Your browser doesn't support javascript.
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 55
Filtrar
1.
J Med Toxicol ; 16(1): 12-16, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31823333

RESUMO

INTRODUCTION: Bupropion is the only Food and Drug Administration-approved synthetic cathinone. It increases the release of norepinephrine in the locus coeruleus and dorsal raphe nucleus, causing an increase in the frequency of serotonergic neuron firing. The diagnosis of serotonin toxicity (ST) from bupropion poisoning is controversial due to the lack of direct serotonergic activity. Nonetheless, there is one documented report of ST after single-agent bupropion overdose and multiple reports describing polypharmacy overdoses where bupropion may have contributed to ST. METHODS: This is a retrospective analysis of data collected by the Toxicology Investigators Consortium (ToxIC), a prospective multi-center toxico-surveillance and research network registry, from 2014 to 2017. Cases were identified if ST was a clinical effect and bupropion was the single agent listed. Data is presented descriptively. RESULTS: Of the 266 recorded single bupropion overdoses, the most common symptoms were seizures (47.1%), tachycardia (greater than 140 bpm) (33.9%), agitation (31.7%), toxic psychosis (20.4%), and myoclonus/tremor/hyperreflexia (19%). Benzodiazepines were the most common therapy (69.2%). Thirteen patients (5.9%) were diagnosed with ST by a medical toxicologist. CONCLUSION: Bupropion overdose is primarily associated with seizures, tachycardia, and agitation; bupropion may be an atypical cause of serotonin toxicity.

2.
J Med Toxicol ; 16(1): 41-48, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31471760

RESUMO

INTRODUCTION: Illicitly manufactured fentanyl (IMF) is responsible for a growing number of deaths. Some case series have suggested that IMF overdoses require significantly higher naloxone doses than heroin overdoses. Our objective was to determine if the naloxone dose required to treat an opioid overdose is associated with the finding of fentanyl, opiates, or both on urine drug screen (UDS). METHODS: A retrospective chart review was conducted at a single emergency department and its affiliated emergency medical services (EMS) agency. The charts of all patients who received naloxone through this EMS from 1/1/2017 to 6/15/2018 were reviewed. The study included patients diagnosed with a non-suicidal opioid overdose whose UDS was positive for opiates, fentanyl, or both. Data collected included demographics, vital signs, initial GCS, EMS and ED naloxone administrations, response to treatment, laboratory findings, and ED disposition. The fentanyl-only and fentanyl + opiate groups were compared to the opiate-only group using the stratified (by ED provider) variant of the Mann-Whitney U test. RESULTS: Eight hundred and thirty-seven charts were reviewed, and 121 subjects were included in the final analysis. The median age of included subjects was 38 years and 75% were male. In the naloxone dose analysis, neither the fentanyl-only (median 0.8 mg, IQR 0.4-1.6; p = 0.68) nor the fentanyl + opiate (median 0.8 mg, IQR 0.4-1.2; p = 0.56) groups differed from the opiate-only group (median 0.58 mg, IQR 0.4-1.6). CONCLUSION: Our findings refute the notion that high potency synthetic opioids like illicitly manufactured fentanyl require increased doses of naloxone to successfully treat an overdose. There were no significant differences in the dose of naloxone required to treat opioid overdose patients with UDS evidence of exposure to fentanyl, opiates, or both. Further evaluation of naloxone stocking and dosing protocols is needed.

