Captive psittacine birds are predisposed to lipid disorders, which include atherosclerosis, hepatic lipidosis, xanthomas, and obesity, with atherosclerosis being one of their most common lipid disorders. Similar to humans, increased plasma cholesterol levels are associated with increased risk of atherosclerosis in birds.1 Decreasing blood cholesterol and low-density lipoprotein (LDL-C) levels are some of the principal therapeutic goals for preventing heart disease in humans, with statin drugs commonly being prescribed. In addition, statin drugs have direct antiatherosclerotic effects independent from their lipid-lowering effects.2 Atorvastatin is one of the most common drugs used in human medicine for the prevention and treatment of atherosclerosis and associated dyslipidemias.3
It has been hypothesized that statin drugs, including atorvastatin, may be able to help reduce plasma cholesterol and be of therapeutic use to birds with dyslipidemias.4 Atorvastatin works by inhibiting 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase in the liver. HMG-CoA reductase is an important rate-limiting enzyme involved in cholesterol synthesis that converts HMG-CoA to mevalonic acid, a cholesterol precursor.5 Through this pathway, statins are able to decrease plasma cholesterol, specifically LDL-C.5,6 Atorvastatin has also been found to increase high-density lipoprotein cholesterol concentrations and decrease triglyceride concentrations in humans.6
The clinical dosage for atorvastatin in humans ranges from 10 to 80 mg/d.3 The oral bioavailability of atorvastatin is low, approximately 12%.6 Atorvastatin administered at higher doses (such as 40 to 80 mg/day) can have an LDL-C–lowering effect of at least 50% in humans.5 When dosed as a single dose of 40 mg orally, atorvastatin has been measured to have a maximum plasma concentration (Cmax) level between 19.8 to 66 ng/mL.7,8 Atorvastatin has a half-life of 14 hours in humans, with a peak plasma concentration being reached 4 hours after administration.6 Atorvastatin also has 2 active metabolites, orthohydroxy- and parahydroxyatorvastatin acid, which are the dominant metabolites detected in plasma, indicating the need to measure these concentrations in conjunction with atorvastatin levels.5,6 These 2 metabolites are equipotent to the parent drug.6
Multiple studies have been performed evaluating the use of statins in birds. A study9 evaluating the effect of atorvastatin in hyperlipidemic chickens found that atorvastatin decreased plasma cholesterol and triglycerides and had some anti-inflammatory effects on the liver. Most of the research evaluating the use of statins in psittacines has been conducted in various species of Amazon parrots.9–11 In studies evaluating the use of rosuvastatin and atorvastatin in Hispaniolan Amazon parrots (Amazona ventralis), rosuvastatin was unable to reach quantifiable plasma concentrations when dosed at 10 to 25 mg/kg PO,10 and atorvastatin did not result in a significant decrease in plasma cholesterol when dosed at 10 mg/kg PO every 24 hours.9 A more recent pharmacokinetic study has shown that an oral dose of 20 mg/kg atorvastatin in orange-winged Amazon parrots (A amazonica) was able to reach plasma concentrations considered to be therapeutic in humans.11 In Quaker parrots (Myiopsitta monachus), neither an oral dose of rosuvastatin or atorvastatin 10 mg/kg PO every 12 to 24 hours for 14 days nor an oral dose of atorvastatin 20 mg/kg PO every 12 hours for 14 days caused any significant decrease in the concentrations of plasma cholesterol, triglycerides, or other lipids.12 The cockatiel (Nymphicus hollandicus) is one of the most common companion birds and has been shown to be at increased odds of developing clinically important atherosclerotic lesions.13 However, there is currently no data on the use of lipid-lowering drugs in this species.
The objectives of this study were to evaluate the plasma concentrations and determine the pharmacokinetic parameters of atorvastatin and its primary active metabolites (ortho- and parahydroxyatorvastatin) following administration of a single oral dose in cockatiels of 20 mg/kg. It was hypothesized that the plasma concentration would be similar to the human atorvastatin plasma concentration that shows clinical beneficial lipid-lowering effects.
