| Comment Record|
Dr. Earle Nestmann ||
2003-04-04 10:12:05 |
Cantox Health Sciences Inc. |
| Comments for FDA General |
1. General Comments
COMMENTS ON PROPOSED RULE FOR DIETARY SUPPLEMENTS CONTAINING EPHEDRINE ALKALOIDS; FOOD AND DRUG ADMINISTRATION; HHS
[DOCKET NO. 95N-0304]
These comments are provided by Earle Nestmann on behalf of Cantox Health Sciences International (Cantox), a consulting company with expertise in toxicology and product safety. In these comments on the Notice of Proposed Rule, reference is made to a comprehensive review and risk assessment entitled “Safety Assessment and Determination of a Tolerable Upper Limit for Ephedra” that was prepared for the Council for Responsible Nutrition (CRN) by Cantox. The focus of the Cantox report (Cantox, 2000), already submitted to a separate FDA docket on ephedra, Docket No. 00N-1200, is safety rather than any consideration of efficacy, as is the recent Notice of Proposed Rule from FDA. Based on a rigorous evaluation of all available information on the safety of ephedrine alkaloids in ephedra, using a risk assessment approach, a tolerable upper intake level (UL) was determined. According to basic scientific principles in toxicology and medicine, every substance at some dose level is safe, and sufficiently high doses may lead to adverse effects. Objectives of Cantox (2000) were to determine levels at which no adverse effects are observed in people and to propose a safe level for the general adult population.
Recent developments have led to the publication of the Notice of Proposed Rule, most of all publicity attendant to continuing analysis of and reference to the FDA database of adverse event reports (SN/AEMS). Of the 7 references cited in the Notice of Proposed Rule, two are clinical trials, (Boozer et al., 2001; 2002) results from which were used in the Cantox (2000) Report. The other 5 have generated considerable publicity but have added little of scientific merit to the overall consideration of the safety of ephedra supplements. These references, as well as newer clinical trials that also support the conclusions of Cantox (2000), are discussed below, using the Cantox report as a framework for evaluating the safety of ephedra.
As explained below in detail, the relevant scientific databases establish that ephedra products are safe, when used according to proper labeling with appropriate warnings, at a level of consumption of 90 mg/d (30 mg 3 times/d). This daily intake is essentially the same as the industry standard of 100 mg/d (25 mg 4 times/d), and both are supported by clinical studies with daily intakes as high as 150 mg/d. In summary, there is no scientific basis for concluding that properly labeled products, with recommended intakes in the range determined to be safe by Cantox (2000), present a “significant or unreasonable risk of illness or injury” when used according to label directions.
CANTOX (2000): SAFETY ASSESSMENT AND DETERMINATION OF UPPER INTAKE LEVEL (UL)
CRN commissioned Cantox to perform a risk assessment of ephedra in dietary supplements, and based on the available scientific evidence, to determine a tolerable upper intake level (UL) using methodology developed by the Institute of Medicine (IOM) of the National Academy of Sciences (NAS). This approach takes into account all available information that relates to safety and determines a No Observed Adverse Effect Level (NOAEL) based on pivotal studies. An uncertainty factor (UF) is derived on the basis of scientific judgement concerning the strength of the overall database. The tolerable upper intake level (UL) is calculated by dividing the NOAEL by the UF. Such an approach had not been taken before (nor since) the release of the report. The difference between Cantox (2000) and other reviews concerning ephedra is that the Cantox analysis has relied on objective scientific evidence, i.e., published double-blind, placebo-controlled clinical trials and toxicology studies. Other reviews have focused on unsubstantiated adverse event reports (AERs) that by their nature are subjective and poorly documented recollections based on recall and hearsay. Analysis of the AERs follows later in these comments.
The approach taken by Cantox was to include the substantial evidence available on ephedrine which is the principal active ingredient in ephedra which also contains minor amounts of other ephedrine alkaloids. Ephedra as a dietary supplement has not been subjected to the extensive investigation that was undertaken for ephedrine, widely used as an over-the-counter (OTC) medication for many years. Nonetheless, the comprehensive database that supports the safety of ephedrine provides ephedra with a strong foundation of objective scientific study.
