scholarly journals Pharmacokinetic Study of NADPH Oxidase Inhibitor Ewha-18278, a Pyrazole Derivative

Pharmaceutics ◽  
2019 ◽  
Vol 11 (9) ◽  
pp. 482
Author(s):  
Seul Gee Lee ◽  
Jaeok Lee ◽  
Kyung Min Kim ◽  
Kee-In Lee ◽  
Yun Soo Bae ◽  
...  
Keyword(s):  
Statistical Significance ◽  
Oxidase Inhibitor ◽  
High Concentration ◽  
Time Curve ◽  
Suitable Candidate ◽  
Nadph Oxidase Inhibitor ◽  
Concentration Time ◽  
Zero Time

In a previous study, the specific NOX1/2/4 inhibitor Ewha-18278 was confirmed as a possible treatment for osteoporosis both in vitro and in vivo. Here, we investigated the pharmacokinetics (PK) of the compound by intravenous (IV) and oral administrations to rats. Dimethyl sulfoxide (DMSO)-based and diazepam injection-based formulations were used to dissolve the compound. In the latter formulation applicable to humans, the changes in PK parameters were monitored at two different concentrations (1 mg/mL and 2 mg/mL). The area under the plasma concentration-time curve from zero time to infinity (AUCinf) of Ewha-18278 was highest in the DMSO-based formulation (2 mg/mL). Also, the concentration was increased 1.6-fold at the low concentration of the diazepam injection-based formulation compared to the high concentration. There was no statistical significance in the AUCinf of the compound between DMSO-based formulation (2 mg/mL) and diazepam injection-based formulation (1 mg/mL). These results suggest that Ewha-18278 can be delivered to humans by both IV and oral routes. In addition, the diazepam injection-based formulation of Ewha-18278 appears to be a suitable candidate for dosage development for future toxicity test and clinical trial.

scholarly journals Antioxidant protection by PECAM-targeted delivery of a novel NADPH-oxidase inhibitor to the endothelium in vitro and in vivo

2012 ◽  
Vol 163 (2) ◽  
pp. 161-169 ◽  
Author(s):  
Elizabeth D. Hood ◽  
Colin F. Greineder ◽  
Chandra Dodia ◽  
Jingyan Han ◽  
Clementina Mesaros ◽  
...  
Keyword(s):  
Nadph Oxidase ◽  
Targeted Delivery ◽  
Oxidase Inhibitor ◽  
Antioxidant Protection ◽  
Nadph Oxidase Inhibitor

In vitro and in vivo antifungal activities of ER-30346, a novel oral triazole with a broad antifungal spectrum.

1996 ◽  
Vol 40 (10) ◽  
pp. 2237-2242 ◽  
Author(s):  
K Hata ◽  
J Kimura ◽  
H Miki ◽  
T Toyosawa ◽  
T Nakamura ◽  
...  
Keyword(s):  
Amphotericin B ◽  
Candida Glabrata ◽  
Candida Parapsilosis ◽  
Good Activity ◽  
Time Curve ◽  
Concentration Time ◽  
Wide Range ◽  
Systemic Infections

ER-30346 is a novel oral triazole with a broad spectrum of potent activity against a wide range of fungi. ER-30346, with MICs at which 90% of the strains tested are inhibited (MIC90s) ranging from 0.025 to 0.78 microgram/ml, was 4 to 32 times more active than itraconazole, fluconazole, and amphotericin B against Candida albicans, Candida parapsilosis, and Candida glabrata. Against Candida tropicalis, ER-30346, with an MIC90 of 12.5 micrograms/ml, was 2 to > 8 times more active than itraconazole and fluconazole, but was 16 times less active than amphotericin B. ER-30346 (MIC90, 0.78 microgram/ml) was four to eight times more active than fluconazole and amphotericin B and had activity comparable to that of itraconazole against Trichosporon beigelli. The MIC90s of ER-30346 were 0.10 microgram/ml for Cryptococcus neoformans and 0.39 microgram/ml for Aspergillus fumigatus. ER-30346 was 2 to 8 times more active than itraconazole and amphotericin B and 32 to > 256 times more active than fluconazole. ER-30346 also showed good activity against dermatophytes, with MICs ranging from 0.05 to 0.39 microgram/ml, and its activity was comparable to or 2 to 16 times higher than those of itraconazole and amphotericin B and > 32 times higher than that of fluconazole. In vivo activity was evaluated with systemic infections in mice. Against systemic candidiasis and cryptococcosis, ER-30346 was comparable in efficacy to fluconazole and was more effective than itraconazole. Of the drugs tested, ER-30346 was the most effective drug against systemic aspergillosis. We studied the levels of ER-30346 in mouse plasma. The maximum concentration of drug in plasma and the area under the concentration-time curve for ER-30346 showed good linearity over a range of doses from 2 to 40 mg/kg of body weight.

