Development and Comparative Anti-Microbial Evaluation of Lipid Nanoparticles and Nanoemulsion of Polymyxin B

2006 ◽  
Vol 6 (9) ◽  
pp. 2986-2990 ◽  
Author(s):  
A. S. Pattani ◽  
S. D. Mandawgade ◽  
Vandana B. Patravale
Keyword(s):  
Polymyxin B ◽  
Lipid Nanoparticles ◽  
Polydispersity Index ◽  
Significant Activity ◽  
Dependent Manner ◽  
Potent Effect ◽  
Globule Size ◽  
Gram Negative Bacteremia ◽  
Comparable Activity ◽  
Drug Free

Polymyxin B is a decapeptide, mainly used for the treatment of gram-negative bacteremia. It was anticipated that a prolongation of release may lead to a more efficacious therapy. Lipid nanoparticles and nanoemulsion were formulated and comparatively evaluated for their properties. Lipid nanopraticles of Polymyxin B Sulphate with a mean particle size of 186.9 nm (Polydispersity Index 0.235) were prepared by nano-precipitation technique and nanoemulsion was prepared under the conditions of spontaneous formation with a mean globule size 125.0 nm (Polydispersity Index 0.291). The lipid nanoparticles were screened for lipid load from 0.1–1% along with 1–10% surfactant while in the optimization of nanoemulsion different ratios of oil, surfactant, and co-surfactant were evaluated. The developed systems were taken up for comparative anti-microbial study against a sensitive strain of E. coli using Turbidimetry as the method for monitoring the growth of microorganisms in a time dependent manner. Results of the study using ANOVA revealed an initial comparable activity with no statistical difference between the free drug, lipid nanoparticles, and the nanoemulsion. The anti-microbial effect was significantly sustained by lipid nanoparticles over a period of 18 hr but could not be sustained in case of nanoemulsion after 12 hr. Further, in order to assess anti-microbial activity of the developed delivery templates, a similar study was carried out using the lipid nanoparticles and nanoemulsion without the incorporation of drug. The results showed only a mild anti-microbial action for drug-free lipid nanoparticles but significant activity was exerted by drug-free nanoemulsion against plain drug throughout the study. It was concluded that the developed lipid nanoparticles and nanoemulsion are promising delivery vectors for the anti-microbial drugs. Further, lipid nanoparticles could give an initial as well as sustained effect while the nanoemulsion was capable of exerting potent effect for a shorter period of time.

scholarly journals Ceftazidime/avibactam versus standard-of-care agents against carbapenem-resistant Enterobacteriaceae harbouring blaKPC in a one-compartment pharmacokinetic/pharmacodynamic model

2018 ◽  
Vol 73 (9) ◽  
pp. 2405-2410 ◽  
Author(s):  
Katie E Barber ◽  
Jason M Pogue ◽  
Henderson D Warnock ◽  
Robert A Bonomo ◽  
Keith S Kaye
Keyword(s):  
Klebsiella Oxytoca ◽  
Growth Control ◽  
Standard Of Care ◽  
Polymyxin B ◽  
Initial Inoculum ◽  
Comparable Activity ◽  
Free Growth ◽  
Klebsiella Pneumoniae Carbapenemases ◽  
Drug Free

