Cimetidine
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Pronunciation | /sᵻˈmɛtᵻdiːn/ or /saɪˈmɛtᵻdiːn/ |
Trade names | Tagamet |
AHFS/Drugs.com | Monograph |
MedlinePlus | a682256 |
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Oral, parenteral |
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Pharmacokinetic data | |
Bioavailability | 60–70% |
Protein binding | 15–20% |
Metabolism | Hepatic |
Onset of action | 30 minutes[1] |
Biological half-life | 2 hours[1] |
Duration of action | 4–5 hours[1] |
Excretion | Renal |
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Synonyms | cimetidine hydrochloride SKF-92334[2] |
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ECHA InfoCard | 100.052.012 |
Chemical and physical data | |
Formula | C10H16N6S |
Molar mass | 252.34 g/mol |
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Cimetidine, sold under the brand name Tagamet among others, is a histamine H2 receptor antagonist that inhibits stomach acid production.[2][3][4] It is available over-the-counter and is mainly used in the treatment of heartburn and peptic ulcers.[2][4][5]
The development of longer-acting H2 receptor antagonists with fewer drug interactions and adverse effects, such as ranitidine and famotidine, decreased the use of cimetidine, and though it is still used, cimetidine is no longer among the more widely used of the H2-receptor antagonists.[citation needed]
Cimetidine was discovered in 1971 and came into commercial use in 1977.[6][7] Cimetidine was approved in the United Kingdom in 1976, and was approved in the United States by the Food and Drug Administration for prescriptions in 1979.[citation needed]
Contents
Medical uses[edit]
Other uses[edit]
Some evidence suggests cimetidine could be effective in the treatment of common warts, but more rigorous double-blind clinical trials found it to be no more effective than a placebo.[8][9][10]
Another study used cimetidine for the treatment of chronic calcific tendinitis of the shoulder.[11] The small-scale study took 16 individuals with calcific tendinitis in one shoulder, all of which had previously attempted other forms of therapy, including steroid injection and arthroscopic lavage. During the course of the study, 10 patients reported an elimination of pain and nine displayed a complete disappearance of calcium deposits. With results being on a small scale, cimetidine, for the treatment of chronic calcific tendinitis of the shoulder, has been recommended to be opened to large-scale clinical trials.[12]
Tentative evidence supports a beneficial role as add on therapy in colorectal cancer.[13]
Side effects[edit]
Reported side effects of cimetidine include diarrhea, rashes, dizziness, fatigue, constipation, and muscle pain, all of which are usually mild and transient.[14] It has been reported that mental confusion may occur in the elderly.[14] Because of its hormonal effects, cimetidine rarely may cause sexual dysfunction including loss of libido and erectile dysfunction and gynecomastia (0.1–0.2%) in males during long-term treatment.[14][15][16] Rarely, interstitial nephritis, urticaria, and angioedema have been reported with cimetidine treatment.[14] Cimetidine is also commonly associated with transient raised aminotransferase activity; hepatotoxicity is rare.[17]
Overdose[edit]
Cimetidine appears to be very safe in overdose, producing no symptoms even with massive overdoses (e.g., 20 g).[18]
Interactions[edit]
- Cimetidine affects the metabolism of methadone, sometimes resulting in higher blood levels and a higher incidence of side effects, and may interact with the antimalarial medication hydroxychloroquine.[19] Cimetidine is also known to potentiate the effects of several opioids, including oxycodone and tramadol, which are partially metabolized via the cytochrome P450 pathway, by inhibiting their metabolism and a temporary decrease of liver function due to reduced hepatic blood flow. This, in some cases, can lead to extreme plasma levels of these drugs and can easily lead to a fatal overdose.[20]
