By A. Akrabor. Pacific University.

Patients receiving verapamil had a greater reduction in heart rate compared with patients receiving digoxin at 0 order sildigra 50mg. There were no clear adverse events related to the treatments in this study purchase sildigra 100mg line. Some of the symptoms that were reported, such as lightheadedness and palpitations, seem to have been related to AF and not to the study treatments. In summary, there was a consistent benefit of verapamil or diltiazem compared with digoxin across studies (high strength of evidence). Results in Specific Subgroups of Interest One study compared combined treatment with the beta blocker carvedilol plus digoxin with 141 carvedilol alone and with digoxin alone in patients with AF and heart failure in one study. The combination of digoxin plus carvedilol was superior to digoxin alone for rate control at 4 months. At 6 months, there was no difference in rate control between digoxin alone and carvedilol alone. The improvement of AF symptoms was greater in patients receiving combined treatment than in patients receiving digoxin alone. The included studies did not allow a direct comparison of these findings with those in other populations. Other subgroups of interest were not specifically evaluated. Strength of Evidence Our review of rate-control drugs explored the comparative effectiveness of beta blockers, calcium channel blockers, digoxin, and other antiarrhythmics in controlling ventricular rate. The 14 included studies varied in terms of the drugs involved, and the lack of multiple studies exploring similar comparisons decreased our ability to quantitatively synthesize their findings. Our findings highlight the lack of definitive data on the superiority of one beta blocker over another or against calcium channel blockers. Our findings underscore the importance of conducting studies comparing the effectiveness, tolerability and safety of different beta blockers and calcium channel blockers and in different patient populations. Based on a limited number of comparative studies, our analysis suggests that either a calcium channel blocker (verapamil or diltiazem) or amiodarone is beneficial compared with digoxin for rate control. Evidence exploring adverse events and safety and effectiveness of the available agents in specific subgroups of interest was insufficient. Table 4 summarizes the strength of evidence for the studied rate-control drugs and outcomes of interest. In general, the limited number of studies exploring specific comparisons, along with the various metrics used to assess outcomes of interest, reduced our confidence in the findings. Strength of evidence domains for rate-control drugs Domains Pertaining to SOE SOE and Number of Magnitude of Outcome Studies Risk of Consistency Directness Precision Effect (Subjects) Bias (95% CI) Beta Blockers vs. Digoxin Ventricular 1 (47) RCT/ NA Direct Imprecise SOE=Insufficient Rate Control Moderate Beta Blockers vs. Calcium Channel Blockers Ventricular 1 (40) RCT/ NA Direct Imprecise SOE=Insufficient Rate Control Moderate Beta Blockers vs. Calcium Channel Blockers in Patients Taking Digoxin Ventricular 1 (29) RCT/ NA Direct Imprecise SOE=Insufficient Rate Control Moderate Exercise 1 (29) RCT/ NA Direct Imprecise SOE=Insufficient Capacity Moderate Quality of Life 1 (29) RCT/ NA Direct Imprecise SOE=Insufficient Moderate Sotalol vs. Metoprolol in Patients Taking Digoxin Ventricular 1 (23) RCT/ NA Direct Imprecise SOE=Insufficient Rate Control Moderate Amiodarone vs. Calcium Channel Blockers Ventricular 3 (271) RCT/Low Inconsistent Direct Imprecise SOE=Low Rate Control Amiodarone is comparable to the calcium channel blocker diltiazem for rate control Amiodarone vs. Digoxin Ventricular 3 (390) RCT/Low Inconsistent Direct Imprecise SOE=Low Rate Control Amiodarone controlled ventricular rate better than digoxin across 2 studies (both p=0. Digoxin Alone Ventricular 1 (52) RCT/ NA Direct Imprecise SOE=Insufficient Rate Control Moderate Calcium Channel Blockers vs. Digoxin Ventricular 4 (422) RCT/Low Consistent Direct Precise SOE=High Rate Control Consistent benefit of verapamil or diltiazem compared with digoxin (p<0. Strict Versus Lenient Rate-Control Strategies KQ 2: What are the comparative safety and effectiveness of a strict rate- control strategy versus a more lenient rate-control strategy in patients with atrial fibrillation? Do the comparative safety and effectiveness of these therapies differ among specific patient subgroups of interest? Key Points • Based on one RCT and one observational study (both good quality) involving 828 patients, there was low strength of evidence to support a decrease in strokes for patients on lenient rate control. This decrease was statistically significant in the RCT, but not in the observational study. Description of Included Studies 17 152,153 Three studies—one RCT and two observational studies representing secondary analyses of RCTs—were included in our analyses.

