scholarly journals In Vitro and In Vivo Characterization of Tebipenem (TBP), an Orally Active Carbapenem, against Biothreat Pathogens

2021 ◽  
Author(s):  
Nicholas P. Clayton ◽  
Akash Jain ◽  
Stephanie A. Halasohoris ◽  
Lisa M. Pysz ◽  
Sanae Lembirik ◽  
...  
Keyword(s):  
Survival Rates ◽  
Multidrug Resistant ◽  
Positive Control ◽  
Vehicle Control ◽  
Control Group ◽  
Post Challenge ◽  
Vehicle Control Group ◽  
Tebipenem Pivoxil

Bacillus anthracis and Yersinia pestis, causative pathogens for anthrax and plague, respectively, along with Burkholderia mallei and B. pseudomallei are potential bioterrorism threats. Tebipenem pivoxil hydrobromide (TBP HBr, formerly SPR994), is an orally available prodrug of tebipenem, a carbapenem with activity versus multidrug-resistant (MDR) gram-negative pathogens, including quinolone-resistant and extended-spectrum-β-lactamase-producing Enterobacterales. We evaluated the in vitro activity and in vivo efficacy of tebipenem against biothreat pathogens. Tebipenem was active in vitro against 30-strain diversity sets of B. anthracis, Y. pestis, B. mallei, and B. pseudomallei with minimum inhibitory concentration (MIC) values of 0.001 – 0.008 μg/ml for B. anthracis, ≤0.0005 – 0.03 μg/ml for Y. pestis, 0.25 – 1 μg/ml for B. mallei, and 1 – 4 μg/ml for B. pseudomallei. In a B. anthracis murine model, all control animals died within 52 h post challenge. The survival rates in the groups treated with tebipenem were 75% and 73% when dosed at 12 h and 24 h post challenge, respectively. The survival rates in the positive control groups treated with ciprofloxacin were 75% and when dosed 12 h and 25% when dosed 24 h post challenge, respectively. Survival rates were significantly (p=0.0009) greater in tebipenem groups treated at 12 h and 24 h post challenge and in the ciprofloxacin group 12 h post-challenge vs. the vehicle-control group. For Y. pestis, survival rates for all animals in the tebipenem and ciprofloxacin groups were significantly (p<0.0001) greater than the vehicle-control group. These results support further development of tebipenem for treating biothreat pathogens.

scholarly journals Protegrin-1: a broad-spectrum, rapidly microbicidal peptide with in vivo activity.

1997 ◽  
Vol 41 (8) ◽  
pp. 1738-1742 ◽  
Author(s):  
D A Steinberg ◽  
M A Hurst ◽  
C A Fujii ◽  
A H Kung ◽  
J F Ho ◽  
...  
Keyword(s):  
Serial Passage ◽  
Vehicle Control ◽  
Control Group ◽  
Vehicle Control Group ◽  
Mueller Hinton ◽  
Immunocompetent Mice ◽  
Systemic Infections ◽  
Mueller Hinton Broth

Protegrin-1 (PG-1) is a cysteine-rich, 18-residue beta-sheet peptide isolated from porcine leukocytes with antimicrobial activity against a broad range of microorganisms. The MICs of PG-1 against representative gram-positive and gram-negative bacteria ranged from 0.12 to 2 microg/ml. At these levels, PG-1 was rapidly bactericidal in vitro, reducing the number of viable CFU of either methicillin-resistant Staphylococcus aureus (MRSA) or Pseudomonas aeruginosa by more than three log units in less than 15 min. Resistance to PG-1 did not develop after 11 subculturings of P. aeruginosa or 18 subcultures of MRSA in Mueller-Hinton broth containing PG-1 at one-half the MIC. Under similar conditions of serial passage, the MICs of norfloxacin and gentamicin against P. aeruginosa increased 10 and 190 times, respectively. Similarly, the MIC of norfloxacin against MRSA increased 85 times. Immunocompetent mice inoculated intraperitoneally (i.p.) with P. aeruginosa or S. aureus exhibited 93 to 100% mortality in the vehicle control group compared with 0 to 27% mortality in animals that received a single i.p. injection of PG-1 (0.5 mg/kg of body weight). Mice inoculated with S. aureus by intravenous (i.v.) injection and dosed 0 to 60 min later with a single i.v. injection of PG-1 (5 mg/kg) had a mortality of 7 to 33%, compared to a mortality of 73 to 93% in the vehicle controls. In leukopenic mice inoculated i.v. with vancomycin-resistant Enterococcus faecium, mortality was 87% in the vehicle control group and 33% in animals that received a single i.v. injection of PG-1 (2.5 mg/kg). Taken together, these data indicate that PG-1 has potential for use as an antimicrobial agent in the treatment of local or systemic infections caused by clinically relevant pathogens.

