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Glutethimide

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 by route of exposure
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 ANALYSES AND BIOMEDICAL INVESTIGATIONS
   8.1 Material sampling plan
      8.1.1 Sampling and specimen collection
         8.1.1.1 Toxicological analyses
         8.1.1.2 Biomedical analyses
         8.1.1.3 Arterial blood gas analysis
         8.1.1.4 Haematological analyses
         8.1.1.5 Other (unspecified) analyses
      8.1.2 Storage of laboratory samples and specimens
         8.1.2.1 Toxicological analyses
         8.1.2.2 Biomedical analyses
         8.1.2.3 Arterial blood gas analysis
         8.1.2.4 Haematological analyses
         8.1.2.5 Other (unspecified) analyses
      8.1.3 Transport of laboratory samples and specimens
         8.1.3.1 Toxicological analyses
         8.1.3.2 Biomedical analyses
         8.1.3.3 Arterial blood gas analysis
         8.1.3.4 Haematological analyses
         8.1.3.5 Other (unspecified) analyses
   8.2 Toxicological analyses and their interpretation
      8.2.1 Tests on toxic ingredient(s) of material
         8.2.1.1 Simple qualitative test(s)
         8.2.1.2 Advanced qualitative confirmation test(s)
         8.2.1.3 Simple quantitative method(s)
         8.2.1.4 Advanced quantitative method(s)
      8.2.2 Tests for biological specimens
         8.2.2.1 Simple qualitative test(s)
         8.2.2.2 Advanced Qualitative Confirmation Test(s)
         8.2.2.3 Simple Quantitative Method(s)
         8.2.2.4 Advanced quantitative method(s)
         8.2.2.5 Other dedicated method(s)
      8.2.3 Interpretation of toxicological analyses
   8.3 Biomedical investigations and their interpretation
      8.3.1 Biochemical analysis
         8.3.1.1 Blood, plasma or serum
         8.3.1.2 Urine
         8.3.1.3 Other fluids
      8.3.2 Arterial blood gas analyses
      8.3.3 Haematological analyses
      8.3.4 Interpretation of biomedical investigations
      8.3.5 Interpretation of biological investigations
   8.4 Other biomedical (diagnostic) investigations and their interpretation
   8.5 Overall Interpretation of all toxicological analyses and toxicological 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 Acid-base disturbances
         9.4.12.2 Fluid and electrolyte disturbances
         9.4.12.3 Others
      9.4.13 Allergic reactions
      9.4.14 Other clinical effects
      9.4.15 Special risks
   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)



    GLUTETHIMIDE

    International Programme on Chemical Safety
    Poisons Information Monograph 246
    Pharmaceutical

    1.  NAME

        1.1  Substance

             Glutethimide

        1.2  Group

             Minor psychotherapeutic, piperidinedione sedative and
             hypnotic

        1.3  Synonyms

             2-ethyl-2-phenylglutarimide;
             3-ethyl-3-phenyl-2,6-piperidinedione;
             Alpha-ethyl-alpha-phenyl glutarimide.

        1.4  Identification numbers

             1.4.1  CAS number

                    77-21-4

             1.4.2  Other numbers

                    No data available.

        1.5  Main brand names, main trade names

             Doridene, Doriden, Dorimide, Glimid, Elrodorm.

        1.6  Main manufacturers, main importers

    2.  SUMMARY

        2.1  Main risks and target organs

             The main target organ is the central nervous system
             causing coma with fluctuations in depth, and various degrees
             of hypotension.  Anticholinergic effects often occur.

        2.2  Summary of clinical effects

             At lower doses, acute intoxication may cause somnolence,
             ataxia, tonic muscle spasms and abnormal reflexes.  In severe
             intoxication, hypotension, hypothermia, shock, coma,

             respiratory depression and acidosis may occur.  Effects on
             other organs are usually secondary to coma and shock.

        2.3  Diagnosis

             Diagnosis is based mainly on the history of the patient
             and clinical features observed (see 2.2) and also on
             toxicological analyses.
    
             Serum glutethimide is rarely measured since it is poorly
             correlated with the clinical manifestation of the acute
             poisoning and requires the use of advanced analytical
             techniques.

        2.4  First aid measures and management principles

             If ingestion is recent and the patient is still fully
             conscious with a normal pharyngeal reflex, induce vomiting. 
             The obtunded, comatose patient should be intubated before
             gastric lavage is performed.  Stomach emptying more than four
             hours after ingestion is probably ineffective.  Give
             activated charcoal.  Administer a cathartic.
    
             Respiratory depression presents the greatest risk to the
             patient. Ensure that oxygenation is adequate. Optimize airway
             position of the patient, perform endotracheal intubation and
             assist ventilation in severe cases.  Blood gases should be
             monitored in patients with patients with respiratory
             failure.
    
             Pneumonia must be treated with appropriate antibiotics.
    
             Open and maintain an intravenous route.  Give adequate fluids
             to maintain diuresis of 2.5 to 3 L/day.  Catheterize
             bladder.
    
             Severe hypotension should be treated with fluid replenishment 
             (dopamine or other vasoactive drugs might be needed).
    
             In comatose patients, especially with signs of shock, renal
             function should be monitored (renal output, plasma urea and
             creatinine, electrolytes, acid-base balance).  Pre-renal
             uraemia occurs rarely but must be taken into
             consideration.
    
             Cerebral oedema (papilloedema) may require treatment with
             mannitol.
    
             Enhanced elimination procedures are not recommended:  forced
             diuresis is ineffective, and the efficacy of haemodialysis 
             (even using oil as dialysis fluid) and of haemoperfusion has
             not been satisfactory proved.

    
             Glutethimide is often ingested with other toxic substances: 
             mixed poisoning with codeine or paracetamol must always be
             considered, especially in drug addicts.
    
             Glutethimide is habit forming.

    3.  PHYSICO-CHEMICAL PROPERTIES

        3.1  Origin of the substance

             Synthetic.

        3.2  Chemical structure
    
    STRUCTURAL FORMULA 1
    
             Chemical names: 2 ethyl-2-phenylglutarimide
             alpha-ethyl-alpha-phenyl glutarimide
             3-ethyl-3-phenylpiperidine-2,6-dione
    
             Molecular weight:  217.26
    
             Molecular formula: C13H15NO2
    
             (Conversion of traditional units into SI: multiply the value
             in mg/L by 4.603 to get the result in micromol per
             litre.)

        3.3  Physical properties

             3.3.1  Colour

                    Colourless or white.

             3.3.2  State/form

             3.3.3  Description

                    Odourless and colourless crystals or white
                    crystalline powder, practically insoluble in water,
                    soluble one in five of ethanol, one in less than one
                    chloroform and one in 12 of ether, freely soluble in
                    acetone and ethyl acetate, soluble in methyl alcohol
                    (Reynolds, 1989).
    
