Recurrent ischaemic cerebrovascular events as presenting manifestations of myeloproliferative neoplasms.

BACKGROUND AND PURPOSE: Myeloproliferative neoplasms (MPNs) - polycythemia vera, essential thrombocythemia and primary myelofibrosis - are associated with increased risk for ischaemic cerebrovascular events (ICVEs). Due to their low prevalence, MPNs often remain undiagnosed as the cause of ICVEs. METHODS: Case records at the University of Tübingen between 2014 and 2017 were screened to identify patients with MPN-related ICVEs. Clinical features, brain imaging, laboratory findings, applied treatments and neurological outcomes were assessed. RESULTS: In all, 3318 patients with ICVEs were identified, and amongst them 17 patients with MPN-related ICVEs were included in a retrospective study. In 58% of these patients, ICVEs were the first manifestation of the underlying MPN; 24% presented with transient ischaemic attack and 76% with ischaemic stroke. Potentially concurrent ICVE etiologies were noted in 70% of the patients. The majority (94%) of patients were positive for the JAK2 V617F mutation, whilst in 29% recurrent ICVEs (range two to three) were noted prior to MPN diagnosis. Early MPN diagnosis and management was the only significant prognostic factor for ICVE recurrence (P < 0.001). DISCUSSION: Evidence is provided that, although rare, MPNs represent an underdiagnosed cause of recurrent ICVEs. High clinical awareness is warranted to identify an underlying MPN in patients presenting with sustained, abnormal blood count findings. Clinical algorithms for prompt MPN diagnosis and initiation of MPN treatment (e.g. cytoreductive therapy, phlebotomy) are required. As MPN management comprises a significant protective factor against ICVE recurrence, induction of MPN treatment should be regarded as an integral component of secondary stroke prevention in MPN-associated ICVEs.

Patient-centered communication, patient satisfaction, and retention in care in assisted reproductive technology visits.

PURPOSE: To explore the association between patient-centered communication, patients' satisfaction, and retention in care in assisted reproductive technology (ART) visits. METHODS: ART visits at eight Italian clinics were videotaped and coded using the Roter Interaction Analysis System, which includes a Patient-Centered Index (PCI), a summary "patient-centered communication" ratio. After the visit, patients completed a satisfaction questionnaire (SATQ). After 3 months, patients were asked about their retention in care. Spearman correlations and Mann-Whitney tests were used to test associations between the study variables; the open-ended item of SATQ was analyzed through content analysis. RESULTS: Eighty-five visits were videotaped (involving 28 gynecologists and 160 patients). PCI score (µ = 0.51 ± 0.28) revealed a more disease-oriented communication during the visit. Patients reported high levels of satisfaction with the visit and identified in the information provision or in the doctor's humanity or kindness the main reasons of satisfaction. At the follow-up, the majority of the couples declared to have followed the clinicians' recommendations and to have remained related to the ART center. No associations were found among the study variables, except for a lower male satisfaction among couples who declared to have changed ART clinic. CONCLUSIONS: Contrary to what was expected, the style of physician-patient communication was not found to be associated with patient satisfaction and retention in care. However, patients were highly satisfied and engaged. The actual meaning of a communication that is "patient-centered" in the ART context might be wider, including the couples' need for information, as suggested by qualitative findings.

Do dogs exhibit jealous behaviors when their owner attends to their companion dog?

Jealousy appears to have clear adaptive functions across species: it emerges when an important social relationship with a valued social partner is threatened by third-party that is perceived as a rival. Dyads of dogs living together and their owners were tested adapting a procedure devised to study jealousy in young human siblings. Owners at first ignored both dogs while reading a magazine (Control episode), and then petted and praised one of the dogs while ignoring the other, and vice versa (Experimental episodes). We found several differences in the dogs' behavior between the Experimental episodes and the Control episode, even though only monitoring (gazing at the owner) was exhibited for a significantly greater amount of time in the Experimental episodes. Remarkable individual behavioral differences emerged, suggesting that the dogs' reactions could be influenced by the relationships that they establish with their owner and the companion dog. Overall, current results do not clearly support our prediction that the ignored dogs would exhibit more behaviors aimed at regaining the owner's attention when their owner directed attention and care to a companion dog, compared to the control situation. The great intra- and inter-dyad behavioral variability and the choice to test cohabiting dogs could have prevented the emergence of a clear jealous reaction. These findings do not exclude that dogs may exhibit a primordial form of jealousy in a realistic situation, but an additional research is needed to fully gauge which situations, if any, could trigger jealousy in dogs and to rule out alternative explanations.

