Nitrofurans toxicity

Nifurtimox, a nitrofuran, is a prodrug that is reduced to unstable nitroanion radicals, which react to produce highly toxic oxygen metabolites, such as superoxide and peroxide. Oxidative stress subsequently kills the parasite, which seems to lack effective enzymatic pathways to detoxify oxygen metabolites. 

Chagas disease is caused by a kinetoplastid trypanosoma parasite and affects millions of people in Latin America. The disease is currently incurable. Chemotherapy is based mainly on nitrofuran and nitroimidazole compounds and sterol biosynthesis inhibitors such as ketoconazole (337). Toxicity and high doses are the major problems for these organic drugs. Urbina et al. (338, 339) have found that com-plexation of antiparasitic organic agents such as chloroquine (78)... 

A number of 5-nitro-2-furaldehyde derivatives, called nitrofurans, are used in the treatment and/or prophylaxis of microbial infections, primarily in the urinary tract. Recent evidence suggests that the reduction of the 5-nitro group to the nitro anion results in bacterial toxicity. Intermediate metabolites modify various bacterial macromolecules that affect a variety of biochemical processes (e.g., DNA and RNA synthesis, protein synthesis) this observation may explain the lack of resistance development to these drugs. Evidence also indicates that the nitro anion undergoes recycling with the production of superoxide and other toxic oxygen compounds. It is presumed that the nitrofurans are selectively toxic to microbial cells because in humans, the slower reduction by mammalian cells prevents high serum concentrations. 

Nifurtimox (Lampit) is a nitrofuran derivative whose likely mechanism of action for kUhng of trypanosomes is through the production of activated forms of oxygen. Nifurtimox is reduced to the nitro anion radical, which reacts with oxygen to produce superoxide and hydrogen peroxide. The free radical metabolites, an absence of parasite catalase, and a peroxide dehciency lead to hpid peroxidation and cell damage. This production of activated oxygen results in toxicity to the protozoal cells. 

Chemotherapy of trypanosomiasis and leishmaniasis remains somewhat primitive and is often less than effective. In fact, it is doubtful that these diseases can be controlled by chemotherapeutic measures alone, without succc.ssful control of Ihc intermediate hosts and vectors that transmii them. Heavy metal compounds, such as Ihc urscnicals and aniimonials. arc somciimcs effective but frequently toxic. The old standby suramin appears to be of some value in long- and short-term prophylaxis. The nitrofuran derivative nifurtimox may be a major asset in the control of these diseases, but its potential toxicity remains lo be fully determined. 

A few nitrothiophenes have been shown to possess marked schistosomicidal activity, though weaker than nitrofurans or nitrothiazoles. Of these, compounds 9 and 10 exhibited potent activity. Compound 9, which bears a close resemblance with furapyrimidone, caused 100% elimination of S. mansoni from mice at a dose of 250 mg/kg [19], while 10 was found to be active against S. mansoni, S. japoniaim and S. haematobium infections in experimental animals and also proved to be less toxic in dogs and cebus monkeys [20a]. Alaimo and Hatton [20b] have prepared a... 

The 5-nitrofuran derivatives were the first nitroheterocycles of therapeutic value (Fig. 7-3). They are all synthesized from 5-nitro-2-furancarboxyaldehyde (5-nitrofurfural) or its diacetate by azomethine (Schiff base) formation with the appropriate amino compound (Eq. 7.1). The important nitrofurans in use today are shown in Figure 7-4. Since the first report of their antibacterial activity about 4,000 nitrofuran compounds have been synthesized and tested. Those that reached commercial use in human and veterinary medicine, including farm animal husbandry, did so because of their broad spectrum of activity including Gm+ and Gm- bacteria (except P. aeruginosa and some Klebsiella and Proteus strains), relatively low toxicity, and infrequent development of resistance. 

