By L. Stejnar. Central State University.
For sexually active women or metronidazole twice a day at 500 mg orally for 7 days cheap 0.2 mg tamsulosin with mastercard. Patients with an immediate-type allergy to a nitroimidazole Rescreening 3 months after completion of therapy should be can be managed by metronidazole desensitization in consulta- considered among HIV-positive women with trichomoniasis order tamsulosin 0.4 mg with visa, tion with a specialist (364–366). Topical therapy with drugs a recommendation based on the high proportion of recurrent other than nitroimidazoles can be attempted, but cure rates or persistent infection and the association between HIV and are low (<50%). Pregnancy A recent randomized clinical trial involving women coin- Vaginal trichomoniasis has been associated with adverse fected with trichomoniasis and HIV demonstrated that a pregnancy outcomes, particularly premature rupture of single dose of metronidazole 2 gm orally was not as efective membranes, preterm delivery, and low birth weight. Treatment with azoles results in relief of symptoms and negative cultures in 80%–90% of patients who complete therapy. Vulvovaginal Candidiasis Recommended Regimens VVC usually is caused by C. Typical symptoms of Butoconazole 2% cream 5 g intravaginally for 3 days VVC include pruritus, vaginal soreness, dyspareunia, external OR dysuria, and abnormal vaginal discharge. None of these symp- Clotrimazole 1% cream 5 g intravaginally for 7–14 days toms is specifc for VVC. An estimated 75% of women will OR have at least one episode of VVC, and 40%–45% will have Clotrimazole 2% cream 5 g intravaginally for 3 days two or more episodes within their lifetime. On the basis of OR clinical presentation, microbiology, host factors, and response Miconazole 2% cream 5 g intravaginally for 7 days to therapy, VVC can be classifed as either uncomplicated or OR complicated (Box 3). Approximately 10%–20% of women Miconazole 4% cream 5 g intravaginally for 3 days will have complicated VVC that necessitates diagnostic and OR therapeutic considerations. Miconazole 100 mg vaginal suppository, one suppository for 7 days OR Uncomplicated VVC Miconazole 200 mg vaginal suppository, one suppository for 3 days Diagnostic Considerations OR A diagnosis of Candida vaginitis is suggested clinically by the Miconazole 1,200 mg vaginal suppository, one suppository for 1 day presence of external dysuria and vulvar pruritus, pain, swelling, OR and redness. Signs include vulvar edema, fssures, excoriations, Tioconazole 6. Te diagnosis can be made Prescription Intravaginal Agents: in a woman who has signs and symptoms of vaginitis when Butoconazole 2% cream (single dose bioadhesive product), 5 g intravaginally for 1 day either 1) a wet preparation (saline, 10% KOH) or Gram stain OR of vaginal discharge demonstrates yeasts, hyphae, or pseudohy- Nystatin 100,000-unit vaginal tablet, one tablet for 14 days phae or 2) a culture or other test yields a yeast species. Candida OR vaginitis is associated with a normal vaginal pH (<4. Use of 10% OR KOH in wet preparations improves the visualization of yeast Terconazole 0. Examination of a wet mount with Terconazole 80 mg vaginal suppository, one suppository for 3 days KOH preparation should be performed for all women with Oral Agent: symptoms or signs of VVC, and women with a positive result Fluconazole 150 mg oral tablet, one tablet in single dose should receive treatment. For women with negative wet mounts who are symptomatic, vaginal cultures for Candida should be considered. If the wet mount is negative and Candida cultures Te creams and suppositories in this regimen are oil-based cannot be done, empiric treatment can be considered for and might weaken latex condoms and diaphragms. Patients symptomatic women with any sign of VVC on examination. Women whose condition has previously been diag- healthy women with uncomplicated VVC have no identifable nosed with VVC are not necessarily more capable of diagnosing precipitating factors. Unnecessary or inappropriate use of OTC preparations mens of 1–3 days) efectively treat uncomplicated VVC. Te is common and can lead to a delay in the treatment of other 62 MMWR December 17, 2010 Box 3. Classifcation of vulvovaginal candidiasis (VVC) Complicated VVC Uncomplicated VVC Recurrent Vulvovaginal Candidiasis (RVVC) • Sporadic or infrequent vulvovaginal candidiasis RVVC, usually defned as four or more episodes of symp- OR tomatic VVC in 1 year, afects a small percentage of women • Mild-to-moderate vulvovaginal candidiasis (<5%). Te pathogenesis of RVVC is poorly understood, and OR most women with RVVC have no apparent predisposing or • Likely to be C. Vaginal cultures should be obtained OR from patients with RVVC to confrm the clinical diagnosis • Non-immunocompromised women and to identify unusual species (including nonalbicans