H. Jerek. Heidelberg College.
Homotarrine cluding the VTA and NAC order nizagara 100mg, and may exert inhibitory con- (Acamprosate) nizagara 50mg line, a structural analogue of glutamate and an trol on mesolimbic dopamine neuron activity (29) (see NMDA-receptor antagonist, has been shown to almost dou- Chapter 95). Alcohol, psychostimulants, opiates, and nicotine (as well Some of the rewarding effects of ethanol result from acti- as tetrahydrocannabinol and phencyclidine) exert their pri- mary reinforcing or reward effects by releasing dopamine vation of opioid receptors in the VTA and/or receptors (DA) in the NAC. The acute reinforcing actions of psycho- in the NAC by the ethanol-induced release of endogenous stimulant drugs is mediated both by the blockade of DA -endorphin from terminals of the VTA and NAC as well binding to its transporter, preventing the reuptake of DA as release of enkephalins from intrinsic enkephalin neurons from the synaptic cleft (20), and by interaction with multi- in the NAC (34). The success of the opioid antagonist nal- ple DA receptors including D1, D2, and D3 (28). Cocaine trexone in modifying drinking behavior, controlling craving blocks the reuptake of serotonin (5-HT) and norepineph- and preventing relapse in alcoholics indicates that opioid rine in a similar fashion. A functional down-regulation of receptor-mediated mechanisms are activated by alcohol (34, 5-HT3 receptors in the NAC may contribute to cocaine 40). Chronic cocaine and (27) may relate to the finding that ethanol enhancement of alcohol administration also disrupts the endogenous opioid DA release in the NAC appears to require activation of system (20). Neuronal nicotinic acetyl- tion of nicotinic receptors in the VTA, ultimately leading choline receptors are structurally related to GABAAreceptors 1416 Neuropsychopharmacology: The Fifth Generation of Progress (41). Activation of these nicotinic receptors may enhance the development of alcoholism. One gene variant (allele) is ethanol reinforcement and voluntary intake (42). Alcohol Some studies have implicated involvement of the seroto- dehydrogenase (ADH) metabolizes ethanol to acetaldehyde, nin receptors 5-HT3 and possibly 5-HT4 in DA release a toxic intermediate, which is in turn converted to acetate in the NAC (31,43). Approximately half receptor that directly gates an ion channel and hence ethanol the population of Southeast (SE) Asian countries such as directly potentiates the effects of serotonin at this site (44). China, Japan, and Korea have functional polymorphisms at Chronic alcohol intake increases the sensitivity of 5-HT3 four different genes: ADH2, ADH3, ALDH1, and ALDH2. Across populations, the ALDH2-2 variant appears on a sim- The 5-HT3 antagonist ondansetron has been shown to re- ilar genetic background (haplotype) and thus has probably duce alcohol consumption in alcoholics (45). The most important variants are ALDH2-2 (Glu487–Lys487) and ADH2-2 GENETIC STUDIES OF ALCOHOLISM IN (Arg47–His47). ALDH2-2 dominantly inactivates ALDH2, HUMANS the ALDH that is mitochondrially localized and responsible for most acetaldehyde metabolism in cells. ADH2-2 is a In a heterogeneous disease such as alcoholism it is likely superactive variant. Allelic variation at ADH3 apparently that there are different environment-related thresholds and exerts no independent effect on the risk for alcoholism; different genes and gene variants. In addition there could however, ADH3-1 is in linkage disequilibrium with ADH2- be additive or nonadditive (epistatic) interactions between 2 (48,49) and is thus also predictive of vulnerability. Classic genetic analyses in ro- 2 and ALDH2-2 raise the levels of acetaldehyde by increas- dents show that certain alcohol-related phenotypes (e. On the other hand, lism, and by interacting additively, but not synergistically human data showing an approximately 2:1 MZ/DZ twin (50). The result is that ingestion of even small amounts of ratio of concordance for alcoholism and high recurrence ethanol produces an unpleasant reaction characterized by rates in first-degree relatives of alcoholics