Insertable cardiac monitors after cryptogenic stroke--a risk factor based approach to enhance the detection rate for paroxysmal atrial fibrillation.

BACKGROUND AND PURPOSE: Recently, the CRYSTAL AF trial detected paroxysmal atrial fibrillation (AF) in 12.4% of patients after cryptogenic ischaemic stroke (IS) or cryptogenic transient ischaemic attack (TIA) by an insertable cardiac monitor (ICM) within 1 year of monitoring. Our aim was (i) to assess if an AF risk factor based pre-selection of ICM candidates would enhance the rate of AF detection and (ii) to determine AF risk factors with significant predictive value for AF detection. METHODS: Seventy-five patients with cryptogenic IS/TIA were consecutively enrolled if at least one of the following AF risk factors was present: a CHA2DS2-VASc score ≥4, atrial runs, left atrium (LA) size >45 mm, left atrial appendage (LAA) flow ≤0.2 m/s, or spontaneous echo contrast in the LAA. The electrocardiographic and echocardiographic criteria were chosen as they have been repeatedly reported to predict AF; the same applies for four of the six items of the CHA2DS2-VASc score. The study end-point was the detection of one or more episodes of AF (≥2 min). RESULTS: Seventy-four patients underwent implantation of an ICM; one patient had AF at the date of implantation. After 6 months, AF was detected in 21/75 patients (28%), after 12 months in 25/75 patients (33.3%). 92% of AF episodes were asymptomatic. LA size >45 mm and the presence of atrial runs were independently associated with AF detection [hazard ratio 3.6 (95% confidence interval 1.6-8.4), P = 0.002, and 2.7 (1.2-6.7), P = 0.023, respectively]. CONCLUSIONS: The detection rate of AF is one-third after 1 year if candidates for an ICM after cryptogenic IS/TIA are selected by AF risk factors. LA dilation and atrial runs independently predict AF.

Single-crystal X-ray diffraction and resonant X-ray magnetic scattering at helium-3 temperatures in high magnetic fields at beamline P09 at PETRA III.

The resonant scattering and diffraction beamline P09 at PETRA III at DESY is equipped with a 14 T vertical field split-pair magnet. A helium-3 refrigerator is available that can be fitted inside the magnet's variable-temperature insert. Here the results of a series of experiments aimed at determining the beam conditions permitting operations with the He-3 insert are presented. By measuring the tetragonal-to-orthorhombic phase transition occurring at 2.1 K in the Jahn-Teller compound TmVO4, it is found that the photon flux at P09 must be attenuated down to 1.5 × 10(9) photons s(-1) for the sample to remain at temperatures below 800 mK. Despite such a reduction of the incident flux and the subsequent use of a Cu(111) analyzer, the resonant X-ray magnetic scattering signal at the Tm LIII absorption edge associated with the spin-density wave in TmNi2B2C below 1.5 K is intense enough to permit a complete study in magnetic field and at sub-Kelvin temperatures to be carried out.

Association of non-diabetic hyperglycemia with autonomic shift in acute ischaemic stroke.

