Activity of oxantel pamoate monotherapy and combination chemotherapy against Trichuris muris and hookworms : revival of an old drug

BACKGROUND: It is widely recognized that only a handful of drugs are available against soil-transmitted helminthiasis, all of which are characterized by a low efficacy against Trichuris trichiura, when administered as single doses. The re-evaluation of old, forgotten drugs is a promising strategy to identify alternative anthelminthic drug candidates or drug combinations. METHODOLOGY: We studied the activity of the veterinary drug oxantel pamoate against Trichuris muris, Ancylostoma ceylanicum and Necator americanus in vitro and in vivo. In addition, the dose-effect of oxantel pamoate combined with albendazole, mebendazole, levamisole, pyrantel pamoate and ivermectin was studied against T. muris in vitro and additive or synergistic combinations were followed up in vivo. PRINCIPAL FINDINGS: We calculated an ED50 of 4.7 mg/kg for oxantel pamoate against T. muris in mice. Combinations of oxantel pamoate with pyrantel pamoate behaved antagonistically in vitro (combination index (CI) = 2.53). Oxantel pamoate combined with levamisole, albendazole or ivermectin using ratios based on their ED50s revealed antagonistic effects in vivo (CI = 1.27, 1.90 and 1.27, respectively). A highly synergistic effect (CI = 0.15) was observed when oxantel pamoate-mebendazole was administered to T. muris-infected mice. Oxantel pamoate (10 mg/kg) lacked activity against Ancylostoma ceylanicum and Necator americanus in vivo. CONCLUSIONSIGNIFICANCE: Our study confirms the excellent trichuricidal properties of oxantel pamoate. Since the drug lacks activity against hookworms it is necessary to combine oxantel pamoate with a partner drug with anti-hookworm properties. Synergistic effects were observed for oxantel pamoate-mebendazole, hence this combination should be studied in more detail. Since, of the standard drugs, albendazole has the highest efficacy against hookworms, additional investigations on the combination effect of oxantel pamoate-albendazole should be launche

Drycore Appears to Result from an Interaction between Rhizoctonia solani and Wireworm ( Agriotes ssp.)—Evidence from a 3-Year Field Survey

Drycore is an important quality deficiency in Europe especially in organic potato production and after grass clover leys. The drycore symptom is attributed to Rhizoctonia solani Kühn (teleomorph: Thanatephorus cucumeris (Frank) Donk). In the framework of a 3-year survey (2001-2003), data concerning potato quality, crop rotation, management, and site parameters were analysed from 185 potato fields. The hypothesis was tested that injuries on potatoes caused by wireworms facilitate the penetration of R. solani and favour the formation of drycore. Analysis of variance showed a significant influence of wireworm damage, seed quality, and grass clover leys in the crop on the level of drycore damage. On fields which had both a low occurrence of black scurf on the seed tubers and a low occurrence of wireworm damage at harvest, significant drycore damage was never observed. The relative risk for drycore damage on tubers was significantly higher if black scurf or wireworm damage was on the same tuber. In contrast, no higher risk for drycore was observed on tubers with slug damage. Abiotic factors like farm manure application, organic matter content, texture, and pH of the soil also had no significant influence on the level of drycore. Thus, the wounding of potatoes by wireworm could be confirmed as the major variable for drycore. The mode of action has to be clarified under controlled condition

Prevalence of intestinal protozoa infection among school-aged children on Pemba Island, Tanzania, and effect of single-dose albendazole, nitazoxanide and albendazole-nitazoxanide.

Pathogenic intestinal protozoa infections are common in school-aged children in the developing world and they are frequently associated with malabsorption syndromes and gastrointestinal morbidity. Since diagnosis of these parasites is difficult, prevalence data on intestinal protozoa is scarce. We collected two stool samples from school-aged children on Pemba Island, Tanzania, as part of a randomized controlled trial before and 3 weeks after treatment with (i) single-dose albendazole (400 mg); (ii) single-dose nitazoxanide (1,000 mg); (iii) nitazoxanide-albendazole combination (1,000 mg--400 mg), with each drug given separately on two consecutive days; and (iv) placebo. Formalin-fixed stool samples were examined for the presence of intestinal protozoa using an ether-concentration method to determine the prevalence and estimate cure rates (CRs). Almost half (48.7%) of the children were diagnosed with at least one of the (potentially) pathogenic protozoa Giardia intestinalis, Entamoeba histolytica/E. dispar and Blastocystis hominis. Observed CRs were high for all treatment arms, including placebo. Nitazoxanide showed a significant effect compared to placebo against the non-pathogenic protozoon Entamoeba coli. Intestinal protozoa infections might be of substantial health relevance even in settings where they are not considered as a health problem. Examination of a single stool sample with the ether-concentration method lacks sensitivity for the diagnosis of intestinal protozoa, and hence, care is indicated when interpreting prevalence estimates and treatment effects