scholarly journals Comparative Efficacies of Tedizolid Phosphate, Vancomycin, and Daptomycin in a Rabbit Model of Methicillin-Resistant Staphylococcus aureus Endocarditis

2015 ◽  
Vol 59 (6) ◽  
pp. 3252-3256 ◽  
Author(s):  
Liana C. Chan ◽  
Li Basuino ◽  
Etyene C. Dip ◽  
Henry F. Chambers
Keyword(s):  
Staphylococcus Aureus ◽  
Rabbit Model ◽  
Time Curve ◽  
Methicillin Resistant ◽  
Content Type ◽  
Treatment Groups ◽  
Concentration Time ◽  
Dose Ranging

ABSTRACTTedizolid, the active component of the prodrug tedizolid phosphate, is a novel oxazolidinone that is approximately 4 times more active by weight than linezolid againstStaphylococcus aureusin vitro. Thein vivoefficacy of tedizolid phosphate (15 mg/kg body weight intravenous [i.v.] twice a day [b.i.d.]) was compared to those of vancomycin (30 mg/kg i.v. b.i.d.) and daptomycin (18 mg/kg i.v. once a day [q.d.]) in a rabbit model of aortic valve endocarditis (AVE) caused by methicillin-resistantS. aureusstrain COL (infection inoculum of 107CFU). Median vegetation titers of daptomycin-treated rabbits were significantly lower than those of rabbits treated with tedizolid phosphate (15 mg/kg b.i.d.) (P= 0.016), whereas titers for vancomycin-treated compared to tedizolid-treated rabbits were not different (P= 0.984). The numbers of organisms in spleen and kidney tissues were similar for all treatment groups. A dose-ranging experiment was performed with tedizolid phosphate (2, 4, and 8 mg/kg b.i.d.) compared to vancomycin (30 mg/kg b.i.d.), using a higher infecting inoculum (108CFU) to determine the lowest efficacious dose of tedizolid phosphate. Tedizolid phosphate (2 mg/kg) (equivalent to 60% of the area under the concentration-time curve from 0 to 24 h (AUC0–24) for the human 200-mg dose approved by the U.S. Food and Drug Administration) was not efficacious. Tedizolid phosphate at 4 mg/kg (equivalent to 75% of the AUC0–24for the human 400-mg dose) and 8 mg/kg produced lower vegetation titers than the control, but neither was as efficacious as vancomycin.

scholarly journals Pharmacokinetic-Pharmacodynamic Target Attainment Analyses To Support Dose Selection for ME1100, an Arbekacin Inhalation Solution

2020 ◽  
Vol 64 (10) ◽  
Author(s):  
Sujata M. Bhavnani ◽  
Jeffrey P. Hammel ◽  
Elizabeth A. Lakota ◽  
M. Courtney Safir ◽  
Brian D. VanScoy ◽  
...  
Keyword(s):  
Compartment Model ◽  
Simulated Patients ◽  
Population Pharmacokinetic ◽  
Total Drug ◽  
Target Attainment ◽  
Time Curve ◽  
Content Type ◽  
Concentration Time

