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Aquaculture
journal homepage:www.elsevier.com/locate/aquaculture
Pharmacokinetic/pharmacodynamic integration of marbo
floxacin after oral
and intravenous administration in rainbow trout (Oncorhynchus mykiss)
Orhan Corum
a,⁎, Ertugrul Terzi
b, Duygu Durna Corum
a, Osman Nezih Kenanoglu
b, Soner Bilen
b,
Kamil Uney
caDepartment of Pharmacology and Toxicology, Faculty of Veterinary Medicine, University of Kastamonu, Kastamonu 37200, Turkey bFaculty of Fisheries, University of Kastamonu, Kastamonu 37200, Turkey
cDepartment of Pharmacology and Toxicology, Faculty of Veterinary Medicine, University of Selcuk, Konya 42031, Turkey
A R T I C L E I N F O Keywords: Pharmacokinetics Pharmacodynamics Marbofloxacin Rainbow trout A B S T R A C T
The pharmaco-kinetic/dynamic of marbofloxacin was investigated after single intravenous (IV) and oral ad-ministration of 10 mg/kg in 192 healthy rainbow trout at 13 ± 1.2 °C. The plasma concentrations of marbo-floxacin were determined by high-performance liquid chromatography-ultraviolet detection. After IV and oral administration, the plasma concentration–time data were described by a noncompartmental analysis. The minimal inhibitory concentration (MIC) of marbofloxacin against Yersinia ruckeri, Aeromonas hydrophila, Pseudomonasfluorescens and P. putida were determined by broth dilution method at 13 °C. After IV adminis-tration, the elimination half-life (t1/2ʎz), area under the concentration-versus time curve (AUC0-∞), apparent
volume of distribution at steady-state and total body clearance of marbofloxacin were 18.05 h, 354.63 h ∗ μg/ mL, 0.65 L/kg and 0.03 L/h/kg, respectively. After oral administration, t1/2ʎz, AUC0-∞,the peak plasma
con-centration, time of maximum concentration and bioavailability were 27.51 h, 135.29 h∗ μg/mL, 3.74 μg/mL, 4 h and 38.15%, respectively. The respective MICs of marbofloxacin against Y. ruckeri, A. hydrophila, P. fluorescens and P. putida were determined as 0.02μg/mL, 2.5 μg/mL, 2.5 μg/mL and 5 μg/mL, respectively. Following IV and oral administration of 10 mg/kg marbofloxacin, AUC/MIC and Cmax/MIC values were above the target levels
for Y. ruckeri, while this dose was not sufficient for A. hydrophila and Pseudomonas spp. Because the pharma-cokinetics and pharmacodynamics of a drug infish are significantly affected by temperature, the dosage regimen of marbofloxacin should be modified according to temperature.
1. Introduction
Rainbow trouts are one of the most culturedfish species worldwide. Several Gram-negative and Gram-positive bacteria play an important role in the etiology of diseases that cause significant economic losses and deaths in trouts. Aeromonas hydrophila, Yersinia ruckeri, Pseudomonas putida, and P.fluorescens are some of the Gram-negative bacteria that cause diseases such as motile Aeromonas septicemia, en-teric red mouth, and pseudomoniasis in trouts (Ozturk and Altinok, 2014). Excessive and inappropriate use of antibiotics infishes generates antibiotic residues and may result in an increased risk of antimicrobial resistance (Capkin et al., 2015). In addition, consumption offishes with such antibiotic residues and increased risk of antimicrobial resistance
may cause allergies, toxic effects, and changes in intestinal microflora in both humans and animals (Rodgers and Furones, 2009; Serrano, 2005; Vignesh et al., 2011). Therefore, appropriate dosage regimens should be determined by obtaining data on pharmacokinetics (PK) and pharmacodynamics (PD) prior to the use of any antibiotics in fishes (Serrano, 2005).
