CBD for Autoimmune Diseases
Can CBD help with autoimmune diseases, and if so, how?
Autoimmunity is an "attack on the self."(1) When the body's natural defense system is unable to tell the difference between its innate cells and foreign cells, autoimmune disease happens (2).
When the immune system gets triggered, it thinks that the body's healthy tissues are invaders, causing the body to attack normal cells mistakenly.
Adaptive immune cells T cells (thymus cells) and B cells (bone marrow-derived cells) are the primary cellular components of the adaptive immune response of the body’s immune system.
In an autoimmune response, T cells take action, as if the body's cells were foreign, to bring the body back into homeostasis. This self-attack is the root of autoimmune diseases (3).
Traditional medications that are used to treat autoimmune conditions are immunosuppressive and synthetically produced.
Unfortunately, as these medicines shut down the overactive immune system, they also leave individuals more susceptible to infection and illness.
CBD and Autoimmune Diseases: What the Research Says
Data from a review published in Cannabis and Cannabinoid Research in 2020 overwhelmingly support the concept that CBD is immunosuppressive (suppresses immune response) (4).
Cannabis is known to be immune-modulating, meaning they can bring an over- or under-reacting immune system back into balance (5).
Research has shown that cannabis therapies may provide benefits for autoimmune diseases in three ways: modulating the immune system, reducing general inflammation, and helping with the digestive system (6).
Cannabis medicine has been shown to help treat symptoms of specific autoimmune diseases (also called autoimmune disorders), such as amyotrophic lateral sclerosis (ALS), rheumatoid arthritis, multiple sclerosis, Crohn's disease, fibromyalgia, and Huntington disease.
CBD may also help reduce chronic pain, inflammation, and spasms associated with some of these conditions (7).
CBD’s potent anti-inflammatory properties were demonstrated in a 2018 study published in the Journal of Pharmacology and Experimental Therapeutics (8).
Extensive studies have also reported the anti-inflammatory benefits of CBD for specific autoimmune disorders, like multiple sclerosis and rheumatoid arthritis (9).
How CBD Works to Control Immune Response
The therapeutic effects of cannabinoids, such as CBD (cannabidiol) and THC (tetrahydrocannabinol), are realized by their interaction with the body's endocannabinoid system (ECS) and its cannabinoid receptors.
Integral to the body's physiologies, the ECS is responsible for regulating various body functions, such as immune response, pain sensation, metabolism, anxiety, sleep, mood, appetite, and memory.
For instance, it is through the interaction with cannabinoid receptors that anandamide, an intestinal cannabinoid, functions. Anandamide regulates appetite and stress response (10).
CB1 and CB2 receptors are found in specific parts of the human body, and each type of receptors have particular roles in the ECS.
CB1 receptors are mostly located in the central nervous system and the brain (11). Meanwhile, CB2 receptors are mostly found on cells in the immune system and its associated structures.
Once the CB2 receptor is triggered, it stimulates a response that combats inflammation, reducing pain and minimizing tissue damage.
This anti-inflammatory response is useful for treating inflammation-related conditions, such as Crohn's disease, arthritis, and inflammatory bowel syndrome (12).
CBD indirectly acts against cannabinoid agonists, which are substances that attach to a cannabinoid receptor and induce the same action as the substances that typically bind to the receptor.
CBD also interacts with other receptors in the body, such as the 5-HT1A receptor, which is linked to serotonin, a neurotransmitter believed to contribute to feelings of well-being. Through this interaction, these cannabinoids promote healing and balance (13).
Autoimmune conditions are an area of medicine that remain widely misunderstood. While more than 80 registered autoimmune disorders are affecting various parts of the body, more conditions may prove to be also autoimmune-related (14).
Many causes of autoimmune diseases are shared or linked to other causes. Thus, people living with an autoimmune disease are more likely to suffer from more than one of these conditions (15).
Cannabinoid therapies may help decrease inflammation, modulate the immune system, and help bring the system back into balance (16).
Studies have shown that CBD’s anti-inflammatory benefits might help treat symptoms of specific autoimmune disorders.
However, more research is needed to understand CBD’s impact on autoimmunity and determine CBD’s long-term side effects.
Before using CBD or any CBD products, such as CBD tincture (CBD oil), gummies, salves, lotions, and patches, consult with a doctor experienced in cannabis use for advice.
NEUROLEPTIC MALIGNANT SYNDROME DEFINITION A life-threatening idiosyncratic reaction characterized by muscle rigidity and hyperthermia, related to acute dopamine depletion, either from the use of neuroleptic drugs or of dopamine antagonists, or the withdrawal of dopamine agonists. TOXIC CAUSES Exposure to therapeutic doses of potent neuroleptic drugs (eg, haloperidol, fluphenazine) or the sudden cessation of dopamine agonists such as amantidine. Reported risk factors include dehydration and the concurrent use of lithium and tricyclic antidepressants. CLINICAL FEATURES Extreme hyperpyrexia, lead-pipe muscular rigidity, autonomic dysfunction (tachycardia, elevated or fluctuating blood pressure), sweating, tachypnoea, respiratory failure, altered mental status (confusion, delirium, stupor and coma), extrapyramidal signs (e.g. cogwheel hypertonia). Acute myoglobinuric renal failure may occur. The condition is fatal in up to 12 % of cases DIFFERENTIAL DIAGNOSIS Anticholinergic poisoning Catatonia CNS infections CNS mass lesions Ethanol or sedative-hypnotic drug withdrawal Extrapyramidal symptoms with fever Heat-stroke (environmental or exertional) Malignant hyperthermia Metal fume fever Psychiatric disorders Septicaemia Strychnine poisoning Thyroid storm Tetanus Tetany RELEVANT INVESTIGATIONS Laboratory tests are generally non-specific, but may be used to exclude alternative diagnoses. Arterial blood gases - metabolic acidosis is usually present. Creatinine phosphokinase activity - commonly elevated; marked elevations may indicate a serious risk of acute renal failure. CT scan of the head may be obtained to rule out CNS lesions. Electrolytes - hyperkalaemia, hyper- or hyponatraemia, hypocalcaemia. Liver function tests are not characteristic, but may be elevated. Lumbar puncture to rule out CNS infection. Renal function - urea, creatinine. Standard fever work-up to rule out infections. Urinalysis - urinary myoglobin or myoglobin casts may be present White blood cell count - leukocytosis may be present, (between 12,000 and 30,000 /mm3, with or without left shift). TREATMENT 1. Intravenous fluids should be given to rapidly expand intravascular volume which is depleted due to dehydration, fever, shivering, tremors and vasodilation. Crystalloid solutions are preferred. 2. Cooling measures should be instituted immediately to control hyperthermia. 3. Muscle relaxants should be administered when hypertonia is present. Dantrolene has been reported successful in several case reports, and is given at a dose of 1 mg/kg IV push, then repeated every 1 to 3 minutes until muscle relaxation is obtained (total dose not to exceed 10 mg/kg). In certain cases, muscle paralysis (with pancurorium) may be required. 4. The dopamine agonist, bromocriptine, may be given orally or by gastric tube, at a dose of 2.5 to 10 mg from 2 to 6 times per day (total dose of 5 to 30 mg/day). 5. Calcium channel blockers, such as nifedipine have been reported to reverse many NMS signs, such as hypertension, fever, tachycardia, urinary incontinence, rigidity and stupor. The mechanism is not yet clear. LONG-TERM COMPLICATIONS Brain damage (coma, brain lesions, irreversible brain damage). AUTHOR(S)/REVIEWERS Author: Dr Anthony Wong, Director, Jabaquara Poisons Center, Sao Paulo, Brazil. Peer review: Berlin 10/95, Cardiff 9/96: V. Afanasiev, M. Burger, T. Della Puppa, L. Fruchtengarten, K. Olsen, J. Szajewski.