- Cimetidine can also interact with a number of psychoactive medications, including tricyclic antidepressants and selective serotonin reuptake inhibitors, causing increased blood levels of these drugs and the potential of subsequent toxicity.[citation needed]
- Following administration of cimetidine, the half-life and area-under-curve of zolmitriptan and its active metabolites were roughly doubled.[21]
- Cimetidine is a potent inhibitor of tubular creatinine secretion. Creatinine is a metabolic byproduct of creatine breakdown. Accumulation of creatinine is associated with uremia, but the symptoms of creatinine accumulation are unknown, as they are hard to separate from other nitrogenous waste buildups.[22]
- Like several other medications, the most obvious being erythromycin, cimetidine interferes with the body's metabolization of sildenafil, causing its strength and duration to increase (therefore also its side effects to be more likely and prominent).[citation needed]
- Clinically significant drug interactions with the CYP1A2 substrate theophylline, the CYP2C9 substrate tolbutamide, the CYP2D6 substrate desipramine, and the CYP3A4 substrate triazolam have all been demonstrated with cimetidine, and interactions with other substrates of these enzymes are likely as well.[23]
- Cimetidine has been shown clinically to reduce the clearance of mirtazapine, imipramine, timolol, nebivolol, sparteine, loratadine, nortriptyline, gabapentin, and desipramine in humans.[24]
- Cimetidine inhibits the renal excretion of metformin and procainamide, resulting in increased circulating levels of these drugs.[14]
- Interactions of potential clinical importance with cimetidine include warfarin, theophylline, phenytoin, carbamazepine, pethidine and other opioid analgesics, tricyclic antidepressants, lidocaine, terfenadine, amiodarone, flecainide, quinidine, fluorouracil, and benzodiazepines.[14][25]
- Cimetidine may decrease the effects of CYP2D6 substrates that are prodrugs, such as codeine, tramadol, and tamoxifen.[26]
- Cimetidine reduces the absorption of ketoconazole and itraconazole (which require a low pH).[14]
- Cimetidine has a theoretical but unproven benefit in paracetamol toxicity.[17] This is because N-acetyl-p-benzoquinone imine (NAPQI), a metabolite of paracetamol (acetaminophen) that is responsible for its hepatotoxicity, is formed from it by the cytochrome P450 system (specifically, CYP1A2, CYP2E1, and CYP3A4).[27]
- Numerous other drug interactions.
Pharmacology[edit]
H2 receptor antagonist[edit]
Cimetidine's mechanism of action as an antacid is as a histamine H2 receptor antagonist.[28]
Metabolism[edit]
Cimetidine is S-oxygenated by human flavin-containing monooxygenases, specifically FMO1 and FMO3.[29]
Cytochrome P450 inhibitor[edit]
Cimetidine is a potent cytochrome P450 (CYP450) enzyme inhibitor.[18] It is not a universal inhibitor of the CYP450 oxidative system,[30] but it inhibits a broad array of CYP450 isoforms, including CYP1A2, CYP2C9, CYP2C19, CYP2D6, CYP2E1, and CYP3A4.[18][30][31] The drug is said to be most potent in inhibiting CYP1A2, CYP2D6, and CYP3A4,[32] of which it is described as a moderate inhibitor,[1] and this is notable as these three isoenzymes are involved in the majority of CYP450-mediated drug biotransformations;[33] also, CYP1A2, CYP2C9, CYP2C19, CYP2D6, CYP2E1, and CYP3A4 have been identified as involved in the oxidative metabolism of most commonly used drugs.[34] As such, cimetidine has the potential for a large number of drug interactions.[18][30][31] Cimetidine is reported to be a competitive, reversible inhibitor of the CYP450 enzymes similarly to certain other inhibitors like azole antifungals and quinidine,[17][25][30][35] although mechanism-based (suicide), irreversible inhibition has also been identified for at least CYP2D6.[24] It reversibly inhibits CYP450 enzymes by binding directly with the complexed heme-iron of the active site via one of its imidazole ring nitrogen atoms, thereby blocking the oxidation of other drugs.[30][35][36] The article controdicts itself. "It states it potentates the drug Tramadol but by the same article, it states it inhibits the metabolism of the prodrug Tramadol. So which is it? "Cimetidine may decrease the effects of CYP2D6 substrates that are prodrugs, such as codeine, tramadol, and tamoxifen.[26]"
