Pharmacokinetics and tolerability of single-dose enteral cannabidiol and cannabidiolic acid rich hemp in horses (Equus caballus).

The pharmacokinetics and tolerability of cannabinoids and their metabolites were determined in eight horses after enteral administration of a commercial CBD/CBDA-rich hemp oil product. Each horse was administered 2 mg/kg or 8 mg/kg CBD/CBDA or no treatment in a randomized cross-over design. Serial serum samples collected over 48 h were analyzed by high performance liquid chromatography with tandem mass spectrometry. Plasma chemistry analysis was performed at 0 h and 24 h. Vital parameters, pedometry, and blinded mentation and gait evaluations were recorded at intervals up to 24 h. Manure production and gastrointestinal transit time were tracked for 48 h after oil administration. The median maximal concentration of CBD and CBDA were 5.2 and 36.95 ng/mL in the 2 mg/kg group, respectively; and 40.35 and 353.56 ng/mL in the 8 mg/kg group. The median half-life of elimination was not calculated for the 2 mg/kg CBD treatment due to lack of time points above the lower quantifiable limit beyond the Cmax while it was 7.75 h in the 8 mg/kg group. CBDA absorption was biphasic. Pharmacokinetic parameters for tetrahydrocannabinol, tetrahydrocannabinolic acid, cannabigerolic acid, and 7-carboxy cannabidiol are also reported. No significant differences in any of the measured tolerability parameters were demonstrated between treatment groups. Single-dose enteral administration of CBD/CBDA-rich hemp extract up to 8 mg/kg does not appear to produce neurologic, behavioral, or gastrointestinal effects in horses.

Pharmacokinetics of cannabidiol-/cannabidiolic acid-rich hemp oil in juvenile cynomolgus macaques (Macaca fascicularis).

Introduction: Cannabinoids are increasingly popular in human and veterinary medicine and have been studied as an alternative treatment for a wide range of disorders. The goal of this study was to perform a pharmacokinetic analysis of oral cannabidiol (CBD)-/cannabidiolic acid (CBDA)-rich hemp oil (CBD/ArHO) in juvenile cynomolgus macaques (Macaca fascicularis). Methods: After a 2 mg/kg CBD/ArHO pilot study, 4 and 8 mg/kg direct-to-mouth CBD/ArHO were administered (n = 4 per dose) once daily for 14 days and blood was collected at 0-, 0.5-, 1-, 2-, 4-, 8-, 12-, and 24-h, and on Days 7 and 14, to quantify serum cannabinoid concentrations by high-performance liquid chromatography-tandem mass spectrometry. Serum biochemistries and complete blood counts were performed on Days 0, 1, and 14. Results: The maximum mean serum concentration (Cmax) of CBDA was 28.6-36.2 times that of CBD at 4 and 8 mg/kg. At 8 mg/kg, the Cmax of CBD was 1.4 times higher (p = 0.0721), and CBDA was significantly 1.8 times higher (p = 0.0361), than at 4 mg/kg. The maximum mean serum concentration of ∆9-tetrahydrocannabinol (THC) was 4.80 ng/mL at 8 mg/kg. Changes in serum biochemistries and complete blood counts over time were not clinically significant. Discussion: Given the low serum CBD concentrations, the doses and frequency used in this study may be insufficient for a therapeutic effect of CBD in particular; therefore, clinical studies are needed to determine the therapeutic dose of CBD and CBDA for macaques, which may differ based on the disorder targeted.

Aging Brain, Dementia and Impaired Glymphatic Pathway: Causal Relationships.