Azathioprine 1. NAME 1.1 Substance 1.2 Group 1.3 Synonyms 1.4 Identification numbers 1.4.1 CAS number 1.4.2 Other numbers 1.5 Main brand names/main trade names 1.6 Main manufacturers/main importers 1.7 Presentation/formulation 2. SUMMARY 2.1 Main risks and target organs 2.2 Summary of clinical effects 2.3 Diagnosis 2.4 First-aid measures and management principles 3. PHYSICO-CHEMICAL PROPERTIES 3.1 Origin of the substance 3.2 Chemical structure 3.3 Physical properties 3.3.1 Properties of the substance 188.8.131.52 Colour 184.108.40.206 State/form 220.127.116.11 Description 3.3.2 Properties of the locally available formulation 3.4 Other characteristics 3.4.1 Shelf-life of the substance 3.4.2 Shelf-life of the locally available formulation 3.4.3 Storage conditions 3.4.4 Bioavailability 4. USES 4.1 Indications 4.1.1 Uses 4.1.2 Description 4.2 Therapeutic dosage 4.2.1 Adults 4.2.2 Children 4.3 Contraindications 5. ROUTES OF ENTRY 5.1 Oral 5.2 Inhalation 5.3 Dermal 5.4 Eye 5.5 Parenteral 5.6 Others 6. KINETICS 6.1 Absorption by route of exposure 6.2 Distribution by route of exposure 6.3 Biological half-life by route of exposure 6.4 Metabolism 6.5 Elimination by route of exposure 7. PHARMACOLOGY AND TOXICOLOGY 7.1 Mode of action 7.1.1 Toxicodynamics 7.1.2 Pharmacodynamics 7.2 Toxicity 7.2.1 Human data 18.104.22.168 Adults 22.214.171.124 Children 7.2.2 Relevant animal data 7.2.3 Relevant in vitro data 7.3 Carcinogenicity 7.4 Teratogenicity 7.5 Mutagenicity 7.6 Interactions 7.7 Main adverse effects 9. CLINICAL EFFECTS 9.1 Acute poisoning 9.1.1 Ingestion 9.1.2 Inhalation 9.1.3 Skin exposure 9.1.4 Eye contact 9.1.5 Parenteral exposure 9.1.6 Other 9.2 Chronic poisoning 9.2.1 Ingestion 9.2.2 Inhalation 9.2.3 Skin exposure 9.2.4 Eye contact 9.2.5 Parenteral exposure 9.2.6 Other 9.3 Course, prognosis, cause of death 9.4 Systematic description of clinical effects 9.4.1 Cardiovascular 9.4.2 Respiratory 9.4.3 Neurological 126.96.36.199 CNS 188.8.131.52 Peripheral nervous system 184.108.40.206 Autonomic nervous system 220.127.116.11 Skeletal and smooth muscle 9.4.4 Gastrointestinal 9.4.5 Hepatic 9.4.6 Urinary 18.104.22.168 Renal 22.214.171.124 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 126.96.36.199 Acid-base disturbances 188.8.131.52 Fluid and electrolyte disturbances 184.108.40.206 Others 9.4.13 Allergic reactions 9.4.14 Other clinical effects 9.4.15 Special risks 9.5 Other 10. MANAGEMENT 10.1 General principles 10.2 Relevant laboratory analyses 10.2.1 Sample collection 10.2.2 Biomedical analysis 10.2.3 Toxicological analysis 10.2.4 Other investigations 10.3 Life supportive procedures and symptomatic/specific treatment 10.4 Decontamination 10.5 Elimination 10.6 Antidote treatment 10.6.1 Adults 10.6.2 Children 10.7 Management discussion 11. ILLUSTRATIVE CASES 11.1 Case reports from literature 11.2 Internally extracted data on cases 11.3 Internal cases 12. Additional information 12.1 Availability of antidotes 12.2 Specific preventive measures 12.3 Other 13. REFERENCES 14. AUTHOR(S): 1. NAME 1.1 Substance Azathioprine 1.2 Group ATC Code: L04AX Other Immunosuppressive agents 1.3 Synonyms BW 57322 azothioprine NCI-C03474 NSC-39084 methylnitroimidazolylmercaptopurine 1.4 Identification numbers 1.4.1 CAS number Azathioprine 446-86-6 1.4.2 Other numbers RTECS: UO8925000 1.5 Main brand names/main trade names Azamune, Azanin, Azapress, Berkaprine, Immunoprin, Imuran, Imurek, Imurel, Rorasul, Thioprine. 1.6 Main manufacturers/main importers To be added by the centre using the monograph. 1.7 Presentation/formulation To be added by the centre using the monograph. 2. SUMMARY 2.1 Main risks and target organs Azathioprine is a myelotoxic and hepatotoxic immunosuppressive agent. Bone marrow and liver are the main targets but gastrointestinal tract, kidney, lungs, CNS and skin may also be affected. Transient gastroenteritis may be observed with massive overdose. Leukopenia is the main toxic effect which may occur during azathioprine therapy and in the overdose patients. Liver and kidney function tests may be altered but usually returned to normal after discontinuation of the drug. 2.2 Summary of clinical effects Oral ulceration occurs rarely with therapeutic doses but may be seen with large doses. Gastrointestinal disturbances such as nausea, vomiting, abdominal pain and diarrhoea can appear mainly at higher doses. Acute pancreatitis was also reported following long term azathioprine treatment. Suppression of the bone marrow mainly leukopenia and occasionally pancytopenia may be seen after therapeutic doses and overdoses of azathioprine. Septic shock due to this immunosuppression may occur. Hepatic dysfunction (hepatocellular and cholestatic), venocclusive disease and haemangioma of the liver following azathioprine therapy were documented. Acute restrictive lung disease, interstitial nephritis and a case of progressive leukoencephalopathy after 4 years azathioprine therapy were reported. Skin rash, alopecia and urticaria and a case of palmar-plantar erythema with desquamation and pain were also documented. 2.3 Diagnosis Diagnosis of azathioprine overdose is based on history of the drug taken and clinical findings mainly gastrointestinal dysfunction, leukopenia and liver dysfunction. Peripheral cell blood counts and liver function tests are required. Estimation of 6-thioguanine nucleotide, a cytotoxic metabolite of azathioprine in red blood cell may confirm the diagnosis and could also be used to predict bone marrow toxicity of azathioprine. 2.4 First-aid measures and management principles Emesis may be indicated in substantial recent ingestion of azathioprine. It is most effective if initiated within 30 minutes of ingestion. In massive overdose patients, gastric aspiration and lavage should be performed as soon as possible and within 3 to 4 hours of ingestion. Activated charcoal (1 to 2 g/kg every 3 to 4 hours) as slurry in water or mixture with sorbitol should be given orally or through the gastric tube. Haemodialysis should be used in severe azathioprine overdose patients. 3. PHYSICO-CHEMICAL PROPERTIES 3.1 Origin of the substance Azathioprine is a chemical analogue of the physiologic purines and is of synthetic origin. 