Inhibitor of P-glycoprotein-mediated drug transport by curcumin in broiler chickens.

OBJECTIVE: To investigate the role of curcumin in the regulation of P-glycoprotein (P-gp) and its influence on the pharmacokinetics of P-gp substrates. SAMPLE: 39 broiler chicken and chicken embryonic primary hepatocytes. METHODS: Chicken embryonic primary hepatocytes were treated with curcumin, after which cell viability, P-gp expression, and transport were assessed. Broiler chickens were pretreated with curcumin, after which P-gp expression and the pharmacokinetic behavior of orally administered sulfadiazine (a substrate of P-gp) were measured. RESULTS: The preliminary results showed that the viability of chicken embryonic primary hepatocytes was enhanced by pretreatment with 40, 60, and 100 µM curcumin. Curcumin inhibits the expression and transport of P-gp. In vivo experiments showed that curcumin decreased the expression of P-gp in the broiler chicken liver, kidney, and small intestine. Pretreatment with curcumin changed the pharmacokinetic behavior of orally administered sulfadiazine by increasing the area under the curve (47.36 vs 70.35 h·mg/L, P < .01) and peak concentration (10.1 vs 14.53 µg/mL, P < .01). CLINICAL RELEVANCE: Curcumin inhibited the expression and efflux of chicken P-gp, thereby improving the oral bioavailability of P-gp substrate drugs. These findings provide a rationale for exploiting herbal-drug interactions in veterinary practice to improve the absorption of drugs.

A pH-sensitive oxidized-dextran based double drug-loaded hydrogel with high antibacterial properties.

Delayed healing or non-healing of wounds caused by bacterial infection is still a difficult medical problem. Nowadays, the topical application of antibiotics is a common treatment for infections. However, subinhibitory concentrations or high dose of antibiotics leads to the antibacterial effect counterproductive. So it's necessary to put forward an on-demand drug delivery to solve this tough issue. In this paper, a pH-responsive hydrogel was prepared by oxidized dextran (Dex-CHO), sulfadiazine (SD) and tobramycin (TOB). The hydrogel was designed by the environment in the early immature stage of biofilm (pH 5.0). Schiff bases can release drugs in slightly acidic environment. The hydrogel showed injectable, pH-sensitive drug release, and great biocompatibility. Released SD and TOB exhibited a synergistic effect therefore the hydrogel showed high antibacterial activity. This study provides an easy and promising strategy to develop smart hydrogels that aim at topical administration of antibiotics and come up with a new treatment of local bacterial infections.

Comparative Immunological Response and Pathobiology of Mice Inoculated with Toxoplasma gondii Isolated from Different Hosts.

Toxoplasma gondii is an obligate intracellular parasite that has a worldwide distribution and can infect almost all warm-blood animals. Serological tests are the main detection methods for T. gondii infection in animals and humans. Little is known of biological behavior, antibody responses, and virulence of T. gondii strains in mice from China. Here we document antibody responses, tissue cyst burden, and mouse virulence of T. gondii strains isolated from different hosts in China. All T. gondii strains formed tissue cysts in the brains of mice and positively correlated with the T. gondii antibody titer (R2 = 0.3345). These results should aid in the diagnosis and characterization of T. gondii isolates.

Sulfadiazine pharmacokinetics in grass carp (Ctenopharyngodon idellus) receiving oral and intravenous administrations.

