Antifungal activity of liriodenine on clinical strains of Cryptococcus neoformans and Cryptococcus gattii species complexes

Background: Cryptoccocal meningitis continues to present high incidence among AIDS patients. The treatment of choice is the synergistic combination of flucytosine (5-FC) with amphotericin B deoxycholate (AmBd) or its lipid formulations. However, 5-FC is unavailable in many countries and AmB demands hospitalization. The combination of AmB with the fungistatic fluconazole (FLC) or the use of high FLC daily doses alone became the choice. Nonetheless, sterilization of cerebrospinal fluid is delayed with FLC monotherapy, mainly with high fungal burden. These findings suggest the search for new antifungal compounds, such as liriodenine. Methods: Liriodenine antifungal activity was evaluated by three procedures: determining the minimum inhibitory concentration (MIC) on 30 strains of the Cryptococcus neoformans (C. neoformans) complex and 30 of the Cryptococcus gattii (C. gattii) complex, using EUCAST methodology and amphotericin B deoxycholate as control; performing the time-kill methodology in two strains of the C. neoformans complex and one of the C. gattii complex; and injury to cryptococcal cells, evaluated by transmission electron microscopy (TEM). Liriodenine absorption and safety at 0.75 and 1.50 mg.kg-1 doses were evaluated in BALB/c mice. Results: Liriodenine MICs ranged from 3.9 to 62.5 µg.mL-1 for both species complexes, with no differences between them. Time-kill methodology confirmed its concentration-dependent fungicidal effect, killing all the strains below the limit of detection (33 CFU.mL-1) at the highest liriodenine concentration (32-fold MIC), with predominant activity during the first 48 hours. Liriodenine induced severe Cryptococcus alterations ­ cytoplasm with intense rarefaction and/or degradation, injury of organelles, and presence of vacuoles. Liriodenine was better absorbed at lower doses, with no histopathological alterations on the digestive tract. Conclusion: The fungicidal activity confirmed by time-kill methodology, the intense Cryptococcus injury observed by TEM, the absorption after gavage administration, and the safety at the tested doses indicate that the liriodenine molecule is a promising drug lead for development of anticryptococcal agents.(AU)

Criptococose em gato - Relato de caso / Cryptococcosis in cat Case report

A criptococose é uma doença infecciosa fúngica causada por uma levedura, da espécie Cryptococcus neoformans. Acomete diferentes espécies de animais e também o homem. O presente trabalho tem como por objetivo relatar um caso de criptococose em uma gata atendida na Clínica Veterinária da UNIFAI, com sinais clínicos de dispneia, espirros, secreção nasal bilateral, deformidade nasal com aumento de volume no plano nasal e úlceras no focinho. Foi realizado exame citológico onde foi observado processo inflamatório com presença de macrófagos e neutrófilos, além de estruturas leveduriformes com paredes espessas de formato redondo a oval caracterizando-se como cryptococcus neofarmans. No exame radiográfico foi observado aumento de volume em região de focinho sem alteração de radiopacidade indicando possível granuloma. Através da anamnese, exame físico, exame citológico, foi diagnosticado Criptococose. O tratamento indicado foi administração via oral de Itraconazol 50mg a cada 24 horas durante 60 dias.(AU)

Cryptococcosis is a fungal infectious disease caused by a yeast of the species Cryptococcus neoformans. It is the most common systemic mycosis in cats. The present study has the objective to report a case of cryptococcosis in a cat treated at the Veterinary Clinic of UNIFAI, with clinical signs of dyspnea, sneezing, secretion in the nostrils, nasal deformity with increased, volume and ulcers on the muzzle. Was performed the cytology examination where an inflammatory process was observed with presence of macrophages and neutrophils, as well as leveduriform structures with thick walls of round to oval shape, characterized as cryptococcus neofarmans. In the radiographic examination, a volume increase was observed in the region of muzzle without alteration of radiopacity indicating possible granuloma. Through the anamnesis, physical examination, cytological examination, Cryptococcosis was diagnosed. The indicated treatment was oral administration of Itraconazole 50mg every 24 hours for 60 days.