Marbofloxacin is a third-generation fluoroquinolone antibiotic used only in the veterinaryfield; it exhibits bactericidal effect by inhibiting DNA gyrase (topoisomerase II) and topoisomerase IV enzymes (Giguère and Dowling, 2013). It is a broad spectrum antibiotic that acts against several bacteria including Gram-negative (Escherichia coli, Salmonella, Campylobacter jejuni, Pseudomonas spp. and Yersinia spp.), Gram-posi-tive (Staphylococcus aureus and Streptococcus pneumoniae), anaerobic
https://doi.org/10.1016/j.aquaculture.2019.734510
Received 15 May 2019; Received in revised form 14 June 2019; Accepted 12 September 2019
Abbreviations: AUC, Area under the plasma concentration versus time curve; ClT, Total body clearance; Cmax, Peak plasma drug concentration; HPLC,
High-performance liquid chromatography; MIC, Minimal inhibitory concentration; PK, Pharmacokinetic; PD, Pharmacodynamic; t1/2ʎz, Elimination half-life; Tmax, Time to
peak plasma drug concentration; Vdss, Apparent volume of distribution at steady state ⁎Corresponding author.
E-mail address:[email protected](O. Corum).
Available online 14 September 2019
0044-8486/ © 2019 Elsevier B.V. All rights reserved.
(Clostridium spp. and Bacteroides fragilis) bacteria, and Mycobacterium tuberculosis as well as Mycoplasma pneumoniae (Giguère and Dowling, 2013; Pallo-Zimmerman et al., 2010). Marbofloxacin has a longer elimination half-life and acts better effect against Pseudomonas species compared to enrofloxacin (Bidgood and Papich, 2005; Farca et al., 2007).
The PK of marbofloxacin has been demonstrated in some mammals (Altan et al., 2018;Waxman et al., 2001) and poultry species (Haritova et al., 2006). Although the PK of marbofloxacin has been determined in fish species such as the crucian carp (Zhu et al., 2009) and tilapia (Shan et al., 2017), to the best of our knowledge, no such study has been conducted on rainbow trouts. Due to its PK and PD properties, mar-bofloxacin can be used to treat bacterial diseases in rainbow trouts. However, the PK and PD of marbofloxacin should be determined before its use in the rainbow trouts. The present study aimed to determine (i) the PK of marbofloxacin in rainbow trouts following intravenous (IV) and oral administration at a dose of 10 mg/kg; (ii) the minimal in-hibitory concentration (MIC) of marbofloxacin against A. hydrophila, Y. ruckeri, P. putida, and P.fluorescens that were isolated from rainbow trouts; and (iii) the PK/PD integration using the PK and MIC values obtained in this study.
2. Materials and methods 2.1. Chemical
The analytical standard of marbofloxacin (> 98%) was obtained from Sigma-Aldrich. Acetonitrile, orthophosphoric acid, and triethyla-mine were used to detertriethyla-mine analytical purity (Merck, Darmstadt, Germany). Parenteral (Marbox, 100 mg/mL, injectable solution, Ceva, Turkey) formulation of marbofloxacin for IV and oral administration was diluted at the concentration of 10 mg/mL with sterile distilled water.
2.2. Animals
One hundred and ninety-two clinically healthy rainbow trouts (Oncorhynchus mykiss) weighing 100 to 114 g were obtained from Kastamonu University Inland and Marine Fish Research and Application Center (Kastamonu, Turkey). Rainbow trouts were dis-tributed randomly into 32 aquarium recirculation system with 100 L aerated tap water per aquarium and each aquarium contained 6 fish each. Waterflow from the reserve tank for renewal of water was ad-justed at 30 L/h, and the reserve tank was continuouslyfilled with tap water. Water temperature, concentration of dissolved oxygen, pH, and concentrations of unionized ammonia and nitrite were 13 °C ± 1.2 °C, 8.10 ± 0.25 mg/L, 7.6 ± 0.3, 44.4 ± 3.4 ng/L, and 35 ± 2.3μg/L, respectively. The trouts were kept in aquarium within 2 weeks before the study for acclimation. They were fed twice daily with drug-free pellet trout feed (Sibal Yem, Sinop, Turkey). They were fasted for 12 h before and after oral drug administration to avoid any influence of food content on oral absorption of marbofloxacin. The study protocol was approved by the Kastamonu University Animal Experiments Local Ethics Committee, Turkey.