Methods
Animals
Fourteen adult cockatiels (7 males, 7 females) of about 2 years of age were used in this study. An intake physical examination, packed cell volume and total solids, and manual complete blood count were performed on each cockatiel to ensure appropriate health prior to the study. The mean ± SD body weight was 107.1 ± 16.2 g. Cockatiels were housed in heterosexual pairs and offered pellets (Maintenance diet; Roudybush Inc) and water ad libitum. All birds were exposed to a photoperiod of 12 hours of light and 12 hours of darkness, and the temperature of the room was maintained at approximately 24 °C. The study was approved by the Institutional Animal Care and Use Committee at the University of California, Davis.
Preparation of oral atorvastatin
The oral suspension of 10 mg/mL atorvastatin was prepared using 80 mg atorvastatin calcium tablets (Apotex Corp) in NaCl, Ora-Plus (Paddock Laboratories), and Ora-Sweet (Paddock Laboratories) at a ratio of 2:2:1. Similar compounding suspensions were used in similar studies in parrots,11,12 and adequate stability of compounded atorvastatin suspension was also demonstrated in a variety of different vehicles.14 Atorvastatin tablets were pulverized into a powder using an electric tablet blender. The suspension was made less than 12 hours prior to the study and was vortexed several times, including immediately before administration. It was stored at room temperature before use, and homogeneity was checked by transillumination. Because the resulting consistency was too thick and could not be solubilized into a less viscous liquid, stability could not be checked by mass spectrometry. The suspension was then drawn up into individual 1-mL oral syringes for administration.
Experimental design
The cockatiels were each manually restrained to allow for direct administration of the oral atorvastatin into the crop via a size 14 metal gavage tube. The cockatiels were not fasted prior to administration. Each cockatiel was administered a single oral dose of 20 mg/kg based on their individual body weight. The dose administered was based on a similar study performed in orange-winged Amazon parrots.11 A balanced incomplete block design was used with the 14 cockatiels to minimize the amount of blood collected from each bird as well as to minimize the stress associated with restraint. The design was implemented according to balanced incomplete block designs proposed by Cox and Cochran.15 Three blood samples were collected from each bird, with 6 replications per time point and a total of 7 time points in addition to time 0 (Table 1). The time points selected were 0.5, 1, 2, 3, 4, 12, and 24 hours after administration of oral atorvastatin. Randomization of time sequences and birds was performed using computer software (R; R Foundation for Statistical Computing). The total blood volume harvested was no more than 1% of the bird’s bodyweight over the 24-hour period. For each time point described, approximately 0.2 to 0.3 mL of whole blood was collected using individual U-100 0.5-mL insulin syringes (29-gauge needle) and sampled from the right jugular vein. Blood samples collected were placed in lithium-heparin pediatric collection tubes without plasma separator (Microtainer; BD), kept over ice, and centrifuged for 6 minutes at 3500 X g within 4 hours of collection. Plasma was then transferred into labeled 0.5-mL Eppendorf tubes and stored at −80 °C until analysis.
Experimental design.
| Time point (h) | Bird 1 (F) | Bird 2 (M) | Bird 3 (M) | Bird 4 (F) | Bird 5 (M) | Bird 6 (M) | Bird 7 (F) | Bird 8 (F) | Bird 9 (M) | Bird 10 (F) | Bird 11 (M) | Bird 12 (F) | Bird 13 (F) | Bird 14 (M) |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| 0.5 | X | X | X | X | X | X | ||||||||
| 1 | X | X | X | X | X | X | ||||||||
| 2 | X | X | X | X | X | X | ||||||||
| 3 | X | X | X | X | X | X | ||||||||
| 6 | X | X | X | X | X | X | ||||||||
| 12 | X | X | X | X | X | X | ||||||||
| 24 | X | X | X | X | X | X |
A balanced incomplete block design was used with the 14 cockatiels to minimize the amount of blood collected from each bird as well as to minimize the stress associated with restraint. Three blood samples were collected from each bird, with 6 replicates per time point and a total of 7 time points.
Plasma concentration determinations of atorvastatin, parahydroxyatorvastatin, and orthohydroxyatorvastatin
Plasma calibrators were prepared by dilution of the atorvastatin, orthohydroxyatorvastatin, and parahydroxyatorvastatin (Cayman Chemical Company) working standard solutions with drug-free cockatiel plasma to concentrations ranging from 0.1 to 800 ng/mL. Calibration curves and negative control samples were prepared fresh for each quantitative assay. In addition, quality control samples (cockatiel plasma fortified with analyte at 3 concentrations within the standard curve) were included with each sample set as an additional check of accuracy.