ABSTRACT ME1100 (arbekacin inhalation solution) is an inhaled aminoglycoside that is being developed to treat patients with hospital-acquired and ventilator-associated bacterial pneumonia (HABP and VABP, respectively). Pharmacokinetic-pharmacodynamic (PK-PD) target attainment analyses were undertaken to evaluate ME1100 regimens for the treatment of patients with HABP/VABP. The data used included a population pharmacokinetic (PPK) 4-compartment model with 1st-order elimination, nonclinical PK-PD targets from one-compartment in vitro and/or in vivo infection models, and in vitro surveillance data. Using the PPK model, total-drug epithelial lining fluid (ELF) concentration-time profiles were generated for simulated patients with varying creatinine clearance (CLcr) (ml/min/1.73 m2) values. Percent probabilities of PK-PD target attainment by MIC were determined based on the ratio of total-drug ELF area under the concentration-time curve (AUC) to MIC (AUC/MIC ratio) targets associated with 1- and 2-log10 CFU reductions from baseline for Klebsiella pneumoniae, Pseudomonas aeruginosa, and Staphylococcus aureus. Percent probabilities of PK­PD target attainment based on PK-PD targets for a 1-log10 CFU reduction from baseline at MIC values above the MIC90 value for K. pneumoniae (8 μg/ml), P. aeruginosa (4 μg/ml), and S. aureus (0.5 μg/ml) were ≥99.8% for ME1100 600 mg twice daily (BID) in simulated patients with CLcr values >80 to ≤120 ml/min/1.73 m2. ME1100 600 mg BID, 450 mg BID, and 600 mg once daily in simulated patients with CLcr values >50 to ≤80, >30 to ≤50, and 0 to ≤30 ml/min/1.73 m2, respectively, provided arbekacin exposures that best matched those for 600 mg BID in simulated patients with normal renal function. These data provide support for ME1100 as a treatment for patients with HABP/VABP.

scholarly journals Pharmacokinetics and Pharmacodynamics of Minocycline against Acinetobacter baumannii in a Neutropenic Murine Pneumonia Model

2017 ◽  
Vol 61 (5) ◽  
Author(s):  
Jian Zhou ◽  
Kimberly R. Ledesma ◽  
Kai-Tai Chang ◽  
Henrietta Abodakpi ◽  
Song Gao ◽  
...  
Keyword(s):  
Acinetobacter Baumannii ◽  
Multidrug Resistant ◽  
Time Curve ◽  
Content Type ◽  
Concentration Time ◽  
Dose Linearity ◽  
Unit Reduction ◽  
The Relationship

ABSTRACT Multidrug-resistant (MDR) Acinetobacter baumannii is increasingly more prevalent in nosocomial infections. Although in vitro susceptibility of A. baumannii to minocycline is promising, the in vivo efficacy of minocycline has not been well established. In this study, the in vivo activity of minocycline was evaluated in a neutropenic murine pneumonia model. Specifically, we investigated the relationship between minocycline exposure and bactericidal activity using five A. baumannii isolates with a broad range of susceptibility (MIC ranged from 0.25 mg/liter to 16 mg/liter). The pharmacokinetics of minocycline (single dose of 25 mg/kg of body weight, 50 mg/kg, 100 mg/kg, and a humanized regimen, given intraperitoneally) in serum and epithelial lining fluid (ELF) were characterized. Dose linearity was observed for doses up to 50 mg/kg and pulmonary penetration ratios (area under the concentration-time curve in ELF from 0 to 24 h [AUCELF,0–24]/area under the concentration time curve in serum from 0 to 24 h [AUCserum,0–24]) ranged from 2.5 to 2.8. Pharmacokinetic-pharmacodynamics (PK-PD) index values in ELF for various dose regimens against different A. baumannii isolates were calculated. The maximum efficacy at 24 h was approximately 1.5-log-unit reduction of pulmonary bacterial burdens from baseline. The AUC/MIC ratio was the PK-PD index most closely correlating to the bacterial burden (r 2 = 0.81). The required AUCELF,0–24/MIC for maintaining stasis and achieving 1-log-unit reduction were 140 and 410, respectively. These findings could guide the treatment of infections caused by A. baumannii using minocycline in the future. Additional studies to examine resistance development during therapy are warranted.

The selective NADPH oxidase inhibitor apocynin has potential prophylactic effects on melamine-related nephrolithiasis in vitro and in vivo

2014 ◽  
Vol 399 (1-2) ◽  
pp. 167-178 ◽  
Author(s):  
Xiaoran Li ◽  
Jianzhong Lu ◽  
Panfeng Shang ◽  
Junsheng Bao ◽  
Zhongjin Yue
Keyword(s):  
Nadph Oxidase ◽  
Oxidase Inhibitor ◽  
Nadph Oxidase Inhibitor

scholarly journals Altered Pharmacokinetics of Daunorubicin in Rats with CCl4-Induced Hepatic Injury

