In vitro and in vivo antibacterial activity of FR-31564, a phosphonic acid antimicrobial agent.

The in vitro and in vivo activity of FR-31564 [sodium hydrogen 3-(N-hydroxyformamido)propylphosphate] against gram-positive and -negative aerobic and anaerobic bacteria was investigated and compared with that of fosfomycin, cephalexin, carbenicillin, and trimethoprim-sulfamethoxazole. The in vitro activity of FR-31564 was markedly enhanced when combined with glucose 6-phosphate or fructose 6-phosphate, but not when combined with ribose phosphate, adenosine monophosphate, or glycerol phosphate. In vitro activity of FR-31564 also was enhanced by human or horse blood, but not by human serum. The type of medium had a great effect on the minimal inhibitory concentration, with the lowest minimal inhibitory concentrations achieved on nutrient agar, 8- to 16-fold less than with Mueller-Hinton, heart infusion, or Trypticase soy agars. FR-31564 was more active than fosfomycin, cephalexin, carbenicillin, or trimethoprimsulfamethoxazole against Escherichia coli, Klebsiella pneumoniae, Proteus vulgaris, Enterobacter cloacae, E. aerogenes, and Citrobacter. It was less active than fosfomycin against Serratia marcescens and Proteus mirabilis and did not inhibit gram-positive cocci or anaerobic species. FR-31564 inhibited a number of E. coli, K. pneumoniae, and some Pseudomonas aeruginosa strains resistant to the other agents. In the presence and absence of human blood FR-31564 showed bactericidal activity, and P. aeruginosa exposed to FR-31564 for 3 h showed a 6-h lag in regrowth. FR-31564 administered by the subcutaneous route was more active in protecting mice challenged with P. aeruginosa than was fosfomycin, carbenicillin, or cefoperazone. It was as active by the oral route in protecting mice challenged with E. coli as was fosfomycin, ampicillin, cephalexin, or trimethoprimsulfamethoxazole.     

In vitro study of chitosan-based multi-responsive hydrogels as drug release vehicles: a preclinical study

Systematic administration of painkillers and anti-inflammatory drugs is routinely employed to minimize pain and bodily disorders. Controlled drug delivery has the potential to improve the outcomes of disorders by providing sustained exposure to efficacious drug concentrations. Herein, we report the fabrication of multi-responsive hydrogels using reactive and functional polymers such as chitosan and polyvinyl pyrrolidone by varying the concentration of a cleavable crosslinker, tetraethyl orthosilicate. The swelling indices of the hydrogels were evaluated in distilled water, solutions with different pH values and different electrolytes. FTIR, WAXRD and TGA were conducted to investigate the structures, crystallinities and thermal stabilities of the prepared multi-responsive hydrogels, respectively. The ultimate tensile strength and elongations at break of the fabricated hydrogels were investigated to assess their mechanical stability. Optical microscopy, biodegradation, antimicrobial and cytotoxicity analyses were further carried out to verify the magnified crosslinked and porous structures, biodegradabilities, biocompatibilities and toxic behaviour of the as-prepared hydrogels, respectively. Drug release analysis was conducted to evaluate their release behaviour in PBS, SGF, SIF and electrolyte solutions. The overall results indicate the successful development of novel, non-toxic and sustained drug deliverable hydrogels, which can be considered as a paramount success towards the fabrication of controlled drug delivery systems.

Pictorial diagram of multi-responsive hydrogels for controlled drug release system.     

In vivo and in vitro studies of antisense oligonucleotides – a review

The potential of antisense oligonucleotides in gene silencing was discovered over 40 years ago, which resulted in the growing interest in their chemistry, mechanism of action, and metabolic pathways. This review summarizes the selected mechanisms of antisense drug action, as well as therapeutics which are to date approved by the Food and Drug Administration and European Medicines Agency. Moreover, bioanalytical methods used for ASO pharmacokinetics and metabolism studies are briefly summarized. Special attention is paid to the primary pharmacokinetic properties of the different chemistry classes of antisense oligonucleotides. Moreover, in vivo and in vitro metabolic pathways of these compounds are widely described with the emphasis on the different animal models as well as in vitro models, including tissues homogenates, enzyme solutions, and human liver microsomes.