BACKGROUND AND PURPOSE: The etiology of hyperglycemia in acute stroke remains controversial. It is unclear whether hyperglycemia arises as an epiphenomenon of stroke or as a reflection of underlying diabetes. Autonomic shift to sympathetic overactivity has been repeatedly observed in acute stroke. We hypothesize that hyperglycemia in acute stroke relates to autonomic imbalance and that the respective deleterious effects on stroke outcome may be cross-linked. METHODS: A total of 75 non-diabetic patients with ischaemic stroke were included in a prospective study. Glucose levels at admission, fasting glucose, and glucose profiles were recorded. Autonomic function was quantified by the assessment of spontaneous baroreflex sensitivity (BRS) using a cross-correlation method. Demographic and clinical data including stroke volumes and admission National Institute of Heath Stroke Scale scores were included into the analysis. Functional outcome at 90 days was assessed using the modified Rankin Scale. RESULTS: Hyperglycemia was correlated with decreased BRS independent of stroke severity or volume (r = -0.46, P < 0.001). In two separate regression models, glucose levels and BRS independently predicted unfavorable outcome at 3 months (OR = 1.06, CI = 1.02-1.11, P = 0.004 and OR = 0.75, CI = 0.56-0.99, P = 0.04). However, combining the models, only glucose levels (OR = 1.06, CI = 1.02-1.11, P = 0.004) remained independent predictor of outcome at 3 months. CONCLUSIONS: We observed an association between hyperglycemia and decreased BRS in non-diabetic patients, suggesting that hyperglycemic reaction in acute stroke may reflect stroke-related autonomic changes. Moreover, outcome effects of autonomic changes and hyperglycemia seem to be interdependent, putatively having the sympatho-vagal imbalance as common underlying mechanism. The possible therapeutic relevance of this finding warrants further studies.

Subducted organic matter buffered by marine carbonate rules the carbon isotopic signature of arc emissions.

Ocean sediments consist mainly of calcium carbonate and organic matter (phytoplankton debris). Once subducted, some carbon is removed from the slab and returns to the atmosphere as CO2 in arc magmas. Its isotopic signature is thought to reflect the bulk fraction of inorganic (carbonate) and organic (graphitic) carbon in the sedimentary source. Here we challenge this assumption by experimentally investigating model sediments composed of 13C-CaCO3 + 12C-graphite interacting with water at pressure, temperature and redox conditions of an average slab-mantle interface beneath arcs. We show that oxidative dissolution of graphite is the main process controlling the production of CO2, and its isotopic composition reflects the CO2/CaCO3 rather than the bulk graphite/CaCO3 (i.e., organic/inorganic carbon) fraction. We provide a mathematical model to relate the arc CO2 isotopic signature with the fluid-rock ratios and the redox state in force in its subarc source.

Common disorders in the neurological emergency room--experience at a tertiary care hospital.

BACKGROUND: The profile of patients with neurological diseases referred to specialized emergency rooms (ER) has not been reported and it is unknown whether a setting of decentralized ERs is associated with a high number of referrals because of inappropriate admissions. METHODS: In this prospective study, consecutive patients of a specialized neurological ER were enrolled. Data encompassed time from symptom onset to admission, discharge diagnoses, data on hospitalization and on transfers to and from other ERs. RESULTS: Thousand seven hundred and forty-three patients were enrolled. Most common diagnoses were cerebrovascular events (26.5%), headache disorders (13%) and seizures (12.7%). Time since onset of symptoms depended on who referred the patient (P<0.001); seizure patients presented earlier than other patients (P<0.001) and 30.5% of patients with cerebrovascular events presented within 3 h after symptom onset but did not present sooner than patients with other diagnoses. In 18%, diagnoses did not match neurological disorders, 4.5% of patients suffered from cardiovascular events. Referrals to and from other ERs rarely occurred (10.3% vs. 5.9%). Only 20 patients with acute cerebrovascular events were referred via other ERs (1.1%). CONCLUSION: A system of a specialized neurological ER can quickly clear up uncertainties in interpreting neurological symptoms. Owing to the rising number of neurological patients in ERs, more studies are urgently needed comparing the different organizational forms for emergency services.

Rescue of striatal long-term depression by chronic mGlu5 receptor negative allosteric modulation in distinct dystonia models.

