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As the calbindin-Ca complex dissociates order aurogra online erectile dysfunction protocol amino acids, the free intracellular Ca Lamina propria is actively extruded from the cell by either the Ca-adenosine triphos- phatase (ATPase) or Na-Ca exchanger discount aurogra 100 mg overnight delivery impotence natural. Calcitriol may also increase the synthesis of the plasma membrane Ca-ATPase purchase aurogra 100mg fast delivery jacksonville impotence treatment center, thereby aiding in the active extrusion of Ca into the lamina propria [2 discount aurogra generic erectile dysfunction qatar,7,9,17,18]. Total serum Ca consists of arteriole arteriole ionized, protein bound, and com plexed fractions (47. The com plexed Ca is bound to m olecules such as phosphate and citrate. The ultrafilterable Ca equals the total of the ionized and com plexed fractions. Ca2+ Ca2+ Alkalosis decreases the ionized Ca [1,6,7]. Ca is filtered at the glom erulus, and 1,25(OH)2D3 colocalized here with the ultrafilterable fraction (UFCa) of plasm a Ca entering the Calcitonin proxim al tubule (PT). W ithin the proxim al convoluted tubule Thiazides (PCT) and the proxim al straight tubule (PST), isosm otic reabsorp- CNT tion of Ca occurs such that at the end of the PST the UFCa to TFCa ratio is about 1. Passive paracellular pathways account for about 80% of Ca reabsorption in this segm ent of the nephron, with the PCT rem aining 20% dependent on active transcellular Ca m ovem ent. Cortex CTAL N o reabsorption of Ca occurs within the thin segm ent of the loop of H enle. Ca is reabsorbed in sm all am ounts within the m edullary segm ent of the thick ascending lim b (M AL) of the loop of H enle M edulla M AL and calcitonin (CT) stim ulates Ca reabsorption here. H owever, the cortical segm ents (cTAL) reabsorb about 20% of the initially fil- tered load of Ca. Under norm al conditions, m ost of the Ca reab- Papilla sorption in the cTAL is passive and paracellular, owing to the favorable electrochem ical gradient. Active transcellular Ca trans- port can be stim ulated by both parathyroid horm one (PTH ) and 1,25-dihydroxy-vitam in D3 (1,25(O H )2D3) in the cTAL. In the early distal convoluted tubule (DCT), thiazide-activated Ca trans- port occurs. The DCT is the prim ary site in the nephron at which Ca reabsorption is regulated by PTH and 1,25(O H )2D3. Active 100 PT DT Urine transcellular Ca transport m ust account for Ca reabsorption in the 100 DCT, because the transepithelial voltage becom es negative, which would not favor passive m ovem ent of Ca out of the tubular lum en. ATPase— adenosine triphosphatase; CaBP-D— Ca- 40 (40) binding protein D; DT— distal tubule; VDR— vitam in D receptor. The G-protein also increases 2+ G-protein + ↑Ca IP3 activity of phospholipase A2 (PLA ), which increases the concen- K 2 1 A – PK-C tration of arachidonic acid (AA). Both the lack of m ovem ent of N a – + Hormone into the renal interstitium and inhibition of horm onal (eg, vaso- pressin) effects im pair the ability of the nephron to generate m axi- m ally concentrated urine [3,4,14]. ATP— adenosine triphosphate; PK-C— protein kinase C. FIGURE 5-16 DHP sensitive Thiazide sensitive channel 2+ channel 2+ Postulated m echanism of the Ca transport pathway shared by PTH Ca Ca and 1,25(O H ) D. Cyclic adenosine m onophosphate (cAM P) gener- Tubular lumen 2 3 ated by PTH stim ulation leads to increased influx of Ca into the apical dihydropyridine-sensitive Ca channel. There also is increased + 2+ 2+ Distal activity of the basolateral N a-Ca exchanger and, perhaps, of the Ca Ca convoluted plasm a m em brane–associated Ca-adenosine triphosphatase tubule cell (PM CA), which can rapidly extrude the increased intracellular free Ca (Ca2+). Calcitriol (1,25(O H ) D ), by way of the vitam in D 2 3 CaBP28 receptor (VDR), stim ulates transcription of calbindin D28k (CaBP28) and calbindin D9k (CaBP9). CaBP28 increases apical uptake of Ca by both the dihydropyridine- and thiazide-sensitive Ca CaBP9 channels by decreasing the concentration of unbound free Ca2+ and Ca2+ facilitates Ca m ovem ent to the basolateral m em brane. CaBP stim u- cAM P Nucleus 9 + VDR lates PM CA activity, which increases extrusion of Ca by the cell. Parathyroid glands Hypocalcemia stimulates both parathyroid hormone (PTH) release and PTH synthesis. Both hypocalcemia and PTH increase the activity of the 1- -hydroxylase enzyme in the + proximal tubular (PT) cells of the nephron, Kidney which increases the synthesis of 1,25-dihy- droxy-vitamin D3 (1,25(OH)2D3). PTH and 1,25(OH)2D3 stimulate Ca reab- PTH↑ PTH Gastrointestinal sorption in the distal convoluted tubule tract + (DCT). All these mechanisms aid in returning the serum Ca to normal levels. Lack of parathyroid hormone (PTH) Increased calcium complexation After thyroidectomy or parathyroidectomy “Bone hunger” after parathyroidectomy Hereditary (congenital) hypoparathyroidism Rhabdomyolysis Pseudohypoparathyroidism (lack of Acute pancreatitis effective PTH) Tumor lysis syndrome Hypomagnesemia (blocks PTH secretion) (hyperphosphatemia) Malignancy (increased Lack of Vitamin D osteoblastic activity) Dietary deficiency or malabsorption (osteomalacia) Inadequate sunlight Defective metabolism Anticonvulsant therapy Liver disease Renal disease Vitamin D–resistant rickets Divalent Cation M etabolism: Calcium 5. The decrease in PTH and hypercalcem ia decrease the activity of the C-cells 1- -hydroxylase enzym e located in the Kidney – ↑CT proxim al tubular (PT) cells of the nephron, which in turn, decreases the synthesis of – – + 1,25-dihydroxy-vitam in D3 (1,25(O H )2D3). H ypercalcem ia stim ulates the C cells in the PTH↑ PTH Gastrointestinal thyroid gland to increase synthesis of calci- tract – – tonin (CT). Bone resorption by osteoclasts Parathyroid cell PT DCT Nucleus is blocked by the increased CT and decreased PTH. Decreased levels of PTH and 1,25(O H )2D3 inhibit Ca reabsorption in the distal convoluted tubules (DCT) of – the nephrons and overwhelm the effects of – CT, which augm ent Ca reabsorption in the m edullary thick ascending lim b leading to an increase in renal Ca excretion. The – Bone decrease in 1,25(O H ) D decreases gas- – 2 3 trointestinal (GI) tract absorption of dietary 1,25(OH)2D3↓ Ca. All of these effects tend to return serum Ca to norm al levels. Excess parathyroid hormone (PTH) production Increased intestinal absorption of calcium Primary hyperparathyroidism Vitamin D intoxication “Tertiary” hyperparathyroidism* Milk-alkali syndrome* Excess 1,25-dihydroxy-vitamin D3 (1,25(OH)2D3) Decreased renal excretion of calcium Vitamin D intoxication Familial hypocalciuric hypercalcemia Sarcoidosis and granulomatous diseases Thiazides Severe hypophosphatemia Impaired bone formation and incorporation of Neoplastic production of 1,25(OH)2D3 (lymphoma) calcium Increased bone resorption Aluminum intoxication* Metastatic (osteolytic) tumors (eg, breast, colon, prostate) Adynamic (“low-turnover”) bone disease* Humoral hypercalcemia Corticosteroids PTH-related protein (eg, squamous cell lung, renal cell cancer) Osteoclastic activating factor (myeloma) 1,25 (OH)2D3 (lymphoma) Prostaglandins Hyperthyroidism Immobilization Paget disease Vitamin A intoxication *Occurs in renal failure. Agent Mechanism of action Saline and loop diuretics Increase renal excretion of calcium Corticosteroids Block 1,25-dihydroxy-vitamin D3 synthesis and bone resorption Ketoconazole Blocks P450 system, decreases 1, 25-dihydroxy-vitamin D3 Oral or intravenous phosphate Complexes calcium Calcitonin Inhibits bone resorption Mithramycin Inhibits bone resorption Bisphosphonates Inhibit bone resorption *Always identify and treat the primary cause of hypercalcemia. Secondary Hyperparathyroidism FIGURE 5-22 Renal failure Pathogenesis of secondary hyperparathyroidism (H PT) in chronic renal failure (CRF). Decreased num bers of proxim al tubular (PT) cells, owing to loss of renal m ass, cause a quantitative decrease in ↓Number of nephrons synthesis of 1,25-dihydroxy-vitam in D (1,25(O H ) D ). Loss of 3 2 3 renal m ass also im pairs renal phosphate (P) and acid (H +) excretion. H ypocalcem ia and hyperphosphatem ia stim ulate PTH release and ↓H+ excretion synthesis and can recruit inactive parathyroid cells into activity and ↓P excretion PTH production. H ypocalcem ia also m ay decrease intracellular degradation of PTH. The lack of 1,25(O H )2D3, which would ordi- 1,25(OH)2D3↓ Hyperphosphatemia narily feed back to inhibit the transcription of prepro-PTH and exert an antiproliferative effect on parathyroid cells, allows the ↓Ca absorption Gastrointestinal increased PTH production to continue. In CRF there m ay be tract decreased expression of the Ca-sensing receptor (CaSR) in parathy- roid cells, m aking them less sensitive to levels of plasm a Ca. Patients with the b allele or the bb genotype vitam in D receptor (VDR) m ay be m ore susceptible to H PT, because the VDR- 1,25(O H )2D3 com plex is less effective at suppressing PTH produc- tion and cell proliferation. The deficiency of 1,25(O H )2D3 m ay also decrease VDR synthesis, m aking parathyroid cells less sensitive to Hypocalcemia ↓Activity 1,25(O H )2D3. Although the PTH receptor in bone cells is downreg- ↓Activity ulated in CRF (ie, for any level of PTH , bone cell activity is lower in CRF patients than in norm al persons), the increased plasm a levels of PTH m ay have harm ful effects on other system s (eg, cardiovascu- VDR CaSR lar system , nervous system , and integum ent) by way of alterations of intracellular Ca. Current therapeutic m ethods used to decrease Increased PTH release in CRF include correction of hyperphosphatem ia, transcription ↓Degradation m aintenance of norm al to high-norm al levels of plasm a Ca, adm in- of PTH istration of 1,25(O H )2D3 orally or intravenously, and adm inistra- Release tion of a Ca-ion sensing receptor (CaSR) agonist [14–16,19–22]. CALCIUM PREPARATIONS Calcium (Ca) salt Tablet size, mg Elemental Ca, mg, % Carbonate 1250 500 (40) Acetate 667 169 (25) Citrate 950 200 (21) Lactate 325 42 (13) Gluconate 500 4.
GAD exists as two major isoforms (GAD67 and GAD65) in the brain; each is the product of separate genes (113 order 100 mg aurogra free shipping erectile dysfunction korean red ginseng,114) and each has distinct kinetic prop- erties (114 cheap aurogra 100mg free shipping prostate cancer erectile dysfunction statistics,115) cheap aurogra 100mg overnight delivery erectile dysfunction drugs and nitroglycerin. GAD67 is distributed throughout the cyto- plasm of GABAergic neurons cheap 100 mg aurogra fast delivery erectile dysfunction surgery cost, whereas GAD65 is associated with synaptic terminals. Recently, it was shown that the 67- kd isoform of GAD protein is reduced in response to ele- vated levels of GABA in vitro and in vivo (116,117). Differ- ential control of the GAD isoforms suggests that they may mediate different fluxes. To investigate the effects of ele- vated GABA on GABA synthesis and quantitatively assess the role of the GAD isoforms