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Amodiaquine Hydrochloride

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 Brand names, Trade names
   1.6 Manufacturers, 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 Properties of the substance
      3.3.2 Properties of the locally available formulation
   3.4 Other characteristics
      3.4.1 Shelf-life of the substance
      3.4.2 Shelf-life of the locally available formulation
      3.4.3 Storage conditions
      3.4.4 Bioavailability
      3.4.5 Specific properties and composition
4. USES
   4.1 Indications
   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
   8.4 Other biomedical (diagnostic) investigations and their interpretation
   8.5 Overall Interpretation of all toxicological analyses and toxicological investigations
   8.6 References
9. CLINICAL EFFECTS
   9.1 Acute poisoning
      9.1.1 Ingestion
      9.1.2 Inhalation
      9.1.3 Skin exposure
      9.1.4 Eye contact
      9.1.5 Parenteral exposure
      9.1.6 Other
   9.2 Chronic poisoning
      9.2.1 Ingestion
      9.2.2 Inhalation
      9.2.3 Skin exposure
      9.2.4 Eye contact
      9.2.5 Parenteral exposure
      9.2.6 Other
   9.3 Course, prognosis, cause of death
   9.4 Systematic description of clinical effects
      9.4.1 Cardiovascular
      9.4.2 Respiratory
      9.4.3 Neurological
         9.4.3.1 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 Relevant laboratory analyses
      10.2.1 Sample collection
      10.2.2 Biomedical analysis
      10.2.3 Toxicological analysis
      10.2.4 Other investigations
   10.3 Life supportive procedures and symptomatic/specific treatment
   10.4 Decontamination
   10.5 Elimination
   10.6 Antidote treatment
      10.6.1 Adults
      10.6.2 Children
   10.7 Management discussion
11. ILLUSTRATIVE CASES
   11.1 Case reports from literature
   11.2 Internally extracted data on cases
   11.3 Internal cases
12. Additional information
   12.1 Availability of antidotes
   12.2 Specific preventive measures
   12.3 Other
13. REFERENCES
14. AUTHOR(S), REVIEWER(S), DATE(S) (INCLUDING UPDATES), COMPLETE ADDRESS(ES)
    PHARMACEUTICALS
    1. NAME
     1.1 Substance
       Amodiaquine Hydrochloride (INN)
     1.2 Group
       Antimalarials:  4-aminoquinolines
     1.3 Synonyms
       Amodiachin Hydrochloride
       Amodiaquini Hydrochloridum
     1.4 Identification numbers
       1.4.1 CAS number
             86-42-0
       1.4.2 Other numbers
             6398-98-7 (amodiaquine dihydrochloride, dihydrate)
             69-44-3 (amodiaquine hydrochloride, anhydrous)
     1.5 Brand names, Trade names
       Basoquin
       CAM-AQ1
       Camoquin
       Camoquinal
       Flavoquin
       Fluroquine
       Miaquin
       SN-10,751
       
       Formulations containing combinations of amodiaquine and other 
       antimalarial drugs are also available, e.g. Camoprima Infatabs 
       (containing 75 mg amodiaquine + 15 mg primaquine).
     1.6 Manufacturers, Importers
       Basoquin (Parke, Davis, UK)
       Camoquin (Parke, Davis, Spain, Switzerland, UK)
       Flavoquin (Roussel, France)
    2. SUMMARY
     2.1 Main risks and target organs
       After oral administration amodiaquine hydrochloride is rapidly 
       absorbed,and undergoes rapid and extensive metabolism to 
       desethylamodiaquine which concentrates in red blood cells.  It 
       is likely that desethylamodiaquine, not amodiaquine, is 
       responsible for most of the observed antimalarial activity, 
       and that the toxic effects of amodiaquine after oral 
       administration may in part be due to desethylamodiaquine.
       
       Chloroquine, a 4-aminoquinoline derivative which resembles 
       amodiaquine structurally, is widely distributed into the body 
       tissues, especially in liver, spleen, kidney, lungs, brain, 
       and spinal cord.  It binds to melanin-containing cells in the 
       eyes and skin.  In the blood, chloroquine concentrates in the 
       erythrocytes and binds to platelets and leucocytes.  Since the 
       structure and spectrum of activity of these two 4-
       aminoquinoline derivatives are very similar, it is likely that 
       the distribution of desethylamodiaquine in man mirrors that of 
       chloroquine.
     2.2 Summary of clinical effects
       Gastrointestinal tract:  anorexia, nausea, vomiting, diarrhoea,
        melanosis
       

       Haematopoietic system:  leucopenia, agranulocytosis, aplastic 
       anaemia, pancytopenia
         
       Liver:  toxic hepatitis
       
       Skin:  lichenoid reaction, urticaria, pigmentation of mucous 
       membranes and skin
       
       Nervous system & muscles:  hallucinations, neuronitis, 
       polymyositis
       
       Eye:  corneal irritation, keratitis, retinitis, retinal 
       degeneration 
       
       Heart:  heart block
       
       The usual signs and symptoms of an overdose are headache, 
       vertigo and vomiting; the more severe manifestations including 
       cardiac arrhythmias, convulsions and coma.  The most dramatic 
       feature is visual disturbance, including sudden loss of vision,
        which is usually transitory.
       
       Other symptoms include itching, cardiovascular abnormalities, 
       dyskinesia, neuromuscular and haematological disorders, and 
       hearing loss.
     2.3 Diagnosis
       Nausea, vomiting, diarrhoea, headache, drowsiness, blurred 
       vision, blindness, convulsions, coma, hypotension, cardiac 
       arrhythmias, cardiac arrest and impaired respiration are the 
       characteristic features of amodiaquine poisoning.
       
       Electrocardiography (ECG) may show inverted or flattened T 
       waves, widening of QRS, ventricular tachycardia and 
       fibrillation.
       
       Hypokalaemia may be present.
       
       High serum amodiaquine levels confirm the diagnosis.  
     2.4 First aid measures and management principles
       Treatment of overdosage is supportive and must be prompt since 
       acute toxicity can progress rapidly, possibly leading to 
       vascular collapse and respiratory and cardiac arrest.
       
