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Selectins Leukocytes release proteases purchase noroxin 400mg visa, elastases noroxin 400mg discount, and reactive oxygen radi- L-selectin Leukocytes cals that induce tissue injury buy noroxin 400 mg with visa. Activated leukocytes also elaborate P-selectin Endothelial cells cytokines such as interleukin 1 and tum or necrosis factor which E-selectin Endothelial cells attract additional leukocytes to the site order noroxin 400mg online, causing further injury. Carbohydrate ligands for selectins Sulphated polysacharides Endothelium Oligosaccharides Leukocytes Integrins CD11a/CD18 Leukocytes CD11b/CD18 Leukocytes Immunoglobulin G–like ligands for integrins Intracellular adhesion molecules (ICAM) Endothelial cells FIGURE 14-31 125 Anti-ICAM Anti-ICAM N eutralizing anti–ICAM antibody am elio- antibody 2 antibody rates the course of ischem ic renal failure 100 Vehicle Vehicle with blood urea nitrogen, A, and plasm a 1. Rats subjected to 30 m inutes 75 of bilateral renal ischem ia or a sham -opera- tion were divided into three groups that 50 1 received either anti-ICAM antibody or its vehicle. ICAM antibody am eliorates the severity of renal failure at 0 0 all three tim e points. M yeloperoxidase 1000 antibody is an enzyme specific to leukocytes. Anti-ICAM antibody reduced myeloperoxidase activity (and by inference the number of leuko- 750 cytes) in renal tissue after 30 minutes of ischemia. Cells undergoing necrosis becom e swollen and enlarged. The m ain m orphoplogic features of m itochondrial injury include swelling and flattening of the folds of the inner m itochondrial m em brane (the christae). The cell plasm a m em brane loses its integrity and allows the escape of cytosolic contents including lyzoso- m al proteases that cause injury and inflam m ation of the surrounding tissues. In contrast to necrosis, apoptosis is associated with a progressive decrease in cell size and m aintenance of a functionally and structurally intact plasm a m em brane. The decrease in cell size is due to both a loss of cytosolic volum e and a decrease in the size of the nucleus. The m ost characteristic and specific m orphologic feature of apoptosis is condensation of nuclear chrom atin. Initially the chrom atin condenses against the nuclear m em brane. Then the nuclear m em brane disappears, and the condensed chrom atin fragm ents into m any pieces. The plasm a m em brane undergoes a process of “budding,” which progresses to fragm entation of the cell itself. M ultiple plasm a m em brane–bound fragm ents of condensed DN A called apoptotic bodies are form ed as a result of cell fragm entation. The apoptotic cells and apoptotic bodies are rapidly phagocytosed by neighboring epithelial cells as well as professional phagocytes such as m acrophages. The rapid phagocytosis of apoptotic bod- ies with intact plasm a m em branes ensures that apoptosis does not cause any surrounding inflam m atory reaction. A B FIGURE 14-34 H ypothetical schem a of cellular events trig- gering apoptotic cell death. Activation of Positive feedback loop ICE/ced-3-like proteases? Consequences of permeability transition: Disruption of ∆ψm and mitochondrial biogenesis Breakdown of energy metabolism Uncoupling of respiratory chain Calcium release frommitochondrial matrix Hyperproduction of superoxide anion Depletion of glutathione? ROS Increase in ATP NAD/NADH Tyrosin kinases effects [Ca2+] depletion depletion G-proteins? Epithelial cells dying by apoptosis are not only phagocytosed by macrophages and leukocytes but by neighbouring epithelial cells as well. This electron micrograph