Bioavailability of dissolved and crushed single tablets of bictegravir, emtricitabine, tenofovir alafenamide in healthy adults: the SOLUBIC randomized crossover study.

BACKGROUND: Crushing or dissolving bictegravir/tenofovir alafenamide/emtricitabine (BIC/TAF/FTC) tablets is not recommended because there are no data supporting this practice. METHODS: A crossover, randomized trial in healthy adults (NCT04244448) investigated the bioavailability of two off-label uses of BIC/TAF/FTC (50/200/25 mg), dissolved in water or crushed in apple compote, compared with the solid tablet. Pharmacokinetic (PK) parameters were estimated from sequential intensive plasma antiretroviral concentrations over a 72 h period post dose. Bioequivalence was met if the 90% CIs of the geometric least-squares means ratios comparing BIC/TAF/FTC exposures (AUC and Cmax) from the experimental phases were within 80%-125% of the reference. RESULTS: Eighteen subjects participated in each of the three phases. Dissolved tablet Cmax geometric mean ratio (90% CI) for BIC/TAF/FTC was 105% (93-119)/97% (87-108)/96% (74-124), respectively. Dissolved tablet AUC geometric mean ratio (90% CI) for BIC/TAF/FTC was 111% (100-122)/100% (94 to 105)/99% (81 to 120), respectively. Crushed tablet Cmax geometric mean ratio (90%) CI for BIC/TAF/FTC was 110% (97 to 124)/70% (63-78)/66% (51-85), respectively. Crushed tablet AUC geometric mean ratio (90%) CI for BIC/TAF/FTC was 107% (96-118)/86% (82-91)/84% (69-103), respectively. CONCLUSIONS: Crushing BIC/TAF/FTC tablets may lead to suboptimal emtricitabine and tenofovir alafenamide drug exposures. Dissolving BIC/TAF/FTC in water may be acceptable if the tablet cannot be swallowed whole.

Antifungal Drugs TDM: Trends and Update.

PURPOSE: The increasing burden of invasive fungal infections results in growing challenges to antifungal (AF) therapeutic drug monitoring (TDM). This review aims to provide an overview of recent advances in AF TDM. METHODS: We conducted a PubMed search for articles during 2016-2020 using "TDM" or "pharmacokinetics" or "drug-drug-interaction" with "antifungal," consolidated for each AF. Selection was limited to English language articles with human data on drug exposure. RESULTS: More than 1000 articles matched the search terms. We selected 566 publications. The latest findings tend to confirm previous observations in real-life clinical settings. The pharmacokinetic variability related to special populations is not specific but must be considered. AF benefit-to-risk ratio, drug-drug interaction (DDI) profiles, and minimal inhibitory concentrations for pathogens must be known to manage at-risk situations and patients. Itraconazole has replaced ketoconazole in healthy volunteers DDI studies. Physiologically based pharmacokinetic modeling is widely used to assess metabolic azole DDI. AF prophylactic use was studied more for Aspergillus spp. and Mucorales in oncohematology and solid organ transplantation than for Candida (already studied). Emergence of central nervous system infection and severe infections in immunocompetent individuals both merit special attention. TDM is more challenging for azoles than amphotericin B and echinocandins. Fewer TDM requirements exist for fluconazole and isavuconazole (ISZ); however, ISZ is frequently used in clinical situations in which TDM is recommended. Voriconazole remains the most challenging of the AF, with toxicity limiting high-dose treatments. Moreover, alternative treatments (posaconazole tablets, ISZ) are now available. CONCLUSIONS: TDM seems to be crucial for curative and/or long-term maintenance treatment in highly variable patients. TDM poses fewer cost issues than the drugs themselves or subsequent treatment issues. The integration of clinical pharmacology into multidisciplinary management is now increasingly seen as a part of patient care.

Genital Human Immunodeficiency Virus-1 RNA and DNA Shedding in Virologically Suppressed Individuals Switching From Triple- to Dual- or Monotherapy: Pooled Results From 2 Randomized, Controlled Trials.