in GABA synthesis, rates of turnover of cortical glutamate and GABA were determined in anesthetized rats during an infusion of [1-13C] glucose after administration of the GABA-transaminase inhibitor vigabatrin (500 mg/kg, i. GABA concentration was increased twofold at 24 hours. In vivo H MRS spectra of total edited GABA from the occipital lobe of a patient with epilepsy before and after treatment compared to nontreated rats despite the increased treatment with vigabatrin. An analysis of the turnover data revealed a using spectral editing (112) from a 14-cm3volume centered on the 70% decrease in the rate of GABA synthesis following midline in thevisual cortex. Chronic treatmentwith vigabatrin led to an over twofold increase in the concentration of total edited vigabatrin-treatment (control, 0. The reduction in GABA synthesis concomitant with the selective inhibition of GAD67 suggests that GAD67 accounts for the major fraction of GABA synthesis in the rat cerebral cortex under anesthe- fails to additionally increase GABA concentration (108), (b) tized nonstimulated conditions. This conclusion is sup- GABA concentration reaches a maximum level within 2 ported by studies of GAD67 and GAD65 in knockout mice hours of initial drug administration (109), (c) the effective- (118,119), which have found an order of magnitude greater ness of vigabatrin in controlling seizures depends on elevat- reduction in GABA concentration in the mice with a ing GABA concentration above the mean level found in GAD67 knockout. The isoform composition of human nonepileptic subjects (108), (d) GABA concentration is in- brain is presently unknown. These drugs include GABApentin, topiri- of epilepsy (108,112). The elevation of GABA may be an important mechanism in the effectiveness of these medications as antiepileptic compounds. In addition, these Cortical GABA Synthesis Is Reduced findings provide evidence that the regulation of GABA Following Prolonged GABA-Transaminase metabolism is tightly integrated with the regulation of Inhibition GABAergic function. As with vigabatrin, the concentration of above a dose of 3 g/day (108). The enzymatic mechanisms GABA reaches a maximum of two times the predrug con- controlling GABA levels in vivo are complex, involving centration within 2 hours of drug administration. A similar short-term regulation of GAD by modulators (e. The ability of 1H MRS to track i longer-term regulation involving enzyme protein levels, the response of the GABAergic system to pharmacologic availability of glutamate precursors and their pathways (e. Parsing the Edited GABA Resonance The edited GABA resonance consists of GABA and the GABA derivative homocarnosine, which is a condensation product of GABA and histidine. Homocarnosine is a neuro- modulator present in a specific subclass of GABAergic neu- rons in the primate brain. Short TE 1H MRS with macro- molecule suppression may be used to measure the homocarnosine histidine proton resonances in the down- field region of the short TE spectrum (103,112). A time course of GABA plus homocarnosine con- ing the homocarnosine measurement and the total GABA centration after administration of topiramate. Topiramate at 3 mg/kg was administered to six volunteers without epilepsy. Through modification GABA levels were measured to peak within 3 hours after adminis- of the editing selectivity, the GABA derivative pyrolidinone tration of topiramate at approximately two times the predrug levels. A study looking at the acute effect of topiramate on GABA may also be measured in the edited spectrum (131). It was levels of epileptic patients found that the increase was almost recently shown that GABA, homocarnosine, and pyrolidi- entirely due to GABA (121). The GABA plus homocarnosine con- none have different time courses in response to a first-time centrations are normalized to a creatine concentration of 9 mol/ g for comparison with measurements by Petroff and co-workers challenge with vigabatrin (109). Topira- mate increases cerebral GABA in healthy humans. However, the ability to directly Disease on GABA Concentration measure GABA synthesis at 2. Consistent with this proposal, 1H MRS editing studies have found decreased GABA in Due to the entry of GABA into the glial TCA cycle at adult epilepsy (111,125) and pediatric epilepsy (126). In the level of succinate, the labeling kinetics of C4-glutamine epilepsy the release of cytosolic GABA has been proposed derived from GABA are indistinguishable from label enter- as an important mechanisms for seizure suppression (127, ing through anaplerosis. The finding that a low GABA concentration was the maximum estimate of the rate of the GABA/glutamine strongly associated with poor seizure control in epilepsy sup- cycle, obtained by assuming that Vana, is entirely due to ports this proposal. Further support for a role of cytosolic GABA, would be approximately 10% of the rate of gluta- GABA concentration in inhibiting cortical excitability mine synthesis (29). In addition to epilepsy, reduced GABA concentration has been found in unipolar depression (129), alcohol with- Summary and Remaining Questions drawal, and hepatic encephalopathy (130). These disorders are associated with an alteration in inhibitory GABAergic The ability of 1H MRS to measure regional levels of GABA function. The finding of low GABA associated with these and GABA derivatives has provided a new window on the disorders is additional evidence that the brain metabolic GABAergic system in neurologic and psychiatric disease. GABA pool