Cost-utility analysis of antiviral use under pandemic influenza using a novel approach - linking pharmacology, epidemiology and heath economics.

Simulation models are used widely in pharmacology, epidemiology and health economics (HEs). However, there have been no attempts to incorporate models from these disciplines into a single integrated model. Accordingly, we explored this linkage to evaluate the epidemiological and economic impact of oseltamivir dose optimisation in supporting pandemic influenza planning in the USA. An HE decision analytic model was linked to a pharmacokinetic/pharmacodynamics (PK/PD) - dynamic transmission model simulating the impact of pandemic influenza with low virulence and low transmissibility and, high virulence and high transmissibility. The cost-utility analysis was from the payer and societal perspectives, comparing oseltamivir 75 and 150 mg twice daily (BID) to no treatment over a 1-year time horizon. Model parameters were derived from published studies. Outcomes were measured as cost per quality-adjusted life year (QALY) gained. Sensitivity analyses were performed to examine the integrated model's robustness. Under both pandemic scenarios, compared to no treatment, the use of oseltamivir 75 or 150 mg BID led to a significant reduction of influenza episodes and influenza-related deaths, translating to substantial savings of QALYs. Overall drug costs were offset by the reduction of both direct and indirect costs, making these two interventions cost-saving from both perspectives. The results were sensitive to the proportion of inpatient presentation at the emergency visit and patients' quality of life. Integrating PK/PD-EPI/HE models is achievable. Whilst further refinement of this novel linkage model to more closely mimic the reality is needed, the current study has generated useful insights to support influenza pandemic planning.

Pharmacokinetic-pharmacodynamic determinants of oseltamivir efficacy using data from phase 2 inoculation studies.

Given the limited understanding about pharmacokinetic-pharmacodynamic (PK-PD) determinants of oseltamivir efficacy, data from two phase 2 influenza virus inoculation studies were evaluated. Healthy volunteers in studies 1 and 2 were experimentally infected with influenza A/Texas (the concentration of neuraminidase inhibitor which reduced neuraminidase activity by 50% [IC(50)] = 0.18 nM) or B/Yamagata (IC(50) = 16.76 nM), respectively. In study 1, 80 subjects received 20, 100, or 200 mg of oral oseltamivir twice daily (BID), 200 mg oseltamivir once daily, or placebo for 5 days. In study 2, 60 subjects received 75 or 150 mg of oral oseltamivir BID or placebo for 5 days. Oseltamivir carboxylate (OC) (active metabolite) PK was evaluated using individual PK data and a population PK model to derive individual values for area under the concentration-time curve from 0 to 24 h (AUC(0-24)), minimum concentration of OC in plasma (C(min)), and maximum concentration of OC in plasma (C(max)). Exposure-response relationships were evaluated for continuous (area under composite symptom score curve [AUCSC], area under the viral titer curve, and peak viral titer) and time-to-event (alleviation of composite symptom scores and cessation of viral shedding) efficacy endpoints. Univariable analyses suggested the existence of intuitive and highly statistically significant relationships between OC AUC(0-24 )evaluated as a 3-group variable and AUCSC, time to alleviation of composite symptom scores, and time to cessation of viral shedding. The upper OC AUC(0-24) threshold (~14,000 ng · h/ml) was similar among these endpoints. Multivariable analyses failed to demonstrate the influence of study/strain on efficacy endpoints. These results provide the first demonstration of exposure-response relationships for efficacy for oseltamivir against influenza and suggest that OC exposures beyond those achieved with the approved oseltamivir dosing regimen will provide enhanced efficacy. The clinical applicability of these observations requires further investigation.

Influence of chronic hepatitis C infection on cytochrome P450 3A4 activity using midazolam as an in vivo probe substrate.