Prior to analysis, 50 μL of plasma was diluted with 50 μL of methanol:water:dimethyl sulfoxide (1:1:1, v:v:v) and 150 μL of acetonitrile (ACN):1M acetic acid (9:1, v:v) containing 0.005 ng/μL of d5-atorvastin (Cayman Chemical Company) internal standard, to precipitate proteins. The samples were vortexed for 1 minute to mix, refrigerated for 20 minutes, 159 vortexed for an additional 1 minute, and centrifuged in a Sorvall ST 40R centrifuge (Thermo 160 Scientific) at 4,300 rpm/3,830 X g for 10 minutes at 4 °C, and 30 μL of the supernatant was injected into the liquid chromatography–tandem mass spectrometry system.
The analyte concentrations were measured in plasma by liquid chromatography–tandem mass spectrometry using positive heated electrospray ionization. Quantitative analysis was performed on a TSQ Altis triple quadrupole mass spectrometer coupled with a Vanquish liquid chromatography system (Thermo Scientific). Chromatography used a Kinetex 5 cm X 2 mm 2.6-µm column (Phenomenex) and a linear gradient of ACN in water with a constant 0.2% formic acid at a flow rate of 0.35 mL/min. The initial ACN concentration was held at 1% for 0.2 minutes, ramped to 90% over 6.7 minutes, and held at that concentration for 0.1 minutes before re-equilibrating for 3.35 minutes at initial conditions.
Detection and quantification were conducted using selective reaction monitoring of initial precursor ion for atorvastatin (mass-to-charge ratio [m/z], 559), orthohydroxyatorvastatin and parahydroxyatorvastatin (m/z, 575), and d5-atorvastatin (m/z, 564). The response for the product ions for atorvastatin (m/z, 250, 276, and 440), orthohydroxatorvastatin and parahydroxyatorvastatin (m/z, 250, 292, 440, and 466), and d5-atorvastatin (m/z, 255 and 445) were plotted and peaks at the proper retention time integrated using Quanbrowser software (Thermo Scientific). Quanbrowser software was used to generate calibration curves and quantitate analytes in all samples by linear regression analysis. A weighting factor of 1X was used for all calibration curves.
The responses for all analytes were linear and gave correlation coefficients of 0.99 or better. Accuracy was reported as percentage of nominal concentration and precision as percentage of relative standard deviation (Table 2). The technique was optimized to provide a limit of quantitation of 0.1 ng/mL and a limit of detection of approximately 0.05 ng/mL for all analytes.
Accuracy and precision values for liquid chromatography–tandem mass spectrometry analysis of atorvastatin, orthohydroxyatorvastatin (2-OH), and parahydroxyatorvastatin (4-OH) in cockatiel plasma.
| Analyte | Concentration (ng/mL) | Accuracy (% nominal concentration) | Precision (% relative SD) |
|---|---|---|---|
| Atorvastatin | 0.3 | 100 | 8 |
| 20 | 102 | 3 | |
| 2-OH atorvastatin | 0.3 | 106 | 18 |
| 20 | 98 | 16 | |
| 4-OH atorvastatin | 0.3 | 103 | 5 |
| 20 | 94 | 5 |
Pharmacokinetic analysis
A sparse sampling noncompartmental analysis was performed on the plasma atorvastatin and metabolite concentrations using a commercially available computer software program (Phoenix WinNonlin, version 8.3; Certara Inc). The Cmax and time to maximal plasma concentration (tmax) were obtained directly from the plasma concentration data. The area under the concentration-versus-time curve from time 0 to the last measured concentration at 24 hours (AUClast), the terminal rate constant, and terminal half-life (t1/2) were determined. Pharmacokinetic parameters for atorvastatin, parahydroxyatorvastatin, and orthohydroxyatorvastatin were reported as mean values. Because of the sparse sampling design and pooling of time-concentration values for noncompartmental analysis, standard deviations of the pharmacokinetic parameter estimates could not be determined. However, variability of the concentrations of the compounds over time may be appreciated (Figure 1).
