CBD Oil for Stomach Ulcers

Can CBD oil help with stomach ulcers, and if so, how?

Stomach ulcers, also known as gastric ulcers, are a type of peptic ulcer disease. 'Peptic' ulcer is the umbrella term for any ulcer affecting the stomach and the small intestines.

 

The stomach usually produces acid to help with the digestion of food and protect against bacteria and other microbes. 

 

Meanwhile, cells on the inside lining of the stomach and small intestine (duodenum) produce a natural mucus barrier to protect the tissues of the body from this acid. 

 

There is usually a balance between the amount of acid that the body makes and the mucus defence barrier. 

 

Ulcers may develop if there is an alteration in this balance, allowing the acid to damage the lining of the stomach or duodenum.

 

Stomach ulcers are characterized by open sores in the lining of the stomach. While small ulcers may not cause noticeable symptoms, larger ones can cause pain and discomfort (1).

Ulcer symptoms are often worse on an empty stomach and at night. Ulcer symptoms include:

CBD for Stomach Ulcers: What The Research Says 

There is evidence that cannabinoids like CBD and THC have a positive physiological impact on stomach conditions, including ulcers. 

According to research, there is evidence that CB1 receptor stimulation with cannabinoids inhibits gastric acid secretion in humans and experimental animals (2).

Studies have shown that CBD can decrease gastric acid and increase blood flow to the lining of the stomach.

Researchers of a 2016 study published in Current Neuropharmacology found that direct activation of CB1 receptors by cannabinoids effectively reduces both gastric acid secretion and gastric motor activity and decreases the formation of lesions on the stomach lining (3).

A study examined how cannabinoids impact the gastrointestinal tract of some species, like the mouse, rat, guinea pig, and humans (4).

In another study published in Pharmacology Journal, researchers found that delta-9-tetrahydrocannabinol (THC) inhibited ulcer formation in the animal subjects (5). 

Although the studies did not focus on the cannabinoid CBD, the results are still encouraging. The authors believe the endocannabinoid system represents a promising target in the treatment of gastric mucosal lesions, ulceration and inflammation.

CBD  for Pain Relief

Prescription medication is not the only reliable scientific solution to treating conditions, such as stomach ulcers. 

Chemical-based painkillers have even been known to cause stomach ulcers in the first place.

According to the National Health Service (NHS) of the United Kingdom, taking non-steroidal anti-inflammatory drugs (NSAIDs), such as ibuprofen or aspirin, can cause stomach ulcers, particularly if these pharmaceuticals are taken for an extended period or at high doses (6). 

Meanwhile, CBD may also help provide effective pain relief from the invasion of stomach ulcers. 

Studies have shown that CBD may help provide pain relief. CBD may be useful in treating different types of chronic pain (7). 

Chronic pain, particularly neuropathic pain, is a problem that is difficult to treat, according to the author of a study on neuronal mechanisms for neuropathic pain (8).

CBD for Nausea

Nausea is a feeling or urge to vomit. It can develop for several reasons, including medications, chemotherapy, food poisoning, morning sickness, general anesthesia, and migraines(9).

Nausea and vomiting both play an essential, defensive role by rejecting the ingestion or digestion of potentially harmful substances.

Cannabis has long been known to prevent or regulate nausea and vomiting from a variety of causes (10).

The studies demonstrated that primary cannabinoids, tetrahydrocannabinol (THC) and cannabidiol (CBD), have both been useful at regulating vomiting and nausea because they interact with cannabinoid receptor 1 (CBB1) of the endocannabinoid system. 

Activating the CB1 receptor suppresses vomiting, as noted in the review published in the journal Psychopharmacology (11). 

Studies have shown that CBD’s effectiveness at producing anti-nausea effects may also be in part of its indirect activation of the 5-HT-1A autoreceptors in the brain stem (12).

Activation of 5-HT1A heteroreceptors in these areas releases serotonin  (13). 

Serotonin is found mostly in the digestive system, although it is also in blood platelets and throughout the central nervous system.

Serotonin is sometimes called "the happy chemical" because it contributes to feelings of well-being and happiness.

Conclusion

 

CBD’s purported therapeutic benefits may help with symptoms of stomach ulcers. However, more research is needed to validate the results of the studies.

WHO states that CBD “is generally well-tolerated with a good safety profile.” (14) Still, the long-term effects of CBD remain unknown, and the compound may also interact with other pharmaceuticals.

Thus, individuals looking to try CBD for the first time, or intend to use CBD as an adjunct therapy, should first consult with a doctor experienced in cannabis use for advice.

 

References

  1. WakeMed. Stomach Ulcers. Retrieved from https://www.wakemed.org/stomach-ulcers.
  2. Abdel-Salam O. Gastric acid inhibitory and gastric protective effects of Cannabis and cannabinoids. Asian Pac J Trop Med. 2016;9(5):413–419. DOIi:10.1016/j.apjtm.2016.04.021.
  3. Gyires K, Zádori ZS. Role of Cannabinoids in Gastrointestinal Mucosal Defense and Inflammation. Curr Neuropharmacol. 2016;14(8):935–951. DOI:10.2174/1570159x14666160303110150.
  4. Pertwee RG. Cannabinoids and the gastrointestinal tract. Gut. 2001;48(6):859–867. DOI:10.1136/gut.48.6.859.
  5. Sofia RD, Diamantis W, Harrison JE, Melton J. Evaluation of antiulcer activity of delta9-tetrahydrocannabinol in the Shay rat test. Pharmacology. 1978;17(3):173–177. DOI:10.1159/000136851.
  6. NHS Inform. (2020, Feb 14). Stomach Ulcer. Retrieved from https://www.nhsinform.scot/illnesses-and-conditions/stomach-liver-and-gastrointestinal-tract/stomach-ulcer.
  7. Grinspoon, P. (2019, Aug 27). Cannabidiol (CBD) — what we know and what we don’t. Retrieved from https://www.health.harvard.edu/blog/cannabidiol-cbd-what-we-know-and-what-we-dont-2018082414476.
  8. Zhuo M. Neuronal mechanism for neuropathic pain. Mol Pain. 2007;3:14. Published 2007 Jun 6. DOI:10.1186/1744-8069-3-14.
  9. ECHO. (2017, Feb 17). Nausea: Cannabinoids and CBD Research Overview. Retrieved from https://echoconnection.org/nausea-medical-cannabis-and-cbd-research-overview/.
  10. Parker, L.A., Rock, E.M., Sticht, M.A., Wills, K.L., and Limebeer, C.L. (2015). Cannabinoids suppress acute and anticipatory nausea in preclinical rat models of conditioned gaping. Clinical Pharmacology and Therapeutics, 97(6), 559-61;  Sharkey, K.A., Darmani, N.A., and Parker, L.A. (2014). Regulation of nausea and vomiting by cannabinoids and the endocannabinoid system. European Journal of Pharmacology, 722, 134-4.
  11. Parker, L.A., Mechoulam, R., Schlievert, C., Abbott, L., Fudge, M.L., and Burton, P. (2003, March). Effects of cannabinoids on lithium-induced conditioned rejection reactions in a rat model of nausea. Psychopharmacology, 166(2), 156-62.
  12. Rock EM, Bolognini D, Limebeer CL, et al. Cannabidiol, a non-psychotropic component of cannabis, attenuates vomiting and nausea-like behaviour via indirect agonism of 5-HT(1A) somatodendritic autoreceptors in the dorsal raphe nucleus. Br J Pharmacol. 2012;165(8):2620–2634. DOI:10.1111/j.1476-5381.2011.01621.x.  
  13. Garcia-Garcia AL, Newman-Tancredi A, Leonardo ED. 5-HT(1A) [corrected] receptors in mood and anxiety: recent insights into autoreceptor versus heteroreceptor function [published correction appears in Psychopharmacology (Berl). 2014 Feb;231(4):637]. Psychopharmacology (Berl). 2014;231(4):623–636. doi:10.1007/s00213-013-3389-x. 
  14. WHO. Expert Committee on Drug Dependence. (2017, Nov 6-10). Cannabidiol (CBD). Retrieved from https://www.who.int/medicines/access/controlled-substances/5.2_CBD.pdf.  
INTOX Home Page
SODIUM BICARBONATE ICSC: 1044
Date of Peer Review: April 2004

Carbonic acid monosodium salt
Baking soda
Bicarbonate of soda
Sodium hydrogen carbonate
Sodium acid carbonate
CAS # 144-55-8 NaHCO3
RTECS # VZ0950000 Molecular mass: 84.0
UN #
EC #
TYPES OF HAZARD / EXPOSURE ACUTE HAZARDS / SYMPTOMS PREVENTION FIRST AID / FIRE FIGHTING
FIRE Not combustible.

In case of fire in the surroundings: use appropriate extinguishing media.
EXPLOSION


EXPOSURE


Inhalation


Skin


Eyes Redness.
Safety spectacles.
First rinse with plenty of water for several minutes (remove contact lenses if easily possible), then take to a doctor.
Ingestion


SPILLAGE DISPOSAL PACKAGING & LABELLING
Sweep spilled substance into containers; if appropriate, moisten first to prevent dusting. Wash away remainder with plenty of water.
EU Classification
UN Classification

EMERGENCY RESPONSE STORAGE

Separated from acids.
IPCS
International
Programme on
Chemical Safety
Prepared in the context of cooperation between the International Programme on Chemical Safety and the Commission of the European Communities IPCS, CEC 1999

SEE IMPORTANT INFORMATION ON BACK
SODIUM BICARBONATE ICSC: 1044
IMPORTANT DATA
PHYSICAL STATE; APPEARANCE:
WHITE SOLID IN VARIOUS FORMS.

CHEMICAL DANGERS:
The solution in water is a weak base. Reacts with acids.

OCCUPATIONAL EXPOSURE LIMITS:
TLV not established. MAK not established.
ROUTES OF EXPOSURE:
The substance can be absorbed into the body by ingestion.

INHALATION RISK:
Evaporation at 20C is negligible; a nuisance-causing concentration of airborne particles can, however, be reached quickly when dispersed, especially, if powdered.

EFFECTS OF SHORT-TERM EXPOSURE:
The substance is mildly irritating to the eyes.

PHYSICAL PROPERTIES
Melting point (decomposes): 50C
Density: 2.1 g/cm
Solubility in water, g/100 ml at 20C: 8.7
ENVIRONMENTAL DATA

NOTES

ADDITIONAL INFORMATION


LEGAL NOTICE Neither the CEC nor the IPCS nor any person acting on behalf of the CEC or the IPCS is responsible for the use which might be made of this information
IPCS, CEC 1999

Dextromethorphan

  1. NAME

   1.1 Substance

   1.2 Group

   1.3 Synonyms

   1.4 Identification numbers

      1.4.1 CAS

      1.4.2 Other numbers

   1.5 Brand names/trade names:

   1.6 Manufacturers and importers:

  1. 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

  1. PHYSICO-CHEMICAL PROPERTIES

   3.1 Origin of the substance

   3.2 Chemical structure

   3.3 Physical properties

      3.3.1 Colour

      3.3.2 State/form

      3.3.3 Description

   3.4 Other characteristics

      3.4.1 Shelf-life of the substance

      3.4.2 Storage conditions

  1. USES

   4.1 Indications

      4.1.1 Indications

      4.1.2 Description

   4.2 Therapeutic dosages

      4.2.1 Adults

      4.2.1 Children

   4.3 Contraindications

  1. ROUTES OF EXPOSURE

   5.1 Oral

   5.2 Inhalation

   5.3 Dermal

   5.4 Eye

   5.5 Parental

   5.6 Others

  1. 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

  1. 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

      7.2.3 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

  1. TOXICOLOGICAL/TOXINOLOGICAL 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

  1. 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 contact

      9.2.4 Eye contact

      9.2.5 Parental 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 Neurologic

         9.4.3.1 Central nervous system (CNS)

         9.4.3.2 Peripheral nervous system

         9.4.3.3 Autonomic

         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 Others

      9.4.7 Endocrine and reproductive systems

      9.4.8 Dermatologic

      9.4.9 Eye, ear, throat: local effects

      9.4.10 Hematological

      9.4.11 Immunologic

      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 Others

  1. MANAGEMENT

   10.1 General principles

   10.2 Life supportive procedures and symptomatic treatment

   10.3 Decontamination

   10.4 Enhancd elimination

   10.5 Antidote

      10.5.1 Adults

      10.5.2 Children

   10.6 Management discussion

  1. ILLUSTRATIVE CASES

   11.1 Case report from the literature

  1. ADDITIONAL INFORMATION

   12.1 Specific preventive measures

   12.2 Other

  1. REFERENCES
  2. AUTHOR(S), REVIEWER(S) DATES (INCLUDING EACH UPDATING), COMPLETE ADDRESSES




    DEXTROMETHORPHAN

 

    International Programme on Chemical Safety

    Poisons Information Monograph 179

    Pharmaceutical

 

  1. NAME

 

        1.1  Substance

 

             Dextromethorphan

 

        1.2  Group

 

             Cough and cold preparations (R05)/

             Antitussives, excl. combinations with expectorants

             (R05D)/ Opium alkaloids and derivatives (R05D A)

 

        1.3  Synonyms 

 

             Dextromethorphan hydrobromide monohydrate;

             dextromethorphani hydrobromidum;

             demorphan hydrobromide

 

        1.4  Identification numbers

 

             1.4.1  CAS

 

                    125-69-9 (anhydrous)

 

             1.4.2  Other numbers

 

                    CAS: 6700-34-1 (monohydrate)

 

        1.5  Brand names/trade names:

 

             Polistirex Extended Release suspension.

 

        1.6  Manufacturers and importers:

 

             To be completed by each centre using the mongraph.

 

  1. SUMMARY

 

        2.1  Main risks and target organs

 

             The main risks associated with dextromethorphan are

             ataxia, central nervous system (CNS) stimulation, dizziness,

             lethargy and psychotic behavior. Less frequently with large

             doses seizures and respiratory depression can occur. Nausea,

             vomiting, constipation and tachycardia may occur. The main

             target organ is the central nervous system (CNS).

 

        2.2  Summary of clinical effects

 

             Central nervous system effects include ataxia,

             drowsiness, vertigo and rarely coma. CNS stimulation may be

             observed. Restlessness, increased muscle tone with body    

             rigidity have been reported. With extremely large ingestions

             respiratory depression can occur. Gastrointestinal effects 

             include nausea, vomiting, constipation and dry mouth. Urinary

             retention may be seen. Dextromethorphan abuse has been

             described and produces euphoria, CNS stimulation, visual

             and/or auditory hallucinations. There does not appear to be

             any evidence of dependence of the morphine type.

