Pain associated with intravascular instrumentation reduces orthostatic tolerance and predisposes to vasovagal reactions in healthy young adults without needle phobia: a randomised controlled study.

PURPOSE: Vasovagal syncope (VVS), or fainting, is frequently triggered by pain, fear, or emotional distress, especially with blood-injection-injury stimuli. We aimed to examine the impact of intravenous (IV) instrumentation on orthostatic tolerance (OT; fainting susceptibility) in healthy young adults. We hypothesized that pain associated with IV procedures would reduce OT. METHODS: In this randomised, double-blind, placebo-controlled, cross-over study, participants (N = 23; 14 women; age 24.2 ± 4.4 years) underwent head-up tilt with combined lower body negative pressure to presyncope on three separate days: (1) IV cannulation with local anaesthetic cream (EMLA) (IV + EMLA); (2) IV cannulation with placebo cream (IV + Placebo); (3) sham IV cannulation with local anaesthetic cream (Sham + EMLA). Participants rated pain associated with IV procedures on a 1-5 scale. Cardiovascular (finger plethysmography and electrocardiogram; Finometer Pro), and forearm vascular resistance (FVR; brachial Doppler) responses were recorded continuously and non-invasively. RESULTS: Compared to Sham + EMLA (27.8 ± 2.4 min), OT was reduced in IV + Placebo (23.0 ± 2.8 min; p = 0.026), but not in IV + EMLA (26.2 ± 2.2 min; p = 0.185). Pain was increased in IV + Placebo (2.8 ± 0.2) compared to IV + EMLA (2.0 ± 2.2; p = 0.002) and Sham + EMLA (1.1 ± 0.1; p < 0.001). Orthostatic heart rate responses were lower in IV + Placebo (84.4 ± 3.1 bpm) than IV + EMLA (87.3 ± 3.1 bpm; p = 0.007) and Sham + EMLA (87.7 ± 3.1 bpm; p = 0.001). Maximal FVR responses were reduced in IV + Placebo (+ 140.7 ± 19.0%) compared to IV + EMLA (+ 221.2 ± 25.9%; p < 0.001) and Sham + EMLA (+ 190.6 ± 17.0%; p = 0.017). CONCLUSIONS: Pain plays a key role in predisposing to VVS following venipuncture, and our data suggest this effect is mediated through reduced capacity to achieve maximal sympathetic activation during orthostatic stress. Topical anaesthetics, such as EMLA, may reduce the frequency and severity of VVS during procedures requiring needles and intravascular instrumentation.

Acceptance and commitment therapy for breast cancer survivors with fear of cancer recurrence: A 3-arm pilot randomized controlled trial.

BACKGROUND: Fear of cancer recurrence (FCR) has a profound negative impact on quality of life (QOL) for many cancer survivors. Breast cancer survivors (BCS) are particularly vulnerable, with up to 70% reporting clinically significant FCR. To the authors' knowledge, evidence-based interventions for managing FCR are limited. Acceptance and commitment therapy (ACT) promotes psychological flexibility in managing life's stressors. The current study examined the feasibility and preliminary efficacy of group-based ACT for FCR in BCS. METHODS: Post-treatment BCS (91 patients with stage I-III disease) with clinical FCR randomly were assigned to ACT (6 weekly 2-hour group sessions), survivorship education (SE; 6 weekly 2-hour group sessions), or enhanced usual care (EUC; one 30-minute group coaching session with survivorship readings). FCR severity (primary outcome) and avoidant coping, anxiety, post-traumatic stress, depression, QOL, and other FCR-related variables (secondary outcomes) were assessed at baseline (T1), after the intervention (T2), 1 month after the intervention (T3), and 6 months after the intervention (T4) using intent-to-treat analysis. RESULTS: Satisfactory recruitment (43.8%) and retention (94.5%) rates demonstrated feasibility. Although each arm demonstrated within-group reductions in FCR severity over time, only ACT produced significant reductions at each time point compared with baseline, with between-group differences at T4 substantially favoring ACT over SE (Cohen d for effect sizes, 0.80; P < .001) and EUC (Cohen d, 0.61; P < .01). For 10 of 12 secondary outcomes, only ACT produced significant within-group reductions across all time points. By T4, significant moderate to large between-group comparisons favored ACT over SE and EUC with regard to avoidant coping, anxiety, depression, QOL, and FCR-related psychological distress. CONCLUSIONS: Group-based ACT is a feasible and promising treatment for FCR and associated outcomes in BCS that warrants testing in larger, fully powered trials.

