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Antimony sodium tartrate was formerly used as an emetic. The (BAN, rINN) Profile sodium tartrate and potassium tartrate have also been used as ex- Cambendazole is a carbamate struc- Bithionololum; Bithionolum; Bitionol; Bitionolol; Bitionololi. 2,2′- pectorants. turally related to (p.156). It is used in the treatment Thiobis(4,6-dichlorophenol). of strongyloidiasis. Preparations Битионол Preparations Proprietary Preparations (details are given in Part 3) C12H6Cl4O2S = 356.1. CAS — 97-18-7. Proprietary Preparations (details are given in Part 3) Multi-ingredient: Thai.: Brown Mixture. ATC — D10AB01; P02BX01. Braz.: Cambem†. ATC Vet — QD10AB01; QP52AG07. Multi-ingredient: Braz.: Exelmin†.

Ascaridole Cl Cl Chenopodium Oil Ascaridol. 1-Isopropyl-4-methyl-2,3-dioxabicyclo[2.2.2]oct-5- ene. OH Aceite de quenopodio; Aetheroleum Chenopodii; Esencia de Quenopodio Vermifuga; Oil of American Wormseed; Wurmsa- Аскаридол menöl. C10H16O2 = 168.2. Cl S Cl Амброзиевое Масло; Маревое Масло CAS — 512-85-6. CAS — 8006-99-3. OH Profile Pharmacopoeias. Fr. includes bithionol oxide for veterinary Chenopodium oil is distilled with steam from the fresh flowering use. and fruiting plants, excluding roots, of Chenopodium ambrosio- CH3 ides var. anthelminticum. It contains . It was formerly H3C Adverse Effects used as an anthelmintic for the expulsion of roundworms (As- OO Adverse effects in patients taking bithionol by mouth include an- caris) and hookworms. It is toxic and has caused numerous fatal- CH3 orexia, nausea, vomiting, abdominal discomfort, diarrhoea, sali- ities. vation, dizziness, headache, and skin rashes. Handling. Chenopodium oil may explode when heated. Profile Photosensitivity reactions have occurred in persons using soap Ascaridole is the active principle of chenopodium oil (p.142) and containing bithionol. Cross-sensitisation with other halogenated has the same actions. disinfectants has also occurred. Uses and Administration Clorsulon (BAN, USAN, rINN) Handling. Ascaridole is an unstable liquid which is liable to ex- Bithionol is a chlorinated bis- with bactericidal and an- plode when heated or when treated with organic acids. Clorsulón; Clorsulone; Clorsulonum; MK-401. 4-Amino-6- thelmintic properties. It is active against most trematodes (trichlorovinyl)benzene-1,3-disulphonamide. (flukes). Bithionol is used in preference to in fasci- Клорсулон oliasis (see Liver Fluke , p.137) and is also used in paragonimiasis (see Lung Fluke Infections, p.137) as an alterna- C8H8Cl3N3O4S2 = 380.7. Bephenium Hydroxynaphthoate (BAN, rINN) tive to praziquantel. It may be given in an oral dose of 30 to CAS — 60200-06-8. Bephenii Hydroxynaphthoas; Béphénium, Hydroxynaphtoate de; 50 mg/kg on alternate days for 10 to 15 doses. Alternatively, for Hidroxinaftoato de befenio; Naphthammonum. Benzyldime- fascioliasis, WHO recommends a regimen of 30 mg/kg daily for 5 days. H N thyl(2-phenoxyethyl)ammonium 3-hydroxy-2-naphthoate. 2 O Bithionol was formerly used topically as a bactericide but this S Бефения Гидроксинафтоат use has declined because of photosensitivity reactions. O Cl O C28H29NO4 = 443.5. Preparations S NH CAS — 7181-73-9 (bephenium); 3818-50-6 (bephenium Proprietary Preparations (details are given in Part 3) 2 hydroxynaphthoate). Multi-ingredient: Arg.: Fonergine. Cl O ATC — P02CX02. Cl NH2

CH3 Bromofenofos (rINN) Pharmacopoeias. In US for veterinary use only. USP 31 (Clorsulon). A white to off-white powder. Slightly sol- O COO Bromfenofos; Bromofénofos; Bromofenofós; Bromofenofosum; N uble in water; freely soluble in acetonitrile and in methyl alcohol; Bromophenophos; Bromphenphos. 3,3′,5,5′-Tetrabromo-2,2′- very slightly soluble in dichloromethane. CH3 OH biphenyldiolmono(dihydrogen phosphate). Бромофенофос Profile Clorsulon is an anthelmintic used in veterinary medicine for the Pharmacopoeias. In Int. C12H7Br4O5P = 581.8. treatment of liver fluke infections. CAS — 21466-07-9. Profile ATC Vet — QP52AB02. Bephenium hydroxynaphthoate is an anthelmintic formerly used in the treatment of hookworm infections, ascariasis, and tricho- strongyliasis. Closantel (BAN, USAN, rINN) Br Closantelum; R-31520. 