scholarly journals In vivo efficacy of trovafloxacin (CP-99,217), a new quinolone, in experimental intra-abdominal abscesses caused by Bacteroides fragilis and Escherichia coli.

1997 ◽  
Vol 41 (3) ◽  
pp. 583-586 ◽  
Author(s):  
H Thadepalli ◽  
U Reddy ◽  
S K Chuah ◽  
F Thadepalli ◽  
C Malilay ◽  
...  
Keyword(s):  
Escherichia Coli ◽  
Mortality Rate ◽  
Single Agent ◽  
Bacteroides Fragilis ◽  
Response To Treatment ◽  
Control Group ◽  
Cure Rate ◽  
Necrosis Factor Alpha ◽  
Abdominal Abscesses

The efficacy of trovafloxacin in treating Bacteroides fragilis and Escherichia coli infections was investigated and compared to the efficacy of combined clindamycin and gentamicin therapy in an experimental model of intra-abdominal abscesses in rats. Rats were treated with different doses of CP-116,517-27, a parenteral prodrug of trovafloxacin. Response to treatment was evaluated by mortality rate and elimination of infection (cure rate). Mortality in the control group was 85.4%, whereas in rats treated with trovafloxacin, it was close to 0%. The highest cure rate (89.3%) resulted from the administration of 40 mg of CP-116,517-27 per kg of body weight three times a day (TID) for 10 days (equivalent to 18.15 mg of active drug trovafloxacin per rat per day). The therapeutic response with trovafloxacin was comparable to that of a combination therapy of clindamycin (75 mg/kg) plus gentamicin (20 mg/kg) TID (cure rate, 74%; mortality rate, 5%). The measured peak levels of trovafloxacin in serum and abscess pus were 2.6 +/- 0.3 and 5.2 micrograms/ml, respectively. The tumor necrosis factor alpha levels in the untreated animals were high compared to those for rats treated with trovafloxacin or clindamycin plus gentamicin. These results demonstrate that trovafloxacin as a single agent appears to be as successful as clindamycin plus gentamicin in the treatment of experimental intra-abdominal abscesses in rats.

scholarly journals Optimized 5-Fluorouridine Prodrug for Co-Loading with Doxorubicin in Clinically Relevant Liposomes

Pharmaceutics ◽  
2021 ◽  
Vol 13 (1) ◽  
pp. 107
Author(s):  
Debra Wu ◽  
Douglas Vogus ◽  
Vinu Krishnan ◽  
Marta Broto ◽  
Anusha Pusuluri ◽  
...  
Keyword(s):  
Single Agent ◽  
Molar Ratio ◽  
Control Group ◽  
Drug Tolerability ◽  
Breast Cancer Model ◽  
In Vivo Testing ◽  
Chemical Profiles ◽  
Hydrolysis Of ◽  
Doxorubicin Liposomes

Liposome-based drug delivery systems have allowed for better drug tolerability and longer circulation times but are often optimized for a single agent due to the inherent difficulty of co-encapsulating two drugs with differing chemical profiles. Here, we design and test a prodrug based on a ribosylated nucleoside form of 5-fluorouracil, 5-fluorouridine (5FUR), with the final purpose of co-encapsulation with doxorubicin (DOX) in liposomes. To improve the loading of 5FUR, we developed two 5FUR prodrugs that involved the conjugation of either one or three moieties of tryptophan (W) known respectively as, 5FUR−W and 5FUR−W3. 5FUR−W demonstrated greater chemical stability than 5FUR−W3 and allowed for improved loading with fewer possible byproducts from tryptophan hydrolysis. Varied drug ratios of 5FUR−W: DOX were encapsulated for in vivo testing in the highly aggressive 4T1 murine breast cancer model. A liposomal molar ratio of 2.5 5FUR−W: DOX achieved a 62.6% reduction in tumor size compared to the untreated control group and a 33% reduction compared to clinical doxorubicin liposomes in a proof-of-concept study to demonstrate the viability of the co-encapsulated liposomes. We believe that the new prodrug 5FUR−W demonstrates a prodrug design with clinical translatability by reducing the number of byproducts produced by the hydrolysis of tryptophan, while also allowing for loading flexibility.

scholarly journals Mechanism of KLF4 Protection against Acute Liver Injury via Inhibition of Apelin Signaling

2019 ◽  
Vol 2019 ◽  
pp. 1-10 ◽  
Author(s):  
Weitao Ji ◽  
Hongyun Shi ◽  
Hailin Shen ◽  
Jing Kong ◽  
Jiayi Song ◽  
...  
Keyword(s):  
Liver Injury ◽  
Signaling Pathway ◽  
Acute Liver Injury ◽  
Control Group ◽  
Necrosis Factor Alpha ◽  
Protein Levels ◽  
Klf4 Expression ◽  
Mrna And Protein Expression