This study aimed to examine the bioavailability (BA) and pharmacokinetic (PK) characteristics of sulfadiazine (SDZ) in grass carp (Ctenopharyngodon idellus) after oral and intravenous administrations. Blood samples were collected at predetermined time points of 0.083, 0.17, 0.5, 1, 2, 4, 8, 16, 24, 48, 72, and 96 hr (n = 6). The samples were extracted and purified by organic reagents and determined by the ultra-performance liquid chromatography. The software named 3P97 was used to calculate relevant PK parameters. The results demonstrated that the concentration-time profile of SDZ was best described by a one-compartmental open model with first-order absorption after a single oral dose. The main PK parameters of the absorption rate constant (Kα ), the absorption half-life (t1/2 Kα ), the elimination rate constant (Ke ), the elimination half-life (t1/2Ke ), and the area under concentration-time profile (AUC0-∞ ) were 0.3 1/h, 2.29 hr, 0.039 1/h, 17.64 hr, and 855.78 mg.h/L, respectively. Following intravenous administration, the concentration-time curve fitted to a two-compartmental open model without absorption. The primary PK parameters of the distribution rate constant (α), the elimination rate constant (ß), the distribution half-life (t1/2α ), the elimination half-life (t1/2ß ), the apparent distribution volume (VSS ), the total clearance (CL), and AUC0-∞ were 9.62 1/hr, 0.039 1/hr, 0.072 hr, 17.71 hr, 0.33 L/kg, 0.013 L h-1  kg-1 , and 386.23 mg.h/L, respectively. Finally, the BA was calculated to be 22.16%. Overall, this study will provide some fundamental information on PK properties in the development of a new formulation SDZ in the future and is partially beneficial for the appropriate usage of SDZ in aquaculture.

Validating an empiric sulfadiazine-trimethoprim dosage regimen for treatment of Escherichia coli and Staphylococcus delphini infections in mink (Neovison vison).

Antimicrobial agents are used extensively off-label in mink, as almost no agents are registered for this animal species. Pharmacokinetic (PK) and pharmacodynamic (PD) data are required to determine antimicrobial dosages specifically targeting mink bacterial pathogens. The aims of this study were to assess, in a PKPD framework, the empirical dosage regimen for a combination of trimethoprim (TMP) and sulfadiazine (SDZ) in mink, and secondarily to produce data for future setting of clinical breakpoints. TMP and SDZ PK parameters were obtained experimentally in 22 minks following IV or oral administration of TMP/SDZ (30 mg/kg, i.e. 5 mg/kg TMP and 25 mg/kg SDZ). fAUC/MIC with a target value of 24 hr was selected as the PKPD index predictive of TMP/SDZ efficacy. Using a modeling approach, PKPD cutoffs for TMP and SDZ were determined as 0.062 and 16 mg/L, respectively. By incorporating an anticipated potentiation effect of SDZ on TMP against Escherichia coli and Staphylococcus delphini, the PKPD cutoff of TMP was revised to 0.312 mg/L, which is above the tentative epidemiological cutoffs (TECOFF) for these species. The current empirical TMP/SDZ dosage regimen (30 mg/kg, PO, once daily) therefore appears adequate for treatment of wild-type E. coli and S. delphini infections in mink.

Arritmias ventriculares como forma de presentación de toxoplasmosis congénita / Ventricular arrhythmia as the first manifestation of congenital toxoplasmosis

No disponible

Cristaluria por sulfadiazina en paciente con toxoplasmosis diseminada / Sulphadiazine crystaluria in a patient with disseminated toxoplasmosis

No disponible

Unexpected Cardiomyopathy and Cardiac Dysfunction after Administration of Sulfadiazine-trimethoprim Medicated Diet to ICR mice (Mus musculus).

For many years, the University of Chicago administered sulfamethoxazole-trimethoprim sulfate (SMZ-TMP) oral suspension to select immunocompromised mouse colonies via the drinking water. In 2014, SMZ-TMP oral suspension was placed on back-order and medicated diet with a different sulfonamide, sulfadiazine-trimethoprim (SDZ-TMP) was used as a replacement. Months after this transition, sentinel mice from the same room as one of the remaining immunocompromised colonies on this diet were found dead or appeared sick. Necropsies revealed cardiomegaly, and histology confirmed myocardial fibrosis in the first 4 sentinel mice examined, consistent with cardiomyopathy. Subsequent sequential monitoring of 2 sentinel mice via echocardiography showed their progression toward decreased cardiac function. Investigation of the housing room revealed that the sentinel mice had been accidently placed on SDZ-TMP diet upon entering the colony housing room. This case report describes cardiomyopathy in 6 ICR mice after long term consumption of SDZ-TMP medicated feed.