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There was NS difference in regression to normoalbuminuria for ACEI compared with ARB buy 120 mg sildigra with visa. Trials of ACE inhibitors were not separated from trials of ARBs buy 25 mg sildigra overnight delivery, thus confounding factors such as differences in drug tolerability could not be separated. Even with these caveats, this meta-analysis was interesting as it provided sensitivity analyses in diabetic and non-diabetic populations. When trials in diabetic and nondiabetic populations were separated from each other, there was NS difference between ACEI or ARB compared with other antihypertensive drugs 238. However, there was significant interstudy heterogeneity (p<0. In studies only including people without diabetes, ACEI or ARBs were associated with a significant reduction in albuminuria compared with other antihypertensive agents (8 trials, N=414 mean difference –32. In a subgroup analysis of studies which used ACEI at the maximum tolerable dose compared with placebo/no treatment, there was a significant decrease in the risk of all-cause mortality (5 studies, N=2034, RR 0. However, the study was underpowered for this outcome. ARB or combination ACEI + ARB use were NS associated with cough compared with placebo. There was a significant increase in the risk of hyperkalaemia with ARB compared with placebo (2 studies, N=2287, RR 5. In people with urinary protein ≥500 mg/day, a substantial treatment effect was seen across all risk groups. By contrast, the GFR decline was significantly slower in the ACEI group than the calcium channel blocker group in people who had a baseline PCR >0. For type 2 diabetes, the direct cost savings totalled $9900 per patient and $45,730 for indirect costs. For type 1 diabetes patients, the estimated increase in life years was 0. For type 2 diabetes patients, the estimated average increase in life years over 12 years was 1. Captopril was also more effective than placebo by resulting 20. Life years saved over 4 years for a cohort of 1000 patients treated with an ACE inhibitor was estimated to be 195. Economic evaluations based on the REIN study: q In the US, Ruggenenti et al. Both models constructed by the authors also predicted a reduced and delayed progression to ESRD and a prolonged patient survival in the ramipril group. Economic evaluations based on the AIPRI study: q In the Netherlands, van Hout et al. As the transition probabilities from the states progressing to ESRD were taken from the IDNT rather than country-specific data, the model produced the same projections for all countries. Over a 10-year time span the mean time to onset of ESRD was 8. The mean cumulative incidence of ESRD over the 10-year time span was 45% for control, 49% for amlodipine and 36% for irbesartan. Although the UK and the USA (and Canada) were simulated using the same model and transition probabilities, it could be expected that the results might be the same for these countries. Treatment with irbesartan was projected to extend life further than that with either amlodipine or control. In the UK, cost savings due to avoided or delayed ESRD were evident after 3 years compared to the amlodipine group and after 4 years compared to the control group. Economic evaluations based on the RENAAL study have looked at the costs and effects in several healthcare settings. Treatment with losartan was associated with a reduced number of ESRD days by an average of 46. The early irbesartan strategy was dominant over both the late irbesartan and conventional antihypertensive therapy strategies. Initiating irbesartan therapy during advanced overt nephropathy was dominant over conventional antihypertensive therapy.

