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CBD and Cancer
Can CBD oil help with cancer, and how? What are the best CBD oil products for cancer? Cancer is the unrestrained proliferation of abnormal cells in the body. Typical side effects of cancer treatments, such as nausea, vomiting, pain, sleep problems, and loss of appetite, can be debilitating. There are promising studies about CBD’s use in cancer treatment, although, to date, there have been no CBD-oil derived products approved by the U.S. Food and Drug Administration (FDA) to treat cancer, its symptoms, or side effects caused by its treatment. The National Cancer Institute (NCI) examined several studies regarding the correlation between cannabis and cancer, and the research showed mixed results. Cannabinoids and cannabis itself may be used either as a health care tool or as a complementary treatment for people who may need help managing the symptoms of cancer and the side effects of cancer therapy. However, if one is planning on adding it to his or her existing treatment plan, it is highly recommended to consult a health professional first. For people looking to include CBD in their cancer treatment, several product recommendations would also be listed in this article. What is Cannabidiol (CBD)? Marijuana and hemp are varieties of the Cannabis sativa plant, and both plants contain varying quantities of cannabidiol (CBD) and delta-9-tetrahydrocannabinol (THC), their active ingredients. Both THC and CBD are extracted from hemp and marijuana using similar processes. However, hemp contains less THC than a typical marijuana plant. Marijuana plants typically contain 5-10% THC, although certain strains may contain more. Also, trace amounts of THC may still be found in CBD oil. CBD is not psychoactive, meaning there is less possibility that CBD could cause drowsiness, mental confusion, or hallucinations that are often associated with THC. The 2018 Farm Bill stipulates that, legally, hemp oil cannot contain more than 0.3 percent THC. Hemp oil or marijuana oil? Marijuana oil is a liquid created by extracting THC and CBD from marijuana buds using a solvent. This type of cannabis oil usually contains high amounts of THC, low quantities of CBD, and other beneficial cannabinoids found in marijuana. Meanwhile, hemp oil is cannabis oil extracted from hemp strains that are rich in CBD with only trace amounts of THC. Aside from being rich in CBD, hemp oil also contains essential fats that our bodies need to function correctly, such as omega 6 and omega 3 fatty acids and linoleic acid. What makes high-quality cannabis oil? Several factors are essential when extracting cannabis oil. Quality of the starting material The quality of strain genetics, the freshness of the starting material, and the part of the plant extracted are all critical considerations. Effective extraction method An excellent extraction method prevents product defects, such as lackluster flavor or contamination. Proper post-processing. Refinement processes involve drying and storing practices, purging excess solvents, and isolating specific cannabinoids. Benefits of CBD Oil There have been reports that certain cannabinoids like THC and CBD may be beneficial for specific ailments and disorders. Researchers conducted a systematic review to carefully examine the effectiveness of medical cannabis for psychiatric, movement, and neurodegenerative disorders. Results of the trials suggest potential benefits of cannabinoids for anxiety, anorexia nervosa, dementia, PTSD, Alzheimer’s disease, Huntington’s disease, Tourette syndrome, and Parkinson’s disease. However, insufficient and low-quality evidence make the results inconclusive. Improved knowledge of the precise action of cannabinoids at the cellular level could facilitate the development of cannabinoid formulations, as well as conduct further clinical trials on the symptoms of the disease. Meanwhile, data from studies show that a single dose of CBD reduces resting blood pressure and blood pressure response to stress, indicating that CBD may be beneficial in the treatment of cardiovascular disorders, such as hypertension. Side Effects of CBD Oil CBD is considered safe. However, some people, particularly those who are taking other prescription medications, could still experience side effects from using CBD oil. It can interact with other pharmaceuticals like blood thinners. CBD can cause side effects, such as dry mouth, diarrhea, fatigue, drowsiness, and changes in appetite, although they are often well-tolerated. The unreliability of the dosage and purity of CBD in products may also be an issue. A Penn Medicine study of 84 CBD products purchased online shows that almost 70 percent of them are either over or under labeled, causing potential serious harm to its consumers. Thus, experts encourage people to talk to their doctor first before adding CBD oil to their existing treatment plan. A discussion on how one should take the oil and what concentration is best for an individual would benefit the patient’s health condition. CBD Oil as a Treatment for Cancer: What the Research Says Whether one is struggling with this disease or know someone diagnosed with it, the question of whether CBD may help has probably crossed someone’s mind. According to a study in animal models of cancer, there is evidence supporting the idea that cannabinoids can impede the growth of tumor cells. CBD may also enhance the uptake or increase the potency of certain drugs used for cancer treatment, as another review suggests. There are several promising studies about CBD’s use in cancer treatment. A study demonstrated that CBD could initiate cell death and make glioblastoma cells more sensitive to radiation, without affecting healthy cells. Glioblastoma is cancer that can occur in the brain or spinal cord. A research that involved experimental models of colon cancer in vivo (within a living organism) suggests that CBD may prevent the proliferation of colorectal cancer cells. A review of several in vitro (outside a living organism), as well as in vivo studies showed that cannabinoids are promising compounds in the treatment of gliomas. Glioma is a tumor type that starts in the glial cells that surround nerve cells and help them function. Other research showed the efficacy of CBD in pre-clinical representations of metastatic breast cancer. The researchers found that CBD significantly reduced breast cancer cell invasion and proliferation. The results of a study revealed that cannabis-based medicines are useful supplemental treatments in cancer patients. Researchers concluded that CBD could inhibit colorectal cancer cells from proliferating. On the other hand, a recent review focused on pancreatic cancer. Data support the potential benefit of cannabinoids to help slow down the growth and invasion of tumors. Researchers found that cannabinoids help trigger tumor cell death as well. Data presented in a review indicate that CBD may have had a role in the striking response in one lung cancer patient as a result of self-administration of CBD oil for a month and in the absence of any other distinct lifestyle, drug, or dietary changes. In another study, the authors found a promising relationship between cannabis and bladder cancer. After adjusting for age, race or ethnicity, and body mass index, researchers found that using tobacco only was linked to an increased risk of bladder cancer. Cannabis use only was connected to a 45% reduction in bladder cancer incidence. While research has demonstrated that cannabis smoke still generates carcinogens, the correlation between inhaled marijuana and cancer remains inconclusive. Still, further work is necessary, both in vitro and in vivo, to better assess the impact of CBD on malignant cells and its potential application in the treatment of cancer. CBD for Symptoms of Cancer According to the Centers for Disease Control and Prevention (CDC), “In 2016, 1,658,716 new cases of cancer were reported, and 598,031 people died of cancer in the United States. For every 100,000 people, 436 new cancer cases were reported, and 156 died of cancer. One of every four deaths in the United States is due to cancer.” To date, Epidiolex is the only CBD product that has received FDA approval, and it is only used in the treatment of seizures associated with Lennox-Gastaut syndrome (LGS) or Dravet syndrome (DS) in patients 2 years of age and older. No CBD products have been FDA-approved to cure cancer or its symptoms or to alleviate the side effects of cancer treatment. However, two marijuana-based drugs, dronabinol and nabilone, have been approved to help with nausea and vomiting caused by chemotherapy. Dronabinol (Marinol) is available in capsule form and contains THC. Nabilone (Cesamet) is a synthetic cannabinoid that acts similarly to THC. If one is considering using medical marijuana or medical cannabis as a supplement to his or her cancer therapy, a consultation with a doctor about how best to administer it is the best course of action. CBD for Nausea and Vomiting The National Cancer Institute, under the National Institutes of Health, describes chemotherapy as a cancer treatment that uses drugs to kill cancer cells. Doctors use chemotherapy to cure cancer, reduce the prospect of its return, or slow or stop its growth. Chemotherapy can also be used to shrink tumors. While this treatment is valuable, it also brings about side effects, such as hair loss, fatigue, nausea, and vomiting, that patients may feel the need to delay or quit the treatment altogether. In these situations, CBD can help. Studies show that as an antiemetic (preventing nausea), CBD may reduce nausea and vomiting induced by chemotherapy. However, the antiemetic effect appears to come from THC in cannabis, rather than from CBD. Patients trying cannabis to counter nausea also find themselves experiencing the potential psychoactive effects of THC. Still, many people find relief from consuming low doses of THC. Prescription synthetic THC that have fewer side effects are available. CBD for Chronic Pain Relief Cancer and its treatment can both lead to pain, and most people with cancer go through severe pain chronically. Cancer often causes pain due to pressure on internal organs, inflammation, or nerve injury. While there are medications prescribed to ease their discomfort, they come with severe side effects, such as vomiting, extreme sleepiness, constipation, and addiction. When the pain is severe, it can become resistant to opioids, which are great pain relievers. A study shows that THC:CBD extract is efficacious for pain relief in patients with advanced cancer pain not fully relieved by potent opioids. Some patients may not respond well to opioids. CBD indirectly impacts the CB2 receptors, which may help with pain relief by reducing inflammation, while THC triggers the CB1 receptors, which may be helpful for pain resulting from nerve damage. However, the results of a review published by Cochrane indicate that there was no high-quality evidence that any cannabis-derived product works for any chronic neuropathic pain. Given that more people reported dizziness, sleepiness, dizziness, and confusion with all cannabis-based medicines pooled together than with placebo, researchers say their potential harms might outweigh the potential benefits of cannabis in chronic neuropathic pain. CBD for Appetite People who go through cancer treatment may experience nausea and loss of appetite, which can make it challenging to maintain a healthy weight. When cannabis is ingested, it delivers THC and other cannabinoids to the bloodstream, helping stimulate the appetite. However, there is no high-quality evidence that CBD alone can have this effect. Meanwhile, a study on the relationship between cannabinoids and food intake suggests that endocannabinoids can impact energy balance and food intake within the brain. CBD for Anxiety and Sleep Problems Sleep problems are quite typical among cancer patients. Some of the sleep issues take the form of insomnia, while in some cases, they manifest as chemotherapy-related fatigue. Not getting enough sleep is disadvantageous for patients dealing with cancer as it worsens mood, weakens one’s immune system, adversely impacts mood, and impairs cognitive performance. Studies suggest that medium or high-dose CBD is associated with an increase in the percentage of total sleep. Research indicates that taking CBD oil may help address anxiety and sleep disorders, as it helps the patients fall asleep and reduces the frequency of waking up at night. The data also support the use of cannabis for treating chemotherapy-induced nausea and vomiting, loss of appetite, pain, and chemotherapy-induced peripheral neuropathy. CBD for Tumor Growth Several studies showed that CBD-induced cell death of breast cancer cells, suggesting that the use of CBD oil may also suppress tumor growth. In a study, the results show that the use of CBD in conjunction with anti-leukemia drugs made the drugs more effective. Researchers found that when certain cannabinoids are paired together, the resulting product can be combined with conventional anti-leukemia drugs, allowing the dose of the toxic agents to be substantially reduced yet remain effective. Research demonstrates that cannabinoids can also prove beneficial in certain types of cancers that are activated by chronic inflammation. In such instances, cannabinoids, as anti-inflammatory agents, can either directly prevent tumor growth or suppress inflammation. How CBD Oil Helps in Apoptosis A review was conducted to examine apoptosis, the process of programmed cell death. The results of the study indicate that apoptosis has to be carefully regulated because too little or too much cell deaths may lead to diseases, including developmental abnormalities, autoimmune diseases, neurodegeneration, or cancer. Apoptosis, also referred to as cellular suicide, is a normal process of cellular self-destruction that serves a healthy and defensive role in the body. Cancer cells no longer acknowledge the body’s signals that encourage or destroy cell growth. Thus, as these cells grow and divide, they proliferate uncontrollably. The endocannabinoid system is essential in the body because it also helps in regulating cell growth and death. As cancer cells reproduce more rapidly than the endocannabinoid system can manage, metastasis occurs. Metastasis is the process where cancer cells invade through the healthy tissues from the place where they first formed and spread to another part of the body. The endocannabinoid system has two primary receptors: CB1 receptors are mostly found in the brain, while CB2 receptors are situated in the immune system. THC is the cannabinoid that latches onto the CB1 receptors and is responsible for mood, behavior, and other brain functions. On the other hand, CBD binds to CB2 receptors, signaling for ‘invaders’ that are damaging to the body. Apoptosis helps support the immune system through the critical role it plays during viral infections, killing off invaded cells before they spill over with virus particles. This act of self-sacrifice hampers the spread of viruses and can save the whole organism. The receptor activation helps the endocannabinoid system signal a warning to counteract the formation of tumors, impeding cancer development through inhibiting reproduction, metastasis, and tumor development. Mixed Results The National Cancer Institute (NCI) reviewed numerous studies on the correlation between cannabis and cancer and found that the research has varied results. A study of 64,855 patients in a health checkup in Kaiser Permanente in the United States was conducted to examine the relationship of marijuana use to cancer incidence. Researchers found that cannabis use did not increase the risk of tobacco-related cancers. Neither was cannabis associated with colorectal, lung, melanoma, prostate, breast, or cervix cancer. However, this same study also found that among nonsmokers of tobacco cigarettes, having used marijuana was linked to a higher risk of cervical cancer and prostate cancer. The authors of the study concluded that marijuana use and cancer were not associated with overall analyses, but marijuana use might affect certain site-specific cancer risks. Other studies on the role of cannabinoids in the development of cancer also generated mixed results. Cannabinoids show antitumor activity in animal models of cancer, but experts still do not have data from longitudinal clinical trials concerning their efficacy and safety on humans. In a study, researchers recognized the antitumor effects of cannabinoids in various cancer types. However, these antitumor effects of cannabinoids have to prevail over their known immunosuppressive effects, which can potentially promote the production or formation of tumors. In a study published in 2010 in the European Journal of Immunology, researchers using a mouse model found that cannabinoids can initiate the suppression of the immune system. Although this particular research involved cannabis containing THC, the results indicate that cannabinoids could make users more susceptible to some types of cancer. CBD research is still limited when it comes to cancer prevention. Scientists would have to conduct longitudinal studies of humans using specific CBD products, controlling for frequency of use and dosing. Best CBD Oil Products for Cancer As more and more people turn towards safe and alternative therapies, the interest in plant-derived medicines grows exponentially. This trend is excellent news for everyone, but particularly for people who live with cancer. In 2018, cancer was responsible for nearly 10 million deaths around the world. This number is appalling considering the technological advances in modern medicine in the past years. While the survival rates after a cancer diagnosis are on the upsurge, this figure still emphasizes the necessity for more research and treatment options. The following list is a consolidation of the best CBD oils for cancer. The following brands are recommended for their high quality, based on potency, extraction methods, and the soil in which the hemp has been cultivated. Cancer in Pregnancy Cancer during pregnancy is not a typical occurrence. Pregnancy-associated cancer constitutes a clinical situation that is difficult to manage. According to statistics, 1 in every 1000 pregnant women is diagnosed with cancer. Studies indicate that breast cancer, melanoma, cervical cancer, lymphoma, and acute leukemia are commonly diagnosed malignancies during pregnancy. Among these types of malignancies, breast cancer is the most common. A review revealed that breast cancer affects approximately 1 in 3000 pregnant women. Experts at the Canadian Cancer Society expects that the number of pregnant women with cancer could increase as more women are waiting until they are older to have children. Risks of developing most cancers increases as women age. Cancer Treatment while Pregnant Years ago, many doctors recommended terminating the fetus when treating cancer during pregnancy. Today, however, more women are choosing to treat their disease while they are pregnant. Every situation is different. Although treatment choices for pregnant women with cancer are the same as those for non-pregnant women with cancer, when and how treatments are given might be different for pregnant women. Thus, a discussion with a health professional of all the advantages and disadvantages of receiving cancer treatment during pregnancy is an excellent course of action. A pregnant woman’s treatment options would depend on many factors, including the type of cancer she has, where her cancer is located, her cancer stage, how far along she is in her pregnancy, and her personal choices. Say No to CBD When Pregnant The U.S. Food and Drug Administration (FDA) has informed the public of the severe risks related to the use of cannabis products, including those containing CBD, for women who are pregnant or breastfeeding. There are numerous potential adverse health effects from using marijuana and other products containing THC during pregnancy and while breastfeeding. The U.S. Surgeon General advised consumers against marijuana use during pregnancy, as it may affect fetal brain development. THC could enter the fetal brain from the mother’s bloodstream. The Surgeon General VADM Jerome said, “I am emphasizing the importance of protecting our nation from the health risks of marijuana use in adolescence and during pregnancy. Recent increases in access to marijuana and its potency, along with misperceptions of the safety of marijuana, endanger our most precious resource, our nation’s youth.” The Surgeon General also advised that marijuana may intensify the risk of a newborn with lower than average birth weight. Research also suggests an increased risk of preterm birth and stillbirth. Conclusion There is still a lot to know about the mechanisms of CBD and its impact on the body of a cancer patient to make sure that it does not interact adversely with existing cancer treatments or other medications. CBD oil may complement other treatments for cancer. However, if one is planning on adding it to his or her existing treatment plan, it is an excellent idea to discuss it with a doctor first. For more information on cancer and the different types of cancer, cancer.gov may be an excellent resource. Cancer.gov is the website for the National Cancer Institute (NCI), the U.S. government’s principal agency for cancer research.

Jatropha curcas L.