             The possibility of bromide poisoning should be considered in

             the long term abuser.

 

        2.3  Diagnosis

 

             Diagnosis of dextromethorphan toxicity is primarily

             based on the history of an ingestion of dextromethorphan or

             dextromethorphan containing products. The presence of

             dextromethorphan may be confirmed by qualitative

             determination of the drug in urine.

 

        2.4  First aid measures and management principles

 

             Assess and support airway, respiration and

             cardiovascular function if needed. Gastric decontamination is

             recommended for recent ingestions of more than 10 mg/kg.

             Seizures and/or CNS depression have occurred within 30

             minutes of ingesting dextromethorphan. 

    

             ACTIVATED CHARCOAL/CATHARTIC.

             Activated charcoal may be given alone or with a cathartic  

             such as sorbitol or magnesium citrate even though at this   

             time there is no data concerning the adsorption or clinical

             efficacy of activated charcoal in the treatment of

             dextromethorphan ingestions.

    

             GASTRIC LAVAGE followed by activated charcoal may be

             indicated for the treatment of recent large ingestions, or in

             patients who are comatose or at risk of convulsing.  NALOXONE

             may be of benefit to reverse the respiratory and CNS effects

             of dextromethorphan although its efficacy is yet to be

             adequately determined.

 

  1. PHYSICO-CHEMICAL PROPERTIES

 

        3.1  Origin of the substance

 

             Dextromethorphan is a synthetic compound.

             Dextromethorphan has been abused and is claimed to be habit

             forming but has not been reported to produce physical

             dependence (Ellenhorn & Barceloux 1988). It is not a

             substitute for opiates in dependent individuals.

 

        3.2  Chemical structure

 

             Chemical name:

             Dextromethorphan is 3 Methoxy-17-methylmorphinan monohydrate,

             which is the d isomer of levophenol, a codeine analogue and

             opioid analgesic.

    

             Molecular formula: (Dextromethorphan Hydrobromide):

             C18H25NO.HBr.H2O

    

             Molecular weight 370.3

 

        3.3  Physical properties

 

             3.3.1  Colour

 

                    White

 

             3.3.2  State/form

 

                    Solid-crystals

                    Solid-powder

 

             3.3.3  Description

 

                    Odourless verging on a faint odour. Solubility

                    in water 1.5 g/100 mL at 25 C.

                    Soluble 1 in 10 of ethanol.

                    Practically insoluble in ether.

                    Freely soluble in chloroform.

                    pH of a 1% aqueous solution 5.2 to 6.5 (Budavari,

                    1996).

 

        3.4  Other characteristics

 

             3.4.1  Shelf-life of the substance

 

                    No information available.

 

             3.4.2  Storage conditions

 

                    Powder should be preserved in air-tight

                    containers and solutions stored in light-resistant

                    containers (USP National Formulary).

    

 

                    Lozenges: store between 15 and 30 degrees C in well

                    closed containers.

                    Syrup USP: Store between 15 and 30 degrees C in light,

                    resistant container, protected from freezing.

 

  1. USES

 

        4.1  Indications

 

             4.1.1  Indications

 

                    Cough/cold preparation

                    Antitussive (not with expectorant); 

                    cough/cold

                    Opioid; 

                    antitussive

 

             4.1.2  Description

 

                    Antitussive.

 

        4.2  Therapeutic dosages

 

             4.2.1  Adults

 

                    Oral doses of 10 to 20 mg every four hours or

                    30 mg every 6 to 8 hours not to exceed 120 mg

                    daily.

    

                    Long-acting preparations: 60 mg twice a day.

 

             4.2.1  Children

 

                    Children aged 6 to 12 years may be given 5 to

                    10 mg every 4 hours or 15 mg every six to eight hours,

                    not to exceed 60 mg daily.

 

                    Children aged 2 to 6 years 2.5 to 5.0 mg every 4 hours

                    or 7.5 mg every 6 to 8 hours not to exceed 30 mg

                    daily.

                    The recommended dose in a child is 1 mg/kg/day to 2

                    mg/kg/day given in three to four divided doses (Benitz

                    & Tatro, 1988). 

                    Dextromethorphan is not generally recommended in

                    children less than two years of age unless under

                    medical supervision (USPC, 1991).

    

                    Long-acting preparations: children aged 6 to 12 years

                    30 mg twice a day and children aged 2 to 6 years 15 mg

                    twice a day (AHFS, 1992).

 

        4.3  Contraindications

 

             Dextromethorphan should not be administered in patients

             taking selective serotonin reuptake inhibitors (eg

             fluoxetine, paroxetine) (Skop et al., 1994) and monoamine

 

             oxidase inhibitors (Rivers & Horner, 1970). This may produce

             a life threatening serotonergic syndrome which consists of:

             restlessness, sweating, hypertension, hyperthermia, tremor,

             myoclonus and seizures.

    

             Dextromethorphan may be associated with histamine release and

             should not be used in atopic children. Dextromethorphan

             should not be taken for persistent or chronic cough (e.g.

             with smoking, emphysema, asthma) or when coughing is

             accompanied by excessive secretions, unless directed by a

             physician (AHFS, 1992).

             Alcohol and CNS depressants should be avoided with    

             dextromethorphan.

 

  1. ROUTES OF EXPOSURE

 

        5.1  Oral

 

             Dextromethorphan is usually taken orally.

             It has been abused orally.

 

        5.2  Inhalation

 

             Dextromethorphan has been sniffed in the abuse setting.

 

        5.3  Dermal

 

             No data available

 

        5.4  Eye

 

             No data available

 

        5.5  Parental

 

             No data available

 

        5.6  Others

 

             No data available

 

  1. KINETICS

 

        6.1  Absorption by route of exposure

 

             Dextromethorphan is well absorbed from the

             gastrointestinal tract with maximum serum level occurring at

             2.5 hours (Barnhart et al., 1979).  Peak concentration of the

             major metabolite dextrorphan) was 1.6  to 1.7 hours (Silvasti

             et al., 1987).  Onset of effect is rapid, often beginning 15

             to 30 minutes after oral ingestion (Pender & Parks, 1991).

    

 

             Peak levels for sustained release products generally occur

             about 6 hours after ingestion (Amsel, 1981) although

             absorption may be erratic.

 

        6.2  Distribution by route of exposure

 

             There is no information about the volume of distribution

             in humans. In dogs, the volume of distribution is reported to

             range from 5.0 to 6.4 L/Kg (Baselt & Cravey, 1989).

 

        6.3  Biological half-life by route of exposure

 

             The half life of the parent compound is approximately 2

             to 4 hours in people with normal metabolism.

 

        6.4  Metabolism

 

             There is a clear first pass metabolism and it is

             generally assumed that the therapeutic activity is primarily

             due to its active metabolite, dextrophan (Silvasti et al.,

             1987; Baselt & Cravey, 1982).

             Genetic polymorphism has profound effects on its metabolism

             (Hildebrand et al 1989).  Dextromethorphan undergoes

             polymorphic metabolism depending on variation in cytochrome

             P-450 enzyme phenotype. The specific cytochrome P-450 enzyme

             is P450 2D6(CYP2D6) (Schadel et al., 1995).

             Fast metabolizers constitute about 84% of the population.

             After a 30 mg dose plasma levels are less than 5 ng/mL four

             hours postingestion (Woodworth et al., 1987). Intermediate

             metabolizers constitute about 6.8% of the population. After

             an oral dose of 30 mg plasma levels are 10 to 20 ng/mL at 4

             hours and less than 5 ng/mL at 24 hours postingestion

             (Woodworth et al., 1987).  Poor metabolizers constitute 5% to

             10% of the Caucasian population. The ratio of metabolite to

             parent drug in 8 hour urine sample is less than 10 to 1 after

             a 15 mg dose (Hildebrand et al., 1989).  After an oral dose

             of 30 mg plasma levels are greater than 10 ng/mL at 4 hours

             and greater than 5 ng/mL at 24 hours (Woodworth et al.,

             1987).

             It is metabolized in the liver by extensive metabolizers to

             dextrorphan. Dextrorphan is itself an active antitussive

             compound (Baselt & Cravey, 1982). Only small amounts are

             formed in poor metabolizers (Kupfer, 1986).  Less than 15% of

             the dose form minor metabolites including D-methoxymorphinane

             and D-hydroxmorphinane (Kupfer, 1986).

 

        6.5  Elimination by route of exposure

 

             Dextromethorphan and its metabolites are excreted via

             the   kidney. Depending on the metabolism phenotype up to 11%

             may be excreted unchanged or up to 100% as demethylated

 

             conjugated morphinan compounds (Hildebrand, 1989).  In the

             first 24 hours after dosing, less than 0.1% is eliminated in

             the faeces (Baselt & Cravey, 1989).

 

  1. PHARMACOLOGY AND TOXICOLOGY

 

        7.1  Mode of action

 

             7.1.1  Toxicodynamics

 

                    The toxicodynamic actions of dextromethorphan

                    are not completely defined. Dextromethorphan enhances

                    serotonin activity by inhibiting the reuptake of

                    serotonin (Kramei et al., 1992; Bem & Peck, 1992)

                    Specific non-opioid dextromethorphan binding sites are

                    present in the central nervous system (CNS) which

                    mediate the antitussive effects, separate from codeine

                    and other opioids (Hardman et al., 1996).

                    Dextromethorphan and dextrorphan both affect the NMDA 

                    receptor (Carpenter et al., 1988; Reynolds, 1993).

 

             7.1.2  Pharmacodynamics

 

                    The antitussive effects of dextromethorphan and

                    the metabolite dextrorphan are secondary to binding in

                    the CNS at non-opioid receptors. Dextromethorphan does

                    not have analgesic or addictive properties, although

                    abuse and dependence have been described(Hardman et

                    al, 1996). One of the major metabolites, dextrorphan

                    has cough suppressant activity.

 

        7.2  Toxicity

 

             7.2.1  Human data

 

                    7.2.1.1  Adults

 

                             Coma was reported in an adult who

                             ingested 720 mg over 36 hours (Schneider,

                             1991).  Rated as lethal at oral doses of 50

                             to 500 mg/kg (Gosselin, 1981).

                             Death has been reported after overdose in two

                             cases but quantity was uncertain (Rammer et

                             al., 1988).

                             Long-acting products: adults have tolerated

                             up to 960 mg/day with minor adverse effects

                             (Walker and Hunt, 1989).

                             Abuse: Has been used for abuse. Orally in

                             doses of 300 mg to 1800 mg in adults it can

                             cause intoxication with hyperexcitability,

                             visual and/or auditory hallucinations (Dodds

                             & Revai, 1967; Orrell & Campbell, 1986). It

 

                             has been reported that sniffing 0.25 g two to

                             three times a day over 2 to 3 months produced

                             euphoria and restlessness for up to 2 hours

                             followed by dizziness, nausea, depression and

                             fatigue (Fleming, 1986).

                             Chronic effects: It should be noted that

                             dextromethorphan is marketed as the

                             hydrobromide and can produce bromide toxicity

                             with chronic use.

                             Dextromethorphan has been abused at doses of

                             2160 to 2880 mg daily for up to five years

                             producing hallucinations, euphoria,

                             disorientation, insomnia and nausea.

                             Withdrawal produced dysphoria and craving for

                             the drug (Wolf and Caravati 1995).

 

                    7.2.1.2  Children

 

                             Toxicity may be variable in

                             children. Ingestion of as little as 17 mg/Kg

                             has resulted in signs and symptoms of

                             toxicity.  At this dosage range some children

                             have shown no symptoms whilst others have

                             shown ataxia, stupor, transient fever,

                             lethargy or nystagmus (Versie et al., 1962;

                             Katona & Wason, 1986). Seizures have been

                             reported.

                             Long-acting products may be more toxic in

                             children, producing prolonged CNS depression

                             at 10 mg/kg (Devlin, 1985).

 

             7.2.3  Animal data

 

                    LD 50 in mice 165 mg/kg

                    LD 50 in rats 350 mg/kg (Gosselin, 1981)

                    LD 50 in mice 39 mg/Kg (Benson, 1953)

 

             7.2.3  Relevant in-vitro data

 

                    No data available

 

        7.3  Carcinogenicity:

 

             No data available

 

        7.4  Teratogenicity

 

             There was no association between dextromethorphan and

             malformations (Heinonen et al., 1977). Dextromethorphan is

             generally considered safe to use during pregnancy (Berkowitz

             et al., 1981).

 

        7.5  Mutagenicity

 

             No data available

 

        7.6  Interactions

 

             Concomitant use of monoamine oxidase inhibitors has

             caused toxicity leading to death (Rivers & Horner, 1970;

             Hansten, 1989).

             Not to be taken with serotonin re-uptake inhibitors

             (Skop et al., 1994)

             Alcohol and drugs causing CNS depression should be avoided

             when taking dextromethorphan.

 

        7.7  Main adverse effects

 

             Adverse effects are very uncommon with therapeutic doses.

             Infrequent adverse effects include dizziness, drowsiness,

             nausea, vomiting and stomach ache (USPC, 1989).

 

  1. TOXICOLOGICAL/TOXINOLOGICAL 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

 

             Monitoring dextromethorphan serum levels is not useful

             clinically in the overdose situation because a correlation 

             between levels and clinical effects has yet to be determined

             (Walker & Hunt, 1989). However plasma levels may be measured

             to determine metabolizer phenotype.  The presence of

             dextromethorphan may be confirmed by qualitative

             determination of the drug in urine or serum.

    

             Plasma dextromethorphan concentrations have not been

             correlated with clinical toxicity. Monitoring concentrations

             of dextromethorphan, therefore, would not be useful

             (Ellenhorn & Barceloux, 1983; Walker & Hunt, 1989) Plasma

             dextromethorphan concentrations are used to determine hepatic

             metabolism phenotype.

    

             Sample collection

             If required arterial blood for blood gasses.

    

             Biomedical analysis

             Arterial blood gasses to determine the degree of ventilatory

             depression.

    

             Toxicological analysis

             The presence of dextromethorphan may be confirmed by

             qualitative determination of the drug in urine or blood, see

             Section 8. Plasma levels may be used to determine metabolizer

             phenotype.

