A Pharmacokinetic Study of Ephedrine and Pseudoephedrine after Oral Administration of Ojeok-San by Validated LC-MS/MS Method in Human Plasma.

A sensitive and reproducible liquid chromatography-tandem mass spectrometry (LC-MS/MS) system was developed and fully validated for the simultaneous determination of ephedrine and pseudoephedrine in human plasma after oral administration of the herbal prescription Ojeok-san (OJS); 2-phenylethylamine was used as the internal standard (IS). Both compounds presented a linear calibration curve (r2 ≥ 0.99) over a concentration range of 0.2-50 ng/mL. The developed method was fully validated in terms of selectivity, lower limit of quantitation, precision, accuracy, recovery, matrix effect, and stability, according to the regulatory guidelines from the U.S. Food and Drug Administration and the Korea Ministry of Food and Drug Safety. This validated method was successfully applied for the pharmacokinetic assessment of ephedrine and pseudoephedrine in 20 healthy Korean volunteers administered OJS.

Therapeutic appraisal of ephedrine against rheumatoid arthritis: A new indication.

Ephedra, natural flora has been used traditionally to treat rheumatism since decades. The scientific evidence of anti-rheumatic effect of this plant has also been reported. But the anti-rheumatic activity of major constituent of this plant (ephedrine) has not been evaluated. Based on this, the current study was aimed to assess anti-arthritic activity of ephedrine by using in vitro and in vivo approaches. Correspondingly, enzyme linked immunosorbent assay was performed for the estimation of prostaglandins E2 (PGE2) and tumor necrosis factor-α (TNF-α) in serum of formaldehyde-induced arthritic animals. The results elaborated significant reduction in albumin denaturation and remarkable progress on stabilization of red blood cells outer membrane at higher concentration during in vitro experiments. The ephedrine (40mg/kg) revealed noteworthy (p<0.001) inhibition in paw swelling in animals intoxicated with albumin as well as formaldehyde as compared to animals of control group by in vivo results. In this assay, ephedrine (20 & 40 mg/kg orally) significantly suppressed the level of these inflammatory markers (PGE2 & TNF-α). Ephedrine exhibited anti-arthritic effect by decreasing pro-inflammatory cytokines (PGE2 & TNF-α). This experimental work pharmacologically supports the use of ephedrine as anti-rheumatic drug but limited to evaluate in immunological arthritic model.

Ephedrine Alkaloids-Free Ephedra Herb Extract, EFE, Has No Adverse Effects Such as Excitation, Insomnia, and Arrhythmias.

Ephedrine alkaloids-free Ephedra Herb extract (EFE) has been developed to eliminate the adverse effects caused by ephedrine alkaloid-induced sympathetic hyperactivation. Previously, we reported that EFE possesses analgesic, anti-influenza, and cancer metastatic inhibitory effects at comparable levels to that of Ephedra Herb extract (EHE). However, it has not yet been demonstrated that EFE is free from the known side effects of EHE, such as excitation, insomnia, and arrhythmias. In this study, the incidence of these adverse effects was compared between mice administered EHE and those administered EFE. Increased locomotor activity in an open-field test, reduced immobility times in a forced swim test, and reduced sleep times in a pentobarbital-induced sleep test were observed in EHE-treated mice, when compared to the corresponding values in vehicle-treated mice. In contrast, EFE had no obvious effects in these tests. In electrocardiograms, atrial fibrillation (i.e., irregular heart rhythm, absence of P waves, and appearance of f waves) was observed in the EHE-treated mice. It was suggested that this atrial fibrillation was induced by stimulation of adrenaline ß1 receptors, but not by hypokalemia. However, EFE did not affect cardiac electrophysiology. These results suggest that the abovementioned side effects are caused by ephedrine alkaloids in EHE, and that EFE is free from these adverse effects, such as excitation, insomnia, and arrhythmias. Thus, EFE is a promising new botanical drug with few adverse effects.

History full circle: 'Novel' sympathomimetics in supplements.

