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Background: To enhance the utility of functional hemodynamic monitoring, the variables systolic slope (dP/dt) and dynamic arterial elastance (Ea dyn ) are calculated by the Hypotension Prediction Index (HPI) Acumen® Software. This study was designed to characterize the effects of phenylephrine and ephedrine on dP/dt and Ea dyn ., Methods: This was a retrospective, non-randomized analysis of data collected during two clinical studies. All patients required intra-operative controlled mechanical ventilation and had an indwelling radial artery catheter connected to an Acumen IQ sensor. Raw arterial pressure waveform data was downloaded from the patient monitor and all hemodynamic measurements were calculated off-line. The anesthetic record was reviewed for bolus administrations of either phenylephrine or ephedrine. Cardiovascular variables prior to drug administration were compared to those following vasopressor administrations. The primary outcome was the difference for dP/dt and Ea dyn at baseline compared with the average after the bolus administration. All data sets demonstrated non-normal distributions so statistical analysis of paired and unpaired data followed the Wilcoxon matched pairs signed-rank test or Mann-Whitney U test, respectively., Results: 201 doses of phenylephrine and 100 doses of ephedrine were analyzed. All data sets are reported as median [95% CI]. Mean arterial pressure (MAP) increased from 62 [54,68] to 78 [76,80] mmHg following phenylephrine and from 59 [55,62] to 80 [77,83] mmHg following ephedrine. Stroke volume and cardiac output both increased. Stroke volume variation and pulse pressure variation decreased. Both drugs produced significant increases in dP/dt, from 571 [531, 645] to 767 [733, 811] mmHg/sec for phenylephrine and from 537 [509, 596] to 848 [779, 930] mmHg/sec for ephedrine. No significant changes in Ea dyn were observed., Conclusion: Bolus administration of phenylephrine or ephedrine increases dP/dt but does not change Ea dyn . dP/dt demonstrates potential for predicting the inotropic response to phenylephrine or ephedrine, providing guidance for the most efficacious vasopressor when treating hypotension., Trial Registration: Data was collected from two protocols. The first was deemed to not require written, informed consent by the Institutional Review Board (IRB). The second was IRB-approved (Effect of Diastolic Dysfunction on Dynamic Cardiac Monitors) and registered on ClinicalTrials.gov (NCT04177225)., (© 2024. The Author(s).)

Although various anti-inflammatory medications, such as ephedrine, are employed to manage cough-variant asthma, their underlying mechanisms are yet to be fully understood. Recent studies suggest that exosomes derived from airway epithelial cells (AECs) contain components like messenger RNAs (mRNAs), micro-RNAs (miRNAs), and long noncoding RNA (lncRNA), which play roles in the occurrence and progression of airway inflammation. This study investigates the influence of AEC-derived exosomes on the efficacy of ephedrine in treating cough-variant asthma. We established a mouse model of asthma and measured airway resistance and serum inflammatory cell levels. Real-time polymerase chain reaction (RT-qPCR), Western blotting, and enzyme-linked immunosorbent assay (ELISA) analyses were used to assess gene and protein expression levels. Exosomes were isolated and characterized. RNA immunoprecipitation (RIP) and RNA pull-down assays were conducted to examine the interaction between hnRNPA2B1 and lnc-TRPM2-AS1. In the ovalbumin (OVA)-challenged mouse model, ephedrine treatment reduced inflammatory responses, airway resistance, and Th1/Th2 cell imbalance. Exosomes from OVA-treated AECs showed elevated levels of lnc-TRPM2-AS1, which were diminished following ephedrine treatment. The exosomal lnc-TRPM2-AS1 mediated the Th1/Th2 imbalance in CD4 + T cells, with its packaging into exosomes being facilitated by hnRNPA2B1. This study unveils a novel mechanism by which ephedrine ameliorates OVA-induced CD4 + T cell imbalance by suppressing AEC-derived exosomal lnc-TRPM2-AS1. These findings could provide a theoretical framework for using ephedrine in asthma treatment., (Copyright © 2024 China Pharmaceutical University. Published by Elsevier B.V. All rights reserved.)

A total of 147 oral Kampo prescriptions, which are used clinically in Japan, were evaluated for their anti-glycation activity. Kakkonto demonstrated significant anti-glycation activity, prompting further analysis of its chemical constituents using LC-MS, which revealed the presence of two alkaloids, fourteen flavonoids, two but-2-enolides, five monoterpenoids, and four triterpenoid glycosides. To identify the components responsible for its anti-glycation activity, the Kakkonto extract was reacted with glyceraldehyde (GA) or methylglyoxal (MGO) and analyzed using LC-MS. In LC-MS analysis of Kakkonto reacted with GA, the peak intensity of ephedrine was attenuated, and three products from ephedrine-scavenging GA were detected. Similarly, LC-MS analysis of Kakkonto reacted with MGO revealed two products from ephedrine reacting with MGO. These results indicated that ephedrine was responsible for the observed anti-glycation activity of Kakkonto. Ephedrae herba extract, which contains ephedrine, also showed strong anti-glycation activity, further supporting ephedrine's contribution to Kakkonto's reactive carbonyl species' scavenging ability and anti-glycation activity.

Purpose: It was aimed to investigate the biochemical and immunohistochemical effects of ephedrine (EPH) in bilateral ovariectomized rats., Methods: Twenty-four Sprague Dawley female rats were divided into three groups: control group: The abdomen was opened and closed without any treatment; ischemia-reperfusion (IR) group: 2 h of ischemia followed by 2 h of reperfusion were allowed to cause IR injury; IR+EPH group: oral EPH solution (5 mg/kg) was administered for 28 days., Results: Biochemical parameters were statistically significant in group comparisons. Increased interleukin-6 (IL-6) expression, degenerative preantral and antral follicle cells and inflammatory cells around blood vessels were seen in IR group. Negative IL-6 expression was observed in seminal epithelial cells, preantral and antral follicle cells in IR+EPH group. While caspase-3 activity increased in granulosa cells and stromal cells in IR group, caspase-3 expression was negative in preantral and antral follicle cells in the germinal epithelium and cortex in IR+EPH group., Conclusions: The effect of apoptosis, which occurs with the signaling that starts in the cell nucleus, caused the cessation of the stimulating effect at the nuclear level after EPH administration, and a decrease in the antioxidative effect in IR damage and inflammation in the apoptotic process.

Background: The speculation that cerebral tissue oxygen saturation (SctO 2 ) measured using tissue near-infrared spectroscopy reflects the balance between cerebral metabolic rate of oxygen and cerebral oxygen delivery has not been validated. Our objective was to correlate SctO 2 with cerebral oxygen extraction fraction (OEF) measured using positron emission tomography; OEF is the ratio between cerebral metabolic rate of oxygen and cerebral oxygen delivery and reflects the balance between these 2 variables., Materials and Methods: This cohort study was based on data collected in a previously published trial assessing phenylephrine versus ephedrine treatment in anesthetized patients undergoing brain tumor surgery. The variables of interest were measured twice over the healthy hemisphere before surgery: the first measurement performed after anesthesia induction and the second measurement performed after induction of a ∼20% increase in blood pressure using either phenylephrine or ephedrine., Results: Data from 24 patients were analyzed. The overall vasopressor-induced relative changes in SctO 2 (ΔSctO 2 ) and OEF (ΔOEF) were 3.16% [interquartile range, -0.73% to 6.04%] and -12.5% [interquartile range, -24.0% to -6.19%], respectively. ΔSctO 2 negatively correlated with ΔOEF after phenylephrine treatment (Spearman rank correlation coefficient [ rs ]=-0.76; P =0.007), ephedrine treatment ( rs =-0.76; P =0.006), and any treatment ( rs =-0.79; P <0.001). ΔSctO 2 significantly associated with ΔOEF based on multivariable analysis with ΔOEF, relative changes in mean arterial pressure, arterial blood oxygen tension, and the bispectral index as covariates ( P =0.036)., Conclusions: The negative correlation between changes in SctO 2 and OEF suggests that SctO 2 may reflect the cerebral metabolic demand-supply balance during vasopressor treatment. The generalizability of our findings in other clinical scenarios remains to be determined., Competing Interests: L.M. received consultant fees from Edwards Lifesciences. M.R. has received funding from the Health Research Foundation of Central Denmark Region. The remaining authors have no conflicts of interest to disclose., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

The use of recreational drugs like ephedrine, norephedrine, 3,4-methylenedioxymethamphetamine (MDMA), and mescaline can lead to intoxication and, at worst, to death. One reason for a fatal course of intoxication with these drugs might lie in cardiac arrhythmias. To the best of our knowledge, their inotropic effects have not yet been studied in isolated human cardiac preparations. Therefore, we measured inotropic effects of the hallucinogenic drugs ephedrine, norephedrine, mescaline, and MDMA in isolated mouse left atrial (mLA) and right atrial (mRA) preparations as well as in human right atrial (hRA) preparations obtained during cardiac surgery. Under these experimental conditions, ephedrine, norephedrine, and MDMA increased force of contraction (mLA, hRA) and beating rate (mRA) in a time- and concentration-dependent way, starting at 1-3 µM but these drugs were less effective than isoprenaline. Mescaline alone or in the presence of phosphodiesterase inhibitors did not increase force in mLA or hRA. The positive inotropic effects of ephedrine, norephedrine, or MDMA were accompanied by increases in the rate of tension and relaxation and by shortening of time of relaxation and, moreover, by an augmented phosphorylation state of the inhibitory subunit of troponin in hRA. All effects were greatly attenuated by cocaine (10 µM) or propranolol (10 µM) treatment. In summary, the hallucinogenic drugs ephedrine, norephedrine, and MDMA, but not mescaline, increased force of contraction and increased protein phosphorylation presumably, in part, by a release of noradrenaline in isolated human atrial preparations and thus can be regarded as indirect sympathomimetic drugs in the human atrium., (© 2022. The Author(s).)

