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1.
J Clin Psychiatry ; 77(8): 1080-6, 2016 08.
Artigo em Inglês | MEDLINE | ID: mdl-26579723

RESUMO

OBJECTIVE: Irritability is a significant component in the clinical manifestation of major depressive disorder (MDD). The Sheehan Irritability Scale (SIS) was developed to assess irritability-related symptoms in patients with psychiatric disorders. Data from a phase 2 clinical trial (June 2008-July 2009) was utilized to evaluate the psychometric properties of the SIS. The trial population included patients diagnosed with MDD, according to DSM-IV and confirmed via the MINI diagnostic scale, who had inadequate response to citalopram. METHOD: The secondary analyses included 586 patients from the United States and India. Data from the SIS, depression severity measures (17-item Hamilton Depression Rating Scale [HDRS-17], Montgomery-Asberg Depression Rating Scale [MADRS], Quick Inventory of Depressive Symptomatology-Self-Report [QIDS-SR]), and other measures (Sheehan Disability Scale [SDS], Clinical Global Impressions-Severity of Illness scale [CGI-S]) were used in the psychometric evaluation. All statistical tests used a significance level of .05 unless otherwise noted. RESULTS: Internal consistency (0.92-0.99) and test-retest reliability (0.83 to 0.98) were excellent. Concurrent validity was demonstrated through strong correlations between the SIS total score and HDRS-17, QIDS-SR, SDS, CGI-S, and MADRS scores. SIS total scores were significantly different by clinical severity level (P < .001). Minimally important difference estimates suggest that a 7- to 8-point change in the SIS total score may be clinically meaningful. CONCLUSIONS: The SIS has excellent reliability, acceptable validity, and good responsiveness, making the SIS appropriate for use in clinical research and practice. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT00692445.


Assuntos
Transtorno Depressivo Maior/diagnóstico , Humor Irritável/fisiologia , Escalas de Graduação Psiquiátrica/normas , Psicometria/instrumentação , Adulto , Transtorno Depressivo Maior/fisiopatologia , Feminino , Humanos , Índia , Masculino , Pessoa de Meia-Idade , Reprodutibilidade dos Testes , Estados Unidos
2.
Int Clin Psychopharmacol ; 31(2): 110-7, 2016 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-26655731

RESUMO

The Sheehan Irritability Scale (SIS) measures the frequency, severity, and impairment associated with irritability in psychiatric patients. The content validity of the SIS in patients with major depressive disorder (MDD) has not been evaluated. A cross-sectional, qualitative research study was conducted to assess the content validity of the SIS among patients with MDD. One-on-one interviews were conducted, starting with open-ended questions to evaluate the consistency of the SIS content with patient experiences of irritability. Participants then completed the SIS and cognitive interviews around the comprehension of the SIS content (instructions, items, response options). Participants included 24 patients diagnosed with MDD who had an inadequate response to an antidepressant treatment. The sample was: 50.4 mean years, 66.7% female, and 91.7% white racial background. All concepts on the SIS were spontaneously mentioned by at least one participant, and when probed about the symptoms, the majority of participants (66.7-100%) reported the concepts being part of their experience. The majority of participants (70.8-100%) understood the SIS instructions, items, and response scales. This study provides evidence of content validity of the SIS in patients diagnosed with MDD, supporting the use as a measure of irritability in patients with depression.


Assuntos
Transtorno Depressivo Maior/diagnóstico , Humor Irritável , Escalas de Graduação Psiquiátrica , Inquéritos e Questionários , Adulto , Idoso , Antidepressivos/uso terapêutico , Cognição , Compreensão , Estudos Transversais , Transtorno Depressivo Maior/tratamento farmacológico , Transtorno Depressivo Maior/psicologia , Feminino , Humanos , Entrevistas como Assunto , Humor Irritável/efeitos dos fármacos , Masculino , Pessoa de Meia-Idade , Valor Preditivo dos Testes , Psicometria , Pesquisa Qualitativa , Reprodutibilidade dos Testes , Estados Unidos , Adulto Jovem
3.
Schizophr Bull ; 42(2): 335-43, 2016 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-26071208

