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Serotonin reuptake inhibitor antidepressants such as fluoxetine are widely used to treat mood disorders. The mechanisms of action include an increase in extracellular level of serotonin, neurogenesis, and growth of vessels in the brain. We investigated whether fluoxetine could have broader peripheral regenerative properties. Following prolonged administration of fluoxetine in male mice, we showed that fluoxetine increases the number of muscle stem cells and muscle angiogenesis, associated with positive changes in skeletal muscle function. Fluoxetine also improved skeletal muscle regeneration after single and multiples injuries with an increased muscle stem cells pool and vessel density associated with reduced fibrotic lesions and inflammation. Mice devoid of peripheral serotonin treated with fluoxetine did not exhibit beneficial effects during muscle regeneration. Specifically, pharmacological, and genetic inactivation of the 5-HT1B subtype serotonin receptor also abolished the enhanced regenerative process induced by fluoxetine. We highlight here a regenerative property of serotonin on skeletal muscle., (© 2024. The Author(s).)

Insulin-like growth factor-I (IGF-I) and its analogs LongR 3 -IGF-I, Des(1-3)-IGF-I, and R 3 -IGF-I are prohibited substances in sport. Although they were never approved for use in humans, they are readily available as black market products for bodybuilding and can be used to enhance physical performance. This study's aims were to validate a fast and sensitive detection method for IGF-I analogs and to evaluate their detectability after intramuscular administration in rats. The sample preparation consisted of an immunopurification on MSIA™ microcolumns using a polyclonal anti-human-IGF-I antibody. The target substances were then directly analyzed by nano-liquid chromatography coupled with high-resolution mass spectrometry. Abundant signs of lower quality, oxidized peptide forms were found in black market products, justifying the need to monitor at least both the native and mono-oxidized forms. The analytical performance of this method (linearity, carry over, detection limits, precision, specificity, recovery, and matrix effect) was studied by spiking the analogs into human serum. Following a single intramuscular administration (100 μg/kg) in rats, detection was evaluated up to 36 h after injection. While unchanged Des(1-3)-IGF-I and R 3 -IGF-I were detected until 24 h after administration, LongR 3 -IGF-I disappeared rapidly after 4 h. Des(1)-LongR 3 -IGF-I, a new N-terminal Long-R 3 -IGF-I degradation product, was detected in addition to Des(1-10)-LongR 3 -IGF-I and Des(1-11)-LongR 3- IGF-I: the latter was detected up to 16 h. The same products were found after in vitro incubation of the analogs in human whole blood, suggesting that observations in rats may be extrapolated to humans and that the validated method may be applicable to antidoping testing., (© 2021 John Wiley & Sons, Ltd.)

Background : Community pharmacists are among the frontline health professionals who manage patients with an opioid-related disorder (ORD). Pharmacists frequently have a negative attitude toward these patients, which could have a negative impact on their management. However, education on ORD may improve the attitude of future healthcare professionals. This cross-sectional study aimed to assess French pharmacy students' perceptions of ORD. Methods : This online survey was performed by emails sent to French pharmacy schools (between January 14, 2019 and May 31, 2019). The primary outcome was the perception (visual analogic scale) of ORD as a disease, the roles of community pharmacies (delivery of opioid agonist therapy-OAT and harm reduction kits), and the efficacy of OAT. The secondary outcomes assessed professional experience, university experience of and education on ORD, and the individual characteristics of students. Results : Among the 1,994 students included, 76.3% perceived ORD as a disease and felt that it was normal for pharmacists to deliver OAT (78.9%) and harm reduction kits (74.6%). However, only 46.9% perceived OAT as being effective. Multivariable analyses showed that females had a more positive perception in recognizing ORD as a disease. The progression through university years increased the positive perception of ORD as a disease and the delivery of OAT and harm reduction kits by pharmacists. Education on substance-related disorders had no impact on any scores. Students who had already delivered OAT had a negative perception of their efficacy. The students who had already performed pharmacy jobs or traineeships had a negative perception of harm reduction kit delivery. Conclusion : Education on substance-related disorders had no impact on students' perceptions. It seemed that the maturity acquired through university years had a stronger impact on the students' perceptions of ORD. Efforts must be made to improve our teaching methods and reinforce the confidence of students in the roles of community pharmacists.

Background:  IGF-I is used as a biomarker to detect Growth Hormone doping in athletes' blood samples. Objective: Our aim was to develop and validate a fast, high-throughput and accurate quantification of intact IGF-I from volumetric absorptive microsampling (VAMS) dried blood using LC coupled to high resolution mass spectrometry (LC-HRMS). Methodology & results: IGF-I was extracted from the VAMS, released from its binding proteins, concentrated using microelution SPE and analyzed by LC-HRMS. The method was successfully validated in accordance with the World Anti-Doping Agency's requirements. Subsequently, IGF-I measurements from capillary dried blood and serum were compared. Conclusion: The combination of VAMS, microelution SPE and LC-HRMS is a promising strategy applicable to IGF-I quantification in athletes' samples.

