Bromo-Seltzer was invented in 1888 by  Isaac E. Emerson  and produced by the Emerson Drug Company of  Baltimore, Maryland . It was sold in the United States in the form of  effervescent  granules that were mixed with water before  ingestion . [ 1 ]  The product took its name from a component of the original formula,  sodium bromide ; each dose contained 3.2  mEq /teaspoon of it.  Bromides  are a class of tranquilizers that were withdrawn from the U.S. market in 1975 due to their toxicity. Their  sedative  effect probably accounted for Bromo-Seltzer's popularity as a  hangover remedy . Early formulas also used  acetanilide  as the  analgesic  ingredient; it is now known to be toxic. [ 2 ]  Acetanilide was replaced with its metabolite  acetaminophen , and its current formulation uses  aspirin ,  sodium bicarbonate , and  citric acid , the latter two of which provide the  carbonation .


Bromo-Seltzer's main offices and factory were located in downtown Baltimore, Maryland, at the corner of West Lombard and South Eutaw streets. [ 3 ]  The factory's most notable feature was the  Emerson Bromo-Seltzer Tower , built in 1911, whose four clock faces are ringed by letters spelling out the product name. The tower was patterned on the  Palazzo Vecchio  in  Florence, Italy , and is listed on the  National Register of Historic Places . The tower originally held a 51-foot (16m) representation of a Bromo-Seltzer bottle at its top, glowing blue and rotating on a vertical axis. The sign weighed 20 tons (18.1 tonnes), included 314 incandescent light bulbs, and was topped with a crown. The sign was removed in 1936 because of structural concerns. [ 1 ]


Emerson, who traveled widely, said the fizz reminded him of the bubbling action of  Mount Bromo , a volcano in Java. [ 4 ]


Bromo-Seltzer is mentioned in several films and TV shows, including  The Crooked Circle  (1932),  Bed of Roses  (1933),  Topper  (1937),  Wonder Man  (1945),  Somewhere in the Night  (1946),   The Postman Always Rings Twice  (1981),  The Hudsucker Proxy  (1994), [ 5 ]  the 1998  The Simpsons  episode " Bart Carny ", and in  Golden Girls  (Season 4, Episode 1).


It is mentioned in  John Steinbeck 's 1939 novel  The Grapes of Wrath .


Drugstore Bromo-Seltzer dispensers are mentioned in  Georges Simenon 's 1949 detective novel  Maigret chez le coroner  that takes place in Arizona.


It was a sponsor of the old time radio program, “The Inner Sanctum”.


It is mentioned in several songs, including " Bewitched, Bothered and Bewildered " by  Rodgers and Hart , " Adelaide's Lament " in the musical  Guys and Dolls , and " Pachuco Cadaver " by  Captain Beefheart and his Magic Band . In  Spike Jones ' version of   Laura , the chorus chants "Bromo-Seltzer, Bromo-Seltzer..." to evoke the sound of a chugging train.


Camicinal  was a  motilin   agonist  investigated for the treatment of  gastroparesis . [ 1 ] [ 2 ] [ 3 ]  It did not improve enteral feeding intolerance. [ 4 ]


Candoxatril  is the orally active  prodrug [ 1 ]  of candoxatrilat (UK-73967).


Human neutral endopeptidase ( neprilysin ) as the neutral endopeptidase 24.11 [ 2 ]  complexed ( RB-101 ) with phosphoramidon degrades and inactivates [ 3 ]  a number of bioactive peptides. Two multiply connected folding domains [ 3 ]  of the neutral endopeptidase locus [ 3 ]  splicing of exons 1, 2a, or 2b to the common exon 3 composed of  24 exons of the human CALLA/NEP gene [ 2 ]  containing the active site, it is known as peptidase family M13 (neprilysin family, clan MA(E)) the gluzincins a faint but significant structural relationship of the metzincins [ 4 ] [ 5 ] [ 6 ] [ 7 ]   to the  thermolysin -like enzymes, [ 5 ]  Zincin is the simplest descriptor of biological space. [ 8 ]  The structure reveals two multiply connected folding domains which embrace a large central cavity containing the active site of the 5-indanyl ester prodrug candoxatril [ 9 ]  and differs from  phosphoramidon  [N-(N-(((6-Deoxy-α-L-mannopyranosyl)oxy)hydroxyphosphinyl)-L- leucyl)- L-tryptophan ] in several respects the structure of human  neutral endopeptidase  complexed with phosphoramidon is lost due to desolvation [ 9 ]  of the enzyme and ligand on formation of the complex candoxatril.


Candoxatril is the first drug of its kind to be released for clinical trials regarding heart failure. [ medical citation needed ]   This is because candoxatril produces favorable haemodynamic effects in patients with chronic heart failure. It has been demonstrated that candoxatril is associated with a beneficial hemodynamic effect that is useful both in rest and exercise. In several different studies, candoxatril has been shown to improve performance in people with heart failure. In one study, 12 different patients were selected, all with moderately severe heart failure.  On day one of this study, the candoxatril had increased plasma ANP levels, suppressed aldosterone and decreased right atrial and pulmonary capillary wedge pressures. After treatment for 10 days, patients health had improved with an increase of basal ANP and a decrease of aldosterone, along with a reduced body weight that could be a reflection of chronic natriuretic, diuretic effects, or both.  It was decided that on day 10 of the study, the effects of candoxatril were similar to that on day one. [ 10 ]


In a separate study, patients were gathered throughout the United Kingdom from 16 different centers. Over a four-week bind, the patients were either given candoxatril or placebo for the 84 days and every 28 days, patients were reassessed.  Out of the 110 patients, 56 received candoxatril and 54 received the placebo.  Over the time of the study, the patients who were taking candoxatril had an overall improvement in exercise time compared to the patients taking the placebo. [ 11 ]


In a third study, there was only one patient who experienced worsening heart failure during this particular study.  However, the frequency was not statistically significantly different from another observed group that was on placebo. Together, the results of this study show the candoxatril offers a new, effective therapeutic  in the treatment of people with mild heart failure. The beneficial effects may begin to  improve the well-being of patients during everyday activities. [ 12 ]


Carbenoxolone  ( CBX ) is a  glycyrrhetinic acid  derivative with a steroid-like structure, similar to substances found in the root of the  licorice plant . Carbenoxolone is used for the treatment of peptic, esophageal and oral  ulceration  and inflammation. Electrolyte imbalance is a serious side effect of carbenoxolone when used systemically. [ 1 ]


Carbenoxolone reversibly inhibits the conversion of inactive  cortisone  to  cortisol  by blocking  11β-hydroxysteroid dehydrogenase  (11β-HSD). 11β-HSD also reversibly catalyzes the conversion of 7-ketocholesterol to 7-beta-hydroxycholesterol. [ 2 ] [ 3 ]


Carbenoxolone is a modestly potent, reasonably effective, water-soluble blocker of  gap junctions . [ 4 ]


Carbenoxolone has also been used in topical creams such as Carbosan gel, marketed for treatment of lip sores and mouth ulcers.


Carbenoxolone has also been investigated for  nootropic  effects. [ 5 ]  This research started from an observation that long-term exposure to  glucocorticoids  may have negative effects on cognition. Carbenoxolone may decrease the amount of active glucocorticoid in the brain, because the drug inhibits 11β-HSD, an enzyme which regenerates  cortisol , an active glucocorticoid, from inactive  cortisone .


In the research trial investigating this use of carbenoloxone, it was shown that the drug improved verbal fluency in elderly healthy men (aged 55–75). In type 2 diabetics aged 52–70, the drug improved verbal memory. However,  potassium-sparing diuretic   amiloride  was co-administered with carbenoxolone, since carbenoxolone used by itself may cause  hypertension  by increasing cortisol in the kidneys.


A  carminative , known in Latin as  carminativum  ( plural   carminativa ), is a herb or preparation intended to combat  flatulence  either by preventing formation of gas in the gastrointestinal tract or facilitating its expulsion. [ clarify ]


The word  carminative  is a derivative of Latin  cārmen  " card for wool ", according to Hensley Wedgewood, on the   humoral theory  that carminatives "dilute and relax the gross humours from whence the wind arises, combing them out like the knots in wool". [ 1 ]


Carminatives are often mixtures of  essential oils  and  spices  with a tradition in  folk medicine . [ citation needed ]  Some examples include:


Modern drugs used for the same purpose include  simethicone , [ citation needed ]  which simply lowers the  surface tension  of gas bubbles rather than having  physiological effects. [ clarify ] [ citation needed ]


The dictionary definition of  carminative  at Wiktionary


Cetraxate  ( INN ) is an oral  gastrointestinal   medication  which has a cytoprotective effect. [ 1 ] [ 2 ]


Chlordiazepoxide/clidinium bromide  (marketed as  Librax ) is a  fixed-dose combination  medication used to treat  peptic ulcers ,  irritable bowel syndrome  (IBS), and  gastritis . [ 2 ]  It contains  chlordiazepoxide  and  clidinium bromide . It helps relieve stomach spasms, abdominal cramps, and anxiety related to gastric disorders. [ 3 ]  Librax is a fixed ratio of these two medications and, as such, is not typically prescribed with an accompanying dosage, but rather directions on how many capsules to take per day. It comes in a capsule taken by mouth, usually three or four times daily, before meals and at bedtime. [ 3 ]   Chlordiazepoxide is an anti-anxiety medication belonging to the  benzodiazepine  class. [ 4 ]   Its use in IBS is thought to be due to its calming ability for patients that have IBS symptoms that are worsened by anxiety.  Clidinium bromide is a synthetic quaternary ammonium  antimuscarinic , [ 5 ]  a sub-class of a family of drugs known as  anticholinergics . It treats IBS by decreasing gastrointestinal  motility .


Chlordiazepoxide can be habit-forming. Tolerance may develop with long-term or excessive use, making this medication less effective. This medication must be taken regularly to be effective. Stopping the drug suddenly can worsen the condition and cause withdrawal symptoms (anxiousness, sleeplessness, and irritability). [ 3 ]


It was approved for medical use in the United States in 1966. [ 6 ] [ 7 ]  It is available as a generic medication. [ 8 ]


Chlordiazepoxide/clidinium bromide is indicated to control emotional and somatic factors in gastrointestinal disorders. [ 7 ]  It may also be used as adjunctive therapy in the treatment of peptic ulcer and in the treatment of the irritable bowel syndrome (irritable colon, spastic colon, mucous colitis) and acute enterocolitis. [ 7 ]


Dalby's Carminative  was one of the two most widely used  patent medicines  given to babies and children at the end of the 18th and beginning of the 19th centuries. Together with its rival,  Godfrey's Cordial , they were known as "mother's friends" and were used (often against a doctor's advice) for everything from colic and coughs to typhoid.


A  carminative  is a drug that relieves gas from the digestive tract, flatulence and   colic  in infants. The formula claimed to aid “infants afflicted with wind, watery gripes, fluxes and other disorders of the stomach and bowels”. The main active ingredient in both formulas was opium. There are stories of nurses who overdosed the babies in their care to keep them quiet and no bother, [ 1 ]  and babies did die from time to time. [ 2 ]  Today, the medicine is mostly known by collectors of old glass bottles.


The formula for Dalby's Carminative was created by Joseph Dalby, [ 3 ]  surgeon and apothecary of  London ,  England , in the 1770s. Born Joseph Dolby, Joseph changed the spelling of his name to "Dalby" when he married Anne Sparrow in 1739. [ 4 ]


In a 1773 Act of the Parliament of Great Britain, Dalby's Carminative is listed with other "medicinal preparations" as a product liable for  stamp duties , giving it official status.


Joseph Dalby died in 1784. He left the recipe for the carminative to his daughter Frances (174–-1845), who married Anthony Gell. Joseph's son James (1750–1815) kept the blue J. Dalby bottles and set up manufacturing himself, claiming to be the original creator. Frances and her husband then "rebranded" the product as Gell-Dalby, which was sold in brown bottles. Both children claimed to have the original recipe. [ 5 ]


The Will of Joseph Dalby, proved at London 27 July 1784 is often held up as one of the most eccentric Georgian wills. [ 6 ]  He is buried in  Westminster Abbey , South Cloister.


