Concealed for a Long Time on the Marches of Empires: Hepatitis B Virus Genotype I.

Genotype I, the penultimate HBV genotype to date, was granted the status of a bona fide genotype only in the XXIst century after some hesitations. The reason for these hesitations was that genotype I is a complex recombinant virus formed with segments from three original genotypes, A, C, and G. It was estimated that genotype I is responsible for only an infinitesimal fraction (<1.0%) of the chronic HBV infection burden worldwide. Furthermore, most probably due to its recent discovery and rarity, the natural history of infection with genotype I is poorly known in comparison with those of genotypes B or C that predominate in their area of circulation. Overall, genotype I is a minor genotype infecting ethnic minorities. It is endemic to the Southeast Asian Massif or Eastern Zomia, a vast mountainous or hilly region of 2.5 million km2 spreading from Eastern India to China, inhabited by a little more than 100 million persons belonging primarily to ethnic minorities speaking various types of languages (Tibeto-Burman, Austroasiatic, and Tai-Kadai) who managed to escape the authority of central states during historical times. Genotype I consists of two subtypes: I1, present in China, Laos, Thailand, and Vietnam; and I2, encountered in India, Laos, and Vietnam.

Estimating the burden of hepatitis B virus infection in Laos between 2020 and 2021: A cross-sectional seroprevalence survey.

Background: Laos is considered highly endemic for persistent infection with hepatitis B virus (HBV). To eliminate this burden, it has gradually implemented universal anti-hepatitis B immunisation of newborns over the past two decades. Methods: Using VIKIA® HBsAg, a rapid test for the qualitative detection of the HBV surface antigen, we conducted between Sep 1st, 2020 and Aug 31st, 2021 the largest prospective prevalence survey ever in Laos. This survey included blood donors (BD, n = 42,277), patients attending care in capital and provincial hospitals (n = 37,347) including attending mothers (n = 20,548), HIV-infected patients (n = 7439, recruited from 2009 to 2020), students from the Health Sciences University (n = 609), and outpatients (n = 350) coming for diagnosis at the Center Infectiology Lao-Christophe Mérieux in Vientiane. In total, 88,022 persons were tested, representing approximately 1.22% of the national population. To reach a reasonable estimate of HBsAg prevalence in Laos, we segmented the population according to three variables, age (≤20 years as a cut-off), sex, and geographical origin. BD values were used to estimate HBsAg prevalence in patients aged <20 while hospital survey prevalence was used to estimate the prevalence in those aged older than 20 years. Findings: We observed an HBsAg seroprevalence ranging from 2.6% in blood donors to 8.0% in HIV-infected patients. In BD, men were significantly more at risk to be carriers than women (RR = 1.2, P = 0.00063). For BD, attending mothers, or HIV-infected patients, HBsAg was significantly more prevalent in northern Laos (5.1-8.4%) than in central (2.0-8.1%) or southern parts of the country (2.2-6.9%), thereby delineating a North-to-South gradient. Interpretation: We considered that HBsAg prevalence probably ranges between 5.0% and 6.0% of the total population. Thus, we consider that Laos may no longer be highly endemic for chronic HBV infection but rather a country with intermediate endemicity. Funding: The funding sources were the Agence Universitaire de la Francophonie, the French Government, the French Institute for Sustainable Development (IRD), and European Union's Horizon 2020 Marie Sklodowska-Curie Actions (MSCA) - Research and Innovation Staff Exchange - (RISE) under grant agreement N° 823935.

Exposure assessment of 170 pesticide ingredients and derivative metabolites in people from the Central Andes of Peru.

The Central Andes of Peru are a region of great concern regarding pesticide risk to the health of local communities. Therefore, we conducted an observational study to assess the level of pesticide contamination among Andean people. Analytical chemistry methods were used to measure the concentrations of 170 pesticide-related compounds in hair samples from 50 adult Andean subjects living in rural and urban areas. As part of the study, a questionnaire was administered to the subjects to collect information regarding factors that increase the risk of pesticide exposure. Our results indicate that Andean people are strongly exposed to agrochemicals, being contaminated with a wide array of pesticide-related compounds at high concentration levels. Multivariate analyses and geostatistical modeling identified sociodemographic factors associated with rurality and food origin that increase pesticide exposure risk. The present study represents the first comprehensive investigation of pesticide-related compounds detected in body samples collected from people living in the Central Andes of Peru. Our findings pinpoint an alarming environmental situation that threatens human health in the region and provide a rationale for improving public policies to protect local communities.