Mean plasma atorvastatin, parahydroxyatorvastatin (4-OH), and orthohydroxyatorvastatin (2-OH) concentrations plotted over time (hours) in 14 cockatiels administered a single oral dosage of 20 mg/kg atorvastatin.
Citation: American Journal of Veterinary Research 85, 7; 10.2460/ajvr.24.03.0068
Results
Plasma concentrations of atorvastatin, parahydroxyatorvastatin, and orthohydroxyatorvastatin after a single oral administration of 20 mg/kg atorvastatin to the 14 cockatiels are depicted in Figure 1. Specific pharmacokinetic parameters for atorvastatin, parahydroxyatorvastatin, and orthohydroxyatorvastatin are listed (Table 3). The estimated Tmax for atorvastatin, parahydroxyatorvastatin, and orthohydroxyatorvastatin was 3 hours for each. The Cmax for atorvastatin, parahydroxyatorvastatin, and orthohydroxyatorvastatin was 152.6 ng/mL, 172.4 ng/mL, and 68.8 ng/mL, respectively. The t1/2 was 4 hours, 6.8 hours, and 4.6 hours for atorvastatin, parahydroxyatorvastatin, and orthohydroxyatorvastatin, respectively.
Pharmacokinetic parameters for atorvastatin, 4-OH, and 2-OH after administration of 20 mg/kg of atorvastatin as a 10-mg/mL oral suspension to cockatiels (n = 14).
| Pharmacokinetic parameter | Atorvastatin | 2-OH atorvastatin | 4-OH atorvastatin |
|---|---|---|---|
| Cmax (ng/mL) | 152.6 | 68.8 | 172.4 |
| tmax (h) | 3 | 3 | 3 |
| Lambdaz (1/h) | 0.173 | 0.25 | 0.102 |
| t1/2 (h) | 4 | 4.62 | 6.78 |
| AUClast (h * ng/mL) | 1,080 | 455.5 | 1,737.3 |
All parameters were generated using noncompartmental analysis.
AUClast = Area under the curve to the last time point collected. Cmax = Maximum plasma concentration. Lambdaz = Terminal rate constant. t1/2 = Elimination half-life. tmax = Time of maximal plasma concentration.
The atorvastatin concentration at 0.5 hours for one bird was not included in the analysis as the concentration was extremely high (21,144.1 ng/mL) when compared to the other birds’ samples, suggesting sample contamination or other error. Additionally, the other atorvastatin concentrations in this bird were much lower than this first measurement (44 ng/mL at 6 hours and 13.2 ng/mL at 24 hours), and the 2 metabolites yielded expected concentrations, further supporting potential contamination. No adverse effects (vomiting, diarrhea, hyporexia/anorexia, or lethargy) were detected in any of the birds throughout the course of the study.
Discussion
After the administration of a 20-mg/kg-body-weight dose of oral compounded atorvastatin, plasma concentrations of atorvastatin and its primary active metabolites (para- and orthohydroxyatorvastatin) were detected at each time point. The drug was well tolerated in all study birds.
A compounded atorvastatin suspension was prepared from commercially available tablets as it was necessary to be able to administer this drug orally to cockatiels. The drug was used extralabel as no statin is FDA-approved for use in Psittaciformes. Veterinarians should adhere to compounding regulations and be aware that pharmacokinetic properties may differ between compounded and FDA-approved products.
When comparing the pharmacokinetic parameters of atorvastatin in cockatiels to humans, where clinically effective plasma concentrations are known, drug concentrations in cockatiels achieved levels considered to be therapeutic in humans. In humans that were hemodialysis patients receiving a single dose of 40 mg atorvastatin, the average Cmax was 28.6 ng/mL at 1 to 2 hours, compared with an average Cmax of 152.6 ng/mL at 3 hours in cockatiels receiving a single dose of 20 mg/kg oral atorvastatin.8 In that same study, the average t1/2 was 11.8 hours in human patients, which is longer than that reported for cockatiels in the current study (4 hours).8 The shorter t1/2 may be attributable to a higher rate of metabolism and therefore systemic clearance in cockatiels compared to humans. This is further supported by cockatiels having a shorter t1/2 of orthohydroxyatorvastatin compared to humans, where the orthohydroxyatorvastatin t1/2 in humans was 18 hours, while the t1/2 of orthohydroxyatorvastatin was reported to be 4.6 hours for cockatiels in the current study.8 The t1/2 of parahydroxyatorvastatin was not measured in this human study due to orthohydroxyatorvastatin being the major active metabolite of atorvastatin in humans. Nonetheless, cockatiels may have a higher rate of systemic clearance of atorvastatin compared to humans due to their higher metabolism and faster t1/2 of atorvastatin and one of its major metabolites.