By the 1770s, Dalby's Carminative and many other English medicines were also North American hits. Shipments of all sorts of medicines were sent from England to the colonies. The  American War of Independence  involved a blockade and ships carrying commodities from England were often sunk or captured. Many a bottle of medicine had to be smuggled to the new United States. It was not long before Americans found that they could wash out the distinctive Dalby's and other bottles and refill them with their own concoctions and the patent medicine business took off in America. Soon American glass companies were making knock-off bottles. Recipes were being traded around by apothecaries, and by the mid-1780s, Dalby's was actually no longer shipping overseas, although "Dalby's Carminative" was sold everywhere in the United States. Pirated versions were being manufactured and sold there until after 1900. [ 7 ]


As listed in  The Lancet , a recipe consists of:


Drotaverine  ( INN , also known as  drotaverin ) is an  antispasmodic  drug, used to enhance  cervical dilation  during  childbirth  and to relieve  smooth muscle   spasms  in the  gastrointestinal tract ,  urinary system , and  gall bladder . [ 2 ] [ 3 ] [ 4 ] [ 5 ]


It is structurally related to  papaverine , and is a selective  inhibitor of phosphodiesterase-4 , and has no  anticholinergic  effects. [ 6 ]


It is available in  Asia , [ specify ]   Central and Eastern Europe  (Poland, [ 7 ]  Hungary, [ 8 ]  Estonia, [ 9 ]  Latvia, [ 10 ]  Lithuania [ 11 ] ) under several brand names. [ 12 ]  A popular brand is  No-Spa,  owned by  Sanofi ). It is distributed by Sanofi as  Но-Шпа  (No-shpa) in Russia. [ 13 ]


Drotaverine hydrochloride has a  spasmolytic , myotropic,  vasodilation ,  hypotensive  action. [ 5 ]


Drotaverine decreases active ionized calcium supply binding to smooth muscle cells due to inhibition of  phosphodiesterase  and intracellular accumulation of  cAMP . It has an apparent and prolonged action on smooth muscles of internal organs and blood vessels and it moderately decreases  arterial blood pressure , increases  cardiac output  (minute volume of heart), and has some  antiarrhythmic  potential. [ 5 ]


Drotaverine decreases  vascular tone  of  cerebral blood vessels  and increases blood-filling. Practically, Drotaverine does not influence the  autonomic nervous system  and does not penetrate into the  central nervous system . [ 5 ]


Possible side effects include: heating sensation, dizziness, headache (rarely), insomnia. May be observed: arrhythmia (rarely), hypotension, tachycardia, sweating, nausea. [ 5 ]


Overdose of Drotaverine potentially can cause  atrioventricular (AV) block ,  cardiac arrest , paralysis of respiratory system. [ 5 ]


In  Israel  the product is known under the brand name "No-Spa" by the general public [ 14 ]  which did not receive a permit to be distributed by the  health ministry , [ 15 ]  however due to high demand local medical counterfeiters have managed to smuggle No-Spa tablets over the years. [ 15 ]


In 2008, the Israeli health organization warned consumers against counterfeit No-Spa pills after a smuggler had been arrested at the  Ben Gurion Airport  with several thousand pills. [ 16 ] [ 17 ]


In 2011, the Israeli patent and trademark office declined the use of No-SPA. [ 14 ]


An article from 2013 described the effects from overdose (in a 19-year-old female) as including vomiting, seizures and fatal cardiac toxicity. [ 18 ]


In 2016, the young Russian chess player  Ivan Bukavshin  died of a massive overdose (or poisoning) of the drug, which was initially thought to be a stroke; the dose detected in his blood was 17 mg/kg. [ 19 ]


Ecadotril  is a  neutral endopeptidase  inhibitor ((NEP [ 1 ] ) EC 3.4.24.11 [ 2 ] ) and determined by the presence of peptidase family M13 as a neutral endopeptidase inhibited by  phosphoramidon . Ecadotril is the ( S )- enantiomer  of  racecadotril .  NEP-like enzymes include the  endothelin - converting enzymes . [ 3 ]   The peptidase M13 family  believed to activate or inactivate oligopeptide (pro)-hormones such as opioid peptides, [ 3 ]   neprilysin [ 3 ]  is another member of this group,  in the case of the metallopeptidases and aspartic, the nucleophiles clan or family for example MA, is an activated water molecule. [ 1 ]  The peptidase domain for members of this family also contains a bacterial member and resembles that of  thermolysin  the predicted active site residues for members of this family and thermolysin occur in the motif HEXXH. [ 4 ]  Thermolysin complexed with the inhibitor ( S )- thiorphan  are isomeric thiol-containing inhibitors of endopeptidase EC 24-11 [ 5 ]  (also called " enkephalinase ").


Eupatilin  (5,7-Dihydroxy-3',4',6-trimethoxyflavone) is an  O-methylated flavone , a type of flavonoids. It can be found in  Artemisia asiatica  (Asteraceae). [ 1 ]


Ferrous tartrate  is a  chemical compound  and the  iron(II)   salt  of  tartaric acid . [ 1 ]


Ferrous tartrate has been used as a steel medicine. [ 2 ] [ 3 ]  It was generally prescribed during the 19th and early 20th centuries. It is usually prepared by  digesting  for 30 days, 2 ounces (880 grains)  tartarated  iron [ 4 ]  in a pint of  sherry . [ 5 ]  It can be difficult to prepare. [ 6 ]


Historically, it was used as a  stomachic  and tonic, at a dose of 2 tbsp. [ 5 ]   It was also used to treat  anemia , dose 1 to 2 fl. dr. [ 7 ]


Festal  is a brand name drug containing  pancreatin ,  hemicellulase , and certain  bile  components. [ 1 ]  It is indicated for use in people with gastrointestinal problems, in order to help actively digest food (especially fatty meals that require pancreatic  enzymes ).


Gefarnate  is a drug used for the treatment of  gastric ulcers . [ 1 ]


It also has been proposed for use in the treatment of  dry eye syndrome . [ 2 ] [ 3 ]


This article about an  alkene  is a  stub . You can help Wikipedia by  expanding it .


A  gastrointestinal cocktail , (also known as a  GI cocktail  or  gastric cocktail ), is a mixture of medications used to treat symptoms of  dyspepsia . [ 1 ]  The GI cocktail generally contains a mixture of viscous  lidocaine , an  antacid , and an  anticholinergic . [ 1 ] [ 2 ]  The GI cocktail is commonly prescribed in the hospital or emergency department, and has been used to help distinguish chest pain as either gastrointestinal or cardiac. [ 1 ]  While it has been widely used in the treatment of dyspepsia, studies have suggested that the GI cocktail is only as effective as antacids alone. [ 1 ]


The "GI cocktail" does not refer to a specific product. Rather, it refers to a mixture of viscous  lidocaine , an  antacid , and an  anticholinergic . [ 1 ] [ 2 ]  Viscous  lidocaine  works as an anesthetic to numb pain in the throat, esophagus, and stomach.  Antacids  work to neutralize stomach acid.  Anticholinergics  work to ease symptoms that accompany dyspepsia including nausea,  vomiting , and abdominal cramping.


The GI cocktail is a mixture of a viscous anesthetic, an antacid, and an anticholinergic. [ 1 ] [ 2 ]  Common viscous anesthetics use are viscous lidocaine or  xylocaine . Common antacids used are  magnesium hydroxide ,  aluminum hydroxide , or  simethicone  (more commonly known as  Mylanta  or  Maalox ). [ 3 ]  Common anticholinergics used are  hyoscyamine sulfate ,  atropine sulfat e,  scopolamine hydrobromide , and  phenobarbital  (more commonly known as  Donnatal ). [ 3 ]  Typical dosing is 5ml of viscous anesthetic, 30ml of liquid antacid, and 10ml of anticholinergic. [ 3 ]


The GI cocktail is commonly prescribed in the hospital or emergency department to treat symptoms of  dyspepsia . [ 4 ]  These symptoms include: belching,  heartburn , chest pain, abdominal discomfort, abdominal bloating, nausea, loss of appetite, and flatulence. Dyspepsia itself is not an illness, rather it is an indicator of chronic underlying gastrointestinal issues such as  peptic ulcer disease ,  gastro-esophageal reflux disease ,  H. pylori  gastritis,  gastroparesis , or upper gastrointestinal cancers. [ 5 ] [ 6 ]  Dyspepsia can additionally be contributed to medications such as potassium supplements,  NSAIDs , digitalis, iron,  glucocorticoids , and  colchicine , as well as lifestyle factors such as diet, stress, and cigarette smoking. [ 5 ] [ 6 ]


Some people experience side effects that are the result of the individual medications used to make the GI cocktail. They include:


Viscous lidocaine : [ 7 ]


Antacid : [ 8 ]


Anticholinergic : [ 9 ]


Prior studies regarding the GI cocktail for management of dyspepsia in the emergency department have varied in quality of methodology and have demonstrated mixed results. A 1990 single-blind study performed by Welling and Watson [ 4 ]  compared 30 mL of antacid with or without the addition of 15 mL of viscous lidocaine and concluded that the addition of viscous lidocaine provided a significantly greater degree of immediate pain relief than antacids alone in patients with dyspepsia. A 2004 single-blind study performed by Vike and Davis, [ 7 ]  compared treatment with antacids plus either viscous lidocaine or benzocaine solution and did not find a statistically significant difference between the two treatment arms – however the study lacked an antacid monotherapy arm. A robust double-blind clinical trial performed in 2003 by Berman et al. [ 1 ]  compared 30 mL of antacid monotherapy, antacid with the addition of 10 ml of an anticholinergic, and an antacid with anticholinergic with the addition of 10 mL of 2% viscous lidocaine. That study demonstrated no statistically significant difference in pain relief between treatment arms and concluded that all treatments were clinically effective. The ultimately recommended antacid monotherapy alone in the treatment of dyspepsia.


Glucose-elevating agents  are medications used to treat  hypoglycemia  (low blood sugar) by raising  blood glucose . In diabetics, hypoglycemia can occur as a result of too much  insulin  or  antidiabetic medication , insufficient food intake, or sudden increase in physical activity or exercise. The most common glucose-elevating agents used to treat  diabetic hypoglycemia  are  glucose  (in the form of tablets or liquid) and  glucagon  injections when severe hypoglycemia occurs.  Diazoxide , which is used to counter hypoglycemia in disease states such as  insulinoma  (a tumor producing insulin) [ 1 ]  or  congenital hyperinsulinism , increases blood glucose and decreases  insulin  secretion and glucagon accelerates breakdown of  glycogen  in the liver ( glycogenolysis ) to release glucose into the bloodstream. [ 2 ]


Imiglucerase  is a medication used in the treatment of  Gaucher's disease . [ 2 ] [ 3 ]


It is a  recombinant DNA -produced  analogue  of the human enzyme β- glucocerebrosidase .
 Cerezyme  is a  freeze-dried  medicine containing imiglucerase, manufactured by  Genzyme Corporation . It is given  intravenously  after reconstitution as a treatment for Type 1 and Type 3 [ 4 ]  Gaucher's disease. It is available in formulations containing 200 or 400 units per vial.  The specific activity of highly purified human enzyme is 890,000 units/mg, [ 5 ]  meanwhile the enzyme activity produced by recombinant DNA technology is approximately 40 units/mg. [ 6 ]  A typical dose is 2.5U/kg every two weeks, up to a maximum of 60 U/kg once every two weeks, and safety has been established from ages 2 and up. [ 7 ]   It is one of more expensive medications, with an annual cost of $200,000 per person in the United States. [ 8 ]  Imiglucerase has been granted  orphan drug  status in the United States, Australia, and Japan. [ 9 ]


Cerezyme was one of the drugs manufactured at  Genzyme's  Allston, Massachusetts plant, for which production was disrupted in 2009 after contamination with  Vesivirus  2017. [ 10 ]


The most common side effect is  hypersensitivity , which occurs in about 3% of patients. It is associated with symptoms such as cough,  shortness of breath ,  rashes , itching, and  angiooedema . Less common side effects include dizziness, headache, nausea, diarrhea, and reactions at the injection site; they are found in less than 1% of patients. [ 4 ]


No clinical interaction studies have been conducted. [ 4 ]   Miglustat  appears to increase the clearance of imiglucerase by 70%, resulting in decreased enzyme activity. [ 11 ]


Larazotide  ( INN ; also known as AT-1001; formulated as the  salt  with  acetic acid ,  larazotide acetate ) is a synthetic eight  amino acid   peptide  that functions as a  tight junction  regulator and reverses leaky junctions to their normally closed state. It has been studied in people with  coeliac disease .