2.3. Experimental designs
Rainbow trouts were randomly divided into two groups equally according to the IV or oral administrations of marbofloxacin. A 10 mg/ kg dose of marbofloxacin was intravenously administered via the caudal vein (n = 96) and orally administered via the gastric gavage (n = 96). The drugs were administered and blood samples were then collected under MS-222 (tricaine methanesulphonate, 200 mg/L) an-esthesia. Six trouts were used at each sampling time. Blood samples of 0.5 mL were collected into anticoagulant (heparin)-containing tubes before (0 h) and after (0.25, 0.5, 1, 2, 4, 8, 12, 18, 24, 36, 48, 72, 96,
120, and 144 h) drug administration using a 26-gauge needle. All blood samples were centrifuged (4000 g, 10 min) to separate the plasma from the blood and then stored at−70 °C until analysis.
2.4. Analytical procedure
Plasma concentrations of marbofloxacin were determined by HPLC-UV according to previously validated method (Potter et al., 2013;Real et al., 2011). The 200μL of acetonitrile was added to 100 μL of plasma samples, and vortexing for 1 min. Then, the samples were centrifuged for 10 min at 10000 g, 100μL of supernatant was harvested and added to 100μL pure water. Then, 10 μL of supernatant was injected onto HPLC system (Shimadzu, Tokyo, Japan), which consisted of pump (LC-20AT), degasser (DGU-20A), column oven (CTO-10A), autosampler (SIL-20A), and UV-VIS (SPD-20A). A Gemini™ C18 column (250 × 4.6 mm; internal diameter, 5μm; Phenomenex, Torrance, CA), which was kept at 40 °C, was used for chromatographic separation. The mobile phase consisted of acetonitrile (18%), and 0.4% triethylamine (82%), including 0.4% orthophosphoric acid. Theflow rate was 1.0 mL/ min and the detection wavelength was 280 nm.
Marbofloxacin calibration standard curve was linear (R2> 0.9996)
between 0.04 and 40μg/mL. The limit of detection and limit of quan-titation for the plasma were 0.02μg/mL and 0.04 μg/mL, respectively. Quality control samples, which were prepared in six replicate analyses of each level at the concentration of 0.2, 2 and 20μg/mL within 1 day or on 6 consecutive days, were used to determine the recovery and precision of assay. The recovery of marbofloxacin ranged from 98% to 105%. The intra-assay and the inter-assay coefficients of variation for marbofloxacin were < 6.7 and < 5.3%, respectively.
2.5. Pharmacokinetic analysis
The mean concentrations of marbofloxacin at each sampling time were calculated following the IV and oral administration. The mean plasma concentrations and time data were then subjected to non-compartmental analysis using WinNonlin 6.1.0.173 software (Pharsight Corporation, Scientific Consulting Inc., North Carolina, USA) to calcu-late the PK parameters of marbofloxacin. Following IV administration, the terminal elimination half-life (t1/2ʎz), AUC, mean residence time
(MRT), total clearance (ClT), and volume of distribution at steady state
(Vdss) were calculated. Following oral administration, t1/2ʎz, AUC, MRT,
peak plasma concentration (Cmax), time to reach the Cmax(Tmax), mean
absorption time (MAT), and bioavailability (F) were calculated. The Cmax and Tmax were determined by direct examination of the mean
plasma concentration-versus-time curve of thefish. t1/2ʎzwas estimated
by ln 2/kel. The AUC was calculated according to the log-trapezoidal rule. The MAT was calculated as follows: MRTOR− MRTIV.Following
oral administration, absolute bioavailability was calculated according to the following formula:
= ×
F 100 (AUCOR/AUC )IV
2.6. Determination of minimal inhibitory concentrations
Broth dilution method of Clinical and Laboratory Standards Institute was used to determine the MICs of marbofloxacin for fish pathogenic bacteria (A. hydrophila, Y. ruckeri, P. putida and P.fluorescens kindly provided from Prof. Dr. Ilhan ALTINOK) previously isolated from rainbow trout (CLSI, 2018). For this purpose, 11 dilutions of marbo-floxacin ranging from 10 to 0.0098 μg/mL was prepared in Mueller Hinton Broth medium and a total of 2 mL of each dilution per tube was used for the MIC test at 13 °C. The lowest concentration of antibiotic that visibly inhibited bacterial growth was considered as MIC.
