Avaliação do uso de antimicrobianos e suas interações medicamentosas em cães e gatos hospitalizados / Evaluation of antimicrobial use and their drug interactions in hospitalized dogs and cats

Os antimicrobianos são amplamente utilizados na medicina veterinária, portanto são necessários critérios na hora da prescrição desses fármacos a fim de evitar a resistência bacteriana que se tornou uma grande preocupação tanto para a saúde humana quanto para a medicina veterinária, devido ao seu uso indiscriminado. Uma técnica muito utilizada na rotina, são as associações entre antimicrobianos, que combinam o mecanismo de ação de cada fármaco para se obter os efeitos desejados, acarretando nas interações medicamentosas. Porém, se utilizado de forma incorreta, essas interações podem ser prejudiciais para a saúde dos pacientes. O objetivo desse estudo foi analisar prontuários de pacientes caninos e felinos hospitalizados afim de avaliar os critérios de seleção para o uso de antimicrobianos e suas associações. Foram analisados 112 prontuários, sendo eles 24 felinos e 88 caninos atendidos e hospitalizados no Hospital Veterinário "Prof. Ricardo Alexandre Rippler" da Universidade Vila Velha-UVV. O estudo demonstrou que o metronidazol foi o antimicrobiano mais utilizado em cães e a amoxicilina com clavulanato de potássio foi o mais utilizado nos felinos, além disso, a amoxicilina com clavulanato de potássio e metronidazol foi a associação mais observada em cães e gatos. A maior parte dos pacientes fizeram uso dos antibióticos de forma empírica, o que pode contribuir para a resistência microbiana. Além disso, foram encontradas algumas interações entre antimicrobianos de efeitos antagônicos, porém a maioria das associações foram realizadas de forma correta provocando efeito sinérgico no organismo dos pacientes. Conclui-se que o conhecimento sobre a utilização dos antimicrobianos na rotina da internação de cães e gatos é importante e com base nesses conhecimentos podemos aplicar medidas para atenuar a resistência aos antimicrobianos.

Antimicrobials are widely used in veterinary medicine, so criteria are needed when prescribing these drugs in order to avoid bacterial resistance, which has become a major concern for both human health and veterinary medicine, due to its indiscriminate use. A technique widely used in routine is the association between antimicrobials, which combine the mechanism of action of each drug to obtain the desired effects, resulting in drug interactions. However, if used incorrectly, these interactions can be harmful to the health of patients. The aim of this study was to analyze the medical records of hospitalized canine and feline patients in order to assess the selection criteria for the use of antimicrobials and their associations. 112 medical records were analyzed, of which 24 were cats and 88 canines treated and hospitalized at the "Prof. Ricardo Alexandre Rippler" from Universidade Vila Velha-UVV. The study showed that metronidazole was the most used antimicrobial in dogs and amoxicillin with potassium clavulanate was the most used in felines. Furthermore, amoxicillin with potassium clavolanate and metronidazole was the most observed association in dogs and cats. Most patients used antibiotics empirically, which may contribute to microbial resistance. In addition, some interactions were found between antimicrobials with antagonistic effects, but most associations were correctly performed, causing a synergistic effect in the patients' bodies. It is concluded that knowledge about the use of antimicrobials in the routine hospitalization of dogs and cats is important and based on this knowledge we can apply measures to mitigate antimicrobial resistance.

Phenolic and flavonoid content and in vitro inhibitory effect of some Amazonian fruit juices on CYP3A4 activity / Conteúdo fenólico e flavonoídico e efeito inibitório in vitro de alguns sucos de frutas da Amazônia sobre a atividade de CYP3A4