3.2 Chemical structure 6-(1-Methyl-4-nitroimidazol-5-ylthio)purine Relative molecular mass: 277.3 Molecular formula: C9H7N7O2S 3.3 Physical properties 3.3.1 Properties of the substance 220.127.116.11 Colour Pale yellow. 18.104.22.168 State/form Powder. 22.214.171.124 Description Odourless. Insoluble in water and very slightly soluble in ethanol. Solutions of azathioprine sodium for injection have a pH of 9.8 to 11.0. 3.3.2 Properties of the locally available formulation To be filled in by centre using the monograph. 3.4 Other characteristics 3.4.1 Shelf-life of the substance Azathioprine tablets have a shelf-life of five years and the azathioprine injection has a shelf-life of three years (Dollery, 1991). 3.4.2 Shelf-life of the locally available formulation To be added by the centre using the monograph. 3.4.3 Storage conditions Azathioprine tablets should be protected from light and stored at a temperature that does not exceed 35 °C. The azathioprine injection should be stored in a dry place at a temperature that does not exceed 25 °C(Dollery, 1991). 3.4.4 Bioavailability To be added by the Center using the monograph. 4. USES 4.1 Indications 4.1.1 Uses 4.1.2 Description Azathioprine is used as an adjunct for the prevention of the rejection of kidney allografts. The drug is used in conjunction with other immunosuppressive therapy including local radiation therapy, corticosteroids, and other cytotoxic agents. Azathioprine may be used for the treatment of conditions which involve derangement of the immune system including chronic active hepatitis, severe rheumatoid arthritis, systemic lupus erythematosus, dermatomyositis, pemphigus vulgaris, polyarteritis nodosa, acquired haemolytic anaemia, Crohn's disease and idiopathic thrombocytopenia. (Dollery, 1991; McEvoy, 1993). 4.2 Therapeutic dosage 4.2.1 Adults Prophylatic therapy is usually initiated in a dose of 3 to 10 mg/kg one or two days prior to renal transplantation, or on the day of the operation (Calabresi and Chabner, 1990). Maintenance doses are lower. For the treatment of conditions which involve derangement of the immune system the dose of the drug is usually decided by titration against the clinical activity of the disease, in the range of 1 to 3 mg/kg daily (Dollery, 1991). 4.2.2 Children The dose in children is the same (per kilogram body weight) as in adults. 4.3 Contraindications Azathioprine is contraindicated in patients who are hypersensitive to the drug. If severe, continuous rejection occurs, it is probably preferable to use another agent, rather than to increase the dosage of azathioprine to very toxic levels (McEvoy, 1993). Azathioprine is also contraindicated in those patients with renal failure, impaired hepatic function and in pregnant women (Dollery, 1991). 5. ROUTES OF ENTRY 5.1 Oral Azathioprine is usually administered orally. 5.2 Inhalation Not known 5.3 Dermal Not known 5.4 Eye Not known 5.5 Parenteral Following renal transplantation, azathioprine may initially be given intravenously to patients unable to tolerate oral medication. Oral therapy should replace parenteral therapy as soon as possible. 5.6 Others Not known 6. KINETICS 6.1 Absorption by route of exposure Azathioprine is readily absorbed from the gastrointestinal tract with only 12.6% of the dose being detected in the stool over a 48 hour period. After oral administration of 100 mg of azathioprine the peak levels of azathioprine and its metabolites are equivalent to 2 mg.L-1 (Dollery, 1991) 6.2 Distribution by route of exposure Azathioprine is rapidly distributed throughout the body with peak plasma concentrations being reached at 1 to 2 hours after dosing. Small amounts of azathioprine bind to plasma proteins (to a maximum of 30%) and only very small amounts enter the brain(Dollery, 1991). Azathioprine crosses the placenta and trace amounts of the 6- mercaptopurine metabolite have been detected in foetal blood (Briggs et al., 1990). 6.3 Biological half-life by route of exposure The plasma half-life of azathioprine is 3 to 5 hours (Dollery, 1991). 6.4 Metabolism Azathioprine is metabolized in vivo to mercaptopurine, apparently by sulphydryl compounds such as glutathione. Mercaptopurine is oxidised and methylated to several derivatives among which 6-thiouric acid predominates; the proportion of metabolites varies amongst individuals. The fate of the nitromethylimidazole portion of azathioprine has not been completely elucidated. Small amounts of azathioprine are also split to give 1-methyl-4-nitro-5-thioimidazole (McEvoy, 1993). The active metabolites, 6-thioguanine nucleotides, responsible for the therapeutic action, are formed intracellularly and appear to have very long half- lives (Maddocks et al., 1986). 6.5 Elimination by route of exposure The metabolites of azathioprine are excreted by the kidneys; only small amounts of azathioprine and mercaptopurine are excreted intact (McEvoy, 1993). In the 24 hour period after administration up to 50% of the dose is excreted in the urine with 10% as the parent drug. There is no data concerning azathioprine excretion in breast milk (Briggs et al., 1990). 7. PHARMACOLOGY AND TOXICOLOGY 7.1 Mode of action 7.1.1 Toxicodynamics The principal toxic effect of azathioprine is bone marrow depression manifested by leukopenia, macrocytic anaemia, pancytopenia, and thrombocytopenia, which may result in prolongation of clotting time and eventual haemorrhage (McEvoy, 1993). In a concentration of 50 œg. mL-1, azathioprine produced cytogenetic damage to human lymphocytes in vitro (Dollery, 1991). 7.1.2 Pharmacodynamics The exact mechanism of immunosuppressive activity of azathioprine has not been determined. Azathioprine which is an antagonist to purine metabolism, may inhibit RNA and DNA synthesis. The drug may also be incorporated into nucleic acids resulting in chromosome breaks, malfunctioning of the nucleic acids, or synthesis of fraudulent proteins. The drug may also inhibit coenzyme formation and functioning, thereby interfering with cellular metabolism. Mitosis may be inhibited by the drug. In patients who undergo renal transplantation, azathioprine suppresses hypersensitivities of the cell-mediated type and causes variable alterations in antibody production (McEvoy, 1993). 