                    Stability:  at pH 5 the chemical half life was 28.3
                    years at 25蚓 and 1.02 months at pH 8, the
                    decomposition being due to hydrolysis.

        3.4  Other characteristics

             3.4.1  Shelf-life of the substance

             3.4.2  Storage conditions

                    Store in well closed, airtight  containers,
                    protected from humidity and light (Wesolowski et al.,
                    1968).

    4.  USES

        4.1  Indications

             4.1.1  Indications

             4.1.2  Description

                    Used as an hypnotic in insomnia but rarely as a
                    sedative, glutethimide was initially believed to be
                    almost free from side effects (Banen & Resnik, 1973). 
                    However, further experience of its toxicity and
                    because its dependence liability (Sramek & Klajawal,
                    198l; Shamoian, 1975), glutethimide has been banned in
                    many countries and many companies have stopped
                    production.

        4.2  Therapeutic dosage

             4.2.1  Adults

                    The usual oral adult dose is 250 - 500 mg at
                    bedtime  (Reynolds, 1989).

             4.2.2  Children

                    It is not recommended for paediatric use (Reynolds,
                    1989).

        4.3  Contraindications

             Glutethimide is contraindicated in porphyria.  Due to
             its anti-muscarinic action, it should be given with great
             care to patients with closed-angle glaucoma, prostatic
             hypertrophy or urinary tract obstruction, and certain cardiac
             arrhythmias.  Alcohol enhances absorption and the hypnotic
             effects of glutethimide.  Like barbiturates, glutethimide
             induces microsomal hepatic enzymes and enhances the
             metabolism of coumarin anticoagulants and other drugs,
             lowering their plasma concentrations. Chronic administration
             of glutethimide may also enhance vitamin D metabolism
             (Reynolds, 1989).

    5.  ROUTES OF ENTRY

        5.1  Oral

             This is the only likely route of administration in man.

        5.2  Inhalation

             Unknown.

        5.3  Dermal

             Unknown.

        5.4  Eye

             Unknown.

        5.5  Parenteral

             Unknown.

        5.6  Other

             Unknown.

    6.  KINETICS

        6.1  Absorption by route of exposure

             Oral:  In six healthy volunteers given a dose of 500 mg,
             absorption was irregular and peak plasma concentrations
             occurred over one to six hours. However, in four of the six
             subjects absorption was biphasic (Curry et al., 1971). 
             Erratic absorption may be due to the poor solubility of
             glutethimide in water.  The onset of sedation usually occurs
             in 15 to 30 minutes (Baum et al., 1965).
    
             Parenteral:  following intraperitoneal administration of 70
             mg/kg studies in the rat, most of drug was found in the brain
             and spinal cord and other fat-containing tissues after 20
             minutes (Keberle et al., 1962).

        6.2  Distribution by route of exposure

             Oral:  following oral administration of 500 mg of
             glutethimide to healthy subjects, peak plasma concentrations
             of 2.85 to 7.05 駪/mL were achieved within two to six hours. 
             Plasma protein binding of glutethimide was about 50%. Mean
             glutethimide concentrations in the breast milk of 13 nursing
             mothers given 500 mg were: 0.27, 0.22, 0.12 and 0.04 駪/mL at
             8, 12, 16 and 23 hours, respectively, but levels were
             undetectable in one-third of the samples (Curry et al.,
             1971).
    
             Glutethimide is highly lipophilic and rapidly concentrates in
             brain and adipose tissue (Hansen & Fischer, 1974).

        6.3  Biological half-life by route of exposure

             Oral:  The elimination half-life is 10 to 12 hours
             (Kastrup, 1987) but may increase in severe poisoning (Maher,
             1970).  In six healthy subjects, initial half-lives after
             ingestion of 500 mg were 2.7 to 4.3 hours and subsequent
             half-lives ranged from 5.1 to 22 hours (Curry et al.,
             1971).

        6.4  Metabolism

             Glutethimide is partially metabolized by hydroxylation
             into 4-hydroxy-2-ethyl-2-phenylglutarimide. In the mouse,
             this appears to be twice as potent as the parent compound in
             mice and is believed to contribute to prolonged coma
             following overdosage (Hansen et al., 1975).  Hydroxylated

             metabolites are conjugated and excreted mainly in the urine
             but also in bile (Keberle et al., 1962).

        6.5  Elimination by route of exposure

             Oral:  glutethimide is inactivated by conjugation and
             the metabolites are excreted in urine, only 2% of the parent
             substance is excreted in urine, up to 2% of the dose has been
             reported to be found in the faeces (Curry et al.,
             1971).

    7.  PHARMACOLOGY AND TOXICOLOGY

        7.1  Mode of action

             7.1.1  Toxicodynamics

             7.1.2  Pharmacodynamics

                    Glutethimide directly blocks electron transfer
                    in cellular respiration (Reynolds, 1989).

        7.2  Toxicity

             7.2.1  Human data

                    7.2.1.1  Adults

                             In adults, death has been reported
                             after 5 g. The usual lethal dose is 10 to 20
                             g, although survival after a dose of 28 g has
                             been reported  (Skoutakis & Acchiardo,
                             1982).

                    7.2.1.2  Children

                             One 500 mg tablet may produce severe
                             toxicity in a small child (Sramek & Klajawal,
                             1981).

             7.2.2  Relevant animal data

                    Not relevant.

             7.2.3  Relevant in vitro data

                    Not relevant.

        7.3  Carcinogenicity

             Unknown.

        7.4  Teratogenicity

             There is no evidence of teratogenicity from therapeutic
             use (Keberle et al., 1962).

        7.5  Mutagenicity

             Unknown.

        7.6  Interactions

             The effects of glutethimide are additive with those of
             benzodiazepines, barbiturates, codeine and other CNS
             depressants. Concomitant administration of antidepressants,
             antiparkinsonian drugs or other anticholinergic agents may
             cause additive anticholinergic effects such as urinary
             retention, exacerbation of glaucoma, or adynamic ileus. 
             Ethanol enhances the effects of glutethimide.
    
             Glutethimide induces the hepatic metabolism of some drugs,
             such as dicoumarol derivatives, the dose of drugs taken
             concomitantly may require adjustment (Hansten & Horn,
             1989).

        7.7  Main adverse effects

             Common adverse effects are as follows: nausea, headache,
             hangover, blurred vision, occasional skin rashes, blood
             disorders (megaloblastic anaemia) (Pearson, 1965). 
             Osteomalacia (Greenwood et al., 1973) peripheral neuropathy
             and cerebral impairment (Nover, 1967) after prolonged use may
             also occur. Glutethimide is a drug of abuse and may cause
             dependence.