followed by a pro- facial flushing, headache, hypotension, palpitations, tachy- gressively decreasing risk in proportion to relatedness are cardia, nausea, and vomiting (51). In an analogous fashion, compatible with additivity of inheritance, and do not favor disulfiram, used in the treatment of alcoholism, and some multiple genes. The alcoholism genes identified so antiprotozoal drugs such as metronidazole, inhibit ALDH2 far—ALDH2 and ADH2—were discovered individually and thereby cause a flushing reaction after alcohol consump- but act additively when they co-occur (vide infra). Therefore, the protective effect of ALDH2 genotypes To dissect the multiple genetic influences on alcoholism can be regarded as analogous to protection with disulfiram, vulnerability, it may be necessary or useful to consider sev- as this flushing reaction, severe in homozygotes but milder eral phenotypes representing different aspects of the disease. The allele frequency of the homogeneous clinical groups by severity (dependence or dominantly acting ALDH2-2 is 0. Cloninger (46) divided alcoholics on flushing after alcohol consumption. Their risk of alcoholism a clinical and genetic epidemiologic basis into type 1 (mi- is reduced about four- to tenfold. Approximately 10% of lieu-limited, later onset) and type 2 (early onset, male domi- Japanese are ALDH2-2/ALDH2-2 homozygotes. Thus far, nated, associated with ASPD), thus linking premorbid per- only one alcoholic ALDH2-2/ALDH2-2 homozygote has sonality with alcoholism vulnerability and identifying an been observed across a series of studies in which several alcoholism subtype, type II, with a stronger genetic predis- hundred alcoholics have been genotyped, and that individ- position. This classification is supported by a study involv- ual is the focus of a report (52). Tu and Israel underlying dimensions of liability for alcoholism, drug dis- (53) found that acculturation accounted for some of the orders, ASPD, MD, and GAD that are familially transmit- variance (7–11%) in alcohol consumption for SE Asian ted with moderate specificity: (a) chronic dysphoric symp- males born in North America, although the ALDH2 poly- toms of anxiety and depression, and (b) acting-out behaviors morphism predicted two-thirds of the alcohol consumption and harmful substance use. Also, there are large differences in the prevalence of alcohol dependence in populations that GeneticsOf Alcohol Metabolism have similar ALDH2 allele frequencies. The frequencies of At the present time, the genes for alcohol metabolism are the ADH2 and ALDH2 variants are similar, but the preva- the only genes that are known to have a major impact on lence of alcoholism is 2. Such endophenotypes may be influenced by AND ADH2 GENOTYPES AND THE RISK FOR variation at fewer genes. The brain is relatively inaccessible, ALCOHOLISM IN SOUTHEAST ASIANS (48) so it has been more difficult to obtain biochemical and ALDH2 ADH2 Protective Factor physiologic measures that identify more specific genetic sub- types as was done decades ago for certain other common, ∗2/∗2 ∗2/∗2, ∗1/∗2, or ∗1/∗1 High ∗ ∗ ∗ ∗ ∗ ∗ broadly defined diseases (e. Association studies 2/ 1 2/ 2 or 2/ 1 ∗ ∗ of candidate genes, although laborious, have far greater 1/ 1 ∗1/∗1 ∗2/∗2 power for untangling the genetics of complex diseases than ∗2/∗1 linkage analysis (60). New approaches, including TDT ∗1/∗1 None (transmission disequilibrium test) analysis (61,62) and eth- nic matching using informative markers (63), have been ADH, alcohol dehydrogenase; ALDH, aldehyde dehydrogenase. Korea, suggesting that there are interactions with other ge- Rodent Models: Quantitative Trait Locus netic and environmental factors (54). Analyses The ADH2 genotype has been shown to be an indepen- Rodent strains are inbred to produce large numbers of ge- dent factor contributing to the risk of alcoholism (50) and netically identical animals that can be maintained under acts additively with the ALDH2-2 variant (Table 99. A controlled environmental conditions and intercrossed when pilot study found that the ADH2-2 allele accounts for 20% required.
