Crofelemer

Crofelemer (USAN, trade name Mytesi) is an antidiarrheal indicated for the symptomatic relief of non-infectious diarrhea in adult patients with HIV/AIDS on antiretroviral therapy.[1] Other possible uses include diarrhea in children, acute infectious diarrhea, and diarrhea in patients with irritable bowel syndrome.[2] It is a purified oligomeric proanthocyanidin from "dragon's blood", the sap of the South American tree Croton lechleri.[3]

Crofelemer
Clinical data
Trade namesMytesi
Other namesSP-303
AHFS/Drugs.comMonograph
MedlinePlusa613016
License data
Routes of
administration		By mouth (oral tablets)
ATC code
Legal status
Legal status
Pharmacokinetic data
BioavailabilityLittle or no absorption from the gut
Identifiers
CAS Number
PubChem SID
DrugBank
ChemSpider
  • none
UNII
KEGG
CompTox Dashboard (EPA)
Chemical and physical data
Formula(C15O6,7H12)n
Molar mass860–9100 g·mol−1

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 for diarrhea in HIV patients was completed in 2012, and the drug was approved by the US Food and Drug Administration (FDA) on 31 December 2012.[4][5][6]

Mechanism of action

The drug is taken orally and works by modulating cystic fibrosis transmembrane conductance regulator (CFTR) and the calcium-activated chloride channel (CaCC), two chloride ion channels from the luminal side of the gastrointestinal tract.[3] 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 ions are secreted into the gut, which decreases the associated secretion of sodium ions and accompanying water, thus improving stool consistency and reducing the frequency of watery stools and duration of the diarrhea.[4][7] The mechanism is selective for the CFTR and CaCC, as other channels involved in intestinal fluid secretion, namely sodium and potassium channels, are not affected by crofelemer, nor is cAMP or calcium signaling.[3]

Crofelemer is minimally, if at all, absorbed from the gut into the bloodstream, and is mostly excreted in the stools.[7]

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.[7] The most common adverse reactions (≥ 3%) are: upper respiratory tract infection, bronchitis, cough, flatulence and increased bilirubin.[1]

Origin and chemistry
Croton lechleri bark with a few drops of dragon's blood

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 oligomeric proanthocyanidin from the sap, or more correctly the latex, of the South American tree Croton lechleri (locally called Sangre de Grado or Sangre de Drago). This is one of several plants producing bright red latex or resin called "dragon's blood".[3] Crofelemer is a complex mixture of procyanidins and prodelphinidins with up to 30 (epi)catechin or (epi)gallocatechin units per molecule, resulting in a molecular mass of up to 9 kDa.[3]

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, tumors, insect bites, and other conditions.[3][8] 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).[9] Immunomodulatory, antioxidative, antiproliferative and mutagenic 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 drug,[10] but a study testing it for the treatment of herpes simplex did not show any benefit.[11] In 1999, crofelemer was reported to improve the symptoms of cholera toxin induced diarrhea in mice.[12] Crofelemer demonstrated reduction of duration of diarrhea and frequency of watery stools in patients with traveler's diarrhea[13] and patients with HIV/AIDS.[14] Crofelemer has also shown benefit in adult patients with acute infectious diarrhea from E. coli and salmonella,[15] 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.[16][17]

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,[18] and to Salix Pharmaceuticals for exclusive development and marketing rights in North America, the European Union and Japan, in 2008.[19] Subsequently, Napo sued Salix and terminated the agreements with Salix and Glenmark in 2011, alleging that they were stalling the drug's development.[20] 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".[2][6]