1. NAME 1.1 Scientific name 1.2 Family 1.3 Common name(s) 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 2.5 Poisonous parts 2.6 Main toxins 3. 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 4. USES/CIRCUMSTANCES OF POISONING 4.1 Uses 4.2 High risk circumstances 4.3 High risk geographical areas 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. 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 8. 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 Biochemcial 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 8.5 Overall Interpretation of all toxicological analyses and 8.6 References 9. CLINICAL EFFECTS 9.1 Acute poisoning 9.1.1 Ingestion 9.1.2 Inhalation 9.1.3 Skin exposure 9.1.4 Eye contact 9.1.5 Parenteral exposure 9.1.6 Other 9.2 Chronic poisoning 9.2.1 Ingestion 9.2.2 Inhalation 9.2.3 Skin exposure 9.2.4 Eye contact 9.2.5 Parenteral exposure 9.2.6 Other 9.3 Course, prognosis, cause of death 9.4 Systematic description of clinical effects 9.4.1 Cardiovascular 9.4.2 Respiratory 9.4.3 Neurological 9.4.3.1 CNS 9.4.3.2 Peripheral nervous system 9.4.3.3 Autonomic nervous system 9.4.3.4 Skeletal and smooth muscle 9.4.4 Gastrointestinal 9.4.5 Hepatic 9.4.6 Urinary 9.4.6.1 Renal 9.4.6.2 Others 9.4.7 Endocrine and reproductive systems 9.4.8 Dermatological 9.4.9 Eye, ears, nose, throat: local effects 9.4.10 Hematological 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 10. 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 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/antitoxins 12.2 Specific preventive measures 12.3 Other 13. REFERENCES 13.1 Clinical and toxicological 13.2 Botanical 14. AUTHOR(S), REVIEWER(S), DATE(S) (INCLUDING UPDATES), COMPLETE ADDRESS(ES) POISONOUS PLANTS 1. NAME 1.1 Scientific name Jatropha curcas 1.2 Family Euphorbiaceae 1.3 Common name(s) Barbados nut Black vomit nut Curcas bean Kukui haole Physic nut Purge nut Purgeerboontjie Purging nut tree 2. SUMMARY 2.1 Main risks and target organs Dehydration and cardiovascular collapse as a result of haemorrhagic gastro-enteritis. Central nervous system depression. 2.2 Summary of clinical effects Symptoms are largely those associated with gastro-intestinal irritation. There is acute abdominal pain and a burning sensation in the throat about half an hour after ingestion of the seeds, followed by nausea, vomiting and diarrhoea. The vomitus and faeces may contain blood. In severe intoxications dehydration and haemorrhagic gastroenteritis can occur. There may be CNS and cardiovascular depression and collapse; children are more susceptible. 2.3 Diagnosis Diagnosis by case history and presenting symptoms. A definite diagnosis can only be made if there is a history of ingestion and the ingested plant material has been positively identified as Jatropha. 2.4 First-aid measures and management principles INGESTION: Unless the patient is unconscious, convulsing, or unable to swallow give fluids (milk or water) to dilute. Seek medical assistance. In hospital or a health care facility induce vomiting unless the patient has already vomited, or perform gastric lavage. Administer activated charcoal and a cathartic to hasten elimination, although in the presence of diarrhoea this is unecessary. SKIN: Wash the affected area well with plenty of water and use a mild soap. EYE: Flush the eye with copious amounts of water for at least 15 minutes. If irritation persists seek medical assistance. 2.5 Poisonous parts All parts are considered toxic but in particular the seeds. 2.6 Main toxins Contains a purgative oil and a phytotoxin or toxalbumin (curcin) similar to ricin in Ricinis. 3. CHARACTERISTICS 3.1 Description of the plant 3.1.1 Special identification features Jatropha curcas is a large coarse annual shrub or small short lived tree which can grow 3.5 to 4.5 metres (8-15 feet) tall. It has thin, often greenish bark which exudes copious amounts of watery sap when cut. Leaves: dark green; alternate, simple,ovate to slightly lobed with 3-5 indentations. Up to 15 cm wide. Petioles 10cm (4 inches) long. Flowers: yellow to green in colour, borne in axils of the leaves and being small are mostly hidden by foliage. Fruit: small capsule-like, round fruit; about 2.5 - 4 cm (1-1.5 inches) in diameter. These are green and fleshy when immature, becoming dark brown when ripe and splitting to release 2 or 3 black seeds each about 2 cm (3/4 inch) long. The meat of the seeds is white and oily in texture and are reported to have an agreeable taste. (Micromedex, 1974-1994) 3.1.2 Habitat Widely cultivated as an ornamental. Prefers arid environments. 3.1.3 Distribution Native to tropical America, but is now cultivated widely in tropical countries throughout the world. It is grown occasionally in warmer parts of Australia and is naturalised in a few places in Queensland and the Northern Territory. In Florida it is found chiefly south of Orlando. It is also a common plant in the Hawaiian Islands. Introduced to southern Africa, the plant has spread from Mozambique through Zambia to the Transvaal and Natal. This species is also found throughout the warmer parts of Asia. 3.2 Poisonous parts of the plant 3.3 The toxin(s) 3.3.1 Name(s) MAIN TOXINS: Curcin - a phytotoxin (toxalbumin), found mainly in the seeds and also in the fruit and sap. Purgative oil - the seed yields 40% oil, known as hell oil, pinheon oil, oleum infernale or oleum ricini majoris, which contains small amounts of an irritant curcanoleic acid, which is related to ricinoleic acid and crotonoleic acid, the principle active ingredients of castor oil and croton oil respectively (Joubert et al., 1984). OTHER TOXINS: This genera also may contain hydrocyanic acid (CRC Critical Reviews in Toxicology 1977). There may be a dermatitis producing resin (Lampe & Fagerstrom, 1968). There may be an alkaloid, and a glycoside which produce cardiovascular and respiratory depression. Tetramethylpyrazine (TMPZ), an amide alkaloid has been obtained from the stem of J. podagrica (Ojewole & Odebiyi, 1981). Atropine-like effects have also been reported following ingestion of Jatropha multifida (Aplin 1976). 3.3.2 Description, chemical structure, stability Curcin: Phytotoxins or toxalbumins are large, complex protein molecules of high toxicity. They resemble bacterial toxins in structure and physiological effects. Phytotoxins are heat labile, and can be positively identified by precipitin reactions with sera containing known antibodies (Kingsbury 1964). Curcin is said to be highly irritant and remains in the seed after the oil has been expressed. Tetramethylpyrazine (TMPZ): CAS: 1124-11-4 MW: 136.22 Molecular formula: C8-H12-N2 3.3.3 Other physico-chemical characteristics Curcin is unable to penetrate cell walls, this has been indicated by the fact that these proteins do not affect protein synthesis by Ehrlich ascites cells. This is thought to be because they lack a carrier moiety or at least the galactose-binding groups by which ricin binds to cell membranes. This was discovered when it was found that the activity of curcin in cell-free systems is not increased by treatment with 2-mercaptoethanol, which greatly enhances the inhibitory effect of ricin and abrin by splitting their molecules into an effector and a carrier moiety (Stirpe et al.,1976). 3.4 Other chemical contents of the plant No further information was available at the time of preparation of the monograph. 4. USES/CIRCUMSTANCES OF POISONING 4.1 Uses Jatropha is an ornamental plant naturalised in many tropical areas. The roots, stems, leaves seeds and fruits of the plant have been widely used in traditional folk medicine in many parts of West Africa. The seeds of J. curcas have been used as a purgative, antihelminthic and abortifacient as well as for treating ascites, gout, paralysis and skin diseases. The seed oil of the plant has been used as an ingredient in the treatment of rheumatic conditions, itch and parasitic skin diseases, and in the treatment of fever, jaundice and gonorrhoea, as a diuretic agent, and a mouth-wash. The leaf has been used as a haemostatic agent and the bark as a fish poison. In certain African countries people are accustomed to chewing these seeds when in need of a laxative. J. curcas seeds have been found to be highly effective against Strongyloides papillosus infection in goats (Adam & Magzoub, in press). It has also been suggested that J. curcas seeds could be a useful chemotherapeutic agent provided that it is active at a non-lethal dose (Adam, 1974). This may be because of it's reported antihelminthic activity. 4.2 High risk circumstances As these plants are grown as an ornamental they will often be found in gardens and public areas and therefore will be easily accessible. As Jatropha are fruit bearing and the seeds have a pleasant taste, the plants are particularly attractive to children. This species of plant is not usually eaten by animals but drought leading to an acute shortage of grass creates a situation in which animals are forced to consume the plants and their constituents in varying amounts. 4.3 High risk geographical areas Found in tropical countries throughout the world; including tropical America, warmer parts of Australia (Queensland and the Northern Territory), Florida (chiefly south of Orlando), Hawaiian Islands and Africa (Mozambique, Zambia, Transvaal, Natal), Asia. 5. ROUTES OF ENTRY 5.1 Oral All cases of systemic poisoning have resulted from ingestion of plant material (in most cases the seeds). 5.2 Inhalation No relevant information at the time of preparation of the monograph. 5.3 Dermal No relevant information at the time of preparation of the monograph. 5.4 Eye No relevant information at the time of preparation of the monograph. 5.5 Parenteral No relevant information at the time of preparation of the monograph. 5.6 Others No relevant information at the time of preparation of the monograph. 6. KINETICS 6.1 Absorption by route of exposure INGESTION: Phytotoxins are well absorbed from the gastrointestinal tract. The onset of symptoms may be developed one or more hours. 6.2 Distribution by route of exposure No relevant information at the time of preparation of the monograph. 6.3 Biological half-life by route of exposure No relevant information at the time of preparation of the monograph. 6.4 Metabolism Curcin - phytotoxins are partly metabolised in the digestive tract. 6.5 Elimination by route of exposure No relevant information at the time of preparation of the monograph. 7. TOXICOLOGY/TOXINOLOGY/PHARMACOLOGY 7.1 Mode of action Phytotoxins (toxalbumins): It has been suggested that in vivo phytotoxins act as proteolytic enzymes, owing their toxicity to the breakdown of critical proteins and the accumulation of ammonia (Kingsbury, 1964). Tetramethylpyrazine (TMPZ): Has been found to possess a non- specific spasmolytic and vasodilator activity (Ojewole & Odebiyi, 1981). These actions may account, at least in part, for the reported hypotensive (depressor) effects of the amide alkaloid in experimental animals. TMPZ has also been found to possess neuromuscular-blocking effects similar to d-tubocurarine (Ojewole & Odebiyi, 1980). 7.2 Toxicity 7.2.1 Human data 7.2.1.1 Adults In some instances as few as three seeds have produced toxic symptoms. In others, consumption of as many as 50 seeds has resulted in relatively mild symptoms. There is one report where the ingestion of only one seed in an adult has produced toxic symptoms. It has been suggested that there may be two strains one with toxic seeds and one without (Kingsbury, 1964). Curcin, the phytotoxin or toxalbumin found in Jatropha curcas is similar to ricin the phytotoxin found in the castor bean (Ricinis). The minimum lethal dose of ricin, when administered by injection, may be as small as 0.00000001% of body weight, although oral toxicity is probably several hundred times less (Kingsbury, 1964). 7.2.1.2 Children Toxicity is thought to be the same as for adults, thus, as few as 1-3 seeds may produce toxic symptoms. 7.2.2 Animal data Poisoning from ingestion of the seeds of the Jatropha plant is well known in veterinary practice and autopsy findings include, severe gastro-enteritis, nephritis, myocardial degeneration, haemagglutination, and subepicardial and subendocardial haemorrhages as well as renal subcortical and subpleural bleeding. One study found a high mortality rate in mice fed 50% and 40% J. curcas. The important symptoms of poisoning included diarrhoea, inability to keep normal posture, depression and lateral recumbency. The degree of the pathological changes observed in the small intestines, liver, heart, kidneys, and lungs was related to the level of Jatropha in the diet. The most marked pathological changes were catarrhal enteritis, erosions of the intestinal mucosa, congestion and haemorrhages in small intestines, heart and lungs and fatty changes in the liver and kidneys (Adam, 1974). Another oral dosing study undertaken using mice found that curcin, as compared with crotin found in the seeds of croton tiglium, had a slightly more rapid action with symptoms beginning at 12 hours and most deaths occurring within 48 hours of poisoning. An acute LD50 of 9.11mg/mouse was calculated at 48 hours and a delayed LD50 of 5.83mg/mouse was calculated at 7 days. The behaviour of the animals was similar to that of mice treated with crotins, except for some neurological symptoms (waddling, fine tremors, rocking, occasionally convulsions), which were present especially among animals poisoned with the highest doses of curcin. Post-mortem examinations showed lesions in the liver, pancreas and spleen, hyperaemia of the intestine, sometimes ascites; the whole picture resembled that of rats poisoned with ricin. (Stirpe et al.,1976) In young ruminants oral doses of 0.5 to 10g/kg/day caused death after dosing for periods ranging from 1 day to 2 weeks. The clinical, haematological, and pathological changes indicated that J. aceroides reduced the ability of the liver to synthesize protein, although there was no evidence of interference with the excretion of bilirubin. Kidney dysfunction and haemoconcentration also occurred. Postmortem and histological findings were similar to those found above in studies with mice. (Barri et al., 1983) A study assessing the acute oral toxicity of J. curcas showed that different ruminants had different susceptibilities to the effect of J. curcas. Calves which received 0.25 or 1g/kg died within 19 hours of administration, whilst goats given similar daily doses were either killed or died within 7 to 21 days. It was not established whether this species difference lies in direct cytotoxic action or in the capacity with which the active substances contained in J. curcas seed are converted in vivo to metabolites more or less toxic than the parent compounds. (Ahmed & Adam, 1979) Feeding chicks seeds produced growth depression, hepatonephropathies, and haemorrhages. (Micromedex 1974-1994) 7.2.3 Relevant in vitro data In vitro phytotoxins cause agglutination of erythrocytes (Joubert et al., 1984). It has been observed that the seeds of J. curcas contain proteins that are toxic to animals and inhibit protein synthesis in a cell-free system (lysate of rabbit reticulocytes), but not in whole cells (Stirpe et al., 1976). 7.3 Carcinogenicity The seed oil of J. curcas was found to contain skin tumour promoters in a two-stage mouse carcinogenesis experiment. The "irritant fraction" contained in the methanol extract of the seed oil when partially purified induced ornithine decarboxylase in mouse skin and inhibited the specific binding of 3H-12-O-tetradecanoylphorbol-13-acetate to a particulate fraction of mouse skin. After initiation with 7, 12-dimethylbenz[a]anthracene (DMBA), this "irritant fraction" induced tumours in the skin of 36% of the mice tested in 30 weeks (Horiuchi et al., 1987). 7.4 Teratogenicity No relevant information at the time of preparation of the monograph. 7.5 Mutagenicity No relevant information at the time of preparation of the monograph. 7.6 Interactions No relevant information at the time of preparation of the monograph. 8. TOXICOLOGICAL/TOXINOLOGICAL ANALYSES AND BIOMEDICAL INVESTIGATIONS 8.1 Material sampling plan 8.1.1 Sampling and specimen collection 8.1.1.1 Toxicological analyses No relevant information at the time of preparation of the monograph. 8.1.1.2 Biomedical analyses No relevant information at the time of preparation of the monograph. 8.1.1.3 Arterial blood gas analysis No relevant information at the time of preparation of the monograph. 8.1.1.4 Haematological analyses No relevant information at the time of preparation of the monograph. 8.1.1.5 Other (unspecified) analyses No relevant information at the time of preparation of the monograph. 8.1.2 Storage of laboratory samples and specimens 8.1.2.1 Toxicological analyses No relevant information at the time of preparation of the monograph. 8.1.2.2 Biomedical analyses No relevant information at the time of preparation of the monograph. 8.1.2.3 Arterial blood gas analysis No relevant information at the time of preparation of the monograph. 8.1.2.4 Haematological analyses No relevant information at the time of preparation of the monograph. 8.1.2.5 Other (unspecified) analyses No relevant information at the time of preparation of the monograph. 8.1.3 Transport of laboratory samples and specimens 8.1.3.1 Toxicological analyses No relevant information at the time of preparation of the monograph. 8.1.3.2 Biomedical analyses No relevant information at the time of preparation of the monograph. 8.1.3.3 Arterial blood gas analysis No relevant information at the time of preparation of the monograph. 8.1.3.4 Haematological analyses No relevant information at the time of preparation of the monograph. 8.1.3.5 Other (unspecified) analyses No relevant information at the time of preparation of the monograph. 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) No relevant information at the time of preparation of the monograph. 8.2.1.2 Advanced Qualitative Confirmation Test(s) Extraction of J. curcas seeds for the preparation of crude curcin has used 8 x 250ml of ethyl ether. The ether has been removed by filtering. The resulting powder is then dried and then extrated with 1L of cold 0.005M-sodium phosphate buffer, pH 7.2, containing 0.2M-NaCl/100g of seeds. The mixture is stirred and left overnight. After centrifugation the supernatant is brought to 100% saturation with solid (NH4)2SO4. The protein precipitate is then collected by centrifugation and dissolved in a minimum amount of phosphate/NaCl buffer and then dialysed for 24-48 hour against a continuous flow of the same buffer. At the end of dialysis a brown precipitate remains and is removed by centrifugation. (Stirpe et al., 1976) Analysis of this crude preparation using a column of Sephadex G-100 has eluted three peaks referred to as curcin I, II and III. These proteins were found to have different properties, curcin I is more toxic and brings about different symptoms and lesions in vivo, whereas curcin II was much more active on protein synthesis (Stirpe et al., 1976). 