An impairment of long-term synaptic plasticity is considered as a peculiar endophenotype of distinct forms of dystonia, a common, disabling movement disorder. Among the few therapeutic options, broad-spectrum antimuscarinic drugs are utilized, aimed at counteracting abnormal striatal acetylcholine-mediated transmission, which plays a crucial role in dystonia pathophysiology. We previously demonstrated a complete loss of long-term synaptic depression (LTD) at corticostriatal synapses in rodent models of two distinct forms of isolated dystonia, resulting from mutations in the TOR1A (DYT1), and GNAL (DYT25) genes. In addition to anticholinergic agents, the aberrant excitability of striatal cholinergic cells can be modulated by group I metabotropic glutamate receptor subtypes (mGlu1 and 5). Here, we tested the efficacy of the negative allosteric modulator (NAM) of metabotropic glutamate 5 (mGlu) receptor, dipraglurant (ADX48621) on striatal LTD. We show that, whereas acute treatment failed to rescue LTD, chronic dipraglurant rescued this form of synaptic plasticity both in DYT1 mice and GNAL rats. Our analysis of the pharmacokinetic profile of dipraglurant revealed a relatively short half-life, which led us to uncover a peculiar time-course of recovery based on the timing from last dipraglurant injection. Indeed, striatal spiny projection neurons (SPNs) recorded within 2 h from last administration showed full expression of synaptic plasticity, whilst the extent of recovery progressively diminished when SPNs were recorded 4-6 h after treatment. Our findings suggest that distinct dystonia genes may share common signaling pathway dysfunction. More importantly, they indicate that dipraglurant might be a potential novel therapeutic agent for this disabling disorder.

Phonon- and surface-roughness-limited mobility of gate-all-around 3C-SiC and Si nanowire FETs.

We present numerical simulations of gate-all-around (GAA) 3C-SiC and Si nanowire (NW) field effect transistors (FETs) using a full quantum self-consistent Poisson-Schrödinger algorithm within the non-equilibrium Green's function (NEGF) formalism. A direct comparison between Si and 3C-SiC device performances sheds some light on the different transport properties of the two materials. Effective mobility extraction has been performed in a linear transport regime and both phonon- (PH) and surface-roughness-(SR) limited mobility values were computed. 3C-SiC FETs present stronger acoustic phonon scattering, due to a larger deformation potential, resulting in lower phonon-limited mobility values. Although Si NW devices reveal a slightly better electrostatic control compared to 3C-SiC ones, SR-limited mobility shows a slower degradation with increasing charge density for 3C-SiC devices. This implies that the difference between Si and 3C-SiC device mobility is reduced at large gate voltages. 3C-SiC nanowires, besides their advantages compared to silicon ones, present electrical transport properties that are comparable to the Si case.

Silicate dissolution boosts the CO2 concentrations in subduction fluids.

Estimates of dissolved CO2 in subduction-zone fluids are based on thermodynamic models, relying on a very sparse experimental data base. Here, we present experimental data at 1-3 GPa, 800 °C, and ∆FMQ ≈ -0.5 for the volatiles and solute contents of graphite-saturated fluids in the systems COH, SiO2-COH ( + quartz/coesite) and MgO-SiO2-COH ( + forsterite and enstatite). The CO2 content of fluids interacting with silicates exceeds the amounts measured in the pure COH system by up to 30 mol%, as a consequence of a decrease in water activity probably associated with the formation of organic complexes containing Si-O-C and Si-O-Mg bonds. The interaction of deep aqueous fluids with silicates is a novel mechanism for controlling the composition of subduction COH fluids, promoting the deep CO2 transfer from the slab-mantle interface to the overlying mantle wedge, in particular where fluids are stable over melts.Current estimates of dissolved CO2 in subduction-zone fluids based on thermodynamic models rely on a very sparse experimental data base. Here, the authors show that experimental graphite-saturated COH fluids interacting with silicates at 1-3 GPa and 800 °C display unpredictably high CO2 contents.

[From stroke to reperfusion : How can we be faster?] / Vom Schlaganfall zur Reperfusion : Wie geht es schneller?

