Hyperbaric oxygen therapy (HBOT) has beneficial effects on avascular necrosis of femoral head (ANFH), but its mechanism of action is still unclear. We investigated if HBOT upregulates serum osteoprotegerin (OPG) and/or inhibits osteoclast activation. 23 patients with unilateral ANFH at stage I, II and III consented to the study: the patients received standard HBOT. Serum OPG levels were obtained at the beginning of HBOT (T0), after 15 sessions (T1), 30 sessions (T2), after a 30-day break (T3), and after 60 sessions (T4). Magnetic resonance imaging (MRI) was obtained at T0 and about one year from the end of HBO treatments. Lesion size was compared between pre- and post-HBOT. 19 patients completed the study. HBOT reduced pain symptoms in all patients. HBOT significantly reduced lesion size in all stage I and II patients and in 2 of 11 stage III patients. HBOT increased serum OPG levels but receptor activator of nuclear factor kappa-B ligand (RANKL) levels did not change.
Rationale
Escitalopram is a superior antidepressant to racemic citalopram. It has been hypothesized that binding of R-citalopram to the serotonin transporter (SERT) antagonizes escitalopram binding to and inhibition of the SERT, curtailing the elevation of extracellular 5-hydroxytryptamine (5-HTExt), and antidepressant efficacy. Further, it has been suggested that a putative allosteric binding site is important for binding of escitalopram to the primary, orthosteric, site, and for R-citalopram’s inhibition hereof.
Objectives
Primary: Investigate at the human (h)SERT, at clinical relevant doses, whether R-citalopram antagonizes escitalopram-induced 5-HTExt elevation. Secondary: Investigate whether abolishing the putative allosteric site affects escitalopram-induced 5-HTExt elevation and/or modulates the effect of R-citalopram.
Methods
Recombinant technology; in vivo microdialysis; receptor binding; pharmacokinetics; 5-HT sensitive behaviors (tail suspension, marble burying).
Results
We generated mice expressing either the wild-type human SERT (hSERTWT) or hSERT carrying amino acid substitutions (A505V, L506F, I507L, S574T and I575T) collectively abolishing the putative allosteric site (hSERTALI/VFL+SI/TT). One mg/kg escitalopram yielded clinical relevant plasma levels and brain levels consistent with therapeutic SERT occupancy. Importantly, escitalopram-induced 5-HTExt elevation was not decreased by R-citalopram co-treatment. Further, escitalopram-induced 5-HTExt elevation was not affected by loss of the allosteric site. The behavioral effects of the clinically relevant escitalopram dose were small, tending to be enhanced by R-citalopram co-administration.
Conclusions
We find no evidence that R-citalopram directly antagonizes escitalopram or that the putative allosteric site is important for hSERT inhibition by escitalopram. Our findings points to mechanisms for R-citalopram antagonism of escitalopram’s antidepressant action other than direct antagonistic binding interactions at the hSERT.
Background: Systemic intraoperative lidocaine has been seen to decrease postoperative pain following abdominal surgery, but few studies have examined its use in morbidly obese patients. Objective: We sought to evaluate the safety and effects of intravenous lidocaine in obese patients undergoing laparoscopic Roux-en-Y gastric bypass (RYGB) surgery. Methods: Setting: University-affiliated, private hospital, United States. In this preliminary prospective, double-blinded, and placebo-controlled safety study, we enrolled 21 patients and 20 completed the study. Ten patients were randomly assigned to the study group and received a continuous infusion of lidocaine intravenously from induction of general anesthesia until the end of the operation. Ten other patients were assigned to the control group and received a dextrose placebo intravenously over the same time period. Subjects were followed for 24 hours postoperatively. The primary endpoint was the presence of symptoms of lidocaine toxicity at 1 hour postoperatively. Exploratory outcomes were adverse events, visual analog scale (VAS) pain scores, opioid consumption, time to first passage of flatus and bowel movement, and length of hospital stay. Results: No significant differences were seen between groups for overt signs of lidocaine toxicity or adverse events, opioid consumption, postoperative pain scores, time to first passage of flatus or first bowel movement, or length of hospital. We identified a trend towards less opioid consumption in patients receiving lidocaine. We were underpowered to detect statistical differences due to our pilot study design; addressing safety as the primary outcome measure as opposed to efficacy. Conclusions: In this study, intravenous lidocaine in RYGB surgery was found to be safe without differences in postoperative pain or adverse effects.
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