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    QUININE

    First draft prepared by
    Professor R. Walker
    University of Surrey
    Guildford, Surrey, 
    United Kingdom

    1.  EXPLANATION

         Quinine, as quinine salts or extracts from cinchona bark, is
    used as a bittering agent in tonic type drinks, usually at a
    concentration of approximately 80 mg quinine hydrochloride per
    litre. Quinine is also used in some bitter alcoholic beverages and
    to a small extent in flour confectionery. Quinine and its
    derivatives have also been widely used therapeutically in the
    treatment of protozoal infections, such as malaria, and of nocturnal
    leg cramps.

         The major dietary source of quinine is from soft drinks of the
    tonic or bitter lemon type and the Committee received details of a
    consumption study conducted in the United Kingdom, France and Spain,
    among users of quinine-containing soft drinks. These data indicated
    that while the 90th percentile intake averaged over 14 days was
    between 6.1 and 9.3 mg/person/day, the maximum intake on a single
    day varied from 75 mg/person in France to 104.4 mg/person in the
    United Kingdom (Cadbury Beverages, Inc., 1991).

         Quinine hydrochloride was evaluated at the thirty-fifth meeting
    of the Committee (Annex 1, reference 88) when a toxicological
    monograph was prepared (Annex 1, reference 89). A temporary ADI of
    0-0.9 mg quinine/kg bw was allocated on the basis of human data but
    the Committee considered that data from more extensive human studies
    should be submitted by 1992.

         Since the previous evaluation further data have become
    available and are summarized in the following monograph addendum.

    2.  BIOLOGICAL DATA

    2.1  Biochemical aspects

         No new information available.

    2.2  Toxicological studies

         No new information available.

    2.3  Observations in humans

         A double-blind four-way crossover study was carried out in
    which 32 healthy volunteers (20 males, 12 females) aged between 18
    and 50 years were given daily doses of 0 (lactose placebo), 80, 120
    or 160 mg quinine hydrochloride for periods of 21 days. The test
    substance was administered in gelatin capsules as four equal doses
    at intervals of 5 h starting at 0800 h with a 9 h overnight
    interval. The different dose regimes were separated by at least two
    weeks.

         Prior to commencement and at intervals throughout the period of
    administration, haematology, serum and urine chemistry profiles were
    examined together with other physiological, ophthalmic and
    audiometric examinations as indicated in Table 1. Quinine
    concentrations were determined on all serum and urine samples.

         The serum quinine concentration plateaued by day 3 of dosing
    and the mean concentrations (expressed as quinine hydrochloride)
    were approximately 0.45, 0.65 and 0.9 µg/ml in the groups receiving
    80, 120 and 160 mg/d, respectively. The corresponding mean urine
    concentrations were 8.0-9.2, 10.6-14.0 and 15.8-21.0 µg/ml,
    respectively.

         No treatment-related effects were observed in urine output,
    ECG, heart rate, blood pressure, peripheral fields, funduscopy,
    colour vision, visual acuity, opticokinetic nystagmus response nor
    audiometric parameters when compared with the period when placebo
    was administered; serum chemistry and haematological parameters were
    within normal ranges pre- and post-dosing.

    
    Table 1. Measurement intervals
                                                                                  

    Examination                              Time of exposure (days)

                           Pre-dose      3      7     10    14     17      21
                                                                                  

    Physiological

    24h urine*, serum         +          +      +     +     +      +       +
    chemistry+,
    haematology°

    ECG, heart rate,          +                 +           +              +
    blood pressure

    Ophthalmic

    ENG                       +          +      +     +     +      +       +

    OKN, peripheral           +          +            +            +       +
    fields

    Funduscopy                +                 +           +              +

    Colour vision             +                                            +
    Visual acuity

    Audiometric

    Pure tone                 +                                            +
    threshold
    0.25-8 kHz
                                                                                  

    ENG  = electronystagmography; OKN = Opticokinetic nystagmus

    *    pH, S.G., protein, blood, bilirubin, glucose, ketones, nitrite

    +    bilirubin, cholesterol, creatinine, glucose, total protein,
         albumin, triglycerides, urea, Cl, PO43-, Na, K, Ca, Mg, alk-P-ase,
         alanine aminotransferase, aspartate aminotransferase, GGT.

    °    WBC, RBC, Hb, PCV, MCV, MCHC, platelets, prothrombin time, activated
         partial thromboplastin time.
    
         During ENG examination, ocular flutter was noted on at least
    one occasion in six volunteers but was unrelated to treatment,
    occurring more frequently when volunteers were receiving placebo.
    Nystagmus was displayed sporadically, on at least one occasion by
    4/32 (12.5%) volunteers when receiving placebo or 80 mg quinine
    hydrochloride/day and by 6/32 (18.8%) receiving 120 or 160 mg
    quinine hydrochloride/day. The total number of observations of
    nystagmus (out of 224 observations at each dose) was 10, 9, 18 and
    18 at doses of 0, 80, 120 and 160 mg/d, respectively. The transitory
    nystagmus was usually low-grade and no volunteer showed nystagmus on
    every observation at any treatment level. Statistical analysis
    indicated no significant difference in the occurrence of nystagmus
    between the placebo and 80 mg/d treatment periods (group 1) nor
    between the 120 and 160 mg/d (group 2); there was a significant
    difference, p <0.05, between the two higher and lower treatments
    (i.e., groups 1 and 2).

         No subjective symptoms were attributable to treatment and there
    were none of the other symptoms of intoxication reported at high
    doses in other studies (BIBRA, 1991).

    3.  COMMENTS

         The Committee concluded that the data demonstrated a clear NOEL
    with respect to the ocular effects of 80 mg of anhydrous quinine
    hydrochloride per day, equivalent to 72 mg of quinine free base. No
    treatment-related effects on audition or clinical biochemical
    abnormalities were observed at doses up to 160 mg of anhydrous
    quinine hydrochloride per day.

    4.  EVALUATION

         The previously established temporary ADI was withdrawn and, in
    the light of data on levels of use in beverages, the results of the
    consumption study and the additional data on humans, the Committee
    concluded that current use levels in soft drinks of up to 75 mg/l
    (as quinine base) were not of toxicological concern. However, the
    Committee noted that a small group of consumers shows an
    idiosyncratic hyper-reactivity to quinine, and recommended that the
    consumer should be informed by appropriate means of the presence of
    quinine in foods and beverages in which it is used. The contribution
    of other uses of quinine in food and alcoholic beverages to daily
    intakes was considered to be negligible.

    5.  REFERENCES

    BIBRA (1991). Report on a study to investigate possible effects of
    three dose levels of quinine hydrochloride on the vestibular,
    auditory, and visual parameters of healthy volunteers - Main study.
    BIBRA Project No. 3.0921/3. Unpublished report of BIBRA
    International submitted to WHO.

    CADBURY BEVERAGES INC. (1991). Quinine consumption study.
    Unpublished report submitted to WHO by Cadbury Beverages Inc.


    See Also:
       Toxicological Abbreviations
       Quinine (PIM 464)
       Quinine (UKPID)