shows a normal-looking epithelial cell containing an apoptotic body within a lyzosome. The nucleus of an epithelial cell that has ingested the apoptotic body is normal (white arrow). The wall of the lyzosome containing the apoptotic body (black arrow) is clearly visible. The apoptotic body consists of condensed chromatin surrounded by plasma membrane (black arrowheads). FIGURE 14-36 DN A fragm entation in apoptosis vs necrosis. Each Nucleosome nucleosom e of DN A is about 200 base pairs in size and is surrounded by histones. Between ~200 bp nucleosom es are sm all stretches of DN A that are not surrounded by histones and are called linker regions. During apoptosis, early activation of endonuclease(s) causes double-strand Internucleosome breaks in DN A between nucleosom es. N o fragm entation occurs in nucleosom es because the "Linker" regions DN A is “protected” by the histones. Because of the size of nucleosom es, the DN A is frag- m ented during apoptosis into m ultiples of 200 base pair pieces (eg, 200, 400, 600, 800). W hen the DN A of apoptotic cells is electrophoresed, a characteristic ladder pattern is found. DNA fragmentation In contrast, necrosis is associated with the early release of lyzosom al proteases, which cause proteolysis of nuclear histones, leaving “naked” stretches of DN A not protected by histones. Activation of endonucleases during necrosis therefore cause DN A cleavage at m ultiple sites into double- and single-stranded DN A fragm ents of varying size. Apoptosis Necrosis Electrophoresis of DN A from necrotic cells results in a sm ear pattern. Loss of histones 800 bp 600 bp 400 bp 200 bp DNA electrophoresis Apoptic Necrotic "ladder" "smear" pattern pattern 14. The IN ACUTE RENAL FAILURE sam e cytotoxic stim uli that induce necrosis cause apoptosis. The m echanism of cell death induced by a specific injury depends in large part on the severity of the injury. Because m ost cells require Loss of survival factors constant external signals, called survival signals, to rem ain viable, Deficiency of renal growth factors (eg, IGF-1, EGF, HGF) the loss of these survival signals can trigger apoptosis. In ARF, a deficiency of growth factors and loss of cell-substrate adhesion are Loss of cell-cell and cell-matrix interactions potential causes of apoptosis. The death pathways induced by Receptor-mediated activators of apoptosis engagem ent of tum our necrosis factor (TN F) with the TN F recep- Tumor necrosis factor tor or Fas with its receptor (Fas ligand) are well known causes of Fas/Fas ligand apoptosis in im m une cells. TN F and Fas can also induce apoptosis Cytotoxic events in epithelial cells and m ay contribute to cell death in ARF. Ischemia; hypoxia; anoxia Oxidant injury Nitric oxide Cisplati FIGURE 14-38 Apoptotic Trigger Apoptosis is m ediated by a highly coordinated and genetically pro- gram m ed pathway. The response to an apoptotic stim ulus can be divided into a com m itm ent and execution phases. During the com - m itm ent phase the balance between a num ber of proapoptotic and Commitment phase antiapoptotic m echanism s determ ine whether the cell survives or dies by apoptosis. The BCL-2 fam ily of proteins consists of at least Anti-apoptic factors Pro-apoptic factors 12 isoform s, which play im portant roles in this com m itm ent phase. Som e of the BCL-2 fam ily of proteins (eg, BCL-2 and BCL-XL) pro- BclXL BAD tect cells from apoptosis whereas other m em bers of the sam e fam ily Bcl–2 Bax (eg, BAD and Bax) serve proapoptotic functions. Apoptosis is exe- cuted by a final com m on pathway m ediated by a class of cysteine proteases-caspases.