7.2 Toxicity 7.2.1 Human data 126.96.36.199 Adults Severe pancytopenia has been observed in about 1% of patients who receive more than 2.5 mg.kg-1. A renal patient who took 7500 mg of azathioprine with 1000 mg of prednisone developed leucopenia and the drug was discontinued for 11 days (Carney et al., 1974). 188.8.131.52 Children Lymphopenia, decreased IgG and IgM concentrations, cytomegalovirus infection, and a decreased thymic shadow were observed in one infant whose mother had received 150 mg of azathioprine and 30 mg of prednisone daily throughout pregnancy; most of these findings had apparently normalised by 10 weeks of age. Pancytopenia and severe immunodeficiency were reported in a premature infant whose mother received 125 mg of azathioprine and 12.5 mg of prednisone throughout pregnancy (McEvoy, 1993). 7.2.2 Relevant animal data Studies with animals have shown that the haemopoietic system is affected by azathioprine with depression of granulopoiesis, megakaryocytes and, hence, platelet formation. Reversible hepatoxicity has been observed in dogs at doses of 5 mg.kg-1 (Dollery, 1991). Various teratogenic effects have been observed in rabbits, showing skeletal abnormalities at doses of 5 to 15 mg.kg-1 given daily on days 6 to 14 of pregnancy, and in mice where azathioprine was lethal to the embryos at doses of 1 to 2 mg.kg-1 on days 3 to 12 of pregnancy (Dollery, 1991). 7.2.3 Relevant in vitro data Cytogenetic damage was observed in human lymphocytes in vitro at a dose of 50 µg.mL-1 (Dollery, 1991). 7.3 Carcinogenicity Azathioprine is carcinogenic in animals and may increase the risk of neoplasia in humans. The exact risk of neoplasia asscoiated with azathioprine use has not been defined; however, evidence suggests that the risk may be elevated both in patients with rheumatoid arthritis and in renal allograft recipients receiving the drug. Acute myelogenous leukemia and solid tumours have occurred in patients with rheumatoid arthritis who received the drug (McEvoy, 1993). 7.4 Teratogenicity Azathioprine is teratogenic in rabbits and mice when given in dosages equivalent to the human dosage (5 mg/kg daily). Abnormalities included skeletal malformations and visceral anomalies. Immunologic and other abnormalities have been reported in newborn infants who were exposed to azathioprine during pregnancy. However, the association that may exist between these abnormalities and azathioprine has not been determined (Briggs et al., 1990). 7.5 Mutagenicity Azathioprine is mutagenic in animals and humans. Chromosomal abnormalities have been documented in humans receiving azathioprine, but the abnormalities were reversed following discontinuance of the drug (McEvoy, 1993). Azathioprine is mutagenic in the Ames test (Dollery, 1991). 7.6 Interactions Azathioprine dose should be reduced 75% when administered with allopurinol, as allopurinol affects the metabolism of mercaptopurine, a metabolite of azathioprine (Dollery, 1991). Azathioprine may reduce the effect of certain neuromuscular blocking agents including curare and related non-depolarizing drugs (Dollery, 1991). Certain cytotoxic agents may be additive or synergistic in producing toxicity when used in conjunction with azathioprine (Dollery, 1991). The Committee on Safety of Medicines have advised that azathioprine and penicillamine should not be used concurrently (Dollery, 1991). The effects of azathioprine and corticosteroids could be synergistic (Dollery, 1991). Azathioprine may reduce the anticoagulant effect of warfarin (Reynolds, 1993). 7.7 Main adverse effects The principal toxic effect of azathioprine is bone marrow depression. Adverse GI effects (nausea, vomiting, anorexia and diarrhoea) caused by azathioprine may be minimized by giving the drug in divided doses and/or after meals. Hepatoxicity may occur in patients receiving azathioprine principally in allograft patients. Rare, but life-threatening hepatic veno-occlusive disease has occurred during chronic azathioprine therapy. Azathioprine may also cause rash, infection, drug fever, serum sickness, alopecia, arthralgia, retinopathy, Raynaud's disease, and pulmonary edema. Some of these adverse effects can occur as manifestations of rare hypersensitivity reactions. (McEvoy, 1993). 9. CLINICAL EFFECTS 9.1 Acute poisoning 9.1.1 Ingestion Oral ingestion of azathioprine tablets is the primary route of its administration. It may affect taste and smell (Ellenhorn & Barcelux,1988). It is well absorbed from the GI tract (Dorr & Fritz,1980). The oral bioavailability of therapeutic doses is approximately 60%. Acute overdosage with 850 mg of azathioprine has been tolerated by an adult without producing symptoms. An overdose of 7500 mg azathioprine produced mild transient alteration of liver enzymes and leukopenia which was delayed. The usual therapeutic dose of azathioprine is about 1 to 5 mg/kg/day (Calabresi and Chabner, 1991). 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 Acute poisoning due to parenteral exposure of azathioprine has not been reported. However, transient side effects following therapeutic intravenous administration of 100 mg azathioprine may occur. There has been no specific toxic effects following parenteral exposure of azathioprine. Idiosyncratic reactions such as dizziness, nausea, vomiting and reversible shock may appear during and or right after I.V. injection of azathioprine (Reynolds, 1989). 9.1.6 Other No data available. 9.2 Chronic poisoning 9.2.1 Ingestion Chronic poisoning due to oral ingestion of azathioprine has not been reported. However, long term oral therapeutic administration to 64 patients revealed reversible leukopenia in 22%, macrocytosis in 20%, systemic illness (vomiting, abdominal pain, anorexia, rash or urticaria) in 12% and hepatotoxicity in 9% (Kissel et al, 1986). 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 Parenteral administration of azathioprine may induce toxic effects such as dizziness, nausea, vomiting, allergic reactions, hypotension and delayed leukopenia (Reynolds,1989). Parenteral overdose cases of azathioprine has not been reported. 