scholarly journals The pharmacokinetics of epinephrine/adrenaline autoinjectors

2021 ◽  
Vol 17 (1) ◽  
Author(s):  
Sten Dreborg ◽  
Harold Kim
Keyword(s):  
Heart Rate ◽  
Intramuscular Injection ◽  
Limited Data ◽  
Subcutaneous Injections ◽  
Drug Of Choice ◽  
Proportional Increase ◽  
The Impact ◽  
Dose Dependent Increase ◽  
Dose Dependent ◽  
Higher Doses

Abstract Background For a century, epinephrine has been the drug of choice for acute treatment of systemic allergic reactions/anaphylaxis. For 40 years, autoinjectors have been used for the treatment of anaphylaxis. Over the last 20 years, intramuscular epinephrine injected into the thigh has been recommended for optimal effect. Objective To review the literature on pharmacokinetics of epinephrine autoinjectors. Results Six studies assessing epinephrine autoinjector pharmacokinetics were identified. The studies, all on healthy volunteers, were completed by Simons, Edwards, Duvauchelle, Worm and Turner over the span of 2 decades. Simons et al. published two small studies that suggested that intramuscular injection was superior to subcutaneous injection. These findings were partially supported by Duvauchelle. Duvauchelle showed a proportional increase in Cmax and AUC0-20 when increasing the dose from 0.3 to 0.5 mg epinephrine intramuscularly. Turner confirmed these findings. Simons, Edwards and Duvauchelle documented the impact of epinephrine on heart rate and blood pressure. Turner confirmed a dose-dependent increase in heart rate, cardiac output and stroke volume. Based on limited data, confirmed intramuscular injections appeared to lead to faster Cmax. Two discernable Cmax’s were identified in most of the studies. We identified similarities and discrepancies in a number of variables in the aforementioned studies. Conclusions Intramuscular injection with higher doses of epinephrine appears to lead to a higher Cmax. There is a dose dependent increase in plasma concentration and AUC0-20. Most investigators found two Cmax’s with Tmax 5–10 min and 30–50 min, respectively. There is a need for conclusive trials to evaluate the differences between intramuscular and subcutaneous injections with the epinephrine delivery site confirmed with ultrasound.

scholarly journals The synthetic opioid fentanyl enhances viral replication in vitro

PLoS ONE ◽  
2021 ◽  
Vol 16 (4) ◽  
pp. e0249581
Author(s):  
Ling Kong ◽  
Rebekah Karns ◽  
Mohamed Tarek M. Shata ◽  
Jennifer L. Brown ◽  
Michael S. Lyons ◽  
...  
Keyword(s):  
Cell Death ◽  
Viral Replication ◽  
Cell Lines ◽  
Replicative Fitness ◽  
Synthetic Opioids ◽  
The Impact ◽  
Dose Dependent Increase ◽  
Dose Dependent ◽  
Higher Doses

The US is in the midst of a major drug epidemic fueled in large part by the widespread recreational use of synthetic opioids such as fentanyl. Persons with opioid use disorder are at significant risk for transmission of injection-associated infections such as hepatitis B virus (HBV) and hepatitis C virus (HCV). Commonly abused substances may antagonize immune responses and promote viral replication. However, the impact of synthetic opioids on virus replication has not been well explored. Thus, we evaluated the impact of fentanyl and carfentanil using in vitro systems that replicate infectious viruses. Fentanyl was used in cell lines replicating HBV or HCV at concentrations of 1 ng, 100 ng, and 10 ug. Viral protein synthesis was quantified by ELISA, while apoptosis and cell death were measured by M30 or MTT assays, respectively. HCV replicative fitness was evaluated in a luciferase-based system. RNAseq was performed to evaluate cellular gene regulation in the presence of fentanyl. Low dose fentanyl had no impact on HCV replication in Huh7.5JFH1 hepatocytes; however, higher doses significantly enhanced HCV replication. Similarly, a dose-dependent increase in HCV replicative fitness was observed in the presence of fentanyl. In the HepG2.2.15 hepatocyte cell line, fentanyl caused a dose-dependent increase in HBV replication, although only a higher doses than for HCV. Addition of fentanyl resulted in significant apoptosis in both hepatocyte cell lines. Cell death was minimal at low drug concentrations. RNAseq identified a number of hepatocyte genes that were differentially regulated by fentanyl, including those related to apoptosis, the antiviral / interferon response, chemokine signaling, and NFκB signaling. Collectively, these data suggest that synthetic opioids promote viral replication but may have distinct effects depending on the drug dose and the viral target. As higher viral loads are associated with pathogenesis and virus transmission, additional research is essential to an enhanced understanding of opioid-virus pathogenesis and for the development of new and optimized treatment strategies.

