trimethoprim--sulfamethoxazole-drug-combination and Toxoplasmosis--Animal

Toxoplasmic encephalitis (TE) is the second most common AIDS-related opportunistic infection of the CNS. It occurs in 10%-50% of patients with AIDS who are seropositive for antibodies to Toxoplasma gondii and have CD4+ T lymphocyte counts of < 100/mm3. Primary toxoplasmic infection usually is acquired by ingestion of T. gondii oocysts from soil contaminated by cat feces or by ingestion of tissue cysts present in undercooked red meats. In patients with AIDS, TE probably results from the reactivation of Toxoplasma tissue cysts that remained latent after the primary infection. Detection of IgG antibodies to Toxoplasma indicates prior infection and the possible presence of tissue cysts and, thus, risk for developing TE. A regimen of trimethoprim-sulfamethoxazole or dapsone plus pyrimethamine with leucovorin is recommended for persons infected with the human immunodeficiency virus (HIV) and who are seropositive for IgG to Toxoplasma after their CD4+ T lymphocyte counts fall to < 100/mm3. HIV-infected persons who are seronegative for IgG to Toxoplasma should be counseled to protect themselves from primary toxoplasmic infection by eating only well-cooked meats and washing their hands after outdoor activities involving soil contact; if they have a cat, they should feed it only commercial or well-cooked foods, keep it indoors, and make sure that the litter box is changed daily. HIV-infected persons who are Toxoplasma seropositive may also be advised about these preventive behavioral practices.

Topics: AIDS-Related Opportunistic Infections; Animals; Anti-Infective Agents; Cats; Dapsone; Drug Therapy, Combination; Encephalitis; Humans; Incidence; Leucovorin; Pyrimethamine; Recurrence; Risk Factors; Toxoplasmosis, Animal; Toxoplasmosis, Cerebral; Trimethoprim, Sulfamethoxazole Drug Combination; United States

Toxoplasmosis is an immunologically complex disease, particularly in immunocompromised patients. Although there are several therapeutic regimens for such disease, the majority of them have many drawbacks. Therefore, it is of utmost importance to improve the current regimen in an effort to achieve a well-tolerated therapy while also enhancing the host immune response. Famous for their immunomodulatory effect, Lactobacillus delbrueckii and Lactobacillus fermentum probiotics were chosen to be evaluated in this study as an adjuvant therapy against the virulent RH Toxoplasma gondii (T. gondii) strain. Experimental mice were divided into control and treated groups. The control group was further subdivided into two groups: group I: 10 uninfected mice and group II: 20 infected untreated mice. The treated experimental group was subdivided into three groups (20 mice each); group III: sulfamethoxazole-trimethoprim (SMZ-TMP) treated, group IV: probiotics treated, and group V: SMZ-TMP combined with probiotics. The results obtained revealed that combined therapy increased survival rate and time up to 95% and 16 days, respectively, with an 82% reduction of tachyzoites and marked distortion, as detected by the scanning electron microscope (SEM). Additionally, combined therapy alleviated the severity and the extent of the inflammatory cells' infiltration, thereby reducing hepatocyte degeneration. Intriguingly, serum IF-γ level showed a significant increase to 155.92 ± 10.12 ng/L with combined therapy, reflecting the immunological role of the combined therapy. The current results revealed that probiotics have a high adjuvant potential in alleviating the impact of toxoplasmosis. Using probiotics as a synergistic treatment to modulate conventional therapy in systemic toxoplasmosis may gain popularity due to their low cost and current availability.

Topics: Animals; Lactobacillus delbrueckii; Limosilactobacillus fermentum; Mice; Probiotics; Toxoplasma; Toxoplasmosis; Toxoplasmosis, Animal; Trimethoprim, Sulfamethoxazole Drug Combination

