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Search Results: 1 - 10 of 66 matches for " Wilbur Milhous "
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7,8,15,16-tetraoxa-dispiro[]hexadecane-3-carboxylic acid derivatives and their antimalarial activity
Journal of the Serbian Chemical Society , 2004,
Abstract: Several C2 symmetrical mixed tetraoxanes were prepared starting from a gemdihydroperoxide and a ketone. The obtained tetraoxanes showed pronounced antimalarial activity against P. falciparum chloroquine resistant W2 and chloroquine susceptible D6 strains, with N-(2-dimethylamino)ethyl-7,8,15,16-tetraoxa-dispiro[] hexadecane-3-carboxamide being as active as artemisinin.
Antimalarial peroxides: the first intramolecular 1,2,4,5-tetraoxane
Journal of the Serbian Chemical Society , 2002,
Abstract: An intramolecular steroidal 1,2,4,5-tetraoxane has been synthesised in six steps starting from methyl 3-oxo-7a,12a-diacetoxy-5b-cholan-24-oate. The synthesised 1,2,4,5-tetraoxane has moderate in vitro antimalarial activity against P. falciparum strains (IC50 (D6) = 0.35 mg/mL; IC50 (W2) = 0.29 mg/mL).
Antimalarial, antimycobacterial and antiproliferative activity of phenyl substituted mixed tetraoxanes
Journal of the Serbian Chemical Society , 2003,
Abstract: Mixed tetraoxanes of the 4 -phenyl-substituted cyclohexyl-spirotetraoxacyclohexyl-spirocholate series have been prepared and evaluated as possible antimalarials, antiproliferatives and antimycobacterials. The activity of the (4 R or S)-phenyl series against P. falciparum D6 and W2 strains was found to be at the level of artemisinin, with two compounds, the acid 4 and the amide 6, exhibiting encouraging anti-TB activity as well. Very promising in vitro results of the said tetraoxanes were obtained against solid tumours and, in some instances, the activity against a selected number of cell lines was higher than that of the antitumor drug paclitaxel.
Establishment of an In Vitro Assay for Assessing the Effects of Drugs on the Liver Stages of Plasmodium vivax Malaria
Rana Chattopadhyay,Soundarapandian Velmurugan,Chinnamma Chakiath,Lucy Andrews Donkor,Wilbur Milhous,John W. Barnwell,William E. Collins,Stephen L. Hoffman
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0014275
Abstract: Plasmodium vivax (Pv) is the second most important human malaria parasite. Recent data indicate that the impact of Pv malaria on the health and economies of the developing world has been dramatically underestimated. Pv has a unique feature in its life cycle. Uninucleate sporozoites (spz), after invasion of human hepatocytes, either proceed to develop into tens of thousands of merozoites within the infected hepatocytes or remain as dormant forms called hypnozoites, which cause relapses of malaria months to several years after the primary infection. Elimination of malaria caused by Pv will be facilitated by developing a safe, highly effective drug that eliminates Pv liver stages, including hypnozoites. Identification and development of such a drug would be facilitated by the development of a medium to high throughput assay for screening drugs against Pv liver stages. We undertook the present pilot study to (1) assess the feasibility of producing large quantities of purified, vialed, cryopreserved Pv sporozoites and (2) establish a system for culturing the liver stages of Pv in order to assess the effects of drugs on the liver stages of Pv. We used primaquine (PQ) to establish this assay model, because PQ is the only licensed drug known to clear all Pv hepatocyte stages, including hypnozoites, and the effect of PQ on Pv hepatocyte stage development in vitro has not previously been reported. We report that we have established the capacity to reproducibly infect hepatoma cells with purified, cyropreserved Pv spz from the same lot, quantitate the primary outcome variable of infected hepatoma cells and demonstrate the inhibitory activity of primaquine on the infected hepatoma cells. We have also identified small parasite forms that may be hypnozoites. These data provide the foundation for finalizing a medium throughput, high content assay to identify new drugs for the elimination of all Pv liver stages.
