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Lafutidine, a Newly Developed Antiulcer Drug, Elevates Postprandial Intragastric pH and Increases Plasma Calcitonin Gene-Related Peptide and Somatostatin Concentrations in Humans: Comparisons with Famotidine

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Abstract

Lafutidine, a newly developed histamine H2-receptor antagonist, inhibits daytime (i.e., postprandial) as well as nighttime gastric acid secretion in clinical studies. It also has gastroprotective activity that particularly affects mucosal blood flow in rats. This study focused on the efficacy of lafutidine on plasma concentrations of gastrointestinal peptides in humans. Six healthy male volunteers aged 23–32 years without Helicobacter pylori infection were orally administered either 10 mg lafutidine, 20 mg famotidine, or water only (control) 30 min after a standard meal (650 kcal). Plasma concentrations of lafutidine and famotidine were highest from 90 to 150 min after administration. Intragastric pH was elevated after both lafutidine and famotidine compared with the control. Plasma concentrations of calcitonin gene-related peptide (CGRP) and somatostatin were significantly increased after lafutidine at 60 and 90 min. We concluded that lafutidine increases plasma concentrations of CGRP and somatostatin in humans, which may result in inhibition of postprandial acid secretion and gastroprotective activity.

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References

  1. Bertaccini G, Scarpignato C: Histamine H2-antagonists modify gastric emptying in the rat. Br J Pharmacol 77:443–448, 1982

    CAS  PubMed  Google Scholar 

  2. Kounenis G, Voutsas D, Koutsoviti-Papadopoulou M, Elezoglou V: Inhibition of acetylcholinesterase by the H2-receptor antagonist nizatidine. J Pharmacobio-Dyn 11:767–771, 1988

    CAS  PubMed  Google Scholar 

  3. Ueki S, Seiki M, Yoneta T, Aita H, Chaki K, Hori Y, Morita H, Tagashira E, Itoh Z: Gastroprokinetic activity of nizatidine, a new H2-receptor antagonist, and its possible mechanism of action in dogs and rats. J Pharmacol Exp Ther 264:152–157, 1993

    CAS  PubMed  Google Scholar 

  4. Ueki S, Matsunaga Y, Yoneta T, Tamaki H, Itoh Z: Gastroprokinetic activity of nizatidine during the digestive state in the dog and rat. Arzneimittelforschung 49(II):618–625, 1999

    CAS  PubMed  Google Scholar 

  5. Adachi K, Ono M, Kawamura A, Yuki M, Fujishiro H, Kinoshita Y: Nizatidine and cisapride enhance salivary secretion in humans. Aliment Pharmacol Ther 16:297–301, 2002

    Article  CAS  PubMed  Google Scholar 

  6. Adachi K, Furuta K, Katsube T, Fujisawa T, Azumi T, Fujishiro H, Ishihara S, Amano Y, Kinoshita Y: Nizatidine and cisapride increase salivary secretion in rats. Dig Dis Sci 49:399–403, 2004

    Article  CAS  PubMed  Google Scholar 

  7. Takahashi S, Okabe S: A histamine H2 receptor antagonist, roxatidine, stimulates mucus secretion and synthesis by cultured rabbit gastric mucosal cells. J Physiol Pharmacol 46:503–511, 1995

    CAS  PubMed  Google Scholar 

  8. Ichikawa T, Ishihara K, Saigenji K, Hotta K: Structural requirements for roxatidine in the stimulant effect of rat gastric mucin synthesis and the participation of nitric oxide in this mechanism. Br J Pharmacol 122:1230–1236, 1997

    Article  CAS  PubMed  Google Scholar 

  9. Tarnawski A, Hollander D, Gergely H, Stachura J: Comparison of antacid, sucralfate, cimetidine, and ranitidine in protection of the gastric mucosa against ethanol injury. Am J Med 79:19–23, 1985

