Propylthiouracil – Uses, Dosage, Side Effects, Interactions

Propylthiouracil is a Thyroid Hormone Synthesis Inhibitor. The mechanism of action of propylthiouracil is as a Thyroid Hormone Synthesis Inhibitor.

6-propyl-2-thiouracil is a pyrimidine-thione consisting of uracil in which the 2-oxo group is substituted by a thio group and the hydrogen at position 6 is substituted by a propyl group. It has a role as an antithyroid drug, a carcinogenic agent, an antimetabolite, a hormone antagonist, an EC 1.14.13.39 (nitric oxide synthase) inhibitor, an antioxidant, and an antidote to paracetamol poisoning. It is functionally related to a uracil.

A thiourea antithyroid agent. Propylthiouracil inhibits the synthesis of thyroxine and inhibits the peripheral conversion of thyroxine to tri-iodothyronine. It is used in the treatment of hyperthyroidism. (From Martindale, The Extra Pharmacopeia, 30th ed, p534)

A thiourea antithyroid agent. Propylthiouracil inhibits the synthesis of thyroxine and inhibits the peripheral conversion of thyroxine to tri-iodothyronine. It is used in the treatment of hyperthyroidism.

Mechanism of Action

Propylthiouracil binds to thyroid peroxidase and thereby inhibits the conversion of iodide to iodine. Thyroid peroxidase normally converts iodide to iodine (via hydrogen peroxide as a cofactor) and also catalyzes the incorporation of the resulting iodide molecule onto both the 3 and/or 5 positions of the phenol rings of tyrosines found in thyroglobulin. Thyroglobulin is degraded to produce thyroxine (T4) and tri-iodothyronine (T3), which are the main hormones produced by the thyroid gland. Therefore propylthiouracil effectively inhibits the production of new thyroid hormones

or

Propylthiouracil inhibits the synthesis of thyroid hormones by interfering with the incorporation of iodine into tyrosyl residues of thyroglobulin; the drug also inhibits the coupling of these iodotyrosyl residues to form iodothyronine. Although the exact mechanism(s) have not been fully elucidated, propylthiouracil may interfere with the oxidation of iodide ion and iodotyrosyl groups. Based on limited evidence it appears that the coupling reaction is more sensitive to antithyroid agents than the iodination reaction. Propylthiouracil does not inhibit the action of thyroid hormones already formed and present in the thyroid gland or circulation nor does the drug interfere with the effectiveness of exogenously administered thyroid hormones. Patients whose thyroid gland contains a relatively high concentration of iodine (e.g., from prior ingestion or from administration during diagnostic radiologic procedures) may respond relatively slowly to antithyroid agents. Unlike methimazole, propylthiouracil inhibits the peripheral deiodination of thyroxine to triiodothyronine. Although the importance of this inhibition has not been established, propylthiouracil has a theoretical advantage compared with methimazole or carbimazole in patients with thyrotoxic crisis, since a decreased rate of conversion of circulating thyroxine to triiodothyronine may be clinically beneficial in these patients.

Propylthiouracil is a thiourea antithyroid agent. Grave’s disease is the most common cause of hyperthyroidism. It is an autoimmune disease where an individual’s own antibodies attach to thyroid-stimulating hormone receptors within cells of the thyroid gland and then trigger the overproduction of thyroid hormone. The two thyroid hormones manufactured by the thyroid gland, thyroxine (T4) and triiodothyronine (T3), are formed by combining iodine and a protein called thyroglobulin with the assistance of an enzyme called peroxidase. PTU inhibits iodine and peroxidase from their normal interactions with thyroglobulin to form T4 and T3. This action decreases thyroid hormone production. PTU also interferes with the conversion of T4 to T3, and, since T3 is more potent than T4, this also reduces the activity of thyroid hormones. The actions and use of propylthiouracil are similar to those of methimazole.