Krüppel-like factor 4 (KLF4) is a key transcription factor that regulates genes involved in the proliferation or differentiation in different tissues. Apelin plays roles in cardiovascular functions, metabolic disease, and homeostatic disorder. However, the biological function of apelin in liver disease is still ongoing. In this study, we investigated the mechanism of KLF4-mediated protection against acute liver injury via the inhibition of the apelin signaling pathway. Mice were intraperitoneally injected with carbon tetrachloride (CCl4; 0.2 mL dissolved in 100 mL olive oil, 10 mL/kg) to establish an acute liver injury model. A KLF4 expression plasmid was injected through the tail vein 48 h before CCl4 treatment. In cultured LX-2 cells, pAd-KLF4 or siRNA KLF4 was overexpressed or knockdown, and the mRNA and protein levels of apelin were determined. The results showed that the apelin serum level in the CCl4-injected group was higher than that of control group, and the expression of apelin in the liver tissues was elevated while KLF4 expression was decreased in the CCl4-injected group compared to the KLF4-plasmid-injected group. HE staining revealed serious hepatocellular steatosis in the CCl4-injected mice, and KLF4 alleviated this steatosis in the mice injected with KLF4 plasmid. In vitro experiments showed that tumor necrosis factor-alpha (TNF-α) could downregulate the transcription and translation levels of apelin in LX-2 cells and also upregulate KLF4 mRNA and protein expression. RT-PCR and Western blotting showed that the overexpression of KLF4 markedly decreased basal apelin expression, but knockdown of KLF4 restored apelin expression in TNF-α-treated LX-2 cells. These in vivo and in vitro experiments suggest that KLF4 plays a key role in inhibiting hepatocellular steatosis in acute liver injury, and that its mechanism might be the inhibition of the apelin signaling pathway.

Activity of metronidazole on Bacteroides fragilis and/or Escherichia coli in vitro and in vivo

1981 ◽  
Vol 7 (3) ◽  
pp. 257-267 ◽  
Author(s):  
Margareta Rylander ◽  
Slig E. Holm ◽  
John-Erik Brorson ◽  
Jan Johnsson ◽  
Ragnar Norrby
Keyword(s):  
Escherichia Coli ◽  
Bacteroides Fragilis

Yogurt Containing Bioactive Molecules Produced by Lactobacillus acidophilus La-5 Exerts a Protective Effect against Enterohemorrhagic Escherichia coli in Mice

2012 ◽  
Vol 75 (10) ◽  
pp. 1796-1805 ◽  
Author(s):  
MOHAMED ZEINHOM ◽  
ANGELA M. TELLEZ ◽  
VERONIQUE DELCENSERIE ◽  
A. M. EL-KHOLY ◽  
S. H. EL-SHINAWY ◽  
...  
Keyword(s):  
Escherichia Coli ◽  
Protective Effect ◽  
Lactobacillus Acidophilus ◽  
Virulence Genes ◽  
Clinical Manifestations ◽  
Enterohemorrhagic Escherichia Coli ◽  
Bioactive Molecules ◽  
Necrosis Factor Alpha ◽  
In Vivo Effects

An active fraction extracted from Lactobacillus acidophilus La5 cell-free spent medium (LAla-5AF) was incorporated in a dairy matrix and tested to assess its antivirulent effect against enterohemorrhagic Escherichia coli (EHEC). Mice in experimental groups were fed for 4 days with yogurt supplemented with LAla-5AF. On the fifth day, mice were challenged with a single dose (107 CFU per mouse) of E. coli O157:H7. The clinical manifestations of the infection were significantly less severe in mice fed the yogurt supplemented with LAla-5AF. EHEC attachment and colonization was attenuated by LAla-5AF. Tumor necrosis factor alpha production was down-regulated, which might indicate a protective effect in the kidney during EHEC infection. To investigate the mechanisms associated with the in vivo effects observed, LAla-5AF was tested by reverse transcription real-time PCR to confirm its effects on the expression of several virulence genes of EHEC O157. The results showed that these fractions were able to down-regulate several virulence genes of EHEC, including stxB2, qseA, luxS, tir, ler, eaeA, and hlyB.

scholarly journals Forsythiaside attenuates Escherichia coli lipopolysaccharide-induced liver acute inflammatory response in chicken

2019 ◽  
Vol 17 ◽  
pp. 205873921982679 ◽  
Author(s):  
Jingwen Bai ◽  
Xiaoting Wang ◽  
Meiqi Hao ◽  
He Li ◽  
Guangdong Cheng ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Escherichia Coli ◽  
Inflammatory Response ◽  
Mrna Expression ◽  
Control Group ◽  
Interleukin 17 ◽  
Acute Inflammatory Response ◽  
Total Proteins ◽  
Necrosis Factor Alpha ◽  
Escherichia Coli Lipopolysaccharide