Many foods interact with drugs and may cause changes in the pharmacological effects of the co-administered therapeutic agent. The enzyme CYP3A4, which belongs to the cytochrome P450 enzyme complex, is responsible for the metabolism of most drugs currently on the market and is involved in many drug interactions. Hence, the interaction of this enzyme with juices of some fruits, such as grapefruit, can affect the pharmacokinetics of various drugs. However, native fruits from the Amazon region have not yet been the target of this type of research. We determined total polyphenols and flavonoids of the Amazonian fruits açaí (Euterpe precatoria), buriti (Mauritia flexuosa), camu-camu (Myrciaria dubia), cubiu (Solanum sessiliflorum), cupuaçu (Theobroma grandiflorum), jenipapo (Genipa americana), and taperebá (Spondias mombin) and evaluated the effects of each fruit juice on CYP3A4 activity, using the star fruit (Averrhoa carambola) juice as positive control. Açaí juice presented the highest content of total polyphenols and flavonoids (102.6 ± 7.2 µg gallic acid equivalent (GAE) per mL and 7.2 ± 0.6 µg quercetin equivalent (QE) per mL, respectively). All juices were able to inhibit the activity of CYP3A4. There was no residual activity of the drug-metabolizing enzyme for açai, buriti, cubiu, camu-camu, and taperebá juice, while for cupuaçu, jenipapo and the positive control, the residual activity was 44.3, 54.3 and 20.2%, respectively. Additional studies should identify the phytocompound(s) responsible for this inhibition activity, to clarify the mechanisms involved in this phenomenon.(AU)

Muitos alimentos interagem com medicamentos e podem causar alterações nos efeitos farmacológicos do agente terapêutico coadministrado. A enzima CYP3A4, que pertence ao complexo enzimático do citocromo P450, é responsável pelo metabolismo da maioria dos medicamentos atualmente no mercado e está envolvida em muitas interações medicamentosas. Assim, a interação dessa enzima com sucos de algumas frutas, como a toranja, pode afetar a farmacocinética de vários medicamentos. No entanto, frutas nativas da região amazônica ainda não foram alvo desse tipo de pesquisa. Determinamos polifenóis e flavonoides totais dos frutos amazônicos de açaí (Euterpe precatoria), buriti (Mauritia flexuosa), camu-camu (Myrciaria dubia), cubiu (Solanum sessiliflorum), cupuaçu (Theobroma grandiflorum), jenipapo (Genipa americana) e taperebá (Spondias mombin) e avaliamos os efeitos de cada suco de fruta sobre a atividade de CYP3A4, utilizando o suco de carambola (Averrhoa carambola) como controle positivo. O suco de açaí apresentou o maior teor de polifenóis totais e flavonóides (102,6 ± 7,2 µg equivalente de ácido gálico (GAE) por mL e 7,2 ± 0,6 µg equivalente de quercetina (QE) por mL, respectivamente). Todos os sucos foram capazes de inibir a atividade de CYP3A4. Não houve atividade residual da enzima metabolizadora de fármacos para os sucos de açaí, buriti, cubiu, camu-camu e taperebá, enquanto para cupuaçu, jenipapo e o controle positivo, a atividade residual foi de 44,3, 54,3 e 20,2%, respectivamente. Estudos adicionais devem identificar o(s) fitocomposto(s) responsável(is) por esta atividade de inibição, para esclarecer os mecanismos envolvidos neste fenômeno.(AU)

Toxicidade reprodutiva da associação de itraconazol e beta-glucana em ratas e sua progênie / Reproductive toxicity of itraconazole in combination with beta-glucan in female rats and their offspring

Background: Reports of yeast isolates resistant to traditional antifungal drugs have become common. Similarly, refractory clinical cases treated with these traditional antifungal drugs have also been reported. These cases ‘may or may not be related to pregnancy. Newly developed therapeutic approaches, such as the immunostimulant β-glucan combined with the traditional antifungal agents show promising results. Therefore, knowledge of the effects of these new associations is essential. The aims of this study were to evaluate the effects of the combination of itraconazole and β (1-3) glucan on fertility in female rats and its interference in the development of their offspring, including teratogenic potential.Materials, Methods & Results: A total of 180 female Wistar rats (90 days old) separated into six groups were used (n = 30 per group): Negative Control - treated daily with the volume corresponding to 10 mL.kg-1 of sterile distilled water orally, and 0.25 mL of sterile 0.9% NaCl solution subcutaneously weekly; IT - treated daily with itraconazole at a dose of 10 mg.kg-1 orally, and 0.25 ml of sterile 0.9% NaCl solution subcutaneously weekly; Beta - treated daily with the volume corresponding to 10 mL.kg-1 of sterile distilled water orally, and 0.5 mg of β (1-3) glucan subcutaneously weekly; DT - treated daily with itraconazole at a dose of 10 mg.kg-1 orally, and 0.5 mg of β (1-3) glucan subcutaneously weekly; DT5x - treated daily with itraconazole at a dose of 50 mg.kg-1 orally, and 0.5 mg of β (1-3) glucan subcutaneously weekly; DT10x - treated daily with itraconazole at a dose of 100 mg.kg-1 orally, and 0.5 mg of β (1-3) glucan subcutaneously weekly. The rats were treated before (14 days) and during the mating period (up to 21 days), pregnancy (21 days) and lactation (21 days).[...](AU)

