Thiamine amprolium

A compound that includes an aminopyrimidine ring as well as the quaternary salt present in thiamine shows preferential inhibition of absorption of that co-factor by coccidia parasites over uptake by vertebrates. The compound is thus used in poultry where coccidiosis is an economically important disease. Condensation of ethoxymethylenemalononitrile (42-1) with the amidine (42-2) leads to the aminopyrimidine (42-4), probably via the intermediate addition-elimination intermediate (42-3). The nitrile group is then reduced to the methylamino derivative (42-5) by means of hthium aluminum hydride. Exhaustive methylation, for example by reaction with formaldehyde and formic acid, followed by methyl iodide leads to the quaternary methiodide (42-6). The quaternary salt is then displaced by bromine, and the resulting benzyhc-like cylic halide (42-7) is displaced by 2-picoline (42-8). There is thus obtained amprolium (42-9) [43]. 

Amprolium (Fig. 5.7) is a vitamin IT analogue. It is a competitive antagonist of the thiamine transport mechanism. Amprolium has been used as a coccidi-ostat mainly in chickens, laying hens, turkeys, and ruminants. It is available as a soluble powder for addition to drinking water (60-240 mg/L) or as a premix, usually in combination with ethopabate and/or sulfaquinoxaline, for mixing with the feed (125-500 mg/kg feed). A withdrawal period of 3 days is required for chickens. 

The higher potency of nicarbazin (57) compared with earlier agents then set a standard for new compounds. Moreover, parasite resistance to the existing agents was becoming problematic. In 1960 amprolium (58) was introduced. This compound had an entirely different mode of action. That the drug reduces the uptake of thiamine (59) by (or... 

Carbohydrate metabolism provides the main energy source in coccidia. Diets deficient in thiamin, riboflavin, or nicotinic acid—all cofactors in carbohydrate metabolism—result in suppression of parasitic infestation of chickens by E tenella and E acervulina. A thiamin analog, amprolium—1-[(4-amino-2-propyl-5-pyrimidinyl)-methyl]-2-picolinium chloride—has long been used as an effective anticoccidial agent in chickens and cattle with relatively low host toxicity. The antiparasitic activity of amprolium is reversible by thiamin and is recognized to involve inhibition of thiamin transport in the parasite. Unfortunately, amprolium has a rather narrow spectrum of antiparasitic activity it has poor activity against toxoplasmosis, a closely related parasitic infection. 

The poultry industry employs the sulfonamides sulfaquinoxaline (114), also known as Diamprim, and sulfadimidine (115) for treatment of coccidiosis. The antimalarial pyrimethamine (116) (see Chapter 1) exhibits anti-coccidial properties, as does amprolium, APL, l-[(4-amino-2-propyl-5-pyrimidinyl)methyl]-2-methylpyridinium chloride hydrochloride (116a), a thiamine antagonist73. 

A) Amprolium is an inhibitor of thiamin transport in eimeria species... 

Amprolium 9.37), an analogue of thiamine (2.7), has proved highly successful in coccidiosis of poultry. This drug acts by inhibiting the transport of thiamine, in Eimeria, 50 times more strongly than in cells of the chicken gut (James, 1980). 

Cells in culture allow much more detailed studies of mechanism than in vivo. Cultured cerebellar granule neurons were treated with amprolium, a potent inhibitor of thiamine transport. Exposure to amprolium causes apoptosis and the generation of reactive... 

Amprolium Hydrochloride, C14H19CINH4HCI is of low molecular weight, 315.25 daltons. It is a white, odourless substance, readily soluble in water. It is a thiamine antagonist and is used in poultry feeds to prevent coccidioidomycosis. 

Bizon-Zygmahska, D., Jankowska-Kulawy, A., Bielarczyk, H., Pawelczyk, T., Ronowska, A., Marszall, M., and Szutowicz, A., 2011. Acetyl-CoA metabolism in amprolium-evoked thiamine pyrophosphate deficits in cholinergic SN56 neuroblastoma cells. Neurochemistry International. 59 208-216. 

Figure 34.1 Thiamine deficiency (TD) increased intracellular calcium concentration in in cultured cortical neurons. Cortical neurons were isolated from the cerebral cortex of mice and maintained in vitro for seven days (DFV7). TD was induced in these neurons by the treatment of amprolium (1 mmol/L) for one or four days (TDl or TD4). The intracellular calcium concentration was measured. Short-term TD (TDl) had little effect on calcium homeostasis longer duration of TD (TD4) caused a significant increase in intracellular calcium concentration. The results are the mean SEM of three repeated experiments.

B. Amprolium is a competitive antagonist of thiamine used as a coccldiostat in poultry and ---- cattle. 

Amprolium (Figure 9.7) is a thiamine antagonist. Its oral use as a veterinary drug is permitted for control of coccidiosis in poultry.However, its use as a feed additive is no longer permitted. Authorisation as a coccidiostatic feed additive was withdrawn in 1992 when data requested by SCAN for evaluation of amprolium-containing products (Pancoxin and Pancoxin Plus) were not provided. 

Excellent prophylaxis, and even cure, of the disease can be obtained with the following drugs mixed with the food (a) sulphonamides, especially sulfaquinoxaline, (b) amprolium (9.27), a metabolite analogue of thiamine, or (c) nitrofurazone (4.25). 

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