Ethnopharmacological Relevance: In our previous study, we reported that Ephedra Herb extract (EHE) increased the locomotor activity of mice in the open-field test and reduced the immobility time in the forced swim test. Ephedrine alkaloids (EAs) are thought to be responsible for the adverse effects of Ephedra Herb. However, there are no reports to verify that the adverse effects of Ephedra Herb are caused by the amount of EAs in the herb. Therefore, we investigated whether these adverse effects of EHE are caused by the amounts of ephedrine (Eph) and pseudoephedrine (Pse) in the herbal extract. In a preliminary study of the time course analysis of the open field test, we newly observed that EHE evoked switching from transient sedation to sustained excitement., Aim of the Study: We aimed to confirm whether EHE evokes switching from transient sedation to sustained excitement, investigate whether these actions of EHE are caused by the amount of ephedrine (Eph) and pseudoephedrine (Pse) in the herbal extract, and clarify the molecular mechanism of the transient sedative effect., Materials and Methods: The locomotor activity of mice was tested using the open-field test. The immobility times were measured using a forced swim test, and the motor dysfunction in mice was tested using the rotarod test., Results: EHE, Eph, and Pse induced transient motionlessness between 0 and 15 min after oral administration, however, they did not induce depression-like behavior and motor dysfunction in mice, suggesting that the motionlessness induced by EHE, Eph, or Pse resulted from sedation. The α2a adrenoceptor inhibitor, atipamezole, decreased their sedative effects. Thus, immediately after EHE administration, the transient sedative effect is mediated through the activation of the α2a adrenoreceptor by Eph and Pse. EHE and Eph increased total locomotor activity for 15-120 min after oral administration; however, Pse had no effect. Therefore, the slow-onset and sustained excitatory effects of EHE are mediated by Eph., Conclusions: We discovered for the first time that EHE evokes diphasic action by switching from transient sedation to sustained excitement. The transient sedation was evoked by the Eph and Pse in the herbal extract via activation of the α2a adrenoceptor and the sustained excitement was caused by the Eph in the herbal extract., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Sumiko Hyuga, and Hiroshi Odaguch received research funds from KYUSHIN PHARMACEUTICAL CO., LTD; Sumiko Hyuga, Hiroshi Odaguchi, and Yoshinori Kobayashi received research funds from Tsumura Co., Ltd; Kitasato University, National Institute of Health Sciences, Matsuyama University, Tokiwa Pharmaceutical Co., Ltd., and Zeria Pharmaceutical Co., Ltd. are coapplicants for the relevant patent., (Copyright © 2022 The Authors. Published by Elsevier B.V. All rights reserved.)

Ephedrae Herba ( Ephedra ), known as "MaHuang" in China, is the dried straw stem that is associated with the lung and urinary bladder meridians. At present, more than 60 species of Ephedra plants have been identified, which contain more than 100 compounds, including alkaloids, flavonoids, tannins, sugars, and organic phenolic acids. This herb has long been used to treat asthma, liver disease, skin disease, and other diseases, and has shown unique efficacy in the treatment of COVID-19 infection. Because alkaloids are the main components causing toxicity, the safety of Ephedra must be considered. However, the nonalkaloid components of Ephedra can be effectively used to replace ephedrine extracts to treat some diseases, and reasonable use can ensure the safety of Ephedra . We reviewed the phytochemistry, pharmacology, clinical application, and alkaloid toxicity of Ephedra , and describe prospects for its future development to facilitate the development of Ephedra .

One of the main concerns of intraoperative hypotension is adequacy of cerebral perfusion, as cerebral blood flow decreases passively when mean arterial pressure falls below the lower limit of cerebral autoregulation. Treatment of intraoperative hypotension includes administration of drugs, such as inotropes and vasopressors, which have different pharmacological effects on cerebral hemodynamics; there is no consensus on the preferred drug to use. We performed a network meta-analysis (NMA) to pool and analyze data comparing the effect on cerebral oxygen saturation (ScO 2 ) measured by cerebral oximetry of various inotropes/vasopressors used to treat intraoperative hypotension. We searched randomized control trials in Embase, Ovid Medline, Scopus, Cochrane Central Register of Controlled Trials, and Web of Science. We included studies that enrolled adult patients undergoing surgery under general/spinal anesthesia that compared at least 2 inotropes/vasopressors to treat hypotension. We reviewed 51 full-text manuscripts and included 9 randomized controlled trials in our study. The primary outcome was change in ScO 2 . Our results showed the likelihood that dopamine, ephedrine, and norepinephrine had the lowest probability of decreasing ScO 2 . The suggested rank order to maintain ScO 2 , from higher to lower, was dopamine

Objective: Endogenous pain inhibition can be investigated using conditioned pain modulation (CPM). CPM efficacy has been reported to be influenced by various factors, such as gender and cardiovascular (autonomic) activity. The aim of this study is to describe the effect of pharmacological manipulations of autonomic activity on CPM efficacy., Methods: Thirty healthy participants were enrolled to assess CPM efficacy in 4 experimental sessions. The first session consisted of the determination of baseline CPM effectiveness. The three following sessions were performed in a randomized order and consisted of the injection of (1) esmolol, (2) ephedrine, or (3) placebo, before the conditioning stimulus. Pain intensity induced by using a contact heat stimulation thermode was compared before and after a cold-pressure conditioning stimulus to evaluate CPM effectiveness., Results: Our results show that inhibiting sympathetic nervous activity with esmolol did not have a significant effect on CPM. Conversely, enhancing sympathetic nervous activity with ephedrine increased CPM effectiveness in healthy women but decreased it in men., Conclusions: Increasing sympathetic activity with adrenergic agonists, such as ephedrine, could improve CPM effectiveness in women. It will be interesting to verify if the same results are present in patients suffering from chronic pain and if adrenergic agonists could have better therapeutic effects in women showing reduced CPM effectiveness., Competing Interests: The authors declare that there are no conflicts of interest regarding the publication of this article., (Copyright © 2022 Marie-Philippe Harvey et al.)

Background: While non-invasive assessment of macro- and micro-circulation has the promise to optimize anesthesia management, evidence is lacking for the relationship between invasive and non-invasive measurements of cardiac output and microcirculatory indices., Aims: We aimed to compare the abilities of non-invasive techniques to detect changes in macro- and micro-circulation following deep anesthesia and subsequent restoration of the compromised hemodynamic by routinely used vasopressors in a randomized experimental study., Methods: A 20%-25% drop in mean arterial pressure was induced by sevoflurane in anesthetized mechanically ventilated just-weaned piglets (n = 12) prior to the administration of vasopressors in random order (dopamine, ephedrine, noradrenaline, and phenylephrine). Simultaneous transpulmonary thermodilution cardiac output assessment with the invasive pulse index continuous contour (PiCCO) method was compared with non-invasive estimates obtained with electrical conductivity (ICON) and echo Doppler (Cardio Q). Changes in microcirculation were characterized by sublingual red blood cell velocity, jugular cerebral venous oxygen saturation, and arterial lactate., Main Outcome Measures: Cardiac output indices obtained by invasive and non-invasive methods., Results: Changes in cardiac output measured invasively and non-invasively correlated significantly after sevoflurane (r = .78, p = .003 and r = .76, p = .006 between PiCCO and ICON or Cardio Q, respectively). Following the administration of vasopressors, invasive and non-invasive cardiac output assessments were unrelated with significant correlations observed only between PiCCO and ICON after dopamine and ephedrine. Sevoflurane-induced hypotension decreased jugular cerebral venous oxygen saturation significantly and was recovered by all vasopressors. Sevoflurane and vasopressors had no effect on red blood cell velocity, which increased only after dopamine. No consistent changes in lactate were observed during the study period., Conclusions: The results of this study suggest that non-invasive cardiac output measurements may not accurately reflect changes in macrocirculation after hemodynamic optimization by vasopressors. Due to the incoherence between macro- and micro-circulation, monitoring microcirculation is essential to guide patient management., (© 2022 John Wiley & Sons Ltd.)

