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Schizophrenic and medical inpatients as informed chiatry 1999;46:1106–1119 generic fertomid 50 mg fast delivery. False hopes and best drug discontinuation studies in schizophrenia fertomid 50 mg without a prescription. Arch Gen Psychia­ data: consent to research and the therapeutic misconception. Preliminary findings on uation and symptom-provoking studies. Biol Psychiatry 1999;46: psychiatric patients as research participants: a population at risk? Psychopharmacol Bull 1982;18: Ethics in psychiatric research: a resource manual for human subjects 102–104. Washington, DC: American Psychiatric Association, 66. Missing the boat: competence and consent in probabilistic inference task. Ethical aspects of demen­ Arch Gen Psychiatry 1997;54:117–120. Am J Psychiatry formed consent: myths and realities. Abilities of patients to consent to psychiatric and medi­ for informed consent: a review of empirical research. Medical decision- informed consent in schizophrenia research. Arch Gen Psychiatry making among elderly people in long-term care. The Unethical use of persons with mental illness 734–737. Mentally disabled research subjects: the enduring pol- Subcommittee of the National Bioethics Advisory Commission icy issues. Research with cognitively impaired subjects: unfin­ vanced directives with cognitively impaired research subjects. In: ished business in the regulation of human research. A statement of principles of ethical conduct for neuro­ ton, DC: American Psychiatric Association, 1999. Alzheimer Dis ment of ethical guidelines for neuropsychopharmacologic re- Assoc Dis 1994;4:19–27. Surrogate decision-making for severely cognitively American College of Neuropsychopharmacology (ACNP). April impaired research subjects: the continuing debate. Proxy decision-making in Alzheimer disease research: 16, 1999, p 12. When the of an NDA for the product prior to marketing it. Impor- premarket clearance system was first introduced in 1938 in tantly, although it is not widely appreciated, NDAs are not the aftermath of the Elixir of Sulfanilamide tragedy in which approved for drug substances (i. By law, authority to approve NDAs APPLICATION resides with the Secretary of the Department of Health and Human Services, but the Secretary delegates the actual au- Because the Act forbids the introduction into interstate thority to review and approve NDAs to the Food and Drug commerce of new drugs unless they are the subjects of an Administration (FDA, the agency). Paul Leber: Neuro-Pharm Group, LLC, Potomac, Maryland. The original FFDCA (1938), accordingly, provided for 486 Neuropsychopharmacology: The Fifth Generation of Progress precisely such an exemption, known then as a 'Notice of ulations and policies necessary to secure the aims Congress Claimed Investigational Exemption for a New Drug. Initially, an investigational exemption could be obtained Safety largely for the asking. Between 1938 and 1963, the sponsor Insofar as safety is concerned, the Act demands that a spon- of an IND had only to agree to keep records and clearly sor provide full reports of all tests necessary to establish that label its new drug as to its status as an unapproved investiga- its product will be safe for use. The Act instructs the agency tional new drug, but little else. Congress was led to alter the quate to show that the drug, as recommended for use, is requirements for investigational use because of yet another safe for use, or show that the drug, again as recommended public health disaster involving a drug product. However, the potent teratogen thalidomide was widely dis- Efficacy tributed under INDs in the United States; worse, when its The Act instructs the FDA to approve an NDA unless, on teratogenicity was recognized and efforts were undertaken review of the reports submitted, it concludes there is a lack to recall the supplies of it that had been distributed, the of 'substantial evidence' that the drug is effective as claimed extent of domestic distribution was not easily determined. Although very few American women who had received thalidomide under an IND bore children with limb reduc- tion defects, the episode raised substantial concerns about the safety of human research subjects (2,3). Under the 1962 amendments, the agency gained explicit No pharmacologically active drug substance is ever likely authority not only to establish mandatory prerequisites for to be entirely free of risk.

