Etizolam (PIM 926) (original) (raw)

Etizolam

International Programme on Chemical Safety
Poisons Information Monograph 926
Pharmaceutical

This monograph does not contain all of the sections completed. This
mongraph is harmonised with the Group monograph on Benzodiazepines
(PIM G008).

1.  NAME

    1.1  Substance

         Etizolam

    1.2  Group

         ATC classification index

         Psycholeptics (N05)/  Anxiolytics (N05B)/
         Benzodiazepine derivatives (N05BA)

    1.3  Synonyms

         AHR-3219; Y-7131

    1.4  Identification numbers

         1.4.1  CAS number

                40054-69-1

         1.4.2  Other numbers

    1.5  Main brand names, main trade names

         Depas; Pasaden

    1.6  Main manufacturers, main importers

2.  SUMMARY

    2.1  Main risks and target organs

         Central nervous system, causing depression of
         respiration and consciousness.

    2.2  Summary of clinical effects

         Central nervous system (CNS) depression and coma, or
         paradoxical excitation, but deaths are rare when
         benzodiazepines are taken alone. Deep coma and other

         manifestations of severe CNS depression are rare. Sedation,
         somnolence, diplopia, dysarthria, ataxia and intellectual
         impairment are the most common adverse effects of
         benzodiazepines. Overdose in adults frequently involves co-
         ingestion of other CNS depressants, which act synergistically
         to increase toxicity. Elderly and very young children are
         more susceptible to the CNS depressant action. Intravenous
         administration of even therapeutic doses of benzodiazepines
         may produce apnoea and hypotension.
         Dependence may develop with regular use of benzodiazepines,
         even in therapeutic doses for short periods. If
         benzodiazepines are discontinued abruptly after regular use,
         withdrawal symptoms may develop.  The amnesia produced by
         benzodiazepines can have medico-legal consequences.

    2.3  Diagnosis

         The clinical diagnosis is based upon the history of
         benzodiazepine overdose and the presence of the clinical
         signs of benzodiazepine intoxication.
         Benzodiazepines can be detected or measured in blood and
         urine using standard analytical methods. This information may
         confirm the diagnosis but is not useful in the clinical
         management of the patient.
         A clinical response to flumazenil, a specific benzodiazepine
         antagonist, also confirms the diagnosis of benzodiazepine
         overdose, but administration of this drug is rarely
         justified.

    2.4  First aid measures and management principles

         Most benzodiazepine poisonings require only clinical
         observation and supportive care. It should be remembered that
         benzodiazepine ingestions by adults commonly involve co-
         ingestion of other CNS depressants and other drugs. Activated
         charcoal normally provides adequate gastrointestinal
         decontamination. Gastric lavage is not routinely indicated.
         Emesis is contraindicated. The use of flumazenil is reserved
         for cases with severe respiratory or cardiovascular
         complications and should not replace the basic management of
         the airway and respiration. The routine use of flumazenil is
         contraindicated because of potential complications, including
         seizures.  Renal and extracorporeal methods of enhanced
         elimination are not effective.

3.  PHYSICO-CHEMICAL PROPERTIES

    3.1  Origin of the substance

    3.2  Chemical structure

         Chemical Name:
         4-(2-Chlorophenyl)-2-ethyl-9-methyl-6H-thieno(3,2-f)-s-
         triazolo(4,3-a) (1,4)diazepine

         Molecular Formula: C17H15ClN4S

         Molecular Weight: 342.9

    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 EXPOSURE

    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 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
                         "Basic analyses"
                         "Dedicated analyses"
                         "Optional analyses"
                8.3.1.2  Urine
                         "Basic analyses"
                         "Dedicated analyses"
                         "Optional analyses"
                8.3.1.3  Other fluids
         8.3.2  Arterial blood gas analyses
         8.3.3  Haematological analyses
                "Basic analyses"
                "Dedicated analyses"
                "Optional analyses"
         8.3.4  Interpretation of biomedical investigations

    8.4  Other biomedical (diagnostic) investigations and their
         interpretation

    8.5  Overall interpretation of all toxicological analyses and
         toxicological investigations

         Sample collection
         For toxicological analyses: whole blood 10 mL; urine 25 mL
         and gastric contents 25 mL.