Indications

  •  Antimetabolites, Antithyroid Agents
  • Used to manage hyperthyroidism which is due to an overactive thyroid gland (Grave’s disease).
  • Propylthiouracil is an antithyroid medication used in the therapy of hyperthyroidism and Graves disease. Propylthiouracil has been linked to serum aminotransferase elevations during therapy as well as to a clinically apparent, idiosyncratic liver injury that can be severe and even fatal.
  • Propylthiouracil /is/ indicated in the treatment of hyperthyroidism, including prior to surgery or radiotherapy, and as adjuncts in the treatment of thyrotoxicosis or thyroid storm. Propylthiouracil may be preferred over methimazole for use in thyroid storms since propylthiouracil inhibits peripheral conversion of thyroxine (T4) to triiodothyronine (T3).
  • Paradoxically propylthiouracil has been shown to reverse histological changes of alcoholic hepatitis in rats and has been proposed as a possible treatment for this condition in men.
  • Twelve-day pretreatment with PTU prevented the Tylenol-induced increase in transaminase activities. An increase in hepatic reduced glutathione levels and prevention of inflammatory response to necrotic liver tissue appeared to be mechanisms in the protective action of hypothyroidism.
  • Hyperthyroidism treatment
  • Used if methimazole or radioactive iodine treatment is contraindicated or as an alternative treatment option in a patient with Graves disease or toxic multinodular goiter
  • Used before thyroidectomy or radioactive iodine therapy to treat hyperthyroidism
  • In thyroid storm and thyrotoxicosis crisis (off-label treatment), to treat the hyperthyroidism.
  • It is a preferred antithyroid drug in the first trimester of pregnancy.
  • For patients with Graves’ disease and hyperthyroidism or toxic multinodular goiter who are intolerant of methimazole and for whom surgery or radioactive iodine therapy is not an appropriate treatment option.
  • To ameliorate symptoms of hyperthyroidism in preparation for thyroidectomy or radioactive iodine therapy in patients who are intolerant of methimazole.

Contraindications

  • Contraindications include a previous history of hypersensitivity to PTU or any of its drug components. Caution is advised in patients with hepatic impairment or myelosuppression and pediatric patients.

Dosages

Strengths: 50 mg

Hyperthyroidism

  • Initial dose: 100 mg orally every 8 hours
  • Maintenance dose: 100 to 150 mg orally daily administered in 3 equally divided doses approximately every 8 hours
  • For patients with severe hyperthyroidism, very large goiters, or both, the initial dose may be increased to 400 mg, or for the occasional patient, up to 600 to 900 mg daily initially (administered in 3 equally divided doses as approximately 8-hour intervals).

Thyroid Storm

  • Initial dose: 100 mg orally every 8 hours
  • Maintenance dose: 100 to 150 mg orally daily administered in 3 equally divided doses approximately every 8 hours
  • For patients with severe hyperthyroidism, very large goiters, or both, the initial dose may be increased to 400 mg, or for the occasional patient, up to 600 to 900 mg daily initially (administered in 3 equally divided doses as approximately 8-hour intervals).

Pediatric Dose for Hyperthyroidism

6 years or older:

  • Initial dose: 50 mg orally daily in 3 equally divided doses approximately every 8 hours
  • Carefully titrate based on clinical response and evaluation of TSH and free T4 levels

OR,
6 to 10 years of age:

  • Initial dose: 50 to 150 mg orally daily in 3 equally divided doses approximately every 8 hours

10 years or older:

  • Initial dose: 150 to 300 mg orally daily in 3 equally divided doses approximately every 8 hours
  • Maintenance dose: 50 mg orally twice a day when euthyroid
  • Although cases of severe liver injury have been reported with doses as low as 50 mg per day, most cases were associated with doses of 300 mg per day and higher.

or

The available propylthiouracil tablet has 50 mg of the drug, and storage should be at room temperature. The dosage is as follows:

  • Adults: Propylthiouracil is administered orally, initially as 300 mg/day in three divided doses every 8 hours (may reach up to 600 to 900 mg/day). After the initial treatment, the general maintenance dose is 100 to 150 mg/day. The dose is adjusted to maintain normal TSH, T3, and T4 levels.

