Comments Regarding Docket: 95N-0304

Dietary Supplements Containing Ephedrine Alkaloids

As a cardiac pathologist, and paid consultant to the Ephedra Education
Council and Metabolife™, I have personally reviewed each of the 15,951
Metabolife™ HealthLine contacts analyzed by the Rand Corporation. Copies
of my analyses of those contacts are appended. In addition, I also acted
as a peer-reviewer for the Rand Report itself. I am the author of
Karch's Pathology of Drug Abuse, 3rd edition, (2002, CRC Press) and have
published extensively, in the peer-reviewed literature, about the
problems of stimulant-related cardiovascular toxicity. The first edition
of my textbook was published in 1993, long before the passage of DSHEA.
It was cited as an authority in the FDA's review of ephedra, published
in the Federal Register in June of 1997.

# Introduction

A consumer's decision to use any nutritional supplement must ultimately
be based on his or her own, albeit informal and unarticulated,
risk/benefit analysis. The results of the Rand Report, not to mention
the results of recently published, peer-reviewed, clinical trials, show
that at least one of the benefits accruing to ephedra-product users is
weight loss (Boozer, Nasser et al. 2001; Boozer, Daly et al. 2002; De
Matteis, Arch et al. 2002). According to the FDA, the numerator in this
equation, risk, is also confirmed, and so substantial, that ephedra/
ephedrine-containing supplements should carry a warning of possible
lethal side effects. This is also the position of the mass media, but
that does not necessarily prove it to be the case.

Anyone who has actually read the published peer-reviewed literature
knows that evidence of toxicity with the use of
ephedra/ephedrine-containing supplements (except, of course, for
overdose), is essentially nonexistent. This is not the first time that
scientific common sense has been subordinated to media judgment. Not
that many years ago, the FDA caused silicon breast implants to be
withdrawn from the market because they presented a clear and present
danger (Council on Scientific Affairs 1993). Now it seems that the
danger was neither clear nor present, and that the results of
observational studies suggesting danger from the implants were
incorrect. Incorrect or not, thousands of cancer victims, having already
undergone reconstructive breast surgery, needlessly subjected themselves
to additional surgery to have the implants removed. This unnecessary
surgery, and needless concern and worry, came about because of FDA
decisions that were based solely on observational studies, and on the
wisdom of the mass media.

In a similar fashion, over reliance on case reports and observational
studies, not to mention hundreds, if not thousands of self-help books
and articles, led millions of women to initiate hormone replacement
therapy (HRT). Now that the results of adequately designed clinical
trials have become available, it is clear that, even though the benefits
of HRT were obvious and "known" to all, they were also illusory (Laine
2002, Harrington, 2003), though the increased risk for cancer and heart
disease associated with HRT is not. Now "it is clear" that the use of
ephedra/ephedrine is associated with the occurrence of "heart attack,
seizure, stroke, and death." Past experience suggests that in the
absence of controlled clinical trials, facts known by everyone, but
unsupported by any sort of clinical trial, sometimes prove to be
incorrect.

# Biological Plausibility and Scientific Reasoning

The two controlled clinical trials by Boozer, et al., were included
among the seven studies "coming to light" in the FDA notice, but the
fact that neither study found any evidence of clinically significant
cardiovascular effects, and that both found evidence of
treatment-related weight loss, was not mentioned. The omission is
especially worrisome because it goes to the issue of "biological
plausibility." If the oral ingestion of clinically relevant doses of
ephedra/ ephedrine has no clinically significant effect on pulse, or
blood pressure, and produces no measurable alterations in myocardial
function (and no controlled clinical trial has ever found otherwise),
why do so many people share the mistaken belief that ephedra/ephedrine
products cause stroke, or heart attack? In large part, because all of
the published observational studies, including the FDA's own reports,
routinely ignore established scientific facts that do not mesh with
their foregone conclusions. Selective literature citation might be
appropriate for writing of legal briefs, but it does little to help
resolve complex scientific issues.

Reference #4 in the FDA notice is a good example of the selective
citation process. This paper described the results of an uncontrolled,
open label pharmacokinetic trial of an ephedrine/caffeine (20 mg/200 mg)
combination (Haller, Jacob et al. 2002). The mean systolic pressure
transiently increased by 14 mmHg above baseline. The authors then cite
this observation as proof that "significant" cardiovascular responses
can occur after a single dose, although they fail to mention that in an
earlier study, by one of the same authors, similar systolic pressure
elevations occurred when just caffeine was ingested! The p value in the
new study is less than .001, so the results are statistically
significant, but are they clinically significant? Are they, in the other
accepted meaning of the word significant, important? The implication is
that they are. In fact, systolic pressure increases of more than 80 mm
are routine during normal exercise, and systolic pressure increases of
up to 220 mm are considered a normal response to the standard Bruce
treadmill testing protocol (Rosenberg, Froom et al. 1990). Indeed,
studies of ambulatory blood pressure have shown that mean systolic
pressure increases by 11.6 mmHg in individuals who change from a very
low level of physical activity, such as watching television, and then go
to the store to buy more snack foods (Cavelaars, M. et al. 2002).

By making it appear as if a transient 14 mmHg systolic blood pressure
elevation was significant, the study's authors leave readers with the
false impression that an important clinical finding has been reported,
even though nothing could be farther from the truth. As a consequence,
the suggestion that oral ephedra/ephedrine causes dangerous blood
pressure elevation then becomes embedded in the literature, where it is
endlessly repeated as established fact in other case reports, which are
then reported in the popular press.

FDA Reference #2 (Morgenstern, Viscoli et al. 2003) provides a good
example of how the process works. The paper, which was prepared with the
assistance of the author of FDA Reference #4, is listed as one of the
new studies "coming to light." It was included, presumably, because it
was thought to shed light on the possibility that use of ephedra
supplements was, in some way, related to the occurrence of hemorrhagic
stroke. Actually, the authors of the study concluded that their findings
"did not indicate an association between use of Ephedra-containing
products and risk for hemorrhagic stroke." This statement was reaffirmed
in post publication peer-reviewed comments published by the original
journal (Karch, 2003, Kernan et al. 2003).

In their reanalysis of the phenylpropanolamine data, the authors state
the "favored pathophysiologic basis for an association between Ephedra
and hemorrhagic stroke is enhanced catecholaminergic effects leading to
sharp blood pressure spikes." As proof that ephedra enhances
"catecholaminergic effects," the authors cite (what else?) FDA Reference
#4! In one stroke, what was an uncontrolled study of ephedra/ephedrine
pharmacokinetics is, thereby, transformed into established science,
proving not only that ephedra/ephedrine causes dangerous blood pressure
elevation, but that it also causes stroke (even though the authors of
the study did not find any evidence of causation for either).

Recently, suggestions have appeared in the popular press (but not in the
peer-reviewed medical literature) suggesting that ephedra/ephedrine can
result in dangerous body temperature elevation. In spite of the complete
lack of scientific evidence to support this contention, or perhaps
because of it, the reasoning of those making this claim follows much the
same pattern as the arguments made about ephedra and blood pressure. No
published peer-reviewed paper containing evidence of
ephedra/ephedrine-related hyperthermia has ever been published.
Ephedra/ephedrine does cause modest increases in energy expenditure, but
these increases are only on the order of 10 kcal per hour (Astrup,
Buemann et al. 1992). Normal physical exertion, such as slow- or
moderate-speed jogging, produces an increase in energy expenditure
amounting to more than 1000 calories per hour. Is it "biologically
plausible" to suggest that an increase in energy expenditure of less
than a 1% in any way increases the risk for hyperthermia? This line of
reasoning seems to confuse logical possibility with physical
possibility, and it ignores (selective citation again) the growing body
of evidence indicating that hyperthermia and sudden death in athletes
and young soldiers, is due to a genetic defect (Porter 2003).

Also arguing against the notion of biologic plausibility are the basic
facts of molecular biology, specifically basic receptor physiology.
Beta-receptor down regulation and internalization occurs fairly quickly
with ephedra/ephedrine use (Neve and Molinoff 1986; Williams, Barber et
al. 2000). Ephedra was displaced as a first-line asthma medication
because it rapidly loses its effect. As a consequence of these receptor
changes, the longer ephedra is used, the less likely it is to cause an
adverse event.

# Evidence Provided

Nearly six years have elapsed since the FDA's proposed rule on ephedra
was first published, and billions of servings of ephedra supplements
have been sold to million of users. In the interim, new controlled
clinical trials of ephedra/ ephedrine/caffeine combinations have been
published. These studies have confirmed the results of earlier studies,
and provided the authors of the Rand Report with sufficient data to
allow them to conclude that use of ephedra- and ephedrine-containing
supplements, resulted in weight loss. None of the recent controlled
trials, and none of the many earlier published clinical trials has
provided any evidence of cardiovascular toxicity.

The FDA notice reopening the period of comment, states, "recently, more
scientific evidence has come to light concerning the risks posed by
ephedrine alkaloids\..." The evidence appears to be comprised mainly of
the Rand Report, and six additional papers published since 2001. The FDA
provides, without comment, very brief summaries of the "new" studies,
but fails to mention other studies published contemporaneously with them
(Boozer, Nasser et al. 2001; Boozer, Daly et al. 2002; De Matteis, Arch
et al. 2002; Kalman, Incledon et al. 2002), let alone the large number
of previous published, peer reviewed, placebo controlled, clinical
trials that came before, none of which recorded any evidence of
cardiovascular toxicity. Even though the FDA notice also fails to
mention the existence of many early, controlled clinical trials, each of
these other control trials found that, in clinically relevant doses (or
"servings"), the cardiovascular effects of ephedra/ephedrine were
similar to those of placebo. Summaries of 56 of previously published
controlled clinical trials comparing ephedrine's effects, including
effects on pulse and blood pressure, to those of placebo are attached.

With the exception of the two clinical trials published by Boozer et
al., the new studies are all observational in nature, describing
possible relationships between ephedra/ephedrine use and adverse events.
Association is not the same thing as causation, especially when the
adverse event observed is very common. According to the American Heart
Association, every day more than 5000 Americans experience a myocardial
infarction. Some, no doubt, used ephedra/ephedrine-containing
supplements. It does not necessarily follow that ephedrine caused their
infarction.

One of the studies listed by the FDA, Reference #3, "evaluated the
adverse cardiovascular events from the FDA database that were temporally
associated with the use of ephedra (Reference #3) (Samenuk, Link et al.
2002)." This paper is a review of AERs received by the FDA from 1995 to
1997. Because the AERs are comprised of passively collected anecdotal
data, the authors of Reference #3 felt compelled to include in their
paper a disclaimer stating that "Our report does not prove causation,
nor does it provide quantitative information with regard to risk."

Another new piece of "scientific evidence" which recently came to
"light" was the Rand Report. That report is, in fact, a metanalysis of
previously published literature (excluding most of the 56 studies
attached to this letter), combined with still another analysis of the
same MedWatch reports already analyzed by Haller and Benowitz in their
New England Journal of Medicine article, of which Haller and Benowitz
have already written "Our report does not prove causation, nor does it
provide quantitative information with regard to risk (Haller and
Benowitz 2001)," and still another analysis of the 16,000 Metabolife
HealthLine contacts, comprised of data even less complete than MedWatch
reports.

