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Thiamine and salts

1. NAME
   1.1 Substance
   1.2 Group
   1.3 Synonyms
   1.4 Identification Numbers
      1.4.1 CAS Number
      1.4.2 Other Numbers
   1.5 Main brand names, main trade names
   1.6 Main manufacturers, main importers
2. SUMMARY
   2.1 Main risks and target organs
   2.2 Summary of clinical effects
   2.3 Diagnosis
   2.4 First aid measures and management principles
3. PHYSICO-CHEMICAL PROPERTIES
   3.1 Origin of the substance
   3.2 Chemical structure
   3.3 Physical Properties
      3.3.1 Colour
      3.3.2 State / Form
      3.3.3 Description
   3.4 Other characteristics
      3.4.1 Shelf-life of the substance
      3.4.2 Storage Conditions
4. USES
   4.1 Indications
      4.1.1 Indications
      4.1.2 Description
   4.2 Therapeutic Dosage
      4.2.1 Adults
      4.2.2 Children
   4.3 Contraindications
5. ROUTES OF ENTRY
   5.1 Oral
   5.2 Inhalation
   5.3 Dermal
   5.4 Eye
   5.5 Parenteral
   5.6 Other
6. KINETICS
   6.1 Absorption by route of exposure
   6.2 Distribution by route of exposure
   6.3 Biological half-life by route of exposure
   6.4 Metabolism
   6.5 Elimination and excretion
7. PHARMACOLOGY AND TOXICOLOGY
   7.1 Mode of Action
   7.2 Toxicity
      7.2.1 Human Data
         7.2.1.1 Adults
         7.2.1.1 Children
      7.2.2 Relevant animal data
      7.2.3 Relevant in vitro data
   7.3 Carcinogenicity
   7.4 Teratogenicity
   7.5 Mutagenicity
   7.6 Interactions
8. TOXICOLOGICAL ANALYSES AND BIOMEDICAL INVESTIGATIONS
   8.1 Material sampling plan
      8.1.1 Sampling and specimen collection
         8.1.1.1 Toxicological analyses
         8.1.1.2 Biomedical analyses
         8.1.1.3 Arterial blood gas analysis
         8.1.1.4 Haematological analyses
         8.1.1.5 Other (unspecified) analyses
      8.1.2 Storage of laboratory samples and specimens
         8.1.2.1 Toxicological analyses
         8.1.2.2 Biomedical analyses
         8.1.2.3 Arterial blood gas analysis
         8.1.2.4 Haematological analyses
         8.1.2.5 Other (unspecified) analyses
      8.1.3 Transport of laboratory samples and specimens
         8.1.3.1 Toxicological analyses
         8.1.3.2 Biomedical analyses
         8.1.3.3 Arterial blood gas analysis
         8.1.3.4 Haematological analyses
         8.1.3.5 Other (unspecified) analyses
   8.2 Toxicological Analyses and Their Interpretation
      8.2.1 Tests on toxic ingredient(s) of material
         8.2.1.1 Simple Qualitative Test(s)
         8.2.1.2 Advanced Qualitative Confirmation Test(s)
         8.2.1.3 Simple Quantitative Method(s)
         8.2.1.4 Advanced Quantitative Method(s)
      8.2.2 Tests for biological specimens
         8.2.2.1 Simple Qualitative Test(s)
         8.2.2.2 Advanced Qualitative Confirmation Test(s)
         8.2.2.3 Simple Quantitative Method(s)
         8.2.2.4 Advanced Quantitative Method(s)
         8.2.2.5 Other Dedicated Method(s)
      8.2.3 Interpretation of toxicological analyses
   8.3 Biomedical investigations and their interpretation
      8.3.1 Biochemical analysis
         8.3.1.1 Blood, plasma or serum
         8.3.1.2 Urine
         8.3.1.3 Other fluids
      8.3.2 Arterial blood gas analyses
      8.3.3 Haematological analyses
      8.3.4 Interpretation of biomedical investigations
   8.4 Other biomedical (diagnostic) investigations and their interpretation
   8.5 Overall interpretation of all toxicological analyses and toxicological investigations
   8.6 References
9. CLINICAL EFFECTS
   9.1 Acute Poisoning
      9.1.1 Ingestion
      9.1.2 Inhalation
      9.1.3 Skin Exposure
      9.1.4 Eye contact
      9.1.5 Parenteral Exposure
      9.1.6 Other
   9.2 Chronic Poisoning
      9.2.1 Ingestion
      9.2.2 Inhalation
      9.2.3 Skin Exposure
      9.2.4 Eye Contact
      9.2.5 Parenteral Exposure
      9.2.6 Other
   9.3 Course, prognosis, cause of death
   9.4 Systematic description of clinical effects
      9.4.1 Cardiovascular
      9.4.2 Respiratory
      9.4.3 Neurological
         9.4.3.1 Central nervous system (CNS)
         9.4.3.2 Peripheral nervous system
         9.4.3.3 Autonomic nervous system
         9.4.3.4 Skeletal and smooth muscle
      9.4.4 Gastrointestinal
      9.4.5 Hepatic
      9.4.6 Urinary
         9.4.6.1 Renal
         9.4.6.2 Other
      9.4.7 Endocrine and reproductive systems
      9.4.8 Dermatological
      9.4.9 Eye, ear, nose, throat: local effects
      9.4.10 Haematological
      9.4.11 Immunological
      9.4.12 Metabolic
         9.4.12.1 Acid-base disturbances
         9.4.12.2 Fluid and electrolyte disturbances
         9.4.12.3 Others
      9.4.13 Allergic Reactions
      9.4.14 Other Clinical Effects
      9.4.15 Special Risks
10. MANAGEMENT
   10.1 General Principles
   10.2 Life supportive procedures and symptomatic/specific treatment
   10.3 Decontamination
   10.4 Enhanced elimination
   10.5 Antidote treatment
      10.5.1 Adults
      10.5.2 Children
   10.6 Management discussion
11. ILLUSTRATIVE CASES
   11.1 Case reports from literature
12. ADDITIONAL INFORMATION
   12.1 Specific preventive measures
   12.2 Other
13. REFERENCES
14. AUTHOR(S), REVIEWER(S), DATE(S) (INCLUDING UPDATES) COMPLETE ADDRESS(ES)




