Artemether-lumefantrine co-administration with antiretrovirals: population pharmacokinetics and dosing implications

AIM

Drug–drug interactions between antimalarial and antiretroviral drugs may influence antimalarial treatment outcomes. The aim of this study was to investigate the potential drug–drug interactions between the antimalarial drugs, lumefantrine, artemether and their respective metabolites desbutyl-lumefantrine and dihydroartemisinin, and the HIV drugs efavirenz, nevirapine and lopinavir/ritonavir.

METHOD

Data from two clinical studies, investigating the influence of the HIV drugs efavirenz, nevirapine and lopinavir/ritonavir on the pharmacokinetics of the antimalarial drugs lumefantrine, artemether and their respective metabolites, in HIV infected patients were pooled and analyzed using a non-linear mixed effects modelling approach.

RESULTS

Efavirenz and nevirapine significantly decreased the terminal exposure to lumefantrine (decrease of 69.9% and 25.2%, respectively) while lopinavir/ritonavir substantially increased the exposure (increase of 439%). All antiretroviral drugs decreased the total exposure to dihydroartemisinin (decrease of 71.7%, 41.3% and 59.7% for efavirenz, nevirapine and ritonavir/lopinavir, respectively). Simulations suggest that a substantially increased artemether-lumefantrine dose is required to achieve equivalent exposures when co-administered with efavirenz (250% increase) and nevirapine (75% increase). When co-administered with lopinavir/ritonavir it is unclear if the increased lumefantrine exposure compensates adequately for the reduced dihydroartemisinin exposure and thus whether dose adjustment is required.

CONCLUSION

There are substantial drug interactions between artemether-lumefantrine and efavirenz, nevirapine and ritonavir/lopinavir. Given the readily saturable absorption of lumefantrine, the dose adjustments predicted to be necessary will need to be evaluated prospectively in malaria-HIV co-infected patients.     

Measuring allelic heterogeneity in Plasmodium falciparum by a heteroduplex tracking assay

We developed a novel Plasmodium falciparum genotyping strategy based on the heteroduplex tracking assay (HTA) method commonly used to genotype viruses. Because it can detect both sequence and size polymorphisms, we hypothesized that HTA is more sensitive than current methods. To test this hypothesis, we compared the ability of HTA and a nested polymerase chain reaction (PCR) to detect genetic diversity in 17 Thai samples. The HTA detected more MSP1 sequence variants in eight isolates (47%), less sequence variants in three isolates (18%), and an equal number of sequence variants in six isolates (35%), suggesting that HTA is equal to or more sensitive than the nested PCR. This study is a proof of concept that HTA is a sensitive allelic discrimination method able to determine genetic diversity in P. falciparum and warrants its use in studies of antimalarial drug efficacy.     

Simple immunoblot and immunohistochemical detection of Penaeus stylirostris densovirus using monoclonal antibodies to viral capsid protein expressed heterologously

Penaeus stylirostris densovirus (PstDNV), called formerly infectious hypodermal and hematopoietic necrosis virus (IHHNV), is an important shrimp pathogen which can cause mortality in the blue shrimp Penaeus (Litopenaeus) stylirostris and stunting in the whiteleg shrimp Penaeus (Litopenaeus) vannamei. Five monoclonal antibodies (MAbs) were produced against the 37 kDa capsid protein 3 (CP3) of PstDNV expressed heterologously in the form of a fusion protein with glutathione-S-transferase called GST-CP3. All MAbs belonged to the IgG2b subclass and could bind to GST-CP3 at 300 pg/spot in immunodot-blot tests. They could detect CP3 in naturally infected shrimp extracts by Western blotting and dot blotting and in shrimp tissues by immunohistochemistry without cross-reactivity to extracts from uninfected shrimps or shrimps infected with several other viruses. Although dot blot assay sensitivity was approximately 1000 times lower than that of one step PCR for PstDNV, it easily detected PstDNV infections in field samples of Penaeus monodon and Penaeus vannamei.     

Non-invasive fetal sex determination using a conventional nested PCR analysis of fetal DNA in maternal plasma

BACKGROUND: In order to provide a reliable non-invasive method for fetal sex determination in a routine setting, we evaluated the possibility of identifying the fetal Y chromosome-specific sequence in maternal plasma using conventional PCR analysis. METHODS: Fetal gender was determined in 31 pregnant women including one with a dizygotic twin pregnancy between 7 and 32 weeks of gestation using DNA extracted from 200 microl of each maternal plasma. The 198 bp SRY gene-specific sequence on Y chromosome and the 261 bp ATL1 gene-specific sequence on X chromosome were co-amplified in a multiplex nested PCR manner. The result was confirmed by routine analysis of fetal tissue obtained by invasive procedure or examination of newborns after delivery. RESULTS: The 198 bp SRY-specific sequence was detected in 15 plasma samples obtained from pregnant women carrying male fetuses. In the remaining cases bearing female fetuses, only the 261 bp ATL1 gene sequence was detected, producing 100% sensitivity and specificity of fetal sex prediction. The result was completely concordant with the conventional fetal tissue analysis and examination of the newborns after delivery. CONCLUSIONS: A conventional nested PCR analysis of maternal plasma could be used for accurate fetal gender detection and enable a reliable prospective non-invasive fetal sex determination which should enhance prenatal diagnostic options especially for sex-linked disorders.     