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Depression is the most common comorbid diagnosis with OCD 400 mg noroxin mastercard. The pres- Tryptophan ence of concurrent depression at the start of treatment was Tryptophan buy noroxin 400mg on line, a 5-HT precursor buy generic noroxin 400 mg line, has shown varying degrees not found to predict whether SRIs were effective in reducing of effectiveness in case reports of SRI augmentation in OCD obsessive-compulsive symptoms (100) noroxin 400mg on-line. Hollander and asso- (68,149), but has been removed from the market because ciates (141) reported that select measures of serotonergic of side effects. They found that nonresponders to SRIs were likely to experience worsening of OCD symptoms and to have a blunted prolactin response on being challenged Lithium with the partial 5-HT agonist m-chlorophenylpiperazine Lithium, which is thought to enhance presynaptic 5-HT (m-CPP). Also, OCD release in the brain (150) and influence second messenger patients with increased neurologic soft-signs, a measure of systems coupled to 5-HT receptors, was reported to improve subtle neurologic dysfunction, had a worse response to SRIs OC symptoms in three out of four patients treated with (22). However, in a 4-week double-blind study of lithium aug- mentation to 16 OCD partial responders on clomipramine, AUGMENTATION STRATEGIES there was no further decrease in OC symptoms reported after lithium (152). In two double-blind, placebo-controlled Augmentation strategies play an important role in OCD trials of lithium, addition to ongoing fluvoxamine treatment pharmacotherapy for SRI partial and nonresponders, as in OCD nonresponders (2-week study [20 points] and 4- 40% to 60% of patients with OCD will not respond to an week study [10 points]), only a small statistically significant adequate treatment trial of an SRI. Augmentation agents reduction in OCD symptoms was reported from the 2-week added to SRIs include both serotonin enhancers and agents trial, but not from the 4-week trial (153). Other cases of risperidone augmenta- erties, has been efficacious in augmentation to SRIs in the tion reported effectiveness in reducing OC symptoms in patients with OCD in case series (154) and in a double- patients who had failed SRI trials (164,165). A chart review, blind, controlled augmentation trial with fluoxetine or including eight OCD patients treated with the combination clomipramine (155). Trazodone Trazodone, a 5-HT2 and -adrenergic blocker with weak Olanzapine 5-HT reuptake properties, which has m-CPP as a minor Case series (167,168) and open-label trials (169) have re- metabolite, was recently reported effective in augmentation ported benefits of adding titrated doses of olanzapine (10 to various SRIs in five cases of refractory OCD (156). Thus, olanzapine might also be considered in the augmenta- Pindolol tion of severe forms of OCD, although careful monitoring of the potential interaction with SSRIs is suggested because Pindolol is a -adrenergic blocker with 5-HT1B and 5- this combination may produce idiosyncratic effect on HT1A receptor antagonist activity. One study of pindolol augmentation to GABA/Second Messenger Systems paroxetine in resistant OCD resulted in mild improvement Gabapentin, a -aminobutyric acid (GABA) analogue, was (158), whereas another report found that pindolol did not reported to improve OC symptoms in 5/5 partial responders shorten the latency of fluvoxamine antiobsessional response in a 6-week pilot study of fluoxetine augmentation within (159). Thus, the utility of pindolol in non-depressed OCD 2 weeks of treatment (170). Dopamine antagonist/SRI combina- tions have been reported to be effective in OCD. NOVEL PHARMACOTHERAPIES Haloperidol Some individuals with OCD remain refractory even to aug- In a double-blind, placebo-controlled study of OCD pa- mentation strategies. For them, alternate pharmacotherapy tients on fluvoxamine monotherapy, haloperidol augmenta- may provide relief. Intravenous clomipramine was first reported successful in treating obsessive symptoms in 1967 (46). A review of the literature found over 100 cases of successful treatment with Pimozide intravenous clomipramine (172). In a double-blind, pla- Open case series have shown the effectiveness of pimozide/ cebo-controlled trial of intravenous versus oral pulse loading SRI combinations in OCD patients with and without com- of clomipramine in 15 OCD patients, six of seven patients orbid tic-related disorders (161). This may be In an open trial of risperidone/SRI combination treatment, owing to avoidance of the first-pass liver metabolism of 87% (14/16) of patients with refractory OCD had substan- clomipramine, resulting in a greater clomipramine/des- tial reduction in OC symptoms (162). In another open trial, methyl clomipramine ratio, more potent central 5-HT ef- Chapter 114: Current and Experimental Therapeutics of OCD 1657 fects, and fewer side effects. The superiority