RESUMO

OBJECTIVES: This trial was conducted to test the effects of an alpha7 nicotinic receptor full agonist, TC-5619, on negative and cognitive symptoms in subjects with schizophrenia. METHODS: In 64 sites in the United States, Russia, Ukraine, Hungary, Romania, and Serbia, 477 outpatients (18-65 years; male 62%; 55% tobacco users) with schizophrenia, treated with a new-generation antipsychotic, were randomized to 24 weeks of placebo (n = 235), TC-5619, 5mg (n = 121), or TC-5619, 50 mg (n = 121), administered orally once daily. The primary efficacy measure was the Scale for the Assessment of Negative Symptoms (SANS) composite score. Key secondary measures were the Cogstate Schizophrenia Battery (CSB) composite score and the University of California San Diego Performance-Based Skills Assessment-Brief Version (UPSA-B) total score. Secondary measures included: Positive and Negative Syndrome Scale in Schizophrenia (PANSS) total and subscale scores, SANS domain scores, CSB item scores, Clinical Global Impression-Global Improvement (CGI-I) score, CGI-Severity (CGI-S) score, and Subject Global Impression-Cognition (SGI-Cog) total score. RESULTS: SANS score showed no statistical benefit for TC-5619 vs placebo at week 24 (5 mg, 2-tailed P = .159; 50 mg, P = .689). Likewise, no scores of CSB, UPSA-B, PANSS, CGI-I, CGI-S, or SGI-Cog favored TC-5619 (P > .05). Sporadic statistical benefit favoring TC-5619 in some of these outcome measures were observed in tobacco users, but these benefits did not show concordance by dose, country, gender, or other relevant measures. TC-5619 was generally well tolerated. CONCLUSION: These results do not support a benefit of TC-5619 for negative or cognitive symptoms in schizophrenia.


Assuntos
Benzofuranos/farmacologia , Agonistas Nicotínicos/farmacologia , Avaliação de Resultados em Cuidados de Saúde , Quinuclidinas/farmacologia , Esquizofrenia/tratamento farmacológico , Esquizofrenia/fisiopatologia , Índice de Gravidade de Doença , Receptor Nicotínico de Acetilcolina alfa7/agonistas , Adulto , Benzofuranos/administração & dosagem , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Agonistas Nicotínicos/administração & dosagem , Quinuclidinas/administração & dosagem , Adulto Jovem
4.
World J Biol Psychiatry ; 16(7): 483-501, 2015 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-25602163

RESUMO

OBJECTIVES: To evaluate the neuronal nicotinic channel modulator TC-5214 (dexmecamylamine) as adjunct therapy in patients with major depressive disorder (MDD) and inadequate response to prior antidepressant treatment. METHODS: Study 004 (D4130C00004) and Study 005 (D4130C00005) comprised an 8-week open-label antidepressant (SSRI/SNRI) treatment period followed by an 8-week randomised, active treatment with twice-daily TC-5214 (0.5, 2 or 4 mg in Study 004; 0.1, 1 or 4 mg in Study 005) or placebo, adjunct to ongoing SSRI/SNRI. Primary efficacy endpoint was change in MADRS total score from randomisation (Week 8) to treatment end (Week 16). Secondary endpoints included MADRS response and remission, and changes in SDS and HAM-D-17-item scores. Safety and tolerability were monitored throughout. RESULTS: Studies 004 and 005 randomised 640 and 696 patients, respectively, to TC-5214 or placebo. No statistically significant improvements in MADRS total score or any secondary endpoints were seen with TC-5214 versus placebo in either study at treatment end. The most commonly reported adverse events (> 10%) with TC-5214 were constipation, dizziness and dry mouth. CONCLUSIONS: TC-5214 adjunct to antidepressant was generally well tolerated. However, the studies were not supportive of an antidepressant effect for TC-5214 in patients with MDD and inadequate response to prior antidepressant therapy.