Antiandrogen and estrogen potentiator[edit]
Cimetidine has been found to possess clinically significant albeit weak antiandrogen activity at high doses.[28][37][38][39] It has been found to directly and competitively displace testosterone and dihydrotestosterone (DHT) and antagonize the androgen receptor (AR) in animals.[40][41] In addition, cimetidine has been found to inhibit 2-hydroxylation of estradiol (via inhibition of CYP450 enzymes, which are involved in the metabolic inactivation of estradiol), resulting in increased levels of estrogen.[42][43][44][45][46][47] By increasing estrogen levels, cimetidine can also decrease testosterone and increase prolactin levels.[48] In accordance with these antiandrogen and estrogenic activities, cimetidine has been found to be effective in small clinical trials for the treatment of acne and androgenic alopecia,[49][50] though not in hirsutism[37] or in sex hormone-associated cancers such as breast and prostate cancer.[51][52] Also, these activities likely explain certain side effects that are sometimes seen with the chronic administration of cimetidine, such as galactorrhea and amenorrhea in women and gynecomastia and impotence in men.[39][39][53]
History[edit]
Cimetidine, approved by the FDA for inhibition of gastric acid secretion, has been advocated for a number of dermatological diseases.[54] Cimetidine was the prototypical histamine H2 receptor antagonist from which the later members of the class were developed. Cimetidine was the culmination of a project at Smith, Kline and French (SK&F; now GlaxoSmithKline) by James W. Black, C. Robin Ganellin, and others to develop a histamine receptor antagonist to suppress stomach acid secretion.[55] This was one of the first drugs discovered using a rational drug design approach. Sir James W. Black shared the 1988 Nobel Prize in Physiology or Medicine for the discovery of propranolol and also is credited for the discovery of cimetidine.
At the time (1964), histamine was known to stimulate the secretion of stomach acid, but also that traditional antihistamines had no effect on acid production. In the process, the SK&F scientists also proved the existence of histamine H2 receptors.
The SK&F team used a rational drug-design structure starting from the structure of histamine — the only design lead, since nothing was known of the then hypothetical H2 receptor. Hundreds of modified compounds were synthesized in an effort to develop a model of the receptor. The first breakthrough was Nα-guanylhistamine, a partial H2 receptor antagonist. From this lead, the receptor model was further refined and eventually led to the development of burimamide, the first H2 receptor antagonist. Burimamide, a specific competitive antagonist at the H2 receptor, 100 times more potent than Nα-guanylhistamine, proved the existence of the H2 receptor.
Burimamide was still insufficiently potent for oral administration, and further modification of the structure, based on modifying the pKa of the compound, led to the development of metiamide. Metiamide was an effective agent; it was associated, however, with unacceptable nephrotoxicity and agranulocytosis.[55] The toxicity was proposed to arise from the thiourea group, and similar guanidine analogues were investigated until the ultimate discovery of cimetidine. The compound was synthesized in 1972 and evaluated for toxicology by 1973. It passed all trials.