Controlled Clinical Studies
The best evidence to assess safety and to identify possible risks is the database of clinical investigations in normal healthy individuals as well as special populations (e.g., overweight subjects, asthmatic patients; etc.). A long history of safe use of ephedrine by asthmatic patients has been documented in the clinical literature (Bierman et al., 1975; Wilson et al., 1976; Blanc et al., 1997). Randomized, double-blind, placebo-controlled studies are recognized to be an objective and unbiased means to evaluate potential benefits and possible undesirable side effects. Many clinical trials on ephedra and ephedrine are focused on weight loss, and many of these monitored the control and test subjects for reports of side effects. A core of 24 such clinical studies provides the basis of determining a NOAEL. These studies (Astrup et al., 1985, 1992; Pasquali et al., 1985, 1987, 1992; Krieger et al., 1990; Daly et al., 1993; Molnár, 1993; Toubro et al., 1993a,b; Breum et al., 1994; Buemann et al., 1994; Kaats and Adelman, 1994; Ingerslev et al., 1997; Moheb et al., 1998; Waluga et al., 1998; Huber, 2000; Molnár et al., 2000; Boozer et al., 2001, 2002; de Jonge et al., 2001; Greenway, 2001; Kalman et al., 2002; Filozof et al., 2002) involved overweight but otherwise healthy individuals consuming ephedrine alkaloids (50 to 150 mg/d) or placebo for durations ranging from 10 d to 26 m. Two of these studies (Boozer et al., 2001; 2002) were referenced in the Notice of Proposed Rule, and results from the latter were identified in Cantox (2000) as representative of the pivotal core of 10 studies, most of which involved combinations with other substances, principally caffeine. At the dose levels tested, no truly adverse effects, irreversible effects, or toxicological effects were observed, but only minimal side effects were observed (e.g., dry mouth, heartburn, insomnia) consistent with sympathomimetic agents. Based on the 6 m study by Boozer et al. (2002) and supported by the weight of evidence from other studies, 90 mg/d (30 mg 3 times/d) was selected as the NOAEL for adults (>18 years). Since the release of the Cantox (2000) report, 4 new clinical studies (2 of them d-blind, placebo-controlled for 3 m with ephedra; 1 for 11 m with ephedrine) have appeared (Greenway et al., 2000; de Jonge et al., 2001; Belfie et al., 2001; Filozof et al., 2002), supporting the conclusions of the report. A clinical study by Haller et al. (2002) has been included in the references listed in the Notice of Proposed Rule, but this single-dose study is difficult to interpret in the absence of a placebo control group.
Since metabolism data for ephedrine alkaloids show similarity between laboratory animals and humans, the extensive toxicological database on ephedrine (and ephedra) was considered for consistency with results from clinical trials. Studies ranged from acute (single exposure) and short-term (14 d to 13 wk) studies to lifetime (2 y) exposures to ephedrine (Chen 1925b, 1926b; Law et al., 1996; Massoudi and Miller, 1977; Yen et al., 1981; NTP, 1986; Miller et al., 1998; Ramsey et al., 1998). In the short-term studies, clinical observations included hypersensitivity and excitability, and reductions in weight gain were observed in both male and female mice and rats (NTP, 1986) as well as in monkeys (Ramsey et al., 1998). Lower body weight in the lifetime rodent studies appeared to lead to increased survival of female rats, an outcome that has been noted in other studies that have linked reduced weights to enhanced survival in rodents. Overall, the toxicology studies show no adverse, toxicological effects, even at high doses.
In summary, the toxicological database is extremely important in the consideration of the safety of ephedra/ephedrine alkaloids. It is an extensive database, much of it performed by the National Toxicology Program (NTP, 1986), consisting of studies that by their nature are objective and controlled. Even at high doses for a lifetime, few side effects are observed, and there are no toxicological effects. Unfortunately, other reviews of ephedra completely ignore the toxicological database that supports the safety of ephedrine alkaloids in agreement with results from controlled clinical trials, as discussed above.
Case studies can serve as important signals of possible adverse reactions, subject to verification of plausibility as well as quantitation with epidemiological or clinical studies. Although a case report cannot be relied upon to demonstrate a cause-and-effect relationship, well-documented reports of consistent findings published by attending medical authorities lead to increased confidence in a reported association. With respect to ephedrine alkaloids, there appears to be a sufficient number of published case reports in the medical literature to strongly suggest that prolonged use of doses that are considerably higher than those found safe by Cantox (2000) may result in serious pharmacological effects. Such a conclusion is consistent with the basic pharmacological principle of dose response.