    8.  TOXICOLOGICAL ANALYSES AND BIOMEDICAL INVESTIGATIONS

        8.1  Material sampling plan

             8.1.1  Sampling and specimen collection

                    8.1.1.1  Toxicological analyses

                             Toxic ingredient: suspect materials
                             e.g. tablets, liquids

                             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  Biomedical analyses

                             Plasma (lithium heparin as
                             anticoagulant) or serum and urine for
                             standard biochemical analyses.

                    8.1.1.3  Arterial blood gas analysis

                             Heparinized arterial blood sample
                             (in severe cases).

                    8.1.1.4  Haematological analyses

                             Not necessary.

                    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

                             Store separated serum in
                             refrigerator (4蚓).

                    8.1.2.2  Biomedical 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

                             Acute glutethimide poisoning is not
                             associated with specific biochemical effects
                             other than changes secondary to coma,
                             respiratory failure and shock.  Routine
                             analyses for assessing the patient's general
                             clinical condition are necessary.
    
                             Chronic glutethimide abuse may lead to
                             conditions such as megaloblastic anaemia
                             (Pearson, 1965) or osteomalacia (Greenwood et
                             al., 1973). Bone marrow biopsy,
                             calcium/phosphate studies and serum
                             phosphatase determinations may be
                             necessary.

             8.1.3  Transport of laboratory samples and specimens

                    8.1.3.1  Toxicological analyses

                    8.1.3.2  Biomedical analyses

                             In acute glutethimide poisoning, an
                             isoelectric encephalogram may not indicate
                             brain death or a fatal prognosis
                             (Huttenlocher, 1963).

                    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)

                             The presence of glutethimide in
                             materials can be inferred by a number of
                             simple colour tests. Details of the reagents
                             and procedures for these tests can be found
                             in Moffat et al. (1986).  Results of colour
                             tests must be taken as presumptive only,
                             since many other drugs give similar
                             reactions, and the limitations of each are
                             given where these are known.
    

                             Koppanyi-Zwikker test.  Dissolve
                             approximately 1 mg of the material in 1 mL
                             ethanol.  Add 1 drop of 1% cobalt nitrate in
                             ethanol, followed by 10 無 pyrrolidine.  A
                             violet reaction is given by compounds which
                             have >C=O and >NH groups adjacent within a
                             ring (i.e. by glutethimide and by
                             barbiturates).  Note that hydrochloride salts
                             give a blue colour before addition of
                             pyrrolidine.
    
                             Liebermann's test.  To 1 mg of material on a
                             white tile, add 2 drops 0.1% sodium nitrite
                             in concentrated sulphuric acid.  A red colour
                             is produced by glutethimide, and by
                             phenobarbital, but not by other barbiturates. 
                             Since many substances give a red colour with
                             sulphuric acid, all positive materials should
                             be re-tested with sulphuric acid.
    
                             Mercurous nitrate test.   To freshly prepared
                             saturated mercurous nitrate add solid sodium
                             bicarbonate until effervescence ceases and
                             the precipitate becomes yellow.  Shake before
                             use, and use within 1 hour.  Dissolve a small
                             amount of test material in a minimum of
                             ethanol, and add one drop of reagent.  A dark
                             grey / black colour within 2 minutes is given
                             by ring imides or sulphonamides with an
                             additional ring.  The barbiturate reaction is
                             quicker and more intense than that of
                             glutethimide.
    
                             UV spectrophotometry gives rather more
                             specificity.  Dissolve a portion of material
                             in ethanol to achieve an appropriate
                             instrument response.  If necessary,
                             centrifuge or filter the mixture and analyse
                             the clear supernatant.  The spectrum in
                             ethanol gives deltamax at 252 nm, 258 nm (A|
                             = 18) and 264 nm.  Glutethimide is unstable
                             at alkaline pH, due to hydrolysis of the
                             glutarimide ring.  Adjustment of the pH to
                             >11 (e.g. by addition of 4M NaOH or ammonium
                             hydroxide) to the ethanolic solution of
                             glutethimide results in a characteristic

                             decline in absorbance at 230 - 235 nm over a
                             time period of some 20 minutes. 
    
                             Immunoassays for barbiturates (e.g. TDx 
                             [Abbott Laboratories, Abbott Park, Illinois
                             60064 USA] or EMIT [Syva-Behring Diagnostics,
                             Cupertino, California 95014 USA]) do not
                             usually have sufficient cross-reactivity to
                             respond to glutethimide.  However,
                             cross-reactivity varies between
                             manufacturers, and for polyclonal assays,
                             between lot numbers of the same kit.  More
                             than 25 mg/L glutethimide is usually required
                             to obtain a positive result, corresponding to
                             a cross reactivity of less than 1%.  Since
                             the concentration in a suspect material is
                             likely to exceed this concentration by
                             several-fold, it is always worth testing the
                             cross-reactivity of available kit by the
                             addition of known amounts of glutethimide to
                             drug free urine.  Once the cut-off
                             concentration has been determined in this
                             way, the test substance dissolved in drug
                             free urine can then be examined.
    
                             Thin layer chromatography is highly
                             appropriate for identification of
                             glutethimide, and may be either an in-house
                             system or a commercially-available system
                             such as Toxi-Lab [Ansys Inc, Irvine,
                             California 92718, USA].  The material can be
                             dissolved in an organic solvent such as
                             methanol or dichloromethane and applied
                             directly to the plate.  Using silica plates
                             without modifiers and standard systems, the
                             Rf of glutethimide is 0.75 on methanol /
                             concentrated ammonia (100: 1.2), and 0.62 on
                             ethyl acetate / methanol / ammonia (85:15:6).
                             Several locating reagents can be used. 
                             Mercurous nitrate reagent is the most
                             specific, and gives a dark grey response with
                             a sensitivity of approximately 10 ng. 
                             However, the purple response produced by
                             mercuric chloride-diphenylcarbazone reagent,
                             and the positive reaction to Dragendorff or
                             acidified iodoplatinate are also useful but
                             are less characteristic (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
                             glutethimide is 1836 on OV1, SE30, DB5 or
                             similar phases.  Isothermal analysis may be
                             performed at about 220蚓, without the need
                             for derivatization.  Flame ionization
                             detection gives adequate sensitivity (2 to 5
                             ng on column), and nitrogen-phosphorus
                             detection gives additional selectivity (see
                             for example Gold et al., 1974; Hansen &
                             Fischer, 1974; Flanagan & Berry, 1977). Mass
                             spectrometry can be applied to the gas
                             chromatographic identification of
                             glutethimide in suspect materials. 
                             Characteristic fragmentation is achieved
                             without the need for derivatization, and the
                             most abundant ions are  m/z 189, 132, 117,
                             160 and 217 (Kennedy et al., 1978).
    