Temocillin is a β-lactamase-resistant penicillin used for the treatment of multiple drug-resistant Gram-negative bacteria. To maximize efficacy and avoid adverse effects, the dose regimen has to be quickly adjusted to the clinical situations. This necessitates the development of a rapid, reliable and accurate analytical method. Temocillin and the stable isotopically labeled internal standard ([ 13 C 6 ]-amoxicillin) were extracted from either serum or cerebrospinal fluid by a turbulent flow liquid chromatographic method and eluted onto an octadecyl-silica phase with polar endcapping. Mass spectrometry was conducted using an exact mass determination method by electrospray positive ionization high-resolution mass spectrometry. The LLOQ and ULOQ of the present method were determined to be 0.4 and 200 μg/ml for serum and cerebrospinal fluid samples, respectively. The total analysis time was <7 min. The recovery ranged from 87.7 to 120.8%. Intra- and inter-day precision and trueness were tested at four concentration levels: 0.4, 8, 40 and 160 μg/ml. Values were 6.33 ± 1.53, 8.8 ± 1.3, 8.8 ± 0.36 and 2.1 ± 0.76%, and 5.0 ± 0.54, 9.9 ± 1.0, 5.8 ± 1.6 and 0.1 ± 1.1%, for inter- and intra-day analysis, respectively. Temocillin was found to be stable under all relevant laboratory conditions. The method was cross-validated with a microbiological assay. This method is suitable for accurate measurement of temocillin concentration in small volumes of serum or cerebrospinal fluid. Thanks to the online extraction procedure, the overall analytical time is compatible with high-throughput analysis for clinical application., (© 2019 John Wiley & Sons, Ltd.)

Purpose: Oxaliplatin is a platinum compound widely used in gastrointestinal cancer treatment but produces dose-limiting peripheral neuropathy. New insights into oxaliplatin-induced peripheral neuropathy (OIPN) assessment are needed to detect more effectively this condition. In this context, we conducted Canaloxa study, a prospective preliminary clinical trial that aimed to investigate how Electrochemical Skin Conductance (ESC), a parameter used in small fiber neuropathy assessment, could be helpful in OIPN diagnosis., Methods: Cancer patients treated for at least three months with oxaliplatin and suffering from clinically OIPN were included. Electrochemical Skin Conductance, thermal thresholds, and neuropathic pain were assessed in all included patients., Results: During one year, 36 patients were included. The main result was the correlation between ESC and Neuropathic Pain Symptom Inventory score for hands (rho value = -0.69, p < 0.0001) and feet (rho value = -0.79, p < 0.0001). ESC values were lower in neuropathic patients with painful symptoms than in ones without painful symptoms ( p = 0.0003 and p < 0.0001 for hands and feet, respectively). No correlation was observed between ESC and thermal thresholds., Conclusion: These preliminary data suggest that ESC could be a useful objective marker of painful oxaliplatin-induced neuropathy and could complement the use of subjective clinical scales. This study was prospectively registered on clinicaltrials.gov (NCT02827916) before patient recruitment has begun .

Purpose: To better understand how quantitative sensory testing could help the clinician in the management of oxaliplatin-induced peripheral neuropathy in terms of earlier and more reliable detection, we conducted a two-year prospective study., Methods: Thermal sensory assessment, tactile sensory assessment, neuropathic pain assessment and adverse events gradation (NCI-CTC) were performed during treatment and 6 months after treatment completion., Results: 35 patients were enrolled and followed-up during one year. Cold and Warm Detection Thresholds were higher 6 months after treatment completion than at enrollment. Mechanical detection thresholds didn't change significantly. Neurotoxicity was mostly grade-1, only 18% grade-2 and no grade-3. Grade-2 patients received lower oxaliplatin cumulative dose than grade-1, which reveals effective dose adaptation and grade-2 patients were more likely to develop painful neuropathy., Conclusion: Thermal thresholds impairment emerges too late to help the clinician in the prophylaxis of neuropathy. Management of OXA-treatment based on NCI-CTC, as currently recommended, remains the best way to detect neuropathy and ensure treatment adaptation., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Purpose: Oxaliplatin is a platinum derivate widely used in cancer treatment but producing dose-limiting peripheral neurotoxicity. Acute neuropathy is characterized by a transient cold-induced distal allodynia, whereas chronic neuropathy leads to sensory loss. To design a method for quantitative assessment of oxaliplatin-induced peripheral neuropathy, we developed a study that aims to characterize the most appropriate skin area of the hand to perform sensory tests., Methods: We included patients treated for at least 6 months with oxaliplatin. Thermal sensory tests are assessed using the Thermotest (Somedic) and consist in measuring thermal thresholds in the thenar and in the fingertips of the opposite hand. Results are analyzed using T-Tests comparing thermal sensory thresholds between the two areas of the hand, globally and then individually., Results: In 7 weeks, 12 patients (7 men and 5 women; mean age: 64.5 years) were included, all treated with FOLFOX protocol. Thermal detection thresholds measured on the fingertips are 146% and 108% greater than the ones measured on the palm for cold and warm, respectively (P < 0.0001). Thermal pain thresholds are difficult to interpret. Regarding individual tests, 9/12 patients and 8/12 patients experienced hypesthesia to cold and warm, respectively., Conclusions: These results reveal that distal hypesthesia occurring under treatment with oxaliplatin is markedly pronounced in the fingertips; however, as thermal threshold is unknown before treatment, it is difficult to assert that fingertip thermal hypesthesia has developed under treatment. Finally, this short study may be useful to design a method for quantifying oxaliplatin-induced neuropathy.

