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Genetic Analysis of HIV Is Potent Surveillance Tool Even In Low-Infection-Rate States
Dr Lewi's enthusiasm for science remains a source of inspiration for all of us. Kevin K. Pre-exposure prophylaxis and topical microbicides are important strategies in the prevention of sexual HIV transmission, especially since partial protection has been shown in proof-of-concept studies. In search of new candidate drugs with an improved toxicity profile and with activity against common non-nucleoside reverse transcriptase inhibitor NNRTI -resistant HIV, we have synthesized and investigated a library of 60 new diaryltriazine analogues.
From this library, 15 compounds were evaluated in depth using a broad armamentarium of in vitro assays that are part of a preclinical testing algorithm for microbicide development. Toxicity towards primary blood-derived cells, cell lines originating from the female reproductive tract and female genital microflora was also studied.
We identified several compounds with highly potent antiviral activity and toxicity profiles that are superior to that of dapivirine. In particular, compound UAMC is an interesting new candidate that warrants further investigation because of its superior toxicity profile and potent activity against dapivirine-resistant viruses. In the absence of a preventive vaccine and in circumstances where systematic and correct condom use is difficult, an effective microbicide and oral pre-exposure prophylaxis PrEP may be the best way to offer a discreet method for protection against HIV infection.
Occasional and incorrect usage of topically applied products might result in cross-resistance towards drugs used for HIV treatment. For this purpose we have investigated a series of novel diaryltriazine DATA analogues as potential intravaginal microbicides. We identified several highly potent compounds with a toxicity profile superior to that of the most advanced NNRTI-based microbicide candidate, dapivirine.
Lersivirine and the library of 60 triazine analogues were synthesized by the Medicinal Chemistry Group of Antwerp University, as per previously reported procedures. A replication-competent site-directed mutant SDM virus carrying the prototypic dapivirine resistance-associated mutation EK was made, starting from wild-type pNL4. Cells were split twice a week and plated at 10 6 cells in tissue culture flasks and at 10 4 cells in well plates.
Human peripheral blood mononuclear cells PBMCs were used to propagate HIV stocks and to determine the antiviral activity of a selection of compounds. Supernatant was harvested 48 h later and passed over a 0.
Each compound was tested in triplicate and each experiment was repeated in at least three independent runs. Antiviral activity was expressed as the percentage of viral inhibition compared with the untreated control and plotted against the compound concentration. Next, TCID 50 of virus was added to each well and cultures were incubated for 48 h before luciferase activity was quantified.
Each compound was tested in triplicate. Next, non-linear regression analysis was used to calculate the EC The WST-1 cell proliferation assay is based on the cleavage of the tetrazolium salt WST-1 to a formazan dye by a complex cellular mechanism. Because this bioreduction is dependent on the glycolytic production of NAD P H in viable cells, the amount of formazan dye formed correlates directly with the number of viable cells in a culture.
Quantification is achieved by measuring absorbance at nm in a multi-well plate reader. In addition, TSA blood plates without compounds were inoculated and incubated under the same conditions to control for growth of the strains. The MIC was determined as the lowest concentration of compound at which growth of the microorganism was inhibited.
A rapid but basic toxicity evaluation was done on all active compounds using a cell proliferation-based assay WST-1 assay and selectivity indices SIs were calculated.
It was investigated whether the replacement of the p -methyl group in the prototypic DATA UAMC Figure S2, available as Supplementary data at JAC Online by a cyanovinyl group could increase the antiviral activity, analogous to the cyanovinyl substitution in the DAPY rilpivirine, and whether the addition of an amino group in the 6-position of the central triazine ring could decrease cellular toxicity.
Compounds from group B had a more diverse spectrum of antiviral activity and cytotoxicity. Of note, the introduction of bromo substituents at positions 2 and 6 of the left aromatic ring only minimally affected antiviral activity but did cause an increase in cytotoxicity and hence lowered the SI of the otherwise highly potent compounds UAMC, UAMC and UAMC In group C, the influence of the cyano group on antiviral activity was studied.