    Thiamine and salts

    International Programme on Chemical Safety
    Poisons Information Monograph G015 (Group PIM)
    Pharmaceutical


    1.  NAME

        1.1  Substance

             Thiamine

        1.2  Group

             This group includes:

             Acetiamine Hydrochloride
             Benfotiamine
             Bisbentiamine
             Bisbutiamine
             Cetotiamine Hydrochloride
             Cycotiamine
             Fursultiamine
             Octotiamine
             Prosultiamine
             Sulbutiamine
             Thiamine Hydrochloride
             Thiamine Nitrate

        1.3  Synonyms

             Acetiamine Hydrochloride (r INNM)
             Acethiamine Hydrochloride
             Diacethiamine Hydrochloride

             Benfotiamine (r INN)
             S-Benzoylthiamine  O-Monophosphate

             Bisbentiamine (r INN)
             O-Benzoylthiamine Disulphide

             Bisbutiamine
             O-Butyrylthiamine Disulphide

             Cetotiamine Hydrochloride (r INNM)
             Dicethiam Hydrochloride

             Cycotiamine (r INN)
             CCT
             Cyclorcabolthiamine

             Fursultiamine (r INN)
             Thiamine Tetrahydrofurfuryl Disulphide
             TTFD


             Octotiamine (r INN)
             TATD
             Thioctothiamine

             Prosultiamine (r INN)
             DTPT
             Thiamine Propyl Disulphide

             Sulbutiamine (r INN)
             Bisibutiamine
             O-Isobutyrylthiamine Disulphide

             Thiamine Hydrochloride (BANM, INNM)
             Aneurine Hydrochloride
             Thiamin Hydrochloride
             Thiamine Chloride
             Thiamini Hydrochloridum
             Thiaminii Chloridum
             Vitamin B1

             Thiamine Nitrate (BANM, INNM)
             Aneurine Mononitrate
             Thiamine Mononitrate
             Vitamin B1 Mononitrate

