Inhibitory effects and mechanisms of the anti-covid-19 traditional Chinese prescription, Keguan-1, on acute lung injury.

ETHNOPHARMACOLOGICAL RELEVANCE: Keguan-1, a new traditional Chinese medicine (TCM) prescription contained seven Chinese herbs, is developed to treat coronavirus disease 19 (COVID-19). The first internationally registered COVID-19 randomised clinical trial on integrated therapy demonstrated that Keguan-1 significantly reduced the incidence of ARDS and inhibited the severe progression of COVID-19. AIM OF THE STUDY: To investigate the protective mechanism of Keguan-1 on ARDS, a lipopolysaccharide (LPS)-induced acute lung injury (ALI) model was used to simulate the pathological state of ARDS in patients with COVID-19, focusing on its effect and mechanism on ALI. MATERIALS AND METHODS: Mice were challenged with LPS (2 mg/kg) by intratracheal instillation (i.t.) and were orally administered Keguan-1 (low dose, 1.25 g/kg; medium dose, 2.5 g/kg; high dose, 5 g/kg) after 2 h. Bronchoalveolar lavage fluid (BALF) and lung tissue were collected 6 h and 24 h after i.t. administration of LPS. The levels of inflammatory factors tumour necrosis factor alpha (TNF-α), interleukin (IL)-6, IL-1ß, keratinocyte-derived chemokine (KC or mCXCL1), macrophage inflammatory protein 2 (MIP2 or mCXCL2), angiotensin II (Ang II), and endothelial cell junction-associated proteins were analysed using ELISA or western blotting. RESULTS: Keguan-1 improved the survival rate, respiratory condition, and pathological lung injury; decreased the production of proinflammatory factors (TNF-α, IL-6, IL-1ß, KC, and MIP2) in BALF and the number of neutrophils in the lung tissues; and ameliorated inflammatory injury in the lung tissues of the mice with LPS-induced ALI. Keguan-1 also reduced the expression of Ang II and the adhesion molecule ICAM-1; increased tight junction proteins (JAM-1 and claudin-5) and VE-cadherin expression; and alleviated pulmonary vascular endothelial injury in LPS-induced ALI. CONCLUSION: These results demonstrate that Keguan-1 can improve LPS-induced ALI by reducing inflammation and pulmonary vascular endothelial injury, providing scientific support for the clinical treatment of patients with COVID-19. Moreover, it also provides a theoretical basis and technical support for the scientific use of TCMs in emerging infectious diseases.

Acute L-Citrulline Supplementation Increases Nitric Oxide Bioavailability but Not Inspiratory Muscle Oxygenation and Respiratory Performance.

The present study aimed to investigate whether acute L-citrulline supplementation would affect inspiratory muscle oxygenation and respiratory performance. Twelve healthy males received 6 g of L-citrulline or placebo in a double-blind crossover design. Pulmonary function (i.e., forced expired volume in 1 s, forced vital capacity and their ratio), maximal inspiratory pressure (MIP), fractional exhaled nitric oxide (NO•), and sternocleidomastoid muscle oxygenation were measured at baseline, one hour post supplementation, and after an incremental resistive breathing protocol to task failure of the respiratory muscles. The resistive breathing task consisted of 30 inspirations at 70% and 80% of MIP followed by continuous inspirations at 90% of MIP until task failure. Sternocleidomastoid muscle oxygenation was assessed using near-infrared spectroscopy. One-hour post-L-citrulline supplementation, exhaled NO• was significantly increased (19.2%; p < 0.05), and this increase was preserved until the end of the resistive breathing (16.4%; p < 0.05). In contrast, no difference was observed in the placebo condition. Pulmonary function and MIP were not affected by the L-citrulline supplementation. During resistive breathing, sternocleidomastoid muscle oxygenation was significantly reduced, with no difference noted between the two supplementation conditions. In conclusion, a single ingestion of 6 g L-citrulline increased NO• bioavailability but not the respiratory performance and inspiratory muscle oxygenation.

Mechanism deconvolution of Qing Fei Pai Du decoction for treatment of Coronavirus Disease 2019 (COVID-19) by label-free integrative pharmacology assays.