has an important role in GABAergic function. Reduced levels of cerebral cortex GABA have been found The finding in unipolar depression appears paradoxical be- in patients with adult and pediatric epilepsy, depression, cause the condition is not associated with enhanced cortical and alcohol withdrawal. A potential explanation of this finding is that the new generation of antiepileptic drugs raise GABA levels, 332 Neuropsychopharmacology: The Fifth Generation of Progress and GABA elevation may be related to their effectiveness surements of the Rate of the Glutamate/Glutamine Cycle: in seizure depression. The recently demonstrated ability to Findings and Validation, and Determination of the In Vivo perform GABA spectroscopic imaging (105) opens up the Coupling Between the Rate of the Glutamate/Glutamine potential for using regional variations in GABA level diag- Neurotransmitter Cycle and Neuronal Glucose Oxidation). As discussed below (see Implications of MRS What is the relationship between GABA levels and the rate Studies for Understanding Brain Function), the ambiguity of the GABA/glutamine cycle? What is the relationship be- created by the variable degree of uncoupling between glu- tween the GABA/glutamine cycle and cortical excitability? This strategy, in of metabolic coupling between glucose and oxygen by allow- combination with the manipulation of GABA levels either ing measurements of the rates of nonoxidative glycolysis pharmacologically or through transgenic methods, may pro- and glucose oxidation. MRS experiments have shown that vide significant insight into how the regulation of GABA under stimulated conditions the majority of energy for func- concentration affects GABAergic function. They have also confirmed the presence of metabolic uncoupling at high levels of brain activity (136–138). A model has been IN VIVO MRS MEASUREMENTS OF proposed to explain the uncoupling of glucose consumption NEUROENERGETICS DURING FUNCTIONAL and oxidation during certain types of stimulation as an ex- ACTIVATION tension of the normal energetic processes used to support the glutamate/glutamine cycle (139). Under physiologic conditions brain oxygen and glucose consumption are tightly coupled (49), with between 90% MRS Studiesof Lactate Generation and and 95% of glucose uptake being completely oxidized. The Glucose Oxidation During Sensory tightness of this coupling during brain activation was ques- Stimulation tioned when Fox and co-workers (132) measured by PET a mean increase of 51% in CMRglc in the primary visual A prediction of the presence of uncoupling of the increase cortex of humans during stimulation by a flashing checker- of glucose consumption and oxidation during visual activa- board pattern accompanied by only a 5% increase in oxygen tion is that there will be an elevation of lactate in the visual consumption (CMRO2). Several laboratories have found an increase in lactate cause of the 16- to 18-fold lower ATP production from concentration (136–138) during visual stimulation of the nonoxidative glycolysis compared with the complete oxida- human visual cortex by 1H MRS of approximately 0. It was concluded from these 4 mol/g-min within 2 to 6 minutes of activation.
Similarly purchase 100 mg aurogra fast delivery erectile dysfunction cycling, these mice other 5-HT receptor subtypes in processes related to stress had lower levels of activity in the bright portion of a light- and anxiety and will aid in drug development purchase aurogra line erectile dysfunction no xplode. It should be mentioned that GAD65 / mice also displayed an elevation in the occur- The GABA System rence of spontaneous and stress-induced seizures order 100mg aurogra mastercard erectile dysfunction treatment old age, and that these mice had a dramatically increased mortality rate start- The primary inhibitory neurotransmitter in the CNS is ing at 4 to 5 weeks after birth (151) aurogra 100 mg on line impotence mayo. Thus, although the GABA; GABA-synthesizing cells are distributed throughout behavioral profile of GAD65 knockout mice is suggestive the brain (128). The actions of GABA are mediated by two of increased anxiety-like responses, it is possible that these major classes of receptors, GABAA and GABAB, both of effects are secondary to the occurrence of seizures and to which modulate the activity of ion channels. The principal the factors leading to early lethality. The usefulness of this mode of inactivation of GABA transmission is the presynap- knockout as a model for anxiety-related deficits may there- tic reuptake of GABA by its transporter protein. Given that benzodiazepines and barbiturates both types of GABA receptors are widely distributed act as positive modulators of GABA transmission at the through the CNS, several important differences exist be- GABA receptor by enhancing GABA-induced chloride A tween the two. Relevant to psychopharmacology is the find- channel opening, it is of interest to note that GAD65 / ing that traditional anxiolytics (benzodiazepines) do not mice were not sensitive to the effects of either benzodiaze- bind to GABAB receptors, but rather mediate their effects pines or barbiturates, but did respond to the direct GABA A through GABAA receptors. GABAA receptors consist of a agonist muscimol, which binds directly to the GABA site of chloride channel formed by the pentameric arrangement of the GABA receptor and increases opening of the chloride A at least 18 different protein subunits ( 1–6, 1–4, 1-3, , channel in the absence of GABA (152). This pharmacologic , , 1–3), thus allowing for considerable heterogeneity of profile is consistent with the finding that GABA synthesis the GABAA receptor isoforms (148). Typically, benzodiaze- is blocked by the GAD65 null mutation, but that GABA A pine-responsive GABAA receptors consist of , , and receptor binding is unaffected by this change. Furthermore, subunits; in addition to the benzodiazepine site, these recep- this mutation does not seem to alter the functioning of tors also contain distinct sites for the binding of GABA, GABA receptors because direct agonists stimulate the recep- barbiturates, and ethanol. These various regions act as allo- tor but indirect modulators of GABA do not. Although psychotherapeutic effects such as anxiolysis receptor subunits in the regulation of stress- and anxiety- are achieved through facilitation of GABA transmission at related behaviors, investigators have generated mutant mice this receptor, drugs that act as GABAA receptor agonists with alterations in the expression of specific GABA recep- A also produce several deleterious side effects. It was initially reported that deletion of the which differences in GABAA receptor subunit composition subunit led to a selective (94%) reduction in the expres- 2 might contribute to possible dissociations between the bene- sion of benzodiazepine sites in the CNS without alterations ficial and negative effects of these compounds is currently in the level of GABA sites or changes in the expression of being investigated. Thus, knockout A 2 mice possessed functional GABAA receptors that responded normally to GABA site ligands or barbiturates, but did not GABA System Transgenic Mice respond to benzodiazepines; these findings led to the con- The synthesis of GABA is regulated by two isoforms of the clusion that the 2subunit is not necessary for the formation enzyme glutamate decarboxylase (GAD), GAD67, and the of functional GABAA receptors, but is required to create 894 Neuropsychopharmacology: The Fifth Generation of Progress the benzodiazepine-responsive site of those receptors. Mice rated from the negative side effects of these compounds, that were homozygous for the mutation, however, did not and that the 1 subunit of the GABAA receptor is likely live past weaning in this study. In mice carrying only one to mediate some of these potentially harmful properties of copy of the functional 2 gene, a 20% reduction in benzodi- benzodiazepines. Interestingly, McKernan and colleagues azepine sites was observed, but these mice did not show (160) demonstrate that a novel benzodiazepine-site ligand overt developmental deficits. In a recent study, a detailed that binds to GABAA receptors containing 2, 3,or 5 characterization of the behavioral profile of these animals subunits but avoids receptors with the 1 subunit produces was carried out. Heterozygotes displayed a decrease in the a behavioral profile that is identical to that of the 1 subunit number of entries into and amount of time spent in the knockout mice; in normal mice, this compound decreases open arms of an elevated plus maze and the bright compart- murine anxiety-like behaviors without eliciting sedation or ment of a light-dark box. Finally, 2 heterozygotes Stress-Related Disorders were found to react to partially conditioned stimuli (only weakly paired with aversive consequences) as if they were As stated above, the most widely used GABA system-based full and potent predictors of threat; compared to wild-types, drugs for the treatment of anxiety are the benzodiazepines, which showed low levels of defensive behaviors to the par- which facilitate GABA transmission through the GABAA tially conditioned stimulus, heterozygotes displayed high receptor. As outlined in the previous section, the search for levels of conditioned freezing to the partial conditioned novel compounds that may act selectively at specific GABAA stimulus that were identical to those displayed by all animals subunits is ongoing, with the ultimate hope of discovering in response to the full conditioned stimulus. This profile ligands that produce anxiolysis but do not cause some of has been proposed to be a model for the tendency to inter- the serious side effects that are commonly associated with pret neutral situations as threatening that is seen in anxiety benzodiazepines. Taken together, the results from this extensive be- leagues (160), drugs that selectively target certain GABAA havioral profile indicate that / mice have increased receptor subunits may hold great promise for the treatment 2 neophobia and stress-like responses and may thus provide of anxiety without harmful side effects. This development a model for increased anxiety-like behaviors (154—156). The use of targeted genetic in 2 heterozygotes were blocked by the benzodiazepine alterations in identifying the roles of various GABAA sub- diazepam, suggesting that this animal model may also have units will undoubtedly aid in this effort to create 'designer good predictive validity for identifying clinically effective drugs' for the treatment of anxiety (158). It is also extremely important to mention the 1 subunit General Issues and Caveats of Transgenic transgenic mice, whose behavioral profiles have been thor- Animal Studies oughly and insightfully reviewed in recent articles (157, 158). In these mice, a single amino acid is altered (histidine As mentioned above, mice carrying certain mutations replaced by arginine at the 101 position of the peptide) in within either the CRH, the 5-HT, or the GABA system the 1 subunit