Objectives: We assessed the influence of medication adherence on blood pressure (BP) control and target organ damage in a pre-specified analysis of a published trial comparing sequential nephron blockade (SNB) or sequential renin-angiotensin system blockade (SRASB) in patients with resistant hypertension., Methods: Patients were randomized to SNB (n = 82) or SRASB (n = 82) and studied at baseline and after 12 weeks. BP was measured by ambulatory blood pressure monitoring. Carotid-femoral pulse wave velocity (PWV) was measured by applanation tonometry and left ventricular mass (LVM) by echocardiography. Low medication adherence was assessed through plasma irbesartan concentration below 20 ng/ml; urinary N-acetyl-seryl-aspartyl-lysyl-proline/creatinine ratio below 4  nmol/mmol; last medication intake before visit greater than 24 h and pill counting below 80% of theoretical intake. Medication adherence score (sum of items, max = 4) is defined as low (medication adherence score <2) or acceptable (medication adherence score ≥2)., Results: Among 164 patients, 134 (81.7%) had acceptable medication adherence and 30 (18.3%) low medication adherence, with similar proportions in the SNB and SRASB arms. After 12 weeks, in patients with acceptable medication adherence, BP was more frequently controlled in those treated with SNB (64%), than SRASB (18%; P < 0.001). The difference in daytime SBP was -11.5  mmHg [95% confidence interval (CI) -15.4 to -7.5, P < 0.0001] in patients with acceptable medication adherence. In contrast, in patients with low medication adherence, the difference between groups was smaller and not significant (-9.4  mmHg, 95% CI -20.4 to 1.7, P = 0.09). Independently of BP changes, PWV and LVM decreased more in the SNB than in the SRASB arm when medication adherence was acceptable (-0.52 m/s, 95% CI -1.3 to -0.007, P = 0.047; and -24 g/m, 95% CI -36 to -12, P = 0.0003), whereas no significant changes were observed in low medication adherence patients., Conclusion: Medication adherence contributes to BP-lowering and regression of target organ damage. The differential effects of SNB and SRASB is observed in patients with acceptable medication adherence, and not in patients with low medication adherence.

Background: Chronic neuropathic pain can lead to anxiety and depression. Drugs that block reuptake of serotonin, norepinephrine and/or dopamine are widely used to treat depression, and have emerged as useful drugs in the treatment of neuropathic pain. This study compared the acute antinociceptive effects of NS18283, a novel triple monoamine reuptake inhibitor (MRI) with indatraline, venlafaxine and escitalopram in a mouse model of neuropathic pain., Method: Neuropathic pain-like behaviours were induced in mice by repeated injections of oxaliplatin (OXA), and assessed using the von Frey hair test, the cold plate test and the thermal preference plate test. Anxio/depressive phenotype and antidepressant-like properties of compounds were assessed by the novelty suppressed feeding test and the tail suspension test, respectively., Results: In vivo microdialysis experiments showed that each MRI increased extracellular serotonin, norepinephrine and/or dopamine levels in the cingulate cortex, in agreement with their in vitro reuptake inhibitory properties. Indatraline (3 mg/kg) reversed the full repertoire of OXA-induced neuropathic hypersensitivity. NS18283 (10 mg/kg) reversed OXA-induced mechano-hypersensitivity and cold allodynia. Venlafaxine (16 mg/kg) and escitalopram (4 mg/kg) only reversed cold allodynia and mechano-hypersensitivity, respectively. All MRIs produced antidepressant-like activity in anxio/depressive phenotype of OXA mice., Conclusions: Acute administration of drugs that enhance the activity of serotonin, norepinephrine and dopamine neurotransmission within nociceptive pathways may provide a broader spectrum of antinociception than dual or selective reuptake inhibitors in animal models of neuropathic pain. Whether similar observations would occur after repeated administration of such compounds in an attempt to simulate dosing in humans, or be compromised by dopaminergic-mediated adverse effects warrants further investigation., (© 2014 European Pain Federation - EFIC®)

Limited information is available regarding the cellular mechanisms of oxaliplatin-induced painful neuropathy during exposure of patients to this drug. We therefore determined oxidative stress in cultured cells and evaluated its occurrence in C57BL/6 mice. Using both cultured neuroblastoma (SH-SY5Y) and macrophage (RAW 264.7) cell lines and also brain tissues of oxaliplatin-treated mice, we investigated whether oxaliplatin (OXA) induces oxidative stress and apoptosis. Cultured cells were treated with 2-200 µM OXA for 24 h. The effects of pharmacological inhibitors of oxidative stress or inflammation (N-acetyl cysteine, ibuprofen, acetaminophen) were also tested. Inhibitors were added 30 min before OXA treatment and then in combination with OXA for 24 h. In SH-SY5Y cells, OXA caused a significant dose-dependent decrease in viability, a large increase in ROS and NO production, lipid peroxidation and mitochondrial impairment as assessed by a drop in mitochondrial membrane potential, which are deleterious for the cell. An increase in levels of negatively charged phospholipids such as cardiolipin but also phosphatidylserine and phosphatidylinositol, was also observed. Additionally, OXA caused concentration-dependent P2X7 receptor activation, increased chromatin condensation and caspase-3 activation associated with TNF-α and IL-6 release. The majority of these toxic effects were equally observed in Raw 264.7 which also presented high levels of PGE2. Pretreatment of SH-SY5Y cells with pharmacological inhibitors significantly reduced or blocked all the neurotoxic OXA effects. In OXA-treated mice (28 mg/kg cumulated dose) significant cold hyperalgesia and oxidative stress in the tested brain areas were shown. Our study suggests that targeting P2X7 receptor activation and mitochondrial impairment might be a potential therapeutic strategy against OXA-induced neuropathic pain.

