Treatment Of Toxoplasmic Encephalitis Research Articles

Eudragit coated microemulsion for enhanced efficacy of spiramycin against toxoplasmic encephalitis

The study investigated Eudragit coated microemulsion (ME) for oral delivery of spiramycin in treatment of toxoplasmic encephalitis. The goal was to augment the efficacy of ME by protection from gastrointestinal conditions and/or providing bioadhesion. Uncoated and coated MEs comprise labrafil as oil, cremophore EL as surfactant and labrasol as cosurfactant were prepared. The MEs were characterized with respect to shape, droplet size and in vitro drug release. Optimum formulations were assessed against cerebral toxoplasmosis. This involved oral administration of spiramycin solution, uncoated and coated MEs to Me49 Toxoplasma gondii infected mice at early and late stages. The uncoated ME droplets were spherical with average size of 147 nm. The coated ME droplets were polygonal with average size of 142 nm. Spiramycin release rate was significantly higher from uncoated ME. The parasitic load and histopathology reflected superiority of spiramycin coated ME over uncoated ME and both were more effective than spiramycin solution. The same trend was evident in early and late stages of infection. Interestingly, all formulations showed better efficiency in late stage of infection. The study introduced eudragit coating of ME as a tool to augment oral delivery from microemulsions. The developed system hastened the efficacy of spiramycin against toxoplasmic encephalitis.

SDS-coated atovaquone nanosuspensions show improved therapeutic efficacy against experimental acquired and reactivated toxoplasmosis by improving passage of gastrointestinal and blood–brain barriers

Toxoplasmic encephalitis (TE) is the most common clinical manifestation of reactivated infection with Toxoplasma gondii in immunocompromised patients that is lethal if untreated. The combination of pyrimethamine plus sulfadiazine or clindamycin is the standard therapy for the treatment of TE, but these combinations are associated with hematologic toxicity and/or life-threatening allergic reactions. Therefore, alternative treatment options are needed. Atovaquone is safe and highly effective against T. gondii in vitro, but the oral micronized solution shows poor bioavailability. We synthesized atovaquone nanosuspensions (ANSs) coated with poloxamer 188 (P188) and sodium dodecyl sulfate (SDS) to improve oral bioavailability and passage through the blood–brain barrier (BBB). Coating of ANSs with SDS resulted in enhanced oral bioavailability and enhanced brain uptake of atovaquone compared to Wellvone® in murine models of acute and reactivated toxoplasmosis as measured by high performance liquid chromatography (HPLC). Parasite loads and inflammatory changes in brains of mice treated with SDS-coated ANS were significantly reduced compared to untreated controls and to Wellvone®-treated mice. In conclusion, nanosuspensions coated with SDS may ultimately lead to improvements in the treatment of TE and other cerebral diseases.

Randomized Controlled Trial of Pyrimethamine Plus Sulfadiazine Versus Trimethoprim Plus Sulfamethoxazole for Treatment of Toxoplasmic Encephalitis in AIDS Patients

Toxoplasmic encephalitis (TE), caused by Toxoplasma gondii, is common in AIDS patients. TE can result in tissue destruction via massive inflammation and brain abscess formation. Randomized controlled trials were performed in AIDS patients to assess which drug regimen was optimally effective for the treatment of TE. AIDS patients with TE were randomly divided into 3 groups that received a 6-week course of either pyrimethamine (50 mg/day or 100 mg/day) plus sulfadiazine (4 g/day) and folinic acid (25 mg/day) or trimethoprim (10 mg/kg/day) plus sulfamethoxazole (50 mg/kg/day) (TMP-SMX), and results were evaluated with respect to clinical response, mortality, morbidity, and serious adverse events. The primary outcome was defined as death in the first 6-week period. The secondary outcome was successful treatment within 6 weeks without severe adverse events, bone marrow suppression, drug-induced rash, or any other event that caused a change in the treatment regimen. The results from this study showed that in AIDS patients, TE was most successfully treated with the combination of pyrimethamine (50 mg/day) plus sulfadiazidine (4 g/day) and folinic acid (25 mg/day); failure rates were not significantly different among the 3 treatment groups. Available data suggest that of the currently available options, treatment of TE with pyrimethamine at 50 mg/day plus sulfadiazidine at 4 g/day provides the best primary outcome for AIDS patients with TE; however, because this study was terminated prematurely, we suggest that treatment with intravenous TMP-SMX be further evaluated to determine its efficacy.

Alternative Treatments for AIDS-Associated Toxplasmic Encephalitis

Standard treatment for toxoplasmic encephalitis in AIDS patients is pyrimethamine combined with either sulfadiazine or clindamycin. Although response

Nonionic block copolymers potentiate activities of drugs for treatment of infections with Toxoplasma gondii.