3.
J Med Toxicol ; 2019 Dec 20.
Artigo em Inglês | MEDLINE | ID: mdl-31863312

RESUMO

BACKGROUND: Despite significant efforts, deaths due to drug overdose remain at near record levels. In efforts combat this crisis, the Joint Commission now requires that accredited hospitals implement safe opioid prescribing practices. Emergency department visits and hospitalizations related to opioid use disorder (OUD) provide an opportunity to initiate evidence-based treatment. However, both situations require the presence of qualified physician leaders and clinicians, which many facilities lack. Medical toxicologists have the expertise needed to fill these voids, but the scope and prevalence of their involvement are unknown. We sought to determine the engagement of medical toxicologists in leading opioid stewardship initiatives and the treatment of patients with OUD. METHODS: Members of the American College of Medical Toxicology (ACMT) were surveyed about their leadership roles in opioid stewardship and clinical practices regarding OUD from March-June 2019. ACMT represents more than 80% of the nation's board-certified medical toxicologists. The electronic survey utilized branching logic and results are presented descriptively; thus, responses are presented as a percentage of the number of respondents to individual questions rather than the total number of participants. RESULTS: One hundred and thirty-one out of 382 eligible individuals from at least 76 institutions responded to the survey. A majority (60%) had a DATA 2000 X-waiver, 21% were board-certified in addiction medicine (AM), and an additional 22% were definitely or possibly planning to pursue board certification in AM. Sixteen percent of respondents reported having a formal leadership role to address opioid pain management and stewardship, and 17% had a formal leadership role that specifically addresses clinical treatment for OUD within their institution. Fifty-seven respondents prescribed buprenorphine in emergency medicine practice, 41 as inpatient consultants, and 23 in an outpatient clinic. CONCLUSIONS: Medical toxicologists can serve as leaders to promote safe opioid prescribing practices through both institutional and governmental opioid task forces and opioid stewardship programs. They also provide important addiction-related clinical care to patients with OUD.

4.
J Med Toxicol ; 2019 Dec 17.
Artigo em Inglês | MEDLINE | ID: mdl-31848906

RESUMO

INTRODUCTION: Diabetes disproportionately affects American Indians/Alaskan Natives (AI/AN). Bisphenol A (BPA) and arsenic (As), environmental toxicants which may be associated with diabetes, have not been well studied in this population. Our objectives were to determine if urinary BPA and As are associated with diabetes among adults in the Cheyenne River Sioux Tribe (CRST), and to compare their urinary levels with the general US population. METHODS: We performed a case-control study among 276 volunteers. We matched our cases (persons with diabetes) and controls (persons without diabetes) using age. We collected questionnaire data and urine samples which were tested for BPA and speciated As analytes. We used paired t tests and McNemar's chi-square test to compare continuous and categorical variables, respectively, between cases and controls and linear regression to assess the association between self-reported exposures and BPA and As levels. We used conditional logistic regression to investigate the association between case status and BPA and As levels. BPA and As levels among participants were compared with those from the 2011-2012 National Health and Nutrition Examination Survey (NHANES). RESULTS: The average age of participants was 46 years. The majority identified as AI/AN race (97%) and 58% were female. The geometric means from CRST participant urine specimens were 1.83 ug/L for BPA and 3.89 ug/L for total As. BPA geometric means of CRST participants were higher than NHANES participants while total As geometric means were lower. BPA and As were not associated with case status. CONCLUSION: The results of this study are consistent with others that have reported no association between diabetes and exposure to BPA or As.

5.
Clin Psychol Rev ; 74: 101785, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31751877

RESUMO

Trait mindfulness appears to be related to lower levels of negative affective symptoms, but it remains uncertain which facets of mindfulness are most important in this relationship. Accordingly, the present meta-analysis examined studies reporting correlations between affective symptoms and trait mindfulness as assessed by the Five Facet Mindfulness Questionnaire. A comprehensive search yielded 148 eligible studies, comprising 157 distinct samples and 44,075 participants. The weighted mean correlation for affective symptoms and overall trait mindfulness was r = -0.53. Among mindfulness facets, Nonjudge (r = -0.48) and Act with Awareness (r = -0.47) demonstrated the largest correlations, followed by Nonreact (r = -0.33) and Describe (r = -0.29). Observe was not significantly correlated with affective symptoms. No significant differences in the strength of correlations were found between anxiety, depression and posttraumatic stress disorder (PTSD) symptoms, though symptoms of generalized anxiety disorder exhibited a weaker negative relationship with the Describe facet compared to PTSD symptoms. Describe also showed a stronger relationship with affective symptoms in Eastern samples compared to Western samples, whereas Western samples had a stronger relationship with Nonjudge. These results provide insight into the nature of the association between trait mindfulness and negative affect.