       Because of the importance of supporting ventilation, early 
       endotracheal intubation and mechanical ventilation may be 
       necessary.  Early gastric lavage followed by administration of 
       activated charcoal may provide some benefit in reducing 
       absorption of the drug.  These should be preceded by measures 
       to correct cardiac and severe ardiovascular disturbances, if 
       present, and by respiratory support.  Diazepam IV may control 
       seizures and other manifestations of CNS stimulation.  
       Seizures caused by anoxia should be corrected by oxygen and 
       other respiratory support.  Defibrillators and cardiac 
       pacemakers may be required.
    3. PHYSICO-CHEMICAL PROPERTIES
     3.1 Origin of the substance

       Synthesised from 4,7-dichloroquinoline and 4-acetamido- -
       diethylamino-o-cresol.  Alternative synthesis from 2-
       aminomethyl-p-aminophenol and 4,7-dichloroquinoline (The Merck 
       Index, 1983).
       
       US patents 2,474,819 : 2,474,821 (1949 to Parke, Davis)
     3.2 Chemical structure
       Aminodiaquine Hydrochloride is 4-[(7-chloro-4-quinolyl)amino]-
       2-[(diethylamino)methyl] phenol dihydrochloride dihydrate.
       
       Structural formula: C20H22ClN3O,2HCl,2H2O 

       STRUCTURAL FORMULA;pim030.bmp

       
       Molecular weight:   464.8
     3.3 Physical properties
       3.3.1 Properties of the substance
             A yellow crystalline powder;  odourless (or 
             almost odourless); with a bitter taste.  
             
             Soluble 1 in 22 parts water
                     1 in 70 parts ethanol (96%)
             Practically insoluble in benzene, chloroform and 
             ether.
             
             A 2% solution in water has a pH of 2.6 - 4.6.
             pH of 1% aqueous solution : 4.0 to 4.8 (Merck, 
             1989)
             
             Decomposition: 150-160 C 
       3.3.2 Properties of the locally available formulation
             To be added by the Poison Control Centre.
     3.4 Other characteristics
       3.4.1 Shelf-life of the substance
             No data available.
       3.4.2 Shelf-life of the locally available formulation
             To be added by the Poison Control Centre.
       3.4.3 Storage conditions
             Store in an air-tight container, in child-resistant 
             packaging out of the reach of children.
       3.4.4 Bioavailability
             To be added by the Poison Control Centre.
       3.4.5 Specific properties and composition
             To be added by the Poison Control Centre.

    4. USES
     4.1 Indications
       For treatment of acute malarial attacks in non-immune 
       subjects.  It is at least as effective as chloroquine, 
       and is effective against some chloroquine-resistant 
       strains, although resistance to amodiaquine has been 
       reported.
       
       Amodiaquine hydrochloride has been tried in the 
       treatment of giardiasis and hepatic amoebiasis.  It has 
       also been tried, with variable success, in the treatment 
       of lepra reactions, lupus erythematosus, rheumatoid 
       arthritis, and urticaria (Martindale, 1989).
     4.2 Therapeutic dosage
       4.2.1 Adults
             For the treatment of acute malarial attacks in non-
             immune subjects: 600 mg of the base, followed by 200 mg 
             after 6 hours, then 400 mg daily on each of the 
             subsequent two days.  Doses may be taken with meals to 
             lessen gastric upset.
             
             A number of variations of this regimen have been used.  
             For partially immune subjects a single dose of 600 mg of 
             the base is often sufficient (Martindale, 1989).
             
             Prophylactic dose: for children 15 years of age and 
             younger: 7 mg base/kg body weight to be given once 
             weekly and continued for six weeks after the last 
             exposure.
             
             Because of the narrow margin between the therapeutic and 
             toxic concentrations in children, amodiaquine should not 
             be administered parenterally in this age group (AHFS, 
             1988) (see section 7.2.1.2).
       4.2.2 Children
     4.3 Contraindications
       The US Center for Disease Control (CDC) has stated that any 
       possible prophylactic advantage that amodiaquine may afford is 
       not justified by the possible risk of agranulocytosis 
       associated with the use of the drug (CDC, 1985).
       
       The manufacturer of Camoquin (Parke-Davis) has advised in a 
       data sheet to health professionals that the prophylactic use 
       of amodiaquine as a first line agent has been restricted to 
       chloroquine-resistant areas (Neftel et al., 1986).  They have 
       also stated that agranulocytosis has occurred in association 
       with the use of amodiaquine in malaria prophylaxis.  Although 
       agranulocytosis has been reported following the sole use of 
       amodiaquine, most cases have occurred when other anti-
       malarials have been taken concurrently.  Therefore, the 
       prescribing physician should assess the advantages and 
       disadvantages of amodiaquine in malaria prophylaxis but if the 
       decision is made to so prescribe the drug, concomitant use 
       with other anti-malarials should be performed to assure that 
       blood values and liver function tests remain within normal 
       limits. 

       
       Because amodiaquine may concentrate in the liver, the drug 
       should be used with caution in patients with hepatic disease 
       or alcoholism, and in patients receiving hepatotoxic drugs.
       
       Children are especially sensitive to 4-aminoquinoline 
       derivatives (see Section 7.2.1.2).  Because of the narrow 
       margin between the therapeutic and toxic concentrations in 
       children, amodiaquine should not be administered parenterally 
       in this age group (AHFS, 1988).
       
       Amodiaquine is contraindicated in patients who are 
       hypersensitive
    5. ROUTES OF ENTRY
     5.1 Oral
       This is the usual route of administration for therapeutic use.
     5.2 Inhalation
       Unknown.
     5.3 Dermal
       Unknown.
     5.4 Eye
       Unknown.
     5.5 Parenteral
       Amodiaquine has been given by both constant rate intravenous 
       injection and constant rate infusion in volunteers and 
       patients (White et al., 1987).
       
       Because of the narrow margin between the therapeutic and toxic 
       concentrations in children, amodiaquine should not be 
       administered parenterally in this age group (AHFS, 1988).
     5.6 Other
       Unknown.
    6. KINETICS
     6.1 Absorption by route of exposure
       Oral
       
       After oral administration amodiaquine hydrochloride is rapidly 
       absorbed, and undergoes rapid and extensive metabolism to 
       desethylamodiaquine which concentrates in blood cells.  It is 
       likely that desethylamodiaquine, not amodiaquine, is 
       responsible for most of the observed antimalarial activity, 
       and that the toxic effects of amodiaquine after oral 
       administration may in part be due to desethylamodiaquine 
       (Winstanley et al., 1987).
     6.2 Distribution by route of exposure
       Oral
       
       After oral administration of amodiaquine (600 mg) to 7 healthy 
       adult males, amodiaquine underwent rapid conversion to 
       desethylamodiaquine. The peak concentration of amodiaquine was 
       32 + 3 ng/ml at 0.5 + 0.03h.  The peak concentrations of 
       amodiaquine in whole blood and packed cells were 60 + 10 and 
       42 + 6 ng/ml respectively, reached at 0.5+ 0.1h in both.  
       Thereafter the concentration of amodiaquine declined rapidly, 
       and was detectable for no more than 8 h.

