Phenothiazines anthelmintic

Although several chemicals, e.g. arsenicals and organophosphorus compounds, had been used with some effect to treat specific helminth infections, the introduction in 1930 of phenothiazine (1) was a revolutionary event in the control of gastrointestinal worms. Although its spectrum of activity was narrow compared to modern anthelmintics and its dose level was rather high (600-800 mg kg-1), it was the veterinary anthelmintic of choice until the 1960s. 

The next novel anthelmintic after phenothiazine (1) was methyridine (2) which was active at 200 mg kg-1 both orally and parenterally (i.e. other than intestinally). It had a wide range of activity but was erratic against abomasal parasites and did not have a wide safety margin. 

Substituted phenothiazines are antihistaminics and show powerful depressant effects on the central nervous system. Two well-known drugs of this type are promethazine (287) and chloropromazine (288). Phenothiazine itself is a veterinary anthelmintic agent as well as an insecticide, and methylene blue (284 R = Me) has long been used as a biological stain. 

The first synthesis of phenothiazine was reported by Bernthsen about 80 years ago. In the evolution of the chemistry of this heterocycle, three periods can be discerned. First, phenothiazine was of interest owing to its quinonoid derivatives—an important chapter in sulfur dye chemistry. Research work in the field of phenothiazine was then stimulated by the discovery of the anthelmintic action of unsubstituted and of some C -substituted phenothiazines. During the last two decades, the exceptional pharmacological properties of some A-substituted phenothiazines, e.g., the antihistaminic activity of promethazine, 10-(2-dimethylamino-l-propyl)phenothiazine, and particularly the psychotherapeutic action of chlorpromazine, 2-chloro-10-(3-dimethylamino-1 -propyl )phenothiazine, focused interest mainly on the synthesis and testing of a great number of compounds of this type. The phenothiazine drugs now play a very important part in chemotherapy. 

The existence of a correlation between anthelmintic activity and redox potentials of phenothiazine derivatives stimulated extensive work on oxidation of (7-substituted phenothiazines, and some results are presented in Table III. 

In vivo hydrolysis of 10-formylphenothiazine to phenothiazine has been claimed to account for the anthelmintic action of the formyl derivative. ... 

The great amount of research on the mode of action and the metabolism of phenothiazine derivatives is a natural result of their application in human and veterinary medicine. In the early years (1935-1940) the main object of investigation was the metabolism of phenothiazine, its 5-oxide, and some of their G-substituted derivatives in animal organisms, arising out of the anthelmintic action of these substances. During the postwar period, comparatively little attention was paid to these topics recent research has confirmed the principal conclusions of the earlier work, namely that the main metabolic pathway followed by simple phenothiazines is the oxidation to the 5-oxide and hydroxylation in positions 3 and 7. 4-448 After the... 

It was with the action of phenothiazine that the importance of particle size was first recognised, in 1939, in relation to its toxicity to codling moth larvae, and in 1940 in relation to its anthelmintic effect, in both of which it was shown that reduction in particle size increased activity. The improvement in biological response to griseofulvin on microni-sation is well known similar blood levels of the dmg were obtained with half the dose of micronised dmg compared to those of non-micronised griseofulvin. The influence of... 

These include amitraz (110), prepared from 54, a member of the form amidine class, active against mites and ticks, that have replaced organophosphorus compounds. Notably, amitraz is active against newer strains of pyrethroid-resistant ticks. The reaction of diphenylamine (8) with sulfur in the presence of iodine as catalyst yields the anthelmintic (worming agent) phenothiazone (phenothiazine) (111) (Scheme 24). It is too toxic for human use, though it is an intermediate in the production of antipsychotic drugs. 

Phenothiazine and many of its substituted derivatives possess important and various biological activities, and have been shown to present significant insecticidal, antifungal, antibacterial and anthelmintic properties. Unsubstituted phenothiazine has also been used for vermifugal application, which has earned this molecule a good place alongside penicillin and DDT for its great impact on mankind, as recently pointed out by Mitchell [111]. 

Phenothiazine drugs have been the subjects of various electrochemical investigations. The motivation for these studies has been the search for means of analyzing drugs and their derivatives. Tozer et examined the correlation between C-substitution, standard electrode potential, cation-radical formation constants, and the anthelmintic activity of the heterocycles. 