Larazotide is an octapeptide whose structure is derived from a protein (zonula occludens toxin) secreted by  Vibrio cholerae .  It has the amino acid sequence GGVLVQPG,  IUPAC  condensed descriptor of H-Gly-Gly-Val-Leu-Val-Gln-Pro-Gly-OH, and the systematic name glycylglycyl- L -valyl- L -leucyl- L -valyl- L -glutaminyl- L -prolyl-glycine. [ 1 ] [ 2 ]


Larazotide is an inhibitor of paracellular permeability.  In  celiac disease , one pathway that allows fragments of  gliadin  protein to get past the intestinal epithelium and subsequently trigger an  immune response  begins with binding of indigestible gliadin fragments to the  chemokine  CXC motif receptor 3 ( CXCR3 ) on the  luminal  side of the intestinal epithelium (see  this page ). This leads to the induction of myeloid differentiation factor 88 ( MYD88 ) and the release of zonulin into the lumen. Zonulin then binds to  epidermal growth factor receptor (EGFR)  and  protease-activated receptor 2 (PAR2)  in the intestinal epithelium. This complex then initiates a signalling pathway that eventually results in tight junction disassembly and increased intestinal permeability. Larazotide acetate intervenes in the middle of this pathway by blocking zonulin receptors, thereby preventing tight junction disassembly and associated increase in intestinal permeability. [ 3 ] [ 4 ]


Larazotide acetate is a  synthetic peptide  based on a  Vibrio cholerae   enterotoxin  called zonula occludens toxin that decreases  intestinal permeability . An investigation was carried out to discover which specific part of this toxin was responsible for this activity. Several mutants were constructed, and tested for their biological activity and their ability to bind to intestinal epithelial cells in  culture . The responsible region was located near the  carboxyl terminus  of the toxin protein. This region coincided with a peptide product generated by  Vibrio cholerae . The eight amino acid sequence in this region was shared with  zonulin , an endogenous protein involved in tight junction modulation. This sequence was later designated larazotide acetate. [ 5 ]


It has been used in experiments related to coeliac disease and  rheumatoid arthritis . [ 6 ]


9 Meters Biopharma was conducting clinical trials for larazotide for Celiac Disease, but announced in 2022 that it would discontinue their Phase 3 clinical trial.  [ 7 ]


Linaclotide , (sold under the brand name  Linzess  in the US and Mexico, and as  Constella  elsewhere) [ 6 ]  is a drug used to treat  irritable bowel syndrome  with  constipation  and  chronic constipation with no known cause . [ 4 ] [ 3 ]  It has a  black box warning  about the risk of serious  dehydration  in children in the US; the most common adverse effects in others include diarrhea. [ 4 ]


It is an  oligopeptide   agonist  of  guanylate cyclase 2C  and remains in the  GI tract  after it is taken  by mouth . It was approved in the US and the European Union in 2012. [ 7 ]


It is marketed by  Abbvie  (formerly   Allergan ) in the United states and by  Astellas  in Asia; [ citation needed ]   Ironwood Pharmaceuticals  was the originator. [ 8 ] [ failed verification ]  In 2022, it was the 189th most commonly prescribed medication in the United States, with more than 2   million prescriptions. [ 9 ] [ 10 ]


Linaclotide is  indicated  to treat  irritable bowel syndrome  with constipation and chronic constipation with no known cause. [ 4 ] [ 3 ]


In June 2023, the indication was expanded in the US to include the treatment of  functional constipation . [ 4 ] [ 11 ]


The US label has a black box warning to not use linaclotide in children less than six years old and to avoid in people from 6 to 18 years old, due to the risk of serious dehydration. [ 4 ]


More than 10% of people taking linaclotide have diarrhea. Between 1% and 10% of people have decreased appetite, dehydration, low potassium,  dizziness when standing up too quickly , nausea, vomiting, urgent need to defecate, fecal incontinence, and bleeding in the colon, rectum, and anus. [ 3 ]


It has not been tested in pregnant women and it is unknown if it is excreted in breast milk. [ 3 ]


Systemic absorption of the globular tetradecapeptide is minimal. [ 12 ] [ 13 ]


Linaclotide, like the  endogenous   guanylin  and  uroguanylin  it mimics, is an  agonist  that activates the  cell surface receptor  of  guanylate cyclase 2C  (GC-C). [ 12 ] [ 4 ] [ 14 ]  The medication binds to the surface of the  intestinal   epithelial  cells. [ 4 ]  Linaclotide is minimally absorbed and it is undetectable in the systemic circulation at therapeutic doses. [ 12 ]  Activation of GC-C increases  cyclic guanosine monophosphate  (cGMP). [ 4 ]  Elevated cGMP stimulates secretion of chloride and bicarbonate and water into the intestinal lumen, mainly by way of  cystic fibrosis transmembrane conductance regulator  (CFTR)  ion channel  activation. [ 4 ] [ 15 ]  This results in increased intestinal fluid and accelerated transit. [ 4 ]


Linaclotide is a hybrid  peptide  design of the  E.coli  heat-stable  enterotoxin  (STa) and the endogenous peptide hormones  endogenous   guanylin  and  uroguanylin . [ 16 ] [ 12 ] [ 14 ]  It is a  synthetic  tetradecapeptide (14  amino acid  peptide) with the sequence CCEYCCNPACTGCY by one-letter abbreviation, [ citation needed ]  or by three-letter abbreviation: [ 17 ]


H– Cys 1 –Cys 2 – Glu 3 – Tyr 4 –Cys 5 –Cys 6 – Asn 7 – Pro 8 – Ala 9 –Cys 10 – Thr 11 – Gly 12 –Cys 13 –Tyr 14 –OH


However, the actual structure of linaclotide is not fully specified without the three  disulfide  (R-S-S-R) bonds it contains, which are between Cys 1  and Cys 6 , between Cys 2  and Cys 10 , and between Cys 5  and Cys 13 ; [ 17 ]  these are shown in exaggerated fashion in the line-angle graphic showing the chemical bonds within and between each amino acid (and their stereochemistries, see the infobox, above right), and are represented using a one-letter abbreviations in the following additional schematic: [ citation needed ]


A study in discovery synthesis reported that 2 of 14 strategies available to synthesize linaclotide were successful—the successful ones involving  trityl   protection  of all cysteines, or trityl protection of all cysteines except Cys 1  and Cys 6 , which were protected with  tert -butylsulphenyl groups . The study also reported that solution-phase oxidation (disulfide formation) was advisable over solid-supported synthesis for linaclotide, and that the Cys 1 –Cys 6  disulfide bridge was the most favored energetically. [ 17 ]


The drug was discovered at  Microbia, Inc , which had been spun out of the  Whitehead Institute  in 1998 by postdocs from the lab of  Gerald Fink  to commercialize the lab's know-how and inventions related to microbial pathogens and biology. [ 18 ] [ 19 ]  In 2002 the company hired Mark Currie who had worked at the  Searle  division of  Monsanto  and then had gone to  Sepracor . [ 18 ]  Currie directed the efforts that led to the discovery of linaclotide, which was based on an  enterotoxin  produced by some strains of  Escherichia coli  that cause  traveler's diarrhea . [ 20 ] [ 21 ]  The company started Phase I trials in 2004. [ 18 ]


Under a partnership agreement announced in 2007, between  Forest Laboratories  and Microbia, Forest would pay $70 million in licensing fees towards the development of linaclotide, with profits shared between the two companies in the US; Forest obtained exclusive rights to market in Canada and Mexico. [ 22 ]  By 2010, Microbia had changed its name to Ironwood Pharmaceuticals and had licensed rights to distribute the drug in Europe to  Almirall  and had licensed Asian rights to  Astellas Pharma . [ 23 ]


It was approved in the United States and in the European Union in 2012. [ 7 ]


Forest was acquired in 2014 and eventually became part of  Allergan . [ 24 ]  Allergan acquired rights from Almirall in 2015, [ 25 ]  and in 2017, acquired remaining rights in most of the rest of the world, excluding North America, Japan, and China. [ 26 ]   Allergan has since been acquired by AbbVie in 2020. [ 27 ]


In 2014, Ironwood and Forest then Allergan began running  direct-to-consumer advertising  which raised sales by 21%; campaigns in 2015 and 2016 raised sales by 27% and 30%. [ 28 ]


In 2017, the list price for linaclotide in the US was  US$378  for 30 pills; Allergan and Ironwood increased the price of linaclotide to around $414 in 2018. [ 8 ]


Lubiprostone , sold under the brand name  Amitiza  among others, is a  medication  used in the management of  chronic idiopathic constipation , predominantly  irritable bowel syndrome -associated constipation in women and  opioid-induced constipation . The drug is owned by  Mallinckrodt  and is marketed by  Takeda Pharmaceutical Company .


The drug was developed by  Sucampo Pharmaceuticals  and approved by the  Food and Drug Administration  (FDA) in 2006. [ 2 ] [ 3 ] [ 4 ]  It was recommended for use in the UK by the  National Institute for Health and Care Excellence  (NICE) in July 2014. [ 5 ]   Health Canada  approved the drug in 2015. [ 6 ]  Lubiprostone received approval from the Food and Drug Administration in 2008, to treat irritable bowel syndrome with  constipation  (IBS-C), [ 7 ]  and in 2013, for the treatment of  opioid-induced constipation in adults with chronic noncancer pain. [ 4 ]  It is available as a  generic medication . [ 8 ]


Lubiprostone is a laxative used for the treatment of constipation, specifically: [ 9 ]


Lubiprostone has not been studied in children. [ 10 ] [ 12 ]  There is current research under way to determine the safety and efficacy in postoperative bowel dysfunction.


It comes in a liquid filled capsule and is available only with a doctor's prescription. [ 10 ]  If one misses a dose it should be taken as soon as possible unless it is almost time for the next dose, in which case it should be skipped and the user should return to their regular dosing schedule. [ 10 ]


In clinical trials, the most common adverse event was  nausea  (31%). Other adverse events (≥5% of patients) included  diarrhea  (13%),  headache  (13%),  abdominal distension  (5%),  abdominal pain  (5%),  flatulence  (6%),  sinusitis  (5%),  vomiting  (5%), and  fecal incontinence  (1%).