                             HPLC may be used to identify glutethimide,
                             and most published methods involve reverse
                             phase chromatography with UV detection. 
                             Dissolve a small amount of the suspect
                             material in the mobile phase, and filter if
                             necessary to obtain a clear supernatant. 
                             Kabra et al. (1978) used a C18 column with a
                             mobile phase of acetonitrile / phosphate
                             buffer (300 無 1M KH2PO4 and 50 無 0.9 M
                             phosphoric acid in 1800 mL water) [215:785]. 
                             Using isocratic elution at 50蚓 glutethimide
                             was detected at 195 nm with a relative
                             retention of 0.55 to the internal standard
                             methylphenytoin.  Svinarov & Dotchev (1989)
                             used a C8 column with a mobile phase of
                             acetonitrile / water (1:4), performing
                             isocratic elution at ambient temperature. 
                             Glutethimide was detected at 208 nm with a
                             relative retention of 1.57 to the internal
                             standard tolylphenobarbital.  Additional
                             confirmation of identity may be obtained by
                             performing a full scan analysis on the
                             appropriate portion of the HPLC
                             effluent.

                    8.2.1.3  Simple quantitative method(s)

                             Direct quantitative 
                             spectrophotometric analysis of glutethimide
                             has been described.  The decline in
                             absorbance in alkaline solution at 233 nm due
                             to hydrolysis of the glutarimide ring
                             directly correlates with the amount of
                             glutethimide present.  The test is performed
                             by dissolving a small amount of material in

                             chloroform.  Five volumes of the test
                             solution are mixed with one volume of 3M NaOH
                             solution.  Absorbance at 233 nm is measured
                             at one and five minutes after addition of the
                             alkali.  Alternatively, the difference in
                             absorbance at 233 nm at time zero and 20
                             minutes (by which time the degradation will
                             be completed) can be used.  Quantitation is
                             performed by comparison to the analysis of
                             known amounts of glutethimide prepared
                             similarly.  If a scanning spectrophotometer
                             is available, this test can be combined
                             effectively with the Broughton method for
                             barbiturate determination by following the
                             differential absorbance of pH 9.5 and pH 13
                             sample extracts over the wavelength range 220
                             to 320 nm (Dain & Trainer, 1970).

                    8.2.1.4  Advanced quantitative method(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
                             glutethimide is 1836 on OV1, SE30, DB5 or
                             similar phases. Isothermal analysis may be
                             performed at about 220蚓, without the need
                             for derivatization.  Flame ionization
                             detection gives adequate sensitivity (2 to 5
                             ng), although nitrogen-phosphorus detection
                             gives additional selectivity.  Quantitation
                             is performed by addition of an internal
                             standard (e.g. p-dimethylaminobenzaldehyde,
                             piperidone, p-hydroxybenzophenone or a 
                             non-prescription barbiturate) and direct
                             comparison to known amounts of glutethimide
                             subjected to similar dilution.  Using mass
                             spectrometry detection quantification of
                             glutethimide in materials is achieved in SIM
                             mode (using  m/z 189; qualifier  m/z 160)
                             without the need for derivatization (Kennedy
                             et al., 1978).
    
                             HPLC may be used to quantify glutethimide in
                             residues, and most published methods involve
                             reverse phase chromatography with UV
                             detection.  The material should be dissolved
                             in mobile phase (e.g. 10 mg in 10 mL) and
                             filtered to provide a clear supernatant if
                             necessary.  Kabra et al. (1978) used a C18
                             column with a mobile phase of acetonitrile /
                             phosphate buffer (300 無 1M KH2PO4 and 50
                             無 0.9 M phosphoric acid in 1800 mL water)

                             [215:785].  Using isocratic elution at 50蚓
                             glutethimide was detected at 195 nm with a
                             relative retention of 0.55 to the internal
                             standard methylphenytoin.  Svinarov & Dotchev
                             (1989) used a C8 column with a mobile phase
                             of acetonitrile / water (1:4), performing
                             isocratic elution at ambient temperature. 
                             Glutethimide was detected at 208 nm with a
                             relative retention of 1.57 to the internal
                             standard tolylphenobarbital.  Quantitation is
                             achieved by comparison to known amounts of
                             glutethimide subjected to similar
                             dilution.

             8.2.2  Tests for biological specimens

                    8.2.2.1  Simple qualitative test(s)

                             Commonly-available immunoassay kits
                             for barbiturate detection do not have
                             sufficient cross-reactivity to respond to
                             glutethimide or its metabolites in biological
                             specimens: sensitivity is usually less than
                             25 mg/L, which is less than 1% cross
                             reactivity (see under 8.2.1.1 above).
    
                             Direct UV methods may be applied to the
                             detection of glutethimide in gastric
                             contents, but are not useful for the analysis
                             of other fluids.  Dilute a portion of gastric
                             contents in ethanol to achieve an appropriate
                             instrument response.  The spectrum in ethanol
                             gives deltamax at 252 nm, 258 nm (A| = 18)
                             and 264 nm.  Glutethimide and its common
                             metabolites are unstable in alkaline solution
                             (pH>11) due to hydrolysis of the glutarimide
                             ring.  For the spectrophotometric
                             identification of glutethimide in urine or
                             serum, the drug must first be extracted from
                             the matrix at neutral pH into a polar solvent
                             (e.g. dichloromethane, ethyl acetate) to
                             maximize response from the metabolites. 
                             After solvent evaporation, the residue is
                             taken up in water.  The pH is adjusted to 13
                             by the addition of one part of 3M NaOH
                             solution to five parts of test solution. 
                             Absorbance at 233 nm is monitored, where a
                             characteristic decline over a time period of
                             some 20 minutes will be observed.  If a
                             scanning spectrophotometer is available, this
                             test can be combined effectively with the
                             Broughton method for barbiturate
                             determination by following the differential

                             absorbance of pH 9.5 and pH 13 sample
                             extracts over the wavelength range 220 to 320
                             nm (Dain & Trainer, 1970).
    
                             Thin layer chromatography can then be used
                             after extraction from the samples (urine or
                             gastric contents - 10 to 20 mL) into an
                             organic solvent at pH 5 to 7 (glutethimide is
                             unstable under alkaline conditions).  The use
                             of a polar extraction solvent (e.g.
                             dichloromethane, ethyl acetate) ensures good
                             recovery of glutethimide and a number of
                             metabolites, whereas the use of a non-polar
                             solvent (e.g. hexane, petroleum ether)
                             excludes virtually all the metabolites from
                             the extraction.  Concentration of the extract
                             may be performed 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 standard solvent systems, the 
                             Rf is 0.75 on methanol / concentrated ammonia
                             (100: 1.2), and 0.62 on ethyl acetate / 
                             methanol / ammonia (85:15:6) (Moffat et al., 
                             1986). Chromatograms of urine samples 
                             extracted with polar solvents typically show 
                             up to six distinctive spots when eluted in 
                             cyclohexane / ethanol (80:20). Rf values on 
                             this system are: glutethimide 0.53;
                             4-hydroxyglutethimide 0.42; other
                             metabolites at 0.05, 0.13, 0.30 and 0.38
                             (Sunshine et al., 1969).  Several locating
                             reagents can be used.  Mercurous nitrate
                             reagent is the most specific, and gives a
                             dark grey response with a sensitivity in the
                             region of 1 mg/L in the original sample (50
                             ng on plate).  However, the purple response
                             produced by mercuric
                             chloride-diphenylcarbazone reagent, and the
                             positive reaction to Dragendorff or acidified
                             iodoplatinate are also useful but are less
                             sensitive and less characteristic (Moffat et
                             al., 1986).