On the other side of a spectrum of case reports are voluntary adverse event reports (AERs) such as those collected under the FDA Special Nutritionals/Adverse Event Monitoring System (SN/AEMS). The Cantox (2000) report included a detailed analysis, classification, and evaluation of the FDA AER database, finding the individual records to be incomplete and unreliable. Nevertheless, several publications have drawn widespread publicity by accepting certain of the AERs at face value and suggesting that a variety of reported disease conditions were caused by ephedrine alkaloids by virtue of their inclusion in this database. Indeed, the Notice of Proposed Rule includes references to 2 studies (Samenuk et al., 2002; Shekelle et al. in press) that are based on these AERs. In the review by Samenuk et al. (2002), the authors have accepted dosing information at face value, even apparently for 11 cases of sudden death. [A subsequent letter to the Editor (Hutchins, 2002), which takes issue with the details of the AERs cited by Samenuk et al. (2002), was not referenced in the Notice of Proposed Rule.] Both reviews are careful to state that conclusions of causality cannot be drawn from AER analysis, and both call for more research. The review by Shekelle et al. (in press), also known as the “Rand Report”, essentially confirmed the conclusion of Cantox (2000), by stating that further analysis of the AERs is not helpful, but excusing their effort by reference to the direction and scope of their review in the statement of work from the study’s sponsors. The report, however, goes on to cloud the issue by using terminology to describe certain AERs as “sentinel events” or “possible sentinel events” which implies causality ranking that is inconsistent with these and other authors’ agreement that interpretation of these reports is subjective and of no real scientific value.
Additional observations can be made about the reported AERs. First of all, whatever the cause, these reports represent unfortunate even tragic events that have affected the lives of the subjects and their families. In a scientific analysis of such events, there can be little dispute that serious events have occurred, but their cause requires objective consideration of all the evidence and relevant factors. It has been estimated that there are more than 10 million people using ephedra products for weight loss and athletic performance (Shekelle et al. in press) and up to 3 billion units of ephedra sold annually (GAO, 1999; AHPA, 2000). With such a large population of “users”, it can be expected that a certain number of symptoms and events will occur from spontaneous or unknown causes. What isn’t known are the numbers of symptoms and events in a similar population of “non-users”, which points out the value of controls in any such analysis. Consideration of background incidence is especially relevant for certain members of these population groups who are known to experiment with different substances, including illicit drugs. How likely and how often will subjects admit to or will surviving family know about such behavior?
Admittedly, there are differences of opinion about the meaning to be drawn from the AERs. Everyone concurs that they can’t be used to prove causality (e.g., Samenuk et al., 2002; Shekelle et al. in press), but various authors and groups, including the FDA, draw inferences from the AERs to support a position that ephedra is not safe for consumption as a dietary supplement. There is an atmosphere of “better to be safe than sorry” that is akin to the Precautionary Principle. Is it unethical or unscientific to come to a conclusion that ephedra can be safe just because AERs cannot be used to prove otherwise? If no scientific information existed to support a safe level of ephedra, then it might be. In this instance for ephedra, however, there is substantial clinical and toxicological information to support a safe level. The AERs can be used to formulate a hypothesis to be tested with properly designed studies, as suggested by Shekelle et al. (in press) and others. Well-documented case reports published by physicians confirm the dose response principle and demonstrate that there should be no surprise to find AERs resulting from consumption of high doses.
The Notice of Proposed Rule also included 2 other references that should be mentioned. One purports to evaluate the safety of ephedra from the perspective of reports to poison control centers (Bent et al., 2003). The methodology used in this study, to define risk as dividing ratio of adverse reactions by ratio of market share for ephedra versus other products, is described as a commonly used technique. Clearly, however, as also pointed out in the report, this straight-forward method can be influenced by the relative rates of reporting of adverse events, as well as by estimates of market share. All things being equal, the extent of reporting of adverse events should be dependent only on the adverse event itself being worthy of reporting. In this case, however, as mentioned by the authors, the topic of ephedra safety is “extremely controversial” with a very high level of publicity. This in itself can have a marked influence on the extent of reporting, not to mention types of questions posed during inquiries to poison control centers all over the United States. These types of influence raise questions about any possible conclusions that might be drawn from this type of analysis.
Another reference cited in the Notice of Proposed Rule is a report by Morgenstern et al. (2002) that analyzed results from an earlier study to examine a possible link between ephedra products and risk for hemorrhagic stroke. The analysis suggested a possible association with higher doses. Although the authors believe that bias is unlikely, they pointed out obvious limitations in study design and statistical power. It is also likely that known confounding risk factors may not have been fully considered. The study is so underpowered as to be of little if any value. It is just as unacceptable to conclude from the study that doses greater than 32 mg/d of ephedrine alkaloids increase stroke risk as it would be to say that lower doses dramatically reduce stroke risk – which the data suggest but no one is discussing as a finding from this study.