 

  1. CLINICAL EFFECTS

 

        9.1  Acute poisoning

 

             9.1.1  Ingestion

 

                    Oral ingestion is the most common route of

                    acute poisoning. The most common clinical effects

                    involve the central nervous system (CNS).

                    Neurologic: drowsiness, lethargy, ataxia, nystagmus,

                    CNS stimulation, vertigo, coma, psychosis and

                    hyperreflexia (Cetaruk & Aaron, 1995; Wolfe &

 

                    Caravati, 1995; Devlin et al., 1985; Shaul et al.,

                    1977; Schneider et al., 1991).

                    Seizures have been reported within 30 minutes of

                    ingestion.

                    Respiration: Respiratory depression has been noted

                    (Katona and Wason, 1986; Shaul et al., 1977).

                    Cardiovascular: Long-acting preparations may cause

                    tachycardia (Devlin et al.,  1985).

                    Gastrointestinal: Nausea, vomiting (Versie at al.,

                    1962) constipation and dry mouth may occur.

                    Eye: Mydriasis, miosis and nystagmus may be seen.

                    Genitourinary: Retention of urine may be seen.

                    Skin: Urticaria was noted after ingestion of a long-

                    acting preparation in a child (Devlin et al.,

                    1985).

                    Long-acting preparations: With 10 mg/Kg or more taken

                    orally ataxia, lethargy, nystagmus and tachycardia

                    have been reported.

 

             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.

 

                    No data available

 

             9.1.6  Other

 

                    No data available.

 

        9.2  Chronic Poisoning

 

             9.2.1  Ingestion

 

                    The daily abuse of oral dextromethorphan has

                    been described as causing hallucinations (visual and

                    auditory), dyspnea, floating and flying sensations,

                    and increased perception (Wolfe & Caravati, 1995). 

                    Central nervous system (CNS) stimulation has also been

                    reported (Dodds & Revai, 1967; Orrell & Campbell,

                    1986). When the drug was stopped no withdrawal

                    symptoms were noted, however, craving for

                    dextromethorphan continued.

    

 

                    It should be noted that dextromethorphan may be

                    marketed as the hydrobromide salt and can produce

                    bromide toxicity with chronic use.

 

             9.2.2  Inhalation

 

                    No data available.

 

             9.2.3  Skin contact

 

                    No data available

 

             9.2.4  Eye contact

 

                    No data available

 

             9.2.5  Parental exposure

 

                    No data available

 

             9.2.6  Other

 

                    It has been reported that sniffing 0.25 g two

                    to three times a day over 2 to 3 months produced

                    euphoria and restlessness for up to 2 hours followed

                    by dizziness, nausea, depression and fatigue (Fleming,

                    1986).  This patient did not demonstrate withdrawal

                    symptoms on cessation but did complain of continuing

                    craving for dextromethorphan.

 

        9.3  Course, prognosis, cause of death:

 

             Following overdose of short acting dextromethorphan

             patients may become clumsy, hyperkinetic and ataxic a few

             hours after the ingestion. There may be vomiting, drowsiness,

             dizziness, blurred vision, nystagmus, and visual and auditory

             hallucinations. Later unsteadiness and unstable gait are

             observed with truncal ataxia. In severe cases, shallow

             respirations, urinary retention, stupor, or coma may

             supervene, especially if high doses of alcohol have been

             ingested. The prognosis for recovery is good (Ellenhorn &

             Barceloux, 1988).

             Following ingestion of long acting dextromethorphan symptoms

             of over use in children include urticaria, restlessness,

             lethargy, nystagmus, ataxia, tachycardia and blood pressure

             elevation. This may require admission to an intensive care

             unit. Long acting preparations may produce a higher rate of

             toxic symptoms in children than short-acting

             dextromethorphan. There does not appear to be a correlation

             between the amount of long-acting dextromethorphan ingested

             and the severity of symptoms (Ellenhorn & Barceloux,

             1988).

 

        9.4  Systematic description of clinical effects:

 

             9.4.1  Cardiovascular

 

                    Long-acting preparations may cause tachycardia

                    (Devlin et al., 1985).  No reports of chronic effects

                    were found in the literature.

 

             9.4.2  Respiratory

 

                    Respiratory depression has been noted following

                    large doses (Katona and Wason, 1986; Shaul et al.,

                    1977). No reports of chronic effects were found in the

                    literature.

 

             9.4.3  Neurologic

 

                    9.4.3.1  Central nervous system (CNS)

 

                             In acute overdose ataxia, drowsiness

                             (Devlin et al., 1985; Shaul et al., 1977)

                             vertigo and coma (Schneider et al.,

                             1991).

                             CNS stimulation may be noted.  Restlessness,

                             increased muscle tone with body rigidity have

                             been reported (Benson et al., 1953). 

                             Seizures have been reported within 30 minutes

                             of ingestion.

                             In the abuse situation it can cause CNS

                             stimulation and visual and/or auditory

                             hallucinations (Dodds & Revai, 1967; Orrell &

                             Campbell, 1986). It has been reported that

                             sniffing 0.25 g two to three times a day over

                             2 to 3 months produced euphoria and

                             restlessness for up to 2 hours followed by

                             dizziness, nausea, depression and fatigue

                             (Fleming, 1986).

                             Cognitive deterioration resulting from

                             prolonged abuse has been reported (Hinsberger

                             et al., 1994).

 

                    9.4.3.2  Peripheral nervous system

 

                             No data available

 

                    9.4.3.3  Autonomic

 

                             No data available

 

                    9.4.3.4  Skeletal and smooth muscle

 

                             No data available

 

             9.4.4  Gastrointestinal

 

                    After acute overdose nausea, vomiting (Versie

                    et al., 1962), constipation and dry mouth may occur. 

                    No chronic effects were found.

 

             9.4.5  Hepatic

 

                    No data available.

 

             9.4.6  Urinary

 

                    9.4.6.1  Renal

 

                             No data available.

 

                    9.4.6.2  Others

 

                             Urinary retention has been seen.

 

             9.4.7  Endocrine and reproductive systems

 

                    No data available.

 

             9.4.8  Dermatologic

 

                    Urticaria was reported in a child after acute

                    overdose of a long-acting preparation (Devlin et

                    al.,1985).

 

             9.4.9  Eye, ear, throat: local effects

 

                    After acute overdose mydriasis or miosis

                    (Schneider et al.,  1991) and nystagmus (Katona &

                    Wason, 1986; Devlin et al., 1985) may be noted.

                    Nystagmus may persist from 7 to 8 hours with long-

                    acting preparations (Devlin et al., 1985). No chronic

                    effects were found.

 

             9.4.10 Hematological

 

                    No data available.

 

             9.4.11 Immunologic

 

                    No data available.

 

             9.4.12 Metabolic

 

                    9.4.12.1 Acid-base disturbances

 

                             No data available.

 

                    9.4.12.2 Fluid and electrolyte disturbances

 

                             No data available.

 

                    9.4.12.3 Others

 

                             No data available.

 

             9.4.13 Allergic reactions

 

                    A cutaneous lesion consistent with a fixed-

                    drug reaction was reported after ingestion over 2 to 3

                    weeks in therapeutic doses (Stubb & Reitamo,

                    1990).

 

             9.4.14 Other clinical effects

 

                    No data available.

 

             9.4.15 Special risks

 

                    Pregnancy:

                    Ingesting dextromethorphan during the first trimester 

                    demonstrated no association between the drug and

                    malformations (Heinonen, 1989).  Dextromethorphan is

                    generally considered safe during pregnancy (Berkowitz,

                    1981).

    

                    Breast feeding:

                    No data available.

    

                    Enzyme deficiencies:

                    No data available.

 

                    Serotonergic Syndrome (see 4.3)

 

        9.5  Others

 

             Dextromethorphan has been used for abuse however there

             were no withdrawal symptoms on cessation but there was a

             continued craving for the drug.

 

  1. MANAGEMENT

 

        10.1 General principles

 

             Assess and support airway, ventilation, and

             circulation. Naloxone may antagonize respiratory depression. 

             Gastric decontamination is recommended for recent ingestions

             of more than 10 mg/kg of dextromethorphan.  Patients with

             respiratory depression may require admission to an intensive

             care unit. Others can be observed in the emergency facility

             for 4 to 6 hours and then discharged. A small number of

             patients with minor symptoms (such as ataxia or restlessness)

 

             may be sent home under careful supervision. (Ellenhorn &

             Barceloux, 1988) Children who have ingested a long-acting

             preparation should be hospitalized.

 

        10.2 Life supportive procedures and symptomatic treatment

 

             Assess and support airway, ventilation, and

             circulation. Naloxone may antagonize respiratory depression. 

             Patients with respiratory depression may require admission to

             an intensive care unit. Other patients can be observed in the

             emergency facility for 4 to 6 hours and then discharged.

             Patients with minor symptoms (such as ataxia or restlessness)

             may be sent home under supervision. (Ellenhorn & Barceloux,

             1988) Children who have ingested a long-acting preparation

             should be hospitalized for 24 observation.

 

        10.3 Decontamination

 

             Gastric decontamination is recommended for a recent

             ingestion of more than 10 mg/kg. Seizures and/or central

             nervous system (CNS) depression have occurred within 30

             minutes of ingesting dextromethorphan.

    

             GASTRIC LAVAGE followed by activated charcoal may be used

             within 1 to 2 hours of ingestion and may be indicated in

             recent large ingestions or in patients who are comatose or at

             risk of convulsing. Gastric lavage in a comatose patient

             should be preceded by intubation.

    

             ACTIVATED CHARCOAL/CATHARTIC. Activated charcoal may be given

             alone or with a cathartic such as sorbitol or magnesium

             citrate, even though at this time there is no data concerning

             the adsorption of dextromethorphan by charcoal.

             Because there is no data concerning the adsorption of

             dextromethorphan by charcoal if routine gastric emptying is

             omitted the patient may receive inadequate treatment if

             charcoal alone is used. A reasonable approach might be to

             consider gastric lavage in patients ingesting more than 10

             mg/Kg of dextromethorphan, those with clinical features of

             overdose, or those where the time and quantity of ingestion

             is unknown.

             The optimum dose of activated charcoal has not been

             established, but as a guide 1 g to 2 g/kg of activated

             charcoal is recommended, particularly in infants. The adult

             dose may therefore be 30 g to 100 g and the dose in children

             15 g to 30 g.  If a patient vomits the dose it may be

             repeated.  Do not use charcoal tablets or universal antidote

             as a substitute for activated charcoal.

    

             WHOLE BOWEL LAVAGE. If a long-acting dextromethorphan

             preparation has been ingested whole bowel lavage may be

             considered.

    

 

             CATHARTIC. A saline cathartic or sorbitol may be administered

             with the first dose of activated charcoal or it may be given

             separately.  Although there is little evidence to support the

             use of cathartics (McNamara, 1988; Stewart, 1983) their use

             would seem logical to shorten transit time and avoid the

             constipation caused by charcoal. Repeated doses of cathartics

             is not recommended especially in children. If the dose is

             repeated this should be done with extreme caution.

 

        10.4 Enhancd elimination

 

             There is no information currently available on the

             effectiveness of forced diuresis, alkalinization,

             acidification, haemoperfusion, or dialysis for the treatment

             of dextromethorphan overdose.  The use of these methods of

             potentially increasing drug elimination are not recommended

             for the treatment of dextromethorphan poisonings.

 

        10.5 Antidote

 

             10.5.1 Adults

 

                    NALOXONE may be of benefit to reverse the

                    respiratory and CNS effects of dextromethorphan. 

                    Although there have been reports concerning the

                    response to naloxone (Katona & Wason, 1986; Shaul et

                    al, 1977), in most cases improvement in, and

                    resolution of, neurologic symptoms occurred over three

                    to eight hours after naloxone administration, and this

                    may represent the natural course of dextromethorphan

                    toxicity rather than a response to naloxone

                    (Pender,1991).  There is currently no evidence which

                    suggests significant efficacy associated with naloxone

                    administration (Wolfe & Caravati, 1995).

 

             10.5.2 Children

 

                    No data available.

 

        10.6 Management discussion

 

             Many references still recommend the use of Ipecac to

             induce emesis in dextromethorphan overdose.  However there

             have been reports of seizures following overdose and thus

             this monograph does not advocate the induction of emesis.

             Also, most dextromethorphan ingestions are the liquid

             formulation which are most likely absorbed quickly. Emesis

             may thus be ineffective and contraindicated due to rapid CNS

             depression, and may delay the administration of activated

             charcoal. Charcoal has been recommended without reports

             proving or disproving its efficacy. However it is commonly

 

             used for dextromethorphan overdose and is likely to be

             effective and safe. Research on this matter would determine

             if this is so.

             Further information is required before naloxone can be

             accepted as an antidote for dextromethorphan toxicity.  The

             cases presented to date do not support reversal of

             dextromethorphan toxicity by naloxone. This is supported by

             the pharmacology of dextromethorphan (Wolfe & Caravati, 1995;

             Hardman et al., 1996).

 

  1. ILLUSTRATIVE CASES

 

        11.1 Case report from the literature

 

             Case 1

             A 41 year old female ingested 720 mg of dextromethorphan over

             a 36 hour period. She presented lethargic and responding only

             to painful stimuli. Respirations were shallow and sporadic,

             pupils pinpoint and minimally reactive to light. Because of

             her decreased level of consciousness and miosis, 1 mg of

             naloxone intravenous (IV) was administered with some

             improvement of consciousness. An additional 2 mg naloxone was

             administered with further improvement and ultimate return to

             normal mental status. Serum samples showed dextromethorphan

             level of 100 ng/mL (Schneider et al., 1991).

    

             Case 2

             A report is given of two young adults who died after overdose

             of dextromethorphan. How much was taken is uncertain (Rammer

             at al 1988).

    

             Case 3

             A 23 year old male presented with psychosis after an acute

             overdose of dextromethorphan. He demonstrated

             hyperexcitability and hallucinations which he compared to his

             experience with LSD.(Dodds & Revai, 1967).

    

             Case 4

             A 26 year old female took approximately 60ml of a cough

             medicine containing dextromethorphan about six hours after

             ingesting 30 mg of phenelzine (Nardil). Thirty minutes later

             she felt nauseated, dizzy and collapsed. Within one hour she

             was brought to the hospital unconscious with rigid

             extremities and fixed, dilated pupils.  She was severely

             hypotensive with a systolic blood pressure that did not rise

             above 70 mm of mercury and a temperature that ranged from

             42°C to 42.2°C. Despite vasopressors, anti-arrhythmics and

             adrenaline, approximately four hours after arriving at the 

             hospital she had a cardiac arrest and died (Rivers & Horner,

             1970).