                    8.2.2.2  Advanced Qualitative Confirmation Test(s)

                             Gas chromatography can be used after
                             extraction into an organic solvent from a pH
                             adjusted to 4 to 7 using a phosphate buffer. 
                             The use of a polar solvent (e.g.
                             dichloromethane or ethyl acetate) ensures
                             good recovery of glutethimide and

                             metabolites, whereas the use of a non-polar
                             solvent (e.g. hexane or petroleum ether)
                             excludes the extraction of up to 90% of the
                             metabolites. The recovery of metabolites from
                             urine can be greatly enhanced by incubation
                             of the sample with glucuronidase prior to
                             extraction (e.g. at pH5 for one hour at
                             50蚓). Isothermal analysis may be performed
                             at about 220蚓, without the need for
                             derivatization. Urine extracted with polar
                             solvents typically show up to six peaks in
                             addition to glutethimide: two elute before,
                             and four elute after glutethimide. The major
                             urinary metabolites are immediately adjacent
                             to the glutethimide peak.  The retention
                             index for glutethimide is 1836 on OV1, SE30,
                             DB5 or similar phases; the major metabolites
                             4-hydroxyglutethimide and 2-phenylglutarimide
                             run at 1875 and 1778 respectively.  Flame
                             ionization detection gives adequate
                             sensitivity (2 to 5 ng), and
                             nitrogen-phosphorus detection gives
                             additional selectivity, but does not give
                             improved sensitivity.  Mass
                             spectrophotometric detection can be applied
                             to the gas chromatographic detection of
                             glutethimide and several metabolites in
                             plasma and urine.  Characteristic
                             fragmentation of glutethimide,
                             2-phenylglutarimide and desethylglutethimide
                             is achieved without the need for
                             derivatization, although the hydroxylated
                             metabolites are chromatographed as
                             trifluoroacetate derivatives (Kennedy et al.,
                             1978).
    
                             HPLC may be used to identify glutethimide,
                             and most published methods involve reverse
                             phase chromatography with UV detection, and
                             do not discuss analysis of urine specimens. 
                             The drug must first be extracted from the
                             specimen, and the precipitation of plasma
                             with an equal volume of acetonitrile as
                             described by Kabra et al. (1978) is easily
                             performed and reliable.  Kabra et al. (1978)
                             used a C18 column with a mobile phase of
                             acetonitrile / phosphate buffer (300 無 1M
                             KH2PO4 and 50 無 0.9 M phosphoric acid in
                             1800 mL water) [215:785].  Using isocratic
                             elution at 50蚓 glutethimide was detected at
                             195 nm with a relative retention of 0.55 to
                             the internal standard methylphenytoin. 
                             Svinarov & Dotchev (1989) used a C8 column

                             with a mobile phase of acetonitrile / water
                             (1:4), performing isocratic elution at
                             ambient temperature.  Glutethimide was
                             detected at 208 nm with a relative retention
                             of 1.57 to the internal standard
                             tolylphenobarbital.  Neither method shows
                             chromatograms from specimens taken following
                             glutethimide ingestion, nor give mention of
                             glutethimide metabolites. 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 spectrophotometric
                             analysis of glutethimide in biological fluids
                             has been described.  The analysis is based on
                             the observation that the decline in
                             absorbance in alkaline solution at 230 nm,
                             due to hydrolysis of the glutarimide ring
                             directly correlates with the amount of
                             glutethimide present.  The test is performed
                             by extracting the drug from the matrix at
                             neutral pH (at pH 5.5 the recovery of
                             barbiturates and glutethimide is higher, but
                             this introduces the possibility of 
                             co-extraction of salicylates which will
                             interfere with the absorption spectrum). 
                             Care should be taken to select a non-polar
                             solvent such as hexane or petroleum ether, as
                             the use of a polar solvent co-extracts
                             glutethimide metabolites which will interfere
                             with the analysis and produce falsely
                             elevated results, particularly in the later
                             stages of intoxication.  Some methods which
                             use dichloromethane as extraction solvent
                             employ a washing step with NaOH to remove 
                             co-extracted metabolites, but it is thought 
                             that contact with the alkali initiates the
                             degradation process and makes the timing of
                             the assay critical.  The extract is
                             evaporated to dryness and the residue is
                             taken up in water (methods which use ethanol
                             as the reconstitution solvent suffer
                             interference from the dissolution of fatty
                             deposits from serum).  Five volumes of the
                             test solution are mixed with one volume of 3M
                             NaOH solution. Absorbance at 233 nm is
                             measured at one and five minutes after
                             addition of the alkali.  Alternatively, the

                             difference in absorbance at 233 nm at time
                             zero and 20 minutes (by which time the
                             degradation will be completed) can be used. 
                             Quantitation is performed by comparison to
                             the analysis of known amounts of glutethimide
                             prepared in a similar matrix and extracted
                             similarly. (Dain & Trainer, 1970).  A
                             modification of this procedure is given by
                             Finkle (1975).  If a scanning
                             spectrophotometer is available, this test can
                             be combined effectively with the Broughton
                             method for barbiturate determination by
                             following the differential absorbance of pH
                             9.5 and pH 13 sample extracts over the
                             wavelength range 220 to 320 nm (Dain &
                             Trainer, 1970).