6.
PLoS One ; 14(10): e0223729, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31622374

RESUMO

Preclinical and clinical data have shown that D-cycloserine (DCS), a partial agonist at the N-methyl-d-aspartate receptor complex, augments the retention of fear extinction in animals and the therapeutic learning from exposure therapy in humans. However, studies with non-clinical human samples in de novo fear conditioning paradigms have demonstrated minimal to no benefit of DCS. The aim of this study was to evaluate the effects of DCS on the retention of extinction learning following de novo fear conditioning in a clinical sample. Eighty-one patients with social anxiety disorder were recruited and underwent a previously validated de novo fear conditioning and extinction paradigm over the course of three days. Of those, only 43 (53%) provided analyzable data. During conditioning on Day 1, participants viewed images of differently colored lamps, two of which were followed by with electric shock (CS+) and a third which was not (CS-). On Day 2, participants were randomly assigned to receive either 50 mg DCS or placebo, administered in a double-blind manner 1 hour prior to extinction training with a single CS+ in a distinct context. Day 3 consisted of tests of extinction recall and renewal. The primary outcome was skin conductance response to conditioned stimuli, and shock expectancy ratings were examined as a secondary outcome. Results showed greater skin conductance and expectancy ratings in response to the CS+ compared to CS- at the end of conditioning. As expected, this difference was no longer present at the end of extinction training, but returned at early recall and renewal phases on Day 3, showing evidence of return of fear. In contrast to hypotheses, DCS had no moderating influence on skin conductance response or expectancy of shock during recall or renewal phases. We did not find evidence of an effect of DCS on the retention of extinction learning in humans in this fear conditioning and extinction paradigm.

7.
J Emerg Med ; 57(3): 339-344, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31279637

RESUMO

BACKGROUND: Despite multiple treatment options, antihypertensive overdose remains a cause of significant morbidity and mortality. Intravenous angiotensin II (AG II) is approved for use in vasodilatory shock. We describe 2 cases of refractory shock from antihypertensive overdose that were successfully treated using AG II. CASE REPORTS: A 24-year-old female presented after an overdose of multiple antihypertensive medications, including an angiotensin converting enzyme inhibitor (ACEI). She developed hypotension that was refractory to norepinephrine, epinephrine, and vasopressin, with a mean arterial pressure (MAP) of 57 mm Hg 9 h after emergency department arrival. Fifteen minutes after starting AG II at 10 ng/kg/min, her heart rate and MAP rose by 7 beats/min and 12 mm Hg, respectively. Her hemodynamic parameters continued to improve thereafter. She developed acute kidney injury, which resolved prior to discharge. The second patient, a 65-year-old male, presented after an overdose of multiple antihypertensive medications, including an ACEI. Despite norepinephrine, epinephrine, and hyperinsulinemia-euglycemia, he remained bradycardic and hypotensive, with a heart rate of 47 beats/min and MAP of 59 mm Hg. Thirty minutes after starting AG II at 10 ng/kg/min, his heart rate was 61 beats/min and MAP was 66 mm Hg. He recovered without apparent sequelae. WHY SHOULD AN EMERGENCY PHYSICIAN BE AWARE OF THIS?: Antihypertensive overdose can lead to shock refractory to catecholamine and vasopressin therapy. Our experience suggests that AG II is efficacious in antihypertensive overdose and may be particularly efficacious in instances of ACEI overdose. However, further study is required to confirm the appropriate indication(s).