scholarly journals Effects of Vitrification on the Blastocyst Gene Expression Profile in a Porcine Model

2021 ◽  
Vol 22 (3) ◽  
pp. 1222
Author(s):  
Cristina Cuello ◽  
Cristina A. Martinez ◽  
Josep M. Cambra ◽  
Inmaculada Parrilla ◽  
Heriberto Rodriguez-Martinez ◽  
...  
Keyword(s):  
Gene Expression ◽  
Gene Expression Analysis ◽  
Survival Rates ◽  
Control Group ◽  
P Value ◽  
Transcriptome Profile ◽  
Embryo Viability ◽  
The Impact

This study was designed to investigate the impact of vitrification on the transcriptome profile of blastocysts using a porcine (Sus scrofa) model and a microarray approach. Blastocysts were collected from weaned sows (n = 13). A total of 60 blastocysts were vitrified (treatment group). After warming, vitrified embryos were cultured in vitro for 24 h. Non-vitrified blastocysts (n = 40) were used as controls. After the in vitro culture period, the embryo viability was morphologically assessed. A total of 30 viable embryos per group (three pools of 10 from 4 different donors each) were subjected to gene expression analysis. A fold change cut-off of ±1.5 and a restrictive threshold at p-value < 0.05 were used to distinguish differentially expressed genes (DEGs). The survival rates of vitrified/warmed blastocysts were similar to those of the control (nearly 100%, n.s.). A total of 205 (112 upregulated and 93 downregulated) were identified in the vitrified blastocysts compared to the control group. The vitrification/warming impact was moderate, and it was mainly related to the pathways of cell cycle, cellular senescence, gap junction, and signaling for TFGβ, p53, Fox, and MAPK. In conclusion, vitrification modified the transcriptome of in vivo-derived porcine blastocysts, resulting in minor gene expression changes.

scholarly journals In Vitro and In Vivo Anti-Salmonella Evaluation of Pectin Extracts and Hydrolysates from “Cas Mango” (Spondias dulcis)

2019 ◽  
Vol 2019 ◽  
pp. 1-10 ◽  
Author(s):  
Denis Zofou ◽  
Golda Lum Shu ◽  
Josepha Foba-Tendo ◽  
Merveille Octavie Tabouguia ◽  
Jules-Clement N. Assob
Keyword(s):  
Multidrug Resistant ◽  
Positive Control ◽  
Resistant Bacteria ◽  
Therapeutic Effects ◽  
Diffusion Technique ◽  
Resistant Strains ◽  
Almost All ◽  
Broth Dilution

