CARAZOLOL
First draft prepared by
Dr F.X.R. van Leeuwen
Toxicology Advisory Centre
National Institute of Public Health
and Environmental Protection, Bilthoven, Netherlands
1. EXPLANATION
Carazolol is a ß-adrenoceptor blocking agent primarily used in
pigs to prevent sudden death due to stress during transport, thus
preventing death losses and deterioration of meat quality. It may
also be used to relieve stress associated with mating in pigs and
parturition in cattle and pigs. Carazolol was previously evaluated
at the thirty-eighth Meeting of the Committee (Annex 1, reference
97) when a temporary ADI of 0-0.1 µg/kg bw/day was established.
Further information was requested concerning the pharmacological no-
effect level in humans.
For the present meeting additional data to satisfy this request
were provided.
2. BIOLOGICAL DATA
2.1 Effects in humans
Twenty patients (16 males and 4 females aged 17 to 61 years)
with sympathicotonic cardiovascular disorder (a condition in which
there is increased tonus of the sympathetic nervous system and a
marked tendency to vascular spasm and high blood pressure) were
treated with an oral dose of 5 mg carazolol three times daily for 7
days (9 patients) or 2.5 mg carazolol three times daily for 7 days
(11 patients). Following this test, two 7-day treatment periods
were conducted in which the same 20 patients received either placebo
or carazolol serially in a randomized and double-blind order at a
dose of 5 mg three times daily (9 patients) or 2.5 mg three times
daily (11 patients).
The mean and standard deviations of heart rate, blood pressure,
and pressure-rate product, at rest and during exercise before and
after the administration of carazolol were recorded.
A significant fall in heart rate, blood pressure and pressure-
rate product both at rest and after exercise in both carazolol dose
groups were reported.
Based on effects on the pressure-rate product the no-effect
level was 0.12 mg/person, equivalent to 1.6 µg/kg bw (Scholtze &
Smolarz, 1978).
The hypotensive effect of carazolol was investigated in 20
patients (13 male and 7 females, 32 to 70 years old) with essiential
(19/20) or renal (1/20) forms of hypertension. Following a 7-day
observation period during which no anti-hypertensive drugs were
administered, these patients were administered an oral dose of 15 mg
carazolol/person/day (5 mg three times daily) for a period of 4
weeks. Blood pressure and heart rate were monitored before and
during the treatment period. Serum chemistry and haematology
parameters were evaluated before and after the treatment period.
A marked decrease in blood pressure and heart rate was noted
after the start of treatment, which reached statistical significance
(both the systolic and diastolic values) by the end of the first
week of treatment. Slight decreases in blood pressure and heart
rate values occurred over the subsequent 3-week treatment period.
Haematology findings were unremarkable. A significant fall in
serum-cholesterol and triglycerides was noted.
A no-effect level could not be extrapolated because only one
dose level was used (Smolarz, 1978).
Thirty patients (aged 46 to 64 years, sex distribution not
provided) with angina pectoris were randomly divided into 3 groups
of 10 patients/group. Following a 7-day treatment-free control
period, an ergometric exercise test was carried out prior to the
start of treatment. Patients were then treated orally with 5 mg
prindolol (a standard ß-blocking drug) or 2.5 or 5 mg carazolol 3
times daily for a period of 2 weeks. The ergometric test was carried
out again on the 8th day and the last day of treatment. Each time,
the test was initiated 1 to 2 hours following treatment. Heart
rate, blood pressure, pressure-rate product, ECG (PQ interval and ST
depression), nitrate consumption, exercise tolerance, effect on
subjective symptoms, and tolerance were evaluated. From the results
of ergometric exercise tests, a no-effect level of 10.6 µg/kg bw was
calculated (Loskot et al ., 1976; 1980).
In 3 studies the effect of carazolol in patients (61 total, 45
males, 16 females, 20 to 79 years old) with various types of cardiac
arrhythmia were investigated. In these studies an oral dose of 5 mg
carazolol, 3 times daily for 4-7 days, was administered. Because
only one dose level was used a no-effect level could not be
extrapolated (Smolarz, 1976; Schaumann, 1977; Samek, 1977).
A single oral dose of 0.1 or 0.7 mg carazolol/person was
administered to 2 groups of 5 patients (9 males, 1 female aged 40 to
69 years) with chronic bronchitis or asthma. Bronchospastic effects
associated with treatment were studied. Pulmonary parameters
evaluated included reduction in volume capacity (VC) and forced
expiratory volume in one second (FEV1). Reductions in VC and FEV1
were detected 2 hours after administration at both dose levels. A
no-effect level of 0.4 µg/kg bw was extrapolated for the effect on
VC, whereas the effect on the FEV1 provided an extrapolated no-
effect level of 0.1 µg/kg bw. However, after correcting the
difference in starting values of both parameters between the two
dose groups, the Committee determined that the overall no-effect
level was 0.5 µg/kg bw (Huckauf, 1981)
Eleven healthy male subjects received single increasing oral
doses of 2.5, 5 and 10 mg carazolol on 3 consecutive days.
Respiratory tract resistance, intrathoracic gas volume, blood
pressure and heart rate were evaluated. No bronchospasmic effects
were observed, but blood pressure and heart rate were decreased. The
effect was similar at all 3 dose levels, therefore a dose-effect
extrapolation was not possible (Von Wichert, 1977).
In 12 healthy subjects (sex and age distribution not specified)
the effects of a single oral dose of 5 or 7.5 mg carazolol/person on
the pressure-rate product were determined in ergometric exercise
tests. From the area under the curve for relative inhibition versus
time, a no-effect level of 10 µg/kg bw was calculated by
extrapolation (Abshagen & Von Möllendorff, 1980).
