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Antimicrobial Agents and Chemotherapy, August 2006, p. 2621-2625, Vol. 50, No. 8
0066-4804/06/$08.00+0     doi:10.1128/AAC.00451-06
Copyright © 2006, American Society for Microbiology. All Rights Reserved.

Combination Chemotherapy with the Nitroimidazopyran PA-824 and First-Line Drugs in a Murine Model of Tuberculosis

Eric Nuermberger,^1,2* Ian Rosenthal,^1,2 Sandeep Tyagi,¹ Kathy N. Williams,¹ Deepak Almeida,¹ Charles A. Peloquin,^3,4 William R. Bishai,^1,2 and Jacques H. Grosset¹

Center for Tuberculosis Research, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland,¹ Department of International Health, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland,² Infectious Diseases Pharmacokinetics Laboratory, National Jewish Medical and Research Center, Denver, Colorado,³ Departments of Pharmacy and Medicine, University of Colorado, Denver, Colorado⁴

Received 11 April 2006/ Returned for modification 16 May 2006/ Accepted 2 June 2006

Top Abstract Introduction Materials and Methods Results Discussion References

 
The creation of new chemotherapeutic regimens that permit shortening the duration of treatment is a major priority for antituberculosis drug development. In this study, we used the murine model of experimental tuberculosis therapy to determine whether incorporation of the investigational new nitroimidazopyran PA-824 into the standard first-line regimen has the potential to shorten the 6-month duration of treatment. As demonstrated previously, PA-824 alone had significant bactericidal activity over the first 2 months of treatment. Moreover, the substitution of PA-824 for isoniazid led to significantly lower lung CFU counts after 2 months of treatment and to more rapid culture-negative conversion compared to the standard regimen of rifampin, isoniazid, and pyrazinamide. Despite this, there was no difference in the proportion of mice relapsing after completing 6 months of therapy (2 of 19 mice treated with PA-824 in place of isoniazid relapsed versus 0 of 46 mice treated with the standard regimen). Meanwhile, no other PA-824-containing regimen tested was superior to the standard regimen on any assessment. Thus, we were unable to establish a clear role for PA-824 in a treatment-shortening regimen that includes two or more of the current first-line drugs. Future preclinical studies should include the evaluation of novel combinations of PA-824 with new drug candidates in addition to existing antituberculosis drugs for their potential to substantially improve the treatment of both drug-susceptible and multidrug-resistant tuberculosis.

Top Abstract Introduction Materials and Methods Results Discussion References

 
The creation of new chemotherapeutic regimens that permit shortening the duration of treatment is a major objective of antituberculosis (anti-TB) drug development. Shorter regimens are expected to reduce the burden of therapy for patients and health care delivery systems, leading to increased global coverage with directly observed therapy, higher completion rates, and improved control of TB (12).

The duration of treatment necessary to sterilize tuberculous lesions and prevent relapse after treatment is determined largely by the ability of the component drugs to eradicate the small population of bacilli capable of persisting in a viable state despite months of intensive combination chemotherapy (5, 9, 10). Since the current first-line drugs either have limited sterilizing activity (e.g., isoniazid [INH] and ethambutol) or are already used in a way that is felt to optimize their sterilizing activity (e.g., rifampin [RIF] and pyrazinamide [PZA]), it is widely believed that improving upon the sterilizing activity of the current standard regimen (i.e., to shorten therapy) will require a new drug or drugs with special activity against these persisters (12).

We recently demonstrated that the investigational new nitroimidazopyran PA-824 has substantial bactericidal activity against both actively multiplying bacilli and against the above-mentioned persisters in the murine model (14). In that study, the activity of PA-824 alone against persisters was greater than that of INH alone or moxifloxacin alone and approached that of the combination of INH plus RIF. While the experimental design did not include an assessment of relapse after completion of treatment, these results suggested that PA-824 alone had remarkable sterilizing activity. What remains to be determined is whether the apparent sterilizing activity of PA-824 will be additive with that of the available anti-TB drugs in a way that could significantly reduce the duration of treatment. We therefore conducted a long-term study of combination chemotherapy in the murine model of tuberculosis to determine whether the incorporation of PA-824 into the standard 6-month treatment regimen of RIF, INH, and PZA would lead to more rapid reductions in the bacillary burden during treatment and lower rates of relapse after treatment.

