Global Health AN ONLINE JOURNAL FOR THE DIGITAL AGE 1 and Zollinger-Ellison syndrome. For the millions of patients ingesting ranitidine daily or even twice daily for one or more of these concurring gastrointestinal diseases, this meant an immediate change in their therapy to a different H2RA. This recall resulted in clinicians having a need to find alternate therapy for their patients, and pharmaceutical manufacturers struggled to conduct Matthew Buchfellner, PharmD student, independent studies on their own drugs to meet University of Findlay this increased raise in demand. The drug Findlay, OH, USA 45840 companies Amneal Pharmaceuticals and Mylan Email – [email protected] have recalled and ceased production of another H2RA Axid (generic drug nizatidine) for the AN ANALYSIS OF HISTAMINE 2 exact same reason that their drug had trace RECEPTOR ANTAGONISTS AND A amounts of NDMA.2 The FDA has since started PROPOSAL FOR LAFUTIDINE reviewing other H2RA’s and proton pump inhibitors for this contaminant.1 As far as On April 1st, 2020, the Food and Drug antagonists for the histamine-2 receptor in the Administration (FDA) made national gastrointestinal system, there now exists only headlines when it published a press release on two drugs that have been approved by the FDA, a popular gastrointestinal drug used in the Tagamet (generic drug cimetidine) and Pepcid United States. FDA requested withdrawal of (generic drug famotidine). Zantac (generic drug ranitidine) from all prescription and over-the-counter use The popularity of famotidine and cimetidine immediately, due to concerns of a N- had ultimately led to backorders for these Nitrosodimethylamine (NDMA) contaminant medications and difficulty for procuring these in the formulations.1 Sustained exposure to medications by multiple health systems. NDMA might increase the risk of cancer. FDA Additionally, it has made many health care has investigated Ranitidine, a histamine-2 professionals overly aware of cimetidine’s receptor antagonist (H2RA), from September many drug-drug interactions. Cimetidine alters of 2019 to April of 2020 for this issue.1 This the liver enzymes that break down other drugs to such an extent that prescribers are wary to press release was the final conclusion of a 2 gradual mass recall of ranitidine across the prescribe this to patients. Health systems and United States by many different drug retail pharmacies are thus turning to the companies, and also led to ranitidine’s alternative best option - famotidine, leading to suspension in the European Union and a serious drug shortage in the United States of Australia.1 The withdrawal was met with this drug. According to the FDA, 20 and 40 mg subsequent investigation by the FDA into famotidine tablets from manufacturers Teva Pharmaceuticals, Aurobindo Pharma, and other gastrointestinal medications that utilizes 2 similarly chemical synthetic process, such as Carlsbad Technology are all on shortage. proton pump inhibitors, antacids, and other histamine receptor antagonists. Histamine-2 receptor antagonists (H2RA’s) were first discovered and synthesized in the late Zantac had previously been approved by the 1960’s, after discovering that the classical FDA for treatment of gastroesophageal reflux antihistamines, the histamine-1 (H1) receptor disease (GERD), peptic ulcer disease (PUD), antagonists, could not antagonize every type of THE UNIVERSITY OF FINDLAY Global Health AN ONLINE JOURNAL FOR THE DIGITAL AGE histamine receptor in the body.3 The idea was especially the misuse of these medications due for scientists to synthesize specialized to the lack of adequate supply of H2RA’s. compounds to attempt to block the effects of According to a study at the Hospital de histamine specifically in the stomach. After Guadalajara, among patients taking PPI’s upon the discovery of the histamine-2 (H2) receptor admission to the hospital, 73% had inadequate and its presence in the gastrointestinal system indication for taking it and 38% were in addition to the heart, uterus, and smooth discharged with a PPI without the correct muscles, the structure of the receptor was indication.4 The overuse of PPI’s can lead to discovered through utilization of lab processes serious adverse effects; the stronger acid such as PCR.3 Discovery of the H2 receptor suppression may increase chance of was followed by synthesis of compounds Clostridium difficile infections, bone fracture, selectively binding to this receptor. In humans, or even anemia due to chronic vitamin B12 endogenous histamine is produced from deficiency.4 Furthermore, studies have enterochromaffin-like (ECL) cells located in associated PPI’s with issues such as lowering the gastric mucosa and aid in production of serum magnesium, a critical element taking part stomach