Metabolism of ASOs is based on exonucleases degradation of subsequent nucleotides, with the activity of endonucleases in the case of some modifications.     

In vitro and in vivo evaluation of a novel mitomycin nanomicelle delivery system

Mitomycin C (MMC), naturally synthesized by Streptomyces caespitosus, is a potent antineoplastic antibiotic for the treatment of various solid tumors. However, the defects of conventional MMC injections have greatly limited its clinical application due to its toxic side effects and non-specific interactions. To solve this problem, the PEG_2k-Fmoc-Ibuprofen (PEG-FIbu) micellar nanocarrier was synthesized and the MMC-loaded micelles (PEG-FIbu/MMC) were prepared by thin film hydration method and characterized. Ibuprofen was used as a hydrophobic domain of PEG-FIbu nanocarrier, and we expect it to synergize with codelivered MMC in the overall antitumor activity. The in vitro release of PEG-FIbu/MMC was examined by dialysis method using MMC injection as a control. Our data suggested that PEG-FIbu/MMC micelles presented appropriate particle size, low CMC value, good stability, high drug loading efficiency and sustained release properties. In vitro cytotoxicity studies with several tumor cell lines showed that the carrier was effective in mediating intracellular delivery of MMC to tumor cells. In vivo pharmacokinetics, tissue distribution and therapeutic study proved that PEG-FIbu/MMC micelles prolonged blood circulation, significantly improved the tumor accumulation and therapeutic efficacy, and reduced undesirable side effect on normal tissues compared to MMC injection. In general, PEG-FIbu/MMC micelles represented an effective strategy to improve the performance for the delivery of MMC and safety of medication.

The introduction of a micellar delivery system of MMC increase efficiency, reduce toxicity and enhance specific interactions in tumor.     

In vitro and in vivo biocompatibility and inflammation response of methacrylated and maleated hyaluronic acid for wound healing

Over the past few years, different in vitro and in vivo studies have been highlighting the great potentiality of hyaluronic acid (HA) as a biomaterial in wound healing treatment thanks to its good capability to induce mesenchymal and epithelial cell growth and differentiation, angiogenesis, and collagen deposition. However, the need to improve its mechanical properties as well as its residence time has led scientists to study new functionalization strategies. In this work, chemically modified HA-based hydrogels were obtained by methacrylic and maleic functionalization. Methacrylated (MEHA) and maleated HA (MAHA) hydrogels have shown important physico-chemical properties. The present study provides a deeper insight into the biocompatibility of both synthesized materials and their effects on tissue inflammation using in vitro and in vivo models. To this aim, different cell lines involved in wound healing, human dermal fibroblasts, human adipose-derived stem cells and human umbilical vein endothelial cells, were seeded on MEHA and MAHA hydrogels. Furthermore, an inflammation study was carried out on a murine macrophage cell line to assess the effects of both hydrogels on inflammatory and anti-inflammatory interleukin production. The results showed that both MAHA and MEHA supported cell proliferation with anti-inflammation ability as highlighted by the increased levels of IL-10 (57.92 ± 9.87 pg mL⁻¹ and 68.08 ± 13.94 pg mL⁻¹, for MEHA and MAHA, respectively). To investigate the inflammatory response at tissue/implant interfaces, an in vivo study was also performed by subcutaneous implantation of the materials in BALB/c mice for up to 28 days. In these analyses, no significant chronic inflammation reaction was demonstrated in either MEHA or MAHA in the long-term implantation.

From synthesis to the in vitro and in vivo biological evaluation of two types of hyaluronan derivatives.     