        1.4  Identification Numbers

             1.4.1 CAS Number

                    Acetiamine Hydrochloride     299-89-8
                    Benfotiamine                 2457-89-2
                    Bisbentiamine                2667-89-2
                    Bisbuntiamine                18481-23-7
                    Cetotiamine                  137-76-8
                    Cetotiamine Hydrochloride    616-96-6
                    Cycotiamine                  6092-18-8
                    Fursultiamine                804-30-8
                    Octotiamine                  137-86-0
                    Prosultiamine                59-58-5
                    Sisbutiamine                 3286-46-2
                    Thiamine Hydrochloride       67-03-8
                    Thiamine                     59-43-8
                    Thiamine Nitrate             532-43-4

             1.4.2  Other Numbers

        1.5  Main brand names, main trade names

             Monocomponent Products
             Aneurin (Germany); Benerva (Eire, Italy, Spain, Sweden, UK,
             Brazil); Bénerva (France, Switzerland); Betamin (Australia);
             Betalin S (USA); Betabion (Germany); Betatabs (Australia);

             Beta-Sol (Australia); Betaxin (Canada); Bewon (Canada);
             Bisolvit (Italy) Invite B(1) (Australia);
    
             Multicomponent Products
             Alcacyl B1 (Switzerland); Alegrina (Spain); Algimax (France)
             Antiadiposo (Italy);Banikol Vitaminé B1 (France); Benexol B1
             B6; B12 (Spain); Bénexol (Switzerland); Benevit (Italy);
             Benerva (UK); Cheihepan (Germany); Emazian B12 (Italy);
             Milgamma (Germany); Neurobion (Germany);

        1.6  Main manufacturers, main importers

             Wander (Switzerland); Rorer (Australia); Lilly (USA); E.
             Merck (Germany); Fawns & McAllan (Australia); Winthrop
             (Canada); Wyeth (Canada); Nuovo (Italy); Nelson (Australia);
             BioIndustria (Italy); Worwag (Germany); Roche (Switzerland,
             Spain, UK); Salus (Italy); Steigerwald (Germany); Martinet
             (France)

    2.  SUMMARY

        2.1  Main risks and target organs

             Hypersensitivity reactions have occurred, sometimes
             progressing to death. Thiamine is relatively non-toxic and
             poisoning usually follows a benign course.

        2.2  Summary of clinical effects

             Adverse effects are highly unusual.
             Headache, irritability, tremors, nausea, vomiting, anorexia
             and palpitations may occur.
             Eczematus reactions and precipitation of episodes of herpes
             zoster were reported.
             Anaphylactoid reactions: anxiety, pruritus, respiratory
             distress, nausea, abdominal pain, angioneurotic edema and 
             cardiovascular collapse were noted.

        2.3  Diagnosis

             Diagnosis is based on the above mentioned clinical signs
             and symptoms.
             Vomitus or gastric aspirate may be collected in clean bottles
             for identification.
             Blood levels are not needed for diagnosis.

        2.4  First aid measures and management principles

             Induced vomiting and gastric lavage may be indicated but
             must be carefully considered.
             Activated charcoal may be useful.
             Most cases can be managed with the basic symptomatic and
             supportive care.


    3.  PHYSICO-CHEMICAL PROPERTIES

        3.1  Origin of the substance

             It is obtained either naturally from rice husk, cereal
             grains, liver, yeast,  eggs, green beans, milk, tubers and
             roots; vegetables, plants, meat and fish . It may also be
             obtained synthetically.
             (Budavari, 1996; Reynolds, 1996).

