Stressful life events contribute to the development of many neuropsychiatric disorders including depression and anxiety. Animal studies based on the relationship of stress and depression or anxiety are scarce and controversial. Moreover, neither the neurobiological basis of anxiety and depression nor the mechanisms responsible for neurochemical regulation by stressful stimuli are well understood. This study was designed to investigate the possible contribution of both acute (2 h) and chronic (2 h X 15 d) restraint stress in the generation of anxiety and depression, and also to find out whether nitric oxide (NO) has a modulatory role in these behavioral reactions. Elevated plus-maze and forced swimming test (FST) were chosen for assessment of anxiety and depression, respectively, and N(G)-nitro L-arginine methyl ester (L-NAME, 10 mg/kg), a NO synthase (NOS) inhibitor, and L-arginine (50 mg/kg), a NO precursor, were used to evaluate the role of nitrergic system in restraint exposed rats. The results showed that acute and chronic stress caused depression-like and anxiety-like behaviors in rats and the acute inhibition of NOS by L-NAME prevented these acute and chronic stress-induced anxiogenesis and depression. These data lead to the conclusion that stress and NO seem to be involved in the generation of anxiety and depression.
IntroductionThis open-label pilot study aimed to investigate the efficacy of canakinumab in colchicine-resistant familial Mediterranean fever (FMF) patients.MethodPatients with one or more attacks in a month in the preceding 3 months despite colchicine were eligible to enter a 30-day run-in period. Patients who had an attack during the first run-in period advanced to a second 30-day period. At the first attack, patients started to receive three canakinumab 150 mg subcutaneous injections at 4-week intervals, and were then followed for an additional 2 months. Primary efficacy outcome measure was the proportion of patients with 50 % or more reduction in attack frequency. Secondary outcome measures included time to next attack following last canakinumab dose and changes in quality of life assessed by SF-36.ResultsThirteen patients were enrolled in the run-in period and 9 advanced to the treatment period. All 9 patients achieved a 50 % or more reduction in attack frequency, and only one patient had an attack during the treatment period. C-reactive protein and serum amyloid A protein levels remained low throughout the treatment period. Significant improvement was observed in both physical and mental component scores of the Short Form-36 at Day 8. Five patients had an attack during the 2-month follow-up, occurring median 71 (range, 31 to 78) days after the last dose. Adverse events were similar to those observed in the previous canakinumab trials.ConclusionCanakinumab was effective at controlling the attack recurrence in patients with FMF resistant to colchicine. Further investigations are warranted to explore canakinumab’s potential in the treatment of patients with colchicine resistant FMF.Trial registrationClinicalTrials.gov NCT01088880. Registered 16 March 2010.Electronic supplementary materialThe online version of this article (doi:10.1186/s13075-015-0765-4) contains supplementary material, which is available to authorized users.
ABSTRACT.Purpose: To compare visual outcomes, number of visits and ranibizumab injections in patients treated with a Wait & Extend (W&E) or Treat & Observe (T&O) regimen. Methods: This 12-month, randomized, multicentre, open-label study enrolled patients aged ≥50 years with choroidal neovascularization (CNV) secondary to AMD who had not received anti-VEGF agents. Patients received three monthly injections of ranibizumab before randomization (1:1): (i) T&O patients were examined monthly and retreated if needed, (ii) W&E patients had a follow-up visit 1 month later. If no lesions were active, the interval to the next visit was extended by 2 weeks to a maximum of 8 weeks. Active lesions were re-treated and the follow-up schedule restarted. Primary end-point was change in BCVA at Month 12. Conclusion: W&E regimen resulted in a similar efficacy and safety profile to the labelled T&O regimen in patients with CNV secondary to AMD, and may help reduce the burden of follow-up visits.
Therapeutic drug monitoring (TDM) has assumed an important place in patient management in the last few decades. In this study, serum drug levels determined in 7759 specimens sent to the Department of Pharmacology and Clinical Pharmacology in 1994 and 1998 for TDM were retrospectively evaluated. Monitored drugs were carbamazepine, valproate, phenytoin, phenobarbital, digoxin, theophylline, and salicylate. The comparison of the results obtained for the relevant 2 years showed that there was a remarkable increase in the number of requests for TDM per year and in the rate of serum drug levels that were within therapeutic range. Serum antiepileptic drug level monitoring accounted for a major part of the data. Overall data suggest that the use of TDM in antiepileptic drugs is improving; conversely, digoxin and theophylline are still not being properly monitored. In this study, the results are discussed in the light of rational TDM criteria.
-We examined the role of nitrergic, glutamatergic and gamma-aminobutyric acid (GABA)-ergic systems in the mechanism(s) underlying lithium induced acute toxicity. With this aim, lithium (18 mEq/kg, i.p.) intoxicated rats were observed for 3 hr recording their clinical signs and death. Lithium exposure at the dose used produced central nervous system (CNS) depression. Pre-treatment of N w -nitro-L-arginine methyl ester (L-NAME) a nonselective nitric oxide synthase inhibitor (10 mg/kg, i.p.), 7-nitroindazole (7-NI) a selective neuronal nitric oxide synthase inhibitor (25 mg/kg, i.p.), nitric oxide precursor L-arginine (1,000 mg/kg, i.p.) and MK-801 a noncompetitive antagonist of N-methyl-D-aspartic acid class of glutamate receptors (0.5 mg/kg, i.p.) all increased CNS depression and mortality in lithium group however, no change was seen in GABA receptor agonist GABA (1,000 mg/kg, i.p.) or D-arginine (1,000 mg/kg, i.p.) a biologically inactive enantiomer of L-arginine pre-treated rats. Glutamic acid decarboxylase (GAD) enzyme activity was measured in hippocampus, cerebral cortex and cerebellum of the different groups of animals. GAD enzyme activity reduced in cerebral cortex but not altered in hippocampus or cerebellum by lithium as compared to the control (saline) group. We conclude that an interaction with nitrergic and glutamatergic systems may have a role in the acute toxicity of lithium in rats.The inhibition of glutamate metabolism may arise from this interaction and the involvement of GABA-ergic system should be further investigated in this toxicity.
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