of the GABAA receptor complex. It appears that these change does not produce any overt alterations in baseline genetically engineered mouse models also have some predic- responses to stress in the genetically altered mice; these ani- tive validity; the stress-like endophenotype observed in at mals behave similarly to wild-type controls in tests such least two of the aforementioned models is normalized by as the elevated plus maze and the fear-potentiated startle administration of a clinically effective antianxiety agent that paradigm, a measure of conditioned fear (159,160). Thus, acts within the system that was genetically targeted. It re- under drug-free, normal conditions, these animals do not mains to be determined, however, the extent to which these display a behavioral pattern that is consistent with an anxi- genetically altered models serve to identify potential anti- ety-like endophenotype. When these mice are treated with anxiety agents from different chemical classes. For example, conventional benzodiazepines, however, they react very dif- do benzodiazepines reduce stress-like effects of CRH over- ferently to the drug than their wild-type counterparts. The extent to which the stress-like endopheno- with the mutation in the 1 subunit display a normal reduc- type in these animals is altered by compounds that act on tion of stress-induced anxiety-like behaviors after benzodi- systems that were not directly targeted by the genetic muta- azepine treatment, but fail to display some of the more tion will aid in determining the generalizability and utility deleterious side effects associated with this class of drugs of these models as predictors of novel anxiolytic agents. These results indicate one assumes that these animals provide a model of inherent that the anxiolytic effects of benzodiazepines can be sepa- trait-like anxiety, they can serve as a powerful tool for Chapter 62: Animal Models and Endophenotypes of Anxiety and Stress Disorders 895 screening new potential anxiolytics. These models do pro- contributions to the development of stress and anxiety-like vide a sound approach to study the long-term effects of endophenotypes in animals, further information is needed congenital abnormalities in these neurotransmitter and neu- to understand the precise nature of gene–environment in- ropeptide systems. It is likely that a particular Several broad issues should be considered when inter- stressor results in alterations of gene expression in myriad preting studies utilizing genetically altered mice. Generally, systems and that the overall response to stress involves the the hypotheses regarding the behavioral profiles of coordination of gene activation and/or suppression within transgenic mice are based on earlier findings from psycho- these various systems. For example, within the CRH field, have recently been developed that enable the expression of the prediction that CRH overexpressers would display in- thousands of genes to be assayed at once. When the outcome of the particular environmental perturbation or disease state (163, transgenic studies agrees with the psychopharmacology- 164). This approach and its application to psychiatry re- based prediction, the findings are taken as a confirmation search have been discussed comprehensively in a recent re- of that hypothesized mechanism of action. Briefly, gene chip and DNA array tech- come of the transgenic studies disagrees with the predicted nology involve the hybridization of gene transcripts from a phenotype, however, concerns about possible develop- tissue sample onto a glass slide or filter that contains up mental confounds are raised. One of the most commonly to 10,000 different nucleotide sequences. The amount and cited drawbacks of the transgenic/knockout strategy is that pattern of the signal hybridized to the array are then as- the gene of interest is altered from the embryonic stage, sessed; this method thus permits a rapid analysis of changes therefore possibly influencing other genes involved in the in the expression of multiple genes. This technology can normal development of the animal. Thus, it is difficult to also be used to identify single nucleotide polymorphisms in tease apart the effects of under- or overexpression of that a particular gene by comparing the hybridization patterns gene on the endpoints under study from effects due to com- of samples from different candidate populations on chips pensatory or downstream developmental changes that may that contain multiple copies of the gene of interest, each have occurred as a result of the mutation (86,87,161). Theoretically, depending on the size of the excellent method for modeling a congenital abnormality that leads to a disease state, but this approach may be less gene, it would be possible to carry out a base-by-base exami- useful for identifying the discrete functions of a specific nation of the entire gene on a single gene chip. However, gene product because of the problems of interpretation that it is important to realize that although a broad approach arise from the developmental confound. Indeed, with regard can be taken with this technology, it may not be sensitive to all of the studies discussed in this section on genetically enough to detect small but functionally important changes altered mice, it will be important in future studies to deline- in gene expression. This technology can be applied to pre- ate the compensatory alterations that occur in response to clinial and clinical questions regarding the complex genetic the congenital mutation, and that may indirectly contribute control of stress and anxiety by examining event-related to the adult endophenotypes that are reported for these gene expression changes and also baseline differences in gene animals. Future studies utilizing novel inducible-knockout sequences (polymorphisms) that might contribute to differ- strategies will circumvent the developmental issue; inducible ential stress responsivity (165).
