scholarly journals Pharmacokinetic Profile of Oral Administration of Mefloquine to Clinically Normal Cats: A Preliminary In-Vivo Study of a Potential Treatment for Feline Infectious Peritonitis (FIP)

Animals ◽  
2020 ◽  
Vol 10 (6) ◽  
pp. 1000
Author(s):  
Jane Yu ◽  
Benjamin Kimble ◽  
Jacqueline M. Norris ◽  
Merran Govendir
Keyword(s):  
Plasma Concentration ◽  
Peak Plasma ◽  
Peak Plasma Concentration ◽  
Plasma Concentrations ◽  
Pharmacokinetic Profile ◽  
Feline Calicivirus ◽  
Potential Treatment ◽  
Feline Infectious Peritonitis ◽  
Feline Coronavirus

The pharmacokinetic profile of mefloquine was investigated as a preliminary study towards a potential treatment for feline coronavirus infections (such as feline infectious peritonitis) or feline calicivirus infections. Mefloquine was administered at 62.5 mg orally to seven clinically healthy cats twice weekly for four doses and mefloquine plasma concentrations over 336 h were measured using high pressure liquid chromatography (HPLC). The peak plasma concentration (Cmax) after a single oral dose of mefloquine was 2.71 ug/mL and time to reach Cmax (Tmax) was 15 h. The elimination half-life was 224 h. The plasma concentration reached a higher level at 4.06 ug/mL when mefloquine was administered with food. Adverse effects of dosing included vomiting following administration without food in some cats. Mild increases in serum symmetric dimethylarginine (SDMA), but not creatinine, concentrations were observed. Mefloquine may provide a safe effective treatment for feline coronavirus and feline calicivirus infections in cats.

scholarly journals Pharmacokinetics of Lornoxicam in rabbits after single intravenous bolus and intramuscular administrations

2016 ◽  
Vol 4 (1) ◽  
pp. 66
Author(s):  
Abubakr El-Mahmoudy
Keyword(s):  
Plasma Concentration ◽  
Half Life ◽  
Peak Plasma ◽  
Peak Plasma Concentration ◽  
Plasma Concentrations ◽  
Pharmacokinetic Profile ◽  
Volume Of Distribution ◽  
Bolus Administration ◽  
Systemic Bioavailability ◽  
Total Body

The pharmacokinetics of lornoxicam (a non-steroidal anti-inflammatory drug) at a dose of 0.4 mg/Kg body weight was evaluated after single intravenous (i.v.) and intramuscular (i.m.) bolus administrations in rabbits. An HPLC assay using pure lornoxicam base as a standard was used to measure its concentrations in plasma at prefixed time points up to 12 hours post administration. Following an i.v. bolus injection, the plasma concentration-time curves of lornoxicam were best represented by two-compartment open model. The drug was rapidly distributed and moderately eliminated with half-lives of distribution (t1/2α) and elimination (t1/2β) of 0.238 and 2.611 h, respectively. The volume of distribution was large with (Vdss) value of 1.499 L. The total body clearance (ClB) was 0.413 L/h. After i.m. bolus administration of the same dose, lornoxicam was moderately and completely absorbed in rabbits with an absorption half-life (t½ab) of 1.228 h with peak plasma concentration (Cmax) of 0.463 μg/mL attained at 1.512 h (Tmax) and systemic bioavailability of 99.79%. The elimination half-life following i.m. administration was 2.283 h. The extent of plasma protein binding percent was 98.9%. The study recommends the use of lornoxicam in rabbits because of its good pharmacokinetic profile indicated by good absorption, bioavailability and plasma concentrations.

scholarly journals Pharmacokinetics of clarithromycin after single intravenous and intracrop bolus administrations to broiler chickens