PURPOSE: Inflammation-related changes in pharmacokinetics have been described for a number of disease-states including cancer, infection, and autoimmune disorders. This study examined the impact of chronic hepatitis C infection (CHC) on the pharmacokinetics of the cytochrome P450 3A probe midazolam in patients without significant liver disease who were either treatment naïve or prior interferon null-responders. METHODS: Data were pooled from three studies which compared the pharmacokinetics of oral midazolam in healthy volunteers (n = 107) and in treatment-naive patients (n = 35) and interferon-null responders (n = 24) with CHC but without significant liver disease. Oral midazolam was administered as a single 2 mg oral dose, followed by frequent pharmacokinetic sampling and determination of the pharmacokinetics of midazolam and its α-hydroxy metabolite. CYP3A activity was determined by the metabolic ratio (MR) of the AUC metabolite/AUC parent and compared across groups as the mean effect ratio (test/reference). RESULTS: The midazolam MR was lower in treatment-naïve patients with CHC than in health volunteers with a mean effect ratio of 0.63 [90 % confidence interval (CI) 0.56-0.72]. The effect was more pronounced in null-responders, who demonstrated a mean MR effect ratio of 0.46 (90 % CI 0.39-0.53) compared to volunteers. The mean area under the concentration-time curve (AUCinf) for midazolam in healthy volunteers, naïve patients, and null-responders was 32.3 [coefficient of variation (CV%) 41], 36.5 (CV% 33.5), and 55.3 (CV% 36.9) ng.h/mL, respectively. CONCLUSIONS: The results of this study demonstrate a reduction in CYP3A4 activity between healthy volunteers and patients with CHC, with interferon null-responders demonstrating the most substantial difference. These results may have implications for the pharmacotherapy of patients infected with CHC.

Domestic cattle as a non-conventional amplifying host of vesicular stomatitis New Jersey virus.

The role of vertebrates as amplifying and maintenance hosts for vesicular stomatitis New Jersey virus (VSNJV) remains unclear. Livestock have been considered dead-end hosts because detectable viraemia is absent in VSNJV-infected animals. This study demonstrated two situations in which cattle can represent a source of VSNJV to Simulium vittatum Zetterstedt (Diptera: Simuliidae) by serving: (a) as a substrate for horizontal transmission among co-feeding black flies, and (b) as a source of infection to uninfected black flies feeding on sites where VSNJV-infected black flies have previously fed. Observed co-feeding transmission rates ranged from 0% to 67%. Uninfected flies physically separated from infected flies by a distance of up to 11 cm were able to acquire virus during feeding although the rate of transmission decreased as the distance between infected and uninfected flies increased. Acquisition of VSNJV by uninfected flies feeding on initial inoculation sites at 24 h, 48 h and 72 h post-infection, in both the presence and absence of vesicular lesions, was detected.

Limits on the spin-dependent WIMP-nucleon cross sections from the first science run of the ZEPLIN-III experiment.

We present new experimental constraints on the WIMP-nucleon spin-dependent elastic cross sections using data from the first science run of ZEPLIN-III, a two-phase xenon experiment searching for galactic dark matter weakly interacting massive particles based at the Boulby mine. Analysis of approximately 450 kg x days fiducial exposure allow us to place a 90%-confidence upper limit on the pure WIMP-neutron cross section of sigma(n)=1.9x10(-2) pb at 55 GeV/c(2) WIMP mass. Recent calculations of the nuclear spin structure based on the Bonn charge-dependent nucleon-nucleon potential were used for the odd-neutron isotopes 129Xe and 131Xe. These indicate that the sensitivity of xenon targets to the spin-dependent WIMP-proton interaction could be much lower than implied by previous calculations, whereas the WIMP-neutron sensitivity is impaired only by a factor of approximately 2.

New software dedicated to virtual mazes for human cognitive investigations.

BACKGROUND: Compared to previous neuropsychological investigations with standard paper-pen tests limited to test complex spatial learning and memory processes, 3-D virtual immersive technology might offer new tools for research purposes and for diagnosis in patients suffering from mild cognitive impairment or dementia. COMPARISON WITH EXISTING METHODS: Current software proposes a customizable VR environment combined with an analyser module based on regions of interest and some parameters of analysis or pre-calibrated VR mazes with raw data. NEW METHOD: We attempted to create the VRmaze software offering either turnkey mazes with automatic tracking and analysis, or more complex and specific virtual mazes for human brain-behavioural research adaptable to all desired settings and parameters of analysis. The software combines 3D pre-calibrated VR tests or free customizable VR tests with digitized neuropsychological 2D standard and validated tests or tasks. RESULTS: We have tested an ERAM, a MWM and a reverse T-maze on 44 healthy subjects, showing gender differences in terms of navigation strategy. We have observed that the choice of benchmarks, instructions, and experimental parameters influence the performances. CONCLUSION: VRmaze software offers a translational approach for research units that wish to combine animal models and patient evaluations as well as complex 3D tasks and standardized neuropsychological tests combined with an automatic analysis opening a large perspective in the neurosciences to investigate cognitive functions. A clinical module with preconfigured 2- and 3-D tasks should offer clinicians an easy way to evaluate their patients routinely.