Radical curative efficacy of tafenoquine combination regimens in Plasmodium cynomolgi-infected Rhesus monkeys (Macaca mulatta)
Geoffrey S Dow, Montip Gettayacamin, Pranee Hansukjariya, Rawiwan Imerbsin, Srawuth Komcharoen, Jetsumon Sattabongkot, Dennis Kyle, Wilbur Milhous, Simon Cozens, David Kenworthy, Anne Miller, Jim Veazey, Colin Ohrt
Malaria Journal , 2011, DOI: 10.1186/1475-2875-10-212
Abstract: In 2005, the radical curative efficacy of tafenoquine combinations was investigated in Plasmodium cynomolgi-infected na?ve Indian-origin Rhesus monkeys. In the first cohort, groups of two monkeys were treated with a three-day regimen of tafenoquine at different doses alone and in combination with a three-day chloroquine regimen to determine the minimum curative dose (MCD). In the second cohort, the radical curative efficacy of a single-day regimen of tafenoquine-mefloquine was compared to that of two three-day regimens comprising tafenoquine at its MCD with chloroquine or artemether-lumefantrine in groups of six monkeys. In a final cohort, the efficacy of the MCD of tafenoquine against hypnozoites alone and in combination with chloroquine was investigated in groups of six monkeys after quinine pre-treatment to eliminate asexual parasites. Plasma tafenoquine, chloroquine and desethylchloroquine concentrations were determined by LC-MS in order to compare doses of the drugs to those used clinically in humans.The total MCD of tafenoquine required in combination regimens for radical cure was ten-fold lower (1.8 mg/kg versus 18 mg/kg) than for monotherapy. This regimen (1.8 mg/kg) was equally efficacious as monotherapy or in combination with chloroquine after quinine pre-treatment to eliminate asexual stages. The same dose of (1.8 mg/kg) was radically curative in combination with artemether-lumefantrine. Tafenoquine was also radically curative when combined with mefloquine. The MCD of tafenoquine monotherapy for radical cure (18 mg/kg) appears to be biologically equivalent to a 600-1200 mg dose in humans. At its MCD in combination with blood schizonticidal drugs (1.8 mg/kg), the maximum observed plasma concentrations were substantially lower than (20-84 versus 550-1,100 ng/ml) after administration of 1, 200 mg in clinical studies.Ten-fold lower clinical doses of tafenoquine than used in prior studies may be effective against P. vivax hypnozoites if the drug is deployed in
Confirmation of emergence of mutations associated with atovaquone-proguanil resistance in unexposed Plasmodium falciparum isolates from Africa
Christian T Happi, Grace O Gbotosho, Onikepe A Folarin, Danny Milner, Ousmane Sarr, Akintunde Sowunmi, Dennis E Kyle, Wilbur K Milhous, Dyann F Wirth, Ayoade MJ Oduola
Malaria Journal , 2006, DOI: 10.1186/1475-2875-5-82
Abstract: The prevalence of codon-268 mutations in the cytb gene of African P. falciparum isolates from Nigeria, Malawi and Senegal, where atovaquone-proguanil has not been introduced for treatment of malaria was assessed. Genotyping of the cytb gene in isolates of P. falciparum was performed by PCR-restriction fragment length polymorphism and confirmed by sequencing.295 samples from Nigeria (111), Malawi (91) and Senegal (93) were successfully analyzed for detection of either mutant Tyr268Ser or Tyr268Asn. No case of Ser268 or Asn268 was detected in cytb gene of parasites from Malawi or Senegal. However, Asn268 was detected in five out of 111 (4.5%) unexposed P. falciparum isolates from Nigeria. In addition, one out of these five mutant Asn268 isolates showed an additional cytb mutation leading to a Pro266Thr substitution inside the ubiquinone reduction site.No Tyr268Ser mutation is found in cytb of P. falciparum isolates from Nigeria, Malawi or Senegal. This study reports for the first time cytb Tyr268Asn mutation in unexposed P. falciparum isolates from Nigeria. The emergence in Africa of P. falciparum isolates with cytb Tyr268Asn mutation is a matter of serious concern. Continuous monitoring of atovaquone-proguanil resistant P. falciparum in Africa is warranted for the rational use of this new antimalarial drug, especially in non-immune travelers.The rapid development and spread of drug resistant Plasmodium falciparum is a serious global health problem in the management of malaria infections. Increasing resistance to antimalarials by P. falciparum has led to renewed search for alternative effective new drugs with unique cellular targets. In the 1990s, the urgent need for new anti-malarial drugs for treatment and chemoprophylaxis led to the development of atovaquone (2-[trans-4-(4'-chlorophenyl) cyclohexyl]-3-hydroxy-1,4-hydroxynaphtoquinone)[1]. This anti-malarial compound has broad spectrum activity against human protozoan pathogens [2,3] among which are the Plasmodium s