2016 ◽  
Vol 4 (1) ◽  
pp. 12 ◽  
Author(s):  
Hanady AwadAllah ◽  
Shaban Awidat ◽  
Abubakr El-Mahmoudy
Keyword(s):  
Plasma Concentration ◽  
Half Life ◽  
Broiler Chickens ◽  
Peak Plasma ◽  
Peak Plasma Concentration ◽  
Plasma Concentrations ◽  
Pharmacokinetic Profile ◽  
Volume Of Distribution ◽  
Bolus Administration ◽  
Systemic Bioavailability

<p>The pharmacokinetics of clarithromycin at a dose of 7.5 mg/kg body weight was evaluated after single intravenous (i.v.) and intracrop (i.c.) bolus administrations in broilers. An HPLC assay using pure clarithromycin base as a standard was used to measure its concentrations in plasma. Following an i.v. bolus injection, the plasma concentration-time curves of clarithromycin were best represented by two-compartment open models. The drug was rapidly distributed and moderately eliminated with half-lives of distribution (<em>t</em><sub>1/2α</sub>) and elimination (<em>t</em><sub>1/2β</sub>) of 0.38 and 4.58 h, respectively. The volume of distribution was large with (V<sub>dss</sub>) value of 6.89 L. The total body clearance (<em>Cl</em><sub>B</sub>) was 1.2 L/h. After i.c. bolus administration of the same dose, clarithromycin was moderately absorbed in broilers with an intermediate absorption half-life (<em>T</em><sub>½ab</sub>) of 0.72 h with peak plasma concentration (<em>C</em><sub>max</sub>) of 1.69 μg/ml attained at 1.7 h (<em>T</em><sub>max</sub>) and systemic bioavailability of 66.54%. The elimination half-life following i.c. administration was 2.11 h. The extent of plasma protein binding percent was 52%. The study recommends the use of clarithromycin in broilers because of its good pharmacokinetic profile indicated by good absorption, bioavailability and plasma concentrations ≥ MICs of many sensitive microorganisms.</p>

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 Assessment of Metabolic Interaction between Repaglinide and Quercetin via Mixed Inhibition in the Liver: In Vitro and In Vivo

Pharmaceutics ◽  
2021 ◽  
Vol 13 (6) ◽  
pp. 782
Author(s):  
Ji-Min Kim ◽  
Seong-Wook Seo ◽  
Dong-Gyun Han ◽  
Hwayoung Yun ◽  
In-Soo Yoon
Keyword(s):  
Plasma Concentration ◽  
Liver Microsome ◽  
Peak Plasma ◽  
Peak Plasma Concentration ◽  
Systemic Exposure ◽  
Concurrent Administration ◽  
Time Curve ◽  
Mixed Inhibition

Repaglinide (RPG), a rapid-acting meglitinide analog, is an oral hypoglycemic agent for patients with type 2 diabetes mellitus. Quercetin (QCT) is a well-known antioxidant and antidiabetic flavonoid that has been used as an important ingredient in many functional foods and complementary medicines. This study aimed to comprehensively investigate the effects of QCT on the metabolism of RPG and its underlying mechanisms. The mean (range) IC50 of QCT on the microsomal metabolism of RPG was estimated to be 16.7 (13.0–18.6) μM in the rat liver microsome (RLM) and 3.0 (1.53–5.44) μM in the human liver microsome (HLM). The type of inhibition exhibited by QCT on RPG metabolism was determined to be a mixed inhibition with a Ki of 72.0 μM in RLM and 24.2 μM in HLM as obtained through relevant graphical and enzyme inhibition model-based analyses. Furthermore, the area under the plasma concentration versus time curve (AUC) and peak plasma concentration (Cmax) of RPG administered intravenously and orally in rats were significantly increased by 1.83- and 1.88-fold, respectively, after concurrent administration with QCT. As the protein binding and blood distribution of RPG were observed to be unaltered by QCT, it is plausible that the hepatic first-pass and systemic metabolism of RPG could have been inhibited by QCT, resulting in the increased systemic exposure (AUC and Cmax) of RPG. These results suggest that there is a possibility that clinically significant pharmacokinetic interactions between QCT and RPG could occur, depending on the extent and duration of QCT intake from foods and dietary supplements.