    

 

             Case 5

             An 11 week old infant was given inappropriate doses of a

             dextromethorphan/guaifenesin mixture over a period of 24

             hours. Doses were more frequent and larger than those

             recommended, but the exact amount was unable to be

             determined.  The infant was alert and noted to be

             hyperexcitable with intermittent periods of extremity

             stiffening and cutaneous mottling.  He was given naloxone 0.1

             mg/Kg intravenously.  Within 30 minutes of the naloxone he

             was noted to be calmer and within two hours all signs had

             resolved (Pender & Parks, 1991).

    

             Case 6

             A 3 year old boy ingested an unknown amount of

             dextromethorphan and presented with lethargy, somnolence,

             ataxia and nystagmus. Vital signs were normal, and

             respirations adequate. He awoke after he was given

             intravenous naloxone (0.4 mg).  Twenty five grams of charcoal

             was given and during the next three hours his condition

             steadily improved and he was discharged (Katona & Wason,

             1986).

 

  1. ADDITIONAL INFORMATION

 

        12.1 Specific preventive measures

 

             Dextromethorphan must not be used with monoamine

             oxidase inhibitors (MAOIs) since death has occurred.

             Dextromethorphan should not be used with other CNS

             depressants.

             Dextromethorphan should not be used with serotonin re-uptake

             inhibitors.

             Care should be taken that dextromethorphan is not given in

             overdose, especially to children.

             Medicines containing dextromethorphan are best store in child

             resistant containers.

             Dextromethorphan has been abused and care should be taken not

             to supply it to susceptible individuals.

 

        12.2 Other

 

             No data available.

 

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        Devlin KM, Hall AH, Smolinske SC, et al (1985) Toxicity from

        long-acting dextromethorphan preparations (abstract). Vet Hum

        Toxicol 28:296.

    

        Dodds A, Revai E (1967)  Toxic psychosis due to dextromethorphan.

        Med J Aust 2:231.

    

        Ellenhorn MJ, Barceloux DG (1988) Medical toxicology: diagnosis

        and treatment of human poisoning. New York: Elsevier.

    

 

        Elliot C, Colby T, Hicks (1989) Charcoal lung. Bronchiolitis

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        Fleming PM (1986) Dependence on dextromethorphan hydrobromide

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        Garelts JC, Watson WA, Holloway KD et al (1989) Magnesium toxicity

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        Gosselin GE, Roger PS, Harold CH (1981) Clinical Toxicology of

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        Hansten PD, Horn JR (1989) Drug Interactions, 6th Ed.  Lea and

        Febiger, Philadelphia, PA.

    

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        York.

    

        Harsch HH (1986) Aspiration of activated charcoal. N Engl J Med

        314:318.

    

        Heinonen OP, Slone D, Shapiro S (1977) Birth Defects and Drugs in

        Pregnancy. PSG Publishing Co, Littleton, MA.

    

        Hildebrand M, Seifert W, Reichenberger A (1989) Determination of

        dextromethorphan metabolizer phenotype in healthy volunteers. Eur

        J Clin Pharmacol 36:315-318.

    

        Hinsberger A, Sharma V, Mazmanian D (1994). Cognitive

        deterioration  from long-term abuse of dextromethorphan: a case

        report. J Psychiatr Neurosci 19(5):375-377.

    

        Jawary D, et al (1992) Drug overdose-reducing the load.  Med J

        Aust 156:343-346.

    

        Kamei J, Mori T, Igarashi H et al (1992) Serotonin release in

        nucleus of the solitary tract and its modulation by antitussive

        drugs.  Res Commun Chem Pathol Pharmacol 76:371-374.

    

        Katona B & Wason S (1986) Dextromethorphan danger (letter). N Eng

        J Med 314:993.

    

        Kupfer A, Schmid B, Pfaff G (1986) Pharmacogenetics of

        dextromethorphan O-demethylation in man. Xenobiotica 16:421-

        433.

    

        Mansky P, Jasinski DR (1970) Effects of dextromethorphan in man.

        Pharmacologist 12:231.

    

 

        Matthys H, Bleicher B, Bleicher U (1983) Dextromethorphan and

        codeine: Objective assessment of antitussive activity in patients

        with chronic cough. J Int Med Res 11:92-100.

    

        McNamara RM, Aaron CK, Gemborys M, Davidheiser S (1988) Sorbitol

        catharsis does not enhance the efficacy of charcoalin a simulated

        acetaminophen overdose. Ann Emerg Med 17:243-246.

    

        Menzies DG, Busuttil A, Prescott LF (1988) Fatal pulmonary

        aspiration of oral activated charcoal.  Brit Med J 297:459-

        460.

    

        Orrell MW, Campbell PG (1986) Dependence on dextromethorphan

        hydrobromide. Br Med J 293:1242-1243.

    

        Pender ES & Parks BR (1991) Toxicity with dextromethorphan

        containing preparations: a literature review and report of two

        additional cases. Pediatr Emerg Care: 163-165.

    

        Rammer L, Holmgren P, Sandler H (1988)  Fatal intoxication by

        dextromethorphan: a report on two cases. Forensic Sci Int 37:233-

        236.

    

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  1. Pharmaceutical Press. London.

    

        Rivers N & Horner B (1970) Possible lethal reaction between nardil

        and dextromethorphan. Can Med Assoc J 103:85.

    

        Schadel M, Wu D, Otton SV, Kalow W, Sellers EM (1995) The

        pharmacokinetics of dextromethorphan and metabolites in humans:

        influence of the CYP2D6 phenotype and quinidine inhibition.  J

        Clin Psychopharmacol 15(4):263-269.

    

        Schneider SM, Michelson EA, Boucek CD et al (1991)

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        9:237-238.

    

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        reversal by naloxone. Pediatrics 59:117-119.

    

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        of dextromethorphan and dextrorphan: a single dose comparison of

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        Toxicol 9:493-497.

    

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        Med 12:642-644.

    

 

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        after magnesium containing cathartics. J Toxicol Clin Toxicol

        26:51-65.

    

        Stewart JJ (1983)  Effects of emetic and cathartic agents on the

        gastrointestinal tract and the treatment of toxic ingestion. J

        Toxicol Clin Toxicol 20:199-253.

    

        Stubb S, Reitamo S (1990)  Fixed-drug eruption due to

        dextromethorphan (letter). Arch Dermatol 126:970-971.

    

        Thompsom A, Robins J, Prescott L (1987) Changes in

        cardiorespiratory function during gastric lavage for drug

        overdose. Hum Toxicol 6:215-218.

    

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        Inc, Rockville, Maryland.

    

        USP (1991) Drug information for the Health Care Professional, 11th

        ed, Vol 1. US Pharmacoepial Convention, Inc, Rockville,

        Maryland.

    

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        Walker FO, Hunt VP (1989) An open label trial of dextromethorphan

        in Huntington's Disease. Clin Neuropharmacol 12:322-330.

    

        Watson WA, Cremer K, Chapman (1986) Gastrointestinal obstruction

        associated with multiple dose activated charcoal. J Emerg Med

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        Wolfe TR, Caravati ME (1995) Massive Dextromethorphan Ingestion

        and Abuse. Am J Emerg Med 13;174-176.

    

        Woodworth JR, Dennis SRK, Moore L et al (1987) The polymorphic

        metabolism of dextromethorphan. J Clin Pharmacol 27:139-143

 

  1. AUTHOR(S), REVIEWER(S) DATES (INCLUDING EACH UPDATING), COMPLETE

        ADDRESSES

 

        Author: Jim Magarey

        Poisons Information Centre

        Royal Childrens Hospital

        Flemington Rd, Parkville

        Melbourne, Victoria

        AUSTRALIA   3052

    

        Telephone 03 93455680  Fax 03 93491261

 

        Date of writing: 1992

    

 

        Updated by same author August 1996

    

        Peer review: Dr. A.N.P. van Heijst, August 1996

        Dr. W. Watson August, 1996

    

        PIM review group: Intox 9, September, 1996, Cardif, Wales

    

        Editor: Dr M. Ruse (August, 1997)

    



    

Abrus precatorius L.

  1. NAME

   1.1 Scientific name

   1.2 Family

   1.3 Common name(s)

  1. 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

   2.5 Poisonous parts

   2.6 Main toxins

  1. CHARACTERISTICS

   3.1 Description of the plant

      3.1.1 Special identification features

      3.1.2 Habitat

      3.1.3 Distribution

   3.2 Poisonous parts of the plant

   3.3 The toxin(s)

      3.3.1 Name(s)

      3.3.2 Description, chemical structure, stability

      3.3.3 Other physico-chemical characteristics

   3.4 Other chemical contents of the plant

  1. USES/CIRCUMSTANCES OF POISONING

   4.1 Uses

   4.2 High risk circumstances

   4.3 High risk geographical areas

  1. ROUTES OF ENTRY

   5.1 Oral

   5.2 Inhalation

   5.3 Dermal

   5.4 Eye

   5.5 Parenteral

   5.6 Others

  1. 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

  1. TOXICOLOGY/TOXINOLOGY/PHARMACOLOGY

   7.1 Mode of action

   7.2 Toxicity

      7.2.1 Human data

         7.2.1.1 Adults

         7.2.1.2 Children

      7.2.2 Animal data

      7.2.3 Relevant in vitro data

   7.3 Carcinogenicity

   7.4 Teratogenicity

   7.5 Mutagenicity

   7.6 Interactions

  1. TOXICOLOGICAL/TOXINOLOGICAL 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

  1. 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 Others

      9.4.7 Endocrine and reproductive systems

      9.4.8 Dermatological

      9.4.9 Eye, ears, 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 Others

   9.6 Summary

  1. MANAGEMENT

   10.1 General principles

   10.2 Relevant laboratory analyses and other investigations

      10.2.1 Sample collection

      10.2.2 Biomedical analysis

      10.2.3 Toxicological/toxinological analysis

      10.2.4 Other investigations

   10.3 Life supportive procedures and symptomatic treatment

   10.4 Decontamination

   10.5 Elimination

   10.6 Antidote/antitoxin treatment

      10.6.1 Adults

      10.6.2 Children

   10.7 Management discussion

  1. ILLUSTRATIVE CASES

   11.1 Case reports from literature

   11.2 Internally extracted data on cases

   11.3 Internal cases

  1. ADDITIONAL INFORMATION

   12.1 Availability of antidotes/antitoxins

   12.2 Specific preventive measures

   12.3 Other

  1. REFERENCES

   13.1 Clinical and toxicological

   13.2 Botanical

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



    POISONOUS PLANTS

  1. NAME

     1.1 Scientific name

       Abrus precatorius L.

     1.2 Family

       Leguminosae

     1.3 Common name(s)

       Abrus seed

       Aivoeiro

       Arraccu-mitim

       Buddhist rosary bead

       Carolina muida

       Crabs eye

       Deadly crab's eye

       Indian bead

       Indian liquorice

       Jequirite

       Jequirity Bean

       Jumble beads

       Juquiriti

       Lucky bean

       Prayer beads

       Precatory bean

       Rosary beads

       Rosary Pea

       Ruti

       Tentos da America

       Tentos dos mundos

       Weather plant

       Wild liquorice

  1. SUMMARY

     2.1 Main risks and target organs

       The main risk is the severe gastroenteritis leading to 

       dehydration and shock.

       

       Ingested seeds can affect the gastrointestinal tract, the 

       liver, spleen, kidney, and the lymphatic system.  Infusion of 

       seed extracts can cause eye damage after contact.

     2.2 Summary of clinical effects

       The early features of toxicity are burning of the mouth and 

       oesophagus, and severe gastroenteritis with vomiting, 

       haematemesis, diarrhoea, melaena, and abdominal pain.  Later, 

       drowsiness, disorientation, weakness, stupor, convulsions, 

       shock, cyanosis, retinal haemorrhages, haematuria, and 

       oliguria can occur.  Contact with the eyes can cause 

       conjunctivitis and even blindness.

     2.3 Diagnosis

       Diagnosis is made by the presence of the typical 

       manifestations following ingestion:  gastroenteritis with risk 

       of dehydration, haematemesis and melaena.  Drowsiness and 

       convulsions may occur.

       

       Toxicological analysis of body fluids for the poison is not 

       helpful. 

       

       Plant material, seeds or remnants of seeds, vomitus, and 

 

       gastric aspirate should be collected in clean bottles for 

       identification.

     2.4 First-aid measures and management principles

       First-aid measures: Remove all seed particles from the mouth.  

       Induce vomiting and save it for identification.  Ensure that 

       the patient's airway is clear and that there is adequate 

       ventilation.

       

       Do not induce vomiting if the patient is semi-conscious or is 

       at risk of having convulsions.  If the eyes are contaminated, 

       wash eyes with running water for ten minutes.  Medical 

       attention is essential if the seeds were ingested, or if the 

       eyes were contaminated.  Collect remaining seeds or plant 

       material or remnants of seeds for identification.

       

       Management principles: induce emesis or perform gastric 

       lavage.  Supportive measures include parenteral fluids and 

       electrolytes.  Keep the patient in hospital for several days 

       because severe symptoms can develop some time after ingestion.

     2.5 Poisonous parts

       The most poisonous parts of the plant involved in poisoning 

       are the small, scarlet seeds, that have a black eye at the 

       hilum.

     2.6 Main toxins

       The main toxin is abrin, which is concentrated in the seeds.

  1. CHARACTERISTICS

     3.1 Description of the plant

       3.1.1 Special identification features

             Abrus precatorius is a slender, perennial climber that 

             twines around  trees, shrubs, and hedges.  It has no 

             special organs of attachment.  Leaves are glabrous with 

             long internodes.  It has a slender branch and a 

             cylindrical wrinkled stem with a smooth-textured brown 

             bark.  Leaves alternate compound paripinnate with 

             stipules.  Each leaf has a midrib from 5 to 10 cm long.  

             It bears from 20 to 24 or more leaflets, each of which 

             is about 1.2 to 1.8 cm long, oblong and obtuse.  It is 

             blunt at both ends, glabrous on top and slightly hairy 

             below.  Flowers are small and pale violet in colour with 

             a short stalk, arranged in clusters.  The ovary has a 

             marginal placentation.