    • Graves disease (off-label): PTU can be started as an initial dose of 50 to 150 mg three times a day
    • Thyrotoxic crisis/thyroid storm (off-label): The American Thyroid Association recommends 500 to 1000 mg as a loading dose of PTU, which can be followed by 250 mg every 4 hours. Recommendations are widely variable, and comparative trials have not taken place.
    • Pediatric: Due to severe liver toxicity reported with the use of PTU, it is no longer approved by the United States Food and Drug Administration (FDA) in pediatric patients.
    •  Geriatric: Clinical studies incorporating the effects of PTU in patients over 65 years are lacking. PTU should be used cautiously in the geriatric age group, owing to an increased likelihood of co-morbidities and declined organ function in the elderly.

Dose Adjustments

Elderly: Dose selection should be cautious, reflecting the greater frequency of decreased hepatic, renal, cardiac function, and concomitant disease or other drug therapy.

Precautions

US BOXED WARNINGS:

  • Severe liver injury and acute liver failure, in some cases fatal, have been reported in patients treated with this drug. These reports of hepatic reactions include cases requiring liver transplantation in adult and pediatric patients.
  • This drug should be reserved for patients who cannot tolerate methimazole and in whom radioactive iodine therapy or surgery are not appropriate treatments for the management of hyperthyroidism.
  • This drug may be the treatment of choice when an antithyroid drug is indicated during or just prior to the first trimester of pregnancy.
  • Safety and efficacy have not been established in patients younger than 6 years.

Administration advice:

  • Take orally in equally divided doses at approximately 8-hour intervals
  • Missed dose: If a dose is missed, take it as soon as you remember; if it is almost time for your next dose, skip the missed dose. Do not double your dose.

General:

  • Patients treated with this drug should be under close surveillance due to the potential for serious adverse effects.
  • In general, this drug should only be considered in patients who are intolerant of methimazole and for whom surgery or radioactive iodine therapy is not an appropriate treatment option.
  • It may be the treatment of choice for the first trimester of pregnancy due to methimazole use being associated with fetal abnormalities; after the first trimester it may be preferable to switch to methimazole.

Monitoring:

  • Routine monitoring of TSH and free T4 levels is necessary to avoid under or over treatment
  • Consider monitoring prothrombin time if there are concerns of bleeding; prothrombin time should be monitored before surgical procedures
  • Monitor blood counts if there are signs and symptoms of agranulocytosis
  • Routine liver function testing may not attenuate the risk of severe liver injury; however, immediately perform liver function testing if there are any symptoms of hepatic dysfunction

Patient advice:

  • Patient should be instructed to read the US FDA-approved patient labeling (Medication Guide)
  • Patients should understand the importance of contacting their healthcare provider promptly if they experience any signs or symptoms of liver dysfunction, low blood counts, bleeding, or vasculitis.
  • Women should be instructed to speak to their healthcare provider if they are pregnant or plan to become pregnant.
  • This drug may cause dizziness, drowsiness, or sleepiness; do not drive or perform hazardous tasks until you know how this drug affects you.

Side Effects

The Most Common

  • difficulty tasting food
  • numbness, burning, or tingling of the hands or feet
  • joint or muscle pain
  • dizziness
  • swelling of the neck
  • Black, tarry stools
  • chest pain
  • chills
  • cough
  • fever
  • painful or difficult urination
  • shortness of breath
  • sore throat
  • sores, ulcers, or white spots on the lips or in the mouth
  • swollen glands
  • unusual bleeding or bruising
  • unusual tiredness or weakness
  • Dark-colored urine
  • a general feeling of discomfort, illness, or weakness
  • headache
  • light-colored stools
  • nausea or vomiting
  • stomach pain, continuing
  • upper right abdominal or stomach pain
  • yellow eyes and skin