Nevertheless, if nothing else, the references chosen for citation in the Notice of Proposed Rule illustrate the controversy and publicity surrounding the question of ephedra safety. The references to AER analyses are of interest in this respect but, unlike the available toxicological and clinical databases, provide no real scientific information on safety.
The Cantox (2000) report determined a UL, using the totality of scientific literature available, based on the scientific principle that every substance is safe at certain levels of exposure and can possibly be unsafe at exposures that exceed a tolerable upper level. As outlined and discussed above, additional reports have been published since, but none has presented evidence that negates this basic principle as it applies to ephedra, and some additional clinical trials support the conclusions of Cantox (2000). These conclusions can be summarized as follows:
1) evidence from double-blind, placebo-controlled clinical trials is the basis for identifying a NOAEL for ephedra;
2) the extensive toxicological database supports the clinical evidence;
3) published case reports by attending physicians show that serious adverse events can occur following high doses, often over prolonged periods;
4) the voluntary SN/AEMS database is not reliable due to incomplete and unverified information, cannot be used to assess causality, and is not useful in the determination of a safe level; and
5) proper labeling is required that identifies appropriate dosing and features information about contraindications.
Based on these conclusions, and the extensive scientifically objective database of clinical trials and toxicological studies, the uncertainty factor (UF) appropriate to apply in this situation is 1. Therefore, using the NAS methodology for evaluating a tolerable upper intake level (UL) for ephedra, the UL is 90 mg/d (in 3 doses of 30 mg), derived by dividing the NOAEL (90 mg/d) by the UF (1).
Notice of Proposed Rule
Based principally on the rare but well-publicized incidents of adverse events that have been associated with ephedra, the FDA proposes reconsideration of its possible use in the United States. Clearly from a scientific perspective dose levels in the range of 90 mg/d (30 mg 3 times/day) are safe for human consumption, and these amounts do not present “a significant or unreasonable level of risk of disease or injury” when used according to label directions, however that safety standard is defined. As the law appropriately suggests, the FDA cannot assume responsibility for protecting the public from themselves, if they choose to use this or any other product at higher than recommended levels or otherwise misuse properly labeled products. In this regard, the proposed warning should make reference to dose. The overwhelming majority of ephedra users in the United States are responsible consumers who should continue to have access to this and other products that are produced, labeled, and sold by responsible manufacturers.
Earle R. Nestmann, Ph.D.
Cantox Health Sciences International
April 3, 2003
AHPA. (2000). Ephedra Survey Results: 1995-1999. Survey Administered & Results Compiled by: Arthur Andersen LLP prepared for The American Herbal Products Association. April 28, 2000.
Astrup, A., Lundsgaard, C., Madsen, J., and Christensen, N.J. (1985). Enhanced thermogenic responsiveness during chronic ephedrine treatment in man. Am. J. Clin. Nutr. 42, 83-94.
Astrup, A., Breum, L., Tubro, S., Hein, P., and Quaade, F. (1992). The effect and safety of an ephedrine/caffeine compound compared to ephedrine, caffeine and placebo in obese subjects on an energy restricted diet. A double blind trial. Int. J. Obes. Relat. Metab. Disord. 16, 269-277.
Belfie, L., Petrie, H., Chown, S., Duncan, A.M., Gawron, S.J., Conquer, J., and Graham, T.E.. (2001). Safety and effectiveness of an herbal dietary supplement containing ephedra (ma huang) and caffeine (guarana extract) which when used in combination with a supervised diet and exercise intervention. Obes. Res. 9(3):186S [Abstract No. PG26].
Bent, S., Tiedt, T.N., Odden, M.C., and Shlipak, M.G. (2003). The Relative Safety of Ephedra Compared with Other Herbal Products. Annals of Internal Medicine 138:6.
Bierman, C.W., Pierson, W.E., and Shapiro, G.G. (1975). Exercise-induced asthma pharmacological assessment of single drugs and drug combinations. JAMA 234, 295-298.
Blanc, P.D., Kuschner, W.G., Katz, P.P., Smith, S., and Yelin, E.H. (1997). Use of herbal products, coffee or black tea, and over-the-counter medications as self-treatments among adults with asthma. J. Allergy Clin. Immunol. 100, 789-791.
