Plasma Inorganic Fluoride Concentrations after Sevoflurane Anesthesia in Children

1996 ◽  
Vol 84 (2) ◽  
pp. 348-353. ◽  
Author(s):  
M. F. Levine ◽  
J. Sarner ◽  
J. Lerman ◽  
P. Davis ◽  
N. Sikich ◽  
...  
Keyword(s):  
Plasma Concentration ◽  
Elective Surgery ◽  
Plasma Concentrations ◽  
Sevoflurane Anesthesia ◽  
Inorganic Fluoride ◽  
Time Curve ◽  
Plasma Urea ◽  
The Mean ◽  
Group 2

Background Sevoflurane is degraded in vivo in adults yielding plasma concentrations of inorganic fluoride [F-] that, in some patients, approach or exceed the 50- micron theoretical threshold for nephrotoxicity. To determine whether the plasma concentration of inorganic fluoride [F-] after 1-5 MAC x h sevoflurane approaches a similar concentration in children, the following study in 120 children scheduled for elective surgery was undertaken. Methods Children were randomly assigned to one of three treatment groups before induction of anesthesia: group 1 received sevoflurane in air/oxygen 30% (n = 40), group 2 received sevoflurane in 70% N2O/30% O2 (n = 40), and group 3 received halothane in 70% N2O/30% O2 (n = 40). Mapleson D or F circuits with fresh gas flows between 3 and 61/min were used Whole blood was collected at induction and termination of anesthesia and at 1, 4, 6, 12, and 18 or 24 h postoperatively for determination of the [F-]. Plasma urea and creatinine concentrations were determined at induction of anesthesia and 18 or 24 h postoperatively. Results The mean (+/- SD) duration of sevoflurane anesthesia, 2.7 +/- 1.6 MAC x h (range 1.1-8.9 MAC x h), was similar to that of halothane, 2.5 +/- 1.1 MAC x h. The peak [F-] after sevoflurane was recorded at 1 h after termination of the anesthetic in all but three children (whose peak values were recorded between 4 and 6 h postanesthesia). The mean peak [F-] after sevoflurane was 15.8 +/- 4.6 microns. The [F-] decreased to <6.2 microns b 24 h postanesthesia. Both the peak [F-] (r2 = 0.50) and the area under the plasma concentration of inorganic fluoride-time curve (r2 = 0.57) increased in parallel with the MAC x h of sevoflurane. The peak [F-] after halothane, 2.0 +/- 1.2 microns, was significantly less than that after sevoflurane (P<0.00012) and did not correlate with the duration of halothane anesthesia (MAC x h; r2 = 0.007). Plasma urea concentrations decreased 24 h after surgery compared with preoperative values for both anesthetics (P<0.01), whereas plasma creatinine concentrations did not change significantly with either anesthetic. Conclusions It was concluded that, during the 24 h after 2.7 +/- 1.6 MAC x h sevoflurane, the peak recorded [F-] is low (15.8 microns), F- is eliminated rapidly, and children are unlikely to be at risk of nephrotoxicity from high [F-].

scholarly journals Effects of the Antifungals Voriconazole and Fluconazole on the Pharmacokinetics of S-(+)- and R-(−)-Ibuprofen

2006 ◽  
Vol 50 (6) ◽  
pp. 1967-1972 ◽  
Author(s):  
Ville-Veikko Hynninen ◽  
Klaus T. Olkkola ◽  
Kari Leino ◽  
Stefan Lundgren ◽  
Pertti J. Neuvonen ◽  
...  
Keyword(s):  
Plasma Concentration ◽  
Peak Plasma ◽  
Peak Plasma Concentration ◽  
Geometric Mean ◽  
Plasma Concentrations ◽  
Time Curve ◽  
Respective Control ◽  
Control Value ◽  
Racemic Ibuprofen ◽  
The Mean