Novel Triazine JPC-2067-B Inhibits Toxoplasma gondii In Vitro and In Vivo
Ernest J. Mui,Guy A. Schiehser,Wilbur K. Milhous,Honghue Hsu,Craig W. Roberts,Michael Kirisits,Stephen Muench,David Rice,J. P. Dubey,Joseph W. Fowble,Pradipsinh K. Rathod,Sherry F. Queener,Susan R. Liu,David P. Jacobus,Rima McLeod
PLOS Neglected Tropical Diseases , 2008, DOI: 10.1371/journal.pntd.0000190
Abstract: Background and Methodology Toxoplasma gondii causes substantial morbidity, mortality, and costs for healthcare in the developed and developing world. Current medicines are not well tolerated and cause hypersensitivity reactions. The dihydrotriazine JPC-2067-B (4, 6-diamino-1, 2-dihydro-2, 2-dimethyl-1-(3′(2-chloro-, 4-trifluoromethoxyphenoxy)propyloxy)-1, 3, 5-triazine), which inhibits dihydrofolate reductase (DHFR), is highly effective against Plasmodium falciparum, Plasmodium vivax, and apicomplexans related to T. gondii. JPC-2067-B is the primary metabolite of the orally active biguanide JPC-2056 1-(3′-(2-chloro-4-trifluoromethoxyphenyl?oxy)propyloxy)- 5-isopropylbiguanide, which is being advanced to clinical trials for malaria. Efficacy of the prodrug JPC-2056 and the active metabolite JPC-2067-B against T. gondii and T. gondii DHFR as well as toxicity toward mammalian cells were tested. Principal Findings and Conclusions Herein, we found that JPC-2067-B is highly effective against T. gondii. We demonstrate that JPC-2067-B inhibits T. gondii growth in culture (IC50 20 nM), inhibits the purified enzyme (IC50 6.5 nM), is more efficacious than pyrimethamine, and is cidal in vitro. JPC-2067-B administered parenterally and the orally administered pro-drug (JPC-2056) are also effective against T. gondii tachyzoites in vivo. A molecular model of T. gondii DHFR-TS complexed with JPC-2067-B was developed. We found that the three main parasite clonal types and isolates from South and Central America, the United States, Canada, China, and Sri Lanka have the same amino acid sequences preserving key binding sites for the triazine. Significance JPC-2056/JPC-2067-B have potential to be more effective and possibly less toxic treatments for toxoplasmosis than currently available medicines.
Thematic clustering of text documents using an EM-based approach
Kim Sun,Wilbur W
Journal of Biomedical Semantics , 2012, DOI: 10.1186/2041-1480-3-s3-s6
Abstract: Clustering textual contents is an important step in mining useful information on the web or other text-based resources. The common task in text clustering is to handle text in a multi-dimensional space, and to partition documents into groups, where each group contains documents that are similar to each other. However, this strategy lacks a comprehensive view for humans in general since it cannot explain the main subject of each cluster. Utilizing semantic information can solve this problem, but it needs a well-defined ontology or pre-labeled gold standard set. In this paper, we present a thematic clustering algorithm for text documents. Given text, subject terms are extracted and used for clustering documents in a probabilistic framework. An EM approach is used to ensure documents are assigned to correct subjects, hence it converges to a locally optimal solution. The proposed method is distinctive because its results are sufficiently explanatory for human understanding as well as efficient for clustering performance. The experimental results show that the proposed method provides a competitive performance compared to other state-of-the-art approaches. We also show that the extracted themes from the MEDLINE dataset represent the subjects of clusters reasonably well.