       
       Mean peak plasma concentration of the metabolite 
       (desethylamodiaquine) was 181 + 26 ng/ml respectively.  Times 
       to peak for whole blood and packed cells were 2.2 + 0.5 and 
       3.6 + 1.1 h respectively (Winstanley et al., 1987).
       
       Although in use for more than 40 year, there exists little 
       information regarding the disposition of amodiaquine in man.  
       Chloroquine, a 4-aminoquinoline derivative which resembles 
       amodiaquine structurally, is widely distributed into the body 
       tissues, especially in liver, spleen, kidney, lungs, brain, 
       and spinal cord.  It binds to melanin-containing cells in the 
       eyes and skin.  In the blood, chloroquine concentrates in the 
       erythrocytes and binds to platelets and leucocytes.  Since the 
       structure and spectrum of activity of these two 4-
       aminoquinoline derivatives are very similar, it is likely that 
       the distribution of desethylamodiaquine (the major active 
       metabolite of amodiaquine) in man mirrors that of chloroquine.
       
       Parenteral
       
       The distribution half times observed after intravenous 
       injection (3 mg base per kg over 10 minutes) to seven healthy 
       adult male volunteers (geometric mean 1.7; range 0.4 to 55 
       minutes) were significantly faster than those observed after 
       intravenous infusion (10 mg base per kg over 4 hours) to 10 
       adult patients with falciparum malaria (geometric mean 22.2;  
       range 5 to 126 minutes).  The plasma concentration time 
       profiles were biphasic.
       
       After bolus injection the apparent volume of the central 
       compartment (1.1; range 0.3 to 3.6 l/kg) was one-quarter of 
       that estimated after the infusion (4.6;  range 0.5 to 29.3 
       l/kg).
       
       The authors of the study suggested that there was probably an 
       additional distribution phase in the malaria patients obscured 
       by the slower rate of infusion:  it was possible that had the 
       volunteers been able to tolerate a larger dose, a triphasic 
       elimination profile may have become apparent (White et al., 
       1987).
     6.3 Biological half-life by route of exposure
       Oral
       
       Amodiaquine 600 mg was given by mouth (see section 6.2), the 
       apparent terminal half-life of amodiaquine was 5.2 + 1.7 
       (range 0.4 to 5.5) minutes and the geometric mean of the 
       estimated elimination phase half-lives was 2.1 (range 0.5 to 
       5.7) hours (White et al., 1987).
     6.4 Metabolism
       When amodiaquine is given orally relatively little of the 
       parent compound is present in the blood.  Hepatic 
       biotransformation to desethylamodiaquine (the principal 
       biologically active metabolite) is the predominant route of 
       amodiaquine clearance with such a considerable first pass 
       effect that very little orally administered amodiaquine 
       escapes untransformed into the systemic circulation 
       (Winstanley et al., 1987).

     6.5 Elimination by route of exposure
       Amodiaquine and desethylamodiaquine have been detected in the 
       urine several months after administration (Winstanley et al., 
       1987).
    7. PHARMACOLOGY AND TOXICOLOGY
     7.1 Mode of action
       7.1.1 Toxicodynamics
             Amodiaquine, a 4-aminoquinoline similar to chloroquine 
             in structure and activity, has been used as both an 
             antimalarial and an anti-inflammatory agent for more 
             than 40 years.
             
             The mode of action of amodiaquine has not yet been 
             determined.  4-Aminoquinolines depress cardiac muscle, 
             impair cardiac conductivity, and produce vasodilatation 
             with resultant hypotension; they depress  respiration 
             and cause diplopia, dizziness and nausea.
       7.1.2 Pharmacodynamics
             In general, 4-aminoquinoline derivatives appear to bind 
             to nucleoproteins and inhibit DNA an RNA polymerase.
             
             High drug concentrations are found in the malaria 
             parasite's digestive vacuoles (AFHS, 1988).
             
             After oral administration amodiaquine hydrochloride is 
             rapidly absorbed, and undergoes rapid and extensive 
             metabolism to desethylamodiaquine which concentrates in 
             blood cells.  It is likely that desethylamodiaquine, not 
             amodiaquine, is responsible for most of the observed 
             anti-malarial activity, and that the toxic effects of 
             amodiaquine after oral administration may, in part, be 
             due to desethylamodiaquine (Winstanley et al., 1987).
     7.2 Toxicity
       7.2.1 Human data
             7.2.1.1 Adults
                     TDLo (male, oral) 34 mg/kg over a 6 week 
                     interval; agranulocytosis
                     
                     TDLo (female, oral) 160 mg/kg over a 14 week 
                     interval; agranulocytosis
                     
                     (Ref. RTECS, 1985-1986)
                     
                     It is likely that the fatal dose for amodiaquine 
                     would be similar to that of chloroquine 
                     phosphate (2 to 3 g, adult) (Ellenhorn and 
                     Barceloux, 1988) since amodiaquine appears to 
                     completely parallel the adverse effects of those 
                     seen with chloroquine when equivalent doses are 
                     used.
             7.2.1.2 Children
                     Children are especially sensitive to 4-
                     aminoquinoline derivatives; fatalities have been 
                     reported following accidental ingestion of 
                     relatively small doses of chloroquine (a 4-

                     aminoquinoline derivative similar in structure 
                     and activity to amodiaquine).  The toxic dose 
                     range for oral chloroquine phosphate in children 
                     is 0.75 to 1 g (Ellenhorn & Barceloux, 1988).
                     
                     Severe reactions and fatalities have also 
                     occurred in children following parenteral 
                     administration of chloroquine (AFHS, 1988) (see 
                     section 4.2.2).
       7.2.2 Relevant animal data
             LD50 (mouse, intraperitoneal) 225 mg/kg
             LD50 (mouse, oral)            550 mg/kg
             LDLo (mouse, intraperitoneal) 137 mg/kg
                  (as dihydrochloride; no toxic effect noted)
             
             (RTECS, 1985-1986).
       7.2.3 Relevant in vitro data
             No data available.
     7.3 Carcinogenicity
       No data available.
     7.4 Teratogenicity
       Although no data are available for amodiaquine, chloroquine, a 
       structurally similar 4-aminoquinoline with the same spectrum 
       of activity and similar adverse reaction profile, is known to 
       cross the placental barrier.
       