This study aimed to investigate the synergistic effects of resveratrol and sulfamethoxazole-trimethoprim (ST) on the treatment of mice experimentally infected by Toxoplasma gondii during the chronic phase of the disease considering infection, behavior, and oxidative/antioxidants profile aspects. For the study, 60 mice were initially divided into two groups: uninfected (n = 24) and infected by T. gondii (n = 36). These two groups were later subdivided into other groups and treated with resveratrol (free and inclusion complex containing resveratrol) alone and co-administered with ST: groups A to D were composed by healthy mice and groups E to J were consisted of animals infected by T. gondii (VEG strain). Treatments began 20 days post-infection for 10 consecutive days with oral doses of 0.5 mg kg(-1) of ST (groups B and F), 100 mg kg(-1) of free resveratrol (groups C and G) and inclusion complex of resveratrol (nanoparticles containing resveratrol) (groups D and H), and lastly an co-administration of both drugs (groups I and J). Behavioral tests (memory, anxiety and locomotion) were performed after treatment. Liver and brain fragments were collected to evaluate pathological changes, brain cysts counts, as well as oxidant and antioxidant levels. A reduction on the number of cysts in the brain of animals treated with both drugs combined was observed; there was also reduced number of lesions on both organs. This drug combined effect was also able to reduce oxidative and increase antioxidant levels in infected mice, which might be interpreted as a resveratrol protective effect. In addition, the combination of ST and resveratrol was able to prevent behavioral changes in infected mice. Therefore, the use of co-administration drugs enhances the therapeutic effect acting on a synergic way, reducing the oxidizing effects of the chemical treatment for toxoplasmosis. In addition, resveratrol in inclusion complex when co-administered with ST showed an improved therapeutic effect of ST reducing oxidative damage, liver damage and the number of cysts in the brain of T. gondii infected mice.

Topics: Animals; Anti-Infective Agents; Anti-Inflammatory Agents, Non-Steroidal; Antioxidants; Behavior, Animal; Brain; Disease Models, Animal; Drug Synergism; Drug Therapy, Combination; Liver; Mice; Oxidants; Oxidative Stress; Resveratrol; Stilbenes; Toxoplasmosis, Animal; Treatment Outcome; Trimethoprim, Sulfamethoxazole Drug Combination

This study aimed to investigate the influence of sulfamethoxazole-trimethoprim (ST) associated with resveratrol on the enzymatic activities of acetylcholinesterase (AChE), adenylate kinase (AK), pyruvate kinase (PK), and creatine kinase (CK) in the brain of mice experimentally infected by Toxoplasma gondii. For that, 60 mice were divided into ten groups with 6 animals each: groups A to D composed by healthy mice and groups E to J consisting of animals infected by T. gondii (VEG strain). Animals started treatment 20 days post-infection for 10 consecutive days with oral doses of 0.5 mg kg(-1) of ST (groups B and F), 100 mg kg(-1) of free resveratrol (groups C and G) and inclusion complex of resveratrol (nanoparticles containing resveratrol) (groups D and H), as well as with an association of both drugs (groups I and J). The results showed increased (P < 0.001) AChE activity on infected animals (groups E-J) when compared to not-infected (A) animals, and also uninfected animals treated with ST (group B) had increased AChE activity. AK activity decreased (P < 0.001) in the infected and untreated (group E), differently from the other groups that did not differ. PK activity did not differ between groups (P > 0.05). When comparing control groups (uninfected (A) and infected (E)), we verified a significant (P < 0.001) increase in CK activity in the brain, and it is noteworthy that the animals treated with resveratrol associated with ST (group I and J) had similar CK activity to those animals from the group A. Treatment with the combination of ST and resveratrol was able to reduce (P < 0.05) the number of parasitic cysts in the brain, thus reduced inflammatory infiltrates in the liver, and prevented the occurrence of hepatocytes lesions due to toxoplasmosis in mice. Based on these results, it is possible to conclude that increased AChE and CK activities after T. gondii infection did not change with the treatment of ST-resveratrol association. In addition, decreased AK activity caused by T. gondii infection was normalized by ST-resveratrol treatment. T. gondii infection and treatment does not affect PK activity in brain.