Toxicidade reprodutiva da associação de itraconazol e beta-glucana em ratas e sua progênie / Reproductive toxicity of itraconazole in combination with beta-glucan in female rats and their offspring

Background: Reports of yeast isolates resistant to traditional antifungal drugs have become common. Similarly, refractory clinical cases treated with these traditional antifungal drugs have also been reported. These cases ‘may or may not be related to pregnancy. Newly developed therapeutic approaches, such as the immunostimulant β-glucan combined with the traditional antifungal agents show promising results. Therefore, knowledge of the effects of these new associations is essential. The aims of this study were to evaluate the effects of the combination of itraconazole and β (1-3) glucan on fertility in female rats and its interference in the development of their offspring, including teratogenic potential.Materials, Methods & Results: A total of 180 female Wistar rats (90 days old) separated into six groups were used (n = 30 per group): Negative Control - treated daily with the volume corresponding to 10 mL.kg-1 of sterile distilled water orally, and 0.25 mL of sterile 0.9% NaCl solution subcutaneously weekly; IT - treated daily with itraconazole at a dose of 10 mg.kg-1 orally, and 0.25 ml of sterile 0.9% NaCl solution subcutaneously weekly; Beta - treated daily with the volume corresponding to 10 mL.kg-1 of sterile distilled water orally, and 0.5 mg of β (1-3) glucan subcutaneously weekly; DT - treated daily with itraconazole at a dose of 10 mg.kg-1 orally, and 0.5 mg of β (1-3) glucan subcutaneously weekly; DT5x - treated daily with itraconazole at a dose of 50 mg.kg-1 orally, and 0.5 mg of β (1-3) glucan subcutaneously weekly; DT10x - treated daily with itraconazole at a dose of 100 mg.kg-1 orally, and 0.5 mg of β (1-3) glucan subcutaneously weekly. The rats were treated before (14 days) and during the mating period (up to 21 days), pregnancy (21 days) and lactation (21 days).[...]

Effects of the association of beta-glucan and itraconazole on fertility of male Wistar rats / Efeitos da associação de beta-glucana e itraconazol sobre a fertilidade de ratos Wistar machos

Background: In recent years, the number of patients with systemic fungal infections requiring antifungal therapy has increased. As a consequence, antimicrobial resistance to conventional treatment is frequently reported. Due to this reason, new therapies emerge, including the combination of beta (1-3) glucan and itraconazole. However, the reproductive and fertility effects of this association were not known. So, the aim of this study was to identify the effects of the combination of itraconazole and beta (1-3) glucan, extracted from Saccharomyces cerevisiae, on male rats fertility. Materials, Methods & Results: Sixty male Wistar rats with 120-days-old were used. The experimental protocol was approved by Ethics Committee on Animal Use of the Federal University of Rio Grande do Sul (protocol CEUA/UFRGS no. 19452/2010). The animals were placed into six groups (n = 10 animals / group) as following: Negative Control group - treated daily with the volume corresponding to 10 mL.kg-1 of sterile distilled water orally and 0.25 mL of sterile normal saline (NaCl 0.9 %) subcutaneously weekly; Itraconazole (IT) group - treated daily with itraconazole solution at a dose of 10 mg.kg-1 orally and 0.25 mL of sterile 0.9% NaCl subcutaneously weekly; Beta group - treated daily with the volume corresponding to 10 mL. kg-1 of sterile distilled water orally and 0.5 mg of beta (1-3) glucan subcut