Effects of propofol and thiopentone on picrotoxin convulsive threshold in the rabbit

1995 ◽  
Vol 73 (6) ◽  
pp. 714-717 ◽  
Author(s):  
Zyheir Hasan ◽  
Said Khatib ◽  
Ayman Abu-Laban
Keyword(s):  
Intravenous Administration ◽  
Seizure Threshold ◽  
Intravenous Anesthetics ◽  
Threshold Test ◽  
Dose Dependent Increase ◽  
Convulsive Threshold ◽  
Dose Dependent ◽  
Higher Doses

The purpose of the present study was to examine the effect of intravenous administration of propofol and thiopentone on picrotoxin-induced seizures using the picrotoxin convulsive threshold test in the rabbit. Neither propofol nor thiopentone at a dose of 1.25 mg/kg had any significant effect on picrotoxin seizure threshold. However, at higher doses (2.5, 5, 10 mg/kg) both propofol and thiopentone produced a significant and dose-dependent increase in the picrotoxin convulsive threshold. These findings suggest that propofol is an effective anticonvulsant against picrotoxin-induced seizures in the rabbit.Key words: convulsions, intravenous anesthetics, picrotoxin, propofol, thiopentone.

Regional differences in constitutive and induced ICAM-1 expression in vivo

1995 ◽  
Vol 269 (6) ◽  
pp. H1955-H1964 ◽  
Author(s):  
J. Panes ◽  
M. A. Perry ◽  
D. C. Anderson ◽  
A. Manning ◽  
B. Leone ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Regional Differences ◽  
Time Course ◽  
Intercellular Adhesion Molecule ◽  
Intercellular Adhesion Molecule 1 ◽  
Fourfold Increase ◽  
Dose Dependent Increase ◽  
Dose Dependent ◽  
Higher Doses

The aim of the present study was to characterize and compare the expression of intercellular adhesion molecule 1 (ICAM-1) on unstimulated and endotoxin-challenged endothelial cells in different tissues of the rat. ICAM-1 expression was measured using 125I-labeled anti-rat ICAM-1 monoclonal antibody (MAb) and an isotype-matched control MAb labeled with 131I (to correct for nonspecific accumulation of the binding MAb). Under baseline conditions, ICAM-1 MAb binding was observed in all organs. The binding of 125I-ICAM-1 MAb varied widely among organs, with the largest accumulation (per g tissue) in the lung, followed by heart (1/30th of lung activity), splanchnic organs (1/50th of lung activity), thymus (1/100th of lung activity), testes (1/300th of lung activity), and skeletal muscle (1/800th of lung activity). Endotoxin induced an increase in ICAM-1 MAb binding in all organs except the spleen. Endotoxin-induced upregulation of ICAM-1 was greatest in heart and skeletal muscle (5- to 10-fold), whereas the remaining organs exhibited a two- to fourfold increase in ICAM-1 expression. Maximal upregulation of ICAM-1 occurred at 9-12 h after endotoxin administration. A dose-dependent increase in ICAM-1 expression was elicited by 0.1-10 microgram/kg, with higher doses (up to 5 mg/kg) producing no further increment. Induction of ICAM-1 mRNA after endotoxin was observed in all tissues examined (lung, heart, intestine), peaked at 3 h, and then rapidly returned to control levels. These findings indicate that ICAM-1 is constitutively expressed on vascular endothelium in all organs of the rat and that there are significant regional differences in the magnitude and time course of endotoxin-induced ICAM-1 expression.

Effects of intrarenal adenosine on renal function and medullary blood flow in the rat

1988 ◽  
Vol 255 (6) ◽  
pp. F1230-F1234 ◽  
Author(s):  
M. Miyamoto ◽  
Y. Yagil ◽  
T. Larson ◽  
C. Robertson ◽  
R. L. Jamison
Keyword(s):  
Blood Flow ◽  
Sodium Excretion ◽  
Systemic Circulation ◽  
Urinary Flow ◽  
Medullary Blood Flow ◽  
Vasa Recta ◽  
Potent Vasodilator ◽  
Dose Dependent Increase ◽  
Dose Dependent ◽  
Higher Doses

Adenosine is a potent vasodilator of the systemic circulation. Infusion of adenosine into the aorta causes water and sodium retention and a fall in glomerular filtration rate and renal blood flow. The effect of adenosine on medullary blood flow is unknown. Because systemic vasodilatory effects may confound its renal actions, adenosine was infused into the renal artery of anesthetized Munich-Wistar rats at doses of 2, 6, and 15 micrograms/min. A marked dose-dependent increase in urinary flow and sodium excretion was observed. Inulin and p-aminohippuric acid clearance did not change significantly. Blood flow in vasa recta in the exposed renal papilla, as determined by fluorescence videomicroscopy, increased significantly only with the highest dose of adenosine. In control animals infused with the vehicle only, there was no change in any of the above variables. These results indicate that direct intrarenal infusion of adenosine in the rat increases urinary flow and sodium excretion and at higher doses also increases vasa recta blood flow. The effects on urinary flow and sodium excretion were therefore mediated by a mechanism other than an increase in vasa recta blood flow.