8.
J Med Toxicol ; 15(4): 255-261, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31264143

RESUMO

BACKGROUND: Individuals who have tested positive for cocaine have claimed that lidocaine, or its primary metabolite, norlidocaine (monoethylglycinexylidide (MEGX)), have caused false positive results for the cocaine metabolite benzoylecgonine (BE) on urinary immunoassay testing. OBJECTIVE: The goal of the study was to determine if lidocaine exposure from routine medical procedures can result in false positives on a commercially available cocaine immunoassay urine drug screen (UDS). METHODS: We performed a cross-sectional observational study of patients receiving lidocaine as part of their regular care. Standard immunoassay drug screens and confirmatory liquid chromatography-mass spectrometry (LC-MS) were performed on all urine samples to assess for MEGX and BE. RESULTS: In total, 168 subjects were enrolled; 121 samples positive for lidocaine were ultimately included for analysis. One hundred fourteen of the 121 were also positive for MEGX. None of the 121 were positive for cocaine/BE on the UDS (95% CI), 0-3.7% for the full sample and 0-3.9% for the 114 who tested positive for MEGX. CONCLUSION: The present study found no evidence that lidocaine or norlidocaine are capable of producing false positive results on standard cocaine urine immunoassays.

9.
Brain Sci ; 9(7)2019 Jul 11.
Artigo em Inglês | MEDLINE | ID: mdl-31336700

RESUMO

Laboratory models of extinction learning in animals and humans have the potential to illuminate methods for improving clinical treatment of fear-based clinical disorders. However, such translational research often neglects important differences between threat responses in animals and fear learning in humans, particularly as it relates to the treatment of clinical disorders. Specifically, the conscious experience of fear and anxiety, along with the capacity to deliberately engage top-down cognitive processes to modulate that experience, involves distinct brain circuitry and is measured and manipulated using different methods than typically used in laboratory research. This paper will identify how translational research that investigates methods of enhancing extinction learning can more effectively model such elements of human fear learning, and how doing so will enhance the relevance of this research to the treatment of fear-based psychological disorders.

11.
J Emerg Med ; 57(2): 181-186, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31060846

RESUMO

BACKGROUND: The Emergency Department (ED) frequently treats patients with drug overdoses and is an important resource for individuals with opioid use disorder who are seeking treatment. Initiating medication-assisted treatment (MAT) in the ED seems to be an effective way to link patients with opioid use disorder (OUD) to treatment programs. There is ongoing discussion on the best approach to MAT in the ED setting. OBJECTIVE: Describe a new model for managing OUD in the ED. METHOD: Information was obtained retrospectively from the electronic medical records of patients seen in a large county tertiary care center's Clinical Decision Unit (CDU) for OUD between September 1, 2017 and February 6, 2018. Data were summarized descriptively. RESULTS: There were 18 different patients placed in the CDU during the study period. Ninety-five percent were induced with buprenorphine-naloxone in the CDU. The median initial Clinical Opioid Withdrawal Scale score at the time of induction was 10. The median total dose of buprenorphine-naloxone that was administered was 8/2 mg. The median amount of time spent in the CDU and ED combined was 23 h. Approximately (12/19) 63% of subjects went to their initial follow-up appointment in clinic. Nine were still active in clinic at 30 days and 4 were active at 6 months. CONCLUSIONS: This retrospective chart review shows promising preliminary data for managing OUD in an ED CDU. Such strategies have the potential to increase access to care in a vulnerable patient population.

12.
J Am Chem Soc ; 141(22): 8752-8757, 2019 Jun 05.
Artigo em Inglês | MEDLINE | ID: mdl-31117664

RESUMO

We report here a catalytic method for the modular ring expansion of cyclic aliphatic alcohols. In this work, proton-coupled electron transfer activation of an allylic alcohol substrate affords an alkoxy radical intermediate that undergoes subsequent C-C bond cleavage to furnish an enone and a tethered alkyl radical. Recombination of this alkyl radical with the revealed olefin acceptor in turn produces a ring-expanded ketone product. The regioselectivity of this C-C bond-forming event can be reliably controlled via substituents on the olefin substrate, providing a means to convert a simple N-membered ring substrate to either n+1 or n+2 ring adducts in a selective fashion.