ABSTRACT Our objective was to study the effects of the antifungals voriconazole and fluconazole on the pharmacokinetics of S-(+)- and R-(−)-ibuprofen. Twelve healthy male volunteers took a single oral dose of 400 mg racemic ibuprofen in a randomized order either alone, after ingestion of voriconazole at 400 mg twice daily on the first day and 200 mg twice daily on the second day, or after ingestion of fluconazole at 400 mg on the first day and 200 mg on the second day. Ibuprofen was ingested 1 h after administration of the last dose of voriconazole or fluconazole. Plasma concentrations of S-(+)- and R-(−)-ibuprofen were measured for up to 24 h. In the voriconazole phase, the mean area under the plasma concentration-time curve (AUC) of S-(+)-ibuprofen was 205% (P < 0.001) of the respective control value and the mean peak plasma concentration (C max) was 122% (P < 0.01) of the respective control value. The mean elimination half-life (t 1/2) was prolonged from 2.4 to 3.2 h (P < 0.01) by voriconazole. In the fluconazole phase, the mean AUC of S-(+)-ibuprofen was 183% of the control value (P < 0.001) and its mean C max was 116% of the control value (P < 0.05). The mean t 1/2 of S-(+)-ibuprofen was prolonged from 2.4 to 3.1 h (P < 0.05) by fluconazole. The geometric mean S-(+)-ibuprofen AUC ratios in the voriconazole and fluconazole phases were 2.01 (90% confidence interval [CI], 1.80 to 2.22) and 1.82 (90% CI, 1.72 to 1.91), respectively, i.e., above the bioequivalence acceptance upper limit of 1.25. Voriconazole and fluconazole had only weak effects on the pharmacokinetics of R-(−)-ibuprofen. In conclusion, voriconazole and fluconazole increased the levels of exposure to S-(+)-ibuprofen 2- and 1.8-fold, respectively. This was likely caused by inhibition of the cytochrome P450 2C9-mediated metabolism of S-(+)-ibuprofen. A reduction of the ibuprofen dosage should be considered when ibuprofen is coadministered with voriconazole or fluconazole, especially when the initial ibuprofen dose is high.

Area under the Plasma Concentration–Time Curve of Inorganic Fluoride following Sevoflurane Anesthesia Correlates with CYP2E1 mRNA Level in Mononuclear Cells

2000 ◽  
Vol 92 (6) ◽  
pp. 1661-1666 ◽  
Author(s):  
Ichiro Hase ◽  
Susumu Imaoka ◽  
Yutaka Oda ◽  
Toyoko Hiroi ◽  
Tatsuo Nakamoto ◽  
...  
Keyword(s):  
Plasma Concentration ◽  
Mononuclear Cells ◽  
Mrna Level ◽  
Sevoflurane Anesthesia ◽  
Inorganic Fluoride ◽  
Time Curve ◽  
Concentration Time ◽  
Cyp 2E1 ◽  
Plasma Concentration Time Curve ◽  
American Society

Background Because the amount of inorganic fluoride released after anesthesia with sevoflurane depends on the dose of administered sevoflurane and cytochrome P450 (CYP) 2E1 activity in the liver, a reliable and noninvasive probe for CYP2E1 would be useful for predicting plasma inorganic fluoride levels after anesthesia. In this study, the authors evaluated the relation between plasma concentration of inorganic fluoride after sevoflurane anesthesia and CYP2E1 mRNA level in mononuclear cells. Methods Twenty patients (American Society of Anesthesiologists physical status I), aged 20-68 yr undergoing body surface surgery with general anesthesia with sevoflurane were enrolled. One milliliter of blood was obtained before administration of sevoflurane and mononuclear cells were obtained. Levels of CYP2E1 mRNA in mononuclear cells were measured by competitive reverse transcription polymerase chain reaction with a specific primer and competitor for CYP2E1 mRNA. Results There was a significant correlation between level of CYP2E1 mRNA in mononuclear cells and the area under the plasma concentration-time curve of plasma inorganic fluoride from the beginning of sevoflurane administration to infinity in uninduced and uninhibited patients (r2 = 0.56; P &lt; 0.01). Conclusions Area under the plasma concentration-time curve of inorganic fluoride after sevoflurane anesthesia correlates with CYP2E1 mRNA in mononuclear cells in peripheral blood.

