scholarly journals Ampakine CX717 Protects against Fentanyl-induced Respiratory Depression and Lethal Apnea in Rats

2009 ◽  
Vol 110 (6) ◽  
pp. 1364-1370 ◽  
Author(s):  
Jun Ren ◽  
Xiuqing Ding ◽  
Gregory D. Funk ◽  
John J. Greer
Keyword(s):  
Respiratory Depression ◽  
Lethal Dose ◽  
Cognitive Disorders ◽  
Opiate Receptor ◽  
Respiratory Frequency ◽  
Adult Rats ◽  
Analgesic Effects ◽  
Life Threatening ◽  
Nerve Recordings

Background The use of fentanyl as a potent analgesic is contradicted by marked respiratory depression among a subpopulation of patients. The commonly used approach of reversing fentanyl-induced respiratory depression with mu-opiate receptor antagonists such as naloxone has the undesirable effect of blocking analgesia. Here, the authors report a clinically feasible pharmacological solution for countering fentanyl-induced respiratory depression via a mechanism that does not interfere with analgesia. Specifically, to determine if the ampakine CX717, which has been proven metabolically stable and safe for human use, can prevent and rescue from severe fentanyl-induced apnea. Methods Plethsymographic recordings were performed from young and adult rats. Varying doses of fentanyl were administered either intraperitoneally or intravenously to induce moderate to life-threatening apneas. CX717 was administered either before or after fentanyl administration. In addition, phrenic nerve recordings were performed from in situ working heart brainstem preparations from juvenile rats. Results Preadministration of CX717 markedly attenuated fentanyl-induced respiratory depression. Postadministration of CX717 rescued animals from a lethal dose of fentanyl. Significantly, CX717 countered fentanyl-induced depression of respiratory frequency without suppressing analgesia. The effective dose of CX717 was in the range deemed safe on the basis of clinical trials examining its efficacy for cognitive disorders. In situ, fentanyl-induced depression in respiratory frequency and amplitude was alleviated by CX717. Conclusions CX717 is an agent that enhances the safety of using opiate drugs while preserving the analgesic effects. This advancement could significantly improve pain management in a variety of clinical settings.

scholarly journals Coadministration of the AMPAKINE CX717 with Propofol Reduces Respiratory Depression and Fatal Apneas

2013 ◽  
Vol 118 (6) ◽  
pp. 1437-1445 ◽  
Author(s):  
Jun Ren ◽  
Floriane Lenal ◽  
Michael Yang ◽  
Xiuqing Ding ◽  
John J. Greer
Keyword(s):  
Respiratory Depression ◽  
Safety Margin ◽  
Adult Rats ◽  
Control Frequency ◽  
Rat Brainstem ◽  
Nerve Recordings ◽  
Working Heart

Abstract Background: Propofol (2,6-diisopropylphenol) is used for the induction and maintenance of anesthesia in human and veterinary medicine. Propofol’s disadvantages include the induction of respiratory depression and apnea. Here, the authors report a clinically feasible pharmacological solution for reducing propofol-induced respiratory depression via a mechanism that does not interfere with anesthesia. Specifically, they test the hypothesis that the AMPAKINE CX717, which has been proven metabolically stable and safe for human use, can prevent and rescue from propofol-induced severe apnea. Methods: The actions of propofol and the AMPAKINE CX717 were measured via (1) ventral root recordings from newborn rat brainstem–spinal cord preparations, (2) phrenic nerve recordings from an adult mouse in situ working heart–brainstem preparation, and (3) plethysmographic recordings from unrestrained newborn and adult rats. Results: In vitro, respiratory depression caused by propofol (2 μm, n = 11, mean ± SEM, 41±5% of control frequency, 63±5% of control duration) was alleviated by CX717 (n = 4, 50–150 μm). In situ, a decrease in respiratory frequency (44±9% of control), phrenic burst duration (66±7% of control), and amplitude (78±5% of control) caused by propofol (2 μm, n = 5) was alleviated by coadministration of CX717 (50 μm, n = 5). In vivo, pre- or coadministration of CX717 (20–25mg/kg) with propofol markedly reduced propofol-induced respiratory depression (n = 7; 20mg/kg) and propofol-induced lethal apnea (n = 6; 30mg/kg). Conclusions: Administration of CX717 before or in conjunction with propofol provides an increased safety margin against profound apnea and death.

scholarly journals Respiratory depression in rats induced by alcohol and barbiturate and rescue by ampakine CX717