Hippocampal LTP modulation and glutamatergic receptors following vestibular loss.

Vestibular dysfunction strongly impairs hippocampus-dependent spatial memory performance and place cell function. However, the hippocampal encoding of vestibular information at the synaptic level, remains sparsely explored and controversial. We investigated changes in in vivo long-term potentiation (LTP) and NMDA glutamate receptor (NMDAr) density and distribution after bilateral vestibular lesions (BVL) in adult rats. At day 30 (D30) post-BVL, the LTP of the population spike recorded in the dentate gyrus (DG) was higher in BVL rats, for the entire 3 h of LTP recording, while no difference was observed in the fEPSP slope. However, there was an increase in EPSP-spike (E-S) potentiation in lesioned rats. NMDArs were upregulated at D7 and D30 predominantly within the DG and CA1. At D30, we observed a higher NMDAr density in the left hippocampus. NMDArs were overexpressed on both neurons and non-neuronal cells, suggesting a decrease of the entorhinal glutamatergic inputs to the hippocampus following BVL. The EPSP-spike (E-S) potentiation increase was consistent with the dorsal hippocampus NMDAr upregulation. Such an increase could reflect a non-specific enhancement of synaptic efficacy, leading to a disruption of memory encoding, and therefore might underlie the memory deficits previously reported in rats and humans following vestibular loss.

The critical role of vestibular graviception during cognitive-motor development.

Earth's gravity acts both as a mechanical stimulus on the body and as a sensory stimulus to the vestibular organ, which is transmitted into the brain. The vestibular system has been recently highlighted as the cornerstone of the multisensory cortex and of the dorsal hippocampus related to spatial cognition. Consequently, we have hypothesized that the vestibular sensory perception of gravity by the otoliths might also play a crucial role during the first stages of development in both sensorimotor and cognitive functions and the construction and perception of the 'self' and related functions of orientation and navigation. We have investigated an original mouse model (Head Tilted mice, B6Ei.GL-Nox3het/J) suffering from a selective congenital absence of vestibular otolithic gravisensors. We report that mouse pups suffered from a delay in the acquisition of sensorimotor reflexes, spatial olfactory guidance, path integration, and ultrasonic communication, while maternal care remained normal. We demonstrate that development has a critical period dependent on the vestibular otolithic sensory perception of gravity, probably temporally between the somesthetic and visual critical periods. The symptoms expressed by the congenital otolithic-deficient mice are similar to validated mouse models of autism and highlight the significance of vestibular graviception in the pathophysiology of development.

Flow cytometry for receptor analysis from ex-vivo brain tissue in adult rat.

BACKGROUND: Flow cytometry allows single-cell analysis of peripheral biological samples and is useful in many fields of research and clinical applications, mainly in hematology, immunology, and oncology. In the neurosciences, the flow cytometry separation method was first applied to stem cell extraction from healthy or cerebral tumour tissue and was more recently tested in order to phenotype brain cells, hippocampal neurogenesis, and to detect prion proteins. However, it remains sparsely applied in quantifying membrane receptors in relation to synaptic plasticity. NEW METHOD: We aimed to optimize a flow cytometric procedure for receptor quantification in neurons and non-neurons. A neural dissociation process, myelin separation, fixation, and membrane permeability procedures were optimized to maximize cell survival and analysis in hippocampal tissue obtained from adult rodents. We then aimed to quantify membrane muscarinic acetylcholine receptors (mAChRs) in rats with and without bilateral vestibular loss (BVL). RESULTS: mAChR's were quantified for neuronal and non-neuronal cells in the hippocampus and striatum following BVL. At day 30 but not at day 7 following BVL, there was a significant increase (P ≤ 0.05) in the percentage of neurons expressing M2/4 mAChRs in both the hippocampus and the striatum. CONCLUSION: Here, we showed that flow cytometry appears to be a reliable method of membrane receptor quantification in ex-vivo brain tissue.

