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Isoniazid

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
      7.1.1 Toxicodynamics
      7.1.2 Pharmacodynamics
   7.2 Toxicity
      7.2.1 Human data
         7.2.1.1 Adults
         7.2.1.2 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
   7.7 Main adverse effects
8. TOXICOLOGICAL 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 Biochemical 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 Biochemical 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 Biochemical 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 Toxicological Analyses & Biomedical Investigations
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 Acidbase 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
   9.5 Other
   9.6 Summary
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)
    ISONIAZID

    International Programme on Chemical Safety
    Poisons Information Monograph 288
    Pharmaceutical

    1.  NAME

        1.1  Substance

             Isoniazid

        1.2  Group

             Tuberculocidal
             Antimycobacterial agent
             ATC: JO4A CO1

        1.3  Synonyms

             INH; INAH; Isoniazidium;
             Isonicotinic acid hydrazide; 
             Isonicotinyl hydrazide;
             Isonicotinohydrazide; Pycazide;
             Tubazid

        1.4  Identification numbers

             1.4.1  CAS number

                    54-85-3

             1.4.2  Other numbers

                    UPDT: 7911
                    RTECS: NS 175 000

        1.5  Main brand names/main trade names

             Anidrasona (Hortel, Spain); Bacikoch (Ibys, Spain);
             Cemidon (Gayoso Wellcome, Spain); Cin Vis (Vis, Italy);
             Dardex (Llorente, Spain); Diazid (Nippon Shinyaky, Japan);
             Fimazid (Wasserman, Spain); Hidrafasa (Sabater, Spain);
             Hidranic (Spain); Hidranison (Cheminova, Spain); Hidrasolco
             (Inibsa, Spain); Hidrasstol (Sur De Espagna, Spain);
             Hidrazida (Cronofar, Spain; Rovi, Spain); Hidrulta (Euroulta,
             Spain); Hiperazida (Spain); Hydra; Hydronsan (Chugai, Japan);
             Idrazil (bracco, Italy); Iscontin (Daiichi, Japan); Iso-
             Dexter (Spain); Isotamine (ICN, Canada); Isotinyl (USV,
             Australia); Isozid (Saarstickstoff-Fatol, Germany); Kridan
             Simple (Cidan, Spain); Laniazid (Lannett, USA); Lefos
             (Spain); Lubacida (Spain); Midral (Orravan, Spain); Neoteben
             (Bayer, Germany); Nicazide (IFI, Italy); Nicizina

             (Farmitalia, Italy); Nicotibina (Lepetit, Argentine);
             Nicotibine (Belgique); Nicozid (Piam, Italy); Nidrazid
             (Squibb, USA); Panazid (US Products, USA); Pyreazid (Salvat,
             Spain); Rimifon (Roche, Belgique; Roche, Canada; Roche,
             France, Roche Germany; Roche, Portugal; Roche, Spain; Roche,
             Switzerland; Roche, UK); Sumifon (Sumitomo, Japan); Tb-
             Phlogin (Heyl, Germany); Tebesium-S (Hefa-Frenon, Germany);
             Tibinide (Ferrosan, Sweden); Tibizina (Italy); Zidafimia
             (Santos, Spain); Zideluy (Spain).
    
             The following names have been used for multi-ingredient
             preparations containing isoniazid-Inapasade (Smith & Nephew
             Pharmaceuticals, UK); Isoprodian (Kolassa, Australia;
             Saarstickstoff-Fatol, Germany; Saarstickstoff-Fatol, South
             Africa); Mynah (Lederle, UK); Pasinah-D (Wander, UK);
             Rifamate (Merrell Dow, USA); Rifater (Merrell, UK); Rifinah
             (Merrell, UK); Rimactazid (Ciba, UK). 

        1.6  Main manufacturers/main importers

             See section 1.5.

    2.  SUMMARY

        2.1  Main risks and target organs

             CNS is the target organ of INH acute toxicity. INH
             induces generalized convulsions, coma and metabolic acidosis.
             Death may occur from acute respiratory failure or
             hypotension.
    
             Liver and peripheral nervous and haematologic systems are the
             main target organs of INH chronic toxicity. INH may induce
             acute hepatitis, peripheral neuropathy, haemolytic
             anaemia.

        2.2  Summary of clinical effects

             Toxicity appears after a short delay of 0.5 to 4 hours
             following ingestion.
    
             Symptoms may include:
             -      slurred speech, hallucinations, coma
             -      generalized convulsions, status epilepticus
             -      respiratory failure, hypotension
             -      severe metabolic acidosis, fever
             -      rhabdomyolysis
             -      gastrointestinal symptoms (nausea, vomiting) are
                    frequent prior to the onset of convulsions.
    

             Hepatitis, peripheral neuropathy and haemolytic anaemia are
             manifestations of chronic toxicity.

        2.3  Diagnosis

             Severe isoniazid poisoning is characterized by the
             clinical triad of: repetitive convulsions not responsive to
             usual treatment; metabolic acidosis and coma.  
    
             Chronic isoniazid toxicity produces nausea, vomiting,
             restlessness, fever and many other signs and symptons.  Toxic
             hepatitis and hemolytic anemia may be observed, as well as
             other haemotological effects and psychosis.
    
             Blood gases, serum electrolytes, glucose and BUN
             determinations should be performed.  Severe metabolic
             disorders may be observed: lactic acidosis, hyperkalaemia,
             hypocalcaemia, hyperglycaemia and ketonuria increase in
             hepatic and muscle enzymes. Measurement of INH serum levels
             are not useful for the clinical management of INH
             overdose.

        2.4  First-aid measures and management principles

             Patients with INH overdose should always be admitted to
             an emergency or intensive care unit.
    
             Treatment includes:
    
             Supportive measures:
    
             -      control of convulsions by short-acting barbiturates
                    (thiopental) or benzodiazepines (diazepam)
             -      protection of airway (intubation) and maintenance of
                    adequate ventilation (artificial ventilation) if
                    necessary
             -      correction of hypotension by plasma expanders and/or
                    dopamine
             -      rehydration and correction of metabolic acidosis
                    (sodium bicarbonate) and electrolyte
                    abnormalities.
    
             Antidotes:      Convulsions should be treated with
                             intravenous pyridoxine (approximately 1 g
                             pyridoxine for each gram of INH
                             ingested).
    
             Elimination:    Gastric lavage and oral activated charcoal
                             are indicated within 3 to 4 hours following
                             ingestion. Ensure adequate diuresis. The
                             usefulness of forced diuresis is not
                             established. Haemodialysis may be considered
                             in patients unresponsive to supportive

                             treatment, anticonvulsant drugs and
                             intravenous pyridoxine.

    3.  PHYSICO-CHEMICAL PROPERTIES

        3.1  Origin of the substance

             INH is a chemical synthetic molecule (Meyer and Nelly,
             1912), a pyridine derivative of nicotinamide.

        3.2  Chemical structure

    FIGURE 1

             Chemical name: isonicotinic acid hydrazide
    
             Molecular formula: C6H7N3O
    
             Molecular weight: 137.14

        3.3  Physical properties

             3.3.1  Colour

                    Colourless.

             3.3.2  State/form

             3.3.3  Description

                    INH is a colourless, odourless, white
                    crystalline powder slowly affected by exposure to air
                    and to light.
    
                    Solubility: 1 g in 8 g water, 1 g in 50 mL alcohol;
                    slightly soluble in chloroform and very slightly
                    soluble in ether. A 10% solution has a pH of 6.0 to
                    8.0.
    

                    The solution for parenteral injection is a clear,
                    colourless liquid. The pH ranges between 5.6 and 6.0
                    (B.P. injection) or between 6.0 and 7.0 (U.S.P.
                    injection).
    
                    It is recommended that sugars such as glucose,
                    fructose and sucrose should not be used in INH
                    preparations because the absorption of the drug is
                    impaired by the formation of a condensation product.
                    Sorbitol might be a suitable substitute.

        3.4  Other characteristics

             3.4.1  Shelf-life of the substance

                    Three to five years.

             3.4.2  Storage conditions

                    Store in airtight conditions and protect from light.

    4.  USES

        4.1  Indications

             4.1.1  Indications

             4.1.2  Description

                    INH is an antimycobacterial agent which is
                    bactericidal for both extracellular and intracellular
                    organisms. It is the primary drug for the treatment of
                    tuberculosis when the disease is caused by
                    isoniazid-sensitive strains of the M. tuberculosis
                    (Goodman & Gillman, 1990). In combination with
                    rifampicin, ethambutol or pyrazinamide, INH is a first
                    line agent in the treatment of pulmonary and
                    extrapulmonary tuberculosis. It is a component of all
                    combined antituberculosis chemotherapy regimens
                    recommended by WHO.
    
                    INH may be used for tuberculosis prophylaxis.

        4.2  Therapeutic dosage

             4.2.1  Adults

                    (a)  Pulmonary and extrapulmonary tuberculosis
    
                    The usual adult dose of INH is a single dose of
                    5 mg/kg/day up to a maximum of 300 mg daily (PO, IM or
                    as a slow infusion).
    

                    Initial treatment should combine isoniazid
                    (5 mg/kg/day), rifampicin (10 mg/kg/day) and
                    pyrazinamide (30 mg/kg/day) for 2 months. In patients
                    that are known to have been exposed to resistant
                    organisms, a fourth drug should be added: ethambutol
                    (20 mg/kg/day) or streptomycin (20 mg/kg/day)
    
                    After the initial 2 months, isoniazid and rifampicin
                    are used in a 9 months regimen. INH should then be
                    administered as 5 mg/kg/day or 15 mg/kg twice weekly
                    (to a maximum of 900 mg per dose). In some instances
                    (lymphadenitis, bone and joint tuberculosis), longer
                    therapy may be required. 
    
                    (b) Tuberculosis prophylaxis
    
                    300 mg/day orally as a single dose for 6 to 12 months
    
                    (c) Dosage in renal failure
    
                    Glomerular filtration rate (GFR) > 10 mL/min: no
                    dosage adjustment
    
                    GFR < 10 mL/min: reduce to 66 to 75 % of the normal
                    dose when used for tuberculosis therapy and stop when
                    the drug is used for tuberculosis prophylaxis

             4.2.2  Children 

                    (a) Pulmonary and extrapulmonary tuberculosis 
    
                    The usual dosage in infants and children is 10 to 14
                    mg/kg/day up to a maximum of 300 mg
    
                    Initial treatment: Isoniazid, rifampicin and
                    pyrazinamide for 6 months
    
                    After 6th month: isoniazid and rifampicin 3 to 6
                    months
    
                    (b) Pulmonary prophylaxis
    
                    10 mg/kg/day orally as a single dose for 1 year

        4.3  Contraindications

             Known severe adverse reactions or hypersensitivity due
             to the drug. Previous hepatitis associated with INH.  INH
             should not be used in patients with acute liver disease.  INH
             may precipitate porphyria.
    

             Caution: Convulsions may be precipitated in patients with
             epilepsy. Patients at risk of neuropathy should additionally
             receive pyridoxine, 10 mg daily. Liver function should be
             monitored regularly in patients with previous hepatic
             disease.

    5.  ROUTES OF ENTRY

        5.1  Oral

             This is the most frequent route of intoxication because
             the drug is usually administered orally.

        5.2  Inhalation

             No data available.

        5.3  Dermal

             No data available.

        5.4  Eye

             No data available.

        5.5  Parenteral

             No case has been reported, but INH intoxication may
             occur after parenteral administration.

        5.6  Other

             No data available.

    6.  KINETICS

        6.1  Absorption by route of exposure

             Oral
    
             INH is rapidly and almost completely (90-95%) absorbed from
             the gastrointestinal tract. Peak plasma concentrations are
             reached within 1 to 2 hours after ingestion. The peak plasma
             concentration after a dose of 5 mg/kg is 5 mg/L.
    
             When INH is administered with food, the extent of absorption
             and the peak plasma concentration may be reduced (Notterman
             et al., 1986). 

        6.2  Distribution by route of exposure

             Protein binding is less than 10 to 15 % (Boxenbaum &
             Riegelman, 1974; Benett, 1983).
    

             INH is distributed into all body tissues and fluids (pleural,
             ascitic fluids, saliva, CSF) with tissue or fluid levels
             similar to serum levels (Kucers & Bennet, 1979). Skin
             contains large amounts and acts as a storage depot (Rolson
             and Sullivan,1963). INH penetrates well into caseous
             lesions.
    
             INH readily crosses the placenta. The concentrations in milk
             are approximately equal to plasma maternal
             concentrations.
    
             The apparent volume of distribution is 0.6 l/kg (Boxenbaum &
             Riegelman, 1974).