Efectividad y seguridad del escitalopram o bromazepam comparado con fluoxetina, sertralina, fluvoxamina, paroxetina y psicoterapia en pacientes con Trastorno de Ansiedad Generalizada o Trastorno de Fobia Social / Effectiveness and safety of escitalopram or bromazepam compared to fluoxetine, sertraline, fluvoxamine, paroxetine and psychotherapy in patients with Generalized Anxiety Disorder or Social Phobia Disorder

Introducción: En la actualidad el Trastorno de Ansiedad Generalizada y el Trastorno de Fobia Social, son los trastornos de ansiedad de mayor incidencia a nivel mundial; se encuentra que un 12% de la población con trastornos mentales corresponde a TFS y un 6% a TAG En la Encuesta Nacional de Salud Mental realizada en el año 2003, las mujeres presentan una mayor prevalencia global, presentando una edad de inicio más temprana el TFS (14 años) comparado con el TAG (18 años) (1). Objetivo: Examinar los beneficios y riesgos del uso del escitalopram o bromazepam en el Trastorno de Ansiedad Generalizada o Fobia Social, como uno de los criterios para informar la toma de decisiones relacionada con la posible inclusión de tecnologías en el Plan Obligatorio de Salud, en el marco de su actualización integral para el año 2015. Metodología: A partir de la pregunta PICO se establecieron los criterios de elegibilidad para la realización de la búsqueda de la evidencia científica (a ensayos clínicos, revisiones sistemáticas de estudios observacionales y estudios de cohortes analíticas), se realizó la tamización y selección de la evidencia evaluando su calidad y posteriormente se realizó la extracción de datos y la síntesis de la evidencia. Resultados: El escitalopram y el eromazepan es efectivo en el manejo del Trastorno de Ansiedad Generalizada y Fobia Social, pero no muestra ser superior comparado con otros Inhibidores Selectivos de Recaptación de Serotonina. En cuanto a seguridad el escitalopram presentó menos efectos adversos comparados con los otros medicamentos, pero en los niños se documentó el aumento en el riesgo de suicidio e ideación suicida. El bromazepam genera adicción, somnolencia y no es recomendado su uso a largo plazo. Conclusiones: El escitalopram y el bromazepam pueden ser usados en el manejo del Trastorno de Ansiedad Generalizada y Fobia social teniendo en cuenta la evidencia de los estudios reportados.(AU)

Evaluation of the therapeutic response by (99m)Tc-ECD-SPET in a female with non-organic depression, generalized anxiety and heterophobia.

This is the case of a 33 years old female patient who was diagnosed with depression and heterophobia, which progressed to generalized anxiety according to the International Statistical Classification of Diseases and Health Related Problems, 10th Revision (ICD-10), Version for 2010 diagnostic criteria. The clinical symptoms of the patient were significantly improved after effective treatment. The patient underwent before and after treatment 99mTc-ethyl cysteinate dimmer ((99m)Tc-ECD) brain single-photon emission tomography (SPET). A great improvement in regional cerebral blood flow was found after treatment. In conclusion, this case highlights the value of brain perfusion SPET scan in providing objective imaging evidence of diagnosis and treatment evaluation in a patient with non-organic mental disorder.

Sertraline alleviated osmophobia caused by partial hypopituitarism with isolated ACTH deficiency.

OBJECTIVE: Hyperosmia may be an early manifestation of hypocortisolism and may be mistakenly diagnosed as osmophobia. However, sertraline therapy incidentally alleviated the phobic symptoms and hindered accurate diagnosis. CASE REPORT: A 41-year-old man was diagnosed as having osmophobia. Initial sertraline treatment relieved the symptoms, but its cessation resulted in recurrence of osmophobia. Endocrinological examinations revealed severe hypocortisolism and partial hypopituitarism with isolated adrenocorticotropic hormone deficiency. After prednisolone supplementation, his condition dramatically improved. CONCLUSION: We recommend that, before intervention with selective serotonin reuptake inhibitors is performed, the hypothalamic-pituitary-adrenal axis be evaluated in psychiatric patients presenting with co-occurring olfactory change.