BACKGROUND: Increasingly, people living with human immunodeficiency virus (HIV) benefit from lower drug regimens (LDRs). Exploring viral genital shedding during LDRs is crucial to ensure their safety. METHODS: We pooled genital sub-studies from 2 clinical trials in this area. Patients were randomized 1:1 to continue abacavir/lamivudine/dolutegravir or switch to dolutegravir (MONCAY trial), or to continue tenofovir/emtricitabine + a third agent or switch to tenofovir/emtricitabine (TRULIGHT trial). Participants whose plasma HIV-RNA remained <50 copies/mL had sperm or cervicovaginal lavage collected between Weeks 24 and 48. HIV-RNA and HIV-DNA were amplified by ultrasensitive polymerase chain reaction. The main objective was to measure the proportion of participants who had no detectable HIV in genital fluids, both according to each strategy and then in an aggregated analysis (LDR versus triple therapies). RESULTS: There were 64 participants (35 males, 29 females) included: 16 received dual therapies and 16 received triple therapies in TRULIGHT; and 16 received monotherapies and 16 received triple therapies in MONCAY. In TRULIGHT, 13/15 (87%) of evaluable participants on dual therapy had no detectable HIV in their genital fluid, versus 14/15 (93%) under triple therapy (P = 1.0). In MONCAY, these figures were 12/15 (80%) on monotherapy versus 13/16 (81%) on triple therapy (P = 1.0). In the pooled analysis, a similar proportion of participants in the LDR and triple therapy groups had no detectable HIV: 25/30 (83%) and 27/31 (87%), respectively (P = .73). CONCLUSIONS: There was no evidence of increased HIV-RNA and/or -DNA shedding in the genital fluids of people who maintained undetectable plasma HIV-RNA during LDRs. CLINICAL TRIALS REGISTRATION: NCT02302547 and NCT02596334.

Optimization of the treatment with beta-lactam antibiotics in critically ill patients-guidelines from the French Society of Pharmacology and Therapeutics (Société Française de Pharmacologie et Thérapeutique-SFPT) and the French Society of Anaesthesia and Intensive Care Medicine (Société Française d'Anesthésie et Réanimation-SFAR).

BACKGROUND: Beta-lactam antibiotics (ßLA) are the most commonly used antibiotics in the intensive care unit (ICU). ICU patients present many pathophysiological features that cause pharmacokinetic (PK) and pharmacodynamic (PD) specificities, leading to the risk of underdosage. The French Society of Pharmacology and Therapeutics (SFPT) and the French Society of Anaesthesia and Intensive Care Medicine (SFAR) have joined forces to provide guidelines on the optimization of beta-lactam treatment in ICU patients. METHODS: A consensus committee of 18 experts from the two societies had the mission of producing these guidelines. The entire process was conducted independently of any industry funding. A list of questions formulated according to the PICO model (Population, Intervention, Comparison, and Outcomes) was drawn-up by the experts. Then, two bibliographic experts analysed the literature published since January 2000 using predefined keywords according to PRISMA recommendations. The quality of the data identified from the literature was assessed using the GRADE® methodology. Due to the lack of powerful studies having used mortality as main judgement criteria, it was decided, before drafting the recommendations, to formulate only "optional" recommendations. RESULTS: After two rounds of rating and one amendment, a strong agreement was reached by the SFPT-SFAR guideline panel for 21 optional recommendations and a recapitulative algorithm for care covering four areas: (i) pharmacokinetic variability, (ii) PK-PD relationship, (iii) administration modalities, and (iv) therapeutic drug monitoring (TDM). The most important recommendations regarding ßLA administration in ICU patients concerned (i) the consideration of the many sources of PK variability in this population; (ii) the definition of free plasma concentration between four and eight times the Minimal Inhibitory Concentration (MIC) of the causative bacteria for 100% of the dosing interval as PK-PD target to maximize bacteriological and clinical responses; (iii) the use of continuous or prolonged administration of ßLA in the most severe patients, in case of high MIC bacteria and in case of lower respiratory tract infection to improve clinical cure; and (iv) the use of TDM to improve PK-PD target achievement. CONCLUSIONS: The experts strongly suggest the use of personalized dosing, continuous or prolonged infusion and therapeutic drug monitoring when administering ßLA in critically ill patients.

Clinical outcome of cystic fibrosis patients colonized by Scedosporium species following lung transplantation: A single-center 15-year experience.