    Article  CAS  PubMed  Google Scholar 

  10. Shibata M, Yamaura T, Inaba N, Onodera S, Chida Y, Ohnishi H: Gastric antisecretory effect of FRG-8813, a new histamine H2 receptor antagonist, in rats and dogs. Eur J Pharmacol 235:245–253, 1993

    Article  CAS  PubMed  Google Scholar 

  11. Inaba N, Shibata M, Onodera S, Tanaka M, Suzuki T, Yamaura T, Ohnishi H: Studies on histamine H2-receptor antagonistic property of FRG-8813, a novel anti-ulcer drug. Folia Pharmacol Jpn (Nippon Yakurigaku Zasshi) 105:231–241, 1995

    CAS  Google Scholar 

  12. Saitoh T, Otsuka H, Hirakawa J, Ishikawa M, Takahashi H, Mori H, Ohkawa S: Lafutidine, a novel histamine H2-receptor antagonist, inhibits daytime acid secretion in both H. pylori infected and non-infected human subjects. J Gastroenterol Hepatol 17(Suppl):A828, 2002

    Google Scholar 

  13. Shimatani T, Inoue M, Kuroiwa T, Horikawa Y, Mieno H, Nakamura M: Effect of omeprazole 10 mg on intragastric pH in three different CYP2C19 genotypes, compared with omeprazole 20 mg and lafutidine 20 mg, a new H2-receptor antagonist. Aliment Pharmacol Ther 18:1149–1157, 2003

    Article  CAS  PubMed  Google Scholar 

  14. Onodera S, Shibata M, Tanaka M, Inaba N, Arai Y, Aoyama M, Lee B, Yamaura T: Gastroprotective mechanism of lafutidine, a novel anti-ulcer drug with histamine H2-receptor antagonistic activity. Arzneimittelforschung 49:519–626, 1999

    CAS  PubMed  Google Scholar 

  15. Onodera S, Tanaka M, Aoyama M, Arai Y, Inaba N, Suzuki T, Nishizawa A, Shibata M, Sekine Y: Antiulcer effect of lafutidine on indomethacin-induced gastric antral ulcers in refed rats. Jpn J Pharmacol 80:229–235, 1999

    Article  CAS  PubMed  Google Scholar 

  16. Umeda M, Fujita A, Nishiwaki H, Takeuchi K: Effect of lafutidine, a novel histamine H2-receptor antagonist, on monochloramine-induced gastric lesions in rats: role of capsaicin–sensitive sensory neurons. J Gastroenterol Hepatol 14:859–865, 1999

    Article  CAS  PubMed  Google Scholar 

  17. Sato H, Kawashima K, Yuki M, Kazumori H, Rumi MA, Ortega-Cava CF, Ishihara S, Kinoshita Y: Lafutidine, a novel histamine H2-receptor antagonist, increases serum calcitonin gene-related peptide in rats after water immersion-restraint stress. J Lab Clin Med 141:102–105, 2003

    Article  CAS  PubMed  Google Scholar 

  18. Nagahama K, Yamato M, Kato S, Takeuchi K: Protective effect of lafutidine, a novel H2-receptor antagonist, on reflux esophagitis in rats through capsaicin-sensitive afferent neurons. J Pharmacol Sci 93:55–61, 2003

    Article  CAS  PubMed  Google Scholar 

  19. Kato S, Tanaka A, Kunikata T, Umeda M, Takeuchi K: Protective effect of lafutidine against indomethacin-induced intestinal ulceration in rats: relation to capsaicin-sensitive sensory neurons. Digestion 61:39–46, 2000

    Article  CAS  PubMed  Google Scholar 

  20. Tanaka A, Mizoguchi H, Hase S, Miyazawa T, Takeuchi K: Intestinal protection by lafutidine, a histamine H(2)-receptor antagonist, against indomethacin-induced damage in rats—role of endogenous nitric oxide. Med Sci Monit 7:869–877, 2001

