W. Tom. The College of Saint Thomas More. 2019.

Accordingly purchase 15mg pioglitazone otc, the nonspecific group II/III metabo- terneurons by 5-HT via 5-HT2 receptors gives rise to indi- tropic glutamate receptor agonist (1S generic pioglitazone 15mg,3S)-ACPD (118) and rect inhibitory effects order pioglitazone 30 mg with visa. In vitro studies in brain slice activation of receptors discount pioglitazone online amex, located presynaptically on thala- preparations have shown that pyramidal cells in various cor- mocortical inputs, also suppresses 5-HT-induced EPSCs, tical regions respond to 5-HT by either a small hyperpolar- particularly in the medial prefrontal cortex (124). These ization, depolarization, or no change in potential (84–86, results are consistent with the idea that activation of 5-HT2A 110). Depending on the region of cortex under study, as receptors increases the release of glutamate onto layer V described below, the depolarizations appear to be mediated pyramidal cells through a presynaptic mechanism. Such postsynap- 22 Neuropsychopharmacology: The Fifth Generation of Progress tic effects are consistent with the finding of a high level of 5-HT2A-receptor immunoreactivity in the apical dendrites of cortical pyramidal cells (125–127). Ordinarily, tetrodotoxin sensitivity and Ca2 dependence would suggest that activa- tion of glutamatergic cells within the slice by 5-HT had led to an impulse flow-dependent release of glutamate. How- ever, several lines of evidence argue against this conventional interpretation. First, rarely were neurons within the confines of the brain slice induced to fire by bath application of 5- HT. Second, none of the pyramidal cells (a potential source of intracortical excitatory inputs) was depolarized suffi- ciently by 5-HT as recorded under our conditions to reach the threshold for firing. Together, these experiments suggest that the increase in spontaneous EPSCs induced by 5-HT in neocortical py- FIGURE 2. Modulation of excitatory and inhibitory transmis- ramidal cells occurs through a focal action involving a sionby multiple5-hydroxytryptamine(5-HT) receptorsin thecere- Ca2 -dependent mechanism that is not based on an in- bral cortex. One of several distinguishing shown on anatomically distinct GABAergic inputs to the somato- characteristics of this alternative mechanism of transmitter basilar and apical regions, respectively, of the pyramidal cell. This feature ap- pears to be the result of the differential involvement of two isoforms of the calcium-sensing protein synaptotagmin in 5-HT3 Receptors the two alternative release mechanisms (130). Consistent with this idea, Sr2 is highly effective in enabling 5-HT to Excitatory responses to 5-HT have been found in various induce an increase in the frequency of EPSCs in the absence central neurons that have many of the characteristics of of Ca2 (128). In cultured NG108-15 cells, the permeation proper- (131). It is possible that this late component, rather than ties of the 5-HT3 channel are indicative of a cation channel representing conventional polysynaptic transmission, is me- with relatively high permeability to Na and K and low diated through the mechanism of asynchronous transmitter permeability to Ca2 (134). A 5-HT-gated ion channel release, possibly involving a release of intraterminal Ca2 has been cloned that has physiologic and pharmacologic stores via the phospholipase C, inositol triphosphate (IP3) properties appropriate for a 5-HT3 receptor (135). An enhancement of asynchronous evoked EPSPs oocyte expression system, this receptor shows rapid desensi- via 5-HT2A receptors would provide a possible synaptic tization and is blocked by 5-HT3 antagonists (e. Its sequence homology with contrast, 5-HT itself does not promote the late component the nicotinic acetylcholine receptor (27%) and the 1 sub- of electrically evoked release except during the washout phase, unit of the GABAA receptor (22%) indicates that this 5- presumably because of opposing actions at 5-HT1 or other HT3-receptor clone is a member of the ligand-gated ion non-5-HT2A receptors (132). Typically, members of this superfam- posed location of various 5-HT-receptor subtypes and their ily are comprised of multiple subunits; however, only one interactions with other neurotransmitter receptors within 5-HT3-receptor subunit and an alternatively spliced variant cortical circuitry. Chapter 2: Serotonin 23 In hippocampus slices, 5-HT has been reported to in- the ability of these cells to respond to excitatory inputs with crease spontaneous GABAergic IPSPs, most likely through robust spike activity. A similar 5-HT3 receptor-mediated induction of The circadian rhythm in mammals is set by a pacemaker IPSCs has been reported in the neocortex (117). Whole- located primarily in the suprachiasmatic nucleus of the hy- cell patch-clamp recordings have confirmed a direct 5-HT3 pothalamus. This pacemaker activity can be maintained in receptor-mediated excitatory effect on hippocampal in- hypothalamic slices, in which suprachiasmatic neurons dis- terneurons independent of G-protein activation (139). Administration though fast, rapidly inactivating excitation has generally be- of 5-HT appears to produce a phase shift in this activity come accepted as characteristic of 5-HT3 receptors, (150) by acting on a receptor that may be of the 5-HT7 nondesensitizing responses have also been reported. This shift is mediated by stimulation of ade- sal root ganglion cells, a relatively rapid but noninactivating nylate cyclase because it is mimicked by increasing intracel- depolarizing response has been described that has a 5-HT3 lular cyclic adenosine monophosphate (cAMP) and blocked pharmacologic profile (140). In neurons of nucleus tractus by inhibiting protein kinase A (151). However, the precise solitarius brain slices, a postsynaptic depolarizing response mechanism by which 5-HT7 receptors act is not presently to 5-HT3 