        6.3  Biological half-life by route of exposure

             The plasma half-life in patients with normal renal and
             hepatic function is 1 to 4 hours, depending on the rate of
             metabolism (see section 6.4.): it is 0.5 to 1.6 hours in fast
             acetylators and 2 to 5 hours in slow acetylators (Anderson,
             1976; Jeme, 1964; Ellard, 1984). The plasma halflife may be
             prolonged to 4.3 hours in patients with impaired hepatic
             function (Anderson, 1976) or severe renal impairment
             (Bowersox et al., 1973).  Plasma half-life may also be
             prolonged in acute overdose.

        6.4  Metabolism

             Metabolic pathway
    
             The major route of isoniazid metabolism is hepatic
             acetylation by N-acetyl transferase which produces
             acetylisoniazid.  The rate of acetylation is genetically
             determined.  Acetyisoniazid is further hydrolysed to
             isonicotinic acid and acetylhydrazine, both of which are
             excreted in the urine.  Isonicotinic acid is conjugated with
             glycine.  Acetylhydrazine is further metabolised to
             diacetylhydrazine and may be converted by the hepatic
             microsomal enzymes to the reactive metabolite (presumed to be
             hydrazine) which are thought responsible for INH-induced
             hepatotoxicity.  Acid labile hydrazones of isoniazid are
             formed with a-ketoglutarate and pyruvate, but since these do
             not appear to any extent in the blood, they are thought to be
             produced in the bladder (Ellard et al., 1972; Russell, 1972;
             Boxenbaum & Riegelman, 1974).

    FIGURE 2

             Acetylation phenotype
    
             The rate of acetylation is genetically determined and is
             subject to individual variations. Although it may be
             influenced by age and weight it is usually constant for each
             person. Two groups of people can be distinguished: slow
             acetylators and fast acetylators.
    
             The phenotype of slow acetylators is an autosomal recessive
             trait and results from a relative deficiency of the hepatic
             enzyme Nacetyl transferase. The incidence taken from various
             sources estimates 45-55% in Americans, 60% in Europeans, 50-
             65% in Caucasians, Blacks, South Indians, Mexicans. The
             incidence of fast acetylators is 80-90% in Eskimos, Japanese
             and Chinese.
    
             Slow acetylators have higher serum levels of INH at a given
             dose.  Six hours after ingestion of 4 mg/kg INH, plasma
             concentrations are 0.8 mg/L in slow acetylators and only 0.2
             mg/L in fast acetylators (Meyers et al., 1976). It has also
             been suggested that fast acetylators may have a poorer
             response to treatment than slow acetylators (Mitchell, 1958;
             Ellard, 1984). The rate of isoniazid acetylation does not
             appear to alter efficacy when the drug is administered daily
             or 2 or 3 times weekly. However, a relationship between rapid
             inactivation and poor therapeutic response has been noted in
             once-weekly treatments (Lauterburg et al, 1985).

        6.5  Elimination and excretion

             Kidney
    
             In adults with normal renal function, approximately 50 to 70%
             of a 5 mg/kg oral dose is excreted in urine within 24 hours
             as unchanged drug and as metabolites. The percentage of the
             different compounds excreted varies with the acetylator
             phenotype (Kucers & Bennet, 1979).
    
                                Acetyl isoniazid    Free isoniazid and 
                                and metabolites     hydrazone conjugates
    
             Slow acetylators         63%                   37%
             Fast acetylators         94%                    6%
    
             Breast milk
    
             0.75 to 2.3% of the dose is excreted into breast milk in 24
             hours. This corresponds to 6-20% of a usual therapeutic
             paediatric dose.
    
             Other routes
    
             Small amounts of the drug are excreted in saliva, sputum and
             faeces.

    7.  PHARMACOLOGY AND TOXICOLOGY

        7.1  Mode of action

             7.1.1  Toxicodynamics

                    Tonic-clonic seizures and severe metabolic
                    acidosis are the most common features in INH
                    overdose.
    
                    Seizures
    
                    The precipitating mechanism of the seizures is not
                    exactly known but it may be related to the INH-induced
                    deficiency of pyridoxine. INH produces pharmacologic
                    changes in pyridoxine metabolism (Biehl & Vitter,
                    1954):
    
                    -  Increased renal excretion of pyridoxine by
                       formation of INH-pyridoxine hydrazones
    
                    -  The hydrazones competitively inhibit pyridoxine
                       kinase, the activating enzyme that converts
                       pyridoxine to the physiologically active pyridoxal
                       phosphate
    

                    -  Inactivation of the pyridoxal containing enzymes.
    
                    The subsequent reduction in pyridoxine and pyridoxal
                    phosphate inhibits the formation of the inhibitory
                    neurotransmitter, gamma aminobutyric acid or GABA
                    (Wood & Peesker, 1972). This reduction in GABA levels
                    may explain the seizures in patients with INH
                    poisoning.
    
                    Metabolic acidosis
    
                    The metabolic acidosis may be related to:
    
                    -  a lactic acidosis due to the seizures,
    
                    -  a blockage in the conversion of lactate to
                       pyruvate,
    
                    -  an increased metabolism of fatty acids resulting
                       from an impaired glucose metabolism with
                       hyperglycaemia and ketonuria (Terman & Teitelbaum,
                       1970).
    
                    Neuropathy
    
                    Peripheral neuropathy secondary to chronic exposure is
                    due to the deficiency of pyridoxine and pyridoxal
                    phosphate.
    
                    Hepatitis
    
                    Hepatitis is due to a toxic metabolite of monoacetyl
                    hydrazine, which binds covalently to liver proteins
                    (Black et al., 1975). In some patients an allergic
                    mechanism has also been proposed: acylation of hepatic
                    macromolecules by acetyl hydrazine may lead to the
                    release of antigenic macromolecules which induce the
                    formation of antibodies directed against the liver
                    (Davies, 1981).

             7.1.2  Pharmacodynamics

                    The exact mechanism of action of INH is not
                    known. INH may act by inhibition of mycolic acid
                    synthesis and disruption of the cell wall in
                    susceptible organisms.  Since mycolic acids are unique
                    to mycobacteria, this action explains the high degree
                    of selectivity of the antimicrobial activity.
    
                    Mutation conferring resistance may occur in
                    susceptible microorganisms. There is a cross
                    resistance between INH, rifampicin and ethambutol.
                    However the simultaneous use of two of these drugs

                    markedly delays the emergence of resistant mutants
                    either agent.

        7.2  Toxicity

             7.2.1  Human data

                    7.2.1.1  Adults

                             Acute exposure
    
                             Doses of 30 to 40 mg/kg may produce seizures
                             (Manoguerra, 1980). In adults with prior
                             seizure disorders, seizures may occur after
                             ingestion of doses as low as 14 mg/kg.
    
                             Doses of 80 to 150 mg/kg produce seizures and
                             can cause death.
    
                             Dose of 150 to 200 mg/kg are often fatal if
                             not treated (Terman & Teitelbaum, 1970).
    
                             Chronic toxicity
    
                             Symptoms of chronic toxicity may appear after
                             therapeutic doses.

                    7.2.1.2  Children

                             No data available.  See section 7.2.1.1.

             7.2.2  Relevant animal data

                    Species             Route   Effect & Dose
    
                    Rat         oral           LD50    650 mg/kg
                                subcutaneous           329 mg/kg
    
                    Mouse       oral           LD 50   176 mg/kg
                                subcutaneous           160 mg/kg
                                intramuscular          140 mg/kg
                                intravenous            149 mg/kg
    
                    Dog         oral           LD 50   150 mg/kg
    
                    Rabbit      oral           LD 50   250 mg/kg
                                subcutaneous           285 mg/kg
                                intravenous             94 mg/kg
    
                    Guinea Pig  oral           LD 50   450 mg/kg
                                subcutaneous           255 mg/kg
    
                    (RTECS, 1979)

             7.2.3  Relevant in vitro data

                    Not relevant

        7.3  Carcinogenicity

             There is no evidence to support carcinogenic effects in
             humans. A recent study did not detect an increase in cancer
             deaths in a series of 338 women treated with INH for
             pulmonary tuberculosis (Meyer et al., 1988). Several other
             studies fail to show a carcinogenic effect, including a study
             by  the US Public Health Service in 25,000 patients followed
             up for 9 to 14 years; a study by Scott in 3,842 patients in
             the UK; and the studies of Hammond (1967) and Sanders &
             Drayer (1979).

        7.4  Teratogenicity

             INH is classified as category C by Briggs et al. (1986)
             and may be used safely during pregnancy. INH and ethambutol
             are considered the safest drugs for the treatment of
             tuberculosis during pregnancy (Holdiness, 1987; Ludford,
             1973).

        7.5  Mutagenicity

             No data available.

        7.6  Interactions

             Several drugs may interact with INH:
    
             Drugs which interfere with INH pharmacokinetics:
    
             Aminosalicylic acid, procainamide, propranolol increase INH
             serum levels by reduction of the acetylation.
    
             Aluminium-containing antacids decrease the gastrointestinal
             absorption of INH.
    
             Pyrazinamide decreases the serum levels of INH.
    
             Drugs which decrease serum levels when used with INH
    
             Cyclosporine, enflurane, folic acid, ketoconazole,
             verapamil.
    
             Drugs which increase serum levels when used with INH
    
             Carbamazepine, diazepam, dicoumarol, ethosuximide, phenytoin,
             primidone, theophylline.
    

             Other interactions
    
             The concomitant administration of INH and the following drugs
             may produce:
    
             -      psychiatric responses: tricyclic antidepressants
             -      hyperglycaemia: chlorpropamide
             -      agitation or parkinsonian tremor: levodopa
             -      hypotension: pethidine (meperidine)
             -      increased incidence of hepatotoxicity: rifampicin
             -      hypertension, tachycardia, hyperthermia: monoamine
                    oxidase inhibitors

        7.7  Main adverse effects

             (Drugdex, 1991)
    
             Peripheral neuropathy and hepatotoxicity are the most
             frequently observed adverse effects of INH.
    
             Hepatotoxicity 
    
             Asymptomatic elevation of serum aspartate transferase (SGOT)
             is noted in 10-20 % of the patients (Scharer and Smith,
             1969). This increase is usually transient and the level
             returns to normal with continuing therapy. INH should be
             discontinued in patients with a transaminase level three
             times greater than normal.
    
             Hepatitis with jaundice may occur (0.5 %).  In most cases,
             hepatitis occurs within the 3 months following the onset of
             the treatment. Some factors predisposing to INH
             hepatotoxicity include: age, alcohol, rapid acetylator
             status, concomitant administration of isoniazid and
             rifampicin (Acocella, 1972).
    
             Peripheral neuropathies
    
             Peripheral neuropathy is the most common side effect of INH.
             It is secondary to a pyridoxine deficiency. The predisposing
             factors are: alcohol, slow acetylator status, diabetes,
             malnutrition, pregnancy.
    
             Peripheral neuropathy is dose-related: it is uncommon at
             doses below 5 mg/kg and very frequent with doses over 300_mg
             daily.
    
             Treatment and prophylaxis are based on administration of
             pyridoxine.
    
             Other adverse reactions:
    
             (Drugdex, 1991; Davies, 1981)
    

             Haematologic: disseminated intravascular coagulation
            (Roberts, 1976); granulocytosis, eosinophilia, anaemia
            (haemolytic, aplastic, sideroblastic, megaloblastic),
            thrombocytopenia.
    
             Neurologic: peripheral neuropathy (see 7.7.2),
             hypersensitivity meningitis (Goragusi, 1976), dystonias,
             encephalopathy, seizures, cerebellar syndromes.
    
             Psychiatric: confusional states, transient memory
             impairment, delirium.
    
             Endocrine/metabolic: hyperglycaemia, hypocalcaemia,
             porphyria, gynaecomastia.
    
             Gastrointestinal: abdominal pain, acute pancreatitis.
    
             Kidney: nephrotoxicity is a very rare complication, (1 case
             of acute renal insufficiency has been described by Traimis,
             1981).
    
             Ocular: optic neuropathy (especially when combined therapy
             with INH and ethambutol); optic atrophy
    
             Dermatologic: pellagra (due to a nicotinic acid
             deficiency), exfoliative dermatitis (one case described by
             Rosin, 1982), Steven-Johnson syndrome; cutaneous reactions
             (2%), urticaria, angioneurotic oedema, morbilliform
             eruptions, purpura, acneiform eruptions,
             photosensitivity.
    
             Musculoskeletal: arthritis, arthralgias, systemic lupus
             erythematosus; antinuclear antibodies in the serum may
             appear, especially in slow acetylators, approximately five
             months after the onset of therapy.