Topics: Administration, Oral; Animals; Antiprotozoal Agents; Brain; Drug Therapy, Combination; Enzyme Inhibitors; Liver; Mice; Parasite Load; Resveratrol; Stilbenes; Synaptic Transmission; Toxoplasma; Toxoplasmosis, Animal; Treatment Outcome; Trimethoprim, Sulfamethoxazole Drug Combination

The aim of this study was to investigate the effects of resveratrol on its free form and complexed with 2-hydroxypropyl-β-cyclodextrin (HPβCD) when associated with sulfamethoxazole-trimethoprim (ST) on cytokines levels of mice (n = 60) experimentally infected by Toxoplasma gondii. Groups A and E were used as controls (untreated): negative and positive, respectively. The onset of treatment started 20 days post-infection (PI), and it lasted for 10 consecutive days. ST was administered orally in doses of 0.5 mg kg(-1) for groups B and F, while 100 mg kg(-1) was the dose for resveratrol in its free form (groups C - G), inclusion complex (groups D and H), and on free and inclusion complex together (groups I - J). On day 31 PI, blood samples were collected in order to evaluate the cytokine profile. The mice that received drug combination (I and J) showed a significant (P < 0.05) reduction in the number of cysts in the brain compared to other infected groups (E - H). The results showed that mice from the Group E had increased (P < 0.001) levels of pro-inflammatory cytokines, while IL-10 levels were reduced when compared to the Group A. Additionally, there were increased levels of IL-4 and IFN-γ in animals of groups C and D, respectively (P < 0.05). Animals of the Group B showed reduced levels of IL-1, IL-4, IL-6, TNF-α, and IFN-γ (P < 0.05). Mice infected and treated (groups F - J) showed increased levels of pro-inflammatory cytokines along with a reduction of IL-10. Treatment with the combination of drugs (the Group J) led to a protective effect, i.e. reduction in pro-inflammatory cytokines. Therefore, resveratrol associated with ST was able to modulate seric cytokine profile and moderate the tissue inflammatory process caused by T. gondii infection, as well as to reduce parasite multiplication.

Topics: 2-Hydroxypropyl-beta-cyclodextrin; Animals; Antiprotozoal Agents; beta-Cyclodextrins; Brain; Cytokines; Immunologic Factors; Mice, Inbred BALB C; Resveratrol; Serum; Stilbenes; Toxoplasma; Toxoplasmosis, Animal; Treatment Outcome; Trimethoprim, Sulfamethoxazole Drug Combination

Congenital toxoplasmosis is still one of the most frequent causes of fetal death. Despite a significant improvement in diagnosis, particularly in utero diagnosis, maternal treatment is only partially effective in preventing transmission to the fetus and treating fetal infection. Maternal treatment is based on drugs developed 50 years ago, which may have limited efficacy (spiramycin) or serious side-effects (pyrimethamine). Data on the use of cotrimoxazole in mouse models of toxoplasmosis and for preventing toxoplasmic encephalitis in patients suffering from AIDS have led Francis Derouin and colleagues to consider the potential of cotrimoxazole for prenatal prevention and treatment of toxoplasmic fetal death.

Topics: Animals; Anti-Infective Agents; Disease Models, Animal; Female; Humans; Mice; Pregnancy; Pregnancy Complications, Parasitic; Toxoplasmosis; Toxoplasmosis, Animal; Toxoplasmosis, Congenital; Trimethoprim, Sulfamethoxazole Drug Combination

The combination of trimethoprim (TMP) and sulphamethoxazole (SMX) is commonly used for the prevention of cerebral toxoplasmosis although there is no firm experimental basis to support this regimen. We used strain RH tachyzoites for challenge in the acute murine model of toxoplasmosis and found that TMP administered as a single agent, failed to eradicate toxoplasma even at the highest dose (70 mg/kg per day). SMX alone at 600 mg/kg per day, protected ten out of ten mice, although inoculation of brain from surviving animals to naive mice resulted in the development of an encephalitis. When combined, TMP (60 mg/kg per day) and SMX (300 mg/kg per day) protected ten out of ten mice and gave a 'cure' in four out of four mice. In the chronic cystogenic murine models, the combination TMP plus SMX administered from day 5 for 15 days or from day 28 for 288 days, gave protection and even apparent toxoplasmal eradication ('cure') at the highest dosing (60/300 mg/kg per day). However, microscopic severe encephalitis was found in mice classified as 'cured' after reinoculation. This result makes the interpretation of 'cure' very difficult. In conclusion TMP and SMX act synergistically, SMX being the more active arm of the combination. The combination was efficient in preventing the lethal development of chronic toxoplasma encephalitis, but did not guarantee complete recovery.