In vitro and in vivo antibacterial activity of T-3912, a novel non-fluorinated topical quinolone

The in vitro and in vivo activity of T-3912, a novel non-fluorinated topical quinolone, was compared with that of nadifloxacin, ofloxacin, levofloxacin, clindamycin, erythromycin and gentamicin. The in vitro activity of T-3912 against methicillin-susceptible Staphylococcus aureus, ofloxacin-resistant and methicillin-resistant S. aureus, Staphylococcus epidermidis, ofloxacin-resistant S. epidermidis, penicillin-resistant Streptococcus pneumoniae and Propionibacterium acnes was four-fold to 16 000-fold greater than that of other agents at the MIC90 for the clinical isolates. The activity of T-3912 was not influenced by grlA mutation in S. aureus, and the degree of MIC increase of T-3912 for grlA-gyrA double and triple mutants was lowest among the quinolones tested (nadifloxacin, levofloxacin and ofloxacin). The inhibitory activity of T-3912 was compared with other quinolones for DNA gyrase and topoisomerase IV of S. aureus SA113. T-3912 showed the greatest inhibitory activity for both enzymes among the quinolones tested. The isolation frequency of spontaneous mutants resistant to T-3912 was < 1.7 x 10(-9) and < 2.0 x 10(-9) for S. aureus SA113 and P. acnes JCM 6425, respectively. Furthermore, resistance to T-3912 could not be clearly detected in the 28th transfer by the serial passage method. T-3912 exhibited more potent bactericidal activity against S. aureus and P. acnes than nadifloxacin and clindamycin in a short time period. T-3912 in a 1% gel formulation showed good therapeutic activity against a burn infection model caused by S. aureus SA113, P. acnes JCM6425 and multidrug-resistant S. aureus F-2161. These results indicate that T-3912 is potentially a useful quinolone for the treatment of skin and soft-tissue infections and that its potent bactericidal activity might be able to shorten the treatment period.     

In vivo toxicity evaluation of two polyoxotungstates with potential antidiabetic activity using Wistar rats as a model system

In this study, the in vivo hypoglycemic effect of a donut-shaped polyanion salt (NH₄)₁₄[Na@P₅W₃₀O₁₁₀]·31H₂O {NaP₅W₃₀} and its Ag-containing derivative K₁₄[Ag@P₅W₃₀O₁₁₀]·22H₂O·6KCl {AgP₅W₃₀}, as well as their hepatotoxicity and nephrotoxicity, was evaluated. In the screening hypoglycemic study, Wistar albino rats with streptozotocin induced diabetes were treated intraperitoneally with three single doses (5, 10, and 20 mg per kg per b.w.) of both investigated polyoxotungstates. The blood glucose levels, measured before and after 2, 4 and 6 h polyoxotungstate application, showed that both studied compounds induced the most pronounced and time dependent glucose lowering effects at the doses of 20 mg kg⁻¹. Thus, daily doses of 20 mg kg⁻¹ were administered to Wistar albino rats orally for 14 days in further toxicity examinations. The serum glucose concentration and biochemical parameters of kidney and liver function, as well as a histopathological analysis of kidney and liver tissues were evaluated 14 days after the polyoxotungstate administration. Both investigated compounds did not induce statistically significant alterations of the serum glucose and uric acid concentrations, as well as some of the liver function markers (serum alanine and aspartate aminotransferases, and alkaline phosphatase activities). However, the significant decrease in serum total protein and albumin concentrations and the increase in biochemical parameters of renal function – serum urea (up to 63.1%) and creatinine concentrations (up to 23.3%) were observed for both polyoxotungstates. In addition, the detected biochemical changes were in accordance with kidney and liver histhopathological analysis. Accordingly, the hepatotoxic and nephrotoxic effects of these potential antidiabetic polyoxotungstates could be considered as mild.

Study of the in vivo hypoglycemic effect, hepatotoxicity and nephrotoxicity of a donut-shaped polyanion salt (NH₄)₁₄[Na@P₅W₃₀O₁₁₀]·31H₂O {NaP₅W₃₀} and its Ag-containing derivative K₁₄[Ag@P₅W₃₀O₁₁₀]·22H₂O·6KCl {AgP₅W₃₀}.     

