Cannabidiol inhibits paclitaxel-induced neuropathic pain through 5-HT1A receptors without diminishing nervous system function or chemotherapy efficacy

Background and Purpose

Paclitaxel (PAC) is associated with chemotherapy-induced neuropathic pain (CIPN) that can lead to the cessation of treatment in cancer patients even in the absence of alternate therapies. We previously reported that chronic administration of the non-psychoactive cannabinoid cannabidiol (CBD) prevents PAC-induced mechanical and thermal sensitivity in mice. Hence, we sought to determine receptor mechanisms by which CBD inhibits CIPN and whether CBD negatively effects nervous system function or chemotherapy efficacy.

Experimental Approach

The ability of acute CBD pretreatment to prevent PAC-induced mechanical sensitivity was assessed, as was the effect of CBD on place conditioning and on an operant-conditioned learning and memory task. The potential interaction of CBD and PAC on breast cancer cell viability was determined using the MTT assay.

Key Results

PAC-induced mechanical sensitivity was prevented by administration of CBD (2.5 – 10 mg·kg⁻¹) in female C57Bl/6 mice. This effect was reversed by co-administration of the 5-HT_1A antagonist WAY 100635, but not the CB₁ antagonist SR141716 or the CB₂ antagonist SR144528. CBD produced no conditioned rewarding effects and did not affect conditioned learning and memory. Also, CBD + PAC combinations produce additive to synergistic inhibition of breast cancer cell viability.

Conclusions and Implications

Our data suggest that CBD is protective against PAC-induced neurotoxicity mediated in part by the 5-HT_1A receptor system. Furthermore, CBD treatment was devoid of conditioned rewarding effects or cognitive impairment and did not attenuate PAC-induced inhibition of breast cancer cell viability. Hence, adjunct treatment with CBD during PAC chemotherapy may be safe and effective in the prevention or attenuation of CIPN.     

Acute and subchronic toxicities of QX100626, a 5-HT4 receptor agonist,in rodents and Beagle dogs

Serotonin 5-hydroxytryptamine 4(5-HT4) receptor agonists have been widely prescribed as a prokinetics drug for patients with gastro-esophageal reflux disease and functional dyspepsia. QX100626, one of the 5-HT4 receptor agonists, has been studied as a promising agent for this clinical use. The objective of the present study was to identify possible target organs of toxicity and propose a non-toxic dose of QX100626 for clinical usage. After single lethal dose oral and intravenous testing in rodents, some signs indicative of adverse CNS effects were observed. The minimum toxic dose of QX100626 for a single oral administration for dogs was 90.0 mg/kg b.w., and the severe toxic dose was more than 300 mg/kg b.w. The No Observed Adverse Effect Level (NOAEL) of QX100626 by daily oral administration for rats and dogs was 20 mg/kg and 10 mg/kg, respectively, whereas the minimum toxic dosages were 67 and 30 mg/kg, respectively. All of the adverse effects suggested that kidney, digestive tract, as well as nervous, hematological, and respiratory systems might be the target organs of toxicity for humans induced by QX100626. The compound could be a safe alternative to other existing prokinetic agents for the treatment of functional bowel disorders.     

Buccal absorption of propofol when dosed in 1-perfluorobutylpentane to anaesthetised and conscious Wistar rats and Göttingen mini-pigs

The purpose of this study was to evaluate whether propofol could be absorbed buccally when administered in semifluorinated alkanes (SFAs), here specifically perfluorobutylpentane (F4H5). This was evaluated in anesthetised and conscious rats and mini-pigs, to measure the relative bioavailability of propofol following buccal administration, but also partly to evaluate the animal models used for this investigation. The absolute bioavailability in the conscious animals was approximately 10% for both species and approximately 50% and 30% in the anesthetised rats and mini-pigs, respectively. This clearly demonstrates that propofol can be absorbed buccally, and F4H5 appears to be a relevant excipient for buccal administration of lipophilic drugs like propofol. The lower absorption in the conscious animals clearly indicates the need for an optimisation of the formulation.     

Adenosine dry powder inhalation for bronchial challenge testing,part 1: Inhaler and formulation development and in vitro performance testing

Dry powder administration of adenosine by use of an effective inhaler may be an interesting alternative to nebulisation of adenosine 5′-monophosphate in bronchial challenge testing, because of a shorter administration time and more consistent delivered fine particle dose over the entire dose range. In this study, we tested various powder formulations and classifier based dispersion principles and investigated the in vitro performance of the most promising formulation/classifier combination in a new test inhaler system. Spray-dried formulations of either pure adenosine (100%) or adenosine and lactose as diluent (1% and 10% adenosine) were prepared to cover the entire expected dose range for adenosine (0.01–20 mg). All three powders, in all 12 suggested doses, dispersed well with the newly developed test inhaler with a multiple air jet classifier disperser, into aerosols with an average volume median diameter of 3.1 μm (3.0–3.3 μm). For eleven out of 12 dose steps, the fine particle fractions < 5 μm as percent of the loaded dose varied within the range of 67–80% (mean: 74%). The new test concept allows for more consistent aerosol delivery over the entire dose range with narrower size distributions than nebulisation and thus may improve adenosine administration in bronchial challenge testing.     