Nos últimos anos, observou-se aumento do número de pacientes com risco de infecções fúngicas sistêmicas, tais como portadores de HIV, distúrbios hematológicos graves ou imunossuprimidos, pacientes oncológicos e receptores de transplantes. Tais pacientes necessitam de antifúngicos tanto na forma terapêutica como preventiva. Em contrapartida a estes usos, tornaram-se frequentes os relatos de resistência aos fármacos mais utilizados, incluindo o itraconazol. Esta resistência é bastante relevante nos casos envolvendo o gênero Candida, e descrita com outros agentes, como Sporothrix schenckii e Aspergillus fumigatus, em humanos e animais. Nos casos de resistências aos antifúngicos tradicionais, novas alternativas terapêuticas foram buscadas; dentre essas, a associação de ß-glucana, estimulante do sistema imunológico, a antifúngicos tradicionais, mostram-se promissora. Contudo, não existem estudos sobre os efeitos dessa associação sobre o sistema reprodutivo. [...]

Efeitos da associação de beta-glucana e itraconazol sobre a fertilidade de ratos Wistar machos / Effects of the Association of Beta-glucan and Itraconazole on Fertility of Male Wistar Rats

Background: In recent years, the number of patients with systemic fungal infections requiring antifungal therapy has increased. As a consequence, antimicrobial resistance to conventional treatment is frequently reported. Due to this reason, new therapies emerge, including the combination of beta (1-3) glucan and itraconazole. However, the reproductive and fertility effects of this association were not known. So, the aim of this study was to identify the effects of the combination of itraconazole and beta (1-3) glucan, extracted from Saccharomyces cerevisiae, on male rats fertility. Materials, Methods & Results: Sixty male Wistar rats with 120-days-old were used. The experimental protocol was approved by Ethics Committee on Animal Use of the Federal University of Rio Grande do Sul (protocol CEUA/UFRGS no. 19452/2010). The animals were placed into six groups (n = 10 animals / group) as following: Negative Control group - treated daily with the volume corresponding to 10 mL.kg-¹ of sterile distilled water orally and 0.25 mL of sterile normal saline (NaCl 0.9 %) subcutaneously weekly; Itraconazole (IT) group - treated daily with itraconazole solution at a dose of 10 mg.kg-¹ orally and 0.25 mL of sterile 0.9% NaCl subcutaneously weekly; Beta group - treated daily with the volume corresponding to 10 mL.kg-¹ of sterile distilled water orally and 0.5 mg of beta (1-3) glucan subcutaneously weekly; Therapeutic Dose (TD) group - daily treated with itraconazole at a dose of 10 mg.kg-¹ orally and 0.5 mg of ß (1-3) glucan subcutaneously weekly; TD5x - treated daily with itraconazole at a dose of 50 mg.kg-¹ orally and 0.5 mg of beta (1-3 ) glucan subcutaneously weekly; TD10x - daily treated with itraconazole at a dose of 100 mg.kg-¹ orally and 0.5 mg of beta (1-3) glucan subcutaneously weekly. The rats were treated for 91 consecutive days. Individual body mass, organs relative mass and histopathology, number of sperm in the cauda epididymis, daily spermatozoal production, sperm parameters, sperm morphology, serum testosterone concentration and reproductive rates were evaluated. Significant differences were observed in daily spermatozoal production, sperm morphology, serum concentration of testosterone, mating rate and birth rate, with lower results in the TD5x and TD10x groups. Discussion: The systemic toxicity indicators, as body mass variation, water intake and clinical signs, as well as organ histology suggest that systemic toxicity in these animals did not occur. The decrease in serum testosterone concentrations in elevated doses of itraconazole associated with beta (1-3) glucan must be involved in decrease of sperm parameters and in sexual behavior and consequently, in the reproductive rates. Changes in sperm morphology, mainly found in sperm head, indicate sperm immaturity, preamature spermiation, abnormal or degenerate acrosome. Based on these results, it is concluded that beta (1-3) glucan and itraconazole did not affect the male rats reproductive variables when used in therapeutic doses alone or in combination, however these variables were altered with higher doses of itraconazole in the association. These data, added to the absence of histopathological damage of the testes suggest functional effect on male fertility. Caution is advised in the use of high doses of itraconazole with or without beta (1-3) glucan in males, especially in prolonged therapy.