In spite of significant methodological flaws in the Rand Report,
including use of an unpublished method for determining causation, and
the failure to include a pathologist in the panel investigating alleged
ephedra/ephedrine-related deaths, the Rand authors recognized that the
scientific value of observational data remains limited, no matter how
much of it is provided. They observed that (1) "the majority of FDA case
reports are insufficiently documented to make an informed judgment about
the relationship between the use of ephedra-containing supplements and
the adverse event in question," that (2) "nearly all of the (Metabolife)
case reports were too poorly documented to permit us to make any
judgments about the potential relationship between ephedra use and the
event," that (3) "identification of a sentinel event does not imply a
proven cause and effect relationship," and that (4) "scientific studies
(not additional case reports) are necessary in order to assess the
possible association between consumption of ephedra-containing dietary
supplements and these serious events."

The report concludes that, at most, the data provides enough evidence to
"warrant a hypothesis-testing study, such as a case-controlled study, to
support or refute the hypothesis that consumption of ephedra or
ephedrine may be casually related to these serious adverse events." In
fact, such a study has already been done. The paper by Morgenstern et
al. listed by the FDA as Reference #2, states that this is "the largest
case control study to investigate the association between Ephedra
alkaloids and specific adverse vascular effects." They also state that
(see above) their findings "did not indicate an association between use
of Ephedra-containing products and risk for hemorrhagic stroke."

The FDA's hesitancy to accept the result of the Morgenstern study is
understandable, since it was just a reanalysis of previously published
data relating to phenylpropanolamine (PPA) toxicity (Kernan, Viscoli et
al 2000). The methodology and conclusions of the original study have
been heavily criticized, largely because the PPA report also contained
data on non-PPA products such as phenylephedrine. This defect is likely
to be repeated in any attempted case-control study of ephedra/ephedrine
products, and if the results of a PPA study were deemed unreliable, the
similar doubts would apply to a study of ephedra/ephedrine as well.

Actually, the evidence for safety may be stronger than the Rand's
authors seem to realize. Rand expresses concerns that given their
methodology, and the relatively small number of individuals enrolled in
the few controlled trials which the Rand Report was willing to accept,
it is likely that rare, or uncommon, events will go undetected; "there
were no serious adverse events in the controlled trials of ephedrine or
ephedra, but these studies are insufficient to assess adverse events
that occurred at a rate of less than 1.0 per 1000." For rare disorders,
like Stevens-Johnson syndrome, that would certainly be the case.
However, no one has ever suggested that use of ephedra/ephedrine is
associated with the occurrence of exotic or rare disorders. The concern
is that ephedra/ephedrine causes heart attack, seizures, and stroke --
hardly uncommon disorders.

In the United States, the incidence of heart attack and stroke is closer
to 1 in 100 than 1 in 1000. In a recent study designed to measure the
effectiveness of aspirin in the prevention of myocardial infarction, the
rate of infarction in a placebo group of 23,407 volunteers, who had not
previously been diagnosed with heart disease, was 0.52 percent per year
(Mukherjee, Nissen et al. 2001), a frequency rate well within Rand's
stated detection limits. If Rand is, in fact, correct about the
sensitivity of its analysis, then their conclusions should have been
that they detected no evidence of increased risk with ephedra/ephedrine
use.

Finally, the "comparative case series," by Bent et al. (Reference #1) is
also based upon passively collected anecdotal case reports; in this
instance, telephone calls made to participating Poison Control Centers
(Bent, Tiedt et al. 2003). One observer determined the presence or
absence of ephedra/ephedrine toxicity by reviewing telephone calls logs,
using unspecified criteria. Many would question the value of such an
uncontrolled study.

# Omitted Trials

Both the FDA and Rand seem to have ignored clinical trials that did not
fit their preconceived hypothesis (that ephedra/ephedrine use is
associated with "heart attack, seizure, stroke, and death."). It may
well be that officials at Rand and the FDA reviewed all of the earlier
placebo-controlled clinical trials of ephedra and ephedrine and found
every one to be scientifically flawed, not worthy of mention. But, if
that were the case, the interest of science (and the public) would have
been better served if the studies had at least been acknowledged, and
the reasons for their rejection stated.

For example, a randomized double blind clinical trial of
ephedra/ephedrine's cardiovascular effects, including serial
electrocardiograms and Doppler echocardiography was not even mentioned
(Kalman, Incledon et al. 2002), and neither was a controlled clinical
trial of morbidly obese patients undergoing baratric surgery (De
Matteis, Arch et al. 2002). Treatment for one month with the
ephedrine/caffeine combination produced no measurable cardiovascular
effects, but it did upregulate the number of Beta3 receptors in white
fat cells, providing a scientific basis for the reality of
ephedra-related weight loss. A controlled clinical trial presented at
the 2002 International Congress of Obesity reported sustained (11
months) weight loss in obese volunteers treated with an
ephedrine/caffeine mixture (Filozof, et al., presented at the 2002
International Congress of Obesity, Sao Paolo, Brazil). It is difficult
to understand how the withholding of this information serves the public
interest.

It is also difficult to understand why both Rand and the FDA refuse to
consider the older asthma literature, published when the new
sympathomimetic agents, such as albuterol, were first introduced to the
market. Many double blind, placebo-controlled, published clinical trials
compared the effects of synthetic agents to ephedrine and to placebo
were published. For example, Banner et al. compared the respiratory and
circulatory effects of orally administered ephedrine sulfate, 25 mg,
aminophylline, 400 mg, terbutaline sulfate, 5 mg, and placebo in 20
patients with pre-existing ventricular arrhythmias, and severe chronic
lung disease using a double blind crossover method (Banner, Sunderrajan
et al. 1979). No adverse effects from ephedrine were observed. Surely,
the interest of balanced scientific discourse would have been better
served had these earlier studies (attached), been taken into account.

# 

# 

# Concluding Remarks

Anyone who has followed this debate closely knows that the scientific
issues were long ago eclipsed by concerns for advocacy. Instead of
reasoned-scientific discourse, the public is provided with sound bite
science, and arguments made by advocates who seem to ignore any data
contrary to their position. When the evidence against their position is
too great, they fall back to circular reasoning.

How else to explain the FDA's statement that "...This long experience
with synthetic ephedrine (in over-the-counter \[OTC\] drug products, not
in dietary supplements) suggests that significant restrictions on
labeling, marketing, and/or access to ephedrine might effectively
address unreasonable risks associated with certain forms of ephedra
today..."

How, one might ask, does it follow that the absence of problems with OTC
ephedra/ephedrine proves that problems are actually occurring with
ephedra/ ephedrine supplements? The possibility that ephedra/ephedrine
contained in herbal supplements is no more toxic than the
ephedra/ephedrine contained in OTC products, and that an illusory
increase in risk is only apparent because of a distorted reporting
system, is never even considered.

The new evidence that "has come to light" in no way justifies any of the
proposed label changes. There is already ample evidence, in published
placebo-controlled clinical trials, that use of
ephedra/ephedrine/caffeine combinations, in the form of dietary
supplements or prescription medications, causes people to lose weight,
and that it does so without posing any unreasonable risk.

Very truly yours,

Steven B. Karch, M.D.

References:

Astrup, A., B. Buemann, et al. (1992). "The effect of ephedrine/caffeine
mixture on energy expenditure and body composition in obese women."
Metabolism 41(7): 686-8.

Banner, A. S., E. V. Sunderrajan, et al. (1979). "Arrhythmogenic effects
of orally administered bronchodilators." Arch Intern Med 139(4): 434-7.

Bent, S., T. N. Tiedt, et al. (2003). "The relative safety of ephedra
compared with other herbal products." Ann Intern Med 138(6): 468-71.

Boozer, C. N., P. A. Daly, et al. (2002). "Herbal ephedra/caffeine for
weight loss: a 6-month randomized safety and efficacy trial." Int J Obes
Relat Metab Disord 26(5): 593-604.

Boozer, C. N., J. A. Nasser, et al. (2001). "An herbal supplement
containing Ma Huang-Guarana for weight loss: a randomized, double-blind
trial." Int J Obes Relat Metab Disord 25(3): 316-24.

Cavelaars, M., J. Tulen, J. van Bemmel, et al. (2002). "Determinants of
ambulatory pressure response to physical activity." J Hypertension
20:2009-2015.

Council on Scientific Affairs, A. M. A. (1993). "Silicone gel breast
implants." JAMA 270(21): 2602-2606.

De Matteis, R., J. R. Arch, et al. (2002). "Immunohistochemical
identification of the beta(3)-adrenoceptor in intact human adipocytes
and ventricular myocardium: effect of obesity and treatment with
ephedrine and caffeine." Int J Obes Relat Metab Disord 26(11): 1442 50.

Harrington DM. "Hormone replacement therapy and heart disease. Replacing
dogma with data." Circulation 2003;107:2-4.

Haller, C. A. and N. L. Benowitz (2001). "Dietary supplements containing
ephedra supplements." N Engl J Med 344(14): 1095-1096.

Haller, C. A., P. Jacob, 3rd, et al. (2002). "Pharmacology of ephedra
alkaloids and caffeine after single-dose dietary supplement use." Clin
Pharmacol Ther 71(6): 421-32.

Kalman, D., T. Incledon, et al. (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(10): 1363-6.

Karch, S. (2003). "Use of Ephedra-containing products and risk for
hemorrhagic stroke." Neurology, in press and online
(<http://www.neurology.org/cgi/eletters?lookup=by_date&days=28>).

Karch, S. (2002). "Karch's pathology of drug abuse, 3^rd^ edition." CRC
Press, Boca Raton, Florida.

Kernan, W. N., C. M. Viscoli, et al. (2000). "Phenylpropanolamine and
the risk of hemorrhagic stroke." N Engl J Med 343(25): 1826-32.

Laine, C. (2002). "Postmenopausal hormone replacement therapy: how could
we have been so wrong?" Ann Intern Med 137(4): 290.

Morgenstern, L. B., C. M. Viscoli, et al. (2003). "Use of
Ephedra-containing products and risk for hemorrhagic stroke." Neurology
60(1): 132-5.

Mukherjee, D., S. E. Nissen, et al. (2001). "Risk of cardiovascular
events associated with selective COX-2 inhibitors." JAMA 286(8): 954-9.

Neve, K. A. and P. B. Molinoff (1986). "Effects of chronic
administration of agonists and antagonists on the density of
beta-adrenergic receptors." Am J Cardiol 57(12): 17F-22F.

Porter, A. M. (2003). "Collapse from exertional heat illness:
implications and subsequent decisions." Mil Med 168(1): 76-81.

Rosenberg, E., P. Froom, et al. (1990). "Blood pressure response to
exercise in normotensive and hypertensive young men." Aviat Space
Environ Med 61(5): 433-5.

Samenuk, D., M. S. Link, et al. (2002). "Adverse cardiovascular events
temporally associated with ma huang, an herbal source of ephedrine."
Mayo Clin Proc 77(1): 12-6.