Pathogenesis of Campylobacter fetus infections. Failure of encapsulated Campylobacter fetus to bind C3b explains serum and phagocytosis resistance.

Campylobacter fetus ssp. fetus strains causing systemic infections in humans are highly resistant to normal and immune serum, which is due to the presence of high molecular weight (100,000, 127,000, or 149,000) surface (S-layer) proteins. Using serum-resistant parental strains (82-40 LP and 23D) containing the 100,000-mol wt protein and serum-sensitive mutants (82-40 HP and 23B) differing only in that they lack the 100,000-mol wt protein capsule, we examined complement binding and activation, and opsono-phagocytosis by polymorphonuclear leukocytes. C3 consumption was similar for all four strains but C3 was not efficiently bound to 82-40 LP or 23D even in the presence of immune serum, and the small amount of C3 bound was predominently the hemolytically inactive iC3b fragment. Consumption and binding of C5 and C9 was significantly greater for the unencapsulated than the encapsulated strains. Opsonization of 82-40 HP with heat-inactivated normal human serum caused greater than 99% killing by human PMN. Similar opsonization of 82-40 LP showed no kill, but use of immune serum restored killing. Findings in a PMN chemiluminescence assay showed parallel results. Association of 32P-labeled 82-40 HP with PMN in the presence of HINHS was 19-fold that for the 82-40 LP, and electron microscopy illustrated that the difference was in uptake rather than in binding. These results indicate that presence of the 100,000-mol wt protein capsule on the surface of C. fetus leads to impaired C3b binding, thus explaining serum resistance and defective opsonization in NHS, mechanisms that explain the capacity of this enteric organism to cause systemic infections.

Further studies of the effects of aging on arginine metabolites in the rat vestibular nucleus and cerebellum.

Some studies have demonstrated that aging is associated with impaired vestibular reflexes, especially otolithic reflexes, resulting in postural instability. However, the neurochemical basis of these age-related changes is still poorly understood. The l-arginine metabolic system has been implicated in changes in the brain associated with aging. In the current study, we examined the levels of l-arginine and its metabolizing enzymes and downstream metabolites in the vestibular nucleus complex (VNC) and cerebellum (CE) of rats with and without behavioral testing which were young (4months old), middle-aged (12months old) or aged (24months old). We found that aging was associated with lower nitric oxide synthase activity in the CE of animals with testing and increased arginase in the VNC and CE of animals with testing. l-citrulline and l-ornithine were lower in the VNC of aged animals irrespective of testing, while l-arginine and l-citrulline were lower in the CE with and without testing, respectively. In the VNC and CE, aging was associated with lower levels of glutamate in the VNC, irrespective of testing. In the VNC it was associated with higher levels of agmatine and putrescine, irrespective of testing. In the CE, aging was associated with higher levels of putrescine in animals without testing and with higher levels of spermine in animals with testing, and spermidine, irrespective of testing. Multivariate analyses indicated significant predictive relationships between the different variables, and there were correlations between some of the neurochemical variables and behavioral measurements. Cluster analyses revealed that aging altered the relationships between l-arginine and its metabolites. The results of this study demonstrate that there are major changes occurring in l-arginine metabolism in the VNC and CE as a result of age, as well as behavioral activity.

Molecular mechanisms of recovery from vestibular damage in mammals: recent advances.