2.7. Pharmacokinetic/pharmacodynamic integration
AUC0–24/MIC and Cmax/MIC were calculated using the MIC values
determined for A. hydrophila, Y. ruckeri, P. fluorescens, and P. putida strains isolated from rainbow trouts and PK parameters obtained fol-lowing the IV and oral administration of 10 mg/kg marbofloxacin. 2.8. Statistical analyses
Plasma concentrations obtained following IV and oral administra-tion are presented as mean ± SD. The following formula was used to evaluate the differences in common PK parameters based on the route of administration: (100 × (Value obtained following oral administration−Value obtained following IV administration)/Value obtained following IV administration). The values of≤%(−)25 and ≥%(+)25 values were accepted as significant (Hudachek and Gustafson, 2013).
3. Results
3.1. Pharmacokinetics of marbofloxacin
Semi-logarithmic plasma concentration-versus-time curves and PK parameters of marbofloxacin following the IV and oral administration of 10 mg/kg in rainbow trouts are presented inFig. 1andTable 1, re-spectively. The marbofloxacin concentrations at the last observational time point (144 h) following IV and oral administration were 0.06 and 0.08μg/mL, respectively. At 144 h, marbofloxacin was detected in all the samples. Following the IV administration of marbofloxacin in the trouts, t1/2ʎz, MRT0-∞, AUC0-∞, ClT, and Vdss were 18.05 h, 22.97 h,
354.63 h∗ μg/mL, 0.03 L/h/kg, and 0.65 L/kg, respectively. Following oral administration, t1/2ʎz, MRT0-∞, AUC0-∞, Tmax, and Cmax were
27.51 h, 40.28 h, 135.29 h∗ μg/mL, 4 h, and 3.74 μg/mL, respectively. After oral administration, t1/2ʎzand MRT0-∞ of marbofloxacin were
longer and AUC0-∞was lower than that after IV administration. The
oral bioavailability of marbofloxacin was 38.15% in the trouts. 3.2. Pharmacokinetic/pharmacodynamic integration
The MIC values of marbofloxacin against Y. ruckeri, A. hydrophila, P. fluorescens, and P. putida isolated from rainbow trouts were 0.02 μg/mL, 2.5μg/mL, 2.5 μg/mL, and 5 μg/mL, respectively. PK/PD indices of marbofloxacin following IV and oral administration of 10 mg/kg dose in rainbow trouts at 13 °C were presented inTable 2. After IV admin-istration of 10 mg/kg marbofloxacin, the AUC/MIC ratio for Y. ruckeri, A. hydrophila, P.fluorescens, and P. putida was 12052, 96, 96, and 48, respectively. After oral administration of 10 mg/kg dose marbofloxacin, the AUC/MIC ratio for Y. ruckeri, A. hydrophila, P.fluorescens, and P. putida was 3092, 25, 25, and 12, respectively, and the Cmax/MIC ratio
for Y. ruckeri, A. hydrophila, P.fluorescens, and P. putida was 187, 1.5, 1.5, and 0.7, respectively.
4. Discussion
In this study, the dose of marbofloxacin (10 mg/kg) in rainbow trout based on the dose used in tilapia and crucian carp (Shan et al., 2017; Zhu et al., 2009). The t1/2ʎzand ClT of marbofloxacin following IV
administration in rainbow trout were 18.05 h and 0.03 L/h/kg, re-spectively, which were consistent with t1/2ʎzvalues ranging from 11.2
to 24.40 h, and ClTvalues ranging from 0.01 to 0.17 L/h/kg previously
reported for some other quinolones in some fish species at 10–25 °C (Björklund and Bylund, 1991;Bowser et al., 1992;Corum et al., 2018; Hansen and Horsberg, 2000;Kim et al., 2006;Koc et al., 2009;Nouws et al., 1988;Yang et al., 2018). However, the Vdssof marbofloxacin in
rainbow trout was 0.65 L/kg, which was smaller than that (0.96–3.93 L/kg) previously reported for some other quinolones in somefish species at 10–24.7 °C (Bowser et al., 1992;Kim et al., 2006; Koc et al., 2009). Also, the small Vdssof marbofloxacin have been
re-ported in Caretta caretta (0.35 L/kg) (Lai et al., 2009) and ducks (0.57 L/kg) (Goudah and Hasabelnaby, 2011). However, marbofloxacin has shown the largest Vdssin some avian (1.40–3.22 L/kg) (de Lucas
et al., 2005;Lashev et al., 2015), mammalian (1.02–2.47 L/kg) (Altan et al., 2018; Belew et al., 2015) and reptile species (1.5 L/kg) (Poapolathep et al., 2017).
