Comparison of Bioavailability Between the Most Available Generic Tablet Formulation Containing Artemether and Lumefantrine on the Tanzanian Market and the Innovator's Product.

Existence of anti-malarial generic drugs with low bioavailability marketed on sub-Saharan Africa has raised a concern on patients achieving therapeutic concentrations after intake of these products. This work compared bioavailability of one generic tablet formulation with innovator's product. Both were fixed dose combination tablet formulations containing artemether and lumefantrine.MethodologyThe study was conducted in Dar Es Salaam, Tanzania, in which a survey of the most abundant generic containing artemether-lumefantrine tablet formulation was carried out in retail pharmacies. The most widely available generic (Artefan(R), Ajanta Pharma Ltd, Maharashtra, India) was sampled for bioavailability comparison with Coartem(R) (Novartis Pharma, Basel, Switzerland) - the innovator's product. A randomized, two-treatment cross-over study was conducted in 18 healthy Tanzanian black male volunteers. Each volunteer received Artefan(R) (test) and Coartem(R) (as reference) formulation separated by 42 days of drug-free washout period. Serial blood samples were collected up to 168 hours after oral administration of a single dose of each treatment. Quantitation of lumefantrine plasma levels was done using HPLC with UV detection. Bioequivalence of the two products was assessed in accordance with the US Food and Drug Authority (FDA) guidelines. The most widely available generic in pharmacies was Artefan(R) from India. All eighteen enrolled volunteers completed the study and both test and reference tablet formulations were well tolerated. It was possible to quantify lumefantrine alone, therefore, the pharmacokinetic parameters reported herein are for lumefantrine. The geometric mean ratios for Cmax, AUC0-t and AUC0-[infinity] were 84% in all cases and within FDA recommended bioequivalence limits of 80% -- 125%, but the 90% confidence intervals were outside FDA recommended limits (CI 49--143%, 53 - 137%, 52 - 135% respectively). There were no statistical significant differences between the two formulations with regard to PK parameters (P > 0.05). Although the ratios of AUCs and Cmax were within the acceptable FDA range, bioequivalence between Artefan(R) and Coartem(R) tablet formulations was not demonstrated due to failure to comply with the FDA 90 % confidence interval criteria. Based on the observed total drug exposure (AUCs), Artefan(R) is likely to produce a similar therapeutic response as Coartem(R)

Patient Uncertainty Questionnaire-Rheumatology (PUQ-R): development and validation of a new patient-reported outcome instrument for systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA) in a mixed methods study

Background An in-depth qualitative exploration of uncertainty in systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA) led to the development of a five-domain conceptual framework of patient uncertainty in these two conditions. The purpose of this study was to develop and evaluate a new patient-reported outcome (PRO) instrument for patient uncertainty in SLE and RA on the basis of this empirically developed conceptual framework. Methods Cognitive debriefing interviews were conducted to pre-test the initial items generated on the basis of the preliminary qualitative exploration of patient uncertainty in SLE and RA. Two separate field tests were conducted in five hospital sites to evaluate the measurement properties of the new instrument; the first to identify and form scales, and the second to assess measurement properties of the final version in an independent sample. Psychometric evaluation was conducted in line with the Rasch Measurement Theory (RMT), examining the extent to which sample to scale targeting was satisfactory, measurement scales were constructed effectively and the sample was measured successfully. Traditional psychometric techniques were also used to provide complementary analyses best understood by clinicians. Results Pre-testing supported the relevance, acceptability and comprehensibility of the initial items. Findings indicated that the Patient Uncertainty Questionnaire for Rheumatology PUQ-R instrument fulfilled the expectations of RMT to a large extent (including person separation index 0.73 – 0.91). The PUQ-R comprises 49 items across five scales; symptoms and flares (14 items), medication (11 items), trust in doctor (8 items), self-management (6 items) and impact (10 items) which further displayed excellent measurement properties as assessed against the traditional psychometric criteria (including Cronbach’s alpha 0.82 – 0.93). Conclusion The PUQ-R has been developed and evaluated specifically for patients with SLE and RA. By quantifying uncertainty, the PUQ-R has the potential to support evidence-based management programmes and research

Oral medicine acceptance in infants and toddlers: measurement properties of the caregiver-administered Children’s acceptance tool (CareCAT)