9.2.6 Other No data available. 9.3 Course, prognosis, cause of death Based on very limited reports and experience on azathioprine overdose, it seems that single overdose up to 850 mg is asymptomatic. In a case of massive overdose with 7500 mg of azathioprine, immediate toxic reactions were nausea, vomiting and diarrhoea followed by mild leukopenia, mild abnormalities in liver and kidney function on the third day after the overdose. On the 6th day of admission white blood cell (WBC) count, liver and kidney function tests returned to normal. The oral azathioprine of 50 mg daily was resumed on this kidney transplant patient, WBC had dropped to 2,800/mm3 on the third day after administration. Azathioprine therapy was again discontinued, and WBC increased to 11,000/mm3 after 11 days. Azathioprine therapy was resumed at 50 mg/day without further suppression of peripheral WBC and the patient survived (Carney et al, 1974). There has been no report of mortality due to azathioprine poisoning. However, several cases of azathioprine induce hepatic venocclusive disease in renal transplant patients with high mortality (6 out of 7 patients) was reported by Katzka et al (1986). Severe bone marrow depression and its complication such as septic shock may also be a cause of death. 9.4 Systematic description of clinical effects 9.4.1 Cardiovascular Arterial hypertension after renal transplantation in patients treated with azathioprine in 72% of the cases compared with cyclosporin (64%) was investigated (Gordjani et al, 1990). Cases of portal hypertension in renal transplant patients after long term azathioprine therapy were reported (Yanagisawa et al, 1990 and Lorenz et al, 1992). 9.4.2 Respiratory A single case of acute restrictive lung disease following long term azathioprine at a dose of 100 mg/day which resolved after the drug was discontinued has been reported (Dorr & Fritz, 1980). A case of pulmonary manifestation (pulmonary infiltrations with haemoptysis) of Goodpasture's syndrome following azathioprine therapy in a renal patients has also been reported (Stetter et al, 1994). 9.4.3 Neurological 184.108.40.206 CNS A case of progressive leukencephalopathy (PML) after a four year azathioprine therapy with difficulty in urinating, articulation, spastic hemiplegia and eye movement malfunction was reported (Schnider,1991). 220.127.116.11 Peripheral nervous system No data available. 18.104.22.168 Autonomic nervous system No data available. 22.214.171.124 Skeletal and smooth muscle There is only a report of artralgia among many othertoxic effects (Osol, 1980). 9.4.4 Gastrointestinal Oral ulceration occur rarely with therapeutic doses but may be seen with large doses (Dorr & Fritz, 1980). Metallic or bitter taste following azathioprine ingestion has been reported (Ellenhorn & Barcelux, 1988). Gastrointestinal disturbances such as nausea, vomiting, abdominal pain and diarrhoea have been reported and appear to occur mainly at higher doses (Assini et al, 1986). The authors classified this as a definite adverse reaction based on a positive rechallenge. Acute pancreatitis with severe vomiting following long term therapeutic administration of azathioprine was also reported (Roblin et al, 1990). 9.4.5 Hepatic Hepatic dysfunction (hepatocellular and cholestatic), manifested by elevation of liver function tests and onset of jaundice and also hepatic venocclusive disease in renal transplant patients given azathioprine therapy have been reported (Read et al,1986; Barrowman et al,1986; Katzka et al,1986; Jeurissen et al,1990; Sternek et al,1991). Hepatic hemangiomas in a patient with rheumatoid arthritis treated with azathioprine was reported by Linana- Santafe et al (1992). Reversible cholestasis with bile duct injury following azathioprine therapy was also described (Horsmans et al,1991). A patient with dermatomyositis developed peliosis hepatis after treatment by azathioprine and corticosteroids. Liver enlargement with signs of portal hypertension disappeared progressively following discontinuation of azathioprine (Lorcerie et al, 1990). 9.4.6 Urinary 126.96.36.199 Renal There has been no report of the direct toxic effects of azathioprine on the kidneys. However, fever, hepatitis and acute interstitial nephritis in a rheumatic patient as concurrent manifestations of azathioprine hypersensitivity was reported (Meys et al,1992). 188.8.131.52 Other No data available. 9.4.7 Endocrine and reproductive systems No data available. 9.4.8 Dermatological A severe palmar-plantar erythema with desquamation and pain was reported in a case receiving allupurinol as well. This was successfully treated by discontinuation of the drugs and initiation of topical steroid therapy. Skin rash, alopecia and urticaria after azathioprine therapy were also reported (Dorr and Fritz,1980; Kissel et al,1986). 9.4.9 Eye, ear, nose, throat: local effects There has been no report on the local effects of azathioprine on the above organs. However, retinophathy among the other toxic effects of azathioprine was reported (Osol, 1980). 9.4.10 Haematological Myelosuppression is an important and potentially lethal complication of azathioprine treatment (Connell et al, 1993). Leukopenia is the primary haematologic finding following azathioprine therapy. A mild leukopenia (4,100/mm3) was found on the third day after a massive azathioprine overdose. It was increased to 7300/mm3 on the 6th day (Carney et al,1974). However, severe bone marrow depression was reported in a 55 year old woman with severe oral lichen planus treated with azathioprine 100 mg/day orally for 28 days. Her white blood count (WBC) continued to fall down to 200/mm3 one week after azathioprinediscontinuation. Her Hb reduced to 8.4 g/dL over this period. Bone marrow aspirated 12 days after the drug withdrawal showed reduced cellularity mainly of WBC precursors. Erythropoiesis was normocellular with megaloblastic change and megacaryocytes werenormal (Maddocks et al, 1986). In a study of 739 patients who were treated with 2 mg/kg/day azathioprine for a median of 12.5 months, 37 patients (5%) developed bone marrow toxicity. Leukopenia (WBC< 3000 /mm3) occurred in 28 (3.8%) patients and 3 of them were pancytopenic of which 2 died from sepsis (Connell et al,1993). Pure red blood cell aplasia was found in a renal transplant patient who was treated by azathioprine. Discontinuation of azathioprine was associated with complete recovery from anaemia as well (Agarwal et al,1993). 