Administration Of Atropine Sulfate Research Articles

Impact of salivary flow inhibition on masticatory behaviours in healthy individuals.

It remains unclear how the salivary flow and the fat content of food affect bolus formation during mastication. We aimed to clarify: (1) how hyposalivation affects jaw-closing and hyoid-elevating muscle activities in bolus formation, and (2) if the effect of hyposalivation on muscle activity depends on the fat content of food. Eighteen healthy male volunteers were instructed to freely ingest four test foods: Plain, Fat without seasoning, Fat with seasoning, and Soft rice crackers. Masseter and suprahyoid electromyographic activities were recorded before and 30 min after the administration of atropine sulfate, a muscarinic receptor antagonist that induces hyposalivation. Hyposalivation extended the masticatory duration significantly in all the test foods except Fat with seasoning. Masticatory cycle time was significantly longer with vs without hyposalivation for the Soft (p = .011). Suprahyoid activity/cycle was significantly greater with vs without hyposalivation (p = .013). Masticatory cycle time was significantly longer at the late stage with vs without hyposalivation for the Soft (p < .001). Suprahyoid activity/cycle was significantly greater at the middle (p = .045) and late stages (p = .002) with vs without hyposalivation for the Soft and greater at the late stage with vs without hyposalivation for the Plain (p = .043). Changes in masticatory cycle time and suprahyoid activity/cycle for these foods had significantly positive relationship (p < .001). Hyposalivation-induced changes in masticatory behaviours resulted from the middle and late stage suprahyoid activity. Fat content and seasoning compensate for salivary flow inhibition.

Repeated complete atrioventricular block during remifentanil administration in a pediatric patient with brain tumor and acute hydrocephalus: a case report

BackgroundRemifentanil, an ultra-short-acting µ-opioid receptor agonist, is commonly used for anesthetic management due to excellent adjustability. Remifentanil is known to cause sinus bradycardia, however, because it has a direct negative chronotropic effect on the cardiac conduction system and there is an indirect negative chronotropic effect via the parasympathetic nervous system.Case presentationAn 8-year-old Japanese boy was diagnosed with acute hydrocephalus due to a brain tumor in the fourth ventricle and underwent emergency surgery. Imaging examination showed brainstem compression. Endoscopic third ventriculostomy and ventriculoperitoneal shunt surgery were scheduled. Remifentanil was started during induction of general anesthesia, but electrocardiogram showed sinus bradycardia, then Wenckebach-type atrioventricular block, and then complete atrioventricular block. Remifentanil was immediately discontinued, and we administered atropine sulfate. Complete atrioventricular block was restored to sinus rhythm. When remifentanil was restarted, however, the electrocardiogram again showed sinus bradycardia, Wenckebach-type atrioventricular block, and then complete atrioventricular block. Remifentanil was again immediately discontinued, we administered adrenaline, and then complete atrioventricular block was restored to sinus rhythm. Fentanyl was used instead of remifentanil with continuous infusion of dopamine. There has since been no further occurrence of complete atrioventricular block.ConclusionsThis is the first known case of complete atrioventricular block in a pediatric patient with increased intracranial pressure seemingly caused by administration of remifentanil.

Safety of propofol sedation administered by interventional radiologists for radiofrequency ablation in patients with hepatocellular carcinoma

PurposeTo evaluate the safety of propofol sedation administered by interventional radiologists during radiofrequency ablation (RFA) for hepatocellular carcinoma (HCC).Materials and methodsPropofol sedation was administered by interventional radiologists in 72 patients (85 procedures, 93 tumors) during RFA for HCC between August 2018 and December 2020. Interventional radiologists equipped with adequate knowledge and skills in sedation and respiratory management were responsible for sedation. Sedation was carefully assessed based on vital signs, including end-tidal carbon dioxide, consciousness status, and bispectral index. The primary endpoint was the incidence of sedation-related complications, which were evaluated separately as respiratory and cardiovascular complications. Secondary endpoints were technical success rate, ablation-related complications, and local tumor control rate. Technical success was defined as completion of ablation in the planned area. Complications were evaluated using the Clavien–Dindo classification. Sedation-related complications, technical success rate, and ablation-related complications were evaluated on a procedure basis, and local tumor control was evaluated on a tumor basis.ResultsRespiratory and cardiovascular complications were observed in eight (8/85, 9.4%) and two (2/85, 2.4%) patients, respectively. Four patients required the jaw thrust maneuver due to glossoptosis, whereas a decrease in oxygen saturation to < 90% was recorded in the other four patients. However, these were temporary, and none required manual ventilation or endotracheal intubation. Bradycardia (< 50 bpm) was detected in two patients; one recovered immediately without treatment, whereas the other rapidly improved after atropine sulfate administration. No severe hypotension (< 80 mmHg) was observed. The technical success rate was 100% (85/85). Grade 3 ablation-related complications were identified in three patients (3/85, 3.5%). The local tumor control rate was 95.7% (89/93).ConclusionPropofol sedation can be safely administered by interventional radiologists during RFA for HCC. Although it requires special safety considerations, it may be a sedation option during hepatic RFA.