    8.  TOXICOLOGICAL AND BIOMEDICAL INVESTIGATIONS

        8.1  Material sampling plan

             8.1.1  Sampling and specimen collection

                    8.1.1.1  Toxicological analyses

                             Toxic ingredient: tablets, capsules,
                             liquids, suspect materials
                             In case of ingestion:
                             -  Vomitus: total amount
                             -  Gastric aspirate: total amount (or gastric
                                lavage - first portion: 100 mL)
                             -  Blood without additives: 10 mL
                             -  Urine (random specimen): 50 mL

                    8.1.1.2  Biochemical analyses

                             Plasma (lithium heparin as
                             anticoagulant) or serum and urine for
                             standard biochemical analyses.  Whole blood
                             with anticoagulant and glycolytic inhibitor
                             (e.g. heparin or fluoride) for lactate
                             determination.

                    8.1.1.3  Arterial blood gas analysis

                             Heparinized arterial blood sample.

                    8.1.1.4  Haematological analyses

                             Anticoagulated blood (e.g. EDTA) for
                             standard haematological analyses and
                             differential blood picture.  Anticoagulated
                             blood for prothrombin time. 

                    8.1.1.5  Other (unspecified) analyses

                             No further materials.

             8.1.2  Storage of laboratory samples and specimens

                    8.1.2.1  Toxicological analyses

                             Serum should be separated and stored
                             in freezer (-20°C).  There is controversy
                             over the stability of INH and acetylINH in
                             serum and urine.  Some early assays based on
                             fluorimetry and colourimetry give apparent
                             loss of INH and acetylINHzid when serum is
                             stored for longer than 1 to 2 hours, even if
                             frozen, and it was recommended that protein
                             be precipitated immediately to ensure
                             reliable results.  However, subsequent
                             substitution of stronger acids as
                             precipitating agents release isoniazid from
                             the proteins to which it becomes bound on
                             storage.  Further investigation shows that
                             isoniazid and acetylisoniazid are almost
                             completely lost from serum after one week at
                             room temperature (acetylINH is hydrolysed to
                             isonicotinic acid by serum enzymes).  Protein
                             precipitation should therefore be performed
                             within 12 hours if frozen storage of
                             separated serum (-20°C) is not possible. 
                             While acetylisoniazid is usually stable in
                             urine, pronounced decay is sometimes observed
                             and is therefore thought to be bacterial
                             (Ellard et al., 1972).

                    8.1.2.2  Biochemical analyses

                             No special requirements, but as
                             usually performed.

                    8.1.2.3  Arterial blood gas analysis

                             No special requirements, but as
                             usually performed.

                    8.1.2.4  Haematological analyses

                             Not applicable.

                    8.1.2.5  Other (unspecified) analyses

                             Not applicable.

             8.1.3  Transport of laboratory samples and specimens

                    8.1.3.1  Toxicological analyses

                             No special requirements, but as
                             usually performed.

                    8.1.3.2  Biochemical analyses

                             No special requirements, but as
                             usually performed.

                    8.1.3.3  Arterial blood gas analysis

                             No special requirements, but as
                             usually performed.

                    8.1.3.4  Haematological analyses

                             No special requirements, but as
                             usually performed.

                    8.1.3.5  Other (unspecified) analyses

                             Not applicable.

        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)

                             The presence of INH in materials can
                             be inferred by a number of chemical tests.
                             Heating of INH (10 mg material) with
                             anhydrous sodium carbonate (200 mg) releases

                             pyridine, which is easily detected by its
                             odour (WHO, 1986).
    
                             Several simple colour tests are available,
                             but results must be interpreted with caution,
                             since many other drugs give similar
                             reactions, and the limitations of each test
                             are given where known.
    
                             Nitroprusside test: INH can be reacted with
                             sodium nitropentacyanoferroate reagent
                             (freshly prepared equal volume mix of sodium
                             nitroprusside and 4M NaOH) to give an intense
                             orange colour which fades slowly (Baselt,
                             1987; Flanagan et al., 1995).
    
                             Nessler's Reagent: Add solid potassium
                             iodide to a saturated solution of mercuric
                             chloride until the initial red precipitate
                             dissolves, then add an equal volume of 10M
                             NaOH solution.  Mix 1 mL of reagent with a
                             small amount (10 mg) of the material. The
                             presence of the -NH-NH2 side chain of INH
                             produces an immediate black colour.  A
                             similar response is given by ortho and para
                             hydroxyl groups, and by the -NH-NH- group.  A
                             number of other compounds produce a similar
                             response if heated (Moffat et al., 1986).
    
                             UV spectrophotometry: Dissolve a portion of
                             material in dilute acid (e.g. 0.1M HCl) or
                             alkali (e.g. 0.1M NaOH) to achieve an
                             appropriate instrument response.  If
                             necessary, centrifuge or filter the mixture
                             and analyse the clear supernatant.  The
                             spectrum in aqueous acid gives two equal
                             9max at 213 and 266 nm (A| = 390); in
                             alkali 9max is at 272 and 298 nm, but are
                             not stable. 
    
                             After dissolving the material in 0.1M HCl,
                             INH can be coupled at room temperature on
                             mixing with several reagents to give products
                             which absorb strongly in the UV region.  For
                             example: 1% trans-cinnamaldehyde in ethanol
                             (358 nm); 2% vanillin in ethanol / water
                             (1:3) (380 nm); (Eidus & Harnanansingh,
                             1971). 
    

                             There are no commonly-available immunoassay
                             kits for drug testing which respond to
                             INH.
    
                             Thin layer chromatography may be used for
                             identification of isoniazid, and may be
                             either an in-house system or a
                             commercially-available system such as
                             Toxi-Lab (Ansys Inc, Irvine, California
                             92718, USA).  Dissolve the material in an
                             organic solvent such as methanol or
                             dichloromethane and apply directly to the
                             plate.  Using silica plates without modifiers
                             and standard systems, the Rf of INH is 0.47
                             on methanol / concentrated ammonia (100:
                             1.2), and 0.29 on ethyl acetate / methanol /
                             ammonia (85:15:6). Acidified iodoplatinate
                             gives an uncharacteristic dark blue response,
                             and a positive reaction is obtained with
                             Dragendorff's with a sensitivity of
                             approximately 50 ng (Moffat et al.,
                             1986).

                    8.2.1.2  Advanced qualitative confirmation test(s)

                             Gas chromatography can be used after
                             dissolving the material in a small amount of
                             organic solvent (e.g. 10 mg in 10 mL
                             methanol).  The retention index for INH is
                             1650 on OV1, SE30, DB5 or similar phases. 
                             Isothermal analysis may be performed at about
                             200°C, although peak shape is improved on
                             temperature-programmed capillary columns. 
                             Flame ionization detection gives adequate
                             sensitivity.  Derivatization of the material
                             improves chromatography (e.g. treatment of
                             the dry residue with TFAA at 60°C for 30
                             minutes (LoDico et al., 1992) or with BSTFA /
                             1% TMCS for 1 hour at 80°C (Frater-Schröder &
                             Zbinden, 1975), or with p-chlorobenzaldehyde
                             in methanol for 30 minutes at room
                             temperature (Timbrell et al., 1977).  Excess
                             derivatizing reagent is evaporated to
                             dryness, and the extract reconstituted in a
                             suitable solvent for GC analysis.  The
                             retention times for the derivatives are
                             broadly in line with that of underivatized
                             INH. Characteristic fragmentation on mass
                             spectrometry is seen, and the most abundant
                             ions are: INH  m/z 78, 106, 51 and 137;
                             INH-TFA  m/z 215, 78, 106 and 146; INH-diTMS
                              m/z 73, 75, 266, 147 and  117. 
    
                             HPLC may be used to identify INH in residues
                             by dissolving a small amount of the suspect
                             material in the mobile phase, and filtering
                             if necessary to obtain a clear solution. 
                             Hutchings et al. (1983) performed
                             chromatography on a Spherisorb nitrile column
                             with a mobile phase of 0.01 M phosphoric acid
                             in acetonitrile / water (80:20).  Detection
                             was at 266 nm, and chromatograms showed good
                             peak shape with separation over 6 min,
                             without interference from other commonly
                             prescribed antituberculous drugs. 
                             Alternatively, Hsu & Ho (1989) used a reverse
                             phase phenyl column with a mobile phase of 10
                             mM phosphate buffer containing 0.25 mM
                             tetrabutylammonium phosphate as paired-ion
                             source (pH 4.1).  Good separation was seen
                             over 20 minutes, with detection at 280 nm.
                             Additional confirmation of identity may be
                             obtained by performing a full scan analysis
                             on the appropriate portion of the HPLC
                             effluent or incorporating a diode array
                             detector.  El-Yazigi & Yusuf (1991) show
                             excellent chromatography on a C18 column in a
                             radial compression (Z) module with a mobile
                             phase of 10 mM sodium dibasic phosphate (pH
                             7.0 with phosphoric acid) and methanol (93.5:
                             6.5); electrochemical detection was at +800
                             mV.

                    8.2.1.3  Simple quantitative method(s)

                             In the methods described below a
                             known mount of the material is weighed into
                             an aqueous solution, and centrifuged or
                             filtered to obtain a clear supernatant for
                             analysis. Quantitation is performed by
                             comparison of the response of the material to
                             the analysis of known amounts of INH prepared
                             similarly.  All methods have adequate
                             sensitivity for residue analysis, but suffer
                             interference from compounds of similar
                             structure.
    
                             Colourimetric assays
    
                             INH can be reacted with sodium
                             nitropentacyanoferroate reagent (freshly
                             prepared equal volume mix of sodium
                             nitroprusside and 4M NaOH) to give an intense
                             orange product absorbing at 440 nm.  The
                             colour is unstable, and measurements should
                             be timed to 2 minutes (Björnesjö & Jarnulf,
                             1967; Baselt, 1987; Flanagan et al.,
                             1995).
    
                             Chlorpromazine free radical solution
                             (prepared by treating chlorpromazine with
                             2-iodoxybenzoic acid in 50% w/v
                             orthophosphoric acid) absorbs at 530 nm, and
                             the addition of INH results in quantitative
                             reduction to colourless chlorpromazine
                             (El-Brashy & El-Ashry, 1992).
    

                             INH in 0.1M HCl can be coupled at room
                             temperature on mixing with several reagents
                             to give products which absorb strongly in the
                             UV region.  For example: 1%
                             trans-cinnamaldehyde in ethanol (358 nm); 2%
                             vanillin in ethanol / water (1:3) (380 nm)
                             (Eidus & Harnanansingh, 1971). 
    
                             Titrimetric determination
    
                             INH solution is titrated with
                             N-bromophthalimide using methyl red
                             indicator.  Alternatively, a known excess of
                             titrant is added to the INH solution, and the
                             residual unreacted reagent determined by
                             iodometric back-titration (El-Brashy &
                             El-Ashry, 1992).

                    8.2.1.4  Advanced quantitative method(s)

                             In the methods described below a
                             known mount of the material is weighed into
                             aqueous solution or a suitable organic
                             solvent. Quantitation is performed by
                             addition of a suitable internal standard, and
                             comparison of the response of the material to
                             the analysis of known amounts of INH prepared
                             similarly.  All methods have adequate
                             sensitivity for residue analysis.
    
                             Gas chromatography can be used directly after
                             dissolving the material in an organic
                             solvent.  The retention index for INH is 1650
                             on OV1, SE30, DB5 or similar phases. 
                             Isothermal analysis may be performed at about
                             200°C, although peak shape is improved on
                             temperature-programmed capillary columns. 
                             Flame ionization detection gives adequate
                             sensitivity. Derivatization of the material
                             improves chromatography (e.g. treatment of
                             the dry residue with TFAA at 60°C for 30
                             minutes using phentermine as internal
                             standard (LoDico et al., 1992), or with
                             eicosan internal standard and BSTFA / 1% TMCS
                             for 1 hour at 80°C (Frater-Schröder &
                             Zbinden, 1975), or with p-chlorobenzaldehyde
                             in methanol for 30 minutes at room
                             temperature, followed by addition of
                             p-bromobenzaldehyde isonicotinyl hydrazone
                             internal standard (Timbrell et al., 1977). 
                             Excess solvent and derivatizing reagents are
                             evaporated to dryness, and the extract
                             reconstituted in a suitable solvent for GC

                             analysis.  The retention times for the
                             derivatives are broadly in line with that of
                             underivatized INH. Characteristic
                             fragmentation is achieved on mass
                             spectrometry, and the most abundant ions are:
                             INH  m/z 78, 106, 51 and 137; INH-TFAA  m/z
                             215, 78, 106, 146; INH-diTMS  m/z 73, 75,
                             266, 147 and 117.
    