        3.2  Chemical structure

             C12 H17 CIN4 OS   - Thiamine Hydrochloride
             C12 H17 N5 O4 S   - Thiamine Nitrate
    
             Molecular weight
             Thiamine Hydrochloride         337.3
             Thiamine Nitrate               327.4
    
             Chemical names
             Thiamine Hydrochloride
             3 - (4 - Amino - 2 - methyl-pyrimidin - 5 - ylmethyl)
             5 - (2 - hydroxyethyl) - 4 - methylthiazolium chloride
             hydrochloride
    
             Thiamine Nitrate
             3 - (4 - Amino - 2 - methylpyrimidin - 5 - ylmethryl)
             5 - (2 - hydroxyethyl) - 4 - methylthiazolium nitrate

        3.3  Physical Properties

             3.3.1  Colour

                    Thiamine Hydrochloride
                    Colourless or white (crystals)
                    White or almost white (powder)
    
                    Thiamine Nitrate
                    Colourless or white (crystals)
                    White or almost white (powder)

             3.3.2  State / Form

                    Thiamine Hydrochloride
                    Solid / crystals
                    Solid / powder

                    Thiamine Nitrate
                    Solid / crystals
                    Solid / powder


             3.3.3  Description

                    Thiamine Hydrochloride
                    Slight thiazole odour
                    Bitter Taste
                    Melting point about 248°C
                    Soluble in 1 in 1 of water and 1 in 100 of ethanol;
                    practically insoluble in dehydrated alcohol and ether;
                    soluble in methanol.
                    The vitamin is stable in the dry form.
                    pH of a 0.1% w/v solution in water 3.58
                    pH of a 1% w/v solution in water 3.13
    
                    Thiamine Nitrate
                    Slight characteristic odour.
                    Affected by light.
                    A 2% solution in water has a pH of 6.0 to 7.6.
                    Soluble in water 2.7 g /100 mL at 25° and
                    approximately
                    30 g /100 mL at 100°.
                    Sparingly soluble in water, freely soluble in boiling
                    water, slightly soluble in alcohol and in methyl
                    alcohol.
                    p.k.a. 4.8 (20°)
                    (Moffat et al, 1986; Reynolds, 1996).

        3.4  Other characteristics

             3.4.1  Shelf-life of the substance

                    No data available

             3.4.2  Storage Conditions

                    Store in airtight, nonmetallic containers.
                    Protect from light.

    4.  USES

        4.1  Indications

             4.1.1  Indications

             4.1.2  Description

                    Thiamine is a water-soluble vitamin that is
                    used in the treatment and prevention of thiamine
                    deficiency (Franco, 1982; Gilman et al., 1990).


        4.2  Therapeutic Dosage

             4.2.1  Adults

                    Thiamine is usually given by mouth, but may
                    also be administered by the intramuscular or
                    intravenous routes.
    
                    Mild chronic deficiency
                    Doses of up to 30 mg daily in single or divided have
                    been recommended.
    
                    Severe deficiency
                    Doses up to 300 mg daily have been given.
    
                    Alcoholic Neuropathy
                    Doses of 40 mg may be administered by the oral route.
    
                    Wernicke - Korsakoff Syndrome
                    Doses of at least 100 mg should be given, preferably
                    intravenously.
    
                    (Gilman et al., 1990; Goldfrank et al., 1990;
                    Reynolds, 1996).

             4.2.2  Children

                    Mild chronic deficiency
                    A dose of 10 to 50 mg given orally 3 times a day
    
                    Severe deficiency
                    A dose of 10 to 25 mg given parenterally 3 times a
                    day.

        4.3  Contraindications

             No data available.

    5.  ROUTES OF ENTRY

        5.1  Oral

             This is the preferred route (Reynolds, 1996).

        5.2  Inhalation

             No data available.

        5.3  Dermal

             No data available.


        5.4  Eye

             No data available.

        5.5  Parenteral

             May be administered by the intramuscular or intravenous
             routes.
             With Wenickeœs encephalopathy thiamine should be given,
             preferably intravenously, to ensure adequate absorption.

        5.6  Other

             No data available.

    6.  KINETICS

        6.1  Absorption by route of exposure

             It is well absorbed from the gastrointestinal tract  by
             Na+ dependent active transport. Absorption is generally
             limited to a maximal daily amount of 8 to 15 mg. However,
             this amount can be exceeded by oral administration in divided
             doses with food.
             It is rapidly absorbed after intramuscular administration
             (Moffat, 1986; Gilman et al., 1990; Baumgartner, 1991;
             Reynolds, 1996).

