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Cimetidine is a potent inhibitor of tubular creatinine secretion. Creatinine is a metabolic byproduct of creatinine breakdown. Accumulation of creatinine is associated with uremia. The symptoms of puts creatinine accumulation are unknown, as they are hard to separate from other nitrogenous waste buildups.<ref>Transcellular Transport of Creatinine in Renal Tubular Epithelial Cell Line LLC-PK1. Drug Metab. Pharmacokinet. 20(3): 200-205 (2005)</ref>
Cimetidine is a potent inhibitor of tubular creatinine secretion. Creatinine is a metabolic byproduct of creatinine breakdown. Accumulation of creatinine is associated with uremia. The symptoms of puts creatinine accumulation are unknown, as they are hard to separate from other nitrogenous waste buildups.<ref>Transcellular Transport of Creatinine in Renal Tubular Epithelial Cell Line LLC-PK1. Drug Metab. Pharmacokinet. 20(3): 200-205 (2005)</ref>


== References ==
==Pharmacology==
Cimetidine's [[mechanism of action]] is as an [[H2 receptor|H<sub>2</sub> receptor]] [[receptor antagonist|antagonist]].<ref name="pmid6317740">{{cite journal | author = Richards DA | title = Comparative pharmacodynamics and pharmacokinetics of cimetidine and ranitidine | journal = Journal of Clinical Gastroenterology | volume = 5 Suppl 1 | issue = | pages = 81–90 | year = 1983 | pmid = 6317740 | doi = | url = }}</ref>
{{reflist}}