8.2.1.3 Simple Quantitative Method(s) No relevant information at the time of preparation of the monograph. 8.2.1.4 Advanced Quantitative Method(s) No relevant information at the time of preparation of the monograph. 8.2.2 Tests for biological specimens 8.2.2.1 Simple Qualitative Test(s) No relevant information at the time of preparation of the monograph. 8.2.2.2 Advanced Qualitative Confirmation Test(s) No relevant information at the time of preparation of the monograph. 8.2.2.3 Simple Quantitative Method(s) No relevant information at the time of preparation of the monograph. 8.2.2.4 Advanced Quantitative Method(s) No relevant information at the time of preparation of the monograph. 8.2.2.5 Other Dedicated Method(s) No relevant information at the time of preparation of the monograph. 8.2.3 Interpretation of toxicological analyses No relevant information at the time of preparation of the monograph. 8.3 Biomedical investigations and their interpretation 8.3.1 Biochemcial analysis 8.3.1.1 Blood, plasma or serum No relevant information at the time of preparation of the monograph. 8.3.1.2 Urine No relevant information at the time of preparation of the monograph. 8.3.1.3 Other fluids No relevant information at the time of preparation of the monograph. 8.3.2 Arterial blood gas analyses No relevant information at the time of preparation of the monograph. 8.3.3 Haematological analyses No relevant information at the time of preparation of the monograph. 8.3.4 Interpretation of biomedical investigations No relevant information at the time of preparation of the monograph. 8.4 Other biomedical (diagnostic) investigations and their interpretation No relevant information at the time of preparation of the monograph. 8.5 Overall Interpretation of all toxicological analyses and toxicological investigations No relevant information at the time of preparation of the monograph. 8.6 References No relevant information at the time of preparation of the monograph. 9. CLINICAL EFFECTS 9.1 Acute poisoning 9.1.1 Ingestion Symptoms of poisoning are likely to be similar for species of Jatropha. There is usually a delay of an hour or more between consumption of the plant and the occurrence of symptoms. Symptoms are largely those associated with gastro-intestinal irritation. There is acute abdominal pain and a burning sensation in the throat about half an hour after ingestion of the seeds followed by nausea, vomiting and profuse watery diarrhoea. In severe poisoning, these symptoms progress to haemorrhagic gastroenteritis and dehydration. Polydipsia can be extreme. Salivation and sweating may occur. There may be skeletal muscle spasm. Intense hyperpnoea or a quick panting respiration is seen together with hypotension and electrocardiographic abnormalities. There may be CNS and cardiovascular depression, children are more susceptible; this may be either a direct effect of toxins or secondary to dehydration. In one report, as well as gastrointestinal symptoms, atropine-like effects developed eight hours after ingestion of Jatropha multifida (Aplin, 1976). Symptoms included sweating, dry skin and mouth, slight mydriasis, mild tachycardia and flushing of facial skin and persisted for four hours. 9.1.2 Inhalation No relevant information at the time of preparation of the monograph. 9.1.3 Skin exposure Primary chemical irritation from mechanical and/or chemical injury (Lampe & Fagerstrom, 1968). 9.1.4 Eye contact Primary chemical irritation from mechanical and/or chemical injury. 9.1.5 Parenteral exposure No relevant information at the time of preparation of the monograph. 9.1.6 Other No relevant information at the time of preparation of the monograph. 9.2 Chronic poisoning 9.2.1 Ingestion No relevant information at the time of preparation of the monograph. 9.2.2 Inhalation No relevant information at the time of preparation of the monograph. 9.2.3 Skin exposure No relevant information at the time of preparation of the monograph. 9.2.4 Eye contact No relevant information at the time of preparation of the monograph. 9.2.5 Parenteral exposure No relevant information at the time of preparation of the monograph. 9.2.6 Other No relevant information at the time of preparation of the monograph. 9.3 Course, prognosis, cause of death In non-fatal cases the course of intoxication is short; the patient may become asymptomatic within 24 hours. Recovery seems to be the rule. 9.4 Systematic description of clinical effects 9.4.1 Cardiovascular Hypotension with a fast weak pulse. Shock due to fluid and electrolyte loss may occur. Electrocardiographic abnormalities. 9.4.2 Respiratory Hyperpnoea. 9.4.3 Neurological 9.4.3.1 CNS There may be CNS depression either as a direct result of toxins or secondary to hypotension. Seizures have been mentioned in association with toxalbumin poisoning, but generally in animal cases or in symptom summaries rather than actual case reports (Micromedex, 1974-1994). 9.4.3.2 Peripheral nervous system No relevant information at the time of preparation of the monograph. 9.4.3.3 Autonomic nervous system There have been reports of salivation, sweating and abdominal cramping occurring in human intoxications of Jatropha macrorhiza root (Consroe and Glow, 1975). This suggests some cholinergic activity. Contrary to this, atropine-like effects have been reported (Aplin, 1976); thus diminished cholinergic stimulation may be evident. Mydriasis, dry mouth, flushed hot dry skin, tachycardia, etc.. 9.4.3.4 Skeletal and smooth muscle The muscles and extremities may be contracted by spasms. Intestinal spasm can be severe. 9.4.4 Gastrointestinal Acute abdominal pain and a burning sensation in the throat about half an hour after ingestion of the seeds. This is followed by nausea, vomiting and profuse watery diarrhoea. The vomitus and faeces may contain blood. Lesions are those of haemorrhagic gastro-intestinal inflammation. 9.4.5 Hepatic Liver damage may occur in serious cases of toxalbumin poisoning. There may be increases ALT, total bilirubin, and AST. (Micromedex, 1974-1994) 9.4.6 Urinary 9.4.6.1 Renal Oliguria, probably secondary to hypotension rather than direct renal toxicity. Urinalysis may reveal haemoglobinuria and albuminuria. 9.4.6.2 Others No relevant information at the time of preparation of the monograph. 9.4.7 Endocrine and reproductive systems No relevant information at the time of preparation of the monograph. 9.4.8 Dermatological Dermatitis as a result of primary chemical irritation possibly in conjunction with mechanical injury can occur in most, if not all, individuals. Reactions occur soon after exposure. The severity of the reaction is dependent on the extent and duration of contact. Hypersensitisation may also develop. 9.4.9 Eye, ears, nose, throat: local effects Retinal haemorrhages, optic nerve injury have been reported in toxalbumin poisoning (Micromedex, 1974- 1994). 9.4.10 Hematological Haemoconcentration secondary to fluid loss. Toxalbumins are haemagluttinating. Effects in poisoning are minimal even though the effect is prominent in vitro. (Micromedex, 1974-1994) 9.4.11 Immunological No relevant information at the time of preparation of the monograph. 9.4.12 Metabolic 9.4.12.1 Acid base disturbances Acid base disturbances are not typical in toxalbumin poisoning (Micromedex, 1974-1994) 9.4.12.2 Fluid and electrolyte disturbances Dehydration which is often severe. Electrolyte disturbances. 9.4.12.3 Others No relevant in formation at the time of prparation of the monograph. 9.4.13 Allergic reactions Stated as being a primary chemical irritant (Lampe & Fagerstrom, 1968), but hypersensitivity reactions may occur in susceptible individuals. The inflammation resulting from primary chemical irritant effects of Jatropha is a predisposing factor to the development of contact allergy. 9.4.14 Other clinical effects Toxoalbumin poisoning may produce fever (Micromedex, 1974-1994). 9.4.15 Special risks No relevant information at the time of preparation of the monograph. 9.5 Others Oedematous swelling of several organs. 10. MANAGEMENT 10.1 General principles The management of Jatropha poisoning is similar to that for the castor bean (Ricinis). Decontamination is indicated for all known or suspected poisonings. There is no antidote. Rehydration, either voluntary water ingestion or i.v. fluid administration, to counteract fluid lost due to vomiting and diarrhoea is critical. Treatment is essentially symptomatic and supportive. The more critical analyses and investigations are fluid and electrolytes, acid-base status, full blood count, and renal and hepatic function. Monitor level of consciousness. Specific therapy may be indicated for haemorrhagic gastrointestinal damage, skeletal muscle and gastrointesinal spasm, excessive salivary secretions and haemoglobinuria. After substantial exposures to toxalbumin containing plants, an observation period of up to 8 hours is advised. 10.2 Relevant laboratory analyses and other investigations 10.2.1 Sample collection Blood and urine sample collection. 10.2.2 Biomedical analysis Complete blood count, electrolytes, blood urea nitrogen, creatinine, acid-base status, glucose, prothrombin time, liver enzymes, amylase, and urinalysis. 10.2.3 Toxicological/toxinological analysis No relevant information at the time of preparation of the monograph. 10.2.4 Other investigations Monitor hepatic, renal, pancreatic, and red blood cell function. 10.3 Life supportive procedures and symptomatic treatment Fluid and electrolyte status may deteriorate suddenly and severely. Give IV fluids and electrolyte as necessary to restore and maintain fluid and electrolyte balance. Monitor renal function and alkalinize urine to minimize effects of haemoglobinuria. Treat haemorrhagic gastro-intestinal damage as for peptic ulceration. Observe for signs of CNS depression and initiate assisted ventilation if necessary. 10.4 Decontamination In all cases of ingestion or suspected ingestion, if the patient is seen sufficiently soon (within 1-2 hours of ingestion), induce emesis with Ipecac Syrup or perform gastric lavage unless vomiting has been extensive. 10.5 Elimination Administer activated charcoal and a cathartic to enhance and hasten elimination, although severe diarrhoea may make this unnecessary. Cathartic administration must be cautious due to the risk of exacerbating purgation and fluid loss. Phytotoxins are non dialysable. However, methods for eliminating the toxins from the blood (haemodialysis, peritoneal dialysis, charcoal haemoperfusion etc.) have been suggested as useful, whether this removes plant toxins other than phytotoxins from the blood and therefore improves the prognosis and hastens the recovery, is yet to be demonstrated. A possible indication for this would be life- threatening CNS or respiratory depression (not secondary to hypovolaemia) which is unresponsive to other supportive measures. 10.6 Antidote/antitoxin treatment 10.6.1 Adults No antidote. Many antidotes have been investigated for toxalbumin poisoning, but no specific treatments are available. (Micromedex, 1974-1994) 10.6.2 Children No antidote. Many antidotes have been investigated for toxalbumin poisoning, but no specific treatments are available. (Micromedex, 1974-1994) 10.7 Management discussion In cases of poisoning where dehydration has been severe close follow up of renal function is imperative. 11. ILLUSTRATIVE CASES 11.1 Case reports from literature Case History: A 3-year-old Hawaiian-Caucasian boy was admitted to Kauikeoani Children's Hospital on September 20, 1958, because of persistent vomiting and diarrhoea. The episodes were of sudden onset following the ingestion of several large black seeds gathered from an over-hanging branch of a neighbour's tree (later identified as Jatropha curcas). He was unable to retain any ingested food or water. Each intake was vomited almost immediately after ingestion. The vomitus was said to contain the white granulated material and the particles of the black shells. After several bouts of vomiting, the child started to have watery bowel movements. The stools contained seed particles also. Three and a half hours following the ingestion of the seeds, the child appeared lethargic. His skin felt cold and clammy. The child was admitted to the hospital in severe dehydration. The family and past history were non-contributory. Blood pressure was 100/70; pulse 130; respiration 40; temperature 99.8°F (rectal). The patient appeared lethargic, cyanotic, and acutely ill. The peripheral vessels were constricted. Severe dehydration was indicated by the poor skin turgor, sunken eyeballs, and deepening periorbital shadows. The bowel sounds were hyperactive. The remainder of the physical examination was within normal limits. The haemoglobin was 14.2gm/100mL, the red blood cell count , 5.4 million, and the platelets were normal. The white blood cell count was 27,000 per cu mm, and the differential was normal. The urine showed a trace of albumin, and elements consisting of 2-4 white blood cells per high power field and many granular and some hyaline casts. The carbon oxide level was 17mEq/L; chlorides, 101mEq/L; and potassium, 4.4mEq/L. The stool cultures were negative for pathogens. The child was given 1000mL of isotonic electrolyte solution. Blood was drawn for type and cross matching. The patient was oliguric for the first 24 hours. He responded to treatment, and twenty hours after admission he was able to tolerate oral feedings without any vomiting or diarrhoea, and was voiding well. He was discharged from the hospital after 3 days without complication. (Ho 1960). Case History: Two sisters aged 5 and 3 years respectively were rushed to Ahmadu Bello University Teaching Hospital, Zaria, Nigeria, with a history of vomiting and drowsiness about 5 hours after ingesting unspecified quantities of ripe seeds of J. curcas. They had each vomited between 6 and 10 times within the hour preceding their arrival. There had been no diarrhoea and the vomitus consisted of a whitish material mixed with the food they had taken 2 hour previously. On examination they were well-fed children, afebrile, not pale, jaundiced or cyanosed but moderately dehydrated. There was neither abdominal tenderness nor any abnormal finding on rectal examination. They were both restless, drowsy but rousable and their pupils were normal and reactive. Laboratory investigations revealed normal haemoglobin, normal liver-function tests and mild alkalosis. Treatment consisted of rehydration with intravenous fluids and sedation with small doses of promethazine hydrochloride. They recovered rapidly and were both discharged some 48 hours after admission. (Abdu-Aguye et al.,1986). Case History: An 18 year old, well developed Caucasian male was admitted to hospital at 11:45 p.m. because of persistent vomiting, diarrhoea and drowsiness. The patient had ingested 3 pieces (about 2 inches in diameter) of a plant root (identified as Jatropha macrorhiza) about 4 hours earlier; symptoms emerged about 1 hour after ingestion. Except for drowsiness and tenderness of all quadrants of the abdomen, physical examination and haematologic and urinary laboratory values of the patient showed no striking abnormalities. Bed rest was prescribed and tap water was given ad libitum to quench the paitients extreme polydipsia. After an uneventful nights sleep, the patient was discharged at 10:30 the next morning without complications. (Consroe and Glow, 1975). Case History: A 48 year old, well developed Caucasian male was admitted to hospital at 3 p.m. because of persistent diarrhoea after ingesting an unknown quantity of a sweet tasting potato-like plant root (identified as Jatropha macrorhiza) at 8 a.m. Bouts of severe vomiting and diarrhoea about every 3 minutes appeared 45 to 60 minutes after ingestion and persisted throughout most of the afternoon. The patient also complained of drowsiness, perspiration, salivation, polydipsia, cramps in the legs and abdomen and of feeling cold and clammy. Physical examination revealed a poor skin turgor, sunken eyeballs excessive salivary secretions and no lesions of mouth or throat. there was tenderness in all quadrants of the abdomen and deep tendon reflexes were hyperactive and intermittent muscle spasms in toes and calfs were apparent. Vital signs and urinary and haematological values were normal except for elevations in haematocrit (60%) and haemoglobin (20.2gm/100ml). Initially, 1 litre of 5% dextrose in water, atropine (0.5mg im.) and diazepam (5mg, im.) every 6-8 hours as needed were prescribed. After a restful night, the patient was discharged at 9 a.m., the following morning without complications. (Consroe and Glow, 1975). 11.2 Internally extracted data on cases No relevant information at the time of preparation of the monograph. 11.3 Internal cases No relevant information at the time of preparation of the monograph. 12. ADDITIONAL INFORMATION 12.1 Availability of antidotes/antitoxins 12.2 Specific preventive measures 12.3 Other 13. REFERENCES 13.1 Clinical and toxicological Abdu-Aguye I, A Sannusi, R A Alafiya-Tayo, S R Bhusnurmath. (Jul 1986) Acute Toxcity Studies with Jatropha curcas L. Human Toxicology, 5(4):269-274. Adam S E I. (Mar 1974) Toxic effects of Jatropha Curcas in mice. Toxicology, 2(1):67-76. Adam S E I, M Magzoub. Preliminary observations on the anthelmintic activity of Jatropha curcas against strongyloides and Haemonchus infections in goats and sheep. Topical Animal Health Production 25: (in press). Cited in Ahmed & Adam, 1979. Ahmed O M M, S E I Adam. (Jul 1979) Effects of Jatropha curcas on Calves. Veterinary Pathology 16(4):476-482. Aplin T E H. (May 1976) Poisonous Garden Plants and Other Plants Harmful to Man in Australia. Western Australia Department of Agriculture, Bulletin 3964. Barri M E S, T O Onsa, A A Elawad, N Y Elsayed, I A Wasfi, E M Abdul Bari, S E I Adam. (1983) Toxicity of Five Sudanese Plants to Young Ruminants. Journal of Comparative Pathology, 93:559-575. Consroe P F, Glow D E. (1975). Clinical Toxicology of the Desert Potato : Two Case Reports of Acute Jatropha Macrorhiza Root Ingestion. Arizona Medicine, 23(6):475-477. CRC Critical Review in Toxicology. (Nov 1977). Higher Plant Genera and their toxins, pp 213-237 Ho Richard K B. (March-April 1960). Acute Poisoning From the Ingestion of Seeds of Jatropha Curcas. Medical Journal of Hawaii, 19(4):421-423. Horiuchi T, H Fujiki, M Hirota, M Suttajit, M Suganuma, A Yoshioka, V Wongchai, E Hecker, T Sugimura. (Mar 1987) Presence of tumor promoters in the seed oil of Jatropha curcas L. from Thailand. Japanese Journal of Cancer Research, 78(3):223-236. Joubert P H, J M M Brown, I T Hay, P D B Sebata. (May 1984). Acute poisoning with Jatropha curcas (purging nut tree) in children. South African Medical Journal, 65:729-730. Kingsbury J M. Poisonous Plants of the United States and Canada, 1964. Lampe and Fagerstrom. (1968). Plant Toxicity and Dermatitis - A Manual for Physicians. The Williams and Wilkins Company, Baltimore. Ojewole J A O, O O Odebiyi. (1980) Neuromuscular and Cardiovascular Actions of Tetramethylpyrazine from the Stem of Jatroha Podagrica. Planta Medica, 38:332-338. Ojewole J A O, O O Odebiyi. (1981) Mechanism of the Hypotensive Effect of Tetramethylpyrazine, an Amide Alkaloid from the Stem of Jatropha podagrica. Stirpe F, A Pession-Brizzi, E Lorenzoni, P Strocchi, L Montanaro, S Sperti. (Apr 1976) Studies on the Proteins from the Seeds of Croton tiglium and of Jatropha curcas. Toxic properties and inhibition of protein synthesis in vitro. Biochemistry Journal, 156(1):1-6. 