BACKGROUND: Developing age-appropriate medications remains a challenge in particular for the population of infants and toddlers, as they are not able to reliably self-report if they would accept and consequently take an oral medicine. Therefore, it is common to use caregivers as proxies when assessing medicine acceptance. The outcome measures used in this research field differ and most importantly lack validation, implying a persisting gap in knowledge and controversy in the field. The newly developed Caregiver-administered Children’s Acceptance Tool (CareCAT) is based on a 5-point nominal scale, with descriptors of medication acceptance behavior. This crosssectional study assessed the measurement properties of the tool with regards to the user’s understanding and its intra- and inter-rater reliability. METHODS: Participating caregivers were enrolled at a primary healthcare facility where their children (median age 6 months) had been prescribed oral antibiotics. Caregivers, trained observers and the tool developer observed and scored on the CareCAT tool what behavior children exhibited when receiving the medicine (n = 104). The videorecords of this process served as replicate observations (n = 69). After using the tool caregivers were asked to explain their observations and the tool descriptors in their own words. The tool’s reliability was assessed by percentage agreement and Cohen’s unweighted kappa coefficients of agreement for nominal scales. RESULTS: The study found that caregivers using CareCAT had a satisfactory understanding of the tool’s descriptors. Using its dichotomized scores the tool reliably was strong for acceptance behavior (agreement inter-rater 84–88%, kappa 0.66–0.76; intra-rater 87–89%, kappa 0.68–0.72) and completeness of medicine ingestion (agreement inter-rater 82–86%, kappa 0.59–0.67; intra-rater 85–93%, kappa 0.50–0.70). CONCLUSIONS: The CareCAT is a low-cost, easy-to-use and reliable instrument, which is relevant to assess acceptance behavior and completeness of medicine ingestion, both of which are of significant importance for developing age-appropriate medications in infants and toddlers

Nitrosylation of Myoglobin and Nitrosation of Cysteine by Nitrite in a Model System Simulating Meat Curing

Demand is growing for meat products cured without the addition of sodium nitrite. Instead of the direct addition of nitrite to meat in formulation, nitrite is supplied by bacterial reduction of natural nitrate often added as vegetable juice/powder. However, the rate of nitrite formation in this process is relatively slow, and the total ingoing nitrite is typically less than in conventional curing processes. The objective of this study was to determine the impact of the rate of addition of nitrite and the amount of nitrite added on nitrosylation/nitrosation reactions in a model meat curing system. Myoglobin was preferentially nitrosylated as no decrease in sulfhydryl groups was found until maximum nitrosylmyoglobin color was achieved. The cysteine–myoglobin model retained more sulfhydryl groups than the cysteine-only model (p \u3c 0.05). The rate of nitrite addition did not alter nitrosylation/nitrosation reactions (p \u3e 0.05). These data suggest that the amount of nitrite but not the rate of addition impacts the nitrosylation/nitrosation reactions this syste

Challenges for Implementing an Ecosystem Approach to Fisheries Management

The ecosystem approach is being promoted as the foundation of solutions to the unsustainability of fisheries. However, because the ecosystem approach is broadly inclusive, the science for its implementation is often considered to be overly complex and difficult. When the science needed for an ecosystem approach to fisheries is perceived this way, science products cannot keep pace with fisheries critics, thus encouraging partisan political interference in fisheries management and proliferation of “faith-based solutions. In this paper we argue that one way to effectively counter politicization of fisheries decision-making is to ensure that new ecosystem-based approaches in fisheries are viewed only as an emergent property of innovation in science and policy. We organize our essay using three major themes to focus the discussion: empirical, jurisdictional, and societal challenges. We undertake at least partial answers to the following questions: (1) has conventional fisheries management really failed?; (2) can short-comings in conventional fisheries management be augmented with new tools, such as allocation of rights?; (3) is the Ecosystem Approach to Fisheries (EAF) equivalent to Ecosystem-Based Management?; and (4) is restoration of degraded ecosystems a necessary component of an EAF

Approval of cancer drugs with uncertain therapeutic value: a comparison of regulatory decisions in Europe and the United States