Due to the method in which we conducted our study (a sparse-sampling noncompartmental analysis), we were unable to evaluate the interindividual variability for the cockatiel data as the concentration data was pooled to generate a single set of pharmacokinetic parameters. However, the variability may be inferred from Figure 1, in which there are 6 replicates (cockatiels) per time point. The sample size may not be enough to give a precise estimate of variability at each time point. In addition, it is possible to statistically compare the pharmacokinetic parameters in cockatiels to orange-winged Amazon parrots utilizing the 95% CI of these parameters obtained from a similar study evaluating the pharmacokinetics of a single dose of oral atorvastatin in orange-winged Amazon parrots.11 When compared to orange-winged Amazon parrots, atorvastatin had a significantly higher Cmax in cockatiels (152.6 ng/mL in cockatiels vs 82.6 [95% CI, 42.2 to 123] ng/mL in Amazon parrots). Additionally, the AUClast was significantly higher in cockatiels (1,080 h·ng/mL in cockatiels vs a mean of 327.5 [95% CI, 217.8 to 437.2] h·ng/mL in Amazon parrots). The substantially higher Cmax and AUClast of atorvastatin for the same oral dose suggests that cockatiels likely have better oral bioavailability of atorvastatin compared with Amazon parrots. In humans, the bioavailability of atorvastatin is generally low (12%).5
Cockatiels had a significantly higher Cmax and AUClast of both active metabolites of atorvastatin compared to Amazon parrots. For orthohydroxyatorvastatin, the Cmax was 68.8 ng/mL in cockatiels versus a mean of 7.35 (95% CI, 4.6 to 10.1) ng/mL in Amazon parrots, and the AUClast was 455.5 ng/mL in cockatiels versus 68.3 (95% CI, 42.6 to 94) ng/mL in Amazon parrots. For parahydroxyatorvastatin, the Cmax was 172.4 ng/mL in cockatiels versus 34.1 (95% CI, 23 to 45.2) ng/mL in Amazon parrots, and the AUClast was 1,737.3 ng/mL in cockatiels versus 347.2 (95% CI, 242.6 to 451.8) ng/mL in Amazon parrots. The significantly higher Cmax and AUClast of both active metabolites also suggests that cockatiels likely have better oral bioavailability of atorvastatin compared with Amazon parrots.
One potential cause of this difference in bioavailability other than species variability is that for this study, an oral sweetener, Ora-Sweet, was added to the compounded atorvastatin and was not included in the compounded formulation of atorvastatin that was administered to the Amazon parrots. It is possible that the inclusion of Ora-Sweet may have improved the absorption of the compounded atorvastatin formulation utilized in the current study. However, it is important to note that in humans, food intake decreases the bioavailability of atorvastatin.5–7 Species-specific differences in gastrointestinal physiology may also account for this difference.
The half-life of atorvastatin is shorter in cockatiels when compared to orange-winged Amazon parrots but not significantly shorter when using the CI calculated with the Amazon parrot data (4 hours in cockatiels vs 5.96 [95% CI, 0 to 14] hours in Amazon parrots), but tremendous interindividual variability was seen in the Amazon parrot study.11 Similar comparisons can be made for the half-lives of orthohydroxyatorvastatin and parahydroxyatorvastatin between cockatiels and Amazon parrots. There does not appear to be a difference in the half-life of atorvastatin nor its active metabolites in cockatiels compared to Amazon parrots, but further research would need to be conducted to confirm this, especially since considerable interindividual variability was seen in the Amazon parrot study.