Cimetidine was first marketed in the United Kingdom in 1976, and in the U.S. in August 1977; therefore, it took 12 years from initiation of the H2 receptor antagonist program to commercialization. By 1979, Tagamet was being sold in more than 100 countries and became the top-selling prescription product in the U.S., Canada, and several other countries. In November 1997, the American Chemical Society and the Royal Society of Chemistry in the U.K. jointly recognized the work as a milestone in drug discovery by designating it an International Historic Chemical Landmark during a ceremony at SmithKline Beecham's New Frontiers Science Park research facilities in Harlow, England.[56]
The commercial name "Tagamet" was decided upon by fusing the two words "antagonist" and "cimetidine".[55] Subsequent to the introduction onto the U.S. drug market, two other H2 receptor antagonists were approved, ranitidine (Zantac, Glaxo Labs) and famotidine (Pepcid, Yamanouchi, Ltd.) Cimetidine became the first drug ever to reach more than $1 billion a year in sales, thus making it the first blockbuster drug.[57]
In a deal expected to take effect in 2012, GlaxoSmithKline sold Tagamet and 16 other brands to Prestige Brands.[58]
Tagamet has now been largely replaced by the proton pump inhibitors for treating peptic ulcers, but is now available as an over-the-counter medicine for heartburn in many countries.[56]
References[edit]
- ^ a b c d Vallerand AH, Sanoski CA, Deglin JH (25 May 2016). Davis's Drug Guide for Nurses. F.A. Davis. pp. 636–. ISBN 978-0-8036-5779-3.
- ^ a b c Elks J (14 November 2014). The Dictionary of Drugs: Chemical Data: Chemical Data, Structures and Bibliographies. Springer. pp. 275–. ISBN 978-1-4757-2085-3.
- ^ Index Nominum 2000: International Drug Directory. Taylor & Francis. January 2000. pp. 234–. ISBN 978-3-88763-075-1.
- ^ a b Morton I, Morton IK, Hall JM (31 October 1999). Concise Dictionary of Pharmacological Agents: Properties and Synonyms. Springer Science & Business Media. pp. 77–. ISBN 978-0-7514-0499-9.
- ^ Burchum J, Rosenthal L (2 December 2014). Lehne's Pharmacology for Nursing Care. Elsevier Health Sciences. pp. 952–. ISBN 978-0-323-34026-7.
- ^ Fischer J, Ganellin CR (24 August 2010). Analogue-based Drug Discovery II. John Wiley & Sons. p. 4. ISBN 978-3-527-63212-1.
- ^ Fischer, Janos; Ganellin, C. Robin (2006). Analogue-based Drug Discovery. John Wiley & Sons. p. 444. ISBN 9783527607495.
- ^ Fit KE, Williams PC (July 2007). "Use of histamine2-antagonists for the treatment of verruca vulgaris". The Annals of Pharmacotherapy. 41 (7): 1222–6. doi:10.1345/aph.1H616. PMID 17535844.
- ^ Glass AT, Solomon BA (June 1996). "Cimetidine therapy for recalcitrant warts in adults". Archives of Dermatology. 132 (6): 680–2. doi:10.1001/archderm.1996.03890300108014. PMID 8651718.
- ^ Karabulut AA, Sahin S, Ekşioglu M (April 1997). "Is cimetidine effective for nongenital warts: a double-blind, placebo-controlled study". Archives of Dermatology. 133 (4): 533–4. doi:10.1001/archderm.133.4.533. PMID 9126017.
- ^ Yokoyama M, Aono H, Takeda A, Morita K (2003). "Cimetidine for chronic calcifying tendinitis of the shoulder". Regional Anesthesia and Pain Medicine. 28 (3): 248–52. doi:10.1053/rapm.2003.50048. PMID 12772145.
- ^ "Musculoskeletal Pain". Archived from the original on 2 October 2008. Retrieved 2008-10-22.
- ^ Deva S, Jameson M (15 August 2012). "Histamine type 2 receptor antagonists as adjuvant treatment for resected colorectal cancer". The Cochrane Database of Systematic Reviews. 8 (8): CD007814. doi:10.1002/14651858.CD007814.pub2. PMID 22895966.
- ^ a b c d e f g Ritter J, Lewis L, Mant T, Ferro A (25 April 2008). A Textbook of Clinical Pharmacology and Therapeutics (5 ed.). CRC Press. pp. 250–. ISBN 978-1-4441-1300-6.