scholarly journals The effects of oral administration of Cola nitida on the pharmacokinetic profile of metoclopramide in rabbits

2020 ◽  
Vol 21 (1) ◽  
Author(s):  
Cecilia Nwadiuto Amadi ◽  
Wisdom Izuchukwu Nwachukwu
Keyword(s):  
Drug Interaction ◽  
Plasma Concentration ◽  
Oral Administration ◽  
Peak Plasma ◽  
Peak Plasma Concentration ◽  
Elimination Rate ◽  
Area Under The Curve ◽  
Pharmacokinetic Profile ◽  
Pharmacokinetic Parameters ◽  
Cola Nitida

Abstract Background Cola nitida is commonly chewed in many West African cultures to ease hunger pangs and sometimes for their stimulant and euphoriant qualities. Metoclopramide is a known substrate for P-gp, SULT2A1 and CYP2D6 and studies have revealed that caffeine- a major component of Cola nitida can induce P-glycoprotein (P-gp), SULT2A1 and SULT1A1, hence a possible drug interaction may occur on co-administration. The aim of this study was to investigate the pharmacokinetic interactions of Cola nitida and metoclopramide in rabbits. Methods The study was performed in two stages using five healthy male rabbits with a 1-week washout period between treatments. Stage one involved oral administration of metoclopramide (0.5 mg/kg) alone while in the second stage, metoclopramide (0.5 mg/kg) was administered concurrently with Cola nitida (0.7 mg/kg). Blood samples were collected after each stage at predetermined intervals and analyzed for plasma metoclopramide concentration using HPLC. Results Compared with control, the metoclopramide/Cola nitida co-administration produced a decrease in plasma concentration of metoclopramide at all the time intervals except at the 7th hour. The following pharmacokinetic parameters were also decreased: area under the curve (51%), peak plasma concentration (39%), half-life (51%); while an increase in elimination rate constant (113%) and clearance rate (98%) were noted indicating rapid elimination of the drug. A minimal decrease in absorption rate (10%) was also observed. Conclusions The results of this study reveal a possible herb-drug interaction between Cola nitida and metoclopramide.

Application of Statistical Tooling Techniques for Designing of Carvedilol Nanolipid Transferosomes and its Dermatopharmacokinetic and Pharmacodynamic Studies

2020 ◽  
Vol 8 (6) ◽  
pp. 452-470
Author(s):  
Brito R. Selvaraj ◽  
Seshaiah K. Sridhar ◽  
Bhaskar R. Kesavan ◽  
Sucharitha Palagati
Keyword(s):  
Particle Size ◽  
Plasma Concentration ◽  
Dosage Form ◽  
Peak Plasma ◽  
Peak Plasma Concentration ◽  
Entrapment Efficiency ◽  
Transdermal Patch ◽  
In Vitro Drug Release