Use of carnauba based carrier for copper sprays reduces infection by Xanthomonas citri subsp. citri and Diaporthe citri in Florida commercial grapefruit groves  [PDF]
Jan Narciso, Wilbur Widmer, Christopher Ference, Mark Ritenour, Ricardo Diaz
Agricultural Sciences (AS) , 2012, DOI: 10.4236/as.2012.37117
Abstract: Citrus canker, caused by Xanthomonas citri subsp. citri (Xcc), is a bacterial disease of citrus and results in peel blemishes rendering fresh fruit unsalable. Xcc is most active in warm, wet Florida summers where tissues are infected during periods of active growth. Melanose, caused by Diaporthe citri, is common in citrus producing countries, but, like canker, is only important for fresh market fruit. To control canker and melanose, Florida growers spray trees with copper formulations (Cu), but these sprays are removed by strong rains and intense radiation of Florida summers. A study was undertaken in FL commercial grapefruit groves in 2009 and 2010 to assess the efficiency of a spray combining copper with a specially formulated, hydrating wax (WashGard?) (WG). Using a 21-day spray schedule for the season, fruit were sprayed with WG + Cu, Cu and Control (no spray). Fruit from trees sprayed with WG + Cu had approximately 10 and17% more canker free fruit in 2009 and 2010 respectively compared to trees sprayed with copper alone. Compared to control trees the canker free fruit incidence was increased by ≈10% in 2009 and 57% in 2010. For melanose there was 40% more disease free fruit (treated) over fruit from trees with no treatment in 2009 and approximately 20% more in 2010. Controlling infection with this spray significantly reduces citrus canker and melanose, increasing the percentage of marketable fruit.
Multilevel Modeling of Binary Outcomes with Three-Level Complex Health Survey Data  [PDF]
Shafquat Rozi, Sadia Mahmud, Gillian Lancaster, Wilbur Hadden, Gregory Pappas
Open Journal of Epidemiology (OJEpi) , 2017, DOI: 10.4236/ojepi.2017.71004
Abstract: Complex survey designs often involve unequal selection probabilities of clus-ters or units within clusters. When estimating models for complex survey data, scaled weights are incorporated into the likelihood, producing a pseudo likeli-hood. In a 3-level weighted analysis for a binary outcome, we implemented two methods for scaling the sampling weights in the National Health Survey of Pa-kistan (NHSP). For NHSP with health care utilization as a binary outcome we found age, gender, household (HH) goods, urban/rural status, community de-velopment index, province and marital status as significant predictors of health care utilization (p-value < 0.05). The variance of the random intercepts using scaling method 1 is estimated as 0.0961 (standard error 0.0339) for PSU level, and 0.2726 (standard error 0.0995) for household level respectively. Both esti-mates are significantly different from zero (p-value < 0.05) and indicate consid-erable heterogeneity in health care utilization with respect to households and PSUs. The results of the NHSP data analysis showed that all three analyses, weighted (two scaling methods) and un-weighted, converged to almost identical results with few exceptions. This may have occurred because of the large num-ber of 3rd and 2nd level clusters and relatively small ICC. We performed a sim-ulation study to assess the effect of varying prevalence and intra-class correla-tion coefficients (ICCs) on bias of fixed effect parameters and variance components of a multilevel pseudo maximum likelihood (weighted) analysis. The simulation results showed that the performance of the scaled weighted estimators is satisfactory for both scaling methods. Incorporating simulation into the analysis of complex multilevel surveys allows the integrity of the results to be tested and is recommended as good practice.
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