BACKGROUND: During the last two decades major efforts in clinical research have led to the establishment of intravenous thrombolysis as the first line acute therapy for ischemic stroke. More recently, data from successful phase III trials have provided proof of the efficiency of mechanical recanalization in acute stroke. The fact that the efficiency of the available therapies can be increased through faster delivery is well documented; however, many institutions dealing with the emergency care of stroke patients lack organizational or infrastructural arrangements to optimize time efficiency in the diagnostic and therapeutic workup. CONCLUSION: Many of these arrangements have been well evaluated, can be implemented at reasonable costs and have been proven to increase the beneficial effects of thrombolytic therapy.

Prevention of cisplatin-induced emesis by the oral neurokinin-1 antagonist, MK-869, in combination with granisetron and dexamethasone or with dexamethasone alone.

PURPOSE: The NK1-receptor antagonist MK-869 (L-754,030) has demonstrated antiemetic activity in humans receiving chemotherapy. Objectives of the present trial included the first assessment of oral MK-869 plus dexamethasone compared with a 5HT(3) antagonist plus dexamethasone for prevention of acute and delayed emesis after high-dose cisplatin. Furthermore, the study sought to confirm that addition of MK-869 to a 5HT(3) antagonist plus dexamethasone was more effective than just the 5HT(3) antagonist plus dexamethasone for prevention of acute and delayed emesis. METHODS: This multicenter, double-blind, parallel-group trial in 351 cisplatin-naïve patients evaluated prevention of acute (0 to 24 hours) and delayed emesis (primary efficacy parameter; days 2 to 5) after cisplatin (> or =70 mg/m(2)). Patients were randomized to four groups (I to IV) (n = number randomized; number evaluable): granisetron (10 microg/kg intravenously) pre-cisplatin followed by placebo on days 2 to 5 (group I) (n = 90; 90); granisetron and MK-869 (400 mg PO [by mouth]) pre-cisplatin, followed by MK-869 (300 mg PO) on days 2 to 5 (group II) (n = 86; 84); MK-869 (400 mg PO) the evening before and pre-cisplatin, followed by MK-869 (300 mg PO) on days 2 to 5 (group III) (n = 89; 88); or MK-869 (400 mg PO) pre-cisplatin, followed by MK-869 (300 mg PO) on days 2 to 5 (group IV) (n = 86; 84). All patients also received dexamethasone (20 mg PO) before cisplatin. Additional medication was available to treat emesis or nausea at any time. RESULTS: In the acute period, 57%, 80%, 46%, and 43% of patients were without emesis in groups I, II, III, and IV, respectively (P <.01 for group II v group I). In the delayed period, the proportion of patients without emesis in groups I, II, III, and IV was 29%, 63%, 51%, and 57%, respectively (P <.01 for groups II, III, and IV v group I). The distribution of nausea scores in the delayed period was lower when comparing group II with group I (P <.05 for days 1 to 5 and days 2 to 5). One serious adverse event (dizziness) was rated as possibly related to MK-869. CONCLUSION: Once daily oral administration of MK-869 was effective in reducing delayed emesis and nausea after high-dose cisplatin. However, the combination of the 5HT3 antagonist plus dexamethasone was numerically superior to MK-869 plus dexamethasone in reducing acute emesis. Confirming and extending previous findings, the triple combination of a 5HT(3) antagonist, MK-869, and dexamethasone provided the best control of acute emesis.

Cytochrome p450 enzymes mechanism based inhibitors: common sub-structures and reactivity.