BACKGROUND: Fungi of the genus Scedosporium are emerging pathogens responsible for severe infections in lung transplant recipients. These infections are associated with poor prognosis and some centers consider now Scedosporium species colonization as a contraindication to lung transplantation (LT) even though no published evidence demonstrates that Scedosporium species colonization is associated with higher morbidity or mortality after LT. METHODS: Here, we aim to describe characteristics and outcome of cystic fibrosis (CF) lung transplant recipients colonized with Scedosporium species in a single center over a 15-year period. RESULTS: During the study period, 14 patients had scedosporial colonization reported. Only one patient, colonized before transplantation by Lomentospora prolificans, developed scedosporial disease. Among the eight patients colonized before transplantation by Scedosporium apiospermum complex, the median survival was 1.92 year (range 0.21-12.5). All these patients except one became free of fungal colonization after transplantation with antifungal prophylaxis including voriconazole or posaconazole. For the five patients colonized after LT, including two with L. prolificans, the median survival was 1.75 years (range 0.1-13); three of them are still alive. CONCLUSIONS: It appears to us that scedosporial colonization may not be a contraindication for LT in CF patients, as long as S. apiospermum complex is involved and a life-long azole prophylaxis prescribed.

N-ethylhexedrone: a very long and bad trip! A Case series.

N-ethylhexedrone (NEH) is a new cathinone derivative with, currently, low toxicocokinetic, and toxicocodynamic knowledge. We present 3 documented clinical cases of NEH intoxication with plasma, and urine concentrations. A thorough search for metabolites was performed. The 3 patients were admitted to the emergency department, and 2 out of the 3 were hospitalized for an extended period. While recovering from the drug effects, 12 to 24 hours after nasal intake of New Psychoactive Substance (NPS), the patients described the following disorders: anxiety, feelings of persecution, asthenia, anhedonia, abulia, psychomotor slowing, and loss of consciousness. NEH was identified in all samples by liquid chromatography-high resolution mass spectrometry (LC-HRMS), and quantified by liquid chromatography coupled to tandem mass spectrometry (LC-MS-MS). Quantitative analysis showed decreasing concentrations over time: for case 1, from 97.2 (Day 1, D1) to 0.7 (Day 7, D7) µg/L for plasma, and from 724 (D1) to 0.5 (D7) µg/L for urine. NEH concentration of 7.9 µg/L was found in the plasma collected at admission for case 2. For case 3: concentrations ranging from 49 (D1) to 1.8 (D7) µg/L in plasma, and from 327.3 (Day 5, D5) to 116.8 (D7) µg/L in urine were found. NEH was no longer detected in the urine sample at Day 10. Elimination half-life was estimated at 19, and 28 hours in patients 1 and 3, respectively. Four metabolites were identified in blood and urine: reduced NEH, dealkyl-NEH, reduced dealkyl-NEH, and hydroxy-NEH. The cases presented highlight the long detectable lifetime of NEH. Characterization of the metabolites will allow better identification of the consumption of this drug. Serious adverse events can be observed after NEH consumption, as 2 out of 3 patients required intubation and ventilation. A syndrome of inappropriate antidiuretic hormone secretion (SIADH) was also diagnosed. Two out of the three cases are notable because of the number of samples collected and because NEH was the only drug of abuse detected.

Analytical methods and biomonitoring results in hair for the assessment of exposure to endocrine-disrupting chemicals: A literature review.

Endocrine-disrupting chemicals (EDC) are compounds that alter functions of the endocrine system due to their ability to mimic or antagonize endogenous hormones, or that alter their synthesis and metabolism, causing adverse health effects. Human biomonitoring (HBM) is a reliable method to assess human exposure to chemicals through measurement in human body fluids and tissues. It identifies new sources of exposure and determines their distribution, thereby enabling detection of the most exposed populations. Blood and urine are commonly used for HBM of EDC, but their interest is limited for compounds presenting short half-lives. Hair appears as an interesting alternative insofar as it provides a large exposure window. For the present study, we evaluated the relevance of hair in determining EDC exposure. With this in mind, we undertook a literature review focusing on the bioanalytical aspects and performances of methods developed to determine EDC in hair. The literature review was performed through methodical bibliographical research. Relevant articles were identified using two scientific databases: PubMed and Web of Science, with search equations built from a combination of keywords, MeSH terms and Boolean operators. The search strategy identified 2949 articles. After duplicates were removed, and following title, abstract, and full-text screenings, only 31 were included for qualitative synthesis. Hair collection was mainly performed in the back of the head and preparation involved two processes: cutting into small pieces or grounding to powder. The off-line LC-MS/MS method remains the main technique used to assess EDC through hair. Differences regarding the validation of analytical methods and interpretation of HBM results were highlighted, suggesting a need for international harmonisation to obtain reliable and comparable results. External contamination of hair was identified as a main limitation in the interpretation of results, highlighting the need to better understand EDC transfers through hair and to develop relevant hair decontamination processes.