Treatment also afect the risk order discount aurogra on-line erectile dysfunction daily pill, frequency cheap aurogra erectile dysfunction caused by heart medication, or severity of recurrences after the is efective in patients with less frequent recurrences generic aurogra 100mg overnight delivery impotence 24. Randomized trials have indicated that and efcacy have been documented among patients receiving three antiviral medications provide clinical beneft for genital daily therapy with acyclovir for as long as 6 years and with herpes: acyclovir 100 mg aurogra erectile dysfunction drugs in homeopathy, valacyclovir, and famciclovir (160–168). Quality of life Valacyclovir is the valine ester of acyclovir and has enhanced is improved in many patients with frequent recurrences who absorption after oral administration. Famciclovir also has high receive suppressive therapy rather than episodic treatment. Topical therapy with antiviral drugs ofers The frequency of recurrent genital herpes outbreaks minimal clinical beneft, and its use is discouraged. Terefore, Newly acquired genital herpes can cause a prolonged periodically during suppressive treatment (e. Even persons with frst-episode herpes who have the patient. Such couples should be encouraged to consider suppressive antiviral therapy as part of a strategy to prevent transmission, in addition to consistent condom use Severe Disease and avoidance of sexual activity during recurrences. Suppressive Intravenous (IV) acyclovir therapy should be provided for antiviral therapy also is likely to reduce transmission when patients who have severe HSV disease or complications that used by persons who have multiple partners (including MSM) necessitate hospitalization (e. Te recommended regimen is acyclovir 5–10 mg/ Recommended Regimens kg IV every 8 hours for 2–7 days or until clinical improvement Acyclovir 400 mg orally twice a day is observed, followed by oral antiviral therapy to complete at OR least 10 days of total therapy. Acyclovir dose adjustment is Famiciclovir 250 mg orally twice a day recommended for impaired renal function. OR Counseling Valacyclovir 500 mg orally once a day* OR Counseling of infected persons and their sex partners is Valacyclovir 1 g orally once a day critical to the management of genital herpes. Te goals of counseling include 1) helping patients cope with the infection * Valacyclovir 500 mg once a day might be less efective than other vala- cyclovir or acyclovir dosing regimens in patients who have very frequent and 2) preventing sexual and perinatal transmission (174,175). Although initial counseling can be provided at the frst visit, many patients beneft from learning about the chronic aspects Acyclovir, famciclovir, and valacyclovir appear equally efec- of the disease after the acute illness subsides. Multiple resources, tive for episodic treatment of genital herpes, but famciclovir including websites (http://www. Ease of administration and cost also are clinicians who become involved in counseling. Although the psychological efect of a serologic diagnosis of HSV-2 infection in a person with asymptomatic or unrecog- Episodic Therapy for Recurrent Genital Herpes nized genital herpes appears minimal and transient (176), some Efective episodic treatment of recurrent herpes requires HSV-infected persons might express anxiety concerning genital initiation of therapy within 1 day of lesion onset or during the herpes that does not refect the actual clinical severity of their prodrome that precedes some outbreaks. Te patient should disease; the psychological efect of HSV infection frequently be provided with a supply of drug or a prescription for the is substantial. Common concerns regarding genital herpes medication with instructions to initiate treatment immediately include the severity of initial clinical manifestations, recurrent when symptoms begin. Te misconception that HSV causes cancer should be dispelled. Acyclovir 400 mg orally three times a day for 5 days Te following recommendations apply to counseling of OR persons with genital HSV infection: Acyclovir 800 mg orally twice a day for 5 days • Persons who have genital herpes should be educated OR concerning the natural history of the disease, with Acyclovir 800 mg orally three times a day for 2 days emphasis on the potential for recurrent episodes, asymp- OR tomatic viral shedding, and the attendant risks of sexual Famciclovir 125 mg orally twice daily for 5 days transmission. OR • Persons experiencing a frst episode of genital herpes Famciclovir 1000 mg orally twice daily for 1 day should be advised that suppressive therapy is available and OR Famciclovir 500 mg once, followed by 250 mg twice daily for 2 days efective in preventing symptomatic recurrent episodes OR Vol. Patients should • All persons with genital HSV infection should be encour- be informed that suppressive antiviral therapy does not aged to inform their current sex partners that they have reduce the increased risk for HIV acquisition associated genital herpes and to inform future partners before with HSV-2 infection (177,178). Management of Sex Partners • Sexual transmission of HSV can occur during asymp- tomatic periods. Asymptomatic viral shedding is more Te sex partners of patients who have genital herpes can frequent in genital HSV-2 infection than genital HSV-1 beneft from evaluation and counseling. Symptomatic sex infection and is most frequent during the frst 12 months partners should be evaluated and treated in the same manner after acquiring HSV-2. Asymptomatic sex part- • All persons with genital herpes should remain abstinent ners of patients who have genital herpes should be questioned from sexual activity with uninfected partners when concerning histories of genital lesions and ofered type-specifc lesions or prodromal symptoms are present. Episodic therapy does not reduce the risk for transmis- Allergy, Intolerance, and Adverse Reactions sion and its use should be discouraged for this purpose Allergic and other adverse reactions to acyclovir, valacyclo- among persons whose partners might be at risk for HSV-2 vir, and famciclovir are rare. Immunocompromised patients can have prolonged or • Sex partners of infected persons should be advised that severe episodes of genital, perianal, or oral herpes. Lesions they might be infected even if they have no symptoms. HSV shedding partners of persons with genital herpes is recommended is increased in HIV-infected persons. Whereas antiretroviral to determine whether such partners are already HSV therapy reduces the severity and frequency of symptomatic seropositive or whether risk for acquiring HSV exists. Pregnant women and ing immune reconstitution after initiation of antiretroviral women of childbearing age who have genital herpes therapy. Pregnant women who are among HIV-positive persons (181–183). Te extent to which not known to be infected with HSV-2 should be advised suppressive antiviral therapy will decrease HSV transmission to abstain from intercourse with men who have genital from this population is unknown. HSV type-specifc serologies herpes during the third trimester of pregnancy. Similarly, can be ofered to HIV-positive persons during their initial pregnant women who are not known to be infected with evaluation if infection status is unknown, and suppressive HSV-1 should be counseled to avoid genital exposure to antiviral therapy can be considered in those who have HSV-2 HSV-1 during the third trimester (e. Persons with HIV • Asymptomatic persons diagnosed with HSV-2 infection Acyclovir 400–800 mg orally twice to three times a day by type-specifc serologic testing should receive the same OR counseling messages as persons with symptomatic infec- Famciclovir 500 mg orally twice a day tion. In addition, such persons should be educated about OR the clinical manifestations of genital herpes. Valacyclovir 500 mg orally twice a day 24 MMWR December 17, 2010 Recommended Regimens for Episodic Infection in Persons pregnancy and avoiding exposure of the infant to herpetic with HIV lesions during delivery. Because the risk for herpes is high in Acyclovir 400 mg orally three times a day for 5–10 days infants of women who acquire genital HSV during late preg- OR nancy, these women should be managed in consultation with Famciclovir 500 mg orally twice a day for 5–10 days an infectious disease specialist. OR Women without known genital herpes should be counseled Valacyclovir 1 g orally twice a day for 5–10 days to abstain from intercourse during the third trimester with partners known or suspected of having genital herpes. In addi- tion, pregnant women without known orolabial herpes should Acyclovir, valacyclovir, and famciclovir are safe for use in be advised to abstain from receptive oral sex during the third immunocompromised patients in the doses recommended for trimester with partners known or suspected to have orolabial treatment of genital herpes. Some specialists believe that type-specifc serologic tests therapy with acyclovir 5–10 mg/kg IV every 8 hours might are useful to identify pregnant women at risk for HSV infec- be necessary. However, the efectiveness of antiviral therapy to persons should be managed in consultation with an HIV decrease the risk for HSV transmission to pregnant women specialist, and alternate therapy should be administered. At the onset of labor, all women every 8 hours until clinical resolution is attained, is frequently should be questioned carefully about symptoms of genital efective for treatment of acyclovir-resistant genital herpes. Imiquimod is a topical alternative, as is topical cido- without symptoms or signs of genital herpes or its prodrome fovir gel 1%, which is not commercially available and must be can deliver vaginally. Although cesarean section does not com- compounded at a pharmacy. Tese topical preparations should pletely eliminate the risk for HSV transmission to the infant, be applied to the lesions once daily for 5 consecutive days. However, experience with Te safety of systemic acyclovir, valacyclovir, and famci- another group of immunocompromised persons (hematopoi- clovir therapy in pregnant women has not been defnitively etic stem-cell recipients) demonstrated that persons receiving established. Available data do not indicate an increased risk daily suppressive antiviral therapy were less likely to develop for major birth defects compared with the general population acyclovir-resistant HSV compared with those who received in women treated with acyclovir during the frst trimester episodic therapy with outbreaks (185).
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