Moreover cheap fertomid 50 mg with visa, the relationship be- hippocampal afferents (46) generic fertomid 50 mg on-line, or amygdala afferents (47) to tween DA neuron firing and release was altered. Thus, al- the accumbens, all of which use glutamate as a transmitter. There is also evidence that glutamate can release chronic antipsychotic drug (60). Thus, correlations between acetylcholine or serotonin in the striatum, which in turn cell firing patterns and DA levels postsynaptically appear to can trigger DA release (43). Glutamate may also stimulate depend on the state of the system. DA release via an action on other local systems, such as It is also possible that there may be local fluctuations in those producing NO. NO is known to be released from tonic DA stimulation that may be a consequence of in- striatal interneurons containing the enzyme NOS, and exert creases in DA neuron firing. Indeed, studies using voltamet- actions on neuronal elements in the vicinity of the release ric measures have shown that brief elevations in extracellular site. Infusion of NOS substrates or NO generator com- DA may occur as a consequence of rapid burst firing, over- pounds was found to facilitate the release of both glutamate whelming the DA uptake process (61). This relationship is and DA within the striatum in a calcium-dependent man- particularly important during administrations of drugs that ner, and is dependent on vesicular stores (52,53). Moreover, interfere with the uptake process, such as cocaine or amphet- the NO-induced efflux of striatal glutamate was found to amine (57,58). Such drugs would cause phasic DA release indirectly enhance extracellular DA levels in the striatum to rapidly augment tonic DA levels, leading to high extracel- in a manner dependent on NMDA and AMPA receptors lular DA and abnormal levels of down-regulation of spike- (53,54). Therefore, it is likely that excitatory amino acids dependent DA release. In a similar nature, in mice lacking and NO interact with DA neuron firing to regulate DA the DA transporter, the extracellular DA is already elevated release from presynaptic sites within the striatum. This tonic/ extracellular DA and glutamate within the striatum (55), phasic balance has been proposed to underlie normal and which would thereby increase in the behavioral response to dysfunctional DA regulation as it relates to the pathophysi- amphetamine (56). Thus, evidence indicates that alterations ology of schizophrenia, drug abuse, and the treatment of in tonic DA levels produced by cortical afferents can po- ADHD (44,57,58). Such tonic down- literature has emerged regarding the functional relevance of modulation of spike-dependent DA release could play a extrasynaptic DA receptors. Indeed, studies have shown that particular role when the uptake system is inactivated by in the PFC, the DA terminals located in the deep layers of psychostimulants. Thus, although the DA transporter is cortex do not contain DA transporters (63). As a conse- normally highly effective at removing DA from the synaptic quence, the DA released from these sites would be free to cleft before it can escape into the extracellular space, block- diffuse to a much greater extent than in areas such as the ade of the DA transporter would allow substantially higher striatum and accumbens. This is further substantiated by levels of DA to escape the cleft and contribute to the tonic evidence that a substantial portion of the DA that is released extracellular DA pool (57). Such a condition is thought to in the PFC is actually taken up and deaminated in norepi- underlie some of the therapeutic actions of psychostimu- nephrine (NE) terminals (64). This arrangement would lants in attention deficit/hyperactivity disorder (ADHD) have substantial functional implications. This was found to be a significant issue when testing Moreover, such a condition could imply that NE uptake Chapter 9: Dopamine 123 blockers could serve to increase the functional actions of DA in the PFC by preventing its removal via NE terminals. This may also have implications regarding the clinical ac- tions of NE-selective antidepressant drugs within this brain region. POSTSYNAPTIC EFFECTS OF DA DA exerts a myriad of actions on postsynaptic systems. These actions can occur at the level of individual cells in terms of direct postsynaptic actions, as well as altering cellu- lar interactions (via presynaptic effects and network modula- tion). Moreover, the nature of these effects can vary depend- ing on both the specific region examined and the time course of DA agonist administration. The DARPP-32 signaling pathway has a central role D1 stimulation decreases excitability of dorsal striatal and in mediating signal transduction within medium spiny neurons in the striatum. A variety of neurotransmitters act on systems accumbens neurons (67–69), although others have reported regulating the phosphorylation of DARPP-32, which in turn mod- excitation by this agonist (70). Within the dorsal striatum, ulatesthe activityof proteinphosphatase-1 (PP-1). DA stimulation D1 receptor stimulation decreases current-evoked action of D1 receptors acts via cAMP and PKA to phosphorylate DARPP- 32, which in turn inhibits PP-1;this works in synergy with different potential discharge in hyperpolarized neurons, although an protein kinases to increase the level of protein phosphorylation enhancement in excitability can be obtained with longer of their targets. In contrast, stimulation of D2 receptors atten- uates D1 activation of adenylate cyclase as well as leading to duration or higher frequency current pulses (71).

