The cost effectiveness of pharmacological smoking cessation therapies in developing countries: a case study in the Seychelles

OBJECTIVE: To examine the incremental cost effectiveness of the five first line pharmacological smoking cessation therapies in the Seychelles and other developing countries. DESIGN: A Markov chain cohort simulation. SUBJECTS: Two simulated cohorts of smokers: (1) a reference cohort given physician counselling only; (2) a treatment cohort given counselling plus cessation therapy. INTERVENTION: Addition of each of the five pharmacological cessation therapies to physician provided smoking cessation counselling. MAIN OUTCOME MEASURES: Cost per life-year saved (LYS) associated with the five pharmacotherapies. Effectiveness expressed as odds ratios for quitting associated with pharmacotherapies. Costs based on the additional physician time required and retail prices of the medications. RESULTS: Based on prices for currently available generic medications on the global market, the incremental cost per LYS for a 45 year old in the Seychelles was 599 US dollars for gum and 227 dollars for bupropion. Assuming US treatment prices as a conservative estimate, the incremental cost per LYS was significantly higher, though still favourable in comparison to other common medical interventions: 3712 dollars for nicotine gum, 1982 dollars for nicotine patch, 4597 dollars for nicotine spray, 4291 dollars for nicotine inhaler, and 1324 dollars for bupropion. Cost per LYS increased significantly upon application of higher discount rates, which may be used to reflect relatively high opportunity costs for health expenditures in developing countries with highly constrained resources and high overall mortality. CONCLUSION: Pharmacological cessation therapy can be highly cost effective as compared to other common medical interventions in low mortality, middle income countries, particularly if medications can be procured at low prices.

Novel action of a wake-promoting neuropeptide in hippocampus : inhibition of nmda receptor function at excitatory synapses through orexin-a