- ^ Sawyer D, Conner CS, Scalley R (February 1981). "Cimetidine: adverse reactions and acute toxicity". American Journal of Hospital Pharmacy. 38 (2): 188–97. PMID 7011006.
- ^ Sabesin SM (1993). "Safety issues relating to long-term treatment with histamine H2-receptor antagonists". Alimentary Pharmacology & Therapeutics. 7 Suppl 2: 35–40. doi:10.1111/j.1365-2036.1993.tb00597.x. PMID 8103374.
- ^ a b c Kelly D (26 January 2009). Diseases of the Liver and Biliary System in Children. John Wiley & Sons. pp. 224–. ISBN 978-1-4443-0054-3.
- ^ a b c d Dart RC (2004). Medical Toxicology. Lippincott Williams & Wilkins. pp. 402–. ISBN 978-0-7817-2845-4.
- ^ Furst DE (June 1996). "Pharmacokinetics of hydroxychloroquine and chloroquine during treatment of rheumatic diseases". Lupus. 5 Suppl 1: S11–5. doi:10.1177/096120339600500104. PMID 8803904.
- ^ Sorkin EM, Darvey DL (February 1983). "Review of cimetidine drug interactions". Drug Intelligence & Clinical Pharmacy. 17 (2): 110–20. PMID 6130930.
- ^ See complete drug interactions for Zomig (zolmitriptan succinate used for migraine relief) in package insert: "Highlights of Zomig Prescribing Information" (PDF). AstraZeneca.
- ^ Urakami Y, Kimura N, Okuda M, Masuda S, Katsura T, Inui K (June 2005). "Transcellular transport of creatinine in renal tubular epithelial cell line LLC-PK1". Drug Metabolism and Pharmacokinetics. 20 (3): 200–5. doi:10.2133/dmpk.20.200. PMID 15988122.
- ^ Rodrigues AD (8 February 2008). Drug-Drug Interactions, Second Edition. CRC Press. pp. 277, 294. ISBN 978-0-8493-7594-1.
- ^ a b Shufeng Zhou (6 April 2016). Cytochrome P450 2D6: Structure, Function, Regulation and Polymorphism. CRC Press. pp. 299–. ISBN 978-1-4665-9788-4.
- ^ a b Rosenfeld GC, Loose DS (2007). Pharmacology. Lippincott Williams & Wilkins. pp. 202–. ISBN 978-0-7817-8074-2.
- ^ Fuller MA, Sajatovic M (2005). Drug Information Handbook for Psychiatry. Lexi-Comp. p. 285.
- ^ Cameron R, Feuer G, de la Iglesias F (6 December 2012). Drug-Induced Hepatotoxicity. Springer Science & Business Media. pp. 140–. ISBN 978-3-642-61013-4.
- ^ a b Richards DA (1983). "Comparative pharmacodynamics and pharmacokinetics of cimetidine and ranitidine". Journal of Clinical Gastroenterology. 5 Suppl 1: 81–90. doi:10.1097/00004836-198312001-00008. PMID 6317740.
- ^ Cashman JR (September 2000). "Human flavin-containing monooxygenase: substrate specificity and role in drug metabolism". Curr. Drug Metab. 1 (2): 181–191. doi:10.2174/1389200003339135. PMID 11465082.
Human FMO3 N-oxygenates primary, secondary and tertiary amines whereas human FMO1 is only highly efficient at N-oxygenating tertiary amines. Both human FMO1 and FMO3 S-oxygenate a number of nucleophilic sulfur-containing substrates and in some cases, does so with great stereoselectivity. ... For amines with smaller aromatic substituents such as phenethylamines, often these compounds are efficiently N-oxygenated by human FMO3. ... (S)-Nicotine N-1'-oxide formation can also be used as a highly stereoselective probe of human FMO3 function for adult humans that smoke cigarettes. Finally, cimetidine S-oxygenation or ranitidine N-oxidation can also be used as a functional probe of human FMO3. With the recent observation of human FMO3 genetic polymorphism and poor metabolism phenotype in certain human populations, variant human FMO3 may contribute to adverse drug reactions or exaggerated clinical response to certain medications.