Shekelle P, Morton, S., Maglione M, et al. Ephedra and Ephedrine for
Weight Loss and Athletic Performance Enhancement: Clinical Efficacy and
Side Effects. Evidence Report/Technology Assessment No. 76 (Prepared by
Southern California Evidence-based Practice Center, RAND, under Contract
No 290-97-0001, Task Order No. 9). AHRQ Publication No. 03-E022.
Rockville, MD: Agency for Healthcare Research and Quality. February
2003.

Williams, B. R., R. Barber, et al. (2000). "Kinetic analysis of
agonist-induced down-regulation of the beta(2)-adrenergic receptor in
BEAS-2B cells reveals high- and low-affinity components." Mol Pharmacol
58(2): 421-30.

## Prior Clinical Trials of Ephedrine

+---+---+----------------+----+---+---+---+-----+----------------------+
| * | * | **Title**      | ** | * | * | * | **  | **Observed Effects** |
| * | * |                | Su | * | * | * | Dos |                      |
| R | Y |                | bj | D | A | T | e** |                      |
| e | e |                | ec | a | g | y |     |                      |
| f | a |                | ts | y | e | p |     |                      |
| \ | r |                | ** | s | * | e |     |                      |
| # | * |                |    | * | * | * |     |                      |
| * | * |                |    | * |   | * |     |                      |
| * |   |                |    |   |   |   |     |                      |
+---+---+----------------+----+---+---+---+-----+----------------------+
| * | 1 | Bronchodilator | 44 | 8 | A | D | 25  | No "side effects     |
| * | 9 | action of drug |    |   | d | B | or  | were noted after     |
| 1 | 6 | combinations   |    |   | u | P | 50  | orally administered  |
| * | 9 | in asthmatic   |    |   | l | C | mg  | ephedrine."          |
| * |   | patients:      |    |   | t |   | sin |                      |
|   |   | decloxizine,   |    |   |   |   | gle |                      |
|   |   | oricprenaline, |    |   |   |   | d   |                      |
|   |   | and ephedrine  |    |   |   |   | ose |                      |
+---+---+----------------+----+---+---+---+-----+----------------------+
| * | 1 | Comparison of  | 10 | 1 | 3 | D | 20  | \(1\) "no            |
| * | 9 | orciprenaline, |    |   | 4 | B | mg  | significant          |
| 2 | 7 | ephedrine and  |    |   | . | P | sin | alteration in pulse  |
| * | 3 | methyphenamine |    |   | 7 | C | gle | rates over the test  |
| * |   | as oral        |    |   |   |   | d   | period, (2) one      |
|   |   | b              |    |   |   |   | ose | given ephedrine      |
|   |   | ronchodilators |    |   |   |   |     | complained of        |
|   |   |                |    |   |   |   |     | tightness of the     |
|   |   |                |    |   |   |   |     | chest."              |
+---+---+----------------+----+---+---+---+-----+----------------------+
| * | 1 | Evaluation of  | 26 | 1 | 2 | D | 25  | "...No consistent    |
| * | 9 | a new beta2    |    |   | 8 | B | mg  | statistically        |
| 3 | 7 | adrenergic     |    |   | - | P | sin | significant          |
| * | 3 | receptor       |    |   | 6 | C | gle | differences in heart |
| * |   | stimulant,     |    |   | 1 |   | d   | rate were            |
|   |   | terbutaline,   |    |   |   |   | ose | observed...(2) no    |
|   |   | in bronchial   |    |   |   |   |     | significant changes  |
|   |   | asthma. Part   |    |   |   |   |     | with time or between |
|   |   | II: Oral       |    |   |   |   |     | the various agents   |
|   |   | comparison     |    |   |   |   |     | was observed with    |
|   |   | with ephedrine |    |   |   |   |     | regard to systolic   |
|   |   |                |    |   |   |   |     | or diastolic blood   |
|   |   |                |    |   |   |   |     | pressure."           |
+---+---+----------------+----+---+---+---+-----+----------------------+
| * | 1 | Evaluation of  | 12 | 7 | 6 | S | 1.3 | \(1\) Differences    |
| * | 9 | oral           |    |   | - | B | or  | from placebo in      |
| 4 | 7 | bronchodilator |    |   | 1 | P | 2.6 | pulse and blood      |
| * | 4 | therapy in     |    |   | 2 | C | mg  | pressure were "not   |
| * |   | asthmatic      |    |   |   |   | /kg | significant..."(2)   |
|   |   | children.      |    |   |   |   | ev  | When ephedrine was   |
|   |   | B              |    |   |   |   | ery | given alone, "little |
|   |   | ronchodilators |    |   |   |   | 6   | difference in the    |
|   |   | in asthmatic   |    |   |   |   | ho  | frequency of         |
|   |   | children       |    |   |   |   | urs | neurologic and       |
|   |   |                |    |   |   |   |     | gastrointestinal     |
|   |   |                |    |   |   |   |     | symptoms could be    |
|   |   |                |    |   |   |   |     | discerned when       |
|   |   |                |    |   |   |   |     | compared with        |
|   |   |                |    |   |   |   |     | placebo."            |
+---+---+----------------+----+---+---+---+-----+----------------------+
| * | 1 | Metaproterenol | 33 | 6 | 1 | D | 25  | Ephedrine caused a   |
| * | 9 | tablets: their |    |   | 8 | B | mg  | modest but           |
| 5 | 7 | duration of    |    |   | - | P | sin | statistically        |
| * | 5 | effect by      |    |   | 6 | C | gle | significant increase |
| * |   | comparison     |    |   | 5 |   | d   | in heart rate of     |
|   |   | with ephedrine |    |   |   |   | ose | 8.4-10.9 beats/min   |
|   |   |                |    |   |   |   |     | but no increases in  |
|   |   |                |    |   |   |   |     | systolic pressure    |
|   |   |                |    |   |   |   |     | and a decreases a    |
|   |   |                |    |   |   |   |     | diastolic pressure.  |
+---+---+----------------+----+---+---+---+-----+----------------------+
| * | 1 | Double-blind   | 20 | 1 | 3 | D | 25  | Modest but           |
| * | 9 | comparison of  |    |   | 6 | B | mg  | statistically        |
| 6 | 7 | acute          |    |   | . | P |     | significant          |
| * | 5 | bronchial and  |    |   | 7 | C |     | increases in heart   |
| * |   | cardiovascular |    |   |   |   |     | rate of 8.4-10.9     |
|   |   | effects of     |    |   |   |   |     | beats/min            |
|   |   | oral           |    |   |   |   |     |                      |
|   |   | terbutaline    |    |   |   |   |     |                      |
|   |   | and ephedrine  |    |   |   |   |     |                      |
+---+---+----------------+----+---+---+---+-----+----------------------+
| * | 1 | Interaction of | 23 | 7 | 4 | D | 1   | "None of the drugs   |
| * | 9 | ephedrine and  |    |   | t | B | 2.5 | given alone was      |
| 7 | 7 | theophylline   |    |   | o | P | or  | associated with      |
| * | 5 |                |    |   | 1 | C | 25  | significant adverse  |
| * |   |                |    |   | 4 |   | mg  | effects...but both   |
|   |   |                |    |   |   |   | ev  | ephedrine            |
|   |   |                |    |   |   |   | ery | theophylline         |
|   |   |                |    |   |   |   | 6   | combinations were    |
|   |   |                |    |   |   |   | ho  | associated with      |
|   |   |                |    |   |   |   | urs | insomnia,            |
|   |   |                |    |   |   |   |     | nervousness, and     |
|   |   |                |    |   |   |   |     | gastrointestinal     |
|   |   |                |    |   |   |   |     | complaints.          |
+---+---+----------------+----+---+---+---+-----+----------------------+
| 8 | 1 | Evaluation of  | 15 | 1 | 4 |   | 25  | "no significant      |
|   | 9 | a new oral     |    |   | 5 |   | mg, | differences were     |
|   | 7 | be             |    |   |   |   | sin | observed in          |
|   | 5 | ta2-adrenergic |    |   |   |   | gle | pretreatment control |
|   |   | stimulant      |    |   |   |   | d   | values. Terbutaline  |
|   |   | b              |    |   |   |   | ose | and ephedrine had    |
|   |   | ronchodilator, |    |   |   |   |     | negligible           |
|   |   | Terbutaline    |    |   |   |   |     | cardiovascular       |
|   |   |                |    |   |   |   |     | effects."            |
+---+---+----------------+----+---+---+---+-----+----------------------+
| * | 1 | Subsensitivity | 7  | 8 | A | O | 25  | Subjects were given  |
| * | 9 | to epinephrine |    |   | d | p | or  | oral ephedrine, 100  |
| 9 | 7 | following the  |    |   | u | e | 3   | or 150 mg/day, then  |
| * | 5 | administration |    |   | l | n | 7.5 | tested on a          |
| * |   | of epinephrine |    |   | t | l | mg  | treadmill after      |
|   |   | and ephedrine  |    |   |   | a | 4   | receiving            |
|   |   | to normal      |    |   |   | b | ti  | epinephrine          |
|   |   | individuals    |    |   |   | e | mes | (adrenaline)         |
|   |   |                |    |   |   | l | a   | intravenously.       |
|   |   |                |    |   |   |   | day | Responses to IV      |
|   |   |                |    |   |   |   |     | adrenaline were much |
|   |   |                |    |   |   |   |     | greater BEFORE       |
|   |   |                |    |   |   |   |     | ephedrine had been   |
|   |   |                |    |   |   |   |     | given -- treatment   |
|   |   |                |    |   |   |   |     | with ephedrine       |
|   |   |                |    |   |   |   |     | diminished the       |
|   |   |                |    |   |   |   |     | normal response to   |
|   |   |                |    |   |   |   |     | adrenaline.          |
+---+---+----------------+----+---+---+---+-----+----------------------+
| 1 | 1 | C              | 41 | 3 | 3 | D | 1   | Cardiovascular       |
| 0 | 9 | ardiopulmonary |    | 6 | 0 | B | 2.5 | changes were of      |
|   | 7 | effects of     |    | 5 |   | P | mg  | "relatively small    |
|   | 6 | long-term      |    |   |   | C | or  | magnitude. Over the  |
|   |   | b              |    |   |   |   | 25  | year of              |
|   |   | ronchiodilator |    |   |   |   | mg  | investigation        |
|   |   | administration |    |   |   |   | ev  | baseline systolic    |
|   |   |                |    |   |   |   | ery | pressure and         |
|   |   |                |    |   |   |   | 6   | diastolic pressure   |
|   |   |                |    |   |   |   | ho  | progressively fell,  |
|   |   |                |    |   |   |   | urs | particularly during  |
|   |   |                |    |   |   |   |     | the last 6           |
|   |   |                |    |   |   |   |     | months...baseline    |
|   |   |                |    |   |   |   |     | heart rate changed   |
|   |   |                |    |   |   |   |     | little..."           |
+---+---+----------------+----+---+---+---+-----+----------------------+
| 1 | 1 | The            | 10 | 1 | A | O | 22  | No significant       |
| 1 | 9 | ph             |    |   | d | p | mg, | effect on blood      |
|   | 7 | armacokinetics |    |   | u | e | one | pressure described   |
|   | 6 | of ephedrine   |    |   | l | n | d   | ."                   |
|   |   | after oral     |    |   | t | l | ose |                      |
|   |   | dosage in      |    |   |   | a |     |                      |