        6.2  Distribution by route of exposure

             It is widely distributed throughout the body and appears
             in breast milk. Thiamine is not stored to any appreciable
             extent in the body.
             Within the cell it is present as the diphosphate
             (Moffat,1986; Gilman et al., 1990; Reynolds, 1996).

        6.3  Biological half-life by route of exposure

             No data available.

        6.4  Metabolism

             About 1 mg. of thiamine is metabolized in the body
             daily.
             Thiamine pyrophosphate functions in carbohydrate metabolism
             as a coenzyme in the decarboxylation of alpha - keto acids,
             such as alpha - keto glutarate and pyruvate, and in the
             utilization of pentose in the hexose monophosphate shunt. The
             latter function involves the thiamine pyrophospate-dependent
             enzyme, transketolase (Moffat, 1986; Gilman et al., 1990).


        6.5  Elimination and excretion

             When intake is at a low level, little or no thiamine is
             excreted in the urine. Amounts ingested in excess of the
             minimal requirement are excreted in the urine as intact
             thiamine or as pyrimidine. As the intake of thiamine is
             further increased, more of the excess is excreted unchanged
             (Moffat, 1986; Gilman et al., 1990).

    7.  PHARMACOLOGY AND TOXICOLOGY

        7.1  Mode of Action

             The physiologically active form of thiamine is the
             thiamine pyrophosphate. In the carbohydrate metabolism, it
             functions as a coenzyme in the decarboxylation of alpha -
             keto acids such as pyruvate and alpha - keto glutarate, and
             in the hexose monophosphate shunt. The latter function
             involves the thiamine pyrophosphate-dependent enzyme
             transketolase. Thiamine also may serve as a modulator of a
             neuromuscular transmission. It binds to isolated nicotinic
             cholinergic receptors(Gilman et al., 1990).

        7.2  Toxicity

             7.2.1  Human Data

                    7.2.1.1  Adults

                             Thiamine is relatively non-toxic and
                             adverse reactions are highly unusual with
                             rare fatalities (Wrenn et al., 1989;
                             Baumgartner, 1991). Untoward effects of
                             thiamine therapy may be either purely
                             allergic, or similar to a thyrotoxic state
                             (Leitner, 1943).

                    7.2.1.1  Children

                             No data available.

             7.2.2  Relevant animal data

                    The direct application of thiamine to a
                    mammalsœ cortex (dogs) causes seizures (Dias, 1947;
                    Snodgrass 1992).
                    Large doses of intravenous injections produce
                    respiratory failure and death in dogs (Smith et al,
                    1948; Snodgrass, 1992).
                    The lethal dose of thiamine hydrochloride by
                    intravenous injection into rabbits is approximately
                    126 mg./kg (Halley & Flesher, 1946).


             7.2.3  Relevant in vitro data

                    No data available.

        7.3  Carcinogenicity

             No data available.

        7.4  Teratogenicity

             No data available.

        7.5  Mutagenicity

             No data available.

        7.6  Interactions

             The risk of an allergic reaction is thought to be
             negligible when it is administered together with other B
             vitamins (Baumgartner, 1991).

