Effect of single doses of pindolol and d-fenfluramine on flumazenil-induced anxiety in panic disorder patients.

The effects of the 5-HT1A receptor blocker pindolol and the 5-HT releasing and uptake blocking agent d-fenfluramine, both used as indirect serotonin agonists, on flumazenil-induced acute anxiety reactions were studied in panic disorder patients to test the hypothesis that serotonin (5-HT) inhibits neural systems mediating panic attacks. Thirty never treated or drug free PD patients (16 females) aged 22-49 y (mean ±â€¯SD, 32.9 ±â€¯8) received single doses of d-fenfluramine (n = 10; 30 mg, p.o.), pindolol (n = 10; 5 mg, p.o.), or placebo (n = 10) 90 and 45 min before a challenge test with flumazenil (1.5 mg, i.v., in 10 min), under double-blind conditions. Panic attacks occurred in 5 control subjects (placebo-flumazenil group), 5 subjects in the pindolol group and in 7 in the d-fenluramine pre-treated patients. Patients experiencing anxiety attacks following flumazenil reported higher increases in anxiety scores. Respiratory rate increases were not different between patients experiencing or not a panic attack. Despite sample size limitation, this study suggests that flumazenil induced anxiety reaction is not a good pharmacological model of panic attacks, considering the absence of serotonergic modulation of its effects.

Genetic variants in genes related to lipid metabolism and atherosclerosis, dyslipidemia and atorvastatin response.

OBJECTIVE: Using candidate gene approach, we have investigated the effect of single nucleotide polymorphism (SNP) in genes related to lipid metabolism and atherosclerosis on dyslipidemia and atorvastatin response. METHODS: The study included 157 patients treated with atorvastatin and 145 controls. Genomic DNA was isolated and genotyped using SNPlex technology. RESULTS: Allele and genotype disease association test revealed that APOB rs693 (OR: 2.2 [1.5-3.2], p=0.0001) and CD36 rs1984112 (OR: 3.7 [1.9-7.0], p=0.0002) SNPs were independent risk factors for hypercholesterolemia. Only APOB rs693 T variant allele was associated with increased LDL cholesterol levels (>160mg/dL). After atorvastatin treatment (10mg/day/4weeks), LIPC -514T allele was positively associated with LDL cholesterol reduction. CONCLUSION: The current study reinforces the current knowledge that carrying APOB rs693 is an independent risk factor for dyslipidemia and higher LDL levels. Furthermore, we found that a variant of CD36 was associated with dyslipidemia as a risk (rs1984112) factor. Finally, atorvastatin response could be predicted by LIPC -514C>T SNP and physical activity. In conclusion, our data evidences the contribution of genetic markers and their interaction with environmental factor in the variability of statin response.

Polimorfismos no receptor Scavenger classe B tipo I e sua relação com perfil lipídico sérico e resposta a atorvastatina em indivíduos brasileiros / Scavenger receptor class B type I polymorphisms and its relation with serum lipids profile and response to atorvastatin in Braszilian individuals

O receptor scavenger BI (SR-BI) é um componente chave do transporte reverso do colesterol. Polimosfismos no gene SCARB1 foram associados com variações no perfil lipídico e outros de risco cardiovascular. Os polimosfismos de nucleotídeo único In5C>T e Ex8C>T no SCARB1 e medidas de lípides e apolipoproteínas foram avaliadas em 79 hipercolesterolêmicos (HC) e 173 normolipidêmicos (NL) provenientes do Brasil. Pacientes HC foram tratados com atorvastatina (10mg/dia/4semanas). Os polimosfismos foram identificados por PCR-RFLP. Os indivíduos HC portadores dos genótipos In5CC+TT mostraram concentrações mais elevadas de LDL-C, apoB, e menores da relação apoAI/apoB. No grupo NL, os genótipos In5CC+TT foram associados com concentrações maiores de LDL-C. Os indivíduos HC portadores de genótipo Ex8CC tiveram uma variação menor da razão apoAI/apoB em resposta à atorvastatina (p<0,05). Nos Hc portadores do haplótipo Ex8CC+CT/In5CT+TT tiveram valores basais elevados de LDL-C e relação apoAI/apoB diminuída. Após o tratamento com atorvastatina, os indivíduos Hc portadores do haplótipo Ex8CC/In5CC tiveram uma variação menor na relação apoAI/apoB. Os genótipos In5CT+TT no SCANB1 conferem um perfil lipídico mais aterogênico. O genótipo Ex8CC e o haplótipo Ex8CC estão associados com uma resposta à atorvastatina menor da razão apoAI/apoB na nossa população.