Background. The threat to human health posed by multidrug-resistant strains of Salmonella typhi (S. typhi) and Salmonella paratyphi (S. paratyphi) is of growing concern. Generally, there has been increasing resistance and even multidrug resistance to almost all classes of antibiotics. This has rendered treatment with antibiotics difficult and costly. The present study investigated the bioactivity of pectin and pectin hydrolysates derived from a local fruit, Spondias dulcis, against four strains of Salmonellae. Methods. Pectin was extracted from alcohol extractives-free peel by acidic hydrolysis at a temperature of 80°C for one hour at pH 2 and 4. The pectin was precipitated with 95% alcohol at an extract to alcohol ratio of 1:10 v/v. Antimicrobial activity was determined using agar well diffusion technique. The minimum inhibitory concentration (MIC) and minimum bactericidal concentration (MBC) values were determined using the broth dilution technique. An in vivo study was then carried out with the bioactive extracts against the most resistant bacteria strain, to fully establish the therapeutic effect of these extracts. Balb/C mice were used, and ciprofloxacin was the positive control antibiotic. The extracts were administered to mice at two doses, 5mg/Kg and 10mg/Kg. The efficacy of extracts in the treatment of typhoid was evaluated based on survival rate, change in body weight, and change in bacteria load. Results. Only one of the extracts (crude pectin pH 2.5) was active against all the Salmonellae by well diffusion, and the growth inhibition varied from 12mm to 15mm at100 μg/ml. Three of the extracts (crude pectin pH 2.5, pH 4, 12h hydrolysate, and pH 4, 1h hydrolysate) had MIC and MBC against all four Salmonellae strains with MIC ranging from 5.68 to 44.45 μg/ml and MBC from 11.36 to 44.45 μg/mL. Three treatments, namely, the pH4-12 hr, hydrolysate at 10mg/Kg and 5mg/Kg, and the pH4-1hr, hydrolysate at 10mg/Kg, had therapeutic effects against Salmonella infection in mice. Conclusion. The present study highlights the potential of pectin oligosaccharides as new source of anti-Salmonella drugs. Further investigations including exploration of mechanism of action of the most active pectin extracts/hydrolysates are envisaged.

scholarly journals In Vitro and In Vivo Characterization of Tebipenem, an Oral Carbapenem

2020 ◽  
Vol 64 (8) ◽  
Author(s):  
Nicole Cotroneo ◽  
Aileen Rubio ◽  
Ian A. Critchley ◽  
Chris Pillar ◽  
Michael J. Pucci
Keyword(s):  
Bacterial Resistance ◽  
Unmet Need ◽  
Multidrug Resistant ◽  
Oral Agent ◽  
Gram Negative ◽  
Improved Stability ◽  
Tebipenem Pivoxil ◽  
Tract Infections

ABSTRACT The continued evolution of bacterial resistance to the β-lactam class of antibiotics has necessitated countermeasures to ensure continued effectiveness in the treatment of infections caused by bacterial pathogens. One relatively successful approach has been the development of new β-lactam analogs with advantages over prior compounds in this class. The carbapenems are an example of such β-lactam analogs possessing improved stability against β-lactamase enzymes and, therefore, a wider spectrum of activity. However, all carbapenems currently marketed for adult patients are intravenous agents, and there is an unmet need for an oral agent to treat patients that otherwise do not require hospitalization. Tebipenem pivoxil hydrobromide (tebipenem-PI-HBr or SPR994) is an orally available prodrug of tebipenem, a carbapenem with activity versus multidrug-resistant (MDR) Gram-negative pathogens, including quinolone-resistant and extended-spectrum-β-lactamase-producing Enterobacterales. Tebipenem-PI-HBr is currently in development for the treatment of complicated urinary tract infections (cUTI). Microbiological data are presented here that demonstrate equivalency of tebipenem with intravenous carbapenems such as meropenem and support its use in infections in which the potency and spectrum of a carbapenem are desired. The results from standard in vitro microbiology assays as well as efficacy in several in vivo mouse infection models suggest that tebipenem-PI-HBr could be a valuable oral agent available to physicians for the treatment of infections, particularly those caused by antibiotic-resistant Gram-negative pathogens.

scholarly journals An Explanation of the Underlying Mechanisms for the In Vitro and In Vivo Antiurolithic Activity of Glechoma longituba

2016 ◽  
Vol 2016 ◽  
pp. 1-11 ◽  
Author(s):  
Qiang Liang ◽  
Xiaoran Li ◽  
Wangning Zhou ◽  
Yu Su ◽  
Shenbao He ◽  
...  
Keyword(s):  
Kidney Injury ◽  
Positive Control ◽  
Potassium Citrate ◽  
Positive Control Group ◽  
Control Group ◽  
Protective Effects ◽  
In Vivo Models ◽  
Glechoma Longituba