The t1/2ʎz of marbofloxacin following oral administration in
rainbow trout was 27.51 h at 13 °C, which was shorter than that pre-viously reported in crucian carp (50 h, 15 °C) (Zhu et al., 2009). Also, rainbow trout (56.3 h, 15 °C) (Bowser et al., 1992) following the oral administration of enrofloxacin at 10 mg/kg dose has shown the shorter t1/2compared with crucian carp (62.17 h, 25 °C) (Shan et al., 2018). In
Fig. 1. Semi-logarithmic plasma concentration-time curves of marbofloxacin following intravenous (IV) and oral (OR) administrations at a single dose of 10 mg/kg in rainbow trout at 13 °C (Mean ± SD, n = 6).
Table 1
Plasma pharmacokinetic parameters of marbofloxacin following intravenous (IV) and oral (OR) administrations of 10 mg/kg dose at 13 °C in rainbow trout (n = 6). Parameter IV OR GD%a t1/2ʎz(h) 18.05 27.51 52.41 AUC0–24(h∗ μg/mL) 241.03 61.83 −74.35 AUC0-∞(h∗ μg/mL) 354.63 135.29 −61.85 MRT0-∞(h) 22.97 40.28 75.36 MAT (h) – 17.31 – ClT(L/h/kg) 0.03 – – Vdss(L/kg) 0.65 – – Cmax(μg/mL) – 3.74 – Tmax(h) – 4 – F (%) – 38.15 –
t1/2ʎz; elimination half-life, AUC; area under the concentration-versus time
curve, MRT; mean residence time, MAT; mean absorption time, ClT; total
clearance, Vdss; volume of distribution at steady state, Cmax; peak concentration,
Tmax; time to reach the peak concentration, F; absolute bioavailability.
a
Refers to percentage (%) difference of OR administration compared to IV administration [100×(OR-IV)/IV].
Table 2
PK/PD indices of marbofloxacin following intravenous (IV) and oral (OR) ad-ministration of 10 mg/kg dose in rainbow trout at 13 °C.
Bacteria (MIC) IV OR
AUC0–24/MIC AUC0–24/MIC Cmax/MIC
Yersinia ruckeri (0.02μg/mL) 12052 3092 187
Aeromonas hydrophila (2.5μg/mL) 96 25 1.5
Pseudomonasfluorescens (2.5 μg/mL) 96 25 1.5
Pseudomonas putida (5μg/mL) 48 12 0.7
MIC; minimal inhibitory concentration, AUC; area under the concentration-versus time curve, Cmax; peak plasma concentration, OR; oral.
this study, the Cmaxand Tmaxfollowing oral administration of
marbo-floxacin at 13 °C in rainbow trout was 3.74 μg/mL and 4 h, which were lower and longer, respectively, than those in crucian carp (6.43μg/mL, 1.74 h, 15 °C) (Zhu et al., 2009). In crucian carp, the increase from 15 °C to 20 °C in water temperature has caused the high Cmaxand short Tmax
of marbofloxacin (Zhu et al., 2009). The increase in water temperature increases the movement of the gastrointestinal tract in fishes. For in-stance, an increase in water temperature from 5 °C to 20 °C accelerates the discharge of the stomach contents by 3–4 folds (Windell et al., 1976). Infishes, the absorption of drugs from the intestinal tract varies among the species (Sekkin and Kum, 2011). PK differences mentioned between the rainbow trout and crucian carp above may be related to absorption and elimination differences in fish species and water tem-perature.