Análise ultraestrutural do colágeno de feridas cutâneas de coelhos tratadas com plasma rico em plaquetas de equino / Ultrastructural analysis of the collagen of rabbit skin wounds treated with platelet-rich equine plasma

O colágeno é sintetizado e segregado no espaço extracelular e organizados em fibrilas estriadas de acordo com o tipo de tecido. Utilizaram-se 24 coelhos brancos da raça Nova Zelândia, com idade de 12 meses e com 3,0kg de peso corporal, para avaliar a porcentagem de colágeno das feridas cutâneas tratadas com plasma rico em plaquetas de equino e pomada contendo gentamicina, sulfanilamida, sulfadiazina, ureia e vitamina A. Os animais foram separados em quatro grupos de igual número e submetidos à remoção de pele na região das linhas médias dorsal torácica (feridas tratadas) e lombar (feridas controle). As feridas torácicas foram tratadas com plasma rico em plaqueta de equino e pomada contendo gentamicina, sulfanilamida, sulfadiazina, ureia e vitamina A, e as do grupo controle somente com a pomada. Dos animais do grupo I, foi coletado tecido cutâneo, para a avaliação histológica e a ultraestrutural, com três dias de pós-operatório; dos animais do grupo II, com sete dias; do grupo III, com 14 dias; e do grupo IV, com 21 dias. Decorrido o período de avaliação de cada grupo, foi coletado fragmento de pele para avaliação da porcentagem de colágeno, bem como do diâmetro e da densidade da fibrila de colágeno por microscopia eletrônica de transmissão. O tratamento com PRP de equino associado à aplicação tópica da pomada mostrou-se eficaz na maturação das fibrilas colágenas e na antecipação do processo cicatricial.(AU)

Collagen is synthesized and secreted into the extracellular space and organized into striated fibrils according to the tissue type. This study evaluated the concentration of collagen in rabbit skin wounds treated with equine platelet-rich plasma (PRP) and ointment containing gentamicin, sulfanilamide, sulfadiazine, urea, and vitamin A. Twenty-four New Zealand white rabbits aged 2 to 12 months and weighing 3.0kg were included. The animals were allocated equally into four groups and the skin was removed from the thoracic dorsal midline (treated wound) and lumbar (control wound) regions. The thoracic wounds were treated with equine PRP and ointment containing gentamicin, sulfanilamide, sulfadiazine, urea, and vitamin A, and the control group was treated with the ointment alone. For histological and ultrastructural assessment, cutaneous tissue was collected on postoperative days 3 (group I), 7 (group II), 14 (group III), and 21 (group IV). After the evaluation period, in each group, a skin fragment was collected for analysis of the collagen concentration, as well as the collagen fibril diameter and density by transmission electron microscopy. The results indicated that treatment with equine PRP combined with topical application of the ointment was effective in facilitating the maturation of collagen fibrils and the wound healing process.(AU)

Co-delivery of superfine nano-silver and solubilized sulfadiazine for enhanced antibacterial functions.

For the effective treatment of bacterial infection, it is essential to find a new strategy to deliver antibacterial agents. In the present study, the co-delivery of superfine nano-silver with solubilized sulfadiazine (SD) using cyclodextrin metal-organic frameworks (CD-MOF) as a carrier exhibited superior antibacterial efficacy to insoluble silver sulfadiazine. The abundant hydroxyl moieties in CD-MOF were utilized to reduce Ag precursor into silver nanoparticles (Ag NPs) of 4-5 nm and immobilized within the nano-sized cavities. Microporous CD-MOF facilitated the inclusion of SD molecules in the hydrophobic cavities of γ-cyclodextrin (γ-CD) molecular pairs. The hydrophilic CD-MOF can easily dissolve within exudates at the wound region to release the drug. This approach improved the aqueous solubility of SD by 50 folds which subsequently enhanced SD release and their antibacterial activity. The CD framework also prevented the aggregation of nano-silver particles, stabilizing the particle size and enhancing the curative effects. Hence, the incorporation of superfine nano-silver with solubilized SD using CD-MOF could be an alternate strategy to co-deliver silver and SD with higher efficacy.