We studied the interaction between drugs and the nonionic block copolymers CRL 8131 and CRL 8142 in the treatment of toxoplasmosis in murine models of the disease. Treatment of acute toxoplasmosis with copolymers alone caused slight prolongation of time to death but not survival. In contrast, significant survival occurred when mice were treated with either copolymer combined with doses of sulfadiazine, pyrimethamine, clindamycin, or atovaquone, which did not prevent mortality when used alone. Treatment with CRL 8131 plus sulfadiazine or pyrimethamine resulted in 50 or 40% survival, respectively. Treatment with the same copolymer plus a dose of clindamycin that protected 40% of the mice when used alone resulted in 100% survival. Treatment of toxoplasmic encephalitis with CRL 8131 plus an ineffective dose of atovaquone reduced the inflammation and numbers of Toxoplasma gondii cysts in the brain. Studies to investigate the drug-enhancing activity of CRL 8131 revealed that mice immunized with toxoplasma lysate plus copolymer had lymphocyte proliferation responses to T. gondii antigens significantly higher than those in mice immunized with lysate alone. Challenge of immunized mice with a lethal inoculum of T. gondii resulted in significant survival. Administration of CRL 8131 alone appeared to cause a down-regulation in the production of gamma interferon and up-regulation in the production of interleukin-2. No differences were noted in the production of tumor necrosis factor alpha between mice treated with CRL 8131 and controls.

Antibody against interleukin-6 reduces inflammation and numbers of cysts in brains of mice with toxoplasmic encephalitis.

Treatment of toxoplasmic encephalitis in C57BL/6 mice with monoclonal antibody (MAb) against interleukin-6 (IL-6) resulted in a remarkable decrease in the number of foci of acute inflammation in their brains caused by proliferation of tachyzoites. In brains of mice treated with isotype control MAb and those treated with anti-IL-6 MAb, tachyzoites were observed only in foci of acute inflammation. Immunoperoxidase staining revealed a greatly diminished frequency of tachyzoites in brains of mice treated with anti-IL-6 MAb. Of interest, treatment with MAb against IL-6 was also associated with reduced numbers of Toxoplasma gondii cysts in the brains and with higher serum levels of gamma interferon than in control mice. Paradoxically, the mice treated with anti-IL-6 MAb had higher serum levels of IL-6 as measured by an enzyme-linked immunosorbent assay than controls. These results revealed the importance of IL-6 in the immunopathogenesis of murine toxoplasmic encephalitis.

ATOVAQUONE: A Review

To review the chemistry, pharmacology, pharmacokinetics, clinical efficacy, and safety of atovaquone. An English-language literature search using MEDLINE (1984-1993), programs and abstracts of the 30th, 31st, and 32nd Interscience Conferences on Antimicrobial Agents and Chemotherapy, program and abstracts of the VIII International Conference on AIDS, and unpublished information from Burroughs Wellcome, the manufacturer of atovaquone. All available pharmacokinetic and clinical trials were reviewed. Study quality was assessed by a critical appraisal of study design and methods. Pharmacokinetic studies were evaluated for sampling, methods used to determine pharmacokinetic properties, and the presence of concentration-response and concentration-toxicity relationships. Clinical trials were assessed primarily for comparative efficacy and toxicity. Atovaquone is a novel hydroxynaphthoquinone with potent activity against Pneumocystis carinii and Toxoplasma gondii. Its pharmacokinetic properties are characterized by relatively poor bioavailability, excretion almost exclusively through the feces, lack of hepatic metabolism and urinary excretion, low steady-state plasma concentrations, high protein binding, and a long elimination half-life (50-70 h). Results from comparative clinical trials in AIDS patients with mild-to-moderate P. carinii pneumonia (PCP) reveal similar overall treatment success rates for atovaquone, trimethoprim/sulfamethoxazole (TMP/SMX), and pentamidine. Treatment failure because of lack of therapeutic response was significantly greater in patients who received atovaquone compared with those treated with TMP/SMX (p = 0.002). More atovaquone-patients experienced treatment failure compared with their pentamidine-treated counterparts, although statistical significance was not achieved. Treatment failure secondary to drug toxicity was significantly higher in the TMP/SMX- and pentamidine-treated patients (p < or = 0.01). Atovaquone has not been studied for PCP prophylaxis. Limited data exist on the use of atovaquone for toxoplasmic encephalitis (TE); however, results from an open trial reveal that the drug may be useful in treating this disorder. To date, atovaquone has been well tolerated by most patients administered the drug. The most common adverse effects include maculopapular rash, gastrointestinal disturbances, and fever. Atovaquone is considerably more costly than other oral agents used to treat PCP. Atovaquone appears to be better tolerated but less effective than TMP/SMX and pentamidine in the treatment of mild-to-moderate PCP. There is not enough information available on the use of atovaquone for PCP prophylaxis or the treatment of TE to definitively describe its efficacy. Comparative clinical trials are needed to assess its role in this clinical setting.

