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Enhanced stimulant effects of combined ephedrine and caffeine
Abstract
Herbal weight loss and athletic performance-enhancing supplements that contain ephedrine and caffeine have been associated with serious adverse health events. We sought to determine whether ephedrine and caffeine have clinically significant pharmacologic interactions that explain these toxicities.
Sixteen healthy adults ingested 25 mg ephedrine, 200 mg caffeine, or both drugs in a randomized, double-blind, placebo-controlled crossover study. Plasma and urine samples were collected over a 24-hour period and analyzed by liquid chromatography-tandem mass spectrometry for ephedrine and caffeine concentrations. Heart rate, blood pressure, and subjective responses were recorded. Serum hormonal and metabolic markers were serially measured during a 3-hour fasting period.
Ephedrine plus caffeine increased systolic blood pressure (peak difference, 11.7 +/- 9.4 mm Hg; compared with placebo, P =.0005) and heart rate (peak difference, 5.9 +/- 8.8 beats/min; compared with placebo, P =.001) and raised fasting glucose, insulin, free fatty acid, and lactate concentrations. Ephedrine alone increased heart rate and glucose and insulin concentrations but did not affect systolic blood pressure. Caffeine increased systolic blood pressure and plasma free fatty acid and urinary epinephrine concentrations but did not increase heart rate. Compared with ephedrine, caffeine produced more subjective stimulant effects. Clinically significant pharmacokinetic interactions between ephedrine and caffeine were not observed. Women taking oral contraceptives had prolonged caffeine elimination (mean elimination half-life, 9.7 hours versus 5.0 hours in men; P =.05), but sex differences in pharmacodynamic responses were not seen.
The individual effects of ephedrine and caffeine were modest, but the drugs in combination produced significant cardiovascular, metabolic, and hormonal responses. These enhanced effects appear to be a result of pharmacodynamic rather than pharmacokinetic interactions.
... Caffeine can well exemplify this condition, as it is considered an apparently innocuous food ingredient, which can enhance the pharmacological effects of adrenergic amines (Haller et al. 2004). This fact underlies the main cause for 95 its widespread use in formulations for weight loss and physical fitness, i.e., not the isolated characteristic effect, but the enhancement of the effect of other stimulants of the central nervous system. ...
... Furthermore, there is no legal over-the-counter botanical supplement that has demonstrated clinical efficacy as a diet pill. The only herbal treatment that can lead to a modest weight loss is Ephedra combined with caffeine, but this cocktail can also cause strokes, 425 heart attacks and sudden death (Haller et al. 2004(Haller et al. , 2005; hence, Ephedra was first banned from the US market in 2004 (Cohen 2014a). Thus, some of the results on weight loss are due to caffeine potentiating the effects of adrenergic compounds, such as ephedrine 430 and synephrine (Haller et al. 2004;Schmitt et al. 2012). ...
... The only herbal treatment that can lead to a modest weight loss is Ephedra combined with caffeine, but this cocktail can also cause strokes, 425 heart attacks and sudden death (Haller et al. 2004(Haller et al. , 2005; hence, Ephedra was first banned from the US market in 2004 (Cohen 2014a). Thus, some of the results on weight loss are due to caffeine potentiating the effects of adrenergic compounds, such as ephedrine 430 and synephrine (Haller et al. 2004;Schmitt et al. 2012). ...
Methyl-xanthines and adrenergic stimulants, such as caffeine and synephrine, are commonly added to food supplements due to their stimulating and thermogenic effects. In addition, the abusive consumption of food supplements with ergogenic and esthetic purposes has been observed worldwide. This work describes the study of caffeine, p-synephrine, hordenine, octopamine, tyramine, ephedrine, and salicin as stimulants in dietary supplements marketed in Brazil for weight loss and physical fitness claims. A total of 94 different products were acquired from 30 Brazilian websites. Thus, the sampling of marketed supplements was performed in virtual commerce with claims of weight loss, appetite reduction, fat burning, and metabolism acceleration. The developed analytical method involved the separation of the stimulants by HPLC with diode array detection (HPLC-DAD) by using a gradient elution of flow rate (0.7-2.5 mL min(-1)) and mobile-phase composition (0.1% H3PO4/methanol). The validated method was applied to the study of 46 dietary supplements. Caffeine, p-synephrine and ephedrine were found to be present as stimulants in 52% of the studied samples marketed as encapsulated or bulk forms. Caffeine was found to be present in concentrations that represent doses from 25.0 to 1476.7 mg/day. Synephrine was found in concentrations that represent doses from 59.1 to 127.0 mg/day. Ephedrine was found to be associated with caffeine in one formulation in a concentration representing a 26.1 mg/day dosage.
... These enhanced responses may be a result of pharmacodynamics, instead of pharmacokinetic interactions. 95 When ephedrine was given as a component of an Ephedra product, its absorption was observed to be much slower compared to its pure form. The time to the maximum plasma concentration (T max ) of an Ephedra product after ingestion was approximately twice its value when ephedrine was given in its pure form. ...
... The time to the maximum plasma concentration (T max ) of an Ephedra product after ingestion was approximately twice its value when ephedrine was given in its pure form. 12 A goal of another investigation was to analyze the data collected from two previous clinical trials 95 to generate a more mechanistic pharmacokinetic model for ephedrine and norephedrine in healthy subjects. This study aimed to determine the differences in pharmacokinetic properties following pharmaceutical or herbal formulations ingestion, and the magnitude of the caffeine effect as a dietary component in beverages on the absorption of ephedrine. ...
Ephedrine, a sympathomimetic amine that exhibits several of 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. Further, 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
... Ephedra is known to be ergogenic during anaerobic exercises, such as bench presses (p < 0.05), especially when taken with caffeine; however, a point to consider is that systolic blood pressure increased significantly before both tests in subjects treated with ephedrine compared to the other tests [96]. A clinical trial by Haller et al. [97] carried out in 16 healthy subjects showed an increment in the stimulating and metabolic effects of combined ephedrine (25 mg) and caffeine (200 mg) as they increased systolic blood pressure (maximum difference of 11.7 ± 9.4 mmHg compared to placebo; p = 0.0005) and heart rate (maximum difference of 5.9 ± 8.8 beats/min; p = 0.001). The study demonstrated that, individually, ephedrine and caffeine had modest effects, but in combination, they produced significant cardiovascular, metabolic, and hormonal responses at moderate doses, data which should be taken into account to avoid such risks when indicating the dose to produce the desired ergogenic effect. ...
... At the same time, a healthy adult can consume up to 400 mg of caffeine/day (equivalent to 6 mg/kg in individuals weighing less than 65 kg) without producing any adverse effects [93]. Studies which have reported changes in heart rate and blood pressure involved the supplementation of caffeine with ephedrine in synergy, such as the works of Haller et al. [97] and Shekelle et al. [95], which observed increases in heart rate and blood pressure and weight loss, respectively, but at moderate doses (200 mg of caffeine and 25 mg of ephedrine) and without the participants reporting any adverse events. Similar results were found in the study of Nowak et al. [124], in which, after ingesting energy drinks containing 80 mg of caffeine, glucose, taurine, vitamins and other ingredients glucuronide, acute intake of energy drinks can increase diastolic blood pressure by more than 8%, blood sugar and discomfort level of healthy young people. ...
The consumption of energy drinks (e.g., containing caffeine and taurine) has increased over the last decade among adolescents and athletes to enhance their cognitive level and improve intellectual and athletic performance. Numerous studies have shown that drinking moderate doses of such drinks produces beneficial effects, as they considerably boost the sporting performance of elite athletes in various sports, including both endurance and explosive events. However, apart from their ergogenic effects, the regular consumption of energy drinks also increases blood pressure and consequently incites problems such as hypertension, tachycardia, and nervousness, all of which can lead to cardiovascular disorders. A potential positive correlation between genetics and the moderate consumption of energy drinks and athletic performance has recently been reported; notwithstanding, a better understanding of the genetic variants involved in metabolism is a key area for future research to optimize the dose of energy drink consumed and obtain the maximal ergogenic effect in elite sports. The aim of this literature review, therefore, is to present the results of recent studies, classifying them according to the differences in the associations between energy drinks and: (i) Athletic performance; (ii) cardiovascular risk factors while practicing sports; and (iii) genetic associations and future prospects between the consumption of energy drinks and performance.
... Hemodynamic parameters such as blood pressure and heart rate are elevated following coadministration of caffeine and other stimulants such as ephedrine. 22 To determine the potential for a pharmacodynamic interaction between theacrine and caffeine, we evaluated systolic and diastolic blood pressure, heart rate, and rate-pressure product following administration of both theacrine (25 and 125 mg) and caffeine (150 mg) alone and in combination (theacrine 125 mg plus caffeine 150 mg). Heart rate decreased slightly over the first 2 hours following administration for each of the four conditions returning to baseline by 24 hours postingestion (Fig. 5A). ...
... Caffeine has often been described as eliciting pharmacokinetic and pharmacodynamic interactions with prescription as well as dietary supplement preparations. 22,25,26 Despite anecdotal evidence, however, there has been no study examining the potential for caffeine to induce either a pharmacokinetic or pharmacodynamic interaction with theacrine. ...
Objective:
Theacrine, a methylurate class purine alkaloid, triggers diverse pharmacologic responses, including psychostimulatory activity by modulation of adenosinergic and dopaminergic pathways. In a double-blind, placebo-controlled study, theacrine increased energy, concentration, and mood, while reducing fatigue. Because caffeine, a methylxanthine purine alkaloid, is frequently coadministered with theacrine, we sought to determine if a pharmacokinetic and/or pharmacodynamic interaction existed between theacrine and caffeine.
Methods:
Eight healthy adults received theacrine, as TeaCrine® (25 or 125 mg), caffeine (150 mg), or a combination of theacrine (125 mg) and caffeine (150 mg) in a randomized, double-blind crossover study. Blood samples were collected over a 24-hour period and analyzed by Liquid chromatrography-mass spectrometry/mass spectrometry (LC-MS/MS) for theacrine, caffeine, and paraxanthine. Pharmacodynamic response markers, heart rate and blood pressure, were recorded.
Results:
Theacrine pharmacokinetics was similar following administration of theacrine alone. Caffeine coadministration increased maximum plasma concentration and area under the curve of theacrine without altering theacrine half-life. Theacrine had no impact on caffeine or paraxanthine pharmacokinetics. There was no difference between treatment groups with regard to heart rate or systolic/diastolic blood pressure.
Conclusions:
Coadministration of theacrine and caffeine results in a clinically significant pharmacokinetic interaction, viz., increased theacrine exposure. Enhanced oral bioavailability is the most likely mechanism by which caffeine alters theacrine exposure. However, further studies examining the contribution of presystemic elimination mechanisms, for example, efflux transport and/or gut metabolism, to theacrine bioavailability are needed to confirm the exact mechanism(s). Hemodynamic parameters were unaltered despite the pharmacokinetic interaction, suggesting that coadministration of caffeine and theacrine is safe at the doses administered.
... What is well recognized, however, is that caffeine can potentiate the cardiovascular and CNS effects of other stimulants. Such stimulants include plant-derived αand β-adrenergic agonists such as those found in Ephedra species (eg, ephedrine, pseudoephedrine, norephedrine, and methylephedrine) [110][111][112] and α 2adrenergic antagonists from the African plant Pausinystalia yohimbe (eg, yohimbine and rauwolscine), 113 as well as synthetic stimulants such as amphetamine, methamphetamine, 3,4-methylenedioxymethamphetamine, and cocaine. [114][115][116] When combined with ephedrine alkaloids or amphetamines, especially in the context of vigorous exercise, caffeine may increase the likelihood of serious adverse health effects, such as arrhythmia, 17 myocardial infarction, 17 stroke 17,117 , seizure, 17,23 hypertensive crisis, 118 and exertional heat illness. ...
... 270 Nevertheless, a surfeit of case reports strongly suggests that exercise may exacerbate DMAA and caffeine toxic effects in susceptible individuals. Caffeine's capacity to augment the toxic effects of other stimulants, [110][111][112][113][114][115][116] coupled with its ability to increase cardiac workload 133 and reduce myocardial blood flow during exercise, 134 render Ephedra-free supplements as irrational ergogenic aids. Besides p-synephrine, yohimbine, and DMAA, other stimulants not listed on product labels (eg, oxilofrine, deterenol, and N,α-diethylphenylethylamine) have also been detected in multiingredient, preworkout supplements, and caffeine may bolster their toxic effects when administered together as an ergogenic supplement. ...
Purpose:
Our objective was to review the history, safety, and efficacy of caffeine-containing dietary supplements in the United States and Canada.
Methods:
PubMed and Web of Science databases (1980-2014) were searched for articles related to the pharmacology, toxicology, and efficacy of caffeine-containing dietary supplements with an emphasis on Ephedra-containing supplements, Ephedra-free supplements, and energy drinks or shots.
Findings:
Among the first and most successful dietary supplements to be marketed in the United States were those containing Ephedra—combinations of ephedrine alkaloids, caffeine, and other phytochemicals. A decade after their inception, serious tolerability concerns prompted removal of Ephedra supplements from the US and Canadian markets. Ephedra-free products, however, quickly filled this void. Ephedra-free supplements typically contain multiple caffeine sources in conjunction with other botanical extracts whose purposes can often be puzzling and their pharmacologic properties difficult to predict. Ingestion of these products in the form of tablets, capsules, or other solid dosage forms as weight loss aids, exercise performance enhancers, or energy boosters have once again brought their tolerability and efficacy into question. In addition to Ephedra-free solid dosage forms, caffeine-containing energy drinks have gained a foothold in the world market along with concerns about their tolerability.
Implications:
This review addresses some of the pharmacologic and pharmaceutical issues that distinguish caffeine-containing dietary supplement formulations from traditional caffeine-containing beverages. Such distinctions may account for the increasing tolerability concerns affiliated with these products.