Group D contained four analogues with a bromo group in position 2 of the left aromatic ring, all having low nanomolar activity but unfortunately also considerable cytotoxicity.
Four analogues, having a chlorine and oxygen atom in positions X and Y, respectively, were clearly less potent. The cytotoxicity was fairly good, with CC 50 values between 4. Groups G and H both consist of two analogues each. Antiviral activity was determined in a TZMbl assay, after a 2 h or 24 h exposure of compound to CVL fluid, compared with cell culture medium alone. The axis shows drug concentrations in nM. Reference compounds are in bold. Of note, the EC 50 of lersivirine increased 7. From the triazines, 11 compounds had decreased antiviral activity in PBMCs.
Of note, small fold changes FCs in EC 50 were observed for etravirine 1. In this respect, we tested our 15 triazines against a series of NNRTI-resistant viruses that we generated in an earlier study.
We performed EC 50 assays using two resistant strains, one with the VA mutation and the other with the YC mutation. Whereas no changes in antiviral activity were seen for the reference compounds dapivirine, etravirine, rilpivirine and MIV against the VA mutant strain, an EC 50 FC of 11 was observed for lersivirine.
Next, the inhibitory activity of all reference compounds and the 15 selected triazine analogues was evaluated against an HIV strain carrying the prototypic efavirenz-associated resistance mutations LI and KN. To further map the antiviral activity of our experimental compounds we evaluated the potency of a selection of compounds against an EK SDM and against dapivirine-resistant strains.
These activities are similar to the activities found for the reference compounds etravirine, rilpivirine and MIV Given the past failure of several microbicide candidates in clinical trials, owing to unforeseen mucosal toxicity that occasionally increased susceptibility for HIV acquisition, a thorough toxicity evaluation is now mandatory. Here, we have investigated cytotoxic effects on PBMCs and on epithelial cells originating from the female genital tract, as well as the capacity to interfere with the growth kinetics of the most important microbial species colonizing the female genital tract.
Cells were exposed to compound continuously for 7 days, followed by microscopic examination and a WST-1 cellular proliferation assay on day 7 post-exposure. Whereas in our assays there was apparently no cytotoxicity associated with lersivirine, the CC 50 values of the PETT compound MIV were at least an order of magnitude lower.
Interestingly, dapivirine appears to be less toxic than etravirine and rilpivirine on cells derived from the female genital tract. The MIC was determined for each of the compounds. Drug concentrations are depicted in nM. Compounds were tested against seven reference strains of different Lactobacillus , Atopobium and Gardnerella in black and against 10 isolates of mainly Lactobacillus and Bifidobacterium in grey.
Of note, for compound UAMC we could not demonstrate cytotoxicity in any of our assays. Furthermore, UAMC affected the growth of the Lactobacillus jensenii clinical isolate only at the highest concentration tested, and not the reference L. Etravirine and rilpivirine were not tested because they are used exclusively for therapy and are not under development for intravaginal application to prevent transmission.
Whereas the Z -isomer was equally active against wild-type HIV-1, its activity against resistant viruses was substantially decreased compared with the E -isomer and the isomer mixture. Altogether, we present solid data showing that DATA analogues are potentially excellent microbicide candidates that may retain potent activity against dapivirine-resistant HIV, with a large SI and no significant bacterial toxicity, with good chemical stability and anti-HIV activity in conditions specific to the female genital tract.
Many extremely potent NNRTIs have been identified over the years and several of these have been tested in animal models for prevention of the sexual transmission of simian—human immunodeficiency virus SHIV. Several investigators have developed test algorithms, which include all of the tests described in this manuscript, to prioritize inhibitors for continued development as topical products for HIV prevention.
We have investigated a series of novel triazines as potential intravaginal microbicides. The rationale for doing this was 3-fold. First, NNRTIs are conceptually interesting for use in topical prevention because they interfere with the pre-integration process of reverse transcription and can thus prevent infection from establishing irreversibly. Second, the partial successes with NNRTI in preventing SHIV infection by mucosal challenge in non-human primates justifies further research to comprehend the reasons underlying incomplete protection.