2007 ◽  
Vol 10 (4) ◽  
pp. 443 ◽  
Author(s):  
Min-Koo Choi ◽  
Im-Sook Song ◽  
Dae-Duk Kim ◽  
Suk-Jae Chung ◽  
Chang-Koo Shim
Keyword(s):  
Hepatic Injury ◽  
Hepatic Metabolism ◽  
Isolated Hepatocytes ◽  
Fasting Period ◽  
Time Curve ◽  
Concentration Time ◽  
Single Intraperitoneal Injection ◽  
In Vivo Pharmacokinetics

PURPOSE. The effect of CCl4-induced experimental hepatic injury (CCl4-EHI) on the pharmacokinetics of daunorubicin was investigated systemically in rats, in an attempt to elucidate the major determinants of the effect of CCl4-EHI on the pharmacokinetics of the drug. METHODS. CCl4-EHI was induced in rats by a single intraperitoneal injection of CCl4 (1mL/kg rat), and a 24 h fasting period. Daunorubicin was administered intravenously to control and EHI rats at a dose of 11.3 mg/mL/kg and the in vivo pharmacokinetics was studied. The in vitro uptake of the drug into isolated hepatocytes and canalicular liver plasma membrane (cLPM) vesicles, as well as the liver microsomal degradation of the drug, were also determined. RESULTS. The area under the plasma concentration-time curve (AUC) of daunorubicin was increased by 1.6 times, resulting in a 34% decrease in the systemic clearance (CL) in rats with CCl4-EHI. The apparent biliary (CLbile) and urinary (CLurine) clearance of the drug were unchanged, whereas the AUC of daunorubicinol, the major metabolite of daunorubicin, was decreased by 66% in rats with CCl4-EHI. EHI seemed to affect the hepatobiliary elimination of the drug in several ways: the in vitro intrinsic sinusoidal uptake clearance was decreased by 20%; the in vitro intrinsic canalicular excretion clearance of the drug was increased by 1.7 times; and the in vitro liver microsomal degradation of daunorubicin was significantly retarded. CONCLUSIONS. CCl4-EHI appears to impair the hepatic metabolism of daunorubicin, thereby decreasing the CL and increasing the AUC of daunorubicin.

scholarly journals DUOX2 is a Generator of ROS in the Ovary and a Potential Mediator of Ovulation

2020 ◽  
Author(s):  
Gil M Yerushalmi ◽  
Yuval Yung ◽  
Oranit Saiagh Dayan ◽  
Ettie Maman ◽  
Sarit Avraham ◽  
...  
Keyword(s):  
Nadph Oxidase ◽  
Granulosa Cells ◽  
Fertility Control ◽  
Oxidase Inhibitor ◽  
Signaling Cascades ◽  
Nadph Oxidase Inhibitor ◽  
Ovulatory Process

Abstract Background: Ovulation is triggered by the preovulatory surge of the pituitary luteinizing hormone (LH). LH/hCG induction of reactive oxygen species (ROS) is required for successful ovulation. H2O2, one of ROS species, was shown to fully mimic the effect of LH/hCG in mice ovulation. However, the molecular process that generates H2O2 in the ovary during ovulation remains largely unknown. DUOX2, a member of the NOX/DUOX family of NADPH oxidase, is capable of generating H2O2. Results: Using global transcriptome RNAseq, we identified that DUOX2 is one of the transcripts that was markedly upregulated in granulosa cells during ovulation. Treatment with human chorionic gonadotropin (hCG), an ovulatory trigger, significantly increases the expression of DUOX2 mRNA and protein in human GCs both in vivo and in vitro. hCG-induced up-regulation of DUOX2 is mediated by the cAMP-PKA and the PKC pathway. A functional test reveals that DUOX2 chemical inhibitor, Diphenyleneiodonium (DPI), an NADPH oxidase inhibitor, decreased H2O2 levels in MGCs (Mural Granulosa Cells) treated with hCG. The inhibition of H2O2 by DPI suggests that DUOX2 activity is required for hCG-induced elevation of extracellular H2O2 in MGCs. In vivo treatment of mice with DPI significantly decreases the number of ovulated oocytes and markedly attenuates the expression of key ovulatory genes. These results support the putative role of DUOX2 in ovulation. Conclusions: DUOX2 is a ROS generator during the ovulatory process and is involved in the LH/hCG-induced signaling cascades leading to ovulation. Treatment with DUOX2 inhibitors may affect late folliculogenesis and ovulation and thus may serve for fertility control.

