2.3 Observations in humans
A single blinded cross-over study was carried out to examine the
acute bronchospasmolytic effect and possible side-effects following
oral administration of placebo and three doses of clenbuterol (1, 2.5
and 5 µg/day) in patients (three male and three female) with chronic
obstructive airway disease over a 3 day period. The drug was given
orally, diluted with water. Observations were carried out over a
2-hour period following dosing. The average age of the patients was
55.7 years and they had an average body weight of 73.16 kg.
None of the 3 doses produced any clear, consistent effects on
bronchial resistance, thoracic gas volume, radial pulse frequency or
blood pressure, and no side effects were seen.
The pharmacological NOEL in this study was 5 µg/day, equivalent
> to 0.08 µg/kg bw per day (Kaik, 1978).
The bronchospasmolytic effect was examined in two groups of
patients:
Group A: ten patients aged 46-75 years with chronic obstructive
respiratory disease resulting from pulmonary tuberculosis.
Group B: five patients aged 56-67 years with chronic obstructive
respiratory disease not related to tuberculosis, plus five
patients aged 34-57 with bronchial asthma.
The bronchospasmolytic effect was examined after single oral doses of
1, 2.5, 5, 10, 20, 25 or 30 µg/person, and after a placebo dose.
In Group A patients, intrathoracic gas volume was significantly
reduced and vital capacity and pneumometer values significantly
increased at all dose levels. In Group B patients, airway resistance
was significantly reduced, but no dose relationship could be
demonstrated. No significant placebo effect was seen in either group.
When compared with placebo values, a significantly greater increase
for both vital capacity and pneumometer values was observed in Group
A, even at the lowest dose used in this group (5 µg). However, at the
two lowest doses used in Group B (1 and 2.5 µg), there were no
significant differences from placebo values. The pharmacological NOEL
> in this study was 2.5 µg, equivalent to 0.042 µg/kg bw (Nolte &
> Laumen, 1972; Nolte, 1980).
Children who consumed between 0.05-0.075 mg of clenbuterol showed
> only mild tachycardia. A 30-year-old woman who consumed 30 tablets
equivalent to 0.6 mg clenbuterol (10 µg/kg approximately) developed
tachycardia and slight hypertension approximately 1 hour after
consumption. No tablet remains were found on gastric lavage, and
medicinal charcoal and a saline laxative were given. The following
day, the patient’s pulse rate and blood pressure had returned to
normal (Boehringer, 1991a).
Patients (100+) administered doses of 20-60 µg/day (0.3-1.0 µg/kg
bw per day) for up to 1 year or 20 µg/day (0.3 µg/kg bw per day) for
up to 6 months showed no adverse effects except for slight tremor and
occasional, mild tachycardia (Laumen, 1978; Tullgren & Lins, 1987).
In humans, clenbuterol produced a bronchiolytic effect when a
single dose of 10 µg (0.167 µg/kg bw) was given by the inhalation
route, but no evidence of tachycardia was seen at this dose. With oral
doses of clenbuterol of up to 5 µg/day (0.08 µg/kg bw per day) over a
3-day period, there were no effects on bronchial resistance, thoracic
gas volume, cardiac rate or blood pressure. The NOEL in this study was
5 µg/day (0.08 µg/kg bw per day). In a study to investigate the
bronchospasmolytic effect in humans, patients with obstructive lung
disease were given oral doses of up to 30 µg per person. Patients
administered doses of 5 µg or more exhibited bronchospasmolytic
effects, and the pharmacological NOEL in this study was 2.5 µg per
person, equivalent to 0.04 µg/kg bw.
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EVALUATION
The Committee considered the most relevant study for determining
the ADI to be that concerning the bronchospasmolytic effect in humans.
The patients had chronic obstructive airway disease and thus were
likely to be a very sensitive population for this effect. The NOEL
identified in this study (2.5 µg per person, equivalent to 0.04 µg/kg
bw) is approximately 25% of the dose in another study in which the
inhalation route was used, but in which cardiac effects were not
observed. This NOEL is approximately 50% of the oral dose used in
another study where, again, cardiac effects did not occur. Hence, this
NOEL for the bronchospasmolytic effect offers an additional safety
margin for cardiac effects. The Committee therefore established an ADI
> of 0-0.004 µg/kg bw, based on the NOEL of 0.04 µg/kg bw per day for
> pharmacodynamic effects in humans and a safety factor of 10.