5′-Chloro-4′-(4-chloro-α-cyanobenzyl)- 3,5-di-iodosalicyl-o-toluidide. OH Клозантел Betanaphthol Br C22H14Cl2I2N2O2 = 663.1. β-Naftol; 2-Naftol; Naphthol. Naphth-2-ol. Br CAS — 57808-65-8. HO ATC Vet — QP52AG09. Бета-нафтол O C H O = 144.2. P 10 8 O CAS — 135-19-3. OH Br Cl I Profile O CH OH Bromofenofos is an organophosphorus compound (see Organo- 3 phosphorus Insecticides, p.2047) used as an anthelmintic in vet- erinary medicine for the treatment of fluke infections. HN IOH Pharmacopoeias. In Pol. and Swiss. Cl N Cambendazole (BAN, USAN, rINN) Profile Betanaphthol was formerly used as an anthelmintic in hook- Cambendazol; Cambendazolum; MK-905. Isopropyl 2-(thiazol-4- worm and tapeworm infections, but it has been superseded by yl)-1H-benzimidazol-5-ylcarbamate. Closantel Sodium (BANM, rINNM) less toxic and more efficient drugs. Камбендазол Closantel sódico; Closantel sodique; Closantelum natricum; Klosanteelinatrium; Klosantel sodná sůl; Klosantelnatrium; Natrii Betanaphthol has a potent parasiticidal effect and has been used C14H14N4O2S = 302.4. topically in the treatment of scabies, ringworm, and other skin CAS — 26097-80-3. Closantelum; R-34828. diseases. ATC Vet — QP52AC08. Натрий Клозантел Betanaphthyl benzoate has been used in preparations for the C22H14Cl2I2N2O2Na = 686.1. treatment of gastrointestinal disorders. H Pharmacopoeias. In Eur. (see p.vii) as the dihydrate for veter- N inary use. Preparations CH3 O S Ph. Eur. 6.2 (Closantel Sodium Dihydrate for Veterinary Use; Proprietary Preparations (details are given in Part 3) Closantel Sodium Dihydrate BP(Vet) 2008). A yellow, slightly N N hygroscopic, powder. It exhibits polymorphism. Very slightly Multi-ingredient: Arg.: Hekabetol; Austria: Salvyl. H3C O N H soluble in water; freely soluble in alcohol; soluble in methyl al- cohol. Store in airtight containers. Protect from light. Ascaridole/ Citrate 143 Profile Pharmacopoeias. In Chin., Eur. (see p.vii), Int., Jpn, and US. normally excluded when diethylcarbamazine is used in Closantel is an anthelmintic used in veterinary medicine for the Ph. Eur. 6.2 (Diethylcarbamazine Citrate). A white or almost mass treatment schedules. treatment of fluke and nematode infections. white, crystalline, slightly hygroscopic powder. Very soluble in Effects on the eyes. Loss of eyesight was reported in 11 wom- water; soluble in alcohol; practically insoluble in acetone. Store Pregnancy. Pregnant women are normally excluded when di- en who received closantel (Flukiver) in mistake for a gynaeco- in airtight containers. ethylcarbamazine is used in mass treatment schedules. logical product.1 Sight was restored after closantel was stopped USP 31 (Diethylcarbamazine Citrate). A white, crystalline, Animal studies1 suggest that the uterine hypermotility induced by but incapacitating eye pain remained. slightly hygroscopic powder, odourless or has a slight odour. diethylcarbamazine is mediated via prostaglandin synthesis; this 1. ’t Hoen E, et al. Harmful human use of donated veterinary drug. Very soluble in water; sparingly soluble in alcohol; practically in- might explain the mechanism of the abortifacient action previ- Lancet 1993; 342: 308–9. soluble in acetone, in chloroform, and in ether. Store in airtight ously reported.2 containers. 1. Joseph CA, Dixon PAF. Possible prostaglandin-mediated effect of diethylcarbamazine on rat uterine contractility. J Pharm Phar- Diamfenetide (BAN, rINN) Adverse Effects macol 1984; 36: 281–2. Adverse effects directly attributable to diethylcar- 2. Subbu VSV, Biswas AR. Ecbolic effect of diethyl carbamazine. Diamfenetida; Diamfénétide; Diamfenetidum; Diamphenethide. Indian J Med Res 1971; 59: 646–7. β,β′-Oxybis(aceto-p-phenetidide). bamazine include nausea and vomiting. Headache, diz- Диамфенетид ziness, and drowsiness may occur. Renal impairment. For a study on the effects of renal impair- C H N O = 372.4. ment on the pharmacokinetics of diethylcarbamazine, see under 20 24 2 5 Hypersensitivity reactions arise from the death of the Pharmacokinetics, below. CAS — 36141-82-9. microfilariae. These can be serious, especially in on- chocerciasis where there may also be sight-threatening Pharmacokinetics O O O O O ocular toxicity; fatalities have been reported. Encepha- Diethylcarbamazine is readily absorbed from the gas- litis may be exacerbated in patients with loiasis and fa- trointestinal tract and also through the skin and con- HC N N CH talities have occurred. H H junctiva. It is widely distributed in tissues and is mainly ◊ Reactions occurring during diethylcarbamazine treatment of excreted in the urine unchanged and as the N-oxide Profile lymphatic filariasis are basically of 2 types: pharmacological metabolite. Urinary excretion and hence plasma half- Diamfenetide is an anthelmintic that has been used in veterinary dose-dependent responses and a response of the infected host to medicine for the control of fascioliasis in sheep. 