2012 ◽  
Vol 113 (7) ◽  
pp. 1004-1011 ◽  
Author(s):  
Jun Ren ◽  
Xiuqing Ding ◽  
John J. Greer
Keyword(s):  
Respiratory Depression ◽  
Circulatory Support ◽  
Respiratory Drive ◽  
Drug Induced ◽  
Adult Rats ◽  
Respiratory Rhythmogenesis ◽  
Life Threatening ◽  
Preclinical And Clinical Studies

Barbiturate use in conjunction with alcohol can result in severe respiratory depression and overdose deaths. The mechanisms underlying the additive/synergistic actions were unresolved. Current management of ethanol-barbiturate-induced apnea is limited to ventilatory and circulatory support coupled with drug elimination. Based on recent preclinical and clinical studies of opiate-induced respiratory depression, we hypothesized that ampakine compounds may provide a treatment for other types of drug-induced respiratory depression. The actions of alcohol, pentobarbital, bicuculline, and the ampakine CX717, alone and in combination, were measured via 1) ventral root recordings from newborn rat brain stem-spinal cord preparations and 2) plethysmographic recordings from unrestrained newborn and adult rats. We found that ethanol caused a modest suppression of respiratory drive in vitro (50 mM) and in vivo (2 g/kg ip). Pentobarbital induced an ∼50% reduction in respiratory frequency in vitro (50 μM) and in vivo (28 mg/kg for pups and 56 mg/kg for adult rats ip). However, severe life-threatening apnea was induced by the combination of the agents in vitro and in vivo via activation of GABAA receptors, which was exacerbated by hypoxic (8% O2) conditions. Administration of the ampakine CX717 alleviated a significant component of the respiratory depression in vitro (50–150 μM) and in vivo (30 mg/kg ip). Bicuculline also alleviated ethanol-/pentobarbital-induced respiratory depression but caused seizure activity, whereas CX717 did not. These data demonstrated that ethanol and pentobarbital together caused severe respiratory depression, including lethal apnea, via synergistic actions that blunt chemoreceptive responses to hypoxia and hypercapnia and suppress central respiratory rhythmogenesis. The ampakine CX717 markedly reduced the severity of respiratory depression.

A Multicentric non-interventional observational study to determine treatment patterns and response of drugs in various stages of breast cancer along with epidemiology

2020 ◽  
Vol 8 (2) ◽  
pp. 71-81
Author(s):  
Mukkamala Durga Niharika ◽  
Shaik Kulsumbi ◽  
Devagiri Anupama ◽  
Tadigiri Vineela Supriya ◽  
Kotari Navya ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Observational Study ◽  
Receptor Expression ◽  
Breast Cancer Patients ◽  
Female Patients ◽  
Life Threatening ◽  
Guntur District ◽  
Study Population ◽  
Hormone Receptor Expression

Cancer is a life-threatening disease which causes to lose cohesiveness and orderliness of normal tissue. These malignant cells can spread to any other organ through blood flow or lymphatic flow and develop malignancy over there; this phenomenon is called metastasis. The aim is to focus on treatment pattern and response of drugs in various stages of breast cancer along with epidemiology. It is a non- interventional multicentric observational study. Female patients confirmed with Breast cancer are included in the study. All the relevant data were collected on a patient demographic form after obtaining informed consent from individual patients. In our study, the mean age of presentation in breast cancer patients was 41.35 years. Further it was found that 40.5% (n = 81) majority-female patients with Breast cancer are from Guntur District and 21.5% (n= 43). The majority of women with Breast cancer have hormone receptor expression of ER+/PR+HER2- was found to be 33% (n= 50). In the study on analyzing comorbidities of the study population, it was noted that 28.5% of women were affected with Diabetes mellitus. In our study, it was found that most of the patients with Breast cancer have been most often prescribed with Adriamycin 27.86%. From these observations, we conclude that late menarche may be one of the etiological causes of breast cancer in women, Invasive carcinoma in situ is the most commonly reported breast cancer in the study. Patients have been diagnosed with breast cancer at their stage 3 of progression, which may be the reason for making it mandatory for more than 50% of patients to undergo 6 to 8 cycles of chemotherapy. Coming to the patterns of drug use, ADRIAMYCIN, CYCLOPHOSPHAMIDE and DOCETAXEL are the three most commonly used single drug and combinational drug therapies among the study population.