Symptoms of posttraumatic stress disorder and depression among children in tsunami-affected areas in southern Thailand

Context  On December 26, 2004, an undersea earthquake occurred off the northwestern coast of Sumatra, Indonesia. The tsunami that followed severely impacted all 6 southwestern provinces of Thailand, where approximately 20 000 children were directly affected. Objective  To assess trauma experiences and the prevalence of symptoms of posttraumatic stress disorder (PTSD) and depression among children in tsunami-affected provinces in southern Thailand. Design, Setting, and Participants  Population-based mental health surveys were conducted among children aged 7 to 14 years in Phang Nga, Phuket, and Krabi provinces from February 15-22, 2005 (2 months posttsunami), and September 7-12, 2005 (9 months posttsunami). Main Outcome Measures  Trauma experiences and symptoms of PTSD and depression as measured by a tsunami-modified version of the PsySTART Rapid Triage System, the UCLA PTSD Reaction Index, and the Birleson Depression Self-Rating Scale. Results  A total of 371 children (167 displaced and living in camps, 99 not displaced from villages affected by the tsunami, and 105 not displaced from unaffected villages) participated in the first survey. The prevalence rates of PTSD symptoms were 13% among children living in camps, 11% among children from affected villages, and 6% among children from unaffected villages (camps vs unaffected villages, P = .25); for depression symptoms, the prevalence rates were 11%, 5%, and 8%, respectively (P = .39). In multivariate analysis of the first assessment, having had a delayed evacuation, having felt one's own or a family member's life to have been in danger, and having felt extreme panic or fear were significantly associated with PTSD symptoms. Older age and having felt that their own or a family member's life had been in danger were significantly associated with depression symptoms. In the follow-up survey, 72% (151/210) of children from Phang Nga participated. Prevalence rates of symptoms of PTSD and depression among these children did not decrease significantly over time. Conclusions  This assessment documents the prevalence of mental health problems among children in tsunami-affected provinces in southern Thailand at 2 and 9 months posttsunami. Traumatic events experienced during the tsunami were significantly associated with symptoms of PTSD and depression. These data may be useful to target mental health services for children and may inform the design of these interventions.      

Mental health problems among adults in tsunami-affected areas in southern Thailand

Context  On December 26, 2004, an undersea earthquake occurred off the northwestern coast of Sumatra, Indonesia. The tsunami that followed severely affected all 6 southwestern provinces of Thailand, where 5395 individuals died, 2991 were unaccounted for, and 8457 were injured. Objective  To assess the prevalence of symptoms of posttraumatic stress disorder (PTSD), anxiety, and depression among individuals residing in areas affected by the tsunami in southern Thailand as part of a public health emergency response and rapid assessment. Design, Setting, and Participants  A multistage, cluster, population-based mental health survey was conducted from February 15 to 22, 2005, of random samples of displaced (n = 371) and nondisplaced persons in Phang Nga province (n = 322) and nondisplaced persons in the provinces of Krabi and Phuket (n = 368). Data were collected using an interviewer-administered questionnaire on handheld computers. A surveillance follow-up survey of the displaced persons (n = 371) and nondisplaced persons (n = 322) in Phang Na was conducted in September 2005. Main Outcomes Measures  Medical Outcomes Study-36 Short-Form Health Survey SF-36 to assess self-perceived general health, bodily pain, and social and emotional functioning; the Harvard Trauma Questionnaire to assess tsunami-specific traumatic events; and the Hopkins Checklist-25 to detect symptoms of anxiety and depression. Results  Participation rates for displaced and nondisplaced persons in the rapid assessment survey were 69% and 58%, respectively. Symptoms of PTSD were reported by 12% of displaced and 7% of nondisplaced persons in Phang Nga and 3% of nondisplaced persons in Krabi and Phuket. Anxiety symptoms were reported by 37% of displaced and 30% of nondisplaced persons in Phang Nga and 22% of nondisplaced persons in Krabi and Phuket. Symptoms of depression were reported by 30% of displaced and 21% of nondisplaced persons in Phang Nga and 10% of nondisplaced persons in Krabi and Phuket. In multivariate analysis, loss of livelihood was independently and significantly associated with symptoms of all 3 mental health outcomes (PTSD, anxiety, and depression). In the 9-month follow-up surveillance survey of 270 (73%) displaced and 250 (80%) nondisplaced participants in Phang Nga, prevalence rates of symptoms of PTSD, anxiety, and depression among displaced persons decreased to 7%, 24.8%, and 16.7%, respectively, and among nondisplaced persons, prevalence rates decreased to 2.3%, 25.9%, and 14.3%, respectively. Conclusions  Among survivors of the tsunami in southern Thailand, elevated rates of symptoms of PTSD, anxiety, and depression were reported 8 weeks after the disaster, with higher rates for anxiety and depression than PTSD symptoms. Nine months after the disaster, the rates of those reporting these symptoms decreased but were still elevated. This information is important for directing, strengthening, and evaluating posttsunami mental health needs and interventions.      

Methylene blue staining method for identification of Opisthorchis viverrini egg

Methylene blue staining method was used to distinguish O. viverrini eggs from Haplorchis taichui and Prosthodendrium molenkampi eggs. All eggs were obtained from dissected adult worms, fixed in 10% formalin, and stained with methylene blue prior to light microscopy observation. The distinct musk-melon-like texture of the O. viverini eggshell surface and the thread-like texture of H. taichui eggshell surface were recognized, while P. molenkampi eggs showed a smooth eggshell. We also evaluated the sensitivity and specificity of the method by training investigators to differentiate surface textures. After training, the investigators were randomly tested with 10 slides containing fluke eggs. The sensitivity and specificity were 95% and 95%, respectively.