Purpose. To use in vitro and in vivo models to evaluate Glechoma longituba extract to provide scientific evidence for this extract’s antiurolithic activity. Materials and Methods. Potassium citrate was used as a positive control group. Oxidative stress (OS) markers and the expression of osteopontin (OPN) and kidney injury molecule-1 (KIM-1) were measured to assess the protective effects of Glechoma longituba. Multiple urolithiasis-related biochemical parameters were evaluated in urine and serum. Kidneys were harvested for histological examination and the assessment of crystal deposits. Results. In vitro and in vivo experiments demonstrated that treatment with Glechoma longituba extract significantly decreased calcium oxalate- (CaOx-) induced OPN expression, KIM-1 expression, and OS compared with the positive control group (P<0.05). Additionally, in vivo rats that received Glechoma longituba extract exhibited significantly decreased CaOx deposits and pathological alterations (P<0.05) compared with urolithic rats. Significantly lower levels of oxalate, creatinine, and urea and increased citrate levels were observed among rats that received Glechoma longituba (P<0.05) compared with urolithic rats. Conclusion. Glechoma longituba has antiurolithic effects due to its possible combined effects of increasing antioxidant levels, decreasing urinary stone-forming constituents and urolithiasis-related protein expression, and elevating urinary citrate levels.

scholarly journals In Vitro and In Vivo Tumor Growth Inhibition by Glutathione Disulfide Liposomes

2017 ◽  
Vol 10 ◽  
pp. 117906441769607 ◽  
Author(s):  
Satya S Sadhu ◽  
Shenggang Wang ◽  
Rakesh Dachineni ◽  
Ranjith Kumar Averineni ◽  
Yang Yang ◽  
...  
Keyword(s):  
Cancer Metastasis ◽  
Cell Function ◽  
Survival Rates ◽  
Significant Inhibition ◽  
Control Group ◽  
Tumor Growth Inhibition ◽  
Tumor Proliferation ◽  
Glutathione Disulfide

Glutathione disulfide (GSSG) is an endogenous peptide and the oxidized form of glutathione. The impacts of GSSG on cell function/dysfunction remain largely unexplored due to a lack of method to specifically increase intracellular GSSG. We recently developed GSSG liposomes that can specifically increase intracellular GSSG. The increase affected 3 of the 4 essential steps (cell detachment, migration, invasion, and adhesion) of cancer metastasis in vitro and, accordingly, produced a significant inhibition of cancer metastasis in vivo. In this investigation, the effect of GSSG liposomes on cancer growth was investigated with B16-F10 and NCI-H226 cells in vitro and with B16-F10 cells in C57BL/6 mice in vivo. Experiments were conducted to elucidate the effect on cell death through promotion of apoptosis and the effect on the cell cycle. The in vivo results with C57BL/6 mice implanted subcutaneously with B16-F10 cells showed that GSSG liposomes retarded tumor proliferation more effectively than that of dacarbazine, a chemotherapeutic drug for the treatment of melanoma. The GSSG liposomes by intravenous injection (GLS IV) and GSSG liposomes by intratumoral injection (GLS IT) showed a tumor proliferation retardation of 85% ± 5.7% and 90% ± 3.9%, respectively, compared with the phosphate-buffered saline (PBS) control group. The median survival rates for mice treated with PBS, blank liposomes, aqueous GSSG, dacarbazine, GLS IV, and GLS IT were 7, 7, 7.5, 7.75, 11.5, and 16.5 days, respectively. The effective antimetastatic and antigrowth activities warrant further investigation of the GSSG liposomes as a potentially effective therapeutic treatment for cancer.

scholarly journals Microbiological and SEM-EDS Evaluation of Titanium Surfaces Exposed to Periodontal Gel: In Vitro Study

Materials ◽  
2019 ◽  
Vol 12 (9) ◽  
pp. 1448 ◽  
Author(s):  
Sara Bernardi ◽  
Serena Bianchi ◽  
Anna Rita Tomei ◽  
Maria Adelaide Continenza ◽  
Guido Macchiarelli
Keyword(s):  
Inflammatory Diseases ◽  
Test Group ◽  
In Vitro Study ◽  
Positive Control ◽  
Control Group ◽  
Anaerobic Conditions ◽  
Titanium Surfaces ◽  
Implant Dentistry