The aim of this review is to summarise and critically evaluate studies of vestibular compensation published over the last 2 years, with emphasis on those concerned with the molecular mechanisms of this process of lesion-induced plasticity. Recent studies of vestibular compensation have confirmed and extended the previous findings that: (i) compensation of the static ocular motor and postural symptoms occurs relatively rapidly and completely compared to the dynamic symptoms, many of which either do not compensate substantially or else compensate variably due to sensory substitution and the development of sensori-motor strategies which suppress or minimize symptoms; (ii) static compensation is associated with, and may be at least partially caused by a substantial recovery of resting activity in the ipsilateral vestibular nucleus complex (VNC), which starts to develop very quickly following the unilateral vestibular deafferentation (UVD) but does not correlate perfectly with the development of some aspects of static compensation (e.g., postural compensation); and (iii) many complex biochemical changes are occurring in the VNC, cerebellum and even areas of the central nervous system like the hippocampus, following UVD. However, despite many recent studies which suggest the importance of excitatory amino acid receptors such as the N-methyl-D-aspartate receptor, expression of immediate early gene proteins, glucocorticoids, neurotrophins and nitric oxide in the vestibular compensation process, how these various factors are linked and which of them may have a causal relationship with the physiological changes underlying compensation, remains to be determined.

The contribution of N-methyl-D-aspartate receptors to lesion-induced plasticity in the vestibular nucleus.

The aim of this paper is to: i) review the behavioural, electrophysiological, pharmacological and biochemical evidence relating to the involvement of N-methyl-D-aspartate (NMDA) receptors in the vestibular compensation process which follows unilateral peripheral vestibular deafferentation (UVD); and ii) suggest a unifying hypothesis based on this literature and recent studies of long-term depression (LTD)-like phenomena in the brainstem vestibular nucleus complex (VNC). It is suggested that NMDA receptors may induce a form of heterosynaptic LTD in the ipsilateral VNC, which is partly responsible for the extent of the hypoactivity which occurs immediately following UVD, and the severity of the associated vestibular syndrome. It is also suggested that vestibular compensation may develop as this LTD dissipates, allowing remaining synaptic inputs and the intrinsic properties of ipsilateral VNC neurons to re-establish the resting activity which is responsible for static vestibular compensation. It is argued that this hypothesis accounts for the majority of the available data on NMDA receptors in relation to vestibular compensation, and may serve as a useful working hypothesis, in order to formulate further experiments to investigate the contribution of NMDA receptors to the compensation process.

The behavioural and neuronal effects of the chronic administration of benzodiazepine anxiolytic and hypnotic drugs.

Benzodiazepine anxiolytic and hypnotic drugs are some of the most widely prescribed drugs in the Western world. Despite this fact, the mechanisms that underlie the development of tolerance to, and dependence upon, benzodiazepines are poorly understood. The aim of this review is to summarize and critically evaluate the experimental evidence relating to the chronic behavioural and neuronal effects of benzodiazepines. Behavioural studies in animals generally indicate that tolerance gradually develops to the muscle relaxant, ataxic, locomotor and anticonvulsant effects of benzodiazepines. The evidence relating to the development of tolerance to the anxiolytic effects of benzodiazepines is less clear. The literature on the possible mechanisms of benzodiazepine tolerance and dependence is large, highly complex and difficult to interpret. The effect of chronic benzodiazepine treatment varies enormously as a function of the benzodiazepine used and the treatment schedule employed. Many studies have demonstrated a down-regulation of benzodiazepine binding sites, although affinity is usually unchanged. The evidence relating to the number and affinity of GABAA binding sites is unclear. Some studies suggest that chronic benzodiazepine administration results in a reduction in the number of Cl- channels associated with the GABAA receptor complex, although it is not clear that the efficacy of the GABA binding site in operating the Cl- channel necessarily changes. There is, however, substantial evidence to support the hypothesis that chronic benzodiazepine treatment results in a reduction in the coupling between the GABAA and benzodiazepine binding sites (the "functional uncoupling hypothesis"). Although some electrophysiological studies suggest that chronic benzodiazepine treatment results in a subsensitivity to GABA, this effect seems to be highly area-specific.

Adrenalectomy-induced neuronal degeneration.

The binding of glucocorticoids to CNS receptors results in the modulation of many processes, ranging from neurotransmission to cell birth and death. It is of no surprise, therefore, that the removal of these steroids following adrenalectomy disrupts a variety of physiological functions throughout the brain. It is the aim of this review to briefly describe the findings of research examining some of these glucocorticoid-mediated CNS effects; however, as many of these areas have been reviewed extensively by others, this review will focus on the recently described phenomenon, adrenalectomy-induced hippocampal cell death.

Platelet-activating factor in the CNS.