       A woman during four of her eight pregnancies was given 
       chloroquine (250 mg daily from the sixth week after 
       conception); two of these children were congenitally deaf with 
       instability of gait.  One of these children had 
       chorioretinitis of the type associated with chloroquine 
       toxicity in the adult.  A third exposed child had 
       hemihypertrophy and developed a Wilm's tumour (Shepard, 1986).
       
       A 1985 report summarized the results of 169 infants exposed in 
       utero to 300 mg of chloroquine base once weekly throughout 
       pregnancy.  The control group consisted of 454 non-exposed 
       infants.  Two infants (1.2%) in the study group had anomalies 
       (tetralogy of Fallot and congenital hypothyroidism) compared 
       to four control infants who had defects (0.9%).  Based on 
       these data the authors concluded that chloroquine does not 
       have a strong teratogenic effect, but a small increase in 
       birth defects could not be excluded (Wolfe & Cordero, 1985).
       
       It is generally believed that the benefits of chloroquine 
       therapy in pregnant women exposed to malaria outweigh the 
       potential risks of the drug to the foetus.
       
       Chloroquine does not appear to be excreted in appreciable 
       amounts in the breast milk (Anderson, 1977).
     7.5 Mutagenicity
       No data available.
     7.6 Interactions
       Since magnesium trisilicate and kaolin are known to decrease 
       the gastrointestinal absorption of chloroquine when 
       administered simultaneously, it is likely that this also 
       follows for amodiaquine (Ellenhorn & Barceloux, 1988).

       
       Concomitant administration of chloroquine at recommended doses 
       for malaria suppression of chemoprophylaxis during pre-
       exposure prophylaxis of rabies with intra-dermally 
       administered rabies vaccine may interfere with the antibody 
       response to the vaccine.  However, the clinical significance 
       of this interaction remains to be clearly established but 
       should be considered and may have relevance in the case of 
       amodiaquine (AHFS, 1988). 
     7.7 Main adverse effects
       Oral administration of a single dose of amodiaquine may be 
       followed by abdominal discomfort, nausea, vomiting, headache, 
       dizziness, blurring of vision, mental and physical weakness, 
       and fatigue.  These symptoms are usually mild and transient.
       
       More severe adverse reactions include itching, cardiovascular 
       abnormalities, dyskinesia, ocular damage, neuromuscular 
       disorders and hearing loss.  There have been several reports 
       of agranulocytosis and these have limited its use in 
       prophylaxis.
       
       Hepatitis and peripheral neuropathy have also been reported 
       (Reynolds, 1989) (see section 9.4).
    8. TOXICOLOGICAL ANALYSES AND BIOMEDICAL INVESTIGATIONS
     8.1 Material sampling plan
       8.1.1 Sampling and specimen collection
             8.1.1.1 Toxicological analyses
             8.1.1.2 Biomedical analyses
             8.1.1.3 Arterial blood gas analysis
             8.1.1.4 Haematological analyses
             8.1.1.5 Other (unspecified) analyses
       8.1.2 Storage of laboratory samples and specimens
             8.1.2.1 Toxicological analyses
             8.1.2.2 Biomedical analyses
             8.1.2.3 Arterial blood gas analysis
             8.1.2.4 Haematological analyses
             8.1.2.5 Other (unspecified) analyses
       8.1.3 Transport of laboratory samples and specimens
             8.1.3.1 Toxicological analyses
             8.1.3.2 Biomedical analyses
             8.1.3.3 Arterial blood gas analysis
             8.1.3.4 Haematological analyses
             8.1.3.5 Other (unspecified) analyses
     8.2 Toxicological Analyses and Their Interpretation
       8.2.1 Tests on toxic ingredient(s) of material
             8.2.1.1 Simple Qualitative Test(s)
             8.2.1.2 Advanced Qualitative Confirmation Test(s)
             8.2.1.3 Simple Quantitative Method(s)
             8.2.1.4 Advanced Quantitative Method(s)
       8.2.2 Tests for biological specimens
             8.2.2.1 Simple Qualitative Test(s)
             8.2.2.2 Advanced Qualitative Confirmation Test(s)
             8.2.2.3 Simple Quantitative Method(s)
             8.2.2.4 Advanced Quantitative Method(s)
             8.2.2.5 Other Dedicated Method(s)

       8.2.3 Interpretation of toxicological analyses
     8.3 Biomedical investigations and their interpretation
       8.3.1 Biochemical analysis
             8.3.1.1 Blood, plasma or serum
             8.3.1.2 Urine
             8.3.1.3 Other fluids
       8.3.2 Arterial blood gas analyses
       8.3.3 Haematological analyses
       8.3.4 Interpretation of biomedical investigations
    8.4 Other biomedical (diagnostic) investigations and their 
       interpretation
     8.5 Overall Interpretation of all toxicological analyses and 
       toxicological investigations
     8.6 References
    9. CLINICAL EFFECTS
     9.1 Acute poisoning
       9.1.1 Ingestion
             Amodiaquine (a 4-aminoquinoline derivative), exhibits 
             symptoms of overdosage typical of the 4-aminoquinoline 
             class of anti-malarial drugs.  Symptoms include headache,
              drowsiness, visual disturbances, vomiting, hypokalaemia,
              cardiovascular collapse and cardiac and respiratory 
             arrest.  Hypotension, if not treated, may progress 
             rapidly to shock.  Electrocardiograms (ECG) may reveal 
             atrial standstill, nodal rhythm, prolonged 
             intraventricular conduction time, broadening of the QRS 
             complex, and progressive bradycardia leading to 
             ventricular fibrillation and/or arrest (AFHS, 1988).
       9.1.2 Inhalation
             No data available.
       9.1.3 Skin exposure
             No data available.
       9.1.4 Eye contact
             No data available.
       9.1.5 Parenteral exposure
             See section 9.1.1 (oral exposure).  Cardiovascular 
             effects may be more commonly observed.
       9.1.6 Other
             No data available.
     9.2 Chronic poisoning
       9.2.1 Ingestion
             Adverse reaction include itching, cardiovascular 
             abnormalities, dyskinesia, ocular damage, neuromuscular 
             disorders and hearing loss.  There have been several 
             reports of agranulocytosis and these have limited its 
             use in prophylaxis.  Hepatitis and peripheral neuropathy 
             have also been reported (Reynolds, 1989) (see section 
             9.4).
       9.2.2 Inhalation
             No data available.
       9.2.3 Skin exposure
             No data available.
       9.2.4 Eye contact
             No data available.