spe- Complicated VVC cies), particularly Candida glabrata. OR Conventional antimycotic therapies are not as efective against • Non-albicans candidiasis these species as they are against C. OR Treatment • Women with uncontrolled diabetes, debilitation, Each individual episode of RVVC caused by C. However, to maintain clinical and mycologic control, some vulvovaginitis etiologies, which can result in adverse clinical specialists recommend a longer duration of initial therapy outcomes. If this regi- VVC is not usually acquired through sexual intercourse; men is not feasible, topical treatments used intermittently as no data support the treatment of sex partners. A minority of a maintenance regimen can be considered. However, 30%–50% of women will have with pruritus or irritation. Tese men beneft from treatment recurrent disease after maintenance therapy is discontinued. Allergy, Intolerance, and Adverse Reactions Severe VVC Topical agents usually cause no systemic side efects, although Severe vulvovaginitis (i. Oral agents occasionally edema, excoriation, and fssure formation) is associated with cause nausea, abdominal pain, and headache. Terapy with the lower clinical response rates in patients treated with short oral azoles has been associated rarely with abnormal elevations of courses of topical or oral therapy. Clinically important interactions can occur when azole or 150 mg of fuconazole in two sequential doses (second these oral agents are administered with other drugs, including dose 72 hours after initial dose) is recommended.
Intrastriatal infusion of ( / )-S- pharmacology 1996;15:87–97 discount 0.4 mg tamsulosin with amex. Electrophysiological evidence for the exis- ionotropic glutamate receptor-mediated mechanism: an in vivo tence of both D-1 and D-2 dopamine receptors in the rat nu- microdialysis study in chloral hydrate-anesthetized rats best 0.2 mg tamsulosin. Prolonged and extrasynaptic excitatory action of do- Chapter 9: Dopamine 131 pamine mediated by D1 receptors in the rat striatum in vivo. Eur J Neurosci 1999;11: J Neurosci 1997;17:5972–5978. Dopamine and N-methyl-D-aspartate activation enhances evoked discharge in neostriatal medium receptor interactions in the neostriatum. Dev Neurosci 1998;20: spiny neurons by modulating an L-type Ca2 conductance. Persistent Na of NMDA-induced whole cell currents in neostriatal neurons conductance in medium-sized neostriatal neurons: characteriza- in slices: contribution of calcium conductances. J Neurophysiol tion using infrared videomicroscopy and whole cell patch-clamp 1998;79:82–94. Dopamine receptor neostriatal neurons: regulation by cAMP-dependent mecha- subtypes colocalize in rat striatonigral neurons. Dopamine D1 receptor mine receptor activation reduces GABA(A) receptor currents in modulates the voltage-gated sodium current in rat striatal neu- neostriatal neurons through a PKA/DARPP-32/PP1 signaling rones through a protein kinase A. Dopamine regulation of neuronal by dopamine and norepinephrine in ventral but not dorsal stria- and network interactions within the striatum. On the distribution by impulse flow in the rat nucleus accumbens in vivo. Neurosci- patterns of D1, D2, tyrosine hydroxylase and dopamine trans- ence 1996;75:13–18. The electrophysiology of dopamine the dorsal striatum and their synaptic relationships with motor (D2) receptors: a study of the actions of dopamine on cortico- corticostriatal afferents. Dopamine selects D2 receptor-like immunoreactivity in midbrain dopamine neu- glutamatergic inputs to neostriatal neurons. Presynaptic D2 dopami- calcium currents by a D1 dopaminergic protein kinase/phospha- nergic receptors mediate inhibition of excitatory synaptictrans- tase cascade in rat neostriatal neurons. Permeation and block of dopa- cortical excitation in nucleus accumbens neurons recorded in mine-modulated potassium channels on rat striatal neurons by vitro. Beyond the dopamine recep- mine receptors are located on striatal glutamatergic nerve termi- tor: the DARPP-32/protein phosphatase-1 cascade. DARPP-32: mate release in striatum as measured by microdialysis. J Neuro- regulator of the efficacy of dopaminergic neurotransmission. Co-localization of D(4) receptor localization in the rat nucleus accumbens shell. Alterations in electrophysiological activity via presynaptic D1-like dopamine receptors. J Neurosci 1996; and dye coupling of striatal spiny and aspiny neurons in dopa- 16:1591–604. Amphetamine withdrawal alters bistable in the rat nucleus accumbens via adenosine release. J Neurosci states and cellular coupling in rat prefrontal cortex and nucleus 1997;17:5271–5280. Repeated treatment with haloperidol and cleus accumbens is attenuated by the protein kinase C inhibitor clozapine exerts differential effects on dye coupling between Ro 32-0432. Unilateral dopamine 132 Neuropsychopharmacology: The Fifth Generation of Progress denervation blocks corticostriatal LTP. The metabolic pathways link- stasis and function as extracellular messengers to regulate ing ATP, ADP, AMP, and adenosine and the potential for cell function. The effects of adenosine and the nucleotides each of these purines to elicit distinct receptor-mediated are mediated by activation of distinct P1 (adenosine) and effects on cell function form the basis of a complex, physio- P2 (ATP) cell-surface receptors present on neurons, astro- logically relevant, purinergic cascade comparable to those cytes, and microglia, as well as other cells that are present involved blood clotting and complement activation (8) (Fig. These receptors are ge- The extracellular effects of ATP on the various members nerically known as purinergic receptors (1). Thus, functional activities, some of which are antagonistic to one the factors regulating their availability in the extracellular another. For instance, ATP antagonizes ADP actions on space as chemical messengers have been an area of active platelet aggregation, whereas adenosine-elicited CNS seda- research and considerable debate since the late 1970s (2). In the broader framework of ATP-modulated pro- acetylcholine, norepinephrine, glutamate, -aminobutyric teins (or ATP-binding cassette proteins), ATP-sensitive po- acid (GABA), calcitonin gene–related peptide, vasoactive tassium channels (KATP) undergo activation when intra- intestinal peptide, and neuropeptide Y (3). ATP is available cellular ATP levels are reduced (10,11). Thus, as P2 on demand, and the body can synthesize its own weight in receptor–mediated responses decrease because of ATP hy- ATP per day (4).
The results indicate that monoamine deficiency LCmode 0.2 mg tamsulosin fast delivery, or switching between modes proven tamsulosin 0.2 mg, may be helpful in alone may not produce depressive symptoms, but that dif- treating this disorder. In fact, many of the stimulants that ferent types of depression exist that respond to manipula- are effective in treating ADHD decrease tonic LCactivity. A role for the LC–NE system in attentional disorders is Advances in understanding the actions of antidepressant also indicated by behavioral pharmacology experiments by drugs have highlighted the possible role of NE systems in Arnsten and colleagues (107). New drugs such as venlafaxine, which inhibits found that overstimulation of 1 receptors in the prefrontal reuptake of both serotonin and NE, have been found to cortex produces deficits in behaviors that depend on pre- be effective, particularly in refractory depression (98). Because ADHD includes symptoms addition, the highly effective antidepressant paroxetine, of prefrontal dysfunction, these findings raise the possibility which was previously thought to act selectively to block that an overactive LCsystem may contribute to ADHD by serotonin reuptake, has recently been found also to inhibit overstimulation of 1 receptors in prefrontal areas (108). These findings confirm long-held beliefs that NE is importantly involved in depression, and indicate that blockers of NE uptake, including drugs that CONCLUSIONS selectively act at the NE transporter, such as reboxetine (101,102), may be effective in treating at least certain types An impressive amount of research on NE systems has been of affective illness (103). This work is revealing an increasingly important transport and immunofluorescence. Neuroscience 1991;41: role for brain NE in mental function and dysfunction. GABA-mediated inhibition of locus Mechanisms by which NE systems are involved in cognitive, coeruleus from the dorsomedial rostral medulla. J Neurosci addictive, stress-related, and other behavioral functions are 1989;9:2973–2981. Robust enkepha- portance of this system for neuropsychopharmacology, but lin innervation of the locus coeruleus from the rostral medulla. Histamine-immunoreac- for discovering new and fruitful approaches to developing tive nerve fibers in the rat brain. Corticotropin- releasing factor-containing axon terminals synapse onto cate- cholamine dendrites and may presynaptically modulate other afferents in the rostral pole of the nucleus locus coeruleus in ACKNOWLEDGMENTS the rat brain. Enkephalin terminals This work was supported by PHS grants NS24698, form inhibitory-type synapses on neurons in the rat nucleus locus coeruleus that project to the medial prefrontal cortex. Morphological substrates underlying opioid, Druhan are greatly appreciated. Electron microscopic evidence for coexistence of leucine 5-enkephalin and gamma-aminobutyric REFERENCES acid in a subpopulation of axon terminals in the rat locus coeru- leus region. Evidence regulation of adenylate cyclase in brain: specific effects in locus for coexistence of enkephalin and glutamate in axon terminals coeruleus. The locus coeruleus