    8.  TOXICOLOGICAL ANALYSES AND BIOMEDICAL INVESTIGATIONS

        8.1  Material sampling plan

             8.1.1  Sampling and specimen collection

                    8.1.1.1  Toxicological analyses

                    8.1.1.2  Biomedical analyses

                    8.1.1.3  Arterial blood gas analysis

                    8.1.1.4  Haematological analyses

                    8.1.1.5  Other (unspecified) analyses

             8.1.2  Storage of laboratory samples and specimens

                    8.1.2.1  Toxicological analyses

                    8.1.2.2  Biomedical analyses

                    8.1.2.3  Arterial blood gas analysis

                    8.1.2.4  Haematological analyses

                    8.1.2.5  Other (unspecified) analyses


             8.1.3  Transport of laboratory samples and specimens

                    8.1.3.1  Toxicological analyses

                    8.1.3.2  Biomedical analyses

                    8.1.3.3  Arterial blood gas analysis

                    8.1.3.4  Haematological analyses

                    8.1.3.5  Other (unspecified) analyses

        8.2  Toxicological Analyses and Their Interpretation

             8.2.1  Tests on toxic ingredient(s) of material

                    8.2.1.1  Simple Qualitative Test(s)

                    8.2.1.2  Advanced Qualitative Confirmation Test(s)

                    8.2.1.3  Simple Quantitative Method(s)

                    8.2.1.4  Advanced Quantitative Method(s)

             8.2.2  Tests for biological specimens

                    8.2.2.1  Simple Qualitative Test(s)

                    8.2.2.2  Advanced Qualitative Confirmation Test(s)

                    8.2.2.3  Simple Quantitative Method(s)

                    8.2.2.4  Advanced Quantitative Method(s)

                    8.2.2.5  Other Dedicated Method(s)

             8.2.3  Interpretation of toxicological analyses

        8.3  Biomedical investigations and their interpretation

             8.3.1  Biochemical analysis

                    8.3.1.1  Blood, plasma or serum

                    8.3.1.2  Urine

                    8.3.1.3  Other fluids

             8.3.2  Arterial blood gas analyses

             8.3.3  Haematological analyses


             8.3.4  Interpretation of biomedical investigations

        8.4  Other biomedical (diagnostic) investigations and their 
             interpretation

        8.5  Overall interpretation of all toxicological analyses and 
             toxicological investigations

             Sample collection
             Collect sample of lavage, vomitus, blood, and urine for
             analysis. Blood levels are not needed to diagnose or treat
             the patient.
    
             Biomedical analysis
             Arterial gases, electrolytes , routine blood may be useful in
             mild to severe hypersensitivity cases.
    
             Toxicological analysis
             Thiamine levels are not clinically useful to manage patients.

        8.6  References

    9.  CLINICAL EFFECTS

        9.1  Acute Poisoning

             9.1.1  Ingestion

                    Ingestion of supraphysiological doses has not
                    usually produced toxic effects (Snodgrass, 1992;
                    Reynolds, 1996).
                    However, an anaphylactic response may occur after
                    multiple administrations of the drug (Stephen et al.,
                    1992).

             9.1.2  Inhalation

                    No data available.

             9.1.3  Skin Exposure

                    No data available.

             9.1.4  Eye contact

                    No data available

             9.1.5  Parenteral Exposure

                    Hypersensitivity reactions have occurred.
                    Pruritus, respiratory distress, nausea, abdominal
                    pain, weakness, anxiety, shock and sudden death have
                    been described. The anaphylactic reactions, were most

                    often seen after multiple administrations of thiamine
                    (Leitner, 1943; Stephen et al., 1992).

             9.1.6  Other

                    No data available.

        9.2  Chronic Poisoning

             9.2.1  Ingestion

                    After large doses, administered over a long
                    period of time a syndrome was described with the
                    following symptoms: hyperthyroidism, nausea and
                    vomiting, anorexia, headache, irritability, tremors,
                    and palpitations  (Stephen et al., 1992).

             9.2.2  Inhalation

                    No data available.

             9.2.3  Skin Exposure

                    Eczamatous reactions to topical exposure in
                    pharmaceutical workers has also been observed (Larsen
                    et al., 1989; Stephen et al., 1992).

             9.2.4  Eye Contact

                    No data available.

             9.2.5  Parenteral Exposure

                    No data available.

             9.2.6  Other

                    No data available.

        9.3  Course, prognosis, cause of death

             Poisoning in most patients follows a benign course.
             Adverse effects are highly unusual.
             Anaphylactic reactions have been described after parenteral
             administration. The severity may be from very mild to rarely
             fatal anaphylactic shock and death may result from
             cardiovascular collapse (Baumgartner, 1991; Stephen et al.,
             1992; Wrenn & Slovis, 1992).


        9.4  Systematic description of clinical effects

             9.4.1  Cardiovascular

                    Acute
                    No data available.
    
                    Chronic
                    Palpitations were described after oral administration of large doses (Stephen et al.,
                    1992; Bryson, 1996).

             9.4.2  Respiratory

                    No data available.