Hypothermia induced by bronchoalveolar lavage with perfluorocarbon liquids as a method for the treatment of the alveolar stage of toxic pulmonary edema. Experimental assessment

Introduction. The rapid development of the chemical industry in the Russian Federation is accompanied by an increase in the production and storage of highly toxic substances belonging to the group of pulmonotoxicantsare able to induce lung injury, the most severe form of which is toxic pulmonary edema (TPE). The treatment of TPE includes medication and respiratory therapy, but such a combination turns out to be insufficient, and therefore the development of new methods of treatment of the alveolar stage is an important task of modern medicine. One such approach is the use of therapeutic hypothermia, which can reduce the severity of TPE in general and the alveolar stage in particular. Recently, the use of various options for liquid ventilation of the lungs with perfluorocarbon (PFC) liquids for the induction of therapeutic hypothermia has attracted increasing attention from specialists. This article will present the results of an experimental assessment of the effect of hypothermia induced by BAL with PFC fluids on the course of the alveolar stage of toxic pulmonary edema. The study aims to determine the effect of hypothermia induced by bronchoalveolar lavage with a pre-cooled PFC liquid on the course of the alveolar stage of toxic pulmonary edema. Materials and methods. The authors conducted a study on male Wistar rats aged 4 months, weighing 200–220 g. TPE was modeled by intratracheal administration of 0.1 m HCl solution at a dose of 2 ml/kg. Specialists pre-injected atropine into the animals, then anesthetized, intubated with cannulas, injected a model substance and connected to a ventilator. After that, the animals were randomized by weight into two groups of 6 individuals each. In animals of the experimental and control groups, with a decrease in oxygen saturation (SpO2) below 80%, the researchers performed 2 procedures of bronchoalveolar lavage (BAL) with PFC liquid in a single dose of 2.0 ml / kg, with different temperatures. Perfluorodecalin was used as a PFC liquid. In the experimental group, the temperature of the PFC liquid during BAL was 0.5°C, in the control group — 38.0°C. Specialists recorded heart rate (HR), oxygen saturation, rectal temperature (Trect) and duration of survival. Results. Immediately after instillation of 0.1 M HCl solution, all animals showed a sharp decrease in SpO2 (from 97±1.3 to 64±11.5) and heart rate (HR), (from 269±8.7 to 123±24.5). Recovery of indicators was observed after administration of atropine sulfate. Over the next 25–30 minutes, the following signs appeared and subsequently intensified: a decrease in SpO2 below 80%, an increase in heart rate (HR) to 302±11.4 beats/min, the presence of wet wheezing in the lungs and the release of exudate from the endotracheal catheter. In response to the BAL, all animals showed an increase in SpO2 and a decrease in heart rate. So, in the control, in response to the BAL, SpO2 increased by 8.0±2.5%, and heart rate decreased by 21.0±5.4 beats /min. While in the experimental group there was an increase in SpO2, which was 11.0±3.1%, and a decrease in heart rate by 57.0±10.2 beats/min. At the same time, during the experiment, the researchers observed an increase in temperature in the control group by 0.08±0.02°C, and in the experimental group — its decrease by 0.70±0.07°C. The average survival time of animals in the control and experimental groups was 64.8±2.2 minutes and 91.2±5.9 minutes, respectively. Conclusion. The use of BAL PFC liquids with a low temperature makes it possible to increase the survival time of small laboratory animals in the alveolar stage of TPE due to the development of local and general hypothermia. The development of local hypothermia during BAL of the lungs makes it possible to remove a significant amount of edematous fluid, which, in turn, manifests itself in less pronounced respiratory and systemic hemodynamic disorders. Ethics. Studies involving laboratory animals were conducted in compliance with the following regulations: Helsinki Declaration of 2000 "On humane treatment of animals", Order of the Ministry of Health of the USSR No. 755 dated 08/12/1977 "Rules for carrying out work using experimental animals", Order of the Ministry of Health and Social Development of Russia No. 199n dated 04/01/2016 "On approval of the rules of laboratory practice". The research protocol was approved by the Ethics Committee of the Izmerov Research Institute of Occupational Health (Protocol No. 4 dated May 25, 2022).