             

             The fruit, which is a pod, is flat, oblong and truncate-

             shaped with a sharp deflexed beak is about 3 to 4.5 cm 

             long, 1.2 cm wide, and silky-textured.  The pod curls 

             back when opened to reveal pendulous seeds.  Each fruit 

             contains from 3 to 5 oval-shaped seeds, about 0.6 cm.  

             They are usually bright scarlet in colour with a smooth, 

             glossy texture, and a black patch on top.

       3.1.2 Habitat

             Abrus precatorius is a wild plant that grows best in 

             fairly dry regions at low elevations.

       3.1.3 Distribution

             It grows in tropical climates such as India, Sri Lanka, 

             Thailand, the Philippine Islands, South China, tropical 

             Africa and the West Indies.  It also grows in all 

 

             tropical or subtropical areas.

     3.2 Poisonous parts of the plant

       The most poisonous part of the plant is the seed. It is 0.6 cm 

       long (although length may vary), and oval-shaped. It is  

       usually bright scarlet, and has a jet-black spot surrounding 

       the hilum which is the point of attachment.  The seed coat, or 

       testa, is smooth and glossy and becomes hard when the seed 

       matures.

     3.3 The toxin(s)

       3.3.1 Name(s)

             Abrin, which consists of abrus agglutinin, and toxic 

             lectins abrins [a] to [d] are the five toxic 

             glycoproteins found in the seeds (Budavari, 1989).

       3.3.2 Description, chemical structure, stability

             Five glycoproteins have been purified from the seeds. 

             They are abrus agglutinin (a haemagglutinin) and the 

             toxic principles abrins [a] to [d].

                  

             Abrus agglutinin is a tetramer with a molecular weight 

             of 134,900. It is non-toxic to animal cells and a potent 

             haemagglutinator.

             

             Abrins a through d (molecular weight: 63,000 - 67,000) 

             are composed of two disulphide-linked polypeptide 

             chains. The larger sub-unit, which is the neutral B-

             chain has a molecular weight of approximately 35,000. 

             The other sub-unit an acidic A-chain has a molecular 

             weight of approximately 30,000 (Windholz, 1983; Budavari,

              1989).

             

             Stability: Pure abrin is a yellowish-white amorphous 

             powder. The toxic portion is heat-stable to incubation 

             at 60°C for 30 minutes. At 80°C most of the toxicity is 

             lost in 30 minutes (Budavari, 1989).

       3.3.3 Other physico-chemical characteristics

             Pure abrin is a yellowish-white amorphous powder. Abrin 

             is soluble in sodium chloride solutions, usually with 

             turbidity (Budavari, 1989).

     3.4 Other chemical contents of the plant

       The seeds also contain an amino acid known as abrine (N-methyl-

       L-tryptophan), glycyrrhizin and a lipolytic enzyme.

       

       The roots, stems, and leaves also contain glycyrrhizin 

       (Windholz, 1983).

  1. USES/CIRCUMSTANCES OF POISONING

     4.1 Uses

       Children are attracted by the brightly-coloured seeds.  

       In some countries theyplay with them and in school use 

       them in their handiwork and to count.  Necklaces and 

       other ornaments made from the seeds are worn by both 

       children and adults.

       

       The seeds were also used to treat diabetes and chronic 

       nephritis.

       

       The plant is also used in some traditional medicine to 

 

       treat scratches and sores, and wounds caused by dogs, 

       cats, and mice, and is also used with other ingredients 

       to treat leucoderma.  The leaves are used for their anti-

       suppurative properties.  They are ground with lime and 

       applied on acne sores, boils, and abscesses.  The plant 

       is also traditionally used to treat tetanus, and to 

       prevent rabies.  Various African tribes use powdered 

       seeds as oral contraceptives (Watt & Breyer, 1962).

       

       Boiled seeds of Abrus precatorius are eaten in certain 

       parts of India (Rajaram& Janardhanan, 1992).

     4.2 High risk circumstances

       Children are attracted to the brightly-coloured seeds and may 

       chew, suck, or swallow them.  Because of the hard and 

       relatively impermeable coat of the mature seeds, they are 

       considerably less toxic if swallowed whole.  They are more 

       dangerous when the seeds are chewed or sucked because the 

       toxic elements in the seeds are extracted and mixed with 

       enzymes.  Immature seeds are also poisonous if ingested 

       because of their soft and easily broken coat.  When the seeds 

       are used as ornaments, such as necklaces, holes are drilled in 

       the seeds, which allows contact between the intestinal 

       secretions and the core of the seed resulting in absorption of 

       the toxic ingredients.

       

       Another reported circumstance is the drinking of beverages 

       where seeds from a necklace have been soaked (Jouglard, 1977). 

        If swallowed, these seeds easily cause poisoning.

     4.3 High risk geographical areas

       The high-risk areas are the dry regions and lowland tropical 

       areas although necklaces are sold in many countries.

  1. ROUTES OF ENTRY

     5.1 Oral

       Abrus precatorius mature or immature seeds are chewed or 

       ingested.

     5.2 Inhalation

       Unknown.

     5.3 Dermal

       Unknown.

     5.4 Eye

       Cold preparations made from soaking the seeds have been used 

       to treat trachoma and corneal opacities (Hart, 1963).

     5.5 Parenteral

       Subcutaneous injections from dried infusions made from the 

       seeds have been used to poison livestock and human beings in 

       India (Hart, 1963).

     5.6 Others

       Unknown.

  1. KINETICS

     6.1 Absorption by route of exposure

       Abrin is very stable in the gastrointestinal tract, from where 

       it is slowly absorbed.  It is considerably less toxic after 

       oral administration than after parenteral injection Gunsolus, 

       1955).

     6.2 Distribution by route of exposure

       Abrin is widely distributed in tissues.

 

     6.3 Biological half-life by route of exposure

       Unknown.

     6.4 Metabolism

       Unknown.

     6.5 Elimination by route of exposure

       Unknown.

  1. TOXICOLOGY/TOXINOLOGY/PHARMACOLOGY

     7.1 Mode of action

       Abrin exerts its toxic action by attaching itself to the cell 

       membranes.  Abrin's toxic effect is due to its direct action 

       on the  parenchymal cells (e.g., liver and kidney cells) and 

       red blood cells (Hart, 1963).  

       

       Both subunits from which abrins [a] through [d] are made up 

       are required for its toxic effects.

       

       The larger subunit, the B chain (haptomere) binds to the 

       galactosyl-terminated receptors on the cell membrane, which is 

       a prerequisite for the entry of the other subunit, the A chain 

       (effectomere).  This inactivates the ribosomes, arrests 

       protein synthesis, and causes cell death (Stirpe & Barbieri, 

       1986).  The A-chain attacks the 60S subunit of the ribosomes 

       and by cutting out elongation factor EF2, stops protein 

       synthesis (Frahne & Pfander, 1983).

       

       Abrus agglutinin agglutinates the red blood cells by combining 

       with the cell stroma (Hart, 1963).

     7.2 Toxicity

       7.2.1 Human data

             7.2.1.1 Adults

                     One seed well masticated can cause fatal 

                     poisoning (Budavari, 1989).

             7.2.1.2 Children

                     One seed well masticated can cause fatal 

                     poisoning (Budavari, 1989).

       7.2.2 Animal data

             Abrin's toxicity has been tested in different animals 

             with widely  divergent results. The lethal dose for 

             animals is about 0.01 mg/kg body weight (Gunsolus, 

             1955).  The intra-peritoneal LD50 value in mice is 0.02 

             mg/kg body weight (Budavari, 1983). The intravenous 

             minimal lethal dose of abrin in mice is 0.7 

             micrograms/kg (Ellenhorn, 1988). Simpson et al. report 

             that 2 ounces of seeds are fatal to horses, but that 

             cows, goats and dogs are more resistant.  The symptoms 

             reported are anorexia, violent vomiting, lassitude, 

             chills, and incoordination.  Severe gastroenteritis is 

             also common in animals (Gosselin, 1984).

       7.2.3 Relevant in vitro data

             No data available.

     7.3 Carcinogenicity

       Unknown.

     7.4 Teratogenicity

       Unknown.

     7.5 Mutagenicity

       Unknown.

 

     7.6 Interactions

       Unknown.

  1. TOXICOLOGICAL/TOXINOLOGICAL 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

  1. CLINICAL EFFECTS

     9.1 Acute poisoning

       9.1.1 Ingestion

             Symptoms and signs can occur after a latent period that 

             ranges from a few hours to several days.  They include a 

             burning sensation in the mouth, dysphagia, nausea, 

             vomiting, bloody diarrhoea, and abdominal cramps.  

             Drowsiness, disorientation, convulsions, cyanosis, 

 

             stupor, circulatory failure, retinal haemorrhages, 

             haematuria and oliguria may occur.

       9.1.2 Inhalation

             Unknown.

       9.1.3 Skin exposure

             Unknown.

       9.1.4 Eye contact

             Eye irritation leads to a dose-related reaction ranging 

             from mild conjunctivitis to a severe damage (Hart, 

             1963).

       9.1.5 Parenteral exposure

             The clinical effects after intravenous and subcutaneous 

             administration are similar to ingestion but 

             gastrointestinal symptoms are lesser.  There is severe 

             inflammation at the injection site.

       9.1.6 Other

             Unknown.

     9.2 Chronic poisoning

       9.2.1 Ingestion

             Unknown.

       9.2.2 Inhalation

             Unknown.

       9.2.3 Skin exposure

             Unknown.

       9.2.4 Eye contact

             Unknown.

       9.2.5 Parenteral exposure

             Unknown.

       9.2.6 Other

             Unknown.

     9.3 Course, prognosis, cause of death

       The major symptoms of poisoning are acute gastroenteritis with 

       nausea, vomiting and diarrhoea leading to dehydration, 

       convulsions, and shock.  Dehydration, as well as direct 

       toxicity on the kidneys, could result in oliguria that might 

       progress to death in uraemia.

                 

       The fatality rate is approximately 5%. 

       

       Reported fatalities occurred after a 3 to 4 day course 

       characterized by persistent gastroenteritis (Ellenhorn, 1988). 

       Death may occur up to 14 days after poisoning from uraemia 

       (Dreisbach & Robertson, 1987).

     9.4 Systematic description of clinical effects

       9.4.1 Cardiovascular

             There is no direct effect on the heart.

             

             Shock, hypotension, and tachycardia may occur after 

             prolonged vomiting and diarrhoea.

       9.4.2 Respiratory

             Cyanosis secondary to hypotension and shock may be seen.

       9.4.3 Neurological

             9.4.3.1 CNS

                     Drowsiness, convulsions, hallucinations, and 

                     trembling of the hands.

             9.4.3.2 Peripheral nervous system

 

                     Unknown.

             9.4.3.3 Autonomic nervous system

                     Unknown.

             9.4.3.4 Skeletal and smooth muscle

                     Unknown.

       9.4.4 Gastrointestinal

             Because of abrin's irritant action, severe 

             gastroenteritis with nausea, vomiting, diarrhoea, 

             dysphagia and abdominal cramps may occur.  Nausea and 

             vomiting are due to direct irritation of the gastric 

             mucosa.  Erosion of  the intestinal mucosa can cause 

             haematemesis and melaena.

       9.4.5 Hepatic

             The necrotizing action of the toxin causes liver damage. 

              Serum levels of liver cell enzymes, i.e., aspartate-

             transferase (AST), alanine-transferase (ALT), and lactic 

             dehydrogenase (LDH) are markedly increased.  The serum 

             bilirubin level is elevated indicating progression of 

             the lesions.  Hypoglycaemia may occur.

       9.4.6 Urinary

             9.4.6.1 Renal

                     Oliguria and anuria may result from prolonged 

                     hypotension, but may also be due to acute renal 

                     failure as a result of focal degeneration of the 

                     tubular cells.  Blocking of the tubules with 

                     haemoglobin from haemolysed red cells may also 

                     contribute to renal failure.

             9.4.6.2 Others

                     Unknown.

       9.4.7 Endocrine and reproductive systems

             Unknown.

       9.4.8 Dermatological

             Skin contact may cause irritation and dermatitis.

       9.4.9 Eye, ears, nose, throat:  local effects

             Eye: Retinal haemorrhages can appear early in the course 

             of intoxication. The patient may complain of impaired 

             vision that is caused by changes in the retina.  Eye 

             contact can cause severe swelling and reddening of the 

             ocular conjunctiva.

             

             Ear, nose, throat: Irritation of the throat may occur 

             after ingestion.

       9.4.10 Haematological

              Abrus agglutinin causes haemagglutination and 

              haemolysis by its direct effect on red cells.  Blood 

              loss may also occur because of haemorrhages in the 

              gastrointestinal tract.

       9.4.11 Immunological

              Unknown.

       9.4.12 Metabolic

              9.4.12.1 Acid base disturbances

                       Prolonged vomiting may cause alkalosis.  Shock 

                       is likely to lead to acidosis.  Acidosis can 

                       also occur from renal failure.

              9.4.12.2 Fluid and electrolyte disturbances

                       Vomiting, diarrhoea, and haemorrhages lead to 

 

                       loss of fluids and electrolytes, thus causing 

                       lethargy, muscle weakness, cardiac  

                       dysrhythmias, and muscle cramps.

              9.4.12.3 Others

                       Liver damage may cause hypoglycaemia.

       9.4.13 Allergic reactions

              Unknown.

       9.4.14 Other clinical effects

              Unknown.

       9.4.15 Special risks

              Unknown.

     9.5 Others

     9.6 Summary

  1. MANAGEMENT

      10.1 General principles

         The management of poisoning cases is mainly symptomatic and 

         supportive.  Induced emesis or gastric lavage are usually 

         indicated (if the conditions of the patient allow the 

         procedures) to remove the seeds from the stomach.  Fluid and 

         electrolyte imbalances should be carefully monitored and 

         corrected.

      10.2 Relevant laboratory analyses and other investigations

         10.2.1 Sample collection

                Collect the seeds or any other plant material for 

                identification, also collect the vomitus or gastric 

                contents in a clean jar.  Seeds may be identified if 

                vomitus is put inside a transparent plastic bag.

         10.2.2 Biomedical analysis

                Full blood count, liver profile, serum electrolytes 

                blood gases, blood urea and creatinine are the 

                essential analyses.  Urinalysis may reveal the 

                presence of protein, red blood cells, haemoglobin, 

                and casts.

         10.2.3 Toxicological/toxinological analysis

                No simple analyses are available in practice.

         10.2.4 Other investigations

                May be indicated according to the patient's 

                condition.