Chlorhexidine: beta-cyclodextrin inhibits yeast growth by extraction of ergosterol

Chlorhexidine (Cx) augmented with beta-cyclodextrin (-cd) inclusion compounds, termed Cx:-cd complexes, have been developed for use as antiseptic agents. The aim of this study was to examine the interactions of Cx:-cd complexes, prepared at different molecular ratios, with sterol and yeast membranes. The Minimal Inhibitory Concentration (MIC) against the yeast Candida albicans (C.a.) was determined for each complex; the MICs were found to range from 0.5 to 2 µg/mL. To confirm the MIC data, quantitative analysis of viable cells was performed using trypan blue staining. Mechanistic characterization of the interactions that the Cx:-cd complexes have with the yeast membrane and assessment of membrane morphology following exposure to Cx:-cd complexes were performed using Sterol Quantification Method analysis (SQM) and scanning electron microscopy (SEM). SQM revealed that sterol extraction increased with increasing -cd concentrations (1.71 × 10³; 1.4 × 10³; 3.45 × 10³, and 3.74 × 10³ CFU for 1:1, 1:2, 1:3, and 1:4, respectively), likely as a consequence of membrane ergosterol solubilization. SEM images demonstrated that cell membrane damage is a visible and significant mechanism that contributes to the antimicrobial effects of Cx:-cd complexes. Cell disorganization increased significantly as the proportion of -cyclodextrin present in the complex increased. Morphology of cells exposed to complexes with 1:3 and 1:4 molar ratios of Cx:-cd were observed to have large aggregates mixed with yeast remains, representing more membrane disruption than that observed in cells treated with Cx alone. In conclusion, nanoaggregates of Cx:-cd complexes block yeast growth via ergosterol extraction, permeabilizing the membrane by creating cluster-like structures within the cell membrane, possibly due to high amounts of hydrogen bonding.

Effects of the association of beta-glucan and itraconazole on fertility of male Wistar rats / Efeitos da associação de beta-glucana e itraconazol sobre a fertilidade de ratos Wistar machos

Background: In recent years, the number of patients with systemic fungal infections requiring antifungal therapy has increased. As a consequence, antimicrobial resistance to conventional treatment is frequently reported. Due to this reason, new therapies emerge, including the combination of beta (1-3) glucan and itraconazole. However, the reproductive and fertility effects of this association were not known. So, the aim of this study was to identify the effects of the combination of itraconazole and beta (1-3) glucan, extracted from Saccharomyces cerevisiae, on male rats fertility. Materials, Methods & Results: Sixty male Wistar rats with 120-days-old were used. The experimental protocol was approved by Ethics Committee on Animal Use of the Federal University of Rio Grande do Sul (protocol CEUA/UFRGS no. 19452/2010). The animals were placed into six groups (n = 10 animals / group) as following: Negative Control group - treated daily with the volume corresponding to 10 mL.kg-1 of sterile distilled water orally and 0.25 mL of sterile normal saline (NaCl 0.9 %) subcutaneously weekly; Itraconazole (IT) group - treated daily with itraconazole solution at a dose of 10 mg.kg-1 orally and 0.25 mL of sterile 0.9% NaCl subcutaneously weekly; Beta group - treated daily with the volume corresponding to 10 mL. kg-1 of sterile distilled water orally and 0.5 mg of beta (1-3) glucan subcut

Nos últimos anos, observou-se aumento do número de pacientes com risco de infecções fúngicas sistêmicas, tais como portadores de HIV, distúrbios hematológicos graves ou imunossuprimidos, pacientes oncológicos e receptores de transplantes. Tais pacientes necessitam de antifúngicos tanto na forma terapêutica como preventiva. Em contrapartida a estes usos, tornaram-se frequentes os relatos de resistência aos fármacos mais utilizados, incluindo o itraconazol. Esta resistência é bastante relevante nos casos envolvendo o gênero Candida, e descrita com outros agentes, como Sporothrix schenckii e Aspergillus fumigatus, em humanos e animais. Nos casos de resistências aos antifúngicos tradicionais, novas alternativas terapêuticas foram buscadas; dentre essas, a associação de ß-glucana, estimulante do sistema imunológico, a antifúngicos tradicionais, mostram-se promissora. Contudo, não existem estudos sobre os efeitos dessa associação sobre o sistema reprodutivo. [...]