Design, Synthesis, and Pharmacokinetic Evaluation of O-Carbamoyl Tizoxanide Prodrugs

2020 ◽  
Vol 16 ◽  
Author(s):  
Xi He ◽  
Wenjun Hu ◽  
Fanhua Meng ◽  
Xingzhou Li
Keyword(s):  
Plasma Concentration ◽  
Broad Spectrum ◽  
Plasma Concentrations ◽  
Antiviral Drug ◽  
Systemic Exposure ◽  
Pharmacokinetic Profile ◽  
Hydroxyl Group ◽  
First Pass

Background: The broad-spectrum antiparasitic drug nitazoxanide (N) has been repositioned as a broad-spectrum antiviral drug. Nitazoxanide’s in vivo antiviral activities are mainly attributed to its metabolitetizoxanide, the deacetylation product of nitazoxanide. In reference to the pharmacokinetic profile of nitazoxanide, we proposed the hypotheses that the low plasma concentrations and the low system exposure of tizoxanide after dosing with nitazoxanide result from significant first pass effects in the liver. It was thought that this may be due to the unstable acyloxy bond of nitazoxanide. Objective: Tizoxanide prodrugs, with the more stable formamyl substituent attached to the hydroxyl group rather than the acetyl group of nitazoxanide, were designed with the thought that they might be more stable in plasma. It was anticipated that these prodrugs might be less affected by the first pass effect, which would improve plasma concentrations and system exposure of tizoxanide. Method: These O-carbamoyl tizoxanide prodrugs were synthesized and evaluated in a mouse model for pharmacokinetic (PK) properties and in an in vitro model for plasma stabilities. Results: The results indicated that the plasma concentration and the systemic exposure of tizoxanide (T) after oral administration of O-carbamoyl tizoxanide prodrugs were much greater than that produced by equimolar dosage of nitazoxanide. It was also found that the plasma concentration and the systemic exposure of tizoxanide glucuronide (TG) were much lower than that produced by nitazoxanide. Conclusion: Further analysis showed that the suitable plasma stability of O-carbamoyl tizoxanide prodrugs is the key factor in maximizing the plasma concentration and the systemic exposure of the active ingredient tizoxanide.

scholarly journals Influence ofABCC2andABCC4Polymorphisms on Tenofovir Plasma Concentrations in Thai HIV-Infected Patients

2015 ◽  
Vol 59 (6) ◽  
pp. 3240-3245 ◽  
Author(s):  
Kanokrat Rungtivasuwan ◽  
Anchalee Avihingsanon ◽  
Narukjaporn Thammajaruk ◽  
Siwaporn Mitruk ◽  
David M. Burger ◽  
...  
Keyword(s):  
Body Weight ◽  
Multivariate Analysis ◽  
Plasma Concentration ◽  
Protease Inhibitors ◽  
Demographic Data ◽  
Plasma Concentrations ◽  
Multidrug Resistant ◽  
Cross Sectional Study ◽  
Cross Sectional ◽  
The Mean