13.2 Botanical 14. AUTHOR(S), REVIEWER(S), DATE(S) (INCLUDING UPDATES), COMPLETE ADDRESS(ES) June 1994 Juliette Begg and Tania Gaskin National Toxicology Group P.O. Box 913 Dunedin NEW ZEALAND See Also: Jatropha gossypiifolia (PIM 643) Jatropha hastafa (PIM 644) Jatropha macrorhiza (PIM 645) Jatropha multifida (PIM 646) Jatropha podagrica (PIM 647) Methandriol 1. NAME 1.1 Substance 1.2 Group 1.3 Synonyms 1.4 Identification numbers 1.4.1 CAS number 1.4.2 Other numbers 1.5 Main brand names, main trade names 1.6 Main manufacturers, main importers 2. SUMMARY 2.1 Main risks and target organs 2.2 Summary of clinical effects 2.3 Diagnosis 2.4 First aid measures and management principles 3. PHYSICO-CHEMICAL PROPERTIES 3.1 Origin of the substance 3.2 Chemical structure 3.3 Physical properties 3.3.1 Colour 3.3.2 State/form 3.3.3 Description 3.4 Other characteristics 3.4.1 Shelf-life of the substance 3.4.2 Storage conditions 4. USES 4.1 Indications 4.1.1 Indications 4.1.2 Description 4.2 Therapeutic dosage 4.2.1 Adults 4.2.2 Children 4.3 Contraindications 5. ROUTES OF EXPOSURE 5.1 Oral 5.2 Inhalation 5.3 Dermal 5.4 Eye 5.5 Parenteral 5.6 Other 6. KINETICS 6.1 Absorption by route of exposure 6.2 Distribution by route of exposure 6.3 Biological half-life by route of exposure 6.4 Metabolism 6.5 Elimination by route of exposure 7. PHARMACOLOGY AND TOXICOLOGY 7.1 Mode of action 7.1.1 Toxicodynamics 7.1.2 Pharmacodynamics 7.2 Toxicity 7.2.1 Human data 7.2.1.1 Adults 7.2.1.2 Children 7.2.2 Relevant animal data 7.2.3 Relevant in vitro data 7.3 Carcinogenicity 7.4 Teratogenicity 7.5 Mutagenicity 7.6 Interactions 7.7 Main adverse effects 8. TOXICOLOGICAL ANALYSES AND BIOMEDICAL INVESTIGATIONS 8.1 Material sampling plan 8.1.1 Sampling and specimen collection 8.1.1.1 Toxicological analyses 8.1.1.2 Biomedical analyses 8.1.1.3 Arterial blood gas analysis 8.1.1.4 Haematological analyses 8.1.1.5 Other (unspecified) analyses 8.1.2 Storage of laboratory samples and specimens 8.1.2.1 Toxicological analyses 8.1.2.2 Biomedical analyses 8.1.2.3 Arterial blood gas analysis 8.1.2.4 Haematological analyses 8.1.2.5 Other (unspecified) analyses 8.1.3 Transport of laboratory samples and specimens 8.1.3.1 Toxicological analyses 8.1.3.2 Biomedical analyses 8.1.3.3 Arterial blood gas analysis 8.1.3.4 Haematological analyses 8.1.3.5 Other (unspecified) analyses 8.2 Toxicological Analyses and Their Interpretation 8.2.1 Tests on toxic ingredient(s) of material 8.2.1.1 Simple Qualitative Test(s) 8.2.1.2 Advanced Qualitative Confirmation Test(s) 8.2.1.3 Simple Quantitative Method(s) 8.2.1.4 Advanced Quantitative Method(s) 8.2.2 Tests for biological specimens 8.2.2.1 Simple Qualitative Test(s) 8.2.2.2 Advanced Qualitative Confirmation Test(s) 8.2.2.3 Simple Quantitative Method(s) 8.2.2.4 Advanced Quantitative Method(s) 8.2.2.5 Other Dedicated Method(s) 8.2.3 Interpretation of toxicological analyses 8.3 Biomedical investigations and their interpretation 8.3.1 Biochemical analysis 8.3.1.1 Blood, plasma or serum 8.3.1.2 Urine 8.3.1.3 Other fluids 8.3.2 Arterial blood gas analyses 8.3.3 Haematological analyses 8.3.4 Interpretation of biomedical investigations 8.4 Other biomedical (diagnostic) investigations and their interpretation 8.5 Overall Interpretation of all toxicological analyses and toxicological investigations 8.6 References 9. CLINICAL EFFECTS 9.1 Acute poisoning 9.1.1 Ingestion 9.1.2 Inhalation 9.1.3 Skin exposure 9.1.4 Eye contact 9.1.5 Parenteral exposure 9.1.6 Other 9.2 Chronic poisoning 9.2.1 Ingestion 9.2.2 Inhalation 9.2.3 Skin exposure 9.2.4 Eye contact 9.2.5 Parenteral exposure 9.2.6 Other 9.3 Course, prognosis, cause of death 9.4 Systematic description of clinical effects 9.4.1 Cardiovascular 9.4.2 Respiratory 9.4.3 Neurological 9.4.3.1 Central nervous system 9.4.3.2 Peripheral nervous system 9.4.3.3 Autonomic nervous system 9.4.3.4 Skeletal and smooth muscle 9.4.4 Gastrointestinal 9.4.5 Hepatic 9.4.6 Urinary 9.4.6.1 Renal 9.4.6.2 Other 9.4.7 Endocrine and reproductive systems 9.4.8 Dermatological 9.4.9 Eye, ear, nose, throat: local effects 9.4.10 Haematological 9.4.11 Immunological 9.4.12 Metabolic 9.4.12.1 Acid-base disturbances 9.4.12.2 Fluid and electrolyte disturbances 9.4.12.3 Others 9.4.13 Allergic reactions 9.4.14 Other clinical effects 9.4.15 Special risks 9.5 Other 9.6 Summary 10. MANAGEMENT 10.1 General principles 10.2 Life supportive procedures and symptomatic/specific treatment 10.3 Decontamination 10.4 Enhanced elimination 10.5 Antidote treatment 10.5.1 Adults 10.5.2 Children 10.6 Management discussion 11. ILLUSTRATIVE CASES 11.1 Case reports from literature 12. Additional information 12.1 Specific preventive measures 12.2 Other 13. REFERENCES 14. AUTHOR(S), REVIEWER(S), DATE(S) (INCLUDING UPDATES), COMPLETE ADDRESS(ES) Methandriol International Programme on Chemical Safety Poisons Information Monograph 906 Pharmaceutical This monograph does not contain all of the sections completed. This mongraph is harmonised with the Group monograph on Anabolic Steroids (PIM G007). 1. NAME 1.1 Substance Methandriol 1.2 Group ATC Classification: A14 (Anabolic Agents for Systemic Use) A14A (Anabolic steroids) 1.3 Synonyms Méthandriol; MAD; Mestenediol; Methylandrostenediol; Methandriolum 1.4 Identification numbers 1.4.1 CAS number 521-10-8 1.4.2 Other numbers 1.5 Main brand names, main trade names Methandrol(R) (Becker, Austria); Methostan(R) (Schering Corp./ Essex); Metildiolo(R) (Orma, Italy); Metocryst(R) (Leo, Denmark); Troformone(R) (Biomedica, Italy) 1.6 Main manufacturers, main importers 2. SUMMARY 2.1 Main risks and target organs There is no serious risk from acute poisoning, but chronic use can cause harm. The main risks are those of excessive androgens: menstrual irregularities and virilization in women and impotence, premature cardiovascular disease and prostatic hypertrophy in men. Both men and women can suffer liver damage with oral anabolic steroids containing a substituted 17-alpha-carbon. Psychiatric changes can occur during use or after cessation of these agents. 2.2 Summary of clinical effects Acute overdosage can produce nausea and gastrointestinal upset. Chronic usage is thought to cause an increase in muscle bulk, and can cause an exageration of male characteristics and effects related to male hormones. Anabolic steroids can influence sexual function. They can also cause cardiovascular and hepatic damage. Acne and male- pattern baldness occur in both sexes; irregular menses, atrophy of the breasts, and clitoromegaly in women; and testicular atrophy and prostatic hypertrophy in men. 2.3 Diagnosis The diagnosis depends on a history of use of oral or injected anabolic steroids, together with signs of increased muscle bulk, commonly seen in "body-builders". Biochemical tests of liver function are often abnormal in patients who take excessive doses of oral anabolic steroids. Laboratory analyses of urinary anabolic steroids and their metabolites can be helpful in detecting covert use of these drugs. 2.4 First aid measures and management principles Supportive care is the only treatment necessary or appropriate for acute intoxication. Chronic (ab)users can be very reluctant to cease abuse, and may require professional help as with other drug misuse. 3. PHYSICO-CHEMICAL PROPERTIES 3.1 Origin of the substance Naturally-occuring anabolic steroids are synthesised in the testis, ovary and adrenal gland from cholesterol via pregnenolone. Synthetic anabolic steroids are based on the principal male hormone testosterone, modified in one of three ways: alkylation of the 17-carbon esterification of the 17-OH group modification of the steroid nucleus (Murad & Haynes, 1985). 3.2 Chemical structure Chemical name: Androst-5-ene-3,17-diol, 17-methyl-, (3beta,17beta)- Molecular formula C20H32O2 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 Protect from light. Vials for parenteral administration should be stored at room temperature (15 to 30°C). Visual inspection for particulate and/or discoloration is advisable. 4. USES 4.1 Indications 4.1.1 Indications Anabolic agent; systemic Anabolic steroid Androstan derivative; anabolic steroid Estren derivative; anabolic steroid Other anabolic agent Anabolic agent for systemic use; veterinary Anabolic steroid; veterinary Estren derivative; veterinary 4.1.2 Description The only legitimate therapeutic indications for anabolic steroids are: (a) replacement of male sex steroids in men who have androgen deficiency, for example as a result of loss of both testes (b) the treatment of certain rare forms of aplastic anaemia which are or may be responsive to anabolic androgens. (ABPI Data Sheet Compendium, 1993) (c) the drugs have been used in certain countries to counteract catabolic states, for example after major trauma. 4.2 Therapeutic dosage 4.2.1 Adults 4.2.2 Children Not applicable 4.3 Contraindications Known or suspected cancer of the prostate or (in men) breast. Pregnancy or breast-feeding. Known cardiovascular disease is a relative contraindication. 5. ROUTES OF EXPOSURE 5.1 Oral Anabolic steroids can be absorbed from the gastrointestinal tract, but many compounds undergo such extensive first-pass metabolism in the liver that they are inactive. Those compounds in which substitution of the 17- carbon protects the compound from the rapid hepatic metabolism are active orally (Murad and Haynes, 1985). There are preparations of testosterone that can be taken sublingually. 5.2 Inhalation Not relevant 5.3 Dermal No data available 5.4 Eye Not relevant 5.5 Parenteral Intramuscular or deep subcutaneous injection is the principal route of administration of all the anabolic steroids except the 17-alpha-substituted steroids which are active orally. 5.6 Other Not relevant 6. KINETICS 6.1 Absorption by route of exposure The absorption after oral dosing is rapid for testosterone and probably for other anabolic steroids, but there is extensive first-pass hepatic metabolism for all anabolic steroids except those that are substituted at the 17-alpha position. The rate of absorption from subcutaneous or intramuscular depots depends on the product and its formulation. Absorption is slow for the lipid-soluble esters such as the cypionate or enanthate, and for oily suspensions. 6.2 Distribution by route of exposure The anabolic steroids are highly protein bound, and is carried in plasma by a specific protein called sex-hormone binding globulin. 6.3 Biological half-life by route of exposure The metabolism of absorbed drug is rapid, and the elimination half-life from plasma is very short. The duration of the biological effects is therefore determined almost entirely by the rate of absorption from subcutaneous or intramuscular depots, and on the de-esterification which precedes it (Wilson, 1992). 6.4 Metabolism Free (de-esterified) anabolic androgens are metabolized by hepatic mixed function oxidases (Wilson, 1992). 6.5 Elimination by route of exposure After administration of radiolabelled testosterone, about 90% of the radioactivity appears in the urine, and 6% in the faeces; there is some enterohepatic recirculation (Wilson, 1992). 7. PHARMACOLOGY AND TOXICOLOGY 7.1 Mode of action 7.1.1 Toxicodynamics The toxic effects are an exaggeration of the normal pharmacological effects. 7.1.2 Pharmacodynamics Anabolic steroids bind to specific receptors present especially in reproductive tissue, muscle and fat (Mooradian & Morley, 1987). The anabolic steroids reduce nitrogen excretion from tissue breakdown in androgen deficient men. They are also responsible for normal male sexual differentiation. The ratio of anabolic ("body-building") effects to androgenic (virilizing) effects may differ among the members of the class, but in practice all agents possess both properties to some degree. There is no clear evidence that anabolic steroids enhance overall athletic performance (Elashoff et al, 1991). 7.2 Toxicity 7.2.1 Human data 7.2.1.1 Adults No data available. 7.2.1.2 Children No data available. 7.2.2 Relevant animal data No data available. 7.2.3 Relevant in vitro data No data 7.3 Carcinogenicity Anabolic steroids may be carcinogenic. They can stimulate growth of sex-hormone dependent tissue, primarily the prostate gland in men. Precocious prostatic cancer has been described after long-term anabolic steroid abuse (Roberts & Essenhigh, 1986). Cases where hepatic cancers have been associated with anabolic steroid abuse have been reported (Overly et al, 1984). 7.4 Teratogenicity Androgen ingestion by a pregnant mother can cause virilization of a female fetus (Dewhurst & Gordon, 1984). 7.5 Mutagenicity No data available. 7.6 Interactions No data available. 7.7 Main adverse effects The adverse effects of anabolic steroids include weight gain, fluid retention, and abnormal liver function as measured by biochemical tests. Administration to children can cause premature closure of the epiphyses. Men can develop impotence and azoospermia. Women are at risk of virilization. 8. TOXICOLOGICAL ANALYSES AND BIOMEDICAL INVESTIGATIONS 8.1 Material sampling plan 8.1.1 Sampling and specimen collection 8.1.1.1 Toxicological analyses 8.1.1.2 Biomedical analyses 8.1.1.3 Arterial blood gas analysis 8.1.1.4 Haematological analyses 8.1.1.5 Other (unspecified) analyses 8.1.2 Storage of laboratory samples and specimens 8.1.2.1 Toxicological analyses 8.1.2.2 Biomedical analyses 8.1.2.3 Arterial blood gas analysis 8.1.2.4 Haematological analyses 8.1.2.5 Other (unspecified) analyses 8.1.3 Transport of laboratory samples and specimens 8.1.3.1 Toxicological analyses 8.1.3.2 Biomedical analyses 8.1.3.3 Arterial blood gas analysis 8.1.3.4 Haematological analyses 8.1.3.5 Other (unspecified) analyses 8.2 Toxicological Analyses and Their Interpretation 8.2.1 Tests on toxic ingredient(s) of material 8.2.1.1 Simple Qualitative Test(s) 8.2.1.2 Advanced Qualitative Confirmation Test(s) 8.2.1.3 Simple Quantitative Method(s) 8.2.1.4 Advanced Quantitative Method(s) 8.2.2 Tests for biological specimens 8.2.2.1 Simple Qualitative Test(s) 8.2.2.2 Advanced Qualitative Confirmation Test(s) 8.2.2.3 Simple Quantitative Method(s) 8.2.2.4 Advanced Quantitative Method(s) 8.2.2.5 Other Dedicated Method(s) 8.2.3 Interpretation of toxicological analyses 8.3 Biomedical investigations and their interpretation 8.3.1 Biochemical analysis 8.3.1.1 Blood, plasma or serum 8.3.1.2 Urine 8.3.1.3 Other fluids 8.3.2 Arterial blood gas analyses 8.3.3 Haematological analyses 8.3.4 Interpretation of biomedical investigations 8.4 Other biomedical (diagnostic) investigations and their interpretation 8.5 Overall Interpretation of all toxicological analyses and toxicological investigations Biomedical analysis The following tests can be relevant in the investigation of chronic anabolic steroid abuse: a) full blood count b) electrolytes and renal function tests c) hepatic function tests d) testosterone e) Lutenizing hormone f) prostatic acid phosphatase or prostate related antigen g) blood glucose concentration h) cholesterol concentration Toxicological analysis -urinary analysis for anabolic steroids and their metabolites Other investigations -electrocardiogram 8.6 References 9. CLINICAL EFFECTS 9.1 Acute poisoning 9.1.1 Ingestion Nausea and vomiting can occur. 9.1.2 Inhalation Not relevant 9.1.3 Skin exposure Not relevant 9.1.4 Eye contact Not relevant 9.1.5 Parenteral exposure Patients are expected to recover rapidly after acute overdosage, but there are few data. "Body- builders" use doses many times the standard therapeutic doses for these compounds but do not suffer acute toxic effects. 9.1.6 Other Not relevant 9.2 Chronic poisoning 9.2.1 Ingestion Hepatic damage, manifest as derangement of biochemical tests of liver function and sometimes severe enough to cause jaundice; virilization in women; prostatic hypertrophy, impotence and azoospermia in men; acne, abnormal lipids, premature cardiovascular disease (including stroke and myocardial infarction), abnormal glucose tolerance, and muscular hypertrophy in both sexes; psychiatric disturbances can occur during or after prolonged treatment (Ferner & Rawlins, 1988; Kennedy, 1992; Ross & Deutch, 1990; Ryan, 1981; Wagner, 1989). 9.2.2 Inhalation Not relevant 9.2.3 Skin exposure Not relevant 9.2.4 Eye contact Not relevant 9.2.5 Parenteral exposure Virilization in women; prostatic hypertrophy, impotence and azoospermia in men; acne, abnormal lipids, premature cardiovascular disease (including stroke and myocardial infarction), abnormal glucose tolerance, and muscular hypertrophy in both sexes. Psychiatric disturbances can occur during or after prolonged treatment. Hepatic damage is not expected from parenteral preparations. 9.2.6 Other Not relevant 9.3 Course, prognosis, cause of death Patients with symptoms of acute poisoning are expected to recover rapidly. Patients who persistently abuse high doses of anabolic steroids are at risk of death from premature heart disease or cancer, especially prostatic cancer. Non-fatal but long-lasting effects include voice changes in women and fusion of the epiphyses in children. Other effects are reversible over weeks or months. 9.4 Systematic description of clinical effects 9.4.1 Cardiovascular Chronic ingestion of high doses of anabolic steroids can cause elevations in blood pressure, left ventricular hypertrophy and premature coronary artery disease (McKillop et al., 1986; Bowman, 1990; McNutt et al., 1988). 9.4.2 Respiratory Not reported 9.4.3 Neurological 9.4.3.1 Central nervous system Stroke has been described in a young anabolic steroid abuser (Frankle et al., 1988). Pope & Katz (1988) described mania and psychotic symptoms of hallucination and delusion in anabolic steroid abusers. They also described depression after withdrawal from anabolic steroids. There is also considerable debate about the effects of anabolic steroids on aggressive behaviour (Schulte et al., 1993) and on criminal behaviour (Dalby, 1992). Mood swings were significantly more common in normal volunteers during the active phase of a trial comparing methyltestosterone with placebo (Su et al., 1993). 