Salivary testosterone: associations with depression, anxiety disorders, and antidepressant use in a large cohort study.

OBJECTIVE: Low circulating levels of testosterone have been associated with major depression, but there is more limited evidence for differences in patients with anxiety disorders. The use of selective serotonin reuptake inhibitors (SSRIs) and other antidepressants is associated with sexual side effects, warranting testing for interactions with testosterone. METHODS: Data are from 722 male and 1380 female participants of The Netherlands Study of Depression and Anxiety (NESDA), who were recruited from the community, general practice care, and specialized mental health care. Depressive and anxiety diagnoses were assessed using the DSM-IV Composite International Diagnostic Interview. To smooth the episodic secretion, the four morning saliva samples per participant and the two evening samples were pooled before testosterone analysis. RESULTS: Morning median testosterone levels were 25.2 pg/ml in men and 16.2 pg/ml in women, with lower evening levels of 18.2 and 14.1 pg/ml, respectively. Significant determinants of testosterone levels were sex, age, time of the day, use of contraceptives, and smoking status. Female patients with a current (1-month) depressive disorder (effect size 0.29; P=0.002), generalized anxiety disorder (0.25; P=0.01), social phobia (0.30; P<0.001), and agoraphobia without panic disorder (0.30; P=0.02) had lower salivary testosterone levels than female controls. Higher testosterone levels were found in male and female participants using SSRIs than in non-users (effect size 0.26; P<0.001). CONCLUSION: Salivary testosterone levels are lower in female patients with a depressive disorder, generalized anxiety disorder, social phobia, and agoraphobia as compared to female controls. SSRIs may increase salivary testosterone in men and women.

Diretrizes da Associação Médica Brasileira para o tratamento do transtorno de ansiedade social / Guidelines of the Brazilian Medical Association for the treatment of social anxiety disorder

INTRODUÇÃO: O transtorno de ansiedade social (TAS) é o transtorno de ansiedade mais comum, freqüentemente sem remissões, sendo comumente associado com importante prejuízo funcional e psicossocial. A Associação Médica Brasileira (AMB), através do "Projeto Diretrizes", busca desenvolver consensos de diagnóstico e tratamento para as doenças mais comuns. O objetivo deste trabalho é apresentar os achados mais relevantes das diretrizes relativas ao tratamento do TAS, servindo de referência para o médico generalista e especialista. MÉTODO: O método utilizado foi o proposto pela AMB. A busca foi realizada nas bases de dados do MEDLINE (PubMed), Scopus, Web of Science e Lilacs, entre 1980 e 2010. A estratégia utilizada baseou-se em perguntas estruturadas na forma P.I.C.O (acrônimo das iniciais "paciente ou população"; "intervenção, indicador ou exposição"; "controle ou comparação" e; "outcome ou desfecho"). RESULTADOS: Estudos evidenciam que o tratamento farmacológico de primeira linha para adultos e crianças são os inibidores seletivos de recaptação de serotonina e os inibidores de recaptação de serotonina e noradrenalina, enquanto que a terapia cognitivo-comportamental é apontada como melhor tratamento psicoterápico. Além disso, algumas comorbidades psiquiátricas foram associadas a uma pior evolução do TAS. CONCLUSÕES: Apesar da alta prevalência, o TAS acaba por não receber a devida atenção e tratamento. A melhor escolha para o tratamento de adultos é a associação psicoterapia cognitivo-comportamental com inibidores seletivos de recaptação de serotonina e os inibidores de recaptação de serotonina e noradrenalina. Outras opções como benzodiazepínicos ou inibidores da monoamino-oxidase devem ser usados como segunda e terceira opção respectivamente.

INTRODUCTION: Social anxiety disorder (SAD) is the most common anxiety disorder, usually with no remission, and is commonly associated with significant functional and psychosocial impairment. The Brazilian Medical Association (BMA), with the project named Diretrizes (Guidelines, in English), seeks to develop consensus for the diagnosis and treatment of common diseases. The aim of this article is to present the most important findings of the guidelines on the treatment of SAD, serving as a reference for the general practitioner and specialist. METHOD: The method used was proposed by the BMA. The search was conducted in the databases of MEDLINE (PubMed), Scopus, Web of Science and LILACS, between 1980 and 2010. The strategy used was based on structured questions as PICO (acronym formed by the initials of "patient or population", "intervention, display or exhibition", "control or comparison" and "outcome"). RESULTS: Studies show that the first-line pharmacological treatment for adults and children are serotonin selective reuptake inhibitors and serotonin and norepinephrine reuptake inhibitors, whereas cognitive-behavioral therapy is considered the best psychotherapeutic treatment. Moreover, some psychiatric comorbidities were associated with a worse outcome of SAD. CONCLUSIONS: Despite its high prevalence, SAD does not receive adequate attention and treatment. The best choice for the treatment of adults is a combination of cognitive-behavioral psychotherapy with serotonin selective reuptake inhibitors and serotonin and norepinephrine reuptake inhibitors. Other options as benzodiazepines or monoamine oxidase inhibitors must be used as second and third choices, respectively.