In vivo optical spectroscopy for improved detection of pancreatic adenocarcinoma: a feasibility study

Pancreatic adenocarcinoma has a five-year survival rate of less than 6%. This low survival rate is attributed to the lack of accurate detection methods, which limits diagnosis to late-stage disease. Here, an in vivo pilot study assesses the feasibility of optical spectroscopy to improve clinical detection of pancreatic adenocarcinoma. During surgery on 6 patients, we collected spectrally-resolved reflectance and fluorescence in vivo. Site-matched in vivo and ex vivo data agreed qualitatively and quantitatively. Quantified differences between adenocarcinoma and normal tissues in vivo were consistent with previous results from a large ex vivo data set. Thus, optical spectroscopy is a promising method for the improved diagnosis of pancreatic cancer in vivo.OCIS codes: (170.6510) Spectroscopy, tissue diagnostics; (170.4580) Optical diagnostics for medicine; (170.3660) Light propagation in tissues     

In vivo detection of salicylic acid in sunflower seedlings under salt stress

Salicylic acid (SA) is an important phytohormone. It plays an essential role in regulating many physiological processes of plants. Most of the conventional methods for SA detection are based on in vitro processes. More attention should be paid to develop in vivo methods for SA detection. In this work, Pt nanoflowers and GO were simultaneously electrodeposited and reduced on a Pt wire microelectrode in one step. The Pt nanoflowers/ERGO modified Pt microsensor demonstrated high sensitivity and selectivity for SA. SA could be detected from 100 pM to 1 μM with a detection limit of 48.11 pM. Then this microsensor was used to detect SA in the stem of sunflower seedlings under different salt stresses in vivo. The result showed that with the increasing concentration of salt, SA levels decreased. Our result was also confirmed by UPLC-MS and gene expression analysis. To the best of our knowledge, this is the first report of in vivo detection of SA in plants using the Pt nanoflowers/ERGO modified Pt microelectrode. It is foreseeable that our strategy could pave the way for the in vivo detection of phytohormones in plants.

A Pt nanoflowers/ERGO modified Pt microelectrode was proposed to detect salicylic acid in plants under salt stress in vivo.     

In vitro and in vivo evaluation of benzathine foscarnet microcrystals as a potential intravitreal drug depot

Sodium foscarnet is an antiviral drug against cytomegalovirus retinitis, and clinically it is used via frequent intravitreal injection which causes various ocular complications. Here we propose to use benzathine foscarnet in a new salt form with much lower aqueous solubility, and as a potential long-acting intravitreally injectable solid form for foscarnet. Benzathine foscarnet (1 : 1) microcrystals were synthesized and evaluated both in vitro and in vivo. The aqueous solubility of benzathine foscarnet was 14.2 mM, which is in between those of the currently-used sodium foscarnet and our previously-reported calcium foscarnet salt. In a rabbit model, the injected microcrystals last for about 3 weeks in the vitreous, suggesting its solubility and dissolution profile is appropriate for its intended use. However, the injected benzathine foscarnet microcrystals also caused adverse effects in vivo.

Benzathine foscarnet microcrystals as a potential intravitreal drug depot.     

In vitro and in vivo activity of combination antimicrobial agents on Haemophilus ducreyi

OBJECTIVES: Development of single dose antibiotic treatments for chancroid has been followed by drug-resistant Haemophilus ducreyi in endemic areas. We examined the activity and interactions of antimicrobial agents and combinations against H. ducreyi. METHODS: We evaluated the in vitro susceptibility of three virulent strains of H. ducreyi to ceftriaxone, azithromycin, rifabutin and streptomycin, and each two-drug combination by the agar dilution method. We then tested each two-antibiotic combination for activity by the chequerboard method. Lastly, we chose the antibiotic combination with the lowest fractional inhibitory concentration index (FICI) and tested combined sub-therapeutic doses, the highest doses which had no effect alone on lesion healing compared with controls, for in vivo interaction in the temperature-dependent rabbit model of H. ducreyi infection. RESULTS: Each H. ducreyi strain was susceptible in vitro to each antibiotic and two-antibiotic combination, and combined ceftriaxone and streptomycin had the lowest FICI at 0.63. In five treated animals versus three untreated controls, combined sub-therapeutic doses of ceftriaxone (0.05 mg/kg) and streptomycin (10 mg/kg) reduced mean (SD) duration of culture positivity from 7.3 (1.1) to 2.6 (1.7) days (P<0.001), time to 50% reduction in lesion size from 9.7 (1.5) to 5.8 (0.8) days (P<0.005), and time to resolution of ulcer from 11.7 (2.3) to 6.6 (1.7) days (P<0.05). CONCLUSIONS: Ceftriaxone and streptomycin have in vivo synergic interaction against H. ducreyi lesions in the temperature-dependent rabbit model of infection. Antibiotic combinations may be evaluated clinically as single-dose therapy for chancroid.     