Pharmacokinetics and pharmacodynamics of standard nerve agent medical countermeasures in Göttingen Minipigs

Animal research continues to serve a critical role in the testing and development of medical countermeasures. The Göttingen minipig, developed for laboratory research, may provide many benefits for addressing research questions within chemical defense. Targeted development of the Göttingen minipig model could reduce reliance upon non-human primates, and improve study design, statistical power, and throughput to advance medical countermeasures for regulatory approval and fielding. In this vein, we completed foundational pharmacokinetics and physiological safety studies of intramuscularly administered atropine sulfate, pralidoxime chloride (2-PAM), and diazepam across a broad range of doses (1–6 autoinjector equivalent) using adult male Göttingen minipigs (n=11; n=4–8/study) surgically implanted with vascular access ports and telemetric devices to monitor cardiovascular, respiratory, arterial pressure, and temperature signals. Pharmacokinetic data were orderly and the concentration maximum mirrored available human data at comparably scaled doses clearly for atropine, moderately for 2-PAM, and poorly for diazepam. Time to peak concentration approximated 2, 7, and 20 min for atropine, 2-PAM, and diazepam, respectively, and the elimination half-life of these drugs approximated 2 hr (atropine), 3 hr (2-PAM), and 8 hr (diazepam). Atropine sulfate dose-dependently increased the magnitude and duration of tachycardia and decreased the PR and ST intervals (consistent with findings obtained from other species). Mild hypothermia was observed at the highest diazepam dose. Göttingen minipigs appear to provide a ready and appropriate large animal alternative to non-human primates, and further development and evaluation of novel nerve agent medical countermeasures and treatment strategies in this model are justified.

Histological Evaluation of Fracture Healing after Thyroidectomy

This study aimed to examine the impact of thyroidectomy on the process of fracture healing. A total of sixteen adult male rabbits of the local breed were utilized. The animals were segregated into two equivalent groups, namely the control group and the treatment group. The animals were administered atropine sulfate (1mg /Kg B.W) intramuscularly as a premedication. Ten minutes later, a combination of xylazine hydrochloride (20mg /Kg B.W) and Ketamine hydrochloride (40 mg /Kg B.W) was administered intramuscularly. The control group had the induction of a mid-shaft femoral fracture, followed by fixation with intramedullary pinning. In the treated group, the identical treatment mentioned above, which involved thyroidectomy, was performed. The clinical examination showed that the inflammatory symptoms, such as swelling, discomfort, and increased temperature in the surgical site, were more severe in the control group compared to the treated group. The indications vanished during a span of four to five days in the treatment group and five to six days in the control group. The histological analysis showed that the control group had a greater presence of granulation tissues, trabecular bone, and compact bone compared to the treated group. Ultimately, it was seen that the fracture healing process was more advanced in the control group compared to the treated group.

Antisialogogue Effect of Atropine Sulfate at Dosages of 0.25 Mg and 0.5 Mg Under General Anesthesia with Ketamin

Introduction: Excessive saliva production can becomes an airway problem in conditions of decreased consciousness where there is impaired swallowing function. It increases the risk of aspiration of saliva into the airways that can result in choking. The use of premedication drugs to reduce the incidence of drug-induced hypersalivation can be done as a prevention. The anticholinergic drug class is the drug of choice for the management of hypersalivation in general anesthesia patients who have been given ketamine and ether. Ketamine as a sedating agent will provide a side effect of hypersalivation, where hypersalivation can cause laryngospasm or aspiration, as a form of prevention, anticholinergic drugs such as atropine can be given. The aim of this research was to compare the effect of antisialagogue on the administration of atropine sulfate at a dose of 0.25 mg and 0.5 mg in intravenous general anesthesia patients without ETT with ketamine at Haji Adam Malik General Hospital Medan and Putri Hijau Hospital Medan. Method: This study used a double blind RCT design. A total of 60 patients with intravenous general anesthesia without ETT with ketamine (1-2 mg/kg BW) were divided into 2 groups of Atropine Sulfas doses (0.25 and 0.5 mg) then the total salivary volume of each patient was measured and analyzed. Results: There was a significant difference between the treatment groups of 0.25 mg and 0.5 mg in the volume of saliva that had been collected (P-value = 0.008). Conclusion: There was a significant comparison between the use of 0.25 mg and 0.5 mg atropine in patients at Haji Adam Malik Hospital and Putri Hijau Hospital Medan.