Background: The hypothesis is to augment the bioavailability and therapeutic potential of low bioavailable Carvedilol (25-35%) through Nanostructured Lipid Carrier (NLC) loaded Transdermal patch (Nanolipid Transferosomes). Methods: Box-Behnken design was designed to formulate NLC through a hot homogenization technique. About 17 formulations (C1-C17) were formulated by varying the critical material attribute and critical process parameter. Optimization was done based on its critical quality attributes like particle size, zeta potential and entrapment efficiency. Selected NLC (C16) has been fabricated into a transdermal patch through solvent evaporation technique and estimated for thickness, weight variation, moisture content, folding endurance, drug content, in vitro drug release, ex vivo skin permeation studies 48 hrs, in vitro drug release kinetic studies and skin irritation studies. In vivo pharmacokinetics and pharmacodynamic study parameters were compared between carvedilol loaded NLC transdermal patch and a conventional formulation (Coreg CR). Results: NLC (C16) was selected as the best formulation based on desirable, less particle size (201.1 ± 2.02 nm), more zeta potential (-37.2 ± 1.84mV) and maximum entrapment efficiency (87.54 ± 1.84%). Experimental investigations of in vivo dermatopharmacokinetic data shown statistically significant changes (p<0.05) in the parameter (increased AUC0-α, MRT with decreased Cmax, Tmax) when administered through the transdermal patch and on compared to the conventional dosage form. It was observed that there was a significant change with p<0.05 among the pharmacokinetic factors of conventional Carvedilol formulation, Carvedilol NLC and Carvedilol NLC loaded Transdermal patch with a maximum time of peak plasma concentration (Tmax) of 4 hrs, 8 hrs and 8 hrs; maximum peak plasma concentration (Cmax) of 0.258 μg/ml, 0.208 μg/ml and 0.108 μg/ml. Area Under Curve (AUC0-α) was established to be 125.127 μg/ml/h, 132.576 μg/ml.h and 841.032 μg/ml.h. Mean Residence Time (MRT0- α) of the drug was established to be 17 hrs, 19 hrs and 82 hrs, respectively. This data reveals the impact of NLC on the enhancement of bioavailability through a transdermal patch. In vivo pharmacodynamic studies confirm that NLC loaded transdermal patch (Nanolipid Transferosomes) shows a significant control in blood pressure for 48 hrs when compared to the conventional dosage form. Conclusion: This research data concludes that NLC loaded transdermal patch (Nanolipid Transferosomes) was a suitable candidate to enhance the bioavailability of low bioavailable drug-like Carvedilol. Lay Summary: It was inferred from the literature that NLC filled transdermal patches were a novel strategy to increase the solubility and permeability of Carvedilol, which has less bioavailability. It reveals that there was no reproducible preparation for the NLC. It also reveals that the option of formulation and process parameters for the formation of NLC is not clearly justified. On account of this, an uniquely validated and optimized formulation technique was developed for NLC with low soluble and poorly bioavailable carvedilol, tested in Albino wistar rats for enhancement of bioavailability, the same study has been performed and proved.

Trigeminal Neuralgia: Time Course of Pain in Relation to Carbamazepine Dosing

Cephalalgia ◽  
1981 ◽  
Vol 1 (2) ◽  
pp. 91-97 ◽  
Author(s):  
Torbjörn Tomson ◽  
Karl Ekbom
Keyword(s):  
Plasma Concentration ◽  
Trigeminal Neuralgia ◽  
Time Course ◽  
Peak Plasma ◽  
Peak Plasma Concentration ◽  
Plasma Concentrations ◽  
Significant Drop ◽  
Idiopathic Trigeminal Neuralgia ◽  
Full Effect ◽  
Pain Distribution

Eight in-patients with idiopathic trigeminal neuralgia (TN) were studied while receiving carbamazepine (CBZ) treatment. The aim was to study diurnal pain distribution, its relation to CBZ dosing and plasma concentration and the effect of decreasing the dose. All pain attacks were registered by the patients at three-hour intervals. CBZ was given b.i.d. in a single blind manner with the patient unaware of dose and dose changes. Plasma concentrations of CBZ were followed every fourth hour during a period of altogether sixteen dosage intervals. The diurnal pain distribution revealed marked intra-individual similarities with pain-free nights and a significant drop in pain during mid-day hours. The latter coincided in time with the peak plasma concentration of CBZ, thus indicating an effect of plasma concentration fluctuations on pain relief. Shorter dosage intervals might therefore be beneficial in problem cases. A significant increase in pain was detected within six to nine hours after a dose reduction, whereas the full effect of the dose change seemed to be established only after one day.