       9.2.5 Parenteral exposure
             See section 9.2.1 (oral exposure).  Cardiovascular 
             effects may be more commonly observed.
       9.2.6 Other
             No data available.
     9.3 Course, prognosis, cause of death
       Because the 4-aminoquinoline derivatives are rapidly and 
       completely absorbed from the Gl tract, symptoms of acute 
       toxicity may occur within 30 minutes following ingestion of 
       the drug.  Death has occurred within two hours following 
       vascular collapse and respiratory and cardiac arrest.
       
       Children are especially sensitive to 4-aminoquinoline 
       derivatives;  however, reports of suicides have indicated that 
       the margin of safety in adults is also small.  Without prompt 
       effective therapy, acute ingestion of 5 g or more of 
       chloroquine in adults has usually been fatal, although death 
       has occurred with smaller doses.  Fatalities have been 
       reported following ingestion of relatively small doses of 
       chloroquine (e.g., 750 mg or 1 g of chloroquine phosphate in a 
       three-year-old child).
     9.4 Systematic description of clinical effects
       9.4.1 Cardiovascular
             Chronic
             
             T-wave changes and prolongation of the QT-interval are 
             not uncommon during high-dose treatment with 4-
             aminoquinoline congeners.  These are probably not 
             significant in themselves (Tester-Dalderup, 1984).
             
             Acute on chronic
             
             Acute intoxication with chloroquine, a 4-aminoquinoline 
             congener structurally similar to amodiaquine, is 
             associated with cardiac arrest.  Complete heart block 
             was observed in a Nigerian male treated with high doses 
             for about two years.  First degree right bundle-branch 
             block was recorded in another male who had taken 8 to 10 
             tablets of 250 mg chloroquine weekly for about three
             years; sudden death was attributed to a Stoke-Adams 
             attack.  Focal convulsions followed by irregular heart 
             action and cardiac arrest were reported during the iv 
             administration of 250 mg chloroquine over a five-minute 
             period.  Acute overdosing is reputed to be particularly 
             dangerous if the drug is given intravenously or if taken 
             by young children (Tester-Dalderup, 1984).
             
             Sudden hypotension may occur, with absence of peripheral 
             pulses, vasodilatation, cyanosis of the lips and face, 
             arrhythmias and cardiac arrest often seen early.  The 
             ECG may reflect bradycardia, atrial standstill, a 
             widened QRS, prolonged intraventricular conduction time, 
             inverted or flattened T waves, S-T segment depression, 
             ventricular tachycardia, nodal rhythm, prolongation of 
             QT interval, complete heart block, ventricular 
             fibrillation, and cardiac arrest (Ellenhorn & Barceloux, 
             1988).

       9.4.2 Respiratory
             Acute
             
             Rapid superficial breathing, Cheyne-Stokes breathing, 
             sudden apnoea, respiratory failure, or, terminally, 
             respiratory arrest may be observed (Ellenhorn & 
             Barceloux, 1988).
       9.4.3 Neurological
             9.4.3.1 CNS
                     Chronic
                     
                     Four patients experienced involuntary movements, 
                     usually with speech difficulty after large, but 
                     not excessive, doses of amodiaquine (Akindele & 
                     Odejide, 1976).
                     
                     Lethargy and drowsiness have been reported as 
                     early side effects following therapeutic doses 
                     (Glickman, 1959).
                     
                     Additional neurological effects following other 
                     4-aminoquinoline derivatives have been 
                     described.  These may occur with amodiaquine 
                     therapy but have not been reported.  A range of 
                     mental changes attributed to the use of 
                     chloroquine has been described namely agitation, 
                     aggressiveness, confusion, personality changes, 
                     psychotic symptoms and depressions (Tester-
                     Dalderup, 1984).
                     
                     Acute
                     
                     Abnormal involuntary movements similar to those 
                     that occur in Parkinsonism have been reported in 
                     some patients treated with amodiaquine.  The 
                     movements mainly affected the tongue and the 
                     facial muscles.  In some patients the limbs were 
                     affected with tremor and ataxia. The symptoms 
                     usually started within 24 hours of taking the 
                     drug.  Left untreated, the disturbance remitted 
                     spontaneously with 48 hours, but it could be 
                     terminated within two hours by giving 
                     anticholinergic drugs like benzhexol and 
                     benztropine (Salako, 1984).
             9.4.3.2 Peripheral nervous system
                     Chronic 
                     
                     Peripheral neuritis has also been described in 
                     association with chloroquine (Tester-Dalderup, 
                     1984).
             9.4.3.3 Autonomic nervous system
                     No data available.
             9.4.3.4 Skeletal and smooth muscle
                     Chronic
                     

                     Neuromyopathy, and myopathy have also been 
                     described in association with chloroquine 
                     (Tester-Dalderup, 1984).
       9.4.4 Gastrointestinal
             Chronic
             
             Nausea, vomiting and diarrhoea have been reported 
             (Glickman et al., 1959).
       9.4.5 Hepatic
             Chronic
             
             Hepatitis developed in seven patients taking amodiaquine 
             for malaria prophylaxis for 4 to 15 weeks.  Liver 
             dysfunction recurred in two patients when amodiaquine 
             was administered subsequently (Larrey et al., 1986) (see 
             section 9.4.11).
             
       9.4.6 Urinary
             9.4.6.1 Renal
                     Chronic
                     
                     Although no data are available for amodiaquine, 
                     it should be noted that haemolysis and acute 
                     renal failure reportedly occurred in a few 
                     patients with glucose-6-phosphate dehydrogenase 
                     deficiency receiving chloroquine (AFHS, 1988).
             9.4.6.2 Other
                     No data available.
       9.4.7 Endocrine and reproductive systems
             No data available.
       9.4.8 Dermatological
             Chronic
             
             A mild degree of itching with or without a rash can 
             follow the use of amodiaquine in all races.  However, in 
             Africans, a more severe itching has been reported (see 
             below).  The itching has a curious biting or pricking 
             character, and affects all parts of the body including 
             the scalp, the palms of the hands, and the soles of the 
             feet.  It is often unassociated with urticaria or any 
             other kind of rash.  It begins within a few hours of 
             taking the drug and often continues for between 48 and 
             72 hours. It is usually severe enough to make sleep 
             impossible for as long as it lasts.  The itching occurs 
             in all age groups but it is unusual for it to be 
             experienced on the first exposure to the drug.
             