Cellular and molecular processes that are of key importance in the development of neuroinflammation and increased cytokine response, activation of microglia and astrogliosis, contributing to the accumulation of metabolites and aberrant proteins in the brain tissue due to their overproduction and insufficient clearance, concomitant disturbance of architecture and sleep patterns are interconnected and induce brain aging with the formation its complex neurobiological mechanism. The study of these processes brings us closer to understanding the main determinants of healthy and unhealthy aging, primary prevention and preclinical diagnosis of age-related diseases, as well as to solving problems of longevity and increasing quality of life. The imbalance of homeostatic functions that support the exchange of fluids and solutes in the brain tissue is observed both in physiological aging and in the development of pathology of the nervous system with long-term consequences - from impaired synaptic signaling to the development of neurodegenerative diseases. Dementia is one of the major health problems worldwide and is very complex in terms of pathophysiology. Therefore, one of the priorities of fundamental neurobiology is to elucidate the main morbid mechanisms of Alzheimer's disease as the most common form of dementia. The hypotheses of ß-amyloid and tau protein largely explain the main pathological features of Alzheimer's disease, however, there remains a need for further research on biomarkers with high validity and predictive applicability in people without cognitive impairment and clinical symptoms and in the early stages of the disease. There is a need to intensify the search for effective solutions to slow or stop the progression of the disease, especially therapeutic approaches that modify the disease at the preclinical stage, when it is most beneficial to change its course. At the same time, the discovery of aquaporin-dependent clearance pathways in the brain made it possible to identify new mechanisms underlying the etiology and progression of neurodegeneration and neuroinflammation. Glial-mediated clearance plays a fundamental role in the process of physiological aging, the development of age-related changes in the brain, and neurodegenerative processes. We analyzed 273 articles posted in PubMed database selected by keywords "glymphatic system, Alzheimer's disease, dementia, amyloid Aß, aquaporin, aging, brain clearance". A total of 102 full-text articles were included in this review. This article presents up-to-date evidence on the causes and consequences in the study of the relationship between dysfunction of the glymphatic pathway and the accumulation of pathological proteins with insufficient excretion of toxic metabolites from the brain parenchyma, which is considered a key factor in the development of Alzheimer's dementia.

Non-invasive EEG-based BCI spellers from the beginning to today: a mini-review.

The defeat of the central motor neuron leads to the motor disorders. Patients lose the ability to control voluntary muscles, for example, of the upper limbs, which introduces a fundamental dissonance in the possibility of daily use of a computer or smartphone. As a result, the patients lose the ability to communicate with other people. The article presents the most popular paradigms used in the brain-computer-interface speller system and designed for typing by people with severe forms of the movement disorders. Brain-computer interfaces (BCIs) have emerged as a promising technology for individuals with communication impairments. BCI-spellers are systems that enable users to spell words by selecting letters on a computer screen using their brain activity. There are three main types of BCI-spellers: P300, motor imagery (MI), and steady-state visual evoked potential (SSVEP). However, each type has its own limitations, which has led to the development of hybrid BCI-spellers that combine the strengths of multiple types. Hybrid BCI-spellers can improve accuracy and reduce the training period required for users to become proficient. Overall, hybrid BCI-spellers have the potential to improve communication for individuals with impairments by combining the strengths of multiple types of BCI-spellers. In conclusion, BCI-spellers are a promising technology for individuals with communication impairments. P300, MI, and SSVEP are the three main types of BCI-spellers, each with their own advantages and limitations. Further research is needed to improve the accuracy and usability of BCI-spellers and to explore their potential applications in other areas such as gaming and virtual reality.

Perceptual Integration Compensates for Attention Deficit in Elderly during Repetitive Auditory-Based Sensorimotor Task.