         Biomedical analysis
         Blood gases, serum electrolytes, blood glucose and hepatic
         enzymes when necessary in severe cases.

         Toxicological analysis
         Qualitative testing for benzodiazepines is helpful to confirm
         their presence, but quantitative levels are not clinically
         useful. More advanced analyses are not necessary for the
         treatment of the poisoned patient due the lack of correlation
         between blood concentrations and clinical severity (Jatlow et
         al., 1979; MacCormick et al., 1985; Minder, 1989).

         TLC and EMIT: These provide data on the presence of
         benzodiazepines, their metabolites and possible associations
         with other drugs.

         GC or HPLC: These permit identification and quantification of
         the benzodiazepine which caused the poisoning and its
         metabolites in blood and urine.

    8.6  References

9.  CLINICAL EFFECTS

    9.1  Acute poisoning

         9.1.1  Ingestion

                The onset of impairment of consciousness is
                relatively rapid in benzodiazepine poisoning.  Onset
                is more rapid following larger doses and with agents
                of shorter duration of action. The most common and
                initial symptom is somnolence.  This may progress to
                coma Grade I or Grade II (see below) following very
                large ingestions.

                Reed Classification of Coma (Reed et al., 1952)

                Coma Grade I:   Depressed level of consciousness,
                                response to  painful stimuli
                                Deep tendon reflexes and vital signs
                                intact

                Coma Grade II:  Depressed level of consciousness, no
                                response to painful stimuli
                                Deep tendon reflexes and vital signs
                                intact

                Coma Grade III: Depressed level of consciousness, no
                                response to painful stimuli
                                Deep tendon reflexes absent. Vital
                                signs intact

                Coma Grade IV:  Coma grade III plus respiratory and
                                circulatory collapse

         9.1.2  Inhalation

                Not relevant.

         9.1.3  Skin exposure

                No data.

         9.1.4  Eye contact

                No data.

         9.1.5  Parenteral exposure

                Overdose by the intravenous route results in
                symptoms similar to those associated with ingestion,
                but they appear immediately after the infusion, and
                the progression of central nervous system (CNS)
                depression is more rapid. Acute intentional poisoning

                by this route is uncommon and most cases are
                iatrogenic. Rapid intravenous infusion may cause
                hypotension, respiratory depression and
                apnoea.

         9.1.6  Other

    9.2  Chronic poisoning

         9.2.1  Ingestion

                Toxic effects associated with chronic exposure
                are secondary to the presence of the drug and
                metabolites and include depressed mental status,
                ataxia, vertigo, dizziness, fatigue, impaired motor
                co-ordination, confusion, disorientation and
                anterograde amnesia. Paradoxical effects of
                psychomotor excitation, delirium and aggressiveness
                also occur. These chronic effects are more common in
                the elderly, children and patients with renal or
                hepatic disease.

                Administration of therapeutic doses of benzodiazepines
                for 6 weeks or longer can result in physical
                dependence, characterized by a withdrawal syndrome
                when the drug is discontinued. With larger doses, the
                physical dependence develops more rapidly.

         9.2.2  Inhalation

                No data.

         9.2.3  Skin exposure

                No data.

         9.2.4  Eye contact

                No data.

         9.2.5  Parenteral exposure

                The chronic parenteral administration of
                benzodiazepines may produce thrombophlebitis and
                tissue irritation, in addition to the usual symptoms
                (Greenblat & Koch-Weser, 1973).

         9.2.6  Other

                No data.

    9.3  Course, prognosis, cause of death

         Benzodiazepines are relatively safe drugs even in
         overdose. The clinical course is determined by the
         progression of the neurological symptoms. Deep coma or other
         manifestations of severe central nervous system (CNS)
         depression are rare with benzodiazepines alone.  Concomitant
         ingestion of other CNS depressants may result in a more
         severe CNS depression of longer duration.

         The therapeutic index of the benzodiazepines is high and the
         mortality rate associated with poisoning due to
         benzodiazepines alone is very low. Complications in severe
         poisoning include respiratory depression and aspiration
         pneumonia. Death is due to respiratory arrest.

