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PubMed1957

The antituberculous activity of ethyl thiolesters with particular reference to diethyl dithiolisophthalate.

Diethyl dithiolisophthalate exerts an antituberculous effect in mice comparable to that of isoniazid and streptomycin. It is effective when given in single doses, and against isoniazidresistant strains. It is most active when given subcutaneously either by injection or by absorption through the skin. Drug resistance has been demonstrated in mice, and isoniazid is active against such strains. The effects of this and other ethyl thiolesters are antagonized by their methyl analogues.

Animals↗
PubMed1959

The effect of treatment with a large dose of isoniazid on an established tuberculous infection in mice.

Mice were infected intracorneally with Mycobacterium tuberculosis var. bovis and the infection allowed to develop for a period of 2 weeks. At this stage the animals were divided into two main groups; one received no treatment, the other was treated with large doses of isoniazid (3.0 mg./mouse/day). The effect of treatment on the primary lesion, the viability of the bacilli, the systemic spread of infection, and the production of immunity were observed. Treatment was continued for 11 months, after which the animals were observed for another 8 months. Within a few days of starting isoniazid treatment the primary lesion stopped increasing in size, regressed slightly and stabilized at a size of about one-third of that of the controls. There was little evidence of any clearing of the bacilli from the lesions; they remained strongly acid-fast and morphologically normal for many months after infection, although by 13 months about half of the organisms in both groups had become very granular. The evidence suggests that in control and treated animals the bacilli in the cornea had usually all died within 8 months after infection. In two treated corneas, living virulent bacilli were demonstrated 15 months after inoculation. In the untreated animals, the disease spread systemically to involve the lungs, liver, and spleen, and by one year after inoculation the systemic tuberculous infection was very heavy, though not enough to kill the animals. The lesions in these animals contained many acid-fast bacilli. In the treated group, systemic spread of infection as judged by the development of small macroscopic lung foci was slight; acid-fast bacilli were found in only one animal. In the treated animals, practically no immunity could be detected 5 months after inoculation and had not reappeared 2 months after cessation of treatment; in the untreated animals immunity was present.

Animals↗
PubMed1960

The antitubercular properties of a series of thiols and sulphides.

The antitubercular activity of a series of thiols, dithiolans, thiol esters, dimercaptopropyl esters, and episulphides has been examined in vitro and in vivo in mice infected with the H(37)Rv strain of Mycobacterium tuberculosis. Most of the thiol compounds were inactive, although dimercaprol (2,3-dimercaptopropanol; B.A.L.) and a few closely related compounds showed slight activity in vivo, the only exception being 2,3-dimercaptopropyl chloride which was very active. The dithiolans were inactive, but some of the thiol esters were moderately active, in particular 2,3-di(acetylthio)propyl acetate and 1,2,3-tri(acetylthio)propane. The majority of the dimercaptopropyl esters had significant activity, the most active compounds being 2,3 - dimercaptopropyl benzoate, 1, 3 - dimercapto - 2 - propyl benzoate, 2, 3 - dimercaptopropyl o-chlorobenzoate, and 2,3-dimercaptopropyl p-chlorobenzoate. All the S-acyl derivatives of 3-mercaptopropylene sulphide had good antitubercular activity, some being more active than streptomycin. The most active compound of the series was 3-(2-furoylthio)propylene sulphide. The activity of the compounds is believed to be due to their conversion in vivo to 3-mercaptopropylene sulphide and not due to the formation of ethanethiol. Slight deviation from the basic structure abolishes antitubercular activity.

Acetates↗
PubMed1960

The antitubercular activity of 3-acetylthiopropylene sulphide and 3-(2-furoylthio) propylene sulphide.

Two derivatives of 3-mercaptopropylene sulphide (B.R.L. 482), 3-acetylthiopropylene sulphide (B.R.L. 459) and 3-(2-furoylthio)propylene sulphide (B.R.L. 658), have been tested in mice for antitubercular activity. The compounds were administered daily in arachis oil by the subcutaneous route. When tested by a prolongation in survival time B.R.L. 459 was less active than streptomycin, while B.R.L. 658 was of the same order of activity. When assessed by the lesions present in the lungs after 14 days' treatment B.R.L. 658 was as active as isoniazid and B.R.L. 459 was of the same order of activity as streptomycin. Neither compound, however, cured an established infection and resistance developed rapidly to both compounds, both in vitro and in vivo. It is concluded that, in view of their adverse physical and pharmacological properties, the compounds are unsuitable for clinical use.

Animals↗
PubMed1960

The accumulation of isoniazid in tissues, and the course of experimental tuberculosis.

In an attempt to find agents enhancing the infiltration of isoniazid into tissues, the authors have investigated the effect of the drug on oedema due to injection of egg white into the rat paw, when it was given alone and in conjunction with histamine, antazoline, carbachol, chlorpromazine, and a pyrogen. Isoniazid increased the oedema. All the substances, except antazoline, increased the rate at which isoniazid disappeared from the blood, and they all favoured accumulation of the drug in tissues. Treatment of experimental tuberculosis with subthreshold doses of isoniazid, in conjunction with the above compounds, gave better results than when isoniazid was used alone.

Animals↗
PubMed1960

Action of two ethyl thiol esters against experimental tuberculosis in the guinea-pig.

Two thiol esters, ethyl dithiolterephthalate (Compound 13,130) and ditophal (ethyl dithiolisophthalate; Etisul), have been tested for their antituberculosis activity in guinea-pigs. Compound 13,130 was active at a dose of 100 mg./Kg. twice daily by mouth in animals infected subcutaneously, but was inactive against an intracerebral infection at 50 mg./kg. Ditophal was active in the subcutaneously infected animals at 200 mg./kg. orally or 50 mg./kg. subcutaneously. Higher doses subcutaneously were irritant.

Animals↗