Top Abstract Introduction Materials and Methods Results Discussion References

 
Bacterial strain. Mycobacterium tuberculosis H37Rv was passaged in mice and frozen in aliquots at –80°C. Upon thawing, aliquots were subcultured in Middlebrook 7H9 broth (Fisher, Pittsburgh, PA) with 10% oleic acid-albumin-dextrose-catalase (OADC) (Difco, Detroit, MI) and 0.05% Tween 80 (Sigma, St. Louis, MO).

Antimicrobials. PA-824 was provided by the Global Alliance for Tuberculosis Drug Development through D. Rouse of Research Triangle Institute (Research Triangle Park, NC) and prepared as previously described (14). Other drugs were purchased from Sigma or Fisher. Except for PA-824, solutions were prepared weekly in distilled water and stored at 4°C. All drugs were administered by gavage 5 days per week. The drugs and dosages were INH (25 mg/kg of body weight), RIF (10 mg/kg), PZA (150 mg/kg), and PA-824 (100 mg/kg) as previously published (11, 14, 15). RIF was given at least 1 h apart from other drugs to prevent pharmacokinetic antagonism as previously demonstrated (3, 4, 7).

Pharmacokinetic studies. Three studies were performed to confirm that the pharmacokinetic profiles of PA-824 and each of the first-line drugs were not altered by coadministration. In the first two studies, the test animals were uninfected 4-week-old female Swiss mice (Charles River, Wilmington, MA). The final multidose study used infected 6-week-old female BALB/c mice (Charles River). Mice had access to food and water ad libitum. Drugs were administered by gavage. RIF was given 1 h before INH, PZA, or INH-PZA. Because it involved a different formulation, PA-824 was administered by a separate gavage immediately after INH, PZA, or INH-PZA. Three to six mice from each group were sacrificed at each indicated time point after administration. Mice were anesthetized with chloroform and exsanguinated by cardiac puncture. Blood was collected in microcentrifuge tubes and left at room temperature for 30 min before being centrifuged to harvest the serum. Samples were then frozen at –80°C before analysis at the Infectious Disease Pharmacokinetics Laboratory at National Jewish Medical and Research Center, Denver, CO, where serum concentrations of each drug were determined by validated high-performance liquid chromatography assay.

(i) Study 1. A single-dose study was performed to ascertain whether serum concentrations of RIF, INH, or PZA were affected by coadministration with PA-824. Mice were administered RIF alone, RIF-INH-PZA, or RIF-INH-PZA plus PA-824. For the group given RIF alone, three mice were sacrificed 2, 4, and 8 h after administration. For the other groups, six mice were sacrificed at the same time points to provide adequate serum for assays of three or four different drug concentrations. Ultimately, three individual serum samples were assayed for each drug at each time point.

(ii) Study 2. A second single-dose study was performed to ascertain whether serum concentrations of RIF, INH, PZA, or PA-824 were affected by coadministration in every possible three- or four-drug combination of RIF, INH, PZA, and PA-824. Mice were administered PA-824 alone or in combination with RIF-INH-PZA, INH-PZA, RIF-PZA, or RIF-INH. For groups receiving multiple drugs, six mice were sacrificed 2, 8, and 25 h after RIF administration (i.e., 1, 7, and 24 h after administration of the other drugs). For the group given PA-824 alone, three mice were sacrificed 1, 7, and 24 h after administration. Ultimately, three individual serum samples were assayed for each drug at each time point.

(iii) Study 3. A multidose study to determine the pharmacokinetic profile of PA-824 over time in infected mice and to ascertain whether PA-824 concentrations were affected by coadministration with RIF-INH-PZA was embedded in the treatment efficacy study described below. After the first dose and after 8 weeks of dosing, three and six mice were sacrificed from the groups given PA-824 and RIF-INH-PZA plus PA-824, respectively, at 1, 2, 4, 8, 16, and 24 h after administration of PA-824. Ultimately, three individual serum samples were assayed for each drug at each time point. Serum concentration data were entered into a WinNonlin worksheet (WinNonlin version 4.0, 2002; Pharsight, Mountain View, CA) and analyzed using standard noncompartmental techniques in order to determine the relevant pharmacokinetic parameters.