Incidence and clinical relevance of uncontrolled ventricular rate during atrial fibrillation in heart failure patients treated with cardiac resynchronization therapy generic 50mg fertomid amex. Ventricular rate control may be an alternative to sinus rhythm control in persistent atrial fibrillation cheap fertomid 50 mg free shipping. Amiodarone for the restoration of sinus rhythm in patients with atrial fibrillation. Ablation of complex fractionated atrial electrogram (CFAE) in addition to pulmonary vein isolation and linear ablation does not improve single procedural success rate of catheter ablation for persistent atrial fibrillation. Efficacy of ganglionated plexi ablation plus pulmonary vein isolation for atrial fibrillation. D-5 Not an RCT of ≥20 Patients or an Observational Study of ≥100 Patients Alcaraz R, Hornero F, Rieta JJ. Enhancement of atrial fibrillation electrical cardioversion procedures through the arrhythmia organization estimation from the ECG. Catheter ablation of typical atrial flutter: a randomized comparison of 2 methods for determining complete bidirectional isthmus block. Importance of left atrial diameter and atrial fibrillatory frequency for conversion of persistent atrial fibrillation with oral flecainide. Atrial fibrillation ablation: importance of cavotricuspid isthmus block. High-flow perfusion of sheaths for prevention of thromboembolic complications during complex catheter ablation in the left atrium. Atrial tachycardia after circumferential pulmonary vein ablation of atrial fibrillation: mechanistic insights, results of catheter ablation, and risk factors for recurrence. Predictors of sinus rhythm after radiofrequency maze and mitral valve surgery. Role of the simultaneous sequential strategy for failed acute sinus restoration after modified left maze procedure for persistent atrial fibrillation with concomitant mitral surgery. The efficacy of inducibility and circumferential ablation with pulmonary vein isolation in patients with paroxysmal atrial fibrillation. Long-term safety and efficacy of circumferential ablation with pulmonary vein isolation. A clinical study of patients with and without recurrence of paroxysmal atrial fibrillation after pulmonary vein isolation. Treatment of atrial fibrillation by silencing electrical activity in the posterior inter-pulmonary-vein atrium. Clinical determinants of sinus conversion by radiofrequency maze procedure for persistent atrial fibrillation in patients undergoing concomitant mitral valvular surgery. Atrial pacemaker complex preserved radiofrequency maze procedure reducing the incidence of sick sinus syndrome in patients with atrial fibrillation. Chiladakis J, Koutsogiannis N, Kalogeropoulos A, et al. Usefulness of rate regulation through continuous ventricular pacing in patients with drug-controlled slower atrial fibrillation and normal or depressed left ventricular systolic function. Chiladakis JA, Koutsogiannis N, Kalogeropoulos A, et al. Adverse effects of continuous ventricular pacing in patients with slower atrial fibrillation and normal left ventricular systolic function. Outcomes in patients requiring cardioversion following catheter ablation of atrial fibrillation. Clinical significance of complete conduction block of the left lateral isthmus and its relationship with anatomical variation of the vein of Marshall in patients with nonparoxysmal atrial fibrillation. Short and midterm results of epi and endocardial cryoablation. Catheter ablation of atypical atrial flutter and atrial tachycardia within the coronary sinus after left atrial ablation for atrial fibrillation. Two Versus One Repeat Freeze-Thaw Cycle(s) After Cryoballoon Pulmonary Vein Isolation: The ALSTER EXTRA Pilot Study. Predictive value of indexes of inflammation and hypercoagulability on success of cardioversion of persistent atrial fibrillation. The duration of atrial fibrillation influences the long-term efficacy of low-energy internal cardioversion. Inflammatory markers are not associated with outcomes following elective external cardioversion. Mechanism of recurrence after radiofrequency catheter ablation of atrial fibrillation guided by complex fractionated atrial electrograms.