    9.4  Systematic description of clinical effects

         9.4.1  Cardiovascular

                Hypotension, bradycardia and tachycardia have
                been reported with overdose (Greenblatt et al., 1977;
                Meredith & Vale 1985). Hypotension is more frequent
                when benzodiazepines are ingested in association with
                other drugs (Hojer et al., 1989). Rapid intravenous
                injection is also associated with hypotension.

         9.4.2  Respiratory

                Respiratory depression may occur in
                benzodiazepine overdose and the severity depends on
                dose ingested, amount absorbed, type of benzodiazepine
                and co-ingestants. Respiratory depression requiring
                ventilatory support has occurred in benzodiazepine
                overdoses (Sullivan, 1989; Hojer et al.,1989). The
                dose-response for respiratory depression varies
                between individuals.  Respiratory depression or
                respiratory arrest may rarely occur with therapeutic
                doses. Benzodiazepines may affect the control of
                ventilation during sleep and may worsen sleep apnoea
                or other sleep-related breathing disorders, especially
                in patients with chronic obstructive pulmonary disease
                or cardiac failure (Guilleminault, 1990).

         9.4.3  Neurological

                9.4.3.1  Central nervous system (CNS)

                         CNS depression is less marked than
                         that produced by other CNS depressant agents
                         (Meredith & Vale, 1985). Even in large
                         overdoses, benzodiazepines usually produce
                         only mild symptoms and this distinguishes

                         them from other sedative-hypnotic agents.
                         Sedation, somnolence, weakness, diplopia,
                         dysarthria, ataxia and intellectual
                         impairment are the most common neurological
                         effects. The clinical effects of severe
                         poisoning are sleepiness, ataxia and coma
                         Grade I to Grade II (Reed). The presence of
                         more severe coma suggests the possibility of
                         co-ingested drugs. Certain of the newer
                         short-acting benzodiazepines (temazepam,
                         alprazolam and triazolam) have been
                         associated with several fatalities and it is
                         possible that they may have greater acute
                         toxicity (Forrest et al., 1986). The elderly
                         and very young children are more susceptible
                         to the CNS depressant action of
                         benzodiazepines.
                         The benzodiazepines may cause paradoxical CNS
                         effects, including excitement, delirium and
                         hallucinations. Triazolam has been reported
                         to produce delirium, toxic psychosis, memory
                         impairment and transient global amnesia
                         (Shader & Dimascio, 1970; Bixler et al,
                         1991). Flurazepam has been associated with
                         nightmares and hallucinations.
                         There are a few reports of extrapyramidal
                         symptoms and dyskinesias in patients taking
                         benzodiazepines (Kaplan & Murkafsky, 1978;
                         Sandyk, 1986).
                         The muscle relaxation caused by
                         benzodiazepines is of CNS origin and
                         manifests as dysarthria, incoordination and
                         difficulty standing and walking.

                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

                Oral benzodiazepine poisoning will produce
                minimal effects on the gastrointestinal tract (GI)
                tract but can occasionally cause nausea or vomiting
                (Shader & Dimascio, 1970).

         9.4.5  Hepatic

                A case of cholestatic jaundice due focal
                hepatic necrosis was associated with the
                administration of diazepam (Tedesco & Mills,
                1982).

         9.4.6  Urinary

                9.4.6.1  Renal

                         Vesical hypotonia and urinary
                         retention has been reported in association
                         with diazepam poisoning (Chadduck et al.,
                         1973).

                9.4.6.2  Other

         9.4.7  Endocrine and reproductive systems

                Galactorrhoea with normal serum prolactin
                concentrations has been noted in 4 women taking
                benzodiazepines (Kleinberg et al., 1977).
                Gynaecomastia has been reported in men taking high
                doses of diazepam (Moerck & Majelung, 1979). Raised
                serum concentrations of oestrodiol were observed in
                men taking diazepam 10 to 20 mg daily for 2 weeks
                (Arguelles & Rosner, 1975).

         9.4.8  Dermatological

                Bullae have been reported following overdose
                with nitrazepam and oxazepam (Ridley, 1971; Moshkowitz
                et al., 1990).
                Allergic skin reactions were attributed to diazepam at
                a rate of 0.4 per 1000 patients (Brigby,
                1986).