Platelet-activating factor (PAF) is a phospholipid synthesized in a variety of cells throughout the body. Platelet-activating factor has been identified in the CNS and has a number of diverse physiological and pathological functions. It has been shown to be a modulator of many CNS processes, ranging from long-term potentiation (LTP) to neuronal differentiation. Excessive levels of PAF appear to play an important role in neuronal cell injury, such as that resulting from ischaemia, inflammation, human immunodeficiency syndrome (HIV) and meningitis. The beneficial effects of PAF receptor antagonists are many and give rise to possible therapeutic strategies for neurotrauma.

Pharmacokinetics, Safety, and CCR2/CCR5 Antagonist Activity of Cenicriviroc in Participants With Mild or Moderate Hepatic Impairment.

Cenicriviroc, a dual CCR2/CCR5 antagonist, is being evaluated for treatment of nonalcoholic steatohepatitis and liver fibrosis (CENTAUR; NCT02217475). As it is metabolized by the liver, cenicriviroc was investigated in hepatic-impaired participants for pharmacokinetic changes. Participants with mild-to-moderate hepatic impairment (HI) (Child-Pugh class A (N  =  7) or B (N = 8)) and matched controls (N = 15) received cenicriviroc 150 mg once daily for 14 days. Serial blood samples were obtained on Days 1 and 14. Safety, tolerability, and effects on CCR2/CCR5 ligands, cytokines, and bacterial translocation biomarkers were evaluated. Cenicriviroc exposures were increased by moderate HI (AUC0-τ  55%, Cmax 29% higher) but were not with mild HI (AUC0-τ 38%, Cmax 40% lower). Cenicriviroc was well tolerated. Rapid and potent CCR2/CCR5 blockade was observed, not associated with increases in hepatic inflammation or bacterial translocation biomarkers. Study findings suggest that cenicriviroc 150 mg can be used in patients with mild-to-moderate HI.

Structure of the oligosaccharide chain of lipoglycan from Acholeplasma granularum.

The membrane associated lipoglycan from Acholeplasma granularum is a linear oligosaccharide attached to a diacylglycerol. The polymer has a monomeric weight of 20000 and is composed of glucose, galactose, N-acetylglucosamine, N-acetylfucosamine, glycerol and fatty acid esters. The proposed structure of the oligosaccharide chain is 12 repeating units of 9 sugars: Glcp(beta 1 leads to 2)-Glcp(alpha 1 leads to 4)-Glcp(alpha 1 leads to 3,4)-FcNAc(beta 1 leads to 3)-Galp(alpha 1 leads to 3)-Galp(alpha 1 leads to 3)-Galp(alpha 1 leads to 3,4)-GlcNAc(beta 1 leads to 3,4)-GlcNAc(beta 1 leads to 4)-[Glcp(beta 1 leads to 2)-Glcp(alpha 1 leads to 4)-Glcp(alpha 1 leads to 3,4)-FcNAc(beta 1 leads to 3)-Galp(alpha 1 leads to 3)-Galp(alpha 1 leads to 3)-Galp(alpha 1 leads to 3,4)-GlcNAc(beta 1 leads to 3,4)-GlcNAc(beta 1 leads to 4)]10-Glcp(beta 1 leads to 2)-Glcp(alpha 1 leads to 4)-Glcp(alpha 1 leads to 3,4)-FcNAc(beta 1 leads to 3)-Galp(alpha 1 leads to 3)-Galp(alpha 1 leads to 3)-Galp(alpha 1 leads to 3,4)-GlcNAc(beta 1 leads to 3,4)-GlcNAc-diacylglycerol. The position of the linkages (3 or 4) on the amino sugars has not been resolved.

Sequence and glycosidic bond arrangement of sugars in lipopolysaccharide from Thermoplasma acidophilum.

The lipopolysaccharide from Thermoplasma acidophilum is a linear polymer with the structure [Manp-(alpha 1 leads to 2)-Manp-(alpha 1 leads to 4)-Manp-(alpha 1 leads to 3)]8-Glcp-(alpha 1 leads to 1)-diglycerol tetraether as established by Smith degradation, methylation, acetolysis and CrO3 oxidation.