Cimetidine has also been found to possess clinically significant [[anti-androgen]] properties at high doses that are especially noticeable in men.<ref name="pmid6317740" /><ref name="pmid6150641">{{cite journal | author = Jensen RT, Collen MJ, McArthur KE, ''et al.'' | title = Comparison of the effectiveness of ranitidine and cimetidine in inhibiting acid secretion in patients with gastric hypersecretory states | journal = The American Journal of Medicine | volume = 77 | issue = 5B | pages = 90–105 | year = 1984 | month = November | pmid = 6150641 | doi = | url = }}</ref><ref name="pmid3921876">{{cite journal | author = Biagi P, Milani G | title = [Dysfunction of the hypothalamo-hypophyseal-gonadal axis induced by histamine H2 antagonists. Review of the literature and personal observations] | language = Italian | journal = Minerva Medica | volume = 76 | issue = 12 | pages = 579–86 | year = 1985 | month = March | pmid = 3921876 | doi = | url = }}</ref> It directly antagonizes the binding of [[testosterone]] and [[dihydrotestosterone|DHT]] to the [[androgen receptor]].<ref name="pmid428705">{{cite journal | author = Winters SJ, Banks JL, Loriaux DL | title = Cimetidine is an antiandrogen in the rat | journal = Gastroenterology | volume = 76 | issue = 3 | pages = 504–8 | year = 1979 | month = March | pmid = 428705 | doi = | url = }}</ref><ref name="pmid6123322">{{cite journal | author = Sivelle PC, Underwood AH, Jelly JA | title = The effects of histamine H2 receptor antagonists on androgen action in vivo and dihydrotestosterone binding to the rat prostate androgen receptor in vitro | journal = Biochemical Pharmacology | volume = 31 | issue = 5 | pages = 677–84 | year = 1982 | month = March | pmid = 6123322 | doi = | url = http://linkinghub.elsevier.com/retrieve/pii/0006-2952(82)90449-X}}</ref> In addition, it interferes with the [[metabolism]] of [[estrogen]] and increases its serum concentrations.<ref name="pmid2747769">{{cite journal | author = Galbraith RA, Michnovicz JJ | title = The effects of cimetidine on the oxidative metabolism of estradiol | journal = The New England Journal of Medicine | volume = 321 | issue = 5 | pages = 269–74 | year = 1989 | month = August | pmid = 2747769 | doi = 10.1056/NEJM198908033210501 | url = http://www.nejm.org/doi/abs/10.1056/NEJM198908033210501?url_ver=Z39.88-2003&rfr_id=ori:rid:crossref.org&rfr_dat=cr_pub%3dpubmed}}</ref> Accordingly, cimetidine has been found to be effective in small [[clinical trial]]s the treatment of [[acne]] and [[androgenic alopecia]],<ref name="pmid2449021">{{cite journal | author = Hatwal A, Bhatt RP, Agrawal JK, Singh G, Bajpai HS | title = Spironolactone and cimetidine in treatment of acne | journal = Acta Dermato-venereologica | volume = 68 | issue = 1 | pages = 84–7 | year = 1988 | pmid = 2449021 | doi = | url = }}</ref><ref name="pmid3570585">{{cite journal | author = Aram H | title = Treatment of female androgenetic alopecia with cimetidine | journal = International Journal of Dermatology | volume = 26 | issue = 2 | pages = 128–30 | year = 1987 | month = March | pmid = 3570585 | doi = | url = }}</ref> though not in [[hirsutism]] or in [[sex hormone]]-associated [[cancer]]s such as [[breast cancer|breast]] and [[prostate cancer]].<ref name="pmid2342735">{{cite journal | author = Golditch IM, Price VH | title = Treatment of hirsutism with cimetidine | journal = Obstetrics and Gynecology | volume = 75 | issue = 6 | pages = 911–3 | year = 1990 | month = June | pmid = 2342735 | doi = | url = }}</ref><ref name="pmid10750671">{{cite journal | author = Rossing MA, Scholes D, Cushing-Haugen KL, Voigt LF | title = Cimetidine use and risk of prostate and breast cancer | journal = Cancer Epidemiology, Biomarkers & Prevention : a Publication of the American Association for Cancer Research, Cosponsored by the American Society of Preventive Oncology | volume = 9 | issue = 3 | pages = 319–23 | year = 2000 | month = March | pmid = 10750671 | doi = | url = http://cebp.aacrjournals.org/cgi/pmidlookup?view=long&pmid=10750671}}</ref> Cimetidine's anti-androgen properties likely explain certain side effects seen with it such as [[galactorrhea]] and [[amenorrhea]] in women and [[gynecomastia]] and [[impotence]] in men.<ref name="pmid429472">{{cite journal | author = Funder JW, Mercer JE | title = Cimetidine, a histamine H2 receptor antagonist, occupies androgen receptors | journal = The Journal of Clinical Endocrinology and Metabolism | volume = 48 | issue = 2 | pages = 189–91 | year = 1979 | month = February | pmid = 429472 | doi = | url = http://jcem.endojournals.org/cgi/pmidlookup?view=long&pmid=429472}}</ref><ref name="pmid3921876">{{cite journal | author = Biagi P, Milani G | title = [Dysfunction of the hypothalamo-hypophyseal-gonadal axis induced by histamine H2 antagonists. Review of the literature and personal observations] | language = Italian | journal = Minerva Medica | volume = 76 | issue = 12 | pages = 579–86 | year = 1985 | month = March | pmid = 3921876 | doi = | url = }}</ref><ref name="pmid3921876">{{cite journal | author = Biagi P, Milani G | title = [Dysfunction of the hypothalamo-hypophyseal-gonadal axis induced by histamine H2 antagonists. Review of the literature and personal observations] | language = Italian | journal = Minerva Medica | volume = 76 | issue = 12 | pages = 579–86 | year = 1985 | month = March | pmid = 3921876 | doi = | url = }}</ref>

==References==
{{Reflist}}


==External links==
==External links==
Line 106: Line 111:
* [http://www.tagamethb.com/ Tagamet HB200]
* [http://www.tagamethb.com/ Tagamet HB200]


⚫
{{Histaminergics}}


{{H2-receptor antagonist}}
{{H2-receptor antagonist}}
⚫
{{Histaminergics}}
{{Androgenics}}



[[Category:Guanidines]]
[[Category:Guanidines]]

Revision as of 04:01, 15 May 2012

Cimetidine
Clinical data
Trade namesTagamet
AHFS/Drugs.comMonograph
MedlinePlusa682256
License data
Pregnancy
category
  • AU: B1
Routes of
administration		Oral, parenteral
ATC code
Legal status
Legal status
  • AU: S4 (Prescription only)
  • UK: POM (Prescription only)
  • OTC/℞-only (U.S., depending on dosage strength)
Pharmacokinetic data
Bioavailability60–70%
Protein binding15–20%
MetabolismHepatic
Elimination half-life2 hours
ExcretionRenal
Identifiers
  • 2-cyano- 1-methyl- 3-(2-[(5-methyl- 1H-imidazol- 4-yl)methylthio]ethyl)guanidine
CAS Number
PubChem CID
IUPHAR/BPS
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
CompTox Dashboard (EPA)
ECHA InfoCard100.052.012 Edit this at Wikidata
Chemical and physical data
FormulaC10H16N6S
Molar mass252.34 g/mol g·mol−1
3D model (JSmol)
  • N#CN\C(=N/C)NCCSCc1ncnc1C
  • InChI=1S/C10H16N6S/c1-8-9(16-7-15-8)5-17-4-3-13-10(12-2)14-6-11/h7H,3-5H2,1-2H3,(H,15,16)(H2,12,13,14) checkY
  • Key:AQIXAKUUQRKLND-UHFFFAOYSA-N checkY
  (verify)

