Pharmacological treatments that facilitate extinction of fear: Relevance to psychotherapy

A great deal is now known about the mechanisms of conditioned fear acquisition and expression. More recently, the mechanisms of inhibition of conditioned fear have become the subject of intensive study. The major model system for the study of fear inhibition in the laboratory is extinction, in which a previously fear conditioned organism is exposed repeatedly to the fear-eliciting cue in the absence of any aversive event and the fear conditioned response declines. It is well established that extinction is a form of new learning as opposed to forgetting or “unlearning” of conditioned fear, and it is hypothesized that extinction develops when sensory pathways conveying sensory information to the amygdala come to engage GABAergic interneurons through forms of experience-dependent plasticity such as long-term potentiation. Several laboratories currently are investigating methods of facilitating fear extinction in animals with the hope that such treatments might ultimately prove to be useful in facilitating exposure-based therapy for anxiety disorders in clinical populations. This review discusses the advances that have been made in this field and presents the findings of the first major clinical study to examine the therapeutic utility of a drug that facilitates extinction in animals. It is concluded that extinction is an excellent model system for the study of fear inhibition and an indispensable tool for the screening of putative pharmacotherapies for clinical use.     

Effect of a single dose of the selectin inhibitor TBC1269 on early and late asthmatic responses

BACKGROUND : Selectins participate in the initial phase of leucocyte migration from circulation to inflamed tissues and may play a role in inflammatory cellular influx into airways in asthma. In the sheep asthma model, TBC1269, a pan-selectin antagonist, reduced late allergen response by 74%. OBJECTIVE : To determine whether a single dose of TBC1269 inhibits early (EAR) and late (LAR) asthmatic responses, and whether it inhibits sputum leucocyte influx after inhalation allergen challenge in atopic asthmatic subjects treated with bronchodilators only. METHODS : Twenty-one asthmatic subjects (mean+/-SD, age=32.5+/-6.7 years, 8 males, FEV1 percent predicted=84+/-15%) with known late asthmatic response based on a screening inhalation allergen challenge were randomly assigned to receive intravenous treatment with either placebo (n=11) or TBC1269 (n=10, 30 mg/kg) infused over 15 min immediately prior to a second (post-treatment) allergen challenge at least 4 weeks after the screening challenge. After each challenge, EAR and LAR were monitored for 7 h. In addition, sputum was induced 1 day before and 1 day after each allergen challenge. RESULTS : TBC1269 did not attenuate the EAR compared with placebo (largest fall in FEV1 within 1 h of 34.1+/-13.9% vs. 31.8+/-12.2% for TBC1269 and placebo groups respectively, P=0.61) or the LAR (largest fall in FEV1 between 3 and 7 h of 39.3+/-15.3% vs. 32.6+/-13.8%, P=0.24). TBC1269 had only minor effects on allergen-induced sputum eosinophilia. CONCLUSION : We conclude that TBC1269 administered before allergen challenge as a single intravenous dose does not attenuate early or late asthmatic responses to allergen in asthmatic subjects.     

The lipoprotein profile of women with hyperprolactinaemic amenorrhoea

The aim of this study was to evaluate the lipoprotein profile in women with hyperprolactinaemic amenorrhoea and to establish whether effective dopamine agonist therapy might have a beneficial effect. Blood samples were collected from women with hyperprolactinaemic amenorrhoea and from controls matched for age, body mass index and smoking. Follow-up blood samples were collected from women on dopamine agonist therapy as treatment for their hyperprolactinaemia. Plasma cholesterol, high density lipoprotein cholesterol, low density lipoprotein (LDL) cholesterol, very low density lipoprotein cholesterol, triglycerides, serum oestradiol and prolactin were measured. No statistically significant differences were found in the lipoprotein profile of the patient (n = 15) and control (n = 15) groups. During treatment with the dopamine agonist, bromocriptine (n = 9), significant reduction in total cholesterol [4.87 (3.98-5.87) versus 5.60 (4.55-6.61) mmol/l, P = 0.024] and LDL cholesterol [3.22 (2.01-4.23) versus 3.72 (2.59-4.93) mmol/l, P = 0.033] was noted. We conclude that beneficial alterations in the lipoprotein profile may occur in response to effective dopamine agonist therapy, presumably as a consequence of return of ovarian function and alleviation of oestrogen deficiency. Women with hyperprolactinaemic amenorrhoea should be encouraged to take effective therapy to improve their lipoprotein profile and potentially reduce their cardiovascular risk.     

Short-term Course and Outcome of Patients Treated with Electroconvulsive Therapy: Irish and British Surveys Compared

Comparison of two independently conducted electroconvulsive therapy (ECT) surveys in Great Britain and Ireland shows remarkable uniformity of opinion and practice in the selection of patients for treatment, treatment technique, and clinical outcome 14 and 28 days after completion of a course of treatment. Short-term outcome reported by a self-selected group of treating psychiatrists in each survey was remarkably similar. Between 75% and 80% of patients were satisfied with the results of ECT as were their treating psychiatrists. The data provide information hitherto unavailable from controlled efficacy studies and indicate the short-term course and outcome of patients treated with ECT in contemporary clinical practice.     

Permanent life support by kidneys perfused with a vitrifiable (7.5 molar) cryoprotectant solution

BACKGROUND: Vitrification (glass formation) is a potential method for indefinite term organ preservation that eliminates all of the conventional problems of freezing and thawing. A 7.5 M mixture of cryoprotectants known as VS4 is sufficiently concentrated, in combination with applied pressure, to preclude ice formation entirely during cooling to below the glass transition temperature (about -125 degrees C), at which point vitrification takes place, arresting further changes over time. METHODS: Rabbit kidneys were perfused with VS4 according to three different protocols. The kidneys were evaluated using an autograft model with immediate contralateral nephrectomy. RESULTS: All three methods permitted long-term survival, but the best results were obtained when the highest concentrations were perfused at about -3 degrees C. Using the latter protocol, the survival rate was 10/10, serum creatinine returned to a normal baseline after transient elevation, other clinical chemistry results normalized, and no histological damage was apparent 3 weeks after autografting. CONCLUSIONS: The results described provide the strongest evidence to date that it may be possible to bank kidneys for unlimited periods in the absence of ice for later transplantation.