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Search Results: 1 - 10 of 171171 matches for " DENNIS E. KYLE "
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Effects of Artesunate on Parasite Recrudescence and Dormancy in the Rodent Malaria Model Plasmodium vinckei
Alexis N. LaCrue, Misty Scheel, Katherine Kennedy, Nikesh Kumar, Dennis E. Kyle
PLOS ONE , 2011, DOI: 10.1371/journal.pone.0026689
Abstract: Artemisinin (ART) is the recommended first line therapy for treating uncomplicated and drug-resistant Plasmodium falciparum, the most pathogenic form of malaria. However, treatment failure following ART monotherapy is not uncommon and resistance to this rapidly acting drug has been reported in the Thai-Cambodian border. Recent in vitro studies have shown that following treatment with dihydroartemisinin (DHA), the development of ring-stage parasites is arrested for up to 20 days. These arrested (i.e. dormant) rings could be responsible for the recrudescence of infection that is observed following ART monotherapy. To develop a better understanding of the stage-specific effects of ART and determine if dormancy occurs in vivo, the ART derivative artesunate (AS) was used to treat mice infected with the synchronous rodent malaria parasites P. vinckei petteri (non-lethal) and P. v. vinckei (lethal). Results show that in both the non-lethal and lethal strains, ring-stage parasites are the least susceptible to treatment with AS and that the day of treatment has more of an impact on recrudescence than the total dose administered. Additionally, 24 hrs post-treatment with AS, dormant forms similar in morphology to those seen in vitro were observed. Finally, rate of recrudescence studies suggest that there is a positive correlation between the number of dormant parasites present and when recrudescence occurs in the vertebrate host. Collectively, these data suggest that dormancy occurs in vivo and contributes to recrudescence that is observed following AS treatment. It is possible that this may represent a novel mechanism of parasite survival following treatment with AS.
Artemisinin-induced parasite dormancy: a plausible mechanism for treatment failure
Andrea Codd, Franka Teuscher, Dennis E Kyle, Qin Cheng, Michelle L Gatton
Malaria Journal , 2011, DOI: 10.1186/1475-2875-10-56
Abstract: In this study, an existing P. falciparum infection model is modified to incorporate the hypothesis of dormancy. Published in vitro data describing the characteristics of dormant parasites is used to explore whether dormancy alone could be responsible for the high recrudescence rates observed in field studies using monotherapy. Several treatment regimens and dormancy rates were simulated to investigate the rate of clinical and parasitological failure following treatment.The model output indicates that following a single treatment with ART parasitological and clinical failures occur in up to 77% and 67% of simulations, respectively. These rates rapidly decline with repeated treatment and are sensitive to the assumed dormancy rate. The simulated parasitological and clinical treatment failure rates after 3 and 7 days of treatment are comparable to those reported from several field trials.Although further studies are required to confirm dormancy in vivo, this theoretical study adds support for the hypothesis, highlighting the potential role of this parasite sub-population in treatment failure following monotherapy and reinforcing the importance of using ART in combination with other anti-malarials.Artemisinin-combination therapy (ACT) is the WHO recommended treatment for uncomplicated Plasmodium falciparum malaria [1]. It is imperative that artemisinin (ART) is used in combination with other anti-malarials partially because parasite recrudescence is common following ART monotherapy. The reported 28-day parasitological failure rates of ART monotherapy vary widely, from 2% to 50% [2,3]. This appears to be a feature of ART monotherapy and is independent of the observation of increased parasite clearance times which is considered the first evidence of ART resistance in the parasite [4]. It had been thought that because the ART class of compounds have a very short half-life they cannot eliminate all parasites during the short treatment time. However, while the rate of parasit
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.
Epigenetic Tailoring for the Production of Anti-Infective Cytosporones from the Marine Fungus Leucostoma persoonii
Jeremy Beau,Nida Mahid,Whittney N. Burda,Lacey Harrington,Lindsey N. Shaw,Tina Mutka,Dennis E. Kyle,Betty Barisic,Alberto van Olphen,Bill J. Baker
Marine Drugs , 2012, DOI: 10.3390/md10040762
Abstract: Recent genomic studies have demonstrated that fungi can possess gene clusters encoding for the production of previously unobserved secondary metabolites. Activation of these attenuated or silenced genes to obtain either improved titers of known compounds or new ones altogether has been a subject of considerable interest. In our efforts to discover new chemotypes that are effective against infectious diseases, including malaria and methicillin-resistant Staphylococcus aureus (MRSA), we have isolated a strain of marine fungus, Leucostoma persoonii, that produces bioactive cytosporones. Epigenetic modifiers employed to activate secondary metabolite genes resulted in enhanced production of known cytosporones B ( 1, 360%), C ( 2, 580%) and E ( 3, 890%), as well as the production of the previously undescribed cytosporone R ( 4). Cytosporone E was the most bioactive, displaying an IC 90 of 13 μM toward Plasmodium falciparum, with A549 cytotoxicity IC 90 of 437 μM, representing a 90% inhibition therapeutic index (TI 90 = IC 90 A459/IC 90 P. falciparum) of 33. In addition, cytosporone E was active against MRSA with a minimal inhibitory concentration (MIC) of 72 μM and inhibition of MRSA biofilm at roughly half that value (minimum biofilm eradication counts, MBEC90, was found to be 39 μM).