In vitro antimicrobial activity of doripenem, a new carbapenem

The doripenem MICs at which 90% of the tested strains were inhibited ranged from 0.03 to 1 microg/ml for 10 species of Enterobacteriaceae (n = 351), from 0.03 to 0.12 microg/ml for oxacillin-susceptible staphylococci (n = 119), from 4 to 32 microg/ml for oxacillin-resistant staphylococci (n = 64), from < or =0.008 to 0.06 microg/ml for penicillin-susceptible streptococci (n = 132), and from 1 to 4 microg/ml for penicillin-resistant streptococci (n = 51). Overall, doripenem demonstrated in vitro activity similar to that of meropenem against gram-negative pathogens and to that of imipenem against gram-positive pathogens.     

In vitro study and in vivo application of a reusable double-channel sphincterotome

BACKGROUND AND STUDY AIMS: Therapeutic endoscopic retrograde cholangiopancreatography (ERCP) has been deemed to be a "cost-prohibitive" procedure, based upon the cumulative costs of one-time-use accessories and current reimbursement plans. One-time-use sphincterotomes comprise a significant component of that cost and, accordingly, we evaluated the disability and clinical usefulness of a recently introduced reusable double-channel sphincterotome. MATERIALS AND METHODS: We studied a reusable 6-Fr sphincterotome at baseline and following contamination with 10(6) Bacillus stearothermophilus. Reprocessing included a unique 30-minute ultrasonic cleaning step in lieu of manual cleaning, followed by steam sterilization. Parameters evaluated included sphincterotome function, electrical integrity, and our ability to sterilize the devices for three in vitro trials. In vivo studies included patient demographics and outcomes, procedural findings, and success rates, and the mean number of times the sphincterotome was used, functional grading at time of use, and reasons for sphincterotome malfunction. RESULTS: Ten out of ten sphincterotomes maintained form, function, and electrical integrity in vitro, and all cultures were negative after sterilization. In the initial in vivo study, ten sphincterotomes were used in 50 patients (mean, 5 uses) with a 94% success rate. Reasons for sphincterotome failure included leak or breakage of the accessory port in 70%, wire fracture in 10%, incorrect wire bow in 10%, and clogged injection port in 10%. Following reconfiguration of the insertion-port polymer, an additional ten sphincterotomes were used in 110 patients (mean, 11 uses). Mechanical failure occurred primarily at the wire-insertion port, resulting in progressive friction with reuse. There were neither electrical nor infectious complications associated with reuse. CONCLUSIONS: A reusable double-channel sphincterotome is available which can theoretically be reprocessed and sterilized without the manual cleaning step of the reprocessing process. Contingent upon both provider and patient, multiple reuse can be anticipated, and contingent upon purchase price and reprocessing costs, the potential for procedural cost savings is significant.     

New vesicular ampicillin-loaded delivery systems for topical application: characterization, in vitro permeation experiments and antimicrobial activity.

In this paper, the experimental conditions for preparing ampicillin-loaded surfactant vesicles (SVs) are described. Our studies are focused on the potential use of a vesicular polymeric dispersion as ampicillin delivery system for topical application. The main components of the formulation are uncharged and charged SVs loaded with ampicillin and dispersed in a gellan solution. The following issues are addressed: the drug encapsulation efficiency (e.e.), the kinetic of drug release from the delivery systems, the antimicrobial activity of vesicle-entrapped ampicillin. The in vitro permeation experiments through a synthetic lipophilic barrier (Silastic) and through porcine skin are carried out to evaluate the potential use as a dermal formulation. The use of both a synthetic and a biological membrane allows to discriminate between the effects related to variations of thermodynamic parameters and those correlated to biological factors. The release rate of ampicillin is increased by encapsulation in neutral and negatively charged SVs and the permeation rate was slowed by dispersion of drug-loaded SVs in gellan solution. Finally, studies of antimicrobial activity on prepared systems evidenced that ampicillin encapsulated in SVs exhibit a higher activity than the free drug.     