ABSTRACTTenofovir (TFV) is eliminated by renal excretion, which is mediated through multidrug-resistant protein 2 (MRP2) and MRP4, encoded byABCC2andABCC4, respectively. Genetic polymorphisms of these transporters may affect the plasma concentrations of tenofovir. Therefore, the aim of this study was to investigate the influence of genetic and nongenetic factors on tenofovir plasma concentrations. A cross-sectional study was performed in Thai HIV-infected patients aged ≥18 years who had been receiving tenofovir disoproxil fumarate at 300 mg once daily for at least 6 months. A middose tenofovir plasma concentration was obtained. Multivariate analysis was performed to investigate whether there was an association between tenofovir plasma concentrations and demographic data, including age, sex, body weight, estimated glomerular filtration rate (eGFR), hepatitis B virus coinfection, hepatitis C virus coinfection, duration of tenofovir treatment, concomitant use of ritonavir-boosted protease inhibitors, and polymorphisms ofABCC2andABCC4. A total of 150 Thai HIV-infected patients were included. The mean age of the patients was 43.9 ± 7.2 years. The mean tenofovir plasma concentration was 100.3 ± 52.7 ng/ml. In multivariate analysis, a low body weight, a low eGFR, the concomitant use of ritonavir-boosted protease inhibitors, and theABCC44131T → G variation (genotype TG or GG) were independently associated with higher tenofovir plasma concentrations. After adjusting for weight, eGFR, and the concomitant use of ritonavir-boosted protease inhibitors, a 30% increase in the mean tenofovir plasma concentration was observed in patients having theABCC44131 TG or GG genotype. Both genetic and nongenetic factors affect tenofovir plasma concentrations. These factors should be considered when adjusting tenofovir dosage regimens to ensure the efficacy and safety of a drug. (This study has been registered at ClinicalTrials.gov under registration no. NCT01138241.)

Diurnal changes in the plasma concentrations of LH and hypothalamic contents of LHRH-I and LHRH-II in the domestic hen

1991 ◽  
Vol 130 (3) ◽  
pp. 457-462 ◽  
Author(s):  
S. C. Wilson ◽  
R. T. Gladwell ◽  
F. J. Cunningham
Keyword(s):  
Plasma Concentration ◽  
Diurnal Rhythm ◽  
Laying Hens ◽  
Plasma Concentrations ◽  
Posterior Hypothalamus ◽  
Anterior Hypothalamus ◽  
Diurnal Changes ◽  
The Mean ◽  
The Times ◽  
Lh Secretion

ABSTRACT Diurnal changes of LH secretion in sexually immature hens of 9, 11, 13 and 15 weeks of age consisted of 25–40% increases in the mean concentrations of LH in plasma between 15.00 and 18.00 h, i.e. between 2 h before and 1 h after the onset of darkness. During this time there was a tendency for the mean contents of LHRH-I in the anterior hypothalamus and posterior hypothalamus to increase by 21–74% and 20–56% respectively. In hens of 9 and 15 weeks, diurnal changes in the plasma concentration of LH closely paralleled those of LHRH-I content in the posterior hypothalamus. In contrast, the diurnal rhythm of LH secretion in hens of 11 and 13 weeks was more marked and plasma concentrations of LH continued to rise steeply between 18.00 and 21.00 h, i.e. between 1 and 4 h after the onset of darkness. At 11 weeks, this was associated with a reduction (P<0·01) in the contents of LHRH-I and LHRH-II, particularly in the anterior hypothalamus. In laying hens, a diurnal decline (P<0·01) in the plasma concentration of LH between 1 and 4 h after the onset of darkness was preceded by a fall (P<0·05) in the content of LHRH-I in the posterior hypothalamus and in the total hypothalamic content of LHRH-II (P<0·01). In all groups of hens, irrespective of the times of day at which tissue was taken, significant (P<0·05–<0·001) correlations between the contents of LHRH-I and LHRH-II in the anterior hypothalamus were observed. It is concluded that a diurnal rhythm of release of LHRH-I may drive the diurnal rhythm of LH secretion. Thus, in sexually immature hens of 9 and 15 weeks and laying hens in which diurnal changes in plasma LH were small there were parallel changes in the content of LHRH-I in the posterior hypothalamus. However, where the plasma concentration of LH was increased substantially, as at 11 weeks, there was a decline in the hypothalamic contents of LHRH-I. A simultaneous fall in the hypothalamic content of LHRH-II raises the possibility of a causal relationship between the activities of LHRH-II, LHRH-I and the release of LH. Journal of Endocrinology (1991) 130, 457–462