Aim: To compare incidences of abnormal heart rate (HR) between the phenylephrine/ephedrine protocol (P/E protocol) against the ephedrine-only (C) protocol, conventionally used for treating predelivery hypotension following spinal anesthesia for cesarean section., Methods: Two hundred and sixty-eight parturients with pre-delivery hypotension after spinal anesthesia were equally randomized to (1) Group P/E (n = 134), phenylephrine 100 mcg in 10 mL intravenously if HR ≥ 60 beats/min (bpm), or ephedrine 6 mg intravenously if HR < 60 bpm, and 2) Group C (n = 134). The primary outcome was the incidence of the parturients with abnormal HR after vasopressor administration. The secondary outcome was the mean differences of HR and hypotensive periods during the pre-delivery period., Results: There was no significant difference of between-group incidences of bradycardia (12.0% in Group P/E vs 6.7% in Group C, p = 0.136) and tachycardia (26.9% vs 35.8%, p = 0.114). Mean HR was 81.9 bpm (95% confidence interval [CI] 79.9, 84.3) in Group P/E, and 88.8 bpm (86.8, 90.6) in Group C (p < 0.001). The duration of hypotension in relation to the time interval from spinal anesthesia to delivery was 20.9% (95% CI 18.4-23.2) in Group P/E, and 26.5% (23.9-29.3) in Group C (p < 0.01). The calculated area under the curve (AUC) of abnormal HR in relation to time was significantly reduced only in Group P/E (p < 0.010)., Conclusions: The incidences of out-of-range HR were comparable, but the P/E protocol resulted in a lower mean HR and better control of systolic blood pressure than the ephedrine-only protocol., (© 2022 Japan Society of Obstetrics and Gynecology.)

Objective: We investigated the protective effects of ephedra herb (HEPH) on adriamycin-induced testicular toxicity in rats and explored the potential mechanisms underlying these effects., Methods: A rat model of adriamycin injury was established, and sperm motility-related indicator and oxidative stress levels in the testis were evaluated. Serum levels of sex hormones and levels of testicular cell apoptosis were detected by enzyme-linked immunosorbent assay and flow cytometry, respectively. Western blotting (WB), immunofluorescence analyses, and reverse transcription-polymerase chain reaction (RT-PCR) were performed to evaluate the gonadotropin-releasing hormone (GnRH) signalling pathway- and meiosis-related genes and proteins. In subsequent in vitro experiments, adriamycin was used to stimulate GC-1 cells, which were treated with HEPH, ephedrine, or pseudoephedrine. Cell viability was assessed using flow cytometry to detect apoptosis and reactive oxygen species, whereas the GnRH signalling pathway and levels of meiosis-related genes and proteins were evaluated by InCell WB, a high-content imaging system, and RT-PCR., Results: Per in vivo experiments, HEPH restored testicular weight and function, sperm characteristics, serum and tissue hormonal levels, and antioxidant defences and significantly activated the GnRH signalling pathway- and meiosis-related protein levels. All protective effects of HEPH against adriamycin-induced injury were antagonised by the GnRH antagonist cetrorelix. In vitro, HEPH, ephedrine, and pseudoephedrine significantly reduced adriamycin-induced GC-1 cell apoptosis and reactive oxygen species levels and increased the expression of GnRH signalling pathway- and meiosis-related proteins. The effect of pseudoephedrine was greater than that of ephedrine, and these findings may be an important basis for understanding the effects of HEPH., (Copyright © 2022 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

Chronic obstructive pulmonary disease (COPD) is a chronic lung disease with limited therapeutic options. Ephedrine (Eph) isolated from Ephedra exerts regulatory role in inflammatory response. However, its effects on COPD development still remain unknown. In the present study, we found that Eph significantly ameliorated apoptosis, oxidative stress and inflammatory response in cigarette smoke extract (CSE)-stimulated human bronchial epithelial cells (HBECs). Moreover, all these cellular events attenuated by Eph were closely associated with reactive oxygen species (ROS) decreasing. Furthermore, we found that the expression of endoplasmic reticulum (ER) stress-associated signaling could be down-regulated by Eph in HBECs without any stimuli. Meanwhile, ER stress was strongly induced by CSE, which was, however, effectively mitigated by Eph exposure in HBECs. Intriguingly, we found that Eph-alleviated cell death, ROS generation and inflammation were almost eliminated by the promotion of ER stress via over-expressing Bip in HBECs upon CSE stimulation. Moreover, Eph administration significantly ameliorated pulmonary indexes and histological impairments in mice with long-term CS exposure, which were largely through the suppression of inflammation, apoptosis and oxidative stress via blocking ER stress as detected in vitro. Collectively, all these findings indicated that Eph exhibited protective effects against CS-caused COPD by hindering ER stress., (Copyright © 2021. Published by Elsevier B.V.)

Maoto, a traditional Japanese medicine (Kampo), is widely used to treat upper respiratory tract infections, including influenza virus infection. Although maoto is known to inhibit pro-inflammatory responses in a rodent model of acute inflammation, its underlying mechanism remains to be determined. In this study, we investigated the involvement of immune responses and noradrenergic function in the inhibitory action of maoto. In a mouse model of polyI:C-induced acute inflammation, maoto was administered orally in conjunction with intraperitoneal injection of PolyI:C (6 mg/kg), and blood was collected after 2 h for measurement of plasma cytokines by ELISA. Maoto significantly decreased PolyI:C-induced TNF-α levels and increased IL-10 production. Neither pretreatment with IL-10 neutralizing antibodies nor T-cell deficiency using nude mice modified the inhibitory effect of maoto, indicating that the anti-inflammatory effects of maoto are independent of IL-10 and T cells. Furthermore, the inhibitory effects of maoto on PolyI:C-induced TNF-α production were not observed in ex vivo splenocytes, suggesting that maoto does not act directly on inflammatory cells. Lastly, pretreatment with a β-adrenergic receptor antagonist partially cancelled the anti-inflammatory effects of maoto. Collectively, these results suggest that maoto mediates its anti-inflammatory effects via β-adrenergic receptors in vivo., (Copyright © 2021 The Authors. Published by Elsevier B.V. All rights reserved.)

Inflammation and oxidative stress are crucial in ischemic stroke. Ephedrine (EPH) has been proven to have anti-inflammatory and anti-oxidative stress effects. The present study analyzes whether EPH possessed neuroprotective effects and explored the underlying mechanisms of EPH based on an experimental model of middle cerebral artery occlusion (MCAO). We found that intraperitoneal injection with EPH attenuated the neurological deficit, cerebral infarction, and cerebral edema induced by MCAO in rats. Besides, EPH treatment alleviated MCAO-induced brain tissue damage and morphological abnormality, as well as neuronal loss. Moreover, EPH treatment upregulated GPx and CAT activity and downregulated MDA and NO content. EPH also evidently decreased the levels of IL-6 and TNF-α but increased IL-4 and IL-10 levels. Of note, EPH treatment promoted the phosphorylation of PI3K and AKT proteins in MCAO rats. Furthermore, administration of PI3K/AKT pathway inhibitor LY294002 abolished the beneficial effects of EPH. These results confirmed that EPH alleviated brain injury induced by MCAO via activating PI3K/AKT signaling pathway.

Ischemic stroke is a leading cause of death and long-term disability worldwide. The aim of this study is to explore the potential function of ephedrine in ischemic stroke and the underlying molecular mechanism. A middle cerebral artery occlusion (MCAO) rat model was established. The potential effects of ephedrine on MCAO rats and LPS-stimulated BV2 microglial cells were evaluated. Ephedrine reduced the infarct volume, cell apoptosis, brain water content, neurological score, and proinflammatory cytokines (TNF-α and IL-1β) production in MCAO rats. Ephedrine treatment also suppressed TNF-α and IL-1β production and NOD-like receptor pyrin domain 3 (NLRP3) inflammasome activation in BV2 microglial cells. The expression of NLRP3, caspase-1, and IL-1β was suppressed by ephedrine. Moreover, ephedrine treatment increased the phosphorylation of Akt and GSK3β and nuclear NRF2 levels in LPS-treated BV2 microglial cells. Meanwhile, LY294002 attenuated the inhibitory effects of ephedrine on NLRP3 inflammasome activation and TNF-α and IL-1β production. In addition, the level of pAkt was increased, while NLRP3, caspase-1, and IL-1β were decreased by ephedrine treatment in MCAO rats. In conclusion, ephedrine ameliorated cerebral ischemia injury via inhibiting NLRP3 inflammasome activation through the Akt/GSK3β/NRF2 pathway. Our results revealed a potential role of ephedrine in ischemic stroke treatment.