Since the banning of ephedrine in over-the-counter nutritional supplements a decade ago, a plethora of untested and/or unsafe sympathomimetic stimulants have taken its place. This paper argues that these 'novel' stimulants in supplements recapitulate the work of synthetic chemists at commercial pharmaceutical firms during the 1930s and 1940s, all seeking substitutes for recently successful products based on ephedrine and amphetamine. Copyright © 2015 John Wiley & Sons, Ltd.

[Correlation between dissolution in vitro and absorption in vivo of chuanping sustained release tablets].

OBJECTIVE: To investigate the correlation between dissolution in vitro and absorption in vivo of Chuanping sustained release tablets. METHOD: The ephedrine, pseudoephedrine were chosen as marker components, dissolution in vitro of Chuanping sustained release tablets in the different pH were tested by the rotating basket method and HPLC; urine drug levels were determined by HPLC and absorption fractions were calculated according to Wagner-Nelson's formula and deconvolution technique. RESULT: The linear regressive equation between the absorption percentage in vivo F and accumulative release percentage in vitro of Chuanping sustained release tablets was established as F(ephedrine) = 1.572 5f-20. 729 (R2 = 0.974 5); F(pseudoephedrine) = 1.237f-0.147 6 (R2 = 0.959 5). CONCLUSION: The results suggested that there was fine correlation between the absorption percentage in vivo and the accumulative release percentage in vitro of Chuanping sustained release tablets.

[Effects of herba ephedrae, honey-fried herba ephedrae and maxingshigan decoction on autonomic activities of mice].

OBJECTIVE: To discuss the significance of processing and complex prescription with Herba Ephedrae, the effects of Herba Ephedrae, Honey-fried Herba Ephedrae and Maxingshigan decoction on autonomic activities in mice were compared. METHODS: 110 female Kunming mice were divided into 11 groups, namely normal saline group (NS), ephedrine group (E), high dose Herba Ephedrae group (MH-H), moderate dose Herba Ephedrae group (MH-M), low dose Herba Ephedrae group (MH-L) ,high dose Honey-fried Herba Ephedrae group (ZMH-H), moderate dose Honey-fried Herba Ephedrae group (ZMH-M),low dose Honey-fried Herba Ephedrae group (ZMH-L), high dose Maxingshigan decoction group (MX-H), moderate dose Maxingshigan decoction group (MX-M) and low dose Maxingshigan decoction group (MX-L). The numbers of autonomic activity in 15 minutes before intragastric administration (ig), and after ig 0.5, 1, 2, 3, 4 h were determined. RESULTS: There was interaction between time and groups. There were very significant differences between before ig and all time-points after ig (P < 0.01). 30 minutes after ig,there were significant differences between E and NS,E and ZMH-L,E and MX-L (P < 0.05). 1 h after ig, there were significant differences between MX-M and NS (P < 0.05). 3 h after ig, there were significant differences between MX-M and MH-L (P < 0.05). 30 minutes after ig, both ZMH-L and MX-L could reduce the number of autonomic activity in some extent compare with MH-L. 1 h or 2 h after ig, ZMH-L could reduce the number of autonomic activity in some extent compare with MH-L 4 h after ig, MX-L could reduce the number of autonomic activity in some extent compare with MH-L. CONCLUSION: Under the condition of this study, regarding autonomic activity as index, both ZMH-L and MX-L can reduce center stimulation in some extent.

Ischemic stroke associated with cough and cold preparation containing methylephedrine and supplement containing Chinese herbal drugs.

Methylephedrine is generally harmless and is contained in many cough and cold preparations. Likewise, Chinese herbal drugs are considered to be effective and to have few side effects. A 32-year-old woman experienced ischemic stroke attributed to concomitant administration of a cough and cold preparation containing methylephedrine and a supplement containing Chinese herbal drugs. Computed tomography and magnetic resonance imaging of the brain showed acute infarctions bilaterally in the cerebellum. Conventional angiography and magnetic resonance angiography showed transient stenosis of the left vertebral artery. These findings suggested vasospasm or dissection, presumably related to hypertension and/or angiitis or vasoconstriction of large cerebral arteries leading to local thrombosis as a result of stasis and sympathomimetic-induced platelet activation. Combining methylephedrine and Chinese herbal drugs might carry a risk of stroke.

[Ephedrine and naloxone promote nerve remodeling after cerebral ischemia].