9.4.3.2 Peripheral nervous system No data available 9.4.3.3 Autonomic nervous system No data available 9.4.3.4 Skeletal and smooth muscle No data available 9.4.4 Gastrointestinal Acute ingestion of large doses can cause nausea and gastrointestinal upset. 9.4.5 Hepatic Orally active (17-alpha substituted) anabolic steroids can cause abnormalities of hepatic function, manifest as abnormally elevated hepatic enzyme activity in biochemical tests of liver function,and sometimes as overt jaundice. The histological abnormality of peliosis hepatis has been associated with anabolic steroid use (Soe et al., 1992). Angiosarcoma (Falk et al, 1979) and a case of hepatocellular carcinoma in an anabolic steroid user has been reported (Overly et al., 1984). 9.4.6 Urinary 9.4.6.1 Renal Not reported 9.4.6.2 Other Men who take large doses of anabolic steroids can develop prostatic hypertrophy. Prostatic carcinoma has been described in young men who have abused anabolic steroids (Roberts & Essenhigh, 1986). 9.4.7 Endocrine and reproductive systems Small doses of anabolic steroids are said to increase libido, but larger doses lead to azoospermia and impotence. Testicular atrophy is a common clinical feature of long-term abuse of anabolic steroids, and gynaecomastia can occur (Martikainen et al., 1986; Schurmeyer et al., 1984; Spano & Ryan, 1984). Women develop signs of virilism, with increased facial hair, male pattern baldness, acne, deepening of the voice, irregular menses and clitoral enlargement (Malarkey et al., 1991; Strauss et al., 1984). 9.4.8 Dermatological Acne occurs in both male and female anabolic steroids abusers. Women can develop signs of virilism, with increased facial hair and male pattern baldness. 9.4.9 Eye, ear, nose, throat: local effects Changes in the larynx in women caused by anabolic steroids can result in a hoarse, deep voice. The changes are irreversible. 9.4.10 Haematological Anabolic androgens stimulate erythropoesis. 9.4.11 Immunological 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 Sodium and water retention can occur, and result in oedema; hypercalcaemia is also reported (Reynolds, 1992). 9.4.12.3 Others Insulin resistance with a fall in glucose tolerance (Cohen & Hickman, 1987), and hypercholesterolaemia with a fall in high density lipoprotein cholesterol, have been reported (Cohen et al., 1988; Glazer, 1991; Webb et al., 1984). 9.4.13 Allergic reactions No data available 9.4.14 Other clinical effects No data available 9.4.15 Special risks Risk of abuse 9.5 Other No data available 9.6 Summary 10. MANAGEMENT 10.1 General principles The management of acute overdosage consists of supportive treatment, with fluid replacement if vomiting is severe. Chronic abuse should be discouraged, and psychological support may be needed as in the treatment of other drug abuse. The possibility of clinically important depression after cessation of usage should be borne in mind. 10.2 Life supportive procedures and symptomatic/specific treatment Not relevant 10.3 Decontamination Not usually required. 10.4 Enhanced elimination Not indicated 10.5 Antidote treatment 10.5.1 Adults None available 10.5.2 Children None available 10.6 Management discussion Not relevant 11. ILLUSTRATIVE CASES 11.1 Case reports from literature A 38-year old man presented with acute urinary retention, and was found to have carcinoma of the prostate. He had taken anabolic steroids for many years, and worked as a "strong-man" (Roberts and Essenhigh, 1986). A 22-year old male world-class weight lifter developed severe chest pain awaking him from sleep, and was shown to have myocardial infarction. For six weeks before, he had been taking high doses of oral and injected anabolic steroids. Total serum cholesterol was 596 mg/dL (HDL 14 mg/dL, LDL 513 mg/dL) (McNutt et al., 1988). Values of total cholesterol concentration above 200 mg/dL are considered undesirable. A 22-year old body builder took two eight-week courses of anabolic steroids. He became severely depressed after the second course, and when the depression gradually receded, he had prominent paranoid and religious delusions (Pope and Katz, 1987). A 19-year old American college footballer took intramuscular testosterone and oral methandrostenolone over 4 months. He became increasingly aggressive with his wife and child. After he severely injured the child, he ceased using anabolic steroids, and his violence and aggression resolved within 2 months (Schulte et al, 1993). 12. Additional information 12.1 Specific preventive measures Anabolic steroid abuse amongst athletes, weight lifters, body builders and others is now apparently common at all levels of these sports. Not all abusers are competitive sportsmen. There is therefore scope for a public health campaign, for example, based on gymnasia, to emphasize the dangers of anabolic steroid abuse and to support those who wish to stop using the drugs. 12.2 Other No data available. 13. REFERENCES ABPI Data Sheet Compendium (1993) Datapharm Publications, London. Bowman S. (1990) Anabolic steroids and infarction. Br Med J; 300: Cohen JC & Hickman R. (1987) Insulin Resistance and diminished glucose tolerance in powerlifters ingesting anabolic steroids. J Clin Endocrinol Metab 64: 960. Cohen JC, Noakes TD, & Spinnler Benade AJ. (1988) Hypercholesterolemia in male power lifters using Anabolic Androgenic Steroids. The Physician and Sports medicine 16: 49-56. Dalby JT. (1992) Brief anabolic steroid use and sustained behavioral reaction. Am J Psychiatry 149: 271-272. Dewhurst J. & Gordon RR (1984). Fertility following change of sex: a follow-up. Lancet: ii: 1461-2. Elashoff JD, Jacknow AD, Shain SG, & Braunstein GD. (1991) Effects of anabolic-androgenic steroids on muscular strength. Annals Inter Med 115: 387-393. Falk H, Thomas LB, Popper H, Ishak KG. (1979). Hepatic angiosacroma associated with androgenic-anabolic steroids. Lancet 2; 1120-1123. Ferner RE & Rawlins MD (1988) Anabolic steroids: the power and the glory? Br Med J 1988; 297: 877-878. Frankle MA, Eichberg R, & Zacharian SB. (1988) Anabolic Androgenic steroids and stroke in an athlete: case report. Arch Phys Med Rehabil 1988; 69: 632-633. Glazer G. (1991) Atherogenic effects of anabolic steroids on serum lipid levels. Arch Intern Med 151: 1925-1933. Kennedy MC. (1992). Anabolic steroid abuse and toxicology. Aust NZ J Med 22: 374-381. Malarkey WB, Strauss RH, Leizman DJ, Liggett M, & Demers LM. (1991). Endocrine effects in femal weight lifters who self- administer testosterone and anabolic steroids. Am J Obstet Gynecol 165: 1385-1390. Martikainen H, Alen M, Rahkila P, & Vihko R. (1986) Testicular responsiveness to human chorionic gonadotrophin during transient hypogonadotrophic hypogondasim induced by androgenic/anabolic steroids in power athletes. Biochem 25: 109-112. McKillop G, Todd IC, Ballantyne D. (1986) Increased left ventricular mass in a body builder using anabolic steroids. Brit J Sports Med 20: 151-152. McNutt RA, Ferenchick GS, Kirlin PC, & Hamlin NJ. (1988) Acute myocardial infarction in a 22 year old world class weight lifter using anabolic steroids. Am J Cardiol 62: 164. Mooradian JE, Morley JE, Korenman SG. (1987) Biological actions of androgens. Endocrine Reviews 8:1-27. Murad F, & Haynes RC. (1985). Androgens. in. Ed: Goodman Gilman A, Goodman L S, Roll T W, Murad F. The Pharmacological Basis of Therapeutics, 7th edition, Macmillan, New York: 1440-1458 Overly WL et al. (1984). Androgens and hepatocellular carcinoma in an athlete. Ann Int Med 100: 158-159. Pope GR, & Katz DL. (1988). Affective and psychotic symptoms associated with anabolic steroid use. Am J Psychiatry 145: 487-490. Reynolds Ed. (1992) Martindale-The Extra Pharmacopeia. The Pharmaceutical Press. London. Roberts JT, & Essenhigh DM. (1986) Adenocarcinoma of prostate in 40-year old body builder. Lancet 2: 742. Ross RB, & Deutsch S I.(1990) Hooked on hormones. JAMA 263: 2048-2049. Ryan A J. (1981) Anabolic steroids are fool's gold. Fed Proc 40: 2682-2688. Schurmeyer T, Belkien L, Knuth UA, & Nieschlag E. (1984) Reversible azoospermia induced by the anabolic steroid 19-nortestosterone. Lancet i: 417-420. Soe KL. Soe M. & Gluud C. (1992). Liver pathology associated with the use of anabolic-androgenic steroids. Liver 12: 73-9. Schulte HM, Hall MJ, & Boyer M. (1993). Domestic violence associated with anabolic steroid abuse. Am J Psychiatr 150: 348. Spano F, & Ryan W G. (1989) Tamoxifen for gynecomastia induced by anabolic steroids? New Engl J Med 311: 861-862. Strauss RH, Liggett MT, & Lanese RR. (1984) Anabolic steroid use and perceived effects in 10 weight-trained women athletes JAMA 253: 2871-2873. Su T-P, Pagliaro M, Schmidt PJ, Pickar D, Wolkowitz O, & Rubinow DR. (1993) Neuropsychiatric effects of anabolic steroids in male normal volunteers. JAMA 269: 2760-2764. Wagner JC (1989). Abuse of drugs used to enhance athletic performance. Am J Hosp Pharm 46: 2059-2067 Webb O L, Laskarzewski P M, & Glueck, CJ. (1984) Severe depression of high-density lipo protein cholesterol levels in weight lifters and body builders by self-administered exogenous testerone and anabolic-andorgenic steroids. Metabolism 33: 971-975. Wilson J D. (1992). Androgens. In: Goodman Gilman A., Rall T W, Nies A S, & Taylor P. Goodman and Gilman's Pharmacological Basis of Therapeutics. McGraw-Hill, Toronto. Pages 1413-1430. 14. AUTHOR(S), REVIEWER(S), DATE(S) (INCLUDING UPDATES), COMPLETE ADDRESS(ES) Author: Dr R. E. Ferner, West Midlands Centre for Adverse Drug Reaction Reporting, City Hospital Dudley Road, Birmingham B18 7QH England. Tel: +44-121-5074587 Fax: +44-121-5236125 Email: fernerre@bham.ac.uk Date: 1994 Peer review: INTOX Meeting, Sao Paulo, Brazil, September 1994 (Drs P.Kulling, R.McKuowen, A.Borges, R.Higa, R.Garnier, Hartigan-Go, E.Wickstrom) Editor: Dr M.Ruse, March 1998 TAMOXIFEN (Group 1) For definition of Groups, see Preamble Evaluation. VOL.: 66 (1996) (p. 253) CAS No.: 10540-29-1 Chem. Abstr. Name: (Z)-2-[4-(1,2-Diphenyl-1-butenyl)phenoxy]-N,N-dimethylethanamine CAS No.: 54965-24-1 Chem. Abstr. Name: (Z)-2-[4-(1,2-Diphenyl-1-butenyl)phenoxy]-N,N-dimethylethanamine, 2-hydroxy-1,2,3-propanetricarboxylate (1:1) 5. Summary of Data Reported and Evaluation 5.1 Exposure data Tamoxifen has been available since the early 1970s for the first-line treatment of metastatic breast cancer in postmenopausal women. Since the 1980s, it has become the therapy of choice for this condition. Tamoxifen has also become the adjuvant therapy of choice for treatment of postmenopausal, node-positive women with positive oestrogen-receptor or progesterone-receptor levels and, since the early 1990s, for the treatment of postmenopausal, node-negative women with positive oestrogen-receptor or progesterone-receptor levels. It is also widely used in treating postmenopausal receptor-negative women and premenopausal women with node-negative, receptor-positive disease. When used as adjuvant therapy, tamoxifen reduces the annual rates of both death from and recurrence of breast cancer by about 25%. Tamoxifen is commonly given at doses of 20 mg daily for periods of two to five years in the adjuvant setting, although doses of up to 40 mg daily have been used in the past. Several clinical trials are in progress to study the efficacy of tamoxifen in preventing breast cancer in healthy women believed to be at high risk of developing the disease. Tamoxifen has been widely adopted as the first-line therapy of choice for hormone-responsive male breast cancer and is frequently used as adjuvant therapy for oestrogen receptor- or progesterone receptor-positive male breast cancer. Tamoxifen is registered for use in nearly 100 countries and cumulative use since 1973 is estimated at 7 million patient-years. 5.2 Human carcinogenicity data The potential effect of tamoxifen in increasing the risk of endometrial cancer has been reported in one adequate cohort study, four adequate case-control studies and 14 randomized controlled trials. In the cohort study, based on follow-up of registered cases of breast cancer in the population-based Surveillance, Epidemiology and End Results (SEER) database in the United States, the only available data on therapy were those reported at the time of initial registration. Both groups of women with reported tamoxifen use and those with no such reported use had elevated rates of endometrial cancer compared with the rates expected from the SEER database as a whole. The risk was significantly greater for women with reported tamoxifen use. The similar stage distribution in the two groups suggests a lack of serious detection bias in this study. The absence of hysterectomies could not be confirmed in this study. The case-control studies were based on the identification of a series of women with breast cancer who had subsequently been diagnosed with endometrial cancer, with tamoxifen exposure assessed in comparison with breast cancer patients who had not developed endometrial cancer. In two of these, case and control selection was based on the records of population-based cancer registries, and two used the same source as well as hospital-based cancer registries. For the Swedish study, although an increased risk of endometrial cancer for tamoxifen use was found, the only information on treatment was that recorded in the cancer registry. Further, the absence of hysterectomy in the control series could not be confirmed. For the remaining three case-control studies, more detailed data on treatment and on hysterectomies were obtained from medical records. In the studies in France and the Netherlands, a nonsignificant elevation of risk for endometrial cancer with use of tamoxifen was found, with a significant increase in risk with increasing duration of therapy in one. In the United States study, which reported on shorter duration of use, the point estimate of risk was less than unity. Although several potential confounders were not systematically addressed in most studies, the Working Group considered that these were unlikely to have had a major effect on the reported relative risks. In most of the randomized trials, small numbers of endometrial cancers were reported, and for many the data were not reported in a way that corrected for the greater survival time in most trials of the tamoxifen-treated patients compared to the control series. In two of the largest trials, however, there was a strong and statistically significant association between risk for endometrial cancer and use of tamoxifen. Although there may have been a tendency for publication bias and there is some possibility of a detection bias as a result of investigations in women with side-effects from tamoxifen, the magnitude of the risk found in the two large trials is unlikely to be explained by such biases. Further, for the trials that reported deaths in women with endometrial cancer, to date there have been eight deaths in women allocated to tamoxifen treatment groups and one in those not allocated to tamoxifen. One case series reported significantly more high-grade endometrial tumours in tamoxifen-treated cancer patients than in patients without prior tamoxifen use. However, in at least six other studies, this difference was not found. The SEER-based cohort study found a significantly reduced risk for contralateral breast cancers in the tamoxifen-treated women, compared with women with no reported tamoxifen use. The case-control study from the United States also reported a significant reduction of risk for contralateral cancers of the breast following tamoxifen use. Although for some small trials there seemed to be little difference in the numbers of contralateral breast cancers in tamoxifen-treated women compared with controls, for the large trials, there was a substantially and significantly reduced risk for contralateral breast cancer in tamoxifen-treated women compared with controls. Further, in an overview analysis of nearly all trials published in 1992 with data available to 1990, there was a significant reduction of 39% in contralateral breast cancers in the tamoxifen-treated groups. For all other cancer sites, no significant excess of any cancer has been found in either the cohort study or the trials. Although an excess of gastrointestinal cancer was reported following a combined analysis of three Scandinavian trials, this has not yet been confirmed by other studies. 5.3 Animal carcinogenicity data Tamoxifen was tested for carcinogenicity by oral administration in one study in mice and in eight studies in rats, only one of which was a formal two-year study. In mice, the incidences of benign ovarian and testicular tumours were increased. In rats, tamoxifen induced preneoplastic liver lesions and benign or malignant liver tumours. In one study, the incidence of some tumours in hormone-dependent tissues was decreased, including in the mammary gland, although reduced weight gain may have been a contributing factor. In two studies in which tamoxifen was tested by subcutaneous implantation in intact or ovariectomized female mice, it inhibited mammary tumour development in both. In mice, tamoxifen was reported to inhibit 3-methylcholanthrene-induced cervical cancer and virus-induced leukaemia. In several studies in both male and female rats, tamoxifen enhanced the hepatocarcinogenicity of previously administered N-nitrosodiethylamine. In one study in rats, tamoxifen enhanced the development of N-nitrosodiethylamine-induced kidney tumours. In a number of studies in rats, tamoxifen inhibited 7,12-dimethylbenz[a]anthracene-induced mammary tumour development. In two studies in hamsters, tamoxifen inhibited hormonal carcinogenesis induced by 17b-oestradiol in the kidney and zeranol in the liver. 