A simple, rapid, sensitive and specific ultra-high-performance liquid chromatography-tandem mass spectrometry method (Waters UPLC-MS-MS) is developed and validated for the quantification of uracil (U) and 5,6-dihydrouracil (UH2) levels in human plasma. Analytes are extracted using ethyl acetate and isopropanol after deproteination, and separated by high-performance liquid chromatography (HPLC) (Acquity UPLC BEH C18 column) in a binary mobile phase system under gradient elution conditions at a flow rate of 0.4 mL/min. 5-Bromo-uracil (UBr) is used as the internal standard. The detection is performed on a triple-quadrupole mass spectrometer via electrospray positive ionization. Multiple reaction monitoring mode using the transitions m/z 112.82 → 70.05, m/z 114.88 → 55.04 and m/z 190.83 → 117.86 is used to quantify U, UH2 and UBr, respectively. The method is linear in the concentration range of 0.625-160.0 ng/mL. The total run time is 4.5 min per injection. Nine-point calibration curve and four-points quality controls are used. Excellent linearity and precision are observed with correlation coefficient (r(2)) > 0.9999. The intra-batch and inter-batch precisions are ≤ 7.3% and ≤ 8.6%, and accuracy is ≤ 17%. The developed method is shown to be suitable for routine quantitative determination of U, UH2 and 5,6-dihydrouracil-to-uracil ratio in clinical practice.

Pain was reported by 60-90% of patients with depression, and chronic pain states are often linked to depression. Animal models of pain/depression are generally lacking for the identification of centrally active drugs. In the present study, pain sensitivity was assessed in a mouse model of anxiety/depression on the basis of chronic corticosterone (CORT) administration through the drinking water (CORT model). We measured thermal hyperalgesia as shown by a decrease in the latency to hind paw licking in the hot plate test and cold allodynia reflected by a decrease in the time spent on the plate set at 20°C in the thermal preference plate test. Subsequently, we determined the effect of chronic administration of the selective serotonin reuptake inhibitor fluoxetine (an antidepressant known to reverse anxiety/depressive-like state in CORT-treated mice) on pain relief. Fluoxetine administration reduced both heat hyperalgesia and cold allodynia, thus unveiling a putative link between mood and nociception in the CORT model. This hypothesis is consistent with previous clinical studies reporting the analgesic efficacy of fluoxetine in depressed patients suffering from pain disorders. Together, these results suggest that the CORT model, with pain/anxiety/depressive-like state, is a good candidate for translational research.

Selective serotonin reuptake inhibitors are widely prescribed drugs without recognized cardiovascular risk. We report the case of a 54-year-old patient who developed QTc interval prolongation, followed by ventricular fibrillation episodes, 10 hours after admission to the ICU, in the setting of a citalopram overdose. Citalopram plasma values dropped from 5.88 to 0.34 mg/L at 9 days postadmission. The patient was treated by oral activated charcoal, and final outcome was favorable.

Pain from anticancer drugs-induced neuropathies is difficult to treat and can significantly alter the patient's quality of life. These neuropathies are considered relatively resistant to conventional analgesic drugs (opioids). Opioids are also P-glycoprotein substrates and it has been demonstrated that the P-glycoprotein is linked to the integrity of blood-brain barrier protecting the nervous system. Previous works presented an increase of P-glycoprotein in vincristine- and cisplatin-induced neuropathy which could potentially decrease opioid efficiency. To test this hypothesis, the efflux inhibition of P-glycoprotein and the antinociceptive effect of morphine were assessed in normal and cisplatin-induced neuropathic rats after the administration of the P-glycoprotein inhibitor (R101933). R101933 (20 mg/kg) inhibited significantly the efflux transporter under the condition of the study and had no analgesic effect. Nociceptive thresholds were measured by the paw pressure test. R101933 (20 mg/kg) enhanced antinociceptive activity of morphine (0.5 mg/kg) to a maximum of +58% and +35%, respectively compared with control animals and animals treated by morphine alone (0.5 mg/kg). R101933 increased morphine (2 mg/kg) antinociceptive activity to a maximum of +105% compared with control animals and to a maximum of +41% compared with morphine alone (2 mg/kg). This study demonstrated that cisplatin-induced neuropathy may present a particular pathophysiology with a multidrug resistance, of the central nervous system, to analgesics. This resistance can be blocked by a P-glycoprotein inhibitor which may enhance analgesia of low doses of morphine.

