Crofelemer (

USAN 280px, "Samguk Sagi" Book 04. Silla's Records. In 512, Usan-guk（于山國）was Ulleungdo（鬱陵島） Usan-guk, or the State of Usan, occupied Ulleung-do and the adjacent islands during the Korean Three Kingdoms period. According to t ...

, trade name Mytesi) is an antidiarrheal indicated for the symptomatic relief of non-infectious diarrhea in adult patients with HIV/AIDS on antiretroviral therapy. Other possible uses include diarrhea in children, acute infectious diarrhea, and diarrhea in patients with

irritable bowel syndrome Irritable bowel syndrome (IBS) is a functional gastrointestinal disorder characterized by a group of symptoms that commonly include abdominal pain, abdominal bloating, and changes in the consistency of bowel movements. These symptoms may ...

. It is a purified

oligomer In chemistry and biochemistry, an oligomer () is a molecule that consists of a few repeating units which could be derived, actually or conceptually, from smaller molecules, monomers.Quote: ''Oligomer molecule: A molecule of intermediate relativ ...

proanthocyanidin Proanthocyanidins are a class of polyphenols found in many plants, such as cranberry, blueberry, and grape seeds. Chemically, they are oligomeric flavonoids. Many are oligomers of catechin and epicatechin and their gallic acid esters. More complex ...

from "

dragon's blood Dragon's blood is a bright red resin which is obtained from different species of a number of distinct plant genera: '' Calamus'' spp. (previously ''Daemonorops'') also including '' Calamus rotang'', '' Croton'', '' Dracaena'' and ''Pterocarpus'' ...

", the

sap Sap is a fluid transported in the xylem cells (vessel elements or tracheids) or phloem sieve tube elements of a plant. These cells transport water and nutrients throughout the plant. Sap is distinct from latex, resin, or cell sap; it is a s ...

of the South American tree ''

Croton lechleri ''Croton lechleri'' is a species of flowering plant in the spurge family, Euphorbiaceae, that is native to northwestern South America. It is commonly known as ''sangre de grado'' (Peruvian Spanish), ''sangre de drago'' (Ecuadorian Spanish) or ' ...

''. Crofelemer treats the symptoms of disease, but it is not used to treat infectious diarrhea (diarrhea caused by infection of the digestive system by a bacterium, virus or parasite). It was initially developed by Napo Pharmaceuticals, which is a wholly owned subsidiary of Jaguar Health, Inc. A Phase III

clinical trial Clinical trials are prospective biomedical or behavioral research studies on human subject research, human participants designed to answer specific questions about biomedical or behavioral interventions, including new treatments (such as novel v ...

for diarrhea in HIV patients was completed in 2012, and the drug was approved by the US

Food and Drug Administration The United States Food and Drug Administration (FDA or US FDA) is a List of United States federal agencies, federal agency of the United States Department of Health and Human Services, Department of Health and Human Services. The FDA is respo ...

(FDA) on 31 December 2012.

Mechanism of action

The drug is taken orally and works by modulating

cystic fibrosis transmembrane conductance regulator Cystic fibrosis transmembrane conductance regulator (CFTR) is a membrane protein and anion channel in vertebrates that is encoded by the ''CFTR'' gene. Geneticist Lap-Chee Tsui and his team identified the ''CFTR'' gene in 1989 as the gene lin ...

(CFTR) and the

calcium-activated chloride channel The Calcium-Dependent Chloride Channel (Ca-ClC) proteins (or calcium-activated chloride channels (CaCCs), are heterogeneous groups of ligand-gated ion channels for chloride that have been identified in many epithelial and endothelial cell types a ...

(CaCC), two chloride ion channels from the luminal side of the gastrointestinal tract. This is a first-in-class antisecretory antidiarrheal mechanism of action and it does not affect gastrointestinal motility, unlike the traditional antimotility drugs. As a result of the channel regulation, fewer

chloride The term chloride refers to a compound or molecule that contains either a chlorine anion (), which is a negatively charged chlorine atom, or a non-charged chlorine atom covalently bonded to the rest of the molecule by a single bond (). The pr ...

ions are secreted into the gut, which decreases the associated secretion of

sodium Sodium is a chemical element; it has Symbol (chemistry), symbol Na (from Neo-Latin ) and atomic number 11. It is a soft, silvery-white, highly reactive metal. Sodium is an alkali metal, being in group 1 element, group 1 of the peri ...

ions and accompanying water, thus improving stool consistency and reducing the frequency of watery stools and duration of the diarrhea. The mechanism is selective for the CFTR and CaCC, as other channels involved in intestinal fluid secretion, namely

and

potassium channel Potassium channels are the most widely distributed type of ion channel found in virtually all organisms. They form potassium-selective pores that span cell membranes. Potassium channels are found in most cell types and control a wide variety of ...

s, are not affected by crofelemer, nor is

cAMP Camp may refer to: Areas of confinement, imprisonment, or for execution * Concentration camp, an internment camp for political prisoners or politically targeted demographics, such as members of national or minority ethnic groups * Extermination ...

calcium signaling Calcium signaling is the use of calcium ions (Ca2+) to communicate and drive intracellular processes often as a step in signal transduction. Ca2+ is important for a wide variety of cellular signaling pathways. Once Ca2+ enters the cytosol of the ...

. Crofelemer is minimally, if at all, absorbed from the gut into the bloodstream, and is mostly excreted in the stools.