Stability of extemporaneous sulfadiazine oral suspensions from commercially available tablets for treatment of congenital toxoplasmosis.

OBJECTIVES: To determine the physicochemical and microbiological stability of sulfadiazine suspensions (100 mg/mL) in simple syrup (A) and sorbitol (B) formulations prepared from commercially available tablets. METHODS: An ultra-performance liquid chromatographic assay was developed and validated to determine the chemical stability of sulfadiazine. Three samples were prepared and stored at 5 and 25 °C and assayed at 0, 7, 14 and 30 days. Physical parameters (appearance, pH, particle size and viscosity) were also monitored. Microbiological examination was performed through the suitable counting method. RESULTS: The formulations presented a sulfadiazine concentration of around 95% at the beginning at both temperatures. There was some variation in pH, viscosity and particle size distribution over time. The samples met the pharmacopoeia criteria of microbiological quality over 30 days, but only sulfadiazine formulated in syrup stored at 25 °C was suitable for use after one week. CONCLUSION: The sulfadiazine suspension in simple syrup was chosen as the most suitable formulation because it demonstrated stability for 14 days at room temperature, providing an alternative liquid dosage form of sulfadiazine for congenital toxoplasmosis treatment.

OBJECTIFS: Déterminer la stabilité physicochimique et microbiologique de suspensions de sulfadiazine (100 mg/mL) dans des formulations de sirop simple (A) et de sorbitol (B) préparées à partir de comprimés disponibles dans le commerce. MÉTHODES: Un test de chromatographie liquide ultra-performante a été développé et validé pour déterminer la stabilité chimique de la sulfadiazine. Trois échantillons ont été préparés et stockés à 5 ºC et à 25 ºC et analysés à 0, 7, 14 et 30 jours. Les paramètres physiques (apparence, pH, granulométrie et viscosité) ont également été contrôlés. Un examen microbiologique a été effectué par la méthode de comptage appropriée. RÉSULTATS: Les formulations présentaient une concentration en sulfadiazine d'environ 95% au début aux deux températures. Il y avait une certaine variation du pH, de la viscosité et de la distribution de la taille des particules au fil du temps. Les échantillons répondaient aux critères de pharmacopée pour la qualité microbiologique aprè 30 jours, mais seule la sulfadiazine formulée dans du sirop conservé à 25 ºC pouvait être utilisée après une semaine. CONCLUSION: La suspension de sulfadiazine dans un sirop simple a été choisie comme la formulation la plus appropriée car elle a démontré une stabilité à 14 jours à température ambiante, fournissant une forme galénique liquide alternative de sulfadiazine pour le traitement de la toxoplasmose congénitale.

Efficacy of antiretroviral compounds against Toxoplasma gondii in vitro.

The obligate intracellular parasite Toxoplasma gondii can infect nearly all warm-blooded animals, including humans. Although infection with this parasite is generally benign, severe illness may occur in infected individuals if their immunity becomes less competent, such as in human immunodeficiency virus (HIV)-infected patients. In this study, the inhibitory activity of 44 commonly used antiretroviral compounds was determined against T. gondii in vitro. Of the 44 tested antiretroviral compounds, 14 showed potency against T. gondii at IC50 concentrations (concentration inhibiting T. gondii tachyzoite growth by 50%) ranging from 1.18 ± 2.21 µM (nelfinavir) to 18.89 ± 1.87 µM (trovirdine). Of the 14 potent antiretroviral compounds, 7 are HIV-1 protease inhibitors. This study also investigated whether co-administration of these 14 antiretroviral compounds interferes with the anti-T. gondii activity of existing anti-T. gondii drugs, namely sulfadiazine and pyrimethamine. The results showed no significant interaction between any of the 14 tested antiretroviral compounds and pyrimethamine or sulfadiazine. These results warrant investigation of whether administration of the lead antiretroviral drugs with highly potent anti-T. gondii activity to HIV patients may help to limit the occurrence of toxoplasmic encephalitis.