1 life is dependent on urinary pH. About 5% of a dose is the destruction and death of parasites. eliminated in the faeces. • Reactions of the first type include weakness, dizziness, lethar- gy, anorexia, and nausea. They begin within 1 to 2 hours of Disposition. A pharmacokinetic study in 6 patients with Dichlorophen (BAN, rINN) taking diethylcarbamazine, and persist for a few hours. onchocerciasis1 indicated that diethylcarbamazine is absorbed Dichlorophène; Dichlorophenum; Diclorofeno; Di-phenthane- • Reactions of the second type are less likely to occur and are quickly and almost completely from the gastrointestinal tract, 70; G-4. 2,2′-Methylenebis(4-chlorophenol). less severe in bancroftian than in brugian filariasis. They may and is eliminated largely as unchanged drug in urine, with rela- be systemic or local, both with or without fever. tively small amounts being excreted as the N-oxide metabolite. Дихлорофен After a single radioactively labelled oral dose of diethylcar- C13H10Cl2O2 = 269.1. Systemic reactions may occur a few hours after the first oral bamazine citrate 0.5 mg/kg given as an aqueous solution, peak CAS — 97-23-4. dose of diethylcarbamazine and generally do not last for more plasma concentrations of 100 to 150 nanograms/mL were ATC — P02DX02. than 3 days. They include headache, aches in other parts of the achieved in 1 to 2 hours, followed by a sharp decline, then a ATC Vet — QP52AG01. body, joint pain, dizziness, anorexia, malaise, transient haem- marked secondary rise 3 to 6 hours after dosing, followed by a aturia, allergic reactions, vomiting, and sometimes attacks of steady decline. The half-life ranged from 9 to 13 hours. Urinary bronchial asthma in asthmatic patients. Fever and systemic re- OH OH excretion of diethylcarbamazine and diethylcarbamazine N-ox- actions are positively associated with microfilaraemia. Sys- ide was complete within 96 hours; between 4 and 5% of the dose temic reactions are reduced if diethylcarbamazine is given in was recovered in the faeces. Disposition was similar in 5 healthy spaced doses or in repeated small doses. They eventually subjects given a single 50-mg tablet of diethylcarbamazine cit- cease spontaneously and interruption of treatment is rarely rate. Peak plasma concentrations were initially 80 to necessary; symptomatic treatment with antipyretics or analge- 200 nanograms/mL, with a secondary rise 3 to 9 hours after dos- sics may be helpful. ing, the terminal half-life ranged from 5 to 13 hours, and urinary Cl Cl Local reactions tend to occur later in the course of treatment excretion of unchanged diethylcarbamazine and the N-oxide was and last longer; they also disappear spontaneously and inter- complete within 48 hours. ruption of treatment is not necessary. Local reactions include Pharmacopoeias. In Br. and Fr. When an alkaline urinary pH was maintained, the elimination lymphadenitis, abscess, ulceration, and transient lymphoede- BP 2008 (Dichlorophen). A white or slightly cream-coloured half-life of diethylcarbamazine and the area under the plasma ma; funiculitis and epididymitis may also occur in bancroftian powder with a not more than slightly phenolic odour. Practically concentration versus time curve were significantly increased filariasis. insoluble in water; freely soluble in alcohol; very soluble in ether. compared with when an acidic urinary pH was maintained.2 It has been suggested that the release of interleukin-6 may be im- Profile 1. Edwards G, et al. Diethylcarbamazine disposition in patients Dichlorophen is an anthelmintic that was used in the treatment of plicated in diethylcarbamazine’s adverse effects in patients with with onchocerciasis. Clin Pharmacol Ther 1981; 30: 551–7. lymphatic filariasis.2 by tapeworms but has been superseded by praziquantel 2. Edwards G, et al. The effect of variations in urinary pH on the or . In most patients with onchocerciasis, the microfilaricidal activi- pharmacokinetics of diethylcarbamazine. Br J Clin Pharmacol Dichlorophen also has antifungal and antibacterial activity and ty of diethylcarbamazine