                             HPLC may be used to quantify INH in residues,
                             and two UV methods are highly suitable.
                             Hutchings et al. (1983) used a Spherisorb
                             nitrile column with a mobile phase of 0.01 M
                             phosphoric acid in acetonitrile / water
                             (80:20).  Detection was at 266 nm, and
                             iproniazid was used as internal standard. 
                             Chromatograms showed good peak shape with
                             separation over 6 min, without interference
                             from other commonly prescribed
                             antituberculous drugs.  Alternatively, Hsu &
                             Ho (1989) used a reverse phase phenyl column
                             with a mobile phase of 10 mM phosphate buffer
                             containing 0.25 mM tetrabutyl-ammonium
                             phosphate as paired-ion source (pH 4.1). 
                             Niacinamide was used as internal standard,
                             and good separation was seen over 20 minutes,
                             with detection at 280 nm. Additional
                             confirmation of identity may be obtained by
                             performing a full scan analysis on the
                             appropriate portion of the HPLC effluent or
                             incorporating a diode array detector. 
                             El-Yazigi & Yusuf (1991) obtained excellent
                             chromatography on a C18 column in a radial
                             compression (Z) module with a mobile phase of
                             10 mM sodium dibasic phosphate solution (pH
                             7.0 with phosphoric acid) / methanol (93.5:
                             6.5).  Electrochemical detection was at +800
                             mV, and diphenylcarbazide was used as
                             internal standard.

             8.2.2  Tests for biological specimens

                    8.2.2.1  Simple qualitative test(s)

                             There are no commonly-available
                             immunoassay kits for drug testing which
                             respond to INH or its metabolites in
                             biological specimens. 
    

                             Direct UV methods may be applied to the
                             detection of INH in gastric contents, but are
                             not useful for the analysis of other fluids.
                             Disperse a portion of gastric contents in
                             dilute acid (e.g. 0.1M HCl) or alkali (e.g.
                             0.1M NaOH) to achieve an appropriate
                             instrument response.  If necessary,
                             centrifuge or filter the mixture and analyse
                             the clear supernatant.  The spectrum in
                             aqueous acid gives 9max at 266 nm (A| =
                             390); in alkali 9max is at 298 nm. 
    
                             Thin layer chromatography can be used after
                             extraction from biological specimens (urine
                             or gastric contents - 10 - 20 mL) at pH 5 to
                             7.  A polar extraction solvent (e.g.
                             dichloromethane, ethyl acetate) and
                             saturation of the aqueous phase with solid
                             sodium chloride are required to maximize
                             recovery of INH and metabolites. Treatment of
                             urine with dilute HCl (15 minutes at room
                             temperature) greatly increases INH recovery.
                             The extract is concentrated by evaporation of
                             the solvent.  Thin layer chromatography may
                             be either an in-house system or a
                             commercially-available system such as
                             Toxi-Lab (Ansys Inc, Irvine, California
                             92718, USA).  Using silica plates without
                             modifiers and the standard methanol /
                             concentrated ammonia (100: 1.2) system, the
                             following Rf data are reported by Walubo et
                             al., 1994.  INH 0.55, acetylINH 0.55,
                             monoacetylhydrazine 0.65, diacetylhydrazine
                             0.45, hydrazine 0.09.  All compounds gave a
                             positive reaction to acidified iodoplatinate
                             (dark blue), and to Dragendorff s with a
                             sensitivity of approximately 50 ng on
                             plate.
    
                             AcetylINH can be detected in urine by mixing
                             1 mL with an equal volume of 0.5M pH 6 buffer
                             (87.7 mL potassium dihydrophosphate and 12.3
                             mL potassium hydrophosphate).  Addition of 1
                             mL freshly prepared 20% potassium cyanide is 
                             followed by 4 mL 12.5% freshly prepared
                             chloramine T.  After 2 minutes, 5 mL of
                             acetone is added and a cherry pink colour is
                             formed.  Increased sensitivity can be
                             obtained by first acetylating INH by shaking
                             the urine with one drop of acetic anhydride,
                             followed by one drop of 7M NaOH, and
                             proceeding as above.  Chlorpromazine
                             interferes (Eidus et al., 1973).
    

                             Identification of toxic amounts of INH in
                             urine or serum by spectrophotometry can be
                             achieved by coupling with chromogenic
                             reagents. There is interference from
                             pyrazinamide and iproniazid.  For serum, a
                             protein free filtrate should be prepared
                             (e.g. with 2 volumes of methanol or
                             acetonitrile, and the organic solvent
                             evaporated off), and the supernatant
                             analysed.  For colourimetry, the supernatant
                             is mixed with 2M acetic acid followed by
                             equal volumes of 2% sodium nitroprusside and
                             4M NaOH (freshly prepared).  The yellow
                             colour has maximum absorbance at 440 nm
                             (Björnesjö & Jarnulf, 1967; Baselt, 1987).
                             Alternatively, for UV spectrophotometry, the
                             supernatant is mixed with 0.04%
                             trans-cinnamaldehyde solution in absolute
                             ethanol.  Absorbance is measured at 340 nm
                             (Eidus & Harnanansingh, 1971;
                             1974).

                    8.2.2.2  Advanced qualitative confirmation test(s)

                             Gas chromatography can be used for
                             identification of INH and metabolites in
                             urine after extraction into a polar organic
                             solvent (e.g methylene chloride or ethyl
                             acetate) from a pH adjusted to 4 to 7 using a
                             phosphate buffer.  Some methods utilize
                             salting-out of the drug and metabolites with
                             solid sodium sulphate.  Urine is generally
                             incubated at room temperature for 15 minutes
                             with 0.1 M HCl to hydrolyze acid-labile
                             hydrazone metabolites back to INH prior to
                             analysis.  Methods have insufficient
                             sensitivity for serum analysis.
    
                             The Retention Index for INH is 1650 on OV1,
                             SE30, DB5 or similar phases, and for
                             acetylINH is 1950.  Isothermal analysis may
                             be performed at about 200°C, although peak
                             shape is improved on temperature-programmed
                             capillary columns.  Flame ionization
                             detection gives poor sensitivity (2 to 5 ng
                             on column), which is improved only slightly
                             by nitrogen-phosphorus detection (Timbrell et
                             al., 1977).  Derivatization improves
                             chromatography (e.g. treatment of the dry
                             extracted residue with TFAA at 60°C for 30
                             min using phentermine as internal standard
                             (LoDico et al., 1992), or with BSTFA / 1%
                             TMCS for 1 hour at 80°C (Frater-Schröder &

                             Zbinden, 1975). The retention times for the
                             derivatives are broadly in line with that of
                             underivatized INH. Characteristic
                             fragmentation is achieved on mass
                             spectrometry without the need for
                             derivatization, and the most abundant ions
                             are: INH  m/z 78, 106, 51 and 137; acetyl
                             INH  m/z 179, 106, 137, and 78. 
                             Fragmentation for the derivatives are:
                             TFAA-INH  m/z 215, 78, 106 and 146,
                             diTMS-INH  m/z 73, 75, 266, 147 and  117,
                             and diTMS-acetylINH 73, 75, 308, 147 and
                             132.
    
                             HPLC is more suited to the identification of
                             INH and acetylINH.  Several approaches have
                             been taken isolate INH and acetylINH from
                             serum.  Preparation of a protein-free
                             filtrate using an centrifugal filter device
                             (e.g. Amicon Centrifree) such as is commonly
                             used for the analysis of unbound drugs in TDM
                             provides clean extracts (Svensson et al.,
                             1985; Kohno et al., 1991).  Altrnatively,
                             salting out with sodium chloride is required
                             if solvent extraction (e.g. dichloromethane /
                             n-butanol (7:3) at neutral or basic pH) is to
                             be used (Hutchings et al., 1983). 
                             Precipitation of proteins with solid ammonium
                             sulphate and phosphoric acid, followed by
                             extraction into acetonitrile has also been
                             reported (Hsu & Ho, 1989).  Urine is
                             generally incubated at room temperature for
                             15 minutes with 0.1 M HCl to hydrolyze
                             acid-labile hydrazone metabolites back to INH
                             prior to analysis (Svensson et al., 1985;
                             Khono et al., 1991).  
    
                             Two UV methods are highly suitable. Hutchings
                             et al. (1983) used a Spherisorb nitrile
                             column with a mobile phase of 0.01 M
                             phosphoric acid in acetonitrile / water
                             (80:20).  Detection was at 266 nm. 
                             Chromatograms showed good peak shape with
                             separation over 6 min, without interference
                             from other commonly prescribed
                             antituberculous drugs.  Alternatively, Hsu &
                             Ho (1989) used a reverse phase phenyl column
                             with a mobile phase of 10 mM phosphate buffer
                             containing 0.25 mM tetrabutylammonium
                             phosphate as paired-ion source (pH 4.1). 
                             Good separation was seen over 20 minutes, and
                             detection was at 280 nm.  El-Yazigi & Yusuf
                             (1991) obtained excellent chromatography on a

                             C18 column in a radial compression (Z) module
                             with a mobile phase of 10 mM sodium dibasic
                             phosphate solution (pH 7.0 with phosphoric
                             acid) and methanol (93.5: 6.5). 
                             Electrochemical detection was at +800 mV, and
                             monoacetylhydrazine and hydrazine were also
                             seen.  Additional confirmation of identity
                             may be obtained by performing a full scan
                             analysis on the appropriate portion of the
                             HPLC effluent or incorporating a diode array
                             detector.

                    8.2.2.3  Simple quantitative method(s)

                             Quantitative colourimetric,
                             spectrophotometric and fluorimetric analysis
                             of INH in biological fluids are widely used. 
                             Some methods additionally quantify acetylINH. 
                             Urine must be treated with dilute
                             hydrochloric acid (15 min room temperature)
                             to ensure conversion of acid labile
                             hydrazones back to INH, to reflect urinary
                             excretion reliably since these compounds are
                             thought to be produced in the bladder.
                             Measurement of INH is not affected by
                             administration of pyridoxine antidote, and
                             although INH pyridoxine hydrazone can be seen
                             in urine, it is also produced post-renally
                             (Russell, 1972).  In all methods,
                             quantitation is performed by comparison to
                             the analysis of known amounts of drug
                             prepared in a similar matrix to the sample
                             and processed similarly.  Note section
                             8.1.2.1 regarding sample preservation. 
    
                             AcetylINH can be quantified in urine by
                             mixing 1 mL of the neutralized acidic
                             hydrolysate (above) with an equal volume of
                             0.5M pH 6 buffer (87.7 mL potassium
                             dihydrophosphate and 12.3 mL potassium
                             hydrophosphate).  Addition of 1 mL freshly
                             prepared 20% potassium cyanide is followed by
                             4 mL 12.5% freshly prepared chloramine T. 
                             After 2 minutes, 5 mL of acetone is added and
                             the pink colour monitored at 550 nm.  INH can
                             also be determined by first acetylating INH
                             by shaking the acidic urine with one drop of
                             acetic anhydride, followed by one drop of 7M
                             NaOH, neutralizing and proceeding as above. 
                             The method gives sufficient sensitivity to
                             determine acetylation status, and the colour
                             obtained by the INH and acetylINH
                             measurements can be compared visually if a

                             spectrophotometer is not available.  Glucose
                             may reduce recovery by 20%; chlorpromazine
                             interferes (Eidus et al., 1973). 
    
                             Colourimetry after derivative formation is
                             suitable for toxic concentrations of INH in
                             plasma.  After protein precipitation (1 mL
                             sample with 2 mL water and 1 mL 20%
                             metaphosphoric acid), the supernatant (2 mL)
                             is mixed with 1 mL 2M acetic acid and 1 mL
                             chromogenic reagent (equal volumes of 2%
                             sodium nitroprusside and 4M NaOH, freshly
                             prepared).  The colour intensity is measured
                             at 440 nm at 2 minutes, and each sample
                             should have a reagent blank since the colour
                             is unstable.  Sensitivity is 5 mg/L, and
                             there is some interference from pyrazinamide
                             and iproniazid, and from p-aminosalicylate at
                             very high concentrations (Björnesjö &
                             Jarnulf, 1967; Baselt, 1987).
    
                             UV spectrophotometry after derivative
                             formation is suitable for therapeutic
                             concentrations of INH in serum. INH is
                             extracted from 3 mL serum with 1 drop 4M NaOH
                             and 3.2 g ammonium sulphate  into 20 mL
                             purified butanol / dichloromethane (3:7) for
                             30 min. The filtered organic phase is
                             re-extracted into 1 mL 0.1M HCl.  0.5 mL of
                             the acid phase is mixed with 0.15 mL 0.04%
                             trans-cinnamaldehyde solution in absolute
                             ethanol.  Absorbance is measured at 340 nm;
                             sensitivity is 0.5 mg/L.  There is some
                             interference from pyrazinamide and iproniazid
                             (Eidus & Harnanansingh, 1971; 1974).
    