Cáncer de hígado: ¿Antigua o nueva amenaza para los jóvenes de países en vía de desarrollo?

Entre las neoplasias malignas más frecuentes del mundo, el carcinoma hepatocelular (CHC) es la segunda causa de muerte relacionada con el cáncer (1). Su incidencia se ha duplicado durante las dos últimas décadas y la mayor carga se produce en los países de ingresos bajos y medianos. Los tumores hepáticos primarios malignos suelen describirse como una patología que afecta principalmente a hombres mayores de 40 años con un hígado cirrótico; rara vez se han registrado en personas más jóvenes y normalmente, en menores de 40, lo más común es el hepatoblastoma

Zootherapeutic uses of animals excreta: the case of elephant dung and urine use in Sayaboury province, Laos.

BACKGROUND: Despite a widespread aversion towards faeces and urine, animal excreta are used in traditional medicine in many countries since centuries, but records are scattered and few therapeutic uses have been accurately documented while in the current context of emerging zoonoses such records may be of major interest. METHODOLOGY: In this study, we investigated the therapeutic uses that mahouts in Xayaboury province, Lao PDR make of elephant urine and faeces as well as of the brood chamber that beetles (Heliocopris dominus) fashion from elephant dung. Semi-structured interviews were conducted with mahouts on elephant diet, health problems and responses to disease, andwhether they use elephant products. Data were supplemented by interviews with traditional healers. RESULTS: Seven respondents reported the use of elephant urine in ethnoveterinary care for elephants and in human medicine in case of diabetes and otitis. 25 respondents reported therapeutic use of elephant faeces (EF) and elephant dung beetle brood chambers. The major indications are gastrointestinal and skin problems. Macerations or decoctions are drunk or used externally as a lotion. The mahouts attribute the therapeutic effectiveness of EFs to their content which includes the remains of many species from the elephant diet which they consider to be medicinal. DISCUSSION: The indications of these uses are consistent with pharmacological and clinical studies highlighting the properties of different animals' urine and faeces and their curative potential tested in vivo. The acknowledgement by the mahouts of medicinal properties of elephant faecal bolus contrasts with the rare justifications of animal material use recorded in zootherapeutic studies, which falls within the symbolic domain. However, numerous studies highlight the preponderant role of the microbiota in physiological processes, raising the hypothesis of a curative action of EF, by rebalancing the user's microbiota. CONCLUSION: The therapeutic uses of EF preparations despite their possible curative properties are a potential source of zoonotic transmission from elephants to humans. In the current context of globalisation of trade which favours the emergence of zoonoses and in relation with the issue of One Health, it becomes crucial to further document the zootherapeutic practices to prevent emerging diseases. As elephants and local related ethnoethological knowledge are threatened, documenting them is urgent to contribute to their preservation.

Mosquito metabolomics reveal that dengue virus replication requires phospholipid reconfiguration via the remodeling cycle.

Dengue virus (DENV) subdues cell membranes for its cellular cycle by reconfiguring phospholipids in humans and mosquitoes. Here, we determined how and why DENV reconfigures phospholipids in the mosquito vector. By inhibiting and activating the de novo phospholipid biosynthesis, we demonstrated the antiviral impact of de novo-produced phospholipids. In line with the virus hijacking lipids for its benefit, metabolomics analyses indicated that DENV actively inhibited the de novo phospholipid pathway and instead triggered phospholipid remodeling. We demonstrated the early induction of remodeling during infection by using isotope tracing in mosquito cells. We then confirmed in mosquitoes the antiviral impact of de novo phospholipids by supplementing infectious blood meals with a de novo phospholipid precursor. Eventually, we determined that phospholipid reconfiguration was required for viral genome replication but not for the other steps of the virus cellular cycle. Overall, we now propose that DENV reconfigures phospholipids through the remodeling cycle to modify the endomembrane and facilitate formation of the replication complex. Furthermore, our study identified de novo phospholipid precursor as a blood determinant of DENV human-to-mosquito transmission.

Alsinol, an arylamino alcohol derivative active against Plasmodium, Babesia, Trypanosoma, and Leishmania: past and new outcomes.