|   |   | asthmatics     |    |   |   | b |     |                      |
|   |   | receiving      |    |   |   | e |     |                      |
|   |   | acute and      |    |   |   | l |     |                      |
|   |   | chronic        |    |   |   |   |     |                      |
|   |   | treatment      |    |   |   |   |     |                      |
+---+---+----------------+----+---+---+---+-----+----------------------+
| * | 1 | The acute and  | 8  | 1 | A | D | 22  | "resulted in a       |
| * | 9 | chronic        |    | 4 | d | B | mg  | significant mean     |
| 1 | 7 | bronchodilator |    |   | u | C | per | increase in heart    |
| 2 | 5 | effects of     |    |   | l |   | day | rate of 9.5          |
| * |   | ephedrine in   |    |   | t |   |     | beats/min...there    |
| * |   | asthmatic      |    |   |   |   |     | was no significant   |
|   |   | patients       |    |   |   |   |     | change in mean       |
|   |   |                |    |   |   |   |     | systolic and         |
|   |   |                |    |   |   |   |     | diastolic blood      |
|   |   |                |    |   |   |   |     | pressure."           |
+---+---+----------------+----+---+---+---+-----+----------------------+
| * | 1 | C              | 41 | 5 | A | O | 25  | "Baseline blood      |
| * | 9 | ardiopulmonary |    | 0 | d | p | mg  | pressure,            |
| 1 | 7 | effects of     |    | 4 | u | e | 3   | particularly         |
| 3 | 7 | long-term      |    |   | l | n | ti  | diastolic, declined  |
| * |   | bronchodilator |    |   | t | L | mes | progressively with   |
| * |   | administration |    |   |   | a | a   | continued drug use.  |
|   |   |                |    |   |   | b | day | No evidence of       |
|   |   |                |    |   |   | e |     | cardiac, hepatic,    |
|   |   |                |    |   |   | l |     | renal, or            |
|   |   |                |    |   |   |   |     | ophthalmologic       |
|   |   |                |    |   |   |   |     | toxicity, or need    |
|   |   |                |    |   |   |   |     | for changes in       |
|   |   |                |    |   |   |   |     | bronchodilator       |
|   |   |                |    |   |   |   |     | agents, was noted    |
|   |   |                |    |   |   |   |     | during the study."   |
+---+---+----------------+----+---+---+---+-----+----------------------+
| * | 1 | Terbutaline    | 24 | 8 | 7 | D | 25  | "clinically          |
| * | 9 | and ephedrine  |    | 4 | t | B | mg  | insignificant        |
| 1 | 7 | in asthmatic   |    |   | o | P | ev  | changes in blood     |
| 4 | 7 | children       |    |   | 1 | C | ery | pressure and pulse." |
| * |   |                |    |   | 3 |   | 8   |                      |
| * |   |                |    |   |   |   | ho  |                      |
|   |   |                |    |   |   |   | urs |                      |
+---+---+----------------+----+---+---+---+-----+----------------------+
| * | 1 | Ephedrine      | 16 | 5 | 7 | D | 25  | "There were no       |
| * | 9 | therapy in     |    | 6 | - | B | mg  | significant changes  |
| 1 | 7 | asthmatic      |    |   | 1 | P | ev  | between groups for   |
| 5 | 7 | children.      |    |   | 3 | C | ery | pulse or blood       |
| * |   | Clinical       |    |   |   |   | 8   | pressure."           |
| * |   | tolerance and  |    |   |   |   | ho  |                      |
|   |   | absence of     |    |   |   |   | urs |                      |
|   |   | side effects.  |    |   |   |   |     |                      |
+---+---+----------------+----+---+---+---+-----+----------------------+
| * | 1 | Clinical       | 28 | 9 | A | D | 24  | \(1\) "no            |
| * | 9 | investigation  |    | 0 | d | B | mg  | appreciable          |
| 1 | 7 | of fenoterol,  |    |   | u | P | 3   | consistent changes   |
| 6 | 7 | a new          |    |   | l | C | or  | in blood pressures   |
| * |   | b              |    |   | t |   | 4   | or pulse were noted; |
| * |   | ronchodilator, |    |   |   |   | ti  | (2) no abnormal      |
|   |   | in asthma      |    |   |   |   | mes | changes were seen in |
|   |   |                |    |   |   |   | a   | the EKG, physical    |
|   |   |                |    |   |   |   | day | examination, or      |
|   |   |                |    |   |   |   |     | blood and urine      |
|   |   |                |    |   |   |   |     | studies in any       |
|   |   |                |    |   |   |   |     | patient."            |
+---+---+----------------+----+---+---+---+-----+----------------------+
| * | 1 | Comparison of  | 20 | 1 | 5 | D | 25  | "no significant      |
| * | 9 | the            |    |   | 4 | B | mg  | drug-response        |
| 1 | 7 | bronchodilator |    |   | . | P |     | relationship was     |
| 7 | 7 | effects of     |    |   | 9 | C |     | noted for pulse rate |
| * |   | oral therapy   |    |   |   |   |     | or blood pressures,  |
| * |   | with Fenoterol |    |   |   |   |     | and side effects     |
|   |   | hydrobromide   |    |   |   |   |     | (eg, shakiness,      |
|   |   | and ephedrine  |    |   |   |   |     | nervousness) were    |
|   |   |                |    |   |   |   |     | minimal"             |
+---+---+----------------+----+---+---+---+-----+----------------------+
| * | 1 | The            | 20 | 1 | 6 | D | 48  | "modest decreases in |
| * | 9 | car            |    | 4 | 1 | B | mg, | systolic and         |
| 1 | 7 | diorespiratory |    |   |   | P | ti  | diastolic blood      |
| 8 | 8 | effects of     |    |   |   | C | med | pressure."           |
| * |   | oral           |    |   |   |   | re  |                      |
| * |   | terbutaline    |    |   |   |   | lea |                      |
|   |   | and an         |    |   |   |   | se, |                      |
|   |   | ephedrin       |    |   |   |   | ev  |                      |
|   |   | e-theophylline |    |   |   |   | ery |                      |
|   |   | -phenobarbital |    |   |   |   | 12  |                      |
|   |   | combination:   |    |   |   |   | ho  |                      |
|   |   | comparison in  |    |   |   |   | urs |                      |
|   |   | patients with  |    |   |   |   |     |                      |
|   |   | chronic        |    |   |   |   |     |                      |
|   |   | obstructive    |    |   |   |   |     |                      |
|   |   | ventilatory    |    |   |   |   |     |                      |
|   |   | disorders      |    |   |   |   |     |                      |
+---+---+----------------+----+---+---+---+-----+----------------------+
| * | 1 | Controlled     | 24 | 2 | 4 | D | 25  | \(1\) Pulse and      |
| * | 9 | comparison of  |    | 4 | 3 | B | mg  | blood pressure       |
| 1 | 7 | Neulin,        |    |   |   | P | 3   | changes were not     |
| 9 | 8 | Theodrox, and  |    |   |   | C | ti  | recorded; no serious |
| * |   | Marax in       |    |   |   |   | mes | adverse events       |
| * |   | asthmatic      |    |   |   |   | a   | reported; (2)        |
|   |   | out-patients   |    |   |   |   | day | "During Marax        |
|   |   |                |    |   |   |   |     | (ephedrine with      |
|   |   |                |    |   |   |   |     | hydroxizine and      |
|   |   |                |    |   |   |   |     | theophylline) the    |
|   |   |                |    |   |   |   |     | patients reported a  |
|   |   |                |    |   |   |   |     | high incidence of    |
|   |   |                |    |   |   |   |     | side-effects,        |
|   |   |                |    |   |   |   |     | especially           |
|   |   |                |    |   |   |   |     | palpitation and      |
|   |   |                |    |   |   |   |     | tremor."             |
+---+---+----------------+----+---+---+---+-----+----------------------+
| * | 1 | A comparison   | 10 | 1 | A | S | 48  | "no significant      |
| * | 9 | of             |    | 4 | d | B | mg  | changes occurred in  |
| 2 | 7 | theophyl       |    |   | u | P | ti  | the mean systolic or |
| 0 | 8 | line-ephedrine |    |   | l | C | med | diastolic blood      |
| * |   | combination    |    |   | t |   | r   | pressure or pulse    |
| * |   | with           |    |   |   |   | ele | rate."               |
|   |   | terbutaline    |    |   |   |   | ase |                      |
|   |   |                |    |   |   |   | ev  |                      |
|   |   |                |    |   |   |   | ery |                      |
|   |   |                |    |   |   |   | 12  |                      |
|   |   |                |    |   |   |   | ho  |                      |
|   |   |                |    |   |   |   | urs |                      |
+---+---+----------------+----+---+---+---+-----+----------------------+
| * | 1 | Comparative    | 16 | 7 | 2 | D | 25  | No adverse events    |
| * | 9 | effects of     |    | - | 3 | B | mg  | reported; pulse and  |
| 2 | 7 | ephedrine on   |    | 1 |   | P | 4   | blood pressure       |
| 1 | 8 | adrenergic     |    | 0 |   | C | ti  | measurements not     |
| * |   | responsiveness |    | d |   |   | mes | reported             |
| * |   | in normal and  |    | a |   |   | per |                      |
|   |   | asthmatic      |    | y |   |   | day |                      |
|   |   | subjects       |    | s |   |   |     |                      |
+---+---+----------------+----+---+---+---+-----+----------------------+
| * | [ | Controlled     | 29 | 1 | 6 | D | 24  | "no distressing      |
| * | 1 | assessment of  |    |   | - | B | mg, | subjective side      |
| 2 | 9 | oral           |    |   | 1 | P | sin | effects were noted"  |
| 2 | 7 | b              |    |   | 6 | C | gle |                      |
| * | 9 | ronchodilators |    |   | y |   | d   |                      |
| * | ] | for asthmatic  |    |   | e |   | ose |                      |
|   | { | children       |    |   | a |   |     |                      |
|   | . |                |    |   | r |   |     |                      |
|   | u |                |    |   | s |   |     |                      |
|   | n |                |    |   |   |   |     |                      |
|   | d |                |    |   |   |   |     |                      |
|   | e |                |    |   |   |   |     |                      |
|   | r |                |    |   |   |   |     |                      |
|   | l |                |    |   |   |   |     |                      |
|   | i |                |    |   |   |   |     |                      |
|   | n |                |    |   |   |   |     |                      |
|   | e |                |    |   |   |   |     |                      |
|   | } |                |    |   |   |   |     |                      |
+---+---+----------------+----+---+---+---+-----+----------------------+
| * | 1 | Arrhythmogenic | 20 | 1 | 6 | D |     | All subjects had     |
| * | 9 | effects of     |    |   | 2 | B |     | preexisting heart    |
| 2 | 7 | orally         |    |   |   | P |     | disease; one patient |
| 3 | 9 | administered   |    |   |   | C |     | in the ephedrine     |
| * |   | b              |    |   |   |   |     | group had            |
| * |   | ronchodilators |    |   |   |   |     | ventricular          |
|   |   |                |    |   |   |   |     | tachycardia BUT      |