... In what form and with whom the bioactive phytochemicals are dispersed determine their delivery, assimilation, acts and metabolism. For instance, when effectively modest ephedrine and caffeine are combined, the pharmacodynamics interactions produce significant cardiovascular, metabolic, and hormonal responses (Haller et al., 2004). ...
... The unexpected profound proliferating activity of ephedrine on the human cervical carcinoma HeLa cells was rather a rare discovery, while other studies conducted on ephedrine-type alkaloids are mostly about their cytotoxicity, stimulant and metabolic effects, often at several orders of magnitude higher concentrations (Lee et al., 2000;Haller et al., 2004). Nevertheless, its growth-promoting effect on carcinoma cells in vitro does not necessarily indicate the carcinogenesis in vivo, evidenced by an animal feeding study found no carcinogenic effects of ephedrine sulfate (NTP, 1986). ...
... Moreover, combining ephedrine and caffeine can enhance sympathetic nervous system stimulation due to their pharmacodynamic interactions. 9 This report is limited because we could not determine which drug component had the largest impact on PCT elevation. In addition, we have detected a narrower range of PCT elevation compared to former studies. ...
Background
Procalcitonin, a biomarker used to detect systemic bacterial infection, can be elevated in other conditions. Some case reports have suggested procalcitonin elevation induced by drug overdose.
Case Presentation
A 20-year-old woman with insignificant medical history presented with vomiting, fever, and impaired consciousness. Her vital signs showed an altered mental status (Glasgow Coma Scale score, 11 [E4V1M6]) and high fever (38.0°C), and no significant neurological signs were detected. Laboratory tests revealed that her serum procalcitonin level was significantly high (>10 ng/dL). Gradually, her level of consciousness improved, and she admitted that she had taken an overdose of sympathomimetic drugs. She was discharged from the hospital on day 5 without any problems.
Conclusion
Drug overdose is seldom mentioned as one of the causes of serum procalcitonin level elevation. Sympathomimetic drug overdose can be one of the causes of procalcitonin elevation.
... Recommended use for those who are overfat was based on the purported impact on metabolism and satiety (see Figure 1) that each of the aforementioned ingredients would produce. The purported benefit metabolically may be through sympathomimetic induction of greater lipolysis and possible upregulation of uncoupling proteins to induce a thermogenic effect, thus allowing for the purported greater reduction in weight (in particular fat mass) from incorporating the use of these substances beyond the recommended lifestyle modifications, i.e. changes in diet and activity level (Clark, 2019;Donsmark et al., 2005;Gurley et al., 1998;Haller et al., 2002;Haller et al., 2004;Jenkinson and Harbert, 2008;Nogiec and Kasif, 2013;Stohs et al., 2011;Coulter et al., 2018) While use of these substances have been touted, anecdotally and through single study reports, as having positive benefits, claims may not always be supported by the available scientific literature (Clark, 2019;Calfee and Fadale, 2006;Kerksick et al., 2018;Saper et al., 2004;Liu et al., 2017). Most studies associated with such substances examine solely acute responses to an exercise session, whereas the time necessary to induce weight loss and improve health status requires prolonged alteration to lifestyle, i.e. significant changes in both diet and addition of exercise to activities of daily living, that goes well beyond the time for many of the acute studies (Clark, 2019;Ekor, 2014;Heuberger and Cohen, 2019;Kerksick et al., 2018;Liu et al., 2017;Shekelle et al., 2003). ...
Background
Those who are overfat face an onslaught of advice for losing weight, including using dietary supplements that purport to have fat burning capabilities to achieve a reduced body mass, fat mass and improvement in cardiometabolic health in combination with exercise or diet and exercise regimens.
Aim
To examine long-term effectiveness of supplements for both weight loss and improvements in cardiometabolic health for these individuals.
Methods
A PRISMA methods of systematic review was conducted from August 2018 through January 2019 using Medline, PubChem, PubMed, EBOSCO CINHAL and SPORTDiscus, and Google Scholar yielding 23,441 returns of which 21 studies (duration greater than 8 weeks with participant populations of BMI greater than 24.9) were included for meta-analysis. Meta-analysis examined pooled effect size and 95% confidence interval for: body mass, fat mass, fat-free mass, total cholesterol, high-density lipoproteins, low-density lipoproteins, resting metabolic rate. Intra-study effect sizes were compared with previously reported results for diet or diet and exercise in a 2x2 chi-square analysis for the number of studies that induced effects greater than or less than the effect size.
Results
There is a general trend to show effectiveness (effect size greater than 0.00) for obtaining beneficial changes from use of thermogenic dietary supplements, yet the 95% confidence interval for effect size crossed 0.00 (indicating no benefit). Chi-square comparison to exercise, or combination of diet and exercise, indicates that responses induced from weight-loss supplements were less effective than what is obtained from utilizing exercise, or diet and exercise, without additional weight-loss supplements.
Conclusion
There appears to be limited benefit that may be derived from the inclusion of thermogenic dietary supplements to reduce body mass and improve cardiometabolic health for individuals who are overfat.
... Ephedrine increases heart rate, glucose, and insulin concentrations without affecting systolic blood pressure [2]. Plant-based stimulants have similar disposition characteristics to drugs and can produce a significant cardiovascular response after a single dose [3]. ...
... Un producto de esta categoría, la Crema Lipolítica Dr. Kuzmar-Advanced Scientific Cosmetics, se anuncia como una crema tópica que ayuda a mejorar la pérdida de grasa que contiene varios ingredientes activos como: cafeína, L-carnitina, α-tocoferol, ácido cítrico, fucus vesiculosus , centella asiática, camellia sinensis, entre otras, que han demostrado ser eficaces para mejorar la composición corporal 8,9 . La cafeína mejora la lipólisis y la oxidación de las grasas y puede magnificarse cuando se combina con otros agentes termogénicos 10,11 . Se ha demostrado que la cafeína es eficaz para penetrar a través de la piel 12 y puede afectar la secreción de catecolaminas, que activan los receptores β-2 adrenérgicos y a su vez, aumentan la concentración de monofosfato de adenosina cíclico (cAMP) en las células que activan la lipasa en el proceso de lipólisis 13 . ...
Efficacy of a lipolytic cream in an overweight and obesity treatment Resumen Objetivo. Evaluar la eficacia coadyuvante de una combina-ción de ingredientes cosméticos en forma de crema lipolítica con dieta hipocalórica y actividad física comparada con dieta hipocalórica y actividad física para el tratamiento del sobre-peso y la obesidad en pacientes. Material y métodos. Se realizó un estudio monocéntrico, abierto y aleatorizado de grupos paralelos de 102 pacientes que consultaron a un centro de nutrición médico-clínico para el tratamiento del sobrepeso y la obesidad. Los perímetros de altura, brazo, cintura, cadera y muslo y el análisis de la composición corporal segmentaria con un equipo de impe-dancia se estudiaron en pacientes de 18 a 99 años de ambos sexos con asistencia voluntaria y con presencia de sobrepe-so u obesidad durante un período de 16 semanas consecu-tivas. Los datos se analizaron estadísticamente comparando los valores iniciales y finales de todos los valores en ambos grupos. La seguridad fue monitoreada por la incidencia de eventos adversos. Un valor de p<0,001 fue considerado como de significación estadística. Resultados. Del total de 102 pacientes, se aplicaron los cri-terios de inclusión y exclusión; se incluyeron y analizaron 45 y 47 casos, respectivamente. La edad oscila entre 39,16 y 42,09 años (p = 0,246); el peso inicial 85,9 kg vs 85,08 kg (p = 0,810); perímetros: cintura inicial de 100,4 cm frente a 99,7 cm (p = 0,826); brazo inicial de 32,9 cm vs 33,4 cm (p = 0,453); cadera inicial: 108,6cm vs 107,7 (p = 0,666). Peso final 82,6 kg vs 78,7 kg (p = 0,227); perímetros: cintura final de 94,9 cm frente a 90,9 cm (p = 0,144); brazo final de 31,8 cm frente a 31,4 cm (p = 0,453); Cadera final: 106,7 cm vs 102,1 (p = 0,074). No hubo ningún informe de efectos secunda-rios no deseados con el uso de crema lipolítica, presentando una buena aceptabilidad. Los pacientes con crema lipolítica como adyuvante en el tratamiento del sobrepeso u obesidad perdieron mayor IMC, mayor porcentaje de peso y mayor porcentaje de grasa (p<0,001). Conclusión. Los pacientes con crema lipolítica como adyuvan-te en el tratamiento del sobrepeso o la obesidad pierden mayor IMC, mayor porcentaje de peso y mayor porcentaje de grasa. Palabras clave: lipólisis, crema para la piel, obesidad, so-brepeso. Objective. To evaluate the coadyouvant efficacy of a combination of cosmetics ingredients in the form of a lipolytic cream with hypocaloric diet and physical activity and compared with hypocaloric diet and physical activity for overweight and obesity treatment in patients. Material and methods. It was conducted a monocentric, open-label, randomized study of parallel groups of 102 patients that consulted in a medical-clinical nutrition center for overweight and obesity treatment. Height, arm, waist, hip and thigh perimeters and the analysis of segmental body composition with an impedance team were studied in patients between 18 and 99 years, of both sexes with voluntary attendance and with presence of overweight or obesity during a period of 16 consecutive weeks. The data were statistically analyzed by comparing the initial and final values of all the values in both groups. Safety was monitored by the incidence of adverse events. A value of p<0.001 was considered as statistical significance. Results. Of the total of 102 patients, the inclusion and exclusion criteria were applied; 45 and 47 cases are included and analyzed respectively. The age ranges between 39.16 vs 42.09 years (p = 0.246); initial weight 85.9 kg vs 85.08 kg (p = 0.810); perimeters: initial waist of 100.4cm vs 99.7cm (p = 0.826); initial arm of 32.9cm vs 33.4cm (p = 0.453); initial hip: 108.6cm vs 107.7 (p = 0.666). Final weight 82.6 kg vs 78.7 kg (p = 0.227); perimeters: final waist of 94.9 cm vs 90.9 cm (p = 0.144); final arm of 31.8 cm vs 31.4 cm (p = 0.453); final hip: 106.7 cm vs 102, 1 (p = 0.074). There was no report of un-wanted side effects with the use of lipolytic cream, presented good acceptability. Patients with lipolytic cream as adjuvant in the treatment of overweight or obesity lose greater BMI, greater percentage of weight and greater percentage of fat (p <0.001). Conclusion. Patients with lipolytic cream as adjuvant in the treatment of overweight or obesity lose greater BMI, greater percentage of weight and greater percentage of fat.
... Acheson et al 8 reported that caffeine supplementation alone enhances lipolysis as well as fat oxidation; however, researchers have suggested that its effectiveness appears to be magnified when combining caffeine with other thermogenic agents. 9 Diepvens et al 10 suggested that caffeine may affect the secretion of catecholamines, which activate β-2 adrenergic receptors and in turn increase the concentration of cyclic adenosine monophosphate (cAMP) in cells that activates lipase in the lipolysis process. Researchers have also reported that caffeine can prevent an accumulation of fats and may speed up lipolysis by blocking α-adrenergic receptors. ...
Background and objective
Topical aminophylline, caffeine, yohimbe, l‐carnitine, and gotu kola (Centella asiatica) may aid in reducing body fat. Lipoxyderm™ contains these ingredients and was used to test if fat loss of the thigh, in conjunction with a low intensity exercise program and restricted calorie intake, was enhanced via the topical application of this lotion.
Methods
This was a double‐blind, placebo‐controlled, within‐group study that investigated the effects of Lipoxyderm™ on thigh fat mass, circumference, and skinfold thickness. Seven participants underwent pre/post‐exercise testing for weight, bilateral thigh circumference/skinfold thickness, and body composition/thigh fat mass assessment via dual‐energy X‐ray absorptiometry. Participants followed a hypocaloric diet, walked 150 minutes/wk, and were randomly assigned to apply a placebo to one leg and Lipoxyderm™ to their other leg for 28 days. Separate two‐way mixed factorial repeated measures ANOVAs were used to compare the effects of Lipoxyderm™ to the placebo on thigh circumference, skinfold thickness, and fat mass.
Results
A significant time x group interaction was found for thigh circumference (F1,6 = 18.2, P = 0.005), skinfold thickness (F1,6 = 14.6, P = 0.009), and fat mass (F1,6 = 37.1, P = 0.001).
Conclusions
A twice‐daily topical application of Lipoxyderm™ for 28 days compared to a placebo combined with a walking program and a restricted caloric intake is more effective at reducing thigh circumference (1.2 vs 0.8 cm), thigh skinfold thickness (3.7 vs 2.0 mm), and thigh fat mass (100.0 g vs 57.3 g).
... Regarding the decrease of plasma amino acids, it was demonstrated in the correlation network analysis that the plasma concentration of ephedrine and its analogs strongly correlated with the content of BCAAs in plasma, and BCAAs were also correlated with essential amino acids (Cluster A in Fig. 6). Oral administration of ephedrine has been reported to increase fasting insulin levels [21]. Insulin stimulates amino acid uptake as well as uptake of glucose and fatty acids [22,23]. ...
