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    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)