Respiratory syncytial virus infection in anesthetized weanling rather than adult rats prolongs the apneic responses to right atrial injection of capsaicin

2007 ◽  
Vol 102 (6) ◽  
pp. 2201-2206 ◽  
Author(s):  
Wenhong Peng ◽  
Jianguo Zhuang ◽  
Kevin S. Harrod ◽  
Fadi Xu
Keyword(s):  
Respiratory Syncytial Virus ◽  
Blood Gases ◽  
Respiratory Frequency ◽  
Right Atrial ◽  
Arterial Blood Gases ◽  
Adult Rats ◽  
Intranasal Inoculation ◽  
Arterial Blood ◽  
Rsv Infection ◽  
Syncytial Virus

Apnea is a common complication in infants infected by respiratory syncytial virus (RSV). A recent study has shown that intranasal inoculation of RSV in conscious weanling rats strengthens the apneic responses to right atrial injection of capsaicin (CAP), leading to 66% mortality. The objectives of the present study were to determine 1) whether RSV infection changes baseline minute ventilation (V̇e) and arterial blood gases in anesthetized rats; 2) what the effects of RSV infection are on the respiratory responses to CAP; and 3) whether the RSV-strengthened apneic responses are age dependent. Our experiments were conducted in anesthetized and spontaneously breathing rats divided into four groups of weanling and adult rats that received either intranasal inoculation of RSV or virus-free medium. Two days after RSV infection (0.7 ml/kg), animal blood gases, baseline V̇e, and V̇e responses to right atrial injection of three doses of CAP (4, 16, and 64 μg/kg) were measured and compared among the four groups. Our results showed that RSV infection increased respiratory frequency (∼25%, P < 0.05) in weanling but not adult rats, with little effect on arterial blood gases. RSV infection amplified the apneic responses to CAP in weanling but not adult rats, characterized by increases in the initial (40%) and the longest apneic duration (650%), the number of apneic episodes (139%), and the total duration of apneas (60%). These amplifications led to 50% mortality ( P < 0.05). We conclude that RSV infection increases respiratory frequency and strengthens the apneic responses to CAP only in anesthetized weanling but not adult rats.

scholarly journals Preliminary Evaluation of the Efficacy and Safety of Brimonidine for General Anesthesia

2021 ◽  
Author(s):  
Bin Chen ◽  
Xiaohui Wang ◽  
Mengrou Shi ◽  
Xin Li ◽  
Ting Zhang ◽  
...  
Keyword(s):  
General Anesthesia ◽  
Effective Dose ◽  
Intraperitoneal Injection ◽  
Chloral Hydrate ◽  
Lethal Dose ◽  
Preliminary Evaluation ◽  
Efficacy And Safety ◽  
Sleeping Time ◽  
Analgesic Effects ◽  
Hypnotic Effect

Abstract Background:To determine the hypnotic and analgesic effects of brimonidine, and evaluate its efficacy and safety for general anesthesia. Potentiation of pentobarbital sleeping time with brimonidine was observed in mice, as was analgesic activity of brimonidine.Methods:The median effective dose (ED50)and lethal dose (LD50) of intraperitoneally injected brimonidine were determined in hypnotized mice. In addition, LD50 of intravenously injected brimonidine, ED50 of intravenously , intramuscularly and intrarectally injected brimonidine in hypnotized rabbits were determined. The synergistic anesthetic effect of brimonidine and chloral hydrate on rabbits was evaluated. Results:Intraperitoneal injection of 10 mg/kg brimonidine enhanced the hypnotic effect of a threshold dose of pentobarbital. Intraperitoneal injection brimonidine produced dose-related analgesic effects in mice. ED50 of intraperitoneally administered brimonidine in hypnotized mice was 75.7 mg/kg, and LD50 was 379 mg/kg. The ED50 of intravenous, intramuscular and intrarectal brimonidine for hypnosis in rabbits were 5.2 mg/kg, 8.8 mg/kg and 8.7mg/kg, respectively, and LD50 of intravenous brimonidine was 146 mg/kg. Combined intravenous administration of 0.6 mg/kg brimonidine and 0.03 g/kg chloral hydrate had a synergistic anesthetic effects.Conclusions:Brimonidine elicited hypnotic and analgesic effects after systemic administration, and exhibited safety. Brimonidine enhanced the effects of other types of narcotics when combined.

scholarly journals Benefit and Risk Evaluation of Biased μ-Receptor Agonist Oliceridine versus Morphine

2020 ◽  
Vol 133 (3) ◽  
pp. 559-568 ◽  
Author(s):  
Albert Dahan ◽  
C. Jan van Dam ◽  
Marieke Niesters ◽  
Monique van Velzen ◽  
Michael J. Fossler ◽  
...  
Keyword(s):  
Utility Function ◽  
Respiratory Depression ◽  
Receptor Agonist ◽  
Ventilatory Response ◽  
Cold Pressor Test ◽  
Cold Pressor ◽  
Population Pharmacokinetic ◽  
Potency Ratio ◽  
Analgesic Effects ◽  
Hypercapnic Ventilatory Response