Resistência ao tratamento nos transtornos de ansiedade: fobia social, transtorno de ansiedade generalizada e transtorno do pânico / Treatment-resistant anxiety disorders: social phobia, generalized anxiety disorder and panic disorder

OBJETIVOS: Os transtornos de ansiedade são condições psiquiátricas prevalentes que determinam importante prejuízo funcional, piora na qualidade de vida do indivíduo e um enorme custo social. Embora diversas medicações eficazes para os transtornos de ansiedade encontrem-se disponíveis, um número significativo de pacientes não responde adequadamente ao tratamento e muitos permanecem com sintomas residuais clinicamente significativos. O objetivo deste estudo é rever aspectos relacionados à resistência ao tratamento e estratégias farmacológicas no manejo dos transtornos de ansiedade resistentes ao tratamento. MÉTODO: Revisão narrativa. RESULTADOS: São discutidos os diversos aspectos conceituais relacionados à resistência ao tratamento, os possíveis preditores de resistência e, finalmente, algumas estratégias a serem utilizadas no manejo dos transtornos de ansiedade (incluindo transtorno de ansiedade social, transtorno de ansiedade generalizada e transtorno do pânico) que não respondem às abordagens terapêuticas convencionais. CONCLUSÃO: A resistência ao tratamento ainda é um desafio para a prática clínica que começa em conceitos não operacionalizados de resposta e resistência e termina na escassez de estudos controlados sobre estratégias de tratamento nesse último cenário clínico.

OBJECTIVES: Anxiety disorders are common psychiatric conditions that cause significant disability, poor quality of life and enormous social cost. Although treatments with demonstrable efficacy are available a great number of patients fail to respond or remains with clinically significant residual symptoms after treatment. The objective of this study is to review aspects related to treatment resistance and pharmacological strategies to deal with anxiety disorders resistant to treatment. METHOD: Narrative review. RESULTS: We discuss conceptual aspects related to treatment resistance or refractoriness, predictors of poor treatment outcome, and finally, some strategies to deal with anxiety disorders (including social anxiety disorder, generalized anxiety disorder and panic disorder) that do not respond to standard therapeutic interventions. CONCLUSION: Treatment resistance in anxiety disorders remains a challenge to clinical practice going from non standardized concepts of response and resistance to a paucity of controlled studies concerning therapeutic strategies.

Aromatase inhibitors and male breast cancer.

The majority of breast cancers in male patients are hormone receptor positive. Tamoxifen has proven to be successful in both adjuvant and metastatic settings and remains the standard of care. Given the improved outcomes in female patients with aromatase inhibitors (AI), these drugs have become a potential therapeutic tool for male patients. Preliminary data show effective suppression of oestradiol levels in males treated with AI and some reports have demonstrated objective responses. Here we report a case of a male patient with metastatic breast cancer treated with letrozole who achieved clinical response associated with a decrease in blood oestradiol levels.

Allopregnanolone produces hyperphagia by reducing neophobia without altering food palatability.

The neurosteroid allopregnanolone may increase feeding by altering food palatability; however, it may also increase feeding by reducing anxiety (neophobia). Moreover, it is unclear whether this induced hyperphagia is selective to safe, palatable foods only. Male rats were injected with allopregnanolone 20 min prior to behavioral testing. The taste reactivity test was used to examine possible shifts in the palatability of a 0.3 M sucrose solution. A lickometer was used to monitor intake and licking of either a sucrose or sucrose-quinine solution. Sucrose palatability was not enhanced; however, allopregnanolone significantly increased sucrose intake and licking on Test Day 1 when the solution was novel, but not on Test Day 2 when the solution was familiar. Sucrose-quinine intake was not enhanced. Allopregnanolone-induced hyperphagia is not a result of altered sucrose palatability, but rather reflects a reduction in the neophobia elicited by a novel solution; an effect that further seems to be selective to safe, palatable foods.