|   |   |                |    |   |   |   |     | before the ephedrine |
|   |   |                |    |   |   |   |     | was given. "No       |
|   |   |                |    |   |   |   |     | significant changes  |
|   |   |                |    |   |   |   |     | in blood pressure"   |
|   |   |                |    |   |   |   |     | compared to placebo, |
|   |   |                |    |   |   |   |     | increase in heart    |
|   |   |                |    |   |   |   |     | rate of 3 beats per  |
|   |   |                |    |   |   |   |     | minutes 3 hours      |
|   |   |                |    |   |   |   |     | after ingestion.     |
+---+---+----------------+----+---+---+---+-----+----------------------+
| * | 1 | A comparative  | 12 | 1 | 3 | D | 25  | \(1\) "no            |
| * | 9 | study of       |    | 0 | 5 | B | mg  | significant change   |
| 2 | 7 | bronchodilator |    |   |   | P | 3   | in heart rate and    |
| 4 | 9 | effects of     |    |   |   | C | ti  | systolic or          |
| * |   | carbuterol and |    |   |   |   | mes | diastolic BP. (2)    |
| * |   | ephedrine      |    |   |   |   | per | CBC, blood chemistry |
|   |   |                |    |   |   |   |     | tests, ECG, and      |
|   |   |                |    |   |   |   | day | urinalysis were      |
|   |   |                |    |   |   |   |     | normal for all       |
|   |   |                |    |   |   |   |     | subjects."           |
+---+---+----------------+----+---+---+---+-----+----------------------+
| * | 1 | Objective and  | 11 | 4 | 4 | D | 25  | "The side-effects    |
| * | 9 | subjective     |    |   | 7 | B | mg  | (tachycardia,        |
| 2 | 7 | assessment of  |    |   | - | P | 3   | sedation, tremor)    |
| 5 | 9 | ephedrine      |    |   | 6 | C | ti  | experienced were not |
| * |   | combinations   |    |   | 7 |   | mes | particularly         |
| * |   | in asthmatic   |    |   |   |   | per | stressing, and they  |
|   |   | outpatients    |    |   |   |   | day | were sometimes       |
|   |   |                |    |   |   |   |     | reported during      |
|   |   |                |    |   |   |   |     | placebo."            |
+---+---+----------------+----+---+---+---+-----+----------------------+
| * | 1 | A comparison   | 16 | 1 | A | D | 48  | "no significant      |
| * | 9 | of the         |    |   | d | B | mg  | changes occurred in  |
| 2 | 7 | bronchodilator |    |   | u | C | ti  | systolic or          |
| 6 | 9 | effects of     |    |   | l |   | med | diastolic pressure   |
| * |   | terbutaline,   |    |   | t |   | re  | following ingestion  |
| * |   | tedral and the |    |   |   |   | lea | of either agent      |
|   |   | simultaneous   |    |   |   |   | se, | singly or in         |
|   |   | use of both    |    |   |   |   | o   | combination."        |
|   |   | agents         |    |   |   |   | nce |                      |
+---+---+----------------+----+---+---+---+-----+----------------------+
| * | 1 | Safety and     | 15 | 8 | 7 | D | 25  | "Treatment was not   |
| * | 9 | effectiveness  |    | 4 | - | V | mg  | associated with any  |
| 2 | 7 | of terbutaline |    |   | 1 | P | 3   | changes in either    |
| 7 | 9 | in children    |    |   | 4 | C | or  | systolic or          |
| * |   | with chronic   |    |   |   |   | 4   | diastolic blood      |
| * |   | asthma         |    |   |   |   | ti  | pressures. The heart |
|   |   |                |    |   |   |   | mes | rate showed          |
|   |   |                |    |   |   |   | a   | significant peak     |
|   |   |                |    |   |   |   | day | increases of 8 to 10 |
|   |   |                |    |   |   |   |     | beats per minute at  |
|   |   |                |    |   |   |   |     | one to two hours     |
|   |   |                |    |   |   |   |     | after                |
|   |   |                |    |   |   |   |     | administration..."   |
+---+---+----------------+----+---+---+---+-----+----------------------+
| * | 1 | C              | 16 | 1 | 5 | D | 25  | Continuous EKG       |
| * | 9 | ardiopulmonary |    |   | 7 | B | mg, | monitoring for 16    |
| 2 | 8 | effects of     |    |   |   | P | sin | hours; (1) no effect |
| 8 | 0 | terbutaline    |    |   |   | C | gle | on "frequency of     |
| * |   | and a          |    |   |   |   | d   | ventricular          |
| * |   | bronchodilator |    |   |   |   | ose | premature beats or   |
|   |   | combination in |    |   |   |   |     | complex              |
|   |   | chronic        |    |   |   |   |     | dysrhythmias; (2)    |
|   |   | obstructive    |    |   |   |   |     | increased heart rate |
|   |   | pulmonary      |    |   |   |   |     | ten beats per        |
|   |   | disease        |    |   |   |   |     | minute, but no       |
|   |   |                |    |   |   |   |     | changes in blood     |
|   |   |                |    |   |   |   |     | pressure occurred."  |
+---+---+----------------+----+---+---+---+-----+----------------------+
| * | 1 | Combined vs.   | 12 | 1 | 2 | D | 25  | "Side effects        |
| * | 9 | single-entity  |    |   | 9 | B | mg  | reported during the  |
| 2 | 8 | pharmacologic  |    |   | . | P | sin | study did not        |
| 9 | 0 | inhibition of  |    |   | 8 | C | gle | significantly        |
| * |   | induced asthma |    |   |   |   | d   | interfere with       |
| * |   |                |    |   |   |   | ose | patients'            |
|   |   |                |    |   |   |   |     | functioning."        |
|   |   |                |    |   |   |   |     | Changes in pulse and |
|   |   |                |    |   |   |   |     | blood pressure not   |
|   |   |                |    |   |   |   |     | specifically         |
|   |   |                |    |   |   |   |     | mentioned.           |
+---+---+----------------+----+---+---+---+-----+----------------------+
| * | 1 | Scopolamine    | 30 | 5 | 2 | D | 25  | Changes in pulse and |
| * | 9 | alone or       |    |   | 0 | B | mg  | blood pressure not   |
| 3 | 8 | combined with  |    |   | - | P | 3   | mentioned; no        |
| 0 | 1 | ephedrine in   |    |   | 2 | C | ti  | significant medical  |
| * |   | seasickness: a |    |   | 4 |   | mes | complications        |
| * |   | double-blind,  |    |   |   |   | a   | reported.            |
|   |   | plac           |    |   |   |   | day |                      |
|   |   | ebo-controlled |    |   |   |   |     |                      |
|   |   | study.         |    |   |   |   |     |                      |
+---+---+----------------+----+---+---+---+-----+----------------------+
| * | 1 | An             | 73 | 1 | 2 | S | 15  | Blood pressure and   |
| * | 9 | a              |    | 4 | 8 | B | mg  | pulse not            |
| 3 | 8 | ntihistamine-s |    |   | . | C | t   | specifically stated. |
| 1 | 1 | ympathomimetic |    |   | 5 |   | ime | No medical           |
| * |   | combination in |    |   |   |   | r   | complications        |
| * |   | the treatment  |    |   |   |   | ele | reported. Patients   |
|   |   | of hayfever    |    |   |   |   | ase | taking ephedrine in  |
|   |   |                |    |   |   |   | da  | combination with     |
|   |   |                |    |   |   |   | ily | antihistamine        |
|   |   |                |    |   |   |   |     | reported fewer side  |
|   |   |                |    |   |   |   |     | effects than those   |
|   |   |                |    |   |   |   |     | taking just          |
|   |   |                |    |   |   |   |     | antihistamine.       |
+---+---+----------------+----+---+---+---+-----+----------------------+
| * | 1 | A comparison   | 12 | 1 | A | D | 60  | "Differences (from   |
| * | 9 | of the         |    |   | d | B | mg, | controls) were not   |
| 3 | 8 | bronchodilator |    |   | u | P | one | significant for      |
| 2 | 2 | action of      |    |   | l | C | d   | heart rate or blood  |
| * |   | p              |    |   | t |   | ose | pressure."           |
| * |   | seudoephedrine |    |   |   |   |     |                      |
|   |   | and ephedrine  |    |   |   |   |     |                      |
|   |   | in patients    |    |   |   |   |     |                      |
|   |   | with           |    |   |   |   |     |                      |
|   |   | reversible     |    |   |   |   |     |                      |
|   |   | airway         |    |   |   |   |     |                      |
|   |   | obstruction    |    |   |   |   |     |                      |
+---+---+----------------+----+---+---+---+-----+----------------------+
| * | 1 | Comparison of  | 16 | 1 | 9 | D | 24  | \(1\) "complete      |
| * | 9 | the            |    |   |   | B | mg  | blood count, SMA 12, |
| 3 | 8 | bronchodilator |    |   |   | P | o   | urinalysis and       |
| 3 | 2 | effect of oral |    |   |   | C | nce | electrocardiograms   |
| * |   | fenoterol and  |    |   |   |   |     | were all normal      |
| * |   | ephedrine in   |    |   |   |   |     | before and after     |
|   |   | asthmatic      |    |   |   |   |     | drug administration; |
|   |   | children       |    |   |   |   |     | (2) one patient      |
|   |   |                |    |   |   |   |     | reported tachycardia |
|   |   |                |    |   |   |   |     | while on ephedrine   |
|   |   |                |    |   |   |   |     | and two thought      |
|   |   |                |    |   |   |   |     | their hearts were    |
|   |   |                |    |   |   |   |     | beating faster on    |
|   |   |                |    |   |   |   |     | placebo."            |
+---+---+----------------+----+---+---+---+-----+----------------------+
| * | 1 | A controlled   | 46 | 9 | 3 | D | 25  | "Mean systolic       |
| * | 9 | trial using    |    | 0 | 3 | B | or  | pressure...showed a  |
| 3 | 8 | ephedrine in   |    |   | - | P | 50  | significant decrease |
| 4 | 5 | the treatment  |    |   | 3 | C | mg  | in all               |
| * |   | of obesity     |    |   | 7 |   | 3   | groups...patients    |
| * |   |                |    |   |   |   | ti  | treated with 150 mg  |
|   |   |                |    |   |   |   | mes | per day of ephedrine |
|   |   |                |    |   |   |   | a   | showed a significant |
|   |   |                |    |   |   |   | day | increase in pulse    |
|   |   |                |    |   |   |   |     | rate of 3.6 beats    |
|   |   |                |    |   |   |   |     | per minute." No      |
|   |   |                |    |   |   |   |     | major adverse events |
|   |   |                |    |   |   |   |     | reported, but        |
|   |   |                |    |   |   |   |     | patients receiving   |
|   |   |                |    |   |   |   |     | 150 mg per day       |
|   |   |                |    |   |   |   |     | complained of more   |
|   |   |                |    |   |   |   |     | side effects         |
|   |   |                |    |   |   |   |     | (insomnia, headache, |
|   |   |                |    |   |   |   |     | constipation) than   |
|   |   |                |    |   |   |   |     | placebo controls.    |
+---+---+----------------+----+---+---+---+-----+----------------------+
| * | 1 | The effect of  | 23 | 7 |   |   | 25  | "one subject         |
| * | 9 | d-amphetamine  |    |   |   |   | or  | "tolerated the 25 mg |