                    8.2.2.4  Advanced quantitative method(s)

                             Gas chromatography methods for
                             quantitation of glutethimide and its major
                             metabolites in serum have been described.  In
                             general, most of the methods which have been
                             described for screening of barbiturates and
                             hypnotics in serum can be applied to the
                             analysis of glutethimide.  However, all of
                             the published dedicated gas chromatography
                             methods for glutethimide pre-date the use of
                             capillary columns which offer superior
                             separation over standard packed columns and
                             improved sensitivity for polar metabolites. 
                             After the addition of a suitable internal
                             standard (e.g. p-dimethylaminobenzaldehyde,
                             piperidone, p-hydroxybenzophenone or a
                             non-prescription barbiturate),  the drug is
                             extracted into an organic solvent from a pH
                             adjusted to 4 to 7 using a phosphate buffer. 
                             If non-polar solvents such as hexane are
                             used, metabolites will not be extracted: the
                             use of polar solvents (e.g. dichloromethane
                             or ethyl acetate) ensures that metabolites
                             are also extracted.  Gold et al. (1974)
                             report the presence of up to six metabolites
                             in sera from poisoned patients, only three of
                             which were present in significant quantities. 
                             Chromatography can be performed isothermally
                             at about 220蚓, on a number of common packed
                             column phases (OV1, SE30, OV225, Carbowax
                             20M, PolyA-103) without the need for
                             derivatization: DB5 is a useful capillary
                             column equivalent.  The retention index for
                             glutethimide is 1836 on OV1, SE30, DB5 or
                             similar phases; the major metabolites

                             4-hydroxyglutethimide and 2-phenylglutarimide
                             run at 1875 and 1778 respectively.  Flame
                             ionization detection gives adequate
                             sensitivity (2 to 5 ng), and
                             nitrogen-phosphorus detection gives
                             additional selectivity, but does not improve
                             sensitivity.  Quantitative analysis can be
                             performed by comparison to known amounts of
                             glutethimide dissolved in aqueous solution or
                             preferably plasma / serum and extracted
                             similarly.  Using 0.2 mL of serum a
                             sensitivity of 1 mg/L should easily be
                             achieved.  For example see the methods
                             described by Gold et al., 1974; Hansen &
                             Fischer, 1974; Flanagan & Berry, 1977.  When
                             analysing plasma using a packed column and
                             FID, care should be taken to exclude
                             interference from co-eluting endogenous fatty
                             acids.  The use of a capillary column or a
                             more selective detector (nitrogen-phosphorus)
                             alleviates this problem. Mass Spectrometry in
                             SIM mode has been used with gas
                             chromatography for quantification of
                             glutethimide and its metabolites in plasma
                             and urine.  Glutethimide, 2-phenylglutarimide
                             and dehydroglutethimide are quantified
                             directly, while the hydroxylated metabolites
                             are chromatographed following derivatization
                             with trifluoroacetic anhydride (Kennedy et
                             al., 1978).
    
                             HPLC methods are described for quantitative
                             analysis of glutethimide in plasma.  Most
                             published methods involve reverse phase
                             chromatography with UV detection, and give a
                             sensitivity of 1 mg/L using a 100 無 sample
                             volume. The drug must first be extracted from
                             the specimen, and the precipitation of plasma
                             with an equal volume of acetonitrile as
                             described by Kabra et al. (1978) is easily
                             performed and reliable.  Kabra et al. (1978)
                             used a C18 column with a mobile phase of
                             acetonitrile / phosphate buffer (300 無 1M
                             KH2PO4 and 50 無 0.9 M phosphoric acid in
                             1800 mL water) [215:785].  Using isocratic
                             elution at 50蚓 glutethimide was detected at
                             195 nm with a relative retention of 0.55 to
                             the internal standard methylphenytoin. 
                             Svinarov & Dotchev (1989) used a C8 column
                             with a mobile phase of acetonitrile / water
                             (1:4), performing isocratic elution at
                             ambient temperature.  Glutethimide was
                             detected at 208 nm with a relative retention

                             of 1.57 to the internal standard
                             tolylphenobarbital.  Neither method shows
                             chromatograms of specimens taken following
                             glutethimide ingestion, nor gives mention of
                             glutethimide metabolites.  Analysis of
                             patient samples by HPLC must therefore be
                             undertaken with due attention to the
                             possibility of interference from co-extracted
                             metabolites.  Quantitation is performed by
                             comparison to samples of drug free plasma to
                             which known amounts of glutethimide have been
                             added and treated similarly.

                    8.2.2.5  Other dedicated method(s)

                             Not applicable.

             8.2.3  Interpretation of toxicological analyses

                    There is considerable variation in individual
                    response to a given plasma glutethimide concentration. 
                    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.  As a guide, the following
                    table shows typical concentrations of glutethimide in
                    serum.
    
                                                                           
                                                            mg/L   痠ol/L
                    After single oral dose (1 to 6 hours)   3 - 7  14 - 32
                    Steady-state in therapy                 <4     <18
                    Toxicity apparent (coma, convulsions,
                    pulmonary oedema)                       10     46
                    Potentially fatal (deep coma,
                    sudden apnoea)                          30     138
                                                                           
    
                    After therapeutic doses, peak concentrations of the
                    active metabolite 4-hydroxyglutethimide are in the
                    range 4 to 6 mg/L at about 24 hours.  After overdose,
                    4-hydroxyglutethimide accumulates in plasma, rising to
                    several times the concentration of the parent
                    compound, and peaking on the second day, where after
                    it declines in parallel to glutethimide.  There is
                    disagreement over whether fluctuations in
                    4-hydroxyglutethimide may be responsible for, or
                    contribute to the cyclical and prolonged coma seen
                    after overdose (Gold et al., 1974; Hansen et al.,
                    1975; Curry et al., 1987). There are insufficient data
                    to determine the clinical significance of the
                    concentrations of the other active metabolites

                    2-phenylglutarimide and the gamma-butyrolactone
                    derivative.

        
        8.3  Biomedical investigations and their interpretation

             8.3.1  Biochemical analysis

                    8.3.1.1  Blood, plasma or serum

                             Sodium, potassium, chloride
                             Alanine aminotransferase, aspartate
                             transaminase
                             Glucose, urea, creatinine

                    8.3.1.2  Urine

                             Not applicable.

                    8.3.1.3  Other fluids

                             No dedicated test.

             8.3.2  Arterial blood gas analyses

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

             8.3.3  Haematological analyses

                    Not applicable.

             8.3.4  Interpretation of biomedical investigations

                    Not applicable.

             8.3.5  Interpretation of biological investigations

                    Acute glutethimide poisoning is not associated
                    with specific biochemical effects other than changes
                    secondary to coma, respiratory failure and shock. 
                    Routine analyses for assessing the patient's general
                    clinical condition are necessary.

        8.4  Other biomedical (diagnostic) investigations and their
             interpretation

        8.5  Overall Interpretation of all toxicological analyses and 
             toxicological investigations

             There are no special precautions to be taken for sample
             collection for biomedical or toxicological analyses. Acute
             glutethimide poisoning is not associated with specific
             biochemical effects other than changes secondary to coma,
             respiratory failure and shock.  Routine analyses for

             assessing the patient's general clinical condition are
             necessary.
    
             Presumptive tests on toxic ingredients of materials can be
             performed by colourimetric, spectrophotometric or thin layer
             chromatographic techniques.  Gas chromatography of
             glutethimide (flame ionization detection) is not difficult,
             and is much more specific.
    