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 β2-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 β2-adrenoceptor agonists. Pathway deconvolution assays suggested activation of GPR35 triggered PI3K, MEK, JNK pathways and EGFR transactivation, and the activation of β2-adrenoceptor mediated MEK and Ca 2+ . 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., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Background: This study compared ephedrine versus phenylephrine treatment on cerebral macro- and microcirculation, measured by cerebral blood flow, and capillary transit time heterogeneity, in anesthetized brain tumor patients. The hypothesis was that capillary transit time heterogeneity in selected brain regions is greater during phenylephrine than during ephedrine, thus reducing cerebral oxygen tension., Methods: In this single-center, double-blinded, randomized clinical trial, 24 anesthetized brain tumor patients were randomly assigned to ephedrine or phenylephrine. Magnetic resonance imaging of peritumoral and contralateral hemispheres was performed before and during vasopressor infusion. The primary endpoint was between-group difference in capillary transit time heterogeneity. Secondary endpoints included changes in cerebral blood flow, estimated oxygen extraction fraction, and brain tissue oxygen tension., Results: Data from 20 patients showed that mean (± SD) capillary transit time heterogeneity in the contralateral hemisphere increased during phenylephrine from 3.0 ± 0.5 to 3.2 ± 0.7 s and decreased during ephedrine from 3.1 ± 0.8 to 2.7 ± 0.7 s (difference phenylephrine versus difference ephedrine [95% CI], -0.6 [-0.9 to -0.2] s; P = 0.004). In the peritumoral region, the mean capillary transit time heterogeneity increased during phenylephrine from 4.1 ± 0.7 to 4.3 ± 0.8 s and decreased during ephedrine from 3.5 ± 0.9 to 3.3 ± 0.9 s (difference phenylephrine versus difference ephedrine [95%CI], -0.4[-0.9 to 0.1] s; P = 0.130). Cerebral blood flow (contralateral hemisphere ratio difference [95% CI], 0.3 [0.06 to 0.54]; P = 0.018; and peritumoral ratio difference [95% CI], 0.3 [0.06 to 0.54; P = 0.018) and estimated brain tissue oxygen tension (contralateral hemisphere ratio difference [95% CI], 0.34 [0.09 to 0.59]; P = 0.001; and peritumoral ratio difference [95% CI], 0.33 [0.09 to 0.57]; P = 0.010) were greater during ephedrine than phenylephrine in both regions., Conclusions: Phenylephrine caused microcirculation in contralateral tissue, measured by the change in capillary transit time heterogeneity, to deteriorate compared with ephedrine, despite reaching similar mean arterial pressure endpoints. Ephedrine improved cerebral blood flow and tissue oxygenation in both brain regions and may be superior to phenylephrine in improving cerebral macro- and microscopic hemodynamics and oxygenation., (Copyright © 2021, the American Society of Anesthesiologists. All Rights Reserved.)

Ephedrine, a sympathomimetic amine that exhibits several adrenaline actions, is a plant alkaloid that is a common ingredient in several cold, asthma and narcolepsy treatment preparations, and in obesity management and sport medicine. Its principal action mechanism relies on its direct adrenergic actions as well as indirect role that involves the release of epinephrine and norepinephrine, thus increasing the activity of epinephrine and norepinephrine at the postsynaptic α and β receptors. Nevertheless, its serious side effects, including stroke, heart attack, drug abuse and interactions, have never been comprehensively reviewed. We conducted a systematic review of data on ephedrine, including its occurrence in functional foods, pharmacological aspects, metabolism, pharmaco/toxicokinetics and clinical features. Furthermore, a review of ephedrine natural structural analogues with regards to their differential adrenergic receptor binding affinities, food interaction, and their impact on the pharmacokinetics and effects relative to ephedrine are presented for the first time, and in comparison to its action when present in herbs.

This article has been retracted: please see Elsevier Policy on Article Withdrawal (https://www.elsevier.com/about/our-business/policies/article-withdrawal). This article has been retracted at the request of the Editor-in-Chief. A reader reported that Figure 9 of the above paper contains similar section with Figure 4 of another article authored by the same group in Inflammopharmacology, 29, (2021) 1119-1129, https://doi.org/10.1007/s10787-021-00840-9, and part of the Figure 9 of the above paper is used in Figure 9 of another article authored by the same group in Inflammopharmacology, 29, (2021) 673–682, https://doi.org/10.1007/s10787-021-00804-z. The journal requested the authors to explain the repeated use of the image and provide the raw data. However, the authors were not able to fulfill this request and therefore the Editor-in-Chief has decided to retract the article., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Obesity is known as metabolic syndrome and it affects many tissues including adipose tissue, liver, and central nervous system (CVS). Gambi-jung (GBJ) is a modified prescription of Taeumjowi-tang (TJT), which has been used to treat obesity in Korea. GBJ is composed of 90% Ephedra sinica Stapf (ES). Therefore, the present study was designed to assess the antiobesity effects of GBJ and to compare the effects of GBJ and ES on obesity. GBJ administration remarkably reduced the body weight, Body mass index (BMI), and body fat percentage compared to the ES administration in human subjects. GBJ-treated mice had lower white adipose tissue (WAT) amounts than ES-treated mice. GBJ and ES administration enhanced adenosine monophosphate-activated protein kinase (AMPK) expression in 3T3-L1 adipocytes, epididymal WAT and liver of HFD-induced obese mice. Moreover, GBJ and ES reduced food intake by suppressing the mRNA levels of orexigenic peptides, agouti-related protein (AgRP) and neuropeptide-Y (NPY), as well as AMPK in the brain of HFD-induced obese mice. Furthermore, GBJ-treated mice had dramatically lower expression of macrophage marker F4/80 in epididymal WAT than those of ES-treated mice. Based on these results, we suggest the use of GBJ as a natural drug to control weight gain., (Copyright © 2021. Published by Elsevier Masson SAS.)

The inflammation and immune responses are critical in ischemic stroke and contribute to aggravated brain damage. Ephedrine was reported to play an important role in the control of inflammatory responses. This study was to investigate the repairing effects and potential mechanisms of ephedrine on cerebral ischemic injury in a rat model of focal cerebral ischemia. The rat model of cerebral ischemia/reperfusion injury was established using the middle cerebral artery occlusion (MCAO) method and then rats were treated with ephedrine (5 and 10 mg/kg) for 7 days. The neurobehavioral progression was assessed using the neurological scoring method. The pathology of brain tissue was evaluated by hematoxylin and eosin (H&E) staining. The infarct volume was examined by triphenyltetrazolium chloride (TTC) staining. The apoptosis in ischemic brain tissues was detected by terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) assay. Inflammatory factors were detected by enzyme-linked immunosorbent assay (ELISA). Gene quantification and protein expression were detected by real-time PCR and western blot, respectively. Ephedrine treatment significantly alleviated the cerebral ischemia/reperfusion injury, evidenced by decreased neurological deficit score, infarct volume and water content. Ephedrine also decreased autophagy and apoptosis in brain tissues. Moreover, ephedrine treatment significantly reduced inflammatory responses, associating with decreasing the protein expression of p-NF-κB. These results demonstrated neuroprotective properties of ephedrine and highlighted it as a new potential anti-inflammatory agent against injury of cerebral ischemia/reperfusion.

Traditional Chinese medicines played an important role in the treatment of COVID-19 in 2020. Ephedra sinica, one of the major constituent herbs of multi-component herbal formula, has been widely used to treat COVID-19 in China. However, its active components are still unclear. The objectives of this study are to screen and evaluate active components from the traditional Chinese medicine Ephedra sinica for the treatment of COVID-19. In our study, we established an ACE2/CMC bioaffinity chromatography model, and then developed an ACE2/CMC-HPLC-IT-TOF-MS system for the active compounds screening and identification from Ephedra sinica extract. We performed molecular docking and surface plasmon resonance (SPR) assays to assess the binding characteristics (binding mode and K D value). We used CCK-8 staining to assess the toxicity of screened compounds, and also used SARS-CoV-2 pseudovirus to observe the viropexis effect of screened compounds in ACE2 h cells. In this current work, one fraction was fished out, separated and identified as ephedrine (EP), pseudoephedrine (PEP), and methylephedrine (MEP). Binding assays showed that the three compounds could bind with ACE2 in a special way to some amino acid residues, similar to the way SARS-CoV-2 bound with ACE2. Additionally, the three compounds, especially EP, can inhibit the entrance of SARS-CoV-2 spike pseudovirus into ACE2 h cells because they can reduce the entrance ratio of pseudovirus in the pseudovirus model. Overall, the ACE2/CMC-HPLC-IT-TOF-MS system was established and verified to be suitable for ACE2-targeted bioactive compound screening. EP, PEP, and MEP with ACE2-binding features were screened out from Ephedra sinica, and acted as blockers inhibiting SARS-CoV-2 spike pseudovirus entering ACE2 h cells.