The FDA lists the following: [ 3 ]


For subjects with chronic idiopathic constipation taking Amitiza:


For opioid-induced constipation:


For subjects with irritable bowel syndrome with constipation:


A 2018 pooled analysis from three  phase III , randomized, double-blind, placebo-controlled studies on usage for Opioid-Induced Constipation, found that the numbers of patients reporting adverse effects were similar in both the lubiprostone and placebo treatment groups for all opioid classes (P ≥ 0.125); however, gastrointestinal adverse effects were reported more frequently by those receiving lubiprostone than 2 of the 3 opioid groups. The most commonly reported TEAEs in the lubiprostone treatment groups were nausea (13.4%–18.1%), diarrhea (1.2%–13.9%), and abdominal pain (4.7%–5.6%). In the population overall, the greatest likelihood of experiencing the first episode of any of these three TEAEs was greatest in the first week of treatment and decreased thereafter. [ 4 ]


According to Medscape, the most common (>10%) were: Nausea, Diarrhea (7-12%), Headache (2-11%). Less common side effects (1-10%) included: Abdominal pain (4-8%), Abdominal distension (3-6%), Flatulence (4-6%), Vomiting (3%), Loose stools (3%), Edema (1-3%), Abdominal discomfort (1-3%), Dizziness (3%), Chest discomfort/pain (2%), Dyspnea (2%), Dyspepsia (2%), Fatigue (2%), Dry mouth (1%). [ 13 ]


The effects on pregnancy have not been studied in humans, but testing in  guinea pigs  resulted in fetal loss. [ medical citation needed ]


Lubiprostone is contraindicated in people exhibiting chronic  diarrhea ,  bowel obstruction , or diarrhea-predominant  irritable bowel syndrome . [ medical citation needed ]


Lubiprostone is a bicyclic  fatty acid [ 15 ]  derived from  prostaglandin E1  that acts by specifically activating  ClC-2 chloride channels  on the apical aspect of gastrointestinal  epithelial  cells, producing a chloride-rich fluid secretion. These secretions soften the stool, increase motility, and promote spontaneous bowel movements.


Unlike many  laxative  products, lubiprostone does not show signs of  drug tolerance ,  chemical dependency , or altered serum  electrolyte  concentration. [ 16 ]


Minimal distribution of the drug occurs beyond the immediate gastrointestinal tissues. [ medical citation needed ]  Lubiprostone is rapidly metabolized by  reduction / oxidation , mediated by carbonyl reductase. [ medical citation needed ]  There is no metabolic involvement of the hepatic  cytochrome P450  system. [ medical citation needed ]  The measurable metabolite, M3, exists in very low levels in plasma and makes up less than 10% of the total administered dose. [ medical citation needed ]


Data indicate that metabolism occurs locally in the  stomach  and  jejunum . [ medical citation needed ]


The cost to the  NHS  was £29.68 per 24 mcg 28-cap pack as of April 2017.


Lubiprostone is available in the United States, Japan, Switzerland, India, Bangladesh, the United Kingdom, and Canada. [ citation needed ]


In  Bangladesh  and  India , lubiprostone is sold under the brand name Lubigut by  Ziska Pharmaceuticals , Lubilax by  Beacon Pharmaceuticals , and under the brand name Lubowel by  Sun Pharmaceutical . [ citation needed ]


Maalox  was a brand of  antacid  owned by  Sanofi . Their main product is a flavored liquid containing a suspension of  aluminum hydroxide  and  magnesium hydroxide , which act to neutralize or reduce  stomach acid , for the purpose of relieving the symptoms of  indigestion ,  heartburn ,   gastroesophageal reflux disease , and also  stomach  or  duodenal  ulcers. It also contains  simethicone , an anti-foaming agent which helps eliminate bloating from gas. In large doses, the medicine can act as a  laxative . The trademark is owned by  Novartis International AG , and was first produced commercially in 1949.


The acronym ‘MAALOX’ refers to the solution’s compositional elements:  MA gnesium and  AL uminum as  OX ides. The oxides and hydroxides react with the  hydrochloric acid  in the stomach, neutralizing it.


Some may find certain Maalox medications, such as Maalox Multi-Action, to be a successful anti- diarrhea  treatment due to the aluminum hydroxide content, which in normal situations has a tendency to result in constipation. Maalox may also be used to treat nausea and stomach cramps associated with dyspepsia, diarrhea, or constipation.


Maalox was developed in a collaboration between  William H. Rorer, Inc. , and a medical doctor and researcher specializing in gastrointestinal issues, Alison Howe Price from  Philadelphia . [ 1 ]  The collaboration occurred after  World War II  when Claude Newhart, a salesman and  pharmacist  for the company, had an idea that he thought might change the company's fortunes. According to the Rorer family, he suggested that instead of selling pain relievers manufactured by others, they should create their own products. Gerald Rorer, then President of Rorer, told Newhart to "go and find something." Newhart took up the challenge and contacted an old acquaintance from his student days working at a Philadelphia drugstore, Martin H. Rehfuss, who happened to be chief of medicine at Thomas Jefferson Hospital. It was Rehfuss who introduced Newhart to Price. Soon thereafter, Newhart convinced Price to become a consultant for the  Fort Washington, Pennsylvania  based Willam H. Rorer, Inc. In the end, Maalox became the first product the partnership produced. [ 2 ] [ 3 ]  Maalox eventually became the world's best selling antacid and forever changed the company's fortunes. [ 4 ]


Liquid Maalox contains  aluminum hydroxide ,  magnesium hydroxide , and  simethicone .


Maalox Regular Strength chewable tablets contain 600 mg of calcium carbonate. Maalox Extra Strength + Anti-Gas tablets contain 1000 mg of calcium carbonate and 60 mg of simethicone.


Maalox is used to treat moderate  dyspepsia , which includes symptoms of a burning sensation in the stomach or chest area, bloating, and/or gas pain, especially occurring after meals. It is used in combination with  oxycodone  to treat esophageal pain in cancer therapy patients. It is also a common component of a  GI cocktail  used in emergency rooms.


Maalox is used in scientific research to simulate for silt/mud/soil in water, along with other dissolved particulates. The particulate size exceeds 11 micrometres. [ 5 ]


Maalox can be used as a standalone antacid treatment or in conjunction with prescription strength medication such as  proton pump inhibitors  and H2 blockers.


Activists  in the United States, the Czech Republic, Venezuela, and Turkey have reported using Maalox or other antacid solutions diluted with water as a  home remedy  for  tear gas  attacks. [ 6 ] [ 7 ] [ 8 ]


Maalox generally doesn’t produce serious side effects in individuals who use it for less than two weeks, but some mild side effects may appear. Possible side effects of Maalox include  nausea ,  diarrhea , constipation, and  headaches . These symptoms generally go away without further treatment. It may be necessary to contact a doctor if these symptoms become severe or persist for long periods of time. Maalox has been linked to phosphate deficiencies in some individuals as a result of the aluminum binding to phosphate in the stomach. This causes the body to flush out this important chemical which can lead to a deficiency.  [ medical citation needed ]


Women who are  pregnant  can, with the permission of a health care provider, use this product as the aluminum content is deemed safe for the developing or nursing child. Individuals who suffer from kidney issues, however, should not take this product unless advised to do so by a doctor. [ medical citation needed ]


In February 2012, Novartis Consumer Health announced that they were temporarily, voluntarily suspending operations at the Novartis Consumer Health Lincoln facility that produces Maalox as well as suspending shipments. [ 9 ]


The shutdown was a result of inspections in 2011. "Two FDA inspections that year, about five months apart, noted numerous instances of the company not addressing consumer complaints and, in some cases, ignoring them." [ 10 ]  At that time, Novartis decided to stop manufacturing Maalox at their Lincoln plant and to have third parties produce it. [ 10 ]  The problems at the Lincoln plant included the possibility of chipped particles from one medication being mixed into the bottles of other medications as well as 1,300 other consumer complaints. [ 11 ]


In August 2013, there was a recall of Maalox products. [ 12 ]  "The recall encompasses 9 different types of its Maalox chewable tablets, including more than 3.4 million bottles of Maalox Advanced Maximum Strength Antacid & Antigas." [ 13 ]  They planned to restart production on a line-by-line basis, but the Maalox line had not by then been restarted. [ 13 ]


As of 2014, Novartis's Maalox brand was to be merged, along with other consumer brands, with the consumer brands of  GlaxoSmithKline  (GSK). This was part of a $20 billion exchange of business units between the two companies. [ 14 ]


Malotilate  ( INN ) is a drug that has been used in studies for the treatment of  liver disease . It has been shown to facilitate  liver  regeneration in rats. [ 1 ]


Maralixibat chloride , sold under the brand name  Livmarli , is a  medication  used to treat  cholestatic pruritus  in people with  Alagille syndrome . [ 5 ] [ 6 ]  Maralixibat chloride is an  ileal bile acid transporter  (IBAT) inhibitor. [ 5 ]


The most common side effects include diarrhea and abdominal pain (belly ache). [ 6 ]


Maralixibat chloride was approved for medical use in the United States in September 2021, [ 5 ] [ 7 ] [ 8 ] [ 9 ]  and in the European Union in December 2022. [ 6 ]


Maralixibat chloride is  indicated  for the treatment of cholestatic pruritus in patients with Alagille syndrome. [ 5 ] [ 6 ]


The U.S.  Food and Drug Administration  (FDA) granted the application for maralixibat chloride  orphan drug  designations in 2013, [ 10 ] [ 11 ]  and in 2020. [ 12 ] [ 13 ]


In October 2022, the  Committee for Medicinal Products for Human Use  (CHMP) of the  European Medicines Agency  (EMA) adopted a positive opinion, recommending the granting of a marketing authorization under exceptional circumstances for the medicinal product Livmarli, intended for the treatment of cholestatic pruritus in patients with Alagille syndrome (ALGS). [ 14 ]  The applicant for this medicinal product is Mirum Pharmaceuticals International B.V. [ 14 ]  Maralixibat chloride was approved for medical use in the European Union in December 2022. [ 6 ] [ 15 ]


Maralixibat chloride is the  international nonproprietary name  (INN). [ 16 ]


Obeticholic acid  ( OCA ), sold under the brand name  Ocaliva , is a  semi-synthetic   bile acid  analogue which has the chemical structure  6α-ethyl-chenodeoxycholic acid .  It is used as a  medication  used to treat  primary biliary cholangitis .  Intercept Pharmaceuticals  Inc. hold the worldwide rights to develop OCA outside Japan and China, where it is licensed to  Dainippon Sumitomo Pharma . [ 5 ]


The natural bile acid  chenodeoxycholic acid  was identified in 1999 as the most active physiological  ligand  for the  farnesoid X receptor  (FXR), which is involved in many physiological and pathological processes.  A series of alkylated bile acid analogues were designed, studied and patented by Roberto Pellicciari and colleagues at the  University of Perugia , with 6α-ethyl-chenodeoxycholic acid emerging as the most highly potent FXR agonist. [ 6 ]   FXR-dependent processes in liver and intestine were proposed as therapeutic targets in human diseases. [ 7 ]   Obeticholic acid is the first FXR agonist to be used in human drug studies. [ medical citation needed ]


The  FDA  has flagged cases of serious liver injury associated with the use of obeticholic acid. [ 8 ]  The agency stated that  Intercept Pharmaceuticals ’ liver disease medication, Ocaliva (obeticholic acid), is under scrutiny for causing liver damage in patients without advanced scarring. [ 9 ]  This follows the FDA’s 2021 decision to restrict the drug’s use in patients with advanced  cirrhosis . On Thursday, the FDA revealed its findings of severe liver injury in individuals treated for  primary biliary cholangitis  based on post-market clinical trial data. [ 10 ]


Obeticholic acid is undergoing [ when? ]  development in phase II and III studies for specific liver and gastrointestinal conditions. [ 11 ]  The U.S.  Food and Drug Administration  (FDA) approved obeticholic acid on 27 May 2016, for the treatment of primary biliary cholangitis. It was approved as an  orphan drug  based on its reduction in the level of the biomarker  alkaline phosphatase  as a surrogate endpoint for clinical benefit. [ 12 ]  It is indicated for the treatment of primary biliary cholangitis in combination with ursodeoxycholic acid in adults with an inadequate response to UDCA, or as monotherapy in adults unable to tolerate UDCA. [ 13 ]  Additional studies are being required to prove its clinical benefit. [ 14 ]


Primary biliary cholangitis  (PBC), also known as primary biliary cirrhosis, is an auto-immune, inflammatory liver disease which produces  bile duct  injury,  fibrosis ,  cholestasis  and eventual  cirrhosis . [ 15 ]  It is much more common in women than men and can cause  jaundice , itching ( pruritus ) and fatigue.  Ursodeoxycholic acid  therapy is beneficial, but the disease often progresses and may require  liver transplantation . [ 16 ]  Animal studies suggested that treatment with FXR agonists should be beneficial in cholestatic diseases such as PBC. [ 17 ]  OCA at doses between 10 mg and 50 mg was shown to provide significant biochemical benefit, but pruritus was more frequent with higher doses. [ 18 ] [ 19 ]   The results of a randomized, double-blind phase III study of OCA, 5 mg or 10 mg, compared to placebo (POISE) were presented in April 2014, and showed that the drug met the trial's primary endpoint of a significant reduction in serum  alkaline phosphatase , a  biomarker  predictive of disease progression, liver transplantation or death. [ 20 ]