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A few com- to formalin in gerbils (42) order 50 mg sildigra, to inhibit carrageenan and pounds have high affinity for the rat receptor (e discount sildigra 25 mg free shipping. SR140333), but their utility for in vivo studies may be se- Webb, S. Rupniak, unpublished observa- verely limited by poor brain penetration (31). Although tions; 43), and to attenuate peripheral neuropathy in rats these difficulties may be overcome by administering high and guinea pigs (43,44). Overall, the profile of activity of doses of NK1 receptor antagonists to rats, unspecific phar- NK1 receptor antagonists in a range of assays is comparable macologic effects are then frequently encountered, mostly to that seen with clinically used analgesic agents such as attributable to ion channel blockade. Pharmacologic differences among human, guinea cacy of these compounds in humans and are reviewed in pig, and rat NK3 receptors also exist (32). The patient populations and com- pounds examined included the following: peripheral neu- ropathy, in which CP-99,994 had no analgesic effect (47); POTENTIAL FOR USE OF TACHYKININ molar extraction, in which MK-869 was ineffective (48); RECEPTOR ANTAGONISTS TO TREAT and postherpetic neuralgia, in which MK-869 was ineffec- PSYCHIATRIC AND NEUROLOGIC tive (49). Further unpublished studies with other com- DISORDERS pounds support these conclusions. Thus, clinical studies to date indicate that NK1 receptor antagonists do not have The distribution of neurokinins in the central and periph- major potential as analgesics. The major hypotheses that are supported 10207 completely blocked both facilitation and protective by preclinical data and have been investigated in clinical nociceptive reflex responses (40), and SR48968 reduced re- trials are considered here. Numerous clinical trials have now sponses to both noxious and innocuous pressure applied to been conducted with NK1 receptor antagonists to define their therapeutic potential in psychiatric and neurologic dis- orders. In all these studies, the compounds have been ex- tremely well tolerated, with no significant side effects. PRECLINICAL EVIDENCE OF AN ANALGESIC PROFILE OF NK1 RECEPTOR are as yet no reports of clinical trials with NK2 or NK3 ANTAGONISTS receptor antagonists in patients with CNS disorders. Assay Morphine Indomethacin NK1 Antagonist Tail flick/hot plate √ Pain Paw pressure √ Writhing Radioligand-binding studies confirm the expression of Formalin paw tachykinin NK1 and NK3 (but not NK2) receptors in the Carrageenan paw dorsal horn of the spinal cord (33–35). A role of spinal Nerve injury √ X √ CFA arthritis substance P and NKA in nociception is suggested by the Facilitated spinal reduction in response thresholds to noxious stimuli by cen- reflex tral administration of NK1 and NK2 (but not NK3) agonists 172 Neuropsychopharmacology: The Fifth Generation of Progress the knee joint (50). CP-122,721 was also effective in preventing Migraine postoperative nausea and vomiting after gynecologic surgery (68), a finding suggesting the utility of NK1 receptor antag- The vasculature of meningeal tissues such as the dura mater onists as broad-spectrum antiemetics in humans. There are is densely innervated by nociceptive sensory afferents that no published studies examining the effects of selective NK2 run in the trigeminal nerve and contain substance P and and NK3 receptor agonists and antagonists on emesis. The release of neuropeptides from these sensory fibers during a migraine attack is thought to cause neurogenic inflammation within the meninges and Schizophrenia activation of nociceptive afferents projecting to the trigemi- A rationale that NK1 receptor antagonists may be useful as nal nucleus caudalis (52). In rats, antidromic stimulation antipsychotic drugs has been built on evidence that sub- of the trigeminal nerve increases vascular permeability and stance P modulates the activity of the mesolimbic dopamine causes plasma protein extravasation in the meninges that is system through which established antipsychotic drugs are inhibited by NK1 receptor antagonists (53). Substance P–containing fibers have been suggest that if meningeal plasma extravasation and inflam- shown to make synaptic contact with tyrosine hydroxyl- mation of the meninges is involved in the pathogenesis of ase–positive neurons in the ventral tegmental area (VTA) migraine, then NK1 receptor antagonists should provide an from which the mesolimbic dopamine projection arises effective antimigraine therapy. Infusion of substance P agonists into the VTA stimu- potential analgesic activity, CNS-penetrant NK1antagonists lates locomotor activity in rats, an effect attributed to the may also be able to alleviate headache by preventing activa- activation of dopamine neurons because this is accompanied tion of sensory neurons in the trigeminal nucleus caudalis. Consistent with this in patients with migraine, in whom neither LY 303870 (54) interpretation, the locomotor hyperactivity and changes in nor GR205171 (55) gave headache relief. Emesis The ability of a monoclonal antibody to substance P, Substance P is present in the nucleus tractus solitarius and injected into the nucleus accumbens, to attenuate the loco- the area postrema (56), regions implicated in the control of motor response to amphetamine (72) was consistent with emesis. Local application of substance P in the area postrema the proposal that endogenous substance P modulates the causes retching in ferrets (57), a finding suggesting that NK1 release of dopamine in the mesolimbic system. A subsequent receptor antagonists may be antiemetic. Consistent with this study appeared to support this interpretation because the proposal, these compounds have emerged as an important NK1 receptor antagonist CP-96,345 reduced the firing of new class of antiemetics in preclinical studies using ferrets. However, other studies with CP-99,994 completely abolished cisplatin-induced retching NK1 receptor antagonists are not consistent with these find- and vomiting and exhibited broad-spectrum activity against ings. Surprisingly, intra-VTA coinfusion of CP-96,345 was peripheral and centrally acting emetogens (58–60). Impor- unable to block substance P agonist–induced locomotor tantly, CP-99,994 markedly attenuated both acute and de- activation in rats (71), and amphetamine-induced hyperac- layed emesis induced by cisplatin, a profile that distinguishes tivity in guinea pigs was not selectively inhibited by CP- NK1 receptor antagonists from established antiemetics (61, 99,994.