OBJECTIVE: To investigate the effects of ephedrine combined with various doses of naloxone on neural plasticity in rats after cerebral ischemia/reperfusion injury to explore the possibility of synergistic effect about ephedrine combined with naloxone, promoting the optimum ratio of neural remodeling and its molecular mechanism. METHOD: A total of 192 healthy adult Sprague-Dawley rats, 220-250 g, were used to establish models of left middle cerebral artery occlusion using the suture occlusion method. Were randomly divided into 8 groups: the rats were intraperitoneally injected with 1.5 mg x kg(-1) x d(-1) ephedrine (ephedrine group), with 0.1, 0.2, 0.3 mg x kg(-1) x d(-1) naloxone (low, moderate and high doses of naloxone groups) , with 1.5 mg x kg(-1) x d(-1) ephedrine + 0.1, 0.2, 0.3 mg x kg(-1) x d(-1) naloxone (ephedrine + low, moderate and high doses of naloxone groups), and with 0.5 mL saline (model group), respectively. At 1-4 weeks following cerebral ischemia, sensorimotor integration in rats was assessed using the beam walking test, brain-derived neurotrophic factor (BDNF) expression was detected in the hippocampal CA3 area using immunohistochemistry 1-4 weeks after surgery, immunofluorescence method of detecting ischemic hemisphere hippocampal expression, The number of nerve cells apoptosis was detected using TUNEL assay. RESULT: BWT, BDNF, TUNEL assay results showed three doses of naloxone group had no significant effect, the effects increased together with the quantitative ephedrine, and had the amount-effect relationship, in which ephedrine + high dose of naloxone group the recovery of movement was fastest, BDNF expression in the best and ischemic apoptosis in the hippocampus at least, ischemic injury to the minimum, speed up the process of neural remodeling. CONCLUSION: The ephedrine and ephedrine + naloxone groups were accelerated motor function recovery rate in rat after cerebral ischemia, and the promotion of neural remodeling is closely related to the expression of BDNF, inhibit apoptosis in ischemic area, and with the increase of naloxone amount of additives, its role more clearly, the mechanism may be related to the dose of naloxone can significantly inhibit the ischemic area of apoptosis in early cerebral ischemia, so had the positive synergy effect with ephedrine to speed up the formation of neural remodeling.

Effect of combined therapy with ephedrine and hyperbaric oxygen on neonatal hypoxic-ischemic brain injury.

Perinatal hypoxic-ischemic (HI) is a major cause of brain injury in the newborn, and there is a lack of effective therapies to reduce injury-related disorders. The aim of the present study was to evaluate the effect of a combination of ephedrine and hyperbaric oxygen (HBO) on neonatal hypoxic-ischemic brain injury. 7-day-old Sprague-Dawley rat pups were randomly divided into sham operation, HI, ephedrine, HBO, and combined group. The ephedrine group was intraperitoneally injected with ephedrine, HBO group was treated for 2h at 2.5 absolute atmosphere (ATA) per day, the combined group received both ephedrine and HBO treatments, the sham operation and HI groups were intraperitoneally injected with normal saline. Rat brains at 7 days after HI, were collected to determine histopathological damage and the expression levels of Caspase-3 and Nogo-A. Four weeks after insult, animals were challenged with Morris water maze test. The expressions of Caspase-3 and Nogo-A were reduced in treating groups compared to those in HI group (P<0.01). Compared with the single treatment groups, the expression levels of Caspase-3 and Nogo-A were significantly reduced in the combined group (P<0.01). Compared with the single treatment groups, the average time of escape latency was significantly shorter (P<0.01) and the number of platform location crossing was more (P<0.05) in combined group. These findings indicate that the combination of ephedrine and HBO can enhance the neuroprotective effect in the neonatal rat HI model partially mediated by inhibiting Caspase-3 and Nogo-A pathways.

[Use of high-dose dexmedetomidine infusion for anesthesia and sedation in a patient for microlaryngeal surgery maintained with spontaneous breathing].