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
  1. "Mytesi Full Prescribing Information".
  2. Drugs.com: Crofelemer Approval Status
  3. Tradtrantip L, Namkung W, Verkman AS (January 2010). "Crofelemer, an antisecretory antidiarrheal proanthocyanidin oligomer extracted from Croton lechleri, targets two distinct intestinal chloride channels". Molecular Pharmacology. 77 (1): 69–78. doi:10.1124/mol.109.061051. PMC 2802429. PMID 19808995.
  4. H. Spreitzer (10 September 2012). "Neue Wirkstoffe – Crofelemer". Österreichische Apothekerzeitung (in German) (19/2012): 22.
  5. Clinical trial number NCT00547898 for "Safety and Effectiveness of 3 Doses of Crofelemer Compared to Placebo in the Treatment of HIV Associated Diarrhea (ADVENT)" at ClinicalTrials.gov
  6. "FDA approves first anti-diarrheal drug for HIV/AIDS patients". FDA. Retrieved 31 December 2012.
  7. Cottreau J, Tucker A, Crutchley R, Garey KW (February 2012). "Crofelemer for the treatment of secretory diarrhea". Expert Review of Gastroenterology & Hepatology. 6 (1): 17–23. doi:10.1586/egh.11.87. PMID 22149578. S2CID 5426870.
  8. Jones K (December 2003). "Review of sangre de drago (Croton lechleri)--a South American tree sap in the treatment of diarrhea, inflammation, insect bites, viral infections, and wounds: traditional uses to clinical research". Journal of Alternative and Complementary Medicine. 9 (6): 877–96. doi:10.1089/107555303771952235. PMID 14736360.
  9. Vaisberg AJ, Milla M, Planas MC, Cordova JL, de Agusti ER, Ferreyra R, et al. (April 1989). "Taspine is the cicatrizant principle in Sangre de Grado extracted from Croton lechleri". Planta Medica. 55 (2): 140–3. doi:10.1055/s-2006-961907. PMID 2748730.
  10. Ubillas R, Jolad SD, Bruening RC, Kernan MR, King SR, Sesin DF, et al. (September 1994). "SP-303, an antiviral oligomeric proanthocyanidin from the latex of Croton lechleri (Sangre de Drago)". Phytomedicine. 1 (2): 77–106. doi:10.1016/S0944-7113(11)80026-7. PMID 23195881.
  11. Safrin S, McKinley G, McKeough M, Robinson D, Spruance SL (December 1994). "Treatment of acyclovir-unresponsive cutaneous herpes simplex virus infection with topically applied SP-303". Antiviral Research. 25 (3–4): 185–92. doi:10.1016/0166-3542(94)90002-7. PMID 7710268.
  12. Gabriel SE, Davenport SE, Steagall RJ, Vimal V, Carlson T, Rozhon EJ (January 1999). "A novel plant-derived inhibitor of cAMP-mediated fluid and chloride secretion". The American Journal of Physiology. 276 (1): G58-63. doi:10.1152/ajpgi.1999.276.1.G58. PMID 9886979.
  13. DiCesare, M.D., Daniel (2002). "A Double Blind, Randomized, Placebo-Controlled Study of SP-303 (Provir) in the Symptomatic Treatment of Acute Diarrhea Among Travelers to Jamaica and Mexico". The American Journal of Gastroenterology. 97 (10): 2585–2588. doi:10.1111/j.1572-0241.2002.06027.x. PMID 12385443. S2CID 20877791.
  14. Holodniy, M.D., Mark (1999). "A Double Blind, Randomized, Placebo-Controlled Phase II Study to Assess the Safety and Efficacy of Orally Administered SP-303 for the Symptomatic Treatment of Diarrhea in Patients With AIDS". Spthe American Journal of Gastroenterology. 94 (11): 3267–3273. doi:10.1111/j.1572-0241.1999.01535.x. PMID 10566728. S2CID 23436243.
  15. Sharma, Akhilesh. "Crofelemer Improves Acute Infectious Diarrhea Symptoms". Publication of the 48th Annual Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC) and the Infectious Diseases Society of America (IDSA) 46th Annual Meeting.
  16. Mangel, Allen (December 18, 2008). "Evaluation of Crofelemer in the Treatment of Diarrhea-Predominant Irritable Bowel Syndrome Patients". Digestion. 78 (4): 180–186. doi:10.1159/000185719. PMID 19092244. S2CID 23602684.
  17. Nee, MD, Judy (November 28, 2019). "Randomized Clinical Trial: Crofelemer Treatment in Women With Diarrhea-Predominant Irritable Bowel Syndrome". Clinical and Translational Gastroenterology. 10 (12): e00110. doi:10.14309/ctg.0000000000000110. PMC 6970555. PMID 31800542.
  18. "Glenmark gets an arbitration upshot on anti-diarrheal compound Crofelemer". BusinessLine.
  19. "Napo Terminates Salix for Breach of Agreement for Failure to Commercially Develop Crofelemer" (Press release). BusinessWire. 10 November 2011.
  20. "What's Next In Line For Salix?". RTTNews. 27 August 2012.
  • "Crofelemer". Drug Information Portal. U.S. National Library of Medicine.
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