Malaria, babesiosis, trypanosomosis, and leishmaniasis are some of the most life-threatening parasites, but the range of drugs to treat them is limited. An effective, safe, and low-cost drug with a large activity spectrum is urgently needed. For this purpose, an aryl amino alcohol derivative called Alsinol was resynthesized, screened in silico, and tested against Plasmodium, Babesia, Trypanosoma, and Leishmania. In silico Alsinol follows the Lipinski and Ghose rules. In vitro it had schizontocidal activity against Plasmodium falciparum and was able to inhibit gametocytogenesis; it was particularly active against late gametocytes. In malaria-infected mice, it showed a dose-dependent activity similar to chloroquine. It demonstrated a similar level of activity to reference compounds against Babesia divergens, and against promastigotes, and amastigotes stages of Leishmania in vitro. It inhibited the in vitro growth of two African animal strains of Trypanosoma but was ineffective in vivo in our experimental conditions. It showed moderate toxicity in J774A1 and Vero cell models. The study demonstrated that Alsinol has a large spectrum of activity and is potentially affordable to produce. Nevertheless, challenges remain in the process of scaling up synthesis, creating a suitable clinical formulation, and determining the safety margin in preclinical models.

Forest Fevers: traditional treatment of malaria in the southern lowlands of Laos.

ETHNOPHARMACOLOGICAL RELEVANCE: Malaria is still a highly challenging public health issue in southern Lao PDR, with increasing cases of artemisinin resistance and Plasmodium vivax infections which are more complicated to treat. Traditional medicine has a long history of use in Laos, and is primarily practised by traditional village healers, who possess unique bodies of transmitted knowledge focused on herbal prescriptions, including those for the treatment of malaria. Villagers also use plants for healthcare in the home. The aim of the study is to document local fever concepts and use of herbal remedies, and examine whether they may have potential as complementary treatments against malaria. MATERIALS AND METHODS: The study took place in Champasak province in the far south of Laos, in primarily lowland areas. First, 35 traditional healers across the 10 districts of the province were interviewed to elicit details about knowledge and treatment of fevers. Second, a household survey was conducted in a village in a malaria-endemic area; 97 households were interviewed on fever incidence, differentiation, treatment-seeking behaviour and knowledge of plant-based remedies for fevers. Plants indicated by both healers and villagers were collected and voucher specimens deposited in the herbarium of the National University of Laos for identification. RESULTS: Malaria is a well-known pathology among the healers and villagers of lowland Champasak province; biomedical treatments are preferentially used, but traditional medicine is a popular complementary method, especially in chronic cases with additional symptoms. 30 different fever types were recorded, which were usually named symptomatically, and grouped into 12 categories. Some were described as forms of malaria, which was conceived as a dynamic, changing pathology affecting many body systems. Healers formulate treatments based on symptoms and the person's constitution, and with the intention of creating specific pharmacological actions associated with temperature or flavours. 11 of the healers gave prescriptions for malaria (27 in total), including 47 identified plant species. The most-used plants (4 or more use-reports) were also the most cited in the literature for use against malaria, demonstrating a correspondence between Lao healers and other traditional medical systems. Furthermore, some of these species show promising results for future research, especially Amorphophallus paeniifolius (Dennst.) Nicolson and Alocasia macrorrhizos (L.) G. Don. CONCLUSION: Traditional healers are important actors in the treatment of malaria in southern Laos, and herbal remedies should be evaluated further by the use of reverse treatment outcome trials, especially those which may be of use as complementary remedies in treating P. vivax. Initiatives on knowledge transmission, medicinal plant conservation and healthcare integration are also urgently needed.

Comparison of the antimalarial activity of a Colombian traditional Uitoto remedy with laboratory preparations.