Policy Points Regulatory agencies may have limited evidence on the clinical benefits and harms of new drugs when deciding whether new therapeutic agents are allowed to enter the market and under which conditions, including whether approval is granted under special regulatory pathways and obligations to address knowledge gaps through postmarketing studies are imposed. In a matched comparison of marketing applications for cancer drugs of uncertain therapeutic value reviewed by both the US Food and Drug Administration (FDA) and the European Medicines Agency (EMA), we found frequent discordance between the two agencies on regulatory outcomes and the use of special regulatory pathways. Both agencies often granted regular approval, even when the other agency judged there to be substantial uncertainty about drug benefits and risks that needed to be resolved through additional studies in the postmarketing period. Postmarketing studies imposed by regulators under special approval pathways to address remaining questions of efficacy and safety may not be suited to deliver timely, confirmatory evidence due to shortcomings in study design and delays, raising questions over the suitability of the FDA's Accelerated Approval and the EMA's Conditional Marketing Authorization as tools for allowing early market access for cancer drugs while maintaining rigorous regulatory standards. Context: Regulatory agencies are increasingly required to make market approval decisions for new drugs on the basis of limited clinical evidence, a situation commonly encountered in cancer. We aimed to investigate how regulators manage uncertainty in the benefit-risk profiles of new cancer drugs by comparing decisions for the world's two largest regulatory bodies—the US Food and Drug Administration (FDA) and the European Medicines Agency (EMA)—over a 5-year period. Methods: We systematically identified a set of cancer drug-indication pairs for which data on efficacy and safety was less complete than that required for regular approval at time of market entry from 2009 to 2013, as determined by the FDA's use of Accelerated Approval (AA) or the EMA's use of Conditional Marketing Authorization (CMA) pathways, and matched these across the two agencies. Using publicly available information, we compared regulatory pathways and outcomes, final approved indications, and postmarketing obligations imposed by the agencies. Findings: We identified 21 cancer drug-indication pairs that received FDA AA, EMA CMA, or both. Although most applications relied on identical pivotal trials across the FDA and the EMA, regulatory pathways often differed; 57% of indications received either FDA AA or EMA CMA, and regular approval by the other agency. After approval, the EMA more often accepted single-arm studies to confirm clinical benefit compared to the FDA (75% vs. 29% of indications), and the FDA more commonly requested randomized controlled trials (85% vs. 50%). Forty-one percent of confirmatory trials after FDA AA were conducted in different populations than the approved indication, compared to 13% after EMA CMA. Both agencies relied primarily on surrogate measures of patient benefit for postmarketing obligations. After a median follow-up of 7.25 years, 40% of FDA and 61% of EMA postmarketing obligations after AA and CMA, respectively, were delayed. Conclusions: US and European regulators often deemed early and less complete evidence on benefit-risk profiles of cancer drugs sufficient to grant regular approval, raising questions over regulatory standards for the approval of new medicines. Even when imposing confirmatory studies in the postmarketing period through special approval pathways, meaningful evidence may not materialize due to shortcomings in study design and delays in conducting required studies with due diligence

Considerations for reducing food system energy demand while scaling up urban agriculture

There is an increasing global interest in scaling up urban agriculture (UA) in its various forms, from private gardens to sophisticated commercial operations. Much of this interest is in the spirit of environmental protection, with reduced waste and transportation energy highlighted as some of the proposed benefits of UA; however, explicit consideration of energy and resource requirements needs to be made in order to realize these anticipated environmental benefits. A literature review is undertaken here to provide new insight into the energy implications of scaling up UA in cities in high-income countries, considering UA classification, direct/indirect energy pressures, and interactions with other components of the food–energy–water nexus. This is followed by an exploration of ways in which these cities can plan for the exploitation of waste flows for resource-efficient UA. Given that it is estimated that the food system contributes nearly 15% of total US energy demand, optimization of resource use in food production, distribution, consumption, and waste systems may have a significant energy impact. There are limited data available that quantify resource demand implications directly associated with UA systems, highlighting that the literature is not yet sufficiently robust to make universal claims on benefits. This letter explores energy demand from conventional resource inputs, various production systems, water/energy trade-offs, alternative irrigation, packaging materials, and transportation/supply chains to shed light on UA-focused research needs. By analyzing data and cases from the existing literature, we propose that gains in energy efficiency could be realized through the co-location of UA operations with waste streams (e.g. heat, CO2, greywater, wastewater, compost), potentially increasing yields and offsetting life cycle energy demands relative to conventional approaches. This begs a number of energy-focused UA research questions that explore the opportunities for integrating the variety of UA structures and technologies, so that they are better able to exploit these urban waste flows and achieve whole-system reductions in energy demand. Any planning approach to implement these must, as always, assess how context will influence the viability and value added from the promotion of UA

Colorants in Cheese Manufacture: Production, Chemistry, Interactions, and Regulation

