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

Epileptogenic potential of mefloquine chemoprophylaxis: a pathogenic hypothesis

<p>Abstract</p> <p>Background</p> <p>Mefloquine has historically been considered safe and well-tolerated for long-term malaria chemoprophylaxis, but prescribing it requires careful attention in order to rule out contraindications to its use. Contraindications include a history of certain neurological conditions that might increase the risk of seizure and other adverse events. The precise pathophysiological mechanism by which mefloquine might predispose those with such a history to seizure remains unclear.</p> <p>Presentation of the hypothesis</p> <p>Studies have demonstrated that mefloquine at doses consistent with chemoprophylaxis accumulates at high levels in brain tissue, which results in altered neuronal calcium homeostasis, altered gap-junction functioning, and contributes to neuronal cell death. This paper reviews the scientific evidence associating mefloquine with alterations in neuronal function, and it suggests the novel hypothesis that among those with the prevalent EPM1 mutation, inherited and mefloquine-induced impairments in neuronal physiologic safeguards might increase risk of GABAergic seizure during mefloquine chemoprophylaxis.</p> <p>Testing and implications of the hypothesis</p> <p>Consistent with case reports of tonic-clonic seizures occurring during mefloquine chemoprophylaxis among those with family histories of epilepsy, it is proposed here that a new contraindication to mefloquine use be recognized for people with EPM1 mutation and for those with a personal history of myoclonus or ataxia, or a family history of degenerative neurologic disorder consistent with EPM1. Recommendations and directions for future research are presented.</p

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

The cost of uncomplicated childhood fevers to Kenyan households: implications for reaching international access targets

BACKGROUND: Fever is the clinical hallmark of malaria disease. The Roll Back Malaria (RBM) movement promotes prompt, effective treatment of childhood fevers as a key component to achieving its optimistic mortality reduction goals by 2010. A neglected concern is how communities will access these new medicines promptly and the costs to poor households when they are located in rural areas distant to health services. METHODS: We assemble data developed between 2001 and 2002 in Kenya to describe treatment choices made by rural households to treat a child's fever and the related costs to households. Using a cost-of-illness approach, we estimate the expected cost of a childhood fever to Kenyan households in 2002. We develop two scenarios to explore how expected costs to households would change if more children were treated at a health care facility with an effective antimalarial within 48 hours of fever onset. RESULTS: 30% of uncomplicated fevers were managed at home with modern medicines, 38% were taken to a health care facility (HCF), and 32% were managed at home without the use of modern medicines. Direct household cash expenditures were estimated at $0.44 per fever, while the total expected cost to households (cash and time) of an uncomplicated childhood fever is estimated to be$1.91. An estimated mean of 1.42 days of caretaker time devoted to each fever accounts for the majority of household costs of managing fevers. The aggregate cost to Kenyan households of managing uncomplicated childhood fevers was at least $96 million in 2002, equivalent to 1.00$1.86 because caretakers also save time with prompt treatment if the child has malaria. CONCLUSION: The management of uncomplicated childhood fevers imposes substantial costs on Kenyan households. Achieving substantial improvements in the numbers of fevers treated within 48 hours at a HCF with an effective antimalarial drug (Scenario 1) will not impose additional costs on households. Achieving additional improvements in fevers treated promptly at a HCF (Scenario 2) will impose additional costs on some households roughly equal to average cash expenses for transportation to a HCF. Additional financing mechanisms that further reduce the costs of accessing care at a HCF and/or that make artemisinin-based combination therapies (ACTs) accessible for home management need to be developed and evaluated as a top priority