3. COMMENTS
The Committee considered results from clinical studies using
carazolol in healthy subjects and in patients with sympathicotonia,
hypertension, angina pectoris, cardiac arrythmia, chronic
bronchitis, or asthma. Because pharmacological effects were
observed at all dose levels, no-effect levels were derived from
these results by extrapolation. For this purpose a linear
relationship between the observed pharmacological effects and the
logarithm of the administered dose was assumed. The Committee noted
that this approach resulted in a conservative estimate of the no-
effect levels.
Several of the studies submitted were considered inadequate for
the calculation of a no-effect level, due to the absence of a clear
dose-effect relationship, or because only one dose was used.
In twelve healthy subjects the effect on cardiac function of a
single oral dose of 5 or 7.5 mg carazolol per person was studied in
an ergometric exercise test. From the results, an no-effect level
of 10 µg/kg bw was calculated by extrapolation.
Humans with either chronic bronchitis or asthma received a
single oral dose of 0.1 or 0.7 mg/person (5 patients per dose
group). Reductions in vital capacity and forced expiratory volume
were detected 2 hours after administration of carazolol. From the
results, corrected for the apparent differences in the starting
values of both parameters between the two dose groups, the overall
no-effect level was 0.5 µg/kg bw.
4. EVALUATION
The Committee recognized that humans with chronic bronchitis or
asthma are highly sensitive to the effects of carazolol. It was
also noted that this subgroup is a substantial part of the general
population and that adequate allowance for inter-individual
variation should be provided.
The Committee noted that previous temporary ADI of 0 - 0.1
µg/kg bw/day provided a margin of safety of 100 in relation to the
no-effect level of 10 µg/kg bw derived from healthy subjects. It
also noted that this value provided a margin of safety of 5 in
relation to the no-effect level of 0.5 µg/kg bw derived from highly
sensitive individuals experiencing chronic bronchitis or asthma.
The Committee concluded that these values provide an adequate
allowance for inter-individual variation, and therefore established
an ADI of 0 - 0.1 µg/kg bw.
5. REFERENCES
ABSHAGEN, U. & Von MOLLENDORF, E. (1980). Pharmakokinetik oder
Wirkungskinetik von Carazolol? Therapierelevante Daten. In:
Symposium über den Beta-Rezeptorenblocker Carazolol. 8-9 Februar
1980 München. Submitted to WHO by Praemix Wirkstoff GMBH, Mannheim,
Germany.
HUCKAUF, H. (1981). Klinische Prüfung von Carazolol zur Bestimmung
einer am Bronchialsystem wirksamen Grenzdosis. Unpublished report
dated 22-7-1981, Freie Universität Berlin, Klinikium Steglitz.
Submitted to WHO by Praemix Wirkstoff GMBH, Mannheim, Germany.
LOSKOT, F., SMOLARZ, A. & BARTSCH, W. (1976). Comparison of the new
ß-blocker BM 51.052 with prindolol 14 days treatment in patients
with angina pectoris with ergometric measurement of exercise
tolerance. Unpublished report dated 8 -01-1976 from Boehringer,
Mannheim. Submitted to WHO by Praemix Wirkstoff GMBH, Mannheim,
Germany.
LOSKOT, F., JINDRICHOWSKY, L., SMOLARZ, A. & BARTSCH, W. (1980).
Vergleich antianginöser Wirkungen der Beta-Rezeptorenblocker
Carazolol und Pindolol. In: Symposium über den Beta-
Rezeptorenblocker Carazolol, 8-9 Februar 1980 München . Submitted
to WHO by Praemix Wirkstoff GMBH, Mannheim, Germany.
SAMEK, L. (1977). Clinical trial of BM 51.052 in cardiac
arrhythmias Report dated 11-3-1977 from Mannheim Boehringer.
Submitted to WHO by Praemix Wirkstoff GMBH, Mannheim, Germany.
SCHAUMANN, H.J. (1977). Results of the clinical inverstigation on
the action of the ß-receptor blocker BM 51.052 in arrhytmias.
Unpublished trial report dated 30-9-1977 from Boehringer Mannheim.
Submitted to WHO by Praemix Wirkstoff GMBH, Mannheim, Germany.
SCHMOLARZ, A. (1976). Clinical investigation on the action of the
ß-receptor blocker BM 51.052 on cardiac arrhythmias. Summary report
dated 1-10-1976 from Boehringer Mannheim. Submitted to WHO by
Praemix Wirkstoff GMBH, Mannheim, Germany.
SCHMOLARZ, A. (1978). The treatment of hypertension with carazolol
(BM 51.052). Results of a multicentre study in hospitalized
patients. Unpublished final report dated 6-02-1978 from Boehringer,
Mannheim. Submitted to WHO by Praemix Wirkstoff GMBH, Mannheim,
Germany.
SCHOLZE, J. & SMOLARZ, J. (1978). Demonstration of activity and
tolerance of carazolol in the treament of functional tachycardic
cardiovascular disorders.
Unpublished report dated 24-04-1978 from Boehringer, Mannheim.
Submitted to WHO by Praemix Wirkstoff GMBH, Mannheim, Germany.
VON WICHERT, P. (1977). BM 51.052 Investigations on bronchospastic
action. Unpublished report dated 6-6-1977 from Boehringer Mannheim.
Submitted to WHO by Praemix Wirkstoff GMBH, Mannheim, Germany.
See Also:
Toxicological Abbreviations
Carazolol (WHO Food Additives Series 29)
CARAZOLOL (JECFA Evaluation)