Multidisciplinary Preclinical Investigations on Three Oxamniquine Analogues as Novel Treatment Options for Schistosomiasis

10.26434/chemrxiv.12102894 ◽

2020 ◽

Author(s):

Valentin Buchter ◽

Yih Ching Ong ◽

François Mouvet ◽

Abdallah Ladaycia ◽

Elise Lepeltier ◽

...

Keyword(s):

Treatment Options ◽

Vitro Activity ◽

In Vivo Studies ◽

In Vitro Activity ◽

Liver Model ◽

Novel Treatment ◽

Active Concentration ◽

Dynamics Simulations

<div>Schistosomiasis is a disease of poverty affecting millions of people. Praziquantel (PZQ), with its </div><div>strengths and weaknesses, is the only treatment available. We previously reported 3 lead </div><div>compounds derived from oxamniquine (OXA), an old antischistosomal drug: ferrocene‐containing </div><div>(Fc‐CH2‐OXA), ruthenocene‐containing (Rc‐CH2‐OXA) and benzene‐containing (Ph‐CH2‐OXA). </div><div>These derivatives showed excellent in vitro activity against both Schistosoma mansoni and S. </div><div>haematobium larvae and adult worms, and in vivo against S. mansoni. Encouraged by these </div><div>promising results, we followed a guided drug discovery process and report in this investigation on </div><div>metabolic stability studies, in vivo studies, computational simulations, and formulation studies. </div><div>Molecular dynamics simulations supported the in vitro results on the target protein. Though all </div><div>three compounds were poorly stable within an acidic environment, they were only slightly cleared </div><div>in the in vitro liver model. This is likely the reason as to why the promising in vitro activity did not </div><div>translate to in vivo activity. This limitation could not be saved by the formulation of lipid </div><div>nanocapsules as an intent to improve the in vivo activity. Further studies should focus on increasing </div><div>the compound’s bioavailability, in order to reach an active concentration in the parasite’s </div><div>microenvironment. </div>

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In Vivo Efficacy of Anidulafungin and Caspofungin against Candida glabrata and Association with In Vitro Potency in the Presence of Sera

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.00105-07 ◽

2007 ◽

Vol 51 (5) ◽

pp. 1616-1620 ◽

Cited By ~ 67

Author(s):

Nathan P. Wiederhold ◽

Laura K. Najvar ◽

Rosie Bocanegra ◽

Destiny Molina ◽

Marcos Olivo ◽

...

Keyword(s):

Candida Glabrata ◽

Animal Studies ◽

Kidney Tissue ◽

Vitro Activity ◽

In Vivo Studies ◽

In Vitro Activity ◽

In Vivo Efficacy ◽

Fungal Burden

ABSTRACT In vitro studies have demonstrated that anidulafungin has greater potency than caspofungin against Candida glabrata. However, data from in vivo studies demonstrating that it has superior efficacy are lacking. The objective of this study was to compare the activities of anidulafungin and caspofungin against C. glabrata in a murine model of disseminated candidiasis. Two clinical C. glabrata isolates were used, including one with reduced caspofungin susceptibility. MICs were determined by broth microdilution in the presence and absence of sera. For the animal studies, mice were immunosuppressed with 5-fluorouracil one day prior to intravenous inoculation. Treatment with anidulafungin and caspofungin (0, 0.5, 1, 5, and 10 mg/kg of body weight per day) was begun 24 h later and was continued through day 7 postinoculation. The CFU were enumerated from kidney tissue. According to the standard microdilution methodology, anidulafungin had superior in vitro activity. However, this enhanced potency was attenuated by the addition of mouse and human sera. Caspofungin reduced the kidney fungal burden at lower doses compared to that achieved with anidulafungin in mice infected with the isolate with the lower MIC. Against the strain with the elevated caspofungin MIC, both anidulafungin and caspofungin were effective in reducing the kidney fungal burden at the higher doses studied. Despite the greater in vitro activity of anidulafungin in the absence of sera, both echinocandins were similarly effective in reducing the fungal burden in kidney tissue. The superior in vitro activity of anidulafungin did not confer enhanced in vivo efficacy against C. glabrata.