ETHNOPHARMACOLOGICAL RELEVANCE: Traditional Chinese medicine (TCM) has a long history in the prevention and treatment of pandemics. The TCM formula Lung Cleansing and Detoxifying Decoction (LCDD), also known as Qing Fei Pai Du Decoction, has been demonstrated effective against Coronavirus Disease 2019 (COVID-19). AIM OF THE STUDY: This work aimed to elucidate the active ingredients, targets and pathway mechanism of LCDD related to suppression of inflammatory, immunity regulation and relaxation of airway smooth muscle for the treatment of COVID-19. MATERIALS AND METHODS: Mining chemical ingredients reported in LCDD, 144 compounds covering all herbs were selected and screened against inflammatory-, immunity- and respiratory-related GPCRs including GPR35, H1, CB2, B2, M3 and ß2-adrenoceptor receptor using a label-free integrative pharmacology method. Further, all active compounds were detected using liquid chromatography-tandem mass spectrometry, and an herb-compound-target network based on potency and content of compounds was constructed to elucidate the multi-target and synergistic effect. RESULTS: Thirteen compounds were identified as GPR35 agonists, including licochalcone B, isoliquiritigenin, etc. Licochalcone B, isoliquiritigenin and alisol A exhibited bradykinin receptor B2 antagonism activities. Atractyline and shogaol showed as a cannabinoid receptor CB2 agonist and a histamine receptor H1 antagonist, respectively. Tectorigenin and aristofone acted as muscarinic receptor M3 antagonists, while synephrine, ephedrine and pseudoephedrine were ß2-adrenoceptor agonists. Pathway deconvolution assays suggested activation of GPR35 triggered PI3K, MEK, JNK pathways and EGFR transactivation, and the activation of ß2-adrenoceptor mediated MEK and Ca2+. The herb-compound-target network analysis found that some compounds such as licochalcone B acted on multiple targets, and multiple components interacted with the same target such as GPR35, reflecting the synergistic mechanism of Chinese medicine. At the same time, some low-abundance compounds displayed high target activity, meaning its important role in LCDD for anti-COVID-19. CONCLUSIONS: This study elucidates the active ingredients, targets and pathways of LCDD. This is useful for elucidating multitarget synergistic action for its clinical therapeutic efficacy.

Acute Beetroot Juice Ingestion Does Not Alter Renal Hemodynamics during Normoxia and Mild Hypercapnia in Healthy Young Adults.

Arterial hypercapnia reduces renal perfusion. Beetroot juice (BRJ) increases nitric oxide bioavailability and may improve renal blood flow. We tested the hypothesis that acute consumption of BRJ attenuates both decreases in blood velocity and increases in vascular resistance in the renal and segmental arteries during acute hypercapnia. In fourteen healthy young adults, blood velocity and vascular resistance were measured with Doppler ultrasound in the renal and segmental arteries during five minutes of breathing a carbon dioxide gas mixture (CO2) before and three hours after consuming 500 mL of BRJ. There was no difference between pre- and post-BRJ consumption in the increase in the partial pressure of end-tidal CO2 during CO2 breathing (pre: +4 ± 1 mmHg; post: +4 ± 2 mmHg, p = 0.4281). Segmental artery blood velocity decreased during CO2 breathing in both pre- (by -1.8 ± 1.9 cm/s, p = 0.0193) and post-BRJ (by -2.1 ± 1.9 cm/s, p = 0.0079), but there were no differences between pre- and post-consumption (p = 0.7633). Segmental artery vascular resistance increased from room air baseline during CO2 at pre-BRJ consumption (by 0.4 ± 0.4 mmHg/cm/s, p = 0.0153) but not post-BRJ (p = 0.1336), with no differences between pre- and post-consumption (p = 0.7407). These findings indicate that BRJ consumption does not attenuate reductions in renal perfusion during acute mild hypercapnia in healthy young adults.

Increased cardiorespiratory stress during submaximal cycling after ketone monoester ingestion in endurance-trained adults.