         9.4.9  Eye, ear, nose, throat: local effects

                Brown opacification of the lens occurred in 2
                patients who used diazepam for several years (Pau
                Braune, 1985).

         9.4.10 Haematological

                No data.

         9.4.11 Immunological

                Allergic reaction as above (see 9.4.8).

         9.4.12 Metabolic

                9.4.12.1 Acid-base disturbances

                         No direct disturbances have been
                         described.

                9.4.12.2 Fluid and electrolyte disturbances

                         No direct disturbances have been
                         described.

                9.4.12.3 Others

         9.4.13 Allergic reactions

                Hypersensitivity reactions including
                anaphylaxis are very rare (Brigby, 1986). Reactions
                have been attributed to the vehicle used for some
                parenteral diazepam formulations (Huttel et al.,
                1980). There is also a report of a type I
                hypersensitivity reaction to a lipid emulsion of
                diazepam (Deardon, 1987).

         9.4.14 Other clinical effects

                Hypothermia was reported in 15% of cases in
                one series. (Martin, 1985; Hojer et al., 1989).

         9.4.15 Special risks

                Pregnancy
                Passage of benzodiazepines across the placenta depends
                on the degree of protein binding in mother and fetus,
                which is influenced by factors such as stage of
                pregnancy and plasma concentrations of free fatty
                acids in mother and fetus (Lee et al., 1982). Adverse
                effects may persist in the neonate for several days
                after birth because of immature drug metabolising
                enzymes. Competition between diazepam and bilirubin
                for protein binding sites could result in
                hyperbilirubinemia in the neonate (Notarianni,
                1990).
                The abuse of benzodiazepines by pregnant women can
                cause withdrawal syndrome in the neonate. The
                administration of benzodiazepines during childbirth
                can produce hypotonia, hyporeflexia, hypothermia and
                respiratory depression in the newborn.
                Benzodiazepines have been used in pregnant patients
                and early reports associated diazepam and
                chlordiazepoxide with some fetal malformations, but
                these were not supported by later studies (Laegreid et
                al., 1987; McElhatton, 1994).


                Breast feeding
                Benzodiazepines are excreted in breast milk in
                significant amounts and may result in lethargy and
                poor feeding in neonates.  Benzodiazepines should be
                avoided in nursing mothers (Brodie, 1981; Reynolds,
                1996).

    9.5  Other

         Dependence and withdrawal
         Benzodiazepines have a significant potential for abuse and
         can cause physical and psychological dependence. Abrupt
         cessation after prolonged use causes a withdrawal syndrome
         (Ashton, 1989). The mechanism of dependence is probably
         related to functional deficiency of GABA activity.
         Withdrawal symptoms include anxiety, insomnia, headache,
         dizziness, tinnitus, anorexia, vomiting, nausea, tremor,
         weakness, perspiration, irritability, hypersensitivity to
         visual and auditory stimuli, palpitations, tachycardia and
         postural hypotension. In severe and rare cases of withdrawal
         from high doses, patients may develop affective disorders or
         motor dysfunction: seizures, psychosis, agitation, confusion,
         and hallucinations (Einarson, 1981; Hindmarch et al, 1990;
         Reynolds, 1996).
         The time of onset of the withdrawal syndrome depends on the
         half-life of the drug and its active metabolites; the
         symptoms occur earlier and may be more severe with short-
         acting benzodiazepines. Others risk factors for withdrawal
         syndrome include prolonged use of the drug, higher dosage and
         abrupt cessation of the drug.

         Abuse
         Benzodiazepines, particularly temazepam, have been abused
         both orally and intravenously (Stark et al., 1987; Woods,
         1987; Funderburk et al, 1988)

         Criminal uses
         The amnesic effects of benzodiazepines have been used for
         criminal purposes with medicolegal consequences (Ferner,
         1996).

    9.6  Summary

10. MANAGEMENT

    10.1 General principles

         Most benzodiazepine poisonings require only clinical
         observation and supportive care. It should be remembered that
         benzodiazepine ingestions by adults commonly include other
         drugs and other CNS depressants. Activated charcoal normally
         provides adequate gastrointestinal decontamination. Gastric
         lavage is not routinely indicated. Emesis is contraindicated.