Pathological changes in an Alsatian dog following Amitraz and Sniper (dichlorvos) exposure

Amitraz and Sniper (dichlorvos) are known ectoparasiticides of dogs in Nigeria. Although reports of their toxicosis exist, information on the pathological presentations of their combined toxicosis is scanty hence the present case report. Two dogs both had Amitraz bath with simultaneous fumigation of their immediate environment with Sniper (diclorvos). Excessive salivation, staggering gait, and respiratory distress were observed shortly thereafter with the prompt administration of atropine sulphate which ameliorated it, but a particular dog progressively became weak, inactive and off feed. A vomitus, dark watery stool and blood spots were observed within its kennel before death. The post-mortem examination revealed emaciated, dehydrated and tick infested carcass with pale ocular and oral mucous membranes. There was also ileocolic intestinal intussusception characterized by anal intussusceptum protrusion, congested liver and pulmonary peribronchial haemorrhage with inter-alveoli cellular infiltration including haemorrhagic enteritis. Death might have been due to hypovolemic shock following the observed dehydration, pallor, haematochezia, peritoneal fluid exudation, hepatic congestion, pneumonia characterized by peribronchial haemorrhages, and haemorrhagic enteritis. The observed intussusception was a rare occurrence in a dog following Amitraz and Sniper poisoning in Abuja, Nigeria, which highlighted the need for their cautious and professional use.

Paradoxical Heart Rate Response After Atropine Sulfate Administration in Total Atrioventricular Block Complicating Acute Myocardial Infarction

Abstract Acute myocardial infarction is sometimes complicated by atrioventricular block. Advanced cardiac life support guideline for the treatment of atrioventricular block suggests early use of atropine. Atropine works as a parasympatholytic drug that enhances SA node automaticity and AV node conduction. We report a case of a male patient with inferior myocardial infarction and total atrioventricular block who showed a marked reduction in heart rate after first and second atropine administration, a paradoxical worsening of the block. Atropine has been associated with some adverse consequences, including proarrhythmic effect, worsening of the high-grade atrioventricular block, and worsening of the ischemic situation. In this case of total atrioventricular block caused by acute myocardial infarction, immediate revascularization can be the only required management. Awareness of this potential adverse reaction will help the clinician make a risk/benefit ratio consideration regarding the use of atropine for certain patients.

Evaluation of Clinico-physiological Effects of Ketamine Alone and in Combination with Dexmedetomidine or Butorphanol in Atropinized Dogs

Background: Ketamine is rarely used alone because of its association with poor muscle relaxation, tachycardia, catalepsy or muscle rigidity and therefore commonly used in combination with alpha 2 agonist or opioid to minimize the untoward effects. The aim of the present anaesthetic study was to evaluate the clinico-physiological effects of ketamine alone and in combination with dexmedetomidine or butorphanol for inducing adequate anaesthesia in dogs. Methods: The present anaesthetic study was conducted on 18 (eighteen) healthy dogs of either sex and randomly divided into three groups (K, DK and BK) with six animals in each group. Atropine sulphate @ 0.04 mg/ kg was administered intramuscularly 15 minutes prior to anaesthetic study to all the animals. In group K, ketamine HCl alone was administered @ 5 mg/kg by slow i/v and kept as control. In group DK and BK, after administration of atropine sulphate 15 minutes later dexmedetomidine @ 10 µg/kg i/m and butorphanol @ 0.2 mg/kg i/m were administered respectively. Ten minutes later ketamine HCl was administered @ 5 mg/kg slowly intravenously in both group DK and BK to induce surgical stage of general anaesthesia. The following clinical parameters were recorded viz., onset of sedation, onset of anaesthesia, degree of analgesia, extent of muscle relaxation, duration of anaesthesia and complete recovery. The physiological parameters (rectal temperature, heart rate and respiratory rate) were recorded before anaesthetic study at 0 min. and at 10 minutes after preanaesthetic administration and then at 10, 20, 40, 60, 90, 120 and 180 minutes after ketamine anaesthesia. All the data were analyzed using SPSS v 15.0 statistics software program and presented as mean±Standard Error. Result: The onset of sedation was quicker in group DK followed by group K and BK. Duration of anaesthesia and complete recovery in group DK was significantly (p less than 0.01) longer than in group K and BK. The degree of analgesia was excellent in group DK and good in group K and BK. The extent of muscle relaxation was excellent in group DK, good in group BK and was poor in group K. The physiological parameters showed transient changes which compensated and remained within normal range during the observation period. The above anaesthetic study suggests that ketamine in combination with dexmedetomidine or butorphanol can be safely used for inducing adequate anaesthesia in dogs. However, dexmedetomidine-ketamine can be used safely for longer duration of surgical procedures in dogs.

Computed Tomography Myocardial Perfusion Imaging With Transesophageal Atrial Pacing Stress Test in Patients With Borderline Stenoses in the Coronary Arteries: a Comparison With Fractional Flow Reserve.