Assuntos
Antidepressivos/administração & dosagem , Transtorno Depressivo Maior/tratamento farmacológico , Transtorno Depressivo Resistente a Tratamento/tratamento farmacológico , Mecamilamina/administração & dosagem , Adolescente , Adulto , Idoso , Antidepressivos/efeitos adversos , Citalopram/administração & dosagem , Relação Dose-Resposta a Droga , Método Duplo-Cego , Quimioterapia Combinada , Feminino , Humanos , Modelos Logísticos , Masculino , Mecamilamina/efeitos adversos , Pessoa de Meia-Idade , Escalas de Graduação Psiquiátrica , Sertralina/administração & dosagem , Resultado do Tratamento , Adulto Jovem
5.
J Clin Psychopharmacol ; 35(1): 77-81, 2015 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-25514064

RESUMO

Safety and tolerability are important considerations when selecting patients' treatment for major depressive disorder. We report the long-term safety and tolerability of the nicotinic channel modulator dexmecamylamine (TC-5214), adjunct to selective serotonin reuptake inhibitors (SSRIs)/serotonin-norepinephrine reuptake inhibitors (SNRIs) in patients with major depressive disorder and who had an inadequate response to antidepressants. This 52-week, double-blind, placebo-controlled study explored the long-term safety and tolerability of dexmecamylamine. Patients were randomized 3:1 to receive flexibly dosed dexmecamylamine 1 to 4 mg adjunct to SSRI/SNRI or placebo plus SSRI/SNRI. The patient population comprised inadequate responders from 2 Phase III acute dexmecamylamine studies (NCT01157078 [study 002], NCT01153347 [study 004]) and de novo patients who responded inadequately during a 6-week open-label antidepressant treatment period preceding randomization. Safety and tolerability were assessed by monitoring adverse events, vital signs, and physical and laboratory parameters. Descriptive statistical analyses were performed on most efficacy-related end points. Sustained efficacy was analyzed using logistic regression. Overall, 813 patients were randomized (610 received dexmecamylamine, 203 received placebo). In total, 82.4% and 84.6% of patients, respectively, experienced an adverse event. Adverse events occurring more frequently with dexmecamylamine vs placebo were constipation (19.6% vs 6.0%), dizziness (12.0% vs 7.0%), and dry mouth (9.7% vs 5.0%). Back pain (2.8% vs 8.5%), weight increase (4.4% vs 7.0%), and fatigue (5.6 % vs 7.5%) occurred more frequently in placebo-treated patients. No notable differences were observed between dexmecamylamine and placebo for any secondary end point. In this long-term study, safety and tolerability of dexmecamylamine were consistent with that reported in acute Phase III studies of dexmecamylamine.


Assuntos
Antidepressivos/administração & dosagem , Transtorno Depressivo Maior/diagnóstico , Transtorno Depressivo Maior/tratamento farmacológico , Mecamilamina/análogos & derivados , Mecamilamina/administração & dosagem , Inibidores Seletivos de Recaptação de Serotonina/administração & dosagem , Adulto , Antidepressivos/efeitos adversos , Constipação Intestinal/induzido quimicamente , Constipação Intestinal/diagnóstico , Transtorno Depressivo Maior/psicologia , Tontura/induzido quimicamente , Tontura/diagnóstico , Método Duplo-Cego , Quimioterapia Combinada , Fadiga/induzido quimicamente , Fadiga/diagnóstico , Feminino , Humanos , Estudos Longitudinais , Masculino , Mecamilamina/efeitos adversos , Pessoa de Meia-Idade , Estudos Prospectivos , Inibidores Seletivos de Recaptação de Serotonina/efeitos adversos , Resultado do Tratamento
6.
Eur Neuropsychopharmacol ; 24(4): 564-74, 2014 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-24507016