The plasma concentrations and pharmacokinetic parameters were measured for para- and orthohydroxyatorvastatin due to these active metabolites being a large contributor to atorvastatin’s ability to inhibit HMG-CoA reductase, extend the duration of effect of atorvastatin, and therefore decrease plasma lipid concentrations.5,6 The half-life of parahydroxyatorvastatin was longer than atorvastatin, 6.78 hours and 4 hours, respectively, supporting that para- and orthohydroxyatorvastatin may prolong HMG-CoA reductase ability in cockatiels similarly to humans by staying in the blood longer than the parent drug. When comparing the pharmacokinetic parameters of para- and orthohydroxyatorvastatin, parahydroxyatorvastatin had much higher Cmax, longer half-life, and a much higher AUClast, suggesting that parahydroxyatorvastatin may be the primary metabolite in cockatiels. In humans, orthohydroxyatorvastatin is the primary active metabolite of atorvastatin.8 It can also be inferred from these data that the 2 active metabolites would be expected to be responsible for about two-thirds of HMG-CoA reductase activities. When deciding on a dose of atorvastatin to administer, it is important to take into account the pharmacokinetics of the active metabolites as well, and given that plasma concentrations of atorvastatin and its active metabolites were above 10 ng/mL at 12 hours, and were still measurable but only above 2 ng/mL at 24 hours, a starting dose of 20 mg/kg PO every 12 to 24 hours could be used to treat lipid disorders in this species.
The pharmacokinetic parameters were calculated using a sparse-sampling noncompartmental analysis. This allowed us to pool together the plasma concentrations collected and generate a single set of pharmacokinetic parameters. An alternative model that was considered was a nonlinear mixed-effects model, which also analyzes sparse data but generates a population pharmacokinetic analysis and allows for analysis of variability. It was elected to analyze the data using a noncompartmental analysis to allow for direct comparison with data obtained from a similar study in Amazon parrots.11
The limitations of this study included its sample size of only 14 cockatiels, all around the same age. A larger sample size could help analyze variability between individuals and allow for more measurements to be obtained at each time point. In this current study, blood samples were only collected for analysis from 6 birds at each time point due to the limitation of how much blood could safely be collected from each individual bird over the 24-hour period. Analyzing the pharmacokinetics and plasma concentrations in a group with a wider age variety may also show differences in the parameters evaluated as cockatiels of different ages may metabolize atorvastatin differently. In the Amazon parrot study, the parrots used were of various ages, with the youngest Amazon parrot being 8 years old and the oldest being 32+ years old, which could contribute to the large variability in their data as well as potentially account for some of the differences in bioavailability when compared to this current study of cockatiels all around the age of 2 years old.11 Given this, future studies evaluating the pharmacokinetics and pharmacodynamics of atorvastatin in cockatiels could use larger sample sizes of cockatiels of the same age and potentially repeat the studies in older birds to assess whether age is a cause of variability. One sample had an erroneously extremely high concentration of atorvastatin but normal concentrations of the 2 metabolites, suggesting sample contamination prior to analysis. Given that no other samples exhibited a comparably elevated concentration of the parent drug, it is improbable that it affected the results of this study.
This study determined the plasma concentrations and pharmacokinetic profile of cockatiels administered an oral suspension of atorvastatin at a dose of 20 mg/kg body weight. These results support the therapeutic use of atorvastatin at the dose evaluated in this species based on human pharmacokinetic data. A starting dose of 20 mg/kg PO every 12 to 24 hours could be used to treat lipid disorders pending more data on multidose use and hypolipidemic efficacy. This dosage frequency is recommended since plasma concentrations of atorvastatin and its active metabolites were above 10 ng/mL at 12 hours and were still measurable but only above 2 ng/mL at 24 hours. It is important to note that in humans, plasma atorvastatin concentrations do not necessarily correlate well with lipid-lowering activity and clinical efficacy.6,8 Pharmacological response is better correlated with clinical efficacy,6 so ultimately these starting dosages will have to be adjusted as needed based on response to treatment. It has been suggested that hepatic concentration of statins and their active metabolites would be more correlated to the drug’s clinical efficacy compared to plasma efficacy as HMG-CoA reductase activity primarily occurs in the liver.6 Additional pharmacokinetic (multidose) and pharmacodynamic studies in cockatiels will help determine the utility in prescribing atorvastatin for cockatiels and potentially other psittacines with lipid disorders.
Acknowledgments
None reported.
Disclosures
The authors have nothing to disclose. No AI-assisted technologies were used in the generation of this manuscript.
Funding
The study was partially funded through a UC Davis Academic Senate Small Grants in Aid of Research.
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