Inhibitory Effect of Citalopram on the Pharmacokinetics of Carvedilol in Rats and in vitro Models

Pharmacology ◽  
2017 ◽  
Vol 100 (5-6) ◽  
pp. 301-307
Author(s):  
Maria Bianca Abrudan ◽  
Dana Maria Muntean ◽  
Daniela Saveta Popa ◽  
Ana-Maria Gheldiu ◽  
Maria Adriana Neag ◽  
...  
Keyword(s):  
Drug Interaction ◽  
Plasma Concentration ◽  
Metabolic Rate ◽  
Liver Microsome ◽  
Peak Plasma ◽  
Peak Plasma Concentration ◽  
Femoral Vein ◽  
Plasma Concentrations ◽  
Drug Drug Interaction

Background/Aims: The aim of this study was to investigate the drug-drug interaction between carvedilol and citalopram based on carvedilol metabolism in vitro and his pharmacokinetics (PKs) in vivo after the oral administration of the single drug and both drugs, and reveal citalopram effects on the PKs of carvedilol. Methods: Each rat was cannulated on the femoral vein, prior to being connected to BASi Culex ABC®. Carvedilol was orally administrated in rats (3.57 mg/kg body weight [b.w.]) in the absence of citalopram or after a pre-treatment with multiple oral doses of citalopram (1.42 mg/kg b.w.). Plasma concentrations of carvedilol were determined using high-performance liquid chromatography-MS at the designated time points after drug administration, and the main PK parameters were calculated by noncompartmental analysis. In addition, effects of citalopram on the metabolic rate of carvedilol were investigated using rat-pooled liver microsome incubation systems. Results: During co-administration, significant increases of the area under the plasma concentration-time curve as well as of the peak plasma concentration were observed. The rat-pooled liver microsome incubation experiment indicated that citalopram could decrease the metabolic rate of carvedilol. Conclusion: Citalopram co-administration led to a significant alteration of carvedilol's PK profile in rats; it also demonstrated, in vitro, these effects could be explained by the existence of a drug-drug interaction mediated by CYP2D6 inhibition.

scholarly journals Influence of Bisphosphonates or Recombinant Human Parathyroid Hormone on in Vitro Chemotherapy Sensitivity in Acute Lymphoblastic Leukemia Cells

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 4355-4355
Author(s):  
Demi T.C. de Winter ◽  
Jenneke E. van Atteveld ◽  
Jessica G.C.A.M. Buijs-Gladdines ◽  
Rob Pieters ◽  
Sebastian J.C.M.M. Neggers ◽  
...  
Keyword(s):  
Plasma Concentration ◽  
Peak Plasma ◽  
Lymphoblastic Leukemia ◽  
Peak Plasma Concentration ◽  
Plasma Concentrations ◽  
Leukemia Cell ◽  
Chemotherapeutic Agents ◽  
Mineral Density ◽  
All Treatment