RESUMO

This paper reports the efficacy and tolerability of the nicotinic channel modulator TC-5214 (dexmecamylamine) as adjunct therapy for patients with major depressive disorder who have an inadequate response to initial antidepressant treatment in 2 Phase III studies. These double-blind, placebo-controlled studies (NCT01157078, D4130C00002 [Study 002] conducted in the US and India; NCT01180400, D4130C00003 [Study 003] conducted in Europe) comprised 8 weeks of open-label antidepressant treatment followed by 8 weeks of active treatment during which patients were randomized to flexibly-dosed TC-5214 1-4 mg twice daily (BID) or placebo as an adjunct to ongoing therapy with SSRI/SNRI. The primary efficacy endpoint in both studies was change in Montgomery Åsberg Depression Rating Scale (MADRS) total score from randomization (week 8) to treatment end (week 16). Secondary endpoints included change in Sheehan Disability Scale and Hamilton Depression Rating Scale 17-item scores. Study 002 randomized 319 patients and Study 003 randomized 295 patients to TC-5214 or placebo. At treatment end, no significant differences were seen for change in MADRS total score with TC-5214 versus placebo. Furthermore, there were no significant differences in any of the secondary endpoints. The most commonly reported (≥ 10%) adverse events with TC-5214 in these studies were constipation and headache. In these 2 flexibly-dosed studies, no specific therapeutic effects were observed for TC-5214 (1-4 mg BID) adjunct to antidepressant in the primary endpoint or any secondary endpoint; however, TC-5214 was generally well tolerated. In conclusion, no antidepressant effect of TC-5214 was observed in these studies.


Assuntos
Antidepressivos/administração & dosagem , Transtorno Depressivo Maior/tratamento farmacológico , Resistência a Medicamentos , Mecamilamina/administração & dosagem , Antagonistas Nicotínicos/administração & dosagem , Adolescente , Adulto , Idoso , Antidepressivos/efeitos adversos , Antidepressivos/uso terapêutico , Estudos de Coortes , Manual Diagnóstico e Estatístico de Transtornos Mentais , Método Duplo-Cego , Monitoramento de Medicamentos , Quimioterapia Combinada/efeitos adversos , Feminino , Seguimentos , Humanos , Perda de Seguimento , Masculino , Mecamilamina/efeitos adversos , Mecamilamina/uso terapêutico , Pessoa de Meia-Idade , Antagonistas Nicotínicos/efeitos adversos , Antagonistas Nicotínicos/uso terapêutico , Escalas de Graduação Psiquiátrica , Inibidores Seletivos de Recaptação de Serotonina/efeitos adversos , Inibidores Seletivos de Recaptação de Serotonina/uso terapêutico , Adulto Jovem
7.
Biol Psychiatry ; 75(3): 207-14, 2014 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-23856296

RESUMO

BACKGROUND: Laboratory studies have found that acute stimulation of nicotinic acetylcholine receptors improves cognition in adult attention-deficit/hyperactivity disorder (ADHD). Clinical trials of nicotinic agonists have been mixed, underscoring the need to understand the mechanisms for individual differences in clinical response. Using cognitive models within a clinical trial framework may provide insight into these differences. METHODS: This was a within-subjects, randomized, placebo-controlled double-blind trial of the nicotinic agonist AZD3480 (also termed TC-1734) at doses of 5 mg and 50 mg and placebo in adults with ADHD. The order of the 2-week treatment periods was randomized, and a 3-week wash out separated each drug treatment period. Response inhibition (Stop Signal Task [SST]) and clinical efficacy (Investigator Rated Conners Adult ADHD Rating Scale [CAARS-INV]) were the a priori primary outcome measures of cognitive and clinical effects. We hypothesized that AZD3480 treatment would improve SST performance and clinical symptoms (CAARS-INV Total ADHD Symptoms Score). RESULTS: Thirty subjects were randomized, with 24 included in the intent-to-treat analyses. SST performance and total ADHD symptoms were significantly improved with 50 mg of AZD3480. CAARS-INV ratings of inattention, memory problems, and emotional lability/impulsivity were significantly improved with 50 mg of AZD3480. CONCLUSIONS: These results support previous work suggesting that nicotinic agonists are viable as treatments for adult ADHD. Measuring cognitive endophenotypes related to both the disorder and mechanism of treatment may help further rational drug development for dimensional features that cross-cut psychiatric disorders.