The inhibition of human cytochrome P450s (CYPs) is one of the most common mechanisms which can lead to drug-drug interactions. The inhibition of CYPs can be reversible (competitive or non-competitive) or irreversible. Irreversible inhibition usually derives from activation of a drug by CYPs into a reactive metabolite, which tightly binds to the enzyme active site, leading to a long lasting inactivation. This process is called "mechanism based inhibition" or "suicide inhibition". The irreversible inactivation usually implies the formation of a covalent bond between the metabolite and the enzyme, which can lead to hapten formation and can in some cases trigger an autoimmune-response. For these reasons it is of utmost importance to study the mechanism of the CYP inhibition of new potential drugs as early as possible during the drug discovery process. The literature on CYPs is vast and covers numerous aspects of their biology and biochemistry, however to our knowledge there is no general and systematic review focusing on mechanism-based inhibitors; we have reviewed the literature and compiled all the available data on chemical entities, which are known to be CYP suicide inhibitors. Each compound is reported together with its chemical structure, the CYP isoform and the parameters describing the inactivation. Literature references are reported together with their PMID (PubMed ID number) to allow a fast retrieval of the papers. This review offers a quick reference to help predict liabilities of new chemical entities without carrying out extensive in vitro work, and will hopefully help in designing safer drugs.

Diagnostic approach to pulmonary embolism: our strategy.

The nonspecificity and variety of clinical features in acute pulmonary embolism account for a high suspicion rate, with a further exclusion of the diagnosis in up to 80% of cases. Arterial blood gas analysis and other laboratory tests are highly non-specific, and suggestive signs on the electrocardiogram are uncommon. The plain chest X-ray often yields valuable information. Lung scan, when normal, has the great advantage of excluding pulmonary embolism. At present, no procedure has superseded pulmonary angiography to attest the presence of emboli. Angiography will probably gain widespread acceptance with the larger use of thrombolysis.

Biotransformations on steroid nucleus of bile acids.

The bile acids in mammals are all derivatives of 5 beta-cholan-26-oic acid. They represent the major quantitative pathway by which cholesterol is metabolized in the body. This article covers the microbial and enzymatic transformations of free, saturated bile acids, that kept unaltered the C-24 cyclopentane-perhydrophenantrene nucleus. The bile acids that have been considered include the primary cholic and chenodeoxycholic acids, the secondary deoxycholic and lithocholic acids as well as the relevant dehydrocholic, ursocholic and ursodeoxycholic acids. Among the bile acid biotransformations, attention is paid to reactions that lead to pharmaceutically significant compounds. This is the case of 7 alpha-hydroxy epimerization of chenodeoxycholic acid to ursodeoxycholic acid, currently used for cholesterol galistone dissolution therapy and in the treatment of cholestatic liver diseases. Emphasis has placed on reporting reactions that may be of general interest and on the practical aspects of work in the field of biotransformations.

Effects of subthreshold shocks on wavelet propagation during atrial fibrillation in humans.

OBJECTIVES: Our objectives are: first to investigate the effects of internal cardioversion energies on the wave fronts propagation in the right atrium immediately after the energy delivery; second, to track the time course of these effects. METHODS: The study is based on a measure of organization of the endoatrial electrograms obtained by a multipolar basket catheter inserted in the right atrium. We estimated the level of organization by computing the percentage of points laying on the signal baseline (i.e., number of occurrences, NO). NO values were computed on two-second long windows. Six non-overlapped windows were selected, one just before and five just after the last unsuccessful shock. RESULTS: Immediately after the shock most of the patients exhibited an increase in the organization patterns. This increase was more evident in those patients with rather disorganized patterns and higher energy threshold. This effect fades within a few seconds after the shock delivery. CONCLUSIONS: Our data confirm the idea that the electrical shock causes a widespread extinction of electrical wavefronts, which regenerates after the shock. Since an increase of organization may lead to a reduction of energy threshold, a potential application of these findings might consist in the delivery of multiple subthreshold shocks instead of a single one.

[Health education and the prevention of HIV infection in schools]. / L'educazione alla salute e la prevenzione delle infezioni da HIV nella scuola.

This review describes the HIV prevention strategies adopted since 1990 by the Italian Ministry of Health and Ministry of Education, coordinated by the National Health Institute, for use in Italian schools. It sets out reasons for believing that action in schools is essential in containing the spread of the HIV epidemic and presents teaching materials prepared for school use. An analysis is made of the IV national HIV information campaign, in which the Ministry of Health trained 4,000 middle and senior schools principals. The prospects for continuing the work with these 4,000 principals in the V information campaign, are also reported.