Traditional herbal medicine (THM) consists of a vast number of compounds that exert pharmacological effects throughout the body. Comprehensive phenotyping analysis using omics is essential for understanding the nature of THM in detail. We previously reported that the Japanese Kampo medicine maoto ameliorated flu-like symptoms in a rat infection model and dynamically changed plasma metabolites as indicated by metabolome analysis. The aim of this study was to apply wide-targeted plasma metabolomics with quantitative analysis of maoto compounds in a human clinical trial to evaluate the effect of maoto on plasma metabolites. Four healthy human subjects were recruited. Plasma samples were collected before and 0.25, 0.5, 1, 2, 4 and 8 h after maoto treatment. Wide-targeted metabolomics and quantitative analysis of the main chemical constituents of maoto were then performed. Plasma metabolome analysis revealed that maoto administration decreased essential amino acids including branched-chain amino acids (BCAAs) and increased various kinds of ω-3 fatty acids including eicosapentaenoic acid and docosahexaenoic acid, consistent with previous studies in rats. Fifteen of the major compounds in maoto were identified in the systemic circulation. Finally, the correlation between endogenous metabolites and maoto compounds in plasma was analyzed and the results indicated that the decrease in plasma BCAAs might be caused by ephedrines present in maoto. The present study demonstrated that plasma metabolomic studies of endogenous and exogenous metabolites are useful for elucidating the mechanism of action of THM.
... 18 When administered as proprietary blends, the principal phytochemical culprits (i.e., ephedrine and caffeine) exhibited enhanced pharmacodynamic effects, making it difficult to differentiate the contributions of other phytochemicals from those of ephedrine and caffeine. 14,19 This enhanced effect has kindled an appreciation for the pharmacology of complex phytochemical mixtures. ...
Botanical dietary supplements (BDS) are complex mixtures of phytochemicals exhibiting complex pharmacology and posing complex research challenges. For 25 years, clinical pharmacologists researching BDS have confronted a litany of issues unlike those encountered with conventional medications. Foundational to these concerns is the Dietary Supplement Health and Education Act of 1994, which exempted BDS from premarket safety and efficacy trials. In the ensuing period, safety concerns regarding multi‐ingredient products formulated as “proprietary blends” and herb‐drug interactions have garnered significant attention. Idiosyncrasies unique to BDS can affect the outcome and interpretation of in vitro and in vivo studies, and while “omics” approaches hold promise in uncovering BDS efficacy mechanisms, purposeful adulteration threatens their safety. Despite a quarter century of public use, health care professionals still know little about BDS, thus it falls to industry, government, and academia to join forces in promoting a new paradigm for BDS research and product development. This article is protected by copyright. All rights reserved.
... Through this mechanism, thermogenic agents induce Caloric imbalance and energetic deficits that induce fat mass loss (Belza and Jessen, 2005;Vaughan et al., 2014). The typical chemical contained within this group function as mimic to adrenal hormones (adrenaline and noradrenaline) at peripheral tissues, i.e. sympathomimic effects, Fig. 1 (Gurley et al., 1998;Haller et al., 2002Haller et al., , 2004Persky et al., 2004). The actions of the sympathomimic chemicals as it relates to body compositional changes are two-fold (Donsmark et al., 2005;Stich and Berlan, 2004;Vaughan et al., 2014). ...
... Pharmacodynamic interactions among the various constituents are also likely contributing factors. For example, caffeine, a major constituent of OEP-NF, is recognized for its ability to augment the toxicity of other stimulants and sympathomimetics (Brown et al., 1991;Derlet et al., 1992;Haller et al., 2004;McNamara et al., 2006). Combinations of caffeine and ephedrine alkaloids can produce a host of cardiovascular and central nervous system pathologies that are more remarkable than those observed after administration of each individual component (Brown et al., 2012;Dunnick et al., 2007). ...
Herbal dietary supplements have gained wide acceptance as alternatives to conventional therapeutic agents despite concerns regarding their efficacy and safety. In 2013, a spate of severe liver injuries across the United States was linked to the dietary supplement OxyELITE Pro-New Formula (OEP-NF), a multi-ingredient product marketed for weight loss and exercise performance enhancement. The principal goal of this study was to assess the hepatotoxic potential of OEP-NF in outbred and inbred mouse models. In an acute toxicity study, significant mortality was observed after administering 10X and 3X mouse-equivalent doses (MED) of OEP-NF, respectively. Increases in liver/body weight ratio, ALT and AST were observed in female B6C3F1 mice after gavaging 2X and 1.5X MED of OEP-NF. Similar findings were observed in a 90-day feeding study. These alterations were paralleled by altered expression of gene- and microRNA-signatures of hepatotoxicity, including Cd36, Nqo1, Aldoa, Txnrd1, Scd1 and Ccng1, as well as miR-192, miR-193a and miR-125b and were most pronounced in female B6C3F1 mice. Body weight loss, observed at week 1, was followed by weight gain throughout the feeding studies. These findings bolster safety and efficacy concerns for OEP-NF, and argue strongly for implementation of pre-market toxicity studies within the dietary supplement industry.
... Differences in hemodynamic outcomes are likely due to the caffeine dosage used in the products. Those studies that have reported significant elevations in HR or BP used higher dosages (200-450 mg) (Haller, Jacob, & Benowitz, 2004;Hoffman et al., 2006) compared to those studies that reported no change (100-150 mg) (Campbell et al., 2016;Dulloo et al., 40 1989). ...
The increasing interest in weight loss has seen a concurrent rise in the supplemental use of thermogenics to aid weight loss efforts. To date, the effectiveness and safety of supplemental proprietary blend thermogenics, in conjunction with high-protein energy-restricted diets have not been thoroughly evaluated. The purpose of this study was to investigate the efficacy of a low-calorie, high-protein diet with and without the concomitant use of a thermogenic supplement on body weight and body composition in apparently healthy females. Subjects were divided into three groups, Bizzy Diet+FitMiss Burn (BURN, N = 12), Bizzy Diet+Placebo (PLA, N = 13), and Control (CON, N = 14), and underwent two testing sessions separated by approximately 3 weeks. Resting blood pressure (BP), resting heart rate (RHR), clinical safety markers, body weight (BW), and body composition were assessed during each testing session. Repeated measures analysis of variance (ANOVA) revealed a significant effect for time relative to BW, total body fat mass (FM), leg FM, and trunk FM. Post hoc analysis revealed that the BURN and PLA groups experienced significant decreases in both BW and total body FM compared to CON (p <.05). There were no significant interactions for BP, RHR, or clinical safety markers over the course of the study. The Bizzy Diet, both with and without the addition of FitMiss Burn thermogenic, appears to be safe for short-term use and may lead to greater improvement in body composition and BW in an apparently healthy female population.
... Caffeine was used in order to increase fat loss, due to its supposedly thermogenic effect. However, previous studies reported that caffeine alone offers no benefits over a placebo in thermogenesis 114,115 and fat loss. 116,117 The only evidence for a positive effect of caffeine on body composition seems to be when combined with ephedrine. ...
The purpose of this study was to report and analyze the practices adopted by bodybuilders in light of scientific evidence and to propose evidence-based alternatives. Six (four male and two female) bodybuilders and their coaches were directly interviewed. According to the reports, the quantity of anabolic steroids used by the men was 500–750 mg/week during the bulking phase and 720–1160 mg during the cutting phase. The values for women were 400 and 740 mg, respectively. The participants also used ephedrine and hydrochlorothiazide during the cutting phase. Resistance training was designed to train each muscle once per week and all participants performed aerobic exercise in the fasted state in order to reduce body fat. During the bulking phase, bodybuilders ingested ~2.5 g of protein/kg of body weight. During the cutting phase, protein ingestion increased to ~3 g/kg and carbohydrate ingestion decreased by 10–20%. During all phases, fat ingestion corresponded to ~15% of the calories ingested. The supplements used were whey protein, chromium picolinate, omega 3 fatty acids, branched chain amino acids, poly-vitamins, glutamine and caffeine. The men also used creatine in the bulking phase. In general, the participants gained large amounts of fat-free mass during the bulking phase; however, much of that fat-free mass was lost during the cutting phase along with fat mass. Based on our analysis, we recommend an evidence-based approach by people involved in bodybuilding, with the adoption of a more balanced and less artificial diet. One important alert should be given for the combined use of anabolic steroids and stimulants, since both are independently associated with serious cardiovascular events. A special focus should be given to revisiting resistance training and avoiding fasted cardio in order to decrease the reliance on drugs and thus preserve bodybuilders' health and integrity.
... Although ephedrine has been banned or restricted in several countries, it can be found in some formulations due to adulterations to improve product performance (Schmitt et al., 2012). Caffeine, a stimulant with α-adrenergic-like properties, acts on cardiovascular system (Kalman et al., 2002) and may enhance the effects of sympathomimetics such as ephedrine (Astrup et al., 1992;Haller et al., 2004) and probably synephrine (Schmitt et al., 2012) because their structural similarities (Pellati and Benvenuti, 2007). ...
The association of p-synephrine, ephedrine, salicin, and caffeine in dietary supplements and weight loss products is very common worldwide, even though ephedrine has been prohibited in many countries. The aim of this study was to evaluate a 28-day oral exposure toxicity profile of p-synephrine, ephedrine, salicin, and caffeine mixture (10:4:6:80 w/w respectively) in male and female Wistar rats. Body weight and signs of toxicity, morbidity, and mortality were observed daily. After 28 days, animals were euthanized and blood collected for hematological, biochemical, and oxidative stress evaluation. No clinical signs of toxicity, significant weight loss or deaths occurred, nor were there any significant alterations in hematological parameters. Biochemical and oxidative stress biomarkers showed lipid peroxidation, and hepatic and renal damage (p < 0.05; ANOVA/Bonferroni) in male rats (100 and 150 mg/kg) and a reduction (p < 0.05; ANOVA/Bonferroni) in glutathione (GSH) levels in all male groups. Female groups displayed no indications of oxidative stress or biochemical alterations. The different toxicity profile displayed by male and female rats suggests a hormonal influence on mixture effects. Results demonstrated that the tested mixture can alter oxidative status and promote renal and hepatic damages. © 2016, Faculdade de Ciencias Farmaceuticas (Biblioteca). All rights reserved.
... It is possible that caffeine exerts a significant effect on body weight loss a) when body weight is above the normal range, such as in overweight or obese individuals; b) when it is associated with other synergistic compounds, such as ephedrine; c) when it is associated to physical activity (GREENWAY, 2001;HALLER et al., 2004;HINO et al., 2007;MAGKOS;KAVOURAS, 2004;MELLO et al., 2007). ...
This work aimed at verifying the effect of the chronic ingestion of caffeine on body weight and adiposity of Wistar rats. Sixteen male Wistar rats weighting on average 240 g were divided into two groups, one control and the other caffeine-treated (5 mg kg-1, orally) for five weeks. At the end, the groups were evaluated for their differences in body weight; weight of the periepididymal, retroperitoneal, subcutaneous and mesenteric fat pads; size of the retroperitoneal adipocytes; liver and heart weight; glycemia and plasma lipids. Statistically significant differences were observed in adipocyte size and total serum cholesterol, while the results for the other parameters were not statistically different. Therefore, this study showed that, using an oral dose of caffeine within acceptable (non toxic) limits, it is possible to reduce the size of adipocytes of non-obese Wistar rats, as well as to reduce the serum cholesterol levels, even in the absence of physical activity or other active compounds.
... With ephedrine, the blood pressure increasing effects have been seen in humans after a single oral dose of 25-60 mg. [30,31]. The slow oral absorption of DMAA means a blood pressure increasing effect is expected after a single dose of up to about 100 mg. ...
... En presencia de alcalosis metabólica, como en nuestro caso, la concentración de cloro disminuye para compensar la elevación de bicarbonato, y el AG aumenta en proporción a la severidad de la alcalosis, debido al lactato y a la concentración de proteínas séricas más aniónicas. A su vez, el riñón tiende a aumentar la excrección de bicarbonato a nivel del túbulo proximal y distal donde hay un intercambio Cl -/HCO 3 es un indicador de la acidificación urinaria, valores positivos indican que la acidificación renal está intacta. El tratamiento ha de ser por vía oral. ...
... Metabolite 356, an ephedra-containing product, was the top selling dietary supplement with $70 million in sales a few years ago. However, due to its severe CNS related side effects, the drug was withdrawn from the market [48,49]. ...
Obesity has reached epidemic proportions globally, with more than 1 billion adults overweight - at least 300 million of them clinically obese. In Ayurveda, obesity is called 'medoroga'. The detailed features and treatments of the disease have been described in an old Ayurvedic text, Charak and Sushrut Samhita. There are some native plants that are commonly used for the treatment of obesity in Ayurveda. Unfortunately, only few medications are available in the market, with side effects and unacceptable efficacy. With the current view that botanical drugs can be developed faster and more cheaply than conventional single entity pharmaceuticals, the review mainly focuses on the rationality of their use with appropriate literature data support.
... Dietary supplements containing ephedrine-type alkaloids often include other agents including stimulants, diuretics and cathartics (CANTOX, 2000). The synergistic interaction between ephedrine-type alkaloids and caffeine is well known (Haller et al., 2004). Therefore, it may also be useful to evaluate the interaction between ephedrine-type alkaloids and other functional compounds using this MTT cytotoxicity assessment. ...
... Theobromine, however, at the therapeutic dose of 500 mg/kg has been used in the treatment of cardiac oedema and angina pectoris [Eteng & Ettarh, 2000]. Methylxanthines exert a strong impact on the operation of central and peripheral nervous system [Mandel, 2002], cerebral blood fl ow and metabolism, cardiovascular system, respiratory and renal systems and gastrointestinal system [Greenway et al., 2004;Haller et al., 2004;Ruhl & Everhart, 2005;Westerterp-Plantenga et al., 2006]. There are several recent lines of evidence suggesting that methylxanthines stimulate thermogenesis, promote weight and fat loss [Greenway et al., 2004], as well as inhibit various enzymes, such as PDE, PLA 2 [Mandel, 2002] and chitinase [Rao et al., 2005]. ...