In this study, marbofloxacin exhibited a longer t1/2ʎzfollowing oral
administration than that following IV administration. Some quinolones have also shown longer t1/2ʎzfollowing oral administration infishes
than that following IV administration (Björklund and Bylund, 1991; Bowser et al., 1992;Kim et al., 2006). In this research, the oral bioa-vailability of marbofloxacin was 38.15% in rainbow trout. The oral bioavailability of marbofloxacin has not been previously reported in fish. However, the oral bioavailability of some fluoroquinolones in variousfish species is between 25% and 86% at water temperature of 10 °C–26 °C (Bowser et al., 1992;Fang et al., 2012;Koc et al., 2009;Xu et al., 2016). This difference in bioavailability of fluoroquinolones in fishes might be associated with the water temperature. A decrease in water temperature from 15 °C to 10 °C reduces the oral bioavailability of enrofloxacin from 42% to 25% in rainbow trouts (Bowser et al., 1992). Antibiotic bioavailability of ≥30% is acceptable in fishes (Bowser and Babish, 1991); therefore, the oral administration of mar-bofloxacin may be preferred in the treatment of rainbow trouts.
The inappropriate use offluoroquinolone antibiotics in humans and animals results in failure of the treatment and increases the prevalence of resistant pathogenic bacteria (Bakken, 2004). The clinical success of an antibiotic depends on the relationship between the PD and PK characteristics of the drug against the target pathogen. The AUC0–24/
MIC and Cmax/MIC indices for the PD/PK integration of
fluor-oquinolones that show concentration-dependent activity is calculated to estimate the clinical efficacy of a drug (Lees et al., 2006;McKellar et al., 2004; Toutain and Lees, 2004; Toutain et al., 2002). The AUC0–24/MIC ratio of > 125 indicates that clinical efficacy is > 80%.
The Cmax/MIC ratio should be > 10, which is significant for minimal
bacterial resistance development and effective treatment (McKellar et al., 2004;Toutain and Lees, 2004;Toutain et al., 2002).
The maximum growth and yield temperature of rainbow trout are at 10–18 °C (Hokanson et al., 1977). Therefore, the PKs and MIC of mar-bofloxacin was determined in rainbow trout hold at 13 °C. Because the PKs and PDs of a drug infish is very much affected by temperature, PK/ PD integration would be modified based on the temperature and the strain of pathogen. The effect of temperature on MIC of some fluor-oquinolones forfish pathogens has showed the differences according to antibiotic drug and the strain offish pathogens (Martinsen et al., 1992). Marbofloxacin, enrofloxacin, flumequine and oxolinic acid have ex-hibited higher MIC for A. salmonicida subsp. salmonicida, Vibrio salmo-nicida and A. hydrophila at low temperature than at high temperature, but not for Y. ruckeri (Martinsen et al., 1992). In this study, the MIC values for marbofloxacin at 13 °C in Y. ruckeri, A. hydrophila, P. fluor-escens, and P. putida strains isolated from the rainbow trouts were 0.02μg/mL, 2.5 μg/mL, 2.5 μg/mL, and 5 μg/mL, respectively. While a 10 mg/kg dose of marbofloxacin provided the target AUC0–24/MIC
(> 125, IV and oral) and Cmax/MIC (> 10, oral) values for Y. ruckeri, it
did not provide the target values for A. hydrophila and Pseudomonas spp. However, to provide PK/PD values targeted, the IV dose of 10 mg/kg produced AUC value that would be sufficient to treat diseases caused susceptible pathogens with an MIC≤1.91 μg/mL, and the oral dose of 10 mg/kg produced AUC and Cmaxvalues that would be sufficient to
treat diseases caused susceptible pathogens with an MIC≤0.37 μg/mL. In conclusion, marbofloxacin exhibited a long t1/2ʎz in rainbow
trouts. The oral bioavailability of marbofloxacin was higher than the recommended dose for effective use in fishes (> 30%). Following the IV and oral administration of 10 mg/kg marbofloxacin, AUC/MIC and Cmax/MIC values were above the target levels for Y. ruckeri, whereas
this dose was not sufficient for A. hydrophila and Pseudomonas spp. Following IV and oral administration, marbofloxacin was effective against bacteria with MIC values of≤1.91 μg/mL and ≤0.37 μg/mL, respectively. Because the PKs and PDs of a drug in fishes are sig-nificantly affected by water temperature, the dosage regimens of mar-bofloxacin should be modified according to water temperature. Funding
This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.
Declaration of Competing Interest
The authors declare no conflicts of interest. Acknowledgement
We thank Prof. Dr. Ilhan ALTINOK for providing bacterial species. This study was presented in abstract form as an oral presentation to the 2. International Congress on Engineering and Life Science “ICELIS 2019,” Kastamonu, Turkey, 11–14 April 2019.
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