The nitroaromatic compounds such as the nitrofurans are known to be activated by a bacterial nitroreductase system in susceptible microorganisms. Intermediate, highly reactive species such as free radicals produced during the reduction process are likely responsible for damage to DNA strands that lead to bacterial and protozoal cell death. Thus a reduced nitroaryl anion radical could be oxidized by 02 to produce superoxide anions (Eq. 7.3). Under the influence of superoxide dismutase (SOD) (Chapter 4) hydrogen peroxide can be produced (Eq. 7.4), which, in turn, interacts with additional superoxide anion radical, producing ionizing toxic hydroxyl radicals (Eq. 7.5). 

The search for more effective and less toxic nitrofuran derivatives continues to yield better compounds. Some of the recently discovered products have aroused keen interest in researchers and it is hoped that new compounds of the nitrofuran group can soon be used in medical practice in lieu of the present less specific administration of broad spectrum antibiotics. The interesting history of nitrofurans is treated in detail by Dunlop and Peters. ... 

Most workers agree that the toxicity of nitrofurans, provided average dosages are given, will remain low. In therapeutic doses these compounds do not exhibit acute effects on blood pressure, respiration or heart action in man. The toxicity of nitrofurans is shown in Table 6.18 (the LDjq in mice is included). 

The toxicity of nitrofurans varies with their solubility in water for example, an LDjo of furazolidone which is slightly soluble in water changes according to the size of the crystals, and it is presumably affected by the rate of intestinal absorption. 

Guanofuracin hydrochloride and panfuran hydrochloride are more toxic than other nitrofurans. One gram of each of the compounds will dissolve in about 100 ml. of water. Hence higher toxicity can be ascribed to greater absorption from the intestines. 

Several nitrofurans have been marketed either regionally or woddwide in the human and veterinary areas because of their broad spectrum of activity, relatively mild toxicity, and low tendency for resistance development. However, accurate total volumes or sales of these products on a global basis are not generally available. In the United States, nearly four million prescriptions were written in 1989 for products containing nitrofiirazone or nitrofurantoin. U.S. sales during this period for these products approached 70 miUion thus therapy with this class of compoimds remains a significant therapeutic alternative. 

Nitrofurans are banned substances within the EU and in some other countries because of their mutagenic and geno-toxic characteristics. Nitrofuran metabolites are still found, primarily in aquaculture products originating from Southeast Asia, with SEM (the metabolite of nitrofurazone) having the highest incidence. Methods for detecting residues of nitrofurans aim for protein-bound metabolites that may persist in tissues for considerable periods after treatment. Methods are reported for the detection and identification of nitrofuran metabolites in many different food products. The main difficulty in nitrofuran metabolite analysis is the low selectivity of SEM as a marker metabolite of nitrofurazone. Several other possible sources of SEM have been identified and investigated, the most important of which is the use of... 

McEvoy " reviewed the legislative framework controlling the use of veterinary medicines and zootechnical feed additives in the EU. From a contamination perspective, problem compounds include sulfonamides, tetracyclines, nitroimidazoles, nitrofurans, ionophore coccidiostats, and nicarbazin. The literature on each of these was reviewed and examples of interventions to minimize contamination were given. Examples of contaminants include naturally occurring and synthetic toxic enviromnental compounds (e.g. mycotoxins and dioxins) that may contaminate feed raw materials. Zootechnical feed additives and veterinary medicines may also contaminate unmedicated feeding stuffs due to carry over during feed production. Contaminated feed can cause deleterious health effects in the animals and, through secondary exposure of consumers to products derived from these animals, may be harmful to people. 

The first rec-assay survey on food additives was carried out in 1971 for synthetic dyes, and phloxine (Red Dye No. 104) was found to be positive. The mutagenicity of phloxine was then demonstrated in E. coli WP2 try. AF-2 [2-(2-furyl)-3-(5-nitro-2-furyl)acrylamide], a nitrofuran food preservative, was rec-assayed and found to be a potent mutagen. This substance has been widely used in Japan, and the results initiated a continuing debate on the problem of toxicities due to chemical mutagens. Like other nitrofuran derivatives, AF-2 at first gave negative results with the Ames assay. Positive results appeared later using strains with R plasmid pKMlOl. 

---