Natl Acad SciUSA1998;95:322–327. New York: Academic Press, 1995: ing hypocretin (orexin) project to multiple neuronal systems. Orexins and orexin recep- neurons extend preferentially into two pericoerulear zones. J tors: a family of hypothalamic neuropeptides and G protein- Comp Neurol 1996;365:56–68. Light and electron between hypocretin (orexin) and neuropeptide Y cells in the microscopic evidence for topographic and monosynaptic projec- rodent and primate hypothalamus: a novel circuit implicated tions from neurons in the ventral medulla to noradrenergic den- in metabolic and endocrine regulations. J Neurosci 1999;19: drites in the rat locus coeruleus. The sleep disorder canine narcolepsy tion of locus coeruleus neurons: anatomy, physiology and phar- is caused by a mutation in the hypocretin (orexin) receptor 2 macology. Narcolepsy in orexin cotropin-releasing factor targets locus coeruleus dendrites: sub- knockout mice: molecular genetics of sleep regulation. Cell strate for the co-ordination of emotional and cognitive limbs 1999;98:437–451. Efferent projections ergic locus coeruleus neurons in behaving rats and monkeys of the nucleus of the solitary tract to peri-locus coeruleus den- suggests a role in vigilance. Peripheral, autonomic regulation of locus coeru- Neurol 1999;412:410–428. Activation of locus coeruleus from psychiatry and psychopharmacology. Psychopharmacology (Berl) nucleus paragigantocellularis: a new excitatory amino acid path- 1987;92:1–7. Adrenergic innervation of the noradrenergic neurons by C1 adrenergic cells in the rostral ven- rat nucleus locus coeruleus arises from the C1 and C3 cell groups tral medulla. The brain nucleus 56 Neuropsychopharmacology: The Fifth Generation of Progress locus coeruleus: restricted afferent control of a broad efferent 54. The neurobiology of from the suprachiasmatic nucleus to the locus coeruleus: a trans- opiates. A neural circuit for circa- tivity of locus coeruleus neurons is substantially mediated by dian regulation of arousal. Sleep disturbance in by lesions of the nucleus paragigantocellularis. Brain Res 1989; depression: diagnostic potential and pathophysiology [Proceed- 505:346–350.
Neuroimaging in OCD: disorder in bipolar and unipolar disorders buy cheap tamsulosin 0.4mg. The genetics of obsessive-compulsive disorder and 92 cheap 0.2mg tamsulosin mastercard. Psychiatr Clin North Am 1992; depression Acta Psychiatr Scand 1975;52:336–373. Obsessive com- rosis: record, follow-up, and family studies. Inpatient record pulsive disorder with and without a chronic tic disorder. Agoraphobia and panic 1608 Neuropsychopharmacology: The Fifth Generation of Progress disorder: development, diagnostic stability ad course of illness. Phenomenology of inten- Arch Gen Psychiatry 1986; 43:1029–1036. New York: Guilford Press, disorder among patients with anorexia nervosa and bulimia ner- 1988, 319–355. Anorexia nervosa 6 years anxiety disorder in patients with adult anxiety disorders. KENNEDY Multiple converging lines of evidence suggest that neurobi- At the same time, there has been considerable research ology plays a significant role in the etiology of obsessive- that has documented the familial nature of OCD (7). During the past decade, there family data, when taken together with twin studies, suggest has been considerable progress in the identification of neu- that genetic factors are important in the manifestation of roanatomic substrates involved in the expression of OCD. Segregation, linkage, and association studies The brain areas most frequently identified by in vivo neu- have begun and the results are similar to those observed for roimaging studies as potentially involved in the manifesta- other major psychiatric disorders: The mode of transmission tion of OCD are the orbitofrontal cortex (OFC), the ante- within families is complex and the precise genetic mecha- rior cingulate area (ACA), and the head of the caudate nism is not known. Furthermore, pharmacologic and neurobiologi- In this chapter the main pathophysiologic findings for cal studies have implicated several central neurotransmitter OCD are reviewed as well as the evidence that genetic fac- systems in the pathophysiology of OCD and related condi- tors are of etiologic importance. The strongest pharmacologic evidence concerns the studies examining candidate genes proposed as the result of serotonergic system and the well-established efficacy of po- several lines of investigation that implicate both the seroto- tent serotonin reuptake inhibitors in the treatment of OCD nergic and dopaminergic neurotransmitter systems are sum- (2,3); however, other systems have also been implicated. The most widely accepted alternative neurochemical theory Historically, the serotonin (5-HT) hypothesis has its basis for OCD suggests that the dopamine (DA) neurotransmis- in the pharmacology