Desensitization of the pancreatic β-cell: effects of sustained physiological hyperglycemia and potassium

2006 ◽  
Vol 291 (6) ◽  
pp. E1381-E1387 ◽  
Author(s):  
Hanae Yamazaki ◽  
Kathleen C. Zawalich ◽  
Walter S. Zawalich
Keyword(s):  
Diabetic Patients ◽  
Β Cell ◽  
Physiological Regulation ◽  
Calcium Dependent ◽  
Chronic Hyperglycemia ◽  
Glucagon Like Peptide ◽  
Glucagon Like Peptide 1 ◽  
The Impact ◽  
Dose Dependent Increase ◽  
Dose Dependent

The impact of modest but prolonged (3 h) exposure to high physiological glucose concentrations and hyperkalemia on the insulin secretory and phospholipase C (PLC) responses of rat pancreatic islets was determined. In acute studies, glucose (5–20 mM) caused a dose-dependent increase in secretion with maximal release rates 25-fold above basal secretion. When measured after 3 h of exposure to 5–10 mM glucose, subsequent stimulation of islets with 10–20 mM glucose during a dynamic perifusion resulted in dose-dependent decrements in secretion and PLC activation. Acute hyperkalemia (15–30 mM) stimulated calcium-dependent increases in both insulin secretion and PLC activation; however, prolonged hyperkalemia resulted in a biochemical and secretory lesion similar to that induced by sustained modest hyperglycemia. Glucose- (8 mM) desensitized islets retained significant sensitivity to stimulation by either carbachol or glucagon-like peptide-1. These findings emphasize the vulnerability of the β-cell to even moderate sustained hyperglycemia and provide a biochemical rationale for achieving tight glucose control in diabetic patients. They also suggest that PLC activation plays a critically important role in the physiological regulation of glucose-induced secretion and in the desensitization of release that follows chronic hyperglycemia or hyperkalemia.

Effect of Khatamines and Their Enantiomers on Plasma Triiodothyronine and Thyroxine Levels in Normal Wistar Rats

1990 ◽  
Vol 18 (01n02) ◽  
pp. 71-76 ◽  
Author(s):  
M.W. Islam ◽  
M. Tariq ◽  
F.S. El-Feraly ◽  
I.A. Al-Meshal
Keyword(s):  
Wistar Rats ◽  
Peak Effect ◽  
Pharmacological Effects ◽  
Catha Edulis ◽  
Blood Samples ◽  
Male Wistar Rats ◽  
Dose Dependent Increase ◽  
Dose Dependent ◽  
Higher Doses ◽  
Plasma Triiodothyronine

The effect of cathinone and N-formylnorephedrine, two psychoactive amines of khat (Catha edulis Forsk.) and their enantiomers have been studied on plasma levels of triiodothyronine (T3) and thyroxine (T4) in male Wistar rats. The rats were injected with 5, 10 and 30 mg/kg. body weight of four khatamines and the blood samples were collected 2 h after administration. In the separate set of experiments the effect of these khatamines at 1, 2 and 4 h after their administration was also examined. All khatamines failed to produce a significant dose dependent increase in T3 and T4 levels in the dose of 5 mg/kg. However, all these compounds produced a significant dose dependent increase in T3 and T4 levels at higher doses but only T4 levels were increased following the dose of 10 mg/kg. Our studies on the effect of khatamines in T3 and T4 levels at various time showed a significant increase in T4 levels in all the four groups treated with various khatamines and the peak effect was observed in 2 h in case of (-)- and (+)-cathinone and 4 h in case of (-) and (+)N-formylnorephedrine. This study suggests that the symptoms observed in khat chewers including hyperthermia, anorexia, and metabolic changes may to some extent be attributed to the thyroid stimulating effect of khatamines. However, further studies are needed to establish the mechanism of release of thyroid hormones by these compounds and their involvement in the pharmacological effects.

scholarly journals The selective eosinophil chemotactic activity of histamine.