This study investigated the effects of forsythiaside on the acute inflammatory response induced by Escherichia coli lipopolysaccharide (LPS) in liver of broiler chickens. Fifteen-day-old chickens were randomly assigned to three groups (n = 20 for each group, orally treated with 0, 30, or 60 mg/kg BW of forsythiaside) for 7 days. At 21 days of age, the chickens were intravenously injected with either LPS (200 μg/kg BW) or sterile saline (200 μg/kg BW, control group). All the chickens were humanely euthanized by cervical dislocation 2 h after the LPS injection. The results showed that the injection of LPS induced some indexes, including total proteins, nitric oxide (NO), interleukin-1beta (IL-1β), interleukin-6 (IL-6), and interleukin-17 (IL-17) production ( P < 0.05) and increased the mRNA expression of LPS-induced tumor necrosis factor-alpha (LITAF), IL-1β, IL-17, IL-6, and inducible nitric oxide synthase (iNOS) ( P < 0.05). Forsythiaside supplementation alleviated the LPS-induced inflammatory response by inhibiting the production of total proteins, NO, LITAF, IL-1β, IL-17, and IL-6 and down-regulating the mRNA expression of pro-inflammatory cytokines and iNOS. In conclusion, forsythiaside is a potential treatment for LPS-induced liver acute inflammation in chicken.

Antitumor effect of the combination of proteasome inhibitor (Pi) and histone deacytelase inhibitor (HDACi) in breast cancer (BC).

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. e23156-e23156
Author(s):  
Joseph Kannarkatt ◽  
Omar Abed Alkharabsheh ◽  
Burra V Madhukar ◽  
Cheryl Leece ◽  
Deimante Tamkus
Keyword(s):  
Cell Viability ◽  
Antitumor Effect ◽  
Synergistic Effects ◽  
Single Agent ◽  
Response To Treatment ◽  
Combination Group ◽  
Control Group ◽  
Synergistic Activity ◽  
Tumor Spheroid ◽  
Mcf7 Cells

e23156 Background: Previous studies demonstrated the efficacy of HDACi and Pi as single agents in BC. The synergistic combination of HDACi and Pi has been shown to be effective in clinical studies in other tumor types, including multiple myeloma, non-small cell lung cancer, and pancreatic cancer. In this in vitro study, we explored the hypothesis that combination of these two agents may improve overall antitumor effect in BC. Methods: In the experiment, we used 3 BC cell lines: MCF7 (ER+), MDA-MB-231 (ER-), and BCSV (isolated from metastatic ER+ tumor which lost ER expression with disease progression). The cells were treated with carfilzomib (Pi) and scriptaid (HDACi) as single agents and in combination. Cell viability was determined using MTT assay, and combination indexes were determined using CalcuSyn software. Additionally, cells were cultured in 3D tumor spheroid model, and response to treatment was assessed on day 5, 10, 15 and 20. Results: In comparison with control, single agent HDACi, single agent Pi and combination HDACi/Pi increased cell viability by 6%, decreased cell viability by 60% and by 69% respectively (p < 0.0001) in MCF7 cells; and decreased cell viability by 25%, 59% and 66% respectively (p = 0.0061) in BCSV cells. The combination indexes for most HDACi and Pi combinations were lower than 1.0, indicating synergistic effects in MCF-7 and BCSV cells but not in MDA-MB-231 cells. In 3D cultures, the combination of carfilzomib 1µM and scriptaid 10µM led to significant reduction of tumor spheroid size as compared to single agent. By day 20, BCSV tumor spheroid size increased by 258% in control group and by 50% in Pi, decreased by 17% in HDACi and by 30% in HDACi/Pi combination group (p < 0.0001). Conclusions: Combination of HDACi and Pi exhibited synergistic activity in both MCF7 and BCSV monolayer cultures. Additionally, combination HDACi and Pi significantly decreased 3D tumor spheroid size as compared to either single agent alone. Further study is needed to evaluate the mechanisms of Pi/HDACi combination in estrogen-mediated BC tumorigenesis.