Aim To evaluate the diagnostic accuracy of cardiac perfusion computed tomography (PCT) with transesophageal electrocardiostimulation (TE ECS) for detection of ischemia in patients with borderline coronary stenosis (50-75 %) compared to measurements of fractional flow reserve (FFR).Material and methods The study included 25 patients with borderline (50-75 %) coronary stenosis as per data of computed tomography angiography (CTA) or coronary angiography (CAG). Later the patients underwent invasive measurement of FFR and cardiac PCT on a 320-row detector tomograph in combination with the TE ECS stress test. FFR values &lt;0.8 indicated the hemodynamic significance of stenosis. Myocardial perfusion was evaluated visually based on consensus of two experts.Results All patients completed the study protocol. Cardiac pacing duration was 6 min for all patients. Four patients required intravenous administration of atropine sulphate. PCT with TE ECS detected significant for FFR stenoses with sensitivity, specificity, and predictive value of a positive result and predictive value for a negative result of 47, 90, 87, and 53 %, respectively.Conclusion PCT with TE ECS in combination with CTA can be considered as an informative method for simultaneous evaluation of the condition of coronary arteries and detection of myocardial ischemia. This method is particularly relevant for assessing the hemodynamic significance of borderline coronary stenoses.

Effect of Intramuscular Atropine Sulphate and Glycopyrrolate on Heart Rate and Salivary Secretion in Patients Undergoing Minor Oral Surgical Procedure

IntroductionIn most of the oral surgical procedures performed under local anesthesia, we often face a great difficulty while performing surgeries because of reduced accessibility and visibility which is hampered by blood and saliva at the surgical site. Anticholinergic drugs like atropine sulphate and glycopyrrolate are commonly used as antisialogogue for patients undergoing a surgical procedure under general anesthesia with little or no side effects. Aims and objectivesTo evaluate and compare the antisialogogue effect of atropine sulphate and glycopyrrolate in patients undergoing minor oral surgical procedures. To compare the efficacy of these drugs when administered intramuscularly and to evaluate their effects on heart rate in patients undergoing minor oral surgical procedures.Materials and methodsThirty patients undergoing minor oral surgical procedure were selected for the study. The patients were randomly assigned to receive either 0.6 mg/ml of Atropine Sulphate or 0.2 mg/ml of Glycopyrrolate intramuscularly. Salivary secretion, heart rate and arterial pressure were noted pre-injection and 30 minutes after the administration of the drug.ResultsAtropine sulphate and glycopyrrolate were equally potent as an antisialogogue. There was a significant increase in heart rate 30 min after the administration of atropine sulphate, but there was no significant change in heart rate in glycopyrrolate group.ConclusionIntramuscular gycopyrrolate is safer than intramuscular atropine sulphate as an antisialogogue in minor oral surgical procedures under local anesthesia.

In Vivo Effect of RSH-12, a Novel Selective MMP-9 Inhibitor Peptide, in the Treatment of Experimentally Induced Dry Eye Model

ABSTRACT Purpose To investigate the efficacy of RSH-12, a novel selective matrix metalloproteinase 9 (MMP-9) inhibitor peptide in rabbit models of dry eye syndrome (DES). Methods In vitro toxicity of RSH-12 on cultured human corneal fibroblasts was investigated with MTT. Ocular toxicity of RSH-12 was investigated by clinical examinations, histology, and TUNEL assay. Experimental model of dry eye was induced by 1.0% atropine sulfate administration followed after 15 min by treatment with PBS, RSH-12, and Restasis in individual groups, three times a day for 7 days. In addition to performing Schirmer’s test for evaluating basic tear secretion and tear break-up time test for investigating tear stability, the occurrence of superficial punctate keratopathy was also investigated in the study groups. Results MTT assay demonstrated that RSH-12 was not toxic to human corneal fibroblasts in different concentrations. During the administration of atropine, TBUT values and tear volume were decreased in vehicle group while these indices improved significantly in groups treated with RSH-12 in a promising manner. RSH-12 increased the mean value of tear volume from 4.85 to 10.75 mm (P = .0001) and mean of TBUT values from 20.3 s to 34.5 s (P = .0001) compared with the vehicle. In contrast to the presence of severe superficial punctate keratopathy in the controls, no significant dotted staining was observed in the RSH-12 and Restasis groups. Conclusions These outcomes propose that RSH-12 has a therapeutic effect in the rabbit model of dry eye and might be a potential treatment for severe DES.