Inflammatory diseases affecting the soft and hard tissues surrounding an implant represent a new challenge in contemporary implant dentistry. Among several methods proposed for the decontamination of titanium surfaces, the administration of topical 14% doxycycline gel seems to be a reliable option. In the present study, we evaluated the microbial effect of 14% doxycycline gel applied on titanium surfaces and exposed to human salivary microbes in anaerobic conditions. We also examined the composition of the exposed surfaces to assess the safe use of periodontal gel on titanium surfaces. Six anatase and six type 5 alloy titanium surfaces were used and divided into two groups: The test group and the positive control group. Both were cultured with human salivary samples in anaerobic conditions. On the test groups, 240 mg of periodontal gel was applied. The microbial assessment was performed with a colony-forming unit (CFU) count and matrix-assisted laser desorption ionization-time of flight (MALDI-TOF) to identify the species. The surface integrity was assessed using scanning electron microscopy-energy dispersive X-ray spectrometry (SEM-EDS). The results demonstrated the microbial efficacy of the 14% doxycycline periodontal gel and its safe use on titanium surfaces. However, the SEM observations revealed the permanence of the gel on the titanium surfaces due to the physical composition of the gel. This permanence needs to be further investigated in vivo and a final polishing protocol on the titanium surface is recommended.

Effects of Soybean Antioxidant Peptides (SAP) on SOD, GSH-Px, CAT Activity and MDA Level in Vivo

2014 ◽  
Vol 1025-1026 ◽  
pp. 476-481 ◽  
Author(s):  
Jia Wang ◽  
Rui Wen Yang ◽  
Jing Bo Liu ◽  
Song Yi Lin
Keyword(s):  
Antioxidant Activities ◽  
Positive Control ◽  
Control Group ◽  
Intragastric Administration ◽  
Antioxidant Peptides ◽  
Sod Activity ◽  
Antioxidant Defense Systems ◽  
Level I

The superoxide dismutase (SOD), glutathione peroxidase (GSH-Px) and catalase (CAT) are important ones of antioxidant defense systems. Malonaldehyde (MDA) is formed as an end product of lipid peroxidation. Soybean peptides possess antioxidant activity. In previous study, the antioxidant activities of soybean peptides were determinedin vitro. The male ICR mice were intragastrically administered by different molecular weight and dose of soybean antioxidant peptides (SAP) for 60 days. Control group was treated with saline by intragastric administration for 60 days. The SOD, GSH-Px, CAT activity and MDA level were determined in serum. The results suggested the SAP of 1-3k Da had the ability to increase significantly GSH-Px and SOD activity and decrease significantly MDA level at different dose (100 and 200 mg/kg/d) compared with control group (P < 0.05). The SAP of 3-10k Da (200 mg/kg/d) enhanced the GSH-Px activity and decreased significantly MDA level compared with the control group (P < 0.05). The SAP of 10-30k Da (200 mg/kg/d) had the lowest MDA level among all the groups. All the SAP groups and positive control group cannot increase the CAT activity.

scholarly journals In Vitro and In Vivo Activities of Newer Fluoroquinolones against Vibrio vulnificus

2002 ◽  
Vol 46 (11) ◽  
pp. 3580-3584 ◽  
Author(s):  
Hung-Jen Tang ◽  
Ming-Chung Chang ◽  
Wen-Chien Ko ◽  
Kun-Yen Huang ◽  
Chih-Lung Lee ◽  
...  
Keyword(s):  
Vibrio Vulnificus ◽  
Survival Rates ◽  
Treated Group ◽  
Inhibitory Effect ◽  
Clinical Strain ◽  
Control Group ◽  
Dilution Method ◽  
Agar Dilution Method