                             Fluorimetry is useful for therapeutic INH
                             concentrations.  Both assays described
                             calculate the acetylINH concentration by
                             difference after hydrolyzing it to INH.  The
                             most sensitive is that described by Ioannou
                             (1988).  Proteins are removed from serum (100
                             µL) by acetonitrile precipitation (200 µL).
                             Supernatant (100 µL) is reacted with 100 µL
                             scandium oxide (10 mM pH 1.1 with sodium
                             hydroxide) and 50 µL
                             2-hydroxy-1-naphthaldehyde (10 mM in
                             acetonitrile) in an ultrasonic bath for 10
                             min.  2 mL working buffer (50:50 acetonitrile
                             and 0.1M sodium acetate with 1%
                             hydroxylammonium chloride, pH 6.3) is added. 
                             The complex formed between scandium and the
                             hydrazone is strongly fluorescent; excitation

                             430 nm, emission 510 nm.  The author
                             describes both a kinetic procedure over 1
                             minute, or an end point reaction at 10 min. 
                             Sensitivity is 0.01 mg/L.  Hydrolysis of
                             acetylINH in a second portion of supernatant
                             is performed by addition of 20 µL M HCl
                             heated to 80 °C for 1 hour.  The acid is
                             neutralized with 20 µL M NaOH, and INH
                             determined as above. No interferences are
                             known.
    
                             The earlier method of Miceli & Olson (1982)
                             is still widely used and is described here
                             since it uses more readily available
                             chemicals.  Protein-free supernate is
                             prepared by addition of 1 mL 10% TCAA to 200
                             µL serum.  INH is measured in one aliquot,
                             and is converted to a non-reactive azide in a
                             second aliquot by addition of 100 µL 0.5%
                             sodium nitrite solution, followed by 5%
                             ammonium sulphamate (100 µL) to destroy
                             excess nitrite.  The acetylINH is then
                             hydrolysed to INH by heating with 100 µL 6M
                             HCl at 80 °C for 1 hour.  The extract is
                             neutralized with 100 µL 6M NaOH.  Both
                             aliquots are then analysed for INH by forming
                             a hydrazone with 0.5 mL salicylaldehyde
                             reagent (combine 100 µL salicylaldehyde in 3
                             mL ethanol with 13.67 g sodium acetate
                             trihydrate and 2.1 mL 10M NaOH in 250 mL
                             water).  The pH is adjusted to 4 (0.5 M HCl
                             or NaOH) and left for 15 minutes. Excess
                             aldehyde is removed by adding 1 mL bisulphite
                             solution (13.1 g sodium acetate trihydrate,
                             0.38g sodium bisulphite, 4.15 mL 10M NaOH in
                             250 mL water), and pH adjusted to 5.7.  Add
                             100 µL 10% ascorbic acid reducing agent, heat
                             at 50°C for 10 min, and then extract with 1.5
                             mL iso-butanol.  Fluorescence is measured
                             (386 nm excitation, 462 nm emission) in the
                             upper organic layer.  Sensitivity is 0.02
                             mg/L, without interference from other
                             commonly prescribed antitubercular drugs
                             (Olson et al., 1977; Miceli & Olson,
                             1982).
    
                             Two groups describe schemes for the
                             measurement of INH, acetylINH, mono- and
                             di-acetylhydrazine, isonicotinic acid and
                             isonicotinylglycine in serum and urine using
                             differential extractions and both

                             colourimetric and fluorimetric procedures
                             with good sensitivity (Ellard et al., 1972;
                             Boxenbaum & Riegelman, 1974).

                    8.2.2.4  Advanced quantitative method(s)

                             A number of HPLC methods are
                             suitable for quantitative analysis of INH and
                             acetylINH in serum and urine.  Older methods
                             were complicated by poor chromatography
                             despite derivatization, and those which aim
                             to detect other antituberculous drugs are
                             encumbered by multiple extractions or
                             multiple chromatography of the same sample
                             extract, or by gradient elution systems.
                             Quantitation is performed by comparison to
                             known amounts of INH and acetylINH in
                             matrix-matched samples extracted under
                             similar conditions.  Several approaches have
                             been taken to recover INH and acetylINH from
                             serum.  Preparation of a protein-free
                             filtrate using an centrifugal filter device
                             (e.g. Amicon Centrifree) such as is commonly
                             used for the analysis of unbound drugs in TDM
                             provides clean extracts (Svensson et al.,
                             1985; Kohno et al., 1991).  Alternatively,
                             salting-out with sodium chloride is required
                             if solvent extraction (e.g. dichloromethane /
                             n-butanol (7:3) at neutral or basic pH) is to
                             be used (Hutchings et al., 1983). 
                             Precipitation of proteins with solid ammonium
                             sulphate and phosphoric acid, followed by
                             extraction into acetonitrile has also been
                             reported (Hsu & Ho, 1989).  Urine is
                             generally incubated at room temperature for
                             15 minutes with 0.1 M HCl to hydrolyze
                             acid-labile hydrazones back to INH prior to
                             analysis in order to reflect urinary
                             excretion reliably since these compounds are
                             thought to be produced in the bladder
                             (Svensson et al., 1985; Khono et al.,
                             1991).
    
                             The best of the UV methods is that of
                             Hutchings et al., (1983) which uses
                             iproniazid as internal standard. 
                             Chromatography was performed at ambient
                             temperature on a Spherisorb nitrile column
                             with a mobile phase of 0.01 M phosphoric acid
                             in acetonitrile / water (80:20).  Detection
                             was at 266 nm.  Chromatograms showed good
                             peak shape with separation over 6 minutes,
                             without interference from other commonly

                             prescribed antituberculous drugs.  The
                             sensitivity was 0.02 mg/L using a 1 mL
                             sample.  Two other useful UV methods are
                             described.  Hsu & Ho (1989) used niacinamide
                             as internal standard, with a reverse phase
                             phenyl column.  The mobile phase was 10 mM
                             phosphate buffer containing 0.25 mM
                             tetrabutylammonium phosphate as paired-ion
                             source (pH 4.1).  Good separation was seen
                             over 20 minutes.  Detection was at 280 nm,
                             with a sensitivity of 0.5 mg/L using a 1 mL
                             sample.  Svensson et al (1985) used UV
                             detection at 270 mn to detect
                             propionylderivatives of INH and acetylINH. 
                             The derivatives form easily by incubation of
                             the protein free extract for 10 minutes at
                             ambient temperature with propionic anhydride
                             in phosphoric acid.  Chromatography was
                             performed on an Ultrasphere ion-pair reverse
                             phase column using a mobile phase of 10 mM
                             sodium dihydrogen phosphate (pH 3 with
                             phosphoric acid) with 1 mM dodecylsulphate
                             and 25% acetonitrile.  Separation was
                             achieved over 6 minutes with a sensitivity of
                             0.2 mg/L from a 1 mL sample.
    
                             Kohno et al. (1991) report a fluorimetric
                             assay with post column deivatization.  INH
                             and metabolites were separated well by
                             reverse phase ion-exchange chromatography
                             (C18 column).  The mobile phase was 0.067 M
                             phosphate buffer (pH 6.98) with 3 mM hydrogen
                             peroxide as fluorogenic agent and 5 mM
                             butanesulfonate as hydrophobic ion-exchanger. 
                             Detection was at 415 nm emission with 317 nm
                             excitation, and the sensitivity 0.2 mg/L. 
                             AcetylINH, isonicotinic acid and
                             isonicotinylglycine were also detected.  The
                             requirement for a 160°C coil/heater module
                             detracts from its routine application. 
    
                             El-Yazigi & Yusuf (1991) report a highly
                             sensitive method for analysis of
                             underivatized INH and acetylINH using
                             electrochemical detection with 
                             diphenylcarbazide internal standard. 
                             Excellent chromatography was produced on a
                             C18 column in a radial compression (Z) module
                             with a mobile phase of 10 mM sodium dibasic
                             phosphate solution (pH 7.0 with phosphoric
                             acid) and methanol (93.5: 6.5).  Detection
                             was at +800 mV, with a sensitivity of 0.1

                             mg/L on a 100 µL sample.  Monoacetylhydrazine
                             and hydrazine were also seen. 
    
                             Gas chromatography is not particularly useful
                             for quantitation of INH in routine clinical
                             settings.  Flame ionization detection gives
                             poor sensitivity even after derivative
                             formation (1 mL of serum gives a sensitivity
                             of only 30 mg/L; Frater-Schröder & Zbinden,
                             1975), and nitrogen-phosphorus detection is
                             not much more successful (Timbrell et al.,
                             1977).  Compounds must first be extracted
                             into a polar organic solvent (e.g. methylene
                             chloride or ethyl acetate) from a pH adjusted
                             to 4 to 7.  Some methods utilize salting-out
                             of the drug and metabolites with solid sodium
                             sulphate.  Urine is generally incubated at
                             room temperature for 15 minutes with 0.1 M
                             HCl to hydrolyze acid-labile hydrazone
                             metabolites back to INH prior to analysis.  
                             Some methods are only suited to the analysis
                             of intact INH (LoDico et al., 1992; Stewart
                             et al., 1995), or are limited by sample
                             volume to urine (Timbrell et al., 1977). 
                             Later methods utilize mass spectrometry but
                             often require deuterated internal standards,
                             or use tedious differential extraction and
                             double-derivatization procedures.  These
                             methods have high specificity and are
                             designed to analyse hydrazine metabolites in
                             addition to INH and acetylINH, for use in
                             metabolic and pharmacokinetic research (see
                             for example, Lauterberg et al.,
                             1981).

                    8.2.2.5  Other dedicated method(s)

                             Not applicable.

             8.2.3  Interpretation of toxicological analyses

                    Specific identification of INH in cases of
                    severe intoxication where the history is not clear, is
                    useful to rule out other causes of seizures, confirm
                    intoxication and ensure appropriate treatment. There
                    is considerable variation in individual response to a
                    given serum INH concentration, in both therapeutic and
                    toxic effects. In overdose, contribution to the
                    overall clinical picture can be made by co-ingested
                    medications, the amount of toxic metabolites produced,
                    the degree of tissue distribution, underlying medical
                    conditions, presence of infective agents etc.  The
                    rapid distribution kinetics of INH, and relatively

                    short elimination half-life (1 to 2 hours in fast, and
                    3 to 5 hours in slow acetylators) means that serum
                    concentrations fall sharply, and can be only a
                    fraction (20%) of the peak within 5 or 6 hours.
                    Measurement is not therefore particularly helpful in
                    the routine management of the poisoned patient, but
                    may be considered if symptoms are unusually severe or
                    prolonged. Case reports with serum concentrations
                    include the following: Brown, 1972; Watson et al.,
                    1981; Parish & Brownstein, 1986; Siefkin et al., 1987;
                    Curnani et al., 1992.  However, much of the published
                    data should be interpreted with caution since authors
                    have employed different analytical methodologies, and
                    attention to sample storage is often not considered
                    (see 8.1.2.1).  As a guide, the following table shows
                    typical concentrations of INH in serum.
    
                                                                      mg/L        µmol/L
                    Single oral dose 15 mg/kg (Weber & Hein, 1979)
                    INH     peak     1 hr   rapid acetylators         10 - 20     73 - 146
                    INH     peak     1 hr   slow acetylators          15 - 25     110 - 183
                    INH              5 hr   rapid acetylators         0.5 - 2.5   3 - 18
                    INH              5 hr   slow acetylators          8 - 12      58 - 88
                    AcetylINH peak   5 hr   rapid acetylators         8 - 12      44 - 67
                    AcetylINH peak   5 hr   slow acetylators          3 - 5       22 -36
                    Toxicity apparent (nausea, dizziness,             >30         >219
                    visual disturbance)
                    Potentially fatal (intractable seizures, coma,    >50         >365
                    respiratory distress, metabolic acidosis)
                    Highest reported concentration in survivor        710         5183 
                    (Watson et al., 1981)
    
                    Measurement of INH is not affected by administration
                    of pyridoxine antidote, and although INH pyridoxine
                    hydrazone can be seen in urine, it is produced
                    post-renally (Russell, 1972).

