Modulation of the hypothalamo-pituitary-adrenocortical axis by caffeine

Although caffeine is the most consumed psychoactive substance in the world, the extents of many of its effects are unknown. High doses of caffeine have been shown to activate the HPA axis while the effects of low to moderate doses have usually not been described in detail. Moreover, although several lines of evidence suggest that low doses of caffeine may restrain some negative affective states, the possible modulatory role of caffeine on HPA axis activation induced by a stressful stimulus has not been described. Thus, the present studies investigated the possible modulatory effects of low to moderate doses of caffeine on moderate to high HPA axis activation induced by different intensities of loud noise. First, in order to test this modulation, time courses for adrenocorticotropic hormone (ACTH) and corticosterone responses to loud noise stress and to caffeine were defined, in rats. Plasma ACTH and corticosterone levels peaked 30 min from the onset of noise presentation, and rapidly declined after noise termination. A low caffeine dose of 2 mg/kg significantly increased plasma corticosterone and ACTH levels 30 min following injections, but levels returned to baseline 60 min following injections. Caffeine doses of 30 mg/kg and higher elevated plasma hormone levels for at least 2h. Doses of 2 or 10mg/kg, however, did not modulate endocrine responses to loud noise presentation. It is concluded that although caffeine activates the HPA axis, low to moderate doses do not modulate HPA axis responses to stressful stimuli.     

Eosinophilic esophagitis in children and adolescents: epidemiology, clinical presentation and seasonal variation

Background

Eosinophilic esophagitis (EoE) is defined by infiltration of eosinophils in the esophageal mucosa (>20 eosinophils/hpf). The epidemiology and seasonal variation have not been well studied in children and adolescents.

Methods

Review of all esophageal biopsies performed from January 2001 to December 2006 on patients younger than 21 year of age, focusing on demographics, onset and duration of presenting symptoms, history of allergies and endoscopic findings.

Results

A total of 753 upper endoscopies were performed, 44 of which showed histologic evidence of EoE (5.8 %). Fifty percent of all EoE endoscopies were grossly normal. Onset of symptoms was 23 % in the spring, 29 % in the summer, 23 % in the fall and 25 % in the winter. More cases (36 %) were diagnosed in the fall. Time between onset of symptoms and diagnosis was 115 ± 145 days (mean ± SD). The most common presenting symptoms were vomiting (61 %), dysphagia (39 %), abdominal pain (34 %), feeding disorders (14 %), heartburn (14 %), food impaction (7 %), vague chest pain (5 %) and diarrhea (5 %). Children presenting with vomiting and feeding disorders were younger (p < 0.02), whereas children presenting with heartburn and dysphagia were older (p < 0.02).

Conclusions

The incidence of EoE did not increase between 2001 and 2006. Onset of symptoms did not vary by season, indicating that allergens triggering EoE are present all year around. Vomiting and feeding disorders are seen in young children, while dysphagia and heartburn are seen in older children. As endoscopic findings were normal in 50 % of cases, an esophageal biopsy should be performed in all patients with suspected EoE.     

Assessment of CYP3A‐mediated drug–drug interaction potential for victim drugs using an in vivo rat model

The present study aims to determine if an in vivo rat model of drug–drug interaction (DDI) could be useful to discriminate a sensitive (buspirone) from a ‘non‐sensitive’ (verapamil) CYP3A substrate, using ketoconazole and ritonavir as perpetrator drugs. Prior to in vivo studies, ketoconazole and ritonavir were shown to inhibit midazolam hydroxylation with IC₅₀ values of 350 ± 60 nm and 11 ± 3 nm , respectively, in rat liver microsomes (RLM). Buspirone and verapamil were also shown to be substrates of recombinant rat CYP3A1/3A2. In the rat model, the mean plasma AUC_0‐inf of buspirone (10 mg/kg, p.o.) was increased by 7.4‐fold and 12.8‐fold after co‐administration with ketoconazole and ritonavir (20 mg/kg, p.o.), respectively. The mean plasma AUC_0‐inf of verapamil (10 mg/kg, p.o.) was increased by 3.0‐fold and 4.8‐fold after co‐administration with ketoconazole and ritonavir (20 mg/kg, p.o.), respectively. Thus, the rat DDI model correctly identified buspirone as a sensitive CYP3A substrate (>5‐fold AUC change) in contrast to verapamil. In addition, for both victim drugs, the extent of DDI when co‐administered was greater with ritonavir compared with ketoconazole, in line with their in vitro CYP3A inhibition potency in RLM. In conclusion, our study extended the rat DDI model applicability to two additional victim/perpetrator pairs. In addition, we suggest that use of this model would increase our confidence in estimation of the DDI potential for victim drugs in early discovery. Copyright © 2013 John Wiley & Sons, Ltd.     

Synthesis and Pharmacological Characterization of Two Novel,Brain Penetrating P2X7 Antagonists

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Beneficial effects of information leaflets before spinal steroid injection

How beneficial is the provision of information leaflets to low back pain patients before steroid injection under fluoroscopy? OBJECTIVES: To compare the value of information leaflets with verbal information on steroid injection under fluoroscopy. METHODS: Alternate month design. One hundred and twenty-three low back pain patients hospitalized for steroid injection under fluoroscopy were enrolled in the trial. Fifty-two patients received both written standardized information and non-standardized verbal information (intervention group), seventy one patients received only non-standardized verbal information (control group). Anxiety assessed at baseline evaluation and just before the injection; satisfaction related to the information received assessed on discharge day; knowledge about steroid injection assessed 4 hours and 1 month after the injection. RESULTS: Patients had a high anxiety level at baseline evaluation. Written standardized information did not decrease significantly anxiety (P = 0.068) before the injection, had no effect on pain during the injection, but increased patients' knowledge about the adverse effects on the day of injection and 1 month later (P = 0.040 and P = 0.084 respectively), and improve satisfaction with information received about potential complications of the steroid injections (P = 0.018). CONCLUSIONS: Providing an information leaflet to low back pain patents undergoing steroid injection under fluoroscopy tends to reduce state anxiety, and increases patients' knowledge and satisfaction with information about the risks of the injection.     

Immunotherapy for neurological diseases

The burden of neurological diseases in western societies has accentuated the need to develop effective therapies to stop the progression of chronic neurological diseases. Recent discoveries regarding the role of the immune system in brain damage coupled with the development of new technologies to manipulate the immune response make immunotherapies an attractive possibility to treat neurological diseases. The wide repertoire of immune responses and the possibility to engineer such responses, as well as their capacity to promote tissue repair, indicates that immunotherapy might offer benefits in the treatment of neurological diseases, similar to the benefits that are being associated with the treatment of cancer and autoimmune diseases. However, before applying such strategies to patients it is necessary to better understand the pathologies to be targeted, as well as how individual subjects may respond to immunotherapies, either in isolation or in combination. Due to the powerful effects of the immune system, one priority is to avoid tissue damage due to the activity of the immune system, particularly considering that the nervous system does not tolerate even the smallest amount of tissue damage.