Investigating new molecules with a superior selective index and enhanced physico-chemical and formulation properties can hence give rise to improved bioavailability and higher tissue concentrations. Third, with NNRTIs being a backbone for therapy in HIV clinical management and the relative ease with which HIV develops resistance, compounds with non-overlapping resistance profiles that are exclusively dedicated to either therapeutic or preventive usage should be developed.
The DATA analogues described in this work are novel structures that are chemically different from dapivirine. Whereas the potent anti-HIV activity is retained, many of the DATA analogues have an improved cellular toxicity profile, including in cells derived from the female genital tract, compared with the microbicide candidate dapivirine. A bacterial growth inhibition assay revealed that compound UAMC does not interfere with the metabolism of the normal female genital tract microbiome, a pre-requisite for advancing a molecule in development for intravaginal use.
Only compound UAMC retained low nanomolar activity against these dapivirine-resistant viruses, with comparable or slightly better EC 50 values than etravirine and rilpivirine. An interesting series of pyrimidinediones PYDs have shown potent activity against the HIV-1 reverse transcriptase of different viral subtypes, and they also possess a second mechanism of action that targets viral entry. We have reported previously on the cross-resistance of NNRTIs used in therapy and those developed for topical prevention.
Although the results from the Phase 3 clinical trial with a dapivirine ring are not expected until late or early , expectations for success are high and it is anticipated that dapivirine will raise the standards for microbicide development.
In this respect, UAMC warrants further investigation because of its superior toxicity profile, excellent chemical stability and activity in CVL fluid, and because it is active against dapivirine-resistant viruses, which might start circulating once dapivirine rings are used widely among high-risk populations.
Together, our current data suggest that UAMC is potentially an excellent successor to dapivirine. All other authors: none to declare. Google Scholar. Oxford University Press is a department of the University of Oxford. It furthers the University's objective of excellence in research, scholarship, and education by publishing worldwide. Sign In or Create an Account. Mills College.
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Transparency declarations. Diaryltriazine non-nucleoside reverse transcriptase inhibitors are potent candidates for pre-exposure prophylaxis in the prevention of sexual HIV transmission Kevin K. Oxford Academic. Muthusamy Venkatraj. Johan Michiels.
Jurgen Joossens. Katleen Vereecken.
Health Impact Assessment
Beer in Health and Disease Prevention is the single comprehensive volume needed to understand beer and beer-related science. Presenting both the concerns and problems of beer consumption as well as the emerging evidence of benefit, this book offers a balanced view of today's findings and the potential of tomorrow's research. Just as wine in moderation has been proposed to promote health, research is showing that beer — and the ingredients in beer — can have similar impact on improving health, and in some instances preventing disease. This book addresses the impact of beer and beer ingredients on cancers, cardiovascular disease, anti-oxidant benefits, and other health related concerns.
Antibiotics are the chemotherapeutic agents that kill or inhibit the pathogenic microorganisms. Resistance of microorganism to antibiotics is a growing problem around the world due to indiscriminate and irrational use of antibiotics. In order to overcome the resistance problem and to safely use antibiotics, the correct measurement of potency and bioactivity of antibiotics is essential. Microbiological assay and high performance liquid chromatography HPLC method are used to quantify the potency of antibiotics. HPLC method is commonly used for the quantification of potency of antibiotics, but unable to determine the bioactivity; whereas microbiological assay estimates both potency and bioactivity of antibiotics.