Validation of the Portuguese version of the Social Adjustment Scale on Brazilian samples.

BACKGROUND: Social dysfunction is reported in several psychiatric diseases and its evaluation is becoming an important measure of treatment outcome. The aim of this study was to obtain normative data, to test the validity and the ability of the Portuguese version of the Self-Report Social Adjustment Scale (SAS-SR) to detect different clinical conditions. METHODS: The Portuguese version of the SAS-SR was applied to a carefully selected non-psychiatric sample, and to depressed, panic, bulimic and cocaine-dependent patients. Depressed and panic patients were evaluated in two different clinical conditions: acutely symptomatic and in remission. RESULTS: SAS overall and sub-scale scores of the normal sample were consistently lower than all patient groups, indicating better social adjustment in all areas. Panic patients were impaired to a lower level than depressed and cocaine-dependent patients in overall adjustment. Depressed patients in remission, although in better condition, were still impaired in relation to normal subjects in overall social functioning, leisure time and marital areas. In panic patients in remission, normalization was not achieved in overall functioning, work and marital areas. LIMITATIONS: Sample size was small in some groups and the evaluation was cross-sectional. CONCLUSIONS: The Portuguese version of SAS-SR is a useful instrument for detecting differences between psychiatric patients and normal subjects and for the evaluation of different clinical conditions, recommending its use in outcome studies.

A dose-finding and discontinuation study of clomipramine in panic disorder.

Eighty-one panic disorder patients with or without agoraphobia were treated with flexible doses of clomipramine under single-blind conditions. Fifty-seven (70.3%) reached operational criteria for full remission in 16.2 +/- 6.5 weeks, with a mean dose of 89.1 +/- 8.2 mg/day. Fifty-four (81%) of them received a continuous post-remission maintenance treatment at full doses of clomipramine for 4-6 months. No patient relapsed during the clomipramine maintenance phase. Their medication was then tappered and discontinued with placebo substitution under double-blind conditions. Fifty-one (63%) patients were followed-up until relapse or recurrence for up to 3 years, with periodic assessments. Three different outcome groups were identified: the first (n = 19, 19; 37.2%) experienced an early/immediate relapse (5.2 +/- 4.9 weeks after drug discontinuation); the second group (n = 22, 22; 43.1%) experienced recurrence after 42.9 +/- 35 weeks following discontinuation; and the third group (n = 10, 10; 19.6%) remained assymptomatic and functionally well throughout the follow-up. Predictors of early relapse were: (1) higher baseline score in the Beck Depression Inventory; (2) higher global score on the phobic avoidance scale after the full remission criteria; and (3) the need for higher clomipramine doses to reach full remission. The need for long-term or intermittent maintenance for most patients is emphasized.

Stressful reactions and panic attacks induced by flumazenil in chronic benzodiazepine users.

The acute effects of flumazenil, a benzodiazepine (BZD) receptor antagonist in long-term BZD users were used as a possible test to detect physiological dependence. Thirty-four subjects (20 females, 14 males) aged 26-48 years (mean + SD, 42.4+/-8.5 years), all chronic users of low doses of diazepam (5-20 mg/day, 14.2+/-4.8 mg/day) for 5 to 28 years (10.5+/-6 years), received a single 1-mg i.v. flumazenil dose or saline, infused slowly under double-blind conditions. Physiological dependence was suggested as all patients receiving flumazenil developed an anxiety reaction while the placebo group did not. Flumazenil triggered a qualitatively different reaction amounting to a panic attack during infusion in nine out of 15 patients. These patients had a diagnosis of panic disorder or a history of panic attacks. Caution should be exercised when giving flumazenil to panic patients who are taking BZDs as maintenance treatment.

The age-related rise of plasma cholesterol in humans is not caused by a cell removal defect of LDL particles: 'in vitro' studies in peripheral mononuclear blood cells.

