Antiprotozoal agent

Although amebiasis is generally thought of as a tnipical disease, it actually has a worldwide distribution. In some areas with temperate climates in which sanitation is poor, the prevalence of amebiasis has been estimated to be as high as 20% of the population. The causative organism. Bila- 

Trichomoniasis, a venereal disease caused by the flagellated protozoan Trichomonas vaginalis, is common in the United States and throughout the world. Although it is not generally considered serious, this affliction can cause serious physical discomfort. Oral metronidazole provides effective treatment against all forms of the disease. It is also u.sed to eradicate the organism from asymptomatic male carriers. 

The combination of the antifolate trimethoprim and the sulfonamide sulfamethoxazole constitutes the treatment of choice for PCP. Other effective drugs include pentamidine, alovaquonc. and a new antifolate, trimetrexate. 

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. 

Emetine and Dehydroemetine. Tlic alkaloids emetine and dehydroemetine are obtained by separation from extracts of ipecac. They occur as Icvorotatnry. light-.sensitivc white powders that are insoluble in water. The alkaloids readily farm water-soluble salts. Solutions of the hydnx hlo-ridc salts intended for intramu.scular injection shnuld be adjusted tn pH 3.5 and. stored in light-resistant containers. 

Protozoa are single-celled organisms that represent the lowest division of the animal kingdom. Of the several 

One relatively common disease caused by protozoal infection is malaria. Malaria is caused by several species of a protozoan parasite known as plasmodia. Although this disease has been virtually eliminated in North America and Europe, malaria continues to be a primary health problem throughout many other parts of the world.44 Individuals who live in these areas, as well as those traveling to parts of the world where malaria is prevalent, must often undergo antimalarial chemotherapy. Hence, drugs that prevent and treat malaria are extremely important. 

In addition to malaria, several other serious infections may occur in humans due to parasitic invasion by protozoa.2,44 Severe intestinal infections (dysentery) produced by various protozoa occur quite frequently, especially in areas where contaminated food and drinking water are prevalent. Infections in tissues such as the liver, heart, lungs, brain, and other organs may also occur because of protozoal infestation. As mentioned in this chapter s introduction, individuals with a compromised immune system may be especially susceptible to these intestinal and extraintestinal infections.2,70 

The primary agents used to treat protozoal infections are listed in Tables 35-3 and 35-4, and each agent is described subsequently. Drugs that are primarily used to treat and prevent malaria are grouped together, followed by drugs that are used to treat other types of protozoal infections (intestinal and extraintestinal infections). 

1 Amebiasis Metronidazole 1 Diloxanide for noninvasive intestinal amebiasis i 

0 Backup drugs hydroxychloroquine, primaquine, pyrimethamine-sulfadoxine 

Chloroquine, Hydroxychloroquine GI distress, pruritus, headache, dizziness, hemolysis, ocular dysfunction. Avoid in psoriasis 

Mefloquine NVD, dizziness, syncope, extrasystoles, CNS effects (rare) Avoid in seizures, psychiatric disorders, and cardiac conduction defects 

Primaquine GI distress, headache, dizziness, neutropenia, hemolysis Avoid in pregnancy, G6PD deficiency, and autoimmune disorders 

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This article discusses the main diseases caused by protozoa and the important chemotherapeutic antiprotozoal agents currently ia use or ia an advanced state of development. Not all alternative proprietary names are given for each dmg. There are excellent sourcebooks on protozoology and parasitology (2—8). 

One such agent is synthesized from 2-methyl imidazole by reaction with epichlorohydrin under acidic conditions. This produces the antiprotozoal agent ornidazole (26). ... 

The occurrence in some plants of secondary metabolites characterized by an 0-heterocyclic structure and exhibiting antimicrobial properties is a well-known phenomenon [2,8-10]. Among them, catechins and proanthocyanidins are two classes of compounds exhibiting antimicrobial properties towards both prokaryotic and eukaryotic microorganisms. Yet, despite the large number of studies published so far, the real potentialities and limitations given by the use of this class of molecules as antiviral or antimicrobial (antibacterial, antimycotic, antiprotozoal) agents have not been critically evaluated. The present chapter represents an overview of the re-... 

In a similar vein condensation with 2-ethylsemi-carbazide leads to the semicarbazone nitfursemi zone (26), an antiprotozoal agent for use in poultry. 

While nitrofurans are often prepared as antibacterial agents, nitroimidazole forms the basis for an extensive class of agents used in the treatment of infections by the protozoans. Unlike bacterial infections, protozoal infections are seldom life-threatening. The physical discomfort occasioned by such infections is, however, of sufficient importance to provide a useful therapeutic place for antiprotozoal agents. A particularly common set of such conditions are parasitic infections of the genitalia caused by Trichomonas vaginalis. These disorders are called trichomoniasis. 

Flubendazole (70) belongs in this chemical class and is synthesized by similar methods but its bioactivity is expressed as an antiprotozoal agent. 