Background To improve understanding of the respiratory behavior of oliceridine, a μ-opioid receptor agonist that selectively engages the G-protein–coupled signaling pathway with reduced activation of the β-arrestin pathway, the authors compared its utility function with that of morphine. It was hypothesized that at equianalgesia, oliceridine will produce less respiratory depression than morphine and that this is reflected in a superior utility. Methods Data from a previous trial that compared the respiratory and analgesic effects of oliceridine and morphine in healthy male volunteers (n = 30) were reanalyzed. A population pharmacokinetic–pharmacodynamic analysis was performed and served as basis for construction of utility functions, which are objective functions of probability of analgesia, P(analgesia), and probability of respiratory depression, P(respiratory depression). The utility function = P(analgesia ≥ 0.5) – P(respiratory depression ≥ 0.25), where analgesia ≥ 0.5 is the increase in hand withdrawal latency in the cold pressor test by at least 50%, and respiratory depression ≥ 0.25 is the decrease of the hypercapnic ventilatory response by at least 25%. Values are median ± standard error of the estimate. Results The two drugs were equianalgesic with similar potency values (oliceridine: 27.9 ± 4.9 ng/ml; morphine 34.3 ± 9.7 ng/ml; potency ratio, 0.81; 95% CI, 0.39 to 1.56). A 50% reduction of the hypercapnic ventilatory response by morphine occurred at an effect-site concentration of 33.7 ± 4.8 ng/ml, while a 25% reduction by oliceridine occurred at 27.4 ± 3.5 ng/ml (potency ratio, 2.48; 95% CI, 1.65 to 3.72; P &lt; 0.01). Over the clinically relevant concentration range of 0 to 35 ng/ml, the oliceridine utility function was positive, indicating that the probability of analgesia exceeds the probability of respiratory depression. In contrast, the morphine function was negative, indicative of a greater probability of respiratory depression than analgesia. Conclusions These data indicate a favorable oliceridine safety profile over morphine when considering analgesia and respiratory depression over the clinical concentration range. Editor’s Perspective What We Already Know about This Topic What This Article Tells Us That Is New

scholarly journals Cell proliferation assay – method optimisation for in vivo labeling of DNA in the rat forestomach

2017 ◽  
Vol 67 (1) ◽  
pp. 1-10
Author(s):  
Gordana Joksić ◽  
Mileva Mićić ◽  
Jelena Filipović ◽  
Dunja Drakulić ◽  
Miloš Stanojlović ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Immunohistochemical Analysis ◽  
Optimal Dose ◽  
Cell Labeling ◽  
Assay Method ◽  
Proliferating Cells ◽  
Adult Rats ◽  
In Vivo Labeling

AbstractThe study of cell proliferation is a useful tool in the fields of toxicology, pathophysiology and pharmacology. Cell proliferation and its degree can be evaluated using 5-bromo-2′-deoxyuridine which is incorporated into the newly synthesized DNA. The aim of this study was the optimization of subcutaneous application of 5-bromo-2′-deoxyuridine implantation for continuous and persistent marking of proliferating cells in the rat forestomach. 3-tert-Butyl-4-hydroxyanisole was used as the agent that ensures cell proliferation. In order to determine the optimal dose for proliferating cells labeling, 5-bromo-2′-deoxyuridine doses of 50 mg, 100 mg, 200 mg or 350 mg were implemented 2 days prior to sacrifice by flat-faced cylindrical matrices. Immunohistochemical analysis using 5-bromo-2′-deoxyuridine in situ detection kit was performed for the detection of 5-bromo-2′-deoxyuridine labeled cells. The results showed that for adult rats, the optimum 5-bromo-2′-deoxyuridine dose is 200 mg per animal for subcutaneous application. The here described manner of 5-bromo-2′-deoxyuridine in vivo labeling provides a simple, efficient, and reliable method for cell labeling, and at the same minimizes stress to animals.