More Common

  • Dermatologic: erythema nodosum, exfoliative dermatitis, urticaria, skin ulcers, skin rash, alopecia, Stevens-Johnson syndrome, toxic epidermal necrolysis
  • Renal: acute kidney injury, acute interstitial nephritis
  • Gastrointestinal: loss of taste, taste perversion, nausea, vomiting, stomach pain, sial adenopathy
  • Neurological: neuritis, headache, paresthesia, drowsiness, vertigo
  • Hematological: lymphadenopathy, splenomegaly, leukopenia, aplastic anemia, lymphadenopathy, hemorrhage, hypoprothrombinemia
  • Respiratory: pulmonary alveolar hemorrhage, interstitial pneumonitis
  • Drug fever
  • Lupus-like syndrome
  • Carcinogenesis: pituitary adenomas, thyroid hyperplasia, and carcinoma after more than one year of continuous PTU usage.
  • Infertility
  • sore throat, fever, chills, cough, or other signs of infection
  • headache
  • skin rash, hives, blisters, bumps or peeling
  • dark, rust-colored, brown or foamy urine
  • swelling of the face, eyes, stomach, arms, hands, feet, ankles, or lower legs
  • chest pain
  • shortness of breath or wheezing
  • coughing up blood

Rare

  • Abdominal or stomach pain
  • agitation
  • bleeding gums
  • bleeding under the skin
  • blood in the urine or stools
  • bloody or cloudy urine
  • burning, crawling, itching, numbness, prickling, “pins and needles”, or tingling feelings
  • coma
  • confusion
  • cough or hoarseness
  • cracks in the skin
  • decreased urine output
  • depression
  • difficulty with breathing
  • difficulty with moving
  • dizziness
  • drowsiness
  • feeling of fullness
  • fever with or without chills
  • general feeling of discomfort, illness, or weakness
  • high blood pressure
  • hostility
  • irritability
  • joint pain
  • lethargy
  • loss of appetite and weight
  • loss of heat from the body
  • lower back or side pain
  • muscle aching or cramping
  • muscle pain or stiffness
  • muscle twitching
  • numbness or tingling of the hands, feet, or face
  • pain in the ankles or knees
  • painful, red lumps under the skin, mostly on the legs
  • pinpoint red spots on the skin
  • rapid weight gain
  • red, swollen skin
  • redness, soreness, or itching skin
  • scaly skin
  • seizures
  • soreness of the muscles
  • sores on the skin
  • sores, ulcers, or white spots on the lips or in the mouth
  • sores, welting, or blisters
  • stupor
  • swelling of the face, ankles, hands, feet, or lower legs
  • swollen joints
  • swollen salivary glands
  • swollen, painful, or tender lymph glands in the neck, armpit, or groin
  • tightness in the chest
  • unusual weight gain
  • wheezing

Drug Interactions

Pregnancy and Lactation

FDA pregnancy category D

Pregnant:

 PTU can cross the placenta and can cause fetal cretinism and goiter. Methimazole causes fetal anatomical abnormalities; hence, if it is necessary to use antithyroid drugs in pregnancy, PTU is preferred in the first trimester with the lowest possible drug dose usage. Due to the increased reported risk of maternal hepatotoxicity from PTU, methimazole is the therapeutic choice in the second and third trimesters.

Propylthiouracil (PTU) had been considered the antithyroid drug of choice during lactation; however, findings that the rates of liver injury are higher with PTU than with methimazole have altered this judgment. Some experts now recommend that methimazole should be considered the antithyroid drug of choice in nursing mothers. No cases of PTU-induced liver damage have been reported in breastfed infants and it is unknown if the small amounts of the drug in breastmilk can cause liver damage. The drug or breastfeeding should be discontinued if liver toxicity is suspected. Dosages of PTU should be limited to 450 mg daily during breastfeeding.

The American Thyroid Association recommends only monitoring infants for appropriate growth and development during routine pediatric health and wellness evaluations and routine assessment of serum thyroid function in the child is not recommended. Rare idiosyncratic reactions (e.g., agranulocytosis) might occur, and the infant should be watched for signs of infection. Monitoring of the infant’s complete blood count and differential is advisable if there is a suspicion of drug-induced blood dyscrasia.