             9.4.3  Neurological

                    9.4.3.1  Central nervous system (CNS)

                             Acute
                             No data available.
    
                             Chronic
                             Headache, irritability and tremours occurred
                             after overdosing over a long period of time
                             (Stephen et al., 1992).

                    9.4.3.2  Peripheral nervous system

                             No data available.

                    9.4.3.3  Autonomic nervous system

                             No data available.

                    9.4.3.4  Skeletal and smooth muscle

                             No data available.

             9.4.4  Gastrointestinal

                    Acute
                    No data available.
    
                    Chronic
                    Nausea, vomiting, and anorexia were reported after
                    large doses (Stephen et al., 1992).

             9.4.5  Hepatic

                    No data available.


             9.4.6  Urinary

                    9.4.6.1  Renal

                             No data available.

                    9.4.6.2  Other

                             No data available.

             9.4.7  Endocrine and reproductive systems

                    No data available.

             9.4.8  Dermatological

                    Acute
                    No data available.
    
                    Chronic
                    Eczematous reactions to topical exposure and
                    precipitation of episodes of herpes zoster were
                    reported (Steinberg , 1938; Larsen et al., 1989;
                    Stephen et al., 1992).

             9.4.9  Eye, ear, nose, throat: local effects

                    No data available.

             9.4.10 Haematological

                    No data available.

             9.4.11 Immunological

                    No data available.

             9.4.12 Metabolic

                    9.4.12.1 Acid-base disturbances

                             No data available.

                    9.4.12.2 Fluid and electrolyte disturbances

                             No data available.

                    9.4.12.3 Others

                             No data available.


             9.4.13  Allergic Reactions

                    Acute
                    Anaphylactoid reactions have occurred after parenteral
                    administration. They included: respiratory distress,
                    nausea, abdominal pain, angioneurotic edema,
                    cardiovascular collapse, sometimes progressing to
                    death (Baumgartner, 1991; Bryson, 1996; Stephen et
                    al., 1992; Zanini et al.).

             9.4.14 Other Clinical Effects

                    No data available.

             9.4.15 Special Risks

                    High doses administered during a long period
                    may produce severe symptoms (Leitner, 1943).
    
                    Other
    
                    No data available.
    
                    Summary

    10. MANAGEMENT

        10.1 General Principles

             Supportive and symptomatic treatment is frequently all
             that is needed.
             Emesis may be carefully considered in recent substantial
             ingestion. However, it is not necessary in most cases because
             of the benign nature of thiamine.
             Activated charcoal may be administered.

        10.2 Life supportive procedures and symptomatic/specific treatment

             Make a proper assessment of airway, breathing,
             circulation and neurological status.
             Maintain a clear airway.
             Monitor vital signs.
             Correct hypotension / hypertension as required.

        10.3 Decontamination

             Induced vomiting and gastric lavage is not usually
             necessary because of the benign nature of the intoxication.
             Activated charcoal may be administered.


        10.4 Enhanced elimination

             Because of the usually benign nature of the
             intoxication, methods of elimination would not be expected to
             change the course.

        10.5 Antidote treatment

             10.5.1 Adults

                    None available.

             10.5.2 Children

                    None available.

        10.6 Management discussion

             Not relevant.

    11. ILLUSTRATIVE CASES

        11.1 Case reports from literature

             After administration intravenously of 100 mg of
             thiamine hydrochloride, a patient developed anxiety, diffuse
             and intense erythema, confusion and sinus tachycardia. He was
             discharged on the second day after admission (Stephen et al.,
             1992).
             In a prospective study evaluating the safety of intravenous
             thiamine in emergency department , only one potentially
             serious reaction (pruritus) was reported (Wrenn et al., 1989;
             Wrenn & Slovis, 1992).

    12. ADDITIONAL INFORMATION

        12.1 Specific preventive measures

             Thiamine has an extremely high safety profile. Caution
             is advised in administering large doses over a long period of
             time and multiple parenteral administrations.

        12.2 Other

             No data available.

    13. REFERENCES

        Baumgartner TG (1991) What the practicing nurse should know
        about thiamine. J Intravennurs, 14(2): 130-135.
    
