Effect of fentanyl-oxygen anesthesia during cardiac surgery on serum thyroid hormones

Twenty-five euthyroid patients who underwent cardiac surgery with fentanyl-oxygen anesthesia were studied. The authors confirm that some thyroid hormones undoubtedly take part in a non-specific pool of reactions caused by surgical stress. For one or more days, all the patients had total triiodothyronine (TT3) and free triiodothyronine (FT3) levels clearly below the normal values, with a parallel increase in reverse triiodothyronine (rT3, biologically inactive). Changes in total (TT4) and free thyroxine (FT4), although significant, were smaller and hard to interpret. The most important changes occurred on the first postoperative day. Of seven patients who before the operation had a TT3 value below the lower normal limit, six had at discharge a mean TT3 level significantly above it. Serum TT3 concentrations could be a reliable prognostic index. High-dose fentanyl anesthesia probably does not affect thyroid hormone response to surgical stress. To date, the mechanisms which cause reduction of serum triiodothyronine have not been fully discovered and it is not known for certain whether this reduction is beneficial to the human organism.     

Molecular and neurochemical evaluation of the effects of etizolam on GABAA receptors under normal and stress conditions

The thienobenzodiazepine derivative etizolam (CAS 40054-69-1, 6-(o-chlorophenyl)-8-ethyl-1-methyl-4H-s-triazolo-(3,4-c)thienol(1 ,4) diazepine) is a potent anxiolytic with a pharmacological profile similar to that of classical benzodiazepines. In order to rationalize the therapeutic use of etizolam, its pharmacodynamics properties on GABAA receptors were investigated by a comparative study with other ligands on human recombinant GABAA as well as rat brain native receptors. Etizolam inhibited in a concentration-dependent manner [3H]flunitrazepam (CAS 1622-62-4) binding to rat cortical membranes, with an affinity of 4.5 nmol/l greater than that of alprazolam (CAS 28981-97-7) (7.9 nmol/l). Ethizolam enhanced GABA-induced Cl- currents in oocytes expressing human cloned GABAA receptors. With alpha 1 beta 2 gamma 2S subunit combination, etizolam produced a 73% increase in GABA-induced currents with an EC50 of 92 nmol/l. At the same receptor type, alprazolam showed a higher degree of potentiation and potency (98%, EC50 56 nmol/l). At alpha 2 beta 2 gamma 2S or alpha 3 beta 2 gamma 2S subunit constructs, the effects of etizolam were similar to those of alprazolam. Flumazenil (CAS 78755-81-4) completely blocked both etizolam and alprazolam effects on GABA-induced currents. Etizolam, administered i.p., was uneffective in changing ex vivo t-[35S]butylbicyclophosphorothionate ([35S]-TBPS) binding to rat cerebral cortex, whereas alprazolam and abecarnil (CAS 111841-85-1) significantly reduced this parameter. However, etizolam similarly to abecarnil and alprazolam, antagonized isoniazid-induced increase (61%) in [35S]-TBPS binding to rat cortical membranes. Further, etizolam inhibited in a dose-dependent manner basal acetylcholine release from both hippocampus and prefrontal cortex, and reversed foot-shock-induced increase of basal acetylcholine release to a control level. Altogether, these results suggest that etizolam may have a reduced intrinsic activity, at least at specific subpopulations of GABAA receptors. This property, together with the pharmacokinetic indication of a short-acting drug, may characterize etizolam as a ligand endowed with less side-effects typical of full agonits such as diazepam (CAS 439-14-5) and alprazolam. Finally, given its marked efficacy under conditions of GABAergic deficit, etizolam may represent a possible drug of choice with reduced liability to produce tolerance and dependence after long-term treatment of anxiety and stress syndromes.     

Inhibition of basal and stress-induced dopamine release in the cerebral cortex and nucleus accumbens of freely moving rats by the neurosteroid allopregnanolone

The neurosteroid allopregnanolone is a potent and efficacious modulator of γ-aminobutyric acid (GABA) type A receptors. The effects of intracerebroventricular injection of allopregnanolone (5 to 15 μg in 5 μl) on basal and stress-induced changes in the extracellular concentrations of dopamine were investigated by microdialysis in various brain areas of freely moving rats and compared with those of the benzodiazepine midazolam (1 to 10 μg in 5 μl). Allopregnanolone reduced (by a maximum of 65 to 75%) basal dopamine content in the prefrontal cortex and nucleus accumbens in a dose-dependent manner, but had no effect on dopamine output in the striatum. Allopregnanolone (10 to 15 μg) also completely prevented the increase in extracellular dopamine concentrations in the nucleus accumbens and cerebral cortex induced by foot-shock stress. Midazolam reduced basal dopamine content in all three brain regions studied as well as the stress- induced increase in dopamine content in the nucleus accumbens and cerebral cortex with a greater potency than allopregnanolone. These results suggest that endogenous neurosteroids may participate in the GABAergic modulation of dopaminergic transmission in the rat cerebral cortex and nucleus accumbens, two brain areas which are important in the regulation of emotional processes. These agents do not appear to affect striatal dopaminergic transmission which modulates motor function.     

Hydroxychloroquine decreases Th17-related cytokines in systemic lupus erythematosus and rheumatoid arthritis patients

OBJECTIVES:

Hydroxychloroquine is an antimalarial agent that has been used in systemic lupus erythematosus and rheumatoid arthritis treatment for many years. Recently, novel mechanisms of action have been proposed, thereby broadening the therapeutic perspective of this medication. The purpose of this study was to evaluate the immunomodulatory activity of hydroxychloroquine in T helper 17 (Th17) cytokines in healthy individuals and patients.

METHODS:

Eighteen female patients with systemic lupus erythematosus (mean age 39.0±12.9 years) and 13 female patients with rheumatoid arthritis (mean age 51.5±7.7 years) were recruited from Universidade Federal de Pernambuco-Brazil. The patients were included after fulfilling four classification criteria for systemic lupus erythematosus or rheumatoid arthritis from the American College of Rheumatology. After being stimulated with phorbol 12-myristate 13-acetate and ionomycin in the absence or presence of different concentrations of hydroxychloroquine, the interleukin 6, 17 and 22 levels were quantified with an enzyme-linked immunosorbent assay in culture supernatants of peripheral blood mononuclear cells from healthy individuals and patients.

RESULTS:

We demonstrated that in peripheral blood mononuclear cells from healthy volunteers and in systemic lupus erythematosus and rheumatoid arthritis patients, there was a significant reduction in the IL-6, IL-17 and IL-22 supernatant levels after adding hydroxychloroquine.

CONCLUSIONS

Our in vitro results demonstrated that hydroxychloroquine inhibits IL-6, IL-17 and IL-22 production and contributes to a better understanding of the mechanism of action of this medication.