Prevention serves as potent tool in effort to cut injuries
Account Options Anmelden. Meine Mediathek Hilfe Erweiterte Buchsuche. Oxford University Press Amazon. James Waller. While it is true that genocide prevention is not what tends to land on the front pages of national newspapers today, it is what prevents the worst headlines from ever being made. Despite the post-Holocaust consensus that "Never Again" would the world allow civilians to be victims of genocide, the reality is closer to "Again and Again. Now that we have entered the 21st century, little light has been brought to that darkness as civilians still find themselves under brutal attack in South Sudan, Burma, Syria, the Central African Republic, Burundi, Iraq, and a score of other countries in the world beset by state fragility and extremist identity politics. Drawing on over two decades of primary research and scholarship from a wide range of disciplinary perspectives, Confronting Evil: Engaging Our Responsibility to Prevent Genocide is grounded in the belief that preventing mass atrocity is an achievable goal, but only if we have the collective will to do so. This groundbreaking book from one of the foremost leaders in the field presents a fascinating continuum of research-informed strategies to prevent genocide from ever taking place; to prevent further atrocities once genocide is occurring; and to prevent future atrocities once a society has begun to rebuild after genocide. With remarkable insight, Dr.
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Dr Lewi's enthusiasm for science remains a source of inspiration for all of us. Kevin K. Pre-exposure prophylaxis and topical microbicides are important strategies in the prevention of sexual HIV transmission, especially since partial protection has been shown in proof-of-concept studies. In search of new candidate drugs with an improved toxicity profile and with activity against common non-nucleoside reverse transcriptase inhibitor NNRTI -resistant HIV, we have synthesized and investigated a library of 60 new diaryltriazine analogues.SEE VIDEO BY TOPIC: Elizabeth Stanley helps you Widen Your Window
Antibiotics are the chemotherapeutic agents that kill or inhibit the pathogenic microorganisms. Resistance of microorganism to antibiotics is a growing problem around the world due to indiscriminate and irrational use of antibiotics. In order to overcome the resistance problem and to safely use antibiotics, the correct measurement of potency and bioactivity of antibiotics is essential. Microbiological assay and high performance liquid chromatography HPLC method are used to quantify the potency of antibiotics. HPLC method is commonly used for the quantification of potency of antibiotics, but unable to determine the bioactivity; whereas microbiological assay estimates both potency and bioactivity of antibiotics. Additionally, bioassay is used to estimate the effective dose against antibiotic resistant microbes. Simultaneously, microbiological assay addresses the several parameters such as minimal inhibitory concentration MIC , minimum bactericidal concentration MBC , mutation prevention concentration MPC and critical concentration Ccr which are used to describe the potency in a more informative way. Microbiological assay is a simple, sensitive, precise and cost effective method which gives reproducible results similar to HPLC.
The PTTC Network Marijuana Risk Work Group has created two slide banks for prevention professionals to use in their marijuana prevention and education work in their communities. This slide bank provides a focus on the various forms of marijuana products, the trend in potencies, and current research around health impacts. The goal of this tool is to provide prevention providers with a researched and vetted tool they can feel confident in using in their marijuana prevention presentations.
На нем располагался щедрый набор фирменных открыток отеля, почтовая бумага, конверты и ручки. Беккер вложил в конверт чистый листок бумаги, надписал его всего одним словом: Росио - и вернулся к консьержу. - Извините, что я снова вас беспокою, - сказал он застенчиво.
- Я вел себя довольно глупо.
- Я позвоню Стратмору и попрошу прислать нам письменное подтверждение. - Нет, - сказала Мидж, - игнорируя сарказм, прозвучавший в его словах. - Стратмор уже солгал нам .
Да, сэр, - сказала Мидж.
Ничего подобного ему никогда не приходилось видеть. На каждой руке всего по три пальца, скрюченных, искривленных. Но Беккера интересовало отнюдь не это уродство. - Боже ты мой, - пробормотал лейтенант из другого конца комнаты.
Свернув, оно промчалось через ворота Санта-Крус, обломав в узком проезде боковое зеркало. Беккер знал, что он выиграл. Санта-Крус - самый старый район Севильи, где нет проездов между зданиями, лишь лабиринт узких ходов, восходящих еще к временам Древнего Рима. Протиснуться здесь могли в крайнем случае только пешеходы, проехал бы мопед. Беккер когда-то сам заблудился в его узких проходах.
Хорошо, это ничего не дает. Начнем вычитание. Я беру на себя верхнюю четверть пунктов, вы, Сьюзан, среднюю.