One of the most intriguing functions of the brain is the ability to learn and memorize. The mechanism through which memory and learning are expressed requires the activation of NMDA receptors (NMDARs). These molecular entities are placed at the postsynaptic density of excitatory synapses and their function is tightly controlled by the actions of several modulators at the extracellular, intracellular and pore sites. A large part of the intracellular modulation comes from the action of G-protein coupled receptors (GPCRs). Through intracellular cascades typically involving kinases and phosphatases, GPCRs potentiate or inhibit NMDARs, controlling the conductive state but also the trafficking within the synapse. The GPCRs are involved in the modulation of a variety of brain functions. Many of them control cognition, memory and learning performance, therefore, their effects on NMDARs are extensively studied. The orexinergic system signals through GPCRs and it is well known for the regulation of waking, feeding, reward and autonomic functions. Moreover, it is involved in potentiating hippocampus-related cognitive tasks. Orexin receptors and fibers are present within the hippocampus, but whether these directly modulate hippocampal cells and synapses has not yet been determined. During my thesis, I studied orexinergic actions on excitatory synaptic transmission via whole-cell patch-clamp recordings in rat acute hippocampal slices. I observed that exogenously applied orexin-A (ox-A) exerted a strong inhibitory action on NMDAR-mediated synaptic potentials at mossy fiber (MF)-CA3 synapses, by postsynaptically activating orexin-2 receptors, a minor inhibition at Schaffer collateral-CAl synapses and did not affect other synapses with the CA3 area. Moreover, I demonstrated that the susceptibility of NMDARs to ox- A depends on the tone of endogenous orexin known to fluctuate during the day-night cycle. In fact, in slices prepared during the active period of the rats, when endogenous orexin levels are high, NMDAR-currents were not affected by exogenously applied ox-A. The inhibitory effect of ox-A was, however, reverted when interfering with the orexinergic system through intraperitoneal injections of almorexant, a dual orexin receptor antagonist, during the active phase prior to slice preparation. This thesis work suggests that the orexinergic system regulates NMDAR-dependent information flow through select hippocampal pathways depending on the time-of-day. The specific orexinergic modulation of NMDARs at MFs dampens the excitability of the hippocampal circuit and could impede the mechanisms related to memory formation, possibly also following extended periods of waking. -- La capacité d'apprentissage et de mémorisation est une des fonctions les plus intrigantes de notre cerveau. Il a été montré qu'elles requièrent l'activation des récepteurs NMDA (NMDARs). Ces entités moléculaires sont présentes au niveau de la densité post-synaptique des synapses excitatrices et leur fonction est étroitement contrôlée par l'action de nombreux modulateurs au niveau extracellulaire, intracellulaire et membranaire de ces récepteurs. Une grande partie de la modulation intracellulaire s'effectue via l'action de récepteurs couplés aux protéines G (GPCRs). Grace à leurs cascades intracellulaires typiquement impliquant des kinases et des phosphatases, les GPCRs favorisent l'activation ou l'inhibition des NMDARs, contrôlant ainsi leur perméabilité mais aussi leur mouvement à la synapse. Les GPCRs sont impliquées dans de nombreuses fonctions cérébrales telles que la cognition, la mémoire ainsi que la capacité d'apprentissage c'est pour cela que leurs effets sur les NMDARs sont très étudiés. Le système orexinergique fait intervenir ces GPCRs et est connu par son rôle dans la régulation de fonctions physiologiques telles que l'éveil, la prise alimentaire, la récompense ainsi que d'autres fonctions du système nerveux autonome. De plus, ce système est impliqué dans la régulation de tâches cognitives liées à l'hippocampe. Bien que les fibres et les récepteurs à l'orexine soient présents dans l'hippocampe, leur mécanisme d'action sur les cellules et les synapses de l'hippocampe n'a pas encore été élucidé. Durant ma thèse, je me suis intéressée aux effets de l'orexine sur la transmission synaptique excitatrice en utilisant la méthode d'enregistrement en patch-clamp en configuration cellule entière sur des tranches aiguës d'hippocampes de rats. J'ai observé que l'application exogène d'orexine A d'une part inhibe fortement les courants synaptiques dépendants de l'activation des NMDARs au niveau de la synapse entre les fibres moussues et CA3 via l'activation post-synaptique des orexine récepteurs 2 mais d'autre part n'inhibe que de façon mineure la synapse entre les collatérales de Schaffer et CAI et n'affecte pas les autres synapses impliquant CA3. J'ai également démontré que la sensibilité des NMDARs à l'orexine A dépend de sa concentration endogène qui fluctue durant le cycle éveil-sommeil. En effet, lorsque les coupes d'hippocampes sont préparées durant la période active de l'animal correspondant à un niveau endogène d'orexine élevé, l'application exogène d'orexine A n'a aucun effet sur les courants dépendants de l'activation des NMDARs. Cependant, l'injection dans le péritoine, durant la phase active de l'animal, d'un antagoniste des orexine récepteurs, l'almorexant, va supprimer l'effet inhibiteur de l'orexine A. Les résultats de ma thèse suggèrent donc que le système orexinergique module les informations véhiculées par les NMDARs via des voies de signalisation sélectives de l'hippocampe en fonction du moment de la journée. La modulation orexinergique des NMDARs au niveau des fibres moussues diminue ainsi l'excitabilité du circuit hippocampal et pourrait entraver les mécanismes liés à la formation de la mémoire, potentiellement après de longues périodes d'éveil.

Addressing non-communicable diseases in the Seychelles: towards a comprehensive plan of action.

