Exploring the anthelmintic properties of Australian native shrubs with respect to their potential role in livestock grazing systems

We measured in vitro anthelmintic activity in extracts from 85 species of Australian native shrub, with a view to identifying species able to provide a degree of worm control in grazing systems. Approximately 40% of the species showed significant activity in inhibiting development of Haemonchus contortus larvae. The most active extracts showed IC50 values of 60–300 mg/ml. Pre-incubation with polyvinylpolypyrrolidine removed the activity from some extracts, implicating tannins as the bioactive agent, while in other cases the pre-incubation had no effect, indicating the presence of other anthelmintic compounds. Plant reproductive maturity (onset of flowering or fruiting) was associated with increasing anthelmintic activity in some species. Variability was observed between plants of the same species growing in different environments, while variation between individual plants of the same species within a single field suggests the existence of distinct chemotypes. Significant activity against adult H. contortus worms in vitro was also demonstrated in a limited number of extracts tested against this life stage. Our study indicates that there is potential for Australian native shrubs to play an anthelmintic role in grazing systems, and highlights some plant biology factors which will need to be considered in order to maximize any anthelmintic effects.A. C. Kotze, J. O’Grady, J. Emms, A. F. Toovey, S. Hughes, P. Jessop, M. Bennell P. E. Vercoe and D. K. Revel

The safety of artemisinins during pregnancy: a pressing question

BACKGROUND: An increasing number of countries in sub-Saharan Africa are changing to artemisinins combination therapy (ACT) as first or second line treatment for malaria. There is an urgent need to assess the safety of these drugs in pregnant women who may be inadvertently exposed to or actively treated with ACTs. OBJECTIVES: To examine existing published evidence on the relationship between artemisinin compounds and adverse pregnancy outcomes and consider the published evidence with regard to the safety of these compounds when administered during pregnancy. METHODS: Studies on ACT use in pregnancy were identified via searches of MEDLINE, EMBASE, Cochrane and Current Contents databases. Data on study characteristics, maternal adverse events, pregnancy outcomes and infant follow up were extracted. RESULTS: Fourteen relevant studies (nine descriptive/case reports and five controlled trials) were identified. Numbers of participants in these studies ranged from six to 461. Overall there were reports on 945 women exposed to an artemisinin during pregnancy, 123 in the 1st trimester and 822 in 2nd or 3rd trimesters. The primary end points for these studies were drug efficacy and parasite clearance. Secondary endpoints were birth outcomes including low birth weight, pre-term birth, pregnancy loss, congenital anomalies and developmental milestones. While none of the studies found evidence for an association between the use of artemisinin compounds and increased risk of adverse pregnancy outcomes, none were of sufficient size to detect small differences in event rates that could be of public health importance. Heterogeneity between studies in the artemisinin and comparator drugs used, and in definitions of adverse pregnancy outcomes, limited any pooled analysis. CONCLUSION: The limited data available suggest that artemisinins are effective and unlikely to be cause of foetal loss or abnormalities, when used in late pregnancy. However, none of these studies had adequate power to rule out rare serious adverse events, even in 2(nd )and 3(rd )trimesters and there is not enough evidence to effectively assess the risk-benefit profile of artemisinin compounds for pregnant women particularly for 1(st )trimester exposure. Methodologically rigorous, larger studies and post-marketing pharmacovigilance are urgently required

Examination of the Cytotoxic and Embryotoxic Potential and Underlying Mechanisms of Next-Generation Synthetic Trioxolane and Tetraoxane Antimalarials

Semisynthetic artemisinin-based therapies are the first-line treatment for P. falciparum malaria, but next-generation synthetic drug candidates are urgently required to improve availability and respond to the emergence of artemisinin-resistant parasites. Artemisinins are embryotoxic in animal models and induce apoptosis in sensitive mammalian cells. Understanding the cytotoxic propensities of antimalarial drug candidates is crucial to their successful development and utilization. Here, we demonstrate that, similarly to the model artemisinin artesunate (ARS), a synthetic tetraoxane drug candidate (RKA182) and a trioxolane equivalent (FBEG100) induce embryotoxicity and depletion of primitive erythroblasts in a rodent model. We also show that RKA182, FBEG100 and ARS are cytotoxic toward a panel of established and primary human cell lines, with caspase-dependent apoptosis and caspase-independent necrosis underlying the induction of cell death. Although the toxic effects of RKA182 and FBEG100 proceed more rapidly and are relatively less cell-selective than that of ARS, all three compounds are shown to be dependent upon heme, iron and oxidative stress for their ability to induce cell death. However, in contrast to previously studied artemisinins, the toxicity of RKA182 and FBEG100 is shown to be independent of general chemical decomposition. Although tetraoxanes and trioxolanes have shown promise as next-generation antimalarials, the data described here indicate that adverse effects associated with artemisinins, including embryotoxicity, cannot be ruled out with these novel compounds, and a full understanding of their toxicological actions will be central to the continuing design and development of safe and effective drug candidates which could prove important in the fight against malaria

