150 Anthelmintics

Profile Interactions Morantel Citrate (BANM, pINNM) Melarsomine is a trivalent arsenical derivative used in veterinary Patients treated with metrifonate should not be given Citrato de morantel; Morantel, Citrate de; Moranteli Citras. (E)- practice for the control of canine heartworm (dirofilariasis). depolarising neuromuscular blockers such as suxame- 1,4,5,6-Tetrahydro-1-methyl-2-[2-(3-methyl-2-thienyl)vinyl]pyri- thonium for at least 48 hours.The use of metrifonate midine citrate monohydrate. should be avoided in those recently exposed to insecti- Морантела Цитрат Metrifonate (BAN, rINN) cides or other agricultural chemicals with anti- C12H16N2S,C6H8O7,H2O = 430.5. cholinesterase activity. CAS — 20574-50-9 (morantel); 69525-81-1 (morantel ci- Bayer-L-1359; DETF; Metrifonaatti; Metrifonát; Metrifonat; Met- trate). rifonatas; Métrifonate; Metrifonato; Metrifonatum; Metriphonate; Pharmacokinetics Trichlorfon (USAN); Trichlorphon. Dimethyl 2,2,2-trichloro-1-hy- H C droxyethylphosphonate. Metrifonate is absorbed after oral doses and some is 3 Метрифонат converted to dichlorvos which is considered to be the active moiety. Plasma concentrations of dichlorvos are N C4H8Cl3O4P = 257.4. about 1% of those of metrifonate with peak concentra- S CAS — 52-68-6. tions of both substances occurring within 2 hours. Ex- N ATC — P02BB01. cretion is via the kidney, mainly as glucuronides. ATC Vet — QP52AB01; QP53AF02. CH3 ◊ References. (morantel) 1. Nordgren I, et al. Plasma levels of metrifonate and dichlorvos O during treatment of schistosomiasis with Bilarcil. Am J Trop Med Hyg 1980; 29: 426–30. Morantel Tartrate (BANM, USAN, pINNM) P CCl3 2. Nordgren I, et al. Levels of metrifonate and dichlorvos in plasma H3CO and erythrocytes during treatment of schistosomiasis with Bilar- CP-12009-18; Moranteelivetytartraatti; Morantel, hydrogéno- cil. Acta Pharmacol Toxicol (Copenh) 1981; 49 (suppl V): tartrate de; Morantel, Tartrate de; Morantel-hidrogén-tartarát; H3CO OH 79–86. Morantel-hydrogen-tartarát; Moranteli hydrogenotartras; Mor- 3. Pettigrew LC, et al. Pharmacokinetics, pharmacodynamics, and anteli Tartras; Morantelvätetartrat; Tartrato de morantel; UK- safety of metrifonate in patients with Alzheimer’s disease. J Clin Pharmacopoeias. In Eur. (see p.vii), Int., and US. Pharmacol 1998; 38: 236–45. 2964-18. Ph. Eur. 6.2 (Metrifonate). A white or almost white, crystalline Морантела Тартрат powder. M.p. is between 76° and 81°. Freely soluble in water, in Uses and Administration C12H16N2S,C4H6O6 = 370.4. alcohol, and in acetone; very soluble in dichloromethane. Protect CAS — 20574-50-9 (morantel); 26155-31-7 (morantel from light. Metrifonate is an organophosphorus compound and is tartrate). USP 31 (Metrifonate). A white crystalline powder. M.p. about converted in the body to the active metabolite dichlor- Pharmacopoeias. In Eur. (see p.vii) and US for veterinary use 78° with decomposition. Freely soluble in water, in alcohol, in vos (p.2040), an anticholinesterase. only. acetone, in chloroform, in ether, and in benzene; very soluble in Ph. Eur. 6.2 (Morantel Hydrogen Tartrate for Veterinary Use; dichloromethane; very slightly soluble in hexane and in pentane. Metrifonate has anthelmintic activity against Schisto- Morantel Tartrate BP(Vet) 2008). A white or pale yellow, crystal- Decomposed by alkali. Store at a temperature not exceeding 25°. soma haematobium and has been given orally as an al- line powder. Very soluble in water and