We experienced the anesthetic management using high-dose dexmedetomidine for microlaryngeal surgery maintaining spontaneous breathing. The anesthesia was maintained with dexmedetomidine infusion (initial dose 6 microg x kg(-1) x hr(-1) over 10 min followed by continuous infusion of 0.5 microg x kg(-1) x hr(-1)), intermittent small doses of fentanyl and topical application of lidocaine on the tongue, pharynx and larynx. The infusion of dexmedetomidine was increased over 30 min to 3 microg x kg(-1) x hr(-1) to reach the adequate sedation level and maintained at this rate for a further 15 min during the operation. During the whole perioperative period, there was no respiratory depression as measured by arterial blood gas analysis that recorded normal PaCO2 in the patient breathing supplemental oxygen. Hypotension (systemic arterial blood pressure less than 100 mmHg) occurred twice during dexmedetomidine administration, but was normolized by ephedrine administration. The preservation of respiratory drive offers the possibility that this anesthetic technique may be another method for providing anesthesia for the patient with a difficult airway. Moreover, there is one consensus on the importance of the basic principle that adequate topical or intravenous anesthesia is also essential during high-dose dexmedetomidine infusion.

[Cutaneous permeation comparison of Kechuan acupoint patch and power].

OBJECTIVE: To compare the cutaneous permeation of Kechuan acupoint patch and power, and evaluate the possibility of dosage form reform of Kechuan recipe. METHOD: Take the Eugend and Ephedrine as the indexes, HPLC was employed to determine their contents, the pond with Franz diffusion were used to measured the cutaneous. RESULT: The permeation of Patch matched with Higuchi Equation. Take Eugend as the index, the permeation rate of total of Patch is 2.319 and 1.738 times of the powder, and 1.784 and 1.215 times of the powder with the Ephedrineas as index. CONCLUSION: The permeation rate of Kechuan acupoint patch was more rapid than the powder. Moreover, the total quantity of permeation of patch was also more than the powder.

Evaluation of effect of ephedrine on the transport of drugs from the nasal cavity to the systemic circulation and the central nervous system.

It has been shown that vasoconstrictive drugs such as ephedrine derivatives are able to decrease systemic absorption of drugs administered by mucosal surfaces. The present paper set out to evaluate in the rat model the effect of co-administered nasal ephedrine on the absorption of GR138950 in a simple and in a pectin self-gelling formulation. It was hypothetised that a decrease in nasal systemic absorption would lead to an increase in direct nose-to-brain transport as demonstrated by the drug concentration in the olfactory lobes of the brain. It was found that ephedrine administered nasally with the drug in a simple aqueous solution resulted in a significant increase in nasal systemic absorption and also an increase in brain delivery; however, this trend was not observed with the pectin formulations. The pectin formulation with ephedrine resulted in lower systemic absorption of GR138950 and lower brain uptake compared to the simple solution formulation containing ephedrine.

Popular ergogenic drugs and supplements in young athletes.

Ergogenic drugs are substances that are used to enhance athletic performance. These drugs include illicit substances as well as compounds that are marketed as nutritional supplements. Many such drugs have been used widely by professional and elite athletes for several decades. However, in recent years, research indicates that younger athletes are increasingly experimenting with these drugs to improve both appearance and athletic abilities. Ergogenic drugs that are commonly used by youths today include anabolic-androgenic steroids, steroid precursors (androstenedione and dehydroepiandrosterone), growth hormone, creatine, and ephedra alkaloids. Reviewing the literature to date, it is clear that children are exposed to these substances at younger ages than in years past, with use starting as early as middle school. Anabolic steroids and creatine do offer potential gains in body mass and strength but risk adverse effects to multiple organ systems. Steroid precursors, growth hormone, and ephedra alkaloids have not been proven to enhance any athletic measures, whereas they do impart many risks to their users. To combat this drug abuse, there have been recent changes in the legal status of several substances, changes in the rules of youth athletics including drug testing of high school students, and educational initiatives designed for the young athlete. This article summarizes the current literature regarding these ergogenic substances and details their use, effects, risks, and legal standing.

Acute hemorrhagic myocardial necrosis and sudden death of rats exposed to a combination of ephedrine and caffeine.