Background and objectives: The connections between the imidazoline system and multiple other neurotransmitter systems in the brain (adrenergic, dopaminergic, serotoninergic, glutamatergic, opioid) indicate the complexity of the mechanisms underlying motor activity and behavior. The aim of the present research was to investigate the effects of the combination of ephedrine (EPD) and imidazoline antagonists idazoxan (IDZ) and efaroxan (EFR) on the endurance performance in the treadmill test in rats. Materials and Methods: We used Wistar rats distributed as follows: Group 1 (Control) receiving distilled water 0.3 mL/100 g body weight; Group 2 (EPD) receiving 20 mg/kg ephedrine; Group 3 (EPD + IDZ) receiving 20 mg/kg ephedrine + 3 mg/kg idazoxan; Group 4 (EPD + EFR) receiving 20 mg/kg ephedrine + 1 mg/kg efaroxan. An additional group (C) of animals receiving 0.3 mL/100 g body weight distilled water (but not subjected) to effort was used. Endurance capacity was evaluated using a treadmill running PanLAB assay. The evaluation of the substances' influence on oxidative stress was performed by spectrophotometric determination of superoxide dismutase (SOD) and glutathione peroxidase (GPX) activity. Results: Treatment with EPD-IDZ and EPD-EFR were correlated with a longer distance traveled on the belt and with a decrease in the necessary electric shocks to motivate the animal to continue running in the forced locomotion test. Additionally, an increase in the activity of antioxidant enzymes was found. Conclusions: Idazoxan and efaroxan potentiated the physical effort-related effects of ephedrine with regard to endurance capacity and antioxidant activity in rats.

Asthma is a chronic obstructive lung disorder involving hyperresponsive lung tissue. This study evaluated the protective effects of riparin II against asthma and determined the synergistic effects of riparin II with ephedrine in treatment of asthma. Asthma was induced by intraperitoneal injection of Al(OH) 3 (100 mg) with ovalbumin 1 mg/kg and subsequent exposure to 2% ovalbumin aerosol for 1 week. All animals were treated with riparin II 50 mg/kg and ephedrine 25 mg/kg alone and in combination for the duration of the study. Interleukin levels were assessed in the serum and bronchoalveolar lavage fluid (BALF) of asthmatic rats, while inflammatory cell infiltration was determined in the lungs. Airway remodelling was determined by assessing the lung tissue expression levels of transforming growth factor beta 1 (TGF-β1), Smad, and collagen I in asthmatic rats. There were lower levels of cytokines in the serum and BALF in riparin II-treated rats than in negative control rats. Moreover, inflammatory cell and IgE levels were reduced while interferon level was enhanced in the lungs of riparin II-treated rats, compared to negative control rats. These data reveal that treatment with riparin II ameliorates the altered expression of TGF-β1, Smad, and collagen I in lung tissue of asthmatic rats. In conclusion, riparin II treatment alone and in combination with ephedrine ameliorated the hyperresponsiveness of lung tissue due to reductions in airway remodelling and inflammation in asthmatic rats., (Copyright © 2020. Published by Elsevier B.V.)

Background: Studies in anesthetized patients suggest that phenylephrine reduces regional cerebral oxygen saturation compared with ephedrine. The present study aimed to quantify the effects of phenylephrine and ephedrine on cerebral blood flow and cerebral metabolic rate of oxygen in brain tumor patients. The authors hypothesized that phenylephrine reduces cerebral metabolic rate of oxygen in selected brain regions compared with ephedrine., Methods: In this double-blinded, randomized clinical trial, 24 anesthetized patients with brain tumors were randomly assigned to ephedrine or phenylephrine treatment. Positron emission tomography measurements of cerebral blood flow and cerebral metabolic rate of oxygen in peritumoral and normal contralateral regions were performed before and during vasopressor infusion. The primary endpoint was between-group difference in cerebral metabolic rate of oxygen. Secondary endpoints included changes in cerebral blood flow, oxygen extraction fraction, and regional cerebral oxygen saturation., Results: Peritumoral mean ± SD cerebral metabolic rate of oxygen values before and after vasopressor (ephedrine, 67.0 ± 11.3 and 67.8 ± 25.7 μmol · 100 g · min; phenylephrine, 68.2 ± 15.2 and 67.6 ± 18.0 μmol · 100 g · min) showed no intergroup difference (difference [95% CI], 1.5 [-13.3 to 16.3] μmol · 100 g · min [P = 0.839]). Corresponding contralateral hemisphere cerebral metabolic rate of oxygen values (ephedrine, 90.8 ± 15.9 and 94.6 ± 16.9 μmol · 100 g · min; phenylephrine, 100.8 ± 20.7 and 96.4 ± 17.7 μmol · 100 g · min) showed no intergroup difference (difference [95% CI], 8.2 [-2.0 to 18.5] μmol · 100 g · min [P = 0.118]). Ephedrine significantly increased cerebral blood flow (difference [95% CI], 3.9 [0.7 to 7.0] ml · 100 g · min [P = 0.019]) and regional cerebral oxygen saturation (difference [95% CI], 4 [1 to 8]% [P = 0.024]) in the contralateral hemisphere compared to phenylephrine. The change in oxygen extraction fraction in both regions (peritumoral difference [95% CI], -0.6 [-14.7 to 13.6]% [P = 0.934]; contralateral hemisphere difference [95% CI], -0.1 [- 12.1 to 12.0]% [P = 0.989]) were comparable between groups., Conclusions: The cerebral metabolic rate of oxygen changes in peritumoral and normal contralateral regions were similar between ephedrine- and phenylephrine-treated patients. In the normal contralateral region, ephedrine was associated with an increase in cerebral blood flow and regional cerebral oxygen saturation compared with phenylephrine.

Confusion and misunderstanding exist regarding the lack of cardiovascular and other adverse health effects of p-synephrine and p-octopamine relative to ephedrine and m-synephrine (phenylephrine) which are known for their effects on the cardiovascular system. These four molecules have some structural similarities. However, the structural and stereochemical differences of p-synephrine and p-octopamine as related to ephedrine and m-synephrine result in markedly different adrenergic receptor binding characteristics as well as other mechanistic differences which are reviewed. p-Synephrine and p-octopamine exhibit little binding to α-1, α-2, β-1 and β-2 adrenergic receptors, nor are they known to exhibit indirect actions leading to an increase in available levels of endogenous norepinephrine and epinephrine at commonly used doses. The relative absence of these mechanistic actions provides an explanation for their lack of production of cardiovascular effects at commonly used oral doses as compared to ephedrine and m-synephrine. As a consequence, the effects of ephedrine and m-synephrine cannot be directly extrapolated to p-synephrine and p-octopamine which exhibit significantly different pharmacokinetic, and physiological/pharmacological properties. These conclusions are supported by human, animal and in vitro studies that are discussed., (© 2020 The Authors. Phytotherapy Research published by John Wiley & Sons Ltd.)

The prevailing sandstorm environment of Lop Nur is a high-risk factor which can induce respiratory diseases. Ephedra can cure the patients or relieve the symptom. These may make ancient Lop Nur peoples worship ephedra. Therefore, viewed it as burial objects. From the point of view of some eastern and western religions, ephedra was the elixir of life. Since ephedrine ephedra contains can excite the sympathetic nerves of human body, it makes people have an illusion.Ephedra can restore their youth. Ancient people of Lop Nur viewed ephedra as a holy item. Both the functions of therapy and "youth restoration" from exciting the nerves, meant guarantee for life. For ancient Lop Nur peoples, ephedra has the value of both medicine and religion.

Introduction: We previously reported blood oxygen level dependent MRI (BOLD-MRI) for monitoring placental and fetal hemodynamic changes in mice following maternal hypercapnia. Here we use BOLD-MRI to compare the placental and fetal hemodynamic effects of different maternal vasopressors in mice., Methods: Pregnant ICR mice (n = 16; E17.5) anesthetized with pentobarbital (80 mg/kg i.p.) were placed supine in a 4.7-T Bruker Biospec MRI. Following baseline images, equipotential doses of ephedrine (10 mg/kg) or phenylephrine (10mcg/kg) were administered intravenously. Changes in placental and fetal signal were analyzed from T2*-weighted gradient echo MR images (TR/TE = 147/10 ms). Different regions of interest (placenta, fetal heart, fetal liver and fetal brain) were identified. Percentage change of BOLD-MRI signal intensity (SI) were presented as time curves., Results: Ephedrine and phenylephrine elicited markedly different effects. Phenylephrine caused an approximate 50% reduction in placental, fetal heart and fetal liver BOLD-MRI-SI, but fetal brain BOLD-MRI-SI was unchanged (statistically different from placenta and other fetal organs; p < 0.001), and the fetal brain/liver BOLD-MRI-SI ratio was markedly increased versus baseline (p < 0.001). Following ephedrine, placental BOLD-MRI-SI increased 30% and fetal heart BOLD-MRI-SI was reduced 26%; other fetal organs were unchanged. Blood gases were unchanged., Discussion: Phenylephrine induced BOLD-MRI-SI changes suggestive of placental and fetal hypoperfusion with brain sparing. Ephedrine induced BOLD-MRI-SI changes suggestive of increased cardiac output; we speculate that reduced fetal heart BOLD-MRI-SI may be due to increased fetal myocardial oxygen extraction or metabolic acidosis. The result demonstrates the potential of BOLD-MRI as a non-invasive hemodynamic tool for assessing pharmacodynamics effects in the placental and fetus., Competing Interests: Declaration of competing interest I have no actual or potential conflict of interest including any financial, personal or other relationships with other people or organizations within three years of beginning the submitted work that could inappropriately influence, or be perceived to influence, this work., (Copyright © 2019. Published by Elsevier Ltd.)