             Once itching has started, it usually runs it course of 
             48 to 72 hours, irrespective of treatment with 
             antihistamines.  However, prophylactic administration of 
             an antihistamine usually prevents or reduces the 
             severity of the reaction (Salako, 1984).
             

             Pruritus occurred in 14 (27%) of 52 patients with 
             malaria treated with amodiaquine (25 mg/kg) over three 
             days.  Although the pathogenesis of this adverse 
             reaction is still unknown, it occurs mainly in Blacks, 
             and appears to run in families, suggesting a genetic 
             basis (Sowunmi et al., 1989).
             
             Other dermatological effects have been reported for 
             chloroquine, which may also occur following amodiaquine 
             therapy.  These include pigmentary changes of the skin 
             and mucous membranes, skin eruptions resembling lichen 
             planus, and various dermatoses which may be aggravated 
             by exposure to ultraviolet light.  Additionally, 
             bleaching of hair has been reported occasionally with 
             chloroquine and occurs most frequently in light-haired 
             individuals.  Hair bleaching may affect eye leases and 
             axillary, pubic, scalp, and body hair, and is usually 
             evident after 2 - 5 months post-therapy (AFHS, 1988).
       9.4.9 Eye, ear, nose, throat: local effects
             Chronic:  4-Aminoquinolines cause two typical effects 
             involving the eye, namely keratopathy and retinopathy.  
             Both are associated with the administration of the drug 
             over longer periods of time; the level of daily doses 
             and total doses is of importance.
             
             Retinopathy, sometimes irreversible, was reported 
             following treatment with amodiaquine hydrochloride 200 
             mg daily (Grant, 1986).
             
             Ototoxicity has been reported in association with the 
             use of the 4-aminoquinoline derivative chloroquine 
             (Tester-Dalderup, 1984).
       9.4.10 Haematological
              Chronic
              
              Amodiaquine has reportedly caused blood dyscrasias at 
              therapeutic doses.
              
              Sporadic cases of severe neutropenia were reported as 
              early as 1953, but occurred more commonly in patients 
              receiving amodiaquine in anti-inflammatory doses for 
              rheumatoid arthritis.  However, in 1986, seven cases 
              were described in travellers returning to the UK who 
              were taking amodiaquine for malaria prophylaxis.  The 
              frequency of neutropenia among these has been estimated 
              at about 1 in 2000.  Similar findings were reported in 
              Switzerland.  In all, 23 cases of agranulocytosis 
              associated with the use of amodiaquine were reported in 
              the 12-month period ending in March 1986, seven of 
              which were fatal.  Most cases involved a dosage of 400 
              mg weekly over periods of three to 24 weeks (WHO, 
              1987).
       9.4.11 Immunological
              Chronic
              

              The mechanism for amodiaquine hepatotoxicity is 
              unknown.  It has been postulated that an immunoallergic 
              mechanism is consistent with some extra-hepatic 
              manifestations possibly due to hypersensitivity and 
              with the prompt increase in serum aminotransferase 
              levels after re-challenge (Larry et al., 1986).  
              However, other co-workers favour a toxic rather than an 
              immune mediated mechanism (Neftel et al., 1986) (see 
              section 9.4.5).
       9.4.12 Metabolic
              9.4.12.1 Acid-base disturbances
                       No data available.
              9.4.12.2 Fluid and electrolyte disturbances
                       Hypokalaemia has been reported.
              9.4.12.3 Others
                       No data available.
       9.4.13 Allergic reactions
              Chronic
              
              The pathogenesis of the itching (see section 9.4.8) may 
              be a hypersensitivity or genetic reaction, but is still 
              a matter of debate (Salako, 1984; Sowunmi et al., 
              1989).
       9.4.14 Other clinical effects
              No data available.
       9.4.15 Special risks
              Pregnancy
              
              Although no data are available for amodiaquine, 
              chloroquine is known to cross the placental barrier.
              
              A 1985 report summarized the results of 169 infants 
              exposed in utero to 300 mg of chloroquine base once 
              weekly throughout pregnancy.  The control group 
              consisted of 454 non-exposed infants.  Two infants 
              (1.2%) in the study group had anomalies (tetralogy of 
              Fallot and congenital hypothyroidism) compared to four 
              control infants who had defects (0.9%).  Based on these 
              data the authors concluded that chloroquine does not 
              have a strong teratogenic effect, but a small increase 
              in birth defects could not be excluded (Wolfe & Cordero,
               1985).
              
              It is generally believed that the benefits of 
              chloroquine therapy in pregnant women exposed to 
              malaria outweigh the potential risks of the drug to the 
              foetus.
              
              Breast feeding
              
              Chloroquine does not appear to be excreted in 
              appreciable amounts in the breast milk (Anderson, 
              1977).
              
              Enzyme deficiencies

              
              Since haemolysis and acute renal failure has been 
              reported to occur in a few patients with glucose-6-
              phosphate dehydrogenase deficiency receiving 
              chloroquine, this should also be considered when using 
              amodiaquine (AHFS, 1988).
     9.5 Other
       No data available.
      9.6 Summary
    10. MANAGEMENT
      10.1 General principles
         Treatment of overdosage is supportive and must be prompt 
         since acute toxicity can progress rapidly, leading to 
         vascular collapse and respiratory and cardiac arrest.
         
         Because of the importance of supporting ventilation, early 
         endotracheal intubation and mechanical ventilation may be 
         necessary.  Early gastric lavage followed by administration 
         of activated charcoal may provide some benefit in reducing 
         absorption of the drug, but should be preceded by measures 
         to correct cardiac and severe cardiovascular disturbances, 
         if present, and by respiratory support. Diazepam iv may 
         control seizures and other manifestations of CNS 
         stimulation.  Seizures caused by anoxia should be corrected 
         by oxygen and other respiratory support.  Defibrillators and 
         cardiac pacemakers may be required.
      10.2 Relevant laboratory analyses
         10.2.1 Sample collection
                Blood should be collected on EDTA and centrifuged at 
                2000 g for 15 minutes within two hours of collection 
                and the plasma should be frozen at -20 to -40C.
                