Cimetidine INN (/[invalid input: 'icon']s[invalid input: 'ɨ']ˈmɛt[invalid input: 'ɨ']diːn/ or /saɪˈmɛt[invalid input: 'ɨ']diːn/) is a histamine H2-receptor antagonist that inhibits stomach acid production. It is largely used in the treatment of heartburn and peptic ulcers. It has been marketed by GlaxoSmithKline (which is selling the brand to Prestige Brands) under the trade name Tagamet (sometimes Tagamet HB or Tagamet HB200). Cimetidine was approved in the UK in 1976 and was approved in the US by the Food and Drug Administration for prescriptions starting January 1, 1979.

Clinical use

Main article: H2-receptor antagonist

History and development

Cimetidine, approved by the FDA for inhibition of gastric acid secretion, has been advocated for a number of dermatological diseases.[1] 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.[2] 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; actually, the medicinal chemists would have made the discovery.[3]

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 synthesised 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.[2] The toxicity was proposed to arise from the thiourea group, and similar guanidine-analogues were investigated until the ultimate discovery of cimetidine.

Cimetidine was first marketed in the United Kingdom in 1976; therefore, it took 12 years from initiation of the H2-receptor antagonist program to commercialization. The commercial name "Tagamet" was decided upon by fusing the two words "antagonist" and "cimetidine".[2] 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.[4]

In a deal expected to take effect in 2012, GlaxoSmithKline sold Tagamet and 16 other brands to Prestige Brands.[5]

Other uses

In some studies, cimetidine has been found to reduce the debilitating pain and symptoms of herpes zoster, presumably by blocking the H2-receptors of T-lymphocyte suppressor cells.[6]

A number of "open label" studies showed cimetidine was effective in the treatment of common warts, but more rigorous double-blind clinical trials suggested it to be no more effective than a placebo. However, the researchers in this study admit their results may not be sound, due to small sample size, and did not explore higher dosing options.[7]

Another study by Yokoyama, et al., used cimetidine for the treatment of chronic calcific tendinitis of the shoulder.[8] 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 9 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.[9]

In Asia, cimetidine, which molecularly targets EGF, VEGF and e-selectin associated with sialylated Lewis biomarkers and metastasis, has been combined with long term, continuous low dose 5FU[10] or metronomic tegafur-uracil chemotherapy for advanced epithelial cancers, with unusually long survival[11] including for stage III colorectal cancers,[12] as well as refractory and recurrent cancers.

Cimetidine has been reported for use as an analgesic in experimental treatments of interstitial cystitis.

Pretreatment with cimetidine improves the accuracy of measured creatinine clearance testing when using urine collection analysis.

Adverse effects and interactions

Cimetidine is a known inhibitor of many isozymes of the cytochrome P450 enzyme system[13] (specifically CYP1A2, CYP2C9, CYP2C19, CYP2D6, CYP2E1, and CYP3A4). This inhibition forms the basis of the numerous drug interactions that occur between cimetidine and other drugs. For example, cimetidine may decrease metabolism of some drugs, such as those used in hormonal contraception. Cimetidine interferes with metabolism of the hormone estrogen, enhancing estrogen activity. In women, this can lead to galactorrhea, whereas in men, gynecomastia has been reported;[14] during postmarketing surveillance in the 1980s, cases of male sexual dysfunction were also reported.[15][16] Cimetidine also 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.[17] Cimetidine is also known to Potentiator the effects of several opiods which are partially metabolized via the cytochrome P450 pathway via inhibiting their metabolism and a temporary decrease of liver function due to reduced hepatic blood flow. This can lead to extreme plasma levels of these drugs and can easily lead to a fatal overdose.[18]

It is also important to recognize that cimetidine can interact with a number of different psychoactive medications, including those in the classes of Tricyclic Antidepressants and Selective Serotonin Reuptake Inhibitors, causing increased blood levels of these drugs and subsequent toxicity.