Prostaglandin F(2alpha) (PGF(2alpha)), represses ovarian steroidogenesis and initiates parturition in mammals but its impact on adrenal gland is unknown. Prostaglandins biosynthesis depends on the sequential action of upstream cyclooxygenases (COX) and terminal synthases but no PGF(2alpha) synthases (PGFS) were functionally identified in mammalian cells. In vitro, the most efficient mammalian PGFS belong to aldo-keto reductase 1B (AKR1B) family. The adrenal gland is a major site of AKR1B expression in both human (AKR1B1) and mouse (AKR1B3, AKR1B7). Thus, we examined the PGF(2alpha) biosynthetic pathway and its functional impact on both cortical and medullary zones. Both compartments produced PGF(2alpha) but expressed different biosynthetic isozymes. In chromaffin cells, PGF(2alpha) secretion appeared constitutive and correlated to continuous expression of COX1 and AKR1B3. In steroidogenic cells, PGF(2alpha) secretion was stimulated by adrenocorticotropic hormone (ACTH) and correlated to ACTH-responsiveness of both COX2 and AKR1B7/B1. The pivotal role of AKR1B7 in ACTH-induced PGF(2alpha) release and functional coupling with COX2 was demonstrated using over- and down-expression in cell lines. PGF(2alpha) receptor was only detected in chromaffin cells, making medulla the primary target of PGF(2alpha) action. By comparing PGF(2alpha)-responsiveness of isolated cells and whole adrenal cultures, we demonstrated that PGF(2alpha) repressed glucocorticoid secretion by an indirect mechanism involving a decrease in catecholamine release which in turn decreased adrenal steroidogenesis. PGF(2alpha) may be regarded as a negative autocrine/paracrine regulator within a novel intra-adrenal feedback loop. The coordinated cell-specific regulation of COX2 and AKR1B7 ensures the generation of this stress-induced corticostatic signal.

Among the multiple possibilities to study human depressive disorders, animal models remain important preclinical tools. They allow the understanding of the mechanisms of action of antidepressant drugs. Primarily developed in rat, animal models of depression have been adapted to the mouse, an easy-to-use mammal with better genetic possibilities than rats. As an example, genetic manipulation of the serotoninergic 5-hydroxytryptamine-HT; (5-HT) system provided important opportunities to investigate the role of this monoamine in mood disorders. The contribution of either constitutive knockout (KO), tissue specific, or inducible KO mice and animal models in the current knowledge of the pathophysiology and treatment of depression is unanimously recognized. The phenotype of genetically manipulated animals is strongly influenced by both the genetic background of the animal as well as environmental factors. For these reasons, it is necessary to underline that KO mice have been generated on various genetic backgrounds, which strongly influence the behavioral and neurochemical responses to the tests. The present review will thus focus on KO mice lacking G protein-coupled monoaminergic receptors (e.g; 5-HT1B, 5-HT1A, and 5-HT4 receptors) and the 5-HT serotonin transporter, which is the main target of antidepressant drugs (or strategies). The importance of KO mice for neurotrophic factors, particularly for brain-derived neurotrophic factor and its main receptor displaying a tyrosine kinase activity, will also be addressed to illustrate the fact that in preclinical studies, combination of genetic manipulations with pharmacological ones should allow further progress in the field of neuropsychopharmacology.

Antidepressants such as Selective Serotonin Reuptake Inhibitors (SSRI) act as indirect agonists of serotonin (5-HT) receptors. Although these drugs produce a rapid blockade of serotonin transporters (SERTs) in vitro, several weeks of treatment are necessary to observe clinical benefits. This paradox has not been solved yet. Recent studies have identified modifications of intracellular signaling proteins and target genes that could contribute to antidepressant-like activity of SSRI (e.g., increases in neurogenesis and BDNF protein levels), and may explain, at least in part, their long delay of action. Although these data suggest a positive regulation of 5-HT on the expression of the gene coding for BDNF, the reciprocal effects of BDNF on brain 5-HT neurotransmission remains poorly documented. To study the impact of BDNF on serotonergic activity, a dual experimental strategy was used to analyze neurochemical and behavioral consequences of its decrease (strategy 1) or increase (strategy 2) in the brain of adult male mice. (1) In heterozygous BDNF+/- mice in which brain BDNF protein levels were decreased by half, an enhancement of basal extracellular 5-HT levels (5-HText) that induced a down-regulation of SERT, i.e., a decrease in its capacity to reuptake 5-HT, was found in the hippocampus. In addition, the SSRI, paroxetine, failed to increase hippocampal 5-HText in BDNF+/- mice, while it produces robust effects in wild-type littermates. Thus, BDNF+/- mice can be viewed as an animal model of genetic resistance to serotonergic antidepressant drugs. (2) In wild-type BDNF+/+ mice, the effects of intra-hippocampal (vHi) injection of BDNF (100 ng) in combination with a SSRI was examined by using intracerebral microdialysis and behavioral paradigms that predict an antidepressant- and anxiolytic-like activity of a molecule [the forced swim test (FST) and the open field paradigm (OF) respectively]. BDNF induced a rapid and transient increase in paroxetine response on 5-HText in the adult hippocampus, which was correlated with a potentiation of its antidepressant-like activity in the FST. The effects of BDNF were selectively blocked by K252a, an antagonist of its high-affinity TrkB receptor. Such a correlation between neurochemical and behavioral effects of [BDNF+SSRI] co-administration suggests that its antidepressant-like activity is linked to the activation of 5-HT neurotransmission in the adult hippocampus. BDNF also had a facilitatory effect on anxiety-like behavior in the OF test, and paroxetine prevented this anxiogenesis. What was the mechanism by which BDNF exerted these latter effects? Surprisingly, by using zero net flux method of quantitative microdialysis in vivo, we found that an intra-hippocampal BDNF injection in wild-type mice decreased the functional activity of SERT as observed in BDNF+/- mice. However, the decreased capacity of SERT to reuptake 5-HT was not associated to an increase in basal 5-HText in the hippocampus of WT mice. Interestingly, using in situ hybridization experiments indicated that TrkB receptor mRNA was expressed in the hippocampus and dorsal raphe nucleus in adult mice suggesting that the neurochemical and behavioral effects of intra-hippocampal BDNF injection can mobilize both pre- and post-synaptic elements of the brain 5-HT neurotransmission. Taken together, these set of experiments unveiled a relative opposition of neurochemical and behavioral responses following either a decrease (in BDNF+/- mutant mice) or an increase in brain BDNF levels (bilateral intra-hippocampal injection) in adult mice. In view of developing new antidepressant drug strategy, a poly-therapy combining BDNF with a chronic SSRI treatment could thus improve the efficacy of current medications.