Clinical Evaluation of General Anaesthesia using Ketamine Hydrochloride with and without Diazepam in Sheep

The study has been carried out to evaluate the clinical efficacy of ketamine with or without diazepam in sheep. Six healthy sheep were used in this study and randomly divided into two groups; Group A (atropine-diazepam-ketamine) and Group B (atropine-ketamine). Anaesthesia was induced with administration of diazepam (0.4 mg/kg b.wt) and ketamine (15 mg/kg b.wt) intramuscularly (IM) after five minutes of IM administration of atropine sulphate (0.05 mg/kg b.wt) in group A and ketamine (22 mg/kg b.wt) IM after five minutes of IM injection of atropine sulphate (0.05 mg/kg b.wt) in group B. Clinical parameters were recorded before and after (5, 10, 15, 20, 25, 30 mins, 1h and 24h post- recovery) administration of peripheral blood was collected at the same interval for haemato-biochemical observations. The clinical, hematological and serum biochemical profile differed from the values obtained at pre-experimental control level in both groups A and B. However, in group A, the changes were smooth and steady whereas these were irregular, fluctuated and inconsistent in certain clinical and biochemical parameters in sheep of group B. The present study indicates that the use of atropine-diazepam-ketamine anaesthesia is safe and useful in sheep than atropine-ketamine anaesthesia for major invasive procedures.

Ocular Pharmacological Profile of Hydrocortisone in Dry Eye Disease.

To investigate the ocular pharmacological profile of hydrocortisone (HC) using in vitro and in vivo models of dry eye disease. Rabbit corneal epithelial cells (SIRCs) were used to assess the effect of HC in two paradigms of corneal damage: hyperosmotic stress and scratch-wound assay. Dry eye was induced in albino rabbits by topical administration of atropine sulfate or by injection of concanavalin A (ConA) into the lacrimal gland. TNFα, TNF-related apoptosis-inducing ligand (TRAIL), IL-1β, and IL-8 were determined by ELISA or western blot in a corneal damage hyperosmotic in vitro model, with or without HC treatment. Inflammatory biomarkers, such as TNFα, IL-8, and MMP-9, were evaluated in tears of rabbit eye injected with ConA and treated with HC. Tear volume and tear film integrity, in both in vivo models, were evaluated by the Schirmer test and tear break-up time (TBUT). Ocular distribution of four formulations containing HC (0.001%, 0.003%, 0.005%, and 0.33%) was performed in the rabbit eye. Aqueous humor samples were collected after 15, 30, 60, and 90 min from instillation and then detected by LC-MS/MS. Hyperosmotic insult significantly activated protein expression of inflammatory biomarkers, which were significantly modulated by HC treatment. HC significantly enhanced the re-epithelialization of scratched SIRCs. Treatment with HC eye drops significantly reduced the tear concentrations of TNF-α, IL-8, and MMP-9 vs. vehicle in the ConA dry eye model. Moreover, HC significantly restored the tear volume and tear film integrity to levels of the control eyes, both in ConA- and atropine-induced dry eye paradigms. Finally, we demonstrated that HC crossed, in a dose-dependent manner, the corneal barrier when the eyes were topically treated with HC formulations (dose range 0.003–0.33%). No trace of HC was detected in the aqueous humor after ocular administration of eye drops containing the lowest dose of the drug (0.001%), indicating that, at this very low concentration, the drug did not pass the corneal barrier avoiding potential side effects such as intraocular pressure rise. Altogether, these data suggest that HC, at very low concentrations, has an important anti-inflammatory effect both in vitro and in vivo dry eye paradigms and a good safety profile.

The Additive Effect of Atropine Sulfate during Cardiopulmonary Resuscitation in Out-of-hospital Non-traumatic Cardiac Arrest Patients with Non-shockable Rhythm.

Objective The updated guidelines of 2015 for cardiopulmonary resuscitation (CPR) do not recommend the routine use of atropine for cardiopulmonary arrest. Methods The study population included out-of-hospital cardiac arrest (OHCA) patients with non-shockable rhythm who were encountered at a Japanese community hospital between October 1, 2012 and April 30, 2017. Results At the outcome, the epinephrine with atropine and epinephrine-only groups had a similar survival rate to that at hospital admission (28.7% vs. 26.7%: p=0.723). The odds ratio (OR) for the survival to hospital admission after the administration of atropine with epinephrine was 1.33 (95% CI 1.09-1.62; p<0.01), while that after the administration of epinephrine was 0.64 (95% CI: 0.55-0.74, p<0.01). The ORs for the survival to hospital admission for patients with pulseless electrical activity in the epinephrine-alone group and the atropine with epinephrine group were 0.62 (95% CI 0.49-0.78; p<0.01) and 1.35 (95% CI 0.99-1.83; p=0.06), respectively, and those for such patients with asystole in the epinephrine-alone group and the atropine with epinephrine group were 0.64 (95% CI 0.53-0.76; p<0.01) and 1.39 (95% CI 1.10-1.77; p<0.01), respectively. The OR for the survival to hospital admission after the administration of atropine sulfate (1 mg) was 2.91 (95% CI 1.49-5.67; p<0.01), while that for the survival to hospital admission after the administration of 0, 2 and ≥3 mg atropine sulfate was 0.38 (95% CI 0.29-0.50; p<0.01), 1.54 (95% CI 0.58-4.08; p=0.38) and 0.23 (95% CI 0.09-0.60; p<0.01), respectively. Conclusion The addition of atropine (within 2 mg) following epinephrine was a comprehensive independent predictor of the survival to hospital admission for non-shockable (especially asystole) OHCA adults.