Methylxanthines such as caffeine, theobromine and theophylline are intensively consumed as food components by large proportion of human population all over the world. This class of compounds show various biological activties and have been found to act as broad specificity inhibitors towards numerous enzymes. However, their action on digestive enzymes have not been yet investigated. In this paper we aimed to evaluate the effects of methylxanthines on the human pancreatic lipase activity in vitro. Emulsions of short- and long-chain triglycerides (tributyrin and tripalmitate, respectively) were used as substrates. The concentrations of methylxanthines in the reaction mixtures covered the range between 0.015 mmol/L to 15 mmol/L. We demonstrated that all three tested substances, caffeine, theophylline and theobromine inhibited the hydrolysis of tributyrin and tripalmitate catalysed by human pancreatic lipase in dose-dependent fashion. The highest lipase inhibition ratios during tripalmitate and tributyrin hydrolysis were 25.74% and 79.54% respectively in the presence of caffeine, 29.89% and 62.79% respectively with theophylline and 21.08% and 67.74% respectively in the presence of theobromine. All the tested methylxanthines exert stronger inhibition in the short-chain triglyceride lipolysis comparing to long-chain substrates. Their mechanism of action involves most likely the interaction with enzyme protein but not substrate emulgation. In case of tripalmitate lipolysis all the methylxanthines showed mixed type of inhibition. Interestingly, during tributyrin lipolysis theophylline behaved as classical noncompetitive inhibitor. © Copyright by Institute of Animal Reproduction and Food Research of the Polish Academy of Sciences.
... Wszystkie wykazują szerokie działanie farmakologiczne, do którego należy stymulacja centralnego układu nerwowego i ośrodków wegetatywnych, głównie naczynioworuchowego i oddechowego [17] oraz zmniejszanie napięcia mięśni gładkich naczyń krwionośnych [16]. Znanych jest szereg dowodów świadczących, że przyjmowane wraz z dietą kofeina, teofilina i teobromina przyspieszają lipolizę komórkową [12,27] i stymulują termogenezę [10,3], a w konsekwencji prowadzą do zmniejszenia masy ciała [27,3]. Istnieją także przesłanki pozwalające sądzić, że związki te dzięki właściwościom inhibitującym wobec niektórych enzymów [22,27] oraz chelatowaniu jonów metali [20,14] mogą ograniczać biodostępność przynajmniej niektórych składników diety. ...
The effect was assessed of the N-methylxanthines: caffeine, theophylline, and theobromine, commonly consumed with the diet, on the emulsification of butter lipids and bioavailability thereof under the in vitro simulated conditions of human stomach and intestines. The research material was farmhouse butter containing a 40 μmol/1g addition of the tested compounds. Based on the results obtained, it was found that, in the dose analyzed, each of the alkaloids intensified the process of forming the emulsion by increasing the dispersion degree thereof. The power of the pro-emulsifying activity of alkaloids depended on the arrangement of methyl groups in a molecule and increased according to the order: 1,3-dimethylxanthine (theophylline) → 1,3,7-thrimethylxanthine (caffeine) → 3,7-dimethylxanthine (theobromine). At the same time, each of the alkaloids significantly reduced the bioavailability of lipids. In the case of theophylline, the amount of fatty acids and glycerol, released from the lipids, decreased by 9% on the average compared to the control sample; in the case of caffeine: by 16%, and as for the theobromine by as much as 27%. The results as indicated above suggest that under the conditions of simulated digestion of lipids in the alimentary canal, the alkaloids must have impacted not only the hydrophobic substrate that stimulated emulsification thereof, but, also, the pancreatic lipase. In the latter case, they partially displaced the pancreatic lipase from the micelle's surface, and, thereby, reduced its direct contact with the substrate, and effectively inhibited it.
... Ephedra has additive effects on several decongestants and stimulants, increasing stimulation, heart rate and the possibility of palpitations. 103 In contrast, Ephedra antagonises the effects of antihyopertensives and beta blockers, increasing the blood pressure. ...
Background: Plants have been used therapeutically for thousands of years and continue to be the main treatment
modality for a large percentage of the world’s population. Furthermore, herbal medicine usage is increasing in
Western countries as complementary (and sometimes alternative) treatments in conjunction with allopathic medicine.
At the same time, the usage of allopathic medicines is being increasingly incorporated into the medicinal systems of
developing countries, often resulting in the concurrent usage of both systems. Importance of the Study: Despite the
widespread usage in developing countries and the trend of increasing medicinal plant usage in Western countries,
herbal medicines remain understudied and there are misunderstandings amongst users and practitioners about the
safe usage of these medications, particularly when used in conjunction with other medicines. Herbal medicines
are generally not held to the same rigorous standards as allopathic medicines. There is usually a lack of industry
regulation and manufacturing standards and guidelines, resulting in inferior (or unsafe) medicines being sold to
consumers. Similarly, there is a lack of understanding amongst many medical practitioners of both traditional and
allopathic medicine systems of how drugs from the two systems can be safely used together. Aim: The aim of this
review is to summarise the current knowledge about herbal medicines and how they can be used safely, with the
aim of not only highlighting some of the unsafe uses, but also to stimulate further research. I have also aimed to
highlight the need for greater regulation and standardisation of herbal medicines.
... Em humanos, foram relatados casos de infarto agudo do miocárdio (Nykamp, Fackih e Compton, 2004), isquemia (Bouchard et al., 2005), angina variante (Gange et al., 2006), possivelmente associados aos suplementos contendo C. aurantium ou sinefrina. O aumento da pressão sanguínea foi relatado quando a C. aurantium foi associada à cafeína (Haller, Jacob e Benowitz, 2004). ...
A etnobotânica é uma importante ferramenta para a identificação de espécies da Flora utilizada por comunidades tradicionais para fins medicinais, contribuindo também para a preservação da cultura popular. Esse estudo objetivou avaliar a relação entre o uso de plantas medicinais e a busca por saúde nas comunidades quilombolas da Barra e Bananal, Rio de Contas-BA. O levantamento etnobotânico foi realizado através de entrevistas semi-estruturadas, aplicação de formulários e observação participante a fim de identificar o uso de plantas para fins medicinais. Os sinais e sintomas de doenças citadas para as quais eram utilizadas plantas foram organizados em categorias baseadas na Classificação Internacional de Doenças proposta pela OMS. Foram citadas 71 espécies vegetais sendo Mentha spicata, a mais citada (8,5%) e a família Lamiaceae a mais representativa. As comunidades utilizam principalmente as folhas (55,3%), na forma de chá (64%). A maioria das plantas (62,5%) é obtida nos quintais das casas e cerca de 24% são coletadas em diferentes áreas da região. O maior número de espécies foi indicado para aliviar sintomas em geral (31,5%) seguidos pelos problemas relacionados aos sistemas respiratórios (24,3%) e gastrointestinais (15,8%). As comunidades estudadas fazem intenso uso de plantas medicinais, possuindo amplo conhecimento acerca desses recursos.
... The stimulant properties of ephedrine are well established and the alkaloid has been exploited in numerous over the counter (OTC) medicines [5]. Another problem that has arisen in recent years has been its potential of drug to impair driving ability [5][6][7][8]. This concern is compounded by the exploitation of ephedrine's stimulant properties by transport workers, especially those involved in long distance routes, where they can be used to alleviate the effects of fatigue [7]. ...
A polymer modified glassy carbon electrode was fabricated by electropolymerizing 4-amino-3-hydroxynaphthalene sulfonic acid (AHNSA) in a 0.1 M HNO 3 and was characterized by cyclic voltammetry. The polymer modified electrode showed an excellent electrocatalytic activity towards the electrochemical oxidation of ephedrine. The oxidative peak current response of ephedrine at the polymer modified-glassy carbon electrode was found to show linear dependence on the concentration of ephedrine in the range of 8.0×10 -6 to 1.0×10 -3 mol L -1 with a linear regression equation, correlation coefficient and limit of detection (according to S/N=3; for n=4) of Ip a (µA)=0.971+0.042 C (µM), 0.99913 and 7.9×10 -7 M, respectively. The proposed method was tested for the determination of ephedrine in human urine. Recoveries ranging between 92.06–93.15% for filtered and 81.15–86.30% for unfiltered human urine were achieved validating the developed method.
... One of the most widely consumed central nervous system (CNS) stimulants worldwide, caffeine, is generally perceived by the public to be safe and lacking long-term medical problems. 14 However, caffeine has been shown to exacerbate the stimulant and pressor effects of ephedrine, 15 phenylpropanolamine, 16 amphetamine, 17 and other adrenergic agents. 17,18 Recent studies have also shown that ephedrine, particularly that in the form of Ma Huang (Ephedra), in combination with caffeine can produce myocardial necrosis as well as other structural changes in the heart. ...
Cigarette smokers have an increased risk for coronary artery disease. Nicotine present in cigarettes can adversely affect the cardiovascular system via stimulation of both sympathetic and parasympathetic neurons. Caffeine, another cardiovascular and central nervous system (CNS) stimulant, is commonly found in Ephedra and Ephedra-free dietary supplements. These caffeine-containing supplements also have been linked to cardiovascular toxicities. Although no longer on the U.S market, Ephedra-containing supplements are another source of cardiovascular and CNS stimulants, namely the ephedrine alkaloids. Together caffeine, nicotine, and ephedrine can individually stress the cardiovascular system, and an overlap of these agents is predicted in smokers and dieters. To understand the collective effects of these stimulants on the heart morphology and ultrastructure, rats were exposed to synthetic combinations of nicotine (0.2 mg/kg/day), ephedrine (0-30 mg/kg/day), and/or caffeine (0-24 mg/kg/day) as well as an extract from a caffeine-containing Ephedra supplement (Metabolife 356). After exposure for 3 days, the hearts were removed and examined for hypersensitivity myocarditis and myocardial necrosis. None of the drugs tested alone affected heart tissue morphology, nor were atypical cardiac cells observed. However, in combination, significant interactions were found between caffeine and ephedrine; the interventricular septum was most susceptible, with a significant increase in atypical cardiac cells observed. Nicotine pretreatment caused greater susceptibility to cardiotoxicity associated with combinations of caffeine + ephedrine or Metabolife, particularly in the left ventricle wall. These results indicate that sympathomimetic combinations present in Ephedra supplements may have produced cardiotoxicity reported in consumers of these products. Moreover, the presence of nicotine exacerbates these toxic effects.
... Specifically, heart rate and blood pressure were increased in response to treatment, with the obvious increase in the calculated rate pressure product. Although such changes are common with weight loss supplements, [21][22][23][24][25][26][27] in particular for those including caffeine and other stimulants, some caution should be advised when using this and similar products. This is particularly true for individuals who are hypertensive (resting blood pressure $140/90 mmHg) or for those who are pre-hypertensive (resting blood pressure $120/80 mmHg). ...
Dietary supplements are often marketed to increase lipolysis and thermogenesis, with the proposed end result being weight loss and body fat reduction. It was the purpose of the present investigation to study the acute effects of a weight/fat loss supplement within a sample of healthy human subjects.
Twelve subjects (men 24.8 ± 4.3 yrs; women 22.8 ± 0.4 yrs) ingested a dietary supplement (OxyELITE Pro™) or a placebo, on two separate days in a double-blind, cross-over design. Blood samples were collected immediately before ingestion, and at 60 and 120 minutes post ingestion, and analyzed for plasma glycerol and free fatty acids (FFA). Breath samples were collected immediately before ingestion and at 30, 60, 90, and 120 minutes post ingestion, for a measure of kilocalorie expenditure using indirect calorimetry. Area under the curve (AUC) was calculated. Heart rate and blood pressure were recorded at all times and rate pressure product (RPP) was calculated.
AUC was greater for supplement compared to placebo for glycerol (22.74 ± 1.98 μg · mL(-1) · 2 hr(-1) vs. 15.76 ± 1.36 μg · mL(-1) · 2 hr(-1); P = 0.001), FFA (1.62 ± 0.07 mmol · L(-1) · 2 hr(-1) vs. 0.78 ± 0.12 mmol · L(-1) · 2 hr(-1); P < 0.0001), and kilocalorie expenditure (149 ± 7 kcal · 2 hr(-1) vs. 122 ± 8 kcal · 2 hr(-1); P = 0.005). Heart rate (P = 0.02), systolic blood pressure (P < 0.0001), and RPP (P = 0.002) were higher for supplement compared to placebo.
Ingestion of OxyELITE Pro™ resulted in an increase in blood markers of lipolysis, as well as metabolic rate, during a two-hour post ingestion time period. An increase in hemodynamic variables was also observed. These findings are in reference to a sample of healthy men and women who were naïve to treatment with the dietary supplement. Additional work is needed to determine if the acute changes observed here would persist with chronic use of the supplement and possibly lead to weight/body fat loss over time.
... The incidence of metabolic diseases and obesity is considered a worldwide epidemic (Haller et al. 2004). In this context, so-called "natural" dietary supplements have become very popular, with stimulants being one of the most used pharmacological classes. ...
A reverse-phase (RP)-HPLC method is reported for determining L-tyrosine, p-octopamine, synephrine, tyramine and hordenine as chemical markers of the species Citrus aurantium in raw material, dry extracts and phytotherapeutic herbal formulations. Using RP-HPLC with diode array detection (DAD) and gradient elution, the amines were determined in 12 different products from different Brazilian states labelled as containing C. aurantium. The presence of the amines was confirmed by mass spectrometry using electrospray ionisation (ESI-MS/MS). This RP-HPLC method allowed the separation of the amines from complex mixtures containing caffeine, ephedrine, salicin and other raw materials (e.g. Garcinia camboja, Phaseolus vulgaris, Caralluma fimbriata, Cassia nomane, Ephedra sp. and Cordia ecalyculata). The method proved useful and selective for inspecting herbal medicines containing p-synephrine and structural analogues. The herbal products analysed had a p-synephrine content ranging from 0.005 to 4.0% (w/w).