13.
Behav Ther ; 50(3): 630-645, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-31030879

RESUMO

Poor distress tolerance (DT) is considered an underlying facet of anxiety, depression, and a number of other psychological disorders. Mindfulness may help to increase DT by fostering an attitude of acceptance or nonjudgment toward distressing experiences. Accordingly, the present study examined the effects of a brief mindfulness training on tolerance of different types of distress, and tested whether trait mindfulness moderates the effect of such training. Undergraduates (n = 107) naïve to mindfulness completed a measure of trait mindfulness and underwent a series of stress tasks (cold pressor, hyperventilation challenge, neutralization task) before and after completing a 15-minute mindfulness training or a no-instruction control in which participants listened to relaxing music. Participants in the mindfulness condition demonstrated greater task persistence on the hyperventilation task compared to the control group, as well as a decreased urge to neutralize the effects of writing an upsetting sentence. No effect on distress ratings during the tasks were found. Overall trait mindfulness did not significantly moderate task persistence, but those with lower scores on the act with awareness facet of mindfulness demonstrated greater relative benefit of mindfulness training on the hyperventilation challenge. Mediation analyses revealed significant indirect effects of mindfulness training on cold pressor task persistence and urges to neutralize through the use of the nonjudge and nonreact facets of mindfulness. These results suggest that a brief mindfulness training can increase DT without affecting the subjective experience of distress.


Assuntos
Emoções/fisiologia , Atenção Plena/métodos , Estresse Psicológico/psicologia , Estresse Psicológico/terapia , Adulto , Ansiedade/diagnóstico , Ansiedade/psicologia , Ansiedade/terapia , Conscientização/fisiologia , Temperatura Baixa , Depressão/diagnóstico , Depressão/psicologia , Depressão/terapia , Feminino , Humanos , Hiperventilação/diagnóstico , Hiperventilação/psicologia , Hiperventilação/terapia , Masculino , Estresse Psicológico/diagnóstico , Inquéritos e Questionários , Resultado do Tratamento , Adulto Jovem
15.
Clin Toxicol (Phila) ; 57(8): 692-696, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-30676832

RESUMO

Importance: Tramadol prescriptions have increased as fewer schedule II and III drugs are prescribed. There has been a concomitant increase in overdoses and adverse events recorded in the National Poison Data System. Seizure activity after tramadol overdose or therapeutic use is a well-documented adverse event. The primary objective is to evaluate the characteristics associated with seizures following single agent tramadol ingestion. Secondarily we aim to compare the rate of seizures in individuals treated, and not treated, with naloxone. Methods: We searched the Toxicology Investigators Consortium data registry for all cases of single agent tramadol ingestions from 01/01/2014 through 12/31/2017. Descriptive statistics were used to evaluate characteristics associated with increased risk of seizures. Binary logistic regressions were used to evaluate the associations between seizures and age, race, acuity, intent, toxidromes, symptoms, and treatments. Results: There were 80 single ingestion tramadol cases entered into the registry. Seizures developed in 42 (52.5%) patients. Asian patients (OR = 7.2, 95% CI: 1.9-27.3, p = .004) and patients abusing or misusing tramadol (OR = 3.2, 95% CI: 1.2-8.3, p = .02) more likely to develop seizures. Patients exhibiting an opioid toxidrome were significantly less likely to develop seizures (OR = 0.12, 95% CI: 0.03-0.60). Ingestion of tramadol as a means of self-harm and age were not associated with an increased risk of seizures. There was no significant association between naloxone administration and seizures (OR = 0.30, 95% CI 0.07-1.25). Conclusions: Based on data from the ToxIC registry, tramadol induced seizures are more likely in Asian patients and those abusing or misusing the medication. There was no association found between the development of seizures and the use of naloxone.