The Impact of Organized Interests on Eligibility Determination: The Case of Veterans' Disability Compensation

A bureaucracy has a profound impact on public policy when it determines eligibility for government programs. Organized interest groups can increase the amount of information the target population has about the program, help applicants with their applications, and work to inform policy makers when the process is not working well. By doing these things, interest groups can affect how government programs are implemented. In this paper, we investigate the influence of veterans' interest groups on eligibility determinations in the Veterans' Disability Compensation (VDC) program across the fifty U.S. states to determine whether variations in veterans' organizations can explain why VA programs are implemented differently across the states. We find that the strength of veterans' groups affect demand for, access to, and effectiveness of the Veterans' Disability Compensation program. In states where veterans' groups have greater resources, more veterans file claims, more applications are approved, and, interestingly, the Veterans' Administration makes fewer errors in their eligibility decisions. We find no evidence, however, that the strength of veterans groups explain variation in the number of claims that are appealed, the percent of claims that are pending over 120 days, or the average disability rating given to successful claimants.Includes bibliographical reference

Switching to second-line antiretroviral therapy in resource-limited settings: comparison of programmes with and without viral load monitoring.

In high-income countries, viral load is routinely measured to detect failure of antiretroviral therapy (ART) and guide switching to second-line ART. Viral load monitoring is not generally available in resource-limited settings. We examined switching from nonnucleoside reverse transcriptase inhibitor (NNRTI)-based first-line regimens to protease inhibitor-based regimens in Africa, South America and Asia

Scalable Similarity Search for Molecular Descriptors

Similarity search over chemical compound databases is a fundamental task in the discovery and design of novel drug-like molecules. Such databases often encode molecules as non-negative integer vectors, called molecular descriptors, which represent rich information on various molecular properties. While there exist efficient indexing structures for searching databases of binary vectors, solutions for more general integer vectors are in their infancy. In this paper we present a time- and space- efficient index for the problem that we call the succinct intervals-splitting tree algorithm for molecular descriptors (SITAd). Our approach extends efficient methods for binary-vector databases, and uses ideas from succinct data structures. Our experiments, on a large database of over 40 million compounds, show SITAd significantly outperforms alternative approaches in practice.Comment: To be appeared in the Proceedings of SISAP'1

Preservice Elementary Teachers’ Beliefs about the Role of Definition in the Learning of Mathematics

Answering a call to emphasize the act of defining over the learning of definitions, we have shifted the content of a geometry course for preservice elementary teachers (PSETs) away from comparing and applying pre-written classification structures to classroom episodes centered on authoring definitions for special quadrilaterals. PSETs complete activities using geometry software, and collaboratively create definitions for specific quadrilaterals. In order to fully understand the potential of this curricular shift, we asked preservice elementary mathematics teachers’ to share their perceptions of the process of writing mathematical definitions. Data from participant reflections were analyzed for themes related to mathematical definition and the act of defining. The framework that resulted from iterative discussions by the researchers examined beliefs about the nature of definition and mathematical empathy (Araki, 2015). Findings also suggest that beliefs about authority and positioning students as authors of mathematics are associated with mathematical empathy. Experiences related to the process of defining enabled PSETs to see far greater subjectivity in the discipline of mathematics and to consider, perhaps for the first time, that they, too, were both able and deserving of becoming authors of mathematical ideas

Design, synthesis and evaluation of praziquantel analogues and new molecular hybrids as potential antimalarial and anti-schistosomal agents

Malaria and schistosomiasis are two of the neglected tropical diseases that persistently wreak havoc worldwide. Although many antimalarial drugs such as chloroquine are readily available, the emergence of drug resistance necessitates the development of new therapies to combat this disease. Conversely, Praziquantel (PZQ) remains the sole effective drug against schistosomiasis, but its extensive use raises concerns about the potential for drug resistance to develop. In this project, the concept of molecular hybridization was used as a strategy to design the synthesis of new molecular hybrids with potential antimalarial and antischistosomal activity. A total of seventeen molecular hybrids and two PZQ analogues were prepared by coupling 6-alkylpraziquanamines with cinnamic acids and cyclohexane carboxylic acid, respectively. The synthesised compounds were evaluated for their antimalarial and antischistosomal activity; while all of the above compounds were inactive against Plasmodium falciparum (IC(50) > 6 µM), many were active against schistosomiasis with four particular compounds exhibiting up to 100% activity against newly transformed schistosomula and adult worms at 50 µM. Compared to PZQ, the reference drug, the activity of which is 91.7% at 1 µM, one particular molecular hybrid, compound 32, which bears a para-isopropyl group on the cinnamic acid moiety, exhibited a notable activity at 10 µM (78.2% activity). This compound has emerged as the front runner candidate that might, after further optimization, hold promise as a potential lead compound in the fight against schistosomiasis