In vivo acute toxicity and mutagenic analysis of crude saponins from Chenopodium quinoa Willd husks

Background: As a functional food factor, quinoa saponins are valuable as additives and in medical care, pharmaceutical development, cosmetics and other fields. However, few studies have investigated the toxicity of saponins. The main purpose of this study was to evaluate the toxicity of crude saponins extracted from quinoa husks. Thus, acute toxicity and excretion experiments were carried out in rats. The Ames test, micronucleus test and mouse sperm aberration test were carried out in mice. Results: In the acute toxicity study, the obtained LD₅₀ was more than 10 g per kg per bw for both sexes, the food intake of all rats decreased over a period of time, and some rats developed diarrhea. In the case of large-dose gavage, the saponin excretion time in rats was approximately four days. When the dosage was 10 mg kg⁻¹, quinoa saponins were hydrolyzed into aglycone within 24 hours and excreted out of the body. The results of the mutagenicity experiment showed that saponins had no mutagenicity in mice. Conclusion: This work has demonstrated that quinoa saponins have limited acute toxicity effects, which provides a theoretical basis for their rational utilization.

As a functional food factor, quinoa saponins are valuable as additives and in medical care, pharmaceutical development, cosmetics and other fields.     

In vitro anticancer activity of parent and nano-encapsulated samarium(iii) complex towards antimicrobial activity studies and FS-DNA/BSA binding affinity

Based on the potential anticancer properties of lanthanide complexes, the anticancer activity of the Sm(iii) complex containing a 2,2′-bipyridine ligand (bpy) and its interaction with FS-DNA (Fish-Salmon DNA) and BSA (Bovine Serum Albumin) were examined experimentally and by molecular docking in this paper. Absorption and fluorescence spectroscopic methods were used to define the thermodynamic parameters, binding constant (K_b), and the probable binding mechanism. It was concluded that the Sm complex interacts with FS-DNA through a minor groove with a K_b of 10⁵ M⁻¹. Also, the K_b for the BSA binding at 298 K was found to be 5.89 × 10⁵ M⁻¹, showing relatively a high tendency of the Sm complex to DNA and BSA. Besides, the Sm complex was docked to BSA and DNA by the autodock program. The results of the docking calculations were in good agreement with the experimental examinations. Additionally, the antifungal and antibacterial properties of this complex were investigated. The anticancer tests on the effect of the Sm complex, starch nano-encapsulation, and lipid nano-encapsulation in MCF-7 and A-549 cell lines were performed by the MTT method. It can be observed that the Sm complex and its nanocarriers presented a selective inhibitory effect on various cancer cell growths.

The biological properties of the Sm-complex, such as its interaction with FS-DNA and BSA, anticancer, and antimicrobial activities were studied.     

In vitro toxicity assessment and enhanced drug solubility profile of green deep eutectic solvent derivatives (DESDs) combined with theoretical validation

Green solvents are actively taking over as the absolute replacement of intrinsic toxic volatile organic solvents. This is conspicuously analyzed in this study, which mentions the preparation of green deep eutectic solvent derivatives (DESDs) composed of choline chloride (ChCl) as the hydrogen bond acceptor (HBA) and two acids, viz., oxalic acid (OX) and citric acid (CA) as preliminary hydrogen bond donors (HBDs) with ethylene glycol (EG) and glycerol (GLY) as secondary HBDs in an equimolar ratio. This study exposes the vigilant choice of the type and mole ratio of HBA and HBDs, which permit the extended stability of the formulated DESDs in the liquid state even below the room temperature. The prepared DESDs were well-characterized by FT-IR spectroscopy. Furthermore, this work aimed at investigating their antimicrobial activity towards selected bacterial and fungal strains expressed in terms of viscosity measurements. The in vitro toxicity profiles in terms of cytotoxicity (human cervical cancer cell line) and genotoxicity (DNA fragmentation), which have not been reported to date, were also assessed for the prepared DESDs. Tuning the HBA and HBDs in selected DESDs for promising biological activity was found to have ethical implications. In addition, this study focused on the solubilization enhancement of the local anaesthetic drug lidocaine (LDC) in the stated DESDs as a function of water composition, and higher solubility was observed due to the fair intermolecular hydrogen bonding interactions between LDC and DESDs, which was further validated using the computational simulation approach. In addition, the electron-donating and accepting sites were depicted by 3D-molecular electrostatic potential (3D-MEP) for the examined systems. The observed variations were attributed to the changes in the solvation capacity, viscosity and ionic strength of pure DESDs as a function of water concentration. Finally, this study supports the role of dual HBDs in leading to the formation of stable DESDs with noteworthy action towards drug solubilization and a remarkable biological response.

