Lafutidine

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Lafutidine
Lafutidine.png
Systematic (IUPAC) name
2-[(2-furylmethyl)sulfinyl]-N-((2Z)-4-{[4-(piperidin-1-ylmethyl)pyridin-2-yl]oxy}but-2-en-1-yl)acetamide
Clinical data
AHFS/Drugs.com International Drug Names
Legal status
?
Routes Oral
Identifiers
CAS number 118288-08-7 YesY
ATC code A02BA08
PubChem CID 5282136
ChemSpider 4445337 N
UNII 49S4O7ADLC YesY
KEGG D01131 YesY
Chemical data
Formula C22H29N3O4S 
Mol. mass 431.54 g/mol
 N (what is this?)  (verify)

Lafutidine (INN) is a second generation H2 receptor antagonist having multimodal mechanism of action. It is currently marketed in Japan (Stogar) [1] China (Lemeiting) [2] and India (Lafaxid) [3] It not only suppresses gastric acid secretion, but also has cytoprotective properties by the virtue of its property to induce the collagen synthesis in the gastric mucosa.[4] It has a novel mechanism of action in addition to blocking the H2 receptors, it decreases inflammation by modulating calcitonin gene-related peptide (CGRP) [5] and vanilloid receptors [6] It is also found to stimulate mucin biosynthesis and promote the restitution of damaged mucosa.[7]

Mechanism of Action[edit]

Acid Suppressive action[edit]

Lafutidine is absorbed in the small intestine, reaches gastric cells via the systemic circulation, and then directly and rapidly binds to gastric cell histamine H2 receptors, thereby inhibiting the stimulation of cAMP and a resultant decrease in acid production (antisecretory action).[8] It causes a sustained increase in intracellular Ca2+ ion concentration in endothelial cells resulting in the release of Calcitonin Gene Related Peptide (CGRP), which causes acid suppression by decreasing the vagal tone.[9] Lafutidine also increases plasma somatostatin levels which decreases secretion of gastrin from G cells. This decrease in gastrin causes inhibition of parietal cells, resulting in decrease in gastric acid secretion.[10][11]

Gastroprotective action[edit]

Lafutidine induced CGRP release stimulates nitric oxide (NO) production in endothelial cells, where NO participates in the regulation of gastric mucosal blood flow through vasodilation in the gastric microvasculature and increases mucin biosynthesis resulting in gastroprotection.[12][13] Lafutidine inhibits secretion of interleukin-8, which in turn inhibits sequestration of neutrophils at the site of inflammation, thereby preventing mucosal inflammation [14] It also inhibits neutrophil activation which reduces damage caused by free radicals, thereby reducing inflammation [5] Additionally, Lafutidine has been found to block the attachment of H. pylori with the gastric cells, thereby preventing diseases like peptic ulcer.[14]

Pharmacokinetics[edit]

When 10 mg of lafutidine was orally administered to healthy adult males in fasting conditions, peak plasma concentration of 265.15 ± 49.84 ng/ml was achieved at 0.95 ± 0.24 hours. The plasma half life was 1.92 ± 0.94 hours.[15] Among the elderly, there was no difference in pharmacokinetics parameters between those with normal renal function (Ccr average 88.0±9.4 mL/min) and those with deteriorating renal function (Ccr 20~60ml/min, average 45.2±7.8 ml/min).[14] In dialytic patients when administered without hemodialysis, the Cmax, AUC and the t1/2 values were 336±40 ng/ml, 2278±306 ng.hr/mL and 6.71±0.30 hours respectively while those after hemodialysis were 226±36 ng/ml, 853±128 ng.hr/mL and 4.57±0.2 hours respectively.[16] Therefore lafutidine should be administered carefully with lower dosage in dialytic patients.

Adverse effects[edit]

Antacid preparations such as lafutidine by suppressing acid mediated break down of proteins, leads to an elevated risk of developing food or drug allergies. This happens due to undigested proteins then passing into the gastrointestinal tract where sensitisation occurs. It is unclear whether this risk occurs with only long-term use or with short-term use as well.[17]

References[edit]

  1. ^ Stogar tablets, UCB Japan, Japan.
  2. ^ Lemeiting tablets,Sibao Pharmaceutical, China.
  3. ^ Lafaxid tablets, Zuventus Healthcare Ltd. India
  4. ^ Y.Fukushima, H. Otsuka, M. Ishikawa et al. (2001) Potent and long-lasting action of Lafutidine on the human histamine H(2) receptor, Digestion, Vol. 64, No. 3, pp: 155-60
  5. ^ a b N. Harada, K. Okajima et al. (2007) Inhibition of neutrophil activation by Lafutidine, an H2-receptor antagonist, through enhancement of sensory neuron activation contributes to the reduction of stress-induced gastric mucosal injury in rats, Dig Dis Sci, Vol. 52, No. 2, pp: 469-77
  6. ^ T. Sugiyama, Y. Hatanaka, Y. Iwatani et al. (2008) Lafutidine facilitates calcitonin gene-related peptide (CGRP) nerve-mediated vasodilation via vanilloid-1-receptors in rat mesenteric resistance arteries, J Pharmacol Sci, Vol. 106, No. 3, pp: 505-11
  7. ^ Y. Nozawa, K. Nishihara, Y. Akizawa et al. (2004) Lafutidine inhibits Helicobacter pylori- induced interleukin-8 production in human gastric epithelial cells, J Gasteroenterol Hepatol, Vol. 19, No. 5, pp: 506-11
  8. ^ Kazuro et al. Pharmacokinetic and Pharmacodynamic Properties of Lafutidine after Postprandial Oral Administration in Healthy Subjects: Comparison with Famotidine. Biol. Pharm. Bull., 2007; 30: 1003-1006.
  9. ^ Kunieda et al. Lafutidine-Induced Increase in Intracellular Ca2+ Concentrations in PC12 and Endothelial Cells. J. Pharmacol. Sci., 2005; 97: 67-74
  10. ^ Inamori et al. Early effects of lafutidine or rabeprazole on intragastric acidity: which drug is more suitable for on-demand use? J. Gastroenterol., 2005; 40: 453-458
  11. ^ Itoh et al. Lafutidine changes levels of somatostatin, calcitonin gene-related peptide, and secretin in human plasma. Biol. Pharma. Bull., 2002; 25: 379-382
  12. ^ Chen RYZ, Guth PH. Interaction of endogenous nitric oxide and CGRP in sensory neuron-induced gastric vasodilation. Am. J. Physiol., 1995; 268: G791-G796
  13. ^ Ichikawa et al. Lafutidine induced stimulation of mucin biosynthesis mediated by nitric oxide is limited to surface mucous cells of rat gastric oxyntic mucosa. Life Sci., 1998, 62:259.264
  14. ^ a b c Nozawa et al. Lafutidine inhibits Helicobacter pylori- induced interleukin-8 production in human gastric epithelial cells. J Gasteroenterol Hepatol, 2004, 19:506-511
  15. ^ Haruki, S.et al.:BasicPharmacol. Ther., 23: 3049, 1995
  16. ^ UCB Japan Co. Ltd., STOGAR Tablet, Prescribing Information
  17. ^ Pali-Schöll I, Jensen-Jarolim E (April 2011). "Anti-acid medication as a risk factor for food allergy". Allergy 66 (4): 469–77. doi:10.1111/j.1398-9995.2010.02511.x. PMID 21121928.