Plasma concentration and uterine and ovarian expressions of insulin-like growth factor-2 in dogs with cystic endometrial hyperplasia–pyometra

2021 ◽  
Author(s):  
Nilgün Gültiken ◽  
Murat Yarim ◽  
Gül Fatma Yarim ◽  
Mahmut Sözmen ◽  
Elvan Anadol ◽  
...  
Keyword(s):  
Plasma Concentration ◽  
Growth Factor ◽  
Endometrial Hyperplasia ◽  
Endocrine Cells ◽  
Inflammatory Process ◽  
Plasma Concentrations ◽  
Insulin Like Growth Factor ◽  
Healthy Dogs ◽  
Group 2 ◽  
Group 1

AbstractThe objective of this study was to investigate the plasma concentrations of insulin-like growth factor-2 (IGF-2) as well as its expression in the uterus and ovary of healthy dogs and those with cystic endometrial hyperplasia (CEH)–pyometra complex. Group 1 (n = 10) included bitches with open cervix pyometra, while Group 2 (n = 7) consisted of clinically healthy bitches in dioestrus. The number of IGF-2 immunopositive interstitial cells was significantly higher in Group 1, whereas in Group 2 there were only two cases in which a few cells were IGF-2 immunopositive. IGF-2 immunopositivity was observed in the endometrial glandular epithelium in both groups. Additionally, interstitial fibroblasts and macrophages in the endometrium were also positive in Group 1. The concentration of plasma IGF-2 was higher in Group 1 than in Group 2 (P < 0.05). The concentration was positively correlated with IGF-2 expression in the endometrial glands (r = 0.926; P < 0.001) in Group 1. However, a negative correlation was present between plasma IGF-2 concentration and IGF-2 expression in the interstitial endocrine cells of the ovary in Group 1 (r = −0.652; P < 0.05). The results suggest that IGF-2 plays an important role during the inflammatory process occurring in bitches with CEH–pyometra complex as well as in the endometrium of healthy bitches in dioestrus.

scholarly journals Comparison of Plasma, Epithelial Lining Fluid, and Alveolar Macrophage Concentrations of Solithromycin (CEM-101) in Healthy Adult Subjects

2012 ◽  
Vol 56 (10) ◽  
pp. 5076-5081 ◽  
Author(s):  
Keith A. Rodvold ◽  
Mark H. Gotfried ◽  
J. Gordon Still ◽  
Kay Clark ◽  
Prabhavathi Fernandes
Keyword(s):  
Steady State ◽  
High Performance ◽  
Healthy Adult ◽  
Plasma Concentrations ◽  
Epithelial Lining ◽  
Time Curve ◽  
Epithelial Lining Fluid ◽  
Once Daily ◽  
Drug Concentrations ◽  
The Mean

ABSTRACTThe steady-state concentrations of solithromycin in plasma were compared with concomitant concentrations in epithelial lining fluid (ELF) and alveolar macrophages (AM) obtained from intrapulmonary samples during bronchoscopy and bronchoalveolar lavage (BAL) in 30 healthy adult subjects. Subjects received oral solithromycin at 400 mg once daily for five consecutive days. Bronchoscopy and BAL were carried out once in each subject at either 3, 6, 9, 12, or 24 h after the last administered dose of solithromycin. Drug concentrations in plasma, ELF, and AM were assayed by a high-performance liquid chromatography-tandem mass spectrometry method. Solithromycin was concentrated extensively in ELF (range of mean [± standard deviation] concentrations, 1.02 ± 0.83 to 7.58 ± 6.69 mg/liter) and AM (25.9 ± 20.3 to 101.7 ± 52.6 mg/liter) in comparison with simultaneous plasma concentrations (0.086 ± 0.070 to 0.730 ± 0.692 mg/liter). The values for the area under the concentration-time curve from 0 to 24 h (AUC0–24values) based on mean and median ELF concentrations were 80.3 and 63.2 mg · h/liter, respectively. The ratio of ELF to plasma concentrations based on the mean and median AUC0–24values were 10.3 and 10.0, respectively. The AUC0–24values based on mean and median concentrations in AM were 1,498 and 1,282 mg · h/L, respectively. The ratio of AM to plasma concentrations based on the mean and median AUC0–24values were 193 and 202, respectively. Once-daily oral dosing of solithromycin at 400 mg produced steady-state concentrations that were significantly (P< 0.05) higher in ELF (2.4 to 28.6 times) and AM (44 to 515 times) than simultaneous plasma concentrations throughout the 24-h period after 5 days of solithromycin administration.