This article reviews the different steps taken during the past 20 years for the prevention and control of non-communicable diseases (NCDs) in the Seychelles. National surveys revealed high levels of several cardiovascular risk factors and prompted an organized response, starting with the creation of an NCD unit in the Ministry of Health. Information campaigns and nationwide activities raised awareness and rallied increasingly broad and high-level support. Significant policy was developed including comprehensive tobacco legislation and a School Nutrition Policy that bans soft drinks in schools. NCD guidelines were developed and specialized 'NCD nurses' were trained to complement doctors in district health centers. Decreasing smoking prevalence is evidence of success, but the raising so-called diabesity epidemic calls for an integrated multi-sector policy to mould an environment conducive to healthy behaviors. Essential components of these efforts include: effective surveillance mechanisms supplemented by focused research; generating broad interest and consensus; mobilizing leadership and commitment at all levels; involving local and international expertise; building on existing efforts; and seeking integrated, multi-disciplinary and multi-sector approaches.

Constitutive activity of receptors coupled to guanine nucleotide regulatory proteins.

Adrenoceptors are prototypic members of the superfamily of seven transmembrane domain, G protein-coupled receptors. Study of the properties of several mutationally activated adrenoceptors is deepening understanding of the normal functioning of this ubiquitous class of receptors. The new findings suggest an expansion of the classical ternary complex model of receptor action to include an explicit isomerization of the receptors from an inactive to an active state which couples to the G protein ('allosteric ternary complex model'). This isomerization involves conformational changes which may occur spontaneously, or be induced by agonists or appropriate mutations which abrogate the normal 'constraining' function of the receptor, allowing it to 'relax' into the active conformation. Robert Lefkowitz and colleagues discuss the physiological and pathophysiological implications of these new insights into regulation of receptor activity.

Pharmacological treatment of behavioral and psychological symptoms of dementia (BPSD) in nursing homes: development of practice recommendations in a Swiss canton

OBJECTIVES: In 2002, the canton of Fribourg, Switzerland, implemented a coordinated pharmaceutical care service in nursing homes to promote rational drug use. In the context of this service, a project was conducted to develop recommendations for the pharmacological management of behavioral and psychological symptoms of dementia (BPSD) in nursing home residents. DESIGN AND METHODS: Selected evidence-based guidelines and meta-analysis sources related to the management of depression, insomnia, and agitation in dementia patients were systematically searched and evaluated. Evidence and controversies regarding the pharmacological treatment of the most common BPSD symptoms were reviewed, and treatment algorithms were developed. RESULTS: Ten evidence-based guidelines and meta-analyses for BPSD management were identified, with none specifically addressing issues related to nursing home residents. Based on this literature, recommendations were developed for the practice of pharmacological management of depression, sleep disturbances, and agitation in nursing home residents. For depression, SSRIs are considered the first choice if an antidepressant is required. No clear evidence has been found for sleep disturbances; the underlying conditions need to be investigated closely before the introduction of any drug therapy. Many drugs have been investigated for the treatment of agitation, and if necessary, antipsychotics could be used, although they have significant side effects. Several areas of uncertainty were identified, such as the current controversy about typical and atypical antipsychotic use or the appropriateness of cholinesterase inhibitors for controlling agitation. Treatment algorithms were presented to general practitioners, pharmacists, and medical directors of nursing homes in the canton of Fribourg, and will now be implemented progressively, using educational sessions, pharmaceutical counseling, and monitoring. CONCLUSION: Based on existing evidence-based studies, recommendations were developed for the practice of pharmacological management of depression, sleep disturbances, and agitation in nursing home residents. It should be further studied whether these algorithms implemented through pharmaceutical care services will improve psychotropic drug prescriptions and prevent drug-related problems in nursing home residents

Glucagon-like peptide-I and the control of insulin secretion in the normal state and in NIDDM.