Adverse drug reactions (ADRs) are multifactorial phenomena, and predisposing factors for ADRs can be considered components of a constellation of causes, including the drug, needed for an ADR to be induced. The identification of the predisposing factors for ADRs is an important task of pharmacovigilance, as it may contribute to prevent the occurrence of ADRs. There are four types of predisposing factors: (1) those related to patient characteristics (e.g., age, sex, ethnicity, genetics); (2) those related to the underlying diseases or comorbidities (e.g., renal failure, liver disorders, metabolic disorders); (3) those related to environmental and lifestyle factors (e.g., smoking, alcohol consumption, caffeine use); and (4) those related to the concomitant use of other drugs (e.g., drug–drug interactions, polypharmacy). Predisposing factors interact with the drug to increase the risk of presenting an ADR, and the best tools to identify them are analytical epidemiological studies. Through them, it is possible to estimate the measures of a drug–event association and then assess which factors may strengthen such an association. Once a predisposing factor has been identified, it is necessary to translate this information into appropriate regulatory measures in order to minimize the risk of ADRs. In this context, health-care professionals play a crucial role in implementing risk minimization measures, informing patients, and monitoring the results.
Central stimulatory and hallucinogenic drugs of abuse like amphetamine and most congeners of amphetamine can have cardiac harmful effects. These cardiac side effects can lead to morbidities and death. In this paper, we review current knowledge on the direct and indirect effects of these amphetamine congeners on the mammalian heart—more specifically, the isolated human heart muscle preparation. In detail, we address the question of whether and how these drugs affect cardiac contractility and their mechanisms of action. Based on this information, further research areas are defined, and further research efforts are proposed.
Alkaloids are a type of secondary metabolites that can be found in different parts of plants. This group of compounds is diverse and can be divided into nine subgroups: pyridine, tropane, isoquinoline, phenanthrene, phenylethylamine, indole, purine, imidazole, and terpenoids. Most of these compounds are recognized for their anti-inflammatory, antitumor, antibacterial, antifungal, and antiviral activities, among others. Although more than 27,000 alkaloids have been described up to date, the search for novel compounds with promising therapeutic properties is a hot topic among researchers worldwide. In this line, the production of the currently marketed plant alkaloids including extraction methods, isolation, and purification is reviewed in this chapter. In addition, a deep description of different groups of alkaloids in terms of their chemical structure, plant source, and uses is also presented. Recent advances in the therapeutic potential and biological activities of this vast group of phytochemicals are also included.
Background: Type II diabetes is considered as one of the common diseases. Bangpungtongseong-san (BPS) has been used as a traditional medicine for treating obesity and hypertension in Korea. According to previous reports, it has anti-obesity, anti-chronic asthma, anti-oxidant, and anti-inflammatory properties. However, the effects of BPS on type II diabetes have not yet been eluci-dated. Thus, in this sutudy, we evaluated the water extracts of BPS using type II diabetes animal models. Methods and Results: Each group was orally administered with BPS (170, 850 and 1,700 ㎎/㎏) for approximately 13 weeks. A mixture of 150 ㎎/㎏ metformin and 10 ㎎/㎏ sitagliptin (MS) was used as a positive control. The glycated hemoglobin (HbA1c) and glucose levels, and hematologi-cal parameters including blood urine nitrogen, creatinine, low density lipoprotein and total choles-terol, were measured using blood samples. Treatment with 170 ㎎/㎏ BPS decreased the HbA1c and glucose levels in blood without affecting the weights of the animals. However, threatment with 1,700 ㎎/㎏ BPS reduced the weights and fatty liver, and increased the blood glucose level in type II diabetes animal models Conclusions: These results indicate that a low dose of BPS for 13 weeks, which reduces HbA1c and blood glucose levels, could be used for the treatment of type II diabetes. However, further studies are required to elucidate how active ingredients of BPS influence HbA1c and glucose levels in blood. © 2020, Korean Society of Medicinal Crop Science. All rights reserved.
The popularity of pre-workout supplements is rising amongst professional athletes and fitness enthusiasts. Despite increased usage, the safety profile of pre-workout supplements is likely to be not well understood. Additionally, many different brands use various undisclosed proprietary blends of active ingredients creating safety regulation difficulties. This lack of oversight could prove unsafe for certain patients. This patient MK is a 33-year-old healthy housewife who presented with central chest tightness, pre-syncope and mild dyspnoea to the emergency department via ambulance. The presentation was in the context of recent strenuous exercise and ingestion of a pre-workout supplement (Alpha Lean-7). Most striking in her presentation was a troponin rise of 50 ng/L, while not very high it is unusual given her lack of cardiac risk factors. She had a 3-day uneventful admission with a downtrending troponin prior to discharge. This case highlights the possible dangers of pharmacologically active ingredients in pre-workout supplements.
Numerous food supplements contain phytochemical compounds as active ingredients. Though such supplements are often perceived by consumers as being risk-free, the safety of many of them is currently uncertain. The present review provides two examples for risk assessment for phytochemical ingredients which are used in certain supplements marketed for sportspeople – synephrine (extracted from fruits of Citrus aurantium) and hydroxycitric acid (HCA, isolated from fruits of Garcinia cambogia). Animal and human studies as well as case reports provide evidence for cardiovascular effects due to ingestion of high synephrine doses, especially in combination with caffeine and physical exertion. A dose of up to 6.7 mg synephrine/day, however, which is equivalent to the median dietary intake from conventional foods in Germany, is presumed to represent a safe intake from supplements. In subchronic animal studies, administration of high doses of certain HCA-containing preparations led to testicular toxicity (i. e. testicular atrophy and impaired spermatogenesis), yielding a NOAEL of 389 mg HCA/kg bw and day. In view of lack of adequate human data on the safety of HCA-preparations, particularly with respect to the human male reproductive system, substantial uncertainties exist regarding the safety of supplements containing high amounts of HCA. This article is protected by copyright. All rights reserved
Weight reduction has been shown to improve glycemic control and cardiovascular risk factors associated with insulin resistance in obese individuals with type 2 diabetes mellitus. Therapeutic options for these patients include promoting weight loss (non-pharmacologic and pharmacologic treatment) and improving glycemic control, as well as treating common associated risk factors such as arterial hypertension and dyslipidemias. This article provides an overview of anti-obesity drugs used in the treatment of obese individuals with type 2 diabetes. The most widely investigated drugs, sibutramine and orlistat, result in modest, clinically worthwhile weight loss, with demonstrable improvements in many co-morbidities, among them, type 2 diabetes. Clinical trials with these anti-obesity medications in cohorts of obese diabetic patients have been reviewed as well as cathecolaminergic agents (diethylpropion [amfepramone], fenproporex, mazindol, ephedrine-caffeine combination), serotoninergic drugs (fenfluramine, dexfenfluramine, fluoxetine), and other drugs that have some action on weight loss (the antidiabetic agent metformin, anti-epileptic agents topiramate and zonisamide, and the antidepressive bupropion [amfebutamone]). These trials show variable benefits in terms of effects on glucose profiles.
Background: Caffeine is one of the most widely used ergogenic aids worldwide. Recently, caffeine has been combined with 1,3-dimethylamylamine (1,3-D) in an attempt to improve exercise performance and related variables. We investigated the effect of caffeine and 1,3-D alone and in combination on exercise performance and blood markers of lipolysis and oxidative stress.
Methods: Twelve exercise-trained subjects ingested placebo, caffeine (4 mg·kg⁻¹), 1,3-D (1 mg·kg⁻¹), or caffeine+ 1,3-D, 60 minutes before completing a 10 km run. Blood was collected before intake, immediately pre-exercise, and at 5 and 30 minutes postexercise. Samples were analyzed for glycerol, free fatty acids (FFAs), malondialdehyde, nitrate/nitrite, and trolox equivalent antioxidant capacity (TEAC).
Results: Run time (minutes) was not different for placebo (52.55±1.96), caffeine (52.00±1.88), 1,3-D (52.02±1.86), or caffeine+ 1,3-D (52.46±1.94) (p>0.05). Glycerol and FFA were higher 5 and 30 minutes postexercise compared with pretreatment and pre-exercise (p<0.05). A condition effect was noted for glycerol (p=0.01), with higher values for 1,3-D compared with caffeine+ 1,3-D (p<0.05). A condition effect was noted for TEAC (p=0.0001), with higher values for placebo compared with caffeine and caffeine+ 1,3-D, and higher values for 1,3-D compared with caffeine (p<0.05). No other effects were noted for any measured variable (p>0.05).
Conclusion: We report for the first time that caffeine+ 1,3D does not improve exercise performance as measured by run time. Isolated ingestion of 1,3-D results in the greatest increase in postexercise glycerol and FFA. Caffeine or 1,3-D alone or in combination does not differently affect oxidative stress biomarkers.
Some dietary supplements may contain cardiac stimulants and potential cardiotoxins. In vitro studies may identify ingredients of concern. A beating human cardiomyocyte cell line was used to evaluate cellular effects following phenylethylamine (PEA), higenamine, ephedrine or caffeine treatment. PEA and higenamine exposure levels simulated published blood levels in humans or animals after intravenous administration. Ephedrine and caffeine levels approximated published blood levels following human oral intake. At low or midrange levels, each chemical was examined plus or minus 50 uM caffeine, simulating human blood levels reported after consumption of caffeine-enriched dietary supplements. To measure beats per minute (BPM), peak width, etc., rhythmic rise and fall in intracellular calcium levels following 30 min of treatment was examined. Higenamine 31.3 ng/ml or 313 ng/ml significantly increased BPM in an escalating manner. PEA increased BPM at 0.8 and 8 ug/ml, while 80 ug/ml PEA reduced BPM and widened peaks. Ephedrine produced a significant BPM dose response from 0.5 to 5.0 uM. Caffeine increased BPM only at a toxic level of 250 uM. Adding caffeine to PEA or higenamine but not ephedrine further increased BPM. These in vitro results suggest that additional testing may be warranted in vivo to further evaluate these effects.
Published by Elsevier Ltd.
1,3-dimethylamylamine (a constituent of geranium), alone and in combination with caffeine, is widely used within dietary supplements. We have recently determined the hemodynamic effects of 1,3-dimethylamylamine and caffeine alone and in combination, using a single ingestion study. However, no study has determined the hemodynamic effects of these ingredients following chronic use. Moreover, no study has determined the effects of these ingredients on bloodborne variables related to health and safety. Therefore, the purpose of this investigation was to assess the hemodynamic and hematologic profile of two different dietary supplements containing 1,3-dimethylamylamine and caffeine (in addition to other ingredients), before and after two weeks of daily intake.
7 men (24.9 ± 4.2 yrs) ingested the dietary supplement Jack3d™, while 4 men and 2 women (22.5 ± 1.8 yrs) ingested the dietary supplement OxyELITE Pro™ once per day for two weeks. On days 1 and 15, resting heart rate (HR), systolic (SBP), and diastolic (DBP) blood pressure were measured and rate pressure product (RPP) was calculated. Fasting blood samples were analyzed for complete blood counts, comprehensive metabolic panel, and lipid panel. These tests were done prior to ingestion of supplement. On days 1 and 15 following blood collection, subjects ingested the assigned supplement (2 servings) and HR, SBP, DBP, and RPP were recorded at 30, 60, 90, and 120 minutes post-ingestion.
After 14 days of treatment, resting HR, SBP, DBP, and RPP were not increased (P > 0.05). No significant changes were noted in any measured bloodborne variable, with the exception of an increase in fasting blood glucose with ingestion of Jack3d™ (P = 0.02). In response to acute intake of the supplements, HR, DBP, and RPP were not increased statistically (P > 0.05). SBP was increased with OxyELITE Pro™ (P = 0.03), but not with Jack3d™ (P = 0.09). Compared to pre-ingestion and in general, both supplements resulted in an increase in SBP, DBP, and RPP from 5%-15%, with a peak occurring at the 60 or 90 minute post-ingestion time.
Acute ingestion of OxyELITE Pro™, but not Jack3d™, results in an increase in SBP. Chronic intake of two servings per day of OxyELITE Pro™ or Jack3d™ over a 14 day period does not result in an elevation in resting HR, SBP, DBP, or RPP. No significant changes are noted in any measured bloodborne variable following 14 days of ingestion, with the exception of blood glucose with Jack3d™. Longer term intervention studies inclusive of larger sample sizes are needed to extend these findings.
Background: 1,3-dimethylamylamine (a constituent of geranium), alone and in combination with caffeine, is widely used within dietary supplements. We have recently determined the hemodynamic effects of 1,3-dimethylamylamine and caffeine alone and in combination, using a single ingestion study. However, no study has determined the hemodynamic effects of these ingredients following chronic use. Moreover, no study has determined the effects of these ingredients on bloodborne variables related to health and safety. Therefore, the purpose of this investigation was to assess the hemodynamic and hematologic profile of two different dietary supplements containing 1,3-dimethylamylamine and caffeine (in addition to other ingredients), before and after two weeks of daily intake. Methods: 7 men (24.9 ± 4.2 yrs) ingested the dietary supplement Jack3d™, while 4 men and 2 women (22.5 ± 1.8 yrs) ingested the dietary supplement OxyELITE Pro™ once per day for two weeks. On days 1 and 15, resting heart rate (HR), systolic (SBP), and dia-stolic (DBP) blood pressure were measured and rate pressure product (RPP) was calculated. Fasting blood samples were analyzed for complete blood counts, comprehensive metabolic panel, and lipid panel. These tests were done prior to ingestion of supplement. On days 1 and 15 following blood collection, subjects ingested the assigned supplement (2 servings) and HR, SBP, DBP, and RPP were recorded at 30, 60, 90, and 120 minutes post-ingestion. Results: After 14 days of treatment, resting HR, SBP, DBP, and RPP were not increased (P . 0.05). No significant changes were noted in any measured bloodborne variable, with the exception of an increase in fasting blood glucose with ingestion of Jack3d™ (P = 0.02). In response to acute intake of the supplements, HR, DBP, and RPP were not increased statistically (P . 0.05). SBP was increased with OxyELITE Pro™ (P = 0.03), but not with Jack3d™ (P = 0.09). Compared to pre-ingestion and in general, both supplements resulted in an increase in SBP, DBP, and RPP from 5%–15%, with a peak occurring at the 60 or 90 minute post-ingestion time. Conclusion: Acute ingestion of OxyELITE Pro™, but not Jack3d™, results in an increase in SBP. Chronic intake of two servings per day of OxyELITE Pro™ or Jack3d™ over a 14 day period does not result in an elevation in resting HR, SBP, DBP, or RPP. No signifi-cant changes are noted in any measured bloodborne variable following 14 days of ingestion, with the exception of blood glucose with Jack3d™. Longer term intervention studies inclusive of larger sample sizes are needed to extend these findings.