GABAergic mediation of hippocampal theta rhythm induced by stimulation of the vagal nerve

The key question to be answered in the present study was whether the medial septal GABAergic receptors are engaged in the pharmacological profile of the hippocampal formation (HPC) theta rhythm induced by vagal nerve stimulation (VNS). It was demonstrated that the medial septal microinfusion of GABAA and GABAB agonists (muscimol and baclofen) resulted in a progressive reduction of the power of VNS-induced theta. The medial septal microinfusion of GABAA and GABAB antagonists (bicuculline and 2−OH saclofen) resulted in the generation of VNS-induced theta with increased power. The effect of the combined medial septal microinfusion of GABAA agonist and antagonist and GABAB agonist and antagonist on VNS-induced theta rhythm was also evaluated: in the presence of GABAA,B antagonists the effect of agonists predominated. In separate experiments, GABAA and GABAB antagonists were administrated in anesthetized rats pretreated with i.v. administration of atropine sulfate. Atropine was found to abolish spontaneous theta and VNS-induced theta examined in the presence of bicuculline or 2−OH saclofen. The present data provide evidence that the medial septal GABAA and GABAB receptors are involved in the central mechanisms responsible for modulation of VNS-induced HPC theta oscillations. Furthermore, the results of the present study also demonstrate that, in fact, both GABAergic and cholinergic involvement is necessary for the appearance of VNS-induced theta.

Increased central cholinergic drive contributes to the apneas of serotonin-deficient rat pups during active sleep.

Infant rat pups lacking central nervous system (CNS) serotonin (5-hydroxytryptamine; 5-HT) have unstable breathing during prolonged periods of active sleep. Given that cholinergic neurons are drivers of active sleep and project to respiratory patterning regions in the brainstem, we hypothesized that 5-HT preserves respiratory stability in active sleep by dampening central cholinergic drive. We used whole-body plethysmography coupled with nuchal electromyography to monitor the breathing pattern of 2-wk-old tryptophan hydroxylase 2 (TPH2)+/+ and TPH2-deficient (TPH2-/-) pups in active sleep, before and after muscarinic blockade. For the group 1 experiment we injected methylatropine (Ap-M), a CNS-impermeant form of atropine, followed ~30 min later by an injection of atropine sulfate (Ap-S), the CNS-permeant form (both 1 mg/kg, 10 μl bolus iv); both injections occurred within an active sleep episode. We analyzed the effect of each drug on the coefficient of variation of the respiratory period (CV-P) during active sleep. For the group 2 experiment rats were cycled through several episodes of active and quiet sleep before administration of Ap-S (1 mg/kg, 200 μl ip) or vehicle. We assessed the effect of Ap-S on the apnea indices of both genotypes during quiet and active sleep. In group 1 Ap-S significantly reduced the CV-P of TPH2-/- pups (P = 0.03), an effect not observed in TPH2+/+ pups or following Ap-M. In group 2 the apnea index of TPH2-/- pups was significantly reduced following Ap-S injection (P = 0.04), whereas the apnea index of TPH2+/+ littermates was unaffected (P = 0.58). These findings suggest that central 5-HT reduces apnea and stabilizes breathing by reducing cholinergic signaling through muscarinic receptors. NEW & NOTEWORTHY Serotonin in the central nervous system (CNS) is necessary for maintaining the stability of breathing in the early postnatal period, particularly during active sleep. Here we show that the administration of atropine to the CNS selectively stabilizes the respiratory pattern of tryptophan hydroxylase 2-deficient rat pups and reduces their apneas. This suggests that CNS serotonin stabilizes breathing at least in part by reducing central cholinergic drive.