Criptococose em gato - Relato de caso / Cryptococcosis in cat – Case report

A criptococose é uma doença infecciosa fúngica causada por uma levedura, da espécie Cryptococcus neoformans. Acomete diferentes espécies de animais e também o homem. O presente trabalho tem como por objetivo relatar um caso de criptococose em uma gata atendida na Clínica Veterinária da UNIFAI, com sinais clínicos de dispneia, espirros, secreção nasal bilateral, deformidade nasal com aumento de volume no plano nasal e úlceras no focinho. Foi realizado exame citológico onde foi observado processo inflamatório com presença de macrófagos e neutrófilos, além de estruturas leveduriformes com paredes espessas de formato redondo a oval caracterizando-se como cryptococcus neofarmans. No exame radiográfico foi observado aumento de volume em região de focinho sem alteração de radiopacidade indicando possível granuloma. Através da anamnese, exame físico, exame citológico, foi diagnosticado Criptococose. O tratamento indicado foi administração via oral de Itraconazol 50mg a cada 24 horas durante 60 dias.

Cryptococcosis is a fungal infectious disease caused by a yeast of the species Cryptococcus neoformans. It is the most common systemic mycosis in cats. The present study has the objective to report a case of cryptococcosis in a cat treated at the Veterinary Clinic of UNIFAI, with clinical signs of dyspnea, sneezing, secretion in the nostrils, nasal deformity with increased, volume and ulcers on the muzzle. Was performed the cytology examination where an inflammatory process was observed with presence of macrophages and neutrophils, as well as leveduriform structures with thick walls of round to oval shape, characterized as cryptococcus neofarmans. In the radiographic examination, a volume increase was observed in the region of muzzle without alteration of radiopacity indicating possible granuloma. Through the anamnesis, physical examination, cytological examination, Cryptococcosis was diagnosed. The indicated treatment was oral administration of Itraconazole 50mg every 24 hours for 60 days.

Criptococose nasal e cutânea em felino: relato de caso / Bothrops moojeni experimental envenimation in dogs

O presente trabalho objetivou relatar um caso de criptococose nasal e cutânea em um felino doméstico de três anos de idade, da raça Pêlo Curto Brasileiro 4kg, atendido no Hospital Veterinário da Pontifícia Católica do Rio Grande do Sul (PUCRS) Campus Uruguaiana. O animal chegou ao ambulatório apresentando aumento de volume na região interocular com descarga nasal sanguinolenta e obstrução total, em uma das narinas, por um tecido avermelhado esponjoso. Media 39,0ºC de temperatura/ e, além dos sinais clínicos, apresentava hemograma inflamatório. As análises citológica e histopatológica definiram o diagnóstico de criptococose. Após sete meses de tratamento com cetoconazol, por via oral, o animal apresentou recuperação quase total(AU)

The present work has the objective to describe a case of nasal cutaneous cryptococcosis in a three years-old Brazilian Short Hair domestic feline, weighing 4kg, which was attended at the Hospital Veterinário of the PUCRS Uruguaiana Campus. The animal arrived at the clinic presenting an increased volume on the interocular area, with a bloody nasal discharge and a complete obstruction of one of the nostrils by a red spongy tissue. It presented a temperature of 39,0ºC and, besides the clinical signs, an inflammatory blood cells rate. The cytological and the histopathological analyses defined a cryptococcosis diagnosis. Seven months after the oral treatment with ketoconazol, the animal presented a total recovery(AU)

Criptococose nasal e cutânea em felino: relato de caso / Bothrops moojeni experimental envenimation in dogs

O presente trabalho objetivou relatar um caso de criptococose nasal e cutânea em um felino doméstico de três anos de idade, da raça Pêlo Curto Brasileiro 4kg, atendido no Hospital Veterinário da Pontifícia Católica do Rio Grande do Sul (PUCRS) – Campus Uruguaiana. O animal chegou ao ambulatório apresentando aumento de volume na região interocular com descarga nasal sanguinolenta e obstrução total, em uma das narinas, por um tecido avermelhado esponjoso. Media 39,0ºC de temperatura/ e, além dos sinais clínicos, apresentava hemograma inflamatório. As análises citológica e histopatológica definiram o diagnóstico de criptococose. Após sete meses de tratamento com cetoconazol, por via oral, o animal apresentou recuperação quase total

The present work has the objective to describe a case of nasal cutaneous cryptococcosis in a three years-old Brazilian Short Hair domestic feline, weighing 4kg, which was attended at the Hospital Veterinário of the PUCRS – Uruguaiana Campus. The animal arrived at the clinic presenting an increased volume on the interocular area, with a bloody nasal discharge and a complete obstruction of one of the nostrils by a red spongy tissue. It presented a temperature of 39,0ºC and, besides the clinical signs, an inflammatory blood cells rate. The cytological and the histopathological analyses defined a cryptococcosis diagnosis. Seven months after the oral treatment with ketoconazol, the animal presented a total recovery