Coping, Not Choking, Under the Pressure of a Terrorist Attack: A Crisis Leadership Coping Model

2021 ◽  
pp. 002188632110665
Author(s):  
Synnøve Nesse ◽  
Inger G. Stensaker
Keyword(s):  
Crisis Management ◽  
Terrorist Attack ◽  
Crisis Leadership ◽  
Mass Casualties ◽  
Holding Environment ◽  
Three Phase ◽  
Organizational Crises ◽  
Life Threatening ◽  
Coping Model

Organizational crises, especially those of an extreme nature that include threats to survival and mass casualties, are deeply psychologically challenging for leaders. Previous research has focused on the effectiveness of leaders’ crisis management without much consideration for how leaders manage their own crisis reactions. This study was carried out in the crisis management facilities at the headquarters of a multinational energy corporation while a terrorist attack was ongoing in one of its subsidiaries. The unique access and data provide insights into how leaders react to crises and seek support by using different coping strategies. We develop a three-phase model (acceptance, psychological flexibility, and commitment) that illustrates the in-situ creation of a holding environment to support leaders in coping, not choking, under the pressure of a life-threatening crisis.

Development of fatty acid esterification mechanisms in rat small intestine.

1979 ◽  
Vol 237 (5) ◽  
pp. E399 ◽  
Author(s):  
Y F Shiau ◽  
C Umstetter ◽  
K Kendall ◽  
O Koldovsky
Keyword(s):  
Small Intestine ◽  
Fatty Acid ◽  
Total Fatty Acid ◽  
Fetal Programming ◽  
Rat Small Intestine ◽  
Adult Rats ◽  
Major Pathway ◽  
Acid Esterification ◽  
Fatty Acid Esterification

Fatty acid esterification was measured in fetal jejunal and ileal isografts implanted under the kidney capsules of adult host rats and compared to the age-controlled intestine grown in situ. Studies were conducted on the 21st, 35th, 49th, and 63rd postconceptional days, corresponding to prenatal, suckling, weaning, and weaned rats. Substantial fatty acid esterification activity was found in prenatal jejunum but not in ileum. A proximal-distal gradient of fatty acid esterification was observed in all groups grown in situ, but not in isografts. The monoglyceride pathway (MG-P) accounted for about one-third of total fatty acid esterification (TFAE) in jejunum grown in situ and remained constant through the study. In the ileum, MG-P was the major esterification pathway during the first 4 postnatal weeks, but decreased progressively after weaning to become insignificant in adult rats. TFAE fell in the jejunal isografts, whereas it increased in the ileum. MG-P remained as the major pathway in the implanted jejunum and ileum. Our studies suggest that luminal contents are probably the most important modulator for the development and maintenance of intestinal fatty acid esterification, and "fetal programming" manifested by changes in fatty acid esterification mechanisms in the isografts is less important.

Naloxone attenuates poststimulatory respiratory depression of laryngeal origin in the adult cat

1995 ◽  
Vol 269 (1) ◽  
pp. R113-R123 ◽  
Author(s):  
D. Mutolo ◽  
F. Bongianni ◽  
M. Corda ◽  
G. A. Fontana ◽  
T. Pantaleo
Keyword(s):  
Respiratory Depression ◽  
Time Course ◽  
Superior Laryngeal Nerve ◽  
Endogenous Opioids ◽  
Respiratory Frequency ◽  
Inspiratory Activity ◽  
Stimulation Period ◽  
Adult Cat ◽  
Adult Cats ◽  
Alpha Chloralose

Poststimulatory depression in respiratory activity induced by superior laryngeal nerve (SLN) stimulation was quantitatively investigated in 20 adult cats. The role played in this phenomenon by endogenous opioids was studied using the opiate antagonist naloxone. The effects of hypercapnia on the same phenomenon were also investigated for comparison. Experiments were performed on cats anesthetized with pentobarbitone or alpha-chloralose, vagotomized, paralyzed, and artificially ventilated with 100% O2. Some animals were also carotid sinus denervated. Respiratory output was monitored as integrated phrenic nerve activity. SLN stimulation produced apnea, which outlasted the stimulation period; when respiration resumed, it was markedly depressed as revealed mainly by a decrease in phrenic minute output, respiratory frequency, and rate of rise of inspiratory activity. Phrenic output recovered gradually to control levels following an exponential time course. These effects varied as a function of the duration of SLN stimulation. Naloxone administration (0.8 mg/kg iv) significantly reduced the duration of poststimulatory apnea and attenuated the depression of phrenic minute output of the first recovery breath as a result of changes in peak phrenic activity; it also accelerated the time course of recovery. Hypercapnia did not affect the duration of poststimulatory apnea, but attenuated the initial poststimulatory depression because of changes in respiratory frequency; the rate of recovery was reduced. The results provide characterization of poststimulatory respiratory depression of laryngeal origin in the adult cat and suggest a role of endogenous opioids in its genesis or modulation.

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