Sensorimotor integration (SI) brain functions that are vital for everyday life tend to decline in advanced age. At the same time, elderly people preserve a moderate level of neuroplasticity, which allows the brain's functionality to be maintained and slows down the process of neuronal degradation. Hence, it is important to understand which aspects of SI are modifiable in healthy old age. The current study focuses on an auditory-based SI task and explores: (i) if the repetition of such a task can modify neural activity associated with SI, and (ii) if this effect is different in young and healthy old age. A group of healthy older subjects and young controls underwent an assessment of the whole-brain electroencephalography (EEG) while repetitively executing a motor task cued by the auditory signal. Using EEG spectral power and functional connectivity analyses, we observed a differential age-related modulation of theta activity throughout the repetition of the SI task. Growth of the anterior stimulus-related theta oscillations accompanied by enhanced right-lateralized frontotemporal phase-locking was found in elderly adults. Their young counterparts demonstrated a progressive increase in prestimulus occipital theta power. Our results suggest that the short-term repetition of the auditory-based SI task modulates sensory processing in the elderly. Older participants most likely progressively improve perceptual integration rather than attention-driven processing compared to their younger counterparts.

Properties of TiAlN Coatings Obtained by Dual-HiPIMS with Short Pulses.

The paper focuses on the dual high-power impulse magnetron sputtering of TiAlN coatings using short pulses of high power delivered to the target. The surface morphology, elemental composition, phase composition, hardness, wear resistance, and adhesive strength of TiAlN coatings with different Al contents were investigated on WC-Co substrates. The heat resistance of the TiAlN coating was determined with synchrotron X-ray diffraction. The hardness of the TiAlN coating with a low Al content ranged from 17 to 30 GPa, and its wear rate varied between 1.8∙10-6 and 4.9∙10-6 mm3·N-1·m-1 depending on the substrate bias voltage. The HF1-HF2 adhesion strength of the TiAlN coatings was evaluated with the Daimler-Benz Rockwell C test. The hardness and wear rate of the Ti0.61Al0.39N coating were 26.5 GPa and 5.2∙10-6 mm3·N-1·m-1, respectively. The annealing process at 700 °C considerably worsened the mechanical properties of the Ti0.94Al0.06N coating, in contrast to the Ti0.61Al0.39N coating, which manifested a high oxidation resistance at annealing temperatures of 940-950 °C.

Twice-daily oral administration of a cannabidiol and cannabidiolic acid-rich hemp extract was well tolerated in orange-winged Amazon parrots (Amazona amazonica) and has a favorable pharmacokinetic profile.

OBJECTIVE: To determine the pharmacokinetics of 8 cannabinoids and 5 metabolites after oral administration of single and multiple doses of a cannabidiol (CBD)-cannabidiolic acid (CBDA)-rich hemp extract to orange-winged Amazon parrots (Amazona amazonica) as well as to evaluate the extract's adverse effects. ANIMALS: 12 birds. PROCEDURES: Based on pilot studies, a single-dose study based on 30/32.5 mg/kg of cannabidiol/cannabidiolic acid of a hemp extract was administered orally to 8 fasted parrots, and 10 blood samples were collected over 24 hours after administration. After a 4-week washout period, the hemp extract was administered orally to 7 birds at the previous dose every 12 hours for 7 days, and blood samples were collected at the previous time points. Cannabidiol, Δ9-tetrahydrocannabinol, cannabinol, cannabichromene, cannabigerol, cannabidiolic acid, cannabigerolic acid, Δ9-tetrahydrocannabinolic acid, and 5 specific metabolites were measured by liquid chromatography-tandem/mass-spectrometry, and pharmacokinetic parameters were calculated. Adverse effects and changes in the plasma biochemistry and lipid panels were evaluated. RESULTS: Pharmacokinetic parameters for cannabidiol, cannabidiolic acid, Δ9-tetrahydrocannabinol, Δ9-tetrahydrocannabinolic acid, and the metabolite 11-hydroxy-9-tetrahydrocannabinol were established. For the multiple-dose study, cannabidiol/cannabidiolic acid mean Cmax was 337.4/602.1 ng/mL with a tmax of 30 minutes and a terminal half-life of 8.6/6.29 hours, respectively. No adverse effects were detected during the multidose study. The predominant metabolite was 11-hydroxy-9-tetrahydrocannabinol. CLINICAL RELEVANCE: Twice daily oral administration of the hemp extract based on 30 mg/kg/32.5 mg/kg of cannabidiol/cannabidiolic acid was well tolerated and maintained plasma concentrations considered to be therapeutic in dogs with osteoarthritis. Findings suggest different cannabinoid metabolism from mammals.