Aerosol infection. All procedures involving animals were approved by the institutional Animal Care and Use Committee. Six-week-old female BALB/c mice (Charles River, Wilmington, MA) were infected with approximately 3.5 log₁₀ CFU of M. tuberculosis H37Rv using the Glas-col inhalation exposure system (Glas-col Inc., Terre Haute, Ind.) and a late-log-phase broth culture (optical density at 600 nm of 1.0). Six mice (two from each of three aerosol runs) were sacrificed the following day to determine the number of CFU implanted in the lungs.

Efficacy of regimens incorporating PA-824. After infection, mice were randomized into the treatment groups described in Table 1. Treatment began 19 days later (on day 0 [D0]). Six mice (two from each aerosol run) were sacrificed to determine the CFU count in lungs and spleen at the initiation of treatment. All regimens were administered for 6 months. Five mice per group were sacrificed after 2, 4, and 6 months of treatment for determination of lung and spleen CFU counts. After completing 6 months of treatment, an additional 46 mice in the positive-control group (2 months of RIF, INH, and PZA and 4 months of RIF-INH [2 mo. RIF-INH-PZA + 4 mo. RIF-INH]) and 19 mice each in the three experimental groups (2 months of RIF, INH, PZA, and PA-824 and 4 months of RIF, INH, and PA-824 [2 mo. RIF-INH-PZA-PA-824 + 4 mo. RIF-INH-PA-824], 2 mo. RIF-PA-824-PZA + 4 mo. RIF-PA-824, and 6 mo. RIF-INH-PA-824) were held without treatment for 3 additional months before sacrifice to determine the proportion of mice with culture-positive relapse. Because mice treated with 2 mo. PA-824-INH-PZA + 4 mo. PA-824-INH were uniformly culture positive with approximately 100 CFU in the lungs at the completion of 6 months of treatment, no additional mice were kept to monitor relapse. Quantitative lung and spleen cultures were performed from organ homogenates using OADC-enriched 7H10 agar medium (Difco) as previously described (11). However, our laboratory instituted a change to OADC-enriched 7H11 agar (Difco) during the experiment that resulted in the lung homogenates from the 6- and 6(+3)-month (mice sacrificed 3 months after treatment for 6 months) time points being plated on this medium. When CFU counts below 300 CFU were anticipated, including the 6(+3) time point for all mice, the entire organ homogenate was plated. At the 6-month time point, lung homogenates from mice treated with PA-824 alone were plated on medium containing PA-824 concentrations of 2 and 10 µg/ml in addition to the non-PA-824-containing plates described above.

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TABLE 1. Experimental scheme to evaluate the addition or substitution of PA-824 in the standard 6-month regimen for treatment of TB

Statistical analysis. For pharmacokinetic parameters, mouse body weights, and spleen weights, group means were compared by t test or by one-way analysis of variance with Bonferroni's posttest where indicated. For the efficacy study, CFU counts were log transformed before analysis. Group means for experimental groups were compared with that of the standard treatment control by one-way analysis of variance with Dunnett's posttest. Group proportions were compared to the standard treatment regimen using Fisher's exact test and adjusting for multiple comparisons. All analyses were performed with GraphPad Prism v.4.01 (GraphPad, San Diego, CA).

Top Abstract Introduction Materials and Methods Results Discussion References

 
Pharmacokinetics of PA-824 and first-line drugs in combination regimens. Because coadministration of drugs can affect bioavailability in the murine model (4, 7), adverse pharmacokinetic interactions were excluded before evaluating PA-824-containing combinations. Anticipating a treatment study comparing the efficacy of the standard RIF-INH-PZA-based regimen to combination regimens containing PA-824, we began by determining whether serum concentrations of RIF, INH, or PZA were significantly affected when RIF-INH-PZA was coadministered with PA-824. Because its bioavailability is most commonly affected by coadministration with other drugs, serum RIF concentrations were also assessed after administration of RIF alone. As can be seen in Tables S1a, S1b, and S1c in the supplemental material, the serum concentrations of RIF, INH, and PZA over the first 8 h were not significantly different whether administered as RIF alone, RIF-INH-PZA, or RIF-INH-PZA-PA-824. The only statistically significant difference was seen in the PZA concentrations at the 7-hour time point when concentrations in both groups were well below the MIC of the organism and not expected to influence the results.