        8.3  Biomedical investigations and their interpretation

             8.3.1  Biochemical analysis

                    8.3.1.1  Blood, plasma or serum

                             -  Sodium, potassium, calcium
                             -  Alanine aminotransferase, aspartate
                                aminotransferase
                             -  gamma-Glutamyltransferrase, alkaline
                                phosphatase, bilirubin (total and direct),
                                creatine kinase
                             -  Creatinine (urea), protein
                             -  Glucose, lactate
                             -  Optional: ß-hydroxybutyrate
                             -  Dedicated analysis: pyridoxine

                    8.3.1.2  Urine

                             Qualitative testing for glucose,
                             ketone bodies, sediment, haeme
                             proteins

                    8.3.1.3  Other fluids

                             No dedicated test

             8.3.2  Arterial blood gas analyses

                    pH, pCO2, pO2, actual HCO3-
                    concentration, base excess, O2-saturation

             8.3.3  Haematological Analyses

                    Count of red and white blood cells, platelets
                    Haemoglobin, haematocrit
                    Differential blood picture
                    Prothrombin time

             8.3.4  Interpretation of biomedical investigations

                    In severe cases of INH poisoning metabolic
                    acidosis occurs.  It is partially caused by elevation
                    of lactic acid, which cannot be metabolized into
                    pyruvate as NAD+ production is blocked by INH.  The
                    presence of seizures will contribute to the acidosis,
                    and cause rhabdomyolysis with elevation in CK and the
                    appearance of haemeproteinuia.  Disseminated
                    intravascular coagulation may result from
                    rhabdomyolysis.  Liver disease may develop especially
                    in case of concomitant treatment with carbamazepine,
                    rifampicin, and phenobarbital.  Activity of
                    transaminases will be elevated as well as bilirubin
                    concentration.  Coagulation profile is changed
                    likewise.  Hyperglycaemia may occur as well as
                    ketonuria.  Renal insufficiency may develop and cause
                    uraemia.  Proteinuria was observed occasionally. 
                    Osmolal as well as anion gap may be enlarged.  In
                    chronic poisoning anaemia may occur as well as
                    leukocytosis and eosinophilia.  Phenytoin metabolism
                    is inhibited by INH. 

        8.4  Other biomedical (diagnostic) investigations and their 
             interpretation

             In case of coma, EEG monitoring is recommended.

        8.5  Overall Interpretation of Toxicological Analyses & Biomedical 
             Investigations

             Specific identification of INH in cases of intoxication
             with seizures is useful to rule out other causes, confirm

             intoxication and ensure appropriate treatment. Presumptive
             tests on toxic ingredients of materials can be performed by
             colourimetric, spectrophotometric or thin layer
             chromatographic techniques.  High performance liquid
             chromatography or gas chromatography of INH are much more
             specific.
    
             Measurement of serum concentrations of INH may be useful in
             cases where symptoms are particularly severe.  INH and
             acetylINH are unstable in serum at room temperature, and
             unless serum can be stored frozen, the serum proteins should
             be precipitated (e.g. with 2 volumes 10% trichloroacetic
             acid) as soon as possible. Urine must be treated with dilute
             hydrochloric acid (15 minutes at room temperature) to ensure
             conversion of acid labile hydrazones back to INH, to reflect
             urinary excretion reliably since these compounds are thought
             to be produced in the bladder. Measurement of INH is not
             affected by administration of pyridoxine antidote, and
             although INH pyridoxine hydrazone can be seen in urine, it is
             also produced post-renally.
    
             Sensitive fluorescence methods can be applied to the
             quantitative analysis of INH and its acetyl metabolite in
             serum by differential analysis.  Colourimetric and
             spectrophotometric methods are less sensitive and less
             specific. The degree of specificity is highly
             method-dependent.  Chromatographic measurement of INH and
             metabolites in biological materials is possible after
             extraction into a polar organic solvent or precipitation of
             proteins.  Metabolites (particularly acetylINH, and the
             hydrazine derivatives) are seen by most advanced techniques. 
             Qualitative analysis is easily performed by thin layer
             chromatography.  High performance liquid chromatography
             allows for both qualitative and quantitative analysis, and UV
             detection gives adequate sensitivity for most applications. 
             Gas chromatography and gas chromatography / mass spectrometry
             methods usually require derivatization and are rarely used
             for clinical analysis.  
    
             Typical concentrations of INH in serum are:
    
                                                                        mg/L       µmol/L
             Single oral dose 15 mg/kg (Weber & Hein, 1979)
             INH            peak   1 hr   rapid acetylators             10 - 20    73 - 146
             INH            peak   1 hr   slow acetylators              15 - 25    110 - 183
             INH                   5 hr   rapid acetylators             0.5 - 2.5  3 - 18
             INH                   5 hr   slow acetylators              8 - 12     58 - 88
             AcetylINH      peak   5 hr   rapid acetylators             8 - 12     44 - 67
             AcetylINH      peak   5 hr   slow acetylators              3 - 5      22 -36
             Toxicity apparent (nausea, dizziness, visual disturbance)  >30        >219
             Potentially fatal (intractable seizures, coma,             >50        >365
             respiratory distress, metabolic acidosis)
             Highest reported concentration in survivor                 710        5183 
             (Watson et al., 1981)
    

             INH toxicity manifests as metabolic acidosis, repetitive
             refractive convulsions, and coma.  Blood gases, pH,
             coagulation and hepatic function, renal status, muscle
             enzymes and electrolytes should be monitored in the usual
             manner.

    9.  CLINICAL EFFECTS

        9.1  Acute poisoning

             9.1.1  Ingestion

                    Toxic manifestations usually appear after a
                    delay of 1 to 2 hours but they may occur from 30
                    minutes up to 7 hours following ingestion.  The higher
                    the dose, the shorter the delay of onset of
                    symptoms.
    
                    The first manifestations include: nausea, vomiting,
                    blurred vision, coloured lights, spots, dizziness,
                    slurred speech.
    
                    A second phase follows rapidly, including severe grand
                    mal seizures, respiratory distress, coma and severe
                    metabolic acidosis.
    
                    Signs and symptoms may include: fever, lethargy,
                    stupor, coma, tonicclonic seizures, respiratory
                    depression, respiratory distress during seizures,
                    vomiting, nausea, abdominal pain, tachycardia,
                    hypotension.

             9.1.2  Inhalation

                    Not relevant.

             9.1.3  Skin exposure

                    Not relevant.

             9.1.4  Eye contact

                    Not relevant.

             9.1.5  Parenteral exposure

                    The clinical course is similar to that observed
                    after ingestion. The delay of onset of symptoms may be
                    shorter, depending on the dose and the rate of
                    injection.

             9.1.6  Other

                    No data available.

        9.2  Chronic poisoning 

             9.2.1  Ingestion

                    Chronic overdose of isoniazid may induce
                    similar toxicity similar to that of acute poisoning.
                    Chronic administration may also induce several adverse
                    effects (see section 7.7).  Hepatitis, peripheral
                    neuropathy are the most frequent manifestations of
                    chronic ingestion.

             9.2.2  Inhalation

                    Not relevant.

             9.2.3  Skin exposure 

                    Not relevant.

             9.2.4  Eye contact

                    Not relevant.

             9.2.5  Parenteral exposure

                    Similar to acute poisoning.

             9.2.6  Other

                    No data available.

        9.3  Course, prognosis, cause of death

             Course: acute overdose results in seizures associated
             with metabolic acidosis, coma and respiratory distress. The
             onset of seizure may occur from a few minutes to 3 to 5 hours
             post-ingestion
    
             Prognosis: the prognosis depends on the ingested dose and
             on the promptness of the treatment. With adequate treatment
             and in the absence of complications the prognosis is usually
             good after 24-48 hours.
    
             Cause of death: at the early stage (1 to 12 hours) of the
             intoxication, death is due to respiratory distress and/or
             cardiac arrest (acidosis, hypoxemia) as a result of
             seizures.
    

             Deaths due to acute hepatitis, acute pancreatitis, postanoxic
             coma have also been reported.

        9.4  Systematic description of clinical effects

             9.4.1  Cardiovascular

                    Acute:
    
                    -  tachycardia and hypotension are common
                    -  cardiac arrest may occur and is due to severe
                       hypoxemia (respiratory distress) and/or metabolic
                       acidosis
                    -  no direct cardiotoxicity of INH has been reported
    
                    Chronic: no data available.

             9.4.2  Respiratory 

                    Acute:
    
                    -  Respiratory depression with resultant hypoxemia and
                       cyanosis is frequent during seizures or intractable
                       grand mal seizures 
                    -  aspiration pneumonia may occur
                    -  hypoventilation with Kussmaul-type respiration may
                       be observed between the periods of seizure
                       activity
    
                    Chronic: no data available.

             9.4.3  Neurological

                    9.4.3.1  Central Nervous System (CNS)

                             Acute:
    
                             -  dizziness, slurred speech, stupor,
                                hallucinations, coma
                             -  tonic-clonic seizures
                             -  areflexia, Babinski sign
    
                             Chronic:
    
                             Adverse CNS effects following chronic therapy
                             are rare but may include: stupor, euphoria,
                             dizziness, memory impairment, ataxia,
                             cerebellar syndromes, encephalopathy,
                             seizures (usually dose dependent), psychosis
                             (Shazma, 1979).

                    9.4.3.2  Peripheral nervous system

                             Acute: No data available.
    
                             Chronic:
    
                             -  peripheral neuropathy occurs in about 20 %
                                of the patients receiving 6 mg/kg/day INH
                                without supplemental pyridoxine.
                                Predisposing factors are: slow
                                acetylation, alcohol, diabetes,
                                malnutrition. The neuropathy occurs from 3
                                to 35 weeks after the start of therapy. It
                                is usually reversible with high doses of
                                pyridoxine (100 to 200 mg/day). 
                                Administration of small doses of
                                pyridoxine is recommended in order to
                                prevent the neuropathy. Symptoms include:
                                cramps, leg pains, weakness of distal
                                extremities, decreased tendon
                                reflexes.
    
                             -  optic neuropathy (Kass, 1957) has been
                                reported
    
                             -  trigeminal neuropathy (Kay, 1972) has been
                                noted.

                    9.4.3.3  Autonomic nervous system

                             Acute:  fever is frequently noted as
                             a result of seizures.
    
                             Chronic: fever has been noted in about 1 to
                             2% of patients during the course of
                             treatment.  This fever is not a prodrome to
                             other complications.

                    9.4.3.4  Skeletal and smooth muscle
    

                             Acute: rhabdomyolysis is a potential
                             complication of seizures.
    
                             Chronic: rhabdomyolysis may also be seen
                             after therapeutic dose (Caskright, 1989). 
                             Arthritis, arthralgias and bilateral
                             shoulder-hand syndrome have also been
                             reported.

             9.4.4  Gastrointestinal

                    Acute: Nausea, vomiting, abdominal pain are
                    often the initial presentation (Brown, 1972).
    
                    Chronic: Nausea, vomiting, abdominal pain may occur
                    (10% of the patients treated).  Acute pancreatitis has
                    also been reported (Larsen, 1962).

             9.4.5  Hepatic

                    Acute: Mild hepatic dysfunction with elevation
                    of transaminases has been observed in a 7-year-old
                    child after ingestion of 125 mg/kg INH (Oclavski,
                    1988).
    
                    Chronic: An asymptomatic increase of transaminases
                    occur in 10 to 20% of patients within the first 2
                    months of therapy (Smith and Sharer, 1969); Byrd,
                    1972; Kester, 1971).
    
                    Hepatitis with jaundice is less common and occurs in
                    0.1% of the patients treated (Garibaldi, 1972; Maddrey
                    and Boitmatt, 1973).  The clinical presentation is
                    similar to viral hepatitis.
    
                    Fulminant hepatitis has been reported by Pessayre et
                    al. (1977) in 6 patients, 6 to 10 days after starting
                    Rifampicin and INH.

             9.4.6  Urinary 

                    9.4.6.1  Renal

                             Acute: Direct INH nephrotoxicity is
                             not recognized, however, albuminuria and
                             oliguria progressing to anuria have been
                             noted in severe poisoning and are probably
                             secondary to seizure activity and
                             rhabdomyolysis.
    
                             Chronic: Nephrotoxicity is very rare. 
                             Nephrosis may occur when INH is used in
                             combination with other antituberculosis
                             agents.  One case of acute renal
                             insufficiency (acute renal nephritis) has
                             been reported (Trainis, 1981) in a patient
                             treated for 4 months with INH
                             alone.

                    9.4.6.2  Other

                             No data available.

             9.4.7  Endocrine and reproductive systems

                    Acute: No data available.
    
                    Chronic: Gynaecomastia - Bergogne-Berezin (1976) has
                    reported a case of a 52-yearold man, a slow
                    acetylator, receiving 10 mg/kg/day INH for 4 months
                    who developed bilateral gynaecomastia despite a normal
                    hormonal balance.

             9.4.8  Dermatological

                    Acute: no data available.
    