    CAS  PubMed  Google Scholar 

  21. Okayama M, Tsubouchi R, Kato S, Takeuchi K: Protective effect of lafutidine, a novel histamine H2-receptor antagonist, on dextran sulfate sodium-induced colonic inflammation through capsaicin-sensitive afferent neurons in rats. Dig Dis Sci 49:1696–1704, 2004

    Article  CAS  PubMed  Google Scholar 

  22. Onodera S, Shibata M, Tanaka M, Inaba N, Yamaura T, Ohnishi H: Gastroprotective activity of FRG-8813, a novel histamine H2-receptor antagonist, in rats. Jpn J Pharmacol 68:161–173, 1995

    CAS  PubMed  Google Scholar 

  23. Sewing KF, Hagie L, Ippoliti AF, Isenberg JI, Samloff IM, Sturdevant RA: Effect of one-month treatment with cimetidine on gastric secretion and serum gastrin and pepsinogen levels. Gastroenterology 74:376–379, 1978

    Google Scholar 

  24. Itoh H, Naito T, Takeyama M: Lafutidine changes levels of somatostatin, calcitonin gene-related peptide, and secretin in human plasma. Biol Pharm Bull 25:379–382, 2002

    CAS  PubMed  Google Scholar 

  25. Dowling TC, Frye RF: Determination of famotidine in human plasma and urine by high-performance liquid chromatography. J Chromatogr B Biomed Sci Appl 732:239–243, 1999

    Article  CAS  PubMed  Google Scholar 

  26. Nagano T, Ikawa K, Takeyama M: Enzyme immunoassay of calcitonin gene-related peptide-like immunoreactive substance in human plasma and saliva. Jpn J Hosp Pharm 24:363–369, 1998

    CAS  Google Scholar 

  27. Takeyama M, Yanaga N, Yarimizu K, Ono J, Takaki R, Fujii N, Yajima H: Enzyme immunoassay of somatostatin (SS)-like immunoreactive substance in bovine milk. Chem Pharm Bull (Tokyo) 38:456–459, 1990

    CAS  Google Scholar 

  28. Takeyama M, Matsuo H, Mori K: Enzyme immunoassay of gastrin in human plasma. Chem Pharm Bull (Tokyo) 41:2197–2199, 1993

    CAS  Google Scholar 

  29. Kitagawa T, Shimozono T, Aikawa T, Yoshida T, Nishimura H: Preparation and characterization of hetero-bifunctional cross-linking reagents for protein modifications. Chem Pharm Bull (Tokyo) 29:1130–1135, 1981

    CAS  Google Scholar 

  30. Haruki S, Matsumoto H, Kodama K, Tanabe M, Takayanagi H, Cyong J: Pharmacokinetic studies of lafutidime (FRG–8813) in man. Jpn Pharmacol Ther 23: 3049–3059, 1995 (in Japanese)

    CAS  Google Scholar 

  31. Esplugues JV, Ramos EG, Gil L, Esplugues J: Influence of capsaicin-sensitive afferent neurones on the acid secretory responses of the rat stomach in vivo. Br J Pharmacol 100:491–496, 1990

    CAS  PubMed  Google Scholar 

  32. Holzer P, Peskar BM, Peskar BA, Amann R: Release of calcitonin gene-related peptide induced by capsaicin in the vascularly perfused rat stomach. Neurosci Lett 108:195–200, 1990

    Article  CAS  PubMed  Google Scholar 

  33. Sternini C, Reeve JR Jr, Brecha N: Distribution and characterization of calcitonin gene–related peptide immunoreactivity in the digestive system of normal and capsaicin–treated rats. Gastroenterology 93:852–862, 1987

    CAS  PubMed  Google Scholar 

  34. Onodera S, Shibata M, Tanaka M, Suzuki T, Inaba N, Fujii S, Yamaura T: Gastroprotective mechanism of a newly developed H2-receptor antagonist, FRG-8813. Ulcer Res 21:54–57, 1994