Corneal regeneration by conditioned medium of human uterine cervical stem cells is mediated by TIMP-1 and TIMP-2

The aim of the present study was to evaluate the effect and the mechanism of action of the conditioned medium from human uterine cervical stem cells (CM-hUCESC) on corneal wound healing in a rabbit dry eye model. To do this, dry eye and corneal epithelial injuries were induced in rabbits by topical administration of atropine sulfate and NaOH. Hematoxylin-Eosin (H&E) and Ki-67 immunostaining were carried out to evaluate corneal damage and cell proliferation, and real-time PCR was used to evaluate proinflammatory cytokines in the cornea. In addition, in order to investigate possible factors involved in corneal regeneration, primary cultures of rat corneal epithelial cells (rCECs) were used to evaluate cell migration, proliferation, and apoptosis before and after immunoprecipitation of specific factors from the CM-hUCESC. Results showed that CM-hUCESC treatment significantly improved epithelial regeneration in rabbits with dry eye induced by atropine and reduced corneal pro-inflammatory TNF-α, MCP-1, MIP-1α and IL-6 cytokines. In addition, metalloproteinase inhibitors TIMP-1 and TIMP-2, which are present at high levels in CM-hUCESC, mediated corneal regenerative effects by both inducing corneal epithelial cell proliferation and inhibiting apoptosis. In summary, CM-hUCESC induces faster corneal regeneration in a rabbit model of dry eye induced by atropine than conventional treatments, being TIMP-1 and TIMP-2 mediators in this process. The results indicate that an alternative CM-based treatment for some corneal conditions is achievable, although future studies would be necessary to investigate other factors involved in the multiple observed effects of CM-hUCESC.

Muscarinic blockade stabilizes the breathing pattern of serotonin‐deficient rat pups during active sleep

Infant rats deficient in tryptophan hydroxylase 2 (TPH2−/−) and hence lacking central serotonin (5‐hydroxytryptamine; 5‐HT) display abnormally destabilized breathing during active sleep; their breathing pattern is punctuated with periods of apnea and tachypnea. Given that acetylcholine is a key driver of active sleep, as well as the fact that muscarinic receptors are abundantly expressed within key respiratory patterning regions, we hypothesized that increased central muscarinic drive contributes to the unstable breathing pattern of infant TPH2−/− rats during active sleep. To test this hypothesis, we conducted two separate experiments using whole‐body plethysmography coupled with nuchal EMG to monitor the breathing pattern of 2‐week‐old TPH2−/− and WT pups during active sleep. Experiment 1: following ~1 hr settling period to allow for the appearance of active sleep, we injected atropine methyl nitrate (Ap‐M), a CNS‐impermeant form of atropine, followed ~30 min later by an injection of atropine sulfate (Ap‐S), a CNS‐permeant form (both 1mg/kg, 10 ul bolus i.v.) (n= 8 and 10 TPH2−/− for Ap‐M and Ap‐S, respectively; n=8 WT for both drugs). Each drug was injected during a period of active sleep. For most animals, arousal did not occur and the effect of the drugs on the co‐efficient of variation in the respiratory period (CV‐P%) could be determined within one episode of active sleep. If arousal occurred, CV‐P% prior to injection was compared to CV‐P% in the next episode of active sleep. Experiment 2: the breathing pattern of TPH2−/− pups was monitored over 2 hrs before and after the administration of Ap‐S (1 mg/kg, 200 ul bolus i.p; n=17) or vehicle (saline; n=16). Tachypnea and apnea indices (# events/hr) were calculated for the active sleep episodes before and after Ap‐S. Administration of Ap‐M increased heart rate (~30–50 beats/min) and decreased heart rate variability for the duration of the experiment. In WT pups, CV‐P% tended to increase after i.v. administration of Ap‐M, but was not significantly changed following Ap‐S. In contrast, the CV‐P% of TPH2−/− pups was significantly increased after Ap‐M (p&lt;0.01) and significantly reduced following Ap‐S (p=0.01). Ap‐S significantly reduced the tachypnea index of TPH2−/− pups relative to TPH2−/− pups given vehicle alone (p=0.04), but had no significant effect on apnea index. The reduced CV‐P% of TPH2−/− pups after Ap‐S relative to values after Ap‐M suggest that muscarinic blockade in the CNS by Ap‐S reverses the destabilizing effect of 5‐HT deficiency on the respiratory pattern. This occurs in spite of a destabilizing peripheral effect of Ap‐M on the breathing pattern. These data also suggest that during active sleep, 5‐HT signaling helps stabilize the breathing pattern of infant rats mainly by inhibiting muscarinic drive to patterning neurons promoting tachypnea.Support or Funding InformationFunding for this research was provided by an American Heart Association Scientist Development Grant (14SDG18560022; PI: KJC) and a Ruth L. Kirschstein National Research Service Award (NRSA) Individual Predoctoral Fellowship (F31) to JLM.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.