Previously, we reported that the c-Met inhibitory effect of Ephedra Herb extract (EHE) is derived from ingredients besides ephedrine alkaloids. Moreover, analgesic and anti-influenza activities of EHE and ephedrine alkaloids-free Ephedra Herb extract (EFE) have been reported recently. In this study, we examined the fractions containing c-Met kinase inhibitory activity from EHE and the fractions with analgesic and anti-influenza activities from EFE, and elucidated the structural characteristics of the active fractions. Significant c-Met kinase activity was observed in 30, 40, and 50% methanol (MeOH) eluate fractions obtained from water extract of EHE using Diaion HP-20 column chromatography. Similarly, 20 and 40% MeOH, and MeOH eluate fractions obtained from water extract of EFE were found to display analgesic and anti-influenza activities. Reversed phase-HPLC analysis of the active fractions commonly showed broad peaks characteristic of high-molecular mass condensed tannin. The active fractions were analyzed using 13 C-NMR and decomposition reactions; the deduced structures of active components were high-molecular mass condensed tannins, which were mainly procyanidin B-type and partly procyanidin A-type, including pyrogallol- and catechol-type flavan 3-ols as extension and terminal units. HPLC and gel permeation chromatography (GPC) analyses estimated that the ratio of pyrogallol- and catechol-type was approximately 9 : 2, and the weight-average molecular weight based on the polystyrene standard was >45000. Furthermore, GPC-based analysis was proposed as the quality evaluation method for high-molecular mass condensed tannin in EHE and EFE.

Ephedra is a classic herb in traditional Chinese medicine( TCM). The new effects of ephedra were gradually found,and the contraindications of the drug were broken in later ages. Because the principles of expanded application were not well elucidated,it is difficult to use in the clinical flexibility. Based on the characteristics of ephedra and its classic clinical application,the authors summarized the possible principles of clinical application of ephedra and the drug property and pharmacological characteristics of ephedra.Studies showed that ephedrine substances are an important material basis for the efficacy of ephedra,and its adrenergic action is the pharmacological basis of its efficacy. It is the key to grasp the autonomic function and the interaction between sympathetic/adrenal medulla and adrenal cortex for the clinical application of ephedra. The authors discussed the principles of clinical application of ephedra and the effects of processing of ephedra. Finally,the authors put forward the basic research process of clinical application of drugs,and provide ideas for the inheritance and further development of TCM experience.

Human brown adipose tissue (BAT) has attracted clinical interest not only because it dissipates energy but also for its potential capacity to counteract obesity and related metabolic disorders (e.g., insulin resistance and dyslipidemia). Cold exposure is the most powerful stimulus for activating and recruiting BAT, and this stimulatory effect is mediated by the transient receptor potential (TRP) channels. BAT can also be activated by other receptors such as the G-protein-coupled bile acid receptor 1 (GPBAR1) or β-adrenergic receptors. Interestingly, these receptors also interact with several dietary components; in particular, capsinoids and tea catechins appear to mimic the effects of cold through a TRP-BAT axis, and they consequently seem to decrease body fat and improve metabolic blood parameters. This systematic review critically addresses the evidence behind the available human studies analyzing the effect of several dietary components (e.g., capsinoids, tea catechins, and ephedrine) on BAT activity. Even though the results of these studies are consistent with the outcomes of preclinical models, the lack of robust study designs makes it impossible to confirm the BAT-activation capacity of the specified dietary components. Further investigation into the effects of dietary components on BAT is warranted to clarify to what extent these components could serve as a powerful strategy to treat obesity and related metabolic disorders., (© 2019 American Society for Nutrition.)

Compromised perfusion due to ligation of arteries and veins in esophagectomy with gastric tube reconstruction often (5-20%) results in necrosis and anastomotic leakage, which relate to high morbidity and mortality (3-4%). Ephedrine is used widely in anesthesia to treat intraoperative hypotension and may improve perfusion by the increase of cardiac output and mean arterial pressure (MAP). This study tests the effect of ephedrine on perfusion of the future anastomotic site of the gastric conduit, measured by laser speckle contrast imaging (LSCI). This prospective, observational, in vivo pilot study includes 26 patients undergoing esophagectomy with gastric tube reconstruction from October 2015 to June 2016 in the Academic Medical Center (Amsterdam). Perfusion of the gastric conduit was measured with LSCI directly after reconstruction and after an increase of MAP by ephedrine 5 mg. Perfusion was quantified in flux (laser speckle perfusion units, LSPU) in four perfusion locations, from good perfusion (base of the gastric tube) toward decreased perfusion (fundus). Intrapatient differences before and after ephedrine in terms flux were statistically tested for significance with a paired t-test. LSCI was feasible to image gastric microcirculation in all patients. Flux (LSPU) was significantly higher in the base of the gastric tube (791 ± 442) compared to the fundus (328 ± 187) (P < 0.001). After administration of ephedrine, flux increased significantly in the fundus (P < 0.05) measured intrapatients. Three patients developed anastomotic leakage. In these patients, the difference between measured flux in the fundus compared to the base of the gastric tube was high. This study presents the effect of ephedrine on perfusion of the gastric tissue measured with LSCI in terms of flux (LSPU) after esophagectomy with gastric tube reconstruction. We show a small but significant difference between flux measured before and after administration of ephedrine in the future anastomotic tissue (313 ± 178 vs. 397 ± 290). We also show a significant decrease of flux toward the fundus.

Hypotension commonly accompanies combined epidural and general anesthesia, and intravenous bolus ephedrine and etilefrine are widely used to correct hypotension. We have noticed that systemic vascular resistance (SVR) transiently decreases just after intravenous bolus administration of these drugs. The goal of the present study was to investigate whether bolus administration of these drugs decrease SVR just after intravenous administration in combined epidural and general anesthesia patients. We investigated 40 patients who were scheduled for elective abdominal surgery. Patients were chosen as subjects if their systolic arterial pressure decreased by 20% or to <100 mmHg at 30 min after the induction of general anesthesia. Baseline hemodynamic values were recorded, and after ephedrine 10 mg injection or etilefrine 2 mg injection (equipotent), the parameters were recorded again at 0.5 min and once each min for the next 5 min thereafter. The 40 patients were enrolled into the ephedrine (n = 20) or etilefrine (n = 20) treatment groups. Patient characteristics were comparable in both groups. After ephedrine injection, SVR decreased significantly at the 1-min time point, whereas after etilefrine injection, SVR decreased significantly at the 0.5- to 2-min time points compared with baseline values. SVR at the 0.5- to 1-min time points was lower in the etilefrine versus the ephedrine group. Both drugs transiently decreased SVR after intravenous injection, but etilefrine decreased SVR much more than ephedrine, indicating that more vasodilation occurred after the injection of etilefrine than after ephedrine. It is thus important to recognize the different characteristics of these drugs.

We investigated the effects of flumazenil, aminophylline, and ephedrine on the excitatory amino acid transporter type 3 (EAAT3) activity and the interaction with propofol. EAAT3 was expressed in the Xenopus oocytes. L-Glutamate-induced membrane currents were measured using the two-electrode voltage clamp at various drug concentrations. Oocytes were preincubated with protein kinase C- (PKC-) activator, or inhibitor, and phosphatidylinositol 3-kinase (PI3K) inhibitor. To study the interaction with propofol, oocytes were exposed to propofol, propofol + aminophylline, or ephedrine. Aminophylline and ephedrine significantly decreased EAAT3 activity. Aminophylline (95  μ M) and ephedrine (1.19  μ M) significantly decreased V max, but not Km of EAAT3, for glutamate. The phorbol 12-myristate-13-acetate-induced increase in EAAT3 activity was abolished by aminophylline or ephedrine. The decreased EAAT3 activities by PKC inhibitors (staurosporine, chelerythrine) and PI3K inhibitor (wortmannin) were not significantly different from those by aminophylline or ephedrine, as well as those by PKC inhibitors or PI3K inhibitor + aminophylline or ephedrine. The enhanced EAAT3 activities induced by propofol were significantly abolished by aminophylline or ephedrine. Aminophylline and ephedrine inhibit EAAT3 activity via PKC and PI3K pathways and abolish the increased EAAT3 activity by propofol. Our results indicate a novel site of action for aminophylline and ephedrine.