Study design A prospective observational cohort study assessed the impact of the introduction of telemedicine on the quality of paediatric care purchase 50 mg fertomid amex. Te added value order fertomid 50 mg mastercard, as perceived by local clinicians using the service, was also assessed using a questionnaire 67 Research for universal health coverage Summary of fndings of interest among those using telemedicine is Of 3920 paediatric admissions, 346 (9%) were unlikely to explain this fnding as all children referred to the telemedicine service. In 222 chil- with the described conditions were systemati- dren (64% of those referred), a signifcant change cally referred for telemedicine according to the was made to initial case management by the study protocol and cases were reviewed by the specialist paediatrician, and in 88 children (25% same specialist physician. Adverse outcomes of those referred) a life-threatening condition (deaths and losses to follow-up) on paediatric that had initially been missed was diagnosed. All seven period there was a progressive improvement in clinicians involved with telemedicine rated it as the capacity of clinicians to manage complicated having high added value in improving the rec- cases, as demonstrated by a signifcant linear ognition of risk signs and prescription practices. Loss after telemedicine consultations with a specialist in Kenya (expressed as a percentage of all Table 3. However, and enrolment to treatment is the inadequacy of the efectiveness, feasibility and acceptability of diagnostic tools. For decades, the mainstay of TB introducing such technology, and its impact on diagnosis has been sputum-smear microscopy improving access to and quality of care, in simi- for patients with suspected pulmonary TB, fol- lar and post-confict settings need to be evalu- lowed by chest radiography in those with negative ated, ideally with a more rigorous experimental sputum smears. Tis is especially true for HIV-infected TB ■ Eforts towards achieving universal health patients, among whom a signifcant proportion coverage must include people who are hard has negative sputum smears and a normal chest to reach and those who are afected by X-ray (particularly those with advanced HIV/ confict. Furthermore, smear microscopy ■ In Somalia, telemedicine technology cannot diagnose MDR-TB. USA), which uses a common platform to diag- nose mycobacterium tuberculosis (MTB) and rifampicin resistance (RIF) (Fig. Te car- Case-study 5 tridge-based system requires minimal laboratory expertise and fully automated results are avail- New diagnostics for tuberculosis: able in less than two hours. Te performance of a validity assessment of the Xpert® Xpert MTB/RIF was assessed in health facilities in Azerbaijan, India, Peru and South Africa (8). MTB/RIF assay in Azerbaijan, India, Peru and South Africa Summary of fndings Tere were 1730 patients with suspected drug-sensi- The need for research tive or multidrug resistant pulmonary tuberculosis, Despite widespread implementation of the WHO each of whom submitted three sputum specimens, Stop TB Strategy, TB remains a major public and 1462 eligible patients were included in the main health problem. In the Te overall sensitivity (% of true positives detected) same year, there were an estimated 310 000 cases for one sputum specimen in patients with smear- of multidrug-resistant TB (MDR-TB), resistant to positive tuberculosis was 97. Xpert® MTB/RIF machine being used in a health facility in South Africa TB, sensitivity increased with the number of smears procured in the public sector in 73 of the 145 tested (Fig. Te overall sensitivity and speci- countries eligible for concessional pricing (39). It may also be used as a follow-on RIF also depends on the link between diagnosis test to microscopy, especially for patients with and subsequent treatment. As of September National TB control programmes need to 2012, a total of 898 GeneXpert instruments and fnd optimal diagnostic algorithms tailored to 1 482 550 Xpert MTB/RIF cartridges had been local epidemiological conditions to make the 70 Chapter 3 How research contributes to universal health coverage ■ Following WHO recommendations in Fig. Sensitivity of Xpert MTB/RIF December 2010, approximately 900 Xpert assay with multiple smears for MTB/RIF instruments had been procured smear-negative, culture-positive for the public sector in 73 countries by the tuberculosis (commonly seen in end of September 2012. HIV-positive individuals) ■ Further research is under way to confront operational and logistic challenges in laboratory and feld areas, and to assess afordability, epidemiological impact and cost–efectiveness. Case-study 6 The “polypill” to reduce deaths from cardiovascular disease: a randomized controlled trial in India The need for research HIV, human immunodefciency virus. Tere is a growing global epidemic of noncom- Source: Boehme et al. Tese are responsible for two and related research have the potential to bring thirds of the 57 million deaths worldwide each diagnosis closer to patients. Further operational year, with 80% of deaths occurring in low- and studies are under way to investigate the cost, middle-income countries. Deaths from noncom- optimal location and use of the assay within municable diseases are projected to rise from 36 health systems and in combination with other million in 2008 to 52 million in 2030 (42). As investigations of the response to this epidemic, WHO Member States performance of Xpert MTB/RIF have prolifer- have agreed on a set of targets to reduce deaths ated, study design also appears to have improved caused by the four main noncommunicable (K Weyer, WHO, personal communication), diseases by 25% in people aged 30–70 years by indicating an instance of technological develop- 2025 (43). WHO has proposed 10 targets to reach ment boosting the quality of research (38). One of these targets is drug therapy to reduce the prevalence of risk factors for heart Main conclusions attack and stroke (42). Several dif- allowing the diagnosis of patients earlier in ferent drugs (aspirin, beta blockers, angiotensin- the course of their disease. Combining Te results of the study showed that each of the several drugs into a single polypill is appealing components of the polypill reduced the risk of because of its simplicity and acceptability, and cardiovascular disease. Several other trials have because one pill is more likely to be taken rou- since been carried out to demonstrate the efects tinely than several will be. Te gate the efcacy of the polypill in reducing the study was designated “Te Indian Polycap Study” incidence of cardiovascular disease and stroke, (TIPS) (9).