Protozoal infections agents

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. 

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]. 

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). 

Pyrimethamine may also be combined with other antimalarials such as artemisinin derivatives, but these regimens should only be used if the malarial parasites are not resistant to the specific drugs in the regimen.13 Pyrimethamine can also be combined with a sulfonamide drug such as dapsone, sulfadiazine, or sulfamethoxazole to treat protozoal infections that cause toxoplasmosis, or fungal infections that cause Pneumocystis pneumonia.These agents are administered orally. 

Clinical Use. Emetine and dehydroemetine (Mebadin) are used primarily to treat protozoal infections in the intestinal tract and extraintestinal sites such as the lungs and liver. These drugs are powerful amebicides and are generally reserved for severe, acute cases of intestinal amebiasis (dysentery).51 Because of the potential for adverse effects, these drugs are no longer marketed in the United States, and safer agents like metronidazole are often used in their place. Emetine and dehydroemetine are typically administered by deep subcutaneous injection or intramuscular injection. 

Clinical Use. lodoquinol (Diquinol, Yodoxin, other names) is used primarily to treat protozoal infections within the intestinal tract,51 and it is often combined with a second tissue amebicide, which kills protozoa at extraintestinal sites. For instance, iodoqui-nol may be combined with metronidazole to ensure the destruction of parasites throughout the body, lodoquinol is usually administered orally. Because iodoquinol is relatively toxic, the routine use of this drug has been replaced somewhat by other agents such as paromomycin, which may be somewhat safer. 

Clinical Use. Paromomycin (Humatin) is an aminoglycoside antibacterial (see Chapter 33) that is used primarily to treat mild to moderate intestinal infections (amebiasis).51 This drug may also be used as an adjunct to other amebicides during the treatment of more severe protozoal infections. Paromomycin is also effective against some bacteria and tapeworms, and may be used as a secondary agent in certain bacterial or helminthic infections. This drug is administered orally. 

Quinine is a cinchona alkaloid that acts rapidly against all four species of Plasmodium. It is used to treat protozoal infections and leg cramps, and as a bitter and flavoring agent. However, the drug is not used prophylactically for malaria. Quinines are contraindicated in patients with a history of hypersensitivity to quinine or quinidine. They should not be used in the presence of hemolysis and should be used with caution in patients with atrial fibrillation, cardiac conduction defects, or heart block. Quinine administration in myasthenia gravis may aggravate the disease, hence it should be avoided. Quinine can be used in pregnancy.37 Intravenous infusion of quinine should be slow, and the patient should be monitored for cardiotoxicity.38 Cinchonism, which is characterized by tinnitus, GI disturbances, and impaired vision may occur with therapeutic doses of quinine.39... 

Fig. 12.1 Schematic diagram of a typical bacterial cell showing the sites of action of the major classes of antibiotics and antimicrobial agents used to treat infections. Agents listed without brackets are used to treat bacterial infections. Agents used against mycobacterial, fungal or protozoal infections are indicated by theuseofQ, [] and brackets, respectively.

The use of trimethoprim-sulfamethoxazole in cancer patients at risk for P. jiwveci pneumonia has reduced the incidence of this protozoal infection substantially. Antiviral prophylaxis with acyclovir or newer agents (valacyclovir and famciclovir) is employed in most centers to reduce the risk of HSV reactivation in patients with acute leukemia undergoing intensive chemotherapy. Varicella vaccine provides good protection (90%) in leukemic children and also may be useful in seronegative adults, although the vaccine has been less well studied in this population. 

Other Infections. The slowly excreted sulfonamides (eg, sulfamethoxypyridazine, sulfadimethoxine) are used for treatment of minor infections such as sinusitis or otitis, or for prolonged maintenance therapy. Soluble sulfonamides are sometimes used for protozoal infections in combination with other agents. Pyrimethamine, combined with sulfonamides, has been used for toxoplasmosis or leishmaniasis, and trimethoprim with sulfonamides has been used in some types of malaria. In nocardiosis, sulfonamides have been used with cycloserine [68-41-7] (17). 

Starting with benzenamine, propose a synthesis of aklomide, an agent used to treat certain exotic fungal and protozoal infections in veterinary medicine. Several intermediates are shown to give you the general route. Fill in the blanks that remain each requires as many as three sequential reactions. (Hint Review the oxidation of amino- to nitroarenes in Section 16-5.)... 

Metronidazole is an antimicrobial agent used for treating anaerobic bacterial and protozoal infections. It is administered in tablet form or as a suppository, but has low aqueous solubility, rendering it unsuitable for parenteral administration in life-threatening cases. It is weakly basic with a pKa of 2.5 (the electron-withdrawing effect of the aromatic nitro-group renders the lone pair on the imidazole-nitrogen much less available for proton acceptance compared with imsubstituted imidazoles), which means that water soluble chloride salts are not particularly stable for parenteral administration, readily... 

Table 8.10 Some pathogens (bacterial, fungal and protozoal) whose phagocytic-mediated destruction is impaired in persons suffering from CGD. Administration of IFN-y, in most cases, enhances the phagocyte s ability to destroy these pathogens. These agents can cause hepatic and pulmonary infections, as well as genitourinary tract, joint and other infections...

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