Niclosamide

Absorption

Niclosamide appears to be minimally absorbed from the gastrointestinal tract—neither the drug nor its metabolites have been recovered from the blood or urine.

Toxicity

Infrequent, mild, and transitory adverse events include nausea, vomiting, diarrhea, and abdominal discomfort.

Description

Niclosamide (50-65-7) reversibly inhibits mTORC1 signaling and stimulates autophagy.1 Inhibits activation and nuclear translocation of STAT3 selectively over STAT1 and STAT5. Niclosamide inhibits transcription of STAT3 target genes and induces cell cycle arrest and apoptosis in cells with constitutively active STAT3.2

Chemical properties

Yellowish-white or yellowish, fine crystals.Yellow-white crystalline powder, odorless, tasteless. Melting point 225-230 ℃. Insoluble in water, soluble in hot ethanol, chloroform, cyclohexanone, diethyl ether and sodium hydroxide solution.

Originator

Yomesan,Bayer,W. Germany,1960

The Uses of Niclosamide

Niclosamide has been used extensively in the treatment of tapeworm infections caused by Taenia saginata, Taenia solium, Diphyllobothrium latum, Fasciolopsis buski, and Hymenolepis nana. It is an effective alternative to praziquantel for treating infections caused by T. saginata (beef tapeworm), T. solium (pork tapeworm), and D. latum (fish tapeworm) and is active against most other tapeworm infections. It is absorbed by intestinal cestodes but not nematodes.A single dose is usually adequate to produce a cure rate of 95%.With H. nana (dwarf tapeworm), a longer treatment course (up to 7 days) is necessary. Niclosamide is administered orally after the patient has fasted overnight and may be followed in 2 hours by purging (magnesium sulfate 15–30 g) to encourage complete expulsion of the cestode, especially T. solium, although this is not always considered necessary. Cure is assessed by follow-up stool examination in 3 to 5 months.With the availability of other agents, niclosamide is no longer widely used.The most widely employed agents are praziquantel and the benzimidazoles.

The Uses of Niclosamide

An inhibitor of the Stat3 signaling pathway and also a FRAP inhibitor.

The Uses of Niclosamide

Niclosamide is a teniacide in the anthelmintic family. It is effective against cestodes that infect humans. Niclosamide is used to study the Wnt/Frizzled-1 signaling pathway. It is used to inhibit transcription and DNA binding of the NF-?B pathway and it increases ROS levels to induce apoptosis in acute myelogenous leukemia (AML) cells.

Background

Niclosamide is an antihelminthic used for the treatment of tapeworm infections. Helminths (worms) are multicellular organisms that infect very large numbers of humans and cause a broad range of diseases. Over 1 billion people are infected with intestinal nematodes, and many millions are infected with filarial nematodes, flukes, and tapeworms. They are an even greater problem in domestic animals.
Niclosamide, once marketed in the US under the brand name Niclocide, was voluntarily withdrawn from market by Bayer in 1996.

Indications

For the treatment of tapeworm and intestinal fluke infections: Taenia saginata (Beef Tapeworm), Taenia solium (Pork Tapeworm), Diphyllobothrium latum (Fish Tapeworm), Fasciolopsis buski (large intestinal fluke). Niclosamide is also used as a molluscicide in the control of schistosomiasis.

What are the applications of Application

Niclosamide is an inhibitor of the Stat3 signaling pathway and also a FRAP inhibitor

Definition

ChEBI: Niclosamide is a secondary carboxamide resulting from the formal condensation of the carboxy group of 5-chlorosalicylic acid with the amino group of 2-chloro-4-nitroaniline. It is an oral anthelmintic drug approved for use against tapeworm infections. It has a role as a piscicide, a molluscicide, an antiparasitic agent, an anticoronaviral agent, an anthelminthic drug, an apoptosis inducer and a STAT3 inhibitor. It is a member of monochlorobenzenes, a member of salicylanilides, a C-nitro compound, a secondary carboxamide and a member of benzamides. It is functionally related to a 5-chlorosalicylic acid.

Manufacturing Process

17.2 g of 5-chlorosalicylic acid and 20.8 g of 2-chloro-4-nitroaniline are dissolved in 250 ml of xylene. While boiling, there are introduced slowly 5 g of PCl3.Heating is continued for 3 further hours. The mixture is then allowed to cool down and the crystals which separate are filtered off with suction. The crude product may be recrystallized from ethanol, melting at 233°C.

brand name

Niclocide (Bayer).

Therapeutic Function

Anthelmintic

Antimicrobial activity

Useful activity is restricted to intestinal tapeworms, including Taeniarhynchus saginatus (syn. Taenia saginata), Taenia solium, Diphyllobothrium latum and Hymenolepis nana. It is not effective against larval stages of tapeworms.