Recent Advances in the Diagnosis and Treatment of Influenza Pneumonia

A potentially fatal complication of influenza infection is the development of pneumonia, caused either directly by the influenza virus, or by secondary bacterial infection. Pneumonia related to the 2009 influenza A pandemic was found to be underestimated by commonly used pneumonia severity scores in many cases, and to be rapidly progressive, leading to respiratory failure. Confirmation of etiology by laboratory testing is warranted in such cases. Rapid antigen and immunofluorescence testing are useful screening tests, but have limited sensitivity. Confirmation of pandemic H1N1 influenza A infection can only be made by real-time reverse-transcriptase polymerase chain reaction (rRT-PCR) or viral culture. The most effective preventive measure is annual influenza vaccination in selected individuals. Decisions to administer antiviral medications for influenza treatment or chemoprophylaxis should be based upon clinical and epidemiological factors, and should not be delayed by confirmatory laboratory testing results. Neuraminidase inhibitors (NI) are the agents of choice

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

Estimating the malaria risk of African mosquito movement by air travel

BACKGROUND: The expansion of global travel has resulted in the importation of African Anopheles mosquitoes, giving rise to cases of local malaria transmission. Here, cases of 'airport malaria' are used to quantify, using a combination of global climate and air traffic volume, where and when are the greatest risks of a Plasmodium falciparum-carrying mosquito being importated by air. This prioritises areas at risk of further airport malaria and possible importation or reemergence of the disease. METHODS: Monthly data on climate at the World's major airports were combined with air traffic information and African malaria seasonality maps to identify, month-by-month, those existing and future air routes at greatest risk of African malaria-carrying mosquito importation and temporary establishment. RESULTS: The location and timing of recorded airport malaria cases proved predictable using a combination of climate and air traffic data. Extending the analysis beyond the current air network architecture enabled identification of the airports and months with greatest climatic similarity to P. falciparum endemic regions of Africa within their principal transmission seasons, and therefore at risk should new aviation routes become operational. CONCLUSION: With the growth of long haul air travel from Africa, the identification of the seasonality and routes of mosquito importation is important in guiding effective aircraft disinsection and vector control. The recent and continued addition of air routes from Africa to more climatically similar regions than Europe will increase movement risks. The approach outlined here is capable of identifying when and where these risks are greatest

Travel risk behaviours and uptake of pre-travel health preventions by university students in Australia

<p>Abstract</p> <p>Background</p> <p>Forward planning and preventative measures before travelling can significantly reduce the risk of many vaccine preventable travel-related infectious diseases. Higher education students may be at an increased risk of importing infectious disease as many undertake multiple visits to regions with higher infectious disease endemicity. Little is known about the health behaviours of domestic or international university students, particularly students from low resource countries who travel to high-resource countries for education. This study aimed to assess travel-associated health risks and preventative behaviours in a sample of both domestic and international university students in Australia.</p> <p>Methods</p> <p>In 2010, a 28 item self-administered online survey was distributed to students enrolled at the University of New South Wales, Sydney, Australia. Multiple methods of distributing links to the online survey were utilised. The survey examined the international travel history, travel intentions, infection control behaviours and self-reported vaccination history.</p> <p>Results</p> <p>A total of 1663 respondents completed the online survey, 22.1% were international students and 83.9% were enrolled at an undergraduate level. Half had travelled internationally in the previous 12 months, with 69% of those travelling only once during that time with no difference in travel from Australia between domestic and international students (<it>p </it>= 0.8). Uptake of pre-travel health advice was low overall with 68% of respondents reporting they had not sought any advice from a health professional prior to their last international trip. Domestic students were more likely to report uptake of a range of preventative travel health measures compared to international students, including diarrhoeal medication, insect repellent, food avoidance and condoms (<it>P </it>< 0.0001). Overall, students reported low risk perception of travel threats and a low corresponding concern for these threats.</p> <p>Conclusions</p> <p>Our study highlights the need to educate students about the risk associated with travel and improve preventative health-seeking and uptake of precautionary health measures in this highly mobile young adult population. Although immunisation is not an entry requirement to study at Universities in Australia, large tertiary institutions provide an opportunity to engage with young adults on the importance of travel health and provision of vaccines required for travel, including missed childhood vaccines.</p