BACKGROUND & OBJECTIVES: In Colombian Amazonia, Uitoto indigenous people use a preparation of Curarea toxicofera (Menispermaceae) to prevent and treat malaria. To open the way for the production of a standardized herbal remedy, we compared the activity of the traditional preparation with laboratory preparations. METHODS: People were interviewed on their mode of use and preparation of what is considered the best remedy against fevers in this area. The herbal remedy was prepared according to the healer's recommendations. The plant was also submitted to continuous distillation and percolation extraction. The preparations were then tested against Plasmodium falciparum, in vitro. Traditional preparation and extract obtained by percolation were tested on Plasmodium berghei infected mice. Chemical profiles were also explored by thin-layer chromatography. RESULTS: Yields of extraction were around 7% in the preparations (percolation was the most efficient). The phytochemical profile showed a mix of steroids, flavonoids and alkaloids qualitatively similar in all preparations. In vitro, the extracts showed inhibitory concentration 50 <10µg/mL: the traditional preparation was almost three times less active than laboratory preparations. In vivo, percolation was also more active than traditional preparation, inhibiting 78% of the parasite growth at 400mg/kg/day by oral route. INTERPRETATION & CONCLUSION: Pharmacological activities suggest that both the original remedy (prepared according to traditional pharmacopeia) and the extracts obtained by percolation extraction exhibit relevant antiparasitic activity. C. toxicofera should therefore be considered for the elaboration of an improved traditional medicine by implementing toxicological studies and carefully following quality control guidelines for its preparation.

Antileishmanial Compounds Isolated from Psidium Guajava L. Using a Metabolomic Approach.

With an estimated annual incidence of one million cases, leishmaniasis is one of the top five vector-borne diseases. Currently available medical treatments involve side effects, including toxicity, non-specific targeting, and resistance development. Thus, new antileishmanial chemical entities are of the utmost interest to fight against this disease. The aim of this study was to obtain potential antileishmanial natural products from Psidium guajava leaves using a metabolomic workflow. Several crude extracts from P. guajava leaves harvested from different locations in the Lao People's Democratic Republic (Lao PDR) were profiled by liquid chromatography coupled to high-resolution mass spectrometry, and subsequently evaluated for their antileishmanial activities. The putative active compounds were highlighted by multivariate correlation analysis between the antileishmanial response and chromatographic profiles of P. guajava mixtures. The results showed that the pooled apolar fractions from P. guajava were the most active (IC50 = 1.96 ± 0.47 µg/mL). Multivariate data analysis of the apolar fractions highlighted a family of triterpenoid compounds, including jacoumaric acid (IC50 = 1.318 ± 0.59 µg/mL) and corosolic acid (IC50 = 1.01 ± 0.06 µg/mL). Our approach allowed the identification of antileishmanial compounds from the crude extracts in only a small number of steps and can be easily adapted for use in the discovery workflows of several other natural products.

Dengue virus reduces AGPAT1 expression to alter phospholipids and enhance infection in Aedes aegypti.

More than half of the world population is at risk of dengue virus (DENV) infection because of the global distribution of its mosquito vectors. DENV is an envelope virus that relies on host lipid membranes for its life-cycle. Here, we characterized how DENV hijacks the mosquito lipidome to identify targets for novel transmission-blocking interventions. To describe metabolic changes throughout the mosquito DENV cycle, we deployed a Liquid chromatography-high resolution mass spectrometry (LC-HRMS) workflow including spectral similarity annotation in cells, midguts and whole mosquitoes at different times post infection. We revealed a major aminophospholipid reconfiguration with an overall early increase, followed by a reduction later in the cycle. We phylogenetically characterized acylglycerolphosphate acyltransferase (AGPAT) enzyme isoforms to identify those that catalyze a rate-limiting step in phospholipid biogenesis, the acylation of lysophosphatidate to phosphatidate. We showed that DENV infection decreased AGPAT1, but did not alter AGPAT2 expression in cells, midguts and mosquitoes. Depletion of either AGPAT1 or AGPAT2 increased aminophospholipids and partially recapitulated DENV-induced reconfiguration before infection in vitro. However, only AGPAT1 depletion promoted infection by maintaining high aminophospholipid concentrations. In mosquitoes, AGPAT1 depletion also partially recapitulated DENV-induced aminophospholipid increase before infection and enhanced infection by maintaining high aminophospholipid concentrations. These results indicate that DENV inhibition of AGPAT1 expression promotes infection by increasing aminophospholipids, as observed in the mosquito's early DENV cycle. Furthermore, in AGPAT1-depleted mosquitoes, we showed that enhanced infection was associated with increased consumption/redirection of aminophospholipids. Our study suggests that DENV regulates aminophospholipids, especially phosphatidylcholine and phosphatidylethanolamine, by inhibiting AGPAT1 expression to increase aminophospholipid availability for virus multiplication.