Objective: This study was undertaken to determine the effects of an ephedrine- and synephrine-based compound on body mass, body composition, metabolic variables, and mood states in healthy overweight adults.Methods: Thirty subjects with a body mass index > 27 kg/m2 were assigned randomly to the experimental group or the placebo group. The experimental group received a capsule containing ephedrine alkaloids 20 mg, synephrine 5 mg, caffeine 200 mg, and salicin 15 mg twice daily for 8 weeks, whereas the other group received a matching placebo. A registered dietitian instructed all patients about a 22-kcal/kg National Cholesterol Education Program Step One diet. In addition, all patients performed a cross-training exercise program 3 days per week under the guidance of an exercise physiologist. During the exercise sessions, patients achieved ∼70% of age-predicted maximum heart rate.Results: The experimental group had a significantly greater weight loss compared with the placebo group (3.14 kg vs 2.05 kg, respectively; P < 0.05). The experimental group experienced a 16% decrease in body fat compared with a 1% increase for the placebo group. The between-group difference was significant (P = 0.005). Both groups achieved a significant reduction in fat-free mass; however, the reduction in the placebo group was greater than that of the experimental group. This suggests a muscle-sparing effect in the experimental group. No significant changes in blood pressure, serial electrocardiograms, pulse rate, serum chemistry, or caloric intake were noted.Conclusions: These findings indicate the apparent safety and efficacy of the ephedrine- and synephrine-based compound within the confines of this study.
The pharmacokinetic and pharmacodynamic interaction between caffeine and phenylpropanolamine has been investigated in six normal subjects in a double-blind, placebo-controlled, Latin-square design study. After 3 days on a 100 mEq sodium, xanthine-free diet, fasting subjects were placed in a supine position and were given 25 mg phenylpropanolamine and placebo, 250 mg caffeine and placebo, or 25 mg phenylpropanolamine and 250 mg caffeine in random order. Blood pressure, pulse, plasma renin activity, and plasma catecholamine levels were measured before and for 3 hours after drug administration. Plasma and urinary phenylpropanolamine, caffeine, and caffeine metabolite levels were measured serially for 48 hours. Coadministration of caffeine and phenylpropanolamine produced an additive increase in blood pressure. This effect could not be explained by any pharmacokinetic interaction between the two drugs and occurred even though phenylpropanolamine attenuated the epinephrine and renin response to caffeine. These data suggest that a clinically relevant interaction between caffeine and phenylpropanolamine does occur in drug-free subjects and that this interaction cannot be explained by a mechanism involving the sympathetic or renin-angiotensin systems.
This study investigated the effects of acute ingestion of caffeine (C), ephedrine (E) and their combination (C+E) on time to exhaustion during high-intensity exercise. Using a repeated-measures, double-blind design, eight male subjects exercised on a cycle ergometer at a power output that led to exhaustion after about 12.6 min during a placebo (P) control trial. They did this 1.5 h after ingesting either C (5 mg · kg−1), E (1 mg · kg−1), C+E, or P. Trials were separated by 1 week. Venous blood was sampled before and during exercise. The mean (SD) times to exhaustion were 12.6 (3.1) (P), 14.4 (4.1) (C), 15.0 (5.7) (E) and 17.5 (5.8) (C+E) min. Only the C+E treatment significantly increased time to exhaustion compared to P. Oxygen consumption (V˙O2), carbon dioxide production (V˙CO2), minute ventilation (V˙
E) and the respiratory exchange ratio (RER) were similar during exercise for all trials. Heart rate during exercise was significantly increased for the C+E and C trials compared to P. Subjective ratings of perceived exertion during exercise were significantly lower after C+E compared to P. All treatments significantly increased lactate levels. Free fatty acid (FFA) levels were significantly increased by C ingestion. Glycerol levels were increased by C+E and C ingestion. Glucose levels were also higher with the drug treatments compared to P. Increased monamine availability after C+E treatment was suggested by measurements of catecholamines and dopamine. In conclusion, the combination of C+E significantly prolonged exercise time to exhaustion compared to P, while neither C nor E treatments alone significantly changed time to exhaustion. The improved performance was attributed to increased central nervous system stimulation.
Effects of coffee on the gastrointestinal system have been suggested by patients and the lay press, while doctors tend to discourage its consumption in some diseases.
The literature on the effects of coffee and caffeine on the gastrointestinal system is reviewed with emphasis on gastrointestinal function.
Although often mentioned as a cause of dyspeptic symptoms, no association between coffee and dyspepsia is found. Heartburn is the most frequently reported symptom after coffee drinking. It is demonstrated that coffee promotes gastro-oesophageal reflux. Coffee stimulates gastrin release and gastric acid secretion, but studies on the effect on lower oesophageal sphincter pressure yield conflicting results. Coffee also prolongs the adaptive relaxation of the proximal stomach, suggesting that it might slow gastric emptying. However, other studies indicate that coffee does not affect gastric emptying or small bowel transit. Coffee induces cholecystokinin release and gallbladder contraction, which may explain why patients with symptomatic gallstones often avoid drinking coffee. Coffee increases rectosigmoid motor activity within 4 min after ingestion in some people. Its effects on the colon are found to be comparable to those of a 1000 kCal meal. Since coffee contains no calories, and its effects on the gastrointestinal tract cannot be ascribed to its volume load, acidity or osmolality, it must have pharmacological effects. Caffeine cannot solely account for these gastrointestinal effects.
Coffee promotes gastro-oesophageal reflux, but is not associated with dyspepsia. Coffee stimulates gallbladder contraction and colonic motor activity.
To examine in overweight humans the short-term safety and efficacy for weight loss of an herbal supplement containing Ma Huang, Guarana and other ingredients.
An 8 week randomized, double-blind placebo controlled study of a herbal dietary supplement (72 mg/day ephedrine alkaloids and 240 mg/day caffeine).
Overweight men and women (body mass index, > or =29 and < or =35 kg/m2).
The primary outcome variable was body weight change. Secondary variables included anthropometric, metabolic and cardiovascular changes.
Sixty-seven subjects were randomized to either placebo (n=32) or active Ma Huang/Guarana (n=35). Twenty-four subjects in each group completed the study. Active treatment produced significantly (P<0.006) greater loss of weight (X+/-s.d.,-4.0+/-3.4 kg) and fat (-2.1+/-3.0% fat) over the 8-week treatment period than did placebo (-0.8+/-2.4 kg and 0.2+/-2.3% fat). Active treatment also produced greater reductions in hip circumference and serum triglyceride levels. Eight of the 35 actively treated subjects (23%) and none of the 32 placebo-treated control subjects withdrew from the protocol because of potential treatment-related effects. Dry mouth, insomnia and headache were the adverse symptoms reported most frequently by the herbal vs placebo group at the final evaluation visit.
This herbal mixture of Ma Huang and Guarana effectively promoted short-term weight and fat loss. Safety with long-term use requires further investigation.
Caffeine is a central stimulant that increases the release of catecholamines. As a component of popular beverages, caffeine is widely used around the world. Its pharmacological effects are predominantly due to adenosine receptor antagonism and include release of catecholamines. We hypothesized that caffeine reduces insulin sensitivity, either due to catecholamines and/or as a result of blocking adenosine-mediated stimulation of peripheral glucose uptake.
Hyperinsulinemic-euglycemic glucose clamps were used to assess insulin sensitivity. Caffeine or placebo was administered intravenously to 12 healthy volunteers in a randomized, double-blind, crossover design. Measurements included plasma levels of insulin, catecholamines, free fatty acids (FFAs), and hemodynamic parameters. Insulin sensitivity was calculated as whole-body glucose uptake corrected for the insulin concentration. In a second study, the adenosine reuptake inhibitor dipyridamole was tested using an identical protocol in 10 healthy subjects.
Caffeine decreased insulin sensitivity by 15% (P < 0.05 vs. placebo). After caffeine administration, plasma FFAs increased (P < 0.05) and remained higher than during placebo. Plasma epinephrine increased fivefold (P < 0.0005), and smaller increases were recorded in plasma norepinephrine (P < 0.02) and blood pressure (P < 0.001). Dipyridamole did not alter insulin sensitivity and only increased plasma norepinephrine (P < 0.01).
Caffeine can decrease insulin sensitivity in healthy humans, possibly as a result of elevated plasma epinephrine levels. Because dipyridamole did not affect glucose uptake, peripheral adenosine receptor antagonism does not appear to contribute to this effect.
To examine long-term safety and efficacy for weight loss of an herbal Ma Huang and Kola nut supplement (90/192 mg/day ephedrine alkaloids/caffeine).
Six-month randomized, double-blind placebo controlled trial.
A total of 167 subjects (body mass index (BMI) 31.8+/-4.1 kg/m(2)) randomized to placebo (n=84) or herbal treatment (n=83) at two outpatient weight control research units.
Primary outcome measurements were changes in blood pressure, heart function and body weight. Secondary variables included body composition and metabolic changes.
By last observation carried forward analysis, herbal vs placebo treatment decreased body weight (-5.3+/-5.0 vs. -2.6+/-3.2 kg, P<0.001), body fat (-4.3+/-3.3 vs. -2.7+/-2.8 kg, P=0.020) and LDL-cholesterol (-8+/-20 vs. 0+/-17 mg/dl, P=0.013), and increased HDL-cholesterol (+2.7+/-5.7 vs. -0.3+/-6.7 mg/dl, P=0.004). Herbal treatment produced small changes in blood pressure variables (+3 to -5 mm Hg, P< or =0.05), and increased heart rate (4+/-9 vs. -3+/-9 bpm, P<0.001), but cardiac arrhythmias were not increased (P>0.05). By self-report, dry mouth (P<0.01), heartburn (P<0.05), and insomnia (P<0.01) were increased and diarrhea decreased (P<0.05). Irritability, nausea, chest pain and palpitations did not differ, nor did numbers of subjects who withdrew.
In this 6-month placebo-controlled trial, herbal ephedra/caffeine (90/192 mg/day) promoted body weight and body fat reduction and improved blood lipids without significant adverse events.
Ephedra and ephedrine sometimes are used for weight loss or enhanced athletic performance, but the efficacy and safety of these compounds are uncertain.
To assess the efficacy and safety of ephedra and ephedrine used for weight loss and enhanced athletic performance.
We searched 9 databases using the terms ephedra, ephedrine, adverse effect, side effect, efficacy, effective, and toxic. We included unpublished trials and non-English-language documents. Adverse events reported to the US Food and Drug Administration MedWatch program were assessed.
Eligible studies were controlled trials of ephedra or ephedrine used for weight loss or athletic performance and case reports of adverse events associated with such use. Eligible studies for weight loss were human studies with at least 8 weeks of follow-up; and for athletic performance, those having no minimum follow-up. Eligible case reports documented that ephedra or ephedrine was consumed within 24 hours prior to an adverse event or that ephedrine or an associated product was found in blood or urine, and that other potential causes had been excluded. Of the 530 articles screened, 52 controlled trials and 65 case reports were included in the adverse events analysis. Of more than 18 000 other case reports screened, 284 underwent detailed review.
Two reviewers independently identified trials of efficacy and safety of ephedra and ephedrine on weight loss or athletic performance; disagreements were resolved by consensus. Case reports were reviewed with explicit and implicit methods.
No weight loss trials assessed duration of treatment greater than 6 months. Pooled results for trials comparing placebo with ephedrine (n = 5), ephedrine and caffeine (n = 12), ephedra (n = 1), and ephedra and herbs containing caffeine (n = 4) yielded estimates of weight loss (more than placebo) of 0.6 (95% confidence interval, 0.2-1.0), 1.0 (0.7-1.3), 0.8 (0.4-1.2), and 1.0 (0.6-1.3) kg/mo, respectively. Sensitivity analyses did not substantially alter the latter 3 results. No trials of ephedra and athletic performance were found; 7 trials of ephedrine were too heterogeneous to synthesize. Safety data from 50 trials yielded estimates of 2.2- to 3.6-fold increases in odds of psychiatric, autonomic, or gastrointestinal symptoms, and heart palpitations. Data are insufficient to draw conclusions about adverse events occurring at a rate less than 1.0 per thousand. The majority of case reports are insufficiently documented to allow meaningful assessment.
Ephedrine and ephedra promote modest short-term weight loss (approximately 0.9 kg/mo more than placebo) in clinical trials. There are no data regarding long-term weight loss, and evidence to support use of ephedra for athletic performance is insufficient. Use of ephedra or ephedrine and caffeine is associated with increased risk of psychiatric, autonomic, or gastrointestinal symptoms, and heart palpitations.