Non-alcoholic steatohepatitis  is a common cause of abnormal liver function with  histological  features of  fatty liver ,   inflammation  and  fibrosis . It may progress to  cirrhosis  and is becoming an increasing indication for  liver transplantation . It is increasing in prevalence. OCA is proposed to treat NASH. [ 21 ]  A phase II trial published in 2013, showed that administration of OCA at 25 mg or 50 mg daily for six weeks reduced markers of liver inflammation and fibrosis and increased insulin sensitivity. [ 22 ]


The Farnesoid X Receptor Ligand Obeticholic Acid in Nonalcoholic Steatohepatitis Treatment (FLINT) trial, sponsored by  NIDDK , was halted early in January 2014, after about half of the 283 subjects had completed the study, when a planned interim analysis showed that a) the primary endpoint had been met and b) lipid abnormalities were detected and arose safety concerns. Treatment with OCA (25 mg/day for 72 weeks) resulted in a highly statistically significant improvement in the primary histological endpoint, defined as a decrease in the NAFLD Activity Score of at least two points, with no worsening of fibrosis. 45% (50 of 110) of the treated group had this improvement compared with 21% (23 of 109) of the placebo-treated controls. [ 23 ]  However concerns about longterm safety issues such as increased cholesterol and adverse cardiovascular events may warrant the concomitant use of statins in OCA-treated patients. [ 24 ]


In 2023, a FDA panel voted against approval of obeticholic acid for NASH, citing a lack of evidence that the benefits of the drug outweighed the risks. [ 25 ] [ 26 ]


Animal studies suggest that OCA improves intrahepatic vascular resistance and so may be of therapeutic benefit in  portal hypertension . [ 27 ]  An open label phase IIa clinical study is under way. [ when? ] [ citation needed ]


Bile acid diarrhea  (also called  bile acid malabsorption ) can be secondary to  Crohn's disease  or be a primary condition.  Reduced median levels of  FGF19 , an  ileal  hormone that regulates increased hepatic bile acid synthesis, have been found in this condition. [ 28 ]  FGF19 is potently stimulated by bile acids and especially by OCA. [ 29 ]  A proof of concept study of OCA (25 mg/d) has shown clinical and biochemical benefit. [ 30 ]


In June 2024, the  Committee for Medicinal Products for Human Use  of the  European Medicines Agency  concluded its review of the medicine Ocaliva (obeticholic acid) and recommended that the medicine's marketing authorization be revoked, because its benefits are no longer considered to outweigh its risks. [ 3 ] [ 31 ] [ 32 ]  Ocaliva is used to treat adults with primary biliary cholangitis, an autoimmune condition that causes gradual destruction of the bile ducts in the liver, which can lead to liver failure and increase the risk of liver cancer. [ 31 ]


A systematic review and meta-analysis of obeticholic acid, published in 2024, found that its effects on lipid parameters and its other adverse effects warrant further investigation. [ 33 ]


Pegunigalsidase alfa , sold under the brand name  Elfabrio , is an  enzyme replacement therapy  for the treatment of  Fabry disease . [ 2 ] [ 4 ]  It is a recombinant human  α-galactosidase-A . [ 4 ]  It is a hydrolytic lysosomal neutral glycosphingolipid-specific enzyme. [ 2 ]


The most common side effects are infusion-related reactions, hypersensitivity and asthenia. [ 4 ]


Pegunigalsidase alfa was approved for medical use in both the European Union and the United States in May 2023. [ 4 ] [ 3 ]


Pegunigalsidase alfa is  indicated  for long-term enzyme replacement therapy in aduls with a confirmed diagnosis of Fabry disease (deficiency of alpha-galactosidase). [ 2 ] [ 4 ]


On 23 February 2023, the  Committee for Medicinal Products for Human Use  (CHMP) of the  European Medicines Agency  (EMA) adopted a positive opinion, recommending the granting of a marketing authorization for the medicinal product Elfabrio, intended for the treatment of Fabry disease. [ 4 ]  The applicant for this medicinal product is Chiesi Farmaceutici S.p.A. [ 5 ] [ 6 ]  Elfabrio was approved for medical use in the European Union in May 2023. [ 4 ]


Pegvaliase , sold under the brand name  Palynziq , is a medication used for the treatment of the genetic disease  phenylketonuria  (PKU). [ 5 ] [ 9 ] [ 10 ]  It is a phenylalanine (Phe)‑metabolizing enzyme. [ 5 ]  Chemically, it is a  pegylated   derivative  of the enzyme  phenylalanine ammonia-lyase  that metabolizes  phenylalanine  to reduce its blood levels. [ 5 ]


The most common adverse events include injection site reactions, joint pain, hypersensitivity reactions, headache, generalized skin reactions lasting at least 14 days, pruritus (itchy skin), nausea, dizziness, abdominal pain, throat pain, fatigue, vomiting, cough and, diarrhea. [ 9 ]


It was approved by the US  Food and Drug Administration  (FDA) for use in the United States in 2018. [ 9 ]  The FDA considers it to be a  first-in-class medication . [ 11 ]


Pegvaliase is  indicated  to reduce blood Phe concentrations in adults with phenylketonuria who have uncontrolled blood Phe concentrations greater than 600 micromol/L on existing management. [ 5 ]


The FDA label for pegvaliase includes a  boxed warning  for anaphylaxis.


The safety and efficacy of pegvaliase were studied in two clinical trials in adult participants with PKU with blood phenylalanine concentrations greater than 600 μmol/L on existing management. [ 9 ]  Most PKU participants in the pegvaliase trials were on an unrestricted diet prior to and during the trials. [ 9 ]  The first trial was a randomized, open-label trial in participants treated with increasing doses of pegvaliase administered as a subcutaneous injection up to a target dose of either 20 mg once daily or 40 mg once daily. [ 9 ]  The second trial was an 8-week, placebo-controlled, randomized withdrawal trial in participants who were previously treated with pegvaliase. [ 9 ]  Participants treated with pegvaliase achieved statistically significant reductions in blood phenylalanine concentrations from their pre-treatment baseline blood Phe concentrations. [ 9 ]


The FDA granted approval of Palynziq to BioMarin Pharmaceutical. [ 9 ]


Plaunotol  ( 18-hydroxygeranylgeraniol ) is a chemical compound with the molecular formula C 20 H 34 O 2 .  It is a  diterpene  that was first isolated from  Croton sublyratus . [ 1 ]


Plaunotol has been identified as present in  Croton sublyratus [ 1 ]  and  Croton stellatopilosus . [ 2 ]   In plants, the compound is  biosynthesized  by  hydroxylation  of  geranylgeraniol , a reaction which is catalyzed by the enzyme  geranylgeraniol 18-hydroxylase . [ 3 ]   A laboratory synthesis of plaunotol has been reported. [ 4 ]


Plaunotol has antibacterial activity against  Helicobacter pylori , the bacteria that causes  gastric ulcers . [ 5 ]   In Japan, plauntool is used as a pharmaceutical drug under the trade name Kelnac for the treatment of  gastritis  and gastric ulcers. [ 6 ]


Plecanatide , sold under the brand name  Trulance , is a  medication  for the treatment of  chronic idiopathic constipation  (CIC) [ 4 ]  and  irritable bowel syndrome  with constipation. [ 5 ]   It is available in India under the brand name  Plectide  (OQM Div, MSN Laboratories, India). Plecanatide is an  agonist  of  guanylate cyclase-C . Plecanatide increases intestinal transit and fluid through a buildup of  cGMP . [ 6 ] [ 7 ]


As of January 2017, plecanatide is approved in the United States for the treatment of  chronic idiopathic constipation  in adults. [ 4 ]  later it was also approved for irritable bowel syndrome with constipation (IBS-C). [ 8 ]


The presence of this condition is determined using the  Rome  III diagnostic criteria for chronic constipation which requires that the patient meet stool frequency, stool consistency, incomplete evacuation, and straining requirements in addition to not being a likely candidate for irritable bowel syndrome. [ 5 ] [ 9 ]  The symptoms should also have been present for at least three of the last six months to establish the chronic nature of the condition before treatment with plecanatide is indicated. [ 9 ]


Plecanatide has been shown to be safe and effective. It has shown to be at least equally as effective as its main competitor,  linaclotide  (brand name Linzess), but has been shown to have a lower rate of diarrhea as an adverse drug reaction. [ 10 ]


The recommended dosage of plecanatide is 3 mg taken by mouth once daily. [ 8 ] [ 11 ]


A plecanatide tablet can be taken with or without food and should be swallowed whole. For adults with swallowing difficulties, plecanatide tablets can be crushed and administered orally either in apple sauce or with water or administered with water via a nasogastric or gastric feeding tube. [ 11 ]


Plecanatide has not been shown to be safe or effective in persons 6 years to 18 years of age. [ 12 ]  Use of plecanatide by persons under the age of 6 poses a serious dehydration risk and studies have demonstrated plecanatide can cause death in juvenile mice due to this dehydrating effect. [ 12 ]


Use of plecanatide is also contraindicated in persons who are suspected of having a mechanical gastrointestinal obstruction. [ 12 ]


Plecanatide is a 16 amino acid peptide with the amino acid sequence:


(one-letter sequence: NDECELCVNVACTGCL). Plecanatide is nearly structurally identical to human  uroguanylin , apart from the substitution of Asp 3  with Glu 3 . [ 13 ]   Disulfide bonds  exist between Cys 4  and Cys 12 , as well as Cys 7  and Cys 15 . [ 14 ]


Plecanatide has two important motifs. The first being the acidic residues Asp 2  and Glu 3  which modulate the affinity for its receptor in response to environmental pH. [ 12 ] [ 13 ] [ 15 ]  Simulations predict the optimal activity of Plecanatide to occur at pH 5,  making it suitable for targeting cells within the proximal intestine, which has a pH of between 5 and 6. [ 12 ]  The second is the ACTGC motif (residues Ala 11  to Cys 15 ) which is the region responsible for its binding to the receptor, guanylate cyclase-C. [ 16 ]


Plecanatide works as a laxative by drawing water in to the gastrointestinal tract thereby softening stool and encouraging its natural passage.


Similar to its endogenous counterpart, plecanatide activates guanylate cyclase-C on endothelial cells within the gastrointestinal tract. [ 13 ]   The activation of guanylate cyclase-C catalyses the production of the second messenger guanosine 3’,5’-cyclic monophosphate (cGMP) which leads to the protein kinase A (PKA) and protein kinase G II (PKGII)-mediated phosphorylation of the  cystic fibrosis transmembrane conductance regulator  (CFTR) protein. [ 17 ] [ 18 ]  CFTR is an anion channel and upon activation it will secrete negatively charged ions, particularly chloride (Cl − ) and bicarbonate (HCO 3 − ) in to the GI tract lumen. [ 19 ] [ 20 ]  This disruption to the electrochemical gradient is in part rectified by the passive secretion of positively charged sodium ions in to the lumen and water follows by osmosis. [ 19 ]


Plecanatide is also known to have an anti-nociceptive effect in animal models, however the exact mechanism of action is not yet fully elucidated. [ 12 ]  It has been suggested that this may be in part to the anti-inflammatory action of guanylate cyclase-C by its inhibition of pro-inflammatory cytokines, or through the inhibition of associated sensory neurons. [ 21 ]


As plecanatide acts on receptors present on the apical side of endothelial cells lining the gastrointestinal tract it is able to impart its effect without ever entering circulation. [ 13 ]  As with most orally ingested peptides, plecanatide is degraded by intestinal enzymes, and so very little of the active drug enters systemic circulation. [ 12 ]  Minimal amounts of the drug are expected to be transported in to the body, and concentrations of plecanatide and its metabolites are undetectable in plasma following the recommended dosage of 3 mg. [ 12 ] [ 13 ]  It has also been shown that dosages up to 48.6 mg produced no detectable concentration of plecanatide in human plasma at any time point after ingestion. [ 13 ]


Polymethylsiloxane polyhydrate  ( PMSPH ), or methylsilicic acid hydrogel (brand name —  Enterosgel ), is an enterosorbent [ 1 ]  used for binding and removing various toxic substances, infectious agents and metabolites from the gastrointestinal tract. It is available in the form of a homogeneous pasty mass of white or almost white colour, odorless and tasteless.