Clinical and neurophysiological characteristics of 89 patients with narcolepsy and cataplexy from the Russian Narcolepsy Network.

STUDY OBJECTIVES: The first reports of narcolepsy with cataplexy in Russia were made by Mankovsky (The pathogenesis of narcolepsy (the case of epidemic encephalitis with cataplexy) published in the Sovremennaya psihonevrologia) in 1925. The largest series of patients (n = 110) was reported by A. Vein (doctoral thesis: Hypersomnia Syndrome) in 1964. However, until today, narcolepsy remained relatively unknown in Russia. The aim of this study is to report clinical and polysomnography (PSG)/multiple sleep latency test (MSLT) results in the Russian population and compare them with the European Narcolepsy Network (EU-NN) data (n = 1099) reported. METHODS: Eleven sleep centers from Russia agreed to participate and completed a questionnaire including 58 questions concerning demographic, clinical, PSG, and MSLT data. RESULTS: There were 89 patients with a mean age of 35.6 ± 16.9 years (± here and further indicates standard deviation), 58% males, and 42% females. Narcolepsy started at a mean age of 25.6 ± 14.6 years (range 5-74 years). The mean Epworth Sleepiness Scale score was 18.4 ± 3.5 points (range: 11-24). Sleep paralysis was reported by 59.1%, and hallucinations by 82% of patients. In MSLT, ≥ 2 sleep-onset REM (rapid eye movement) periods (SOREMPs) were found in 81.6%. No center provided human leukocyte antigen (HLA) or cerebral spinal fluid hypocretin data. CONCLUSIONS: Clinical and neurophysiological data from this first study of the Russian Narcolepsy Network suggest a similar profile to the recently reported EU-NN data. The more severe and higher percentage of patients with cataplexy and presenting with both excessive daytime sleepiness and cataplexy may reflect low awareness of narcolepsy in Russia. CLINICAL TRIAL REGISTRATION: Registry: ClinicalTrials.gov; URL: https://clinicaltrials.gov/ct2/show/NCT05375890; Name: Clinical and Neurophysiological Characteristics of Narcolepsy; Identifier: NCT05375890. CITATION: Kuts A, Poluektov M, Zakharov A, et al. Clinical and neurophysiological characteristics of 89 patients with narcolepsy and cataplexy from the Russian Narcolepsy Network. J Clin Sleep Med. 2023;19(2):355-359.

Analysis of herpesvirus infection and genome single nucleotide polymorphism risk factors in multiple sclerosis, Volga federal district, Russia.

Multiple sclerosis (MS) is a heterogeneous disease where herpesvirus infection and genetic predisposition are identified as the most consistent risk factors. Serum and blood samples were collected from 151 MS and 70 controls and used to analyze circulating antibodies for, and DNA of, Epstein Barr virus (EBV), human cytomegalovirus (HCMV), human herpes virus 6 (HHV6), and varicella zoster virus (VZV). The frequency of selected single nucleotide polymorphisms (SNPs) in MS and controls were studied. Herpesvirus DNA in blood samples were analyzed using qPCR. Anti-herpesvirus antibodies were detected by ELISA. SNPs were analyzed by the allele-specific PCR. For statistical analysis, Fisher exact test, odds ratio and Kruskall-Wallis test were used; p<0.05 values were considered as significant. We have found an association between circulating anti-HHV6 antibodies and MS diagnosis. We also confirmed higher frequency of A and C alleles in rs2300747 and rs12044852 of CD58 gene and G allele in rs929230 of CD6 gene in MS as compared to controls. Fatigue symptom was linked to AC and AA genotype in rs12044852 of CD58 gene. An interesting observation was finding higher frequency of GG genotype in rs12722489 of IL2RA and T allele in rs1535045 of CD40 genes in patient having anti-HHV6 antibodies. A link was found between having anti-VZV antibodies in MS and CC genotype in rs1883832 of CD40 gene.