ABSTRACT The MICs of six fluoroquinolones as well as minocycline and cefotaxime for 46 clinical isolates of Vibrio vulnificus were determined by the agar dilution method. All the drugs tested had good activities against all isolates, with the MICs at which 90% of the isolates tested were inhibited (MIC90s) by five of the fluoroquinolones ranging between 0.03 and 0.06 μg/ml. The MIC90 of lomefloxacin, on the other hand, was 0.12 μg/ml. Time-kill studies were conducted with these agents and a clinical strain of V. vulnificus, VV5823. When approximately 5 × 105 CFU of V. vulnificus/ml was incubated with any one of the above-mentioned six fluoroquinolones at concentrations of two times the MIC, there was an inhibitory effect on V. vulnificus that persisted for more than 48 h with no noted regrowth. The efficacies of the fluoroquinolones were further evaluated in vivo in the mouse model of experimental V. vulnificus infection and compared to the efficacy of a combination therapy using cefotaxime plus minocycline. With an inoculum of 1.5 × 107 CFU, 28 (87.5%) of 32 mice in the cefotaxime-minocycline-treated group survived and 29 (91%) of the 32 mice in the moxifloxacin-treated group survived while none of the 32 mice in the control group did. With an inoculum of 3.5 × 107 CFU, the difference in survival rates among groups of 15 mice treated with levofloxacin (13 of 15), moxifloxacin (10 of 15), gatifloxacin (10 of 15), sparfloxacin (11 of 15), ciprofloxacin (12 of 15), or lomefloxacin (10 of 15) was not statistically significant while none of the 15 mice treated with saline survived. We concluded that the newer fluoroquinolones as single agents are as effective as the cefotaxime-minocycline combination in inhibiting V. vulnificus both in vitro and in vivo.

scholarly journals Preliminary study of the toxicity and radioprotective effects of zymosan in vitro and in vivo

2021 ◽  
Vol 22 (1) ◽  
Author(s):  
Yue-zhi Zhang ◽  
Shu-jing Ge ◽  
Qing-zhen Leng ◽  
Jian-jun Ma ◽  
Han-chen Liu
Keyword(s):  
Flow Cytometry ◽  
Protective Effect ◽  
Cell Viability ◽  
Treatment Time ◽  
Survival Rates ◽  
Positive Control ◽  
X Rays ◽  
Spleen Index

Abstract Background This study aimed to confirm the cytotoxicity of zymosan in vitro and in vivo and determine the appropriate treatment time and the dose of zymosan. Methods AHH-1 cells and HIECs were administered by 0, 20, 40, 80 or 160 μg/mL zymosan. The CCK-8 assay and flow cytometry were used to evaluate the cell viability and apoptosis 24 h, 48 h, and 72 h after administration. Furthermore, 12 h before irradiation, the cells were treated with 0, 5, 10, or 20 μg/mL zymosan and then irradiated with 4 Gy X-rays. Cell viability and apoptosis were measured by the CCK-8 assay and flow cytometry at 24 h. In addition, the protective effect of zymosan against radiation in vitro was compared to that of 20 μg/mL LPS. In vivo, weight, the spleen index, and the thymus index were measured to evaluate the toxicity of 0, 5, 10, 20, and 10 mg/kg zymosan. In addition, rats were treated with 0, 2, 4, 8, or 10 mg/kg zymosan and then irradiated with 7 Gy X-rays. The survival rate, organ index were evaluated. The protective effect of zymosan against radiation in vivo was compared to that of 10 mg/kg LPS a positive control. Results The viability and apoptosis of cells treated with different doses and treatment times of zymosan were not different from those of control cells (p < 0.05). Furthermore, cell viability and apoptosis were clearly improved after zymosan preadministration (p < 0.05). The radioprotective effect of zymosan was dose-dependent. In addition, the viability of cells pretreated with zymosan was higher than that of cells pretreated with LPS, and the apoptosis rate of zymosan-treated cells was lower than that of cells pretreated with LPS (p < 0.05). In vivo, weight, the spleen index and the thymus index were significantly decreased by zymosan at a concentration of 20 mg/kg (p < 0.05). Further experiments showed that the concentration at which zymosan exerted radioprotective effects was 10 mg/kg. The survival curves in the irradiated rats were barely separated between the LPS treatment and zymosan treatment. Conclusion Zymosan administration before radiation exposure significantly increased cell viability and the survival rates of rats.

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