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It is now well I am grateful to all of the authors for their painstaking established that depression is an independent risk factor for contributions and accept all responsibility for any shortcom- ings in this section discount sildigra 25 mg amex. This section contains much information unknown when the last edition of this book was published cheap sildigra 50 mg fast delivery. Charles Nemeroff: Department of Psychiatry and Behavioral Sciences, We can all be heartened by the fact that the next edition Emory University School of Medicine, Atlanta, Georgia. KELLER Long-term naturalistic studies have changed the way we remission, an individual still has more than minimal view depression. Full remission is defined as the point at an episodic disease, the past two decades of research have which an individual no longer meets criteria for the dis- underscored the importance of understanding depression as order and has no more than minimal symptoms. Recovery, defined as a full remission that lasts for a de- An appreciation of this longitudinal data is crucial to fined period of time. Conceptually, it implies the end understanding all aspects of depression. Cross-sectional of an episode of an illness, not of the illness per se. Relapse, defined as a return of symptoms sufficient to nostic information. It occurs in an interval nosis or likely treatment response also requires a longitudi- of time before what is defined as 'recovery. Which patient is likely to recover fully, and tually, this refers to the return of an episode, not a new who will suffer from a chronic mood disorder? Recurrence, defined as a return of full symptomatology Studies within the last decade have helped to shed light occurring after the beginning of the recovery period. This chapter examines some of these Conceptually, this represents the beginning of a new studies, and discusses their implications for our approach episode of an illness. REPRESENTATIVE STUDIES THE CHANGE POINTS OF DEPRESSION A relatively small number of studies have been particularly Considerable confusion has resulted from the use of various influential in shedding light on the course of depression. Similar terms, such as 'relapse' and 'recur- rence' have been used interchangeably and inconsistently The Collaborative Depression Study in different studies. As a result, the MacArthur Foundations (CDS) Research Network on the Psychobiology of Depression (1) The CDS (2) is a prospective long-term naturalistic study recommended using the following terms: of the natural course of depression. Episode, defined as a certain number of symptoms for a from patients with depression seeking psychiatric treatment certain period of time. Remission, defined as a period of time in which an indi- Boston, Chicago, Iowa City, New York, and St. In partial This study included programs in biological and clinical studies. The data presented here are from the clinical studies program; 555 subjects in the clinical studies program had an Robert J. Boland: Department of Psychiatry and Human Behavior, index episode of unipolar major depression. Subjects were Brown University; Department of Psychiatry, Miriam Hospital, Providence, examined at 6-month intervals for 5 years and then annually Rhode Island. Keller: DepartmentofPsychiatryandHumanBehavior,Brown University; Department of Psychiatry, Butler Hospital and Brown Affiliated Mental Health (NIMH) funding will extend the follow-up Hospitals, Providence, Rhode Island. However, for those patients who did not recover in the first year, most still had not recovered within 5 years. Thus Angst (3), in Zurich, has conducted the only other long- by 2 years, about 20% of the original sample were still term prospective study of mood disorders. In that study, depressed—two-thirds of those still depressed at 1 year were 173 hospitalized patients with unipolar depression were still in their index episode of depression at 2 years. This group was then years, 12% of patients had still not recovered (6), by 10 evaluated every 5 years for up to 21 years of follow-up. These data are presented The Medical Outcomes Study(MOS) in Fig. The MOS (4) examined the course of several diseases (myo- The long duration of the CDS allowed the investigators cardial infarction, congestive heart failure, hypertension, di- to observe subsequent episodes of major depression begin- abetes, and depression) in a variety of health care settings, ning during the study.

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