AbstractBackground‘Last-line’ antimicrobial usage has promoted the emergence of MDR bacteria. Production of Klebsiella pneumoniae carbapenemases (KPCs) is increasingly common and leads to resistance to most antimicrobials. However, ceftazidime/avibactam demonstrates activity against KPC-producing strains. Ceftazidime/avibactam in the empirical setting remains unknown.MethodsStrains underwent genetic analysis evaluating blaKPC presence/production and MICs were determined. Four strains were assessed in an in vitro, one-compartment pharmacokinetic (PK)/pharmacodynamic (PD) model for 96 h. The following bolus dosing exposures were tested: 2.5 g of ceftazidime/avibactam every 8 h, 2 g of meropenem every 8 h, 1.25 mg/kg polymyxin B every 12 h, amikacin ‘once-daily dosing’ (peak of 70–80 mg/L), tigecycline at 200 mg ×1 dose followed by 100 mg every 12 h, and a drug-free growth control.ResultsThirty blaKPC-producing strains were evaluated; 97% of strains were ceftazidime/avibactam susceptible with MIC50/MIC90 values of 0.38/1.5 mg/L (range 0.032–16 mg/L). Two K. pneumoniae strains, one Klebsiella oxytoca strain and one Citrobacter freundii strain underwent further analysis in PK/PD models. Ceftazidime/avibactam displayed potent activity with a reduction of 4.23 ± 0.42 cfu/mL from the initial inoculum at 96 h. Against susceptible isolates, amikacin displayed similar activity compared with ceftazidime/avibactam at 96 h, although this was not demonstrated against all strains. Polymyxin B produced comparable activity to ceftazidime/avibactam against two strains. Neither meropenem nor tigecycline produced effective killing and were comparable to the drug-free growth control at 96 h.Conclusionsbla KPC-producing organisms demonstrated susceptibility to ceftazidime/avibactam and bactericidal activity was observed in the PK/PD model. Based on these data, ceftazidime/avibactam is a valuable agent for treating KPC-producing organisms and should be considered for treatment of infections caused by these pathogens.

Bacteriophages immunomodulate the response of monocytes

2021 ◽  
pp. 153537022199515
Author(s):  
Lídia Perea ◽  
Lorena Rodríguez-Rubio ◽  
Juan C Nieto ◽  
Carlos Zamora ◽  
Elisabet Cantó ◽  
...  
Keyword(s):  
Cytokine Production ◽  
Statistical Significance ◽  
Control Sample ◽  
Polymyxin B ◽  
Dependent Manner ◽  
Direct Role ◽  
Gram Positive Bacteria ◽  
Hla Dr ◽  
Tnf Α

Bacteriophages are present in fluids from cirrhosis patients. However, their effect on the immune response is unknown. In this work, we explore the role of phages in the phenotype, function, and cytokine production of monocytes. We stimulated healthy monocytes with five different butanol-purified phage suspensions infective for Gram-negative and Gram-positive bacteria. We studied the expression of the monocyte markers involved in lipopolysaccharide recognition (LPS; CD14), antigen presentation (HLA-DR) and co-stimulation (CD86), and the concentration of induced cytokines (TNF-α, IFN-α, and IL-10) by phages. To confirm the direct role of phages without the interference of contaminating soluble LPS in phage suspensions, polymyxin B was added to the cell cultures. Phagocytosis experiments were assessed by flow cytometry using labeled phage suspensions. We observed that butanol-purified phages reduced the surface levels of CD14 and CD86 in monocytes and increased the secreted levels of TNF-α and IL-10 compared with the control sample containing only butanol buffer. All phage suspensions showed downregulation of HLA-DR expression but only Staphylococcus aureus phage contaminated with Escherichia coli reached statistical significance. The addition of polymyxin B did not restore the monocytic response induced by phages, suggesting that the effect was not caused by the presence of LPS. Monocytes were able to phagocyte phages in a dose- and time-dependent manner. To conclude, the phagocytosis of butanol-purified phages altered the phenotype and cytokine production of monocytes suggesting they become tolerogenic.