                    Chronic: isoniazid may produce a great variety of
                    cutaneous effects (Meyler & Peck, 1976):
    
                    -  atrophic striae may occur after prolonged
                       therapy
                    -  pruritus (50 % of patients)
                    -  morbilliform eruptions
                    -  pellagra-like syndrome in alcoholic patients
                    -  exfoliative dermatitis has been reported in a
                       75-year-old man (Rosin & Krig, 1982)
                    -  Stevens Johnson syndrome may occur (Drugdex, 1991)
                    -  acneiform eruptions
                    -  photosensitivity
                    -  syndrome similar to lupus erythematosus

             9.4.9  Eye, ear, nose, throat: local effects

                    Acute: No data available.
    
                    Chronic: Optic neuritis with a disturbance of colour
                    vision and/or decreased visual acuity have been
                    reported (Kass, 1957; Garrett, 1985; Karmon, 1979).
                    Optic atrophy may follow optic neuropathy.

             9.4.10 Haematological 

                    Acute: Leukocytosis may be observed.
    
                    Chronic: Several haematological disturbances may be
                    observed during INH therapy. 
    
                    Anaemia (haemolytic, sideroblastic, aplastic,
                    megaloblastic), agranulocytosis, eosinophilia,
                    thrombocytopenia; disseminated intravascular
                    coagulation (Stuart & Roberts, 1976); lymphadenopathy
                    due to hypersensitivity reactions has been
                    reported.

             9.4.11 Immunological 

                    Acute: no data available.
    
                    Chronic: systemic lupus erythematosus with
                    polyarthralgias, fever, skin rash, lymphadenopathy,
                    hepatosplenomegaly, pleural and pericardial effusions,
                    haemolytic anaemia has been reported (Hothersall,
                    1986; Rothfield, 1971; Gaulier, 1972; Greenberg, 1972;
                    Grunwald, 1982).  LE cells may be found and
                    antinuclear antibodies are found in 5-33% of treated
                    patients (Rothfield, 1971).
    
                    A positive direct Coombs test has been reported in
                    patients with haemolytic anaemia (Robinson,
                    1969).

             9.4.12 Metabolic

                    9.4.12.1 Acidbase disturbances 

                             Severe metabolic acidosis with
                             increased anion gap is common. This acidosis
                             is due to an increase of lactate secondary to
                             anoxia following seizures and to impaired
                             metabolic conversion of lactate to
                             pyruvate.

                    9.4.12.2 Fluid and electrolyte disturbances

                             Hyperkalaemia has been reported
                             with high doses of INH (Hanster, 1979) but
                             hypokalaemia is more frequently observed
                             (Rouge et al., 1983; Parish & Brownstein,
                             1986).
    
                             Hypocalcaemia has been reported, especially
                             in Asian patients (Perry, 1982).

                    9.4.12.3 Others

                             Hypo- or hyperthermia; hypo- or
                             hyperglycaemia has been observed.
    
                             Acute hyperglycaemia with ketonuria and
                             glycosuria have been reported.
    
                             Chronic:  elevation of bilirubin, alkaline
                             phosphatase, liver transaminases and LDH may
                             be seen with INH therapy (Mitchell, 1976;
                             Beaudry, 1974; Black et al., 1975).
    
                             Low serum folate levels have been reported.

             9.4.13 Allergic reactions

                    Acute: no data available.
    
                    Chronic: one case of hypersensitivity-type reaction
                    resulting in subconjunctival haemorrhage, optic
                    neuritis, iridoplegia has been reported (Ahmad-Clark,
                    1967).
    
                    Lymphadenopathy attributed to a hypersensitivity
                    reaction has also been reported (< 1%).
    
                    One case of hypersensitivity meningitis has been
                    reported (Garageisi, 1976) in a 27-yearold man on
                    prophylactic INH therapy.

             9.4.14 Other clinical effects

                    Acute: no data available.
    
                    Chronic: porphyria may be precipitated by INH.

             9.4.15 Special risks

                    Acute: no data available.
    
                    Chronic: 0.75 to 2.3% of the dose is excreted into
                    breast milk in 24 hours. This corresponds to 6 to 20%
                    of an usual therapeutic paediatric dose.  INH is
                    classified as category C by Briggs et al. (1986) and
                    may be used safely during pregnancy.

        9.5  Other

             No data available.

        9.6  Summary

    10. MANAGEMENT

        10.1 General principles

             Patients with INH overdose should always be admitted to
             an emergency or intensive care unit.  Patients who are
             asymptomatic 6 hours after ingestion are unlikely to develop
             complications.  Monitor vital signs (ECG, BP,
             respiration).
    
             Treatment depends on the dose ingested, the symptomatology
             and the delay following ingestion.  It includes: 
    
             -  Early gastric lavage after control of seizures and
                protection of airway
    

             -  Oral activated charcoal
    
             -  Supportive treatment:
    
                -   control seizures with diazepam and or pentothal
                -   correct metabolic acidosis by infusion of sodium
                    bicarbonate solution
                -   manage respiratory failure by oxygen and artificial
                    ventilation
                -   correct hypotension and shock by plasma expanders
                    and/or dopamine
    
             -  Antidote: administration of pyridoxine. Intravenous: 1 g
                pyridoxine for each 1 g INH ingested.  If the dose
                ingested is unknown, initial administration of pyridoxine
                may be 5 g intravenously in severly poisoned patients, and
                repeated until seizures are under control (see Section
                10.6.1).

        10.2 Life supportive procedures and symptomatic/specific
             treatment

             Supportive care with early artificial ventilation,
             administration of pyridoxine and anticonvulsant drugs are
             indicated in severe poisoning with seizures.
    
             Observation and monitoring
    
             Systematically monitor vital signs, ECG, blood pressure,
             respiration and diuresis.
    
             Immediate venous access is indicated for alkalinization, drug
             injection and hydration.
    
             Seizures
    
             Treat seizures with intravenous diazepam: initial dose
             5 to 10 mg IV and increase the dose if needed.
    
             Artificial ventilation should be performed if respiratory
             depression occurs.
    
             Correct pyridoxine deficiency with intravenous pyridoxine.
             Recent reports suggest that administration of 1 g pyridoxine
             for each gram of isoniazid ingested, abolishes isoniazid-
             induced seizure activity (Wasan, 1981; Marbrough, 1983;
             Kurtz, 1970).  See section 10.6.
    
             Correct severe metabolic acidosis by administration of IV
             sodium bicarbonate.
    
             If refractory seizures occur after diazepam and pyridoxine,
             barbiturates may be indicated (thiopental 2.5% 5 mg/kg).
    

             EEG monitoring in order to confirm the cessation of cerebral
             seizure activity.
    
             Acidosis
    
             The acidosis may be severe with a pH < 7.2
    
             Control of seizures using anticonvulsant drugs (diazepam,
             thiopental) and pyridoxine may resolve the acidosis without
             the use of IV sodium bicarbonate.
    
             Sodium bicarbonate should be used if the pH is below 7.2
             (molar bicarbonate infusion via venous a catheter at a dose
             of 1 to 3 mEq/kg).
    
             Monitor arterial blood gases as a guide to therapy.
    
             Respiratory depression
    
             Respiratory failure may occur during seizures, and is common
             after the use of anticonvulsant drugs.Therefore, protection
             of airway with cuffed endotracheal intubation and artificial
             ventilation are indicated in severe intoxications with
             seizures.
    
             If aspiration pneumonia has occurred, appropriate treatment
             should be instituted.
    
             Hypotension, shock
    
             Correct metabolic acidosis.
             Administer fluids (crystalloids or plasma expander solutions)
             and dopamine with central monitoring.
    
             Rhabdomyolysis
    
             Perform urine alkalinization and maintain adequate diuresis
             by infusion of fluids and mannitol.

        10.3 Decontamination

             Emesis may be useful in very recent ingestion, but its
             risk with impending seizures should be considered very
             carefully.
    
             Gastric lavage is indicated in recent ingestion.
    
             In severe cases of acute poisoning, first control seizures
             and protect airway by tracheal intubation before performing
             gastric lavage.
    

             Oral activated charcoal reduces the absorption and the
             toxicity of isoniazid.  One dose (50 g) should be given at
             the end of the gastric lavage and repeated every 4-6
             hours.
    
             The usefulness of cathartics has not been established.

        10.4 Enhanced elimination

             Diuresis:
    
             4 to 27% of INH is eliminated as free drug in the urine.
    
             Conclusive evidence of efficacy of forced diuresis is not
             established although some authors suggests that forced
             diuresis enhances INH elimination (Corger, 1976; Terman &
             Teitelbaum, 1970; Brown, 1972; Sievers, 1975)
    
             Forced diuresis is therefore not recommended but maintain
             adequate urine output.
    
             Dialysis:
    
             Peritoneal dialysis and haemodialysis have been used (Maher,
             1967, Cocco, 1963; Brown, 1972; Orlowski et al., 1988).
    
             INH is a small, watersoluble molecule which is poorly protein
             bound and distributes in a small volume (0.6 l/kg)).  Based
             on these properties, INH would efficiently be removed from
             the body by dialysis procedures.
    
             However, the relative merits of peritoneal clearance and
             total body clearance are not clear. Therefore, haemodialysis
             should be reserved for the patients who do not respond to
             correct supportive care and adequate doses of pyridoxine. 
             Because pyridoxine is also dialyzed, the dose may require
             adjustment.
    
             Haemoperfusion:  No data available. available.
    
             Exchange transfusion: one exchange transfusion has been
             performed in a 19-month-old child (Katz, 1956).  However,
             considering INH kinetics, this procedure is not
             recommended.

        10.5 Antidote treatment

             10.5.1 Adults

                    INH induces pharmacologic changes in
                    pyridoxine metabolism (see section 7.1.1.) and
                    pyridoxine is used as antidote.
    

                    Pure pyridoxine (vitamin B6) is recommended as the
                    antidote for INH poisoning.  In situations where this
                    is not available and a combination vitamins B1, B6 and
                    B12 is used, there is a risk of anaphylactoid
                    reactions if vitamin B1 (thiamine) is given in doses
                    of more than 1 g. Pyridoxine may be given in smaller
                    aliquots every 10 minutes until the pyridoxine
                    deficiency is corrected.
    
                    Acute poisoning:
    
                    Correction of pyridoxine deficiency contributes to the
                    control of seizures and the correction of metabolic
                    acidosis (Wason, 1981; Parish & Brownstein, 1986;
                    Sievers, 1982; Coger, 1976; Yarbrough, 1983)
    
                    In acute ingestion of more than 80 mg/Kg,
                    administration of IV pyridoxine should be considered,
                    even in asymptomatic patients 
    
                    The recommended dose is 1 g of pyridoxine for each
                    gram of isoniazid ingested. Administer 5 g IV in the
                    first minutes in severely symptomatic patients with
                    seizures and acidosis, and repeat administration until
                    seizures are controlled (Poisindex). If the dose
                    ingested is known follow the same protocol.
    
                    Chronic poisoning:
    
                    Treatment of isoniazid-induced neuropathy is effected
                    with pyridoxine 100 to 200 mg daily and withdrawal of
                    INH when possible.
    
                    For the prevention of isoniazid-induced neuropathy: 10
                    mg pyridoxine daily is adequate in high risk patients
                    (Katcher, 1982). Higher doses could interfere with
                    antibacterial efficacy and are unnecessary.

             10.5.2 Children

                    See 10.6.1.

        10.6 Management discussion

             Asymptomatic patients with suspected isoniazid
             poisoning should be monitored for at least 6 hours.
    
             Give an intravenous bolus of pyridoxine (5 g in adults, 1 g
             in children) as soon as isoniazid toxicity is suspected. The
             total dose of pyridoxine required is 1 g per gram of INH
             ingested.
    

             Potentiate the antidotal (anticonvulsant) effects of
             pyridoxine with diazepam.
    
             Administration of sodium bicarbonate should be reserved to
             cases with severe acidosis (pH < 7.2).
    
             After pyridoxine treatment and supportive care, gastric
             lavage and administration of activated charcoal may be
             performed.
    
             Blood samples should be sent for monitoring of biological
             parameters.
    
             Ensure adequate diuresis. Forced diuresis is not useful.
    
             Dialysis is only indicated in the most severe cases
             unresponsive to adequate supportive care, anticonvulsant
             drugs and pyridoxine therapy.
    
             Rhabdomyolysis, neuropathy and coagulopathy may occur and
             should be treated appropriately.

    11. ILLUSTRATIVE CASES

        11.1 Case reports from literature

             Wason (1981) reported 5 cases of isoniazid poisoning
             treated with IV pyridoxine at a dose of 1 g per gram of INH
             ingested. The doses ingested ranged from 4 to 25 g (mean 204
             mg/kg).  The delay before admission was  1 hour in all cases.
             Initial serum levels ranged from 26 to 128 mg/L. Grand mal
             seizures had occurred in every patient before admission and
             continued after adequate doses of diazepam or phenytoin.
             After pyridoxine therapy, none of the 5 patients developed
             recurrent seizures and metabolic acidosis resolved. All
             patients recovered.
    