There is growing interest in the effect of exogenous ketone body supplementation on exercise responses and performance. The limited studies to date have yielded equivocal data, likely due in part to differences in dosing strategy, increase in blood ketones, and participant training status. Using a randomized, double-blind, counterbalanced design, we examined the effect of ingesting a ketone monoester (KE) supplement (600 mg/kg body mass) or flavour-matched placebo in endurance-trained adults (n = 10 males, n = 9 females; V̇O2peak = 57 ± 8 mL/kg/min). Participants performed a 30-min cycling bout at ventilatory threshold intensity (71 ± 3% V̇O2peak), followed 15 min later by a 3 kJ/kg body mass time-trial. KE versus placebo ingestion increased plasma ß-hydroxybutyrate concentration before exercise (3.9 ± 1.0 vs 0.2 ± 0.3 mM, p < 0.0001, dz = 3.4), ventilation (77 ± 17 vs 71 ± 15 L/min, p < 0.0001, dz = 1.3) and heart rate (155 ± 11 vs 150 ± 11 beats/min, p < 0.001, dz = 1.2) during exercise, and rating of perceived exertion at the end of exercise (15.4 ± 1.6 vs 14.5 ± 1.2, p < 0.01, dz = 0.85). Plasma ß-hydroxybutyrate concentration remained higher after KE vs placebo ingestion before the time-trial (3.5 ± 1.0 vs 0.3 ± 0.2 mM, p < 0.0001, dz = 3.1), but performance was not different (KE: 16:25 ± 2:50 vs placebo: 16:06 ± 2:40 min:s, p = 0.20; dz = 0.31). We conclude that acute ingestion of a relatively large KE bolus dose increased markers of cardiorespiratory stress during submaximal exercise in endurance-trained participants. Novelty: Limited studies have yielded equivocal data regarding exercise responses after acute ketone body supplementation. Using a randomized, double-blind, placebo-controlled, counterbalanced design, we found that ingestion of a large bolus dose of a commercial ketone monoester supplement increased markers of cardiorespiratory stress during cycling at ventilatory threshold intensity in endurance-trained adults.

The effects of temperature on oil-induced respiratory impairment in red drum (Sciaenops ocellatus).

The 2010 Deepwater Horizon (DWH) crude oil spill, among the largest environmental disasters in U.S. history, affected numerous economically important fishes. Exposure to crude oil can lead to reduced cardiac function, limiting oxygen transport, ATP production, and aerobic performance. However, crude oil exposure is not the only stressor that affects aerobic performance, and increasing environmental temperatures are known to significantly increase metabolic demands in fishes. As the DWH spill was active during warm summer months in the Gulf of Mexico, it is important to understand the combined effects of oil and temperature on a suite of metabolic parameters. Therefore, we investigated the effects of 24h crude oil exposure on the aerobic metabolism and hypoxia tolerance of red drum (Sciaenops ocellatus) following 3 week chronic exposure to four ecologically relevant temperatures (18 °C, 22 °C, 25 °C, 28 °C). Our results show that individuals acclimated to higher temperatures had significantly higher standard metabolic rate than individuals at lower temperatures, which resulted in significantly decreased critical oxygen threshold and reduced recovery from exercise. As predicted, crude oil exposure resulted in lower maximum metabolic rates (MMR) across the temperature range, and a significantly reduced ability to recover from exercise. The lowest temperature acclimation showed the smallest effect of oil on MMR, while the highest temperature showed the smallest effect on exercise recovery. Reduced respiratory performance and hypoxia tolerance are likely to have meaningful impacts on the fitness of red drum, especially with climate-induced temperature increases and continued oil exploration in the Gulf of Mexico.

Central deficiency of norepinephrine synthesis and norepinephrinergic neurotransmission contributes to seizure-induced respiratory arrest.

Sudden unexpected death in epilepsy (SUDEP) is the leading cause of mortality in patients with intractable epilepsy. However, the pathogenesis of SUDEP seems to be poorly understood. Our previous findings showed that the incidence of seizure-induced respiratory arrest (S-IRA) was markedly reduced by atomoxetine in a murine SUDEP model. Because the central norepinephrine α-1 receptor (NEα-1R) plays a vital role in regulating respiratory function, we hypothesized that the suppression of S-IRA by atomoxetine was mediated by NE/NEα-1R interactions that can be reversed by NEα-1R antagonism. We examined whether atomoxetine-mediated suppression of S-IRA evoked by either acoustic stimulation or pentylenetetrazole (PTZ) in DBA/1 mice can be reversed by intraperitoneal (IP) and intracerebroventricular (ICV) administration of prazosin, a selective antagonist of NEα-1R. The content and activity of tyrosine hydroxylase (TH), a rate-limiting enzyme for NE synthesis, in the lower brainstem was measured by ELISA. Electroencephalograms (EEG) were obtained from using the PTZ-evoked SUDEP model. In our models, atomoxetine-mediated suppression of S-IRA evoked by either acoustic stimulation or PTZ was significantly reversed by low doses of IP and ICV prazosin. Neither repetitive acoustic stimulation nor S-IRA reduced TH levels in lower brainstem. However, the enzyme activity of TH levels in lower brainstem was significantly increased by mechanical ventilation with DBA/1 mice, which makes the dying DBA/1 mice suffering from S-IRA and SUDEP recover. EEG data showed that although the protective effect of atomoxetine was reversed by prazosin, neither drug suppressed EEG activity. These data suggest that deficient synthesis of NE and norepinephrinergic neurotransmission contributed to S-IRA and that the NEα-1R is a potential therapeutic target for the prevention of SUDEP.