      10.3 Life supportive procedures and symptomatic treatment

         Make a proper assessment of airway, breathing, circulation 

         and neurological status of the patient.

         

         Monitor vital signs.

                   

         Maintain a clear airway. Administer oxygen if the patient is 

         in shock.

         

         Monitor acid base balance, and fluid and electrolyte 

         balance.

                                     

         Give adequate oral fluids by mouth, if possible.  If the 

         patient is unable to swallow, administer intravenous fluids 

         and electrolytes, according to the severity of the symptoms 

         and the results of serum electrolyte analysis.  Correct 

         metabolic acidosis if present.

         

 

         Fluid loss may lead to hypovolaemic shock with hypotension.  

         If the intravenous fluid therapy does not raise the blood 

         pressure, insert a central venous pressure line and give 

         plasma or dextran to expand the intravascular volume. If 

         hypotension still persists consider administration of 

         dopamine or dobutamine in a continuous infusion.

         

         No cases of severe haemolysis have been reported.  However, 

         if significant haemolysis occurs, and if kidney function is 

         normal, maintain the urine output at over 100 ml/hour with 

         alkaline fluids. 

         

         If anuria persists after receiving fluid replacement, 

         consider the possibility of dialysis.

         

         If convulsions occur, administer anti-convulsant drugs 

         (diazepam, intravenously or intrarectally in paediatric 

         emergencies).

                   

         Demulcents may relieve oropharyngeal and gastric irritation. 

      10.4 Decontamination

         Emesis with syrup of ipecacuanha is the best way to remove 

         the seeds or pieces of plant from the stomach unless 

         contraindications to induced emesis exist or orpharyngeal 

         oedema is present.

         

         If emesis induction is not possible, gastric lavage may be 

         performed if the condition of the patient allows it.  If the 

         patient is obtunded, convulsing or comatose, insert an oro- 

         or naso-gastric tube and lavage after endotracheal 

         intubation. 

         

         Cathartics should not be used because they can aggravate 

         diarrhoea and fluid loss.

         

         In case of eye exposure, irrigate eyes with copious amounts 

         of water or saline.

      10.5 Elimination

         No method has proved to be beneficial.

      10.6 Antidote/antitoxin treatment

         10.6.1 Adults

                There is no specific antidote available.

                

                An anti-serum used to be supplied under the name of 

                "anti-abrin" or "jequiritol" (Gunsolus, 1955) but is 

                no longer available.

         10.6.2 Children

                There is no specific antidote available.

                

                An anti-serum used to be supplied under the name of 

                "anti-abrin" or "jequiritol" (Gunsolus, 1955) but is 

                no longer available.

      10.7 Management discussion

         Gastric lavage may be difficult to perform and may not be 

         successful if the size of the seeds is large.  Induction of 

         emesis may be preferred.

 

         

         A cathartic can be administered to accelerate intestinal 

         transit in cases where entire seeds have been recently 

         ingested and no clinical features of poisoning are present. 

         Cathartics are contraindicated in the symptomatic patient.  

         Magnesium sulphate should be avoided when gastrointestinal 

         irritation is present because it may be absorbed 

         systemically.

  1. ILLUSTRATIVE CASES

      11.1 Case reports from literature

         Adults: Some investigators have reported that abrin is 

         poorly absorbed from the intestine.  However, there have 

         been reports of severe, sublethal toxicity in adults after 

         ingestion of only one-half to two seeds (Hart, 1963).  

         

         A 37-year-old man was severely poisoned after ingesting half 

         a seed (Gunsolus, 1955). 

         

         A 19-year-old girl died after she was treated for trachoma 

         with jequirity infusions (Gunsolus, 1955).

         

         An adult, who homogenized 20 seeds in a blender and a 

         portion of the mixture died (Davis, 1978). 

         

         Children: Deaths in children have been reported in Florida, 

         USA, in 1949, 1958 and 1962 after ingestion of one or more 

         seeds.  In 1955, two seeds caused severe but non-fatal 

         poisoning (Hart, 1963).  In Missouri, USA, a child who 

         ingested exactly one-half seed was immediately made forced 

         to vomit.  The remainder of the swallowed half seed, whose 

         coat was broken, was found in the vomitus.  He was treated 

         immediately and did not develop any symptoms (Kinamore, 

         1980).  In most of the cases, the quantity of the seed 

         ingested has been described as the potentially lethal dose 

         in children.

      11.2 Internally extracted data on cases

         To be added by the centre.

      11.3 Internal cases

         To be added by the centre.

  1. ADDITIONAL INFORMATION

      12.1 Availability of antidotes/antitoxins

         No antidotes are available at present.

      12.2 Specific preventive measures

         Do not allow children to play with seeds of Abrus 

         precatorius.

         

         Keep seeds or ornaments made out of seeds away from 

         children.

         

         Do not grow Abrus precatorius plants in home gardens.

         

         Educate older children and the public of the dangers of 

         ingesting seeds.

      12.3 Other

         No data available.

  1. REFERENCES

 

      13.1 Clinical and toxicological

         Budavari S ed. (1989) The Merck Index: an encyclopedia of 

         chemicals, drugs, and biologicals, 10th ed. Rahway, New 

         Jersey, Merck and Co., Inc.

         

         Davis JH (1978)  Abrus precatorius (rosary pea).  The most 

         common lethal plant poison. Journal of Florida Medical 

         Association, 65: 189-191.

         

         Dreisbach RH & Robinson WO eds. (1987)  Handbook of 

         Poisoning: Prevention, Diagnosis & Treatment, Los Altos, 

         California, Appleton and Lange. p 497.

         

         Ellenhorn MJ & Barceloux DG. eds (1988). Medical Toxicology. 

         New York, Elsevier Science Publishing Company, Inc. 1224-

         1225.

         

         Gosselin RE, Smith RP, & Hodge HC (1984) ed. Clinical 

         Toxicology of Commercial Products, Baltimore/London, 

         Williams & Wilkins.

         

         Gunsolus JM (1955).  Toxicity of Jequirity beans.  J Amer 

         Med Assoc, 157: 779.

         

         Hart M (1963).  Jequirity bean Poisoning.  N Engl J Med, 

         268: 885-886.

         

         Hoehne FC (1978). Plantaxe substancias vegetais toxicase 

         medicinais. Sao Paulo, Novos Horizontes, 355p

         

         Jouglard J (1977).  Intoxications d'origine vegetale In: 

         Encycl. Med. Chir.; Intoxication Paris, Editions Techniques, 

         16065 A-10-A-20.

         

         Kinamore PA, Jager RW, De Castro FJ, & Peck KO (1980).  

         Abrus & Ricinus Ingestion:  Management of three cases.  

         Clinical Toxicology, 17(3): 401-405.

         

         Kunkel DB (1983).  Poisonous Plants in: Haddad LM & 

         Winchester JF.  ed. Clinical Management of Poisoning & Drug 

         Overdosage, Canada, W.B. Saunders Company. pp 1012.

         

         Lampe KF (1976).  Changes in therapy in Abrus precatorius & 

         Ricinus communis poisoning suggested by recent studies in 

         their mechanism of Toxicity.  Clinical Toxicology, 9(1): 21.

         

         Lin JY, Tserng, KY, Chen CC, Lin LT, & Tung TC (1970).  

         Abrin & Ricin:  New Anti-tumour Substances.  Nature, 227: 

         292 - 293.

         

         Reynolds JEF, ed (1982) Martindale, The Extra Pharmacopoeia, 

         28th ed. London, Pharmaceutical Press, p 2025 

         

         Rajaram N & Janardhanan K (1992)  The chemical composition 

         and nutritional potential of the tribal pulse, Abrus 

         precatorius L.  Plant Foods Hum Nutr, 42(4): 285-290.

 

         

         Schvartsman S (1979) Plantas venenosas.  Sao Paulo, Sarvier.

         

         Stripe F & Barbieri L (1986).  Symposium: Molecular 

         Mechanisms of Toxicity, Toxic Lectins from Plants.  Human 

         Toxicology, 5(2): 108-109.

         

         Windholz M. ed (1983) The Merck Index: an encyclopedia of   

         chemicals, drugs, and biologicals, 10th ed. Rahway, New 

         Jersey, Merck and Co., Inc.

      13.2 Botanical

         Frohne D & Pfander HJ (1983) ed. A Colour Atlas of Poisonous 

         Plants, Germany, Wolfe Publishing Ltd. pp 291.

  1. AUTHOR(S), REVIEWER(S), DATE(S) (INCLUDING UPDATES), COMPLETE 

    ADDRESS(ES)

    Author:   Dr Ravindra Fernando

              National Poisons Information Centre

              Faculty of Medicine

              Kynsey Road

              Colombo 8

              Sri Lanka

    

              Tel: 94-1-94016

              Fax: 94-1-599231

    

    Date:     September 1988

    

    Reviewer: Dr A. Furtado Rahde

              Poisons Control Centre

              Rua Riachuelo 677/201

              90100 Porto Alegre

              Brazil

    

              Tel: 55-512-275419

              Fax: 55-512-391564

    

    Date:     November 1988

    

    Peer Review:   London, United Kingdom, March 1990

    

    Update:   Dr R. Fernando, London, United Kingdom, June 1993

    

    Review:   IPCS, May 1994

CIMETIDINE

(Group 3)

For definition of Groups, see Preamble Evaluation.

 

VOL.: 50 (1990) (p. 235)

 

CAS No.: 51481-61-9

Chemical Abstr. Name: Guanidine N-cyano-N'-methyl-N"-(2-{[(5-methyl-1H-imidazol-

4-yl)methyl]thio}ethyl)-

 

  1. Summary of Data Reported and Evaluation

5.1 Exposure data

Cimetidine is a histamine H2-receptor antagonist which inhibits gastric acid secretion. Since its introduction in the mid-1970s, it has been used widely by oral administration for the treatment of duodenal and gastric ulcers.

 

Although cimetidine can be nitrosated in vitro in the presence of nitrite under acidic conditions to form N-nitrosocimetidine, no study in experimental animals or in humans has demonstrated that this reaction occurs in vivo.

 

5.2 Experimental carcinogenicity data

Cimetidine was tested for carcinogenicity by oral administration in single studies in mice, rats and dogs. In the experiment in mice, dams were treated throughout life beginning two weeks prior to pregnancy, with no increase in tumour incidence. In female progeny that were exposed throughout life from conception, there was an increase in the incidence of lymphomas, although these tumours also occurred at relatively high rates in control animals. In rats, an increase in the incidence of benign Leydig-cell tumours of the testis was observed in the low- and high-dose groups but not in the mid-dose group. The study in dogs was inadequate for evaluation.

 

In a study in which mice were exposed from conception throughout life to a combination of cimetidine and sodium nitrite, males had an increased incidence of lung neoplasms, although these tumours also occurred at a high frequency in control animals.

 

N-Nitrosocimetidine was tested for carcinogenicity by oral administration in mice and rats and by skin application in mice. The experiments in rats and three of the studies in mice were inadequate for evaluation. In one study by oral administration in mice, there was no increase in the incidence of tumours.

 

5.3 Human carcinogenicity data

In a large number of case reports, cancer, particularly gastric cancer, was diagnosed at various intervals after the start of cimetidine therapy. These reports are difficult to interpret because gastric cancer is a common malignancy and cimetidine is a commonly used drug, and coincidence cannot be ruled out.

 

Three cohort studies showed increased incidences of gastric cancer but also of other gastrointestinal cancers among cimetidine users; however, as for the case reports, the association could well have been due to the drug being given for symptoms of pre-existing cancers. This interpretation is supported by a diminution of the association with increasing duration of follow-up. Two of the studies also showed an association between cimetidine use and lung cancer, but confounding with cigarette smoking could well have been the explanation.

 

5.4 Other relevant data

Cimetidine has been associated with reversible impotence and other antiandrogenic effects in men.

 

N-Nitrosocimetidine is rapidly converted to cimetidine in vivo in experimental animals.

 

Cimetidine did not induce single-strand breaks in DNA from rats treated in vivo, nor did it methylate DNA in a variety of tissues of rats in vivo. It did not induce single-strand breaks in the DNA of rat cells treated in vitro. Cimetidine was not mutagenic to and did not cause DNA damage in Salmonella typhimurium or Escherichia coli. Cimetidine hydrochloride induced single-strand breaks and unscheduled DNA synthesis in rat but not human cells in vitro. It did not cause sister chromatid exchange in human cells in vitro.

 

Cimetidine in combination with sodium nitrite did not induce DNA damage in vivo or methylate DNA in a variety of tissues of rats in vivo. Gastric juice from cimetidine-treated patients was mutagenic to bacteria when enriched with nitrite.

 

N-Nitrosocimetidine has not been demonstrated in gastric juice of humans; however, increased gastric concentrations of nitrite and total N-nitroso compounds have been reported in some studies of patients taking cimetidine. N-Nitrosocimetidine induced DNA damage, sister chromatid exchange, chromosomal aberrations and morphological transformation in mammalian cells in vitro and caused DNA damage and mutation in bacteria. Radiolabelled N-nitrosocimetidine methylated DNA in a variety of tissues of rats in vivo.

 

5.5 Evaluation

There is inadequate evidence for the carcinogenicity of cimetidine in humans.

 

There is inadequate evidence for the carcinogenicity of cimetidine in experimental animals.

 

Overall evaluation

Cimetidine is not classifiable as to its carcinogenicity to humans (Group 3).

 

For definition of the italicized terms, see Preamble Evaluation.

 

Synonyms

Acibilin

Aciloc

Acinil

Altramet

Cianosel

'Cim'

Cimal

Cimegan

Cimet

Cimetid

Cimetidina

Cimetin

Cimetum

Cinamet

Cinulcus

Citimid

Citius

Climatidine

2-Cyano-1-methyl-3-[2-(5-methylimidazo-4-ylmethylthio)ethyl]guanidine

Dina

Duncamet

Duogastril

Duractin

Dyspamet

Edalene

Etidine

Eureceptor

Evicer

Fisiol

Fremet

Gasmetin

Gastrobitan

Gastro H2

Gastromet

Himetin

Itacem

Lucimet

Lucomet

Mansal

Nimus (Udine) gadol

Notrul

Novocimetine

Peptol

Prometidine

Regastric

SKF 92334

Stomakon

Tagacid

Tagama

Tagagel

Tagamet

Tametin

Temic

Tratul

Tratul Retard (SR)

Ulcedine

Ulcenon

Ulcerdine

Ulcerfen

Ulcestop

Ulcidin

Ulcimet

Ulcodina

Ulcomedina

Ulhys

Vagolisal

Valmagen

Last updated: 11 November 1997

    



Myristica fragrans Houtt.