9.4.11 Immunological Azathioprine is an immunosuppressive agent which induce myelosuppression. However, hypersensitivity reactions and shock have been observed during azathioprine treatment (Wilson et al,1993; Jones and Ashworth,1993). Gastrointestinal type I hypersensitivity to azathioprine with a massive duodenal eosinophilia without peripheral blood eosinophilia was reported (Riedel et al, 1990). 9.4.12 Metabolic No data available. 184.108.40.206 Acid-base disturbances No data available. 220.127.116.11 Fluid and electrolyte disturbances No data available. 18.104.22.168 Others No data available. 9.4.13 Allergic reactions Dermatologic and gastrointestinal allergic reaction such as rash, urticaria and gastroentritis during azathioprine therapy were reported (Jeurissen et al,1990; Riedel et al, 1990). 9.4.14 Other clinical effects No data available. 9.4.15 Special risks Pregnancy & Lactation: There has been no report of bona fide cases of human malformations attributed to maternal treatment with azathioprine. There are 77 cases of normal infants born under azathioprine treatment (Schardein,1985). Despite the lack of foetal damage associated with azathioprine, it seems prudent to avoid its use in pregnancy if possible. There has been no report of azathioprine excretion in breast milk (Briggs et al., 1990). 9.5 Other No data available. 10. MANAGEMENT 10.1 General principles Special attention should be given to the haemopoietic system and liver function. In severe intoxication with azathioprine, respiratory and cardiovascular functions shouldbe monitored and supported. 10.2 Relevant laboratory analyses 10.2.1 Sample collection Blood and urine samples should be collected for analyses. Gastric contents may also be used for toxicological analysis (presence of azathioprine) in azathioprine overdose patient who was admitted early after ingestion. Blood samples should be collected in different tubes with and without anticoagulant (EDTA) for haematological, biochemical and toxicological tests. Red blood cells have been used in one case for the estimation of a cytotoxic metabolite of azathioprine (6-thioguanine nucleotide) (Maddocks et al., 1986). 10.2.2 Biomedical analysis Regular white blood cell count monitoring is required during and 1 to 2 weeks after taking azathioprine therapy and after overdose as leukopenia is the most common toxic effect of azathioprine in humans. Liver and kidney function tests should also be performed to detect the azathioprine toxicity on these organ. 10.2.3 Toxicological analysis Estimation of azathioprine and its metabolites concentrations in blood and urine may be required. Concentration of 6-thioguanine nucleotide (TGN) a cytotoxic metabolite of azathioprine was assayed in red blood cells 12, 44 and 55 days after intoxication which were much higher than the control group. The authors concluded that this active metabolite which is also produced with 6-mercaptopurine and 6- thioguanine therapy is related to neutropenia and can be used to predict bone marrow toxicity of these drugs (Maddocks et al., 1986). 10.2.4 Other investigations In severe azathioprine intoxicated patient, other paramedical investigations such ECG and chest X- ray may be required and should be performed whenever indicated. 10.3 Life supportive procedures and symptomatic/specific treatment Treatment should be supportive and symptomatic. Make a proper assessment of airway, breathing, circulation and neurological status of the patient. Open and maintain at least one intravenous route. Administer intravenous fluid. Monitor vital signs in severe intoxicated patients. Monitor fluid and electrolytes and acid-base balance. Haemodialysis has been reported to remove azathioprine and its metabolites. It can therefore be used in severe overdose patients (Bennett et al,1980). 10.4 Decontamination Emesis may be indicated in substantial recent ingestion of azathioprine. It is most effective if initiated within 30 minutes of ingestion. If emesis is unsuccessful following 2 doses of ipecac, the decision to gastric lavage should be made on an individual basis. In massive overdose patients, gastric aspiration and lavage may be performed as soon as possible. Activated charcoal (1-2 g/kg every 3-4 h) as slurry in water or mixed with sorbitol should be given orally or through the gastric tube. Cathartics should not be used in patients with an ileus or impaired renal function. In case of skin and eye exposure, irrigate with copious amounts of water and saline. 10.5 Elimination Azathioprine and its metabolites are haemodialysable. About 44% of the total amount of Azathioprine in 3 men and 3 women on chronic haemodialysis(95.4ñ31.0 ml/min) was removed during 8 hours. Haemodialysis should be used in severe azathioprine intoxicated patients (Schusziarra et al, 1976). 10.6 Antidote treatment There is no antidote for azathioprine toxicity. 10.6.1 Adults 10.6.2 Children 10.7 Management discussion There have been reports only on two azathioprine overdose cases. One had taken 850 mg and was asymptomatic and other who had taken 7500 mg, revealed mild transient gastroenteritis, leukopenia and hepatic function and survived. However, azathioprine toxicity has mainly been reported in patients already taking this immunosuppressive agent. Regular monitoring of peripheral blood count and liver function is required to detect the toxicity in advance. In severe azathioprine intoxicated patients, Supportive and critical care management including barrier nursing, particularly in those with severe leukopenia <1000/Cub.mm or septic shock, is required (Carney et al, 1974; Connel et al, 1993). Administration of granulocyte colony stimulating factor (GCS-F) may reduce morbidity in patients with severe neutropenia after cytotoxic chemotherapy, and would be expected to reduce the severity and duration of neutropenia after azathioprine poisoning. 