Selective COX-2 inhibitors after bariatric surgery: Celecoxib, etoricoxib and etodolac post-bariatric solubility/dissolution and pharmacokinetics.

Anatomical/physiological gastrointestinal changes after bariatric surgery may influence the fate of orally administered drugs.Since non-selective NSAIDs are not well-tolerated post-surgery, selective cyclooxygenase-2 (COX-2) inhibitors may be important for these patients. In this work we investigated celecoxib, etoricoxib and etodolac, for impaired post-bariatric solubility/dissolution and absorption. Solubility was studied in-vitro, and ex-vivoin aspirated gastric contents from patients pre- vs. post-surgery. Dissolution was studied in conditions simulating pre- vs. post-surgery stomach. Finally, the experimental solubility data were used in physiologically-based biopharmaceutics model (PBBM) (GastroPlus®) to simulate pre- vs. post-surgery celecoxib/etoricoxib/etodolac pharmacokinetic (PK) profiles.For etoricoxib and etodolac (but not celecoxib), pH-dependent solubility was demonstrated: etoricoxib solubility decreased âˆ¼1000-fold, and etodolac solubility increased 120-fold, as pH increased from 1 to 7, which was also confirmed ex-vivo. Hampered etoricoxib dissolution and improved etodolac dissolution post-surgery was revealed. Tablet crushing, clinically recommended after surgery, failed to improve post-bariatric dissolution. PBBM simulations revealed significantly impaired etoricoxib absorption post-surgery across all conditions; for instance, 79% lower Cmax and 53% decreased AUC was simulated post-gastric bypass procedure, after single 120 mg dose. Celecoxib and etodolac maintained unaffected absorption after bariatric surgery.This mechanistically-based analysis suggests to prefer the acidic drug etodolac or the neutral celecoxib as selective COX-2 inhibitors, over the basic drug etoricoxib, after bariatric surgery.

Antiallergic Treatment of Bariatric Patients: Potentially Hampered Solubility/Dissolution and Bioavailability of Loratadine, but Not Desloratadine, Post-Bariatric Surgery.

Gastrointestinal anatomical/physiological changes after bariatric surgery influence variables affecting the fate of drugs after ingestion, and medication management of these patients requires a thorough and complex mechanistic analysis. The aim of this research was to study whether loratadine/desloratadine antiallergic treatment of bariatric patients is at risk of being ineffective due to impaired solubility/dissolution. The pH-dependent solubility of loratadine/desloratadine was studied in vitro, as well as ex vivo, in gastric content aspirated from patients before versus after bariatric surgery. Then, a biorelevant dissolution method was developed to simulate the gastric conditions after sleeve gastrectomy (SG) or one-anastomosis gastric bypass (OAGB), accounting for key variables (intragastric volume, pH, and contractility), and the dissolution of loratadine/desloratadine was studied pre- versus post-surgery. Dissolution was also studied after tablet crushing or syrup ingestion, as these actions are recommended after bariatric surgery. Finally, these experimental data were implemented in a newly developed physiologically based pharmacokinetic (PBPK) model to simulate loratadine/desloratadine PK profiles pre- versus post-surgery. For both drugs, pH-dependent solubility was demonstrated, with decreased solubility at higher pH; over the pH range 1-7, loratadine solubility decreased ∼2000-fold, and desloratadine decreased ∼120-fold. Ex vivo solubility in aspirated human gastric fluid pre- versus post-surgery was in good agreement with these in vitro results and revealed that while desloratadine solubility still allows complete dissolution post-surgery, loratadine solubility post-surgery is much lower than the threshold required for the complete dissolution of the drug dose. Indeed, severely hampered loratadine dissolution was revealed, dropping from 100% pre-surgery to only 3 and 1% post-SG and post-OAGB, respectively. Tablet crushing did not increase loratadine dissolution in any post-bariatric condition, nor did loratadine syrup in post-OAGB (pH 7) media, while in post-laparoscopic SG conditions (pH 5), the syrup provided partial improvement of up to 40% dissolution. Desloratadine exhibited quick and complete dissolution across all pre-/post-surgery conditions. PBPK simulations revealed pronounced impaired absorption of loratadine post-surgery, with 84-88% decreased Cmax, 28-36% decreased Fa, and 24-31% decreased overall bioavailability, depending on the type of bariatric procedure. Desloratadine absorption remained unchanged post-surgery. We propose that desloratadine should be preferred over loratadine in bariatric patients, and as loratadine is an over-the-counter medication, antiallergic therapy after bariatric surgery requires special attention by patients and clinicians alike. This mechanistic approach that reveals potential post-surgery complexity, and at the same time provides adequate substitutions, may contribute to better pharmacotherapy and overall patient care after bariatric surgery.

