dosage , Malaria, Vivax/drug therapy , Plasmodium vivax/drug effects , Primaquine/administration & dosage , Adult , Aminoquinolines/adverse effects , Animals , Antimalarials/adverse effects , Australia , Dose-Response Relationship, Drug , Female , Humans , Malaria, Vivax/prevention & control , Male , Military Personnel , Primaquine/adverse effects , Statistics as Topic , Young Adult
2.
Eur J Clin Pharmacol ; 63(3): 271-8, 2007 Mar.
Article in English | MEDLINE | ID: mdl-17216435

ABSTRACT

OBJECTIVE: The purpose of this study was to determine the population pharmacokinetics of mefloquine in healthy military personnel during prophylaxis for malaria infections. METHODS: The subjects were 1,111 Australian soldiers participating in two studies: a randomised double-blinded study (group A, 161 subjects) and an open-label study (group B, 950 subjects). Following a loading dose (250 mg mefloquine base daily, 3 days), subjects received an oral weekly maintenance dose of 250 mg over 6 months. Blood was collected after the last split loading dose then at weeks 4, 8 and 16 for group A, and at weeks 13 and 26 for group B. Plasma mefloquine concentrations were measured by high-performance liquid chromatography (HPLC). Pharmacokinetic modelling was performed using NONMEM. RESULTS: A two-compartment model with inter-occasion variability (IOV) for clearance satisfactorily described the pharmacokinetics. Typical values were clearance (CL/F, 2.09 l/h), central volume of distribution (V1/F, 528 l), absorption rate constant (KA, 0.24 h(-1)), inter-compartmental clearance (Q/F, 12.5 l/h), peripheral volume of distribution (V2/F, 483 l) and elimination half-life (t (1/2), 14.0 days). Weight had a positive influence on central volume but was insufficient to warrant dosage adjustments. The inter-individual variability (coefficient of variation, CV%) for CL/F and V1/F was 24.4% and 29.6%, respectively. The IOV for CL/F was 17.8%. The proportional residual error (CV%) for groups A and B was 11.5% and 19.5%, respectively, and the additive error standard deviation (SD) was 57 ng/ml and 149 ng/ml, respectively. CONCLUSION: The typical parameter values were comparable with those estimated in much smaller cohorts of healthy subjects and in malaria patients treated with single-dose mefloquine. The lower unexplained variability in the blinded study suggested these subjects may have been more compliant in taking their medication than soldiers in the open-label study.


Subject(s)
Antimalarials/pharmacokinetics , Malaria/prevention & control , Mefloquine/pharmacokinetics , Military Personnel , Adolescent , Adult , Double-Blind Method , Female , Humans , Male , Middle Aged , Models, Biological
3.
Trans R Soc Trop Med Hyg ; 101(3): 226-30, 2007 Mar.
Article in English | MEDLINE | ID: mdl-16814823

ABSTRACT

In an open-label sequential cohort study, we compared gastrointestinal (GI) disturbances and plasma tafenoquine concentrations after administration of single-dose (400mg daily x 3 days; n=76 males, 11 females) and split-dose (200 mg twice daily x 3 days; n=73 males, 13 females) tafenoquine regimens in healthy Australian Defence Force volunteers for post-exposure malaria prophylaxis. The female and male volunteers had comparable demographic characteristics (age, weight, height) in the single- and split-dose treatment groups. GI disturbances were generally mild and self-limiting for both groups. The frequency of nausea and abdominal distress was over two-fold higher in females than in males for both treatment groups. Reporting of GI disturbances in the single-dose group differed significantly between males and females, but this gender difference was not seen for the split-dose group. In those volunteers who experienced GI disturbances, the mean plasma tafenoquine concentrations 12 h after the last dose of tafenoquine were approximately 1.3-fold higher in females than in males (means+/-SD: 737+/-118 ng/ml vs. 581+/-113 ng/ml). These preliminary findings suggest that further studies are required in a larger number of females to determine whether there is a need to reduce the dose of tafenoquine to minimise GI disturbances in females.


Subject(s)
Aminoquinolines/adverse effects , Antimalarials/adverse effects , Gastrointestinal Diseases/chemically induced , Malaria, Vivax/prevention & control , Adult , Aminoquinolines/blood , Aminoquinolines/therapeutic use , Antimalarials/blood , Antimalarials/therapeutic use , Drug Administration Schedule , Drug Monitoring/methods , Female , Gastrointestinal Diseases/blood , Humans , Male , Nausea/blood , Nausea/chemically induced , Sex Characteristics
4.
Med Trop (Mars) ; 61(1): 56-8, 2001.
Article in English | MEDLINE | ID: mdl-11584657

ABSTRACT

Since the eighties, the Australian Defence Force has deployed soldiers in malaria-endemic areas: Cambodia, Somalia, Rwanda, Bougainville, and East Timor. Currently, doxycycline is used as first line prophylactic drug and mefloquine is recommended for those who cannot tolerate the antibiotic. In 1998, the Australian Defence Force participated in the evaluation of tafenoquine for prophylaxis of both falciparum and vivax malaria in Thai soldiers. At the completion of this six-month study, 29 of 205 soldiers had come down with malaria including eight with falciparum malaria, 20 with vivax malaria, and one with mixed infection. A total of 28 of the 101 soldiers in the placebo group were infected with malaria as compared with only one of the 104 soldiers in the tafenoquine group. In 1999, another study was started on the island of Bougainville to compare the effectiveness a 3-day course of tafenoquine and a 14-day course of primaquine for radical cure of vivax malaria. At the present time, 411 soldiers have completed the study including 201 in tafenoquine arm and 210 in primaquine arm. Seven soldiers in each arm developed vivax malaria after returning to Australia. These results indicate that tafenoquine is not superior to primaquine in preventing vivax malaria. However study participants preferred the shorter course using tafenoquine and operationally it was found to be more suitable than primaquine.


Subject(s)
Antimalarials/therapeutic use , Malaria/drug therapy , Malaria/prevention & control , Military Personnel , Aminoquinolines/therapeutic use , Australia , Controlled Clinical Trials as Topic , Endemic Diseases , Humans , Malaria/epidemiology , Malaria, Falciparum/drug therapy , Malaria, Falciparum/prevention & control , Malaria, Vivax/drug therapy , Malaria, Vivax/prevention & control , Primaquine/therapeutic use
5.
Aust J Exp Biol Med Sci ; 56(4): 493-7, 1978 Aug.
Article in English | MEDLINE | ID: mdl-728004

ABSTRACT

On the isolated, perfused rabbit ear artery methysergide 10(-9) mol.1(-1) only potentiated the constrictor response to serotonin while at a concentration of 2.5 x 10(-8) mol.1(-1) it only blocked the response. At an intermediate concentration (2.5 x 10(-9) mol.1(-1)) it produced initial potentiation followed by subsequent blockade. In contrast, at all three concentrations it only potentiated the constrictor response to noradrenaline. The results thus show that methysergide can exert a dual effect on the constrictor response to serotonin with the actual effect produced being dependent not only on the concentration of methysergide used but also on the period of time the artery is exposed to methysergide.


Subject(s)
Arteries/physiology , Methysergide/pharmacology , Serotonin/pharmacology , Vasoconstriction/drug effects , Animals , Ear/blood supply , In Vitro Techniques , Norepinephrine/pharmacology , Rabbits
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