Acute carnosine and ß-alanine supplementation increase the compensated part of the ventilation versus work rate relationship during a ramp incremental cycle test in physically active men.

BACKGROUND: Chronic supplementation with carnosine and ß-alanine (Carn-ßA) has been proposed to improve muscle contractility and reduce muscle fatigue mainly through an increase in intracellular pH buffering capacity. However, the acute ergogenic effects of Carn-ßA supplementation are poorly investigated. This study aimed at evaluating the acute effects of a single Carn-ßA supplementation on the cardiorespiratory and metabolic response during a ramp cycle-ergometric test. METHODS: This randomized, double-blind, placebo-controlled study, involved 10 healthy males (age: 22.2±1.9 years, body mass: 72.5±7.9 kg, stature: 1.72±0.08 m, Body Mass Index: 24.47±1.91 kg/m2, mean±standard deviation). All the participants performed two maximal incremental ramp tests on a cycle ergometer, with a prior randomized assumption of 2.5 g L-carnosine plus 2.5 g ß-alanine (Carn-ßA) or placebo (PLA). During exercise, gas exchange parameters were measured breath-by-breath, heart rate was monitored by electrocardiography and rate perceived exertion was determined on Borg scales. From the ramp test, peak cardiorespiratory and metabolic parameters and ventilatory thresholds (VT1 and VT2) were calculated offline. RESULTS: No differences between the experimental conditions emerged at peak exercise. However, despite acute Carn-ßA supplementation did not affect the single ventilatory thresholds, the compensated portion of the ramp test (i.e. the difference between VT2 and VT1) was significantly larger (P=0.043) in Carn-ßA. CONCLUSIONS: These findings demonstrate a positive effect of acute Carn-ßA supplementation on the compensated part of the exercise. This should be taken into account by nutritionists and athletes searching for nutritional supplements, when a quick effect based on an acute dose is required.

QOLEC2: a randomized controlled trial on nutritional and respiratory counseling after esophagectomy for cancer.

BACKGROUND: Esophagectomy for cancer strongly impairs quality of life. The aim of this trial was to evaluate the effect of the nutritional and respiratory counseling on postoperative quality of life. METHODS: At hospital discharge, patients were randomized into four groups receiving respectively: nutritional and respiratory counseling, nutritional counseling alone, respiratory counseling alone, or standard care. The main endpoint was the impairment in quality of life in the first month after surgery. Linear mixed effect models were estimated to assess mean score differences (MDs) in quality of life scores. RESULTS: Patients receiving nutritional counseling reported less appetite loss (MD - 17.7, 95% CI - 32.2 to -3.3) than those not receiving nutritional counseling at 1 month after surgery. Dyspnea was similar between patients receiving vs. those not receiving respiratory counseling (MD - 3.1, 95% CI - 10.8 to 4.6). Global quality of life was clinically similar between patients receiving vs. those not receiving nutritional counseling over time (MD 0.9, 95% CI - 5.5 to 7.3), as well as in patients receiving vs. those not receiving respiratory counseling over time (MD 0.7, 95% CI - 5.9 to 7.2). CONCLUSIONS: Intensive postoperative care does not affect global quality of life even if nutritional counseling reduced appetite loss.

Serotonin 1A agonist and cardiopulmonary improvements with whole-body exercise in acute, high-level spinal cord injury: a retrospective analysis.