11. ILLUSTRATIVE CASES 11.1 Case reports from literature There is two case reports from the medical literature. First was asymptomatic who had taken 850 mg azathioprine. The second is as follows: A 44 year old disable heavy equipment operator who had suffered from chronic renal failure. He received a cadaver kidney transplantation on September 18, 1970 and went under azathioprine and corticosteroid treatment. On February 8, 1972 at 18h ingested 200 x 5mg prednisolone tablets as instructed and 150 x 50 (7500)mg tablets of azathioprine by mistake. He vomited 6 and again 8 hours later and noticed diarrhoea. He was then hospitalised on the following morning for observation. The patient was asymptomatic thereafter for 6 days. His white blood cell counts (WBC) decreased from 7500/Cub.mm on the first day to 4100/Cub.mm on the third day after overdose and returned to 7300/Cub.mm on the 6th day. There was also a mild transient liver enzymes transaminase alteration. He received no treatment for his overdosage. Azathioprine oral administration, 50 mg/day was resumed. 3 days later, the total WBC decreased to 2800/Cub.mm. Azathioprine therapy was again discontinued for 11 days when his WBC increased to 11,000/Cub.mm. Azathioprine was resumed again at 50 mg daily and subsequently to 100 mg daily without further suppression of WBC and the patient survived (Carney et al, 1974). 11.2 Internally extracted data on cases To be added by the Center using the monograph. 11.3 Internal cases To be added by the Center using the monograph. 12. Additional information 12.1 Availability of antidotes No antidote is available. 12.2 Specific preventive measures Azathioprine is a myelotoxic and hepatotoxic agent. It is therefore advisable to monitor the peripheral blood counts and liver function regularly to detect the early toxic effects. Estimation of 6-thioguanine nucleotide, a cytotoxic metabolite of azathioprine was assayed in red blood cell of a patient 12, 14 and 55 days after stopped taking azathioprine. It was found much higher than the controls. The authors believed that this metabolite is responsible for neutropenia and could be used to predict bone marrow toxicity of azathioprine (Maddocks et al, 1986). 12.3 Other No data available. 13. REFERENCES Agarwal SK, Mittal D, Tiwari SC, Dash SC, Saxena S, Saxena R, & Mehta SN (1993) Azathioprine-induced pure red blood cell aplasia in a renal transplant recipient. Nephron. 63(4):471 Assini JF, Hamilton R & Strosberg JM (1986) Adverse reactions to azathioprine mimiking gastroentritis. J Rheumatol 13:1117- 1118. Barrwman JA, Kutty PK, Ra MU & Huang SN (1986) Sclerosing hepatitis and azathioprine. Dig Dis Sci 31(2): 221-223. Bennett WM, Muther RS, Parker RA et al (1980) Drug therapy in renal failure: dosing guidelines for adults. Part II Ann Intern Med, 93:286-325. Briggs GG, Freeman RK, Sumner JY (1990) A Reference Guide to Fetal and Neonatal Risk, Drugs in Pregnancy and Lactation (4th Ed.) Williams and Wilkins, London, 79a-82a. Calabresi P & Chabner BA (1991) Chemotherapy in neoplastic diseases in: Goodman and Gilman's The pharmacological basis of therapeutics (eds: Goodman Gilman A, Rall TW, Nies AS & Taylor P) 8th edition, Pergamon press, New York, 1236. Carney DM, Zukoski CF & Ogden DA (1974) Massive azathioprine overdose-case report and review of the literature. AM J Med 56(1): 133-136. Connell WR, Kam MA, Ritchic JK & Lennard-Jones JE (1993) Bone marrow toxicity caused by azathioprine in inflammatory bowel disease: 27 years of experience. Gut, 34(8): 1081-1085. Dollery C (1991) Therapeutic Drugs, Volume 1, Churchill Livingstone, London, A181-A185. Dorr RT & Fritz WL (1980) Cancer chemotherapy handbook. Elsevier, Amsterdam, 246-250. Ellenhorn MJ & Barceloux DG (1988) Medical toxicology, Elsevier, New York, 31. Gordjani N, Offner G, Hoyer PF & Brodehl J (1990) Hypertension after renal transplantation in patients treated with cyclosporin and azathioprine. Arch Dis Child, 65(3): 275-279. Horsmans Y, Rahier J & Geubel AP (1991) Reversible cholestasis with bile duct injury following azathioprine therapy. A case report. Liver, 11(2): 89-93. Jeurissen ME, Boerhooms Am, Van-de-Putte LB & Kuijsen NM (1990) Azathioprine induced fever, chills, rash and hepatotoxicity in rheumatoid arthritis. Ann Rheum Dis, 49(1): 25-27. Jones JJ & Ashworth J (1993) Azathioprine-induced shock in dermatology patients. J. Am. Acad. Dermatol. 29(5):795-6 Katzka DA, Saul SH, Jorkasky D, Sigal H, Reynolds JC & Soloway RD (1986) Azathioprine and hepatic venoclusive disease in renal transplant patients. Gastroenterology 90:446-454. Kissel JT, Levy RJ, Mendell JR & Griggs RC (1986) Azathioprine toxicity in neuromuscular disease. Neurology 36(1): 35-39. Linana-Santafe JJ, Calvo-Catal FJ, Hortelano-Martinez E, Gonzalez- Cruz I & Martinez-Sam-Juan V (1992) Hepatic hemangiomas and rheumatoid arthritis in patients treated with azathioprine. An Med Interna 9(10): 498-500 (in Spanish). Lorcerie B, Grobost O, Lalu-Fraisse A, Piard F, Camus P & Portie H (1990) Peliosis hepatis in dermatomyositis treated with azathioprine and cortioids. Rev Med Interne 11(1): 25-28 (in French). Lorenz R, Brauer M, Classen M, Tornieporth N & Becker K (1992) Idiopathic portal hypertension in a renal transplant patient after long-term azathioprine therapy. Clin Investig 70(2): 152-155. Maddocks JL, Lennard L, Amess J, Amos R & Meyrick-Thomas R (1986) Azathioprine and severe bone marrow depression. Lancet 1:156. McEvoy GK (1993) Drug Information The American Hospital Formulary Service, American Society of Health-System Pharmacists, Inc., MD. 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Hepatol. 