Histones of Plasmodium falciparum represent a new target for antimalarials. Apicidin [Cyclo (N-O-methyl-L-tryptophanyl-L-isoleucinyl-D-pipecolinyl-L-2-amino-oxodecanoyl] is a potent, broad spectrum antiprotozoal agent. The target of apicidin is Histone deacetylases HDA (Darkin Rattray et al., 1996), evidenced as hyperacetylation of histones in treated parasites. 

Darkin-Rattray SJ, Gurnett AM, Myers RW, Dulski PM, Crumley TM, Allocco JJ, Cannova C, Meinke PT, Colletti SL, Bednarek MA, Singh SB, Goetz MA, Dombrowski AW, Polishook JD, Schmatz DM (1996) Apicidin A novel antiprotozoal agent that inhibits parasite histone deacetylase. Proc Natl Acad Sci USA 93(23) 13143-13147... 

Metronidazole is an antiprotozoal agent that, if taken concomitantly with alcohol, may result in a disulfiram-like reaction characterised by intense vasodilation, headache, tachycardia, sweating and vomiting. 

Apicidin (Fig. 10) was first isolated from fimgus Fusarium pallidoroseum ATCC 74289, MF6040, from Acacia sp. (collected from Santa Rosa National Park Costa Rica) as an antiprotozoal agent. It was found that apicidin was active against wide range of protozoans specially Apicomplexan parasites. The underlying mechanism for this cidal activity was found out to be HDAC inhibition of protozoas. It was also observed that they were very potent HDAC inhibitors when compared to similar cyclopeptide inhibitors known at that time (Table 5). 

Colletti SL, Myers RW, Darkin-Rattray SJ, Gumett AM, Dnlski PM, Galuska S, Allocco JJ, Ayer MB, Li C, Lim J, Crumley TM, Cannova C, Schmatz DM, Wyvratt MJ, Fisher MH, Meinke PT. (2001) Broad spectrum antiprotozoal agents that inhibit histone deacetylase Strnctnre-activity relationships of apicidin. Part 2. Bioorg Med Chem Lett 11 113-117. 

The mechanism of inhibition of these protozoal infections by the most active drugs, puromycin and the aminonucleoside, is not known. Puromycin and nucleocidin both interfere with protein synthesis, but the aminonucleoside does not. It is known to be demethylated to 3 -amino-3-deoxyadenosine, which is phosphorylated and interferes with nucleic acid metabolism (see above). Whether puromycin must be converted to the aminonucleoside before it can inhibit protozoa has not been established. Some purine analogues known to interfere with nucleic acid metabolism, however, are less effective as antiprotozoal agents, even in vitro, perhaps because their effects are primarily on the de novo pathway which many, if not all, protozoa do not use [406]. 

Myers, R.W., Dulski, P.M., Crumley, T.M., Allocco, J.J. et al. (1996) Apicidin A novel antiprotozoal agent that inhibits parasite HDAC. Proceedings ofthe National Academy of Sciences of the United States of America, 93, 13143-13147. 

As noted above, nitrofurans and nitroimidazoles have proven useful moieties for the preparation of antibacterial and antiprotozoal agents. It is thus of note that nitrothiazoles have also been used successfully in the preparation of antiparasitic agents. Condensation of 6-nitro-2-aminothiazole (194, available from nitration of aminothiazole) with ethylisocyanate yields the antiprotozoal agent... 

Pharmacology Pentamidine isethionate, an aromatic diamidine antiprotozoal agent, has activity against P. carinii. In vitro studies indicate that the drug interferes with nuclear metabolism and inhibits the synthesis of DNA, RNA, phospholipids, and protein synthesis. 

Eflornithine (difluoromethyl ornithine, Ornidyl) is a unique antiprotozoal agent in that its mode of action involves inhibition of a specific enzyme, ornifhine decarboxylase. In eukaryofes, decarboxylafion of ornifhine is required for biosynfhesis of polyamines, which are im-porfanf in cell division and differenfiafion. 

K. Chibale (2002). Towards broad spectrum antiprotozoal agents. ARKIVOC 9 93-98. 

Infestations with parasitic worms and flukes are widespread both in humans and in animals, and their treatment requires drugs that act in a different manner from antibacterial and antiprotozoal agents. It is desirable for worms to be expelled from the body intact since the presence of dead worms in the tissues can provoke severe reactions. Such reactions are seen when filarial worms which circulate in the blood and lymph are killed by diethylcar-bamazine (264). Intestinal worms may be expelled when they are paralyzed by neuromuscular blockers such as piperazine citrate or pyrantel (265), or their metabolism may be disrupted by the anthelmintic drugs tetramisole and thiabendazole (266) which inhibit fumarate reductase, or mebendazole (267) which prevents glucose uptake by the worms. The anthelmintic activity of tetramisole is due to its laevo isomer levamisole (186). The dextro isomer has antidepressant activity. 

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