In healthy subjects with a normal body mass index, total plasma cholesterol, low-density lipoprotein (LDL) cholesterol, and apoB lipoprotein levels are higher in older individuals (n = 34) than in younger subjects (n = 43). The two groups studied ranged in age from 60 to 93 years and from 17 to 30 years, respectively. The cholesterol synthesis rates of peripheral mononuclear blood cells from 14C-acetate, total and unesterified cholesterol concentrations in freshly isolated cells, and the rates of uptake of pooled donor LDL, labeled with 125I- or 14C-cholesteryl oleoyl ether, by cells derepressed in a lipoprotein-free medium were similar in both experimental groups. Thus, the rise of LDL cholesterol with age would seem to be likely secondary to the higher rate of very-low-density lipoprotein production, as shown by other investigators.

Encoding, remembering and awareness in lorazepam-induced amnesia.

The effects of lorazepam (1,2 mg) and placebo on encoding, remembering and awareness were assessed in a study with 54 healthy volunteers. All subjects studied stimulus materials in a levels of processing (L-o-p) task. Half the subjects were assessed on an explicit memory task of word recognition and the other half were given an implicit memory task of word-stem completion. Following the implicit task, awareness of retrieval was further investigated by questions and by subjects' recollective experience in recognising the actual words they had completed from stems. L-o-p effects and marked lorazepam-induced impairments were found in the implicit task of word-stem completion although the interaction between L-o-p and drug effects emerged only as a trend in the data. Lorazepam-induced impairments on stem-completion may then be explained at least in part as being due to contamination by explicit retrieval processes, but we cannot rule out the possible role of drug effects on perceptual processes at encoding. Results from responses to "awareness" questions and from analysis of subsequent recollective experience indicated that subjects were not aware of using explicit retrieval during the implicit task. Results also replicated previous findings showing that both lorazepam and L-o-p independently affect performance in an explicit memory task of word recognition. Thus drug-induced deficits at encoding persist regardless of the level at which information is initially processed.

Impairment of performance associated with long-term use of benzodiazepines.

The long-term effects of benzodiazepines (BDZ) on psychomotor and cognitive functions were assessed in 28 out patients, users of low therapeutic doses of diazepam (13.6 ± 4.9 mg/day, range: 5-20 mg/day) for 5-20 years (10.1 ± 5.0 years). These patients' performance was compared with two control groups: 53 BDZ-free anxious out patients and 56 healthy volunteers. The three groups were similar in sex, age and education. BDZ chronic users were tested before and after short-term (3 weeks) and long-term discontinuation (at an average of 10 months). Performance of chronic users of BDZ was consistently worse than those of the control groups, suggesting an impairment in these patients on both psychomotor and cognitive functions. These were not related to either dose or cumulative exposure to BDZ, and were also independent of diagnosis and levels of anxiety and depression. Moreover, these deficits were persistent as their performance failed to improve after drug discontinuation.

Differential acute psychomotor and cognitive effects of diazepam on long-term benzodiazepine users.

The aim of this study is to determine whether long-term use (5-20 years) of therapeutic doses of diazepam (5-20 mg/day) in anxious patients (n = 28) is associated with tolerance to its psychomotor and cognitive effects. Patients were tested at baseline, before and after a 10 mg oral dose of diazepam during chronic use, and at 3 weeks and 10 months after benzodiazepine (BZ) discontinuation. The effects of a single i.v. dose of flumazenil (1 mg administered 5 days before baseline) on reversing tolerance were also assessed. No acute effect of diazepam was observed on the psychomotor performance of patients both under BZ treatment and after short- and long-term discontinuation, suggesting persistence of tolerance. In contrast, acute effects of diazepam were observed in memory measures at all times. Given subjects' very prolonged BZ use, it is possible to predict that tolerance to the memory effects never fully develops. Flumazenil administration did not reverse tolerance. This suggests that neuroadaptative mechanisms, other than benzodiazepine receptor set-point shift, occur after long-term use.

Clomipramine, a better reference drug for panic/agoraphobia. I. Effectiveness comparison with imipramine.