Estado del arte sobre el tratamiento de la fobia social / State of the art about the treatment of social phobia

El objetivo de este trabajo es realizar un análisis crítico de la efectividad de las principales opciones de tratamiento de la fobia social, específicamente la farmacoterapia, las terapias conductuales y cognoscitivas y el tratamiento cognoscitivo conductual. Para ello se presenta, inicialmente, los aspectos descriptivos fundamentales de dicho trastorno, incluyendo sus criterios diagnósticos, comorbilidad y características asociadas. Posteriormente se reseñan dichas opciones de tratamiento y los datos de efectividad sobre las mismas reportados en la literatura especializada. Se concluye que la terapia de exposición y la combinación de exposición y reestructuración cognoscitiva son las opciones terapéuticas que cuentan con el mayor respaldo empírico en términos de efectividad, evitación de efectos iatrogénicos y medidas de seguimiento.

Drug targets in stress-related disorders.

Nervous and immune systems mutually cooperate via release of mediators of both neurological and immunological derivation. Adrenocorticotropin hormone (ACTH) is a product of the hypothalamus-pituitary adrenal axis (HPAA) which stimulates secretion of corticosteroids from adrenals. In turn, corticosteroids modulate the immune response in virtue of their anti-inflammatory activity. On the other hand, catecholamines, products of the sympathetic nervous system (SNS), regulate immune function by acting on specific beta-adrenergic receptors. Conversely, cytokines released by monocytes/macrophages and lymphocytes, upon antigenic stimulation, are able to cross the blood-brain-barrier, thus modulating nervous functions (e.g., thermoregulation, sleep, and appetite). However, cytokines are locally produced in the brain, especially in the hypothalamus, thus contributing to the development of anorexic, pyrogenic, somnogenic and behavioural effects. Besides pathogens and/or their products, the so-called stressors are able to activate both HPAA and SNS, thus influencing immune responses. In this respect, many studies conducted in medical students taking exams have evidenced an array of stress-induced immune alterations. Phobic disorders and migraine without aura (MWA) represent examples of stress-related disorders in which phagocytic immune deficits, endotoxemia and exaggerated levels of proinflammatory cytokines [Tumor Necrosis Factor-alpha (TNF- alpha), and interleukin- 1 beta] have been detected. Quite interestingly, administration of a thymic hormone could ameliorate clinical symptoms in phobic patients. In MWA patients, a beta-blocker, propranolol, could mitigate migraine, whose cessation coincided with a drop of TNF-alpha serum concentration. In phobic disorders and in MWA, benzodiazepines are very often administered and, in this respect, some of them, such as diazepam, inhibit immune functions, while others, e.g., alprazolam, enhance immune responses. Alprazolam could improve clinical symptoms in MWA patients. Chronic Fatigue Syndrome (CFS) is a disorder whose etiology and pathogenesis are still unknown. In this syndrome both abnormalities of nervous and immune systems have been reported. Despite many immune parameters evaluated in CFS no specific biomarkers of disease have been found. Our own data are in agreement with current literature in that we found decreased levels of serum (IFN)-gamma in these patients, thus indicating a predominance of T helper (h)1 response in CFS. Also leptin, a hormone which regulates food intake, fluctuates within normal ranges in CFS individuals. Quite interestingly, in depressed patients, used as controls, leptinaemia was more elevated than in CFS. Finally, in a series of recent therapeutic trials several immunomodulating agents have been used, such as staphypan Berna, lactic acid bacteria, kuibitang and intravenous immunoglobulin. In conclusion, it seems that major drug targets in stress-related disorders are immune cells in terms of inhibition of proinflammatory cytokines and modulation of Th responses. In particular, according to recent evidences, antidepressants seem to exert beneficial effects in experimental autoimmune neuritis in rats by decreasing IFN- beta release or augmenting NK activity in depressed patients.