26(5):233 Schardein JL (1985) Chemically induced birth defects. Marcel Dekker Inc, New York. Schneider F (1991) Progressive multifocal leukoencephalopathy as a cause of neurologic symptoms in sharp syndrome. Z-Rheumatol 50(4): 222-224 (in German). Schusziarra V, Zukuzsch V & Schalmp R (1976) Pharmacokinetics of azathioprine under haemodialysis. Int J Clin Pharmacol, 14: 298- 302. Sterneck M, Wiesner R, Ascher N, Roberts J, Ferrell L, Ludwig J & Lake J (1991) Azathioprine hepatotoxicity after liver transplantation. Hepatology, 14(5): 806-810. Stetter M, Schmidl M & Krapf R (1994) Azathioprine hypersensitivity mimicking Goodpasture's syndrome. Am J Kidney Dis 23(6): 874-877. Wilson BE & Parsonnet J (1993) Azathioprine hypersensitivity mimicking sepsis in a patient with Crohn's disease. Clin. Infect. Dis. 17(5): 940-1 Yanagisawa N, Sugaya H, Yunomura K, Harada T & Hisauchi T (1990) A case of idiopathic portal hypertension after renal transplantation. Gastroenterol JPn, 25(5): 643-648. 14. AUTHOR(S): M. Balali-Mood, M.D., Ph.D., Professor of Medicine and Clinical Toxicology, Director, Poisons Control Centre, Imam Reza Hospital, Mashhad University of Medical Sciences, Mashhad 91735, I.R.Iran. Tel: 9851 - 93043 / 889301 Fax: 9851 - 93038 / 883714 Peer reviewed: Berlin, October 1995 Finalised: IPCS, September 1996 See Also: Azathioprine (IARC Summary & Evaluation, Supplement 7, 1987) Azathioprine (IARC Summary & Evaluation, Volume 26, 1981) ANAPHYLAXIS DEFINITION Anaphylaxis is an immunological description of a type I hypersensitivity reaction mediated by IgE or IgG. Clinically, the term is used to describe a group of symptoms (see "clinical diagnosis" for complete description) irrespective of the mechanism. Where an immunological basis for the syndrome is unproven, the term "anaphylactoid" is used. Clinical expression of anaphylaxis is variable in severity but cardiovascular collapse is the most common life-threatening feature and bronchospasm occurs frequently. TOXIC CAUSES Innumerable substances may cause anaphylaxis. Common causative agents include: Antivenoms Blood products Chemicals Drugs: Antibiotics Antiinflammatory agents Analgesics Chemotherapeutic agents Local anaesthetic agents Neuromuscular blocking drugs Radiocontrast agents Foods: Nuts Shellfish Insect stings Latex Plants CLINICAL FEATURES History of exposure to a substance capable of producing anaphylaxis and appropriate clinical manifestations. These may include: hypotension, bronchospasm, upper airways obstruction, pulmonary oedema, angioedema, generalized oedema, pruritus, rash, vomiting, diarrhoea and abdominal pain. In some cases, there may not be a clear history of exposure. DIFFERENTIAL DIAGNOSIS Anxiety Asthma Bronchospasm or laryngeal oedema due to inhalation of irritant gases. Cardiogenic shock Foreign body in upper airway Hypovolaemia Pulmonary embolism Vasovagal episode RELEVANT INVESTIGATIONS In such an emergency situation, no biomedical investigations are required to commence treatment. TREATMENT Epinephrine (Adrenaline) Epinephrine is the preferred treatment for anaphylaxis and should be administered as soon as practicable while assessing and supporting vital functions. It is usually given intramuscularly but may be given subcutaneously in mild cases. Intravenous administration is only indicated in severe cases because of the risk of ventricular dysrhythmias. In the intubated patient, endotracheal installation is possible if intravenous access is unavailable. Doses of epinephrine: 1) Intramuscular/subcutaneous: Adult: 0.5 to 1.0 mg Paediatric: 0.01 mg/kg or Age Epinephrine 1:1000 solution < 1 year 0.05 mL 1 year 0.1 mL 2 years 0.2 mL 3-4 years 0.3 mL 5 years 0.4 mL 6-12 years 0.5 mL > 12 years 0.5 to 1 mL The appropriate dose should be repeated every 3 to 10 minutes until an adequate response in pulse and blood pressure is observed. 2) Intravenous: Adult: 0.1 mg (1 mL of 1:10000 solution made by diluting 1 mg of epinephrine in 10 mL of normal saline) over 2 to 3 minutes. Paediatric: 0.01 mg/kg over 2 to 3 minutes. The appropriate dose should be repeated until an adequate response in pulse and blood pressure is observed. Notes on epinephrine therapy: The dosage of epinephrine is NOT one ampoule. For the intubated patient, if intravenous injection is not possible, intratracheal instillation (1 to 3 mg) is an alternative. Patients on beta-blockers may require larger doses of epinephrine. Oxygen Supplemental oxygen should be administered to all patients. In severe cases, especially those with airways obstruction, establishment of an adequate airway (endotracheal intubation or tracheotomy) and/or assisted ventilation may be necessary. Fluids In patients presenting with hypotension, one to two litres of intravenous fluids should be given as soon as intravenous access is established. Colloid is preferable to crystalloid but either is acceptable. Persistent hypotension should be treated with further doses of epinephrine. Further administration of intravenous fluids should be cautious and ideally titrated against central venous pressure. Corticosteroids are not life-saving and are never the primary therapy of acute anaphylaxis. They may be useful in the treatment of bronchospasm and in the prevention of relapses. An intravenous dose of 200 to 300 mg of hydrocortisone (or equivalent dose of another corticosteroid) may be given. Nebulized salbutamol (albuterol) may be useful for refractory bronchospasm, particularly in children. CLINICAL COURSE AND MONITORING There is usually a rapid response to therapy and recovery is complete. Pulse, blood pressure, respiration and oxygen saturation must be monitored until full recovery. LONG TERM COMPLICATIONS Recurrent episodes of anaphylaxis. The agent that caused the anaphylaxis should be identified where possible and the patient adequately advised regarding the avoidance of further reactions. A warning device or letter should be issued. Patients who suffered life-threatening anaphylaxis should be instructed in the self-use of epinephrine. The need for desensitization to the allergen should be considered. AUTHOR(S)/REVIEWERS Author: Dr R. Fernando, National Poison Information Centre, Colombo, Sri Lanka. Reviewers: Cardiff 3/95, Berlin 10/95: A. Jaeger, R. Dowsett, J. Szajewski, V. Danel, A. Wong. Cardiff 9/96: V Afanasiev, T Della Puppa, J Huang, G Muller, L Murray, J Szajewski, C Warden.