         The use of flumazenil is reserved for cases with severe
         respiratory or cardiovascular complications and should not
         replace the basic management of the airway and respiration.
         Renal and extracorporeal elimination methods are not
         effective.

    10.2 Life supportive procedures and symptomatic/specific treatment

         The patient should be evaluated to determine adequacy
         of airway, breathing and circulation. Continue clinical
         observation until evidence of toxicity has resolved.
         Intravenous access should be available for administration of
         fluid. Endotracheal intubation, assisted ventilation and
         supplemental oxygen may be required on rare occasions, more
         commonly when benzodiazepines are ingested in large amounts
         or with other CNS depressants.

    10.3 Decontamination

         Gastric lavage is not routinely indicated following
         benzodiazepine overdose. Emesis is contraindicated because of
         the potential for CNS depression. Activated charcoal can be
         given orally.

    10.4 Enhanced elimination

         Methods of enhancing elimination are not
         indicated.

    10.5 Antidote treatment

         10.5.1 Adults

                Flumazenil, a specific benzodiazepine
                antagonist at central GABA-ergic receptors is
                available. Although it effectively reverses the CNS
                effects of benzodiazepine overdose, its use in
                clinical practice is rarely indicated.
                Use of Flumazenil is specifically contraindicated when
                there is history of co-ingestion of tricyclic
                antidepressants or other drugs capable of producing
                seizures (including aminophylline and cocaine),
                benzodiazepine dependence, or in patients taking
                benzodiazepines as an anticonvulsant agent. In such
                situations, administration of Flumazenil may
                precipitate seizures (Lopez, 1990; Mordel et al.,
                1992).
                Adverse effects associated with Flumazenil include
                hypertension, tachycardia, anxiety, nausea, vomiting
                and benzodiazepine withdrawal syndrome.
                The initial intravenous dose of 0.3 to 1.0 mg may be
                followed by further doses if necessary. The absence of
                clinical response to 2 mg of flumazenil within 5 to 10

                minutes indicates that benzodiazepine poisoning is not
                the major cause of CNS depression or coma.
                The patient regains consciousness within 15 to 30
                seconds after injection of flumazenil, but since it is
                metabolised more rapidly than the benzodiazepines,
                recurrence of toxicity and CNS depression can occur
                and the patient should be carefully monitored after
                initial response to flumazenil therapy.  If toxicity
                recurs, further bolus doses may be administered or an
                infusion commenced at a dose of 0.3 to 1.0 mg/hour
                (Meredith et al., 1993).

         10.5.2 Children

                The initial intravenous dose of 0.1 mg should
                be repeated each minute until the child is awake.
                Continuous intravenous infusion should be administered
                at a rate of 0.1 to 0.2 mg/hour (Meredith et al.,
                1993).

    10.6 Management discussion

         Most benzodiazepine poisonings require only clinical
         observation and supportive care. Flumazenil is the specific
         antagonist of the effects of benzodiazepines, but the routine
         use for the treatment of benzodiazepine overdosage is not
         recommended. The use of Flumazenil should only be considered
         where severe CNS depression is observed. This situation
         rarely occurs, except in cases of mixed ingestion. The
         administration of flumazenil may improve respiratory and
         cardiovascular function enough to decrease the need for
         intubation and mechanical ventilation, but should never
         replace basic management principles.
         Flumazenil is an imidazobenzodiazepine and has been shown to
         reverse the sedative, anti-convulsant and muscle-relaxant
         effects of benzodiazepines. In controlled clinical trials,
         flumazenil significantly antagonizes benzodiazepine-induced
         coma arising from anaesthesia or acute overdose. However, the
         use of flumazenil has not been shown to reduce mortality or
         sequelae in such cases.
         The administration of flumazenil is more effective in
         reversing the effects of benzodiazepines when they are the
         only drugs producing CNS toxicity. Flumazenil does not
         reverse the CNS depressant effects of non-benzodiazepine
         drugs, including alcohol. The diagnostic use of flumazenil in
         patients presenting with coma of unknown origin can be
         justified by its high therapeutic index and the fact that
         this may limit the use of other diagnostic procedures (CT
         scan, lumbar puncture, etc).
         Flumazenil is a relatively expensive drug and this may also
         influence its use, especially in areas with limited
         resources.