Adverse effects and interactions

Crofelemer is well tolerated; and the only adverse effects found in clinical studies were mild gastrointestinal effects at the same level as under

placebo A placebo ( ) can be roughly defined as a sham medical treatment. Common placebos include inert tablets (like sugar pills), inert injections (like saline), sham surgery, and other procedures. Placebos are used in randomized clinical trials ...

. The most common adverse reactions (≥ 3%) are: upper respiratory tract infection, bronchitis, cough, flatulence and increased bilirubin.

Origin and chemistry

Crofelemer is an oligomeric proanthocyanidin mixture primarily composed of (+)–catechin, (–)–epicatechin, (+)–gallocatechin, and (–)–epigallocatechin monomer units linked in random sequence, as represented below. The average degree of polymerization for the oligomers ranges between 5 and 7.5, as determined by phloroglucinol degradation. The substance is a purified

from the sap, or more correctly the

latex Latex is an emulsion (stable dispersion) of polymer microparticles in water. Latices are found in nature, but synthetic latices are common as well. In nature, latex is found as a wikt:milky, milky fluid, which is present in 10% of all floweri ...

, of the South American tree ''

'' (locally called ''Sangre de Grado'' or ''Sangre de Drago''). This is one of several plants producing bright red latex or resin called "

". Crofelemer is a complex mixture of

procyanidin Procyanidins are members of the proanthocyanidin (or condensed tannins) class of flavonoids. They are oligomeric compounds, formed from catechin and epicatechin molecules. They yield cyanidin when depolymerized under oxidative conditions. See th ...

s and

prodelphinidin Prodelphinidin is a name for the polymeric tannins composed of gallocatechin. It yields delphinidin during depolymerisation under oxidative conditions. Natural occurrences Prodelphinidins are one of the two sorts of tannins in grape (the other ...

s with up to 30 (epi)catechin or (epi)gallocatechin units per molecule, resulting in a molecular mass of up to 9

kDa The dalton or unified atomic mass unit (symbols: Da or u, respectively) is a unit of mass defined as of the mass of an unbound neutral atom of carbon-12 in its nuclear and electronic ground state and at rest. It is a non-SI unit accepted f ...

History of Crude Plant Latex (Dragon's Blood) and Crofelemer

The crude plant latex of ''C. lechleri'' is traditionally used in South American medicine for the treatment of diarrhea, wounds, inflammations,

tumor A neoplasm () is a type of abnormal and excessive growth of tissue. The process that occurs to form or produce a neoplasm is called neoplasia. The growth of a neoplasm is uncoordinated with that of the normal surrounding tissue, and persists ...

s, insect bites, and other conditions. A number of chemicals were isolated in the late 1980s and 1990s and tested in cellular and animal models, for example identifying taspine as a cicatrizant (wound healing promoter). Immunomodulatory, antioxidative,

antiproliferative Cytostasis (cyto – cell; stasis – stoppage) is the inhibition of cell growth and multiplication. Cytostatic refers to a cellular component or medicine that inhibits cell division and induce cell death. Cytostasis is an important prerequisite ...

and

mutagenic In genetics, a mutagen is a physical or chemical agent that permanently changes genetic material, usually DNA, in an organism and thus increases the frequency of mutations above the natural background level. As many mutations can cause cancer in ...

effects of dragon's blood and its components also received some attention from the scientific community. The purified oligomeric proanthocyanidin fraction was first described in 1994 under the name SP-303 as an

antiviral Antiviral drugs are a class of medication used for treating viral infections. Most antivirals target specific viruses, while a broad-spectrum antiviral is effective against a wide range of viruses. Antiviral drugs are a class of antimicrobials ...

drug, but a study testing it for the treatment of

herpes simplex Herpes simplex, often known simply as herpes, is a viral disease, viral infection caused by the herpes simplex virus. Herpes infections are categorized by the area of the body that is infected. The two major types of herpes are Cold sore, ora ...

did not show any benefit. In 1999, crofelemer was reported to improve the symptoms of

cholera toxin Cholera toxin (also known as choleragen, CTX, CTx and CT) is a potent enterotoxin produced by the bacterium Vibrio cholerae which causes severe watery diarrhea and dehydration that define cholera infections. The toxin is a member of the heat-l ...

induced diarrhea in mice. Crofelemer demonstrated reduction of duration of diarrhea and frequency of watery stools in patients with traveler's diarrhea and patients with HIV/AIDS. Crofelemer has also shown benefit in adult patients with acute infectious diarrhea from ''E. coli'' and ''salmonella'', and in patients with moderate to severe watery diarrhea from ''vibrio cholerae''. Crofelemer has also been shown to improve abdominal pain and discomfort in patients with diarrhea-predominate irritable bowel syndrome. SP-303 was eventually named crofelemer and patented by Napo Pharmaceuticals, which licensed it to Glenmark Pharmaceuticals in 2005, for exclusive development and marketing rights in 140 emerging markets including India, and to Salix Pharmaceuticals for exclusive development and marketing rights in North America, the European Union and Japan, in 2008. Subsequently, Napo sued Salix and terminated the agreements with Salix and Glenmark in 2011, alleging that they were stalling the drug's development. In 2012, crofelemer completed a Phase III trial, and it was approved in December 2012 by the FDA for the indication "symptomatic relief of non-infectious diarrhea in patients with HIV/AIDS on anti-retroviral therapy". The drug substance is manufactured by Glenmark Pharmaceuticals, and is manufactured as 125 mg delayed-release tablets by Patheon Pharmaceuticals Inc. for Napo Pharmaceuticals.

References

External links

* {{Portal bar , Medicine Antidiarrhoeals Condensed tannins Natural phenol oligomers Botanical drugs