Amitriptyline and imipramine inhibit the release of acetylcholine from parasympathetic nerve terminals in the rat iris

1984 ◽  
Vol 62 (7) ◽  
pp. 857-859 ◽  
Author(s):  
J. S. Richardson ◽  
T. G. Mattio ◽  
E. Giacobini
Keyword(s):  
Nerve Terminals ◽  
Dependent Manner ◽  
Parasympathetic Nerve ◽  
Drug Concentrations ◽  
Release Of Acetylcholine ◽  
Rat Iris ◽  
Anticholinergic Side Effects ◽  
Dose Dependent ◽  
Drug Free

The electrically stimulated release of [3H]acetylcholine from the parasympathetic nerve terminals of the rat iris in vitro is increased in a dose-dependent manner by scopolamine but is decreased by the tricyclic antidepressants amitriptyline and imipramine. The increased release in the presence of scopolamine seems to be due to the blockade of a presynaptic muscarinic autoreceptor that, in the drug-free state, inhibits the release of acetylcholine. However, at drug concentrations that should have comparable antimuscarinic potency, the antidepressants inhibit the release of acetylcholine. This suggests that the anticholinergic side effects of the antidepressants may be due to the reduced release of acetylcholine from parasympathetic nerve terminals as well as a possible direct postsynaptic muscarinic receptor blocking action. Whatever the mechanism of this action, the antidepressants do not have the same effect as scopolamine at the presynaptic muscarinic autoreceptor in the rat iris.

In Vitro Attenuation of Thermal-Induced Protein Denaturation by Aerial Parts of Artemisia scoparia

2014 ◽  
Vol 20 (1) ◽  
pp. 9-12 ◽  
Author(s):  
Murad Ali Khan ◽  
Haroon Khan ◽  
Shafiq Ahmad Tariq ◽  
Samreen Pervez
Keyword(s):  
Crude Extract ◽  
Protein Denaturation ◽  
Total Flavonoid ◽  
Significant Activity ◽  
Dependent Manner ◽  
Concentration Dependent Manner ◽  
Aqueous Fraction ◽  
Denatured Protein ◽  
Aerial Parts ◽  
Artemisia Scoparia

The goal of this study was to explore the aerial parts of Artemisia scoparia (crude extract, total flavonoid contents, and aqueous fraction) for protein denaturation potential. The crude extract provoked marked attenuation of thermal-induced denatured protein in a concentration-dependent manner with maximum inhibition of 54.05 μg/mL at 500 μg/mL and IC50 of 449.66 μg/mL. When total flavonoid contents were studied, it illustrated most dominant activity concentration dependently with maximum amelioration of 62.16 μg/mL at 500 μg/mL and IC50 of 378.35 μg/mL. The aqueous fraction also exhibited significant activity with maximum of 56.75% inhibition at 500 μg/mL and IC50 of 445.10 μg/mL. It can be concluded on the basis of the results that the crude extract, flavonoid contents, and aqueous fraction of the plant possessed significant inhibition on thermal-induced denatured protein.

SEB is cytotoxic and alters EC barrier function through protein tyrosine phosphorylation in vitro

1997 ◽  
Vol 273 (1) ◽  
pp. L31-L39 ◽  
Author(s):  
W. N. Campbell ◽  
M. Fitzpatrick ◽  
X. Ding ◽  
M. Jett ◽  
P. Gemski ◽  
...  
Keyword(s):  
Barrier Function ◽  
Tyrosine Kinases ◽  
Polymyxin B ◽  
Time Dependent ◽  
Dependent Manner ◽  
Gap Formation ◽  
Barrier Dysfunction ◽  
Effector Cells ◽  
Protein Tyrosine

We studied whether Staphylococcal enterotoxin B (SEB) has direct effects on endothelial cells (EC) in the absence of effector cells or their products. Bovine or human pulmonary artery EC were grown to confluence on filters mounted in chemotaxis chambers. Barrier function was assessed by placing [14C]bovine serum albumin in the chamber and sampling the lower well for 14C activity. SEB exposures induced a significant (P < 0.001) dose- and time-dependent increase in albumin flux across both bovine and human EC monolayers. Albumin flux was temperature dependent, and cycloheximide pretreatment of the monolayers did not block the SEB-induced increase in permeability. Preincubation of SEB with trypsin or anti-SEB antibody significantly (P < 0.0001) reduced the effect, whereas pretreatment with polymyxin B did not. SEB at > or = 10 micrograms/ml significantly (P < 0.03) increased EC injury as measured by 51Cr release in a dose- and time-dependent manner. Herbimycin and genistein, inhibitors of protein tyrosine kinases, each protected against SEB-induced cytotoxicity, barrier dysfunction, and intercellular gap formation. We conclude that SEB perturbs endothelial barrier function and viability in the absence of effector cells or their mediators.