16.
Clin Toxicol (Phila) ; 57(4): 282-286, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30430874

RESUMO

IMPORTANCE: Exposures to novel psychoactive substances are reported with increasing frequency in both the medical literature and the lay press. While the majority of reports describe synthetic cannabinoids and cathinones, a lesser understood family is the "designer benzodiazepines". The current literature describing human exposures to these compounds is comprised of case reports and small case series. OBJECTIVE: The primary objectives of this study are to describe epidemiologic trends and clinical effects of designer benzodiazepine use. METHODS: Data regarding single agent exposures to designer benzodiazepines between 1 January 2014 and 31 December 2017 was obtained from the National Poison Data System. Substances queried include: adinazolam, clonazolam, cloniprazepam, diclazepam, etizolam, flubromazepam, flubromazolam, meclonazepam, nifoxipam, norflurazepam, and pyrazolam. Data was summarized descriptively. RESULTS: 234 single agent exposures in 40 states were reported during the study period. The annual number of exposures increased each year, from 26 in 2014 to 112 in 2017, amounting to a 330% increase. The most common exposures were etizolam (n = 162) and clonazolam (n = 50). The most common clinical effects were drowsiness/lethargy (65%), and slurred speech (17%). 3% required intubation, 36% of cases required hospital admission, 22% to the intensive care unit. There was 1 death in the study population. CONCLUSIONS: The incidence of exposures to designer benzodiazepines is rising. Clinical effects are generally consistent with a sedative-hypnotic toxidrome. Severe effects, including death, seemed relatively uncommon in the study population.


Assuntos
Benzodiazepinas/toxicidade , Drogas Desenhadas/toxicidade , Envenenamento/epidemiologia , Adolescente , Adulto , Diazepam/análogos & derivados , Diazepam/toxicidade , Feminino , Humanos , Letargia/induzido quimicamente , Masculino , Pessoa de Meia-Idade , Centros de Controle de Intoxicações/estatística & dados numéricos , Envenenamento/etiologia , Estudos Retrospectivos , Estados Unidos/epidemiologia , Adulto Jovem
17.
Behav Res Ther ; 117: 40-53, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-30348451

RESUMO

For decades the development of evidence-based therapy has been based on experimental tests of protocols designed to impact psychiatric syndromes. As this paradigm weakens, a more process-based therapy approach is rising in its place, focused on how to best target and change core biopsychosocial processes in specific situations for given goals with given clients. This is an inherently more idiographic question than has normally been at issue in evidence-based therapy over the last few decades. In this article we explore methods of assessment and analysis that can integrate idiographic and nomothetic approaches in a process-based era.

18.
J Spec Oper Med ; 18(4): 24-26, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30566719

RESUMO

Smoke grenades are used during drills, police and military exercises, and crowd control. We report on a 25-year-old man who was exposed to a Superior 3C smoke bomb. He was initially stable but developed respiratory distress after 3 days and ultimately developed pulmonary fibrosis with marked loss in pulmonary function. The Superior 3C smoke bomb is similar in composition to the British Military's L83A1/2 and L132A1 and the US M18 smoke grenades, all commonly used as multipurpose smoke-producing devices for combat and training. They are primarily composed of zinc oxide and hexachlorethane, the combustion of which produces zinc chloride. These devices are safe when used properly in open air but can cause significant morbidity in an enclosed space. This case emphasizes the potential hazards of using smoke bombs even in semienclosed spaces and the potential delay in the development of significant pulmonary complications.


Assuntos
Bombas (Dispositivos Explosivos) , Pneumonia/diagnóstico , Insuficiência Respiratória/diagnóstico , Lesão por Inalação de Fumaça/complicações , Adulto , Humanos , Masculino , Pneumonia/etiologia , Insuficiência Respiratória/etiologia
19.
Depress Anxiety ; 35(6): 502-514, 2018 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-29451967