Introduction: The clinical signs of acute trichlorethylene overdose are commonly coma, cardiac conduction disturbances, diarrhea, and vomiting. We report a case of intentional massive trichlorethylene ingestion inducing a fatal abdominal compartment syndrome (ACS)., Case Report: A 47-year-old woman was admitted to the emergency department after intentionally ingesting 500 mL of trichlorethylene and benzodiazepines. She rapidly developed coma and abdominal distension leading to multiple organ failure. Subsequent surgical evaluation revealed abdominal perforation and necrosis, and life-sustaining treatments were therefore withdrawn., Discussion: This is a primary ACS that can be explained from experimental data on the pathophysiology of pneumatosis cystoides coli. For this case, we discuss multiple etiological factors for intra-abdominal hypertension (IAP), such as paralytic ileus and massive fluid resuscitation due to the direct toxicity of ingested trichlorethylene., Conclusion: Patients ingesting trichlorethylene need to be closely evaluated for risk of digestive damage and perforation. Early prompt laparotomy must be performed in cases of ACS.

A single infusion of oxaliplatin, a drug active against colorectal cancer, induces specific painful syndrome characterized by neurosensitive symptoms triggered or aggravated in cold conditions. In an animal model that reproduces such hypersensitivity to cold for five days after a single oxaliplatin administration (6mg/kg, i.p.), we assessed the antinociceptive efficacy of intravenously administered drugs such as morphine, lidocaine and pregabalin using the rat tail immersion test in cold water (10 degrees C). The antinociceptive efficacy was first ranked by ratio of the pharmacological effect (versus time) to dose: pregabalin (2mg/kg)>lidocaine (3mg/kg)>morphine (4mg/kg). Our results show that pregabalin may be a good choice to treat cold hypersensitivity after one oxaliplatin injection.

In vivo intracerebral microdialysis is an important neurochemical technique that has been applied extensively in genetic and pharmacological studies aimed at investigating the relationship between neurotransmitters. Among the main interests of microdialysis application is the infusion of drugs through the microdialysis probe (reverse dialysis) in awake, freely moving animals. As an example of the relevance of intracerebral microdialysis, this review will focus on our recent neurochemical results showing the impact of Brain-Derived Neurotrophic Factor (BDNF) on serotonergic neurotransmission in basal and stimulated conditions. Indeed, although the elevation of 5-HT outflow induced by chronic administration of selective serotonin reuptake inhibitors (SSRIs) causes an increase in BDNF protein levels and expression (mRNA) in the hippocampus of rodents, the reciprocal interaction has not been demonstrated yet. Thus, the neurochemical sight of this question will be addressed here by examining the consequences of either a constitutive decrease or increase in brain BDNF protein levels on hippocampal extracellular levels of 5-HT in conscious mice.

The objective of this study was to measure the plasma cotinine levels in pregnant women and their newborns using a gas chromatography-mass spectrometry (GC-MS) method in an epidemiological-delivered population with a wide range of tobacco intakes. Nearly 1000 pregnant women from regional maternity wards (n=1007) were selected for the study. Each patient kept a tobacco diary and underwent a blood test to assess cotinine levels and at the same time that the newborns' cordonal plasma was taken. These values were then cross-checked. Cotinine was estimated using a selected-ion monitoring mode with a 1.5 ng/ml quantification limit. The cotinine levels in mothers and newborns were highly correlated, whatever the mother's smoking status, with a calculated cut-off for cotinine levels in active smokers of 21.5 ng/ml. Finally, the cotinine determined through this GC-MS method offered a sensitive and accurate measure of tobacco exposition of the pregnant women and their babies.

In clinical use, a single infusion of oxaliplatin, widely used to treat metastatic colorectal cancer, induces specific sensory neurotoxicity signs triggered or aggravated by exposure to cold. To study the pathophysiology of these symptoms, we developed and characterized an animal model that reproduces the effects of a single intraperitoneal oxaliplatin administration (3, 6 and 12 mg/kg). Significant allodynia and hyperalgesia to cold stimuli were rapidly observed from 24 h to day 5 with a maximum lowering of 76% at t+30 h versus control. Other behavioral assessments revealed rapid persistent mechanical allodynia, but no thermal hyperalgesia or allodynia to heat and no hyperalgesia to mechanical stimuli. An immunohistochemical study in the superficial layers of the spinal dorsal horn revealed a marked increase in substance P immunoreactivity versus controls (12% versus 4%), whereas calcitonin gene-related peptide (CGRP) immunoreactivity was unchanged. This new animal model for the first time closely mimics the effects observed in humans after a single oxaliplatin infusion, especially onset and highly intense sensory disturbances, hypersensitivity to cold with allodynia and hyperalgesia signs. This model may help to elucidate the mechanisms of this thermal hypersensitivity, especially the possible involvement of small-diameter A-fibers in cold allodynia symptoms. These selective effects may clue up the mechanistic basis for the acute oxaliplatin neuropathy leading to a better understanding of the clinical condition and to optimize its treatment.