Because of possible side effects of herbal medicines containing ephedrine and guarana-derived caffeine, including increased risk of stroke, myocardial infarction, and sudden death, the Food and Drug Administration recently banned the sale of ephedra-containing products, specifically over-the-counter dietary supplements. We report cardiac in 7- and 14-week-old male F344 rats exposed by gavage to ephedrine(25 mg/kg) and caffeine (30 mg/kg) administered in combination for one or two days. The ephedrine-caffeine dosage was approximately 12- and 1.4-fold, respectively, above average human exposure, based on a mg/m2 body surface-area comparison. Several (5/7) of the exposed 14-week-old rats died or were sacrificed in extremis 4-5 h after the first dosing. In these hearts, changes were observed chiefly in the interventricular septum but also left and right ventricular walls. Massive interstitial hemorrhage, with degeneration of myofibers, occurred at the subendocardial myocardium of the left ventricle and interventricular septum. Immunostaining for cleaved caspase-3 and hyperphosphorylated H2A.X, a histone variant that becomes hyperphosphorylated during apoptosis, indicated multifocal generalized positive staining of degenerating myofibers and fragmenting nuclei, respectively. The Barbeito-Lopez trichrome stain revealed generalized patchy yellow myofibers consistent with degeneration and/or coagulative necrosis. In ephedrine-caffeine-treated animals terminated after the second dosing, foci of myocardial degeneration and necrosis were already infiltrated by mixed inflammatory cells. The myocardial necrosis may occur secondarily to intense diffuse vasoconstriction of the coronary arterial system with decreased myocardial perfusion. Our work shows the direct relationship between combined ephedrine and caffeine exposure and cardiac pathology.

A randomized double-blind placebo-controlled clinical trial of a product containing ephedrine, caffeine, and other ingredients from herbal sources for treatment of overweight and obesity in the absence of lifestyle treatment.

OBJECTIVE: To evaluate the efficacy and side effects of an herbal formulation to promote weight loss, as compared to placebo. DESIGN: 12-week multicenter double-blind, placebo-controlled, randomized parallel groups design. Study conducted at three clinical sites in New York State. Subjects were randomized to receive either the 'active' product or a 'placebo' supplement for 12 weeks. Minimal steps were taken to influence lifestyle changes with regard to diet or exercise. SUBJECTS: 102 overweight/obese (30

Reinforcing effect of pseudoephedrine isomers and the mechanism of action.

It has been proposed that ephedrine and its isomers may have abuse potential. When made available to rhesus monkeys (n = 4) for self-administration, +-pseudoephedrine functioned as a positive reinforcer in all monkeys, as did (-)-pseudoephedrine in two of three monkeys. Pseudoephedrine isomers were 10- to 33-fold less potent than cocaine. In in vitro binding in monkey brain tissue, both isomers had low affinity for dopamine and serotonin transporters by at least 200-fold relative to cocaine, but comparable affinity for norepinephrine transporters. +-Pseudoephedrine also blocked dopamine uptake in 293 hDAT cells with low potency relative to cocaine. When given in vivo +-pseudoephedrine significantly displaced radioligand binding to dopamine transporters with a potency comparable to that in self-administration. Therefore, pseudoephedrine isomers can function as reinforcers and the mechanism at dopamine transporters may underlie this effect. However, pseudoephedrine appears to be a weak reinforcer and may have relatively low abuse potential.

Acute myocardial infarction induced by ephedrine alkaloids.

A 45-year-old woman was hospitalized to rule out acute myocardial infarction after coming to the emergency department with a complaint of substernal chest pressure. Her initial electrocardiogram indicated normal sinus rhythm with T-wave inversion and nonspecific ST changes suggestive of possible ischemia. She had no medical problems and took no prescription drugs. Further evaluation revealed that for approximately 4 years she had been taking Metabolife 356 preparations--a source of ephedrine alkaloids--for weight loss, and that she was at low risk for atherosclerotic coronary artery disease. Due to elevated cardiac markers, cardiac catheterization was performed, which revealed no atherosclerosis in the coronary arteries. The patient's acute myocardial infarction was attributed to coronary artery vasospasm induced by ephedrine alkaloids. Clinicians should be aware of the growing evidence that supports life-threatening cardiovascular toxicities associated with these substances.