Breastfed Infants

PTU is excreted in breast milk in small amounts and delivered to infants. There are no clear-cut recommendations for its use in nursing. (AAP suggests it is compatible with nursing while AAFP says it is safe with nursing).

A mother was taking oral propylthiouracil 100 mg daily during pregnancy and 125 mg daily after delivery. In her infant, serum thyroxine (T4) concentration dropped slightly below the lower limit of normal on day 4 of life, but both T4 and thyrotropin (TSH) concentrations were normal on day 19 with continued maternal PTU therapy. The drop in T4 was possibly due to propylthiouracil in breastmilk, but more likely from PTU received transplacentally.

An infant whose mother was taking propylthiouracil 200 to 300 mg daily was followed for 5 months and found to have normal thyroid function tests.

A mother took PTU in a starting dose of 100 mg 3 times daily that was tapered to 50 mg twice daily over a period of 6 months. Her breastfed infant had normal thyroid function tests during this period at the ages of 9 to 13 months of age.

Eight mothers taking PTU during pregnancy and doses of 50 to 300 mg daily after delivery exclusively or nearly exclusively breastfed their infants. The infants all had slightly low free T4 levels at birth and TSH levels were above normal in 7 of the 8, indicating that they had been affected by PTU in utero. All of their infants had normal free T4 and TSH levels when measured between 18 days and 8 months of age and none had any adverse effects reported from PTU in milk.

The mothers of 11 fully breastfed infants were taking 300 to 750 mg daily of PTU starting at various times between delivery and 11 months postpartum. One infant had a slightly elevated TSH level at 19 weeks of age when his mother was taking PTU 450 mg daily. Two other infants had elevated TSH levels at birth. TSH normalized in both infants with maternal PTU doses of 600 mg daily in one and a dose starting at 300 mg daily at term and increasing to 600 mg daily in the other.

Two other infants were reported to be hypothyroid at birth but to have normal thyroid function at 1 month of age despite maternal PTU therapy during breastfeeding.

Why is this medication prescribed?

Propylthiouracil is used to treat hyperthyroidism (a condition that occurs when the thyroid gland produces too much thyroid hormone, speeding the body’s metabolism, and causing certain symptoms) in adults and children 6 years of age or older. Propylthiouracil is in a class of medications called antithyroid agents. It works by stopping the thyroid gland from making thyroid hormone.

How should this medicine be used?

Propylthiouracil comes as a tablet to take by mouth. It is usually taken three times a day, once every 8 hours. Follow the directions on your prescription label carefully, and ask your doctor or pharmacist to explain any part you do not understand. Take propylthiouracil exactly as directed. Do not take more or less of it or take it more often than prescribed by your doctor.

Your doctor may decrease your dose of propylthiouracil once your condition is controlled.

Continue to take propylthiouracil even if you feel well. Do not stop taking propylthiouracil without talking to your doctor.

Other uses for this medicine

This medication may be prescribed for other uses; ask your doctor or pharmacist for more information.

What special precautions should I follow?

Before taking propylthiouracil,

  • tell your doctor and pharmacist if you are allergic to propylthiouracil, any other medications, or any of the ingredients in propylthiouracil tablets. Ask your doctor or pharmacist or check the Medication Guide for a list of the ingredients.
  • tell your doctor and pharmacist what prescription and nonprescription medications, vitamins, nutritional supplements, and herbal products you are taking or plan to take. Be sure to mention any of the following: anticoagulants (‘blood thinners’) such as warfarin (Coumadin), beta blockers such as atenolol (Tenormin), labetalol (Normodyne), metoprolol (Lopressor, Toprol XL), nadolol (Corgard), and propranolol (Inderal); digoxin (Digitek, Lanoxin), and theophylline (Theo-24, Theochron, Theolair). Your doctor may need to change the doses of your medications or monitor you carefully for side effects. Many other medications may also interact with propylthiouracil, so be sure to tell your doctor about all the other medications you are taking, even if they do not appear on this list.
  • tell your doctor if you have or have ever had leukopenia (decreased white blood cells) , thrombocytopenia (decreased platelets), or aplastic anemia (condition in which the body does not make enough new blood cells), or other conditions that cause low numbers of red blood cells, white blood cells, or platelets; or liver disease.
  • tell your doctor if you are pregnant, plan to become pregnant, or are breast-feeding. If you become pregnant while taking propylthiouracil, call your doctor.Your doctor may tell you to take propylthiouracil during the first months of your pregnancy only and then may switch you to methimazole for the rest of your pregnancy. Propylthiouracil may cause severe liver problems in pregnant women and may harm the fetus.
  • if you are having surgery, including dental surgery, tell the doctor or dentist that you are taking propylthiouracil.