(Cr1-xAlx)N Coating Deposition by Short-Pulse High-Power Dual Magnetron Sputtering.

The paper deals with the (Cr1-xAlx)N coating containing 17 to 54 % Al which is deposited on AISI 430 stainless steel stationary substrates by short-pulse high-power dual magnetron sputtering of Al and Cr targets. The Al/Cr ratio in the coating depends on the substrate position relative to magnetrons. It is shown that the higher Al content in the (Cr1-xAlx)N coating improves its hardness from 17 to 28 GPa. Regardless of the Al content, the (Cr1-xAlx)N coating manifests a low wear rate, namely (4.1-7.8) × 10-9 and (3.9-5.3) × 10-7 mm3N-1m-1 in using metallic (100Cr6) and ceramic (Al2O3) counter bodies, respectively. In addition, this coating possesses the friction coefficient 0.4-0.7 and adhesive strength quality HF1 and HF2 indicating good interfacial adhesion according to the Daimler-Benz Rockwell-C adhesion test.

The Effects of Transcranial Magnetic Stimulation on Cognitive Functioning in Bipolar Depression: A Systematic Review.

BACKGROUND: The features of bipolar affective disorder (BAD) include mood swings, recurring episodes of mania, depression, and mixed states. Numerous studies of people living with BAD have found the presence of cognitive impairments that affect patients' daily social functioning and quality of life. Transcranial magnetic stimulation (TMS) is a non-invasive brain stimulation technique recommended for the treatment of bipolar depression (BD). The effect of TMS on cognitive function in BD patients remains mostly unclear. SUBJECTS AND METHODS: We carried out a systematic search in the databases of PubMed and Scopus for the whole publication period until March 30th, 2022. PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analysis) was used to identify all data published in English language and related to the use of TMS in the treatment of depression in BAD and its impact on cognitive function. Articles related to TMS, cognition, and BD were identified using predefined term search algorithms. Articles on clinical trials and case reports were included, but reviews were excluded. The PICOS (Population Intervention Comparison Outputs Study) formula in our review included: P - patients with bipolar depression, I - TMS treatment, C - patients without TMS treatment / placebo TMS, O - changes in cognitive functions, S - all types of original studies. RESULTS: Within the primary screening for assessment of full texts, 25 documents met our selection criteria to test the effect of TMS on cognitive functioning in BD. Based on a secondary screening of the full-text analysis, 10 articles (N=259 patients) were included into the current review. Among these, the majority of articles were based on the randomized controlled trials (RCTs, N=6), whereas the remaining four presented a case report, an open unblinded study, an open-label study, and a pilot study, respectively. Most of the studies produced mixed result. However, the limited data strongly suggested that TMS is without detriment to cognition in BD patients and is indeed beneficial in specific domains of cognitive function, namely (i) verbal fluency, (ii) verbal memory, and (iii) executive functioning. Small sample sizes, heterogeneity across the study designs, lack of the control groups data in some of the trials, different TMS protocols parameters and outcome measures represent significant limitations for comparing and analyzing the available results. CONCLUSIONS: Thus, present data on the effects of TMS in improving cognition in BD patients remains limited. To our mind, in order to evaluate properly the effectiveness of TMS in cognitive functioning improvement in BD, there is need for further randomized controlled trials and the corresponding development of the clinical standards for research recommendations. Such studies could define the appropriate methods for valid assessments of cognitive functions, and guide the selection of optimal TMS protocols when planning RCTs. We suggest that efforts should be expended to organize centralized large-scale clinical trials to determine the optimal parameters of TMS procedures and the range of effects of this treatment on various indicators of cognitive functioning in BD. This applies equally to other socially significant mental disorders marked by perturbations in cognitive functioning.