The position of mefloquine as a 21st century malaria chemoprophylaxis

BACKGROUND: Malaria chemoprophylaxis prevents the occurrence of the symptoms of malaria. Travellers to high-risk Plasmodium falciparum endemic areas need an effective chemoprophylaxis. METHODS: A literature search to update the status of mefloquine as a malaria chemoprophylaxis. RESULTS: Except for clearly defined regions with multi-drug resistance, mefloquine is effective against the blood stages of all human malaria species, including the recently recognized fifth species, Plasmodium knowlesi. New data were found in the literature on the tolerarability of mefloquine and the use of this medication by groups at high risk of malaria. DISCUSSION: Use of mefloquine for pregnant women in the second and third trimester is sanctioned by the WHO and some authorities (CDC) allow the use of mefloquine even in the first trimester. Inadvertent pregnancy while using mefloquine is not considered grounds for pregnancy termination. Mefloquine chemoprophylaxis is allowed during breast-feeding. Studies show that mefloquine is a good option for other high-risk groups, such as long-term travellers, VFR travellers and families with small children. Despite a negative media perception, large pharmaco-epidemiological studies have shown that serious adverse events are rare. A recent US evaluation of serious events (hospitalization data) found no association between mefloquine prescriptions and serious adverse events across a wide range of outcomes including mental disorders and diseases of the nervous system. As part of an in-depth analysis of mefloquine tolerability, a potential trend for increased propensity for neuropsychiatric adverse events in women was identified in a number of published clinical studies. This trend is corroborated by several cohort studies that identified female sex and low body weight as risk factors. CONCLUSION: The choice of anti-malarial drug should be an evidence-based decision that considers the profile of the individual traveller and the risk of malaria. Mefloquine is an important, first-line anti-malarial drug but it is crucial for prescribers to screen medical histories and inform mefloquine users of potential adverse events. Careful prescribing and observance of contraindications are essential. For some indications, there is currently no replacement for mefloquine available or in the pipeline

Special infectious disease risks of expatriates and long-term travelers in tropical countries. Part II: Infections other than malaria

The definitive version is available at www3.interscience.wiley.comA wide range of viral, bacterial, and protozoal diseases pose risk to long-term tropical travelers. Risk varies geographically and with lifestyle. For some infections, risk increases with duration of stay, coming to resemble that of the local population. Risk management strategies include vaccination, chemoprophylaxis, avoidance measures, and screening, where appropriate. Vaccination against hepatitis A and B, typhoid, and rabies is recommended for all long-term travelers to (sub-)tropical areas. Lowering of the vaccination threshold for Japanese encephalitis is suggested. Meningococcal disease is rare in travelers, but vaccination is safe and acceptable. The efficacy of Bacillus Calmette-Guérin (BCG) is uncertain; immunological testing avoids BCG's confounding of tuberculin testing. Diarrhea is common, and self-treatment may be recommended. Sexually transmitted infections including human immunodeficiency virus (HIV) are serious risks; education, screening, and HIV postexposure prophylaxis following involuntary exposure are recommended. Many infections are chronic or asymptomatic, and appropriate screening is recommended on return or after prolonged exposure

Special infectious disease risks of expatriates and long-term travelers in tropical countries. Part I: malaria

The definitive version is available at www3.interscience.wiley.comMalaria risk is dependent upon the entomological inoculation rate actually faced by the long-term traveler. Risk is cumulative, increases with duration of exposure, is greatest in rural and periurban areas, and least in urban centers. Risk may be zero in some urban centers, especially during dry seasons. Chemoprophylaxis compliance is hindered by the high adverse event rate often reported by users, is often suboptimal in expatriates, and decreases with duration of stay. Compliance with personal protection measures may also be suboptimal, and use of insecticide-treated nets and effective repellents should be encouraged. Alternative strategies to mitigate risk include seasonal chemoprophylaxis, nonuse of chemoprophylaxis with rapid treatment, self-testing, self-treatment where competent care and quality drugs are unavailable, and vector control. Choice of strategies will depend upon assessment of actual risk and likely compliance, with a combination of measures usually appropriate

Four week repeatability of daily and one hour methane production of mature merino wethers fed 'ad libitum'

Daily methane production (DMP) and 1-hour methane production (1-h MP) were measured twice, 4 weeks apart, on Merino wethers fed 'ad libitum'. This study aimed to determine the 4-week repeatability of DMP and 1-h MP as well as determine how well 1-h MP predicts DMP. After a 4-week interval, the repeatability of DMP was 0.49, while the repeatability of 1-h MP was 0.24. The correlation between DMP and 1-h MP was 0.56 for the first measurement and 0.66 for the second. It was estimated that the mean of 3 independent 1-hour measurements would be at least as repeatable as the DMP measurement. A 1-h MP measurement is a moderate predictor of DMP when sheep are fed 'ad libitum', which may occur during generous grazing conditions, and thus using 1-h MP as tool to select animals for low methane production may be feasible

Genetic and environmental variation in methane emissions of sheep at pasture

A total of 2,600 methane (CH4) and 1,847 CO2 measurements of sheep housed for 1 h in portable accumulation chambers (PAC) were recorded at 5 sites from the Australian Sheep CRC Information Nucleus, which was set up to test leading young industry sires for an extensive range of current and novel production traits. The final validated dataset had 2,455 methane records from 2,279 animals, which were the progeny of 187 sires and 1,653 dams with 7,690 animals in the pedigree file. The protocol involved rounding up animals from pasture into a holding paddock before the first measurement on each day and then measuring in groups of up to 16 sheep over the course of the day. Methane emissions declined linearly (with different slopes for each site) with time since the sheep were drafted into the holding area