| 3 | 8 | and ephedrine  |    |   |   |   | 50  | ephedrine three      |
| 5 | 4 | on smoking     |    |   |   |   | mg  | times a day without  |
| * |   | attitude and   |    |   |   |   | 3   | ill effect...on the  |
| * |   | behavior       |    |   |   |   | ti  | higher dose of       |
|   |   |                |    |   |   |   | mes | ephedrine (he)       |
|   |   |                |    |   |   |   | a   | experience           |
|   |   |                |    |   |   |   | day | pronounced sleep     |
|   |   |                |    |   |   |   |     | disturbance,         |
|   |   |                |    |   |   |   |     | anxiety, and         |
|   |   |                |    |   |   |   |     | difficulty           |
|   |   |                |    |   |   |   |     | controlling his      |
|   |   |                |    |   |   |   |     | temper." No medical  |
|   |   |                |    |   |   |   |     | complications        |
|   |   |                |    |   |   |   |     | reported; pulse and  |
|   |   |                |    |   |   |   |     | blood pressure not   |
|   |   |                |    |   |   |   |     | specifically stated. |
+---+---+----------------+----+---+---+---+-----+----------------------+
| * | 1 | Does ephedrine | 10 | 6 | 2 | D | 50  | "None of the         |
| * | 9 | promote weight |    | 0 | 8 | B | mg  | patients showed      |
| 3 | 8 | loss in        |    |   | . | P | 3   | clinically important |
| 6 | 7 | low-energy     |    |   | 7 | C | ti  | side effects." Pulse |
| * |   | adapted obese  |    |   |   |   | mes | and blood pressure   |
| * |   | women?         |    |   |   |   | a   | not specifically     |
|   |   |                |    |   |   |   | day | stated               |
+---+---+----------------+----+---+---+---+-----+----------------------+
| * | 1 | Ephedrine,     | 29 | 7 |   |   | 25  | "No differences      |
| * | 9 | caffeine and   |    | 0 |   |   | mg  | between the groups   |
| 3 | 9 | aspirin        |    |   |   |   | 3   | were noted in        |
| 7 | 0 | promote weight |    |   |   |   | ti  | resting heart rate,  |
| * |   | loss in obese  |    |   |   |   | mes | blood pressure,      |
| * |   | subjects       |    |   |   |   | day | fasting plasma       |
|   |   |                |    |   |   |   | for | glucose, insulin or  |
|   |   |                |    |   |   |   | 4   | total cholesterol    |
|   |   |                |    |   |   |   | wee | concentrations.      |
|   |   |                |    |   |   |   | ks, | Although the         |
|   |   |                |    |   |   |   | t   | treatment subjects   |
|   |   |                |    |   |   |   | hen | tended to report     |
|   |   |                |    |   |   |   | 50  | transient            |
|   |   |                |    |   |   |   | mg  | jitteriness and      |
|   |   |                |    |   |   |   | 4   | transient dry mouth, |
|   |   |                |    |   |   |   | ti  | there were no        |
|   |   |                |    |   |   |   | mes | difference in these  |
|   |   |                |    |   |   |   | da  | side effects between |
|   |   |                |    |   |   |   | ily | treatment and        |
|   |   |                |    |   |   |   | for | placebo."            |
|   |   |                |    |   |   |   | 4   |                      |
|   |   |                |    |   |   |   | we  |                      |
|   |   |                |    |   |   |   | eks |                      |
+---+---+----------------+----+---+---+---+-----+----------------------+
| * | 1 | Thermogenic,   | 6  | 1 | 2 | D | 10, | \(1\) "Ephedrine     |
| * | 9 | metabolic, and |    |   | 5 | B | 20, | increased heart rate |
| 3 | 9 | cardiovascular |    |   |   | P | and | dose dependently,    |
| 8 | 3 | responses to   |    |   |   | C | 40  | however the average  |
| * |   | ephedrine and  |    |   |   |   | mg  | increases were       |
| * |   | caffeine in    |    |   |   |   | do  | small, apart from    |
|   |   | man.           |    |   |   |   | ses | the 40 mg dose which |
|   |   |                |    |   |   |   |     | increase heart rate  |
|   |   |                |    |   |   |   |     | by 7 beats per       |
|   |   |                |    |   |   |   |     | minute; (2)          |
|   |   |                |    |   |   |   |     | Ephedrine had no     |
|   |   |                |    |   |   |   |     | statistically        |
|   |   |                |    |   |   |   |     | significant effect   |
|   |   |                |    |   |   |   |     | on arterial blood    |
|   |   |                |    |   |   |   |     | pressure."           |
+---+---+----------------+----+---+---+---+-----+----------------------+
| * | 1 | Exercise       | 6  | 1 | 2 | D | 50  | "ephedrine increased |
| * | 9 | alters the     |    |   | 1 | B | mg  | heart rate and       |
| 3 | 9 | ph             |    |   |   | P | sin | systolic blood       |
| 9 | 2 | armacokinetics |    |   |   | C | gle | pressure 2 hours     |
| * |   | of midazolam   |    |   |   |   | d   | after drug           |
| * |   |                |    |   |   |   | ose | administration. The  |
|   |   |                |    |   |   |   |     | heart rate was even  |
|   |   |                |    |   |   |   |     | higher after         |
|   |   |                |    |   |   |   |     | exercise. Diastolic  |
|   |   |                |    |   |   |   |     | blood pressure       |
|   |   |                |    |   |   |   |     | remained             |
|   |   |                |    |   |   |   |     | unaffected..."       |
+---+---+----------------+----+---+---+---+-----+----------------------+
| * | 1 | The effect of  | 14 | 5 | A | D | 20  | No side effects      |
| * | 9 | ephe           |    | 6 | d | B | mg  | described; effects   |
| 4 | 9 | drine/caffeine |    |   | u | P | 3   | on pulse and blood   |
| 0 | 2 | mixture on     |    |   | l | C | ti  | pressure not         |
| * |   | energy         |    |   | t |   | mes | reported.            |
| * |   | expenditure    |    |   |   |   | a   |                      |
|   |   | and body       |    |   |   |   | day |                      |
|   |   | composition in |    |   |   |   |     |                      |
|   |   | obese women    |    |   |   |   |     |                      |
+---+---+----------------+----+---+---+---+-----+----------------------+
| 4 | 1 | The effect and | 1  | 1 | 3 | D |     | "Side effects        |
| 1 | 9 | safety of an   | 80 | 6 | 6 | B |     | (tremor, insomnia    |
|   | 9 | ephe           |    | 8 |   | P |     | and dizziness)) were |
|   | 3 | drine/caffeine |    |   |   | C |     | transient and after  |
|   |   | compound       |    |   |   |   |     | eight weeks of       |
|   |   | compared to    |    |   |   |   |     | treatment they had   |
|   |   | ephedrine,     |    |   |   |   |     | reached placebo      |
|   |   | caffeine and   |    |   |   |   |     | levels. Systolic and |
|   |   | placebo in     |    |   |   |   |     | diastolic blood      |
|   |   | obese subjects |    |   |   |   |     | pressure fell        |
|   |   | on an energy   |    |   |   |   |     | similarly in all     |
|   |   | restricted     |    |   |   |   |     | four groups."        |
|   |   | diet -- a      |    |   |   |   |     |                      |
|   |   | double blind   |    |   |   |   |     |                      |
|   |   | trial          |    |   |   |   |     |                      |
+---+---+----------------+----+---+---+---+-----+----------------------+
| * | 1 | Safety and     | 45 | 1 | 3 | D | 20  | \(1\) "Systolic and  |
| * | 9 | efficacy of    |    | 6 | 6 | B | mg  | diastolic blood      |
| 4 | 9 | long-term      |    | 8 |   | P | 3   | pressure decreased   |
| 2 | 3 | treatment with |    |   |   | C | ti  | significantly in all |
| * |   | ephedrine,     |    |   |   |   | mes | treatment            |
| * |   | caffeine and   |    |   |   |   | a   | groups...mean heart  |
|   |   | an             |    |   |   |   | day | rate decreased 4-6   |
|   |   | ephe           |    |   |   |   |     | beats/min only in    |
|   |   | drine/caffeine |    |   |   |   |     | the caffeine and     |
|   |   | mixture        |    |   |   |   |     | placebo treated      |
|   |   |                |    |   |   |   |     | groups; (2) All      |
|   |   |                |    |   |   |   |     | measured variables   |
|   |   |                |    |   |   |   |     | such as full blood   |
|   |   |                |    |   |   |   |     | count, sodium,       |
|   |   |                |    |   |   |   |     | potassium,           |
|   |   |                |    |   |   |   |     | bilirubin, liver     |
|   |   |                |    |   |   |   |     | enzymes, creatinine, |
|   |   |                |    |   |   |   |     | uric acid, and       |
|   |   |                |    |   |   |   |     | urinalysis all were  |
|   |   |                |    |   |   |   |     | without any          |
|   |   |                |    |   |   |   |     | significant group    |
|   |   |                |    |   |   |   |     | differences."        |
+---+---+----------------+----+---+---+---+-----+----------------------+
| * | 1 | Ephedrine,     | 24 | 7 | 3 | D | 75  | "no significant      |
| * | 9 | caffeine and   |    | 2 | 6 | B | or  | changes in heart     |
| 4 | 9 | aspirin:       |    |   |   | P | 150 | rate, blood          |
| 3 | 3 | safety and     |    |   |   | C | mg  | pressure, blood      |
| * |   | efficacy for   |    |   |   |   | per | glucose, insulin,    |
| * |   | treatment of   |    |   |   |   | day | and cholesterol      |
|   |   | human obesity  |    |   |   |   |     | levels..."           |
+---+---+----------------+----+---+---+---+-----+----------------------+
| 4 | 1 | The acute and  | 1  | 1 | 3 | O | 20  | \(1\) "side effects  |
| 4 | 9 | chronic        | 27 | 7 | 7 | p | mg  | are minor and        |
|   | 9 | effects of     |    | 8 |   | e | 3   | transient, (2) All   |
|   | 3 | ephe           |    |   |   | n | ti  | measured variables   |
|   |   | drine/caffeine |    |   |   | l | mes | such as full blood   |
|   |   | mixtures on    |    |   |   | a | a   | count, sodium,       |
|   |   | energy         |    |   |   | b | day | potassium,           |
|   |   | expenditure    |    |   |   | e |     | bilirubin, liver     |
|   |   | and glucose    |    |   |   | l |     | enzymes, creatinine, |
|   |   | metabolism in  |    |   |   |   |     | uric acid, and       |
|   |   | humans         |    |   |   |   |     | urinalysis all were  |
|   |   |                |    |   |   |   |     | without significant  |
|   |   |                |    |   |   |   |     | group differences,"  |
|   |   |                |    |   |   |   |     | (3) changes in pulse |
|   |   |                |    |   |   |   |     | and blood pressure   |
|   |   |                |    |   |   |   |     | not specifically     |
|   |   |                |    |   |   |   |     | mentioned.           |
+---+---+----------------+----+---+---+---+-----+----------------------+
| * | 1 | Comparison of  | 50 | 1 | A | D | 20  | "...systolic and     |
| * | 9 | an             |    | 0 | d | B | mg  | diastolic BP         |
| 4 | 9 | ephe           |    | 5 | u | P | 3   | declined in both     |