From plant selection by elephants to human and veterinary pharmacopeia of mahouts in Laos.

ETHNOPHARMACOLOGICAL RELEVANCE: To what extent has animal observation contributed to the development of human pharmacopeias? We approach this question here through the study of mahouts' knowledge regarding the responses by elephants to their health problems, and the human medicinal uses of plants and the care of domestic animals that result from their observations. MATERIALS AND METHODS: 32 mahouts were interviewed in Thongmyxay district and 28 at the Elephant Conservation Center in the province of Xayabury. Interviews focused on the elephants' diet, health problems, plant items they consume in particular physiological or pathological contexts and the treatments that mahouts provide them. For each plant mentioned, the part of the plant consumed and mode of preparation and administration if used by mahouts were recorded. Species samples were then collected and later identified by specialists. RESULTS: 114 species were recorded as being consumed by elephants during interviews with mahouts and forest outings with them to collect samples. Twenty species were identified as used by elephants in particular pathological conditions or physiological states. According to interviewed mahouts, the consumption of certain plants improves the health of the elephant. We observed clear convergences between the observations interpreted by the mahouts as self-medication behaviour from elephants and their own medicinal practices (for human and veterinary purposes). CONCLUSION: Beyond a mere reproduction of elephant self-medication behaviours observed, the human or veterinary medicinal cares derived from these observations are the result of complex arrangements integrating all available medicinal and conceptual resources into elaborate preparations. We recommend that mahouts' knowledge about traditional medicinal care given to elephants be further compiled, as it could have a beneficial impact on veterinary health care provided in elephant resorts and elephants' well-being.

Hmong herbal medicine and herbalists in Lao PDR: pharmacopeia and knowledge transmission.

BACKGROUND: In Lao PDR, the Hmong ethnic group has extensive knowledge about the use of medicinal plants. However, despite the importance of the Hmong pharmacopeia as a primary health care resource, no study has been undertaken to thoroughly document medicinal plant knowledge and its transmission. Objectives of this study are (i) to describe and characterize Hmong pharmacopeia, and (ii) to understand how medicinal plant knowledge is transmitted and spread among Hmong in Lao PDR, in order to assess whether this knowledge base is under threat. METHODS: In order to describe Hmong pharmacopeia, a total of 14 interlocutors were interviewed in three provinces (Bokeo, Xieng Khouang, and Vientiane), using "walk in the wood" methodology. To gain insight about knowledge transmission, semi-structured interviews were conducted with 28 people. Twenty of them were herbalists. Data analysis was performed using univariate analysis for the description of the pharmacopeia. Medicinal plant knowledge consistency was assessed through use and plant name overlapping. Answers to the semi-structured interview on knowledge transmission were analyzed qualitatively. RESULTS: Three hundred thirty-three different medicinal species were collected. The majority of uses attributed to plants were gastrointestinal conditions (22% of total use reports), gynecological conditions and sexually transmitted disease (12%), skin affections (8%), kidney and bladder problems (5%), physical traumas (5%), and aphrodisiac (or male tonics; 5%). Use convergences are more marked in the gynecological sphere, but there is a strong heterogeneity in practices and knowledge. Medicinal plant knowledge transmission is oral, gained from direct experience since childhood, matrilineal, and kept strictly within the family lineage. Apparent limited consensus on uses might stem from the method of knowledge transmission and to the economic value given to medicinal plants. DISCUSSION: Use pattern of species from the Hmong pharmacopeia does not appear to be strikingly different from the national Lao pharmacopeia. Differences may lie in the methods and reasons for knowledge transmission. It can be proposed that the economic value given to plants helps in keeping the knowledge alive, and encourages its transmission. CONCLUSION: Hmong traditional medicine is constantly evolving in a dynamic process and aims to respond to health problems faced by the local population. Herbalists appear as health fully fledged actors and should be recognized and valued as such.

On hepatocellular carcinoma in South America and early-age onset of the disease.

Hepatocellular carcinoma (HCC) is one of the most predominant tumor types worldwide, being particularly prevalent in sub-Saharan Africa and East Asia. However, HCC is inexplicably underreported in South America, despite unsettling clinical epidemiological trends of the disease on this continent. Here, we review the current knowledge on HCC presentation in Peru. We emphasize the well-documented occurrence of an early-age nosological form of the disease in Andean descent populations. We further discuss the reasons for such HCC clinical presentation, as well as the implications for liver cancer screening, management, and prevention.