Ansiedade social e abuso de propranolol: relato de caso / Social anxiety and propranolol abuse: a case study

Paciente com grave ansiedade social automedicou-se com propranolol durante seis anos, em doses de até 320 mg/d. Além do tratamento psicanalítico que já havia iniciado, foi tratada com tranilcipromina, apresentando melhora parcial do quadro fóbico e do abuso do betabloqueador. Após introdução de paroxetina, houve melhora ainda mais pronunciada. Apesar da automedicação com uma substância potencialmente eficaz em alguns casos, perpetuou-se durante anos um grave padrão fóbico de comportamento. O caso exemplifica as dificuldades de procura de tratamento específico pela população de fóbicos sociais. Levanta-se a hipótese da existência de uma prática crescente de automedicação com betabloqueadores entre fóbicos sociais e pessoas com ansiedade de desempenho, problema cuja relevância para a saúde pública ainda não foi pesquisada

[Measuring of preoperative anxiety by three self-reporting scales: State Trait Anxiety Inventory, Symptoms CheckList 92 and visual analogue scale]. / Måling af praeoperativ angst med tre selvrapporteringsskalaer: State Trait Anxiety Inventory, Symptoms CheckList 92 og visuel analogskala.

INTRODUCTION: Preoperative anxiety is a common phenomenon. It is therefore necessary to investigate whether quantitative self-reporting anxiety scales can be helpful in the anaesthetic clinic and research. The aim of this study was to compare the state trait anxiety inventory (STAI), symptoms checklist 92 (SCL 92), the subscales anxiety and phobic anxiety, and a visual analogue scale for anxiety (VAS). MATERIAL AND METHODS: Thirty-eight women consecutively referred for elective breast surgery filled in the rating scales the day before the operation. RESULTS: A statistically significant correlation was found between STAI, SCL 92, anxiety, and VAS. The patients' STAI and SCL 92 anxiety scores were markedly higher than that of the background population. DISCUSSION: In this study the STAI scale, SCL 92 anxiety, and VAS measure all essential features of the phenomenon. SCL 92 anxiety is nevertheless considered to be the most appropriate rating scale, because it has been validated in a Danish population.

Using test dose challenges to restore essential therapy in patients with idiopathic anaphylaxis and pharmacophobia: report of a patient with idiopathic anaphylaxis and statin phobia.

Idiopathic anaphylaxis (IA) is a well-documented condition in which anaphylaxis occurs in the absence of an identifiable precipitant. However, many patients with IA find it difficult to accept this diagnosis and continue to search for an external cause. It is not uncommon for these highly anxious patients to discontinue essential medications that they feel are responsible for the reaction despite reassurance from their physicians to the contrary. In extreme cases, these patients may develop an actual phobia to preexisting medications and avoid them despite adverse consequences to their health. To illustrate this concept, we report a case involving a female patient with familial hypercholesterolemia who experienced a single episode of IA and developed a "statin phobia," falsely implicating her medication (lovastatin) for the reaction. After 5 years of failed therapy with other antihyperlipidemic agents, the patient finally agreed to undergo test dosing to a similar statin agent atorvastatin. On successful completion of the test, she resumed therapy with atorvastatin and her low-density lipoprotein (LDL) levels were reduced by 50% over 5 months. We conclude that patients with a confirmed diagnosis of IA who manifest phobic responses to beneficial medications should be reassured of the diagnosis promptly by their physician. When reassurance fails and the medication is essential to the patient's health, test dose challenges may be conducted to reintroduce the drug to the patient's regimen.

The inhibitory effect of Selank on enkephalin-degrading enzymes as a possible mechanism of its anxiolytic activity.

Examination of patients with various forms of anxiety and phobic disorders (according to DSM-4 criteria) demonstrated a considerable shortening of enkephalin half-life and reduced total enkephalinase activity in the blood during generalized anxiety, but not during panic disorders and agoraphobia. This was probably related to low blood concentration of endogenous inhibitors of enkephalin-degrading enzymes in patients with generalized anxiety disorders. Heptapeptide Selank (Thr-Lys-Pro-Arg-Pro-Gly-Pro), which attenuates behavioral anxiety reactions and does not cause side effects typical of most anxiolytics, dose-dependently inhibited enzymatic hydrolysis of plasma enkephalin (IC50 15 microM). Selank was more potent than peptidase inhibitors bacitracin and puromycin in inhibiting enkephalinases. These results suggest that high efficiency of Selank in the therapy of anxiety and phobic disorders, including generalized anxiety, is due to its ability to inhibit enkephalin hydrolysis.