Perhaps the attributed to effects on noradrenergic transmission nizagara 25mg without prescription. In general buy 50mg nizagara with visa, these values done on serotoninergic or noradrenergic systems is their tend to be sixfold to 10-fold higher (i. They are very weak than those found to inhibit such uptake into rat brain synap- inhibitors of NE reuptake and relatively weak inhibitors tosomes. An interesting specific difference is seen with ven- of 5-HT reuptake (167). If enhancement of serotoninergic lafaxine; its potency to inhibit 3H-NE uptake by rat brain transmission is a mechanism that ultimately leads to clinical is five to eight times greater than its potency on the other efficacy, it is not clear how antagonism of the 5-HT2Arecep- noradrenergic parameters. For serotoninergic parameters tor produces such enhancement. Some data indicate that also, the rankorder of potencies appears reasonably similar 5-HT2-receptor antagonism enhances 5-HT1A-receptor re- irrespective of the specific parameter—namely, paroxetine sponsivity (168,169), or that 5-HT2-receptor antagonists sertraline citalopram fluoxetine imipramine share discriminative stimulus properties with 5-HT1A- venlafaxine amitriptyline nortriptyline desipramine receptor antagonists (170). However, the potencies found for most of such effects (171), and whether such an effect would en- the drugs to inhibit hSERT binding are greater than those hance endogenous serotoninergic transmission is uncertain. Subsequently, radioligand binding increases the likelihood that an effect will occur clinically, techniques were developed such that the potencies of antide- and low potency (e. VALUES (nM) OF THE INHIBITION CONSTANT (Ki) 3H-NE Uptake 3H-NE Uptake Drug (Rat) rNET Binding (Human) hNET Binding Amitriptyline 14 9 102 27 Citalopram >3,000a >3,000 >30,000 >5,500 Desipramine 0. These values tend to be in good agreement with those reported by others. Potencies for drugs to inhibit the binding of radioligands to the NET or SERT in rat brain synaptosomes were taken from Owens et al. Potencies of drugs to inhibit the binding of selective radioligands to the hNET and hSERT were averaged from results in Owens et al. In general, the results obtained in these two studies are in remarkably close agreement. Finally, potencies of drugs to inhibit uptake of 3H-NE and 3H-5-HT by the hNET and hSERT, respectively, were taken from Owens et al. Such values tend to be in good agreement with those obtained by others using transfected cell systems, such as Eshleman et al. VALUES (nM) OF THE INHIBITION CONSTANT (Ki) 3H-5-HT Uptake 3H-5-HT Uptake Drug (Rat) rSERT Binding (Human) hSERT Binding Amitriptyline 84 16 36 4 Citalopram 1. These values tend to be in good agreement with those reported by others. Potencies for drugs to inhibit the binding of radioligands to the NET or SERT in rat brain synaptosomes were taken from Owens et al. Potencies of drugs to inhibit the binding of selective radioligands to the hNET and hSERT were averaged from results in Owens et al. In general, the results obtained in these two studies are in remarkably close agreement. Finally, potencies of drugs to inhibit uptake of 3H-NE and 3H-5-HT by the hNET and hSERT, respectively were taken from Owens et al. Such values tend to be in good agreement with those obtained by others using transfected cell systems, such as Eshleman et al. It is possible, then, to reaches its presumed site(s) of action (i. Because these drugs must act on brain values for the inhibition of uptake or ligand binding, shown to exert their beneficial effects, a factor that substantially in Tables 79. For a drug such as citalopram, it influences how much reaches the brain is the extent to which is obvious that its concentration in CSF is much greater than they are protein-bound. Because of the blood–brain barrier, that required to inhibit serotoninergic uptake or binding to the amount of drug in the extracellular fluid of brain (i. It is also obvious tion of non–protein-bound drug in plasma (i. Normal CSF contains so little protein that it may CSF to blockNE reuptake, again irrespective of the nora- be regarded as an ultrafiltrate of serum. Because most, but drenergic parameter or type of tissue. Considerable data not all, antidepressants are extensively bound to plasma pro- indicate that citalopram maintains selectivity as a 5-HT up- teins (180,181), their concentration in CSF is only a small take inhibitor in vivo (162). It is also apparent that desipra- fraction of the total concentration in serum. However, the potency of desipramine to block plasma concentrations of drug and concentrations in CSF. Although treatment with desipra- bound concentration in plasma. For this reason, also shown mine does lower concentrations of the serotonin metabolite in Table 79. TOTAL PLASMA AND CEREBROSPINAL FLUID CONCENTRATIONS OF SOME ANTIDEPRESSANTS Concentration (nM) in Protein Binding CSF CSF Drug (%)a Plasma (measured) (estimated) Reference Amitriptyline 95 512 33 Hanin et al. Even though such hydrophylic metabolites may have diminished lipid solubility, the penetration of some hydroxylated metabolites into CSF may be somewhat greater than that of the parent compounds, presumably because of decreased protein binding [Nordin et al. Nevertheless, such metabolites more often than not are more weakly potent than their parent compounds, so it is not likely as a rule that such metabolites contribute substantially to pharmacologic activity in brain. Chapter 79: Mechanism of Action of Antidepressants and Mood Stabilizers 1151 (192), it is unlikely that this observation directly reflects to blockNE uptake in vivo, especially at higher doses (206, the ability of the drug to block5-HT uptake. Thus, it seems reasonable to speculate that the most more likely to be some indirect effect. The clinical efficacy clinically relevant potency for venlafaxine at a noradrenergic of desipramine does not appear to depend on the availability parameter is its potency to block 3H-NE uptake by rat brain of 5-HT (194). Given this, any of the other three reached about selectivity (or nonselectivity) in vivo based serotoninergic values for desipramine, which are quite simi- on concentrations achieved in CSF and any of the noradren- lar, would seem to be a better indicator of what happens ergic or serotoninergic parameters.
J Sch Health 2006;76:307–12 Bruzzese JM discount nizagara 100mg with visa, Unikel L generic nizagara 50mg visa, Gallagher R, Evans D, Colland V. Feasibility and impact of No eligible economic a school-based intervention for families of urban adolescents with asthma: results from a outcomes randomized pilot trial. Fam Process 2008;47:95–113 Buchner DA, Butt LT, De Stefano A, Edgren B, Suarez A, Evans RM. Effects of an asthma No comparator; adult/child management program on the asthmatic member: patient-centered results of a 2-year study mixed data in a managed care organization. Am J Manag Care 1998;4:1288–97 Buelow JM, Johnson CS, Perkins SM, Austin JK, Dunn DW. Creating Avenues for Parent No eligible economic Partnership (CAPP): an intervention for parents of children with epilepsy and learning outcomes problems. Epilepsy Behav 2013;27:64–9 Butz AM, Malveaux FJ, Eggleston P, Thompson L, Schneider S, Weeks K, et al. Use of Absent/ineligible