PURPOSE: High-level spinal cord injury (SCI) can result in spinal and supraspinal respiratory control deficits leading to insufficient ventilatory responses to exercise and training-related adaptations. We hypothesized a serotonin agonist, known to improve respiratory function in animal models, would improve adaptations to whole-body functional electrical stimulation (FES) exercise training in patients with acute high-level SCI. METHODS: We identified 10 patients (< 2 years of injury with SCI from C4 to T3) in our program who had performed 6 months of FES-row training while on Buspirone (29 ± 17 mg/day) between 2012 and 2018. We also identified well-matched individuals who trained for six months but not on Buspirone (n = 11). A peak incremental FES-rowing exercise test and resting pulmonary function test had been performed before and after training. RESULTS: Those on Buspirone demonstrated greater increases in peak oxygen consumption (VO2peak: + 0.24 ± 0.23 vs. + 0.10 ± 0.13 L/min, p = 0.08) and peak ventilation (VEpeak: + 6.5 ± 8.1 vs. - 0.7 ± 6.9 L/min, p < 0.05) compared to control. In addition, changes in VO2peak and VEpeak were correlated across all patients (r = 0.63, p < 0.01), but most strongly in those on Buspirone (r = 0.85, p < 0.01). Furthermore, changes in respiratory function correlated with increased peak tidal volume in the Buspirone group (r > 0.66, p < 0.05). CONCLUSION: These results suggest Buspirone improves cardiorespiratory adaptations to FES-exercise training in individuals with acute, high-level SCI. The strong association between increases in ventilatory and aerobic capacities suggests improved respiratory function is a mechanism; however, controlled studies are needed to determine if this preliminary finding is reproducible.

Effects of Anisodine Hydrobromide on the Cardiovascular and Respiratory Functions in Conscious Dogs.

PURPOSE: Anisodine hydrobromide (Ani) is isolated from the medicinal plant Anisodus tanguticus (Maxim.) Pascher for clinical use. Although considerable research regarding Ani has been reported, the safety profiles of Ani are currently unknown. This study investigated the cardiorespiratory effects of Ani in conscious dogs to provide clinicians a detailed safety profile of Ani on the cardiorespiratory system. MATERIALS AND METHODS: Using the Latin square design, the study was divided into six phases, where in each phase, six telemetered beagle dogs received one dose of normal saline or sotalol hydrochloride or Ani (0.1, 0.4, 1.6, or 6.4 mg/kg). Electrocardiogram, blood pressure (BP) and respiratory parameters were collected before and after administration for 24 hours. Statistical comparisons were performed at scheduled time-points. RESULTS: The heart rate was significantly increased, PR and QTCV intervals were significantly shortened in Ani 0.4, 1.6, 6.4 mg/kg treatment group after drug administration. Compared with the saline group, a significant increase in heart rate and shortening of PR, QTCV intervals were observed in the Ani 1.6, 6.4 mg/kg treatment groups from 5 min to 4 h time-points. Diastolic and mean BP were significantly increased in Ani 1.6, 6.4 mg/kg from 1 h to 2 h time-points compared to those of the saline control. Accelerated breathing was observed in the first 20 min after Ani 0.4, 1.6, and 6.4 mg/kg treatment, although not statistically significant. Furthermore, no significant differences were observed in any of the corresponding indexes of Ani 0.1 mg/kg treatment group at different time-points compared to those of the saline group. CONCLUSION: Ani may have adverse effects on the cardio-respiratory systems of dogs at doses above 0.4 mg/kg, whereas Ani 0.1 mg/kg was devoid of potentially deleterious effects on cardiorespiratory function.

Effect of very low-protein diets supplemented with branched-chain amino acids on energy balance, plasma metabolomics and fecal microbiome of pigs.

Feeding pigs with very-low protein (VLP) diets while supplemented with limiting amino acids (AA) results in decreased growth. The objective of this study was to determine if supplementing VLP diets with branched-chain AA (BCAA) would reverse the negative effects of these diets on growth and whether this is associated with alterations in energy balance, blood metabolomics and fecal microbiota composition. Twenty-four nursery pigs were weight-matched, individually housed and allotted into following treatments (n = 8/group): control (CON), low protein (LP) and LP supplemented with BCAA (LP + BCAA) for 4 weeks. Relative to CON, pigs fed with LP had lower feed intake (FI) and body weight (BW) throughout the study, but those fed with LP + BCAA improved overall FI computed for 4 weeks, tended to increase the overall average daily gain, delayed the FI and BW depression for ~ 2 weeks and had transiently higher energy expenditure. Feeding pigs with LP + BCAA impacted the phenylalanine and protein metabolism and fatty acids synthesis pathways. Compared to CON, the LP + BCAA group had higher abundance of Paludibacteraceae and Synergistaceae and reduced populations of Streptococcaceae, Oxyphotobacteria_unclassified, Pseudomonadaceae and Shewanellaceae in their feces. Thus, supplementing VLP diets with BCAA temporarily annuls the adverse effects of these diets on growth, which is linked with alterations in energy balance and metabolic and gut microbiome profile.