1975 ◽  
Vol 142 (6) ◽  
pp. 1462-1476 ◽  
Author(s):  
R A Clark ◽  
J I Gallin ◽  
A P Kaplan
Keyword(s):  
Diamine Oxidase ◽  
Cellulose Nitrate ◽  
Boyden Chamber ◽  
Immediate Hypersensitivity ◽  
Eosinophil Migration ◽  
Dose Dependent Increase ◽  
Dose Dependent ◽  
Higher Doses ◽  
Cellulose Nitrate Filter ◽  
Stimulation By Histamine

Histamine diphosphate was shown to selectively attract human eosinophils from mixed granulocyte populations when over 20% eosinophils were used in a modified Boyden chamber chemotactic assay system. This effect of histamine is abolished by incubation with diamine oxidase (histaminase) and was generated by decarboxylation of L-histidine. A linear dose dependent increase in eosinophil migration was observed between 3 X 10(-7) M and 1.25 X 10(-6) M, while higher concentrations of histamine inhibited the migration of eosinophils. The attractant activity of histamine was not inhibited by H-1 or H-2 receptor antagonists, however, the inhibition of migration observed at higher histamine concentrations was reversed by metiamine, an H-2 receptor antagonist. The effects of histamine upon eosinophil migration were demonstrable using three different assays: (a) counting cells that had traversed 5-mum pore, 12-mum thick polycarbonate filters, (b) counting cells that had migrated various distances into a 3-mum pore, 145-mum cellulose nitrate filters, or (c) measuring the number of cells that had traversed an upper polycarbonate filter and migrated into a lower cellulose nitrate filter using 15Cr-labeled cells. The ability of histamine to enhance eosinophil migration was shown to be dependent upon the presence of a concentration gradient; histamine did not cause a dose-dependent increase in random motility. Furthermore, preincubation of the eosinophils with histamine deactivate the cells to further stimulation by histamine or by C5a. It is concluded that in low doses histamine is a chemoattractant for human eosinophils, while in higher doses histamine inhibits eosinophil migration. These observations may relate to the influx and localization of eosinophils in immediate hypersensitivity reactions.

scholarly journals Insect cardioactive peptides. II. Neurohormonal control of heart activity by two cardioacceleratory peptides in the tobacco hawkmoth, Manduca sexta

1985 ◽  
Vol 114 (1) ◽  
pp. 381-395 ◽  
Author(s):  
N. J. Tublitz ◽  
J. W. Truman
Keyword(s):  
Heart Rate ◽  
Manduca Sexta ◽  
Gel Filtration ◽  
Dependent Manner ◽  
Heart Activity ◽  
High Potassium ◽  
Calcium Dependent ◽  
Dose Dependent Increase ◽  
Dose Dependent

The physiological characteristics of two cardioacceleratory peptides (CAPs) were analysed in the tobacco hawkmoth, Manduca sexta, to determine if either CAP functioned as a cardioregulatory neurohormone. In vivo heart recordings from pharate and newly emerged adults revealed a dramatic increase in heart rate associated with wing-spreading behaviour. Bioassay of whole blood taken from wing-spreading (WS) animals indicated the presence of a stage-specific, blood-borne cardioacceleratory factor(s). Gel filtration of WS blood identified two cardioacceleratory factors which co-eluted with the two CAPs. A depletion of the ventral nerve cord levels of both CAPs was observed during WS behaviour. Measurements of blood CAP levels showed that the peak CAP titres were coincident with the initiation of WS behaviour. Experimental manipulations that delayed the onset of WS behaviour also prevented CAP release. High potassium incubation evoked the release of both CAPs in a calcium-dependent manner. In vivo injections of CAP1 or CAP2 caused a dose-dependent increase in heart rate. These results confirm the hypothesis that both CAPs function as cardioregulatory neurohormones during wing-spreading behaviour in Manduca sexta.

scholarly journals Hemodynamic effects elicited by microinjection of glutamatergic agonists into NTS of conscious rats

2001 ◽  
Vol 281 (3) ◽  
pp. H1026-H1034 ◽  
Author(s):  
Ana Carolina Rodrigues Dias ◽  
William T. Talman ◽  
Eduardo Colombari
Keyword(s):  
Heart Rate ◽  
Mean Arterial Pressure ◽  
Arterial Pressure ◽  
Hemodynamic Effects ◽  
Vascular Conductance ◽  
Conscious Rats ◽  
Dose Dependent ◽  
Higher Doses ◽  
Preferential Activation ◽  
Biphasic Responses