                The blood sample should be transported under 
                refrigerated and separated within two hours of 
                collection.
         10.2.2 Biomedical analysis
                Regular laboratory investigations should be performed 
                to assure that blood cell counts remain within normal 
                limits.
                
                Perform liver function tests and monitor serum 
                electrolytes.
                
                Arterial blood gases should be determined.
                
                Electrocardiography is helpful assess cardiotoxicity.
         10.2.3 Toxicological analysis
                Measuring the blood levels of amodiaquine and its 
                major metabolite desethylamodiaquine is not 
                considered to be of practical assistance in the 
                clinical management of amodiaquine poisoning.
                
                Both simple qualitative and quantitative tests may be 
                found in the USP (1974).
                

                A sensitive and selective HPLC method for the 
                determination of amodiaquine in plasma has been 
                reported by Mihaly et al., 1985).  This has been 
                modified to permit the determination of both 
                amodiaquine and the major active metabolite, 
                desethylamodiaquine, in plasma, urine, whole blood 
                and packed red blood cells (Winstanley et al., 1987).
         10.2.4 Other investigations
                No data available.
      10.3 Life supportive procedures and symptomatic/specific 
         treatment
         Treatment is largely supportive.  Cardiac and respiratory 
         arrest may quickly supervene, therefore preparations should 
         be made for tracheal airway protection (endotracheal 
         intubation) and mechanical ventilation.  Defibrillators and 
         cardiac pacemakers may be required.  Check adequacy of tidal 
         volume (normal 10 to 15 ml/kg).  Control seizures, if 
         present, before emptying stomach.  The seizures may result 
         from the following:
         
         - anoxia: administer 100% oxygen, begin assisted 
         ventilation;
         
         - CNS stimulation: diazepam (up to 10 mg iv slowly in 
         adults; 0.1 to 0.2 mg/kg iv slowly in children).  If 
         unresponsive: phenytoin (15 mg/kg iv slowly, at up to 0.5 
         mg/kg/minute, with ECG monitoring);
         
         - hypotension: intravenous fluids.  If unresponsive, 
         administer dopamine:  5 to 15 g/kg/minute (after correction 
         of hypovolemia); watch for ventricular arrhythmias.
      10.4 Decontamination
         Emesis may be induced if there is evidence of overdose, if 
         the patient is not comatose, is not convulsing, and has not 
         lost the gag reflex.  It is preferable that gastric emptying 
         be performed more rapidly by gastric lavage with prior 
         endotracheal intubation.  The drug is rapidly absorbed, and 
         if symptoms are already present, gastric aspiration may not 
         be effective.  It should be attempted in any case.
         
         Activated charcoal (adults, 60 to 100 g; children, 30 to 60 
         g) may be placed as a slurry with a cathartic into the 
         gastric lavage tube.
      10.5 Elimination
         Forced diuresis and/or urinary acidification may increase 
         excretion of unchanged amodiaquine, but neither procedure 
         can be recommended at present on the basis of clinical 
         evidence.
         
         Peritoneal dialysis and haemodialysis are not effective.  In 
         the case of chloroquine as a comparison, dialysis and 
         haemoperfusion techniques are limited by the high apparent 
         volume of distribution of chloroquine in the tissue.
         

         Charcoal haemoperfusion may be effective if begun very early 
         after ingestion in a severely toxic patient.  Clinical 
         studies have not established its usefulness.  The total body 
         clearance of chloroquine (a 4-aminoquinoline similar to 
         amodiaquine), is increased only slightly after haemodialysis 
         and haemoperfusion.
      10.6 Antidote treatment
         10.6.1 Adults
                There are no antidotes.  Although diazepam has been 
                shown to have a protective effect in diminishing 
                chloroquine (a related 4-aminoquinoline) toxicity in 
                animals this, however, has not been clearly 
                established for humans (Crouzette et al., 1983).
         10.6.2 Children
                There are no antidotes.  Although diazepam has been 
                shown to have a protective effect in diminishing 
                chloroquine (a related 4-aminoquinoline) toxicity in 
                animals this, however, has not been clearly 
                established for humans (Crouzette et al., 1983).
      10.7 Management discussion
         Despite the widespread therapeutic use of amodiaquine for 
         the past 40 years, there remains a paucity of both clinical 
         and experimental data on this drug. In particular, there 
         appear to be no useful literature reports from acute 
         amodiaquine poisoning.
         
         Further research into the possible role that diazepam may 
         play as an antagonist in acute amodiaquine poisoning is 
         indicated (see section 10.6).
    11. ILLUSTRATIVE CASES
      11.1 Case reports from literature
         Children, oral ingestion
         
         A report (WHO 1979) cites a case in June 1965 from Pakistan. 
          Severe haemoglobinuria had occurred in seven children 
         following ingestion of an unknown amount of Camoprima 
         Infatabs (each tablet containing 75 mg amodiaquine + 15 mg 
         primaquine).  No details could be obtained regarding the 
         approximate number of tablets ingested, the age of the 
         children and the circumstances in which the tablets had been 
         taken.  However, certain indications strongly suggested that 
         the reported toxic reactions were not related to any regular,
          supervised drug administration, but were accidents in that 
         the children had got hold of the drug and surreptitiously 
         swallowed a number of tablets.
      11.2 Internally extracted data on cases
         To be added by the Poison Control Centre.
      11.3 Internal cases
         To be added by the Poison Control Centre.
    12. Additional information
      12.1 Availability of antidotes
         No specific antidotes are available.
      12.2 Specific preventive measures
         Store in an air-tight container, in child-resistant 
         packaging out of the reach of children.
         

         The manufacturer of Camoquin (Parke-Davis) has advised in a 
         data sheet to health professionals that the prophylactic use 
         of amodiaquine as a first line agent has been restricted to 
         chloroquine-resistant areas.  If the decision is made to so 
         prescribe the drug, concomitant use with other anti-
         malarials should be avoided and regular laboratory 
         investigations should be performed to assure that blood 
         values and liver function tests remain within normal limits.
         
         Because amodiaquine may concentrate in the liver, the drug 
         should be used with caution in patients with hepatic disease 
         or alcoholism, and in patients receiving hepatotoxic drugs.
         
         Amodiaquine is contraindicated in patients who are 
         hypersensitive to other 4-aminoquinolines.
         
         Since haemolysis and acute renal failure has been reported 
         to occur in a few patients with glucose-6-phosphate 
         dehydrogenase deficiency receiving chloroquine, this should 
         also be considered when using amodiaquine.
         