in alcohol; practically in- ternative to praziquantel in the treatment of schisto- soluble in ethyl acetate. A 1% solution in water has a pH of 3.3 Adverse Effects, Treatment, and Precau- somiasis due to S. haematobium. It has usually been to 3.9. Protect from light. tions given in three doses of 7.5 to 10 mg/kg at intervals of USP 31 (Morantel Tartrate). A white or pale yellow, crystalline Metrifonate is generally well tolerated, but may cause 2 weeks. powder. Very soluble in water and in alcohol; practically insolu- nausea, vomiting, abdominal pain, diarrhoea, head- ble in ethyl acetate. pH of a 1% solution in water is between 2.8 and 3.9. Store at a temperature of 25°, excursions permitted be- ache, dizziness, and weakness. Metrifonate has also been used as an insecticide and as a parasiticide in fish and domestic animals. tween 15° and 30°. Protect from light. It is an organophosphorus compound and because of its Profile anticholinesterase properties depresses plasma- Alzheimer’s disease. Metrifonate, like a number of other Morantel is an analogue of pyrantel. The citrate and the tartrate cholinesterase inhibitors, has been tried in the treatment of are used as anthelmintics in veterinary medicine for the treatment cholinesterase concentrations. For a description of the 1,2 Alzheimer’s disease (see Dementia, p.362). Clinical studies of gastrointestinal roundworms. toxic effects of organophosphorus compounds and the produced modest benefits but research was stopped after reports treatment of acute poisoning, see Organophosphorus of muscle weakness, sometimes requiring respiratory support. Insecticides, p.2047. Atropine has been used to relieve 1. Becker RE, et al. Effects of metrifonate on cognitive decline in cholinergic adverse effects without affecting metri- Alzheimer disease: a double-blind, placebo-controlled, 6-month Moxidectin (BAN, USAN, rINN) fonate’s activity against Schistosoma haematobium. study. Alzheimer Dis Assoc Disord 1998; 12: 54–7. CL-301423; Moksidektiini; Moxidectina; Moxidectine; Moxidecti- 2. Morris JC, et al. Metrifonate benefits cognitive, behavioral, and num; Moxidektin. (6R,15S)-5-O-Demethyl-28-deoxy-25-[(E)- Anticholinesterase effects. Metrifonate depresses global function in patients with Alzheimer’s disease. Neurology 1998; 50: 1222–30. 1,3-dimethylbut-1-enyl]-6,28-epoxy-23-oxomilbemycin B (E)- cholinesterase activity and there has been the occasional report 23-O-methyloxime. of severe cholinergic adverse effects.1 However, it does not usu- Schistosomiasis. While praziquantel is now the main treat- Моксидектин ally give rise to troublesome effects at doses normally used, even ment for schistosomiasis (p.138), metrifonate is an alternative for C H NO = 639.8. though there may temporarily be almost complete inhibition of infection due to Schistosoma haematobium. Cure rates with 37 53 8 plasma cholinesterase and considerable inhibition of erythrocyte CAS — 113507-06-5. 2 standard doses in schistosomiasis control programmes range cholinesterase (but see also under Alzheimer’s Disease, below). from 40 to more than 80%, with a reduction of more than 80% in ATC Vet — QP54AB02. The environmental aspects of metrifonate usage have been con- egg counts among those not cured, but a comparison with prazi- sidered by WHO.3 quantel has shown praziquantel to be the more effective drug.1 In addition, metrifonate’s dosage schedule of 3 doses at intervals of O 1. Jamnadas VP, Thomas JEP. Metriphonate and organophosphate N CH3 poisoning. Cent Afr J Med 1979; 25: 130. 