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
World Antimalarial Resistance Network (WARN) II: In vitro antimalarial drug susceptibility
David J Bacon, Ronan Jambou, Thierry Fandeur, Jacques Le Bras, Chansuda Wongsrichanalai, Mark M Fukuda, Pascal Ringwald, Carol Sibley, Dennis E Kyle
Malaria Journal , 2007, DOI: 10.1186/1475-2875-6-120
Abstract: In the last five years, new antimalarial drug combinations have been deployed rapidly in a wide range of settings. Most of these combinations contain an artemisinin derivative. Although the artemisinin derivatives retain excellent efficacy, the selection of resistance to the artemisinins is only a matter of time. Since treatment courses are generally short, the artemisinin component is dependent upon the partner drug for adequate clinical efficacy. When resistance to the latter reaches a critical level, the efficacy of the ACT falls, and it is no longer a suitable treatment for malaria. Thus, it is crucial to establish systems for detection of the earliest possible signs of resistance to both components of ACTs. Because validated molecular markers are lacking for resistance to artemisinins and because effective partner drugs used in ACTs will mask early clinical indicators of resistance, in vitro surveillance will be the critical surveillance tool for the emergence or artemisinin resistance.Longitudinal in vitro analysis of the susceptibility of Plasmodium falciparum strains to antimalarial drugs has three important attributes. First, this approach allows the response of clinical isolates to individual drugs to be assayed, unmodified by important host factors that influence drug efficacy in vivo. This capacity is crucial because it allows surveillance for resistance to both components of an ACT. Second, the progressive decline in drug sensitivity of isolates from the same site is likely to be the most sensitive method to identify incipient resistance in the parasite population [1]. Finally, strains with reduced antimalarial susceptibilities can then be established in continuous culture to provide the tools needed to investigate novel molecular mechanisms of resistance and for tests of susceptibility to other antimalarial agents.Despite its obvious value, the wide variance associated with the estimates derived from the in vitro assay makes the comparison of data betw
Another Way to Use the Laryngeal Mask Airway (LMA)  [PDF]
James Smit, Dennis E. Feierman
Open Journal of Anesthesiology (OJAnes) , 2016, DOI: 10.4236/ojanes.2016.64011
Abstract: The laryngeal mask airway (LMA) has changed airway management. Besides its use as an airway conduit, it is also used to help obtain a secure airway, i.e., it is used to facilitate the placement of an endotracheal tube. We describe a new technique to use in potential difficult pediatric airway.
Screening Mangrove Endophytic Fungi for Antimalarial Natural Products
Laurent Calcul,Carrie Waterman,Wai Sheung Ma,Matthew D. Lebar,Charles Harter,Tina Mutka,Lindsay Morton,Patrick Maignan,Alberto Van Olphen,Dennis E. Kyle,Lilian Vrijmoed,Ka-Lai Pang,Cedric Pearce,Bill J. Baker
Marine Drugs , 2013, DOI: 10.3390/md11125036
Abstract: We conducted a screening campaign to investigate fungi as a source for new antimalarial compounds. A subset of our fungal collection comprising Chinese mangrove endophytes provided over 5000 lipophilic extracts. We developed an accelerated discovery program based on small-scale cultivation for crude extract screening and a high-throughput malaria assay. Criteria for hits were developed and high priority hits were subjected to scale-up cultivation. Extracts from large scale cultivation were fractionated and these fractions subjected to both in vitro malaria and cytotoxicity screening. Criteria for advancing fractions to purification were developed, including the introduction of a selectivity index and by dereplication of known metabolites. From the Chinese mangrove endophytes, four new compounds ( 14– 16, 18) were isolated including a new dimeric tetrahydroxanthone, dicerandrol D ( 14), which was found to display the most favorable bioactivity profile.
Aqueous Ti(IV)-Catalyzed Diels-Alder Reaction
Kyle E. Litz
Molecules , 2007, DOI: 10.3390/12081674
Abstract: The aqueous Diels-Alder reaction of 1,3-cyclohexadiene with 1,4-benzoquinone was compared and contrasted to the same reaction catalyzed with Flextyl P?, a novel Ti(IV) performance catalyst. The catalyst improved conversion by 22% versus the uncatalyzed reaction and represents a rare example of a Ti(IV) catalyzed Diels-Alder reaction in water.
Failure to prevent medication errors: We need smarter nearly error proof systems  [PDF]
Loren G. Yamamoto, Kyle M. Watanabe, Joan E. Kanemori
Open Journal of Pediatrics (OJPed) , 2013, DOI: 10.4236/ojped.2013.32013
Abstract: Purpose: To determine if nurses are able to identify medication errors that have the potential to bypass computer physician order entry (CPOE) and smart ordering systems. Background: Medical care systems employ computer “smart” systems to reduce medication errors by using artificial intelligence (preprogrammed methods of decision support and error reduction). However, these systems are not perfect and they can be bypassed. Nurses who carry out the order represent the last check point in error prevention prior to the administration of medication orders. Methods: A paper exercise was created with 513 physician orders. Nurses were asked to indicate whether they would carry out the order, refuse to carry out the order, consult a pharmacist for clarification, or carry out the order with special precautions. Nurses were given the option of using any nursing or medical reference. Results: The rate of correctly identifying 23 of the contraindicated orders was low. Both experienced and inexperienced nurses had high rates of not identifying the errors despite similar use of references and requests for assistance from pharmacists. Conclusions: This study demonstrates that if an error escapes a smart system, nurses were able to identify most of these errors, but not all of these. The current system features high stress, self-esteem issues, time pressure, high volume, and high risk. The system must change radically to meet the public’s expectations of being nearly error free which can only be achieved with smarter systems that are more resistant to human errors.
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