5.4 Other relevant data Orally administered tamoxifen is well absorbed and maximum plasma levels are reached in about 5 h. Steady-state concentrations of tamoxifen in humans are reached in 3-4 weeks and those of the primary metabolite, N-desmethyltamoxifen, in about eight weeks. Tissue concentrations tend to be higher than plasma concentrations. Metabolism involves phenyl hydroxylation, alkyl hydroxylation, demethylation and N-oxide formation. Metabolism results in more products in man and rats than in mice. Much higher oral doses of tamoxifen are required for rats or mice to achieve plasma concentrations similar to human levels. Tamoxifen is an antioestrogen with complex pharmacology encompassing variable species-, tissue-, cell-, gene-, age- and duration of administration-specific effects from oestrogen-like agonist actions to complete blockade of oestrogen action. This complexity is consistent with the various, and sometimes paradoxical, effects that have been associated with tamoxifen administration in animals and humans. The most frequent side-effects of tamoxifen administration are hot flushes and vaginal discharge. Tamoxifen has effects on the human uterus, inducing atrophy, hyperplasia and, less frequently, polyps. Randomized placebo-controlled trials revealed a slight increase of thromboembolic events, but also a protective effect regarding myocardial diseases, according to hospital admission rates and deaths. Tamoxifen administration has been shown to decrease blood total cholesterol and low-density lipoprotein-cholesterol concentrations in a number of studies. Several preliminary trials have suggested mildly positive effects of tamoxifen in preserving bone mineral density in postmenopausal women, but much longer follow-up is required to confirm t his potentially beneficial effect. The acute toxicity of tamoxifen in experimental animals is low. In repeated-dose studies in rats, tamoxifen induced hypertrophy, but not cell proliferation, in the endometrial epithelium; endometrial hyperplasia was, however, reported in mice. Furthermore squamous metaplasia and atrophy of the uterine epithelium was observed in chronic studies in rats. Induction of cytochromes P450 and preneoplastic lesions have been detected in the livers of rats. Ocular toxicity, including lipidosis of the retina and cornea and increased incidence of cataract, was reported in studies in rats of chronic exposure to tamoxifen. In the presence of human, mouse, rat and hamster microsomes, tamoxifen binds covalently to protein. Tamoxifen has oestrogenic effects on human fetal genital tracts grown in athymic mice. In rats, doses above 2 mg/kg body weight produce irregular ossification of ribs in the fetus, which is thought to be secondary to reduction of the size of the uterus of the dam. No effects on the fetus have been reported in rabbits, marmosets or cynomolgus monkeys. There is no direct evidence that tamoxifen is active in tests for gene mutation. Evidence for the genotoxic potential of tamoxifen is supported by data obtained on DNA adduct formation in rodent liver cells in vitro and in vivo, and in rodent and human liver microsomal systems; on unscheduled DNA synthesis in rat hepatocytes in vitro; and on the induction of clastogenic events both in vitro, in genetically-engineered human cells, and in vivo in rat liver. There is evidence from 32P-postlabelling studies that three metabolites, (a-hydroxytamoxifen, 4-hydroxytamoxifen and (Z)-1,2-diphenyl-1-(4-hydroxyphenyl)but-1-ene (metabolite E) can be further metabolized to products that react with DNA. The major DNA adduct formed in rodent liver cells has been identified as (E)-(a-(N2-deoxyguanosinyl) tamoxifen. Human hepatocytes do not form detectable DNA adducts when treated in vitro with tamoxifen; they form 300-fold lower levels of adducts than rat and mouse hepatocytes when treated with a-hydroxytamoxifen. Preliminary studies indicate that tamoxifen does not give rise to detectable levels of DNA adducts in human liver in vivo or in human endometrium in vitro and in vivo. Mechanistic considerations Tamoxifen increases liver tumour incidence in rats, which may involve both DNA damage leading to increased numbers of initiated cells and oestrogen receptor-mediated clonal expansion of those initiated cells. The available evidence suggests that tamoxifen is carcinogenic in rat liver by a genotoxic mechanism. Preliminary information from studies of human tissues suggests that humans are less susceptible to the genotoxicity of tamoxifen. Tamoxifen also possesses tumour-promoting activity in the rat liver. Several studies have shown that the liver contains significant quantities of oestrogen receptor in hepatocytes, Kupffer cells and endothelial cells. Tamoxifen acts as an oestrogen agonist and/or antagonist by binding directly to the oestrogen receptor. In some tissues, such as breast, tamoxifen exhibits antioestrogenic properties by binding to the oestrogen receptor with high affinity. The tamoxifen-oestrogen receptor complex is incapable of binding to DNA-responsive elements. Thus, oestrogen receptor binding does not result in normal transcriptional activity. In other tissues, such as bone and liver, tamoxifen acts as a partial agonist, possibly because cells from those tissues contain a different array of DNA binding sites, thereby leading to typical oestrogen-mediated changes in gene expression and subsequent biological effects on growth and differentiation. Therefore, tissue-specific effects of tamoxifen-oestrogen receptor on gene expression may be involved in the ability of tamoxifen to increase or decrease tumour risk. 5.5 Evaluation There is sufficient evidence in humans for the carcinogenicity of tamoxifen in increasing the risk for endometrial cancer and there is conclusive evidence that tamoxifen reduces the risk for contralateral breast cancer in women with a previous diagnosis of breast cancer. There is inadequate evidence in humans for the carcinogenicity of tamoxifen in other organs. There is sufficient evidence in experimental animals for the carcinogenicity of tamoxifen. Overall evaluation Tamoxifen is carcinogenic to humans (Group 1) and there is conclusive evidence that tamoxifen reduces the risk of contralateral breast cancer. (Dr Cuzick dissociated himself from the evaluation process because he considered that the range of evaluation statements available within the framework of the Monographs was not suitable for this agent.) For definition of the italicized terms, see Preamble Evaluation Synonyms for Tamoxifen 1-para-b-Dimethylaminoethoxyphenyl-trans-1,2-diphenylbut-1-ene (Z)-2-[4-(1,2-Diphenylbut-1-enyl)phenoxy]ethyldimethylamine Synonyms for Tamoxifen citrate Apo-Tamox Citofen Dignotamoxi Duratamoxifen 5 Emblon ICI-46474 Jenoxifen Kessar Ledertam Noltam Nolvadex Nourytam Novofen Oestrifen Oncotam Retaxim Tafoxen Tam Tamaxin Tamifen Tamofen Tamone Tamoplex Tamoxasta Tamox-Gry Z-Tamoxifen citrate Tamoxigenat Tamox-Puren Taxfeno Terimon Valodex Zemide Zitazonium Last updated 05/22/97 See Also: TAMOXIFEN CITRATE (PIM 517) Tamoxifen citrate 1. NAME 1.1 Substance 1.2 Group 1.3 Synonyms 1.4 Identification numbers 1.4.1 CAS number 1.4.2 Other numbers 1.5 Brand names, Trade names 1.6 Manufacturers, Importers 2. SUMMARY 2.1 Main risks and target organs 2.2 Summary of clinical effects 2.3 Diagnosis 2.4 First aid measures and management principles 3. PHYSICO-CHEMICAL PROPERTIES 3.1 Origin of the substance 3.2 Chemical structure 3.3 Physical properties 3.3.1 Properties of the substance 3.3.2 Properties of the locally available formulation 3.4 Other characteristics 3.4.1 Shelf-life of the substance 3.4.2 Shelf-life of the locally available formulation 3.4.3 Storage conditions 3.4.4 Bioavailability 3.4.5 Specific properties and composition 4. USES 4.1 Indications 4.2 Therapeutic dosage 4.2.1 Adults 4.2.2 Children 4.3 Contraindications 5. ROUTES OF ENTRY 5.1 Oral 5.2 Inhalation 5.3 Dermal 5.4 Eye 5.5 Parenteral 5.6 Other 6. KINETICS 6.1 Absorption by route of exposure 6.2 Distribution by route of exposure 6.3 Biological half-life by route of exposure 6.4 Metabolism 6.5 Elimination by route of exposure 7. PHARMACOLOGY AND TOXICOLOGY 7.1 Mode of action 7.1.1 Toxicodynamics 7.1.2 Pharmacodynamics 7.2 Toxicity 7.2.1 Human data 7.2.1.1 Adults 7.2.1.2 Children 7.2.2 Relevant animal data 7.2.3 Relevant in vitro data 7.3 Carcinogenicity 7.4 Teratogenicity 7.5 Mutagenicity 7.6 Interactions 7.7 Main adverse effects 8. TOXICOLOGICAL ANALYSES AND BIOMEDICAL INVESTIGATIONS 8.1 Material sampling plan 8.1.1 Sampling and specimen collection 8.1.1.1 Toxicological analyses 8.1.1.2 Biomedical analyses 8.1.1.3 Arterial blood gas analysis 8.1.1.4 Haematological analyses 8.1.1.5 Other (unspecified) analyses 8.1.2 Storage of laboratory samples and specimens 8.1.2.1 Toxicological analyses 8.1.2.2 Biomedical analyses 8.1.2.3 Arterial blood gas analysis 8.1.2.4 Haematological analyses 8.1.2.5 Other (unspecified) analyses 8.1.3 Transport of laboratory samples and specimens 8.1.3.1 Toxicological analyses 8.1.3.2 Biomedical analyses 8.1.3.3 Arterial blood gas analysis 8.1.3.4 Haematological analyses 8.1.3.5 Other (unspecified) analyses 8.2 Toxicological Analyses and Their Interpretation 8.2.1 Tests on toxic ingredient(s) of material 8.2.1.1 Simple Qualitative Test(s) 8.2.1.2 Advanced Qualitative Confirmation Test(s) 8.2.1.3 Simple Quantitative Method(s) 8.2.1.4 Advanced Quantitative Method(s) 8.2.2 Tests for biological specimens 8.2.2.1 Simple Qualitative Test(s) 8.2.2.2 Advanced Qualitative Confirmation Test(s) 8.2.2.3 Simple Quantitative Method(s) 8.2.2.4 Advanced Quantitative Method(s) 8.2.2.5 Other Dedicated Method(s) 8.2.3 Interpretation of toxicological analyses 8.3 Biomedical investigations and their interpretation 8.3.1 Biochemical analysis 8.3.1.1 Blood, plasma or serum 8.3.1.2 Urine 8.3.1.3 Other fluids 8.3.2 Arterial blood gas analyses 8.3.3 Haematological analyses 8.3.4 Interpretation of biomedical investigations 8.4 Other biomedical (diagnostic) investigations and their interpretation 8.5 Overall Interpretation of all toxicological analyses and toxicological investigations 8.6 References 9. CLINICAL EFFECTS 9.1 Acute poisoning 9.1.1 Ingestion 9.1.2 Inhalation 9.1.3 Skin exposure 9.1.4 Eye contact 9.1.5 Parenteral exposure 9.1.6 Other 9.2 Chronic poisoning 9.2.1 Ingestion 9.2.2 Inhalation 9.2.3 Skin exposure 9.2.4 Eye contact 9.2.5 Parenteral exposure 9.2.6 Other 9.3 Course, prognosis, cause of death 9.4 Systematic description of clinical effects 9.4.1 Cardiovascular 9.4.2 Respiratory 9.4.3 Neurological 9.4.3.1 CNS 9.4.3.2 Peripheral nervous system 9.4.3.3 Autonomic nervous system 9.4.3.4 Skeletal and smooth muscle 9.4.4 Gastrointestinal 9.4.5 Hepatic 9.4.6 Urinary 9.4.6.1 Renal 9.4.6.2 Other 9.4.7 Endocrine and reproductive systems 9.4.8 Dermatological 9.4.9 Eye, ear, nose, throat: local effects 9.4.10 Haematological 9.4.11 Immunological 9.4.12 Metabolic 9.4.12.1 Acid-base disturbances 9.4.12.2 Fluid and electrolyte disturbances 9.4.12.3 Others 9.4.13 Allergic reactions 9.4.14 Other clinical effects 9.4.15 Special risks 9.5 Other 9.6 Summary 10. MANAGEMENT 10.1 General principles 10.2 Relevant laboratory analyses 10.2.1 Sample collection 10.2.2 Biomedical analysis 10.2.3 Toxicological analysis 10.2.4 Other investigations 10.3 Life supportive procedures and symptomatic/specific treatment 10.4 Decontamination 10.5 Elimination 10.6 Antidote treatment 10.6.1 Adults 10.6.2 Children 10.7 Management discussion 11. ILLUSTRATIVE CASES 11.1 Case reports from literature 11.2 Internally extracted data on cases 11.3 Internal cases 12. Additional information 12.1 Availability of antidotes 12.2 Specific preventive measures 12.3 Other 13. REFERENCES 14. AUTHOR(S), REVIEWER(S), DATE(S) (INCLUDING UPDATES), COMPLETE ADDRESS(ES) PHARMACEUTICALS 1. NAME 1.1 Substance Tamoxifen 1.2 Group Anti-oestrogen, non-steroidal derivative of triphenyl ethylene ATC: L02B A01 1.3 Synonyms (Z)-2-[4-(1,2-Diphenylbut-1-enyl)phenoxy]-N,N-dimethylethylamine citrate ICI 46 474 [trans-1-(4-beta-dimethylaminoethoxyphenyl)-1,2-diphenylbut-1-ene] 1.4 Identification numbers 1.4.1 CAS number 10540 1.4.2 Other numbers Tamoxifen citrate: 54965-24-1 1.5 Brand names, Trade names Emblon (Berk) Noltam (Lederle) Nolvadex (ICI) Nolvadex-D (ICI) Nolvadex forte(ICI) Tamofen (Tillotts) 1.6 Manufacturers, Importers Berk Pharmaceuticals Ltd., ICI Pharmaceuticals (UK)., Lederle Laboratories., Tillotts Laboratories. 2. SUMMARY 2.1 Main risks and target organs There is no record of serious effects from tamoxifen after acute overdosage. Adverse effects in therapeutic use are usually mild. They include effects caused by antagonism of endogenous oestrogens: hot flushes, non-specific gastrointestinal effects (nausea and vomiting), central nervous system effects, and rare ocular effects. Adverse haematological effects have been reported, also isolated cases of death from peliosis hepatis and from hyperlipidaemia. In the treatment of breast cancer, hypercalcaemia and tumour flare can occur. 2.2 Summary of clinical effects Anti-oestrogenic effects in women treated with tamoxifen include vasomotor symptoms (hot flushes), vaginal bleeding and (in premenopausal women) irregular menses, and pruritus vulvae. Nausea and vomiting can occur. Dizziness, lethargy, depression, irritability and cerebellar dysfunction have been described. Reversible retinopathy with macular oedema has been reported after high cumulative doses (>7g), and corneal changes can occur. Thrombocytopenia or leukopenia have been associated with tamoxifen treatment. Thromboembolism, which may be due to the disease rather than the treatment, has been recorded in women given tamoxifen for breast cancer. 2.3 Diagnosis Based on history of exposure and occurrence of adverse effects such as hot flushes, nausea, vomiting, ocular disorders, tumour flare, hypercalcemia, vaginal bleeding and CNS signs and symptoms. 2.4 First aid measures and management principles General measures such as inducing emesis or gastric lavage may be indicated in massive overdosage. Treatment is symptomatic. 3. PHYSICO-CHEMICAL PROPERTIES 3.1 Origin of the substance Synthetic. 3.2 Chemical structure (Z)-2-[4-(1,2-Diphenylbut-1-enyl)phenoxy]-N,N- dimethylethylamine citrate C26H29NO, C6H8O7 [trans-1-(4-beta-dimethylaminoethoxyphenyl)-1, 2-diphenylbut-1-ene] Molecular weight = 563.6 pKa = 8.85 3.3 Physical properties 3.3.1 Properties of the substance Solubility in water at 37 °C = 0.05 g/100 ml. 3.3.2 Properties of the locally available formulation No data available. 3.4 Other characteristics 3.4.1 Shelf-life of the substance Assumed to be at least 5 years. 3.4.2 Shelf-life of the locally available formulation Assumed to be at least 5 years. 3.4.3 Storage conditions Store between 15 and 30 °C Protect from light 3.4.4 Bioavailability (to be added) 3.4.5 Specific properties and composition (to be added by centre). 4. USES 4.1 Indications Treatment of advanced breast cancer and adjuvant treatment of early breast cancer. Treatment of anovulatory infertility. 4.2 Therapeutic dosage 4.2.1 Adults Breast cancer: initial dose 10 mg twice daily; if no response after 1 month, 20 mg twice daily. Infertility: regular menstruation, 10 mg twice daily on days 2,3,4 and 5 of cycle, increasing to 20 mg twice daily and 40 mg twice daily in successive cycles if ovulation does not occur. Amenorrhoea: 10 mg twice daily on 4 successive days, increasing to 20 mg twice daily and 40 mg twice daily after intervals of 45 and 90 days if ovulation does not occur. 4.2.2 Children No data available. 4.3 Contraindications Pregnancy is an absolute contraindication because of the anti- oestrogenic effects. 5. ROUTES OF ENTRY 5.1 Oral Usual route of entry 5.2 Inhalation Not relevant. 5.3 Dermal Not relevant. 5.4 Eye Not relevant. 5.5 Parenteral Not relevant. 5.6 Other Not relevant. 6. KINETICS 6.1 Absorption by route of exposure Peak concentrations occur 4-7 h after oral dosing. Peak concentrations after single oral doses of 20 mg are about 40 µ/l. There is no information on absolute bioavailability. (Martindale, 1989; Buckley & Goa, 1989; Lien et al., 1989) 6.2 Distribution by route of exposure Tamoxifen is more than 99% protein-bound in serum, predominantly to albumin. In patients with breast cancer, concentrations of tamoxifen and its metabolites in pleural, pericardial and peritoneal effusion fluid are between 20 and 100% of those in serum, but only trace amounts enter the cerebrospinal fluid. Concentrations in breast cancer tissue exceed those in serum. The volume of distribution is 50-60 l/kg (Martindale, 1989; Buckley & Goa, 1989; Lien et al., 1989) 6.3 Biological half-life by route of exposure The elimination is biphasic, with an initial half-life of around 7 h and a terminal half-life of 7-11 days. (Martindale, 1989; Buckley & Goa, 1989; Lien et al., 1989) 6.4 Metabolism Tamoxifen citrate undergoes extensive hepatic metabolism to: 1-(4-ethanolyloxyphenyl)-1,2-diphenylbut-1-ene (the primary alcohol) N-desmethyl tamoxifen 4-hydroxy tamoxifen 4-hydroxy-N-desmethyl tamoxifen N-desdimethyl tamoxifen (Martindale, 1989; Buckley & Goa, 1989; Lien et al., 1989) 6.5 Elimination by route of exposure The major excretory route is via the bile as metabolites and enterohepatic recirculation occurs. Less than 1% is excreted in the urine. (Martindale, 1989; Buckley & Goa, 1989; Lien et al., 1989). 7. PHARMACOLOGY AND TOXICOLOGY 7.1 Mode of action 7.1.1 Toxicodynamics The adverse effects observed are due mainly to its anti- oestrogen effect, as Tamoxifen and certain of its metabolites antagonise the effects of oestrogens in oestrogen-sensitive tissues. 7.1.2 Pharmacodynamics Tamoxifen and several of its metabolites (particularly 4- hydroxytamoxifen) bind to nuclear oestrogen receptors in oestrogen-sensitive tissues, and also to a microsomal protein termed the 'anti-oestrogen binding site'. Tamoxifen interferes with the physiological sequence by which oestrogen binds to its receptor, is translocated in the nucleus and then activates messenger RNA synthesis. Although the tamoxifen-receptor complex is transported in the nucleus in the same way as oestrogen- receptor complex, it fails to activate synthesis of mRNA. (Buckley & Goa, 1990) A meta-analysis of published trials in breast cancer (Early Breast Cancer Trialists, 1988) demonstrates a reduction in odds of death of about 20% over the first 5 years from diagnosis in women aged over 50 years. 7.2 Toxicity 7.2.1 Human data 7.2.1.1 Adults There is no information on the acute toxicity of tamoxifen in overdosage. The lowest cumulative dose of tamoxifen known to have induced retinopathy, an adverse effect which is recognised to be dose-dependent, is 7.7 g (Griffiths, 1987) 7.2.1.2 Children No data available. 7.2.2 Relevant animal data In some animal species, oestrogenic agonist effects become manifest at dosages equivalent to 10-100 times the human therapeutic dose (ABPI, 1989). 7.2.3 Relevant in vitro data No data available. 7.3 Carcinogenicity A case-control study (Hardell, 1988) showed a significantly increased relative risk of carcinoma of the uterus in women previously treated with tamoxifen AND who had previously had radiotherapy involving the uterus. The study showed an increase in relative risk with tamoxifen treatment alone which was NOT statistically significant (see also Section 7.4). 7.4 Teratogenicity Studies in neonatal male (Taguchi, 1987) and female (Taguchi & Nishizuka, 1985) mice at relative doses 10 times higher than those used in humans have shown genital tract abnormalities similar to those caused by diethylstilboestrol, a known transplacental carcinogen (diethylstilboestrol causes vaginal adenosis, which predisposes to clear cell carcinoma). 7.5 Mutagenicity Tamoxifen is believed not to be mutagenic (Martindale, 1989). 7.6 Interactions Tamoxifen POTENTIATES the anticoagulant effect of warfarin, and this interaction can be life-threatening (Tenni et al, 1989; Ritchie & Grant, 1989). 