scholarly journals In Vivo Therapeutic Effect of Triclabendazole + Levamisole on Hydatid Cyst in Rats

2020 ◽  
Vol 1 (1) ◽  
pp. 18-20
Author(s):  
Peyman Sadeghi ◽  
Yagoob Garedaghi ◽  
Mirhadi Khayatnouri ◽  
Hosein Hashemzade Farhang ◽  
Ramin Kaffash Elahi
Keyword(s):  
Hydatid Cyst ◽  
Close Contact ◽  
Control Group ◽  
Case Group ◽  
Hydatid Cysts ◽  
Group 3 ◽  
The Mean ◽  
Group 2 ◽  
And Control

Introduction: Hydatidosis is a global disease and one of the most dangerous zoonotic diseases which is found in areas where humans, dogs, and herbivores are in close contact with each other. Methods: In this study, a total of 64 rats were divided into control and case groups, and then 3000 protoscolices were injected into the peritoneal cavity. After 2 months, rats in the case group were given triclabendazole + levamisole at a dose of 6 mg + 4.41 mg/mL orally for 60 days, respectively. Then, after 6 months of infection, the rats of the control and case groups were killed by anesthesia and then an autopsy was performed and the viscera were carefully examined for hydatid cyst infection. Results: The results showed that in the control group, 3 cysts were observed in the liver, 10 in the kidney, and 88 in the lung. The mean number of hydatid cysts in this group was determined to be 33.6. In the case group, 2 cysts were observed in the liver, 6 in the kidney, and 64 in the lungs. The mean number of hydatid cysts in the viscera was 24 in the case group. Conclusions: Statistical analysis of the results obtained from the case and control groups showed that the therapeutic efficacy of triclabendazole + levamisole was 31%, which is not enough to treat cases of hydatid cyst.

scholarly journals Pharmacokinetics of Doxycycline in Adults with Cystic Fibrosis

2011 ◽  
Vol 56 (1) ◽  
pp. 70-74 ◽  
Author(s):  
Paul M. Beringer ◽  
Heather Owens ◽  
Albert Nguyen ◽  
Debbie Benitez ◽  
Adupa Rao ◽  
...  
Keyword(s):  
Cystic Fibrosis ◽  
Oral Administration ◽  
Maximum Concentration ◽  
Airway Remodeling ◽  
Plasma Concentrations ◽  
Compartment Model ◽  
Time Curve ◽  
Elimination Half ◽  
Dose Oral