Graphene/CuO2 Nanoshuttles with Controllable Release of Oxygen Nanobubbles Promoting Interruption of Bacterial Respiration.

An oxygen nanoshuttle based on a reduced graphene oxide/copper peroxide (rGO/CuO2) nanocomposite has been presented to deliver in situ oxygen nanobubbles (O2 NBs) for combating bacterial infections. In the presence of rGO, the solid source of oxygen (i.e., CuO2) was decomposed (in response to environmental conditions such as pH and temperature) into O2 NBs in a more controllable and long-lasting trend (from 60 to 144 h). In a neutral buffer, the O2 NBs experienced growth and collapse evolutions, creating a dynamic micro-nanoenvironment around the nanocomposite. In addition to effective battling against methicillin-resistant Staphylococcus aureus bacteria, the O2 NBs demonstrated superior antibacterial properties on Gram-positive S. aureus to those on Gram-negative Escherichia coli bacteria, especially in the presence of rGO. In fact, the rGO contents could provide synergistic effects through harvesting some respiratory electrons (leading to striking interruption of the bacterial respiratory pathway) in one side and transferring them into the O2 NBs, resulting in nanoscale reactive oxygen species (ROS) generation in another side. Moreover, near-infrared laser irradiation induced more damage to the cell membrane due to the synergistic effects of local heat elevation and catalyzing the release/collapse of NBs imposing mechanical disruptions. Our results show that the O2-containing nanoshuttles can effectively be used as intelligent and controllable anti-infection nanorobots in upcoming graphene-based nanobiomedical applications.

Experimental and Preliminary Clinical Study of Real-Time Registration in Liver Tumors During Respiratory Motion Based on a Multimodality Image Navigation System.

PURPOSE: To develop a fusion imaging system that combines ultrasound and computed tomography for real-time tumor tracking and to validate the accuracy of performing registration via this approach during a specific breathing phase. MATERIALS AND METHODS: The initial part of the experimental study was performed using iodized oil injection in pig livers and was focused on determining the accuracy of registration. Eight points (A1-4 and B1-4) at different positions and with different target sizes were selected as target points. During respiratory motion, we used our self-designed system to perform the procedure either with (experimental group, E) or without (control group, C) the respiratory monitoring module. The registration errors were then compared between the 2 groups and within group E. The second part of this study was designed as a preliminary clinical study and was performed in 18 patients. Screening was performed to determine the combination of points on the body surface that provided the highest sensitivity to respiratory motion. Registration was performed either with (group E) or without (group C) the respiratory monitoring module. Registration errors were compared between the 2 groups. RESULTS: In part 1 of this study, there were fewer registration errors at each point in group E than at the corresponding points in group C (P < .01). In group E, there were more registration errors at points A1 and B1 than at the other points (P < .05). There was no significant difference in registration errors among the remaining points. During part 2 of the study, there was a significant difference in the registration errors between the 2 groups (P < .01). CONCLUSIONS: Real-time fusion registration is feasible and can be accurately performed during respiratory motions when using this system.

Thermal antinociceptive, sedative and cardiovascular effects of Governing Vessel 1 dexmedetomidine pharmacopuncture in healthy cats.