[Level of evidence for therapeutic drug monitoring of posaconazole]. / Niveau de preuve du suivi thérapeutique pharmacologique du posaconazole.

Posaconazole, systemic antifungal marketed in France since 2006, is indicated as second line in curative treatment of invasive fungal infections (IFI) (aspergillosis...) and prophylaxis of IFI in patients receiving chemotherapy or hematopoietic stem cell transplantation. The analysis of the literature indicates a concentration-efficacy relationship, but to date, no study has been able to show a concentration-toxicity correlation due to its favourable safety profile and the difficulty to obtain high concentrations. In curative, maintenance of trough plasma concentrations between 0.5 and 1.5 mg/L seems to be associate with an efficacy. In prophylaxis, a threshold of 0.5 mg/L corresponds to a minimal exposure. However this target is not yet well defined. Saturation of absorption above the 800 mg oral dose limits the adjustment of concentrations. As such, the Therapeutic Drug Monitoring of posaconazole can be recommended.

[Level of evidence for therapeutic drug monitoring of vancomycin]. / Niveau de preuve pour le suivi thérapeutique pharmacologique de la vancomycine.

Vancomycin is an antibiotic for exclusive hospital use administrated in intravenous infusion to treat systemic infections. It is mainly eliminated by kidneys and potentially nephrotoxic. Data available show that Therapeutic Drug Monitoring (TDM) of vancomycin is highly recommended. It aims to ensure efficacy and avoid resistance by maintaining trough plasma concentrations above the MIC. Secondary, vancomycine TDM may be indicated to prevent nephrotoxicity in high risk patients. TDM is often underwent at steady state (48 to 72 h after the treatment initiation) unless in case of renal impairment (24 h). While compared with intermittent administration, continuous infusion did not result in prognosis improvement; however it resulted in lower pharmacokinetic variability and better cost-efficiency. Targeted trough concentrations for intermittent infusion are between 15 and 20 mg/L (up to 25-30 mg/L for GISA). In case of continuous infusion, targets are higher (25 to 40 mg/L).

[Not Available]. / Niveau de preuve pour le suivi thérapeutique pharmacologique de la vancomycine.

Level of Evidence for Therapeutic Drug Monitoring of Vancomycin. Vancomycin is an antibiotic for exclusive hospital use administrated in intravenous infusion to treat systemic infections. It is mainly eliminated by kidneys and potentially nephrotoxic. Data available show that Therapeutic Drug Monitoring (TDM) of vancomycin is highly recommended. It aims to ensure efficacy and avoid resistance by maintaining trough plasma concentrations above the MIC. Secondary, vancomycine TDM may be indicated to prevent nephrotoxicity in high risk patients. TDM is often underwent at steady state (48 to 72 h after the treatment initiation) unless in case of renal impairment (24 h). While compared with intermittent administration, continuous infusion did not result in prognosis improvement; however it resulted in lower pharmacokinetic variability and better cost-efficiency. Targeted trough concentrations for intermittent infusion are between 15 and 20 mg/L (up to 25-30 mg/L for GISA). In case of continuous infusion, targets are higher (25 to 40 mg/L).

[Not Available]. / Niveau de preuve du suivi thérapeutique pharmacologique du posaconazole.

Posaconazole, systemic antifungal marketed in France since 2006, is indicated as second line in curative treatment of invasive fungal infections (IFI) (aspergillosis. . . ) and prophylaxis of IFI in patients receiving chemotherapy or hematopoietic stem cell transplantation. The analysis of the literature indicates a concentration-efficacy relationship, but to date, no study has been able to show a concentration-toxicity correlation due to its favourable safety profile and the difficulty to obtain high concentrations. In curative, maintenance of trough plasma concentrations between 0.5 and 1.5 mg/L seems to be associate with an efficacy. In prophylaxis, a threshold of 0.5 mg/L corresponds to a minimal exposure. However this target is not yet well defined. Saturation of absorption above the 800 mg oral dose limits the adjustment of concentrations. As such, the Therapeutic Drug Monitoring of posaconazole can be recommended.