We have investigated the cardiac and pressor responses to (±)-ephedrine and (-)-ephedrine in pentobarbitone anaesthetized male wistar rats. The tachycardiac responses to (±)- and (-)-ephedrine were similar, but pressor responses to (-)-ephedrine (10 mg/kg) were significantly greater than those to (±)-ephedrine, and for both, the pressor response was followed by a small depressor response. Sympathectomy did not affect pressor responses, but significantly increased the later depressor response to both compounds. Sympathectomy did not affect tachycardiac or depressor responses to the β-adrenoceptor agonist isoprenaline, but significantly reduced the tachycardia to (±)-ephedrine. (±)-Ephedrine contracted vas deferens from vehicle treatment animals, but in vas deferens from sympathectomised rats, (±)-ephedrine produced almost no tonic contraction (α 1A -adrenoceptor mediated), but the phasic contraction was unaffected (α 1D -adrenoceptor mediated). It is concluded, firstly, that (-)-ephedrine is more potent than the racemate mixture at producing pressor responses. Secondly, since the depressor response to isoprenaline was unaffected, sympathectomy presumably reduced a pressor component to the response to (±)- and (-)-ephedrine. Hence, a component of the pressor response to both (±)- and (-)-ephedrine is indirect and may involve actions at α 1A -adrenoceptors, at which ephedrine does not have marked direct actions., (Copyright © 2018 Elsevier B.V. All rights reserved.)

The use of herbal medicinal products and supplements has increased during last decades. At present, some herbs are used to enhance muscle strength and body mass. Emergent evidence suggests that the health benefits from plants are attributed to their bioactive compounds such as Polyphenols, Terpenoids, and Alkaloids which have several physiological effects on the human body. At times, manufacturers launch numerous products with banned ingredient inside with inappropriate amounts or fake supplement inducing harmful side effect. Unfortunately up to date, there is no guarantee that herbal supplements are safe for anyone to use and it has not helped to clear the confusion surrounding the herbal use in sport field especially. Hence, the purpose of this review is to provide guidance on the efficacy and side effect of most used plants in sport. We have identified plants according to the following categories: Ginseng, alkaloids, and other purported herbal ergogenics such as Tribulus Terrestris , Cordyceps Sinensis. We found that most herbal supplement effects are likely due to activation of the central nervous system via stimulation of catecholamines. Ginseng was used as an endurance performance enhancer, while alkaloids supplementation resulted in improvements in sprint and cycling intense exercises. Despite it is prohibited, small amount of ephedrine was usually used in combination with caffeine to enhance muscle strength in trained individuals. Some other alkaloids such as green tea extracts have been used to improve body mass and composition in athletes. Other herb (i.e. Rhodiola, Astragalus) help relieve muscle and joint pain, but results about their effects on exercise performance are missing., Competing Interests: Not applicable.Not applicable.The authors declare that they have no competing interests.Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Objective: We investigated the impact of cardiac presynaptic norepinephrine recycling in patients with long-QT syndrome (LQTS) using positron emission tomography (PET) with 11 C-meta-hydroxyephedrine ([ 11 C]mHED-PET)., Methods: [ 11 C]mHED-PET was performed in 25 patients with LQTS (LQT1: n=14; LQT2: n=11) and 20 healthy controls and correlated with clinical parameters. [ 11 C]mHED-PET images were analysed for global and regional retention indices (RI) and washout rates (WO) reflecting dynamic parameters of the tracer activity., Results: Global and regional RI values were similar between patients with LQTS and controls. Although the global WO rates were similar between these groups, regional WO rates were on average higher in the lateral left ventricle (LV) wall in patients with LQTS (dose, mean ±SD; 0.08±0.14 vs 0.00%±0.09% min -1 ; p=0.033). In addition, patients with LQTS with a longer QTc interval showed a higher global WO rate. Clinical symptoms correlated with higher global WO rates. In the presence of normal global WO rates, asymptomatic LQTS patients showed higher global RI values., Conclusion: The increased regional WO rate of [ 11 C]mHED in the lateral LV suggests an imbalance of presynaptic catecholamine reuptake and release, resulting in a higher synaptic catecholamine concentration, in particular in LQT1 patients. This might enhance β-adrenoceptor signalling and thereby aggravate inherited ion channel dysfunction and may facilitate occurrence of ventricular tachyarrhythmias. Detection of regional differences in LV sympathetic nervous function may modify disease expression and potentially serve as a non-invasive risk marker in congenital LQTS., Trial Registration Number: 2006-002767-41;Results., Competing Interests: Competing interests: None declared., (© Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2018. All rights reserved. No commercial use is permitted unless otherwise expressly granted.)

Introduction: Propofol and Ephedrine are commonly used during anesthesia maintenance, the former as a hypnotic agent and the later as a vasopressor. The addition of propofol to ephedrine or administration of ephedrine before propofol injection is useful for decreasing or preventing propofol related hemodynamic changes and vascular pain. This in vitro study evaluated the antibacterial effect on common hospital-acquired infection pathogens of ephedrine alone or combined with propofol., Material and Method: The study was performed in two stages. In the first, the Minimum Inhibitory Concentration of propofol and ephedrine alone and combined was calculated for Escherichia coli, Enterococcus faecium, Staphylococcus aureus, Pseudomonas aeruginosa, and a clinical isolate of Acinetobacter spp. at 0, 6, 12 and 24h, using the microdilution method. In the second stage, the same drugs and combination were used to determine their effect on bacterial growth. Bacterial solutions were prepared at 0.5MacFarland in sterile 0.9% physiological saline and diluted at 1/100 concentration. Colony numbers were measured as colony forming units.mL -1 at 0, 2, 4, 6, 8, 10 and 12th hours., Results: Ephedrine either alone or combined with propofol did not have an antimicrobial effect on Escherichia coli, Enterococcus faecium or Pseudomonas aeruginosa and this was similar to propofol. However, ephedrine alone and combined with propofol was found to have an antimicrobial effect on Staphylococcus aureus and Acinetobacter species at 512mcg.mL -1 concentration and significantly decreased bacterial growth rate., Conclusion: Ephedrine has an antimicrobial activity on Staphylococcus aureus and Acinetobacter species which were frequently encountered pathogens as a cause of nosocomial infections., (Copyright © 2017 Sociedade Brasileira de Anestesiologia. Publicado por Elsevier Editora Ltda. All rights reserved.)

Introduction: During brain tumour surgery, vasopressor drugs are commonly administered to increase mean arterial blood pressure with the aim of maintaining sufficient cerebral perfusion pressure. Studies of the commonly used vasopressors show that brain oxygen saturation is reduced after phenylephrine administration, but unaltered by ephedrine administration. These findings may be explained by different effects of phenylephrine and ephedrine on the cerebral microcirculation, in particular the capillary transit-time heterogeneity, which determines oxygen extraction efficacy. We hypothesised that phenylephrine is associated with an increase in capillary transit-time heterogeneity and a reduction in cerebral metabolic rate of oxygen compared with ephedrine. Using MRI and positron emission tomography (PET) as measurements in anaesthetised patients with brain tumours, this study will examine whether phenylephrine administration elevates capillary transit-time heterogeneity more than ephedrine, thereby reducing brain oxygenation., Methods and Analysis: This is a double-blind, randomised clinical trial including 48 patients scheduled for surgical brain tumour removal. Prior to imaging and surgery, anaesthetised patients will be randomised to receive either phenylephrine or ephedrine infusion until mean arterial blood pressure increases to above 60 mm Hg or 20% above baseline. Twenty-four patients were allocated to MRI and another 24 patients to PET examination. MRI measurements include cerebral blood flow, capillary transit-time heterogeneity, cerebral blood volume, blood mean transit time, and calculated oxygen extraction fraction and cerebral metabolic rate of oxygen for negligible tissue oxygen extraction. PET measurements include cerebral metabolic rate of oxygen, cerebral blood flow and oxygen extraction fraction. Surgery is initiated after MRI/PET measurements and subdural intracranial pressure is measured., Ethics and Dissemination: This study was approved by the Central Denmark Region Committee on Health Research Ethics (12 June 2015; 1-10-72-116-15). Results will be disseminated via peer-reviewed publication and presentation at international conferences., Trial Registration Number: NCT02713087; Pre-results. 2015-001359-60; Pre-results., Competing Interests: Competing interests: None declared., (© Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2017. All rights reserved. No commercial use is permitted unless otherwise expressly granted.)