Topics: Animals; Chronic Disease; Disease Models, Animal; Drug Evaluation; Mice; Sulfamethoxazole; Toxoplasmosis, Animal; Trimethoprim; Trimethoprim, Sulfamethoxazole Drug Combination

Trimethoprim-sulfamethoxazole (TMP-SMX) is the first-line drug for prophylaxis and treatment of Pneumocystis carinii pneumonia (PCP) and for prophylaxis of toxoplasmosis in HIV-infected patients. Evidence indicating intolerance related to the dose of SMX led us to examine the efficacy of altered TMP-SMX ratios in a corticosteroid-treated rat model. Infections were assessed by counting P. carinii cysts in lung and by titration of Toxoplasma gondii burdens in tissue culture. For prophylaxis, the reference regimen of 20 mg/kg TMP plus 100 mg/kg SMX was effective. Reduced doses of SMX (5 and 20 mg/kg) effective against PCP were effective against toxoplasmosis, provided the TMP dose was increased to 100 mg/kg. For curative treatment, the reversed ratio of 100 mg/kg TMP plus 20 mg/kg SMX was not effective. These results may provide a basis for altering the TMP-SMX ratios in setting of prophylaxis for both infections, especially in HIV infected patients who often poorly tolerate sulfonamides.

Topics: Animals; Anti-Infective Agents; Cells, Cultured; Dose-Response Relationship, Drug; Fluorescent Antibody Technique, Indirect; HIV Infections; Lung; Male; Pneumocystis; Pneumonia, Pneumocystis; Rats; Rats, Wistar; Toxoplasma; Toxoplasmosis, Animal; Trimethoprim, Sulfamethoxazole Drug Combination

Prophylactic efficacy of antimicrobial agents against pneumocystosis and toxoplasmosis was examined in a model of concurrent Pneumocystis carinii and Toxoplasma gondii infections in rats. Corticosteroid-treated rats naturally infected by P. carinii were challenged with the RH strain of T. gondii. Infection was assessed by counting P. carinii cysts in lung and by titration of T. gondii in tissues by tissue culture. Untreated rats died after challenge, with P. carinii infection in lungs and T. gondii infection in liver, spleen, lungs, and brain. In rats that received trimethoprim-sulfamethoxazole or pyrimethamine plus dapsone, T. gondii was eradicated and P. carinii pneumonia prevented. Roxithromycin, 200 or 400 mg/kg, provided significant protection against toxoplasmosis but had no efficacy against P. carinii. Atovaquone, 100 or 200 mg/kg, had only partial efficacy against pneumocystosis and toxoplasmosis. These results definitively confirm use of trimethoprim-sulfamethoxazole and pyrimethamine plus dapsone for prophylaxis against combined infection in immunocompromised hosts.

Topics: Animals; Antifungal Agents; Antiprotozoal Agents; Atovaquone; Brain; Dapsone; Drug Therapy, Combination; Liver; Lung; Male; Mice; Naphthoquinones; Pneumocystis; Pneumocystis Infections; Pyrimethamine; Rats; Rats, Wistar; Roxithromycin; Spleen; Toxoplasma; Toxoplasmosis, Animal; Trimethoprim, Sulfamethoxazole Drug Combination

This study was performed to evaluate the prophylactic effects of trimethoprim-sulfamethoxazole (TMP-SMZ) in mice experimentally infected with virulent RH strain and avirulent Beverley strain of T. gondii. The mice infected with 1 x 10(5) tachyzoites were used in the measurement of mean survival days, and the mice infected with 10 cysts were used in the titrations of specific antibodies and enumeration of brain cysts. Mean survival days of mice were significantly increased in mice treated with TMP-SMZ as compared with spiramycin-treated and untreated control group. Mean survival days and survival rates of mice were increased according to the increment of dosages, and TMP-SMZ protected 100% of mice after fifteen daily dose of 24 mg/mouse or more administered orally. Toxoplasma-specific serum IgG and IgM antibody titers were significantly lower in mice treated with TMP-SMZ than those of spiramycin-treated and untreated control group. Toxoplasma cysts were not found in mice treated with TMP-SMZ at a dose of 24 mg/mouse or more per day, but the group of spiramycin treatment and untreated controls were found in the brain from 20 days after infection. The present results revealed that TMP-SMZ can be used as a prophylactic agent against murine toxoplasmosis after intraperitoneally challenges with the virulent or avirulent strain of T. gondii.