         Children are especially sensitive to 4-aminoquinoline 
         derivatives.  Because of the narrow margin between the 
         therapeutic and toxic concentrations in children, 
         amodiaquine should not be administered parenterally in this 
         age group.
         
         It is generally believed that the benefits of chloroquine (a 
         4-aminoquinoline congener similar to amodiaquine in both its 
         structure and activity spectrum) therapy in pregnant women 
         exposed to malaria outweigh the potential risks of the drug 
         to the foetus.  The risk to the foetus is greater if it is 
         glucose-6-phosphate dehydrogenase deficient.  Chloroquine 
         does not appear to be excreted in appreciable amounts in the 
         breast milk.
      12.3 Other
         No data available.
    13. REFERENCES
    AFHS (1988)  American Hospital Formulary Service.  Drug 
    information 88.  McEvoy G K (ed).  American Society of Hospital 
    Pharmacists.  Bethesda, MD, 2222 pp.
    
    Akinedale MO & Odejide AO (1976)  Amodiaquine-induced involuntary 
    movements.  Br Med J, 2: 214-215.
    
    Anderson PO (1977)  Drugs and breast feeding.  Drug Intell Clin 
    Pharm, 11: 210-211.
    
    CDC (1985)  Health information for travel, Atlanta, Georgia;  US 
    Public Health Service, Department of Health and Human Services, 
    CDC Publication Number 85-8280; 73-82.
    
    Crouzette J, Vicaut E, Palombo S, Girre C & Fournier PE (1983) 
    Experimental assessment of the protective activity of diazepam on 
    the acute toxicity of chloroquine.  J Toxicol. Clin. Toxicol, 
    20(3): 271-279.

    
    Ellenhorn MJ & Barceloux DG (1988) Medical toxicology.  Diagnosis 
    and treatment of human poisoning.  Elsevier Science Publishing 
    Company, Inc. New York, New York, 1512 pp.
    
    Glickman FS, Shatin H & Canizares O (1959)  Anti-malarial 
    preparations in treatment of cutaneous disorders.  New York J Med,
     59: 3946-3954.
    
    Grant WM (1986)  Toxicology of the eye.  3rd Edition, Springfield,
     Ill:  Charles C. Thomas.
    
    Katzung BG (ed) (1987)  Basic and clinical pharmacology.  
    Appleton & Lange, Norwalk, Connecticut, USA, 905 pp.
    
    Larrey D, Castot A, Pessayre D, Merigot P, Machayekhy J-P, 
    Feldmann G, Lenoir A, Rueff B & Benhamou J-P.  (1986)  
    Amodiaquine-induced hepatitis.  Ann Int Med, 104-801.
    
    Reynolds JEF (1989) Martindale The extra pharmacopoeia.  The 
    Pharmaceutical Press, London.  1896 pp
    
    Mihaly G, Nicholl D, Edwards G, Ward S, Orme M, Warrell D & 
    Breckenridge A (1985).  High performance liquid chromatographic 
    analysis of amodiaquine in human plasma.  J. Chromatogr, 37: 166-
    171.
    
    Neftel KA, Woodtly W, Schmid M, Frick PG & Fehr J (1986) 
    Amodiaquine induced agranulocytosis and liver disease.  Br Med J. 
    292: 721-723.
    
    Perry HO, Bartholomew LG & Hanlon DG (1962)  Nearly fatal 
    reaction to amodiaquine.  J A M A, 179(8): 598-601.
    
    RTECS (1986-1986)  Registry of toxic effects of chemical 
    substances.
    
    Salako LA (1984)  Toxicity and side effects of antimalarials in 
    Africa:  a critical review.  Bulletin of the WHO, 62 (Suppl.): 63-
    68.
    
    Shepard TH (1986)(ed)  Catalogue of teratogenic agents.  5th 
    edition, The Johns Hopkins University Press, Baltimore MD, 710 
    pp.
    
    Sowunmi A, Walker O & Salako LA  (1989)  Pruritus and 
    antimalarial drugs in Africans.  The Lancet, p.213.
    
    Tester-Dalderup, DBM  (1984)  Antiprotozoal drugs.  In: Dukes MNG 
    (ed)  Meyler's side effects of drugs.  10th edition.  Elsevier 
    Science Publishers BV, Amsterdam, 966 pp.
    
    The Merck Index (1983)  An encyclopedia of chemicals, drugs and 
    biologicals. Windholz M, Budavari S, Blumetti RF & Otterbein ES 
    (eds).  Merck & Co., Inc., Rahway, NJ, USA, 1463 pp. plus 
    Appendices.

    
    USP (1974)  United States Pharmacopoeia XIX.  The United States 
    Pharmacopoeial Convention, Inc., Mack Publishing Company, Easton, 
    Pa.
    
    White NJ, Looareesuwan S, Edwards G, Phillips RE, Karbwang J, 
    Nicholl DD, Bunch C & Warrell DA (1987)  Pharmacokinetics of 
    intravenous amodiaquine.  Br J. Clin. Pharmac. 23: 127-135.
    
    WHO (1979)  Toxicity and side effects of primaquine and other 8-
    aminoquinolines.  Weniger H.  WHO/MAL/79.905, 33 pp.
    
    Winstanley PA, Edwards G, Orme M & Breckinridge AM  (1987)  The 
    disposition of amodiaquine in man after oral administration.  Br 
    J. Clin. Pharmacol., 23: 1-7
    
    Wolfe MS & Cordero JF (1985)  Safety of chloroquine in 
    chemosuppression of malaria during pregnancy.  Br Med. J. 290: 
    1466-1467.
    14. AUTHOR(S), REVIEWER(S), DATE(S) (INCLUDING UPDATES), COMPLETE 
    ADDRESS(ES)
    Authors:  Dr Wayne A. Temple
              National Poisons and Hazardous Chemicals Information
              Centre
              University of Otago Medical School
              P.O. Box 913
              Dunedin
              New Zealand
    
              Tel: 64-3-4797248
              Fax: 64-3-4770509
    
              Dr Nerida A. Smith
              Department of Pharmacy
              University of Otago Medical School
              P.O. Box 913
              Dunedin
              New Zealand
    
    Date:     31 January 1990
    
    Update:   Dr R. Fernando
              National Poisons Information Centre
              Faculty of Medicine
              Kynsey Road
              Colombo 8
              Sri Lanka
    
              Tel: 94-1-686143
              Fax: 94-1-691581
    
    Date:     July 1993



    See Also:
       Toxicological Abbreviations