Scheme illustrating the sustainable preparation of deep eutectic solvent derivatives (DESDs), their biological response and water-insoluble hydrophobic drug dissolution trend.     

In vitro and in vivo evaluation of the antimicrobial activity of azithromycin againstLegionella species

The antimicrobial activity of azithromycin (AZM) was evaluated againstLegionella species using an experimental model of legionellosis. The minimum inhibitory concentration₉₀s (MIC₉₀s) of AZM against 35 standard strains (0.25 mg/L) and 22 Japanese clinical isolates ofLegionella pneumophila (0.063 mg/L) were lower than those of erythromycin (EM) and almost equal to those of clarithromycin and roxythromycin. Using¹⁴C-labeled antibiotic, AZM and EM were observed concentrated inside human polymorphonuclear leukocytes (PMN) with intracellular/extracellular concentration ratios of AZM and EM at 120 minutes after dosing of 27.3 and 22.2, respectively. AZM inhibited the growth ofL. pneumophila (80-045 strain) from cultured guinea pig alveolar macrophages, even when the extracellular AZM was washed out on day 2 of culture. However, the addition of identical concentrations of EM failed to produce a similar inhibition. Pharmacokinetic studies of AZM tissue distribution in guinea pigs infected withL. pneumophila 80-045 revealed high drug concentrations in the lung and liver and a longer half-life in these organs compared with those in plasma. Treatment of guinea pigs with experimentally-induced legionellosis with oral AZM (10 mg/kg/day for 2 days) was more effective than EM treatment (10 mg/kg/day for 4 days) or a placebo, and resulted in a significant improvement in the survival rate. Our results suggest that AZM is a promising new drug for the treatment of legionellosis using a short-term dosing regimen.     

In vivo and in vitro evaluation of dihydroartemisinin prodrug nanocomplexes as a nano-drug delivery system: characterization,pharmacokinetics and pharmacodynamics

To develop new, more effective and lower toxicity antitumor dihydroartemisinin (DHA) nanocomplexes, a DHA prodrug synthesized in this study was used to prepare DHA prodrug self-assembled nanocomplexes (DHANPs) by molecular self-assembly technology. The optimization, pharmacokinetics and in vitro and in vivo antitumor efficiency of DHANPs were assessed. The results showed that the entrapment efficiency, drug loading, particle size and zeta potential of the optimized formulation were 92.37 ± 3.68%, 76.98 ± 3.07%, 145.9 ± 2.11 nm and −16.0 ± 0.52 mV, respectively. DHANPs had a uniform size distribution and good stability during storage. The release of DHA prodrugs from DHANPs was slow in a PBS solution (pH 7.4). The pharmacokinetic study indicated that DHANPs could significantly improve the blood concentration of DHA. DHANPs exhibited lower cytotoxicity to 4T1 cells. More importantly, DHANPs could increase the quality life of mice in comparison with that of the DHA solution in 4T1 tumor-bearing mice. In short, the optimized DHA prodrug nanocomplexes show good long-term stability during the experimental time, extend the life-cycle of DHA in rats and can act as a prospective nano-drug delivery system for future artemisinin-based anti-tumor drugs.

To develop new, more effective and lower toxicity antitumor dihydroartemisinin (DHA) nanocomplexes, a DHA prodrug synthesized in this study was used to prepare DHA prodrug self-assembled nanocomplexes (DHANPs) by molecular self-assembly technology.