Lamotrigine therapy in patients after bariatric surgery: Potentially hampered solubility and dissolution.

Bariatric surgery is an effective treatment of obesity and related comorbidities. With surgery, the stomach undergoes major anatomical/physiological changes that may affect the oral exposure of drugs, especially marginally soluble weak bases, such as lamotrigine. The aim of this work was to study the solubility/dissolution of lamotrigine in conditions simulating the stomach before vs. after bariatric surgery. Lamotrigine solubility was studied in-vitro, as well as ex-vivo in gastric content aspirated from patients before vs. after bariatric surgery. We then compared the dissolution kinetics of various marketed lamotrigine products in pre- vs. post-operative stomach conditions, different in volume, pH, agitation strength and speed. Decreased lamotrigine solubility with increasing pH (from 1.37 ± 0.09 (pH = 1) to 0.22 ± 0.03 mg/mL (pH = 7)) was obtained. Twelve-fold higher lamotrigine solubility was revealed in gastric content aspirated before vs. after surgery (8.5 ± 0.7 and 0.7 ± 0.01 mg/mL, respectively). Dissolution studies showed that only the lowest dose (25 mg) fully dissolved in the post-surgery stomach conditions, while at higher doses, lamotrigine tablet dissolution was impaired. Neither fast-dissolving tablet, nor tablet crushing, helped resolving this problem. Based on these results, and given that dissolution of the drug dose governs the subsequent absorption, close monitoring of this essential drug is advised after bariatric surgery.

The influence of choline treatment on behavioral and neurochemical autistic-like phenotype in Mthfr-deficient mice.

Imbalanced one carbon metabolism and aberrant autophagy is robustly reported in patients with autism. Polymorphism in the gene methylenetetrahydrofolate reductase (Mthfr), encoding for a key enzyme in this pathway is associated with an increased risk for autistic-spectrum-disorders (ASDs). Autistic-like core and associated behaviors have been described, with contribution of both maternal and offspring Mthfr+/- genotype to the different domains of behavior. Preconception and prenatal supplementation with methyl donor rich diet to human subjects and mice reduced the risk for developing autism and autistic-like behavior, respectively. Here we tested the potential of choline supplementation to Mthfr-deficient mice at young-adulthood to reduce behavioral and neurochemical changes reminiscent of autism characteristics. We show that offspring of Mthfr+/- mothers, whether wildtype or heterozygote, exhibit autistic-like behavior, altered brain p62 protein levels and LC3-II/LC3-I levels ratio, both, autophagy markers. Choline supplementation to adult offspring of Mthfr+/- mothers for 14 days counteracted characteristics related to repetitive behavior and anxiety both in males and in females and improved social behavior solely in male mice. Choline treatment also normalized deviant cortical levels of the autophagy markers measured in male mice. The results demonstrate that choline supplementation even at adulthood, not tested previously, to offspring of Mthfr-deficient mothers, attenuates the autistic-like phenotype. If this proof of concept is replicated it might promote translation of these results to treatment recommendation for children with ASDs bearing similar genetic/metabolic make-up.

Significance of the orexinergic system in modulating stress-related responses in an animal model of post-traumatic stress disorder.

Converging evidence indicates that orexins (ORXs), the regulatory neuropeptides, are implicated in anxiety- and depression-related behaviors via the modulation of neuroendocrine, serotonergic, and noradrenergic systems. This study evaluated the role of the orexinergic system in stress-associated physiological responses in a controlled prospective animal model. The pattern and time course of activation of hypothalamic ORX neurons in response to predator-scent stress (PSS) were examined using c-Fos as a marker for neuronal activity. The relationship between the behavioral response pattern 7 days post-exposure and expressions of ORXs was evaluated. We also investigated the effects of intracerebroventricular microinfusion of ORX-A or almorexant (ORX-A/B receptor antagonist) on behavioral responses 7 days following PSS exposure. Hypothalamic levels of ORX-A, neuropeptide Y (NPY), and brain-derived neurotrophic factor (BDNF) were assessed. Compared with rats whose behaviors were extremely disrupted (post-traumatic stress disorder [PTSD]-phenotype), those whose behaviors were minimally selectively disrupted displayed significantly upregulated ORX-A and ORX-B levels in the hypothalamic nuclei. Intracerebroventricular microinfusion of ORX-A before PSS reduced the prevalence of the PTSD phenotype compared with that of artificial cerebrospinal fluid or almorexant, and rats treated with almorexant displayed a higher prevalence of the PTSD phenotype than did untreated rats. Activated ORX neurons led to upregulated expressions of BDNF and NPY, which might provide an additional regulatory mechanism for the modulation of adaptive stress responses. The study indicates that the activated ORX system might promote adaptive responses to PSS probably via stimulation of BDNF and NPY secretion, and early intervention with ORX-A reduces the prevalence of the PTSD phenotype and increases the prevalence of adaptive phenotypes. The findings provide some insights into the mechanisms underlying the involvement of the ORX system in stress-related disorders.