Liver clear cell foci and viral infection are associated with non-cirrhotic, non-fibrolamellar hepatocellular carcinoma in young patients from South America.

We previously described a divergent clinical and molecular presentation of hepatocellular carcinoma (HCC) in Peru. The present study aimed to further characterize the tissue features associated with this singular nosological form of HCC in order to gain insight into the natural history of the disease. We performed an exploratory analysis of the histology of both tumor and non-tumor liver (NTL) tissues from 50 Peruvian HCC patients, and compared with that of 75 individuals with non-HCC liver tumor or benign liver lesions as a baseline for NTL features. We complemented this approach with a transcriptome analysis in a subset of NTL tissue samples and also performed an ultra-sensitive hepatitis B virus (HBV) detection in liver tissues of the patients. Overall, results highlighted the low rate of liver parenchymal alterations in a young patient cohort (median age: 40 years old), despite a strong prevalence of underlying HBV infection (c. 67%). Withal, liver clear cell foci of cellular alteration were genuinely associated with HCC and appended to some changes in immune and G protein-coupled receptor gene expression ontologies. Our findings confirm the occurrence of a particular setting of HCC in South America, a region where the pathophysiology of liver cancer remains largely unexplored.

Early-onset liver cancer in South America associates with low hepatitis B virus DNA burden.

In Peru, hepatocellular carcinoma (HCC) arises in young non-cirrhotic patients. Hepatitis B virus (HBV) is suspected to be the prominent etiological agent. We thus performed a comprehensive molecular study of HBV infection in 65 Peruvian HCC patients. Only 51% were considered as persistently infected at the onset. HBV DNA was found by PCR in the tumor and/or matched non-tumor liver tissues in more than 80% of cases (n = 53/65). HBV DNA was significantly more abundant in livers of younger patients than in those of the older ones. We consistently observed low viral DNA burden (0.1-6.5 copies for 100 cells), with viral genomes in younger patients displaying higher proportion of mutations at di-pyrimidines (TpT and CpC, P = 0.006). A drastic activation of multiple DNA repair pathways in tumors of younger patients was observed. Our observations clearly challenge the current vision that associates high HBV DNA load with earlier tumor development. We concluded that in Peru, and maybe in other populations with Americas' indigenous ancestry, HBV-associated liver tumorigenesis might differ significantly from that generally observed in the rest of the world. Procedures used to screen for HCC development in subjects at risk should be adapted to the local situation.

Hepatitis C in Laos: A 7-Year Retrospective Study on 1765 Patients.

Hepatitis C virus (HCV) is a global health concern, notably in Southeast Asia, and in Laos the presentation of the HCV-induced liver disease is poorly known. Our objective was thus to describe a comprehensive HCV infection pattern in order to guide national health policies. A study on a group of 1765 patients formerly diagnosed by rapid test in health centres was conducted at the Centre of Infectiology Lao Christophe Merieux in Vientiane. The demographic information of patients, their infection status (viral load: VL), liver function (aminotransferases) and treatments were analysed. Results showed that gender distribution of infected people was balanced; with median ages of 53.8 for men and 51.6 years for women (13-86 years). The majority of patients (72%) were confirmed positive (VL > 50 IU/mL) and 28% of them had high VL (> 6log10). About 23% of patients had level of aminotransferases indicative of liver damage (> 40 IU/mL); but less than 20% of patients received treatment. Patients rarely received a second sampling or medical imaging. The survey also showed that cycloferon, pegylated interferon and ribavirin were the drugs prescribed preferentially by the medical staff, without following any international recommendations schemes. In conclusion, we recommend that a population screening policy and better management of patients should be urgently implemented in the country, respecting official guidelines. However, the cost of biological analysis and treatment are significant barriers that must be removed. Public health resolutions should be immediately enforced in the perspective of meeting the WHO HCV elimination deadline by 2030.

Structure-activity relationship of new antimalarial 1-aryl-3-susbtituted propanol derivatives: Synthesis, preliminary toxicity profiling, parasite life cycle stage studies, target exploration, and targeted delivery.

