Cost-utility analysis of expanding the colorectal cancer screening policy in Flanders.

OBJECTIVE: Since 2013, Flanders has introduced a screening programme for colorectal cancer for all citizens aged between 50 and 74 years. The objective of this study was to assess the cost-utility of an expansion of the colorectal cancer screening policy in Flanders (Belgium) and to place these findings in the international context. METHODS: Cost-utility analysis using high-detail data about screening participation, screening results, and epidemiological data, a Markov cohort model has been constructed to study long-term costs and effects. A cost-utility analysis was performed as a three-way comparison between current, expanded (from age 45 years), and no screening scenarios, from a societal and healthcare perspective. Robustness was assessed by both one-way and probabilistic sensitivity analyses. RESULTS: Analyses show that both current and expanded screening result in quality-adjusted life years (QALY) gains and are mostly cost-saving. Overall, 97.5% of Incremental Cost-Effectiveness Ratios (ICERs) remained well below € 2000 per QALY for all comparisons. Parameters related to the colonoscopy that follows a positive test result such as compliance and cost are especially impactful on the cost-effectiveness. CONCLUSIONS: Screening participation and screening costs have remained comparatively stable, making colorectal cancer screening a cost-effective (dominant) policy. Expanding the screen age to 45 years is also cost-effective (dominant) compared with current screening, albeit with a slimmer margin.

Differential effects of acute and repeat dosing with the H3 antagonist GSK189254 on the sleep-wake cycle and narcoleptic episodes in Ox-/- mice.

BACKGROUND AND PURPOSE: Histamine H3 receptor antagonists are currently being evaluated in clinical trials for a number of central nervous system disorders including narcolepsy. These agents can increase wakefulness (W) in cats and rodents following acute administration, but their effects after repeat dosing have not been reported previously. EXPERIMENTAL APPROACH: EEG and EMG recordings were used to investigate the effects of acute and repeat administration of the novel H3 antagonist GSK189254 on the sleep-wake cycle in wild-type (Ox+/+) and orexin knockout (Ox-/-) mice, the latter being genetically susceptible to narcoleptic episodes. In addition, we investigated H3 and H1 receptor expression in this model using radioligand binding and autoradiography. KEY RESULTS: In Ox+/+ and Ox-/- mice, acute administration of GSK189254 (3 and 10 mg x kg(-1) p.o.) increased W and decreased slow wave and paradoxical sleep to a similar degree to modafinil (64 mg x kg(-1)), while it reduced narcoleptic episodes in Ox-/- mice. After twice daily dosing for 8 days, the effect of GSK189254 (10 mg x kg(-1)) on W in both Ox+/+ and Ox-/- mice was significantly reduced, while the effect on narcoleptic episodes in Ox-/- mice was significantly increased. Binding studies revealed no significant differences in H3 or H1 receptor expression between Ox+/+ and Ox-/- mice. CONCLUSIONS AND IMPLICATIONS: These studies provide further evidence to support the potential use of H3 antagonists in the treatment of narcolepsy and excessive daytime sleepiness. Moreover, the differential effects observed on W and narcoleptic episodes following repeat dosing could have important implications in clinical studies.

The brain H3-receptor as a novel therapeutic target for vigilance and sleep-wake disorders.

Brain histaminergic neurons play a prominent role in arousal and maintenance of wakefulness (W). H(3)-receptors control the activity of histaminergic neurons through presynaptic autoinhibition. The role of H(3)-receptor antagonists/inverse agonists (H(3)R-antagonists) in the potential therapy of vigilance deficiency and sleep-wake disorders were studied by assessing their effects on the mouse cortical EEG and sleep-wake cycle in comparison to modafinil and classical psychostimulants. The H(3)R-antagonists, thioperamide and ciproxifan increased W and cortical EEG fast rhythms and, like modafinil, but unlike amphetamine and caffeine, their waking effects were not accompanied by sleep rebound. Conversely, imetit (H(3)R-agonist) enhanced slow wave sleep and dose-dependently attenuated ciproxifan-induced W, indicating that the effects of both ligands involve H(3)-receptor mechanisms. Additional studies using knockout (KO) mice confirmed the essential role of H(3)-receptors and histamine-mediated transmission in the wake properties of H(3)R-antagonists. Thus ciproxifan produced no increase in W in either histidine-decarboxylase (HDC, histamine-synthesizing enzyme) or H(1)- or H(3)-receptor KO-mice whereas its waking effects persisted in H(2)-receptor KO-mice. These data validate the hypothesis that H(3)R-antagonists, through disinhibition of H(3)-autoreceptors, enhancing synaptic histamine that in turn activates postsynaptic H(1)-receptors promoting W. Interestingly amphetamine and modafinil, despite their potent arousal effects, appear unlikely to depend on histaminergic mechanism as their effects still occurred in HDC KO-mice. The present study thus distinguishes two classes of wake-improving agents: the first acting through non-histaminergic mechanisms and the second acting via histamine and supports brain H(3)-receptors as potentially novel therapeutic targets for vigilance and sleep-wake disorders.

BF2.649 [1-{3-[3-(4-Chlorophenyl)propoxy]propyl}piperidine, hydrochloride], a nonimidazole inverse agonist/antagonist at the human histamine H3 receptor: Preclinical pharmacology.

Histamine H3 receptor inverse agonists are known to enhance the activity of histaminergic neurons in brain and thereby promote vigilance and cognition. 1-{3-[3-(4-Chlorophenyl)propoxy]propyl}piperidine, hydrochloride (BF2.649) is a novel, potent, and selective nonimidazole inverse agonist at the recombinant human H3 receptor. On the stimulation of guanosine 5'-O-(3-[35S]thio)triphosphate binding to this receptor, BF2.649 behaved as a competitive antagonist with a Ki value of 0.16 nM and as an inverse agonist with an EC50 value of 1.5 nM and an intrinsic activity approximately 50% higher than that of ciproxifan. Its in vitro potency was approximately 6 times lower at the rodent receptor. In mice, the oral bioavailability coefficient, i.e., the ratio of plasma areas under the curve after oral and i.v. administrations, respectively, was 84%. BF2.649 dose dependently enhanced tele-methylhistamine levels in mouse brain, an index of histaminergic neuron activity, with an ED50 value of 1.6 mg/kg p.o., a response that persisted after repeated administrations for 17 days. In rats, the drug enhanced dopamine and acetylcholine levels in microdialysates of the prefrontal cortex. In cats, it markedly enhanced wakefulness at the expense of sleep states and also enhanced fast cortical rhythms of the electroencephalogram, known to be associated with improved vigilance. On the two-trial object recognition test in mice, a promnesiant effect was shown regarding either scopolamine-induced or natural forgetting. These preclinical data suggest that BF2.649 is a valuable drug candidate to be developed in wakefulness or memory deficits and other cognitive disorders.

[Toxi-infectious shock pneumopathy. A morphological study (author's transl)]. / Pneumopathies due choc-infectieux. Etude morphologique

The lungs of 68 septicaemic patients have been systematically studied and compared. The observed lesions include a whole range if alterations usually described in routine sampling of lungs in cases of deaths from diverse diseases. One lesion however appears more frequent and intense: infection of the pulmonary oedema. Inflammatory reactions are associated to acute arteritis at different stages of evolution which, in these patients, was more frequent in cases of shock.