4,502 research outputs found

    Regulatory enforcement of the marketing of fixed-dose combinations in India: a case study of systemic antibiotics

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    \ua9 2023, The Author(s).Background: In India, states have licensed the manufacture of large numbers of fixed-dose combination (FDC) drugs without the required prior approval of the central regulator. This paper describes two major regulatory initiatives to address the problem, which began in 2007 and 2013, and examines whether they have been sufficient to remove centrally unapproved systemic antibiotic FDCs from the market. Methods: Information was extracted from documents published by the central regulator and the ministry of health, including the National List of Essential Medicines (NLEM), and court judgments, and analysed alongside sales volume data for 2008–2020 using PharmaTrac market dataset. Results: The regulatory initiatives permitted 68 formulations to be given de facto approvals (‘No Objection Certificates’) outside the statutory regime, banned 46 FDCs and restricted one FDC. Market data show that FDCs as a proportion of total antibiotic sales increased from 32.9 in 2008 to 37.3% in 2020. The total number of antibiotic FDC formulations on the market fell from 574 (2008) to 395 (2020). Formulations with a record of prior central approval increased from 86 (2008) to 94 (2020) and their share of the antibiotic FDC sales increased from 32.0 to 55.3%. In 2020, an additional 23 formulations had been permitted de facto approval, accounting for 10.6% of the antibiotic FDC sales. Even in 2020, most marketed formulations (70.4%, 278/395) were unapproved or banned, and comprised a 15.9% share of the antibiotic FDC sales. The share of NLEM-listed antibiotic FDC sales increased from 21.2 (2008) to 26.7% (2020). Conclusion: The initiatives had limited impact. Regulatory enforcement has been slow and weak, with many unapproved, and even banned, FDCs remaining on the market

    On bulk singularities in the random normal matrix model

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    We extend the method of rescaled Ward identities of Ameur-Kang-Makarov to study the distribution of eigenvalues close to a bulk singularity, i.e. a point in the interior of the droplet where the density of the classical equilibrium measure vanishes. We prove results to the effect that a certain "dominant part" of the Taylor expansion determines the microscopic properties near a bulk singularity. A description of the distribution is given in terms of a special entire function, which depends on the nature of the singularity (a Mittag-Leffler function in the case of a rotationally symmetric singularity).Comment: This version clarifies on the proof of Theorem

    Effects of dopamine D2/D3 receptor antagonism on human planning and spatial working memory

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    Psychopharmacological studies in humans suggest important roles for dopamine (DA) D2 receptors in human executive functions, such as cognitive planning and spatial working memory (SWM). However, studies that investigate an impairment of such functions using the selective DA D2/3 receptor antagonist sulpiride have yielded inconsistent results, perhaps because relatively low doses were used. We believe we report for the first time, the effects of a higher (800 mg p.o.) single dose of sulpiride as well as of genetic variation in the DA receptor D2 gene (DA receptor D2 Taq1A polymorphism), on planning and working memory. With 78 healthy male volunteers, we apply a between-groups, placebo-controlled design. We measure outcomes in the difficult versions of the Cambridge Neuropsychological Test Automated Battery One-Touch Stockings of Cambridge and the self-ordered SWM task. Volunteers in the sulpiride group showed significant impairments in planning accuracy and, for the more difficult problems, in SWM. Sulpiride administration speeded response latencies in the planning task on the most difficult problems. Volunteers with at least one copy of the minor allele (A1+) of the DA receptor D2 Taq1A polymorphism showed better SWM capacity, regardless of whether they received sulpiride or placebo. There were no effects on blood pressure, heart rate or subjective sedation. In sum, a higher single dose of sulpiride impairs SWM and executive planning functions, in a manner independent of the DA receptor D2 Taq1A polymorphism.This research work was funded by a Core Award from the Medical Research Council and the Wellcome Trust to the Behavioural and Clinical Neuroscience Institute (MRC Ref G1000183; WT Ref 093875/Z/10/Z). Also supported by a Wellcome Trust Senior Investigator Award (104631/Z/14/Z) awarded to TWR. CE was supported by the Swiss National Science Foundation (PA00P1_134135) and the Vienna Science and Technology Fund (WWTF VRG13-007)