Abstract BACKGROUND Osteonecrosis and low bone mineral density (BMD) are serious osteogenic side effects of acute lymphoblastic leukemia (ALL) treatment. Bisphosphonates and recombinant human parathyroid hormone (rPTH) tend to be used to ameliorate osteonecrosis-related symptoms as well as to enhance bone mineral density in children with ALL and severe bone fragility. Only one preclinical study on the safety of bisphosphonates during ALL treatment is available, which raises concerns about their impact on leukemic drug sensitivity. Here, we assessed the influence of various bone-modifying agents (zoledronate, pamidronate and rPTH) on in vitro cytotoxicity of chemotherapeutic agents (vincristine (VCR), daunorubicin (DNR), dexamethasone (DEXA), 6-mercaptopurine (6-MP), PEG-asparaginase (PEG-ASP)) and prednisone (PRED) that are commonly used in ALL treatment. METHODS Potential cytotoxic effects of the bone-modifying agents on leukemia cell viability and on in vitro cytotoxic responses of chemotherapeutic agents were tested in various T-cell and B-cell leukemia cell lines using methyl-thiazol-tetrazolium (MTT) assays. Bone-modifying agents were added at concentrations up to a five-fold of their physiological peak plasma concentration. For each assay, 50th percentile of maximal inhibitory concentration was determined. To quantify the combined effects of the bone-modifying agents on chemotherapeutic agent-induced cytotoxicity, median (interquartile range) combination indexes (CI) were calculated. We considered a median CI of &lt; 0.8 as synergism and &gt; 1.2 as antagonism (based on the method of Chou). RESULTS Zoledronate, pamidronate or rPTH in combination with DNR, 6-MP and PEG-ASP showed median CI values between 0.8 and 1.2. Variable inconclusive results were obtained in combination with VCR. Only the combination of a five-fold peak plasma concentration of zoledronate or pamidronate with DEXA resulted in median CI values of 1.15 (range, 1.08-1.48), and 1.34 (range, 1.07-1.62), respectively. Additional experiments using DEXA as well as PRED in combination with one-, three- or five-fold physiological peak plasma concentrations of zoledronate or pamidronate revealed that median CI values stay within 0.8 and 1.2, except for DEXA exposed leukemia cells in combination with a five-fold physiological peak plasma concentration of pamidronate which repeatedly showed a median CI value above 1.2 (1.34, range 1.04-1.86). CONCLUSIONS Zoledronate, pamidronate or rPTH do not seem to influence drug sensitivity of DNR, 6-MP or PEG-ASP, even at a five-fold physiological peak plasma concentration. Nevertheless, our findings suggest a minimal effect of pamidronate on DEXA-induced leukemia cell death. This suggests that even though zoledronate or pamidronate do not seem to negatively influence DEXA- or PRED- induced toxicity in expected physiological concentrations (one- to three-fold physiological peak plasma concentrations), these bone-modifying agents may only be considered with caution in individual cases, and preferably in clinical trial settings before being applied on a large scale in children with ALL. Disclosures No relevant conflicts of interest to declare.

Comparative Bioequivalence and Efficacy of Two Sustained-Release Procainamide Formulations in Patients with Cardiac Arrhythmias

1988 ◽  
Vol 22 (7-8) ◽  
pp. 554-558 ◽  
Author(s):  
Daniel E. Hilleman ◽  
Albert J. Patterson ◽  
Syed M. Mohiuddin ◽  
Brian G. Ortmeier ◽  
Christopher J. Destache
Keyword(s):  
Plasma Concentration ◽  
Sustained Release ◽  
Cardiac Arrhythmias ◽  
Peak Plasma ◽  
Statistical Significance ◽  
Peak Plasma Concentration ◽  
Plasma Concentrations ◽  
Blood Sampling ◽  
Time Curve ◽  
Alternate Test

This investigation evaluated the bioequivalence and efficacy of two sustained-release procainamide products. Ten patients with cardiac arrhythmias were randomized to product A (Procan-SR) or product B (Pronestyl-SR). After nine doses of study medication, plasma procainamide and N-acetylprocainamide concentrations were obtained to determine the area under the concentration versus time curve at steady state (AUCss), mean plasma concentration (Cavss), the observed peak plasma concentration (Cmaxss), the observed trough plasma concentration (Cminss), and the apparent time to achieve Cmaxss (tmax). The products were compared on a milligram-equivalent (adjusted) basis. Following completion of blood sampling, patients were crossed-over to the alternate product. There was no washout between treatments. After nine doses of the alternate test medications, blood sampling was repeated. Differences in AUCss, Cavss, Cmaxss, tmax, and intradose peak/trough ratios were not statistically significant. Within-group variability in AUCss, Cavss Cmaxss, and tmax was greater with product B, but this trend did not reach statistical significance. Antiarrhythmic efficacy was not significantly different between the two treatments. Although the greater bioequivalence, lesser variability, and the greater number of tablet dosage sizes would favor product A, patients stabilized on a particular brand of sustained-release procainamide should not be switched to another product without careful monitoring. One patient in this study developed nonsustained ventricular tachycardia with low procainamide plasma concentrations after being switched from product A to product B.

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