The development of longer-acting H2-receptor antagonists with reduced adverse effects, such as ranitidine, proved to be the downfall of cimetidine and, though it is still used, it is no longer among the more widely used H2-receptor antagonists. Side effects can include dizziness, and more rarely, headache.

Following administration of cimetidine, the half-life and AUC of zolmitriptan and its active metabolites were approximately doubled (see CLINICAL PHARMACOLOGY). See complete drug interactions for Zomig (triptan succinate used for migraine relief) in package insert: http://www1.astrazeneca-us.com/pi/Zomig.pdf

Cimetidine is a potent inhibitor of tubular creatinine secretion. Creatinine is a metabolic byproduct of creatinine breakdown. Accumulation of creatinine is associated with uremia. The symptoms of puts creatinine accumulation are unknown, as they are hard to separate from other nitrogenous waste buildups.[19]

Pharmacology

Cimetidine's mechanism of action is as an H2 receptor antagonist.[20]

Cimetidine has also been found to possess clinically significant anti-androgen properties at high doses that are especially noticeable in men.[20][21][22] It directly antagonizes the binding of testosterone and DHT to the androgen receptor.[23][24] In addition, it interferes with the metabolism of estrogen and increases its serum concentrations.[25] Accordingly, cimetidine has been found to be effective in small clinical trials the treatment of acne and androgenic alopecia,[26][27] though not in hirsutism or in sex hormone-associated cancers such as breast and prostate cancer.[28][29] Cimetidine's anti-androgen properties likely explain certain side effects seen with it such as galactorrhea and amenorrhea in women and gynecomastia and impotence in men.[30][22][22]