agonists has been observed that is not rapidly known because it is unclear whether suprachiasmatic neu- desensitizing (141). In addition to these postsynaptic effects, rons themselves express the 5-HT7 receptors (144). Further- a 5-HT receptor-mediated increase in Ca2 influx has more, the effect of 5-HT on the membrane properties of 3 been described in a subpopulation of striatal nerve terminals these cells has not been examined. Another electrophysiologic effect that may be mediated The first known protein G -coupleds 5-HT receptor, the 5- through 5-HT receptors that are positively coupled to ade- HT4 receptor, was identified on the basis of pharmacologic nylate cyclase is the enhancement of the hyperpolarizing- and biochemical criteria (e. The Ih channels, responses to adenylyl cyclase) (9). Subsequently, a receptor which are homologous to cyclic nucleotide-gated channels with matching pharmacologic and other properties was in specialized sensory neurons, are positively modulated by cloned and found to be expressed in various regions of the cAMP (153,154). An increase in Ih tends to prevent exces- brain (143). Two other 5-HT receptors positively coupled sive hyperpolarization and increase neuronal excitability. Because their pharma- a number of regions of the brain, including the thalamus cology differed from that of the previously described 5-HT4 (155), prepositus hypoglossi (156), substantia nigra zona site, they were designated as 5-HT6 and 5-HT7 receptors compacta (157), and hippocampus (158), 5-HT has been (144–146). At this time, electrophysiologic studies are avail- shown to enhance Ih through a cAMP-dependent mecha- able only for the 5-HT4 and 5-HT7 receptors and are de- nism. Results of a pharmacologic analysis with multiple scribed below. Recently, the first drug with selectivity Binding studies using a selective 5-HT4 ligand indicate that toward the 5-HT7 receptor was shown to block activation 5-HT4 receptors are present in several discrete regions of of adenylyl cyclase by 5-HT agonists in guinea pig hippo- the mammalian brain, including the striatum, substantia campus (33). The increasing availability of such selective nigra, olfactory tubercle, and hippocampus (147). Because drugs should greatly enhance the electrophysiologic evalua- these regions also express 5-HT4-receptor mRNA, it appears tion of G -coupleds 5-HT receptors. The best studied of these regions is the hippocampus, in which both biochemical and electro- INTRACELLULAR SIGNAL TRANSDUCTION physiologic studies have provided a detailed picture of the PATHWAYS actions of 5-HT at 5-HT4 receptors. Electrophysiologic Multiple Signaling Pathways: G Proteins studies show that 5-HT4 receptors mediate an inhibition and Second Messengers of a calcium-activated potassium current that is responsible for the generation of a slow after-hyperpolarization in hip- Multiple intracellular signaling pathways constitute a com- pocampal pyramidal cells of the CA1 region (74,148,149). Inhibition of adenylate cyclase 24 Neuropsychopharmacology: The Fifth Generation of Progress was the first intracellular pathway to be described for campal homogenates suggests that both the 5-HT4 and 5- Gi/o protein-coupled receptors, such as the 5-HT1A recep- HT7 receptors are involved in cAMP formation (adenylate tor. However, it is now clear that these receptors regulate cyclase isoform unknown) in the hippocampus (164). Inter- multiple signaling pathways and effector molecules (Fig. Although all these signals are sensitive to pertussis G11,G14, and G15/16) activate phospholipase C in a pertussis toxin, so that Gi/o proteins are implicated, they may be toxin-insensitive manner. Activation of phospholipase C mediated by distinct G protein complexes. For example, was the first signal transduction mechanism identified for coupling to GIRK channels is mediated by subunits the 5-HT2-receptor family and is essentially universal. This released from Gi (and possibly Go) proteins, whereas inhibi- probably reflects the wide distribution of G and the 2 q/11 tion of Ca channels is mediated by subunits released functional redundancy of these two G proteins. The profile of signaling molecules varies HT receptor has been shown to couple in a pertussis 2C from cell to cell, offering diverse signaling possibilities and toxin-sensitive manner to G in Xenopus oocytes (e. In con- receptor activation of phospholipase C is cell-type depen- trast, recent evidence suggests that phospholipase C activa- dent; this signal is mediated by G protein subunits and tion in a native setting (choroid plexus) is mediated entirely thus requires the presence of a -regulated phospholipase by G coupling (167). The subunits, generated by dissociation of to G with subsequent cytoskeletal rearrangement has been 13 the heterotrimeric Gi protein, also activate the type 2 iso- recently described in a transfected cell line (168). This activation is conditional, evidence suggests that 5-HT2A and 5-HT2C receptors cou- dependent on the coactivation by G s (i. Phospholipase A2 is a well-characterized inde- ing actions of G i and G do not offset each other. The pendent signal transduction pathway that leads to arachi- answer may lie in the details. In addition to the large family donic acid, with subsequent prostaglandin and leukotriene of G proteins (21 subunits, 5 subunits, and 11 sub- formation (169). Most of these in vascular smooth muscle and is also thought to be inde- molecules are found in the central nervous system. The G pendent of phospholipase C activation (170,171). The 5- protein that contributes activation of type 2 adenylate HT2Areceptor increases phospholipase D activity via a small cyclase is G i1 or G i2 heterotrimer (160), whereas all three G-protein ARF (adenosine diphosphate ribosylation factor) G i subunits ( i3 i2 i1) have the ability to inhibit pathway, with protein kinase C activation being the princi- adenylate cyclase types 5 and 6 (161).