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In vitro activity of six antiviral drugs against equid alphaherpesvirus type 1 indicates ganciclovir as promising drug for in vivo studies

Ciência Rural ◽

10.1590/0103-8478cr20180085 ◽

2018 ◽

Vol 48 (12) ◽

Cited By ~ 2

Author(s):

Amanda Lovato de Oliveira ◽

Juliana Felipetto Cargnelutti ◽

Ana Paula Gnocato Mortari ◽

Eduardo Furtado Flores ◽

Rudi Weiblen

Keyword(s):

Specific Treatment ◽

Vitro Activity ◽

In Vivo Studies ◽

In Vitro Activity ◽

In Vivo Experiments ◽

Drug Concentrations ◽

Viral Plaque

ABSTRACT: Equid alphaherpesvirus type 1 (EHV-1) is distributed worldwide and is a major agent of abortion, respiratory and neurological disease in horses. No specific treatment is available for EHV-1 infection, yet the potential of antiviral therapy has been explored. In this study we investigated the in vitro activity of Acyclovir, Ganciclovir, Foscarnet, Famciclovir, Vidarabina and Cidofovir against EHV-1. For this, the MTT test was performed, in which all the tested drugs showed no toxicity up to 200μg/mL. Subsequently, different drug concentrations were submitted to viral plaque reduction assays in cell culture. The selectivity index (SI) of the compounds was determined using the cytotoxic concentration for 50% of cells (CC50), obtained by MTT, and effective drug concentration to inhibit by 50% the number of viral plaques (EC50). Ganciclovir (SI: 490; EC50: 1.9 μg/mL) was the most efficient and safest drug against EHV-1, followed by Cidofovir (SI: 150, EC50: 5.7μg/mL), Acyclovir (SI: 37.4, EC50: 22.2μg/mL), Famciclovir (SI: 25.1, EC50: 24.5μg/mL), Vidarabine (SI: 12.2, EC50: 40.9μg/mL) and Foscarnet (SI: 6.9, EC50: 49.5 μg/mL), respectively. These results indicated that Ganciclovir (followed by Cidofovir), is a promising candidate for use in in vivo experiments.

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High in vitro activity of DIS-73285, a novel antimicrobial with a new mechanism of action, against MDR and XDR Neisseria gonorrhoeae

Journal of Antimicrobial Chemotherapy ◽

10.1093/jac/dkaa322 ◽

2020 ◽

Vol 75 (11) ◽

pp. 3244-3247

Author(s):

Susanne Jacobsson ◽

Clive Mason ◽

Nawaz Khan ◽

Paul Meo ◽

Magnus Unemo

Keyword(s):

Neisseria Gonorrhoeae ◽

Small Molecule ◽

Mechanism Of Action ◽

Vitro Activity ◽

In Vivo Studies ◽

In Vitro Activity ◽

Agar Dilution ◽

High Level

Abstract Background The rising incidence of antimicrobial resistance in Neisseria gonorrhoeae may result in untreatable gonorrhoea in certain circumstances and development of novel antimicrobials is urgently needed. Objectives To evaluate the in vitro activity of a novel small-molecule antimicrobial with a new mechanism of action, DIS-73285, against a large geographically, temporally and genetically diverse collection of clinical N. gonorrhoeae isolates and reference strains, including various types of high-level resistant, MDR and XDR gonococcal isolates (n = 262). Methods MICs (mg/L) of DIS-73285 were determined by agar dilution and by Etest for ceftriaxone, cefixime, azithromycin, ciprofloxacin, ampicillin, spectinomycin and tetracycline. Results DIS-73285 was substantially more potent than any of the currently or previously used therapeutic antimicrobials, with MICs ranging from ≤0.001 to 0.004 mg/L, and the MIC50, MIC90 and modal MIC all ≤0.001 mg/L (lowest MIC tested). No correlation with the MICs of DIS-73285 and the MICs of any of the currently or previously used antimicrobials was observed. Conclusions The novel chemotype, small-molecule antimicrobial DIS-73285, demonstrated high in vitro potency against all tested N. gonorrhoeae isolates. Further in vitro and in vivo studies, evaluating efficacy, resistance emergence, pharmacokinetic/pharmacodynamic parameters, toxicity and safety, should be conducted to evaluate DIS-73285 as a therapy specifically for urogenital and extra-genital gonorrhoea.

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In Vitro and In Vivo Antibacterial Activities of DW-224a, a New Fluoronaphthyridone

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.01407-05 ◽

2006 ◽

Vol 50 (6) ◽

pp. 2261-2264 ◽

Cited By ~ 36

Author(s):

Hee-Soo Park ◽

Hyun-Joo Kim ◽

Min-Jung Seol ◽

Dong-Rack Choi ◽

Eung-Chil Choi ◽

...

Keyword(s):

Antibacterial Activities ◽

The Other ◽

Vitro Activity ◽

Gram Negative Bacteria ◽

In Vitro Activity ◽

Gram Positive ◽

Gram Negative ◽

Gram Positive Bacteria

ABSTRACT DW-224a showed the most potent in vitro activity among the quinolone compounds tested against clinical isolates of gram-positive bacteria. Against gram-negative bacteria, DW-224a was slightly less active than the other fluoroquinolones. The in vivo activities of DW-224a against gram-positive bacteria were more potent than those of other quinolones.