Background: Placental transfer of ephedrine causes fetal effects when compared with phenylephrine. This study compared their drug effects on neonatal parameters after cesarean delivery under spinal anesthesia., Methods: Three-hundred-and-fifty-four women undergoing elective cesarean delivery who needed intravenous vasopressor following spinal anesthesia were randomized into two groups. Group E received boluses of ephedrine 6mg, and Group P phenylephrine 100µg, titrated to maintain systolic blood pressure near baseline values. Neonatal heart rates at 10 and 30-45min of age, oxygen saturation and capillary blood glucose at 30min, and capillary blood lactate and urine metamphetamine were recorded., Results: Neonatal heart rate at 10min was significantly higher (mean difference 4.0, 95%CI 0.6 to 7.3, P=0.02) in Group E versus Group P, but this was not clinically relevant. There was a linear correlation between neonatal heart rate at 10min and ephedrine dose in Group E (r 2 =0.29, 95%CI 0.22, 0.74, p<0.01). The decremental changes in neonatal heart rate at 10 and 30min were significantly greater in Group E. Urine metamphetamine tests were positive in 19% of 44 neonatal urine samples. Neonatal heart rates at 30min, oxygen saturation, capillary blood glucose and the incidence of tachycardia, respiratory problems or abnormal glucose, were not significantly different., Conclusions: Ephedrine, compared to phenylephrine as a vasopressor during cesarean delivery, was associated with higher neonatal heart rate in the early post-birth period, but without a significant difference in clinical outcomes in uncomplicated pregnancies., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Background: Based on the traditional application of traditional Chinese Medicines (TCMs), Ephedra Herba (EH) is used to cure cold fever by inducing sweating, whereas Ephedra Radix (ER) is used to treat hyperhidrosis. Although they come from the same plant, Ephedra sinica Stapf, but have play opposing roles in clinical applications. EH is known to contain ephedrine alkaloids, which is the driver of the physiological changes in sweating, heart rate and blood pressure. However, the active pharmacological ingredients (APIs) of ER and the mechanisms by which it restricts sweating remain unknown., Purpose: The current work aims to discover the hidroschesis APIs from ER, as well as to establish its action mechanism., Methods: UPLC-Q/TOF-MS, PCA, and heat map were utilized for identifying the differences between EH and ER. HPLC integrated with a β 2 -adrenoceptor (β 2 -AR) activity luciferase reporter assay system was used to screen active inhibitors; molecular docking and a series of biological assays centered on β 2 -AR-related signaling pathways were evaluated to understand the roles of APIs., Results: The opposite effect on sweating of EH and ER can be attributed to the APIs of amphetamine-type alkaloids and flavonoid derivatives. Mahuannin B is an effective anti-hydrotic agent, inhibiting the production of cAMP via suppression of adenylate cyclase (AC) activity., Conclusion: The effects of EH and ER on sweat and β 2 -AR-related signaling pathway are opposite due to different alkaloids and flavonoids of APIs in EH and ER. The present work not only sheds light on the hidroschesis action of mahuannin B, but also presents a potential target of AC in the treatment of hyperhidrosis., (Copyright © 2017 Elsevier GmbH. All rights reserved.)

Purpose of Review: Hypotension remains one of the most researched subjects in obstetric anaesthesia. The purpose of this study is to review the most recent published articles on the use of vasopressors during spinal anaesthesia for caesarean section., Recent Findings: Despite continued research indicating advantages of phenylephrine over ephedrine, practitioners in some countries continue to favour ephedrine. Recent research has continued to compare the two drugs with some work emerging on high-risk patients. Concern about reflexive bradycardia during phenylephrine use has led to consideration of alternatives. Norepinephrine which has mild β-adrenergic activity has been shown to have equivalent pressor activity but with less depressant effect on heart rate and cardiac output versus phenylephrine. Research continues to focus on methods of vasopressor administration. Prophylactic infusions of phenylephrine have been shown to be effective and may require less physician intervention compared with intermittent boluses. Automated computer-controlled systems have been further investigated using multiple agents and continuous noninvasive blood pressure monitoring., Summary: Evidence continues to support phenylephrine as the first-line vasopressor in obstetrics. However, recent research is emerging to suggest that low-dose norepinephrine may be a better alternative. Prophylactic infusions are effective and automated systems have potential for the future.

This is an update on the treatment of anaphylactic shock in pregnant women. Most guidelines recommend adrenaline as first-line treatment in all patients, but in pregnant patients some recommend ephedrine due to a potential risk of utero-placental hypoperfusion with adrenaline. However, ephedrine is a less potent vasopressor than adrenaline and does not possess the same anti-inflammatory or broncho-dilating effects. As immediate and correct treatment is essential for both the maternal and the fetal outcome, adrenaline should be first-line treatment also in pregnant women.

Maoto, a traditional Japanese Kampo medicine, has been used to treat various respiratory diseases, including respiratory infections and influenza. Ephedrine (EPD), the main ingredient in maoto, is also clinically used to treat respiratory diseases. However, the pharmacokinetics and distribution of EPD in the lungs after the administration of maoto have not been demonstrated. This study aimed to determine the concentrations, distribution, and pharmacokinetics of EPD and its precursor methylephedrine (MEPD) in the lungs of rats orally administered maoto (1 and 4 g/kg). We used liquid chromatography-electrospray ionization-tandem mass spectrometry to measure the ingredient concentrations. Both ingredients were detected in maoto-treated lung homogenates. Next, we examined the distribution of both ingredients in lung sections by using matrix-assisted laser desorption/ionization-mass spectrometry imaging, a powerful tool for the visualization of the distribution of biological molecules. The mass spectrometry imaging analysis detected only EPD and provided the first visual demonstration that EPD is distributed in the alveoli, bronchi, and bronchioles in the lungs of rats orally administered maoto (4 g/kg, three times at 2-h intervals). These results suggest that the pharmacological efficacy of maoto for the amelioration of respiratory symptoms is related to the distribution of EPD in the lung.

We studied the effect and safety of ephedrine as add-on treatment for patients with myasthenia gravis with acetylcholine receptor antibodies (AChR MG), who do not sufficiently respond to standard treatment. Four patients with AChR MG were included in a placebo-controlled, double-blind, and randomised, multiple crossover series of n-of-1 trials. Each n-of-1 trial consisted of 3 cycles, in which two 5-day intervention periods were followed by 2 days washout. In each cycle, ephedrine 50 mg daily in 2 doses was compared with placebo in the alternate treatment period. Primary outcome was a change in QMG score. Add-on treatment with ephedrine compared with placebo improved QMG score by 1.0 point (95% confidence interval 0.21-1.79), which was significant for the group of trial patients as well as for the population treatment effect. Ephedrine also showed a significant trial average treatment effect for all secondary outcomes, improving MG Composite by 2.7, MG-ADL by 1.0 and VAS score for muscle strength by 1.1. Adverse events were mild and included palpitations, tremor and restlessness. Although all ECGs were normal, ephedrine prolonged the corrected QT interval. Ephedrine as add-on treatment for myasthenia gravis resulted in a small but consistent reduction of symptoms and weakness in patients with moderate disease severity., (Copyright © 2016 Elsevier B.V. All rights reserved.)

Background: Ephedrine is often used as nasal decongestant. Yet, the clinical study of intranasal ephedrine is scarce. In addition, the study tools may affect the measurement of the nasal patency. This problem has not been concerned., Objective: To investigate the nasal responses after using a single-dose of calibrated ephedrine nasal spray in Thai healthy male volunteers. The study also compared the differences between two methods of nasal patency measurement., Material and Method: Healthy males (n = 20) were recruited in a randomized, crossover, 2-day study. Each day was studied for anterior rhinomanometry (RN) or peak nasal inspiratory flow (PNIF). On test day, subjects were given ephedrine nasal spray, and measured by the specific tool for two hours. In addition, the visual analogue scale (VAS), cardiovascular (CVS) parameters, and adverse drug reactions were examined., Results: A single-dose ephedrine nasal spray significantly changed the nasal airway resistance (NAR), PNIF, and VAS at 5-minute. The NAR via RN was maximally decreased by 43.74±16.3% at 10-minute and returned to baseline at 90-minute. While, PNIF was maximally increased by 31.20±18.4% at 10-minute and returned to baseline at 60-minute. The nasal responses measured by two methods were significantly different at 5-, 15-, and 45-minute. VAS for nasal patency showed significant increases throughout the study period. CVS effects were negligible. Bitter taste was the most common adverse event reported., Conclusion: Ephedrine nasal spray is a fast-onset, short-acting decongestant. The decongestant effect of the drug varied by study tools. The variations appeared on the degree of nasal response and duration of action. The drug was generally safe.

Background: Drug addiction is classified as a chronic relapse nature brain disease with complicated neurobiology mechanisms. There are an increasing number of researchers that are investigating the possible mechanisms for solving the thorny problem., Methods: The model of chronic addiction of rhesus monkey ephedrine was established, where changes in body weight and behavior were monitored. The expression of cAMP response element binding protein (CREB) in the hippocampus of rhesus monkeys was identified by real-time PCR and Western blot., Results: We were successful in establishing the chronic ephedrine addiction model in the rhesus macaques. They exhibited changes in body weight and behavior. Immunofluorescence showed that CREB was expressed in the nucleus of the hippocampus, and the expression of CREB mRNA and protein in the hippocampus were increased by real-time PCR and Western blot. The CREB positive expression in the hippocampus of the modeling group was significantly higher than in the control group., Conclusions: The changes of body weight and behavior of the rhesus monkeys after ephedrine chronic addiction were significant. The changes of CREB in the hippocampus of rhesus macaques with ephedrine chronic addiction are important molecular mechanisms, and the upregulation of CREB may be involved in the physiological pathology and behavior process in individuals with chronic ephedrine addiction.