  1. NAME

   1.1 Scientific name

   1.2 Family

   1.3 Common name(s) and synonym(s)

  1. 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

   2.5 Poisonous parts

   2.6 Main toxins

  1. CHARACTERISTICS

   3.1 Description of the plant

      3.1.1 Special identification features

      3.1.2 Habitat

      3.1.3 Distribution

   3.2 Poisonous parts of the plant

   3.3 The toxin(s)

      3.3.1 Name(s)

      3.3.2 Description, chemical structure, stability

      3.3.3 Other physico-chemical characteristics

   3.4 Other chemical contents of the plant

  1. USES/CIRCUMSTANCES OF POISONING

   4.1 Uses

      4.1.1 Uses

      4.1.2 Description

   4.2 High risk circumstances

   4.3 High risk geographical areas

  1. ROUTES OF EXPOSURE

   5.1 Oral

   5.2 Inhalation

   5.3 Dermal

   5.4 Eye

   5.5 Parenteral

   5.6 Others

  1. 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

  1. TOXINOLOGY

   7.1 Mode of action

   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

  1. TOXICOLOGICAL/TOXINOLOGICAL 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

  1. CLINICAL EFFECTS

   9.1 Acute poisoning:

      9.1.1 Ingestion

      9.1.2 Inhalation

      9.1.3 Skin exposure

      9.1.4 Eye contact

      9.1.5 Parenteral exposure

      9.1.6 Other

   9.2 Chronic poisoning

      9.2.1 Ingestion

      9.2.2 Inhalation

      9.2.3 Skin exposure

      9.2.4 Eye contact

      9.2.5 Parenteral exposure

      9.2.6 Other

   9.3 Course, prognosis, cause of death

   9.4 Systematic description of clinical effects

      9.4.1 Cardiovascular

      9.4.2 Respiratory

      9.4.3 Neurological

         9.4.3.1 Central nervous system (CNS)

         9.4.3.2 Peripheral nervous system

         9.4.3.3 Autonomic nervous system

         9.4.3.4 Skeletal and smooth muscle

      9.4.4 Gastrointestinal

      9.4.5 Hepatic

      9.4.6 Urinary

         9.4.6.1 Renal

         9.4.6.2 Other

      9.4.7 Endocrine and reproductive systems

      9.4.8 Dermatological

      9.4.9 Eye, ear, nose, throat: local effects

      9.4.10 Haematological

      9.4.11 Immunological

      9.4.12 Metabolic

         9.4.12.1 Acid-base disturbances

         9.4.12.2 Fluid and electrolyte disturbances

         9.4.12.3 Others

      9.4.13 Allergic reactions

      9.4.14 Other clinical effects

      9.4.15 Special risks

   9.5 Other

   9.6 Summary

  1. MANAGEMENT

   10.1 General principles

   10.2 Life supportive procedures and symptomatic/specific treatment

   10.3 Decontamination

   10.4 Enhanced elimination

   10.5 Antidote/antitoxin treatment

      10.5.1 Adults

      10.5.2 Children

   10.6 Management discussion

  1. ILLUSTRATIVE CASES

   11.1 Case reports from literature

  1. ADDITIONAL INFORMATION

   12.1 Specific preventative measures

   12.2 Other

  1. REFERENCES
  2. AUTHOR(S), REVIEWER(S), DATE(S) (INCLUDING UPDATES), COMPLETE ADDRESS(ES)




    MYRISTICA FRAGRANS

 

    International Programme on Chemical Safety

    Poisons Information Monograph 355

    Plant

 

  1. NAME

 

        1.1  Scientific name

 

             Myristica fragrans Houtt.

 

        1.2  Family

 

             Myristicaceae

 

        1.3  Common name(s) and synonym(s)

 

             mace (UK); muscadier (France); Muskatbaum

             (Germany); myristica; nuez moscada (Uruguay, Spain);

             nutmeg (UK); nutmeg tree (UK); nux moschata;

             Myristica officinalis L.

 

  1. SUMMARY

 

        2.1  Main risks and target organs

 

             -transient psychosis

    

             -possibility of fatty liver and hepatic necrosis

    

             -transient renal toxicity

    

             -possible carcinogen and teratogen

    

             -possibility of death occurring

 

        2.2  Summary of clinical effects

 

             Nutmeg intoxication resembles anticholinergic

             intoxication, e.g. profuse sweating, flushed face, delirium,

             dry throat etc.  There is always an altered state of mind,

             e.g. hallucinations, confusion and an impending sense of

             doom.  Clinical symptoms may be contradictory depending on

             the length of time lapsed after ingesting the toxin. 

             Symptoms also vary according to the dose taken and the

             variability between different samples of nutmegs.

 

        2.3  Diagnosis

 

             Blood: for electrolytes, liver enzymes and renal

             function tests; plus urinalysis.

 

        2.4  First-aid measures and management principles

 

             Management

    

             Treatment is symptomatic and supportive.  The use of

             cathartics, gastric lavage or ipecac may be beneficial if

             they are not contraindicated.  A sedative and anticonvulsant

             may be administered to calm the patient and combat seizures

             should they occur.  A liquid diet high in protein and

             carbohydrate, but low in fat, is recommended.

 

        2.5  Poisonous parts

 

             The seeds (nutmeg) and, to a lesser extent, the aril

             (mace).

 

        2.6  Main toxins

 

             Myristicin and elemicin, but intoxication is not thought

             to be due to these alone.

 

  1. CHARACTERISTICS

 

        3.1  Description of the plant

 

             3.1.1  Special identification features

 

  1. fragrans is a spreading aromatic evergreen

                    tree usually growing to around 5 to 13 metres high,

                    occasionally 20 metres.  The bark contains watery pink

                    or red sap.  The pointed dark green leaves (5 to 15 cm

                    × 2 to 7 cm) are arranged alternately along the

                    branches and are borne on leaf stems about 1 cm long. 

                    Upper leaf surfaces are shiny.  Flowers are usually

                    single sexed; occasionally male and female flowers are

                    found on the same tree.  Female flowers arise in

                    groups of 1 to 3; males in groups of 1 to 10.  Flowers

                    are pale yellow, waxy, fleshy and bell-shaped.  Male

                    flowers are 5 to 7 mm long; female flowers are up to

                    1 cm long.  The fruits are fleshy, drooping, yellow,

                    smooth, 6 to 9 cm long with a longitudinal ridge. 

                    When ripe, the succulent yellow fruit coat splits into

                    2 valves revealing a purplish-brown, shiny seed

                    (nutmeg) surrounded by a red aril (mace).  Seeds

                    (nutmegs) are broadly ovoid (2 to 3 cm long), firm,

                    fleshy, whitish and transversed by red-brown veins. 

                    When fresh, the aril (mace) is bright scarlet becoming

                    more horny, brittle and a yellowish-brown colour when

                    dried (Purseglove, 1968).

    

 

                    The tree does not flower until around 9 years old,

                    when it fruits; it can continue to do so for a further

                    75 years.  The tree bears 2 to 3 crops a year.  The

                    seeds (nutmegs) need 3 to 6 weeks to dry before they

                    are ready for use.

 

             3.1.2  Habitat

 

                    Grows wild on rich volcanic soils in lowland

                    tropical rain forests.  Its cultivation as a crop is

                    largely confined to islands in the hot, humid tropics

                    at altitudes up to 4,500 metres (Purseglove,

                    1968).

 

             3.1.3  Distribution

 

                    Indigenous to the Moluccas and Banda Islands in

                    the South Pacific although it is seldom found truly

                    wild.  It is now cultivated in tropical regions,

                    especially Indonesia, Grenada in the West Indies and

                    Sri Lanka (Purseglove, 1968; Bown, 1995).

 

        3.2  Poisonous parts of the plant

 

             Seeds (nutmegs) and to a lesser extent the aril

             (mace).

    

             Nutmeg oil:

    

             Nutmeg oil is also known as oleum myristicae, ol. myrist.,

             myristica oil, essence de muscade, atheririsches muskatol,

             essencia de moscada and essencia de nuez moscada.  It is a

             volatile oil obtained by steam distillation from the seed. 

             It is a colourless or pale yellow liquid with an odour and

             taste of nutmeg.  It is scarcely distinguishable from the

             volatile oil of mace and frequently no commercial distinction

             is made between the two.  There are two types of nutmeg oil,

             mainly East Indian Nutmeg Oil and West Indian Nutmeg Oil. 

             The East Indian Nutmeg Oil has a weight of 0.885 to 0.915

             g/mL and is soluble in 90% alcohol at a ratio of 1 part oil

             to 3 parts alcohol.  West Indian Nutmeg Oil has a weight of

             0.86-0.88 g/mL and is soluble in 90% alcohol at a ratio of 1

             part oil to 4 parts alcohol.  Nutmeg oil should be stored in

             a cool place in well filled airtight containers and protected

             from light.

    

             Nutmeg Butter:

    

             Nutmeg butter, also known as balsam of nutmegs, oil of mace,

             butter of mace, Banda soap and oleum myristicae expressum is

             the fixed oil component of the seed (nutmeg).  It accounts

             for 25 to 40% of the nutmeg's weight and it is a solid at

 

             room temperature.  Sometimes it occurs in the form of

             prismatic crystals.  It is obtained by exposing the nuts to

             hydraulic pressure and heat.

    

             Pharmacologically active parts of the plant:

    

             The most important part of the plant in terms of its

             pharmacological activity and also in commerce, is of course

             the dried kernel (seed), the nutmeg.  Intoxication from the

             use of the aril of the fruit (seed case), generally known as

             mace, has also been reported, but only rarely.  The oil of

             nutmeg has also been used for medicinal purposes and it is

             this fraction of the nutmeg which is strongly suspected of

             harbouring the pharmacologically active components of

             nutmeg.

 

        3.3  The toxin(s)

 

             No single component of the nutmeg has been identified as

             responsible for all the symptoms seen during intoxication. 

             It is widely believed that myristicin is the major component

             responsible, however, it alone cannot reproduce all the

             symptoms.  Shulgin (1966) suggests that myristicin and

             elemicin may not be the active ingredients but they may be

             metabolized in the body to 3-methoxy-4,5-methylenedioxy

             amphetamine (MMDA) and elemicine, an ether analogous to

             myristicin, 3,4,5-trimethoxy amphetamine (TMA).

 

             3.3.1  Name(s)

 

                    Myristicin:

                    CAS number:   607-91-0

                    Molecular formula: C11H12O3

                    Molecular weight: 192.21

    

                    Elemicin:

                    CAS number:  487-11-6

                    Molecular formula:  C12H16O3

                    Molecular weight: 208.26

                    (Harborne & Baxter, 1996).

 

             3.3.2  Description, chemical structure, stability

 

                    Components of nutmeg

    

                    The major components in M. fragrans are terpenes,

                    terpene alcohols and phenolic ethers.  The major

                    phenolic ether is myristicin (4-methoxy-6-(2-

                    propenyl)-1,3-benzadioxole) accompanied by safrole

                    (5-(2-propenyl)-3-benzodioxole) and eugenol methyl

                    ether (3,4,-dimethoxy-(2-propenyl)-benzene). 

                    Myristicin accounts for about 2.12 to 2.88% of the

                    total weight of the nutmeg where as safrole accounts

 

                    for 0.27 to 0.39%.  The volatile oil content of nutmeg

                    depends on the geographical origin and length of

                    storage.  Chemical analysis has shown that even though

                    there is a real variability between the quality

                    (differences in composition) and quantity of nutmeg

                    oil from various samples of nutmegs oil accounts for

                    84 to 95% of the total aromatic fraction of the

                    volatile oil from all the samples tested.  In the

                    samples, myristicin, safrole and elemicin accounted

                    for 3.86 to 12.7%, 0.53 to 3.42% and 0.02 to 2.36%,

                    respectively of the nutmeg oil samples.  Early work on

                    myristicin used myristicin distilled from nutmeg oil. 

                    It has been subsequently proven that myristicin

                    extracted from nutmeg via this method is not elemicin

                    free and therefore the effects reported may be due to

                    either substances found in the extract.

 

             3.3.3  Other physico-chemical characteristics

 

                    No data available.

 

        3.4  Other chemical contents of the plant

 

             No data available.

 

  1. USES/CIRCUMSTANCES OF POISONING

 

        4.1  Uses

 

             4.1.1  Uses

 

                    Miscellaneous pharmaceutical product

                    Other therapeutic preparation

                    Food; 

                    general

                    Beverage; general

 

             4.1.2  Description

 

                    Medicinal:

    

                    Used as an anti-diarrhoea agent for patients with

                    medullary carcinoma of the thyroid.  The effectiveness

                    of the treatment may be due to the inhibition of

                    prostaglandin synthesis in the mucosa and submucosa of

                    the colon.  The dosage given was 9 tablespoons orally

                    per day but it may vary between patients to avoid

                    toxic symptoms.

    

                    Domestic:

    

                    Used as a spice in various dishes, as components of

                    teas and soft drinks or mixed in milk and alcohol.

                    Traditional and folk medicine:

    

 

                    It is widely used as a traditional medicine in the

                    Middle East and Asia.

    

                    In Western medicine nutmeg is sometimes used as a

                    stomachic, stimulant, carminative as well as for

                    intestinal catarrh and colic, to stimulate appetites,

                    to control flatulence, and it has a reputation as a

                    emmenagogue and abortifacient.

 

        4.2  High risk circumstances

 

             Abuse

    

             Nutmeg has been known for its hallucinogenic properties for a

             long time.  Adults may abuse the hallucinogenic properties of

             nutmeg.  Children may be at high risk at home, since nutmeg

             may be widely available as a cooking additive.  In the course

             of its use in traditional medicine, overdose may occur.

 

        4.3  High risk geographical areas

 

             No data available.

 

  1. ROUTES OF EXPOSURE

 

        5.1  Oral

 

             This is the most common method of consuming nutmeg, be

             it as a remedy, a spice or as a psychotropic drug.

 

        5.2  Inhalation

 

             Nutmeg is mixed with tobacco snuff in certain parts of

             southern India.  Intoxication through this method of

             administration is reported to be the same as for intoxication

             through oral administration, except that the onset of

             symptoms is faster.

 

        5.3  Dermal

 

             No data available.

 

        5.4  Eye

 

             No data available.