- ^ a b c d e Lemke TL, Williams DA (2008). Foye's Principles of Medicinal Chemistry. Lippincott Williams & Wilkins. pp. 273–. ISBN 978-0-7817-6879-5.
- ^ a b Karalliedde LD, Clarke SF, Collignon U, Karalliedde J (29 January 2010). Adverse Drug Interactions: A Handbook for Prescribers. CRC Press. pp. 633–. ISBN 978-0-340-92769-4.
- ^ Priskorn M, Larsen F, Segonzac A, Moulin M (1997). "Pharmacokinetic interaction study of citalopram and cimetidine in healthy subjects". European Journal of Clinical Pharmacology. 52 (3): 241–2. doi:10.1007/s002280050282. PMID 9218934.
- ^ Martínez C, Albet C, Agúndez JA, Herrero E, Carrillo JA, Márquez M, Benítez J, Ortiz JA (April 1999). "Comparative in vitro and in vivo inhibition of cytochrome P450 CYP1A2, CYP2D6, and CYP3A by H2-receptor antagonists". Clinical Pharmacology and Therapeutics. 65 (4): 369–76. doi:10.1016/S0009-9236(99)70129-3. PMID 10223772.
- ^ Delafuente JC (November 2003). "Understanding and preventing drug interactions in elderly patients". Critical Reviews in Oncology/Hematology. 48 (2): 133–43. doi:10.1016/j.critrevonc.2003.04.004. PMID 14607376.
- ^ a b Cairns D (2012). Essentials of Pharmaceutical Chemistry. Pharmaceutical Press. pp. 110–. ISBN 978-0-85369-979-8.
Drugs interacting in this way with CYP450 include the histamine H2-receptor antagonist cimetidine, [...] Reversible inhibitors, such as cimetidine, which interact with the complexed iron at the active site of the enzyme to inhibit oxidation of other drugs. The inhibition occurs before any oxidation of the inhibitor occurs and is reversible once the inhibitor is removed.
- ^ Liska DJ (June 1998). "The detoxification enzyme systems". Alternative Medicine Review. 3 (3): 187–98. PMID 9630736.
Cimetidine is an example of a compound that can bind directly to the heme iron of the cytochrome P450 reactive site to inhibit aoll cytochrome-dependent Phase I enzyme activities.13
- ^ a b Becker KL (2001). Principles and Practice of Endocrinology and Metabolism. Lippincott Williams & Wilkins. pp. 1196–. ISBN 978-0-7817-1750-2.
- ^ Jensen RT, Collen MJ, McArthur KE, Howard JM, Maton PN, Cherner JA, Gardner JD (November 1984). "Comparison of the effectiveness of ranitidine and cimetidine in inhibiting acid secretion in patients with gastric hypersecretory states". The American Journal of Medicine. 77 (5B): 90–105. PMID 6150641.
- ^ a b c Biagi P, Milani G (March 1985). "[Dysfunction of the hypothalamo-hypophyseal-gonadal axis induced by histamine H2 antagonists. Review of the literature and personal observations]". Minerva Medica (in Italian). 76 (12): 579–86. PMID 3921876.
- ^ Winters SJ, Banks JL, Loriaux DL (March 1979). "Cimetidine is an antiandrogen in the rat". Gastroenterology. 76 (3): 504–8. PMID 428705.
- ^ Sivelle PC, Underwood AH, Jelly JA (March 1982). "The effects of histamine H2 receptor antagonists on androgen action in vivo and dihydrotestosterone binding to the rat prostate androgen receptor in vitro". Biochemical Pharmacology. 31 (5): 677–84. doi:10.1016/0006-2952(82)90449-X. PMID 6123322.