        Bryson PD (1996) Comprehensive review in toxicology for emergency
        clinicians, 3rd ed. London, Taylor & Francis. pp 404.
    

        Budavari S ed. (1996)  The Merck Index: An Encyclopedia of
        Chemicals, Drugs, and Biologicals. 12th ed. Merck & Co., Inc,
        Whitehouse Station, NJ.
    
        Dias MV (1947) Action of thiamine applied directly to the cerebral
        cortex. Science,105: 211-213.
    
        Franco G (1982) Complexo B. In: Franco G. Nutriçœo texto básico e
        tabela de composiçao química dos alimentos, Rio de Janeiro,
        Livraria Atheneu. pp 31-36.
    
        Gilman AG, Rall TW, Nies AS & Taylor P eds. (1990) Goodman and
        Gilmanœs the pharmacological basis of therapeutics, 8th ed. New
        York, Pergamon Press, pp 1530-1534.
    
        Goldfrank LR, Flomenbaum NE, Lewin NA, Weisman RS, Howland MA &
        Kulberg AG eds. (1990) Goldfrankœs toxicologic emergencies,
        Norwalk, Appleton - Century - Crofts.
    
        Haley TJ & Flesher AM (1946) A toxicity study of thiamine
        hydrochloryde.Science,104:567-568.
    
        Larsen Al, Jepsen JR & Thulin H (1989) Allergic contact dermatitis
        from thiamine. Contact Dermatitis, 20(5): 387-388.
    
        Leitner ZA (1943) Untoward effects of vitamin B1. Lancet, 2:
        474-475.
    
        Moffat AC ed. (1986) Clarkeœs isolation and identification of
        drugs in pharmaceuticals, body fluids, and post-mortem material.
        2nd ed. London, The Pharmaceutical Press. pp 1014-1015.
    
        Reynolds JEF ed. (1996) Martindale: the extra pharmacopoeia, 31st
        ed. London, The Pharmaceutical Press. pp 1381-1383.
    
        Smith JA, Foa PP, Weinstein HR, Ludwig NS & Wertheim JM (1948)
        Some aspects of thiamine toxicity. J. Pharmacol ,93; 294-304.
    
        Snodgrass SR (1992) Vitamin neurotoxicity. Molecualr Neurobiology,
        6(1): 41-73.
    
        Steinberg CL (1938) Untoward effects resulting from the use of
        large doses of vitamin B1. Am J Dig Dis, 5: 680-681.
    
        Stephen JM, Grant R & Yeh CS (1992) Anaphylaxis from
        administration of intravenous thiamine. American Journal of
        Emergency Medicine, 10(1): 61-3.
    
        Wrenn KD, Murphy F & Slovis CM (1989) A toxicity study of
        parenteral thiamine hydrochloride. Ann Emerg Med, 18(8): 867-870.
    
        Wrenn KD & Slovis CM (1992) Is intravenous thiamine safe? Am J
        Emerg Med. 10(2):165


    14. AUTHOR(S), REVIEWER(S), DATE(S) (INCLUDING UPDATES) COMPLETE 
        ADDRESS(ES)

        Authors:    Dr. Rita de Cássia Bomfim Leitœo Higa
                    Dr. Oscar Higa
                    Centro de Assistencia Toxicológica de Presidente
                    Prudente
                    Hospital Estadual Dr. Odilo Antunes Siqueira
                    Universidade do Oeste Paulista
                    Presidente Prudente - Sœo Paulo
                    Brazil
    
                    Address for correspondence:
                    Av. José Soares Marcondes, 3758
                    Bairro: Jardim Bongiovanni
                    Presidente Prudente - Sœo Paulo
                    CEP 19001-000
                    Brazil
    
                    Telephone:              55.18.221.44.22
                                            55.18.221.90.55
                    email:                  ceatox@fipplx.unoeste.br
                    home page:                 http://www.unoeste.br/~ceatox
    
        Date:       July, 1997
    
        Peer review: INTOX meeting, Rio, Brazil, September, 1997
    
        Editor:  Dr. M.Ruse (October, 1998)