A Panchromatic Cyclometalated Iridium Dye Based on 2-Thienyl-Perimidine.

Though 2-arylperimidines have never been used in iridium(III) chemistry, the present study on structural, electronic and optical properties of N-unsubstituted and N-methylated 2-(2-thienyl)perimidines, supported by DFT/TDDFT calculations, has shown that these ligands are promising candidates for construction of light-harvesting iridium(III) complexes. In contrast to N-H perimidine, the N-methylated ligand gave the expected cyclometalated µ-chloro-bridged iridium(III) dimer which was readily converted to a cationic heteroleptic complex with 4,4'-dicarboxy-2,2'-bipyridine. The resulting iridium(III) dye exhibited panchromatic absorption up to 1000 nm and was tested in a dye-sensitized solar cell.

Single dose and chronic oral administration of cannabigerol and cannabigerolic acid-rich hemp extract in fed and fasted dogs: Physiological effect and pharmacokinetic evaluation.

The use of cannabinoids in veterinary medicine has been increasing exponentially recently and there is little information regarding the pharmacokinetics of cannabinoids except for cannabidiol (CBD) and tetrahydrocannabinol (THC), with even more sparse information related to their native acid forms found in cannabis. Cannabigerol (CBG) is the precursor molecule to cannabinoid formation in the cannabis plant which may have medicinal properties as well, yet there are no publications related to CBG or the native cannabigerolic acid (CBGA) in companion animal species. The aim of this study was to investigate similar dosing of CBG and CBGA from hemp plants that have been used for cannabidiol pharmacokinetic studies. Administration in the fed and fasted state was performed to better understand absorption and retention of these unique hemp-derived cannabinoids in dogs. Results suggest that when providing a hemp-derived CBG/CBGA formulation in equal quantities, CBGA is absorbed approximately 40-fold better than CBG regardless of being given to fed or fasted dogs. After twice daily dosing for two weeks at 2 mg/kg in the fasted and then fed state, no differences in the mean serum CBG (5 ng/ml) or CBGA (250 ng/ml) serum concentrations were observed between states. Importantly, physical examination, complete blood counts, and serum chemistry evaluations over the two weeks suggest no adverse events during this short-term dosing trial.

Syntheses and crystal structures of 2-(p-tol-yl)-1H-perimidine hemihydrate and 1-methyl-2-(p-tol-yl)-1H-perimidine.

The title compounds, 2-(4-methylphenyl)-1H-perimidine hemihydrate (1, C18H14N2·0.5H2O) and 1-methyl-2-(4-methylphenyl)-1H-perimidine (2, C19H16N2), were prepared and characterized by 1H NMR and single-crystal X-ray diffraction. The organic mol-ecule of the hemihydrate lies on a twofold rotation axis while the water mol-ecule lies on the inter-section of three twofold rotation axes (point group symmetry 222). As a consequence, the hydrogen atoms that are part of the N-H group and the water mol-ecule as well as the CH3 group of the p-tolyl ring are disordered over two positions. In compound 1, the perimidine and the 2-aryl rings are slightly twisted while its N-methyl-ated derivative 2 has a more distorted conformation because of the steric repulsion between the N-methyl group and the 2-aryl ring. In the crystal structures, mol-ecules of perimidine 2 are held together only by C-H⋯π contacts while the parent perimidine 1 does not exhibit this type of inter-action. Its crystal packing is established by inter-molecular N-H⋯O hydrogen bonds with the solvent water mol-ecules and additionally stabilized by π-π stacking.

Occurrences of Threatened Species included in the Third Edition of the Red Data Book of the Komi Republic (Russia).

BACKGROUND: The purpose of the data paper was to introduce into scientific literature the results of scientific work carried out for the third edition of the 'Red Data Book of the Komi Republic'. The article reflects methodological approaches to the formation of a list of rare and in need of protection species and describes the corresponding datasets published in GBIF. NEW INFORMATION: Information about 7,187 occurrences of 438 rare species and infraspecies included in the third edition of the 'Red Data Book of the Komi Republic' have been published.