Assuntos
Transtorno do Deficit de Atenção com Hiperatividade/tratamento farmacológico , Agonistas Nicotínicos/uso terapêutico , Piridinas/uso terapêutico , Adolescente , Adulto , Idoso , Transtorno do Deficit de Atenção com Hiperatividade/complicações , Transtornos Cognitivos/tratamento farmacológico , Transtornos Cognitivos/etiologia , Relação Dose-Resposta a Droga , Método Duplo-Cego , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Testes Neuropsicológicos , Escalas de Graduação Psiquiátrica , Adulto Jovem
8.
Neuropsychopharmacology ; 38(6): 968-75, 2013 May.
Artigo em Inglês | MEDLINE | ID: mdl-23303043

RESUMO

This exploratory trial was conducted to test the effects of an alpha7 nicotinic receptor partial agonist, TC-5619, on cognitive dysfunction and negative symptoms in subjects with schizophrenia. In the United States and India, 185 outpatients (18-60 years; male 69%; 46% tobacco users) with schizophrenia treated with quetiapine or risperidone monotherapy were randomized to 12 weeks of placebo (n=91) or TC-5619 (n=94; orally once daily 1 mg day 1 to week 4, 5 mg week 4 to 8, and 25 mg week 8 to 12). The primary efficacy outcome measure was the Groton Maze Learning Task (GMLT; executive function) of the CogState Schizophrenia Battery (CSB). Secondary outcome measures included: CSB composite score; Scale for Assessment of Negative Symptoms (SANS); Clinical Global Impression-Global Improvement (CGI-I); CGI-severity (CGI-S); and Subject Global Impression-Cognition. GMLT statistically favored TC-5619 (P=0.036) in this exploratory trial. SANS also statistically favored TC-5619 (P=0.030). No other secondary outcome measure demonstrated a drug effect in the total population; there was a statistically significant drug effect on working memory in tobacco users. The results were typically stronger in favor of TC-5619 in tobacco users and occasionally better in the United States than in India. TC-5619 was generally well tolerated with no clinically noteworthy safety findings. These results support the potential benefits of TC-5619 and alpha7 nicotinic receptor partial agonists for cognitive dysfunction and negative symptoms in schizophrenia.


Assuntos
Benzofuranos/uso terapêutico , Agonistas Nicotínicos/uso terapêutico , Nootrópicos/uso terapêutico , Quinuclidinas/uso terapêutico , Esquizofrenia/tratamento farmacológico , Psicologia do Esquizofrênico , Receptor Nicotínico de Acetilcolina alfa7/fisiologia , Adolescente , Adulto , Antipsicóticos/uso terapêutico , Feminino , Humanos , Índia/epidemiologia , Masculino , Pessoa de Meia-Idade , Esquizofrenia/epidemiologia , Estados Unidos/epidemiologia , Adulto Jovem
9.
J Psychopharmacol ; 25(8): 1020-9, 2011 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-20542923

RESUMO

Cognitive decline is a feature of ageing and can be defined as normal (age-associated memory impairment) or pathological (mild cognitive impairment/Alzheimer's disease). Stimulation of selective brain-specific neuronal nicotinic acetylcholine receptors might offer symptomatic treatment for normal ageing. The objective of this study was to assess the safety, tolerability and efficacy of TC-1734 (AZD3480), a selective α4ß2 nicotinic agonist, in the treatment of age-associated memory impairment. A randomized placebo-controlled trial was conducted in 16 community-based centers within the USA. Subjects who met objective criteria for age-associated memory impairment were recruited between November 2004 and December 2005. Subjects were randomly assigned to receive orally 25 mg (n = 59), 50 mg (n = 68) TC-1734 (AZD3480) or placebo (n = 66) in a double-blind fashion for 16 weeks. Main outcome measures included routine clinical safety measures, tolerability, cognitive assessment via the Cognitive Drug Research computerized test battery and a Subject Global Impression Scale of Cognition (SCI-Cog). Two outcomes from the computerized test battery - a factor assessing attention and one assessing episodic memory, along with the SGI-Cog were defined as co-primary outcome variables. Baseline to Week 16 differences from placebo for 50 mg TC-1734 (AZD3480) were considered of primary importance. For 50 mg TC-1734 (AZD3480) attention factor the mean drug-placebo difference was 22.9 (95% confidence interval 4.8 to 41.4) p = 0.01 for episodic memory factor the difference was -7.6 (95% confidence interval -14.4 to -0.8), p = 0.029, and for the SGI-Cog the difference was 0.99 (95% confidence interval 0.2 to 1.8), p = 0.015. As all three co-primary outcomes were positive it can be concluded the compound likely had a beneficial effect on cognition. TC-1734 (AZD3480) appeared safe and well tolerated in this study.