2 weeks has caused problems of patient compliance;2 giving 2. Pleština R, et al. Effect of metrifonate on blood cholinesterases 5 mg/kg three times in one day has produced similar results to a CH3 CH3 H H in children during the treatment of schistosomiasis. Bull WHO standard dosage schedule.3 O H 1972; 46: 747–59. CH 1. Squires N. Interventions for treating schistosomiasis haemato- 3 3. WHO. Trichlorfon. Environmental Health Criteria 132. Geneva: H O bium. Available in The Cochrane Database of Systematic Re- WHO, 1992. Available at: http://www.inchem.org/documents/ views; Issue 3. Chichester: John Wiley; 1997 (accessed H C CH CH ehc/ehc/ehc132.htm (accessed 16/07/08) 3 3 3 16/05/05). H O O Handling. Bulk metrifonate is very toxic when inhaled, swal- 2. Aden Abdi Y, Gustafsson LL. Poor patient compliance reduces lowed, or spilled on the skin. It can be removed from the skin by the efficacy of metrifonate treatment of Schistosoma haemato- OH H washing with soap and water. Contaminated material should be bium in Somalia. Eur J Clin Pharmacol 1989; 36: 161–4. immersed in a 2% aqueous solution of sodium hydroxide for sev- 3. Aden Abdi Y, Gustafsson LL. Field trial of the efficacy of a sim- eral hours. plified and standard metrifonate treatments of Schistosoma hae- O matobium. Eur J Clin Pharmacol 1989; 37: 371–4. CH3 1 H Pregnancy. WHO reported that metrifonate had not shown H OH embryotoxicity or teratogenicity, but did not recommend the use of metrifonate in pregnant patients unless immediate interven- Pharmacopoeias. In Eur. (see p.vii) for veterinary use. tion was essential. There has been a report of an infant born with Milbemycin Oxime Ph. Eur. 6.2 (Moxidectin for Veterinary Use). A white or pale massive hydrocephalus and a large meningomyelocele whose CGA-179246; Milbemicina oxima. A mixture of milbemycin A yellow, amorphous powder. Practically insoluble in water; very mother had been treated twice with metrifonate during the sec- 4 soluble in alcohol; slightly soluble in hexane. ond month of pregnancy.2 A possible link between congenital 5-oxime and milbemycin A3 5-oxime. abnormalities and the use of metrifonate to eradicate fish para- Мильбемицин Оксим Profile sites has also been postulated.3 Moxidectin is an anthelmintic used in veterinary medicine. It is CAS — 129496-10-2. 1. WHO. The control of schistosomiasis: second report of the also used as a systemic veterinary ectoparasiticide and is under WHO expert committee. WHO Tech Rep Ser 830 1993. Available ATC Vet — QP54AB01. investigation for the treatment of human onchocerciasis. at: http://libdoc.who.int/trs/WHO_TRS_830.pdf (accessed ◊ References. 16/07/08) Profile 2. Monson MH, Alexander K. Metrifonate in pregnancy. Trans R Milbemycin oxime is an anthelmintic used in veterinary medi- 1. Cotreau MM, et al. The antiparasitic moxidectin: safety, tolera- Soc Trop Med Hyg 1984; 78: 565. cine. bility, and pharmacokinetics in humans. J Clin Pharmacol 2003; 43: 1108–15. 3. Czeizel AE, et al. Environmental trichlorfon and cluster of con- genital abnormalities. Lancet 1993; 341: 539–42. Metrifonate/Oxamniquine 151