Design, synthesis, structure-activity relationship, cytotoxicity studies, in silico drug-likeness, genotoxicity screening, and in vivo studies of new 1-aryl-3-substituted propanol derivatives led to the identification of nine compounds with promising in vitro (55, 56, 61, 64, 66, and 70-73) and in vivo (66 and 72) antimalarial profiles against Plasmodium falciparum and Plasmodium berghei. Compounds 55, 56, 61, 64, 66 and 70-73 exhibited potent antiplasmodial activity against chloroquine-resistant strain FCR-3 (IC50s < 0.28 µM), and compounds 55, 56, 64, 70, 71, and 72 showed potent biological activity in chloroquine-sensitive and multidrug-resistant strains (IC50s < 0.7 µM for 3D7, D6, FCR-3 and C235). All of these compounds share appropriate drug-likeness profiles and adequate selectivity indexes (77 < SI < 184) as well as lack genotoxicity. In vivo efficacy tests in a mouse model showed compounds 66 and 72 to be promising candidates as they exhibited significant parasitemia reductions of 96.4% and 80.4%, respectively. Additional studies such as liver stage and sporogony inhibition, target exploration of heat shock protein 90 of P. falciparum, targeted delivery by immunoliposomes, and enantiomer characterization were performed and strongly reinforce the hypothesis of 1-aryl-3-substituted propanol derivatives as promising antimalarial compounds.

A Seven-Year Retrospective Study on the Surveillance of Hepatitis B in Laos.

OBJECTIVE: Lao PDR is one of the most highly endemic countries for hepatitis B in Asia and the second country for liver cancer incidence. Therefore, the follow-up of infected individuals through predictive serological markers is of utmost importance to monitor the progression of the pathology and take the decision on treatment. METHODS: A retrospective-descriptive cohort study was conducted on 3,857 HBV-infected patients. Information about infection status (viral load, VL), liver function (aminotransferases), and treatments was recorded. RESULTS: M/F sex ratio was 1.77 for a median age of 37. Patients under 37 displayed higher VL than older ones and men had higher VL than women. Initial VL ranged from <50 IU/mL to 2.5 1013 IU/mL. Median aminotransferase values were 45.5 U/L for ALAT and 44 U/L for ASAT, ranging from <8 to >2,000 U/L. Men had higher aminotransferase than women. Globally 20% of patients received treatment (mainly immunostimulant and reverse-transcriptase inhibitors); 11% had high levels of VL and liver enzymes, but only 2% of them were treated. CONCLUSION: Public health decisions should be taken urgently to rationalise vaccination and provide fair access to early diagnosis and treatment; otherwise the burden of HBV-associated diseases will be overwhelming for Laos in the near future.

Pharmacological activity of Curarea toxicofera in combination with classical antimalarial treatments.

ETHNOPHARMACOLOGICAL RELEVANCE: In the Leticia-Amazonas area, Uitoto indigenous people use a preparation of Curarea toxicofera (Wedd) Barneby & Krukoff (Menispermaceae) alone or combined with prescribed medications to prevent and treat malaria. AIM OF STUDY: To determine the in vitro and in vivo antiplasmodial activity of traditional preparations of Curarea toxicofera alone and in combination with classical antimalarials. MATERIAL AND METHODS: The traditional preparation was evaluated in vitro against P. falciparum FCR3 CQ resistant strain, alone and combined. The preparation was further administered orally alone or combined with chloroquine and artesunate in mice infected with Plasmodium berghei ANKA strain on the four-day antimalarial test model. RESULTS: The herbal remedy used alone was able to significantly decrease the parasitemia both in vitro (IC50 7.3 µg/ml) and in vivo (ED50 328 mg/Kg) but it was less active than chloroquine (IC50 0.29 µg/ml in vitro and ED50 2.3 mg/Kg/day in vivo), and than artesunate (IC50 0.002 µg/ml and ED50 3.7 mg/Kg/day). Interestingly it presented synergism with chloroquine in vitro (Combination Index: 0.39) and in vivo; and was additive with artesunate in vitro (Combination Index: 0.94) and in vivo. CONCLUSION: The traditional preparation showed potential as an antimalarial and, when used in combination, does not negatively affect the efficacy of the drugs evaluated. Pre-clinical studies should be conducted with a standardized preparation to confirm its efficacy and safety alone and in combination with chloroquine and artesunate.