沃泰西汀的作用机制与临床应用状况

沃泰西汀是一种新型抗抑郁药,其作用机制主要与抑制5－羟色胺的再摄取、增强中枢神经系统5－羟色胺的活性有关,主要用于治疗抑郁症,其安全性和耐受性较好。本文对沃泰西汀的临床药理学、临床评价和安全性等进行介绍。     

Advanced Constitutive Modeling of the Thixotropic Elasto-Visco-Plastic Behavior of Blood: Steady-State Blood Flow in Microtubes

The present work focuses on the in-silico investigation of the steady-state blood flow in straight microtubes, incorporating advanced constitutive modeling for human blood and blood plasma. The blood constitutive model accounts for the interplay between thixotropy and elasto-visco-plasticity via a scalar variable that describes the level of the local blood structure at any instance. The constitutive model is enhanced by the non-Newtonian modeling of the plasma phase, which features bulk viscoelasticity. Incorporating microcirculation phenomena such as the cell-free layer (CFL) formation or the Fåhraeus and the Fåhraeus-Lindqvist effects is an indispensable part of the blood flow investigation. The coupling between them and the momentum balance is achieved through correlations based on experimental observations. Notably, we propose a new simplified form for the dependence of the apparent viscosity on the hematocrit that predicts the CFL thickness correctly. Our investigation focuses on the impact of the microtube diameter and the pressure-gradient on velocity profiles, normal and shear viscoelastic stresses, and thixotropic properties. We demonstrate the microstructural configuration of blood in steady-state conditions, revealing that blood is highly aggregated in narrow tubes, promoting a flat velocity profile. Additionally, the proper accounting of the CFL thickness shows that for narrow microtubes, the reduction of discharged hematocrit is significant, which in some cases is up to 70%. At high pressure-gradients, the plasmatic proteins in both regions are extended in the flow direction, developing large axial normal stresses, which are more significant in the core region. We also provide normal stress predictions at both the blood/plasma interface (INS) and the tube wall (WNS), which are difficult to measure experimentally. Both decrease with the tube radius; however, they exhibit significant differences in magnitude and type of variation. INS varies linearly from 4.5 to 2 Pa, while WNS exhibits an exponential decrease taking values from 50 mPa to zero.     

Electrically Parallel Three-Element 980 nm VCSEL Arrays with Ternary and Binary Bottom DBR Mirror Layers

To meet the performance goals of fifth generation (5G) and future sixth generation (6G) optical wireless communication (OWC) and sensing systems, we seek to develop low-cost, reliable, compact lasers capable of sourcing 5–20 Gb/s (ideally up to 100 Gb/s by the 2030s) infrared beams across free-space line-of-sight distances of meters to kilometers. Toward this end, we develop small arrays of electrically parallel vertical cavity surface emitting lasers (VCSELs) for possible future use in short-distance (tens of meters) free-space optical communication and sensing applications in, for example, homes, data centers, manufacturing spaces, and backhaul (pole-to-pole or pole-to-building) optical links. As a starting point, we design, grow by metal–organic vapor phase epitaxy, fabricate, test, and analyze 980 nm top-emitting triple VCSEL arrays. Via on-wafer high-frequency probe testing, our arrays exhibit record bandwidths of 20–25 GHz, optical output powers of 20–50 mW, and error-free data transmission at up to 40 Gb/s—all extremely well suited for the intended 5G short-reach OWC and sensing applications. We employ novel p-metal and top mesa inter-VCSEL connectors to form electrically parallel but optically uncoupled (to reduce speckle) arrays with performance exceeding that of single VCSELs with equal total emitting areas.     

Responsiveness and Predictive Validity of the Participation Measure–3 Domains, 4 Dimensions in Survivors of Stroke

ObjectivesTo examine the responsiveness and predictive validity of the Participation Measure–3 Domains, 4 Dimensions (PM-3D4D) in people receiving outpatient rehabilitation following stroke.DesignProspective cohort observational study.SettingOutpatient rehabilitation settings.ParticipantsVolunteer patients (N=269) with stroke (mean age ± SD [y], 55.36±12.46; 70.26% male).InterventionsNot applicable.Main Outcome MeasuresThe PM-3D4D was designed to measure 3 domains (Productivity, Social, and Community) and 4 dimensions (Diversity, Frequency, Desire for change, and Difficulty) of participation in individuals with rehabilitation needs. All participants completed the PM-3D4D, the Participation Assessment with Recombined Tools-Objective (PART-O), the Participation Measure for Post-Acute Care (PM-PAC), and the EuroQol-5-Dimension (EQ-5D) at the baseline assessment and again following 3 months of outpatient rehabilitation.ResultsSignificant mean changes in scores were observed for most of the PM-3D4D subscales, with the largest score change observed in the Difficulty subscale (standardized response mean=0.57～0.88). The minimal detectable change and meaningful clinically important differences were calculated for each subscale. The Frequency and Difficulty dimensions of the PM-3D4D demonstrated significantly greater responsiveness than the PART-O and PM-PAC, respectively. The baseline PM-3D4D scores, except for Desire for change subscales, were significantly correlated with the PART-O, PM-PAC, and EQ-5D scores after 3 months of rehabilitation.ConclusionsThis study provides evidence supporting the responsiveness and predictive validity of the PM-3D4D in survivors of stroke. Among all subscales of the PM-3D4D, the Difficulty dimensional scale demonstrated the greatest responsiveness. The Desire for change dimension of the PM-3D4D showed less responsiveness, and we recommend that it be used as a goal-setting tool rather than an outcome measure. The PM-3D4D can potentially be used to predict participation outcomes and the health-related quality of life following rehabilitation interventions.