Naftalofos (BAN, USAN, rINN) Niclosamide Monohydrate (BANM) Niclosamida Mono-hidratada; Niclosamida monohidrato; Bay-9002; E-9002; ENT-25567; Naftalofós; Naftalofosum; Naph- O thalophos; Phthalophos; S-940. Diethyl naphthalimido-oxyphos- Niclosamide monohydraté; Niclosamidum monohydricum; Nik- phonate. losamid monohydrát; Niklosamidimonohydraatti; Niklosamid- monohydrat; Niklozamidas monohidratas; Niklozamid-mono- S Нафталофос hidrát. O2NN C H NO P = 349.3. Никлозамид Моногидрат 16 16 6 Profile CAS — 1491-41-4. C13H8Cl2N2O4,H2O = 345.1. ATC — P02DA01. Nitroscanate is an isothiocyanate anthelmintic used in veterinary ATC Vet — QP52AB06. medicine. Pharmacopoeias. In Eur. (see p.vii). Int. permits the monohydrate or the anhydrous substance under the title Niclosamide. O Ph. Eur. 6.2 (Niclosamide Monohydrate). Yellowish, fine crys- Nitroxinil (BAN, rINN) CH O 3 tals. Practically insoluble in water; slightly soluble in dehydrated Nitroxinilo; Nitroxinilum; Nitroxynil. 4-Hydroxy-3-iodo-5-ni- alcohol; sparingly soluble in acetone. Protect from light. NOPO trobenzonitrile. Нитроксинил OCH3 Adverse Effects C7H3IN2O3 = 290.0. O Gastrointestinal disturbances may occur occasionally CAS — 1689-89-0 (nitroxinil); 27917-82-4 (nitroxinil eg- with niclosamide. Lightheadedness and pruritus have lumine). ATC Vet — QP52AG08. Profile been reported less frequently. Naftalofos is an organophosphorus compound (see Organophos- phorus Insecticides, p.2047) used as an anthelmintic in veteri- Pharmacokinetics OH nary medicine. Niclosamide is not significantly absorbed from the gastrointestinal tract. INO2 Uses and Administration Netobimin (BAN, USAN, rINN) Niclosamide is an anthelmintic which is active against Netobimina; Nétobimine; Netobiminum; Sch-32481. 2-{3-Meth- most tapeworms, including the beef tapeworm (Taenia CN oxycarbonyl-2-[2-nitro-5-(propylthio)phenyl]guanidi- saginata), the pork tapeworm (T. solium), the fish tape- no}ethanesulphonic acid. worm (Diphyllobothrium latum) and the dog tape- Pharmacopoeias. In BP(Vet). Also in Fr. for veterinary use only. Нетобимин worm (Dipylidium caninum); it has also been given for BP(Vet) 2008 (Nitroxinil). A yellow to yellowish brown pow- infections with the dwarf tapeworm, Hymenolepis C14H20N4O7S2 = 420.5. der. Practically insoluble in water; slightly soluble in alcohol; CAS — 88255-01-0. nana. For discussions of the treatment of tapeworm in- sparingly soluble in ether; it dissolves in solutions of alkali hy- fections, see Diphyllobothriasis, p.136, Hymenolepia- droxides. Protect from light. ATC Vet — QP52AC06. sis, p.136, and Taeniasis, p.139. The activity of niclosa- Profile mide against these worms appears to be due to Nitroxinil is an anthelmintic used in veterinary medicine for the inhibition of mitochondrial oxidative phosphorylation; treatment of fascioliasis and some gastrointestinal roundworms HO OCH3 O anaerobic ATP production is also affected. in cattle and sheep. S O O Niclosamide is given as tablets, which must be chewed NH S thoroughly before swallowing and washed down with HN CH3 water. Oxamniquine (BAN, USAN, rINN) N For infections with pork tapeworm a single 2-g dose is Oxamniquina; Oxamniquinum; UK-4271. 1,2,3,4-Tetrahydro-2- given after a light breakfast. Niclosamide is not active isopropylaminomethyl-7-nitro-6-quinolylmethanol. Оксамнихин -O N+ against the larval form (cysticerci) and, although the risk of inducing cysticercosis appears to be theoretical, C14H21N3O3 = 279.3. O a laxative is given about 2 hours after the dose to expel CAS — 21738-42-1. the killed worms and minimise the possibility of the ATC — P02BA02. Profile ATC Vet — QP52AA02. Netobimin is an anthelmintic used in veterinary medicine. migration of ova of T. solium into the stomach; an an- tiemetic may also be given before treatment.