scholarly journals Antineuroinflammatory Activities and Neurotoxicological Assessment of Curcumin Loaded Solid Lipid Nanoparticles on LPS-Stimulated BV-2 Microglia Cell Models

Molecules ◽  
2019 ◽  
Vol 24 (6) ◽  
pp. 1170 ◽  
Author(s):  
Palanivel Ganesan ◽  
Byungwook Kim ◽  
Prakash Ramalingam ◽  
Govindarajan Karthivashan ◽  
Vishnu Revuri ◽  
...  
Keyword(s):  
Solid Lipid Nanoparticles ◽  
Lipid Nanoparticles ◽  
Brain Cells ◽  
No Production ◽  
Dependent Manner ◽  
Microglia Cell ◽  
Solid Lipid ◽  
Cytokine Levels ◽  
The Central Nervous System ◽  
Dose Dependent

Curcumin, which is a potential antineuroinflammatory and neuroprotective compound, exhibits poor bioavailability in brain cells due to its difficulty in crossing the blood–brain barrier and its rapid metabolism during circulation, which decreases its efficacy in treating chronic neuroinflammatory diseases in the central nervous system. The bioavailability and potential of curcumin can be improved by using a nanodelivery system, which includes solid lipid nanoparticles. Curcumin-loaded solid lipid nanoparticles (SLCN) were efficiently developed to have a particle size of about 86 nm and do not exhibit any toxicity in the endothelial brain cells. Furthermore, the curcumin-loaded solid lipid nanoparticles (SLCN) were studied to assess their efficacy in BV-2 microglial cells against LPS-induced neuroinflammation. The SLCN showed a higher inhibition of nitric oxide (NO) production compared to conventional curcumin in a dose-dependent manner. Similarly, the mRNA and proinflammatory cytokine levels were also reduced in a dose-dependent manner when compared to those with free curcumin. Thus, SLCN could be a potential delivery system for curcumin to treat microglia-mediated neuroinflammation.

Effect of Conjugated Bile Salts on Antibiotic Susceptibility of Bile Salt–Tolerant Lactobacillus and Bifidobacterium Isolates

2000 ◽  
Vol 63 (10) ◽  
pp. 1369-1376 ◽  
Author(s):  
WILLIAM P. CHARTERIS ◽  
PHILLIP M. KELLY ◽  
LORENZO MORELLI ◽  
J. KEVIN COLLINS
Keyword(s):  
Bile Salt ◽  
Antibiotic Susceptibility ◽  
Bile Salts ◽  
Polymyxin B ◽  
Drug Combinations ◽  
Penicillin G ◽  
Dependent Manner ◽  
Salt Tolerant ◽  
Intrinsic Resistance ◽  
Conjugated Bile Salts