comparator community health workers with inner-city children who have asthma. Clin Pediatr 1994;33:135–41 Bynum A, Hopkins D, Thomas A, Copeland N, Irwin C. The effect of telepharmacy No eligible economic counseling on metered-dose inhaler technique among adolescents with asthma in rural outcomes Arkansas. Telemed J E Health 2001;7:207–17 Bywater T, Hutchings J, Linck P, Whitaker C, Daley D, Yeo ST, et al. Incredible Years parent Population training support for foster carers in Wales: a multi-centre feasibility study. Child Care Health Dev 2011;37:233–43 Cabral ALB, Carvalho WAF, Chinen M, Barbiroto RM, Boueri FMV, Martins MA. Are Study design International Asthma Guidelines effective for low-income Brazilian children with asthma? Eur Respir J 1998;12:35–40 Catov JM, Marsh GM, Youk AO, Huffman VY. Asthma home teaching: two evaluation No eligible health outcomes approaches. Dis Manag 2005;8:178–87 Charlton I, Charlton G, Broomfield J, Mullee MA. Audit of the effect of a nurse run asthma No eligible health outcomes clinic on workload and patient morbidity in a general practice. Br J Gen Pract 1991;41:227–31 Chase HP, Crews KR, Garg S, Crews MJ, Cruickshanks KJ, Klingensmith G, et al. Clin Pediatr 1992;31:450–6 Chen SH, Yeh KW, Chen SH, Yen DC, Yin TJ, Huang JL. The development and establishment No eligible health outcomes of a care map in children with asthma in Taiwan. J Asthma 2004;41:855–61 104 NIHR Journals Library www. Interactive support interventions for caregivers of No eligible health outcomes asthmatic children. J Asthma 2013;50:649–57 Chiang LC, Ma WF, Huang JL, Tseng LF, Hsueh KC. Effect of relaxation-breathing training Ineligible intervention on anxiety and asthma signs/symptoms of children with moderate-to-severe asthma: a randomized controlled trial. Int J Nurs Stud 2009;46:1061–70 Clark NM, Feldman CH, Evans D, Levison MJ, Wasilewski Y, Mellins RB. The impact of No eligible health outcomes health education on frequency and cost of health care use by low income children with asthma. J Allergy Clin Immunol 1986;78:108–15 Cottrell CK, Young GA, Creer TL, Holroyd KA, Kotses H. The development and evaluation No eligible economic of a self-management program for cystic fibrosis. Pediatr Asthma Allergy Immunol outcomes 1996;10:109–18 Coughey K, Klein G, West C, Diamond JJ, Santana A, McCarville E, et al. The child asthma No eligible health outcomes link line: a coalition-initiated, telephone-based, care coordination intervention for childhood asthma. J Asthma 2010;47:303–9 Creer TL, Backial M, Burns KL, Leung P, Marion RJ, Miklich DR, et al. Genesis and development of a self-management program for childhood asthma. Medications prescribed for children with mood disorders: No eligible health outcomes effects of a family-based psychoeducation program. Exp Clin Psychopharmacol 2007;15:555–62 DePue JD, McQuaid EL, Koinis-Mitchell D, Camillo C, Alario A, Klein RB. Providence school Wrong study design asthma partnership: school-based asthma program for inner-city families. J Asthma 2007;44:449–53 Ducharme FM, Zemek RL, Chalut D, McGillivray D, Noya FJD, Resendes S, et al. Written Ineligible intervention action plan in pediatric emergency room improves asthma prescribing, adherence, and control. Am J Respir Crit Care Med 2011;183:195–203 Ellis DA, Naar-King S, Frey M, Templin T, Rowland M, Greger N. Use of multisystemic No eligible health outcomes therapy to improve regimen adherence among adolescents with type 1 diabetes in poor metabolic control: a pilot investigation. J Clin Psychol Med Settings 2004;11:315–24 Ellis DA, Templin T, Naar-King S, Frey MA, Cunningham PB, Podolski CL, et al.