This product was synthesized in the late 1970s - early 1980s in the  USSR  by I. B. Slinyakova and I. М. Samodumova of L. B. Pisarzhevskiy Institute of Physical Chemistry [ 2 ]  ( Kyiv ), where the theoretical foundations for the formation of the porous structure of organosilicon adsorbents with an adjustable porous structure and a pre-defined chemical nature of the surface were established; there were also efforts to synthesize organosilicon adsorbents, namely porous polymers polyorganosiloxanes. Industrial production of the preparation began in early 1991. [ 3 ]  In 1994, a medicinal drug with methylsilicic acid hydrogel as the active ingredient, marketed under the brand name Enterosgel, was registered in Ukraine and Russia, and active sales of the new product began.


Currently, the product is already available in 40 countries.


The study of the use of the preparation was conducted in cooperation with the Medical Service of Krasnoznamennyi Kiev Military District (Medical Service Colonel Professor F. G. Novikov, Medical Service Colonel N. P. Bezlyuda). [ 4 ]  Since, many clinical trials investigating the preparation have been conducted by Ukrainian and Russian companies in the CIS.


A large-scale study of its effect was conducted in the United Kingdom between 2019 and 2022. It established a proven base of effectiveness of the preparation in the treatment of irritable bowel syndrome with diarrhea, help in relieving bloating, abdominal pain and urgency. [ 3 ]


The preparation is registered in Russia and the CIS countries as a medicinal drug, [ 5 ]  and in the countries of the European Union, Serbia, New Zealand, Africa as a medical device, since the product is not absorbed into the bloodstream and acts as an adsorbent only in the gastrointestinal tract, it fits the relevant definition according to the Classification of the European Commission.


The medical device Enterosgel is produced in a modern high-tech factory in Jeseník, Czech Republic, from where it is exported to all countries of the world, except Russia and the CIS countries. This region supplies production in Russia, where a factory is situated in the city of Dankov.


Enterosgel (PMSPH) or methylsilicic acid hydrogel is a polymeric gelatinous organosilicon compound. The gel is dispersed in water to a particle size of no more than 300 microns. The preparation is a  suspension  which is taken orally


Electron microscopic studies have shown that its gel-forming matrix has a globular structure and consists of an ensemble of fused globules. These globules, bound together by siloxane bonds, form pores. The pores are the spaces between the globules. They are filled with water. Pore size is restricted. [ 6 ] : 38   The presence of methyl groups on the surface ensures its hydrophobic properties. [ 6 ] : 27   Enterosgel particles (PMSPH) tend to form a continuous network in a suspension to reduce the interaction of hydrophobic SiCH 3  with water. These particles can be viewed as two-dimensional sheets rather than three-dimensional solid particles. Aqueous suspensions of polymethylsiloxane polyhydrate are characterized by high viscosity. [ 7 ]


The physical and chemical characteristics of Enterosgel define its absorptive and protective properties:


It absorbs toxic substances produced in the gastrointestinal tract, as well as toxic substances entering the gastrointestinal tract from the environment (e.g., ethyl alcohol). [ 11 ]  It also prevents reabsorption of toxic substances and metabolites excreted into the intestinal lumen from the blood, as well as getting into the intestine with bile.


In an  in vitro  experiment, it reduced the production of staphylococcal enterotoxin and inhibited the growth of  Staphylococcus aureus . [ 12 ]


It reduced malonic dialdehyde formation and increased integral antiradical activity in toxic liver damage  in vivo . [ 13 ]


Due to adsorption in the gastrointestinal tract, it helps reduce blood sugar and  glycated hemoglobin  levels, eliminate lipid distress syndrome, including diabetic dyslipidemia, improves energy processes in liver tissues in experimental diabetes. [ 14 ]


Enterosgel (PMSPH) firmly binds and excretes pathogenic bacteria [ 15 ]  and  rotaviruses . [ 16 ] [ 17 ]


Highly viscous PMSPH particles cover mucosal areas and protect them from the damaging effects of bacterial toxins and various active chemical compounds (e.g., deconjugated bile salts that damage the mucosa of the gastrointestinal tract).


Enterosgel has a pronounced ability to absorb lipopolysaccharide molecules. Large molecules of lipopolysaccharide are co-precipitated in the gel and excreted from the body. [ 9 ]  A daily dose of PMSPH (Enterosgel paste) binds 410 mg of LPS. [ 18 ]


Lipopolysaccharide  (LPS), which has extremely high biological activity, can be found in the outer wall of all  Gram-negative bacteria  and is released only when the bacterium is destroyed, and is also known as  endotoxin  (the prefix endo- means inside, inside the bacterium). The distal section of the intestine is the main reservoir of Gram-negative microflora and lipopolysaccharides. Normally, only a small amount of endotoxin enters the bloodstream because the intestinal wall works as a barrier and limits the inflow of endotoxin into the bloodstream. Most (94%) of the endotoxin entering the bloodstream undergoes detoxification in the liver. However, a small amount of endotoxin bypasses the liver and enters the systemic bloodstream, maintaining physiological concentration of endotoxin in the blood (physiological endotoxinemia).


The process of endotoxin entering the bloodstream can be intensified by various lesions of the intestinal mucosa and by dysbacteriosis, which is accompanied by translocation of bacteria and products of their life activity into the small intestine [ 19 ]  and as a result of antibiotic-induced death of Gram-negative microflora and the release of large amounts of endotoxin. [ 20 ]  It should be particularly emphasized that various stressful situations (severe seizures, burns, trauma, etc.) cause damage to the mucous membrane of the gastrointestinal tract. This damage occurs due to redistribution of energy and structural resources of the body, i.e. transfer from systems not involved in adaptation to the stress factor to systems providing adaptation. [ 21 ]  An increase in the concentration of endotoxin in the blood exceeding the physiological norm leads to a pathological condition known as endotoxin aggression. Endotoxin aggression is a universal factor in the pathogenesis of human diseases, the development of which is caused by an excess of endotoxin entering the general bloodstream and a lack of endotoxin-binding systems. [ 22 ] [ 23 ] [ 24 ] [ 25 ] [ 26 ] [ 27 ]  Excess endotoxin causes endothelial damage [ 28 ]  in the microcirculatory vessels of the intestinal mucosa and leads to the development of mucosal ischemia. This, in turn, causes further damage to the mucosa and a weakening of the intestinal barrier.


Reduction of endotoxin back to physiological levels in the blood prevents damage to the vascular wall and restores impaired blood supply to the intestinal mucosa and eliminates mucosal ischemia. The latter, in turn, contributes to its regeneration and restoration of the barrier function of the intestinal mucosa. The positive effect of using Enterosgel (PMSPH) is primarily aimed at preserving/restoring the intestinal barrier, restoring the physiological level of endotoxin and breaking the vicious circle caused by damage to the mucous membrane. This inhibits the development of endotoxin aggression.


From the left:  As a result of intestinal barrier insufficiency, there is an increase in the concentration of LPS in the mucosal bloodstream, which leads to impaired microcirculation and ischemia of the mucosa, its damage and further development of intestinal barrier insufficiency. Endotoxin aggression develops.


From the right:  The use of Enterosgel ( PMSPH ) reverses the course of events: the level of LPS is reduced, microcirculation processes in the intestinal mucosa are restored, the intestinal mucosa is restored, and the function of the intestinal barrier is restored (more details) .


Notes


Figure 1:  As a result of insufficiency of the intestinal barrier, the concentration of LPS in the blood flow of the mucous membrane increases, which leads to disruption of microcirculation and ischemia of the mucous membrane, its damage and further development of intestinal barrier insufficiency. Endotoxin aggression develops.


Figure 2:  The use of Enterosgel (PMS PH) reverses the course of events: the level of LPS decreases, microcirculation processes in the intestinal mucosa are restored, and so are the intestinal mucosa and the functions of the intestinal barrier (more) .


PMSPH is not absorbed in the gastrointestinal tract and is excreted in an unchanged form within 12 hours.


It binds and removes endogenous and exogenous toxic substances of various nature, including bacteria and bacterial toxins, antigens, food allergens, drugs and poisons, salts of heavy metals, alcohol, from the lumen of the gastrointestinal tract. It also sorbs some metabolic products of metabolism, including excess bilirubin, urea, cholesterol, and lipid complexes, as well as metabolites responsible for the development of endogenous  intoxication . [ 29 ]


Indications for use [ 7 ]


Enterosgel (PMSPH) is used in adults and children for the treatment and prevention of acute and chronic intoxications of various etiology (e.g. alcohol intoxication, [ 30 ]  botulism, [ 31 ]  mushroom poisoning [ 32 ] ) including  viral  and bacterial ones.


The efficacy and safety of the drug for registered indications is continuously monitored as part of routine pharmacovigilance according to Eurasian Union and European Union (GVP) requirements. [ 33 ] [ 34 ]


The results of randomized clinical trials, including double-blind placebo-controlled trials, in Russia, the CIS, Europe, etc., are evaluated.


In the 2022 RELIEVE IBS-D randomized double blinded placebo controlled study was published in the GUT journal. The study confirmed safety and efficacy in treatment of Irritable bowel syndrome with diarrhea. Enterosgel was effective in relieving the abdominal pain, diarrhoea, bloating and urgency. [ 4 ]


Enterosgel is included in the clinical guidelines of state and non-state medical organizations of healthcare professionals in the CIS countries. [ 35 ]


For example in a study in Croatia, it was used as concomitant therapy in women receiving radiotherapy and chemotherapy for pelvic cancer, and the results showed that it had an effect on the reduction of intoxication symptoms (nausea, vomiting, etc.). [ 36 ]


It has been successfully used for hyperbilirubinemia (viral hepatitis, [ 37 ] ) [ 38 ] [ 39 ] [ 40 ]  including for hemolytic disease in newborns. [ 40 ]


Also in chronic renal insufficiency (hyperazotemia). [ 41 ]  It has proved itself in the treatment of allergic diseases such as atopic dermatitis. [ 42 ] [ 43 ]  When indicated, it is used to treat gastroenterological disorders. [ 44 ]  Thus, it is recommended for the treatment of acute [ 45 ] [ 46 ]  and chronic  diarrhea , [ 47 ] [ 48 ]  dysbiosis [ 49 ] [ 50 ]  including diarrhea of non-infectious origin, [ 51 ] [ 4 ]  including for the treatment of  irritable bowel syndrome  with diarrhea. [ 4 ]  In acute and chronic infectious and inflammatory diseases, it is used in obstetrics [ 52 ]  and gynecology, since it is approved for use in pregnant women and children from birth. [ 53 ] [ 54 ]


Proctosedyl  is the brand name for a family of two products with identical  active ingredients  designed to treat a variety of  proctological  disorders. One is a  topical   ointment , the other a  rectal   suppository . In the  United Kingdom  both products are contract manufactured by  Patheon Limited  on behalf of the  Sanofi-Aventis  group. [ 1 ] [ 2 ]  Manufacture and distribution is provided by Sanofi Aventis subsidiaries [ 3 ]   Hoechst and Hoechst Marion Roussel  in other territories worldwide. [ 4 ]


Both the yellowish-white, translucent, greasy ointment [ 1 ]  and the smooth, off-white suppositories [ 2 ]  are formulated for the relief of chronic  pruritus ani  (otherwise known anal itching or anusitis) [ 1 ] [ 2 ] [ 5 ]  and the treatment of pain, irritation, discharge and itching associated with  haemorrhoids  (otherwise known as piles). [ 1 ] [ 2 ] [ 5 ]  However both products are also used to provide pain relief in the treatment of  anal fissure , [ 6 ] [ 7 ] [ 8 ]  for patients undergoing  haemorrhoidectomy , (pre and post-operative), [ 8 ]  in the relief of  post-partum  (otherwise known as post-natal) haemorrhoidal conditions, [ 8 ] [ 9 ]  and in the treatment of non-infective  proctitis . [ 8 ]


Both preparations contain:


Preparations in some territories may also contain:


Prostaglandin analogues  are a  class of drugs  that bind to a  prostaglandin receptor . [ 1 ]


Wider use of prostaglandin analogues is limited by unwanted side effects and their  abortive  potential. [ citation needed ]


Prostaglandin analogues such as  misoprostol  are used in treatment of  duodenal  and  gastric ulcers . [ 2 ]  Misoprostol and other prostaglandin analogues protect the lining of the gastrointestinal tract from harmful stomach acid and are especially indicated for the  elderly  on continuous doses of  NSAIDs .