For infections with beef or fish tapeworms the 2-g dose O CH3 H of niclosamide may be divided, with 1 g taken after N+ N - (BAN, USAN, rINN) breakfast and 1 g an hour later. ONCH3 Niclosamide H In dwarf-tapeworm infections an initial dose of 2 g has HO Anhydrous Niclosamide; Bay-2353; Niclosamida; Niclosamida been given on the first day followed by 1 g daily for 6 Anidra; Niclosamide anhydre; Niclosamidum; Niclosamidum an- days. hydricum; Niklosamid; Niklosamid, vattenfri; Niklosamidi; Niklos- Pharmacopoeias. In Fr. and Int. amidi, vedetön; Niklozamid; Niklozamid bezwodny; Niklozami- Children aged 2 to 6 years are given half the above dos- das, bevandenis; Phenasale; Vízmentes niklozamid. 2′,5-Dichloro- es and those under 2 years of age are given one-quarter Adverse Effects 4′-nitrosalicylanilide; 5-Chloro-N-(2-chloro-4-nitrophenyl)-2-hy- the above doses. Oxamniquine causes severe pain at the injection site droxybenzamide. Unless expulsion of the worm is aided by a laxative, when given intramuscularly and is no longer given by Никлозамид portions are voided in a partially digested form after this route. treatment with niclosamide; the scolex is rarely identi- C13H8Cl2N2O4 = 327.1. It is generally well tolerated after oral doses, although fiable. dizziness with or without drowsiness occurs in at least CAS — 50-65-7. In schistosomiasis (p.138), niclosamide is used as a a third of patients, beginning up to 3 hours after a dose ATC — P02DA01. molluscicide in water-treatment control programmes. and usually lasting for up to 6 hours. Headache and ATC Vet — QP52AG03. Preparations gastrointestinal effects such as nausea, vomiting, and BP 2008: Niclosamide Tablets. diarrhoea are also common. Proprietary Preparations (details are given in Part 3) Allergic-type reactions including urticaria, pruritic OH Belg.: Yomesan; Braz.: Atenase†; Cz.: Yomesan†; Denm.: Yomesan†; Cl Fin.: Kontal; Fr.: Tredemine; Ger.: Yo m e s a n ; Gr.: Tredemine; Yomesan; In- skin rashes, and fever may occur. Liver enzyme values H dia: Niclosan; Israel: Yo m e s a n ; Ital.: Yo m e s a n ; Mex.: Overoid; Neth.: have been raised transiently in some patients. Epilepti- N Yo m e s a n ; S.Afr.: Yo m e s a n ; Swed.: Yo m e sa n ; Thai.: Manozide; Niclosan†; Cl Telmitin; Unicide; Yomesan; Turk.: Yo m e s a n ; UK: Yo m e s a n . form convulsions have been reported, especially in pa- Multi-ingredient: Thai.: Zenda†. tients with a history of convulsive disorders. Hallucina- O tions and excitement have occurred rarely. NO2 A reddish discoloration of urine, probably due to a me- Nitroscanate (BAN, USAN, rINN) Pharmacopoeias. In Chin. and Eur. (see p.vii). tabolite of oxamniquine, has been reported. Int. permits the anhydrous substance or the monohydrate under CGA-23654; Nitroscanato; Nitroscanatum; Nitroskanaatti; Ni- Effects on body temperature. A review1 in 1987 noted that the title Niclosamide. troskanat. 4-(4-Nitrophenoxy)phenyl isothiocyanate. although a modest post-treatment rise in temperature had been Ph. Eur. 6.2 (Niclosamide, Anhydrous). Yellowish-white to yel- Нитросканат reported occasionally, fever was not a common adverse effect of lowish, fine crystals. Practically insoluble in water; slightly solu- C13H8N2O3S = 272.3. oxamniquine, except in Egypt where it appeared to be character- ble in dehydrated alcohol; sparingly soluble in acetone. Store in CAS — 19881-18-6. istic. The cause was not known. Increased immune complexes airtight containers. Protect from light. ATC Vet — QP52AX01. and excretion of antigens occurred in only half the cases, there The symbol † denotes a preparation no longer actively marketed The symbol ⊗ denotes a substance whose use may be restricted in certain sports (see p.vii)