of OCD. In the late 1960s it was sion system also may be important in the pathophysiology observed that clomipramine, the only tricyclic antidepres- of some cases of OCD (3–6). Specifically, the DA hypothe- sant with potent 5-HT reuptake blocking properties, had sis has been proposed for those cases of OCD that appear antiobsessional activity (8,9). Subsequently, several studies to be related to Gilles de la Tourette syndrome (GTS) or have shown that clomipramine and several other selective other tics disorders, and/or those that occur with schizotypal serotonin reuptake inhibitors (SSRIs) are effective antiob- personality disorder and/or poor insight. In fact, results were taken as evidence that etiologic hypothesis for OCD involving an autoimmune serotonin plays a fundamental role in the pathogenesis of mechanism, particularly relevant for early-onset cases. These observations have led to the examina- tion of the serotonin system and its function in OCD pa- tients. Peripheral markers for the 5-HT system and a num- ber of parameters of the 5-HT function have been David L. Pauls: Child Study Center, Yale University School of Medicine, investigated. These include CSF 5-hydroxyindoleacetic acid New Haven, Connecticut. Kennedy: Department of Psychiatry, (the major metabolite of serotonin) (19–22), whole blood University of Toronto, Toronto, Canada. The results of these studies, al- by the well-documented clinical response to haloperidol and though not definitive, suggest that a 5-HT dysfunction is other dopamine antagonists (58), by the exacerbation with present in OCD. More detailed information has come from L-dopa and central nervous system stimulants (such as am- pharmacologic challenge studies in which compounds were phetamines) (59,60), and reports of lower CSF levels of administered that, acting presynaptically or postsynapti- the dopamine metabolite homovanillic acid (HVA) (61). In these studies behav- Moreover, OCD patients with comorbid tic disorder or ioral and neuroendocrine responses in OCD patients were GTS are usually resistant to conventional pharmacotherapy assessed after challenges with meta-chloro-phenyl-pipera- with proserotonergic compounds, and may benefit from zine (mCPP) (20,31–36), intravenous clomipramine (37, adjuvant treatment with dopamine (DA) or DA/5-HT 38), the 5-HT precursor tryptophan (39,40), the 5-HT re- blockers (6,55,56,62,63). This body of evidence suggests leasing agent fenfluramine (41–45), ipsapirone (46), buspir- that there is an involvement of DA in at least some OCD one (47), and sumatriptan (48,49). Overall, about 64), whereas the administration of fenfluramine produced 50% of the OCD patients challenged acutely with prosero- increased inhibition of HVA secretion (33,65). The DA tonergic compounds experienced a transient worsening of involvement has been assessed by measures of growth hor- obsessive symptoms. These results suggest that for some mone response to apomorphine (66,67), and challenge with OCD patients there would be a basal hyperactivity of the d-amphetamine (68) and methylphenidate (69), with con- 5-HT neurotransmission system, owing either to a hyper- flicting results. This could explain both the worsening of OCD been implicated in the pathogenesis of obsessive-compulsive symptoms after acute 5-HT stimulation and the clinical phenomenology by several studies (1,70–72). The involvement of the Other Neurobiological Hypotheses presynaptic desensitization as a key step for the neurobiolog- ical mechanism of the antiobsessional response to prosero- Alternative neurobiological mechanisms have been pro- tonergic compounds is also suggested by both the long la- posed for OCD but they are in need of further confirma- tency of clinical efficacy (6 to 8 weeks, longer than the tion. As already reported, functional neuroimaging studies latency for the antidepressant response induced by the same have demonstrated dysfunction in the orbitofrontal cortex, compounds) and the high doses required (54). Neuroendocrine mechanisms were im- to clomipramine or SSRIs and approximately 40% of them plicated in the pathogenesis of obsessions and compulsions, have no clinical improvement (55,56) may reflect the bio- based on studies employing oxytocin, vasopressin, and so- logical heterogeneity of the OCD phenotype already sug- matostatin (64,80–82). These studies also need further rep- gested by the variability of the response to acute 5-HT chal- lication. Thus, consideration of more homogeneous subgroups of OCD patients defined by response to biologi- The Autoimmune Hypothesis cal challenges or different symptom subtypes could lead to clarification of the pathogenesis of the disease and the role Allen, Leonard, and Swedo first proposed the intriguing of alternative hypotheses to the serotonergic one.
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