Evolution and phenotypic characterization of whole HBV genome in compliant patients experiencing unexplained entecavir treatment failure.

Entecavir treatment failure can be observed in compliant patients despite an absence of detectable resistance mutations by Pol/RT Sanger sequencing. We hypothesized that these unexplained treatment failures could rely on other mechanisms of viral resistance, especially on mutations selected outside of the Pol/RT domain. Partial virological response to entecavir was observed in three patients treated with immunosuppressive drugs, without selection of Pol/RT resistance mutations. Mutations selected in the whole HBV genome during entecavir treatment and potentially associated with resistance were searched for using deep sequencing and characterized using a phenotypic resistance assay. Mutations Q206K (pre-core/core), Q120K (pre-S1/pre-S2, T-cell epitope) and A300E (spacer domain) were selected during entecavir treatment in patient #1 but were not associated with an increased level of resistance to entecavir or an increase in HBV replication capacity. Core promoter mutations T1753G, A1762T and G1764A were present as major mutations before and after treatment in patient #1. HBs Ag immune escape mutations were present as major mutations before and after treatment in patients #2 (sK122R, sT126I, sP127S and sG145R) and #3 (sM133I). We demonstrated that PVR to entecavir does not require selection of any resistance mutation in the whole HBV genome. Our results demonstrate that major mutations can be selected outside of the Pol/RT domain before or during entecavir treatment. These mutations could contribute to entecavir treatment failure by other mechanisms than an increased level of resistance.

Pharmacological considerations for azole antifungal drug management in cystic fibrosis lung transplant patients.

This paper aims to present our experience in the pharmacological approach of the management of azole antifungal drugs in cystic fibrosis lung transplant patients. Cystic fibrosis (CF) lung transplantation is associated with multi-factorial care management, because of immunosuppressive requirements, risk of infections, frequency of gastro-oesophageal reflux disease, hepatic alterations and CF pharmacokinetics (PK) specificities that result in important PK variability. CF is associated with frequent colonization of the airways by filamentous fungi, especially by Aspergillus species. Today the antifungal therapeutic arsenal offers several possibilities for long-term oral therapy including azole drugs (itraconazole, voriconazole and posaconazole). Therefore, nephrotoxic amphotericin B should be avoided. The liver is important in the pharmacological profile of azole drugs, due to metabolic elimination, hepatotoxicity and PK drug-drug interaction (DDI) involving CYP3A4 metabolic inhibition. Targets for such DDI are numerous, but immunosuppressive drugs are of major concern, justifying combined therapeutic drug monitoring (TDM) of both azoles (inhibitors) and immunosuppressants (targets) on an individualized patient basis to adjust the coprescription quantitatively. The risk of long under-dosed periods, frequently addressed in this population, could justify, on a PK basis, the need for combination with an exclusive parenteral antifungal while waiting for azole relevant drug level. High PK variability, the risk of low exposure, therapeutic issues and DDI management in this complex underlying disease justify close monitoring with systematic combined TDM of azole and immunosuppressants, in case of coprescription.

Pharmacokinetic variability of beta-lactams in critically ill patients: A narrative review.

The use of antibacterial drugs is very common in critically ill patients and beta-lactam agents are widely used in this context. Critically ill patients show several characteristics (e.g., sepsis, renal impairment or conversely augmented renal clearance, renal replacement therapy) that may alter beta-lactam pharmacokinetics (PK) in comparison with non-critically ill patients. This narrative literature review aims to identify recent studies quantifying the variability of beta-lactams volume of distribution and clearance and to determine its main determinants. Seventy studies published between 2000 and 2018 were retained. Data on volume of distribution and clearance variability were reported for 5 penicillins, 3 beta-lactamase inhibitors, 6 cephalosporins and 4 carbapenems. Data confirm specific changes in PK parameters and important variability of beta-lactam PK in critically ill patients. Renal function, body weight and use of renal replacement therapy are the principal factors influencing PK parameters described in this population. Few studies have directly compared beta-lactam PK in critically ill versus non-critically ill patients. Conclusions are also limited by small study size and sparse PK data in several studies. These results suggest approaches to assess this PK variability in clinical practice. Beta-lactam therapeutic drug monitoring seems to be the best way to deal with this issue.

Revisiting HBV resistance to entecavir with a phenotypic approach.