RESUMO

The purpose of this study was to examine the efficacy of cognitive behavioral therapy (CBT) for anxiety-related disorders based on randomized placebo-controlled trials. We included 41 studies that randomly assigned patients (N = 2,843) with acute stress disorder, generalized anxiety disorder (GAD), obsessive compulsive disorder (OCD), panic disorder (PD), posttraumatic stress disorder (PTSD), or social anxiety disorder (SAD) to CBT or a psychological or pill placebo condition. Findings demonstrated moderate placebo-controlled effects of CBT on target disorder symptoms (Hedges' g = 0.56), and small to moderate effects on other anxiety symptoms (Hedges' g = 0.38), depression (Hedges' g = 0.31), and quality of life (Hedges' g = 0.30). Response rates in CBT compared to placebo were associated with an odds ratio of 2.97. Effects on the target disorder were significantly stronger for completer samples than intent-to-treat samples, and for individuals compared to group CBT in SAD and PTSD studies. Large effect sizes were found for OCD, GAD, and acute stress disorder, and small to moderate effect sizes were found for PTSD, SAD, and PD. In PTSD studies, dropout rates were greater in CBT (29.0%) compared to placebo (17.2%), but no difference in dropout was found across other disorders. Interventions primarily using exposure strategies had larger effect sizes than those using cognitive or cognitive and behavioral techniques, though this difference did not reach significance. Findings demonstrate that CBT is a moderately efficacious treatment for anxiety disorders when compared to placebo. More effective treatments are especially needed for PTSD, SAD, and PD.


Assuntos
Transtornos de Ansiedade/terapia , Terapia Cognitivo-Comportamental/métodos , Transtorno Obsessivo-Compulsivo/terapia , Ensaios Clínicos Controlados Aleatórios como Assunto/estatística & dados numéricos , Transtornos de Estresse Pós-Traumáticos/terapia , Transtornos de Estresse Traumático Agudo/terapia , Humanos
20.
J Med Chem ; 60(14): 6166-6190, 2017 07 27.
Artigo em Inglês | MEDLINE | ID: mdl-28635286

RESUMO

Agonism of the 5-HT2C receptor represents one of the most well-studied and clinically proven mechanisms for pharmacological weight reduction. Selectivity over the closely related 5-HT2A and 5-HT2B receptors is critical as their activation has been shown to lead to undesirable side effects and major safety concerns. In this communication, we report the development of a new screening paradigm that utilizes an active site mutant D134A (D3.32) 5-HT2C receptor to identify atypical agonist structures. We additionally report the discovery and optimization of a novel class of nonbasic heterocyclic amide agonists of 5-HT2C. SAR investigations around the screening hits provided a diverse set of potent agonists at 5-HT2C with high selectivity over the related 5-HT2A and 5-HT2B receptor subtypes. Further optimization through replacement of the amide with a variety of five- and six-membered heterocycles led to the identification of 6-(1-ethyl-3-(quinolin-8-yl)-1H-pyrazol-5-yl)pyridazin-3-amine (69). Oral administration of 69 to rats reduced food intake in an ad libitum feeding model, which could be completely reversed by a selective 5-HT2C antagonist.


Assuntos
Arginina/análogos & derivados , Flavonas/química , Receptor 5-HT2C de Serotonina/metabolismo , Agonistas do Receptor 5-HT2 de Serotonina/química , Membro 1 da Subfamília B de Cassetes de Ligação de ATP/genética , Membro 2 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/genética , Animais , Arginina/síntese química , Arginina/química , Arginina/farmacologia , Encéfalo/metabolismo , Células CACO-2 , Permeabilidade da Membrana Celular , Comportamento Alimentar/efeitos dos fármacos , Flavonas/síntese química , Flavonas/farmacologia , Células HEK293 , Humanos , Masculino , Membranas Artificiais , Camundongos Knockout , Microssomos Hepáticos/metabolismo , Mutação , Ratos Sprague-Dawley , Receptor 5-HT2A de Serotonina/metabolismo , Receptor 5-HT2B de Serotonina/metabolismo , Receptor 5-HT2C de Serotonina/genética , Agonistas do Receptor 5-HT2 de Serotonina/síntese química , Agonistas do Receptor 5-HT2 de Serotonina/farmacocinética , Agonistas do Receptor 5-HT2 de Serotonina/farmacologia , Relação Estrutura-Atividade
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA