Simulating Intestinal Transporter and Enzyme Activity in a Physiologically Based Pharmacokinetic Model for Tenofovir Disoproxil Fumarate

Tenofovir disoproxil fumarate (TDF), a prodrug of tenofovir, has oral bioavailability (25%) limited by intestinal transport (P-glycoprotein), and intestinal degradation (carboxylesterase). However, the influence of luminal pancreatic enzymes is not fully understood. Physiologically based pharmacokinetic (PBPK) modeling has utility for estimating drug exposure from in vitro data. This study aimed to develop a PBPK model that included luminal enzyme activity to inform dose reduction strategies. TDF and tenofovir stability in porcine pancrelipase concentrations was assessed (0, 0.48, 4.8, 48, and 480 U/ml of lipase; 1 mM TDF; 37°C; 0 to 30 min). Samples were analyzed using mass spectrometry. TDF stability and permeation data allowed calculation of absorption rates within a human PBPK model to predict plasma exposure following 6 days of once-daily dosing with 300 mg of TDF. Regional absorption of drug was simulated across gut segments. TDF was degraded by pancrelipase (half-lives of 0.07 and 0.62 h using 480 and 48 U/ml, respectively). Previously reported maximum concentration (Cmax; 335 ng/ml), time to Cmax (Tmax; 2.4 h), area under the concentration-time curve from 0 to 24 h (AUC0–24; 3,045 ng · h/ml), and concentration at 24 h (C24; 48.3 ng/ml) were all within a 0.5-fold difference from the simulated Cmax (238 ng/ml), Tmax (3 h), AUC0–24 (3,036 ng · h/ml), and C24 (42.7 ng/ml). Simulated TDF absorption was higher in duodenum and jejunum than in ileum (p<0.05). These data support that TDF absorption is limited by the action of intestinal lipases. Our results suggest that bioavailability may be improved by protection of drug from intestinal transporters and enzymes, for example, by coadministration of enzyme-inhibiting agents or nanoformulation strategies

Uninterested youth? Young people's attitudes towards party politics in Britain

Following the outcome of the 2001 and 2005 General Elections, when the numbers of abstainers outweighed the numbers of Labour voters on both occasions, much attention has focused upon the state of British democracy and how to enthuse the electorate, especially young people. While the government is exploring ways to make the whole process of voting easier, it may be failing to tackle the real problem - that youth appear to find the business of politics uninviting and irrelevant. This paper examines data derived from a nationwide survey of over 700 young people in order to shed light on what lies at the heart of young people's apparent disengagement from formal politics in Britain - political apathy or a sense of political alienation. The findings reveal that they support the democratic process, but are sceptical of the way the British political system is organised and led, and are turned off by politicians and the political parties. However, there is no uniform youth orientation to politics, and the data indicate that views differ according to social class, educational history, and also gender. However both ethnicity and region of the country in which young people live seem to have little influence in structuring political attitudes and behaviour

A generation apart? Youth and political participation in Britain

Conventional wisdom holds that young people in Britain are alienated from politics, with some claiming that this reflects a wider crisis of legitimacy that should be met by initiatives to increase citizenship. This article addresses these areas, presenting both panel survey and focus group data from first-time voters. It concludes that, contrary to the findings from many predominantly quantitative studies of political participation, young people are interested in political matters, and do support the democratic process. However they feel a sense of anti-climax having voted for the first time, and are critical of those who have been elected to positions of political power. If they are a generation apart, this is less to do with apathy, and more to do with their engaged scepticism about ‘formal’ politics in Britain

Osjetljiva spektrofotometrijska metoda za određivanje antagonista H2-receptora uz uporabu N-bromsukcinimida i p-aminofenola

A simple, accurate and sensitive spectrophotometric method for determination of H2-receptor antagonists: cimetidine (CIM), famotidine (FAM), nizatidine (NIZ), and ranitidine hydrochloride (RAN) has been full developed and validated The method was based on the reaction of these drugs with NBS and subsequent measurement of the excess N-bromosuccinimide by its reaction with p-aminophenol to give a violet colored product (max at 552 nm). Decrease in the absorption intensity (A) of the colored product, due to the presence of the drug, was correlated with its concentration in the sample solution. Different variables affecting the reaction were carefully studied and optimized. Under optimal conditions, linear relationships with good correlation coefficients (0.9988-0.9998) were found between A values and the corresponding concentrations of the drugs in a concentration range of 830, 622, 625, and 420 g mL1 for CIM, FAM, NIZ, and RAN, respectively. Limits of detection were 1.22, 1.01, 1.08, and 0.74 g mL1 for CIM, FAM, NIZ, and RAN, respectively. The method was validated in terms of accuracy, precision, ruggedness, and robustness; the results were satisfactory. The proposed method was successfully applied to the analysis of the above mentioned drugs in bulk substance and in pharmaceutical dosage forms; percent recoveries ranged from 98.5 0.9 to 102.4 0.8% without interference from the common excipients. The results obtained by the proposed method were comparable with those obtained by the official methods.Razvijena je i validirana ispravna, jednostavna i osjetljiva spektrofotometrijska metoda za određivanje antagonista H2-receptora: cimetidina (CIM), famotidina (FAM), nizatidina (NIZ) i ranitidin hidroklorida (RAN). Metoda se temelji na reakciji tih ljekovitih tvari s N-bromsukcinimidom (NBS). Višak N-bromsukcinimida određuje se nakon reakcije s p-aminofenolom s kojim daje ljubičasti produkt (max pri 552 nm). Smanjenje apsorpcijskog intenziteta (A) obojenog produkta, zbog prisutnosti ljekovite tvari korelirano je s njegovom koncentracijom u otopini uzorka. Proučavane su različite varijable koje utječu na reakciju. Linearno koncentracijsko područje za CIM, FAM, NIZ i RAN, s koeficijentom korelacije od 0,9988 do 0,9998, iznosi 830, 622, 625 odnosno 420 g mL1. Granice detekcije bile su 1,23, 1,02, 1,09 i 0,75 g mL1 za CIM, FAM, NIZ, odnosno RAN. Predložena metoda je uspješno primijenjena za analizu navedenih ljekovitih tvari i ljekovitih pripravaka. Nepreciznost od 0,7 do 1,2% i visoka ispravnost (analitički povrat između 98,5 i 102,4%), bez interferencije uobičajenih pomoćnih tvari, ukazuju na dobru analitičku metodu. Rezultati dobiveni predloženom metodom usporedivi su s rezultatima dobivenim službenom metodom

Online Political Communication Strategies: MEPs, E-Representation, and Self-Representation

Research into the communication strategies of legislators has a long history. The European Parliament offers an opportunity to add to understanding of how legislators prioritize styles of communication, with a comparative perspective across 27 nations. Through content analysis of online communication, we investigate how the Internet is used by members of the European Parliament. Our analysis assesses three communication strategies: homestyle, impression management, and participatory. We find that a homestyle strategy predominates, followed by impression management. Participatory communication is emergent, but may earn legislators political capital, as it appears that proactive communicators who offer participatory opportunities are more likely to build an online following

Power as well as Persuasion: Political Communication and Party Development

This extract is taken from the author's original manuscript and has not been reviewed or edited. The definitive version of this extract may be found in the work, Political Communication Transformed by Bartle and Griffiths, which can be purchased from www.palgrave.com.In the run-up to and during the 1997 general election political discourse was dominated by references to the supposed power and influence of the so-called 'spin doctors' and 'image makers'. These terms are often, and quite erroneously, used interchangeably. Those charged with 'doctoring' the 'spin' are primarily concerned with managing so-called 'free' media which is the coverage given politicians by print and broadcast journalists. Working in tandem with this group, the 'image makers' are those marketing experts charged with interpreting popular opinion and developing a strategy to promote their particular party, candidate or leader by use of 'paid' or 'controlled' communications such as advertising...

SCYX-7158, an Orally-Active Benzoxaborole for the Treatment of Stage 2 Human African Trypanosomiasis

Human African trypanosomiasis (HAT) is caused by infection with the parasite Trypanosoma brucei and is an important public health problem in sub-Saharan Africa. New, safe, and effective drugs are urgently needed to treat HAT, particularly stage 2 disease where the parasite infects the brain. Existing therapies for HAT have poor safety profiles, difficult treatment regimens, limited effectiveness, and a high cost of goods. Through an integrated drug discovery project, we have discovered and optimized a novel class of boron-containing small molecules, benzoxaboroles, to deliver SCYX-7158, an orally active preclinical drug candidate. SCYX-7158 cured mice infected with T. brucei, both in the blood and in the brain. Extensive pharmacokinetic characterization of SCYX-7158 in rodents and non-human primates supports the potential of this drug candidate for progression to IND-enabling studies in advance of clinical trials for stage 2 HAT

Local political marketing in the context of the conservative party

Local political marketing can be defined as marketing related strategy, activities, and tactics implemented by a political party in a local geographic constituency, in order to attempt to maximise aggregate potential voter satisfaction, and therefore maximise total number of votes and electoral support in the constituency. Through 12 in-depth interviews with Local Constituency Party representatives from the Conservative Party, the study found that local political marketing was acknowledged by a majority of respondents although this was not unequivocal, and was frequently conflated with campaigning. Local political marketing was associated with: visual identity, language/messages, values, image, communication devices, awareness raising, data management and targeting, and simplification. The support from higher levels of the party in local political marketing was varied across constituencies. There was evidence of growing coordination /influence by higher levels of the party in local political marketing. However, this tended to be in seats judged as ‘winnable’