ABSTRACTCystic fibrosis (CF) is characterized by a chronic neutrophilic inflammatory response resulting in airway remodeling and progressive loss of lung function. Doxycycline is a tetracycline antibiotic that inhibits matrix metalloproteinase 9, a protease known to be associated with the severity of lung disease in CF. The pharmacokinetics of doxycycline was investigated during the course of a clinical trial to evaluate the short-term efficacy and safety in adults with CF. Plasma samples were obtained from 14 patients following a single intravenous dose and after 2 and 4 weeks of oral administration of doses ranging from 40 to 200 mg daily. The data were analyzed using noncompartmental and compartmental pharmacokinetics. The maximum concentration of drug in serum (Cmax) and area under the concentration-time curve from 0 h to infinity (AUC0-∞) values ranged from 1.0 to 3.16 mg/liter and 15.2 to 47.8 mg/liter × h, respectively, following single intravenous doses of 40 to 200 mg.Cmaxand time to maximum concentration of drug in serum (Tmax) values following multiple-dose oral administration ranged from 1.15 to 3.04 mg/liter and 1.50 to 2.33 h, respectively, on day 14 and 1.48 to 3.57 mg/liter and 1.00 to 2.17 on day 28. Predose sputum/plasma concentration ratios on days 14 and 28 ranged from 0.33 to 1.1 (mean, 0.71 ± 0.33), indicating moderate pulmonary penetration. A 2-compartment model best described the combined intravenous and oral data. Absorption was slow and delayed (absorption rate constant [Ka], 0.414 h−1; lag time, 0.484 h) but complete (bioavailability [F], 1.16). The distribution and elimination half-lives were 0.557 and 18.1 h, respectively. Based on these data, the plasma concentrations at the highest dose, 200 mg/day, are in the range reported to produce anti-inflammatory effectsin vivoand should be evaluated in clinical trials.

scholarly journals In Vivo Pharmacodynamic Characterization of a Novel Odilorhabdin Antibiotic, NOSO-502, against Escherichia coli and Klebsiella pneumoniae in a Murine Thigh Infection Model

2018 ◽  
Vol 62 (9) ◽  
Author(s):  
Miao Zhao ◽  
Alexander J. Lepak ◽  
Karen Marchillo ◽  
Jamie VanHecker ◽  
David R. Andes
Keyword(s):  
Escherichia Coli ◽  
Klebsiella Pneumoniae ◽  
Subcutaneous Administration ◽  
Dose Fractionation ◽  
Infection Model ◽  
Pharmacokinetic Studies ◽  
Time Curve ◽  
Content Type ◽  
The Mean

ABSTRACT NOSO-502 is a novel odilorhabdin antibiotic with potent activity against Enterobacteriaceae. The goal of these studies was to determine which pharmacokinetic/pharmacodynamic (PK/PD) indices and magnitude best correlated with efficacy in the murine thigh infection model. Six Escherichia coli and 6 Klebsiella pneumoniae isolates were utilized. MICs were determined using CLSI methods and ranged from 1 to 4 mg/liter. A neutropenic murine thigh infection model was utilized for all treatment studies. Single-dose plasma pharmacokinetics were determined in mice after subcutaneous administration of 7.81, 31.25, 125, and 500 mg/kg of body weight. Pharmacokinetic studies exhibited peak concentration (Cmax) values of 1.49 to 84.6 mg/liter, area under the concentration-time curve from 0 h to infinity (AUC0–∞) values of 1.94 to 352 mg · h/liter, and beta elimination half-lives of 0.41 to 1.1 h. Dose fractionation studies were performed using total drug doses of 7.81 mg/kg to 2,000 mg/kg fractionated into regimens of every 3 h (q3h), q6h, q12h, or q24h. Nonlinear regression analysis demonstrated that AUC/MIC was the PK/PD parameter that best correlated with efficacy (R2, 0.86). In subsequent studies, we used the neutropenic murine thigh infection model to determine the magnitude of NOSO-502 AUC/MIC needed for the efficacy against a diverse group of Enterobacteriaceae. Mice were treated with 4-fold-increasing doses (range, 3.91 to 1,000 mg/kg) of NOSO-502 every 6 h. The mean 24-h free-drug AUC/MIC (fAUC)/MIC) magnitudes associated with net stasis and 1-log kill endpoint for K. pneumoniae were 4.22 and 17.7, respectively. The mean fAUC/MIC magnitude associated with net stasis endpoint for E. coli was 10.4. NOSO-502 represents a promising novel, first-in-class odilorhabdin antibiotic with in vivo potency against Enterobacteriaceae.

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