Effect of Carbonized Herba schizonepetae on the Bioavailability of Eight Active Components from Pulsatillae Decoction in Its Particular Adsorption and Release Performance

2021 ◽  
Vol 22 ◽  
Author(s):  
Cuiyan Liu ◽  
Yun Zhu ◽  
Yanfei He ◽  
Guangtai Fan ◽  
Jingang Gu ◽  
...  
Keyword(s):  
Herbal Medicine ◽  
Active Pharmaceutical Ingredients ◽  
Active Components ◽  
Time Curve ◽  
Pharmaceutical Ingredients ◽  
Concentration Time ◽  
Adsorption And Release ◽  
Adsorption Rates

Background: Carbonized herbal medicine has been used clinically for centuries in China; however, its influence on the bioavailability of compatible medicinal herbs is still unknown. Objective: To explore the effect of a carbonized herbal medicine on the in vivo adsorption and release and absorption of other active pharmaceutical ingredients in a compound prescription. Methods: The bioavailability of carbonized Herba schizonepetae (CHS) to eight active components (epiberberine, coptisine, palmatine, berberine, phellodendrine, aesculin, aesculetin, and anemoside B4) in the aqueous extract of Pulsatillae Decoction (PDAE) was evaluated by the in vitro adsorption and release and in vivo pharmacokinetics tests. Activated carbon (AC) was used as the control. Results: In vitro experiment showed that the cumulative adsorption rates of CHS to the eight active components were 33.17%, 54.32%, 21.48%, 42.01%, 39.1%, 25.11%, 32.11%, and 23.08% which was characterized by copsitine > berberine > phellodendrine > epiperberine > aesculetin > anemoside B4 > palmatine., and they were significantly lower than those of AC. The stable release concentration in sequence was 3.23, 3.04, 3.32, 7.29, 3.17, 2.80, 1.45, and 3.81 µg/mL, which was characterized by berberine > anemoside B4 > palmatine > epiberberine > phellodendrine > coptisine > aesculin > aesculetin, and they were significantly higher than those of AC. The animal experiment indicated that the areas under the concentration-time curve (AUC0-∞) of epiberberine, berberine, aesculetin, and anemoside B4 in PDAE+CHS group were significantly higher than those in the PDAE and PDAE+AC groups, and the other four components in the PDAE+CHS group were lower than those in PDAE group but higher than those in PDAE+AC group. Conclusion: CHS could significantly improve the bioavailability of epiberberine, berberine, aesculetin, and anemoside B4 in Pulsatillae Decoction and has a sustained-release effect on berberine, aesculin, aesculetin, and anemoside B4.

scholarly journals An Optimized Mouse Thigh Infection Model for Enterococci and Its Impact on Antimicrobial Pharmacodynamics

2014 ◽  
Vol 59 (1) ◽  
pp. 233-238 ◽  
Author(s):  
Carlos A. Rodriguez ◽  
Maria Agudelo ◽  
Javier M. Gonzalez ◽  
Omar Vesga ◽  
Andres F. Zuluaga
Keyword(s):  
Drug Exposure ◽  
Culture Conditions ◽  
Infection Model ◽  
Time Curve ◽  
Unbound Fraction ◽  
Concentration Time ◽  
Inoculum Preparation ◽  
High Level

ABSTRACTNegligiblein vivogrowth of enterococci and high-level dispersion of data have led to inaccurate estimations of antibiotic pharmacodynamics (PD). Here we improved anin vivomodel apt for PD studies by optimizing thein vitroculture conditions for enterococci. The PD of vancomycin (VAN), ampicillin-sulbactam (SAM), and piperacillin-tazobactam (TZP) against enterococci were determinedin vivo, comparing the following different conditions of inoculum preparation: aerobiosis, aerobiosis plus mucin, and anaerobiosis plus mucin. Drug exposure was expressed as the ratio of the area under the concentration-time curve for the free, unbound fraction of the drug to the MIC (fAUC/MIC) (VAN) or the time in a 24-h period that the drug concentration for the free, unbound fraction exceeded the MIC under steady-state pharmacokinetic conditions (fT>MIC) (SAM and TZP) and linked to the change in log10CFU/thigh. Only anaerobiosis plus mucin enhanced thein vivogrowth, yielding significant PD parameters with all antibiotics. In conclusion, robustin vivogrowth of enterococci was crucial for better determining the PD of tested antibacterial agents, and this was achieved by optimizing the procedure for preparing the inoculum.

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