Boozer, C.N., Nasser, J.A., Heymsfield, S.B., Wang, V., Chen, G., and Solomon, J.L. (2001). An herbal supplement containing Ma Huang-Guarana for weight loss: A randomized, double-blind trial. Int. J. Obes. Relat. Metab. Disord. 25, 316-324.
Boozer, C.N., Daly, P.A., Homel, P., Solomon, J.L., Blanchard, D., Nasser, J.A., Strauss, R., and Meredith, T. (2002). Herbal ephedra/caffeine for weight loss: A 6-month randomized safety and efficacy trial. Int. J. Obes. Relat. Metab. Disord. 26, 593-604.
Breum, L., Pedersen, J.K., Ahlstrom, F., and Frimodt-Møller, J. (1994). Comparison of an ephedrine/caffeine combination and dexfenfluramine in the treatment of obesity: A double-blind, multi-centre trial in general practice. Int. J. Obes. Relat. Metab. Disord. 18, 99-103.
Buemann, B., Marckmann, P., Christensen, J.J., and Astrup, A. (1994). The effect of ephedrine plus caffeine on plasma lipids and lipoproteins during a 4.2 MJ/day diet. Int. J. Obes. Relat. Metab. Disord. 18, 329-332.
Cantox, (2000). Safety Assessment and Determination of a Tolerable Upper Limit for Ephedra. Prepared for: Council for Responsible Nutrition, 1875 Eye St., N.W. - Suite 400, Washington, DC 2006-5409.
Daly, P.A., Krieger, D.R., Dulloo, A.G., Young, J.B., and Landsberg, L. (1993). Ephedrine, caffeine and aspirin: Safety and efficacy for the treatment of human obesity. Int. J. Obes. Relat. Metab. Disord. 17, S73-S78.
de Jonge, L., Frisard, M., Blanchard, D., Greenway, F. (2001). Safety and efficacy of an herbal dietary supplement containing caffeine and ephedra for obesity treatment. Obes. Res. 9(Suppl. 3):184S [Abstract No. PG20].
Filozof, C., Gonzalez, C., and Hofman, E. (2002). The effect of ephedrine plus caffeine after 4-week portion-controlled diet. In: International Congress on Obesity. Sao Paolo, Brazil.
GAO. (1999). Dietary Supplements: Uncertainties in Analyses Underlying FDA's proposed Rule on Ephedrine Alkaloids. U.S. General Accounting Office (GAO), Washington, DC.
Greenway, F.L. (2001). The safety and efficacy of pharmaceutical and herbal caffeine and ephedrine use as a weight loss agent. Obes. Rev. 2, 199-211.
Greenway, F., de Jonge, L., Tucker, E., Rood, J., Smith, S. (2001). Caffeine and ephedrine become omre beta-3 selective with time. Obes. Res. 9, (Suppl. 3) [Abstract No. PB10].
Haller, C.A., Jacob, P., Benowitz, N.L. (2002). Pharmacology of Ephedra Alkaloids and Caffeine After Single-dose Dietary Supplement Use. Clinical Pharmacology and Therapeutics. 71(6), 421-432.
Huber, G.L. (2000). Study on dietary supplements for weight loss. Presented at the Office on Women’s Health, U.S. Department of Health and Human Services (HHS) Public Meeting on the Safety of Dietary Supplements Containing Ephedrine Alkaloids, in Washington, D.C., on August 8-9, 2000. [http://www.fda.gov/ohrms/dockets/dockets/00n1200/tr00001g.pdf].
Hutchins, G.M. 2002. Ma huang toxicity. Mayo Clinic Proceedings 77(7):733. [http://www.mayo.edu/proceedings/2002/jul/7707le.pdf].
Ingerslev, J., Svendsen, T.L., and Mørk, A. (1997). Is an ephedrine caffeine treatment contraindicated in hypertension? Int. J. Obes. Relat. Metab. Disord. 21, 666-673.
Kaats, G.R., and Adelman, J.A. (1994). Effects of multiple herbal formulation on body composition, blood chemistry, vital signs and self-reported energy levels and appetite control. Int. J. Obes. Relat. Metab. Disord. 18, 145 [Abstract No. P550].
Kalman, D., Incledon, T., Gaunaurd, I., Schwartz, H., and Krieger, D. (2002). An acute clinical trial evaluating the cardiovascular effects of an herbal ephedra-caffeine weight loss product in healthy overweight adults. Int. J. Obes. Relat. Metab. Disord. 26, 1363-1366.