             Parish & Brownstein (1986) reported the cases of an acute
             poisoning with 6 g of INH in a 14 year-old girl and an acute
             overdosage in a 8 year-old boy treated for several months
             before admission.  Both had developed seizures before
             admission.  Treatment with IV pyridoxine and diazepam was
             quickly successful.
    
             Orlowski et al. (1988) reported the case of a 7-year-old
             child who had ingested 125 mg/kg of INH and had persistent
             metabolic acidosis and coma after 6 g of pyridoxine. A 
             five-hour haemodialysis was performed 11.5 hours after
             ingestion. At the end of dialysis the patient was fully
             conscious and free of seizure activity.
    

             Goldin (1987) reported 2 cases of acute ingestion in patients
             under prophylactic treatment.  One patient (13 years old)
             responded to pyridoxine. The other patient (30 years old) was
             relatively refractory to initial pyridoxine and other
             supportive therapy.
    
             Hartemann et al. (1983) described a case in a 32-month-old
             girl with acute poisoning (190 mg/kg) with generalized
             seizures. Intravenous pyridoxine was successful and she
             recovered.
    
             Rubin (1983) reported a case of chronic ingestion of INH 400
             mg/day in a 7 year-old child who developed seizures and
             vomiting. A decline in his mental alertness was also
             observed; pyridoxine 500 mg IV was administered with
             improvement after 2 hours.

    12. ADDITIONAL INFORMATION

        12.1 Specific preventive measures

             Toxic effects can be minimized by prophylactic therapy
             with pyyridoxine and careful surveillance of the patient
             (Goodman & Gillman, 1990).

        12.2 Other

             No data available.

    13. REFERENCES 

        Anderson PO (1976)  Drugs and breast feeding  a review.  Drug
        Intel Clin Pharm, 11: 208
    
        Baselt RC (1987)  Analytical Procedures for Therapeutic Dug
        Monitoring and Emergency Toxicology.  2nd ed. California,
        Biomedical Publications, pp145-146.
    
        Biehl JP & Vilter RW (1954)  Effects of isoniazid on pyridoxine
        metabolism.  JAMA, 156: 1549.
    
        Björnesjö KB & Jarnulf B (1967)  Determination of isonicotinic
        acid hydrazide in blood serum.  Scand J Clin Lab Invest, 20:
        39-40.
    
        Black M, Mitchell JR, Hyman PD et al. (1975)  Isoniazidassociated
        hepatitis in 114 patients.  Gastroenterology, 69 (2): 289302
    
        Bowersox DW et al. (1973)  Isoniazid dosage in patients with renal
        failure.  N Engl J Med, 289: 84
    

        Boxenbaum HG & Riegelman S (1974)  Determination of isoniazid and
        metabolites and biological fluids.  J Pharm Sci, 63: 1191-1197
    
        Brown CV (1972)  Acute isoniazid poisoning.  Am Rev Resp Dis, 105:
        206216
    
        Curnani A, Chawla R, Kundra P, Bhattacharya A (1992)  Acute
        isoniazid poisoning.  Anesthesia, 47: 781-783.
    
        Davies DM (1981)  Textbook of adverse drug reactions, 2nd ed.
        Oxford University Press, New York
    
        DRUGDEX (1991) Micromedex
    
        Eidus L, Harnanansingh AMT (1971)  A more sensitive
        spectrophotometric method for determination of isoniazid in serum
        or plasma.  Clin Chem, 17: 492-494.
    
        Eidus L, Harnanansingh AMT (1974)  In: Sunshine I (ed). 
        Methodology for Analytical Toxicology. Cleveland, Ohio, CRC Press,
        pp200-201.
    
        Eidus L, Varughese P, Hodgkin MM, Hsu AHE, McRae KB (1973) 
        Simplification of isoniazid phenotyping procedure to promote its
        application in the chemotherapy of tuberculosis.  Bull World
        Health Org, 49: 507-516.
    
        El-Brashy AM & El-Ashry SM (1992)  Colourimetric and titrimetric
        assay of isoniazid.  J Pharmaceut Biomed Anal, 10: 421-426. 
    
        Ellard GA (1984)  The potential clinical significance of the
        isoniazid acetylator phenotype in the treatment of pulmonary
        tuberculosis.  Tubercle, 65: 211227
    
        Ellard GA, Gammon PT, Wallace SM (1972)  The determination of
        isoniazid and its metabolites acetylisoniazid,
        monoacetylhydrazine, diacetylhydrazine, isonicotinic acid and
        isonicotinylglycine in serum and urine.  Biochem J, 126:
        449-458.
    
        El-Yazigi A & Yusuf A (1991)  An expedient liquid chromatographic
        micromeasurement of isoniazid in plasma by use of electrochemical
        detection.  Therapeutic Drug Monitor, 13: 254-259.
    
        Flanagan RJ, Braithwaite RA, Brown SS, Widdop B, deWolff FA (1995) 
        Basic Analytical Toxicology. Geneva, WHO, pp157-158.
    
        Frater-Schröder M, Zbinden G (1975)  A specific rapid gas
        chromatographic assay for the determination of isoniazid
        N-acetylation: observation in rats with induced constant urine
        flow.  Biochem Med, 14: 274-284.
    

        Goodman LS & Gilman A (1990)  The pharmacological basis of
        therapeutics.  8th ed. New York
    
        Hartemann E, Barre M, Frederich M (1983)  Etat de mal convulsif
        par intoxication accidentelle ą l'isoniazide.  Pediatrie, 38 (1):
        4345
    
        Hsu K-Y & Ho Y (1989)  Determination of isoniazid
        methanesulphonate and its metabolites in rabbit blood by
        high-performance liquid chromatography. J Chromatogr, 493:
        305-312.
    
        Hutchings A, Monie RD, Spragg B, Routledge PA (1983) 
        High-performance liquid chromatographic analysis of isoniazid and
        acetylisoniazid in biological fluids.  J Chromatogr, 277:
        385-390.
    
        Ioannou PC (1988)  A more simple, rapid and sensitive fluorimetric
        method for the determination of isoniazid and acetylisoniazid in
        serum.  Application for acetylator phenotyping.  Clin Chim Acta,
        175: 175-182.
    
        Kohno H, Kubo H, Furukawa K, Yoshino N, Nishikawa T (1991) 
        Fluorimetric determination of isoniazid and its metabolites in
        urine by high performance liquid chromatography using in-line
        derivatization.  Therapeutic Drug Monitor, 13: 428-432.
    
        Kucers A & Bennet N (1979) The use of antibiotics, 3rd Ed. William
        Heinemann Medical Books Ltd, London
    
        Lauterberg BH, Smith CV, Mitchell JR (1981)  Determination of
        isoniazid and its hydrazine metabolites, acetylisoniazid,
        acetylhydrazine, and diacetylhydrazine in human plasma by gas
        chromatography-mass spectrometry.  J Chromatogr, 224: 431-438.
    
        LoDico CP, Levine BS, Goldberger BA, Capla YH (1992)  Distribution
        of isoniazid in an overdose death.  J Analyt Toxicol, 16:
        57-59.
    
        Manoguerra AS (1980)  Acute isoniazid toxicity.  Clin Toxicol, 16:
        407408
    
        Meyers FH, Jawetz E, Goldfien A (1976)  Review of medical
        pharmacology, 5th ed. Lange Medical Publications
    
        Meyler L & Peck HM (1976)  Drug induced diseases.  Vol. 4, ed.
        Excerpta Medica, Amsterdam
    
        Miceli JN & Olson WA (1982)  In Sunshine I & Jatlow PI eds. 
        Methodology for Analytical Toxicology Volume II. Cleveland, Ohio,
        CRC Press, pp 117-118.
    

        Moffat AC, Jackson JV, Moss MS, Widdop B eds. (1986)  Clarke's
        Isolation and Identification of Drugs. London, Pharmaceutical
        Press.
    
        Olson WA, Dayton PG, Israili ZH, Pruitt AW (1977) 
        Spectrophotofluorimetric assay for isoniazid and acetylisoniazid
        in plasma adapted to pediatric studies. Clin Chem, 23:
        745-748.
     
        Orlowski JP, Paganini EP, Pippenger CE (1988)  Treatment of a
        potentially lethal dose isoniazide ingestion.  Annals Emerg Med,
        17: 7376
    
        Parish RA & Brownstein D (1986)  Emergency department management
        of children with acute isoniazid poisoning.  Paediatric Emergency
        Care, 2 (2): 8890
    
        Pessayre D, Bentata M, Degott C et al. (1977)  Isoniazidrifampin
        fulminant hepatitis  Gastroenterology, 72: 284289
    
        Rouge P, Cougot P, Virenque C (1983)  Intoxication volontaire par
        l'isoniazide.  Cahiers d'Anesthésiologie, 31 (4): 389390
    
        RTECS (1979) Volume 1.  US Department of Health and human
        services.  Ed. Richard J. Lewis Sr. and Rodger L. Tatken
    
        Russell DW (1972)  Low circulating levels of acid-labile
        hydrazones after oral administration of isonicotinic acid
        hydrazine.  Clin Chim Acta, 41: 163-168.
     
        Siefkin AD, Albertson TE, Corbett MG (1987)  Isoniazid overdose:
        pharmacokinetics of oral charcoal in treatment.  Hum Toxicol, 6:
        497501
    
        Stewart MF, Freemont AJ, Richardson T (1995)  Fatal isoniazid
        poisoning.  Ann Clin Biochem, 32: 229-231.
    
        Svensson J-O, Muchtar A, Ericsson O (1985)  Ion-pair
        high-performance liquid chromatographic determination of isoniazid
        and acetylisoniazid in plasma and urine.  J Chromatogr, 341:
        193-197.
    
        Terman DS & Teitelbaum DT (1970)  Isoniazid self poisoning. 
        Neurology, 20: 299304
    
        Timbrell JA, Wright JM, Smith CM (1977)  Determination of
        hydrazine metabolites of isoniazid in human urine by gas
        chromatography.  J Chromatogr, 138: 165-172.
    

        Walubo A, Smith P, Folb P (1994)  Comprehensive assay for
        pyrizinamide, rifampicin and isoniazid with its hydrazine
        metabolites in human plasma by column liquid chromatography.  J
        Chromatogr, 658: 391-396.
    
        Watson S, Lacouture PG, Lovejoy FH (1981)  Single highdose
        pyridoxine treatment for isoniazid overdose.  JAMA, 246:
        11021104
    
        Weber WW & Hein DW (1979)  Clinical pharmacokinetics of isoniazid. 
        Clin Pharmacokinetics, 4: 401-422.
    
        WHO (1986)  Basic Tests for Pharmaceutical Substances.  Geneva,
        WHO, p96.
    
        Wood JD & Peesker SJ (1972)  A correlation between changes in GABA
        metabolism and isonicotinic acid hydrazine-induced seizures. 
        Brain Res, 45: 489-498.

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

        Authors:  Dr O.J. Kasilo
        Drug & Toxicology Information Service (DaTIS)
        Department of Pharmacy
        University of Zimbabwe Medical School
        P.O. Box A 172 Avondale
        Harare
        Zimbabwe
    
        Dr CFB Nhachi
        Department of Clinical Pharmacology and Toxicology
        University of Zimbabwe Medical School
        P.O. Box A 172 Avondale
        Harare
        Zimbabwe
    
        Tel: 273-4-7902333 or 791631 ext. 117/172
        Fax: 263-4-303 292
    
        Date:   September 1989
    
        Co-Authors: Drs M. Dahlet, F. Flesch, A. Jaeger
                    Service de Réanimation Médicale et Centre AntiPoisons
                    Hōpitaux Universitaires
                    Hōpital Civil
                    67091 Strasbourg Cedex
                    France
    
                    Tel: 33-88161144
                    Fax: 33-88161330
    

        Date:       January 1992
    
        Peer
        Review: Newcastle-upon-Tyne, United Kingdom, February 1992.
    
        Author
        Section 8:  Dr Sheila Dawling
                    Center for Clinical Toxicology
                    Vanderbilt University Medical Center
                    501 Oxford House
                    1161 21st Avenue South
                    Nashville, TN 37232-4632
                    United States of America
        
                    Tel:     1-615-9360760
                    Fax:     1-615-9360756
                    E-mail:  sheila.dawling@mcmail.vanderbilt.edu
    
        Date:       March 1998
    
        Editor:     Mrs J. Duménil
                    International Programme on Chemical Safety
                    Geneva
    
        Date:       May 1999
    


    See Also:
       Toxicological Abbreviations
       Isoniazid (ICSC)