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Search Results: 1 - 10 of 138886 matches for " Wilbur K. Milhous "
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7,8,15,16-tetraoxa-dispiro[5.2.5.2]hexadecane-3-carboxylic acid derivatives and their antimalarial activity
IGOR OPSENICA,NATASA TERZIC,DEJAN OPSENICA,WILBUR K. MILHOUS
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[5.2.5.2] hexadecane-3-carboxamide being as active as artemisinin.
Antimalarial peroxides: the first intramolecular 1,2,4,5-tetraoxane
DEJAN OPSENICA,GABRIELLA POCSFALVI,WILBUR K. MILHOUS,BOGDAN A. SOLAJA
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
DEJAN OPSENICA,DENNIS E. KYLE,WILBUR K. MILHOUS,BOGDAN A. SOLAJA
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.
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.
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
An exploratory study on medications in Qatar homes
Kheir N,El Hajj MS,Wilbur K,Kaissi RML
Drug, Healthcare and Patient Safety , 2011,
Abstract: N Kheir1, MS El Hajj1, K Wilbur1, RML Kaissi1, A Yousif21College of Pharmacy, 2College of Arts and Sciences, Qatar University, Doha, QatarBackground: Drug therapy is the most often used intervention for treatment and prevention of disease. However, if used inappropriately, drugs can cause more harm than good. Improper drug storage and disposal can have a direct impact on public safety, the environment, and the health care services. The purpose of this study was to characterize medications stored in Qatar homes and to explore their methods of storage and disposal, and to identify the public's source of information related to medicines.Methods: For the purpose of this cross-sectional exploratory study, a list of telephone numbers was generated from Qatar's telephone directory using a systematic sampling method. Individuals consenting to participate were interviewed using a multipart pretested survey instrument.Results: Data were collected from a total of 49 homes. Most respondents did not have a designated compartment or box specifically for storing medications. The majority of drugs (48%) were kept in bedrooms and a number of respondents were keeping their drugs in the fridge and in the kitchen. The most often stored classes of medicines were analgesics, antihistamines, nutritional supplements, and medications used for the respiratory system. Most respondents disposed of unwanted medicines by throwing them in the trash. In about 15% of cases, the dosage of drug taken was different from the instructions on the label. Sharing of prescription medicines was not uncommon. The majority of respondents sought information related to drugs from doctors.Conclusion: These findings raise concerns about how medications are stored and disposed of in the community. The fact that no household routinely returned unwanted medications to a pharmacy for proper disposal places the environment at risk. There is a need for more societal awareness about the safe handling and storage of drugs in the home, and about the professional role of the pharmacist.Keywords: medication, home, Qatar, storage, disposal
An exploratory study on medications in Qatar homes
Kheir N, El Hajj MS, Wilbur K, Kaissi RML, Yousif A
Drug, Healthcare and Patient Safety , 2011, DOI: http://dx.doi.org/10.2147/DHPS.S25372
Abstract: n exploratory study on medications in Qatar homes Original Research (2039) Total Article Views Authors: Kheir N, El Hajj MS, Wilbur K, Kaissi RML, Yousif A Published Date December 2011 Volume 2011:3 Pages 99 - 106 DOI: http://dx.doi.org/10.2147/DHPS.S25372 N Kheir1, MS El Hajj1, K Wilbur1, RML Kaissi1, A Yousif2 1College of Pharmacy, 2College of Arts and Sciences, Qatar University, Doha, Qatar Background: Drug therapy is the most often used intervention for treatment and prevention of disease. However, if used inappropriately, drugs can cause more harm than good. Improper drug storage and disposal can have a direct impact on public safety, the environment, and the health care services. The purpose of this study was to characterize medications stored in Qatar homes and to explore their methods of storage and disposal, and to identify the public's source of information related to medicines. Methods: For the purpose of this cross-sectional exploratory study, a list of telephone numbers was generated from Qatar's telephone directory using a systematic sampling method. Individuals consenting to participate were interviewed using a multipart pretested survey instrument. Results: Data were collected from a total of 49 homes. Most respondents did not have a designated compartment or box specifically for storing medications. The majority of drugs (48%) were kept in bedrooms and a number of respondents were keeping their drugs in the fridge and in the kitchen. The most often stored classes of medicines were analgesics, antihistamines, nutritional supplements, and medications used for the respiratory system. Most respondents disposed of unwanted medicines by throwing them in the trash. In about 15% of cases, the dosage of drug taken was different from the instructions on the label. Sharing of prescription medicines was not uncommon. The majority of respondents sought information related to drugs from doctors. Conclusion: These findings raise concerns about how medications are stored and disposed of in the community. The fact that no household routinely returned unwanted medications to a pharmacy for proper disposal places the environment at risk. There is a need for more societal awareness about the safe handling and storage of drugs in the home, and about the professional role of the pharmacist.
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.
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