Treatment of Toxoplasmic Encephalitis in Patients with AIDS

To compare pyrimethamine plus clindamycin (PC) to pyrimethamine plus sulfadiazine (PS) as a treatment for toxoplasmic encephalitis (TE) in patients with the acquired immunodeficiency syndrome (AIDS). Randomized, unblinded phase II, multicenter trial with provision for crossover for failure or intolerance of the assigned regimen. University hospitals. Eighty-four patients with presumptive TE were entered. Thirteen were excluded when they were found to have another diagnosis, and 12 were excluded because they did not meet entry criteria. The baseline characteristics in the remaining 26 patients randomized to PC and 33 randomized to PS were comparable. Patients were treated for 6 weeks with pyrimethamine and folinic acid plus either sulfadiazine or clindamycin. Clindamycin was given intravenously during the first 3 weeks. There was a trend toward greater survival in patients randomized to PS (hazard ratio, 3.25; 95% CI, 0.63 to 16.8; P = 0.13), but most study deaths were not directly related to TE. In contrast, patients randomized to PC appeared more likely to achieve complete clinical (odds ratio, 0.67; CI, 0.2 to 1.97; P greater than 0.2) and radiologic responses (odds ratio, 0.28; CI, 0.08 to 0.96; P = 0.02). Multivariate analysis revealed drug effects to be largely independent of other variables. Similar efficacy of the treatments was also suggested by a hazard analysis of resolution of abnormal mental status, fever, and headache. Skin rash was the most common adverse event in both treatment arms. Because of toxicity, six patients randomized to PC and 11 patients randomized to PS had to switch to the alternate treatment, but only three were unable to complete therapy after crossover. The results of several end points of efficacy, taken together, suggest that the relative efficacy of PC approximately equals that of PS. PC appears to be an acceptable alternative in patients unable to tolerate PS.

Treatment of acute toxoplasmosis with intravenous clindamycin

The interim results are presented of an ongoing large-scale, prospective, randomized study to determine the potential role of clindamycin in the treatment of toxoplasmic encephalitis. Patients were seropositive for Toxoplasma gondii antibodies and had clinical signs compatible with toxoplasmic encephalitis. Data was available on 33 patients, 15 of whom received pyrimethamine p.o./clindamycin i.v. and then p.o., and 18 of whom received pyrimethamine p.o./sulfadiazine p.o. The interim evaluation did not reveal a remarkable difference between the two regimens in the clinical or radiologic response. Adverse reactions to both regimens were common and frequently multiple, there being more adverse gastrointestinal reactions in patients on pyrimethamine/clindamycin and more adverse hematological reactions in those on pyrimethamine/sulfadiazine.

Treatment of toxoplasmic encephalitis in mice with recombinant gamma interferon

The effect of exogenous gamma interferon (IFN-gamma) on toxoplasmic encephalitis in a murine model was evaluated. The brains of CBA/Ca mice chronically infected with the ME49 strain of Toxoplasma gondii have a remarkable inflammatory cell infiltrate. Intravenous administration of six doses (5 x 10(5) U each) of recombinant IFN-gamma (rIFN-gamma) resulted in a remarkable decrease in numbers and foci of inflammatory cells in murine brain parenchyma and perivascular areas 1 day after the last injection of IFN-gamma. Immunoperoxidase staining revealed the presence of tachyzoites only on areas of acute focal inflammation, suggesting that the focal inflammation was caused by the proliferation of tachyzoites. The remarkable reduction in number of foci of acute focal inflammation in the brains of the IFN-gamma-treated mice indicates that the treatment resulted in diminished numbers of tachyzoites in the brains of the infected mice. The effect of rIFN-gamma was dose dependent; injection of 5 x 10(5) U every other day for a total of six doses was effective; injection of either 5 x 10(4), 5 x 10(3), or 5 x 10(2) U was not. This therapeutic effect of rIFN-gamma on encephalitis was not present 2 weeks after the last injection of rIFN-gamma. At that time, mice again had severe inflammation in their brains. Toxoplasma antibody production was not affected by treatment with rIFN-gamma. These results offer support for the value of injection of IFN-gamma in the treatment of toxoplasmic encephalitis in immunosuppressed patients, although its effect appears to be transient.

Treatment of Toxoplasmic Encephalitis With Intravenous Clindamycin

At present, therapy for toxoplasmic encephalitis (TE) is the combination of pyrimethamine with sulfadiazine or trisulfapyrimidines. Unfortunately, due to adverse reactions to sulfonamides, many patients with acquired immunodeficiency syndrome (AIDS) are unable to receive a complete course of therapy. The promising results with clindamycin phosphate therapy in a mouse model of TE prompted us to seek further information about patients with AIDS with TE who had been treated with clindamycin. Fifteen such patients were identified in whom clindamycin was used to treat 18 episodes of TE. Eleven patients showed clinical or radiologic improvement after receiving clindamycin therapy, either alone or in combination with pyrimethamine. Twelve received oral clindamycin as suppressive therapy after discharge from the hospital. Adverse reactions possibly related to clindamycin therapy included diarrhea, reversible granulocytopenia, and skin reactions. The results of this retrospective study suggest that clindamycin, either alone or in combination with pyrimethamine, may represent an effective alternative therapy for TE in patients with AIDS. Whether this supposition can be substantiated by appropriately designed studies is presently being determined.

Treatment of toxoplasmic encephalitis with intravenous clindamycin

Treatment of toxoplasmic encephalitis with intravenous clindamycin