             Specific identification of the causative agent as
             glutethimide in cases of hypnotic intoxication is useful
             since the clinical course of glutethimide poisoning is more
             complicated, and its management is more difficult, than that
             of the barbiturates.  Measurement of serum concentrations of
             glutethimide may be useful in cases where coma is prolonged
             or symptoms are particularly severe.
    
             Measurement of glutethimide in biological materials is
             possible after extraction into an organic solvent, and
             metabolites will be co-extracted if polar solvents are used. 
             Metabolites (particularly 4-hydroxyglutethimide) are seen by
             most advanced techniques.  Qualitative analysis is most
             easily performed by thin layer chromatography.  Gas
             chromatography allows for both qualitative and quantitative
             analysis, and derivatization is not required; flame
             ionization detection gives adequate sensitivity for most
             applications.  Gas chromatography / mass spectrometry has
             been used where confirmatory testing is required.  HPLC has
             not been widely used.
    
             Typical concentrations of glutethimide in serum are:
                                                                           
    
                                                       mg/L    痠ol/L
             After single oral dose (1 to 6 hours)     3 - 7   14 - 32
             Steady-state in therapy                   <4      <18
             Toxicity apparent (coma, convulsions,
             pulmonary oedema)                         10      46
             Potentially fatal (deep coma, sudden
             apnoea)                                   30      138
                                                                           
    
             The metabolite 4-hydroxyglutethimide may contribute to the
             clinical and toxic effects of glutethimide, but there are
             insufficient data to determine the clinical significance of
             the concentrations of the metabolites 4-hydroxyglutethimide,
             2-phenylglutarimide and gamma-butyrolactone, all of which
             have known pharmacological activity.

    9.  CLINICAL EFFECTS

        9.1  Acute poisoning

             9.1.1  Ingestion

                    Ingestion is the only route by which acute
                    poisoning may occur.  Mild intoxication with small
                    doses results in somnolence, ataxia, tonic muscle
                    spasms, abnormal reflexes.
    
                    In severe intoxication coma, hypotension, hypothermia,
                    shock, respiratory depression and cerebral oedema may
                    occur.
    
                    Signs from other organs and systems are usually
                    secondary to coma and shock.

             9.1.2  Inhalation

                    Unknown.

             9.1.3  Skin exposure

                    Unknown.

             9.1.4  Eye contact

                    Unknown.

             9.1.5  Parenteral exposure

                    Unknown.

             9.1.6  Other

                    Unknown.

        9.2  Chronic poisoning

             9.2.1  Ingestion

                    Ingestion is the only route of glutethimide
                    administration in humans.  Prolonged use of the drug
                    may cause peripheral neuropathy (Nover, 1967),
                    hypocalcaemia  (Ober et al., 1981) and osteomalacia
                    (Greenwood et al., 1973).  Acute abstinence syndrome
                    following glutethimide withdrawal has been described
                    (Johnson & Van Buren, 1962).  Chronic ingestion of
                    high doses is associated with impaired memory,
                    inability to concentrate, ataxia, tremors,
                    hyporeflexia, slurring of speech, and convulsions
                    (Reynolds, 1989).

             9.2.2  Inhalation

                    Unknown.

             9.2.3  Skin exposure

                    Unknown.

             9.2.4  Eye contact

                    Unknown.

             9.2.5  Parenteral exposure

                    Unknown.

             9.2.6  Other

                    Unknown.

        9.3  Course, prognosis, cause of death

             Any acute poisoning without loss of consciousness may be
             regarded as mild and the patient is not at risk.
    
             The occurrence of coma, hypotension, hypothermia, shock,
             respiratory depression and complications such as pneumonia
             mean that glutethimide poisoning is potentially serious. 
             However, death is unusual provided the patient is admitted to
             intensive care when needed.  Cerebral oedema may be fatal 
             (Wright & Roscoe, 1970).

        9.4  Systematic description of clinical effects

             9.4.1  Cardiovascular

                    Hypotension, shock and tachycardia have been
                    observed.  Unexplained dysrhythmias may be due to the
                    antimuscarinic effects of the drug or low plasma
                    calcium concentrations (Wright & Roscoe, 1970, Chazan
                    & Garella, 1971).

             9.4.2  Respiratory

                    Respiratory depression with intermittent apnea
                    and or arrest may occur in very severe cases.
                    Pneumonia due to aspiration and pulmonary oedema have
                    been reported  (Wright & Roscoe, 1970, Chazan &
                    Garella, 1971).

             9.4.3  Neurological

                    9.4.3.1  Central Nervous System (CNS)

                             Various degrees of CNS depression
                             may occur, ranging from lethargy to deep
                             coma.  Cerebral oedema, intracranial
                             haemorrhage, tonic muscle spasms and
                             hyperreflexia may occur. Truncal ataxia has
                             been reported in acute glutethimide
                             intoxication in children (Huttenlocher,
                             1963).

                    9.4.3.2  Peripheral nervous system

                             Peripheral neuropathy and diplopia
                             has been reported following chronic
                             use.

                    9.4.3.3  Autonomic nervous system

                             Glutethimide has
                             antimuscarinic/anticholinergic activity,
                             tachycardia, dryness of mouth, mydriasis,
                             irritability, urinary retention and
                             constipation.

                    9.4.3.4  Skeletal and smooth muscle

                             Tonic muscle spasm and paralytic
                             ileus (adynamic ileus) may also be
                             observed.

             9.4.4  Gastrointestinal

                    Gastrointestinal atony due to parasympatholytic
                    activity may occur (Chazan & Garella, 1971).

             9.4.5  Hepatic

                    No direct effects are known.

             9.4.6  Urinary

                    9.4.6.1  Renal

                             With the exception of possible
                             pre-renal uraemia due to severe hypotension,
                             no other renal effects occur (Wright &
                             Roscoe, 1970; Chartier, 1983).

                    9.4.6.2  Other

                             Urinary retention may occur due to
                             the anticholinergic effect of
                             glutethimide.

             9.4.7  Endocrine and reproductive systems

                    No data available.

             9.4.8  Dermatological

                    Bullous changes resembling those seen in
                    barbiturate poisoning (Burdon & Cade, 1979) and
                    erythematous vesicles (Leavell et al., 1972) have been
                    described.

             9.4.9  Eye, ear, nose, throat: local effects

                    Mydriasis and papilloedema have been observed
                    (Wright & Roscoe, 1970).

             9.4.10 Haematological

                    Significant methaemoglobinemia has been
                    reported rarely  (Filippini, 1965); in a further case,
                    megaloblastic anaemia, thrombocytopenia and aplastic
                    anaemia occurred (Pearson, 1965).

             9.4.11 Immunological

                    No data available.

             9.4.12 Metabolic

                    9.4.12.1 Acid-base disturbances

                             Acid base disturbances may occur
                             secondary to coma or shock.