| 5 | 4 | drine/caffeine |    |   | l | C | ti  | groups...mean heart  |
| * |   | combination    |    |   | t |   | mes | rate after 15 weeks  |
| * |   | and            |    |   |   |   | a   | ...increased in the  |
|   |   | d              |    |   |   |   | day | ephedrine/caffeine   |
|   |   | exfenfluramine |    |   |   |   |     | group by 1.1 ± 11.6  |
|   |   | in the         |    |   |   |   |     | beats/minute..."     |
|   |   | treatment of   |    |   |   |   |     |                      |
|   |   | obesity. A     |    |   |   |   |     |                      |
|   |   | double-blind   |    |   |   |   |     |                      |
|   |   | multi-centre   |    |   |   |   |     |                      |
|   |   | trial in       |    |   |   |   |     |                      |
|   |   | general        |    |   |   |   |     |                      |
|   |   | practice       |    |   |   |   |     |                      |
+---+---+----------------+----+---+---+---+-----+----------------------+
| * | 1 | The effect of  | 16 | 5 | A | D | 20  | No medical           |
| * | 9 | ephedrine plus |    | 6 | d | B | mg  | complications        |
| 4 | 9 | caffeine on    |    |   | u | P | 3   | reported; pulse and  |
| 6 | 4 | plasma lipids  |    |   | l | C | ti  | blood pressure not   |
| * |   | and            |    |   | t |   | mes | specifically         |
| * |   | lipoproteins   |    |   |   |   | a   | mentioned.           |
|   |   | during a 4.2   |    |   |   |   | day |                      |
|   |   | MJ/day diet    |    |   |   |   |     |                      |
+---+---+----------------+----+---+---+---+-----+----------------------+
| * | 1 | Ep             | 1  | 3 | 2 | D | 1%  | "no notable adverse  |
| * | 9 | hedrine-saline | 18 | 0 | 5 | B | na  | effects."            |
| 4 | 9 | nasal wash in  |    |   | . | P | sal |                      |
| 7 | 5 | allergic       |    |   | 7 | C | sp  |                      |
| * |   | rhinitis       |    |   |   |   | ray |                      |
| * |   |                |    |   |   |   |     |                      |
+---+---+----------------+----+---+---+---+-----+----------------------+
| * | 1 | The effect of  | 1  | 3 | A | D | 20  | "subjects in the     |
| * | 9 | ephedrine plus | 48 | 6 | d | B | mg  | ephedrine plus       |
| 4 | 9 | caffeine on    |    | 5 | u |   | 3   | caffeine-treated     |
| 8 | 6 | smoking        |    |   | l |   | ti  | group reported       |
| * |   | cessation and  |    |   | t |   | mes | significantly more   |
| * |   | postcessation  |    |   |   |   | a   | palpitations,        |
|   |   | weight gain    |    |   |   |   | day | sweating, dizziness  |
|   |   |                |    |   |   |   |     | and nausea during    |
|   |   |                |    |   |   |   |     | the first week,"     |
|   |   |                |    |   |   |   |     | vitals signs not     |
|   |   |                |    |   |   |   |     | stated; no strokes   |
|   |   |                |    |   |   |   |     | or heart attacks     |
|   |   |                |    |   |   |   |     | reported.            |
+---+---+----------------+----+---+---+---+-----+----------------------+
| * | 1 | Ph             | 12 | 1 | A | O | 25  | No significant       |
| * | 9 | armacokinetics |    |   | d | p | mg  | increase in pulse or |
| 4 | 9 | and            |    |   | u | e | sin | blood pressure was   |
| 9 | 7 | cardiovascular |    |   | l | n | gle | reported             |
| * |   | effects of ma  |    |   | t | l | d   |                      |
| * |   | huang (Ephedra |    |   | s | a | ose |                      |
|   |   | sinica) in     |    |   |   | b |     |                      |
|   |   | normotensive   |    |   |   | e |     |                      |
|   |   | adults         |    |   |   | l |     |                      |
+---+---+----------------+----+---+---+---+-----+----------------------+
| * | 1 | Ephedrine      | 10 | 1 | A | D | 25  | No significant       |
| * | 9 | ph             |    |   | d | B | mg  | increase in pulse or |
| 5 | 9 | armacokinetics |    |   | u | P | sin | blood pressure was   |
| 0 | 8 | after the      |    |   | l | C | gle | reported             |
| * |   | ingestion of   |    |   | t |   | d   |                      |
| * |   | nutritional    |    |   |   |   | ose |                      |
|   |   | supplements    |    |   |   |   |     |                      |
|   |   | containing     |    |   |   |   |     |                      |
|   |   | Ephedra sinica |    |   |   |   |     |                      |
|   |   | (ma huang)     |    |   |   |   |     |                      |
+---+---+----------------+----+---+---+---+-----+----------------------+
| * | 1 | Effects of     | 8  | 1 | 3 | D | 5   | \(1\) "heart rates   |
| * | 9 | caffeine,      |    |   | 5 | B | mg  | (during exercise)    |
| 5 | 9 | ephedrine and  |    |   |   | P | per | were higher after    |
| 1 | 8 | their          |    |   |   | C | kg  | treatment with       |
| * |   | combination on |    |   |   |   | sin | caffeine and         |
| * |   | time to        |    |   |   |   | gle | ephedrine than after |
|   |   | exhaustion     |    |   |   |   | d   | placebo." (2) blood  |
|   |   | during         |    |   |   |   | ose | pressure changes not |
|   |   | high-intensity |    |   |   |   |     | described, no        |
|   |   | exercise       |    |   |   |   |     | significant medical  |
|   |   |                |    |   |   |   |     | complications        |
|   |   |                |    |   |   |   |     | reported             |
+---+---+----------------+----+---+---+---+-----+----------------------+
| * | 1 | \[Is Letigen   | 1  | 4 | A | D | 20  | This study does not  |
| * | 9 | c              | 36 | 2 | d | B | mg  | support the          |
| 5 | 9 | ontraindicated |    |   | u | P | tw  | assumption that      |
| 2 | 8 | in             |    |   | l | C | ice | ephedrine plus       |
| * |   | hypertension?  |    |   | t |   | a   | caffeine causes a    |
| * |   | A double       |    |   | s |   | day | rise in blood        |
|   |   | blind, placebo |    |   |   |   |     | pressure in either   |
|   |   | controlled     |    |   |   |   |     | normotensive or      |
|   |   | multipractice  |    |   |   |   |     | hypertensive obese   |
|   |   | study of       |    |   |   |   |     | patients."           |
|   |   | Letigen        |    |   |   |   |     |                      |
|   |   | administered   |    |   |   |   |     |                      |
|   |   | to             |    |   |   |   |     |                      |
|   |   | normotensive   |    |   |   |   |     |                      |
|   |   | patients\]     |    |   |   |   |     |                      |
+---+---+----------------+----+---+---+---+-----+----------------------+
| [ | 2 | Safety and     | 32 | 1 | 1 | D | 10  | "Blood pressure and  |
| 5 | 0 | efficacy of    |    | 4 | 6 | B | or  | heart rate values    |
| 3 | 0 | treatment with |    | 0 |   | P | 20  | showed no            |
| ] | 0 | an             |    |   |   | C | mg  | significant changes  |
| { |   | ephe           |    |   |   |   | 3   | during the trial..." |
| . |   | drine/caffeine |    |   |   |   | ti  |                      |
| u |   | mixture. The   |    |   |   |   | mes |                      |
| n |   | first double   |    |   |   |   | a   |                      |
| d |   | blind          |    |   |   |   | day |                      |
| e |   | plac           |    |   |   |   |     |                      |
| r |   | ebo-controlled |    |   |   |   |     |                      |
| l |   | study in       |    |   |   |   |     |                      |
| i |   | adolescents.   |    |   |   |   |     |                      |
| n |   |                |    |   |   |   |     |                      |
| e |   |                |    |   |   |   |     |                      |
| } |   |                |    |   |   |   |     |                      |
+---+---+----------------+----+---+---+---+-----+----------------------+
| * | 2 | An herbal      | 35 | 5 | 4 | D | 24  | \(1\) "Mean systolic |
| * | 0 | supplement     |    | 6 | 2 | B | mg  | and diastolic blood  |
| 5 | 0 | containing Ma  |    |   | . | P | 3   | pressure did not     |
| 4 | 1 | Huang-Guarana  |    |   | 2 | C | ti  | differ between       |
| * |   | for weight     |    |   |   |   | mes | groups (i.e.,        |
| * |   | loss: a        |    |   |   |   | a   | placebo) at any time |
|   |   | randomized,    |    |   |   |   | day | nor were they        |
|   |   | double blind   |    |   |   |   |     | different from       |
|   |   | trial          |    |   |   |   |     | baseline in either   |
|   |   |                |    |   |   |   |     | group at the end of  |
|   |   |                |    |   |   |   |     | the study...heart    |
|   |   |                |    |   |   |   |     | rate at Week 8 was   |
|   |   |                |    |   |   |   |     | significantly        |
|   |   |                |    |   |   |   |     | increased over       |
|   |   |                |    |   |   |   |     | baseline (6.9 ± 6.9  |
|   |   |                |    |   |   |   |     | beats per minute.    |
|   |   |                |    |   |   |   |     | (2) no clinically    |
|   |   |                |    |   |   |   |     | significant adverse  |
|   |   |                |    |   |   |   |     | events reported, (3) |
|   |   |                |    |   |   |   |     | no changes in blood  |
|   |   |                |    |   |   |   |     | chemistries or       |
|   |   |                |    |   |   |   |     | electrocardiograms   |
+---+---+----------------+----+---+---+---+-----+----------------------+
| * | 2 | Herbal         | 83 | 1 | 3 | D | 90  | "treatment produced  |
| * | 0 | ep             |    | 8 | 5 | B | mg  | small changes in     |
| 5 | 0 | hedra/caffeine |    | 0 |   | P | per | blood pressure       |
| 5 | 2 | for weight     |    |   |   | C | day | variables (+3 to --5 |
| * |   | loss: a        |    |   |   |   |     | mmHg) and increased  |
| * |   | 6-month        |    |   |   |   |     | heart rate (4 ± 9 vs |
|   |   | randomized     |    |   |   |   |     | 3± 9 bpm) in         |
|   |   | safety and     |    |   |   |   |     | controls."           |
|   |   | efficacy trial |    |   |   |   |     |                      |
+---+---+----------------+----+---+---+---+-----+----------------------+
| * | 2 | Effect of      | 12 | 1 | 3 | D | 4   | The combination of   |
| * | 0 | ingesting      |    |   | 3 | B | mg  | caffeine/ephedrine " |
| 5 | 0 | caffeine and   |    |   |   | P | /kg | produced a slight    |
| 6 | 2 | ephedrine on   |    |   |   | C | sin | but significant      |
| * |   | 10km run       |    |   |   |   | gle | increase in pulse    |
| * |   | performance    |    |   |   |   | d   | throughout the run   |
|   |   |                |    |   |   |   | ose | (176 ± 12 bpm vs 174 |
|   |   |                |    |   |   |   |     | ± 13 bpm)." No       |
|   |   |                |    |   |   |   |     | significant medical  |
|   |   |                |    |   |   |   |     | complications were   |
|   |   |                |    |   |   |   |     | reported.            |
+---+---+----------------+----+---+---+---+-----+----------------------+

