Toxoplasmosis activator

Figure 31-6 Recurrent toxoplasmosis. Active satellite lesion at inferior border of a retinochoroidal scar, with significant vitritis. (Reprinted with permission from Holland GN, O Connor GR, Belfort R Jr, et al.Toxoplasmosis. In Repose JS, Holland GN,Wilhelmus KR, eds. Ocular infection and immunity. St. Louis, MO Mosby, 1996.)...

Pneumogstis carini pneumonia (PCP), the most common of the opportunistic infections, occurs in more than 80% of AIDS patients (13). Toxoplasmosis, a proto2oan infection of the central nervous system, is activated in AIDS patients when the 004 count drops and severe impairment of ceU-mediated immunity occurs. Typically, patients have a mass lesion(s) in the brain. These mass lesions usually respond well to therapy and can disappear completely. Fungal infections, such as CTyptococcalmeningitis, are extremely common in AIDS patients, and Histop/asma capsulatum appears when ceU-mediated immunity has been destroyed by the HIV vims, leading to widespread infection of the lungs, Hver, spleen, lymph nodes, and bone marrow. AIDS patients are particularly susceptible to bacteremia caused by nontyphoidal strains of Salmonella. Bacteremia may be cleared by using antibiotic therapy. 

Sulfouamides have a broad spectrum of antimicrobial activity, including Staphylococcus aureus, nonenterococcal types of Streptococcus, Listeria monocytogenes, Nocardia, Neisseria, Haemophilius influenzae, enteric Gram-negative types of E. coli, Proteus mirabilis, and a few forms of anaerobic bacteria. Above all, sulfonamides are used for treating uncomplicated infections of the urinary tract, infections caused by Nocardia asteroids, streptococcal pharyngitis, menigococcal diseases, toxoplasmosis, and others. 

Sulfonamides are used for controlling urinary tract infections, acute and chronic lung infections (norcadiosis), protozoan infections of the nervous system (i.e., toxoplasmosis), and a variety of infections in humans and livestock. Their mode of activity is by inhibiting the multiplication of bacteria by competitively inhibiting para-aminobenzioc acid (PABA) in the folic acid metabolism cycle (O Neil et al., 2001). More specifically, they block the synthesis of folic acid in bacteria as the drugs are structurally similar to PABA. Folic acid is essential to the synthesis of amino acids and nucleic acids. In bacteria, folic acid is synthesized from PABA... 

Clindamycin is indicated for the treatment of skin and soft-tissue infections caused by streptococci and staphylococci. It is often active against community-acquired strains of methicillin-resistant S aureus, an increasingly common cause of skin and soft tissue infections. Clindamycin is also indicated for treatment of anaerobic infection caused by bacteroides and other anaerobes that often participate in mixed infections. Clindamycin, sometimes in combination with an aminoglycoside or cephalosporin, is used to treat penetrating wounds of the abdomen and the gut infections originating in the female genital tract, eg, septic abortion and pelvic abscesses and aspiration pneumonia. Clindamycin is now recommended rather than erythromycin for prophylaxis of endocarditis in patients with valvular heart disease who are undergoing certain dental procedures. Clindamycin plus primaquine is an effective alternative to trimethoprim-sulfamethoxazole for moderate to moderately severe Pneumocystis jiroveci pneumonia in AIDS patients. It is also used in combination with pyrimethamine for AIDS-related toxoplasmosis of the brain. 

Trimethoprim- sulfamethoxazole Synergistic combination of folate antagonists blocks purine production and nucleic acid synthesis Bactericidal activity against susceptible bacteria Urinary tract infections Pneumocystis jiroveci pneumonia toxoplasmosis nocardiosis Oral, IV renal clearance (half-life 8 h) dosed every 8-12 h t formulated in a 5 1 ratio of sulfamethoxazole to trimethoprim Toxicity Rash, fever, bone marrow suppression, hyperkalemia... 

Antibiotics also are active against other protozoans. Tetracycline and erythromycin are alternative therapies for the treatment of intestinal amebiasis. Clindamycin, in combination with other agents, is effective therapy for toxoplasmosis, pneumocystosis, and babesiosis. Spiramycin is a macrolide antibiotic that is used to treat primary toxoplasmosis acquired during pregnancy. Treatment lowers the risk of the development of congenital toxoplasmosis. 

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 sulfas, including co-trimoxazole (sulfamethoxazole plus trimethoprim, see p. 293), are bacteriostatic. These drugs are active against selected enterobacteria, chlamydia, Pneumocystis, and nocardia. Typical clinical applications are shown in Figure 29.3. In addition, sulfadiazine [sul fa DYE a zeen] in combination with the dihydrofolate reductase inhibitor pyrimethamine [py ri METH a meen] is the only effective form of chemotherapy for toxoplasmosis (p. 353). 

Two other agents show promise in treatment of ocular toxoplasmosis. Atovaquone, primarily used for mild to moderate episodes of Pneumocystis carinii pneumonia, has been effective in small series of patients with toxoplasmosis. It appears to have activity against both tachy-zoites and tissue cysts. More recent studies on atovaquone in toxoplasmosis are limited to murine models, and no further reports on this drug therapy in humans have been published. Azithromycin, a macrolide antibiotic, is efficacious against T. gondii and can also kill tissue cysts. A randomized study of 46 patients compared the combinations of azithromycin plus pyrimethamine versus pyrimethamine plus sulfadiazine in treatment of ocular toxoplasmosis efficacy was similar, but the azithromycin/ pyrimethamine regimen caused less adverse effects. 