Non-Propellant Foams of Green Nano-Silver and Sulfadiazine: Development and In Vivo Evaluation for Burn Wounds.

PURPOSE: A non-propellant based foam (NPF) system was developed incorporating the antibiotics, pectin capped green nano-silver and sulfadiazine (SD) for the topical treatment of burn wounds as a convenient alternative to the existing therapies. METHODS: NPF were prepared using various surfactants and oils forming a nanoemulsion. Anti-microbial studies by resazurin microtitre assay, ex vivo diffusion, in vivo skin permeation and deposition studies, and acute irritation studies were carried out. NPF was applied onto secondary thermal wounds manifested on mice models followed by macroscopic and histological examinations. RESULTS: NPF had an average globule size of <75 nm. The viscosity was ~10 cP indicating the feasibility of expulsion from the container upon actuation. With no skin irritation, the foams showed a higher skin deposition of SD. A high contraction and an evident regeneration of the skin tissue upon treatment with NPF indicated a good recovery from the thermal injury was apparent from the histology studies. CONCLUSION: NPF represents an alternative topical formulation that can be employed as a safe and effective treatment modality for superficial second degree (partial thickness) burn wounds. With a minimal requirement of mechanical force, the no-touch application of NPF makes it suitable for sensitive and irritant skin surfaces.

Prenatal therapy with pyrimethamine + sulfadiazine vs spiramycin to reduce placental transmission of toxoplasmosis: a multicenter, randomized trial.

BACKGROUND: The efficacy of prophylaxis to prevent prenatal toxoplasmosis transmission is controversial, without any previous randomized clinical trial. In France, spiramycin is usually prescribed for maternal seroconversions. A more potent pyrimethamine + sulfadiazine regimen is used to treat congenital toxoplasmosis and is offered in some countries as prophylaxis. OBJECTIVE: We sought to compare the efficacy and tolerance of pyrimethamine + sulfadiazine vs spiramycin to reduce placental transmission. STUDY DESIGN: This was a randomized, open-label trial in 36 French centers, comparing pyrimethamine (50 mg qd) + sulfadiazine (1 g tid) with folinic acid vs spiramycin (1 g tid) following toxoplasmosis seroconversion. RESULTS: In all, 143 women were randomized from November 2010 through January 2014. An amniocentesis was later performed in 131 cases, with a positive Toxoplasma gondii polymerase chain reaction in 7/67 (10.4%) in the pyrimethamine + sulfadiazine group vs 13/64 (20.3%) in the spiramycin group. Cerebral ultrasound anomalies appeared in 0/73 fetuses in the pyrimethamine + sulfadiazine group, vs 6/70 in the spiramycin group (P = .01). Two of these pregnancies were terminated. Transmission rates, excluding 18 children with undefined status, were 12/65 in the pyrimethamine + sulfadiazine group (18.5%), vs 18/60 in the spiramycin group (30%, P = .147), equivalent to an odds ratio of 0.53 (95% confidence interval, 0.23-1.22) and which after adjustment tended to be stronger (P = .03 for interaction) when treatment started within 3 weeks of seroconversion (95% confidence interval, 0.00-1.63). Two women had severe rashes, both with pyrimethamine + sulfadiazine. CONCLUSION: There was a trend toward lower transmission with pyrimethamine + sulfadiazine, but it did not reach statistical significance, possibly for lack of statistical power because enrollment was discontinued. There were also no fetal cerebral toxoplasmosis lesions in the pyrimethamine + sulfadiazine group. These promising results encourage further research on chemoprophylaxis to prevent congenital toxoplasmosis.

Licochalcone A: An effective and low-toxicity compound against Toxoplasma gondii in vitro and in vivo.