                    9.4.12.2 Fluid and electrolyte disturbances

                             Hypocalcaemia has been described
                             (Crawshaw, 1968).

                    9.4.12.3 Others

                             Hypothermia has been described
                             (Skoutakis & Acchiardo, 1982; Ozdemir &
                             Tannenberg, 1972).

             9.4.13 Allergic reactions

                    No data available.

             9.4.14 Other clinical effects

                    No data available.

             9.4.15 Special risks

                    Glutethimide readily crosses the placenta and
                    may cause neonatal respiratory depression (Kurtz et
                    al., 1966, Reveri et al., 1977) and neonatal
                    withdrawal symptoms  (Asnes & Lamb, 1969).
    
                    Eight to 12 hours after a maternal does of 500 mg of
                    glutethimide, a peak concentration of 270 nanogram per
                    mL in breast milk has been reported (Curry et al.,
                    1971).

        9.5  Other

             No data available.

        9.6  Summary

    10. MANAGEMENT

        10.1 General principles

             Patients with mild poisoning who are only sedated need
             little or no treatment.  Emptying the stomach by emesis
             and/or lavage should be done within the first four hours
             after ingestion if the clinical condition of the patient
             allows it.  If the patient is obtunded, gastric lavage should
             be performed after endotracheal intubation.
    
             Coma associated with shock is the most important feature of
             severe poisoning.  Treatment is symptomatic.
    
             There is no specific antidotes.  Procedures to enhance
             elimination are not recommended: forced diuresis has been
             shown to be ineffective; haemodialysis (even using oil as
             dialyzing fluid) and haemoperfusion have not proven to be
             effective.

        10.2 Life supportive procedures and symptomatic/specific treatment

             Patients with mild signs of overdose do not need
             special treatment but should be under continuous clinical
             observation, especially during the early stages of poisoning. 
             Intestinal absorption of additional amounts of glutethimide
             may unpredictably precipitate deep coma requiring intensive
             care.

    
             Severe poisoning with coma always needs intensive care.  It
             is essential to maintain a clear airway and provide oxygen. 
             Perform endotracheal intubation and support ventilation. 
             Frequent change of the position of the patient and vigorous
             physiotherapy are indicated to prevent pneumonia and
             pulmonary infarctions.  Pneumonia must be treated with
             appropriate antibiotics.
    
             Maintain one central or peripheral intravenous route.
    
             Administer intravenous fluids in amounts adequate to maintain
             daily diuresis of two to three litres. Urinary
             catheterization is necessary in the comatose patient to
             measure hourly urine output and obtain urine samples.
    
             In case of significant hypotension, hypovolaemia must be
             considered as a possible cause and be corrected.  If
             hypotension is severe, infusion of dopamine may be required 
             (2 to 5 痢/kg/minute, not more than 10 痢/kg/minute). 
             Monitoring of central venous pressure, and if possible
             pulmonary artery pressures is indicated (Swan-Ganz
             catheter).
    
             Papilledema or other signs of cerebral edema (Wright &
             Roscoe, 1970) may indicate the need for mannitol 20%.
    
             Correct acidosis.

        10.3 Decontamination

             Since ingestion is the route of poisoning only
             decontamination of the gastrointestinal tract should be
             considered.
    
             Induce vomiting and perform gastric lavage within the first
             four hours following ingestion, but only in the conscious
             patient.  If the patient is drowsy or comatose, gastric
             lavage should be done after endotracheal intubation. 
             Activated charcoal and cathartics should be given, unless
             contraindicated (Ellenhorn & Barceloux, 1988).

        10.4 Enhanced elimination

             Forced diuresis does to enhance elimination of
             glutethimide (Wright & Roscoe, 1970). Haemodialysis (even
             using oil as the dialyzing fluid), (Chazan & Garella, 1971);
             and haemoperfusion through charcoal column (Koffler et al.,
             1978) or resin column (Raja, 1986) have not proved effective. 
             Experience at the Warsaw Poison Centre with oil haemodialysis
             and charcoal haemoperfusion is not convincing.

        10.5 Antidote treatment

             10.5.1 Adults

                    No antidote available.

             10.5.2 Children

                    No antidote available.

        10.6 Management discussion

             Supportive treatment is essential for the successful
             management of acute glutethimide poisoning.
    
             The prognosis is favourable even in severe cases but the
             possibility of mixed poisoning must always be
             considered.

    11. ILLUSTRATIVE CASES

        11.1 Case reports from literature

             The most recent publications have reviewed many cases
             of acute poisoning and their conclusions are included in this
             monograph (Wright & Roscoe, 1970; Chazan & Garella, 1971). 
             Short descriptions and discussion of particular cases will be
             presented under 11.2.  Only two cases of chronic poisoning
             are mentioned here.
    
             Case 1 (Nover, 1967):  A 37 year-old woman was treated with
             glutethimide, up to 5 g per day, for five years.  She
             developed sensory neuropathy with glove-and-stocking
             paraesthesias and noted poor recent memory and calculating
             ability.  She felt very weak, was unable to stand or walk
             unaided and complained of ataxia.  Neurological examination
             found absent position, vibration, light touch, and pin prick
             sensations distally in all four extremities.  Decreased nerve
             conduction velocity was found.  Glutethimide was withdrawn
             over 20 days despite a grand mal seizure occurring when the
             patient was changed to phenobarbital.  Even two weeks after
             the complete withdrawal of glutethimide the patient was
             unable to walk or stand without assistance and complained of
             paraesthesias.  Sensory findings were somewhat improved but
             some symptoms and signs persisted for several months.
    
             Case 2 (Pearson, 1965):  A 47-year-old man was treated with
             100 to 400 mg of glutethimide for five years and developed
             megaloblastic anaemia with haemoglobin value as low as 6 g/dL
             and megaloblastic hyperplasia in the bone marrow. 
             Discontinuation of glutethimide and administration of folic
             acid resulted in normalization of the peripheral blood and
             bone marrow.

    12. ADDITIONAL INFORMATION

        12.1 Specific preventive measures

             Since there are safer hypnotic drugs currently
             available, it seems, there is no reason to continue the use
             of glutethimide.

        12.2 Other

             No data available.

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

        Author:     Janusz Szajewski, MD
                    Warsaw Poison Control Centre
                    Szpital Praski III Oddzial
                    Chorob Wewnetrznych
                    Al. Swierczewskiego 67
                    03-701 Warsaw
                    Poland
    
        Date:       August 1992
    
        Peer
        Review:     London, United Kingdom, September 1992
                    (Members of the Group: M. Balali-Mood, J. Szajewski,
                    O. Kasilo, A. Wong, J.F. Deng, J. Higa, S.
                    Shintani)
    
        IPCS
        update:     May 1994
    
        Author
        Section 8:  Dr S. 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. Dum幯il
                    International Programme on Chemical Safety
    
        Date:       May 1999