Although spiramycin is used to treat toxoplasmosis, more potent inhibitors of Toxoplasma gondii have been reported [183-185]. In contrast to derivatives of erythromycin, activity was not observed from several 16-membered macrolides against Mycobacterium avium complex [186]. Similar trends have been noted with several other bacterial and parasitic pathogens in which 16-membered macrolides have not matched the promising activity shown by erythromycin derivatives [177]. 

Trichomoniases immunologicaNy normal patient. Pyrimethamine with sulfadiazine for chorioretinitis.and active toxoplasmosis in imimmodeficicnt patients foilnic add is used to counteract the inevitable megaloblastic anaemia. Alternatives include pyrimethamine with clindamycin or clarithromycin or azithromycin Spiramycin for primary toxoplasmosis in pregnant women. Expert advice is essential. Metronidazole or tinidazole is effective... 

Pyrimethamine is the most active antimalarial of the 2-4-diaminopyrimidines, its effect being due to inhibition of the conversion of foUc acid to its active form, folinic acid. It is also effective in toxoplasmosis. Its antiprotozoal and antimalarial activity is enhanced by the addition of sulfonamides. 

Pyrimethamine is a folic acid antagonist that for many years has been used as an antimalarial drug [193-195], specially for chloroquine-resistant P. falciparum. Due to its synergistic activity, pyrimethamine also has been used, in combination with sulfadiazine or dapsone for the treatment or prophylaxis of cerebral toxoplasmosis or PCP in patients with AIDS [196]. 

AIDS." A primary infection that is treated with the combination is PCP. The sulfonamide-trimethoprim combination can be used fur treatment and prophylaxis. Additionally, cerebral toxoplasmosis con be treated in active infection or prophyluctically. Urinary tract infections and bum therapy" " " round out the list of therapeutic applications. The sulfonamides arc drugs of choice for a few other types of infections, but their u.sc is quite limited in modem antimicrobial chemotherapy." " "... 

Marine alkaloids were also reported to possess activity in vitro against AIDS-opportunistic infectious diseases such as tuberculosis and toxoplasmosis [53,54]. Examples of these alkaloids included the ascidian alkaloids lamellarins. Fig. (5) [55], and dragmacidin F, Fig. (6), a new... 

The esters also react readily with aryl hydrazines to give aryl hydrazone derivatives. Examples of the latter were first synthesized (prior to the availability of tetraalkyl carbonylphosphonates) from tetraalkyl methylenebisphosphonates and aryl diazonium salts, analogously to the phosphonoglyoxylate hydrazone synthesis described in a previous section. First made as possible precursors in a ketone synthesis, several of these compounds, converted to free acid salts by treatment with BTMS followed by dicyclohexylamine in methanol, proved to have unexpected inhibitory activity vs the pyrophosphate-dependent phospho-fructokinase of the parasite T. gondii, which causes a potentially lethal opportunistic infection in immunocompromised persons such as AIDS patients [94]. In fact, the 2,4-dinitrophenylhydrazone of carbonylbisphosphonic acid (as the tetrasodium salt) dramatically abated toxoplasmosis lesions in infected human foreskin fibroblasts [94]. Animal toxicity in this compound, probably arising from in vivo hydrolysis to the highly toxic hydrazine, precluded its future development, but the result remains an interesting lead. 

Toxoplasmosis - Using Toxoplasma gondii in cell culture, the polyether ionophores lasalocid and monensin were highly active whereas ormetoprim and sulfadimethoxime or a combination were inactive or weakly active. 

Pyrimethamine [2,4-diamino-5-(p-chlorophenyl)-6-ethylpyrimidine] is most active against protozoal dihydrofolate reductase. However, there is only a small margin between the dose required to kill the organisms and that which will affect the host. It is most commonly used in the treatment of toxoplasmosis hut more recently has heen used at a lower and safer dose of 25 mg weekly for malarial prophylaxis. This dose is unlikely to produce any adverse hematological complications in the short term. Larger doses are required to treat toxoplasmosis and where it exceeds 25 mg daily a megaloblastic anemia will develop in many of the patients so treated (Nl). 

In vitro studies have shown that azithromycin is active against Toxoplasma gondii, and that this activity is additive with pyrimethamine [291]. In vivo studies have shown that azithromycin has some prophylactic and therapeutic activity [292-294]. Only a handful of human cases of cerebral toxoplasmosis treated with azithromycin have been described in the hterature [295-297]. Early results with escalating doses of oral azithromyein of 900, 1200, or 1500 mg daily plus pyrimethamine in 32 evaluable patients with known or suspected toxoplasma encephalitis have been reported [298]. It was concluded that azithromycin plus pyrimethamine is not as effective as the standard therapy for cerebral toxoplasmosis and should be regarded as second-line or salvage therapy. 

Derouin, R, Ahnadany, R., Chau, R, Rouveix, B., and Pocidalo, J. J. (1992). Synergistic activity of azithromycin and pyrimethamine or sulfadiazine in acute experimental toxoplasmosis. Antimicrob. Agents Chemother. 36, 997—KXll. 

However, NO may also have a role in inhibiting infectious processes. Neutralization of TNF and down-regulation of iNOS promote induction of acute cerebral toxoplasmosis and enhanced pathology in mice chronically infected with Toxoplasma gondii (Gazzinelli et al., 1993). However, N-monomethyl-L-arginine (NMMA) does not affect the antitoxoplasma activity of TNF and IL-6 produced by human microglia in vitro (Chao et al.,... 

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