Combination Therapy With Remdesivir, Dexamethasone, and Tocilizumab in Patients With Severe Corona Virus Disease 2019 in Clinical Practice

2020 ◽  
Author(s):  
Takehiro Izumo ◽  
Minoru Inomata ◽  
Naoyuk Kuse ◽  
Nobuyasu Awano ◽  
Mari Tone ◽  
...  
Keyword(s):  
Clinical Practice ◽  
Mortality Rate ◽  
Combination Therapy ◽  
Adverse Events ◽  
Combination Treatment ◽  
Virus Disease ◽  
Medical Center ◽  
Single Agent ◽  
Red Cross ◽  
Control Group

Abstract BackgroundThe use of several promising drugs for coronavirus disease 2019 (COVID-19) has emerged. However, considering the pathophysiology of COVID-19, the effect of a single agent is limited. Hence, the current study aimed to compare the clinical outcomes between patients who received combination treatment with remdesivir, dexamethasone, and tocilizumab (RDT) and those who did not.MethodsPatients who received combination therapy with RDT at Japanese Red Cross Medical Center were included in the RDT group, and those who did not in the control group. The mortality rate and presence of severe adverse events were compared between the two groups.ResultsIn total, 46 patients (n = 29, control group and n = 17, RDT group) with severe COVID-19 were enrolled in this study. The 28-day mortality rate was significantly lower in the RDT group than in the control group, with 1 (6%) and 9 (31%) deaths recorded, respectively (P = 0.04). Further, both groups did not present with severe adverse events.ConclusionsInformation on the outcomes of combination therapy with RDT was considered useful for the treatment of severe COVID-19.

Triple Combinations of the HDAC Inhibitor Panobinostat (LBH589) + Dexamethasone with Either Lenalidomide or Bortezomib Are Highly Effective in a Multiple Myeloma Mouse Model.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 1514-1514
Author(s):  
Enrique M. Ocio ◽  
David Vilanova ◽  
Laura San-Segundo ◽  
Patricia Maiso ◽  
Mercedes Garayoa ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Median Survival ◽  
Hdac Inhibitor ◽  
Single Agent ◽  
Body Weight Loss ◽  
Control Group ◽  
Synergistic Activity ◽  
Median Volume

Abstract Introduction Panobinostat (LBH589) is a novel histone deacetylase (HDAC) inhibitor being evaluated in clinical trials in hematological and solid malignancies. In multiple myeloma (MM), investigators have demonstrated its in vitro antimyeloma effect in cell lines and patients cells. Cancer treatment is typically based on the concept of combining agents with different mechanisms of action to overcome drug resistance. This was the rationale of the present study in which the in vitro and in vivo benefit of combinations of pabinostat with conventional antimyeloma agents has been explored. Material and Methods The potential in vitro synergism of pabinostat with 6 antimyeloma agents (melphalan, doxorubicin, dexamethasone, thalidomide, lenalidomide, bortezomib) was analyzed in MM1S cell line. The two most favorable combinations were tested in 120 NOD/SCID mice implanted with a human subcutaneous plasmocytoma. Mice were randomized into 12 treatment groups. Drugs were given ip, 5 days/week × 7 weeks. Doses were: pabinostat: 10 mg/Kg × 3 weeks and 5 mg/Kg afterwards; dexamethasone (D): 1 mg/Kg; bortezomib (B): 0.1 mg/Kg; and lenalidomide (L): 15 mg/Kg. Tumor volumes clinical features and weight were monitored three times a week. Mice were sacrificed when their tumors reached 2 cm. Immunohistochemistry was performed in selected tumors. Results Three agents potentiated the effect of pabinostat in vitro: bortezomib, dexamethasone and, to a lesser extent, lenalidomide. Moreover, the triple combination of pabinostat+L+D and pabinostat+B+D resulted in high synergistic activity. These studies provided the rationale for testing these combinations in vivo: Single agent pabinostat at a dose of 10 mg/Kg completely abrogated the growth of plasmocytomas without significant toxicity. In fact, after three weeks of treatment, the median volume of tumors in the pabinostat group was 163±75 mm3 as compared to 1891±1182 mm3 in the control group (p=0.001). Immunohistochemistry of pabinostat treated tumors revealed a decrease in BrdU uptake, an increase in histone acetylation and phosphorylation of H2AX suggesting DNA damage. This antiproliferative action was associated with survival advantage: median survival 70±1.8 vs 30±2.1 days (p&lt;0.001) for the pabinostat and vehicle treated groups respectively. Subsequently the dose of pabinostat was decreased by 50% in order to gain further insights into the potential advantage of the combinations. Interestingly, the addition of D and suboptimal doses of either B or L significantly improved the antimyeloma effect of pabinostat. In this sense, median survival increased up to 86±2.6 days in pabinostat+D+B (p&lt;0.001) and 88±1.2 days for pabinostat+D+L (p&lt;0.001). The efficacy of these triple combinations was significantly higher than any of the respective double combinations (pabinostat+D; pabinostat+B; pabinostat+L; B+D; L+D). Some of these combinations (including or not pabinostat) initially induced a slight toxicity (5%–15% body weight loss) which spontaneously recovered after the third week of treatment. Conclusion Combinations of pabinostat + dexamethasone with either bortezomib or lenalidomide are safe and display promising antimyeloma efficacy. This study provides the rationale for the clinical development of triple combinations of these drugs to improve the outcome of MM patients.

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