7.7 Main adverse effects Adverse effects are usually mild. Thrombocytopenia, leukopenia, thromboembolism, peliosis hepatis and hyperlipidaemia have been mentioned in case reports. Severe hypercalcaemia can occur rarely when treatment is started in patients with metastases to bone. 8. TOXICOLOGICAL ANALYSES AND BIOMEDICAL INVESTIGATIONS 8.1 Material sampling plan 8.1.1 Sampling and specimen collection 8.1.1.1 Toxicological analyses 8.1.1.2 Biomedical analyses 8.1.1.3 Arterial blood gas analysis 8.1.1.4 Haematological analyses 8.1.1.5 Other (unspecified) analyses 8.1.2 Storage of laboratory samples and specimens 8.1.2.1 Toxicological analyses 8.1.2.2 Biomedical analyses 8.1.2.3 Arterial blood gas analysis 8.1.2.4 Haematological analyses 8.1.2.5 Other (unspecified) analyses 8.1.3 Transport of laboratory samples and specimens 8.1.3.1 Toxicological analyses 8.1.3.2 Biomedical analyses 8.1.3.3 Arterial blood gas analysis 8.1.3.4 Haematological analyses 8.1.3.5 Other (unspecified) analyses 8.2 Toxicological Analyses and Their Interpretation 8.2.1 Tests on toxic ingredient(s) of material 8.2.1.1 Simple Qualitative Test(s) 8.2.1.2 Advanced Qualitative Confirmation Test(s) 8.2.1.3 Simple Quantitative Method(s) 8.2.1.4 Advanced Quantitative Method(s) 8.2.2 Tests for biological specimens 8.2.2.1 Simple Qualitative Test(s) 8.2.2.2 Advanced Qualitative Confirmation Test(s) 8.2.2.3 Simple Quantitative Method(s) 8.2.2.4 Advanced Quantitative Method(s) 8.2.2.5 Other Dedicated Method(s) 8.2.3 Interpretation of toxicological analyses 8.3 Biomedical investigations and their interpretation 8.3.1 Biochemical analysis 8.3.1.1 Blood, plasma or serum 8.3.1.2 Urine 8.3.1.3 Other fluids 8.3.2 Arterial blood gas analyses 8.3.3 Haematological analyses 8.3.4 Interpretation of biomedical investigations 8.4 Other biomedical (diagnostic) investigations and their interpretation 8.5 Overall Interpretation of all toxicological analyses and toxicological investigations 8.6 References 9. CLINICAL EFFECTS 9.1 Acute poisoning 9.1.1 Ingestion No data available. 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 Retinal damage and keratitis have been reported in patients after large cumulative doses of tamoxifen, generally over 180 mg per day for more than 1 year (Buckley & Goa, 1989), though sometimes with smaller doses (Griffiths, 1987). There seems to be correlation between long-term tamoxifen administration and endometrical proliferation (Uziely et al, 1993). 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 No data available. 9.3 Course, prognosis, cause of death No data available. 9.4 Systematic description of clinical effects 9.4.1 Cardiovascular No data available. 9.4.2 Respiratory No data available. 9.4.3 Neurological 9.4.3.1 CNS A case of depression, syncope, and incoordination has been described during therapy with 10 mg twice daily (Pluss et al., 1984). The symptoms resolved when tamoxifen was discontinued and reappeared when treatment was restarted. 9.4.3.2 Peripheral nervous system No data available. 9.4.3.3 Autonomic nervous system No data available. 9.4.3.4 Skeletal and smooth muscle No data available. 9.4.4 Gastrointestinal Nausea and vomiting occur with therapeutic doses in some patients, and are anticipated in overdosage (ABPI, 1989) 9.4.5 Hepatic A fatal case of peliosis hepatis has been reported in a woman treated with tamoxifen for 2 years after mastectomy for carcinoma (Loomus et al., 1983). 9.4.6 Urinary 9.4.6.1 Renal No data available. 9.4.6.2 Other A case of persistent nocturnal priapism has been reported (Fernando & Tobias, 1989). 9.4.7 Endocrine and reproductive systems The anti-oestrogenic effects of tamoxifen in premenopausal women receiving therapeutic doses can cause irregular menses. Anti-oestrogenic adverse effects in women treated with tamoxifen include vasomotor symptoms (hot flushes), vaginal bleeding and pruritus vulvae (Buckley & Goa, 1989). 9.4.8 Dermatological No data available. 9.4.9 Eye, ear, nose, throat: local effects Treatment has been associated with retinal and corneal changes: see para 9.2. 9.4.10 Haematological Thromboembolism may be more common in patients treated with tamoxifen, though this is not certain, as patients with cancer are at increased risk anyway. A small reduction in antithrombin III concentration was noted in a study of 11 postmenopausal women treated with tamoxifen, but it was clinically insignificant, and no significant reduction was seen in a group of premenopausal women (Jordan et al., 1987). Thrombocytopenia and leukopenia can occur during therapy, but are not usually severe (ABPI, 1989). One case of severe myelosuppression has been reported (International Adjuvant Therapy Organisation, 1985). 9.4.11 Immunological 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 Severe hypercalcaemia, associated with increased bone resorption, has been noted when patients with bony metastases commenced therapy (Martindale, 1989). 9.4.12.3 Others Severe hyperlipidaemia is occasionally seen, and has been ascribed to an oestrogenic effect (Noguchi et al., 1987) 9.4.13 Allergic reactions No data available. 9.4.14 Other clinical effects No data available. 9.4.15 Special risks Pregnancy, breast feeding, enzyme deficiencies: no data available (see sections 7.3 and 7.4) 9.5 Other No data available. 9.6 Summary 10. MANAGEMENT 10.1 General principles It is unlikely that serious acute toxicity would occur, and management is supportive. The stomach should be emptied after massive overdosage. 10.2 Relevant laboratory analyses 10.2.1 Sample collection No data available. 10.2.2 Biomedical analysis Urea, creatinine and electrolytes may be helpful in the assessment of patients who are vomiting. 10.2.3 Toxicological analysis Not relevant. 10.2.4 Other investigations Not relevant. 10.3 Life supportive procedures and symptomatic/specific treatment Nausea and vomiting may make intravenous fluid replacement necessary. 10.4 Decontamination Gastric lavage may be of value in massive overdosage, but there are no data on this subject. 10.5 Elimination Therapy to enhance elimination is not likely to be effective, given the large volume of distribution. 10.6 Antidote treatment 10.6.1 Adults Not relevant. 10.6.2 Children Not relevant. 10.7 Management discussion No data available. 11. ILLUSTRATIVE CASES 11.1 Case reports from literature No data available. 11.2 Internally extracted data on cases One manufacturer (ICI) is aware of the case of a woman aged 51 years who claimed to have swallowed 100 x 10 mg tablets of tamoxifen, and who suffered no ill effects (JI Landles, personal communication). 11.3 Internal cases No data available. 12. Additional information 12.1 Availability of antidotes Not relevant. 12.2 Specific preventive measures No data available. 12.3 Other No data available. 13. REFERENCES ABPI (Association of the British Pharmaceutical Industry) (1989) Data Sheet Compendium. London. Buckley M M-T, Goa KL (1989). Tamoxifen: a reappraisal of its pharmacodynamic and pharmacokinetic properties and therapeutic use. Drugs, 37: 451-490. Early Breast Cancer Trialists Collaborative Group (1988). Effects of adjuvant tamoxifen and of cytotoxic therapy on mortality in early breast cancer. New Eng. J. Med., 319: 1681- 1692. Fernando IN, Tobias JS (1989). Priapism in patient on tamoxifen. Lancet; i:436 Griffiths MFP (1987). Tamoxifen retinopathy at low dosage. Am. J. Ophthalmol., 104: 185-6. Hardell L (1988). Pelvic irradiation and tamoxifen as risk factors for carcinoma of cervix uteri. Lancet, ii: 1432. International Adjuvant Therapy Group (1985). Myelosuppression occurring after receiving tamoxifen for breast cancer. Br, J. Radiol., 58: 1220. Jordan VC, Fritz NF, Tormey DC (9187). Long-term adjuvant therapy with tamoxifen: effect on sex hormone binding globulin and antithrombin III. Cancer Res., 47: 4517-4519. Lien EA, Solheim E, Lea OA et al (1989). Distribution of 4- hydroxy-N-desmethyltamoxifen and other tamoxifen metabolites in human biological fluids during tamoxifen treatment. Cancer Res., 49: 2175-2183. Lipton A, Harvey HA, Hamilton RW (1984). Venous thrombosis as a side effect of tamoxifen treatment. Cancer Treatment Reports, 68: 887-889. Loomus GN, Aneja P, Bota RA (1983). A case of peliosis hepatis in association with tamoxifen therapy. Am. J. Clin. Path., 80: 881-882. Reynolds EF, Ed (1989). Martindale, The Extra Pharmacopoeia. 29th edition. Pharmaceutical Press, London. Merck Index (1983). 10th edition. Merck & Co., Inc., Rahaway, NJ. Noguchi M, Taniya T, Tajiri K et al (1987). Fatal hyperlipidaemia in a case of metastatic breast cancer treated by tamoxifen. Br. J. Surg., 74: 586-487. Pluss JL, Dibella NJ (1984). Reversible central nervous system dysfunction due to tamoxifen in a patient with breast cancer. Ann. Int. Med., 101: 652. Ritchie LD, Grant SMT (1989). Tamoxifen-warfarin interaction: the Aberdeen Hospitals file. Br. Med. J., 298: 1253. Taguchi O (1987). Reproductive tract lesions in male mice treated neonatally with tamoxifen. Biol. Reproduc., 37: 113-116. Taguchi O, Noguchi M (1985). Reproductive tract abnormalities in female mice treated neonatally with tamoxifen. Am. J. Obs. Gynecol., 151: 675-678. Tenni P, Lalich DL, Byrne MJ (1989). Life threatening interaction between tamoxifen and warfarin. Br. Med. J. 298: 93. Uziely B, Lewin A, Brufman G, Dorembus D, Mor-Josef S- (1993). The effect of tamoxifen on the endometrium. Breast Cancer Res. Treat. 26(1): 101-5. 14. AUTHOR(S), REVIEWER(S), DATE(S) (INCLUDING UPDATES), COMPLETE ADDRESS(ES) Author: Dr R.E. Ferner Northern Drug and Therapeutics Centre The Wolfson Unit Royal Victoria Infirmary Newcastle-upon-Tyne NE1 4LP United Kingdom Tel: 44-91-2328511 Fax: 44-91-2323613 Date: 15 April 1990 Peer Review: Strasbourg, France, April 1990 Review: IPCS, May 1994 See Also: Tamoxifen (IARC Summary & Evaluation, Volume 66, 1996) Nandrolone phenylpropionate 1. NAME 1.1 Substance 1.2 Group 1.3 Synonyms 1.4 Identification numbers 1.4.1 CAS number 1.4.2 Other numbers 1.5 Main brand names, main trade names 1.6 Main manufacturers, main importers 2. SUMMARY 2.1 Main risks and target organs 2.2 Summary of clinical effects 2.3 Diagnosis 2.4 First aid measures and management principles 3. PHYSICO-CHEMICAL PROPERTIES 3.1 Origin of the substance 3.2 Chemical structure 3.3 Physical properties 3.3.1 Colour 3.3.2 State/form 3.3.3 Description 3.4 Other characteristics 3.4.1 Shelf-life of the substance 3.4.2 Storage conditions 4. USES 4.1 Indications 4.1.1 Indications 4.1.2 Description 4.2 Therapeutic dosage 4.2.1 Adults 4.2.2 Children 4.3 Contraindications 5. ROUTES OF EXPOSURE 5.1 Oral 5.2 Inhalation 5.3 Dermal 5.4 Eye 5.5 Parenteral 5.6 Other 6. KINETICS 6.1 Absorption by route of exposure 6.2 Distribution by route of exposure 6.3 Biological half-life by route of exposure 6.4 Metabolism 6.5 Elimination by route of exposure 7. PHARMACOLOGY AND TOXICOLOGY 7.1 Mode of action 7.1.1 Toxicodynamics 7.1.2 Pharmacodynamics 7.2 Toxicity 7.2.1 Human data 7.2.1.1 Adults 7.2.1.2 Children 7.2.2 Relevant animal data 7.2.3 Relevant in vitro data 7.3 Carcinogenicity 7.4 Teratogenicity 7.5 Mutagenicity 7.6 Interactions 7.7 Main adverse effects 8. TOXICOLOGICAL ANALYSES AND BIOMEDICAL INVESTIGATIONS 8.1 Material sampling plan 8.1.1 Sampling and specimen collection 8.1.1.1 Toxicological analyses 8.1.1.2 Biomedical analyses 8.1.1.3 Arterial blood gas analysis 8.1.1.4 Haematological analyses 8.1.1.5 Other (unspecified) analyses 8.1.2 Storage of laboratory samples and specimens 8.1.2.1 Toxicological analyses 8.1.2.2 Biomedical analyses 8.1.2.3 Arterial blood gas analysis 8.1.2.4 Haematological analyses 8.1.2.5 Other (unspecified) analyses 8.1.3 Transport of laboratory samples and specimens 8.1.3.1 Toxicological analyses 8.1.3.2 Biomedical analyses 8.1.3.3 Arterial blood gas analysis 8.1.3.4 Haematological analyses 8.1.3.5 Other (unspecified) analyses 8.2 Toxicological Analyses and Their Interpretation 8.2.1 Tests on toxic ingredient(s) of material 8.2.1.1 Simple Qualitative Test(s) 8.2.1.2 Advanced Qualitative Confirmation Test(s) 8.2.1.3 Simple Quantitative Method(s) 8.2.1.4 Advanced Quantitative Method(s) 8.2.2 Tests for biological specimens 8.2.2.1 Simple Qualitative Test(s) 8.2.2.2 Advanced Qualitative Confirmation Test(s) 8.2.2.3 Simple Quantitative Method(s) 8.2.2.4 Advanced Quantitative Method(s) 8.2.2.5 Other Dedicated Method(s) 8.2.3 Interpretation of toxicological analyses 8.3 Biomedical investigations and their interpretation 8.3.1 Biochemical analysis 8.3.1.1 Blood, plasma or serum 8.3.1.2 Urine 8.3.1.3 Other fluids 8.3.2 Arterial blood gas analyses 8.3.3 Haematological analyses 8.3.4 Interpretation of biomedical investigations 8.4 Other biomedical (diagnostic) investigations and their interpretation 8.5 Overall Interpretation of all toxicological analyses and toxicological investigations 8.6 References 9. CLINICAL EFFECTS 9.1 Acute poisoning 9.1.1 Ingestion 9.1.2 Inhalation 9.1.3 Skin exposure 9.1.4 Eye contact 9.1.5 Parenteral exposure 9.1.6 Other 9.2 Chronic poisoning 9.2.1 Ingestion 9.2.2 Inhalation 9.2.3 Skin exposure 9.2.4 Eye contact 9.2.5 Parenteral exposure 9.2.6 Other 9.3 Course, prognosis, cause of death 9.4 Systematic description of clinical effects 9.4.1 Cardiovascular 9.4.2 Respiratory 9.4.3 Neurological 9.4.3.1 Central nervous system 9.4.3.2 Peripheral nervous system 9.4.3.3 Autonomic nervous system 9.4.3.4 Skeletal and smooth muscle 9.4.4 Gastrointestinal 9.4.5 Hepatic 9.4.6 Urinary 9.4.6.1 Renal 9.4.6.2 Other 9.4.7 Endocrine and reproductive systems 9.4.8 Dermatological 9.4.9 Eye, ear, nose, throat: local effects 9.4.10 Haematological 9.4.11 Immunological 9.4.12 Metabolic 9.4.12.1 Acid-base disturbances 9.4.12.2 Fluid and electrolyte disturbances 9.4.12.3 Others 9.4.13 Allergic reactions 9.4.14 Other clinical effects 9.4.15 Special risks 9.5 Other 9.6 Summary 10. MANAGEMENT 10.1 General principles 10.2 Life supportive procedures and symptomatic/specific treatment 10.3 Decontamination 10.4 Enhanced elimination 10.5 Antidote treatment 10.5.1 Adults 10.5.2 Children 10.6 Management discussion 11. ILLUSTRATIVE CASES 11.1 Case reports from literature 12. Additional information 12.1 Specific preventive measures 12.2 Other 13. REFERENCES 14. AUTHOR(S), REVIEWER(S), DATE(S) (INCLUDING UPDATES), COMPLETE ADDRESS(ES) Nandrolone phenylpropionate International Programme on Chemical Safety Poisons Information Monograph 909 Pharmaceutical This monograph does not contain all of the sections completed. This mongraph is harmonised with the Group monograph on Anabolic Steroids (PIM G007). 1. NAME 1.1 Substance Nandrolone phenylpropionate 1.2 Group ATC Classification: A14 (Anabolic Agents for Systemic Use) A14A (Anabolic steroids) 1.3 Synonyms Nandrolone Hydrocinnamate; Nandrolone Phenpropionate; 19-Norandrostenolone Phenylpropionate; Nortestosterone Phenylpropionate; NSC-23162 1.4 Identification numbers 1.4.1 CAS number 62-90-8 1.4.2 Other numbers 1.5 Main brand names, main trade names Activin; Durabolin; Durabolin; Hybolin; Nandrolone Phenpropionate Injection; 23, Nandrolone Phenylpropionate Injection; Stenabolin; Docabolin (multi-ingredient preparation); Docabolina (multi-ingredient preparation) 1.6 Main manufacturers, main importers 2. SUMMARY 2.1 Main risks and target organs There is no serious risk from acute poisoning, but chronic use can cause harm. The main risks are those of excessive androgens: menstrual irregularities and virilization in women and impotence, premature cardiovascular disease and prostatic hypertrophy in men. Both men and women can suffer liver damage with oral anabolic steroids containing a substituted 17-alpha-carbon. Psychiatric changes can occur during use or after cessation of these agents. 2.2 Summary of clinical effects Acute overdosage can produce nausea and gastrointestinal upset. Chronic usage is thought to cause an increase in muscle bulk, and can cause an exageration of male characteristics and effects related to male hormones. Anabolic steroids can influence sexual function. They can also cause cardiovascular and hepatic damage. Acne and male- pattern baldness occur in both sexes; irregular menses, atrophy of the breasts, and clitoromegaly in women; and testicular atrophy and prostatic hypertrophy in men. 2.3 Diagnosis The diagnosis depends on a history of use of oral or injected anabolic steroids, together with signs of increased muscle bulk, commonly seen in "body-builders". Biochemical tests of liver function are often abnormal in patients who take excessive doses of oral anabolic steroids. Laboratory analyses of urinary anabolic steroids and their metabolites can be helpful in detecting covert use of these drugs. 2.4 First aid measures and management principles Supportive care is the only treatment necessary or appropriate for acute intoxication. Chronic (ab)users can be very reluctant to cease abuse, and may require professional help as with other drug misuse. 3. PHYSICO-CHEMICAL PROPERTIES 3.1 Origin of the substance Naturally-occuring anabolic steroids are synthesised in the testis, ovary and adrenal gland from cholesterol via pregnenolone. Synthetic anabolic steroids are based on the principal male hormone testosterone, modified in one of three ways: alkylation of the 17-carbon esterification of the 17-OH group modification of the steroid nucleus (Murad & Haynes, 1985). 3.2 Chemical structure Chemical Name: 3-Oxoestr-4-en-17beta-yl 3-phenylpropionate; Alternative: 17beta-Hydroxyestr-4-en-3-one 3- phenylpropionate. Molecular Formula: C27H34O3 Molecular Weight: 406.6 3.3 Physical properties 3.3.1 Colour White to creamy-white 3.3.2 State/form Solid-crystals 3.3.3 Description Crystalline powder with a slight characteristic odour. Practically insoluble in water; soluble in alcohol. 3.4 Other characteristics 3.4.1 Shelf-life of the substance 3.4.2 Storage conditions Store in airtight containers. Protect from light. Vials for parenteral administration should be stored at room temperature (15 to 30°C). Visual inspection for particulate and/or discoloration is advisable. 4. USES 4.1 Indications 4.1.1 Indications Anabolic agent; systemic Anabolic steroid Androstan derivative; anabolic steroid Estren derivative; anabolic steroid Other anabolic agent Anabolic agent for systemic use; veterinary Anabolic steroid; veterinary Estren derivative; veterinary 4.1.2 Description The only legitimate therapeutic indications for anabolic steroids are: (a) replacement of male sex steroids in men who have androgen deficiency, for example as a result of loss of both testes (b) the treatment of certain rare forms of aplastic anaemia which are or may be responsive to anabolic androgens. (ABPI Data Sheet Compendium, 1993) (c) the drugs have been used in certain countries to counteract catabolic states, for example after major trauma. 4.2 Therapeutic dosage 4.2.1 Adults 4.2.2 Children Not applicable 4.3 Contraindications Known or suspected cancer of the prostate or (in men) breast. Pregnancy or breast-feeding. Known cardiovascular disease is a relative contraindication. 