Treatment adaptation after hepatitis B virus (HBV) treatment failure relies on genotypic resistance testing. However, the results of such tests are not always consistent with treatment response. These discrepancies may be due to differences in resistance levels between isolates with the same genotypic resistance testing profiles. We explored this hypothesis by investigating six cases of entecavir treatment failure with an integrative strategy combining genotypic and phenotypic resistance testing, medical record review and therapeutic drug monitoring. Among isolates with genotypic reduced susceptibility to entecavir, one displayed a higher level of resistance to entecavir (mean fold change in entecavir IC50 of 1 508 ± 531 vs. 318 ± 53, p = 0.008). This isolate harbored a substitution (rt250L) at a position reported to be associated with resistance (rt250V). Reversion to wild-type amino acid at this position partially restored susceptibility to entecavir, confirming that the rt250L mutation was responsible for the high level of resistance to entecavir. This is the first description of entecavir treatment failure associated with selection of the rt250L mutation without other entecavir resistance mutations. One isolate with genotypic resistance to entecavir, harboring the rt173L mutation, displayed a lower level of resistance than the other, harboring the rt202G mutation (mean fold change of 323 ± 124 vs. 6 036 ± 2 100, p = 0.20). These results suggest that isolates harboring the rt250L mutations should be considered resistant to entecavir, whereas isolates harboring the rt173L mutations should be considered to display reduced susceptibility to entecavir. An integrative approach to antiviral drug resistance in HBV would provide a more accurate assessment of entecavir treatment failures and help to improve the accuracy of genotypic testing algorithms.

Safe management of tacrolimus together with posaconazole in lung transplant patients with cystic fibrosis.

Oral posaconazole (PSZ), an azole antifungal drug, was recently introduced for the treatment of invasive fungal infections. The prescription of PSZ together with the immunosuppressant tacrolimus (TRL) was evaluated in 14 lung transplant patients with cystic fibrosis. PSZ inhibited CYP3A4 TRL metabolism, resulting in a decrease of TRL dose by a factor of 3, with tapering to a mean of 2 mg/d. Previous studies with itraconazole and voriconazole showed that TRL dose could be decreased by factors of 5 and 4, respectively. Joint therapeutic drug monitoring of TRL and PSZ was carried out to investigate the high risk of interindividual variability associated with this coprescription in such patients.

A simple and sensitive liquid chromatography-tandem mass spectrometry assay for the quantification of ertapenem in microdialysate.

A new liquid chromatography assay with isocratic elution and tandem mass spectrometry detection (LC-MS/MS) using an electrospray ionization interface in the multiple reaction monitoring mode was developed and validated for ertapenem determination in microdialysate samples. Linearity was demonstrated between 10ngmL(-1) (lower limit of quantification, LLoQ) and 160ngmL(-1). The precision (CV%) and accuracy (bias%) in microdialysates at the LLoQ were respectively 2.2% and 17.3% within-day and 10.6% and 2.7% between-days. Ertapenem was stable for 1 month at -20 degrees C and -80 degrees C but unstable at +4 degrees C. This new LC-MS/MS assay is simple, rapid and more sensitive than previously described assays.

Rescue of fragile X syndrome phenotypes in Fmr1 KO mice by a BKCa channel opener molecule.

BACKGROUND: Fragile X Syndrome (FXS) is the most common form of inherited intellectual disability and is also associated with autism spectrum disorders. Previous studies implicated BKCa channels in the neuropathogenesis of FXS, but the main question was whether pharmacological BKCa stimulation would be able to rescue FXS neurobehavioral phenotypes. METHODS AND RESULTS: We used a selective BKCa channel opener molecule (BMS-204352) to address this issue in Fmr1 KO mice, modeling the FXS pathophysiology. In vitro, acute BMS-204352 treatment (10 µM) restored the abnormal dendritic spine phenotype. In vivo, a single injection of BMS-204352 (2 mg/kg) rescued the hippocampal glutamate homeostasis and the behavioral phenotype. Indeed, disturbances in social recognition and interaction, non-social anxiety, and spatial memory were corrected by BMS-204352 in Fmr1 KO mice. CONCLUSION: These results demonstrate that the BKCa channel is a new therapeutic target for FXS. We show that BMS-204352 rescues a broad spectrum of behavioral impairments (social, emotional and cognitive) in an animal model of FXS. This pharmacological molecule might open new ways for FXS therapy.