Surprisingly pioglitazone 45 mg on line, the solid tum ors m ost com m only seen in the general population (eg buy 15 mg pioglitazone overnight delivery, of (36%) (24%) the breast purchase discount pioglitazone online, lung buy pioglitazone in united states online, colon, and prostate) do not occur with significantly greater frequency among transplant recipients. N onetheless, long-term care of these patients should involve standard screening for these m alignancies at appropriate intervals. Cutaneous carcinom as (prim arily Posttransplantation lym phoproliferative disease (PTLD): histologic basal cell and squam ous cell) com prise the greatest percentage appearance of a renal allograft infiltrated by a monoclonal proliferation of tum ors in transplant recipients. In im m unocom petent patients the risks of these polyclonal or m onoclonal B-cell com position, with lym phocytes lesions usually are lim ited; however, in transplant recipients driven to proliferate by infection with the Epstein-Barr virus these lesions can be very aggressive and m etastasize locally or [11–13]. Development of PTLD is strongly linked to the intensity even system ically. The best m anagem ent is aggressive prevention: of im m unosuppression and m ay regress with its reduction. W hen suspicious lesions develop, early recognition m ore aggressive unrelenting course despite withdrawal of im m uno- and rem oval are of utm ost im portance. Hematologic Complications is the range of serum erythropoietin levels in norm al persons with- 200 out anem ia. M any patients leave the dialy- 150 sis population with diminished iron stores and are unable to respond to erythropoietin produced by the successful allograft. Iron replace- 100 m ent therapy successfully restores erythropoiesis in these patients. Another common cause of anem ia after transplantation is bone m arrow suppression owing to drug therapy with azathioprine or 50 m ycophenolate m ofetil (M M F), an effect that is usually dose-relat- 25 ed [15,16]. O ther drugs, notably angiotensin-converting enzym e 0 inhibitors and angiotensin receptor antagonists, m ay also inhibit erythropoiesis. Neutropenia also is a common complication after transplantation. Alternatively, neutropenia FIGURE 13-8 can be a m anifestation of system ic viral, fungal, or tubercular infec- The course of norm al erythropoiesis after renal transplantation tions. The approach to the patient with neutropenia usually involves showing m ean serum erythropoietin levels of 31 recipients. In som e settings of refrac- engraftm ent does not result in erythropoiesis. As excellent graft tory neutropenia, adm inistration of filgrastim (granulocyte colony- function is achieved, a second burst of EPO secretion is norm ally stim ulating factor, N eupogen®) reduces the duration and severity of followed by effective production of erythrocytes. PTE usually 52 50 occurs during the first year after transplantation. Although it m ay 48 resolve spontaneously in som e patients, PTE persists in m any. It has 46 44 been linked to an increased risk of throm boem bolic events; howev- 42 40 er, our own experience is that such events are uncom m on. Previous m anagem ent involved serial phlebotom y to m aintain the hem atocrit PRE 1 2 3 4 5 6 9 12 15 at 0. M ore recently, hem atocrit levels have M onths on enalapril (mean 7±4. The pathogenetic m echanism s underlying PTE and its response to these therapies rem ain poorly understood; although elevated serum erythropoietin levels decrease with ACEI use, other pathways also appear to be involved. Cardiovascular Complications 8 FIGURE 13-10 Diabetic Causes of death in renal allograft recipients. Cardiovascular dis- 7 Nondiabetic eases are the m ost com m on cause of death, largely reflecting the 6 high prevalence of coronary artery disease in this population. Effective m anagem ent of cardiac disease after transplan- 2 tation m andates docum entation of preexisting disease in patients 1 at greatest risk. In DEM OGRAPHIC VARIABLES HIGHLY PREDICTIVE OF CORONARY DISEASE patients with diabetes who have end-stage IN RENAL TRANSPLANTATION CANDIDATES W ITH INSULIN-DEPENDENT renal disease with none of the dem ographic DIABETES M ELLITUS characteristics listed, the risk for coronary disease is low. Conversely, in patients who are insulin-dependent and have any of these Age > 45 y risk factors, the prevalence of coronary disease Electrocardiographic abnormality: nonspecific ST-T