In the phenothiazine area, it has been amply demonstrated that structural changes, in addition to producing expected quantitative changes in tranquilizing activity, also produce unexpected qualitative changes in biological activity. As a result antipruritic, antispasmodic, anticonvulsant, antibacterial, antiemetic, antimotion sickness, anthelmintic, and antidepressant compounds have been developed by molecular modification of the phenothiazines. 

Unsubstituted phenothiazine (XVI) is, of course, well known as an anthelmintic agent, and is devoid of tranquilizing properties (12). Another unalkylated phenothiazine, methylene blue (XVII) (21), is known to have antibacterial activity and to be devoid of tranquilizing properties. Antibacterial activity is also claimed for XVIII (28). Compound XIX with a dimethylsul-... 

The tricyclic compound phenothiazine, which has been known since the late nineteenth century, is a toxic compound of little therapeutic interest except as a large-animal anthelmintic at one time. An N-10 derivative, diethazine, was synthesized by French workers in the late 1940s as a possible antihistamine. The added anticholinergic properties it had... 

The discovery of phenothiazine as an anthelmintic dates back to 18 83, however, its antithistaminic aetivity was revealed in 1937. The comintuous seareh for better drugs ultimately resulted into the synthesis of chlorpromazine in the famous Rhone-Poulenc Laboratories in France in the year 1950 whieh was... 

Phenothiazines are not naturally occurring substances but a number of phenothiazine derivatives have useful medicinal applications. For example, phenothiazine and some C-substituted derivatives have anthelmintic properties (i.e., the ability to destroy worms). Various N-substituted phenothiazines have important pharmacological properties. For example, promethazine [10-(2-dimethylamino-l-propyl)phenothiazine] possesses antihistaminic activity and chlorpromazine [2-chloro-10-(3-dimethylamino-l-propyl)phenothiazine] has a profound psychotherapeutic activity and is widely used, as are related phenothiazines, for the treatment of various mental illnesses. 

Similarly phenothiazine, a highly effective oral anthelmintic in sheep, is accumulated by intestinal worms but not by the cells lining the sheep s gut yet, when given intravenously, it is toxic for both species (Lazarus and Rogers, 1951). 

Phenothiazine, the first of the selective anthelmintics for sheep, is now little used because of the large dose needed. 

The same phenothiazines or closely related compounds which are used as psychotropic drugs or as sedatives in humans are used by veterinarians and farmers as insecticides and anthelmintics for animals and birds. Table 8 lists the commercial phenothiazine insecticides and wormers used by veterinarians. Many individuals in these professions have acquired allergic contact dermatitis, photoallergic reactions, or both by spraing such phenothiazines for insect control or feeding these compounds as wormers. Such individuals must avoid using phenothiazine antihistamines because of the likelihood of producing flares of the phenothiazine dermatitis. 

Phenothiazine, an oral insecticide and anthelmintic introduced in 1925, was the earliest organic insecticide known. It is fed in salt or mineral supplements to control fly larvae and certain internal parasites. 

Piperazine, phenothiazine, and levamisole are anthelmintics that may cause allergic contact dermatitis. Allergic contact dermatitis to nitrofurazone has been reported. This anticoccidian is used in cattle feed. Formaldehyde is the allergen in nitrofurazone. Allergic contact dermatitis to 3,5 dinitro-o-toluamide, an anticoccidian used in chicken feeds, has been reported [149]. 

A glucuronoside of leucothionol (21) appears to be excreted by rabbits following oral administration of phenothiazine (LXIX), a compound used in veterinary practice as an anthelmintic. Other products identihed were unchanged phenothiazine, leucothionol (LXX) and thionol (LXXI) (420). The latter two compounds apparently constitute a reversible oxidation-... 

Mebendazole 6.34) and its variants in which the 5-benzoyl-group is replaced by a butyl (parbendazole), phenylthio (fenbendazole) or propylthio (albendazole) group are highly selective variants of thiabendazole. Albendazole has a particularly broad spectrum of activity (Theodorides et al. 1976). Phenothiazine, the first of the selective anthelmintics for sheep, is now little used because of the large dose needed. 

The phenothiazines are readily oxidized to red free-radicals (Borg and Cotzias, 1962) but, at the present time, this is not thought to be correlated with their psycholeptic action. Unsubstituted phenazine, which was formerly much used as an oral anthelmintic in sheep, has been thought to owe its action to a stable free-radical formed in the worm (Craig et aLy i960). 

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