However generic nizagara 100mg online, it is the people who do research – with their curiosity discount 50mg nizagara otc, imagination, motivation, technical skills, experience and connections – that are most critical to the success of the research enterprise. Codes of practice, which are the cornerstone of any research system, are already in use in many countries. Te task ahead is to ensure that such codes of practice are comprehensive and apply in all countries, and to encourage adherence everywhere. Achieving universal health coverage depends on research ranging from studies of causation to studies of how health systems function. However, because many existing cost-efective interventions are not widely used, there is a particular need to close the gap between existing knowledge and action. Areas of research that need special attention concern the implementation of new and existing technologies, health service operations, and the design of efective health systems. To help bridge the gap between science and practice, research should be strengthened not only in academic centres but also in public health programmes, close to the supply of and demand for health services. How can research for universal health coverage be supported nationally and internationally? In the wake of many previous reports, Chapter 4 presents three mechanisms to stimulate and facilitate research for universal health coverage – monitoring, coor- dination and fnancing. Provided there is a commitment to share data, national and global observatories could be established to monitor research activities. Observatories could serve a variety of functions, acting as repositories of data on xv Research for universal health coverage the process of doing research and presenting and sharing the fndings of research studies. Such data would help in tracking progress towards universal health cover- age, country by country. Monitoring supports the second function, coordination, on various levels – by sharing information, by jointly setting research priorities, or by facilitating col- laboration on research projects. Regarding the third function, fnancing, health research is more efective and productive if there is a guaranteed, regular income. Sustained fnancing guarantees that research projects are not interrupted or otherwise compromised by a sudden lack of resources. Various mechanisms for raising and disbursing additional research funds have been proposed and are under discussion. Whatever mecha- nism is adopted, international donors and national governments should measure progress against their own commitments to investing in health research. How will WHO support research for universal health coverage? Chapter 5 draws out the dominant themes of the report, and proposes a set of actions by which the research community, national governments, donors, civil society and international organizations, including WHO, can support the research that is needed if we are to reach universal health coverage. Tis report is closely aligned with the aims of the WHO strategy, which encourages the highest-quality research in order to deliver the greatest health ben- efts to the maximum number of people. Key points ■ The goal of universal health coverage is to ensure that all people obtain the health services they need – prevention, promotion, treatment, rehabilitation and palliation – without risk of financial ruin or impoverishment, now and in the future. This is illustrated by progress towards the health- related Millennium Development Goals (MDGs), and in the widespread fall in cash payments made for using health services. Thus nearly half of all HIV-infected people eligible for antiretroviral therapy were still not receiving it in 2011; and an estimated 150 million people suffer financial catastrophe each year because they have to pay out-of-pocket for health services. Consequently, given limited resources, each nation must determine its own priorities for improving health, the services that are needed, and the appropriate mechanisms for financial risk protection. First, and most important, are questions about improving health and well-being – questions that help us to define the interventions and services that are needed, including financial risk protection, discover how to expand the coverage of these services, including the reduction of inequities in coverage, and investigate the effects of improved coverage on health. The second set of questions is about measurement – of the indicators and data needed to monitor service coverage, financial risk protection, and health impact. One task for research is to help define a set of common indicators for comparing progress towards universal coverage across all countries. Through the cycle of research – questions yield answers which provoke yet more questions – there will always be new opportunities to improve health. As a descendant of the “Health for All” movement (Box 1. Tese services range from clinical care for individual patients to the public services that protect the health of whole populations. Tey include services that come from both within and beyond the health sector. Financial risk protection is one element in the package of measures that provides overall social protection (7). And protection against severe fnancial difculties in the event of illness gives the peace of mind that is an integral part of well-being. Tese are personal and moral choices regarding the kind of society that people wish to live in, taking universal cov- erage beyond the technicalities of health fnancing, public health and clinical care. With a greater understanding of the scope of universal health coverage, many national governments now view progress towards that goal as a guiding principle for the development of health systems, and for human development generally. It is clear that healthier environments mean healthier people (9). Preventive and curative services protect health and protect incomes (10, 11). Healthy children are better able to learn, and healthy adults are better able to contribute socially and economically. Te path to universal health coverage has been dubbed “the third global health transition”, afer the demographic and epidemiological transitions (12). Universal coverage is now an ambition for all nations at all stages of develop- ment.
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