    Google Scholar 

  35. Shibata M, Onodera S, Inaba N, Tanaka M, Suzuki T, Arai Y, Yamaura T: Capsaicin-sensitive afferent nerves in the mechanisms of gastroprotective and antiulcer effects of lafutidine, a novel antiulcer drug. Exp Ulcer 24:33–37, 1997

    Google Scholar 

  36. Nishihara K, Nozawa Y, Nakano M, Ajioka H, Matsuura N: Sensitizing effects of lafutidine on CGRP–containing afferent nerves in the rat stomach. Br J Pharmacol 135:1487–1494, 2002

    Article  CAS  PubMed  Google Scholar 

  37. Manela FD, Ren J, Gao J, McGuigan JE, Harty RF: Calcitonin gene-related peptide modulates acid-mediated regulation of somatostatin and gastrin release from rat antrum. Gastroenterology 109:701–706, 1995

    Article  CAS  PubMed  Google Scholar 

  38. Geppetti P, Tramontana M, Evangelista S, Renzi D, Maggi CA, Fusco BM, Del Bianco E: Differential effect on neuropeptide release of different concentrations of hydrogen ions on afferent and intrinsic neurons of the rat stomach. Gastroenterology 101:1505–1511, 1991

    CAS  PubMed  Google Scholar 

  39. Kato K, Martinez V, St Pierre S, Tache Y: CGRP antagonists enhance gastric acid secretion in 2-h pylorus-ligated rats. Peptides 16:1257–1262, 1995

    Article  CAS  PubMed  Google Scholar 

  40. Kawashima K, Ishihara S, Karim Rumi MA, Moriyama N, Kazumori H, Suetsugu H, Sato H, Fukuda R, Adachi K, Shibata M, Onodera S, Chiba T, Kinoshita Y: Localization of calcitonin gene-related peptide receptors in rat gastric mucosa. Peptides 23:955–966, 2002

    Article  CAS  PubMed  Google Scholar 

  41. Levi S, Beardshall K, Haddad G, Playford R, Ghosh P, Calam J: Campylobacter pylori and duodenal ulcers: the gastrin link. Lancet 1:1167–1168, 1989

    CAS  PubMed  Google Scholar 

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Authors and Affiliations

  1. Department of General Medicine, Hiroshima University Hospital, 1-2-3 Kasumi, Minami-ku, Hiroshima, 734-8551, Japan

    Tomohiko Shimatani MD & Susumu Tazuma MD

  2. Department of Geriatric Health Sciences, Graduate School of Health Sciences, Hiroshima University, Hiroshima, Japan

    Masaki Inoue MD, Tomoko Kuroiwa MS & Jing Xu MD

  3. Department of Internal Medicine, Wakasagi Medical Clinic, Tokyo, Japan

    Masuo Nakamura MD

  4. Department of Clinical Pharmacotherapy, Graduate School of Biomedical Sciences, Hiroshima University, Hiroshima

    Kazuro Ikawa PhD & Norifumi Morikawa PhD

Authors
  1. Tomohiko Shimatani MD
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  2. Masaki Inoue MD
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  3. Tomoko Kuroiwa MS
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  4. Jing Xu MD
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  5. Masuo Nakamura MD
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  6. Susumu Tazuma MD
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  8. Norifumi Morikawa PhD
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Correspondence to Tomohiko Shimatani MD.

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Shimatani, T., Inoue, M., Kuroiwa, T. et al. Lafutidine, a Newly Developed Antiulcer Drug, Elevates Postprandial Intragastric pH and Increases Plasma Calcitonin Gene-Related Peptide and Somatostatin Concentrations in Humans: Comparisons with Famotidine. Dig Dis Sci 51, 114–120 (2006). https://doi.org/10.1007/s10620-006-3094-2

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  • DOI: https://doi.org/10.1007/s10620-006-3094-2

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