ADX71441, a novel, potent and selective positive allosteric modulator of the GABA(B) receptor, shows efficacy in rodent models of overactive bladder.

BACKGROUND AND PURPOSE: The GABAB receptor agonist baclofen reduces urethral resistance and detrusor overactivity in patients with spasticity. However, baclofen's side effects limit its use for the treatment of overactive bladder (OAB). Here, we tested a novel GABAB positive allosteric modulator (PAM) ADX71441 in models of OAB in mice and guinea pigs. EXPERIMENTAL APPROACH: Mice were left untreated or given (p.o.) vehicle (1% CMC), ADX71441 (1, 3, 10 mg kg(-1) ) or oxybutynin (100 mg kg(-1) ; Experiment 1) or vehicle (1% CMC), baclofen (1, 3, 6 mg kg(-1) ) or oxybutynin (Experiment 2). Treated mice were then overhydrated with water, challenged with furosemide, before being placed into micturition chambers and monitored for urinary parameters. In anaesthetized guinea pigs, intravesical infusion of acetic acid was used to induce OAB and the effects of ADX71441 (1, 3 mg kg(-1) ) or baclofen (1 mg kg(-1) ), administered i.v., on cystometric parameters were monitored. KEY RESULTS: In mice, 10 mg kg(-1) ADX71441 increased urinary latencies, reduced the number of urinary events and the total and average urinary volumes. In guinea pigs, ADX71441 (1 and 3 mg kg(-1) ) increased the intercontraction interval (ICI) and bladder capacity (BC), and reduced micturition frequency (MF) compared to vehicle. At 3 mg kg(-1) ADX71441 completely inhibited the micturition reflex and induced overflow incontinence in five out of 10 animals. Baclofen slightly increased ICI and BC and reduced MF. CONCLUSION AND IMPLICATIONS: Our findings demonstrate, for the first time, that a GABAB PAM has potential as a novel approach for the treatment of OAB.

Evaluation of peripheral versus central effects of GABA(B) receptor activation using a novel, positive allosteric modulator of the GABA(B) receptor ADX71943, a pharmacological tool compound with a fully peripheral activity profile.

BACKGROUND AND PURPOSE: The GABA(B) receptor agonist, baclofen, has shown promising effects in patients suffering from pain, post-traumatic stress disorder, alcoholism, overactive bladder and gastroesophageal reflux disease. However, baclofen's short duration of action and side effects limit its wider use. Here we characterized a novel, GABA(B) receptor positive allosteric modulator (PAM) ADX71943. EXPERIMENTAL APPROACH: In vitro, ADX71943 was assessed for pharmacological activity and selectivity using recombinant and native GABA(B) receptors. In vivo ADX71943 was assessed in the acetic acid-induced writhing (AAW) test in mice and formalin tests (FTs) in mice and rats. Marble burying (MB) and elevated plus maze (EPM) tests, rotarod, spontaneous locomotor activity (sLMA) and body temperature (BT) tests in mice and rats were used to investigate centrally-mediated effects. KEY RESULTS: In vitro, in the presence of GABA, ADX71943 increased the potency and efficacy of agonists and showed selectivity at the GABA(B) receptor. ADX71943 reduced pain-associated behaviours in AAW; an effect blocked by GABA(B) receptor antagonist CGP63360. ADX71943 reduced pain in the FT in mice and rats, but was inactive in the MB and EPM despite reaching high concentrations in plasma. ADX71943 had no effect on BT, rotarod and sLMA. CONCLUSIONS AND IMPLICATIONS: ADX71943 showed consistent and target-related efficacy in tests of disorders that have a significant peripheral component (acute and chronic pain), while having no effect in those associated with centrally-mediated anxiety-like reactivity and side effects. Thus, ADX71943 is a useful pharmacological tool for delineation of peripherally- versus centrally-mediated effects of GABA(B) receptor activation.