    Nonlinear Sigma Model for Disordered Media: Replica Trick for Non-Perturbative Results and Interactions

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    In these lectures, given at the NATO ASI at Windsor (2001), applications of the replicas nonlinear sigma model to disordered systems are reviewed. A particular attention is given to two sets of issues. First, obtaining non-perturbative results in the replica limit is discussed, using as examples (i) an oscillatory behaviour of the two-level correlation function and (ii) long-tail asymptotes of different mesoscopic distributions. Second, a new variant of the sigma model for interacting electrons in disordered normal and superconducting systems is presented, with demonstrating how to reduce it, under certain controlled approximations, to known ``phase-only'' actions, including that of the ``dirty bosons'' model.Comment: 25 pages, Proceedings of the NATO ASI "Field Theory of Strongly Correlated Fermions and Bosons in Low - Dimensional Disordered Systems", Windsor, August, 2001; to be published by Kluwe

    Evidence for the classical integrability of the complete AdS(4) x CP(3) superstring

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    We construct a zero-curvature Lax connection in a sub-sector of the superstring theory on AdS(4) x CP(3) which is not described by the OSp(6|4)/U(3) x SO(1,3) supercoset sigma-model. In this sub-sector worldsheet fermions associated to eight broken supersymmetries of the type IIA background are physical fields. As such, the prescription for the construction of the Lax connection based on the Z_4-automorphism of the isometry superalgebra OSp(6|4) does not do the job. So, to construct the Lax connection we have used an alternative method which nevertheless relies on the isometry of the target superspace and kappa-symmetry of the Green-Schwarz superstring.Comment: 1+26 pages; v2: minor typos corrected, acknowledgements adde

    Dynamics of localization in a waveguide

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    This is a review of the dynamics of wave propagation through a disordered N-mode waveguide in the localized regime. The basic quantities considered are the Wigner-Smith and single-mode delay times, plus the time-dependent power spectrum of a reflected pulse. The long-time dynamics is dominated by resonant transmission over length scales much larger than the localization length. The corresponding distribution of the Wigner-Smith delay times is the Laguerre ensemble of random-matrix theory. In the power spectrum the resonances show up as a 1/t^2 tail after N^2 scattering times. In the distribution of single-mode delay times the resonances introduce a dynamic coherent backscattering effect, that provides a way to distinguish localization from absorption.Comment: 18 pages including 8 figures; minor correction

    Negative outcomes evoke cyclic irrational decisions in Rock, Paper, Scissors

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    Rock, Paper, Scissors (RPS) represents a unique gaming space in which the predictions of human rational decision-making can be compared with actual performance. Playing a computerized opponent adopting a mixed-strategy equilibrium, participants revealed a non-significant tendency to over-select Rock. Further violations of rational decision-making were observed using an inter-trial analysis where participants were more likely to switch their item selection at trial n + 1 following a loss or draw at trial n, revealing the strategic vulnerability of individuals following the experience of negative rather than positive outcome. Unique switch strategies related to each of these trial n outcomes were also identified: after losing participants were more likely to ‘downgrade’ their item (e.g., Rock followed by Scissors) but after drawing participants were more likely to ‘upgrade’ their item (e.g., Rock followed by Paper). Further repetition analysis revealed that participants were more likely to continue their specific cyclic item change strategy into trial n + 2. The data reveal the strategic vulnerability of individuals following the experience of negative rather than positive outcome, the tensions between behavioural and cognitive influences on decision making, and underline the dangers of increased behavioural predictability in other recursive, non-cooperative environments such as economics and politics
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