wave changes is sufficiently high to justify angiography. History of cigarette smoking A random ized study of m edical therapy Duration of diabetes > 25 y versus revascularization in transplantation candidates who have insulin-dependent diabetes and coronary disease showed superior outcomes with prophylactic revascularization, FIGURE 13-11 even in the absence of overt sym ptom atol- Demographic variables highly predictive of coronary disease in renal transplantation candidates ogy. M ost transplant centers screen potential candi- coworkers. H ypercholesterolem ia and hyper- triglyceridem ia are com m on after kidney 45 30 transplantation. Approxim ately two thirds of transplant recipients have low density 30 20 lipoprotein (LDL) or total cholesterol levels 74% 63% signifying increased cardiac risk; 29% have 15 10 elevated triglyceride levels 2 years after 0 0 transplantation (Kasiske, Unpublished 100 200 300 400 70 130 190 250 310 data). N ot only is hyperlipidem ia a clear risk factor for coronary disease (see Figs. Cholesterol, mg/dL LDL, mg/dL 13-13 and 13-14), but it may also contribute 75 40 to the progressive graft dysfunction associated n=588 n=430 with chronic rejection [21,22]. In The indications for lipid-lowering therapy and its goals are based addition to elevated low density lipoprotein (LDL) cholesterol levels, on the clinical history, risk factor profile (see Fig. About 40% of recipients are CHD— coronary heat disease. Sm oking, hypertension, and hyperlipidem ia are am ong the risk factors m ost am enable to long-term m odification. Although dose reduction can reduce lipid levels, it m ay also CyA increase the risk of acute rejection. As depicted, early experience in a large m ulticenter p<0. FIGURE 13-17 FIGURE 13-16 In the current era of im m unosuppressive therapy, hypertension A recent m eta-analysis of published trials in renal transplant affects roughly two thirds of transplant recipients. Unlike hyperten- recipients dem onstrated these benefits of the various treatm ents. These m ay be grouped dysfunction or rhabdom yolysis. These adverse events m ay occur conveniently into those originating within the allograft (intrinsic) m ore frequently in transplant recipients owing to the effect of and those originating elsewhere (extrinsic). Levels of 3-hydroxy-3-methylglutaryl coenzyme A (HM G CoA) reductase inhibitors are substantially higher in patients receiving both drugs. HDL— high density lipoprotein; LDL— low density lipoprotein. In these patients it m ay be possible to approach diagnosis and therapy in a fairly Blood pressure ≥140/90 standardized fashion. In transplant recipients with blood pressure readings consistently over 140/90 mm Hg, intervention is warranted. Evaluate allograft function The initial approach includes assessm ent of allograft function, Yes No extracellular fluid volum e (ECF) status, and im m unosuppressive dosing. If these variables are stable, it is reasonable to proceed with Optimal blood levels Reduce dose of antihypertensive therapy. Calcium antagonists (CA) are effective of cyclosporine cyclosporine or or tacrolimus? No tacrolimus agents and m ay offer the added benefit of attenuating cyclosporine- Yes induced changes in renal hem odynam ics. Verapam il, diltiazem , nicardipine, and m ibefradil increase blood levels of cyclosporine ECF volume status Consider salt restriction and tacrolimus and should be used with caution. No and/or diuretic with CAs that m ay lim it their use include cost, refractory edem a, Yes and gingival hyperplasia. Angiotensin antagonists (ACEIs and Administer receptor antagonists) are also effective; their use requires close Intervention fails to antihypertensive agent monitoring of renal function, serum potassium levels, and hematocrit normalize BP (CA, ACEI, or other) levels. Diuretics frequently are useful adjuncts to therapy in recipients owing to the salt retention that often accom panies cyclosporine M ultidrug regimen: Adequate response add agents of different use. O ther antihypertensive m edications offer no particular benefits to therapy? No classes as necessary or drawbacks and can be em ployed as needed. The rationale of Yes m ultidrug therapy is to em ploy agents that block hypertensive responses via interruption of differing pathogenetic pathways. As antihypertensive drugs are added, this consideration should Yes rem ain param ount [31,32].

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