Krieger, D.R., Daly, P.A., Dulloo, A.G., Ransil, B.J., Young, J.B., and Landsberg, L. (1990). Ephedrine, caffeine and aspirin promote weight loss in obese subjects. Trans. Assoc. Am. Physicians 103, 307-312.
Moheb, M.A., Geissler, C.A., and Lancer, K. (1998). Effect of ephedrine, caffeine, and aspirin, in combinations of weight loss in obese women. Int. J. Obes. Relat. Metab. Disord. 22, S264 [Abstract No. P636].
Molnár, D. (1993). Effects of ephedrine and aminophylline on resting energy expenditure in obese adolescents. Int. J. Obes. Relat. Metab. Disord. 17, S49-S52.
Molnár, D., Torok, K., Erhardt, E., and Jeges, S. (2000). Safety and efficacy of treatment with an ephedrine/caffeine mixture: The first double-blind placebo-controlled pilot study in adolescents. Int. J. Obes. Relat. Metab. Disord. 24, 1573-1578.
Morgenstern, L.B., Viscoli, C.M., Kernan, W.N., Brass, L.M., Broderick, J.P., Feldmann, E., Wilterdink, J.L., Brott, T., and Horwitz, R.I. (2003). Use of ephedra-containing products and risk for hemorrhagic stroke. Neurology. 60, 132-135.
NTP. (1986). Toxicology and Carcinogenesis Studies of Ephedrine Sulfate (CAS No. 134-72-5) in F344/N Rats and B6C3F1 Mice (Feed Studies). NTP Technical Report Series, No. 307. National Toxicology Program (NTP), Research Triangle Park, NC.
Pasquali, R., Baraldi, G., Cesari, M.P., Melchionda, N., Zamboni, M., Stefanini, C., and Raitano, A. (1985). A controlled trial using ephedrine in the treatment of obesity. Int. J. Obesity 9, 93-98.
Pasquali, R., Cesari, M.P., Melchionda, N., Stefanini, C., Raitano, A., and Labo, G. (1987). Does ephedrine promote weight loss in low-energy-adapted obese women. Int. J. Obesity 11, 163-168.
Pasquali, R., Casimirri, F., Melchionda, N., Grossi, G., Bortoluzzi, L., Morselli Labate, A.M., Stefanini, C., and Raitano, A. (1992). Effects of chronic administration of ephedrine during very-low-calorie diets on energy expenditure, protein metabolism and hormone levels in obese subjects. Clin. Sci. 82, 85-92.
Ramsey, J.J., Colman, R.J., Swick, A.G., and Kemnitz, J.W. (1998). Energy expenditure, body composition, and glucose metabolism in lean and obese rhesus monkeys treated with ephedrine and caffeine. Am. J. Clin. Nutr. 68, 42-51.
Samenuk, D., Link, M.S., Homoud, M.K., Contreras, R., Theohardes, T.C., Wang, P.J., and Estes, N.A. (2002). Adverse cardiovascular events temporally associated with ma huang, an herbal source of ephedrine. Mayo Clin. Proc. 77, 12-16.
Shekelle, P.G., Hardy, M.L., Maglione, M., Morton, S.C. Ephedra and Ephedrine for Weight Loss and Athletic Performance Enhancement: Clinical Efficacy and Side Effects. Agency for Healthcare Research and Quality (in press).
Toubro, S., Astrup, A.V., Breum, L., and Quaade, F. (1993a). Safety and efficacy of long-term treatment with ephedrine, caffeine and an ephedrine/caffeine mixture. Int. J. Obes. Relat. Metab. Disord. 17, S69-S72.
Toubro, S., Astrup, A., Breum, L., and Quaade, F. (1993b). The acute and chronic effects of ephedrine/caffeine mixtures on energy expenditure and glucose metabolism in humans. Int. J. Obes. Relat. Metab. Disord. 17, S73-S77.
Waluga, M., Janusz, M., Karpel, E., Hartleb, M., and Nowak, A. (1998). Cardiovascular effects of ephedrine, caffeine and yohimbine measured by thoracic electrical bioimpedance in obese women. Clin. Physiol. 18, 69-76.
Wilson, A.F., Novey, H.S., Cloninger, P., Davis, J., and White, D. (1976). Cardiopulmonary effects of long-term bronchodilator administration. J. Allergy Clin. Immunol. 58, 204-212.