Tryparsamide

**Tryparsamide** is an antiparasitic drug that was used in the early 20th century to treat sleeping sickness. It is not used for treatment in modern medicine.

This drug was obtained in 1919 from sodium arsenilate thanks to the research of Walter A. Jacobs and Michael Heidelberger. Studies on its biological activity were carried out in the same year by Wade H. Brown and Louise Pearce, and the first clinical trials took place in 1923 by Carl F. Lorenz and Albert D. Loevenhart (their interest was directed toward the chemotherapy of neurosyphilis.

## Chemistry 
Tryparsamide is a derivative of arsanilic acid that replaces the unsubstituted amine of arsanilic acid with a secondary amine. The other group on nitrogen is derived from glycinamide. It may be prepared from arsanilic acid by reaction with chloroacetamide and base. A simplified version of this reaction is
:
A second reaction with a base like sodium hydroxide makes the free acid into a salt.

Tryparsamide is the N-carbamyl-methyl-p-aminobenzenearsonate of sodium. It appears as a white, crystalline, and stable powder. The pentavalent arsenic content is about 25%. One gram of this active compound can dissolve in about 2 mL of water. A 1:20 solution shows a neutral reaction to litmus paper and is not oxidized by air, either in ampoules or in solution. All organic or inorganic arsenicals, whether pentavalent or trivalent, exert their effect by reacting with cellular sulfhydryl (-SH) groups. Consequently, the sulfhydryl-containing enzymatic systems necessary for cellular metabolism are inhibited. As a medicine, it was used in a solution of 10-20 mL of (sterile) water. 

## Details 
Tryparsamide is an organic arsenical belonging to the category of pentavalent arsonic acids (R–C6H4AsO3H2). Organic arsenicals constitute an important group of antispirillotic and antiprotozoal drugs. The main disadvantage of their use in therapy is the narrow safety margin. In fact, for the treatment of a number of diseases, antibiotics have replaced organic arsenicals, which are no longer used in medicine or for pharmacological treatments.  

The main application of tryparsamide was in the treatment of African trypanosomiasis, or sleeping sickness. The arsenical derivative was used in both early and advanced cases, but its main drawback was impairment of vision. A course of tryparsamide usually consisted of twelve weekly injections, which could be repeated if necessary. Even before its use in the treatment of "sleeping sickness" in Africa. This organic arsenical derivative was often employed in the pharmacological treatment of late syphilis of the central nervous system, until penicillin became the preferred option. 

After determining the dose of tryparsamide, it was dissolved in 10–20 mL of sterile distilled water and then injected intravenously (into the veins). If the patient had inaccessible veins, the arsenical derivative could be injected intramuscularly (into muscles), this time dissolved in 3 mL of water. The dose for the average adult male was 1–3 g; this was not only the dose normally used, but also the maximum amount that could be given. A full treatment cycle consisted of 12 or more weekly doses, but in the case of neurosyphilis, administrations of up to one hundred consecutive weekly injections were reported. 

## Side effects 
Compared to other arsenical derivatives used pharmacologically, tryparsamide did not produce some of the severe reactions caused by arsphenamines, yet serious toxic reactions could still occur. The pharmacological use of this compound could cause liver damage, which, even if mild, could worsen and potentially endanger the patient’s life during therapy. Cases reported for tryparsamide include dermatitis, gastrointestinal disturbances, Jarisch-Herxheimer reaction, severe nitrite crises, and allergic reactions, as well as a case of bilateral adrenal necrosis. 

Toxic reactions occurred with a frequency of 15% or even higher. To counteract this, the use of dimercaprol (BAL – British Anti-Lewisite) was recommended: administration of BAL significantly increases excretion of arsenic in urine, so that the thioarsenate formed from the reaction between BAL and arsenic is removed from tissue receptors and rapidly (fast) expelled by the kidney. The main danger in the use of tryparsamide was visual disturbances, which were frequent. Woods and Moore reported in 1924 an incidence of over 15%, but in 1936 Sloan and Woods, in a literature review, collected 71 cases of objective reactions (3–4%) out of a total of 2,087 patients who had received the arsenical derivative. 

Nearly 10% of subjects receiving tryparsamide experienced visual changes, consisting of “sparkles” or “glare”, which could persist for days or weeks. In about one-third of cases, a concentric reduction of the visual field was also observed, which could lead to blindness if the treatment was not discontinued in time. In some instances, blindness could occur suddenly, especially if the patient already had a pre-existing anterior optic lesion. If side effects did not appear within the first 12 injections, their incidence was much lower. Central visual acuity impairment regressed after abrupt and permanent cessation of therapy, whereas peripheral visual loss persisted.

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