11. ILLUSTRATIVE CASES

    11.1 Case reports from literature

12. Additional information

    12.1 Specific preventive measures

    12.2 Other

13. REFERENCES

    Arguelles AE, & Rosner J. (1975) Diazepam and plasma
    testosterone levels. Lancet, ii: 607.

    Ashton CH (1989) Drug-induced stupor and coma: some physical signs
    and their pharmacological basis. Adverse drug React Acute
    Poisoning Rev, 8: 1-59.

    Bixler EO, Kales A, Manfredi RL, Vgontzas AN, Tyson KL, & Kales JD
    (1991)  Next-day memory impairment with triazolam use.  Lancet,
    337: 827-831.

    Brigby M. (1986) Drug induced cutaneous reactions. JAMA, 256:
    3358-63.

    Brodie RR, Chasseaud LF & Taylor T (1981) Concentrations of N-
    descyclopropylmethyl-prazepam in whole-blood, plasma and milk
    after administration of prazepam to humans. Biopharm Drug Dispos,
    2: 59-68.

    Chadduck WM, Loar CR & Denton IC. (1973)  Vesical hypotonicity
    with diazepam. J Urol, 109: 1005-1007.

    Deardon DJ. (1987) Acute hypersensivity to IV Diazulmuls. Br J
    Anaesth,  59: 391.

    Einarson TR (1981) Oxazepam withdrawal convulsions.  Drug Intell
    Clin Pharm, 15: 487.

    Ellenhorn, M. (1996) Medical Toxicology. 2nd Ed., Elsevier.

    Ferner RE (1996) Forensic Pharmacology, 1st Ed. Oxford University
    Press, Oxford.

    Forrest ARW, Marsh I, Bradshaw C & Braich SK (1986) Fatal
    temazepam overdoses (letter).  Lancet, 2: 226.

    Funderburk FR, Griffiths RR, McLeod DR, Bigelow GE, Mackenzie A,
    Liebson IA & Newmeth-Coslett R (1988) Relative abuse liability of
    lorazepam and diazepam:  an evaluation in "recreational" drug
    users.  Drug Alcohol Depend, 22: 215-222.


    Greenblatt DJ, Allen MD, Noel BJ et al (1977) Acute overdose with
    benzodiazepine derivatives.  Clin Pharm Ther,  21: 497-513.

    Guilleminault C. (1990)  Benzodiazepines, bresthing and sleep.  Am
    J Med, 88 (suppl 3A): 25S - 28S.

    Hindmarch I, Beaumont G, Brandon S, & Leonard, B. (1990) 
    Benzodiazepines Current Concepts, John Wiley & Sons Ltd, UK.

    Hojer J, Baehrendtz S & Gustafsson L. (1989) Benzodiazepine
    poisoning: experience of 702 admissions to an intensive care unit
    during a 14-year period.  J Intern Med, 226: 117-122.

    Huttel MS, Schou Olesen A & Stofferson E (1980) Complement-
    mediated reactions to diazepam with Cremophor as solvent. Br J
    Anaesth,  52:  77-9.

    Hyams SW & Keroub C (1977) Glaucoma due to diazepam. Am J
    Psychiatry, 134: 477-479.

    Kaplan SR, & Murkofsky C (1978) Oral-buccal dyskinesic synptoms
    associated with low dose benzodiazepine treatment. Am J
    Psychiatry, 135: 1558-1559.

    Kleinberg DL, Noel GL & Frantz AG (1977) Galactorrhea a study of
    235 cases. N Eng J Med  296: 589-600.

    Laegreid L, Olegard R, & Wahlstrom J (1987) Abnormalities in
    children exposed to benzodiazepines in utero.  Lancet, 1:108-
    109.

    Lee JN, Chen SS, Richens A, Menabawey m & Chard T (1982) Serum
    protein binding of diazepam in maternal and foetal serum during
    pregnancy. Br J Clin Pharmacol, 14: 551-4.

    Lopez A & Rebollo J (1990) Benzodiazepine withdrawal syndrome
    after a benzodiazepine antagonist.  Crit Care Med, 18:1480-
    1481.