General Description

A cell-permeable salicylanilide that, in addition to its well-known antihelmintic efficacy, acts as a mammalian mTORC1, but not mTORC2, signaling inhibitor mechanistically distinct from rapamycin. Likely a direct consequence of autophagy activation, Niclosamide is demonstrated to induce Wnt-independent Frizzled1 and Dishevelled-2 downregulation. Unrelated to its autophagy induction activity, Niclosamide is also shown to inhibit Stat3 signaling (IC₅₀ = 0.25 M in HeLa reporter assays). Efficiently inhibits breast cancer stem-like cells in vitro and in vivo.

Pharmaceutical Applications

A synthetic chlorinated nitrosalicylanilide available for oral administration.

Biochem/physiol Actions

Niclosamide uncouples oxidative phosphorylation in the tapeworm and inhibits mitochondrial oxidative phosphorylation of parasitic helminths. It blocks tumor necrosis factor-induced IκBα phosphorylation, translocation of p65, and expression of NF-κΒ– regulated genes in AML cells.

Mechanism of action

For many years, niclosamide (Niclocide) was widely used to treat infestations of cestodes. Niclosamide is a chlorinated salicylamide that inhibits the production of energy derived from anaerobic metabolism. It may also have adenosine triphosphatase (ATPase) stimulating properties. Inhibition of anaerobic incorporation of inorganic phosphate into ATP is detrimental to the parasite. Niclosamide can uncouple oxidative phosphorylation in mammalian mitochondria, but this action requires dosages that are higher than those commonly used in treating worm infections.
The drug affects the scolex and proximal segments of the cestodes, resulting in detachment of the scolex from the intestinal wall and eventual evacuation of the cestodes from the intestine by the normal peristaltic action of the host's bowel. Because niclosamide is not absorbed from the intestinal tract, high concentrations can be achieved in the intestinal lumen.The drug is not ovicidal.

Pharmacokinetics

Niclosamide is an antihelminth used against tapeworm infections. It may act by the uncoupling of the electron transport chain to ATP synthase. The disturbance of this crucial metabolic pathway prevents creation of adenosine tri-phosphate (ATP), an essential molecule that supplies energy for metabolism.

Pharmacokinetics

Conflicting data exist relative to the level of absorption of niclosamide from the gut. The metabolized drug is passed in the feces and urine, staining them yellow.

Clinical Use

5-Chloro-N-(2-chloro-4-nitrophenyl)-2-hydroxybenzamideor 2,5 -dichloro-4 -nitrosalicylanilide (Cestocide, Mansonil,Yomesan) occurs as a yellowish white, water-insolublepowder. It is a potent taeniacide that causes rapid disintegrationof worm segments and the scolex. Penetration of thedrug into various cestodes appears to be facilitated by thedigestive juices of the host, in that very little of the drug isabsorbed by the worms in vitro. Niclosamide is well toleratedfollowing oral administration, and little or no systemicabsorption of it occurs. A saline purge 1 to 2 hours after ingestion of the taeniacide is recommended to remove thedamaged scolex and worm segments. This procedure ismandatory in the treatment of pork tapeworm infestation toprevent possible cysticercosis resulting from release of liveova from worm segments damaged by the drug.

Clinical Use

Niclosamide has been used extensively in the treatment of tapeworm infections caused by Taenia saginata, Taenia solium, Diphyllobothrium latum, Fasciolopsis buski, and Hymenolepis nana. It is an effective alternative to praziquantel for treating infections caused by T. saginata (beef tapeworm), T. solium (pork tapeworm), and D. latum (fish tapeworm) and is active against most other tapeworm infections. It is absorbed by intestinal cestodes but not nematodes.A single dose is usually adequate to produce a cure rate of 95%.With H. nana (dwarf tapeworm), a longer treatment course (up to 7 days) is necessary. Niclosamide is administered orally after the patient has fasted overnight and may be followed in 2 hours by purging (magnesium sulfate 15–30 g) to encourage complete expulsion of the cestode, especially T. solium, although this is not always considered necessary. Cure is assessed by follow-up stool examination in 3 to 5 months.With the availability of other agents, niclosamide is no longer widely used.The most widely employed agents are praziquantel and the benzimidazoles.

Side Effects

Very few side effects have been reported, but these include mild nausea, abdominal cramps and dizziness.

Side Effects

No serious side effects are associated with niclosamide use, although some patients report abdominal discomfort and loose stools.

Safety Profile

Poison by intravenous and intraperitoneal routes. Moderately toxic by ingestion. Experimental reproductive effects. Human mutation data reported. When heated to decomposition it emits very toxic fumes of Cl and NOx.

Synthesis

Niclosamide, 2
,5-dichloro-4
nitrosaicylanilide (38.1.34), is made by reacting 5-chlorosalicylic acid with 2-chloro-4-nitroaniline in the presence of phosphorus trichloride.

Metabolism

Not Available

storage

+4°C

References

1) Balgi et al. (2009), Screen for chemical modulators of autophagy reveals novel therapeutic inhibitors of mTORC1 signaling; PloS One, 4 e7124 2) Ren et al. (2010), Identification of Niclosamide as a New Small-Molecule Inhibitor of the STAT3 Signaling Pathway; ACS Med. Chem. Lett., 1 454