OBJECTIVE: To compare the antinociceptive, sedative and cardiovascular effects of dexmedetomidine pharmacopuncture at Governing Vessel 1 (GV 1) with dexmedetomidine intramuscular (IM) administration. STUDY DESIGN: Randomized, masked crossover design. ANIMALS: A group of eight healthy female cats. METHODS: Cats were randomly administered either dexmedetomidine (0.005 mg kg-1; Dex-IM) IM or at acupuncture point GV 1 (Dex-P) separated by 1 week. Prior to and up to 120 minutes posttreatment, skin temperature (ST), thermal threshold (TT), heart rate (HR), respiratory rate (fR), sedation, muscle relaxation and auditory response scores were recorded. Parametric data were analyzed using a two-way repeated measures anova followed by Tukey's test for multiple comparisons. Nonparametric data were analyzed using a Friedman test followed by Dunn's multiple comparisons test, and Wilcoxon signed-rank test with Bonferroni correction for multiple comparisons. Significance was set at p ≤ 0.05. RESULTS: There were no differences within or between treatments for ST, fR and auditory response. TT was significantly higher at 30-90 minutes in Dex-P (p ≤ 0.0285) than baseline. TT was significantly higher at 60-90 minutes for Dex-P than for Dex-IM (p ≤ 0.0252). HR was significantly lower at 10-75 minutes in Dex-P (p ≤ 0.0378) and at 5-75 minutes in Dex-IM (p ≤ 0.0132) than baseline. Compared with baseline, sedation scores were higher at 25 minutes (p = 0.0327) and 30 minutes (p = 0.0327), and muscle relaxation scores were higher at 25 minutes (p = 0.0151) and 35 minutes (p = 0.0151) in Dex-P. There were no differences in HR, sedation and muscle relaxation scores between treatments. CONCLUSIONS AND CLINICAL RELEVANCE: Dex-P increased thermal antinociception compared with Dex-IM at the same dose of dexmedetomidine in cats. This antinociceptive effect must be evaluated under clinical situations.

CNS function and dysfunction during exposure to hyperbaric oxygen in operational and clinical settings.

Hyperbaric oxygen (HBO2) is breathed during hyperbaric oxygen therapy and during certain undersea pursuits in diving and submarine operations. What limits exposure to HBO2 in these situations is the acute onset of central nervous system oxygen toxicity (CNS-OT) following a latent period of safe oxygen breathing. CNS-OT presents as various non-convulsive signs and symptoms, many of which appear to be of brainstem origin involving cranial nerve nuclei and autonomic and cardiorespiratory centers, which ultimately spread to higher cortical centers and terminate as generalized tonic-clonic seizures. The initial safe latent period makes the use of HBO2 practical in hyperbaric and undersea medicine; however, the latent period is highly variable between individuals and within the same individual on different days, making it difficult to predict onset of toxic indications. Consequently, currently accepted guidelines for safe HBO2 exposure are highly conservative. This review examines the disorder of CNS-OT and summarizes current ideas on its underlying pathophysiology, including specific areas of the CNS and fundamental neural and redox signaling mechanisms that are thought to be involved in seizure genesis and propagation. In addition, conditions that accelerate the onset of seizures are discussed, as are current mitigation strategies under investigation for neuroprotection against redox stress while breathing HBO2 that extend the latent period, thus enabling safer and longer exposures for diving and medical therapies.

Cardiovascular and respiratory safety evaluation of Musca Domestica larvae low molecular weight peptide in beagle dogs.

Background: Many studies have demonstrated that the water extracts and low-molecular-weight peptide (LMWP) of the Musca domestica larvae contain significant biological activity. However, the cardiovascular and respiratory safety evaluations of LMWP are yet to be sufficiently investigated. Aim: This study focused on the cardiovascular and respiratory safety evaluations of the M. domestica larvae LMWP in beagle dogs. Methods: Direct cardiovascular and respiratory effects of three different doses of the M. domestica larvae LMWP were investigated following only once oral administration in conscious telemetered dogs, whereby ECG, arterial pressure, and respiratory data were collected using the Data Science International telemetric system. Results: The PR, QT, and QTcf intervals were significantly shortened in the medium-dose LMWP treatment group at 3 h after drug administration. Furthermore, no significant differences were observed in any of the corresponding indexes of other treatment groups at different time points compared to those of the control group. P wave, ST segment, R wave, systolic pressure, diastolic pressure, and mean pressure were significantly different, although these differences had no significant dose-effect relationship. Respiratory frequency significantly increased in the medium-dose LMWP treatment group at 8 h after drug administration compared to that of the control group. Respiratory rate and tidal volume showed no significant differences at varying time points among all LMWP treatment groups. Conclusions: No toxicological effects related to cardiovascular and respiratory safety in beagle dogs were observed at any dose level of the M. domestica larvae LMWP.

Neurological, sensorimotor and cardiorespiratory alterations induced by methoxetamine, ketamine and phencyclidine in mice.