Topics: Animals; Mice; Spiramycin; Toxoplasmosis, Animal; Trimethoprim, Sulfamethoxazole Drug Combination

Experimental study of the intraocular penetration of six drugs with therapeutic effect on toxoplasma. A direct and an indirect method are used. The penetration of six drugs administered sub-conjunctival, retrobulbar and intramuscular in one shot is measured in the anterior chamber, the vitreous and the retina-choroid of a healthy rabbit eye. The best results are obtained for: spiramycin, trimethoprim-sulfamethoxazole and clindamycin. The therapeutic efficiency of four drugs on infected rabbit eyes with toxoplasma are studied using an indirect method: pyrimethamine and especially doxycycline have a positive effect.

Topics: Animals; Blood-Retinal Barrier; Clindamycin; Doxycycline; Drug Therapy, Combination; Female; Male; Pyrimethamine; Rabbits; Spiramycin; Toxoplasmosis, Animal; Trimethoprim, Sulfamethoxazole Drug Combination

The effect of some chemotherapeutics, on the course of acute toxoplasmosis in experimentally infected mice was studied. Obtained results showed that, praziquantel, levamisole had no effect on acute toxoplasmosis, while trimethoprim-sulphamethoxazole and clindamycin showed some prophylactic effect on acute toxoplasmosis in mice.

Topics: Animals; Chloroquine; Clindamycin; Drug Combinations; Levamisole; Mice; Praziquantel; Sulfamethoxazole; Toxoplasmosis, Animal; Trimethoprim; Trimethoprim, Sulfamethoxazole Drug Combination

The effects of cotrimoxazole (CTX) and spiramycin (Spir) in mice infected in midpregnancy with the Beverley (Bev) strain of Toxoplasma gondii were compared. Therapeutic effectiveness was determined according to the following parameters: rate of successful delivery, litter size, offspring weight and survival. When compared with the uninfected untreated control group, CTX showed a more beneficial therapeutic effect than Spir, with a statistically significant increase in the rate of both successful delivery and offspring survival. Results based on antitoxoplasma antibody determinations in the offspring indicated a better in utero control of congenital infection by CTX than by Spir.

Topics: Animals; Antibodies; Birth Weight; Congenital Abnormalities; Delivery, Obstetric; Drug Combinations; Drug Evaluation, Preclinical; Female; Leucomycins; Litter Size; Mice; Pregnancy; Pregnancy Complications, Infectious; Sulfamethoxazole; Toxoplasma; Toxoplasmosis, Animal; Trimethoprim; Trimethoprim, Sulfamethoxazole Drug Combination

Topics: Animals; Drug Combinations; Female; Humans; Mice; Pregnancy; Sulfamethoxazole; Toxoplasmosis; Toxoplasmosis, Animal; Toxoplasmosis, Congenital; Trimethoprim; Trimethoprim, Sulfamethoxazole Drug Combination

The antitoxoplasm effects of cotrimoxazole (Ctx), spiramycin (Spir) and pyrimethamine-sulphadiazine (Pmm-Sdz) were compared during both proliferative and chronic phases of infection of mice with the Beverley (Bev) strain of Toxoplasma gondii of low virulence. The therapeutic efficacy of the drugs was determined according to the following criteria: (i) specific antibody response; (ii) acquired resistance to lethal challenge with the virulent RH strain of Toxoplasma; and (iii) persistence of parasites in tissues (brain, liver, spleen) of treated mice. The results indicated that Ctx, like Pmm-Sdz, had a greater effect than Spir upon toxoplasma organisms during the proliferative phase of infection. In contrast, none of the three drugs tested was active against tissue cysts in chronically infected mice.

Topics: Animals; Drug Combinations; Drug Resistance, Microbial; Drug Therapy, Combination; Female; Leucomycins; Mice; Pyrimethamine; Sulfadiazine; Sulfamethoxazole; Toxoplasma; Toxoplasmosis, Animal; Trimethoprim; Trimethoprim, Sulfamethoxazole Drug Combination; Virulence