Assuntos
Transtornos Cognitivos/tratamento farmacológico , Transtornos da Memória/tratamento farmacológico , Piridinas/uso terapêutico , Administração Oral , Idoso , Idoso de 80 Anos ou mais , Relação Dose-Resposta a Droga , Método Duplo-Cego , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Piridinas/administração & dosagem , Piridinas/efeitos adversos , Resultado do Tratamento
10.
J Psychopharmacol ; 21(2): 171-8, 2007 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-17329297

RESUMO

Cognitive decline seen in the normal elderly is associated with selective loss of neuronal nicotinic acetylcholine receptors (nAChRs). Nicotine given either by inhalation or transdermally helps cognition, but unacceptable side effects limit its utility. The present study assessed the safety, tolerability and effect on cognition of ispronicline, a highly selective partial agonist at the 4beta2 nAChR, in elderly subjects (n =76) with age associated memory impairment (AAMI). This double-blind, placebo-controlled cross-over study explored ascending oral doses of ispronicline in the range 50-150 mg given as a single morning dose for a period of 3 weeks. Pharmacokinetics (PK) were assessed, as well as cognitive function measured by means of the Cognitive Drug Research (CDR) computerized test battery. Ispronicline had a favourable safety profile and was well tolerated at doses below 150 mg. No effect of clinical importance was seen on biochemistry, haematology, urine analysis, vital signs, electrocardiogram (ECG) or Holter monitoring. The most frequent drug induced adverse event was light-headedness (dizziness). A beneficial effect was seen on cognition across the dose range. This was most marked at 50 mg on factors measuring attention and episodic memory. PK analysis indicated a plasma Cmax range of 5-25/35 ng/ml ispronicline was associated with the most beneficial effect. These early results demonstrate ispronicline was well tolerated and did not display the side effects typical of nicotine. Ispronicline also had a beneficial effect on cognition in subjects with AAMI. This was seen most strongly in a Cmax range that had been predicted from pre-clinical animal studies.


Assuntos
Cognição/efeitos dos fármacos , Transtornos da Memória/tratamento farmacológico , Agonistas Nicotínicos/uso terapêutico , Piridinas/uso terapêutico , Idoso , Estudos Cross-Over , Tontura/induzido quimicamente , Relação Dose-Resposta a Droga , Método Duplo-Cego , Eletrocardiografia/efeitos dos fármacos , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Agonistas Nicotínicos/efeitos adversos , Agonistas Nicotínicos/farmacocinética , Piridinas/efeitos adversos , Piridinas/farmacocinética , Receptores Nicotínicos/efeitos dos fármacos
11.
J Mol Neurosci ; 30(1-2): 169-72, 2006.
Artigo em Inglês | MEDLINE | ID: mdl-17192668