acid through binding to those H2 in over 300 enzymes in the human body. receptors on parietal cells of the stomach, leading to heartburn and discomfort.3 In To prevent the side effects of improperly gastrointestinal diseases such as GERD, the prescribed PPI’s, the United States should problem arises from the lower esophageal explore options for alternative H2RA’s, sphincter not closing properly, leading to acid because these medications may be indicated in backflow from the stomach into the esophagus a patient that does not need PPI therapy. and symptoms of heartburn. Preventing acid Unfortunately, aside from ranitidine, nizatidine, production by blocking histamine action has famotidine, and cimetidine, there is not another been safe and effective treatment strategy for H2RA on the market in the United States. many GI issues. However, outside the USA, a different H2RA is gaining traction. The model H2RA drug The discontinuation of Zantac and decreased lafutidine was first marketed in Japan with the H2RA’s prescriptions is accompanied by brand name Stogar by the multinational surge in new prescriptions for proton pump biopharmaceutical company Union Chimique inhibitors. The proton pump inhibitors (PPI’s) Belge (UCB) in April of 2000.5 It was first mechanism of action differs from that of approved for oral treatment of gastric ulcers in H2RA’s, and are classically used today as a 2000, which makes it one of the younger preferred method of treatment for H2RA’s that have been developed.5 In India, gastrointestinal disease. This is because the lafutidine was approved and marketed as the H2RA’s approved in the United States do not brand name Lafaxid by Zuventus Healthcare attain a complete healing of gastric lesions and Limited. In 2010 lafutidine was approved for cannot hold back acid secretion near to the GERD, and in 2012 it was approved to help extent of PPI’s.4 PPI’s inhibit the proton improve symptoms of gastric and duodenal pumps directly that secrete acid in the ulcers in peptic ulcer disease in both countries stomach, unlike the histamine that blocks the respectively.5 Like the other H2RA’s, lafutidine H2RA’s which only indirectly prevents acid prevents secretion of gastric acid by blocking secretion.4 There is no denying that PPI’s are histamine binding to its receptor, and therefore more effective in treatment, the problem lies can be substituted for the discontinued with the misuse of these medications, and ranitidine and shortages of famotidine. THE UNIVERSITY OF FINDLAY Global Health AN ONLINE JOURNAL FOR THE DIGITAL AGE Interestingly, lafutidine has additional benefits vasoconstriction in smooth muscles of the aside from its acid lowering capacity. stomach, and inhibits inflammation due to mast cell activation.7 Chiefly for the purposes of Perhaps the most sought-after benefit of stomach acid, CGRP can facilitate the release lafutidine and its most exciting is its additional of somatostatin from antral D cells.7 gastroprotective activity leading to complete Somatostatin then inhibits gastric acid healing of gastric lesions. During cancer secretion, directly acting on somatostatin treatment, many of the chemotherapeutic receptors in the parietal cells. This function agents used (cisplatin, 5-fluorouracil, etc.) makes lafutidine unique from the other have a possible side effect of mucositis.6 H2RA’s, which do not activate CGRP through Mucositis may occur during chemotherapy this mechanism. In Shimatani, T. et al. it was when treatment inadvertently breaks down the also studied through comparisons of 10 mg rapidly dividing cells lining the gastro- lafutidine to 20 mg famotidine that plasma intestinal tract, leaving the mucosal tissue concentrations of CGRP exceeded 60 pg/ml open to ulcers and infection.6 Shimatani, T. et with lafutidine, while concentrations of CGRP al. demonstrated lafutidine can prevent this did not increase above 30 pg/ml in those treated gastric mucosal injury and accelerate the with famotidine.7 Suppression of the repair process following damage in various transmission of pain to the brain of stomach animal models, while Tanaka, M. et al. found acid secretion or backflow into the esophagus that lafutidine does this through capsaicin- may improve the efficacy of lafutidine to treat sensitive nerves in the enteric nervous system underlying gastrointestinal conditions.7 in rat models.7,8 Despite this promising data, Lafutidine therefore may have therapeutic lafutidine has only begun to be tested in human potential in NSAID-associated gastric mucosal models, but this drug has still found to be safe injury in humans. Essentially, if treatment with in humans. Namikawa, T. et al. concluded that lafutidine means the patient does not have as lafutidine could be used for supportive care to