In the field of  ophthalmology , drugs of this class are used to lower  intraocular pressure  (IOP) in people with  glaucoma .  Up until the late 1970s prostaglandins were thought to raise IOP, but a paper published in 1977 showed that  prostaglandin F2α  lowered it, and subsequent studies found that this was due to increasing the outflow of  aqueous humor , mainly by relaxing the  ciliary muscle , and possibly also due to changes in  extracellular matrix  and to widening of spaces within the  trabecular meshwork . [ 1 ]   This work led to the development of  prodrugs  of PGF2α, including  latanoprost , an isopropyl analogue of PGF2α, approved by the FDA in 1996,  bimatoprost  and  travoprost , both approved in 2001, and  tafluprost , approved in 2012. [ 1 ]    However, there are notable side effects associated with usage, including increased eyelash growth, pigmentation of the iris, and darkening of the skin around the eye. [ 3 ]


This  drug  article relating to the  blood  and  blood forming organs  is a  stub . You can help Wikipedia by  expanding it .


This  drug  article relating to the  genito-urinary system  is a  stub . You can help Wikipedia by  expanding it .


A  reflux suppressant  is any one of a number of  drugs  used to combat  oesophageal reflux . [ 1 ] [ 2 ]  Commonly, following ingestion a 'raft' of  alginic acid  is created, floating on the stomach contents by carbon dioxide released by the drug. This forms a mechanical barrier to further reflux. Some preparations also contain  antacids  to protect the  oesophagus . [ 3 ]


Reflux can also be coincidentally reduced by the  motility stimulants  and  antidopaminergics . [ citation needed ]


Relamorelin  ( INN ,  USAN ) (developmental code names  RM-131 ,  BIM-28131 ,  BIM-28163 ) is a  synthetic   peptide ,  centrally penetrant , selective  agonist  of the  ghrelin/growth hormone secretagogue receptor  (GHSR) which is under development by  Allergan pharmaceuticals  for the treatment of  diabetic gastroparesis ,  chronic idiopathic constipation , and  anorexia nervosa . [ 1 ] [ 2 ] [ 3 ]  It is a  pentapeptide  and an  analogue  of  ghrelin  with improved  potency  and  pharmacokinetics . [ 1 ] [ 2 ]  In humans, relamorelin produces increases in  plasma   growth hormone ,  prolactin , and  cortisol  levels, [ 2 ] [ 4 ]  and, like other GHSR agonists, increases  appetite . [ 3 ]  As of June 2015, relamorelin is in  phase II   clinical trials  for diabetic gastroparesis and constipation. [ 5 ]  The United States  Food and Drug Administration  (FDA) has granted  Fast Track  designation to relamorelin for diabetic gastroparesis. [ 6 ]  The development of the drug is uncertain as the most recent mention of it was in a 2019 SEC filing from the drug manufacturer lists the drug's expected launch year as 2024, but not in subsequent filings or press releases. [ 7 ] [ 8 ]


This  hormonal preparation  article is a  stub . You can help Wikipedia by  expanding it .


Rolaids  is an American brand of calcium and magnesium-based  antacid  produced by  Procter & Gamble .  It was invented by  American   chemist   Irvine W. Grote  in the late 1920s, and originated with manufacturing in  Chattanooga, Tennessee , under one of Chattem's forerunner companies, which manufactured the brand for  Warner-Lambert ; Warner-Lambert merged with Pfizer in 2000.


In 2006,  McNeil Consumer Healthcare , a subsidiary of  Johnson & Johnson , acquired the brand from  Pfizer  Consumer Healthcare. In 2013, McNeil sold the brand to Sanofi, [ 1 ]  following a two-year period where the brand was pulled off the market due to  product recalls  resulting from  quality control  and manufacturing issues that also kept former fellow antacid brand  Pepcid AC 's "chewables" product and other fellow McNeil products like some varieties of  Tylenol  off store shelves for the same period. [ 2 ]  Rolaids returned to the market at the beginning of September 2013 under Chattem ownership with new packaging,  trade dress , and a new liquid variety. On March 27, 2024, the brand was acquired by  Procter & Gamble . [ 3 ]


Rolaids tablets come in many different flavors, including original peppermint, cherry, freshmint, fruit, tropical, punch, cool mint, berry, and apple.


McNeil Consumer Healthcare voluntarily recalled Rolaids products in the Americas, the United Arab Emirates (UAE), and Fiji on January 15, 2010, in consultation with the FDA. The company initiated the recall following an investigation of consumer reports of an unusual moldy, musty, or mildewlike odor that, in a small number of cases, was associated with temporary and nonserious gastrointestinal events. These events included nausea, stomach pain, vomiting, and diarrhea. At that time, the Rolaids website carried the following statement regarding product availability: "You may have noticed that ROLAIDS® products are not available at your local retailers. We are changing some of our manufacturing facilities where our products are made, a process that will take time to complete. We apologize for the inconvenience this may be causing you. Your health and comfort are important to us, and we assure you we are working hard to get ROLAIDS® product back on store shelves." [ 4 ]


Another recall was issued around December 9, 2010, as a result of foreign objects that contained metal and wood particles. [ 5 ]  The foreign materials were caused by a third-party manufacturer during the production process. [ 5 ]  Several people complained when they took the product; they also had vomiting, strange taste, and tooth and gum injury. [ 5 ]  After this recall, beyond the small "candy aisle" rolls and chewable lines, the Rolaids line of products was drastically reduced and disappeared from most American retailers until Chattem returned the product to the market in the fall of 2013.


Rolaids' best-known commercial from the 1970s featured the famous tag line:


In connection with the famous slogan, Rolaids sponsored the  Major League Baseball  award for top  relief pitchers  called the  Rolaids Relief Man of the Year Award . The award was given yearly from 1976 through 2012.


Pfizer  released a new version of Rolaids on April 6, 2006, [ 6 ]  branded  Extra Strength Rolaids Plus Gas Relief Softchews . The product was produced as an alternative for people averse to the chalky consistency of regular Rolaids. They were widely advertised in multiple media formats.


Rolaids Softchews were originally developed and test marketed in Oklahoma City under the brand name Remegel by Warner Lambert in 1984.


The  active ingredients  are  calcium carbonate  (550 mg) and  magnesium hydroxide  (110 mg). The inactive ingredients are  dextrose ,  flavoring ,  magnesium stearate ,  polyethylene glycol ,  pregelatinized starch , sucralose and  sucrose . The new Chattem varieties have increased the amount of the active ingredients in the product, up to 1000 mg of calcium carbonate and 200 mg of magnesium hydroxide for the "ultra strength" varieties.


Minor side effects may include constipation or stomach cramps. Serious side effects include loss of appetite, vomiting, dizziness, and headache. [ 7 ]


Seidlitz powders  is the generic name under which a commonly known  laxative  and digestion regulator was  marketed  and sold by numerous manufacturers under names such as "Rexall Seidlitz Powders", particularly in the late 19th and early 20th centuries. [ 1 ]


The three ingredients of Seidlitz powders ( tartaric acid ,  potassium sodium tartrate  and  sodium bicarbonate ) were manufactured by chemical factories from the mid-19th century onwards. The name 'Seidlitz powders' ultimately derives from the village of  Sedlec  in the  Czech Republic .  See also  § Etymology  below .


The municipality of Sedlec (somewhat confusingly) is also the source of 'Sedlitz bitter water'  ( see also  § Sedlitz water  below ), a naturally occurring  spa  mineral water which has an entirely different chemical composition and side-effects from Seidlitz powders: there is apparently no connection between the two products except the name. [ 2 ]


The powders were often packaged in a small envelope containing two coloured paper wraps, one white and one blue. The white packets contained  tartaric acid , and the blue packets contained a mixture of 75%  w/w  Rochelle salt ( potassium sodium tartrate ) and 25% baking soda ( sodium bicarbonate ). The powdery contents of both packets were stirred or dissolved separately in water and then mixed, giving off carbon dioxide with a characteristic fizzing sound. [ 3 ]  The drink was described as "a cooling, agreeable draught". [ 4 ]


After ingestion, the powder combines with gastric juices to develop  cathartic  intestinal gases which can be somewhat helpful in evacuating the users' bowels. However, their use can also lead to unpleasant side effects, [ 5 ]  and can even be fatal [ 6 ]  in subjects with conditions such as  hernia ,  bowel obstruction  or other ailments.


Seidlitz powders, manufactured by numerous chemical factories from the early 19th century onwards, take their name from the village of  Sedlec  near  Most ,  Czech Republic  (previously in  Bohemia ). The village seems to have received its Germanic name (Seidlitz) some time after 1526, when the  Battle of Mohács  brought about the collapse of  Medieval Hungary . The  Lands of the Bohemian Crown  fell under the control of the  Habsburgs , the German-speaking rulers of Austria (later the  Austro-Hungarian Empire ).


Although Seidlitz powders have a  digestive  effect, they should not be confused with 'Sedlitz water' (also named for Sedlec), a well-known bitter mineral water which has been used since the 16th century as a digestion regulator and  laxative . Sedlec (Seidlitz) was described in an 1867 guide to European  spa towns  as "a wretched-looking place, hardly meriting the name of a village, and the wells - whence the water should be derived - are a few shallow, circular pits, whose contents very seldom find their way to this country [ie England]." The Sedlitz water has a chemical analysis similar to sources in nearby towns such as  Zaječická hořká  from Zajecice (NB German name 'Seidschitz' bitter water'),  Korozluky  (Ger: Kollosoruk) and  Bílina  (Bylany or Püllna). The water itself was characterized as "a yellowish, somewhat oily-looking fluid, with a nauseous, intensely bitter taste." [ 7 ]


These and similar products - with somewhat interchangeable terminology - appear to have no connection with Seidlitz powders. Likewise, the powders have little connection (apart from the digestive effect) with these types of mineral-rich water which were evaporated and the residue formed into pills such as  Bilina  digestive  pastilles , not unlike  Vichy pastilles .


Though rarely used today, the term "Seidlitz powder" lives on as a lyric from the  popular song  " A Fine Romance " by  Jerome Kern  and  Dorothy Fields . Written for the 1936 musical film,  Swing Time , with  Fred Astaire  and  Ginger Rogers , it was released on a 1956 jazz album by  Ella Fitzgerald  and  Louis Armstrong ,  Ella and Louis Again , with the lines "We two should be like clams in a dish of chowder / But we just fizz like parts of a Seidlitz powder."


"Sounds like a seidlitz powder" is in a  O. Henry  story, "The Foreign Policy of Company 99".


One of the four clerks of Dodson and Fogg is mixing a "Seidlitz Powder," perhaps to treat a hangover, in chapter 20 of  Charles Dickens '  Pickwick Papers .