5. ROUTES OF EXPOSURE 5.1 Oral Anabolic steroids can be absorbed from the gastrointestinal tract, but many compounds undergo such extensive first-pass metabolism in the liver that they are inactive. Those compounds in which substitution of the 17- carbon protects the compound from the rapid hepatic metabolism are active orally (Murad and Haynes, 1985). There are preparations of testosterone that can be taken sublingually. 5.2 Inhalation Not relevant 5.3 Dermal No data available 5.4 Eye Not relevant 5.5 Parenteral Intramuscular or deep subcutaneous injection is the principal route of administration of all the anabolic steroids except the 17-alpha-substituted steroids which are active orally. 5.6 Other Not relevant 6. KINETICS 6.1 Absorption by route of exposure The absorption after oral dosing is rapid for testosterone and probably for other anabolic steroids, but there is extensive first-pass hepatic metabolism for all anabolic steroids except those that are substituted at the 17-alpha position. The rate of absorption from subcutaneous or intramuscular depots depends on the product and its formulation. Absorption is slow for the lipid-soluble esters such as the cypionate or enanthate, and for oily suspensions. 6.2 Distribution by route of exposure The anabolic steroids are highly protein bound, and is carried in plasma by a specific protein called sex-hormone binding globulin. 6.3 Biological half-life by route of exposure The metabolism of absorbed drug is rapid, and the elimination half-life from plasma is very short. The duration of the biological effects is therefore determined almost entirely by the rate of absorption from subcutaneous or intramuscular depots, and on the de-esterification which precedes it (Wilson, 1992). 6.4 Metabolism Free (de-esterified) anabolic androgens are metabolized by hepatic mixed function oxidases (Wilson, 1992). 6.5 Elimination by route of exposure After administration of radiolabelled testosterone, about 90% of the radioactivity appears in the urine, and 6% in the faeces; there is some enterohepatic recirculation (Wilson, 1992). 7. PHARMACOLOGY AND TOXICOLOGY 7.1 Mode of action 7.1.1 Toxicodynamics The toxic effects are an exaggeration of the normal pharmacological effects. 7.1.2 Pharmacodynamics Anabolic steroids bind to specific receptors present especially in reproductive tissue, muscle and fat (Mooradian & Morley, 1987). The anabolic steroids reduce nitrogen excretion from tissue breakdown in androgen deficient men. They are also responsible for normal male sexual differentiation. The ratio of anabolic ("body-building") effects to androgenic (virilizing) effects may differ among the members of the class, but in practice all agents possess both properties to some degree. There is no clear evidence that anabolic steroids enhance overall athletic performance (Elashoff et al, 1991). 7.2 Toxicity 7.2.1 Human data 7.2.1.1 Adults No data available. 7.2.1.2 Children No data available. 7.2.2 Relevant animal data No data available. 7.2.3 Relevant in vitro data No data 7.3 Carcinogenicity Anabolic steroids may be carcinogenic. They can stimulate growth of sex-hormone dependent tissue, primarily the prostate gland in men. Precocious prostatic cancer has been described after long-term anabolic steroid abuse (Roberts & Essenhigh, 1986). Cases where hepatic cancers have been associated with anabolic steroid abuse have been reported (Overly et al, 1984). 7.4 Teratogenicity Androgen ingestion by a pregnant mother can cause virilization of a female fetus (Dewhurst & Gordon, 1984). 7.5 Mutagenicity No data available. 7.6 Interactions No data available. 7.7 Main adverse effects The adverse effects of anabolic steroids include weight gain, fluid retention, and abnormal liver function as measured by biochemical tests. Administration to children can cause premature closure of the epiphyses. Men can develop impotence and azoospermia. Women are at risk of virilization. 8. TOXICOLOGICAL ANALYSES AND BIOMEDICAL INVESTIGATIONS 8.1 Material sampling plan 8.1.1 Sampling and specimen collection 8.1.1.1 Toxicological analyses 8.1.1.2 Biomedical analyses 8.1.1.3 Arterial blood gas analysis 8.1.1.4 Haematological analyses 8.1.1.5 Other (unspecified) analyses 8.1.2 Storage of laboratory samples and specimens 8.1.2.1 Toxicological analyses 8.1.2.2 Biomedical analyses 8.1.2.3 Arterial blood gas analysis 8.1.2.4 Haematological analyses 8.1.2.5 Other (unspecified) analyses 8.1.3 Transport of laboratory samples and specimens 8.1.3.1 Toxicological analyses 8.1.3.2 Biomedical analyses 8.1.3.3 Arterial blood gas analysis 8.1.3.4 Haematological analyses 8.1.3.5 Other (unspecified) analyses 8.2 Toxicological Analyses and Their Interpretation 8.2.1 Tests on toxic ingredient(s) of material 8.2.1.1 Simple Qualitative Test(s) 8.2.1.2 Advanced Qualitative Confirmation Test(s) 8.2.1.3 Simple Quantitative Method(s) 8.2.1.4 Advanced Quantitative Method(s) 8.2.2 Tests for biological specimens 8.2.2.1 Simple Qualitative Test(s) 8.2.2.2 Advanced Qualitative Confirmation Test(s) 8.2.2.3 Simple Quantitative Method(s) 8.2.2.4 Advanced Quantitative Method(s) 8.2.2.5 Other Dedicated Method(s) 8.2.3 Interpretation of toxicological analyses 8.3 Biomedical investigations and their interpretation 8.3.1 Biochemical analysis 8.3.1.1 Blood, plasma or serum 8.3.1.2 Urine 8.3.1.3 Other fluids 8.3.2 Arterial blood gas analyses 8.3.3 Haematological analyses 8.3.4 Interpretation of biomedical investigations 8.4 Other biomedical (diagnostic) investigations and their interpretation 8.5 Overall Interpretation of all toxicological analyses and toxicological investigations Biomedical analysis The following tests can be relevant in the investigation of chronic anabolic steroid abuse: a) full blood count b) electrolytes and renal function tests c) hepatic function tests d) testosterone e) Lutenizing hormone f) prostatic acid phosphatase or prostate related antigen g) blood glucose concentration h) cholesterol concentration Toxicological analysis -urinary analysis for anabolic steroids and their metabolites Other investigations -electrocardiogram 8.6 References 9. CLINICAL EFFECTS 9.1 Acute poisoning 9.1.1 Ingestion Nausea and vomiting can occur. 9.1.2 Inhalation Not relevant 9.1.3 Skin exposure Not relevant 9.1.4 Eye contact Not relevant 9.1.5 Parenteral exposure Patients are expected to recover rapidly after acute overdosage, but there are few data. "Body- builders" use doses many times the standard therapeutic doses for these compounds but do not suffer acute toxic effects. 9.1.6 Other Not relevant 9.2 Chronic poisoning 9.2.1 Ingestion Hepatic damage, manifest as derangement of biochemical tests of liver function and sometimes severe enough to cause jaundice; virilization in women; prostatic hypertrophy, impotence and azoospermia in men; acne, abnormal lipids, premature cardiovascular disease (including stroke and myocardial infarction), abnormal glucose tolerance, and muscular hypertrophy in both sexes; psychiatric disturbances can occur during or after prolonged treatment (Ferner & Rawlins, 1988; Kennedy, 1992; Ross & Deutch, 1990; Ryan, 1981; Wagner, 1989). 9.2.2 Inhalation Not relevant 9.2.3 Skin exposure Not relevant 9.2.4 Eye contact Not relevant 9.2.5 Parenteral exposure Virilization in women; prostatic hypertrophy, impotence and azoospermia in men; acne, abnormal lipids, premature cardiovascular disease (including stroke and myocardial infarction), abnormal glucose tolerance, and muscular hypertrophy in both sexes. Psychiatric disturbances can occur during or after prolonged treatment. Hepatic damage is not expected from parenteral preparations. 9.2.6 Other Not relevant 9.3 Course, prognosis, cause of death Patients with symptoms of acute poisoning are expected to recover rapidly. Patients who persistently abuse high doses of anabolic steroids are at risk of death from premature heart disease or cancer, especially prostatic cancer. Non-fatal but long-lasting effects include voice changes in women and fusion of the epiphyses in children. Other effects are reversible over weeks or months. 9.4 Systematic description of clinical effects 9.4.1 Cardiovascular Chronic ingestion of high doses of anabolic steroids can cause elevations in blood pressure, left ventricular hypertrophy and premature coronary artery disease (McKillop et al., 1986; Bowman, 1990; McNutt et al., 1988). 9.4.2 Respiratory Not reported 9.4.3 Neurological 9.4.3.1 Central nervous system Stroke has been described in a young anabolic steroid abuser (Frankle et al., 1988). Pope & Katz (1988) described mania and psychotic symptoms of hallucination and delusion in anabolic steroid abusers. They also described depression after withdrawal from anabolic steroids. There is also considerable debate about the effects of anabolic steroids on aggressive behaviour (Schulte et al., 1993) and on criminal behaviour (Dalby, 1992). Mood swings were significantly more common in normal volunteers during the active phase of a trial comparing methyltestosterone with placebo (Su et al., 1993). 9.4.3.2 Peripheral nervous system No data available 9.4.3.3 Autonomic nervous system No data available 9.4.3.4 Skeletal and smooth muscle No data available 9.4.4 Gastrointestinal Acute ingestion of large doses can cause nausea and gastrointestinal upset. 9.4.5 Hepatic Orally active (17-alpha substituted) anabolic steroids can cause abnormalities of hepatic function, manifest as abnormally elevated hepatic enzyme activity in biochemical tests of liver function, and sometimes as overt jaundice. The histological abnormality of peliosis hepatis has been associated with anabolic steroid use (Soe et al., 1992). Angiosarcoma (Falk et al, 1979) and a case of hepatocellular carcinoma in an anabolic steroid user has been reported (Overly et al., 1984). 9.4.6 Urinary 9.4.6.1 Renal Not reported 9.4.6.2 Other Men who take large doses of anabolic steroids can develop prostatic hypertrophy. Prostatic carcinoma has been described in young men who have abused anabolic steroids (Roberts & Essenhigh, 1986). 9.4.7 Endocrine and reproductive systems Small doses of anabolic steroids are said to increase libido, but larger doses lead to azoospermia and impotence. Testicular atrophy is a common clinical feature of long-term abuse of anabolic steroids, and gynaecomastia can occur (Martikainen et al., 1986; Schurmeyer et al., 1984; Spano & Ryan, 1984). Women develop signs of virilism, with increased facial hair, male pattern baldness, acne, deepening of the voice, irregular menses and clitoral enlargement (Malarkey et al., 1991; Strauss et al., 1984). 9.4.8 Dermatological Acne occurs in both male and female anabolic steroids abusers. Women can develop signs of virilism, with increased facial hair and male pattern baldness. 9.4.9 Eye, ear, nose, throat: local effects Changes in the larynx in women caused by anabolic steroids can result in a hoarse, deep voice. The changes are irreversible. 9.4.10 Haematological Anabolic androgens stimulate erythropoesis. 9.4.11 Immunological 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 Sodium and water retention can occur, and result in oedema; hypercalcaemia is also reported (Reynolds, 1992). 9.4.12.3 Others Insulin resistance with a fall in glucose tolerance (Cohen & Hickman, 1987), and hypercholesterolaemia with a fall in high density lipoprotein cholesterol, have been reported (Cohen et al., 1988; Glazer, 1991; Webb et al., 1984). 9.4.13 Allergic reactions No data available 9.4.14 Other clinical effects No data available 9.4.15 Special risks Risk of abuse 9.5 Other No data available 9.6 Summary 10. MANAGEMENT 10.1 General principles The management of acute overdosage consists of supportive treatment, with fluid replacement if vomiting is severe. Chronic abuse should be discouraged, and psychological support may be needed as in the treatment of other drug abuse. The possibility of clinically important depression after cessation of usage should be borne in mind. 10.2 Life supportive procedures and symptomatic/specific treatment Not relevant 10.3 Decontamination Not usually required. 10.4 Enhanced elimination Not indicated 10.5 Antidote treatment 10.5.1 Adults None available 10.5.2 Children None available 10.6 Management discussion Not relevant 11. ILLUSTRATIVE CASES 11.1 Case reports from literature A 38-year old man presented with acute urinary retention, and was found to have carcinoma of the prostate. He had taken anabolic steroids for many years, and worked as a "strong-man" (Roberts and Essenhigh, 1986). A 22-year old male world-class weight lifter developed severe chest pain awaking him from sleep, and was shown to have myocardial infarction. For six weeks before, he had been taking high doses of oral and injected anabolic steroids. Total serum cholesterol was 596 mg/dL (HDL 14 mg/dL, LDL 513 mg/dL) (McNutt et al., 1988). Values of total cholesterol concentration above 200 mg/dL are considered undesirable. A 22-year old body builder took two eight-week courses of anabolic steroids. He became severely depressed after the second course, and when the depression gradually receded, he had prominent paranoid and religious delusions (Pope and Katz, 1987). A 19-year old American college footballer took intramuscular testosterone and oral methandrostenolone over 4 months. He became increasingly aggressive with his wife and child. After he severely injured the child, he ceased using anabolic steroids, and his violence and aggression resolved within 2 months (Schulte et al, 1993). 12. Additional information 12.1 Specific preventive measures Anabolic steroid abuse amongst athletes, weight lifters, body builders and others is now apparently common at all levels of these sports. Not all abusers are competitive sportsmen. There is therefore scope for a public health campaign, for example, based on gymnasia, to emphasize the dangers of anabolic steroid abuse and to support those who wish to stop using the drugs. 12.2 Other No data available. 13. REFERENCES ABPI Data Sheet Compendium (1993) Datapharm Publications, London. Bowman S. (1990) Anabolic steroids and infarction. Br Med J; 300: Cohen JC & Hickman R. (1987) Insulin Resistance and diminished glucose tolerance in powerlifters ingesting anabolic steroids. J Clin Endocrinol Metab 64: 960. Cohen JC, Noakes TD, & Spinnler Benade AJ. (1988) Hypercholesterolemia in male power lifters using Anabolic Androgenic Steroids. The Physician and Sports medicine 16: 49-56. Dalby JT. (1992) Brief anabolic steroid use and sustained behavioral reaction. Am J Psychiatry 149: 271-272. Dewhurst J. & Gordon RR (1984). Fertility following change of sex: a follow-up. Lancet: ii: 1461-2. Elashoff JD, Jacknow AD, Shain SG, & Braunstein GD. (1991) Effects of anabolic-androgenic steroids on muscular strength. Annals Inter Med 115: 387-393. Falk H, Thomas LB, Popper H, Ishak KG. (1979). Hepatic angiosacroma associated with androgenic-anabolic steroids. Lancet 2; 1120-1123. Ferner RE & Rawlins MD (1988) Anabolic steroids: the power and the glory? Br Med J 1988; 297: 877-878. Frankle MA, Eichberg R, & Zacharian SB. (1988) Anabolic Androgenic steroids and stroke in an athlete: case report. Arch Phys Med Rehabil 1988; 69: 632-633. Glazer G. (1991) Atherogenic effects of anabolic steroids on serum lipid levels. Arch Intern Med 151: 1925-1933. Kennedy MC. (1992). Anabolic steroid abuse and toxicology. Aust NZ J Med 22: 374-381. Malarkey WB, Strauss RH, Leizman DJ, Liggett M, & Demers LM. (1991). Endocrine effects in femal weight lifters who self- administer testosterone and anabolic steroids. Am J Obstet Gynecol 165: 1385-1390. Martikainen H, Alen M, Rahkila P, & Vihko R. (1986) Testicular responsiveness to human chorionic gonadotrophin during transient hypogonadotrophic hypogondasim induced by androgenic/anabolic steroids in power athletes. Biochem 25: 109-112. McKillop G, Todd IC, Ballantyne D. (1986) Increased left ventricular mass in a body builder using anabolic steroids. Brit J Sports Med 20: 151-152. McNutt RA, Ferenchick GS, Kirlin PC, & Hamlin NJ. (1988) Acute myocardial infarction in a 22 year old world class weight lifter using anabolic steroids. Am J Cardiol 62: 164. Mooradian JE, Morley JE, Korenman SG. (1987) Biological actions of androgens. Endocrine Reviews 8:1-27. Murad F, & Haynes RC. (1985). Androgens. in. Ed: Goodman Gilman A, Goodman L S, Roll T W, Murad F. The Pharmacological Basis of Therapeutics, 7th edition, Macmillan, New York: 1440-1458 Overly WL et al. (1984). Androgens and hepatocellular carcinoma in an athlete. Ann Int Med 100: 158-159. Pope GR,, & Katz DL. (1988). Affective and psychotic symptoms associated with anabolic steroid use. Am J Psychiatry 145: 487-490. Reynolds Ed. (1992) Martindale-The Extra Pharmacopeia. The Pharmaceutical Press. London. Roberts JT, & Essenhigh DM. (1986) Adenocarcinoma of prostate in 40-year old body builder. Lancet 2: 742. Ross RB, & Deutsch S I.(1990) Hooked on hormones. JAMA 263: 2048-2049. Ryan A J. (1981) Anabolic steroids are fool's gold. Fed Proc 40: 2682-2688. Schurmeyer T, Belkien L, Knuth UA, & Nieschlag E. (1984) Reversible azoospermia induced by the anabolic steroid 19-nortestosterone. Lancet i: 417-420. Soe KL. Soe M. & Gluud C. (1992). Liver pathology associated with the use of anabolic-androgenic steroids. Liver 12: 73-9. Schulte HM, Hall MJ, & Boyer M. (1993). Domestic violence associated with anabolic steroid abuse. Am J Psychiatr 150: 348. Spano F, & Ryan W G. (1989) Tamoxifen for gynecomastia induced by anabolic steroids? New Engl J Med 311: 861-862. Strauss RH, Liggett MT, & Lanese RR. (1984) Anabolic steroid use and perceived effects in 10 weight-trained women athletes JAMA 253: 2871-2873. Su T-P, Pagliaro M, Schmidt PJ, Pickar D, Wolkowitz O, & Rubinow DR. (1993) Neuropsychiatric effects of anabolic steroids in male normal volunteers. JAMA 269: 2760-2764. Wagner JC (1989). Abuse of drugs used to enhance athletic performance. Am J Hosp Pharm 46: 2059-2067 Webb O L, Laskarzewski P M, & Glueck, CJ. (1984) Severe depression of high-density lipo protein cholesterol levels in weight lifters and body builders by self-administered exogenous testerone and anabolic-andorgenic steroids. Metabolism 33: 971-975. Wilson J D. (1992). Androgens. In: Goodman Gilman A., Rall T W, Nies A S, & Taylor P. Goodman and Gilman's Pharmacological Basis of Therapeutics. McGraw-Hill, Toronto. Pages 1413-1430. 14. AUTHOR(S), REVIEWER(S), DATE(S) (INCLUDING UPDATES), COMPLETE ADDRESS(ES) Author: Dr R. E. Ferner, West Midlands Centre for Adverse Drug Reaction Reporting, City Hospital Dudley Road, Birmingham B18 7QH England. Tel: +44-121-5074587 Fax: +44-121-5236125 Email: fernerre@bham.ac.uk Date: 1994 Peer review: INTOX Meeting, Sao Paulo, Brazil, September 1994 (Drs P.Kulling, R.McKuowen, A.Borges, R.Higa, R.Garnier, Hartigan-Go, E.Wickstrom) Editor: Dr M.Ruse, March 1998 See Also: Nandrolone (PIM 910)
See Also:
        Cobalt (ICSC)
        Cobalt, (ICSC)