of the intrave- agents that release dopamine and dopamine receptor ago- nous route compared to the oral one has been reported in nists may also have efficacy in OCD. Insel and associates a placebo-controlled study (174). After 1 month of intrave- (189) reported that two patients treated with amphetamines nous clomipramine (doses up to 250 mg per day) 58% of 21 (10 to 20 mg) achieved a 'persistent benefit' for a period patient nonresponders to oral administration randomized to of several weeks. He reported an additional two patients receive intravenous clomipramine showed a marked clinical treated with 'low-dose' amphetamines for several months improvement rated by both CGI and Y-BOCS, without who reported a decrease in obsessional symptoms. These reports must be reconciled with reports that chronic administration of Monoamine oxidase inhibitors (MAOIs), which block the methylphenidate and amphetamine may induce ritualized catabolism of serotonin as well as norepinephrine and dopa- behaviors and other OCD-like symptoms (191,192). Case reports of successful treatment reported failure on chronic dopaminergic agonists. In a sur- are available for iproniazid (175) and most substantially for vey by Hewlett (172), five of 28 subjects (19%) achieved phenelzine, which was one of the first pharmacologic agents a good response with chronic amphetamine. These reports primarily combined phenel- these two patients treated with bromocriptine had any im- zine with other medications (176–178). Bupropion, which inhibits dopaminergic reup- week placebo-controlled comparison trial of fluoxetine ver- take, was associated with 15 failed treatments. Conceivably, the response to low- dose neuroleptics in OCD may stem from their effects on Serotonergic Agents blocking presynaptic dopamine D2 receptors, increasing Buspirone monotherapy was reported to be ineffective in an dopamine release (190). Trazodone has been found successful in both Benzodiazepines cases and open trials of comorbid depression with OCD Case reports of clonazepam have also shown its efficacy (181–183); however, it was found ineffective in reducing (172,193). In a double-blind crossover trial, 40% of the OC symptoms in a double-blind, placebo-controlled trial patients who had failed clomipramine treatment had clini- (184). The first treatment response to tryptophan was de- cally significant responses to clonazepam treatment, and clo- scribed in seven patients with OCD (185), with no further nazepam was significantly more effective than clomipramine controlled studies. The role of other serotonergic agents in during the first 3 weeks of treatment (188). However, a treating OCD including 5-HT3 agonists (ondansetron) and double-blind multicenter placebo-controlled trial of clona- 5-HT2 agonists requires further research. Other benzodiaze- pines, such as alprazolam, have also not shown efficacy in Noradrenergic Agents treating OCD (195). The noradrenergic system has also been explored as a novel individual pharmacotherapy in OCD. A case report of clon- idine, an 2-agonist, documented improvement in OCD Anticonvulsants (186). Intravenous clonidine was reported to markedly re- There are three case reports of significant response to non- duce obsessions in six OCD patients (187). However, in benzodiazepine-related anticonvulsants (two of whom had a double-blind controlled crossover trial of clomipramine, clinical epilepsy) all with carbamazepine, and 23 treatment clonazepam, and clonidine in 28 OCD patients, clonidine was found ineffective in reducing OCD symptoms (188). Two patients with OCD and clinical epilepsy responded to clonazepam treatment (196); however, clinical experience with anticonvulsants may be more positive. Two Stimulants and Dopamine Releasers of 12 patients (17%) at two sites had successful trials of Although most attention has focused on the blockade of carbamazepine, and six of 26 patients (23%) at three sites dopaminergic receptors in OCD, there are also reports that had positive outcomes with sodium valproate (172). Controlled trials are required, al- There have been six reported cases of improvement associ- though it has low abuse potential, low physical dependency, ated with antiandrogen treatment, four of which were men- and mild tolerance. Only one antiandro- gen failure has been reported, and one failure of estrogen treatment alone. An open trial with flutamide, an androgen AUTOIMMUNE TREATMENTS receptor antagonist, in eight OCD patients, demonstrated a lack of response (197). None of the OCD centers has Autoimmune mechanisms may also play a role in at least reported using this modality in treating OCD. As such, a subtype of patients with OCD, particularly those who this treatment has not been well studied. In practice, the manifest a sudden onset of OCD symptoms following infec- feminizing effects of these treatments in males limit their tion by group A B-hemolytic streptococci.

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