RESUMO

Cholinergic mechanisms are clearly involved in memory deficits associated with Alzheimer's disease (AD) (Perry et al., 1977). Recently, there has been growing interest in the nicotinic approach to the treatment of AD; however, compounds have failed in the clinic because of a lack of separation between central and peripheral nicotinic effects (Potter et al., 1999). Ispronicline (TC-1734) is an orally active, selective, partial agonist of the central alpha4beta2 neuronal nicotinic acetylcholine receptor (nAChR), with high binding affinity to membrane preparations from rat brain or mammalian cells expressing recombinant human alpha4beta2 receptor (Gatto et al., 2004). Ispronicline has no detectable effects on muscle or ganglionic nAChRs, indicating a marked CNS over PNS selectivity. In animal models ispronicline potently improved cognitive function. A long duration of memory enhancement was displayed in object recognition and radial arm maze tests. Ispronicline pharmacokinetics (half-life of 2 h in rats) contrasts with the long-lasting improvement of working memory (18 h to 2 d) (Gatto et al., 2004).


Assuntos
Cognição/efeitos dos fármacos , Agonistas Nicotínicos/farmacologia , Piridinas/farmacologia , Idoso , Estudos Cross-Over , Eletroencefalografia , Humanos , Receptores Nicotínicos/efeitos dos fármacos , Receptores Nicotínicos/fisiologia , Valores de Referência
12.
CNS Drug Rev ; 10(2): 147-66, 2004.
Artigo em Inglês | MEDLINE | ID: mdl-15179444

RESUMO

The development of selective ligands targeting neuronal nicotinic acetylcholine receptors to alleviate symptoms associated with neurodegenerative diseases presents the advantage of affecting multiple deficits that are the hallmarks of these pathologies. TC-1734 is an orally active novel neuronal nicotinic agonist with high selectivity for neuronal nicotinic receptors. Microdialysis studies indicate that TC-1734 enhances the release of acetylcholine from the cortex. TC-1734, by either acute or repeated administration, exhibits memory enhancing properties in rats and mice and is neuroprotective following excitotoxic insult in fetal rat brain in cultures and against alterations of synaptic transmission induced by deprivation of glucose and oxygen in hippocampal slices. At submaximal doses, TC-1734 produced additive cognitive effects when used in combination with tacrine or donepezil. Unlike (-)-nicotine, behavioral sensitization does not develop following repeated administration of TC-1734. Its pharmacokinetic (PK) profile (half-life of 2 h) contrasts with the long lasting improvement in working memory (18 h) demonstrating that cognitive improvement extends beyond the lifetime of the compound. The very low acute toxicity of TC-1734 and its receptor activity profile provides additional mechanistic basis for its suggested potential as a clinical candidate. TC-1734 was very well tolerated in acute and chronic oral toxicity studies in mice, rats and dogs. Phase I clinical trials demonstrated TC-1734's favorable pharmacokinetic and safety profile by acute oral administration at doses ranging from 2 to 320 mg. The bioavailability, pharmacological, pharmacokinetic, and safety profile of TC-1734 provides an example of a safe, potent and efficacious neuronal nicotinic modulator that holds promise for the management of the hallmark symptomatologies observed in dementia.


Assuntos
Antidepressivos/farmacologia , Cognição/efeitos dos fármacos , Fármacos Neuroprotetores/farmacologia , Agonistas Nicotínicos/farmacologia , Piridinas/farmacologia , Simpatomiméticos/farmacologia , Administração Oral , Adolescente , Hormônio Adrenocorticotrópico/efeitos dos fármacos , Hormônio Adrenocorticotrópico/metabolismo , Adulto , Animais , Córtex Cerebral/efeitos dos fármacos , Córtex Cerebral/metabolismo , Inibidores da Colinesterase/farmacologia , Aprendizagem por Discriminação/efeitos dos fármacos , Cães , Humanos , Masculino , Aprendizagem em Labirinto/efeitos dos fármacos , Memória/efeitos dos fármacos , Camundongos , Pessoa de Meia-Idade , Atividade Motora/efeitos dos fármacos , Fármacos Neuroprotetores/metabolismo , Agonistas Nicotínicos/metabolismo , Piridinas/química , Piridinas/metabolismo , Ratos , Receptores Nicotínicos/metabolismo , Valores de Referência , Simpatomiméticos/metabolismo , Testes de Toxicidade Crônica
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