What special dietary instructions should I follow?

Unless your doctor tells you otherwise, continue your normal diet.

What should I do if I forget a dose?

Take the missed dose as soon as you remember it. However, if it is almost time for the next dose, skip the missed dose and continue your regular dosing schedule. Do not take a double dose to make up for a missed one.

FAQ

◈ What is propylthiouracil?

Propylthiouracil (PTU) is an antithyroid medication used to treat hyperthyroidism (too much or overactive thyroid) and Graves’ disease (a common cause of hyperthyroidism). This medication lowers the amount of thyroid hormone that the thyroid gland makes. One brand name for PTU medication is Propycil ®.

◈ I take PTU. Can it make it harder for me to get pregnant?

Studies have not been done to see if PTU could make it harder for a woman to get pregnant. Untreated thyroid disorders may make it harder to get pregnant.

◈ I just found out I am pregnant. Should I stop taking PTU?

Talk with your healthcare provider(s) before making any changes to this medication. It is important to make sure any medical conditions you have are treated appropriately, especially during pregnancy. Hyperthyroidism can increase the chance of poor outcomes for the pregnancy including miscarriage, preterm delivery, low birth weight, thyroid storm (life-threatening overactive thyroid), and maternal congestive heart failure.

◈ Does taking PTU increase the chance for miscarriage?

Miscarriage can occur in any pregnancy. Two studies did not find a higher chance of miscarriage when using PTU during pregnancy. Hyperthyroidism has been associated with an increase in the chance for miscarriage.

◈ Does taking PTU increase the chance of birth defects?

In every pregnancy, there is a 3-5% chance of having a baby with a birth defect. This is called the background risk.Studies do not agree if hyperthyroidism itself can increase birth defects. Studies also do not agree if PTU alone can increase birth defects. Some studies suggest there could be a small increase in birth defects of around 2% or less. There has not been a confirmed pattern of birth defects to more strongly suggest cause from PTU exposure alone. Additionally, other studies show no increased chance for birth defects. The FDA and ACOG have noted that PTU may be the preferred treatment for hyperthyroidism during the first trimester of pregnancy.In summary, although studies do not agree, there is not strong evidence to say PTU clearly increases birth defects. You and your healthcare team will decide what is best for your specific situation.

◈ Could taking PTU cause other pregnancy complications?

Hyperthyroidism has been found to increase the chance for pregnancy complications like preterm delivery (delivery before week 37) and low birth weight (less than 2lb 3oz). One study did not find a higher chance of preterm delivery when PTU was used during pregnancy. It is not clear if PTU is associated with low birth weight because studies do not agree.Antithyroid medications, like PTU, or having Graves disease, can lead to too low or too high thyroid levels in a baby. If you take PTU, or if you have Grave’s disease, your baby’s thyroid level should be checked after delivery.The FDA has reported that PTU can cause serious liver damage in persons who take PTU including people who are pregnant. You and your healthcare team will decide what is best for your specific situation.

◈ Does taking PTU in pregnancy cause long-term problems in behavior or learning for the baby?

Two studies looking at 44 children (from preschool to adult ages) whose parents took PTU during pregnancy found no difference in intelligence scores compared to their unexposed brothers or sisters. Untreated hyperthyroidism in pregnancy can increase the chance of learning problems in children.

◈ Can I breastfeed while taking PTU?