The combined use of an automatic solid-phase extraction (SPE) apparatus with Oasis MCX cartridges and gas chromatography/mass spectrometry (GC/MS) to rapidly quantify quinine in biological samples with cyproheptadine as the internal standard is described. The selected ion monitoring mode, with the quantification ions m/z 136 and 287 (qualifier ions: m/z 261, 381 and 215, 96), allows the estimation of quinine levels, respectively. Separation was completed within 12.7 min. Excellent linearity was found up to 10 000 microg/L of plasma. The limit of detection (LOD) was 12.2 microg/L and the limit of quantification (LOQ) was 40.6 microg/L. High reproducibility (intra-assay CV range 1.9-4.3%, inter-assay CV range 2.2-11.3%) and accuracy values (intra-assay range 83.2-103.7%, inter-assay range 86.8-103.7%) were obtained. Recoveries were concentration-independent (97.2% and 89.8% for 4000 and 10 000 microg/L, respectively). This sensitive, simple assay for quinine in various matrices meets the current requirements for bioanalytical assays and may be used to monitor quinine levels in patients developing severe malaria with acute renal failure during hemofiltration. The optimal quinine dose in this situation is not really established and to improve clinical care, quinine concentrations might be explored to improve efficacy and minimise potential toxicity., (Copyright (c) 2006 John Wiley & Sons, Ltd.)

A method was developed and validated for the analysis of R(-)-apomorphine, (R-)-apocodeine and R(-)-norapomorphine in human plasma and urine with N-propylnorapomorphine as internal standard using gas chromatography/mass spectrometry (GC/MS) and single-ion monitoring after a single liquid-liquid extraction and silylation of compounds. The quantification limits were 1 ng/ml for apomorphine and apocodeine and 25 ng/ml for norapomorphine. Calibration curves were linear, within the range 1-100 ng/ml. Variation in intraday and interday precision was below 10%. This method was applied to study apomorphine bioavailability in nine patients with Parkinson's disease before and after coadministration of a catechol-O-methyl transferase inhibitor.

To quantify gamma-hydroxybutyrate (GHB) and its physiological metabolites, gamma-aminobutyric acid (GABA), 1,4-butanediol (1,4-BD), and gamma-butyrolactone (GBL) in various animal tissues (kidney, muscle, heart, liver, blood, brain cortex, thalamus, hypothalamus, hippocampus, or pons), an original gas chromatographic/mass spectrometric method with a automated solid-phase extraction by Oasis MCX cartridges on a Gilson Aspec Xli was developed. Using such apparatus allowed the limit of detection (LOD) of target compounds to be significantly lowered (LOD: 0.027, 0.025, and 5.7 microg/mL for GHB, 1,4-BD, and GABA, respectively, in 200 microL or microg of sample). After validation of each analytical step, the satisfactory performances of the apparatus in conjunction with the rapidity and ease of the extraction step make it suitable for simultaneous assay of GHB, 1,4-BD, GBL, and GABA. The method was used to test the correlation between GHB levels in tissues obtained at different times after death of male Sprague-Dawley rats and the postmortem interval. Preliminary results show a linear increase of GHB levels in relation to time of death in thoracic blood and central nervous system of animals kept at 15 and 20 degrees C.

The possibility that chronicle oral ingestion of fluoride-rich water could modify peripheral pain sensitivity was studied in two strains of adult rats, Sprague-Dawley and Lou/C rats. Sodium fluoride was given orally in water to male Sprague-Dawley (75 and 150 ppm) and Lou rats (150 ppm) for 15 and 27 weeks, respectively. Using classical behavioural evaluation methods of pain symptoms, only slight tendencies to a thermal hyperalgia and a mechanical allodynia were observed in Sprague-Dawley rats.

Dimethylsulfoxide (DMSO) is a solvent used to dissolve hydrophobic drugs. Recent studies have demonstrated that repeated administration of DMSO induces significant disorders of the peripheral nervous system. To address this issue, we have studied the behavioural effects of repeated intraperitoneal injections of various concentrations of DMSO (1.8-3.6-7.2%) in male Sprague-Dawley rats. Behavioural effects were assessed with a commonly used battery of sensory and motor tests. The motor tests used were actimeter and grip strength test. Sensory test used noxious and non-noxious mechanical (paw pressure test and von Frey hairs test) and thermal (plantar test and tail immersion test) stimuli. Clinical status of the animals was good throughout the experiment and no motor deficits were observed. Nevertheless, sensory assessment displayed a mechanical allodynia of short duration.

This work describes the behavioural responses of Sprague-Dawley rats to mechanical or thermal stimuli during and after administration of ten intraperitoneal injections of, alternatively, 1 and 2 mg/kg cisplatin every three days (cumulative dose: 15 mg/kg). Nociceptive signs including mechanical allodynia and hyperalgesia appeared after 3 and 6 cisplatin injections, respectively, and were maintained until 15 days after the last injection. The conservation of a good clinical status and fast appearance of symptoms are favourable criteria for using this animal model to understand the pathophysiological mechanisms implicated in the cisplatin-induced sensory peripheral neuropathy.