In this study, we characterized the arterial pressure, heart rate, and regional vascular conductance responses elicited by unilateral microinjection of ionotropic glutamatergic agonists N-methyl-d-aspartic acid (NMDA and non-NMDA) into the nucleus of tractus solitarius (NTS) of conscious rats. Microinjections of NMDA and S-α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) caused changes in mean arterial pressure (MAP). Lower doses elicited decreases in MAP, whereas higher doses elicited biphasic responses (decreases followed by increases). Both agonists induced bradycardia and elicited dose-dependent vasoconstriction in the renal, mesenteric, and hindquarter beds. AMPA elicited delayed vasodilation in the hindquarter bed but NMDA did not. Bradycardia and initial hypotension produced by each agonist were abolished by systemic administration of the muscarinic antagonist methylatropine. However, methylatropine did not affect either the vasoconstriction or the vasodilatation. The contrasting hemodynamic effects produced by NMDA and AMPA could be caused by activation of differential subsets of NTS neurons. Preferential activation of one subset could produce the NMDA-related responses, whereas activation of another subset would elicit AMPA-related responses.

scholarly journals The CD44high Subpopulation of Multifraction Irradiation-Surviving NSCLC Cells Exhibits Partial EMT-Program Activation and DNA Damage Response Depending on Their p53 Status

2021 ◽  
Vol 22 (5) ◽  
pp. 2369
Author(s):  
Margarita Pustovalova ◽  
Lina Alhaddad ◽  
Taisia Blokhina ◽  
Nadezhda Smetanina ◽  
Anna Chigasova ◽  
...  
Keyword(s):  
Epithelial Mesenchymal Transition ◽  
Specific Cell ◽  
Dsb Repair ◽  
Migration Activity ◽  
Mesenchymal Transition ◽  
X Ray ◽  
P53 Status ◽  
The Impact ◽  
Dose Dependent Increase ◽  
Dose Dependent

Ionizing radiation (IR) is used for patients diagnosed with unresectable non-small cell lung cancer (NSCLC). However, radiotherapy remains largely palliative due to the survival of specific cell subpopulations. In the present study, the sublines of NSCLC cells, A549IR (p53wt) and H1299IR (p53null) survived multifraction X-ray radiation exposure (MFR) at a total dose of 60 Gy were investigated three weeks after the MFR course. We compared radiosensitivity (colony formation), expression of epithelial-mesenchymal transition (EMT) markers, migration activity, autophagy, and HR-dependent DNA double-strand break (DSB) repair in the bulk and entire CD44high/CD166high CSC-like populations of both parental and MFR survived NSCLC cells. We demonstrated that the p53 status affected: the pattern of expression of N-cadherin, E-cadherin, Vimentin, witnessing the appearance of EMT-like phenotype of MFR-surviving sublines; 1D confined migratory behavior (wound healing); the capability of an irradiated cell to continue to divide and form a colony of NSCLC cells before and after MFR; influencing the CD44/CD166 expression level in MFR-surviving NSCLC cells after additional single irradiation. Our data further emphasize the impact of p53 status on the decay of γH2AX foci and the associated efficacy of the DSB repair in NSCLC cells survived after MFR. We revealed that Rad51 protein might play a principal role in MFR-surviving of p53 null NSCLC cells promoting DNA DSB repair by homologous recombination (HR) pathway. The proportion of Rad51 + cells elevated in CD44high/CD166high population in MFR-surviving p53wt and p53null sublines and their parental cells. The p53wt ensures DNA-PK-mediated DSB repair for both parental and MFR-surviving cells irrespectively of a subsequent additional single irradiation. Whereas in the absence of p53, a dose-dependent increase of DNA-PK-mediated non-homologous end joining (NHEJ) occurred as an early post-irradiation response is more intensive in the CSC-like population MFR-surviving H1299IR, compared to their parental H1299 cells. Our study strictly observed a significantly higher content of LC3 + cells in the CD44high/CD166high populations of p53wt MFR-surviving cells, which enriched the CSC-like cells in contrast to their p53null counterparts. The additional 2 Gy and 5 Gy X-ray exposure leads to the dose-dependent increase in the proportion of LC3 + cells in CD44high/CD166high population of both parental p53wt and p53null, but not MFR-surviving NSCLC sublines. Our data indicated that autophagy is not necessarily associated with CSC-like cells’ radiosensitivity, emphasizing that careful assessment of other milestone processes (such as senescence and autophagy-p53-Zeb1 axis) of primary radiation responses may provide new potential targets modulated for therapeutic benefit through radiosensitizing cancer cells while rescuing normal tissue. Our findings also shed light on the intricate crosstalk between autophagy and the p53-related EMT, by which MFR-surviving cells might obtain an invasive phenotype and metastatic potential.

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