Noël Coward  would tease the US theatre critic  Alexander Woollcott  “by recalling that one of [the latter’s] critical colleagues had called him ‘the Seidlitz Powder of Times Square’.” [Barry Day (2021), Noël Coward On & In Theatre, Alfred Knopf: New York, p.279]


Sofalcone  ( INN ) is an oral  gastrointestinal   medication  used in Japan. [ 1 ]   It is a synthetic  analog  of  sophoradin , [ 2 ]  a type of natural phenol found in  Sophora tonkinensis , an herb used in  traditional Chinese medicine .


Sucralfate , sold under various brand names, is a  medication  used to treat  stomach ulcers ,  gastroesophageal reflux disease  (GERD),  radiation proctitis , and  stomach inflammation  and to prevent  stress ulcers . [ 3 ] [ 4 ] [ 5 ]  Its usefulness in people infected by  H. pylori  is limited. [ 3 ]  It is used by mouth (for upper GIT ulcers) and rectally (for radiation proctitis). [ 3 ] [ 5 ]


Common side effects include  constipation . [ 3 ]  Serious side effects may include  bezoar  formation and  encephalopathy . [ 6 ]  Use appears to be safe in  pregnancy  and  breastfeeding . [ 6 ]  How it works is unclear but is believed to involve binding to the ulcer and protecting it from further damage. [ 3 ] [ 6 ]


Sucralfate was approved for medical use in the United States in 1981. [ 3 ]  It is available as a  generic medication . [ 6 ] [ 7 ]  In 2022, it was the 214th most commonly prescribed medication in the United States, with more than 1   million prescriptions. [ 8 ] [ 9 ]


Sucralfate is used for the treatment of active  duodenal ulcers  not related to the use of  nonsteroidal anti-inflammatory drugs  (NSAIDs), as the  mechanism  behind these ulcers is due to acid oversecretion. [ 1 ]  It is not FDA approved for  gastric ulcers , but is widely used because of evidence of efficacy. [ 10 ]  The use for sucralfate in  peptic ulcer disease  has diminished recently, but it is still the preferred agent for  stress ulcer  prevention. [ 11 ] [ 12 ] [ 13 ] [ 14 ]


Sucralfate has also been used for the following conditions:


The most common  side effect  seen is  constipation  (2–3%). Less commonly reported side effects (<0.5%) include  flatulence ,  headache ,  hypophosphatemia ,  xerostomia  (dry mouth), and  bezoar  formation. [ 24 ] [ 25 ] [ 26 ]
Use of this drug is not recommended for people with  chronic kidney failure , as it might cause aluminium accumulation and  toxicity .
A few well-controlled studies have been carried out investigating the safety and efficacy of sucralfate in children and pregnant women ( Pregnancy Category  B). [ 1 ] [ 27 ] [ 28 ]


Sucralfate is a locally acting  substance  that in an acidic environment (pH < 4) reacts with  hydrochloric acid  in the  stomach  to form a cross-linking,  viscous , paste-like material capable of acting as an  acid buffer  for as long as 6 to 8 hours after a single  dose . [ 29 ]  It also attaches to  proteins  on the surface of ulcers, such as  albumin  and  fibrinogen , to form stable  insoluble  complexes. These complexes serve as protective barriers at the ulcer surface, preventing further damage from  acid ,  pepsin , and  bile . [ 29 ]  In addition, sucralfate prevents back  diffusion  of  hydrogen ions , and absorbs both pepsin and  bile acids .


It has been thought that sucralfate also stimulates the production of  prostaglandin  E 2 ,  epidermal growth factors  (EGF),  bFGF , and  gastric mucus . [ 1 ] [ 30 ]


Brand names include Carafate in the US, Sucramal in Italy, Sucrafil, Sufrate, Sucralpro, Sucralcoat, Pepsigard, Sucral, Hapifate, Sucralpro tablets and Sucralpro cream in India, Sutra or Musin in parts of South-East Asia, Sulcrate in Canada, Discral (sucralfato) in México, Ulsanic in South Africa and Israel, Andapsin in Sweden, Antepsin in Turkey, Sucracell in India, and Ulsidex in Indonesia


Sulfasalazine , sold under the brand name  Azulfidine  among others, is a  medication  used to treat  rheumatoid arthritis ,  ulcerative colitis , and  Crohn's disease . [ 5 ]  It is considered by some to be a first-line treatment in rheumatoid arthritis. [ 6 ]  It is taken  by mouth  or can be administered rectally. [ 5 ]


Significant side effects occur in about 25% of people. [ 6 ]  Commonly these include loss of appetite, nausea, headache, and rash. [ 5 ]  Severe side effects include  bone marrow suppression ,  liver problems ,  Stevens–Johnson syndrome , and  kidney problems . [ 6 ] [ 7 ] [ 4 ]  It should not be used in people allergic to  aspirin  or  sulfonamide . [ 6 ]  Use during  pregnancy  appears to be safe for the baby. [ 5 ]


Sulfasalazine is in the  disease-modifying antirheumatic drugs  (DMARDs) family of medications. [ 5 ]  It is unclear exactly how it works. [ 5 ]  One proposed mechanism is the inhibition of  prostaglandins , resulting in local  anti-inflammatory  effects in the colon. [ 4 ]  The medication is broken down by  intestinal bacteria  into  sulfapyridine  and  5-aminosalicylic acid . [ 5 ]


Sulfasalazine was approved for medical use in the United States in 1950. [ 5 ]  It is on the  World Health Organization's List of Essential Medicines . [ 8 ]  Sulfasalazine is available as a  generic medication . [ 5 ]  In 2020, it was the 284th most commonly prescribed medication in the United States, with more than 1   million prescriptions. [ 9 ] [ 10 ]


Sulfasalazine is used in the treatment of  inflammatory bowel disease , including  ulcerative colitis  and  Crohn's disease . It is also indicated for use in  rheumatoid arthritis  and used in other types of inflammatory arthritis (e.g.  psoriatic arthritis  and  reactive arthritis ). [ 11 ] [ 3 ] [ 2 ]


It is usually not given to children under two years of age. [ 3 ] [ 2 ]


Use of sulfasalazine is contraindicated in people with  sulfa allergies  and in those with  urinary tract obstructions ,  intestinal obstructions , and severe  liver  or  kidney problems . [ 4 ]


Sulfasalazine metabolizes to sulfapyridine. Serum levels should be monitored every three months, and more frequently at the outset. Serum levels above 50 μg/L are associated with side effects. In rare cases, sulfasalazine can cause severe  depression  in young males. It can also cause oligospermia and temporary  infertility . Immune  thrombocytopenia  has been reported. [ 12 ]


Sulfasalazine inhibits  dihydropteroate synthase , and can cause  folate deficiency  and  megaloblastic anemia . [ 13 ] [ 14 ] [ 15 ]  and various other undesirable effects. [ 16 ]


Sulfasalazine can cause  hemolytic anemia  in people with  G6PD deficiency . [ 17 ]


Sulfasalazine can cause kidney stones. [ 18 ]
Sulfasalazine may cause stomach upset,  nausea , vomiting, loss of  appetite , headache,  dizziness , or unusual tiredness. [ 5 ]  Skin and urine can become orange, with occasional allergic reactions. [ 19 ] [ 5 ]


Sulfasalazine may cause  sulfhemoglobinemia . [ citation needed ]


Around 90% of a dose of sulfasalazine reaches the colon, where most of it is metabolized by bacteria into  sulfapyridine  and  mesalazine  (also known as 5-aminosalicylic acid or 5-ASA). Both metabolites are active; most of the sulfapyridine is absorbed and then further metabolized, but most mesalazine is not, and remains in the colon. [ 3 ]


A mix of unchanged, hydroxylated, and glucuronidated sulfapyridine is eliminated in urine, as is acetylated mesalazine and unmetabolized sulfasalazine. [ 3 ] [ 2 ]


The mechanism of action is not clear, but it appears that sulfasalazine and its metabolites have  immunosuppressive , antibacterial, and anti-inflammatory effects. [ 11 ] [ 3 ]   It also appears to inhibit the  cystine - glutamate   antiporter , [ 20 ]  as well as  sepiapterin reductase . [ 21 ]


It is a  codrug  which is a combination of  sulfapyridine  and  5-aminosalicylic acid  coupled with an azo linkage.


In people with rheumatoid arthritis, the  cost-effectiveness  of sulfasalazine is improved by combining it with other drugs. [ 22 ]   It is commonly used in treating  inflammatory bowel disease  in part due to its cost effectiveness. [ 23 ]


Sulfasalazine has been studied in  cirrhosis , [ 24 ]   psoriasis , [ 25 ]  idiopathic  urticaria , [ 26 ]  and  amyloidosis . [ 27 ]


Sulglicotide  (or  sulglycotide ) is a  drug  used for  peptic ulcer  and  gastro-oesophageal reflux disease . [ 1 ]


A  suppository  is a  dosage form  used to deliver  medications  by insertion into a  body orifice  (any opening in the body), where it dissolves or melts to exert local or systemic effects. There are three types of suppositories, each to insert into a different sections: rectal suppositories into the  rectum , vaginal suppositories into the  vagina , and urethral suppositories into the  urethra of a male .


Suppositories are ideal for infants, elderly individuals and post-operative patients, who are unable to swallow oral medications, and for individuals experiencing severe nausea and/or vomiting. [ 1 ] [ 2 ] [ 3 ]


Several different ingredients can be used to form the base of a suppository:  cocoa butter  or a similar substitute,  polyethylene glycol ,  hydrogels , and glycerinated  gelatin . The type of material used depends on the type of suppository, the type of drug, and the conditions in which the suppository will be stored. [ 4 ]


In 1991, a study on suppository insertion in  The Lancet  found that the "torpedo" shape helps the device to travel internally, increasing its efficacy. [ 5 ]  The findings of this single study have been challenged as there is insufficient evidence on which to base clinical practice. [ 6 ]  Rectal suppositories are intended for localized or systemic action to relieve pain, constipation, irritation, inflammation, nausea and vomiting, fever, migraines, allergies, and sedation. [ 7 ] [ 8 ]  If they cause inflammation, chronic use of suppositories may cause  rectal stricture , [ 9 ]  but overall this is a safe method of drug delivery. [ 10 ]


Alprostadil  pellets are urethral suppositories used for the treatment of severe  erectile dysfunction (impotence) . They are marketed under the name  Muse  in the United States. [ 11 ]  Its use has diminished since the development of oral impotence medications.


Teduglutide , sold under the brand names  Revestive  (EU) and  Gattex  (US), is a 33-membered poly peptide  and  glucagon-like peptide-2  (GLP-2) analog that is used for the treatment of  short bowel syndrome . It works by promoting  mucosal  growth and possibly restoring  gastric emptying  and secretion. [ 7 ]  It was approved in both the European Union [ 5 ]  and the United States in 2012. [ 4 ]


Up to a certain point, the gut can adapt to partial  resections  that result in short bowel syndrome. Still,  parenteral  substitution of water, minerals and vitamins (depending on which part of the gut has been removed) is often necessary. Teduglutide may reduce or shorten the necessity of such infusions by improving the  intestinal mucosa  and possibly by other mechanisms. [ 8 ]


Common adverse effects in clinical studies included abdominal discomfort (49% of patients),  respiratory infections  (28%), nausea (27%) and vomiting (14%), local reactions at the injection site (21%), and headache (17%). [ 8 ]


Teduglutide differs from natural GLP-2 by a single  amino acid : an  alanine  is replaced with a  glycine . This blocks breaking down of the molecule by  dipeptidyl peptidase  and increases its half-life from seven minutes (GLP-2) to about two hours, while retaining its biological actions. These include maintenance of the intestinal mucosa, increasing intestinal blood flow, reducing  gastrointestinal motility  and  secretion  of gastric acid. [ 8 ]


It was approved in both the European Union (brand name Revestive) [ 5 ] [ 6 ]  and the United States (brand name Gattex) in 2012. [ 4 ]  It was granted  orphan drug  designation by the  European Medicines Agency  (EMA). [ 5 ] [ 6 ]