Neuropeptide S in the basolateral amygdala mediates an adaptive behavioral stress response in a rat model of posttraumatic stress disorder by increasing the expression of BDNF and the neuropeptide YY1 receptor.

Neuropeptide S (NPS) is a regulatory peptide that has anxiolytic and arousal-promoting effects in rodents. We used an animal model of posttraumatic stress disorder (PTSD) to assess long-term behavioral effects of a single dose of NPS, microinjected into the basolateral amygdala (BLA) 1h following exposure to predator-scent stress (PSS). To elucidate the molecular mechanism by which NPS attenuates behavioral stress responses, expression levels of neuropeptide Y (NPY), NPY-Y1 receptor (NPY-Y1R), and brain-derived neurotrophic factor (BDNF) were evaluated in the hippocampus. The behavioral and molecular effects of NPS receptor antagonist (NPS-RA), NPY-Y1R antagonist (NPY-Y1RA), or both administered centrally were evaluated in the same manner. Circulating corticosterone levels were measured at different time points following PSS-exposure. Immediate post-exposure treatment with NPS had a marked protective effect; BLA microinfusion of NPS completely abolished the extreme behavioral response to PSS, restored the decreased expression of BDNF and, unexpectedly, PY-Y1R, but didn't affect the decreased expression of NPY. BLA microinfusion of both NPY-Y1RA and NPS-RA together had an additive effect, which completely prevented the anxiolytic effects of NPS in rats exposed to PSS and disrupted the expression of NPY-Y1R in the hippocampus following NPS infusion. It may therefore be hypothesized that NPS acts, directly or indirectly, on both the NPY-Y1R and NPS receptors and that the cross-talk between NPS and NPY-Y1R may be necessary for the anxiolytic effects of NPS post-exposure. The NPS system might thus contribute to a potential endogenous mechanism underlying the shift towards adaptive behavioral response and thereby might be relevant as a pharmacological target for attenuating stress-related sequelae.

Lymphocyte Phospho-Ser-9-GSK-3ß/Total GSK-3ß Protein Levels Ratio Is Not Affected by Chronic Lithium or Valproate Treatment in Euthymic Patients With Bipolar Disorder.

BACKGROUND: Glycogen synthase kinase-3 (GSK-3) inhibition by lithium has been well established in vitro, but proof that this biochemical effect mediates lithium's beneficial action in patients with bipolar disorder is lacking. We studied whether lymphocyte GSK-3ß activity measured indirectly in lithium- or valproate (VPA)-treated euthymic patients with bipolar disorder is different from controls. METHODS: Lymphocyte total and Ser-9-phospho-GSK-3ß (inactive) levels were measured by Western blotting. Forty-seven patients with bipolar disorder and 32 age- and sex-matched control subjects were studied. RESULTS: No significant differences were found between lithium- and VPA-treated patients and controls in phospho-GSK-3ß, total GSK-3ß, or their ratio. CONCLUSIONS: The data do not support the concept that in vivo, during chronic treatment of bipolar illness, GSK-3ß is inhibited either by lithium or by VPA.

Predator-scent stress, ethanol consumption and the opioid system in an animal model of PTSD.

Emerging literature points to stress exposure as a potential contributor to the development of alcohol abuse, but animal models have yielded inconsistent results. Converging experimental data indicate that the endogenous opioid system modulates alcohol consumption and stress regulation. The aim of the present study is to examine the interplay between stress exposure, behavioral stress responses, ethanol (EtOH) consumption and the endogenous opioid system in an animal model of posttraumatic stress disorder. Rats were exposed to stress and then tested in a two-bottle free choice (TBC) assay or in a conditioned place preference paradigm. In some experiments, the endogenous opioid system was pharmacologically manipulated prior to stress exposure. The behavioral outcomes of stress exposure were assessed in an elevated plus-maze, with the acoustic startle response, and by monitoring the freezing response to trauma reminder. Immunoreactivity of phosphorylated opioid receptors in hippocampal subregions was also measured. Stress significantly increased the consumption of EtOH in the TBC assay. The severity of the behavioral response to stress was associated with EtOH consumption, cue-triggered freezing response to a trauma reminder, and endogenous levels of phosphorylated opioid receptors in the hippocampus. Pharmacologically manipulating the endogenous opioid system prior to stress exposure attenuated trauma cue-triggered freezing responses and blocked predator scent stress-induced potentiation of EtOH consumption. These data demonstrate a stress-induced potentiation of EtOH self-administration and reveal a clear association between individual patterns of the behavioral response to stress and alcohol preference, while indicating a role for the endogenous opioid system in the neurobiological response to stress.