Toxoplasma gondii, an obligate intracellular protozoan, is the causative agent of toxoplasmosis, which can cause serious public health problems. The current drugs used to treat toxoplasmosis have many limitations. This study evaluated the anti-T. gondii activity and potential mechanism of Licochalcone A (Lico A) in vitro and in vivo. The safe concentration of Lico A in HFF cells was determined by MTT cell viability assays. The presence of T. gondii was assessed by qPCR and Giemsa staining. Azithromycin and sulfadiazine, commonly used effective treatments, served as drug controls. T. gondii ultrastructural alterations were observed by electron microscopy. The anti-T. gondii activity of Lico A was evaluated using an in vivo mouse infection model. In vitro, Lico A had no negative effect on host cell viability at concentrations below 9 µg/mL; however, it did inhibit T. gondii proliferation in a dose-dependent manner, with a 50% inhibitory concentration (IC50) of 0.848 µg/mL. Electron microscopy analyses indicated substantial structural and ultrastructural changes in tachyzoites after Lico A treatment. Nile Red staining assays demonstrated that Lico A caused lipid accumulation. Lico A treatment significantly increased the survival rate of BALB/c mice infected with T. gondii. Lico A achieved the same therapeutic effect as a commonly used clinical drugs (combination of sulfadiazine, pyrimethamine and folinic acid). In conclusion, Lico A has strong anti-T. gondii activity in vitro and in vivo and might be developed into a new anti-T. gondii drug. Moreover, Lico A may exert these effects by interfering with lipid metabolism in the parasite.

Treatment of cryptosporidiosis in captive green iguanas (Iguana iguana).

There are no standard guidelines for the treatment of cryptosporidiosis in reptiles. The aim of this study was to evaluate the efficacy of two cryptosporidiosis therapies in captive green iguanas. Eight green iguanas aged 2-6 years, including 6 (1 ♂ and 5 ♀) animals with chronic diarrhea, received treatment for cryptosporidiosis. The presence of Cryptosporidium sp. oocysts was determined in 8 iguanas (100%), Isospora sp. oocysts were detected in 3 animals (37.5%), and Oxyuridae eggs were observed in 5 iguanas (62.5%). The animals were divided into two therapeutic groups (A and B). Group A iguanas were administered halofuginone (Halocur, 0,50 mg/ml Intervet Productions S.A., France) at a dose of 110 mg/kg body weight (BW) every 7 days for 5 weeks. Group B animals were administered sulfadiazine and trimethoprim (Norodine Vet Oral Paste sulfadiazine 288,3 mg/g, trimethoprim 58 mg/g, ScanVet Animal Health A/S, Denmark) at 75 mg/kg BW per os every 5 days for 5 weeks and spiramycin and metronidazole (Stomorgyl, spiramycin 1500000 IU, metronidazole 250 mg, Merial, France) at 200 mg/kg BW every 5 days for 5 weeks. Both groups received hyperimmune bovine colostrum and subcutaneous fluids. Before treatment, the average number of Cryptosporidium sp. oocysts in 1 g of feces was determined at 1.71 * 105 (±313,262.44) in group A and 1.56 * 105 (±262,908.53) in group B; the average number of Isospora sp. oocysts was determined at 3.53 * 103 (±1747.38), and the average number of Oxyuridae eggs was determined at 810 (±496.74). Blood tests were performed once before treatment. The results of blood morphology and biochemistry tests before treatment revealed leukocytosis with a significant increase in heterophile and monocyte counts in all animals. Dehydration, elevated hematocrit values and low levels of Na+, Ca2+, PO4- and Cl- ions were observed in 6 iguanas. Two iguanas died during treatment. The gross necropsy revealed acute inflammation of gastric and duodenal mucosa, mucosal ecchymoses in the gastrointestinal tract, hepatomegaly and liver congestion, cholecystitis, enlarged kidneys and renal edema and congestion, cystitis, and an absence of fat bodies. Parasites were not detected in any developmental form after 40 days of therapy and during an monthly 18-month follow-up period. Effective treatment of cryptosporidiosis in reptiles minimizes the adverse consequences of disease, improves the animals' well-being and decreases euthanasia rates.