Topical Delivery of Liposomally Encapsulated Interferon Evaluated by In Vitro Diffusion Studies and in a Cutaneous Herpes Guinea Pig Model

Abstract Background Candida auris is a growing global threat; a pathogen associated with high mortality (up to 60%), multidrug resistance, the ability to spread from person-to-person and surface-to-person, presenting high risk for outbreaks in healthcare facilities. Ibrexafungerp is a novel IV/oral glucan synthase inhibitor (triterpenoid) antifungal with activity against Candida, Aspergillus, and Pneumocystis spp., in Phase 3 development. Methods In vitro studies tested ibrexafungerp against >100 clinical isolates of C. auris. Other in vitro studies evaluated the effects of ibrexafungerp against C. auris biofilms. In vivo activity against C. auris was evaluated using a disseminated murine model and a cutaneous infection guinea pig model. In humans, an ongoing open-label trial of ibrexafungerp for treatment of patients with infections caused by C. auris (the CARES study) has been initiated in the United States and India. Results In vitro and in vivo studies demonstrated that ibrexafungerp is active against C. auris, including MDR strains. The MIC mode for ibrexafungerp was 1 μg/mL and the MIC50 and MIC90 were 0.5 and 1 μg/mL, respectively. Many echinocandin-resistant C. auris isolates have shown susceptibility to ibrexafungerp. Furthermore, ibrexafungerp has been shown to reduce biofilm thickness. In animal models of C. auris infection, treatment with ibrexafungerp resulted in improved survival and reduced fungal burden in both the murine model of disseminated infection and the guinea pig model of cutaneous infection as compared with untreated controls. In humans, two patients with difficult to treat C. auris candidemias were enrolled in the CARES study and responded positively to oral ibrexafungerp with eradication of the infection. Conclusion These data demonstrate that ibrexafungerp possess potent in vitro and in vivo activity as well as promising clinical activity. Therefore, continued clinical evaluation of ibrexafungerp as an option to treat C. auris infections is warranted. Disclosures All authors: No reported disclosures.

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Olorofim effectively eradicates dermatophytes in vitro and in vivo

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.01386-21 ◽

2021 ◽

Author(s):

Esmat Mirbzadeh Ardakani ◽

Atefeh Sharifirad ◽

Nasrin Pashootan ◽

Mahsa Nayebhashemi ◽

Mozhgan Zahmatkesh ◽

...

Keyword(s):

Guinea Pig ◽

Skin Lesions ◽

Growth Patterns ◽

Pig Model ◽

Antifungal Compound ◽

Post Inoculation ◽

Microsporum Gypseum ◽

Guinea Pig Model

Superficial fungal infections are prevalent worldwide, with dermatophytes, as the most common cause. Various antifungal agents including azoles and allylamines are commonly used to treat dermatophytosis. However, their overuse has yielded drug-resistant strains, calling for the development of novel anti-mycotic compounds. Olorofim, is a newly developed antifungal compound, which targets pyrimidine biosynthesis in molds. The purpose of this study was to determine the in vitro and in vivo antifungal effects of olorofim against common dermatophytes. The in vitro activity of olorofim against dermatophytes was assessed by microtiter broth dilution method. Bioinformatic analysis of olorofim binding to dihydroorotate dehydrogenase (DHODH) of dermatophytes was also performed, using Aspergillus fumigatus DHODH as a template. The in vivo efficacy of the drug was investigated, using a guinea pig model, experimentally infected with Microsporum gypseum. Microtiter assays confirmed the high in vitro sensitivity of dermatophytes to olorofim (MIC= 0.015-0.06 mg/L). Amino acid sequence analysis indicated that DHODH is highly conserved among dermatophytes. The critical residues, in dermatophytes, involved in olorofim binding, were similar to their counterparts in A. fumigatus DHODH, which explains their susceptibility to olorofim. Typical skin lesions of dermatophyte infection, were observed in the guinea pig model, at seven days post-inoculation. Following one week of daily topical administration of olorofim, similar to the clotrimazole group, the skin lesions were resolved and normal hair growth patterns appeared. In light of the in vitro and in vivo activity of olorofim against dermatophytes, this novel agent may be considered as a treatment of choice, against dermatophytosis.