leads to a series of events with dermal, 1981; 12: 807–12. has been used topically in the treatment of fungal infections and ocular, and systemic components, known as the Mazzotti reac- 3 Renal impairment. Results in patients with chronic renal im- as a germicide in soaps and cosmetics. tion, within minutes to hours after its use. pairment and in healthy subjects, given a single 50-mg oral dose Preparations • Clinical manifestations can be severe, dangerous, and debili- of diethylcarbamazine citrate, indicated that the plasma half-life tating. Systemic reactions include increased itching, rash, BP 2008: Dichlorophen Tablets. of diethylcarbamazine is prolonged and its 24-hour urinary ex- headache, aching muscles, joint pain, painful swollen and cretion considerably reduced in those with moderate and severe Proprietary Preparations (details are given in Part 3) tender lymph nodes, fever, tachycardia and hypotension, and degrees of renal impairment.1 Mean plasma half-lives in 7 pa- Multi-ingredient: S.Afr.: Mycota†; UK: Mycota. vertigo. Most patients have eye discomfort in the first few tients with severe renal impairment (creatinine clearance less hours after diethylcarbamazine treatment. Punctate keratitis than 25 mL/minute), in 5 patients with moderate renal impair- can develop as can optic neuritis and visual field loss. ment (creatinine clearance between 25 and 60 mL/minute), and in 4 healthy subjects, were 15.1, 7.7, and 2.7 hours, respectively. Diethylcarbamazine Citrate WHO no longer recommends the use of diethylcarbamazine in onchocerciasis as safer alternatives exist. The patient with the longest plasma half-life of 32 hours did not have the poorest renal function, but it was considered likely that (BANM, rINNM) 1. WHO. Lymphatic filariasis: the disease and its control: fifth re- the abnormally slow elimination of diethylcarbamazine was due Citrato de dietilcarbamazina; Diethylcarbam. Cit.; Diethylcar- port of the WHO expert committee on filariasis. WHO Tech Rep Ser 821 1992. to the high urinary pH (7) resulting from sodium bicarbonate bamazine Acid Citrate; Diéthylcarbamazine, citrate de; Diethyl- 2. Yazdanbakhsh M, et al. Serum interleukin-6 levels and adverse therapy. A further patient with a half-life longer than expected carbamazini citras; Diethylkarbamazin-citrát; Dietilkarbamazin- reactions to diethylcarbamazine in lymphatic filariasis. J Infect also had a less acidic urine. citrát; Dietilkarbamazino citratas; Dietylkarbamazincitrat; Dietyy- Dis 1992; 166: 453–4. 1. Adjepon-Yamoah KK, et al. The effect of renal disease on the likarbamatsiinisitraatti; Ditrazini Citras; RP-3799. NN-Diethyl-4- 3. WHO. WHO expert committee on onchocerciasis: third report. pharmacokinetics of diethylcarbamazine in man. Br J Clin Phar- methylpiperazine-1-carboxamide dihydrogen citrate. WHO Tech Rep Ser 752 1987. macol 1982; 13: 829–34. Диэтилкарбамазина Цитрат Precautions C10H21N3O,C6H8O7 = 391.4. Uses and Administration CAS — 90-89-1 (diethylcarbamazine); 1642-54-2 (di- Treatment with diethylcarbamazine should be closely Diethylcarbamazine is an anthelmintic used in the ethylcarbamazine citrate). supervised since hypersensitivity reactions are com- treatment of lymphatic filariasis due to Wuchereria ATC — P02CB02. mon and may be severe, especially in patients with on- bancrofti (bancroftian filariasis), Brugia malayi, or B. chocerciasis or loiasis. Patients with onchocerciasis timori (both known as brugian filariasis and as Malay- should be monitored for eye changes. (The use of di- O an and Timorian filariasis respectively). It is also used ethylcarbamazine to treat onchocerciasis is no longer in loiasis due to Loa loa. It was used in onchocerciasis recommended.) In patients with heavy Loa loa infec- due to Onchocerca volvulus before became N N CH3 tion there is a small risk of encephalopathy and diethyl- available. Diethylcarbamazine is active against both N carbamazine should be stopped at the first sign of cer- CH the microfilariae and adult worms of W. bancrofti, B. H3C 3 ebral involvement. malayi, and Loa loa, but only against the microfilariae (diethylcarbamazine) Infants, pregnant women, the elderly, and the debilitat- of O. volvulus. It has been tried in Mansonella infec- ed, especially those with cardiac or renal disease, are tions and may be most effective against M. streptocer- 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)