 

        5.5  Parenteral

 

             Reported only in experimental animals.  The effects are

             reported to be the same as those when given orally.

 

        5.6  Others

 

             No data available.

 

  1. KINETICS

 

        6.1  Absorption by route of exposure

 

             No detailed studies are available concerning the

             absorption of the active principles involved in nutmeg

             poisoning.  Current literature states that when nutmeg powder

             is administered orally, the toxic effects begin within 1 to

             12 hours.  The effects last generally for 24 hours but may

             continue for as long as a week or more.  When taken as a tea,

             the reaction is reported to be immediate.  Snuffing nutmeg is

             reported to produce a reaction within 15 minutes.

 

        6.2  Distribution by route of exposure

 

             No data available.

 

        6.3  Biological half-life by route of exposure

 

             No data available.

 

        6.4  Metabolism

 

             3,4,5,-trimethoxy amphetamine (TMA):

    

             It has been postulated that elemicin, a major component in

             nutmeg oil, could undergo oxidation of its oleficin side

             chain in the same manner that the mentioned side chain in

             safrole is also oxidized in the body.  This would produce a

             vinyl alcohol which could under go transamination to produce

             TMA.

    

             The potency of TMA is reported to be more than that of

             mescaline as a psychotropic drug.

    

             3-methoxy-4,5-methylenedioxy amphetamine (MMDA):

    

             It has been proposed that myristicin may be metabolized in

             the body to MMDA in a manner similar to the metabolism of

             elimicin into TMA.

    

             MMDA is reported to have a higher potency than TMA as a

             psychotropic  drug, that is, its potency is about three times

             the potency of mescaline.  It has almost the same properties

             as TMA, being both hallucinogenic and permitting total recall

             of the experience.

 

        6.5  Elimination and excretion

 

             No data available.

 

  1. TOXINOLOGY

 

        7.1  Mode of action

 

             3,4,5,-trimethoxy amphetamine (TMA):

 

             It has been postulated that elemicin, a major component in

             nutmeg oil, could undergo oxidation of its oleficin side

             chain in the same manner that the mentioned side chain in

             safrole is also oxidized in the body.  This would produce a

             vinyl alcohol which could under go transamination to produce

             TMA.

    

             The potency of TMA is reported to be more than that or

             mescaline as a psychotropic drug.

    

             3-methoxy-4,5-methylenedioxy amphetamine (MMDA):

    

             It has been proposed that myristicin may be metabolized in

             the body to MMDA in a manner similar to the metabolism of

             elimicin into TMA.

    

             MMDA is reported to have a higher potency than TMA as a

             psychotropic  drug, that is, its potency is about three times

             the potency of mescaline.  It has almost the same properties

             as TMA, being both hallucinogenic and permitting total recall

             of the experience.

    

             Nutmeg has monoamineoxidase inhibition properties (1963). 

             Nutmeg is also known to have anti-prostaglandin synthesis

             effects.

 

        7.2  Toxicity

 

             7.2.1  Human data

 

                    7.2.1.1  Adults

 

                             The dose needed to induce

                             intoxication varies according to the quality

                             and length of storage of the nutmeg.  1 to 3

                             nutmegs (5 to 15 g) is reported as the toxic

                             dose (Haddad & Winchester, 1983).

 

                    7.2.1.2  Children

 

                             Death by nutmeg intoxication has

                             been reported by Cushny (Weil, 1964) in an 8-

                             year-old boy after consuming 2 nutmegs.

 

             7.2.2  Relevant animal data

 

                    In cats, an oral dose of 24 mg nutmeg oil per

                    kg body weight was found to be lethal.

 

             7.2.3  Relevant in vitro data

 

                    No data available.

 

        7.3  Carcinogenicity

 

             Safrole is a known mild hepatocarcinogen.  Although

             safrole itself is not carcinogenic, it is metabolized to form

             1'-hydroxysafrole which is carcinogenic.  Data are not

             available on the carcinogenicity of nutmeg itself.

 

        7.4  Teratogenicity

 

             Verrett (Wulf et al., 1978) reports that myristicin may

             be a strong teratogen.

 

        7.5  Mutagenicity

 

             No data available.

 

        7.6  Interactions

 

             Consideration should be given to possible nutmeg-ethanol

             interaction since nutmeg has hallucinogenic and MAO

             inhibition effects.

 

  1. TOXICOLOGICAL/TOXINOLOGICAL 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

 

        8.6  References

 

  1. CLINICAL EFFECTS

 

        9.1  Acute poisoning:

 

             9.1.1  Ingestion

 

                    In the toxic state, the patient first feels

                    excited and may have psychedelic hallucinations.  This

                    is followed by a period of drowsiness, delirium and,

                    possibly, unconsciousness.  Thirst has been reported.  

                    Mental concentration may either be impaired or

                    enhanced;  delirium with agitation, disorientation and

                    incoherence may develop.  Prison inmates taking nutmeg

                    "trips" have compared it to alcohol, heroin and

                    marihuana and referred to it as making them feel

                    "high", relaxed and drowsy.  Some reported a sleepy

                    feeling, others, restlessness and tense.  Most

                    patients with accidental nutmeg intoxication

                    experience an impending sense of doom after the

                    initial excitation.  The effects of nutmeg are most

                    often compared to those of marihuana.  Although the

                    hallucinogenic effects of nutmeg are satisfactory, the

                    side effects often discourage its use as such an

                    agent.  One reported case of nutmeg intoxication after

                    drinking nutmeg tea, states that the reaction is

                    immediate.

 

             9.1.2  Inhalation

 

                    The effects by inhalation are generally similar

                    to those experienced via oral administration with the

                    exception that onset is faster by 15 minutes.

 

             9.1.3  Skin exposure

 

                    No data available.

 

             9.1.4  Eye contact

 

                    No data available.

 

             9.1.5  Parenteral exposure

 

                    Parenteral exposure in animals has shown to

                    produce the same general effect as that of oral

                    exposure.

 

             9.1.6  Other

 

                    No data available.

 

        9.2  Chronic poisoning

 

             9.2.1  Ingestion

 

                    Chronic poisoning by oral administration has

                    caused temporary (up to six months) psychosis in

                    prison inmates.

 

             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

 

                    No data available.

 

             9.2.6  Other

 

        9.3  Course, prognosis, cause of death

 

             Not all the symptoms listed below appear in every case

             of poisoning.  Contradicting symptoms may occur at different

             times during the course of intoxication.

    

             The subject initially feels excited, then drowsy before a

             delirious state sets in.  This is followed by a deep sleep. 

             During this period, cyanosis of the extremities and

             convulsions may occur.  Generally there is tachycardia and an

             increase in blood pressure.  Acidosis may set in because of

             diarrhoea and vomiting which is usually present along with

             various other gastrointestinal symptoms such as abdominal

             cramps.  The subject may or may not be hallucinating but

             usually expresses a feeling of impending doom.  Nutmeg

             intoxication usually clears by itself within 24 hours,

             however, it has been reported that psychosis may set in. 

             Transient renal toxicity has also been reported causing an

             increase in albumin and non-protein nitrogen content in the

             urine, returning to normal within 24 hours.

    

             Nutmeg has been proven to cause fatty liver in cats which

             have later died from the dose of nutmeg oil but, in the case

             of humans, this is not clear since only one death has been

             attributed to nutmeg toxicity: an 8-year-old boy who became

             comatose and later died after ingesting two nutmegs.

 

        9.4  Systematic description of clinical effects

 

             9.4.1  Cardiovascular

 

                    Tachycardia.

                    Hypertension or hypotension may occur.

                    Chest pains or tightness in chest.

 

             9.4.2  Respiratory

 

                    No data available.

 

             9.4.3  Neurological

 

                    9.4.3.1  Central nervous system (CNS)

 

                             Severe headaches.

                             Drowsiness several hours after taking nutmeg.

                             Fitful sleep/convulsions.

                             Hallucinations (predominantly visual). Colour

                             distortion may also occur.

                             Delirium.

                             Unconsciousness/coma.

                             Agitation.

                             Disorientation.

                             Incoherence.

    

 

                             Sedation.

                             Euphoria.

                             Concentration may be impaired or improved.

                             Excitation resembling that caused by

                             anticholinergic intoxication.

                             Florid paranoia.

                             Belligerence.

                             Vertigo.

                             Stupor.

                             Feeling of impending doom.

    

                             Sometimes unusual behaviour occurs during

                             intoxication such as hysteria and wild

                             trashing of limbs, and behaviour resembling

                             that of a snarling dog.

 

                    9.4.3.2  Peripheral nervous system

 

                             Initial stimulation after

                             administration.

                             Strong tingling in the fingers and toes

                             shortly after snuffing some nutmeg.

                             Numbness in hand and feet half an hour after

                             snuffing nutmeg.

                             Absent limb reflexes.

 

                    9.4.3.3  Autonomic nervous system

 

                             Profuse sweating several hours after

                             administration possibly reflecting

                             amphetamine-type reaction.

                             Absence of salivation.

 

                    9.4.3.4  Skeletal and smooth muscle

 

                             Muscular excitation several hours

                             after administration.

 

             9.4.4  Gastrointestinal

 

                    Nausea.

                    Vomiting.

                    Diarrhoea.

                    Abdominal pain.

 

             9.4.5  Hepatic

 

                    Hepatic necrosis in heavy poisoning.

                    Fatty degradation of liver.

 

             9.4.6 Urinary

 

                    9.4.6.1  Renal

 

                             Transient renal toxicity producing

                             albuminuria.  Non-protein nitrogen content in

                             urine which returns to normal within 24

                             hours.

 

                    9.4.6.2  Other

 

                             No data available.

 

             9.4.7  Endocrine and reproductive systems

 

                    No data available.

 

             9.4.8  Dermatological

 

                    Flushed skin.

 

             9.4.9  Eye, ear, nose, throat:  local effects

 

                    Eyes: A drawing sensation over the eyes after

                    snuffing.

                    Miosis (initially or it may not occur)

                    Mydriasis (occurs less often than miosis)

    

                    Throat: Epigastric pain

 

             9.4.10 Haematological

 

                    No data available.

 

             9.4.11 Immunological

 

                    No data available.

 

             9.4.12 Metabolic

 

                    9.4.12.1 Acid-base disturbances

 

                             Acidosis may be attributed to

                             excessive diarrhoea and vomiting.

 

                    9.4.12.2 Fluid and electrolyte disturbances

 

                             Fluid and electrolyte disturbance

                             may develop because of diarrhoea and

                             vomiting.

 

                    9.4.12.3 Others

 

                             Hypothermia/hyperthermia.

 

             9.4.13 Allergic reactions

 

                    Oedema of eyelids.

                    Possible elevation in body temperature.

                    Marked flushing and itching of face.

                    Allergic reactions tend to subside quickly.

 

             9.4.14 Other clinical effects

 

                    Severe thirst.

 

             9.4.15 Special risks

 

                    Nutmeg has been used as an abortifacient but

                    there are no confirmed clinical accounts.

 

        9.5  Other

 

             No data available.

 

        9.6  Summary

 

  1. MANAGEMENT

 

        10.1 General principles

 

             Treatment is supportive.  Decontamination procedures,

             such as gastric lavage and cathartics, are theoretically

             beneficial within the first few hours but be aware of any

             contraindications before their administration.  Syrup of

             ipecac is not advisable because it may precipitate

             convulsions.  Milk or a demulcent may be given to alleviate

             gastric irritation.

 

        10.2 Life supportive procedures and symptomatic/specific treatment

 

             Nasal oxygen may be administered to patients suffering

             from vertigo.  Barbiturates or diazepam may be given for

             convulsions and analeptics such as chlorpromazine  (25 mg

             every 4 hours) for severe agitation.  Sedatives should be

             administered with caution since the patient goes through

             alternating periods of delirium and lethargy.  A liquid diet

             is recommended, high in protein and carbohydrate and low in

             fat.  Wash eyes if they are physically contaminated by nutmeg

             powder.  Monitor cardiac function and blood pressure and

             treat as necessary.

 

        10.3 Decontamination

 

             Decontamination procedures such as gastric lavage and

             cathartics are theoretically beneficial within the first few

             hours but be aware of any contraindications before their

             administration. Syrup of ipecac is not advisable because it

             may precipitate convulsions.  Milk or a demulcent may be

             given to alleviate gastric irritation.

 

        10.4 Enhanced elimination

 

             No data available.

 

        10.5 Antidote/antitoxin treatment

 

             10.5.1 Adults

 

                    No data available.

 

             10.5.2 Children

 

                    No data available.

 

        10.6 Management discussion

 

             No data available.

 

  1. ILLUSTRATIVE CASES

 

        11.1 Case reports from literature

 

             Two male college students, 19 and 20 years of age, each

             ingested 2 tablespoons (about 14 gm) of powdered nutmeg

             suspended in a glass of milk to produce a sense of

             exhilaration.  Five hours later, rapid heart rates and

             palpitations were noted and both complained of dry mouths and

             thirst.  Onlookers observed that one student became

             hyperactive, agitated and talked incoherently.  Their faces

             were "red as beets".  Nausea, vomiting and abdominal cramps

             were absent.  60 hours were needed for full recovery.

    

             A 37 year old woman drank a nutmeg tea at a party.  The tea

             consisted of two ground nutmegs in a glass of warm water. 

             She had flushed skin, rapid pulse, incoherent speech and felt

             giddy after 4 hours.  Her vision was disturbed and she had

             hallucinations of faces laughing at her and monsters in the

             bed trying to engulf her.  Symptoms gradually diminished and

             recovery made within 24 hours.

 

  1. ADDITIONAL INFORMATION

 

        12.1 Specific preventative measures

 

             No information available.

 

        12.2 Other

 

             No information available

 

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  1. AUTHOR(S), REVIEWER(S), DATE(S) (INCLUDING UPDATES), COMPLETE

        ADDRESS(ES)

 

        Author: UKM

        Kuala Lumpur

        Malaysia

    

        Date: April 1991

    

        Peer Review: Singapore, November 1991

    

        General edit and botanical review:

    

        Christine Leon

        Medical Toxicology Unit

        Guy's & St Thomas Hospital Trust

        c/o Royal Botanic Gardens, Kew

        Richmond

        Surrey

        TW9 3AB

        United Kingdom

    

        Tel: +44 (0) 181 332 5702

        Fax: +44 (0) 181 332 5768

        e-mail: c.leon@rbgkew.org.uk

    

        July 1997