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Defibrotide decreases histamine release in a guinea-pig model of myocardial ischemia and reperfusion “in vitro”

Agents and Actions ◽

10.1007/bf01997366 ◽

1992 ◽

Vol 36 (S2) ◽

pp. C333-C335 ◽

Cited By ~ 3

Author(s):

M. Lupini ◽

F. Gambassi ◽

L. Mugnai ◽

S. Bianchi ◽

E. Masini ◽

...

Keyword(s):

Myocardial Ischemia ◽

Guinea Pig ◽

Histamine Release ◽

Pig Model ◽

Ischemia And Reperfusion ◽

Myocardial Ischemia And Reperfusion ◽

Guinea Pig Model

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Pyronaridine Tetraphosphate Efficacy Against Ebola Virus Infection in Guinea Pig

10.1101/2020.03.20.001081 ◽

2020 ◽

Cited By ~ 4

Author(s):

Thomas R. Lane ◽

Christopher Massey ◽

Jason E. Comer ◽

Alexander N. Freiberg ◽

Huanying Zhou ◽

...

Keyword(s):

Virus Infection ◽

Guinea Pig ◽

Small Molecule ◽

Ebola Virus ◽

Marburg Virus ◽

Pig Model ◽

Significant Efficacy ◽

Guinea Pig Model ◽

Ebola Virus Infection

AbstractThe recent outbreaks of the Ebola virus (EBOV) in Africa have brought global visibility to the shortage of available therapeutic options to treat patients infected with this or closely related viruses. We have recently computationally identified three molecules which have all demonstrated statistically significant efficacy in the mouse model of infection with mouse adapted Ebola virus (ma-EBOV). One of these molecules is the antimalarial pyronaridine tetraphosphate (IC50 range of 0.82-1.30 µM against three strains of EBOV and IC50 range of 1.01-2.72 µM against two strains of Marburg virus (MARV)) which is an approved drug in the European Union and used in combination with artesunate. To date, no small molecule drugs have shown statistically significant efficacy in the guinea pig model of EBOV infection. Pharmacokinetics and range-finding studies in guinea pigs directed us to a single 300mg/kg or 600mg/kg oral dose of pyronaridine 1hr after infection. Pyronaridine resulted in statistically significant survival of 40% at 300mg/kg and protected from a lethal challenge with EBOV. In comparison, oral favipiravir (300 mg/kg dosed once a day) had 43.5 % survival. The in vitro metabolism and metabolite identification of pyronaridine and another of our EBOV active molecules, tilorone, which suggests significant species differences which may account for the efficacy or lack thereof, respectively in guinea pig. In summary, our studies with pyronaridine demonstrates its utility for repurposing as an antiviral against EBOV and MARV, providing justification for future testing in non-human primates.ImportanceThere is currently no antiviral small molecule drug approved for treating Ebola Virus infection. We have previously used machine learning models to identify new uses for approved drugs and demonstrated their activity against the Ebola virus in vitro and in vivo. We now describe the pharmacokinetic properties of the antimalarial pyronaridine in the guinea pig. In addition, we show that this drug is effective against multiple strains of EBOV and MARV in vitro and in the guinea pig model of Ebola virus infection. These combined efforts indicate the need to further test this molecule in larger animal efficacy studies prior to clinical use in humans. These findings also may be useful for repurposing this drug for use against other viruses in future.

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Endoplasmic Reticulum Stress Regulates Scleral Remodeling in a Guinea Pig Model of Form-Deprivation Myopia

Journal of Ophthalmology ◽

10.1155/2020/3264525 ◽

2020 ◽

Vol 2020 ◽

pp. 1-9

Author(s):

Chengcheng Zhu ◽

Qingzhong Chen ◽

Ying Yuan ◽

Min Li ◽

Bilian Ke

Keyword(s):