References:

**1**. Muittari, A., M.J. Mattila, and J. Patiala, Bronchodilator action
of drug combinations in asthmatic patients: decloxizine, orciprenaline,
and ephedrine. *Ann Allergy*, 1969. 27(6): 274-9.

**2**. Kerr, A. and T. Gebbie, Comparison of orciprenaline, ephedrine
and methoxyphenamine as oral bronchodilators. *N Z Med J*, 1973.
77(492): 320-2.

**3**. Dulfano, M.J. and P. Glass, Evaluation of a new B2 adrenergic
receptor stimulant, terbutaline, in bronchial asthma. II. Oral
comparison with ephedrine. *Curr Ther Res Clin Exp,* 1973. 15(4): 150-7.

**4**. Weinberger, M.M. and E.A. Bronsky, Evaluation of oral
bronchodilator therapy in asthmatic children. Bronchodilators in
asthmatic children. *J Pediatr*, 1974. 84(3): 421-7.

**5**. Chervinsky, P. and G. Chervinsky, Metaproterenol tablets: their
duration of effect by comparison with ephedrine. *Curr Ther Res Clin
Exp*, 1975. 17(6): 507-18.

**6.** Tashkin, D.P., et al., Double-blind comparison of acute bronchial
and cardiovascular effects of oral terbutaline and ephedrine. *Chest,*
1975. 68(2): 155-61.

**7**. Weinberger, M., et al., Interaction of ephedrine and
theophylline. *Clin Pharmacol Ther*, 1975. 17(5): 585-92.

**8**. Geumei, A., et al., Evaluation of a new oral beta2-adrenoceptor
stimulant bronchodilator, terbutaline, Pharmacology 1975. 13(3): 201-211

**9**. Nelson, H.S., et al., Subsensitivity to epinephrine following the
administration of epi nephrine and ephedrine to normal individuals. *J
Allergy Clin Immunol*, 1975. 55(5): 299-309.

**10**. Wilson, AF., et al. Cardiopulmonary effects of long-term
bronchodilator administration. J Allergy Clinical Immunology 1976.
58:204-212

**11**. Pickupp, ME, et a., The pharmacokinetics of ephedrine after oral
dosage in asthmatics receiving acute and chronic treatment. Br J Clin
1976 3(1)123-134

**12**. May, C.S., M.E. Pickup, and J.W. Paterson, The acute and chronic
bronchodilator effects of ephedrine in asthmatic patients. *Br J Clin
Pharmacol,* 1975. 2(6): 533-7.

**13**. Wilson, A.F., et al., Cardiopulmonary effects of long-term
bronchodilator administration. *J Allergy Clin Immunol*, 1976. 58 (1 PT.
2): p. 204-12.

**14.** Blumberg, M.Z., et al., Terbutaline and ephedrine in asthmatic
children. *Pediatrics*, 1977. 60(1): 14-9.

**15**. Tinkelman, D.G. and S.E. Avner, Ephedrine therapy in asthmatic
children. Clinical tolerance and absence of side effects. *JAMA*, 1977.
237(6): 553-7.

**16**. Simi, W.W. and W.C. Miller, Clinical investigation of fenoterol,
a new bronchodilator, in asthma. *J Allergy Clin Immunol*, 1977. 59(2):
178-81.

**17.** Steen, S.N., et al., Comparison of the bronchodilator effects of
oral therapy with fenoterol hydrobromide and ephedrine. *Chest*, 1977.
72(3): 291-5.

**18**. Cohen, B.M., The cardiorespiratory effects of oral terbutaline
and an ephedrine-theophylline-phenobarbital combination: comparison in
patients with chronic obstructive ventilatory disorders. *Ann Allergy,*
1978. 40(4): 233-9.

**19**. Stenius, B., T. Haahtela, and H. Poppius, Controlled comparison
of Nuelin, Theodrox and Marax in asthmatic out-patients. *Eur J Clin
Pharmacol,* 1978. 13(3): 179-83.

**20**. Bush, R.K., et al., A comparison of a theophylline-ephedrine
combination with terbutaline. *Ann Allergy*, 1978. 41(1): 13-7.

**21** Morris, H.G., et al., Comparative effects of ephedrine on
adrenergic responsiveness in normal and asthmatic subjects. *J Allergy
Clin Immunol*, 1978. 61(5): 294-302.

**22**. Falliers, C.J., Controlled assessment of beta2 adrenergic
therapy for childhood asthma. *Chest*, 1978. 73(6 Suppl): 1008-10.

**23**. Banner, A.S., et al., Arrhythmogenic effects of orally
administered bronchodilators. *Arch Intern Med*, 1979. 139(4): 434-7.

**24**. James, T.D. and H.A. Lyons, A comparative study of
bronchodilator effects of carbuterol and ephedrine. *JAMA*, 1979.
241(7): 704-5.

**25**. Muittari, A. and M.J. Mattila, Objective and subjective
assessment of ephedrine combinations in asthmatic outpatients. *Ann Clin
Res*, 1979. 11(3): 87-9.

**26.** Plummer, A.L. and B.A. Cassidy, A comparison of the
bronchodilator effects of terbutaline, Tedral and the simultaneous use
of both agents. *Ann Allergy*, 1979. 42(4): 218-23.

**27**. Manaligod, L.M., et al., Safety and effectiveness of terbutaline
in children with chronic asthma. *Chest*, 1979. 76(5): 532-5.

**28**. Pierson, D.J., et al., Cardiopulmonary effects of terbutaline
and a bronchodilator combination in chronic obstructive pulmonary
disease. *Chest*, 1980. 77(2): 176-82.

**29**. Falliers, C.J. and M.A. Redding, Combined vs. single-entity
pharmacologic inhibition of induced asthma. *Ann Allergy*, 1980. 44(6):
335-40.

**30**. Laitinen, L.A., et al., Scopolamine alone or combined with
ephedrine in seasickness: a double-blind, placebo-controlled study.
Aviat Space Environ Med, 1981. 52(1): 6-10.

**31**. An antihistamine-sympathomimetic combination in the treatment of
hayfever. A report from the General Practitioner Research Group.
*Practitioner*, 1981. 225(1356): 929-31.

**32**. Laitinen, L.A., et al., A comparison of the bronchodilator
action of pseudoephedrine and ephedrine in patients with reversible
airway obstruction. *Eur J Clin Pharmacol*, 1982. 23(2): 107-9.

**33.** McLaughlin, E.T., L.H. Bethea, and H.J. Wittig, Comparison of
the bronchodilator effect of oral fenoterol and ephedrine in asthmatic
children. *Ann Allergy*, 1982. 49(4): 191-5.

**34**. Pasquali, R., et al., A controlled trial using ephedrine in the
treatment of obesity. *Int J Obes*, 1985. 9(2): 93-8.

**35**. Low, R.B., et al., The effect of d-amphetamine and ephedrine on
smoking attitude and behavior. *Addict Behav*, 1984. 9(4): 335-45.

**36.** Pasquali, R., et al., Does ephedrine promote weight loss in low
energy-adapted obese women? *Int J Obes*, 1987. 11(2): 163-8.

**37.** Krieger, D.R., et al., Ephedrine, caffeine and aspirin promote
weight loss in obese subjects. *Trans Assoc Am Physicians*, 1990. 103:
307-12.

**38**. Astrup, A. and S. Toubro, Thermogenic, metabolic, and
cardiovascular responses to ephedrine and caffeine in man. *Int J Obes
Relat Metab Disord*, 1993. 17 Suppl 1: S41-3.

**39**. Stromberg, C., et al., Exercise alters the pharmacokinetics of
midazolam. *Clin Pharmacol Ther*, 1992. 51(5): 527-32.

**40**. Astrup, A., et al., The effect of ephedrine/caffeine mixture on
energy expenditure and body composition in obese women. Metabolism,
1992. 41(7): 686-8.

**41**. Astrup, A. et. al. 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, 1992 16(4)269-277

**42.** Toubro, S., et al., Safety and efficacy of long-term treatment
with ephedrine, caffeine and an ephedrine/caffeine mixture. *Int J Obes
Relat Metab Disord*, 1993. 17 Suppl 1: S69-72.

**43**. Daly, P.A., et al., Ephedrine, caffeine and aspirin: safety and
efficacy for treatment of human obesity. *Int J Obes Relat Metab
Disord,* 1993. 17 Suppl 1: S73-8.

**44**. Toubro, S. et al., . The acute and chronic effects of
ephedrine/caffeine mixtures on energy expenditure and glucose metabolism
in humans. Int J Obes Relat Metab Disord. 1993. 17 Suppl 3: S73-7;

**45**. Breum, L., et al., 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*, 1994. 18(2): 99-103.

**46**. Buemann, B., et al., The effect of ephedrine plus caffeine on
plasma lipids and lipoproteins during a 4.2 MJ/day diet. *Int J Obes
Relat Metab Disord*, 1994. 18(5): 329-32.

**47**. Shaikh, W.A., Ephedrine-saline nasal wash in allergic rhinitis.
*J Allergy Clin Immunol*, 1995. 96(5 Pt 1): 597-600.

**48.** Norregaard, J., et al., The effect of ephedrine plus caffeine on
smoking cessation and postcessation weight gain. *Clin Pharmacol Ther,*
1996. 60(6): p. 679-86.

**49**. White, L.M., et al., Pharmacokinetics and cardiovascular effects
of ma-huang (Ephedra sinica) in normotensive adults. *J Clin Pharmacol*,
1997. 37(2): 116-22.

**50**. Gurley, B.J., et al., Ephedrine pharmacokinetics after the
ingestion of nutritional supplements containing Ephedra sinica (ma
huang). *Ther Drug Monit*, 1998. 20(4): p. 439-45.

**51**. Bell, D.G., I. Jacobs, and J. Zamecnik, Effects of caffeine,
ephedrine and their combination on time to exhaustion during
high-intensity exercise. *Eur J Appl Physiol Occup Physiol*, 1998.
77(5): 427-33.

**52**. Svendsen, T.L., J. Ingerslev, and A. Mork, \[Is Letigen
contraindicated in hypertension? A double-blind, placebo controlled
multipractice study of Letigen administered to normotensive and
adequately treated patients with hypersensitivity\]. *Ugeskr Laeger*,
1998. 160(27): 4073-5.

**53**. Molnar, D., et. al. 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 2000.
24(12)1573-1578.

**54**. Boozer CN, et al., An herbal supplement containing Ma
Huang-Guarana for weight loss: a randomized, double-blind trial. *Int J
Obes Relat Metab Disord*, 2001. 25(3): 316-324.

**55.** Boozer, C., et al., Herbal ephedra/caffeine for weight loss: a
6-month randomized safety and efficacy trial. *Int J Obes Relat Metab
Disord,* 2002. 26(5): 593-604.

**56**. Bell, D.G., T.M. McLellan, and C.M. Sabiston, Effect of
ingesting caffeine and ephedrine on 10-km run performance. *Med Sci
Sports Exerc*, 2002. 34(2): 344-9.