- ^ Galbraith RA, Michnovicz JJ (August 1989). "The effects of cimetidine on the oxidative metabolism of estradiol". The New England Journal of Medicine. 321 (5): 269–74. doi:10.1056/NEJM198908033210501. PMID 2747769.
- ^ Michnovicz JJ, Galbraith RA (February 1991). "Cimetidine inhibits catechol estrogen metabolism in women". Metabolism. 40 (2): 170–4. doi:10.1016/0026-0495(91)90169-W. PMID 1988774.
- ^ Pescovitz OH, Walvoord EC (6 June 2007). When Puberty is Precocious: Scientific and Clinical Aspects. Springer Science & Business Media. pp. 203–. ISBN 978-1-59745-499-5.
- ^ Cuhaci N, Polat SB, Evranos B, Ersoy R, Cakir B (March 2014). "Gynecomastia: Clinical evaluation and management". Indian Journal of Endocrinology and Metabolism. 18 (2): 150–8. doi:10.4103/2230-8210.129104. PMC 3987263
. PMID 24741509.
- ^ Rendic S, Di Carlo FJ (2010). "Human cytochrome P450 enzymes: a status report summarizing their reactions, substrates, inducers, and inhibitors". Drug Metabolism Reviews. 29 (1-2): 413–580. doi:10.3109/03602539709037591. PMID 9187528.
- ^ Galbraith RA, Michnovicz JJ (August 1989). "The effects of cimetidine on the oxidative metabolism of estradiol". The New England Journal of Medicine. 321 (5): 269–74. doi:10.1056/NEJM198908033210501. PMID 2747769.
- ^ Deepinder F, Braunstein GD (September 2012). "Drug-induced gynecomastia: an evidence-based review". Expert Opinion on Drug Safety. 11 (5): 779–95. doi:10.1517/14740338.2012.712109. PMID 22862307.
- ^ Hatwal A, Bhatt RP, Agrawal JK, Singh G, Bajpai HS (1988). "Spironolactone and cimetidine in treatment of acne". Acta Dermato-Venereologica. 68 (1): 84–7. PMID 2449021.
- ^ Aram H (March 1987). "Treatment of female androgenetic alopecia with cimetidine". International Journal of Dermatology. 26 (2): 128–30. doi:10.1111/j.1365-4362.1987.tb00546.x. PMID 3570585.
- ^ Golditch IM, Price VH (June 1990). "Treatment of hirsutism with cimetidine". Obstetrics and Gynecology. 75 (6): 911–3. PMID 2342735.
- ^ Rossing MA, Scholes D, Cushing-Haugen KL, Voigt LF (March 2000). "Cimetidine use and risk of prostate and breast cancer". Cancer Epidemiology, Biomarkers & Prevention. 9 (3): 319–23. PMID 10750671.
- ^ Funder JW, Mercer JE (February 1979). "Cimetidine, a histamine H2 receptor antagonist, occupies androgen receptors". The Journal of Clinical Endocrinology and Metabolism. 48 (2): 189–91. doi:10.1210/jcem-48-2-189. PMID 429472.
- ^ Scheinfeld N (March 2003). "Cimetidine: a review of the recent developments and reports in cutaneous medicine". Dermatology Online Journal. 9 (2): 4. PMID 12639457.
- ^ a b c "Tagamet®: Discovery of Histamine H2-receptor Antagonists". National Historic Chemical Landmarks. American Chemical Society. Retrieved June 25, 2012.
- ^ a b Fremantle M. "Tagamet". Chemical and Engineering news. Retrieved 1 July 2013.
- ^ Whitney J (February 2006). "Pharmaceutical Sales 101: Me-Too Drugs". Guernica. Retrieved 2008-07-31.
- ^ Ranii D (21 December 2011). "GSK sells BC, Goody's and other brands". News & Observer. Archived from the original on 2012-04-15.