The effects of caffeine (250 mg orally) on plasma free fatty acids (FFA), urinary catecholamines, and drug binding were studied in 16 normal subjects (six men, five women on oral contraceptives, and five women not on oral contraceptives). FFA doubled 1 hr after caffeine, and remained elevated for at least 4 hr, with elevation of each FFA. Urinary excretion of epinephrine and dopamine increased (p < 0.05) in the first 2 hr, returning to baseline in the next 2 hr. Plasma binding of chlordiazepoxide, diazepam, and propranolol was estimated in each of the hourly plasma samples after caffeine; there was no change in percent unbound drug in any of the samples. In vitro addition of oleic acid to plasma samples of four subjects caused a step-wise increase in percent unbound fraction of all three drugs whereas in vitro addition of caffeine did not further alter drug binding. In our study circulating plasma FFA and urinary catecholamine levels were elevated after caffeine ingestion. In spite of a rise in FFA, there was, however, no change in plasma binding of chlordiazepoxide, diazepam, or propranolol.
Animal and human studies have suggested a thermogenic synergism between ephedrine (E), a beta-agonist, and caffeine (C), an adenosine antagonist, which may be suitable for the treatment of obesity. To study this phenomenon, the thermogenic effect of single doses of oral placebo, E 10 mg, E 20 mg, C 100 mg, and C 200 mg were compared with the effects of three different combinations of E + C, 10 mg/200 mg, 20 mg/100 mg, and 20 mg/200 mg, measured by indirect calorimetry in six healthy, lean subjects. The thermogenic effect after E + C 20 mg/200 mg was larger than that of any of the other combinations. In this dose ratio, ephedrine and caffeine exerted a supra-additive synergism, whereas the thermogenic effects of the other two combinations were only additive. The 3-hour postintake increase in systolic blood pressure after all three combinations averaged 5 to 7 mm Hg more than placebo (P less than .01), which exceeded the predicted additive effect fivefold to sevenfold. Diastolic blood pressure was not increased by E + C 20 mg/200 mg, whereas the other two combinations increased it by approximately 4 mm Hg more than placebo. E + C 20 mg/100 mg and 20 mg/200 mg increased heart rate more than placebo, while E + C 10 mg/200 mg had no effect on heart rate. As expected, all combinations increased plasma glucose, insulin, and C-peptide from their ephedrine content. No significant effects of the combinations were found on plasma lactate, glycerol, nonesterified fatty acids (NEFA), triglyceride, potassium, or sodium.(ABSTRACT TRUNCATED AT 250 WORDS)
Caffeine is the most widely consumed stimulant drug in the world. This chapter reviews the human pharmacology of caffeine; the evidence for its role in causing human disease, including addiction; and its potential usefulness as a therapeutic agent.
The effects of the widely consumed drugs caffeine and phenylpropanolamine are mediated through activation of the central and sympathetic nervous systems. Severe, life-threatening, and occasionally fatal hypertensive reactions have been reported after their combined use. This study examined the possible pharmacokinetic interaction of phenylpropanolamine and caffeine. Sixteen normal subjects received combinations of caffeine, phenylpropanolamine, and placebo. In subjects receiving 400 mg caffeine plus 75 mg phenylpropanolamine, the mean (+/- SEM) peak plasma caffeine concentration of 8.0 +/- 2.2 micrograms/ml was significantly greater than after 400 mg caffeine alone (2.1 +/- 0.3 micrograms/ml; t[24] = 2.4; p less than 0.01). Physical side effects were more frequent after the phenylpropanolamine-caffeine combination than after either drug alone or after placebo. Greater increases in both systolic and diastolic blood pressures occurred after the combination than after either drug alone. Because caffeine levels can be increased greatly when certain other drugs are coconsumed, these data indicate that phenylpropanolamine may enhance absorption or inhibit elimination of caffeine and may explain increased side effects reported after their combined use.
The contents of six Ephedra alkaloids, namely ephedrine, pseudoephedrine, norephedrine, norpseudoephedrine, methylephedrine and methyl-pseudoephedrine, in 12 species of Chinese Ephedra collected in 24 districts were determined by high performance liquid chromatography (HPLC). Zorbax CN column (25 cm x 4.6 mm I.D.) was used and the temperature of column oven was 23-25 degrees C. Dibutylamine phosphate solution 0.0009 mol/L (pH 2.2) was used as the mobile phase at flow rates: 0.8 ml/min for the first 7 minutes, raised to 1.5 ml/min in 30 sec and maintained for 16 minutes. The alkaloids eluted were detected at wave-length 210 nm. The results showed that ephedrine and pseudoephedrine are the main components in these Ephedra herbs, but the contents of the six Ephedra alkaloids vary greatly with the plant species. The contents of total alkaloids are higher and ephedrine is the main component in samples derived from Ephedra sinica, E. equisetina, E. monosperma and E. intermedia var. tibetica; but in E. intermedia and E. lomatolepis, the content of pseudoephedrine is higher than that of ephedrine. Methylephedrine content is higher in E. intermedia var. tibetica produced in Xizang (Tibet) and in E. sinica produced in north-eastern China than that in other species. The results also showed that the samples derived from E. przewalskii and E. lepidosperma contain so little alkaloids (less than 0.1%) that they are considered not suitable to be used as the drug Ma Huang. It is of interest that the cultivated Ephedra sinica showed lower alkaloids content compared with that growing wild.
Chronic ephedrine treatment of man has recently been found to enhance the thermogenic response to an acute dose of ephedrine. Conceivably, this sensitization to beta-adrenergic stimulation might also affect the facultative component of diet-induced thermogenesis. The glucose-induced thermogenesis (GIT) was studied in five healthy female subjects after 3 months of chronic peroral ephedrine treatment. Similar experiments 3 months after cessation of treatment served as controls. During chronic ephedrine treatment a sustained 10% elevation of the metabolic rate was found compared to that in the control study. Plasma epinephrine levels were increased 87% during treatment. These increases tended to be positively correlated (r = 0.54, P less than 0.07). GIT expressed as a percentage of the ingested energy load was unaltered during chronic ephedrine treatment compared with that in the control study (9.0% v 8.9%). The respiratory quotient (RQ) indicate that relatively more lipid was oxidized during chronic ephedrine treatment than in the control study. This change was observed in the fasting state as well as after glucose administration. Certain effects of ephedrine seems to be appropriate to a thermogenic drug for the treatment of obesity: A single dose of ephedrine stimulates thermogenesis, an effect that is enhanced during chronic treatment; Chronic treatment elevates the metabolic rate; and The substrate utilization is changed in favor of lipid oxidation.
The thermogenic effect of an over-the-counter preparation containing 22 mg ephedrine, 30 mg caffeine and 50 mg theophylline was investigated in human volunteers with a predisposition to obesity and also in the lean. The ephedrine/methylxanthines mixture was twice as effective as ephedrine alone in increasing the fasting metabolic rate of both subject groups, and it normalized the reduced thermogenic response to a 1.25-MJ meal observed in those predisposed to obesity. Measurements of 24-h energy expenditure in a respirometer indicate that the mixture had no effect on the daily metabolic rate of the lean, but was effective in causing a significant 8 percent increase in the 24-h energy expenditure of those subjects predisposed to obesity. These studies indicate that relatively mild doses of dietary methylxanthines in combination with ephedrine can raise daily energy expenditure of those predisposed to obesity, mainly by correcting their defective thermogenic response to food. Such ephedrine/methylxanthine preparations could be useful as aids in the treatment of obesity.
The steady-state basal plasma glucose and insulin concentrations are determined by their interaction in a feedback loop. A computer-solved model has been used to predict the homeostatic concentrations which arise from varying degrees beta-cell deficiency and insulin resistance. Comparison of a patient's fasting values with the model's predictions allows a quantitative assessment of the contributions of insulin resistance and deficient beta-cell function to the fasting hyperglycaemia (homeostasis model assessment, HOMA). The accuracy and precision of the estimate have been determined by comparison with independent measures of insulin resistance and beta-cell function using hyperglycaemic and euglycaemic clamps and an intravenous glucose tolerance test. The estimate of insulin resistance obtained by homeostasis model assessment correlated with estimates obtained by use of the euglycaemic clamp (Rs = 0.88, p less than 0.0001), the fasting insulin concentration (Rs = 0.81, p less than 0.0001), and the hyperglycaemic clamp, (Rs = 0.69, p less than 0.01). There was no correlation with any aspect of insulin-receptor binding. The estimate of deficient beta-cell function obtained by homeostasis model assessment correlated with that derived using the hyperglycaemic clamp (Rs = 0.61, p less than 0.01) and with the estimate from the intravenous glucose tolerance test (Rs = 0.64, p less than 0.05). The low precision of the estimates from the model (coefficients of variation: 31% for insulin resistance and 32% for beta-cell deficit) limits its use, but the correlation of the model's estimates with patient data accords with the hypothesis that basal glucose and insulin interactions are largely determined by a simple feed back loop.
The effect of OCS on the disposition and elimination of caffeine was examined. Caffeine (250 mg) was administered orally to 13 healthy males, nine healthy females taking no OCS, and nine healthy females on OCS. The t1/2 (beta) was significantly prolonged in women on OCS (10.7 +/- 3.0 hr vs. 6.2 +/- 1.6) (p less than 0.001) as compared to women taking no OCS. Women on OCS had a significantly lower total plasma clearance (0.79 +/- 0.21 ml/min/kg vs. 1.3 +/- 0.35) and free clearance (1.12 +/- 0.28 ml/min/kg vs. 1.97 +/- 0.57) that women not taking OCS. Volumes of distribution and plasma binding were similar in both groups of females. When women taking no OCS were compared with men, all pharmacokinetic parameters were similar except for volume of distribution, which was significantly larger in the women (p less than 0.05). We conclude that OCS impair the elimination of caffeine.
Ninety-six male Sprague-Dawley rats were trained in one of seven drug versus saline (SAL) discrimination (DD) tasks under a variable-ratio 5-15 schedule of food-motivated lever press responding. Three groups of rats (n = 12/group) were trained to discriminate between one of the legal over-the-counter (OTC) stimulants--caffeine (CAF), ephedrine (EPHED), phenylpropanolamine (PPA), and SAL. Three other groups (n = 12/group) were trained to discriminate between one of three binary stimulant combinations--CAF+EPHED, CAF+PPA, EPHED+PPA, and SAL. The seventh group of rats (n = 24) was trained to discriminate between SAL and a ternary combination of the OTC stimulants, CAF+EPHED+PPA. Generalization tests were conducted with each of the OTC stimulants and the controlled stimulants--amphetamine (AMPHET) and cocaine (COC). The data suggest: 1) there is cross-generalization between some OTC combinations and controlled stimulants; 2) full generalization between the OTC and controlled stimulants were demonstrated in rats trained to discriminate two of the binary stimulant combinations from SAL; 3) drug mixtures are not perceived as new entities distinct from their component elements; 4) training dose-ratio may influence the characteristics of mixture discriminations; 5) stimulus overshadowing may be a factor determining drug mixture cues, and 6) the DD properties of aggregate drug compounds may function within a euclidean metric space. We propose that some binary OTC stimulant combinations may effectively function as a methadone-like replacement therapy in cocaine dependence.
The purpose of this study was to evaluate heart rate and blood pressure responses to a commercially available source of ma-haung, a natural source of the sympathomimetic substance, ephedrine, and to evaluate the pharmacokinetic properties of the product in normotensive, healthy adults. On day 1, twelve study participants were monitored with an ambulatory blood pressure device between hours 7 and 20. On day 2, they ingested four capsules of powdered ma-huang at hours 8 and 17 while again wearing the monitor between hours 7 and 20. Serial plasma samples were obtained and concentrations of ephedrine were analyzed by high-performance liquid chromatography. Pharmacokinetic parameters of ephedrine were determined from plasma concentration-time profiles. The ephedrine alkaloid content of each capsule was also determined by high-performance liquid chromatography. Six participants experienced a statistically significant increase in heart rate, but the effects on blood pressure were variable. The half-life, volume of distribution, clearance, and maximum concentration in plasma of ephedrine in the ma-huang product were similar to values previously reported for a 20 mg, immediate-release ephedrine tablet. Values for the absorption rate were considerably lower and time to reach maximum concentration was longer for the capsules, compared with the standard tablet. Variability in alkaloid content of ephedrine was low and yielded a mean dose of ephedrine at 19.4 mg; pseudoephedrine at 4.9 mg; and methylephedrine at 1.2 mg for a four-capsule dose. In summary, ma-haung had variable effects on blood pressure and increased heart rate in healthy, normotensive adults. Pharmacokinetic parameters for ephedrine were in agreement with those previously reported; however, the absorption rate was much slower after ingestion of ma-huang.
This study was conducted to determine whether gender differences exist in adrenergic receptor sensitivity and baroreflex response. Adrenergic receptor sensitivity was assessed by administering sequentially increasing intravenous doses of phenylephrine and isoproterenol. Baroreflex sensitivity was determined from the slope of pulse intervals plotted against phenylephrine-induced rise in systolic blood pressure (SBP). Drug-induced changes in heart rate, blood pressure, and brachial artery diameter were measured and statistically compared. Women required a lower infusion rate of phenylephrine to increase SBP by 20 mmHg from baseline. There were no statistically significant gender-related differences in baroreflex sensitivity. The dose of isoproterenol needed to increase heart rate by 25 beats per minute from baseline also did not differ significantly between groups. Percent changes from baseline in brachial artery diameters in response to phenylephrine also were similar between groups. These data suggest that women may have greater alpha-adrenergic receptor sensitivity than men, whereas beta1-adrenergic receptor sensitivity is similar between genders. A trend toward a greater baroreflex sensitivity in men than in women was also observed. This study also provides evidence for a possible relationship between adrenergic receptor sensitivity and baroreflex sensitivity.