Virtually every antibiotic may cause in vivo alterations in the number, level, and composition of the indigenous microbiotae. The degree to which the microbiotae are disturbed depends on many factors. Although bile may augment antibiotic activity, studies on the effect of bile on the antibiotic susceptibility of indigenous and exogenous probiotic microorganisms are lacking. It was against this background that the antibiotic susceptibility of 37 bile salt–tolerant Lactobacillus and 11 Bifidobacterium isolates from human and other sources was determined in the presence of 0.5% wt/wt oxgall (conjugated bile salts). Oxgall did not affect the intrinsic resistance of lactobacilli to metronidazole (5 μg), vancomycin (30 μg), and cotrimoxazole (25 μg), whereas it resulted in a complete loss of resistance to polymyxin B (300 μg) and the aminoglycosides gentamicin (10 μg), kanamycin (30 μg), and streptomycin (10 μg) for most strains studied (P &lt; 0.001). Oxgall did not affect the intrinsic resistance of bifidobacteria to metronidazole and vancomycin, whereas polymyxin B and co-trimoxazole resistance was diminished (P &lt; 0.05) and aminoglycoside resistance was lost (P &lt; 0.001). Seven lactobacilli, but no bifidobacteria strain, showed unaltered intrinsic antibiotic resistance profiles in the presence of oxgall. Oxgall affected the extrinsic susceptibility of lactobacilli and bifidobacteria to penicillin G (10 μg), ampicillin (10 μg), tetracycline (30 μg), chloramphenicol (30 μg), erythromycin (15 μg), and rifampicin (5 μg) in a source- and strain-dependent manner. Human strain–drug combinations of lactobacilli (P &lt; 0.05) and bifidobacteria (P &lt; 0.01) were more likely to show no change or decreased susceptibility compared with other strain-drug combinations. The antimicrobial activity spectra of polymyxin B and the aminoglycosides should not be considered limited to gram-negative bacteria but extended to include gram-positive genera of the indigenous and transiting microbiotae in the presence of conjugated bile salts. Those lactobacilli (7 of 37) that show unaltered intrinsic and diminished extrinsic antibiotic susceptibility in the presence of oxgall may possess greater upper gastrointestinal tract transit tolerance in the presence of antibiotics.

scholarly journals Muscle overexpression of Klf15 via an AAV8-Spc5-12 construct does not provide benefits in spinal muscular atrophy mice

Gene Therapy ◽  
2020 ◽  
Vol 27 (10-11) ◽  
pp. 505-515
Author(s):  
Nina Ahlskog ◽  
Daniel Hayler ◽  
Anja Krueger ◽  
Sabrina Kubinski ◽  
Peter Claus ◽  
...  
Keyword(s):  
Spinal Muscular Atrophy ◽  
Muscular Atrophy ◽  
Treatment Options ◽  
Survival Motor Neuron ◽  
Significant Activity ◽  
Dependent Manner ◽  
Patient Response ◽  
High Gene Expression ◽  
Virus Serotype ◽  
High Gene

AbstractSpinal muscular atrophy (SMA) is a neuromuscular disease caused by loss of the survival motor neuron (SMN) gene. While there are currently two approved gene-based therapies for SMA, availability, high cost, and differences in patient response indicate that alternative treatment options are needed. Optimal therapeutic strategies will likely be a combination of SMN-dependent and -independent treatments aimed at alleviating symptoms in the central nervous system and peripheral muscles. Krüppel-like factor 15 (KLF15) is a transcription factor that regulates key metabolic and ergogenic pathways in muscle. We have recently reported significant downregulation of Klf15 in muscle of presymptomatic SMA mice. Importantly, perinatal upregulation of Klf15 via transgenic and pharmacological methods resulted in improved disease phenotypes in SMA mice, including weight and survival. In the current study, we designed an adeno-associated virus serotype 8 (AAV8) vector to overexpress a codon-optimized Klf15 cDNA under the muscle-specific Spc5-12 promoter (AAV8-Klf15). Administration of AAV8-Klf15 to severe Taiwanese Smn−/−;SMN2 or intermediate Smn2B/− SMA mice significantly increased Klf15 expression in muscle. We also observed significant activity of the AAV8-Klf15 vector in liver and heart. AAV8-mediated Klf15 overexpression moderately improved survival in the Smn2B/− model but not in the Taiwanese mice. An inability to specifically induce Klf15 expression at physiological levels in a time- and tissue-dependent manner may have contributed to this limited efficacy. Thus, our work demonstrates that an AAV8-Spc5-12 vector induces high gene expression as early as P2 in several tissues including muscle, heart, and liver, but highlights the challenges of achieving meaningful vector-mediated transgene expression of Klf15.