Potentiation of glucose-induced insulin secretion by intestinal factors has been described for many years. Today, two major peptides with potent insulinotropic action have been recognized: gastric inhibitory peptide and truncated forms of glucagon-like peptide I, GLP-I(7-37) or the related GLP-I(7-36)amide. These hormones have specific beta-cell receptors that are coupled to production of cAMP and activation of cAMP-dependent protein kinase. Elevation in intracellular cAMP levels is required to mediate the glucoincretin effect of these hormones: the potentiation of insulin secretion in the presence of stimulatory concentrations of glucose. In addition, circulating glucoincretins maintain basal levels of cAMP, which are necessary to keep beta-cells in a glucose-competent state. Interactions between glucoincretin signaling and glucose-induced insulin secretion may result from the phosphorylation of key elements of the glucose signaling pathway by cAMP-dependent protein kinase. These include the ATP-dependent K+ channel, the Ca++ channel, or elements of the secretory machinery itself. In NIDDM, the glucoincretin effect is reduced. However, basal or stimulated gastric inhibitory peptide and glucagon-like peptide I levels are normal or even elevated, suggesting that signals induced by these hormones on the beta-cells are probably altered. At pharmacological doses, infusion of glucagon-like peptide I but not gastric inhibitory peptide, can ameliorate postprandial insulin secretory response in NIDDM patients. Agonists of the glucagon-like peptide I receptor have been proposed as new therapeutic agents in NIDDM.

Inhibition of voltage-gated Na(+) currents in sensory neurones by the sea anemone toxin APETx2.

BACKGROUND AND PURPOSE: APETx2, a toxin from the sea anemone Anthropleura elegantissima, inhibits acid-sensing ion channel 3 (ASIC3)-containing homo- and heterotrimeric channels with IC(50) values < 100 nM and 0.1-2 µM respectively. ASIC3 channels mediate acute acid-induced and inflammatory pain response and APETx2 has been used as a selective pharmacological tool in animal studies. Toxins from sea anemones also modulate voltage-gated Na(+) channel (Na(v) ) function. Here we tested the effects of APETx2 on Na(v) function in sensory neurones.¦EXPERIMENTAL APPROACH: Effects of APETx2 on Na(v) function were studied in rat dorsal root ganglion (DRG) neurones by whole-cell patch clamp.¦KEY RESULTS: APETx2 inhibited the tetrodotoxin (TTX)-resistant Na(v) 1.8 currents of DRG neurones (IC(50) , 2.6 µM). TTX-sensitive currents were less inhibited. The inhibition of Na(v) 1.8 currents was due to a rightward shift in the voltage dependence of activation and a reduction of the maximal macroscopic conductance. The inhibition of Na(v) 1.8 currents by APETx2 was confirmed with cloned channels expressed in Xenopus oocytes. In current-clamp experiments in DRG neurones, the number of action potentials induced by injection of a current ramp was reduced by APETx2.¦CONCLUSIONS AND IMPLICATIONS: APETx2 inhibited Na(v) 1.8 channels, in addition to ASIC3 channels, at concentrations used in in vivo studies. The limited specificity of this toxin should be taken into account when using APETx2 as a pharmacological tool. Its dual action will be an advantage for the use of APETx2 or its derivatives as analgesic drugs.

NR2A at CA1 synapses is obligatory for the susceptibility of hippocampal plasticity to sleep loss.

A loss in the necessary amount of sleep alters expression of genes and proteins implicated in brain plasticity, but key proteins that render neuronal circuits sensitive to sleep disturbance are unknown. We show that mild (4-6 h) sleep deprivation (SD) selectively augmented the number of NR2A subunits of NMDA receptors on postsynaptic densities of adult mouse CA1 synapses. The greater synaptic NR2A content facilitated induction of CA3-CA1 long-term depression in the theta frequency stimulation range and augmented the synaptic modification threshold. NR2A-knock-out mice maintained behavioral response to SD, including compensatory increase in post-deprivation resting time, but hippocampal synaptic plasticity was insensitive to sleep loss. After SD, the balance between synaptically activated and slowly recruited NMDA receptor pools during temporal summation was disrupted. Together, these results indicate that NR2A is obligatory for the consequences of sleep loss on hippocampal synaptic plasticity. These findings could advance pharmacological strategies aiming to sustain hippocampal function during sleep restriction.