Nutritional supplements containing Ephedra sinica (ma huang), a botanical source of ephedrine alkaloids, have been linked to several episodes of ephedrine toxicity and at least 17 deaths, yet these products remain unregulated. Ten subjects were enrolled in a randomized, crossover study aimed at characterizing the pharmacokinetics of ephedrine after the ingestion of three commercially available ma huang products compared with a 25-mg ephedrine capsule. Pharmacokinetic parameters for botanical ephedrine were similar to those for synthetic ephedrine hydrochloride. Gender-based comparisons of Vss/F and CL/F revealed higher values for women than for men (Vss/F, 3.49 +/- 1.04 vs 2.98 +/- 0.73 l/kg; CL/F, 0.48 +/- 0.11 vs 0.37 +/- 0.11 l/hour x kg). The current study suggests that the increased incidence of ma huang toxicity does not stem from differences in the absorption of botanical ephedrine compared with synthetic ephedrine; rather, it results from accidental overdose often prompted by exaggerated off-label claims and a belief that "natural" medicinal agents are inherently safe.
Using rats trained to discriminate 1 mg/kg of (+)amphetamine (ED50 = 0.4 mg/kg) from saline vehicle in a two-lever drug discrimination procedure, it was shown that (-)ephedrine (ED50 = 4.5 mg/kg), but not (+)ephedrine, substitutes for the (+)AMPH stimulus. It was also shown that caffeine (ED50 = 12.9 mg/kg) can substitute for (+)amphetamine in a dose-related fashion. Doses of (-)ephedrine and caffeine, which produced < or = 1% drug-appropriate responding when administered alone, were able to enhance each other's stimulus effects when administered in combination such that there was a twofold leftward shift in their respective dose-response curves. Furthermore, stimulus generalization occurred when a dose of caffeine that produced saline-appropriate responding when administered alone was administered in combination with (+)ephedrine. It would appear that low doses of (-)ephedrine and caffeine may mutually potentiate one another's stimulus effects in (+)AMPH-trained rats, and that a combination of caffeine and (+)ephedrine result in altered stimulus character when compared to comparable doses of either agent administered alone.
"Herbal Ecstacy" (sic) is an alternative drug of abuse usually containing both ephedrine and caffeine. Our literature search did not reveal any other reported cases of cardiovascular toxicity related to herbal "drugs of abuse." A case of cardiovascular toxicity following the ingestion of herbal ecstacy is presented. A 21-year-old male presented to the emergency department with an initial blood pressure of 220/110 mmHg and ventricular dysrhythmias after ingesting four capsules of herbal ecstacy. He was treated with lidocaine and sodium nitroprusside, and his symptoms resolved in 9 h. The pathophysiology and clinical course of ephedrine toxicity are discussed. Emergency physicians should consider ephedrine preparations in the differential diagnosis of patients presenting with a sympathomimetic toxidrome. Drugs of abuse containing "herbal" products can produce serious morbidity and mortality.
The ingestion of a combination of caffeine (C) and ephedrine (E) has been reported to prolong exercise time to exhaustion during cycle ergometry at 85% VO2max. The present study was undertaken to investigate whether this enhancement would occur in a field setting and if drug ingestion on 1 d would affect performance 1 d later. Two hours after ingesting either a combination of 375 mg of C and 75 mg E (C+E), or a placebo (P), 9 healthy male recreational runners completed six balanced and double-blind trials of the Canadian Forces Warrior Test (WT), a 3.2 km run wearing "fighting order" which weighed about 11 kg. The trials were performed in sets of two runs, i.e., two runs were done 24 h apart, and these sets were separated by a minimum of 7 d. The sets were: C+E trial on day 1 (D1), placebo on day 2 (P2); placebo first (P1), C+E second (D2); and placebo first (P3), placebo second (P4). In addition, 1 wk before the treatment trials the subjects performed a control trial WT. During the WT, heart rates (HR) were recorded every minute. Plasma C and E levels immediately before the WT were similar for both C+E trials, but were undetectable for all P trials. Run times (mean+/-SD) were 15.3+/-0.6, 15.4+/-0.9, 15.5+/-1.2, 15.4+/-0.9, 15.4+/-0.9, 14.8+/-0.7, and 14.6+/-0.8 min for control, P1, P2, P3, P4, D1, D2 trials, respectively. The two C+E trial run times were similar and both were significantly faster (p < 0.05) than control and all placebo trials. HR during the WT was significantly higher (p < 0.05) for the C+E trials compared with the other trials. WT performance was not impaired by C+E ingestion 24 h earlier. In conclusion, performance of the WT was improved by ingestion of C+E.
We report the first case of extensive cerebral infarct in a young sportsman consuming high doses of MaHuang extract and creatine monohydrate. This should alert the sport community to possible serious adverse effects of energy supplements.
A 33 year old man had a severe aphasia on awakening in the morning of 23 January 1999. He did not complain of headache or of other symptoms. He was referred to our department on 26 January 1999. He had a Wernicke aphasia with a slight right sided face and arm weakness and a right Babinski sign. His blood pressure was 140/60 and his pulse 54 per minute. Brain CT showed signs of extensive left middle cerebral artery infarct. Cervical ultrasound duplex scanning and cerebral angiography were normal. Cerebral …
Dietary supplements that contain ephedra alkaloids (sometimes called ma huang) are widely promoted and used in the United States as a means of losing weight and increasing energy. In the light of recently reported adverse events related to use of these products, the Food and Drug Administration (FDA) has proposed limits on the dose and duration of use of such supplements. The FDA requested an independent review of reports of adverse events related to the use of supplements that contained ephedra alkaloids to assess causation and to estimate the level of risk the use of these supplements poses to consumers.
We reviewed 140 reports of adverse events related to the use of dietary supplements containing ephedra alkaloids that were submitted to the FDA between June 1, 1997, and March 31, 1999. A standardized rating system for assessing causation was applied to each adverse event.
Thirty-one percent of cases were considered to be definitely or probably related to the use of supplements containing ephedra alkaloids, and 31 percent were deemed to be possibly related. Among the adverse events that were deemed definitely, probably, or possibly related to the use of supplements containing ephedra alkaloids, 47 percent involved cardiovascular symptoms and 18 percent involved the central nervous system. Hypertension was the single most frequent adverse effect (17 reports), followed by palpitations, tachycardia, or both (13); stroke (10); and seizures (7). Ten events resulted in death, and 13 events produced permanent disability, representing 26 percent of the definite, probable, and possible cases.
The use of dietary supplements that contain ephedra alkaloids may pose a health risk to some persons. These findings indicate the need for a better understanding of individual susceptibility to the adverse effects of such dietary supplements.
A 22-year-old man was hospitalized after unexplained seizure-like activity and unresponsiveness. A urine toxicology screen was negative for salicylates, acetaminophen, alcohol, and drugs of abuse. Medical history was insignificant with the exception of recent (within 2 wks) ingestion of Hydroxycut is a dietary supplement purported to be energy enhancing, muscle building, and fat burning. The agent contains ephedra alkaloids and caffeine, which are both central nervous system stimulants; the etiology of seizure was attributed to their consumption. Due to a significant number of reported adverse events, the United States Food and Drug Administration (FDA) proposed regulations for dietary supplements containing ephedra alkaloids and requested an independent review of case reports linked to these products. Because herbal products are not subject to the same rigorous FDA regulations required for prescription and over-the-counter products, consumers unknowingly risk adverse effects when taking these products. Questioning patients about consumption of herbal products should be part of routine medical visits.
Background:
Obesity and overweight may soon affect more than half of the population in some regions of the world and are associated with diabetes, hypertension and other diseases that cause morbidity, mortality and high health-care expenditure. No one approach, whether dietetic management, medication, or commercial weight loss programme, can alone solve the problem--all potential treatments need to be investigated and exploited. Among the herbal preparations known to non-western cultures are materials which may have applications in modulating physiological processes which influence gut motility, food intake and energy balance. One such mixed herbal preparation is 'YGD' containing Yerbe Maté (leaves of Ilex paraguayenis), Guarana (seeds of Paullinia cupana) and Damiana (leaves of Turnera diffusa var. aphrodisiaca).
Aims:
This study had two distinct aims: to determine the effect of a herbal preparation 'YGD' containing Yerbe Maté, Guarana and Damiana on gastric emptying; to determine the effect of the same preparation on weight loss over 10 days and 45 days and weight maintenance over 12 months.
Methods:
Gastric emptying was observed using ultrasound scanning in seven healthy volunteers following YGD and placebo capsules taken with 420 mL apple juice. Body weight was observed before and after 10 days of treatment with three YGD capsules or three placebo capsules before each meal for 10 days in 44 healthy overweight patients attending a primary health care centre. Forty-seven healthy overweight patients entered a double-blind placebo-controlled parallel trial of three capsules of YGD capsules before each main meal for 45 days compared with three placebo capsules on body weight. Body weight was monitored in 22 patients who continued active (YGD capsules) treatment for 12 months.
Results:
The herb preparation YGD was followed by a prolonged gastric emptying time of 58 +/- 15 min compared to 38 +/- 7.6 min after placebo (P = 0.025). Body weight reductions were 0.8 +/- 0.05 kg after YGD capsules compared to 0.3 +/- 0.03 kg after placebo capsules over 10 days, and 5.1 +/- 0.5 kg after PGD capsules compared to 0.3 +/- 0.08 kg after placebo over 45 days. Active treatment with YGD capsules resulted in weight maintenance of the group (73 kg at the beginning and 72.5 kg at the end of 12 months).
Conclusions:
The herbal preparation, YGD capsules, significantly delayed gastric emptying, reduced the time to perceived gastric fullness and induced significant weight loss over 45 days in overweight patients treated in a primary health care context. Maintenance treatment given in an uncontrolled context resulted in no further weight loss, nor weight regain in the group as a whole. The herbal preparation is thus shown to be one that significantly modulates gastric emptying. Further clinical studies with dietetic monitoring of energy intake, dietary quality, satiety ratings, body weight and body composition are now indicated, and examination of the active principles contained in the three herbal components may prove rewarding.
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The ingestion of either caffeine (C) or ephedrine (E) has been shown to improve performance during high-intensity aerobic activity lasting 10-20 min, with an additive effect being found when the combination (C + E) was ingested. It was the purpose of this study to determine if the addition of E to C would improve performance in activity lasting longer than 20 min.
One and one half hours after ingesting a placebo (P), C (4 mg/kg), E (0.8 mg/kg), or C + E, 12 subjects performed a 10-km run while wearing a helmet and backpack weighing 11 kg. The trials were performed in a climatic suite at 12-13 degrees C, on a treadmill where the speed was regulated by the subject. VO(2), VCO(2), V(E), heart rate (HR), and rating of perceived exertion (RPE) were measured during the run at 15 and 30 min, and again when the individual reached 9 km. Blood was sampled at 15 and 30 min and again at the end of the run and assayed for lactate, glucose, and catecholamines.
Run times (mean +/- SD), in minutes, were for C (46.0 +/- 2.8), E (45.5 +/- 2.9), C + E (45.7 +/- 3.3), and P (46.8 +/- 3.2). The run times for the E trials (E and C + E) were significantly reduced compared with the non-E trials (C and P). Pace was increased for the E trials compared with the non-E trials over the last 5 km of the run. VO(2) was not affected by drug ingestion. HR was elevated for the ephedrine trials (E and C + E). RPE remained similar for all trails. Caffeine increased the epinephrine and norepinephrine response associated with exercise and also increased blood lactate, glucose, and glycerol levels. Ephedrine reduced the epinephrine response but increased dopamine and FFA levels.
The previously seen additive nature of E and C was not evident in this study, with the primary ergogenic effect being attributed to E.
Serious cardiovascular toxicity has been reported in people taking dietary supplements that contain ma huang (Ephedra) and guarana (caffeine). We assessed the pharmacokinetics and pharmacodynamics of a dietary supplement that contains these herbal stimulants.
Eight healthy adults received a single oral dose of a thermogenic dietary supplement labeled to contain 20 mg ephedrine alkaloids and 200 mg caffeine after an overnight fast. Serial plasma and urine samples were analyzed by use of liquid chromatography-tandem mass spectrometry for ephedrine alkaloid and caffeine concentrations, and heart rate and blood pressure were monitored for 14 hours.
Plasma clearance and elimination half-lives for ephedrine, pseudoephedrine, and caffeine were comparable to published values reported for drug formulations. A prolonged half-life of ephedrine and pseudoephedrine was observed in 1 subject with the highest urine pH. Mean systolic blood pressure increased significantly to a maximum of 14 mm Hg above baseline at 90 minutes after ingestion (P <.001). There was a lag in the mean heart rate response that reached a maximum change of 15 beats/min above baseline at 6 hours after ingestion (P <.001). Diastolic blood pressure changes were insignificant. Two subjects who were taking oral contraceptives had longer caffeine half-lives (15.5 +/- 0.3 hours versus 5.6 +/- 1.7 hours) and lower values for oral clearance (0.34 +/- 0.01 mL/min. kg versus 0.99 +/- 0.41 mL/min. kg) than subjects who were not taking oral contraceptives.
Botanical stimulants have disposition characteristics similar to their pharmaceutical counterparts, and they can produce significant cardiovascular responses after a single dose.
Effects of a weight-loss aid in healthy overweight adults
- Kalman Ds Cm Colker
- Q Shi
- Swain
- Ma
Kalman DS, Colker CM, Shi Q, Swain MA. Effects of a weight-loss aid in healthy overweight adults. Curr Ther Res Clin Exp 2002;61:199-205.
Textbook of pharma-cology
- Bowman
- Rand Wc
- Mj
Bowman WC, Rand MJ, editors. Textbook of pharma-cology. 2nd ed. London: Blackwell Scientific Publica-tions; 1980.
Clinical pharmacokinet-ics concepts and application Lip-pincott Williams & Wilkins
- Rowland M Tozer
- Tn
Rowland M, Tozer TN, editors. Clinical pharmacokinet-ics concepts and application. 3rd ed. Media (PA): Lip-pincott Williams & Wilkins; 1994.