PTU gets into breastmilk in small amounts, which means the amounts ingested by the infant are small. The American Thyroid Association has suggested that if PTU is taken while breastfeeding, doses of PTU should be limited to 450 mg per day due to the lack of research on the chance of liver damage in breastfed infants. No adverse effects have been reported in babies whose mothers used PTU while breastfeeding. Studies show that PTU does not significantly affect breastfed infants’ thyroid function. If you are worried about any symptoms that the baby has, contact the child’s healthcare provider.PTU has not been shown to affect milk production. Untreated hyperthyroidism and hypothyroidism may affect milk production. Be sure to talk to your healthcare provider about all of your breastfeeding questions.

◈ I take PTU. Can it make it harder for me to get my partner pregnant or increase the chance of birth defects?

Studies have not looked at the chance of fertility effects or birth defects if a father takes PTU. In general, exposures that fathers or sperm donors have are unlikely to increase the risks to a pregnancy. For more information, please see the MotherToBaby fact sheet Paternal Exposures at https://mothertobaby.org/fact-sheets/paternal-exposures-pregnancy/.

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    4(1H)-Pyrimidinone, 2,3-dihydro-6-propyl-2-thioxo-

    https://spectrabase.com/spectrum/4nRnUwyLbe4

  45. NIST Mass Spectrometry Data Center
    LICENSE
    Data covered by the Standard Reference Data Act of 1968 as amended.

    https://www.nist.gov/srd/public-law

    6-Propyl-2-thiouracil

    http://www.nist.gov/srd/nist1a.cfm

  46. International Agency for Research on Cancer (IARC)
    https://publications.iarc.fr/Terms-Of-Use
    IARC Classification

    https://www.iarc.fr/

  47. Japan Chemical Substance Dictionary (Nikkaji)
  48. KEGG
    https://www.kegg.jp/kegg/legal.html
    Therapeutic category of drugs in Japan

    http://www.genome.jp/kegg-bin/get_htext?br08301.keg

    Anatomical Therapeutic Chemical (ATC) classification

    http://www.genome.jp/kegg-bin/get_htext?br08303.keg

    Target-based classification of drugs

    http://www.genome.jp/kegg-bin/get_htext?br08310.keg

    Drugs listed in the Japanese Pharmacopoeia

    http://www.genome.jp/kegg-bin/get_htext?br08311.keg

  49. MassBank of North America (MoNA)
    https://mona.fiehnlab.ucdavis.edu/documentation/license
  50. Metabolomics Workbench
  51. NLM RxNorm Terminology
    https://www.nlm.nih.gov/research/umls/rxnorm/docs/termsofservice.html
  52. WHO Anatomical Therapeutic Chemical (ATC) Classification
    https://www.whocc.no/copyright_disclaimer/
  53. Pharos
    https://pharos.nih.gov/about
  54. Protein Data Bank in Europe (PDBe)
  55. PubChem
  56. RCSB Protein Data Bank (RCSB PDB)
    https://www.rcsb.org/pages/policies
  57. Springer Nature
  58. The Cambridge Structural Database
  59. Thieme Chemistry
    https://creativecommons.org/licenses/by-nc-nd/4.0/
  60. WHO Model Lists of Essential Medicines
    https://www.who.int/about/who-we-are/publishing-policies/copyright
  61. Wikidata
    LICENSE
    CCZero

    https://creativecommons.org/publicdomain/zero/1.0/

  62. Wikipedia
  63. Wiley
  64. Medical Subject Headings (MeSH)
    https://www.nlm.nih.gov/copyright.html
  65. UN Globally Harmonized System of Classification and Labelling of Chemicals (GHS)
  66. CAMEO Chemicals
    https://cameochemicals.noaa.gov/help/reference/terms_and_conditions.htm?d_f=false
    CAMEO Chemical Reactivity Classification

    https://cameochemicals.noaa.gov/browse/react

  67. EPA Substance Registry Services
    LICENSE

    https://www.epa.gov/privacy/privacy-act-laws-policies-and-resources

  68. PATENTSCOPE (WIPO)
  69. NCBI

References