Endoplasmic Reticulum ◽

Guinea Pig ◽

Er Stress ◽

Western Blotting ◽

Guinea Pigs ◽

Pig Model ◽

Ultrastructural Changes ◽

Protein Levels ◽

Guinea Pig Model

Purpose. This study aimed to investigate the role of endoplasmic reticulum (ER) stress in scleral remodeling in a guinea pig model of form-deprivation myopia (FDM). Methods. Guinea pigs were form deprived to induce myopia. ER ultrastructural changes in the sclera were examined by transmission electron microscopy (TEM). The protein levels of ER stress chaperones, including GRP78, CHOP, and calreticulin (CRT), were analyzed by western blotting at 24 hours, 1 week, and 4 weeks of FD. Scleral fibroblasts from guinea pigs were cultured and exposed to the ER stress inducer tunicamycin (TM) or the ER stress inhibitor 4-phenylbutyric acid (4-PBA). CRT was knocked down by lentivirus-mediated CRT shRNA transfection. The expression levels of GRP78, CHOP, TGF-β1, and COL1A1 were analyzed by qRT-PCR or western blotting. Results. The sclera of FDM eyes exhibited swollen and distended ER at 4 weeks, as well as significantly increased protein expression of GRP78 and CRT at 1 week and 4 weeks, compared to the sclera of the control eyes. In vitro, TM induced ER stress in scleral fibroblasts, which was suppressed by 4-PBA. The mRNA expression of TGF-β1 and COL1A1 was upregulated after TM stimulation for 24 hours, but downregulated for 48 hours. Additionally, change of TGF-β1 and COL1A1 transcription induced by TM was suppressed by CRT knockdown. Conclusions. ER stress was an important modulator which could influence the expression of the scleral collagen. CRT might be a new target for the intervention of the FDM scleral remodeling process.

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Nanoparticle Encapsulated Lipopeptide Conjugate of Antitubercular Drug Isoniazid: In Vitro Intracellular Activity and in Vivo Efficacy in a Guinea Pig Model of Tuberculosis

Bioconjugate Chemistry ◽

10.1021/bc500476x ◽

2014 ◽

Vol 25 (12) ◽

pp. 2260-2268 ◽

Cited By ~ 28

Author(s):

Kata Horváti ◽

Bernadett Bacsa ◽

Éva Kiss ◽

Gergő Gyulai ◽

Kinga Fodor ◽

...

Keyword(s):

Guinea Pig ◽

Pig Model ◽

Antitubercular Drug ◽

In Vivo Efficacy ◽

Intracellular Activity ◽

Guinea Pig Model

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Topical delivery of liposomally encapsulated interferon evaluated by in vitro diffusion studies.

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.34.1.107 ◽

1990 ◽

Vol 34 (1) ◽

pp. 107-110 ◽

Cited By ~ 48

Author(s):

K Egbaria ◽

C Ramachandran ◽

D Kittayanond ◽

N Weiner

Keyword(s):

Topical Delivery ◽

Diffusion Studies ◽

In Vitro Diffusion

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Chloroquine inhibited Ebola virus replication in vitro but failed to protect against infection and disease in the in vivo guinea pig model

Journal of General Virology ◽

10.1099/jgv.0.000309 ◽

2015 ◽

Vol 96 (12) ◽

pp. 3484-3492 ◽

Cited By ~ 59

Author(s):

Stuart D. Dowall ◽

Andrew Bosworth ◽

Robert Watson ◽

Kevin Bewley ◽

Irene Taylor ◽

...

Keyword(s):

Guinea Pig ◽

Ebola Virus ◽

Pig Model ◽

Human Populations ◽

Therapeutic Effects ◽

Protective Effects ◽

Highly Pathogenic ◽

Guinea Pig Model

Ebola virus (EBOV) is highly pathogenic, with a predisposition to cause outbreaks in human populations accompanied by significant mortality. Owing to the lack of approved therapies, screening programmes of potentially efficacious drugs have been undertaken. One of these studies has demonstrated the possible utility of chloroquine against EBOV using pseudotyped assays. In mouse models of EBOV disease there are conflicting reports of the therapeutic effects of chloroquine. There are currently no reports of its efficacy using the larger and more stringent guinea pig model of infection. In this study we have shown that replication of live EBOV is impaired by chloroquine in vitro. However, no protective effects were observed in vivo when EBOV-infected guinea pigs were treated with chloroquine. These results advocate that chloroquine should not be considered as a treatment strategy for EBOV.

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