An 8-week, double-blind, flexible-dose trial comparing low doses of clomipramine (mean=50 mg) with moderate doses of imipramine (mean=113.8 mg and propanteline (active placebo), was carried out in 60 out-patients with panic disorder with or without agoraphobia. Efficacy evaluation included global, anxiety and depression rating scales, and the determination of rates of relapse over up to 10 weeks of single-blind placebo follow-up. Both tricyclics were significantly more effective than propanteline, but clomipramine tended to act faster and more consistently than imipramine on most measures. Given the degree of blindness achieved and the significantly lower doses of clomipramine, this seems a better reference drug than imipramine for clinical trials in panic/agoraphobia.

[Mitral valve prolapse and panic disorder]. / Prolapso valvar mitral e transtorno do pânico.

PURPOSE: To determine the incidence of mitral valve prolapse (MVP), using echocardiographic and auscultatory criteria, in cases of panic disorder (complicated or not with agoraphobia). PATIENTS AND METHODS: Sixty-five patients (37 women) with panic disorder and without known cardiac disease, mean age 39.8 years (range 19-67) were studied. MVP was diagnosed when there was a typical auscultatory click or when the echocardiographic study (echo) registered one mitral lacinea 2 mm behind the C-D line at the "M" study or a systolic billowing of mitral leaflets in two views to the two-dimensional study. RESULTS: MVP was found in 29 (44.6%) of the patients, 12 (42.7) men and 17 (49.5%) women. A click was found in 19 (24%) of the cases and the Echo was positive in 24 (39.6%) of the patients. Click and a positive Echo finding were identified in 14 patients. CONCLUSION: MVP was found in panic cases, in incidence greater than in the general population.

Flumazenil-precipitated withdrawal symptoms in chronic users of therapeutic doses of diazepam.

A prototype benzodiazepine (BDZ) antagonist, flumazenil (1 mg, i.v.) or placebo was administered to eight chronic users (5-15 years) of therapeutic doses of diazepam (10-25 mg/d), in a double-blind, placebo-controlled design in order to evaluate the presence of physiological dependence. The three patients receiving flumazenil developed anxiety reactions, with significant increases in bodily and psychological symptoms, as measured by rating scales. In two these amounted to a panic attack. Subjects on placebo tended to show decreases in measures of anxiety. The severity of precipitated reactions was not related to the total cumulative exposure to diazepam, but to a history of panic attacks. Previous panic may increase the vulnerability to severe reactions to flumazenil.

[Benzodiazepines: patterns of use, tolerance and dependence]. / Benzodiazepínicos: padrões de uso, tolerância e dependência.

The authors review recent studies on benzodiazepine, the most largely used drug for insomnia and anxiety. In this paper are summarized: the development, patterns of use and abuse, mechanism of action, development of differential tolerance to its many effects, and the phenomena of withdrawal and dependence on the benzodiazepines.

[Benzodiazepines tolerance and dependence: a case report]. / Tolerância e dependência a benzodiazepínicos: a respeito de um caso.

This is a case report of benzodiazepine abuse and dependence with tolerance to some (psychomotor sedative) but not all (memory) of the BDZ effects. A withdrawal syndrome which included intensification of paranoid personality traits, was observed.

Estimulaçäo alfa-adranérgica na secreçäo de hormônio de crescimento: comparaçäo da clonidina com guanabenz / Cepha adrenergic stimulation in growth hormone secretion: comparison between clonidine and guanabenz

Avaliamos o efeito da administraçäo aguda de clonidina e de guanabenz na secreçäo de hormônio de crescimento (GH0 em nove pacientes com deficiência isolada idiopática de GH (DGH), seis do sexo masculino e três do feminino, e em 15 indivíduos de baixa estatura sem deficiência de GH (CN), 11 do sexo masculino e quatro do feminino. Nesses últimos sob hipoglicemia induzida o pico de GH foi de 11,34 ñ 4,48ng/ml e no teste seqüencial exercício L-DOP o pico foi de 12,97 ñ 3,94ng/ml (Mñep). Sob a a çäo da clonidina e do guanabenz os CN apresentaram picos de GH de 22,07 ñ 3,2 e 19,24 ñ 2,26ng/ml respectivamente. Esses resultados näo foram estatisticamente diferentes daqueles obtidos com os testes clássicos de liberaçäo de GH. Os pacientes com DGH näo respoderam a nenhum dos testes de liberaçäo utilizados. Nossos dados sugerem que ambos agonistas alfa-adrenérgicos säo potentes liberadores de GH, podendo ser utilizados na avaliaçäo da reserva hipofisária