Synthesis and comparative structural study of 2-(pyridin-2-yl)-1H-perimidine and its mono- and di-N-methyl-ated analogues.

The title compounds, 2-(pyridin-2-yl)-1H-perimidine (C16H11N3; 1), 1-methyl-2-(pyridin-2-yl)-1H-perimidine (C17H13N3; 2), and 1,3-dimethyl-2-(pyridin-2-yl)-1H-perimidinium iodide (C18H16N3 +·I-; 3) were synthesized under mild conditions and their structures were determined by 1H NMR spectroscopy and single-crystal X-ray analysis. The N-methyl-ation of the nitro-gen atom(s) at the perimidine moiety results in a significant increase of the inter-plane angle between the pyridin-2-yl ring and the perimidine system. The unsubstituted perimidine (1) forms a weak intra-molecular N-H⋯N bond that consolidates the mol-ecular conformation. In the crystal structures of 1-3, the mol-ecular entities all are assembled through π-π and C-H⋯π inter-actions.

Pharmacokinetics of Cannabidiol, Cannabidiolic Acid, Δ9-Tetrahydrocannabinol, Tetrahydrocannabinolic Acid and Related Metabolites in Canine Serum After Dosing With Three Oral Forms of Hemp Extract.

Cannabidiol (CBD)-rich hemp extract use is increasing in veterinary medicine with little examination of serum cannabinoids. Many products contain small amounts of Δ9-tetrahydrocannabinol (THC), and precursor carboxylic acid forms of CBD and THC known as cannabidiolic acid (CBDA) and tetrahydrocannabinolic acid (THCA). Examination of the pharmacokinetics of CBD, CBDA, THC, and THCA on three oral forms of CBD-rich hemp extract that contained near equal amounts of CBD and CBDA, and minor amounts (<0.3% by weight) of THC and THCA in dogs was performed. In addition, we assess the metabolized psychoactive component of THC, 11-hydroxy-Δ9-tetrahydrocannabinol (11-OH-THC) and CBD metabolites 7-hydroxycannabidiol (7-OH-CBD) and 7-nor-7-carboxycannabidiol (7-COOH-CBD) to better understand the pharmacokinetic differences between three formulations regarding THC and CBD, and their metabolism. Six purpose-bred female beagles were utilized for study purposes, each having an initial 7-point, 24-h pharmacokinetic study performed using a dose of 2 mg/kg body weight of CBD/CBDA (~1 mg/kg CBD and ~1 mg/kg CBDA). Dogs were then dosed every 12 h for 2 weeks and had further serum analyses at weeks 1 and 2, 6 h after the morning dose to assess serum cannabinoids. Serum was analyzed for each cannabinoid or cannabinoid metabolite using liquid chromatography and tandem mass spectroscopy (LC-MS/MS). Regardless of the form provided (1, 2, or 3) the 24-h pharmacokinetics for CBD, CBDA, and THCA were similar, with only Form 2 generating enough data above the lower limit of quantitation to assess pharmacokinetics of THC. CBDA and THCA concentrations were 2- to 3-fold higher than CBD and THC concentrations, respectively. The 1- and 2-week steady-state concentrations were not significantly different between the two oils or the soft chew forms. CBDA concentrations were statistically higher with Form 2 than the other forms, showing superior absorption/retention of CBDA. Furthermore, Form 1 showed less THCA retention than either the soft chew Form 3 or Form 2 at weeks 1 and 2. THC was below the quantitation limit of the assay for nearly all samples. Overall, these findings suggest CBDA and THCA are absorbed or eliminated differently than CBD or THC, respectively, and that a partial lecithin base provides superior absorption and/or retention of CBDA and THCA.

Serum cannabidiol, tetrahydrocannabinol (THC), and their native acid derivatives after transdermal application of a low-THC Cannabis sativa extract in beagles.