A procedure that involves a high-performance liquid chromatographic system with silica-bonded columns and reversed-phase eluents was fitted from a previously described method to measure clozapine and desmethylclozapine plasma levels. Clozapine and its demethylated metabolite were extracted from alkalinized serum by a liquid-liquid extraction, separated in 10 min, then quantitated at 254 nm at a minimum concentration of 20 ng/mL. The standard curves were linear over the range of 50-3000 ng/mL (r > 0.99) both for clozapine and desmethylclozapine and the assay had good sensitivity and recovery. Intra- and interday coefficients of variation for 200 and 800 ng/mL controls were less than 11.5% for clozapine and desmethylclozapine. This simple and efficient assay was used to monitor clozapine and desmethylclozapine levels from some treatment-refractory schizophrenic patients.

In order to observe the consequences of chronic ingestion of high fluoride-rich water on plasma potassium levels of hemodialysed subjects, we have conducted a retrospective study on 25 patients with chronic renal failure, treated with a substitute method, six of whom (consumers group, group C) were drinkers of a bicarbonate (about 4500 mg/l) and fluoride-rich (9 mg/l) mineral water, the Vichy Saint-Yorre water. With respect to sodium polystyrene sulfonate consumption (n = 17), there was no significant difference between group C and NC (non-consumers group). A significant correlation between plasma fluoride and potassium levels was observed only before dialysis (P < 1 x 10(-7)) but not after dialysis. A group by group analysis revealed that this correlation was linked to group C (P < 5 x 10(-6)), in which kalemia before dialysis was higher than that observed in group NC (P < 0.005). Moreover, it appeared that the higher fluoride levels were, the higher the kalemia was inclined to be. Thus, the risks of hyperkalemia in dialysed patients, who also drink Vichy St-Yorre water or other fluoride-rich waters, are more important, while not forgetting the risk of fluorosis. The mechanisms by which chronically administered fluoride could increase kalemia are also discussed.

A simple and sensitive high-performance liquid chromatographic method is described for the determination of paclitaxel (Taxol) at 230 nm using a Nucleosil C18 (5 microm) column and a methanol-water (70:30, v/v) mobile phase following a single-step extraction from serum with dichloromethane. The assay was validated against the classical criteria and was applied to a toxicokinetic study in rats after one or five, one per week) intraperitoneal administrations of 16 mg/kg Taxol.

We have conducted a study of the elimination kinetics of fluoride ions by a log linear regression analysis of plasma levels obtained during a bicarbonate hemodialysis session, with a dialyzer in polymercaprin for six patients with chronic renal failure. Using plasma fluoride levels of 35 patients studied for 20 months, we have validated these kinetics for hemodialysis with sodium bicarbonate, acetate-free biofiltration, hemodiafiltration with low flow rate and other dialyzers. Our results show that the decrease in plasma fluoride levels is statistically significant only after the first hour, and the fall reaches approximately 30% after a 4 h dialysis session. We propose that post-dialysis measurements of plasma fluoride are now not necessary if levels before dialysis are known.

Among DNA repair pathways, nucleotide excision repair (NER) is able to recognize and process a wide variety of DNA lesions. The NER mechanism can be summarized in two stages: incision/excision of the lesion and DNA repair synthesis. Here, we have assessed the repair synthesis activity of protein extracts from different rat tissues by an in vitro biochemical assay that reproduces the entire NER reaction. The protein extraction procedure was adapted to rat tissues and the biochemical parameters of the assay (high salt concentration, addition of EGTA) in order to minimize non-specific nuclease activity which allows the measurement of repair activity. Using this repair assay we detected a small increase in the extent of repair synthesis in liver compared to brain and lung tissue protein extracts. Similar results were obtained using a derivative assay that allows the measurement of the incision activity of tissue protein extracts with lower incision activity in lung tissue extract.

The influence of tolcapone, an inhibitor of catechol-O-methyl transferase, was evaluated on the disposition of apomorphine, a dopamine agonist used to treat Parkinson's disease, to explain a previously observed increase of duration of the effect of apomorphine associated with tolcapone. Sampling was performed in rats before and at different times after administration of apomorphine and following that of tolcapone or saline. Both in plasma and striatum, times to reach maximal-concentration and maximal concentrations did not significantly differ between the two groups but the elimination half-life times and areas under the curve were significantly greater following tolcapone treatment than in the saline group. These results show that tolcapone can increase plasma apomorphine bioavailability by modifying its liver catabolism.

Biotransformation of amitriptyline (AMI) was studied at different intervals in freshly isolated hepatocytes from healthy or streptozocin-induced diabetic rats in order to investigate the influence of the diabetic state. Levels of free and conjugated AMI, demethylated and hydroxylated metabolites, were assessed by HPLC analysis. In hepatocytes isolated from diabetic rats, AMI was less completely metabolized and the demethylation reaction became more important than in non-diabetic rat hepatocytes. Although the proportions of hydroxylated metabolites decreased in diabetic rats, it always remained predominant. Furthermore, glucuronidation of metabolites was greater, especially for (Z)-10-hydroxynortriptyline in diabetic animals.

Plasma and brain levels of amitriptyline (AMI), its demethylated and hydroxylated metabolites were determined after acute IP administration of AMI (20 mg/kg) in streptozocin-induced diabetic Sprague-Dawley rats. Results showed 1. in plasma: rapid AMI absorption, but slow elimination; the proportion of AMI similar to those of the rest of compounds; the proportion of its demethylated metabolite, nortriptyline, 1.8-fold higher than that of 10-hydroxy-nortriptyline. 2. in brain: the proportions of AMI and nortriptyline were 9.5- and 2.6-fold higher respectively, than those of whole hydroxylated metabolites, which represented 7.4% of the total amount.