Colored Cheddar cheeses are prepared by adding an aqueous annatto extract (norbixin) to cheese milk; however, a considerable proportion (∼20%) of such colorant is transferred to whey, which can limit the end use applications of whey products. Different geographical regions have adopted various strategies for handling whey derived from colored cheeses production. For example, in the United States, whey products are treated with oxidizing agents such as hydrogen peroxide and benzoyl peroxide to obtain white and colorless spray‐dried products; however, chemical bleaching of whey is prohibited in Europe and China. Fundamental studies have focused on understanding the interactions between colorants molecules and various components of cheese. In addition, the selective delivery of colorants to the cheese curd through approaches such as encapsulated norbixin and microcapsules of bixin or use of alternative colorants, including fat‐soluble/emulsified versions of annatto or beta‐carotene, has been studied. This review provides a critical analysis of pertinent scientific and patent literature pertaining to colorant delivery in cheese and various types of colorant products on the market for cheese manufacture, and also considers interactions between colorant molecules and cheese components; various strategies for elimination of color transfer to whey during cheese manufacture are also discussed

PROMISE: first-trimester progesterone therapy in women with a history of unexplained recurrent miscarriages - a randomised, double-blind, placebo-controlled, international multicentre trial and economic evaluation

BACKGROUND AND OBJECTIVES: Progesterone is essential to maintain a healthy pregnancy. Guidance from the Royal College of Obstetricians and Gynaecologists and a Cochrane review called for a definitive trial to test whether or not progesterone therapy in the first trimester could reduce the risk of miscarriage in women with a history of unexplained recurrent miscarriage (RM). The PROMISE trial was conducted to answer this question. A concurrent cost-effectiveness analysis was conducted. DESIGN AND SETTING: A randomised, double-blind, placebo-controlled, international multicentre study, with economic evaluation, conducted in hospital settings across the UK (36 sites) and in the Netherlands (nine sites). PARTICIPANTS AND INTERVENTIONS: Women with unexplained RM (three or more first-trimester losses), aged between 18 and 39 years at randomisation, conceiving naturally and giving informed consent, received either micronised progesterone (Utrogestan(®), Besins Healthcare) at a dose of 400 mg (two vaginal capsules of 200 mg) or placebo vaginal capsules twice daily, administered vaginally from soon after a positive urinary pregnancy test (and no later than 6 weeks of gestation) until 12 completed weeks of gestation (or earlier if the pregnancy ended before 12 weeks). MAIN OUTCOME MEASURES: Live birth beyond 24 completed weeks of gestation (primary outcome), clinical pregnancy at 6-8 weeks, ongoing pregnancy at 12 weeks, miscarriage, gestation at delivery, neonatal survival at 28 days of life, congenital abnormalities and resource use. METHODS: Participants were randomised after confirmation of pregnancy. Randomisation was performed online via a secure internet facility. Data were collected on four occasions of outcome assessment after randomisation, up to 28 days after birth. RESULTS: A total of 1568 participants were screened for eligibility. Of the 836 women randomised between 2010 and 2013, 404 received progesterone and 432 received placebo. The baseline data (age, body mass index, maternal ethnicity, smoking status and parity) of the participants were comparable in the two arms of the trial. The follow-up rate to primary outcome was 826 out of 836 (98.8%). The live birth rate in the progesterone group was 65.8% (262/398) and in the placebo group it was 63.3% (271/428), giving a relative risk of 1.04 (95% confidence interval 0.94 to 1.15; p = 0.45). There was no evidence of a significant difference between the groups for any of the secondary outcomes. Economic analysis suggested a favourable incremental cost-effectiveness ratio for decision-making but wide confidence intervals indicated a high level of uncertainty in the health benefits. Additional sensitivity analysis suggested the probability that progesterone would fall within the National Institute for Health and Care Excellence's threshold of £20,000-30,000 per quality-adjusted life-year as between 0.7145 and 0.7341. CONCLUSIONS: There is no evidence that first-trimester progesterone therapy improves outcomes in women with a history of unexplained RM. LIMITATIONS: This study did not explore the effect of treatment with other progesterone preparations or treatment during the luteal phase of the menstrual cycle. FUTURE WORK: Future research could explore the efficacy of progesterone supplementation administered during the luteal phase of the menstrual cycle in women attempting natural conception despite a history of RM. TRIAL REGISTRATION: Current Controlled Trials ISRCTN92644181; EudraCT 2009-011208-42; Research Ethics Committee 09/H1208/44. FUNDING: This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 20, No. 41. See the NIHR Journals Library website for further project information