Cannabinoids hold promise for treating health problems related to inflammation and chronic pain in dogs, in particular cannabidiol (CBD), and its native acid derivative cannabidiolic acid (CBDA). Information regarding systemic delivery of cannabinoids through transdermal routes is sparse. The purpose of this study was to determine pharmacokinetics of transdermal administration of a low-THC Cannabis sativa extract in healthy dogs. Six purpose-bred research beagles were treated with a transdermal CBD-CBDA-rich extract, and serum concentrations of CBD, CBDA, tetrahydrocannabinol (THC), and its acid derivative tetrahydrocannabinolic acid (THCA) were examined prior to and at the end of weeks 1 and 2. A 4 mg/kg dose of total cannabinoids twice daily resulted in appx 10 ng/ml of CBD, 21-32 ng/ml of CBDA, trace amounts of THCA, and unquantifiable amounts of THC in serum at the end of weeks 1 and 2 of treatment. Results showed that CBDA and THCA were absorbed better systemically than CBD or THC.

High-loading Gα13-binding EXE peptide nanoparticles prevent thrombosis and protect mice from cardiac ischemia/reperfusion injury.

Inefficient delivery is a major obstacle to the development of peptide-based drugs targeting the intracellular compartment. We recently showed that selectively inhibiting integrin outside-in signaling using a peptide (mP6) derived from the Gα13-binding ExE motif within the integrin ß3 cytoplasmic domain had antithrombotic effects. Here, we engineered lipid-stabilized, high-loading peptide nanoparticles (HLPN), in which a redesigned ExE peptide (M3mP6) constituted up to 70% of the total nanoparticle molarity, allowing efficient in vivo delivery. We observed that M3mP6 HLPN inhibited occlusive thrombosis more potently than a clopidogrel/aspirin combination without adverse effects on hemostasis in rodents. Furthermore, M3mP6 HLPN synergized with P2Y12 receptor inhibitors or the clopidogrel/aspirin combination in preventing thrombosis, without exacerbating hemorrhage. M3mP6 HLPN also inhibited intravascular coagulation more potently than the P2Y12 inhibitor cangrelor. Postischemia injection of M3mP6 HLPN protected the heart from myocardial ischemia-reperfusion injury in a mouse model. This study demonstrates an efficient in vivo peptide delivery strategy for a therapeutic that not only efficaciously prevented thrombosis with minimal bleeding risk but also protected from myocardial ischemia-reperfusion injury in mice.

Stroke Affected Lower Limbs Rehabilitation Combining Virtual Reality With Tactile Feedback.

In our study, we tested a combination of virtual reality (VR) and robotics in the original adjuvant method of post-stroke lower limb walk restoration in acute phase using a simulation with visual and tactile biofeedback based on VR immersion and physical impact to the soles of patients. The duration of adjuvant therapy was 10 daily sessions of 15 min each. The study showed the following significant rehabilitation progress in Control (N = 27) vs. Experimental (N = 35) groups, respectively: 1.56 ± 0.29 (mean ± SD) and 2.51 ± 0.31 points by Rivermead Mobility Index (p = 0.0286); 2.15 ± 0.84 and 6.29 ± 1.20 points by Fugl-Meyer Assessment Lower Extremities scale (p = 0.0127); and 6.19 ± 1.36 and 13.49 ± 2.26 points by Berg Balance scale (p = 0.0163). P-values were obtained by the Mann-Whitney U test. The simple and intuitive mechanism of rehabilitation, including through the use of sensory and semantic components, allows the therapy of a patient with diaschisis and afferent and motor aphasia. Safety of use allows one to apply the proposed method of therapy at the earliest stage of a stroke. We consider the main finding of this study that the application of rehabilitation with implicit interaction with VR environment produced by the robotics action has measurable significant influence on the restoration of the affected motor function of the lower limbs compared with standard rehabilitation therapy.