References

  1. ^ Scheinfeld N (2003). "Cimetidine: a review of the recent developments and reports in cutaneous medicine". Dermatol. Online J. 9 (2): 4. PMID 12639457. {{cite journal}}: Unknown parameter |month= ignored (help)
  2. ^ a b c "Tagamet: A medicine that changed people's lives". American Chemical Society. 2004. Retrieved 2009-09-06.
  3. ^ Silverman, Richard A. (2004). The organic chemistry of drug design and drug action. Amsterdam: Elsevier Academic Press. p. 159. ISBN 0-12-643732-7.
  4. ^ Whitney, Jake (February 2006). "Pharmaceutical Sales 101: Me-Too Drugs". Guernica. Retrieved 2008-07-31.
  5. ^ Ranii, David (21 December 2011). "GSK sells BC, Goody's and other brands". News & Observer.
  6. ^ Faloon, William (March 2001). "Tagemet to Treat Herpes and Shingles". Life Extension Magazine. Retrieved 2009-03-05. {{cite news}}: Unknown parameter |coauthors= ignored (|author= suggested) (help)
  7. ^ Fit KE, Williams PC (2007). "Use of histamine2-antagonists for the treatment of verruca vulgaris". Ann Pharmacother. 41 (7): 1222–6. doi:10.1345/aph.1H616. PMID 17535844. {{cite journal}}: Unknown parameter |month= ignored (help)
  8. ^ Yokoyama M, Aono H, Takeda A, Morita K (2003). "Cimetidine for chronic calcifying tendinitis of the shoulder". Reg Anesth Pain Med. 28 (3): 248–52. doi:10.1053/rapm.2003.50048. PMID 12772145.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  9. ^ "Musculoskeletal Pain". Retrieved 2008-10-22. [dead link]
  10. ^ S Matsumoto, Y Imaeda, S Umemoto, K Kobayashi, H Suzuki1 and T Okamoto S (2002). doi=10.1038/sj.bjc.6600048 "Cimetidine increases survival of colorectal cancer patients with high levels of sialyl Lewis-X and sialyl Lewis-A epitope expression on tumour cells". British Journal of Cancer. 86 (1): 161–167. doi:10.1038/sj.bjc.6600048. PMC 2375187. PMID 11870500. {{cite journal}}: Check |url= value (help); Missing pipe in: |url= (help); Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link) CS1 maint: numeric names: authors list (link)
  11. ^ Matsumoto S, Hayashi A, Kobayashi K, Imaeda Y, Umemoto S (2004). "Cimetidine blocking of E-selectin expression inhibits sialyl Lewis-X-positive cancer cells from adhering to vascular endothelium". {{cite journal}}: Cite journal requires |journal= (help); Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
  12. ^ Matsumoto S, Imaeda Y, Umemoto S, Kobayashi K, Okamoto T (2002). "Cimetidine increases survival of colorectal cancer patients with high levels of sialyl Lewis-X and sialyl Lewis-A epitope expression on tumour cells". British Journal of Cancer. 86 (6): 161–167. doi:10.1038/sj.bjc.6600048. PMC 2375187. PMID 11870500. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
  13. ^ Levine M, Law EY, Bandiera SM, Chang TK, Bellward GD (1998). "In vivo cimetidine inhibits hepatic CYP2C6 and CYP2C11 but not CYP1A1 in adult male rats". The Journal of pharmacology and experimental therapeutics. 284 (2): 493–9. PMID 9454789. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
  14. ^ Michnovicz JJ, Galbraith RA (1991). "Cimetidine inhibits catechol estrogen metabolism in women". Metabolism: clinical and experimental. 40 (2): 170–4. doi:10.1016/0026-0495(91)90169-W. PMID 1988774. {{cite journal}}: Unknown parameter |month= ignored (help)
  15. ^ Sawyer D, Conner CS, Scalley R (1981). "Cimetidine: adverse reactions and acute toxicity". Am J Hosp Pharm. 38 (2): 188–97. PMID 7011006. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
  16. ^ Sabesin SM (1993). "Safety issues relating to long-term treatment with histamine H2-receptor antagonists". Aliment Pharmacol Ther. 7 Suppl 2: 35–40. PMID 8103374.
  17. ^ Furst DE (1996). "Pharmacokinetics of hydroxychloroquine and chloroquine during treatment of rheumatic diseases". Lupus. 5 Suppl 1: S11–5. doi:10.1177/096120339600500104. PMID 8803904. {{cite journal}}: Unknown parameter |month= ignored (help)
  18. ^ Sorkin, E.M. (1983-02-01). "Review of cimetidine drug interactions". Annals of Pharmacotherapy. 17 (2): 110–120. PMID 6130930. Retrieved 2012-04-28. {{cite journal}}: Unknown parameter |coauthors= ignored (|author= suggested) (help)
  19. ^ Transcellular Transport of Creatinine in Renal Tubular Epithelial Cell Line LLC-PK1. Drug Metab. Pharmacokinet. 20(3): 200-205 (2005)
  20. ^ a b Richards DA (1983). "Comparative pharmacodynamics and pharmacokinetics of cimetidine and ranitidine". Journal of Clinical Gastroenterology. 5 Suppl 1: 81–90. PMID 6317740.
  21. ^ Jensen RT, Collen MJ, McArthur KE; et al. (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. {{cite journal}}: Explicit use of et al. in: |author= (help); Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
  22. ^ a b c Biagi P, Milani G (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. {{cite journal}}: Unknown parameter |month= ignored (help)
  23. ^ Winters SJ, Banks JL, Loriaux DL (1979). "Cimetidine is an antiandrogen in the rat". Gastroenterology. 76 (3): 504–8. PMID 428705. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
  24. ^ Sivelle PC, Underwood AH, Jelly JA (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. PMID 6123322. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
  25. ^ Galbraith RA, Michnovicz JJ (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. {{cite journal}}: Unknown parameter |month= ignored (help)
  26. ^ 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.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  27. ^ Aram H (1987). "Treatment of female androgenetic alopecia with cimetidine". International Journal of Dermatology. 26 (2): 128–30. PMID 3570585. {{cite journal}}: Unknown parameter |month= ignored (help)
  28. ^ Golditch IM, Price VH (1990). "Treatment of hirsutism with cimetidine". Obstetrics and Gynecology. 75 (6): 911–3. PMID 2342735. {{cite journal}}: Unknown parameter |month= ignored (help)
  29. ^ Rossing MA, Scholes D, Cushing-Haugen KL, Voigt LF (2000). "Cimetidine use and risk of prostate and breast cancer". Cancer Epidemiology, Biomarkers & Prevention : a Publication of the American Association for Cancer Research, Cosponsored by the American Society of Preventive Oncology. 9 (3): 319–23. PMID 10750671. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
  30. ^ Funder JW, Mercer JE (1979). "Cimetidine, a histamine H2 receptor antagonist, occupies androgen receptors". The Journal of Clinical Endocrinology and Metabolism. 48 (2): 189–91. PMID 429472. {{cite journal}}: Unknown parameter |month= ignored (help)


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