Beyond the HPA-axis: The role of the gonadal steroid hormone receptors in modulating stress-related responses in an animal model of PTSD.

The hypothalamic-pituitary-adrenal (HPA) axis, which plays a major role in the response to stress, and the hypothalamic-pituitary-gonadal (HPG) axis are closely linked with the ability to inhibit the other. Testosterone, a product of the HPG, has many beneficial effects beyond its functions as a sex hormone including anti-anxiety properties. In this study we examined the effect of stress exposure on gonadal hormones, and their efficacy in modulating anxiety-like response in an animal model of PTSD. Male rats were exposed to predator scent stress, followed by analysis of brain expression of androgen receptor (AR) receptor and estrogen receptor α (ERα). The behavioral effects of immediate treatment with testosterone, testosterone receptor antagonist (flutamide) or vehicle were evaluated using the elevated plus-maze, acoustic startle response and trauma-cue response. Levels of circulating corticosterone and testosterone were also measured after treatment. The behavioral effects of delayed testosterone treatment were explored in the same manner. We report that animals whose behavior was extremely disrupted (EBR) selectively displayed significant down-regulation of AR and ERα in the hippocampus. Immediate treatment with flutamide or delayed treatment with testosterone significantly increased prevalence rates of minimal behavioral response (MBR) and decreased prevalence of EBR with favorable behavioral results. Testosterone levels were higher in control un-exposed animals, while corticosterone was higher in control exposed animals. This study suggests that gonadal steroid hormones are involved in the neurobiological response to predator scent stress and thus warrant further study as a potential therapeutic avenue for the treatment of anxiety-related disorders.

Diurnal fluctuations in HPA and neuropeptide Y-ergic systems underlie differences in vulnerability to traumatic stress responses at different zeitgeber times.

The hypothalamic-pituitary-adrenal (HPA) axis displays a characteristic circadian pattern of corticosterone release, with higher levels at the onset of the active phase and lower levels at the onset of the inactive phase. As corticosterone levels modify the response to stress and influence the susceptibility to and/or severity of stress-related sequelae, we examined the effects of an acute psychological trauma applied at different zeitgeber times (ZTs) on behavioral stress responses. Rats were exposed to stress either at the onset of the inactive-(light) phase (ZT=0) or at the onset of the active-(dark) phase (ZT=12). Their behavior in the elevated plus-maze and acoustic startle response paradigms were assessed 7 days post exposure for retrospective classification into behavioral response groups. Serum corticosterone levels and the dexamethasone suppression test were used to assess the stress response and feedback inhibition of the HPA axis. Immunoreactivity for neuropeptide Y (NPY) and NPY-Y1 receptor (Y1R) in the paraventricular (PVN) and arcuate (ARC) hypothalamic nuclei, hippocampus, and basolateral amygdala were measured. The behavioral effects of NPY/Y1R antagonist microinfused into the PVN 30 min before stress exposure during the inactive or active phase, respectively, were evaluated. PVN immunoreactivity for NPY and Y1R was measured 1 day after the behavioral tests. The time of day of the traumatic exposure markedly affected the pattern of the behavioral stress response and the prevalence of rats showing an extreme behavioral response. Rats exposed to the stressor at the onset of their inactive phase displayed a more traumatic behavioral response, faster post-exposure corticosterone decay, and a more pronounced stress-induced decline in NPY and Y1R expression in the PVN and arcuate hypothalamic nuclei. Blocking PVN Y1R before stress applied in the active phase, or administering NPY to the PVN before stress applied in the inactive phase, had a resounding behavioral effect. The time at which stress occurred significantly affected the behavioral stress response. Diurnal variations in HPA and NPY/Y1R significantly affect the behavioral response, conferring more resilience at the onset of the active phase and more vulnerability at the onset of the inactive phase, implying that NPY has a significant role in conferring resilience to stress-related psychopathology.