scholarly journals Formulation and Development of Transferrin Targeted Solid Lipid Nanoparticles for Breast Cancer Therapy

2020 ◽  
Vol 11 ◽  
Author(s):  
Geeta S. Bhagwat ◽  
Rajani B. Athawale ◽  
Rajeev P. Gude ◽  
Shadab Md ◽  
Nabil A. Alhakamy ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Solid Lipid Nanoparticles ◽  
Human Breast Cancer ◽  
Lipid Nanoparticles ◽  
Dependent Manner ◽  
Human Breast ◽  
Solid Lipid ◽  
Receptor Modulation ◽  
Tamoxifen Citrate ◽  
Mcf 7

Breast cancer is conventionally treated by surgery, chemotherapy and radiation therapy followed by post operational hormonal therapy. Tamoxifen citrate is a best option to treat breast cancer because its selective estrogen receptor modulation activity. Owing to its antiestrogenic action on breast as well as uterine cells, Tamoxifen citrate shows uterine toxicity. The dose 20 mg per day of Tamoxifen citrate required to show therapeutic effect causes side effects and toxicity to vital organs such as liver, kidney and uterus. In the present study, transferrin-conjugated solid lipid nanoparticles (SLNs) were successfully prepared to enhance the active targeting of tamoxifen citrate in breast cancer. Developed formulations were evaluated for particle size, surface charge, surface morphology and in vitro dissolution studies. Developed formulations exhibited more cytotoxicity as compared to pure Tamoxifen citrate solution in time as well as concentration dependent manner on human breast cancer MCF-7 cells. Further, cell uptake and flow cytometry studies confirmed the qualitative uptake of developed D-SLN and SMD-SLN by human breast cancer MCF-7 cells. Overall, proposed study highlights that transferrin engineered nanocarriers could enhance the therapeutic response of nanomedicines for breast cancer treatment.

NVP-LAQ824 is a potent novel histone deacetylase inhibitor with significant activity against multiple myeloma

Blood ◽  
2003 ◽  
Vol 102 (7) ◽  
pp. 2615-2622 ◽  
Author(s):  
Laurence Catley ◽  
Ellen Weisberg ◽  
Yu-Tzu Tai ◽  
Peter Atadja ◽  
Stacy Remiszewski ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Bone Marrow ◽  
Histone Deacetylase ◽  
Hdac Inhibitors ◽  
Myeloma Cell ◽  
Parp Cleavage ◽  
Significant Activity ◽  
Dependent Manner

Abstract Histone deacetylase (HDAC) inhibitors are emerging as a promising new treatment strategy in hematologic malignancies. Here we show that NVP-LAQ824, a novel hydroxamic acid derivative, induces apoptosis at physiologically achievable concentrations (median inhibitory concentration [IC50] of 100 nM at 24 hours) in multiple myeloma (MM) cell lines resistant to conventional therapies. MM.1S myeloma cell proliferation was also inhibited when cocultured with bone marrow stromal cells, demonstrating ability to overcome the stimulatory effects of the bone marrow microenvironment. Importantly, NVP-LAQ824 also inhibited patient MM cell growth in a dose- and time-dependent manner. NVP-LAQ824-induced apoptotic signaling includes up-regulation of p21, caspase cascade activation, and poly (adenosine diphosphate [ADP]) ribose (PARP) cleavage. Apoptosis was confirmed with cell cycle analysis and annexin-propidium iodide staining. Interestingly, treatment of MM cells with NVPLAQ824 also led to proteasome inhibition, as determined by reduced proteasome chymotrypsin-like activity and increased levels of cellular polyubiquitin conjugates. Finally, a study using NVP-LAQ824 in a preclinical murine myeloma model provides in vivo relevance to our in vitro studies. Taken together, these findings provide the framework for NVP-LAQ824 as a novel therapeutic in MM. (Blood. 2003;102:2615-2622)

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