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Evaluation of the in vitro activity and in vivo bioavailability of realgar nanoparticles prepared by cryo-grinding

European Journal of Pharmaceutical Sciences ◽

10.1016/j.ejps.2006.05.002 ◽

2006 ◽

Vol 29 (1) ◽

pp. 35-44 ◽

Cited By ~ 75

Author(s):

Jin-Zhu Wu ◽

Paul C. Ho

Keyword(s):

Vitro Activity ◽

In Vitro Activity

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In vivo and in vitro activity of genistein in osteoporosis

Indian Journal of Pharmacology ◽

10.4103/0253-7613.32529 ◽

2007 ◽

Vol 39 (2) ◽

pp. 103 ◽

Cited By ~ 3

Author(s):

Qibing Mei ◽

Jiepin Wang ◽

Fujun Shang ◽

Li Liu ◽

Siwang wang ◽

...

Keyword(s):

Vitro Activity ◽

In Vitro Activity

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1366. In Vitro and In Vivo Activity of Cefiderocol against Stenotrophomonas maltophilia Clinical Isolates

Open Forum Infectious Diseases ◽

10.1093/ofid/ofy210.1197 ◽

2018 ◽

Vol 5 (suppl_1) ◽

pp. S418-S418 ◽

Cited By ~ 2

Author(s):

Akinobu Ito ◽

Merime Ota ◽

Rio Nakamura ◽

Masakatsu Tsuji ◽

Takafumi Sato ◽

...

Keyword(s):

Stenotrophomonas Maltophilia ◽

Systemic Infection ◽

Vitro Activity ◽

Clinical Isolates ◽

Infection Model ◽

In Vitro Activity ◽

In Vivo Efficacy ◽

Broth Microdilution Method

Abstract Background Cefiderocol (S-649266, CFDC) is a novel siderophore cephalosporin against Gram-negatives, including carbapenem (CR)-resistant strains. Its spectrum includes both the Enterobacteriaceae but also nonfermenters, including Stenotrophomonas maltophilia—an opportunistic pathogen with intrinsic resistance to carbapenem antibiotics. In this study, in vitro activity and in vivo efficacy of CFDC and comparators against S. maltophilia were determined. Methods MICs of CFDC and comparators (trimethoprim/sulfamethoxazole (TMP/SMX), minocycline (MINO), tigecycline (TGC), ciprofloxacin (CPFX), cefepime (CFPM), meropenem (MEPM), and colistin (CL)) were determined by broth microdilution method as recommended by CLSI. The MIC against CFDC was determined using iron-depleted cation-adjusted Mueller–Hinton broth. In vivo efficacy of CFDC, CFPM, ceftazidime–avibactam (CAZ/AVI), MEPM, and CL was evaluated using neutropenic murine systemic infection model caused by strain SR21970. The 50% effective doses (ED50s) were calculated by the logit method using the survival number at each dose 7 days after infection. Results MIC90 of CFDC and comparators against the 216 clinical isolates from global countries collected in SIDERO-CR 2014/2016 study are shown in the table. CFDC, TMP/SMX, MINO, and TGC showed good activity with MIC90 of 0.5, 0.25/4.75, 1, and 2 µg/mL, respectively. CFDC, MINO, and TGC inhibited growth of all tested strains at ≤1, ≤4, and ≤8 µg/mL although two strains showed resistance to TMP/SMX. MICs of CFPM, CAZ/AVI, MEPM, and CL were ≥32 µg/mL. The ED50 of CFDC against S. maltophilia SR21970 with MIC of 0.125 mg/mL was 1.17 mg/kg/dose. Conversely, MICs of CFPM, CAZ/AVI, MEPM/CS, and CL against SR21970 were 32 μg/mL or higher, and ED50s were >100 mg/kg/dose, showing that CFDC had potent in vivo efficacy against S. maltophilia strain which was resistant to other antibiotics. Conclusion CFDC showed potent in vitro activity against S. maltophilia, including TMP/SMX-resistant isolates. CFDC also showed potent in vivo efficacy reflecting in vitro activity against S. maltophilia in murine systemic infection model. Disclosures A. Ito, Shionogi & Co., Ltd.: Employee, Salary. M. Ota, Shionogi & Co., Ltd.: Employee, Salary. R. Nakamura, Shionogi & Co., Ltd.: Employee, Salary. M. Tsuji, Shionogi & Co., Ltd.: Employee, Salary. T. Sato, Shionogi & Co., Ltd.: Employee, Salary. Y. Yamano, Shionogi & Co., Ltd.: Employee, Salary.

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