Novel psychoactive substances are intoxicating compounds developed to mimic the effects of well-established drugs of abuse. They are not controlled by the United Nations drug convention and pose serious health concerns worldwide. Among them, the dissociative drug methoxetamine (MXE) is structurally similar to ketamine (KET) and phencyclidine (PCP) and was created to purposely mimic the psychotropic effects of its "parent" compounds. Recent animal studies show that MXE is able to stimulate the mesolimbic dopaminergic transmission and to induce KET-like discriminative and rewarding effects. In light of the renewed interest in KET and PCP analogs, we decided to deepen the investigation of MXE-induced effects by a battery of behavioral tests widely used in studies of "safety-pharmacology" for the preclinical characterization of new molecules. To this purpose, the acute effects of MXE on neurological and sensorimotor functions in mice, including visual, acoustic and tactile responses, thermal and mechanical pain, motor activity and acoustic startle reactivity were evaluated in comparisons with KET and PCP to better appreciate its specificity of action. Cardiorespiratory parameters and blood pressure were also monitored in awake and freely moving animals. Acute systemic administrations of MXE, KET and PCP (0.01-30 mg/kg i.p.) differentially alter neurological and sensorimotor functions in mice depending in a dose-dependent manner specific for each parameter examined. MXE and KET (1 and 30 mg/kg i.p.) and PCP (1 and 10 mg/kg i.p.) also affect significantly cardiorespiratory parameters, systolic and diastolic blood pressure in mice.

Biomarker Evaluation and Toxic Effects of an Acute Oral and Systemic Fumonisin Exposure of Pigs with a Special Focus on Dietary Fumonisin Esterase Supplementation.

The mycotoxin fumonisin B1 (FB1) is a frequent contaminant of feed. It causes a disruption of sphingolipid metabolism and pulmonary, hepatic, and immunological lesions in pigs depending on the exposure scenario. One sensitive biomarker for FB1 exposure is the sphinganine (Sa) to sphingosine (So) ratio in blood. The fumonisin esterase FumD, which can be used as a feed additive, converts FB1 into the much less toxic metabolite hydrolyzed FB1 (HFB1). We conducted a single-dose study with barrows allocated to one of five treatments: (1) control (feed, 0.9% NaCl intravenously iv), (2) 139 nmol FB1 or (3) HFB1/kg BW iv, (4) 3425 nmol FB1/kg BW orally (po), or (5) 3321 nmol FB1/kg BW and 240 U FumD/kg feed po. The Sa/So ratio of iv and po FB1 administered groups was significantly elevated in blood and Liquor cerebrospinalis, but no fumonisin-associated differences were reflected in other endpoints. Neither clinical lung affections nor histopathological pulmonary lesions were detected in either group, while some parameters of hematology and clinical biochemistry showed a treatment⁻time interaction. FumD application resulted in Sa/So ratios comparable to the control, indicating that the enzymatic treatment was effectively preventing the fumonisin-induced disruption of sphingolipid metabolism.

Comparative safety evaluation of riot control agents of synthetic and natural origin.

Riot control agents (RCA) are lachrymatory, irritating compounds which temporarily incapacitate the uncontainable crowd. Ortho-Chlorobenzylidene-malononitrile (CS), 2-chloroacetophenone (CN), dibenz[b,f]1:4-oxazepine (CR), and nonivamide (PAVA) are synthetic RCAs, while oleoresin extract of chili known as oleoresin capsicum (OC) a natural irritant has been in use by various law enforcement agencies. Though efficacy of these agents is beyond doubt, they suffer from certain drawbacks including toxicity, production cost, and ecological compatibility. Presently, we have evaluated the safety of CR, OC, and PAVA on inhalation variables along with oral lethality. Additionally, the liver function test (LFT) in serum and lungs function was evaluated in broncho-alveolar-lavage fluid (BALF), both collected on the 14th day after RCA exposure. Animals then sacrificed and histopathology of liver and lungs was carried out. Results showed OC and PAVA to be more toxic than CR with an oral LD50 of 150 and 200 mg/kg body weight, respectively, while CR was safe at >3 g/kg body weight. All three agents caused severe impairment of respiratory variables bringing down normal respiration by >80% with rise in sensory irritation. Recovery from the irritating effect of CR was more rapid than OC and PAVA. LFT and BALF variables were not significantly different from that of control. There were no remarkable histopathological changes in liver and lungs. Hence, as per results, CR is safest among all synthetic and natural origin RCAs and can be safely used for effective dispersion of disobedient mob.