    Martin SM (1985) The effect of diazepam on body temperature change
    in humans during cold exposure. J Clin Pharmacol,  25: 611-
    613.

    McCormick SR, Nielsen J & Jatlow PI (1985) Alprazolam overdose:
    clinical findings and serum concentrations in two cases.  J Clin
    Psychiatr,  46:247-248.

    McElhatton PR. (1994) The effects of benzodiazepines use during
    pregnancy and lactation. Reprod Toxicol,  8: 461-75.


    Meredith TJ, Jacobsen D, Haines JA, Berger JC (1993) IPCS/CEC
    Evaluation of Antidotes Series, Vol1, Naloxone, flumazenil and
    dantrolene as antidotes, 1st ed. Cambridge University Press,
    Cambridge.

    Meredith TJ, & Vale JA (1985) Poisoning due to psychotropic
    agents. Adverse Drug React Acute Poison Rev,  4: 83-122.

    Minder EI (1989) Toxicity in a case of acute and massive overdose
    of chlordiazepoxide and its correlation to blood concentration. 
    Clin Toxicol,  27: 117-127.

    Moerck HJ, Majelung G (1979) Gynaecomastia and diazepam abuse.
    Lancet, i: 1344-5.

    Mordel A, Winkler E, Almog S, Tirosh M & Ezra D (1992) Seizures
    after flumazenil administration in a case of combined
    benzodiazepine and tricyclic antidepressant overdose. Crit Care
    Med,  12: 1733-1734.

    Notarianni LJ. (1990) Plasma protein binding of drugs in pregnancy
    and neonates. Clin Pharnacokinet, 18: 20-36.

    Pau Braune H (1985) [Eyes effect of diazepam.] Klin Monatsbl
    Augenheilkd, 187: 219-20 (in German).

    Reed C E, Driggs M F, & Foote CC (1952) Acute barbiturate
    intoxication. A study of 300 cases based on a physiologic system
    of classification of the severity of intoxication. Ann Intern Med,
    37: 390-396.

    Reynolds J (1996) Martindale, The Extra Pharmacopeia. 30th ed. The
    Pharmaceutical Press, London, 699-744.

    Ridley CM (1971)  Bullous lesions in nitrazepan overdosage. Br Med
    J,  3: 28-29.

    Sandyk R (1986) Orofacial diskynesias associated with lorazepam
    therapy. Clin Pharm,  5: 419-21.

    Shader RI & Dimascio A (1970) Psychotropic drug side effects, 1st
    ed. Willians & Wilkins, Baltimore.

    Stark C, Sykes R & Mullin P (1987)  Temazepam abuse (letter).
    Lancet,  2:802-803.

    Sullivan RJ Jr (1989) Respiratory depression requiring ventilatory
    support following 0.5 mg of Triazolam. J Am Geriatr,  Soc  37:
    450-452.

    Tedesco FJ, & Mills LR. (1982) Diazepam hepatites. Dig Dis Sci 27:
    470-2.

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

    Author:           Dr Ligia Fruchtengarten
                      Poison Control Centre of Sao Paulo  -  Brazil
                      Hospital Municipal Dr Arthur Ribeiro de Saboya -
                      Coperpas 12
                      FAX / Phone:   55  11  2755311
                      E-mail:   lfruchtengarten@originet.com.br

    Mailing Address:  Hospital Municipal Dr Arthur Ribeiro de Saboya -
                      Coperpas 12
                      Centro de Controle de Intoxica�oes de Sao Paulo
                      Av Francisco de Paula Quintanilha Ribeiro, 860
                      04330 - 020   Sao Paulo  -  SP  -  Brazil.

    Date:             July 1997

    Peer Review:      INTOX 10 Meeting, Rio de Janeiro, Brazil,
                      September 1997.
                      R. Ferner, L. Murray (Chairperson), M-O.
                      Rambourg, A. Nantel,  N. Ben Salah, M. Mathieu-
                      Nolf, A.Borges.

    Review 1998:      Lindsay Murray
                      Queen Elizabeth II Medical Centre
                      Perth, Western Australia.

    Editor:           Dr M.Ruse, April 1998

See Also:
   [Toxicological Abbreviations](../../eintro/eintro/abreviat.htm)