A second pharmacokinetic study demonstrated that PA-824 concentrations were not significantly different when PA-824 was administered alone or in various combinations including RIF, INH and PZA (see Table S2a in the supplemental material). Furthermore, with the exception of PZA concentrations being modestly higher 2 h after administration of RIF-INH-PZA-PA-824 compared to PA-824-INH-PZA and RIF-PA-824-PZA, the concentrations of RIF, INH, and PZA were not significantly different among mice receiving any of the various PA-824-containing drug combinations (see Tables S2b, S2c, and S2d in the supplemental material).

Finally, we made a more comprehensive pharmacokinetic assessment of PA-824 in parallel with the efficacy study described below. In this study, infected BALB/c mice had serum concentrations that were modestly higher than those seen in uninfected Swiss mice. On the basis of the parameters noted in Table 2, the drug exposure was no different whether PA-824 was administered alone or in combination with RIF-INH-PZA. The maximum concentration of drug in serum (C_max) values were 80- to 110-fold higher than the MIC of 0.25 µg/ml (13). Mean C_max and area under the curve (AUC) values were 26% and 18% higher, respectively, after 2 months of administration 5 days per week (P = 0.06 and 0.30, respectively) compared to single-dose values. There appeared to be more rapid absorption of PA-824 at 2 months, resulting in higher C_max and time to maximum concentration of drug in serum (T_max) values, but there was substantial overlap in AUC values between single-dose and 2-month values. Moreover, serum trough concentrations at 24 h postdose were not significantly different for mice receiving a single dose versus those receiving treatment for 2 months, which argues against significant accumulation in the plasma space. These data do not, however, address the potential for accumulation of PA-824 within the tissue space.

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TABLE 2. Pharmacokinetic parameters of PA-824 alone and in combination with RHZ after a single dose and after "daily" (5 days a week) administration for 2 months

Efficacy of regimens incorporating PA-824. (i) Mortality. All untreated mice died within 35 days of infection. There were four deaths among treated mice. One mouse each in the RIF-INH-PA-824 and RIF-INH-PZA groups died on the 2nd and 5th days of treatment. One mouse in the PA-824-INH-PZA group died on both the 46th and 48th days of treatment. All deaths were attributed to gavage accidents rather than the infection.

(ii) Body and spleen weight. Mouse body weights were no different among treated mice throughout the experiment. The mean spleen weight on day 0 was 130 ± 11 mg. After 2 months of treatment, the mean spleen weight for mice receiving RIF-INH-PZA was 142 ± 8 mg. There were no differences in spleen weight among mice treated with combination therapy throughout the experiment. For mice receiving PA-824 alone, the mean spleen weight after 2 months of treatment (177 ± 9 mg) was significantly higher than those for all other treatment groups (P < 0.01) and remained so throughout the experiment (data not shown).

(iii) Quantitative CFU counts. On the day after aerosol infection, lung CFU counts were 3.84 ± 0.27, 3.93 ± 0.05, and 3.54 ± 0.09 log₁₀ (mean, 3.77 ± 0.22 log₁₀) in mice infected in aerosol runs 1, 2, and 3, respectively. Lung and spleen CFU counts at initiation of treatment 18 days later were 8.23 ± 0.21 and 5.29 ± 0.25 log₁₀ CFU, respectively. After 2 months of treatment, lung CFU counts in mice treated with PA-824 alone had fallen by 2 log₁₀ CFU to 6.28 ± 0.07 log₁₀ CFU, indicative of the bactericidal activity of PA-824. For the groups receiving combination regimens, lung CFU counts after 2, 4, and 6 months of treatment are depicted in Fig. 1. Mice treated with the standard regimen of RIF-INH-PZA had a 4.5 log₁₀ decline in counts to 3.69 ± 0.35 log₁₀ CFU. The addition of PA-824 to the standard regimen did not affect the CFU count (3.73 ± 0.41 log₁₀ CFU), whereas the substitution of PA-824 for INH resulted in a significantly lower count (2.38 ± 0.62 log₁₀ CFU; P < 0.01). However, substitution of PA-824 for RIF or PZA was detrimental.

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FIG. 1. Log10 CFU counts from lung homogenates after 0 to 6 months of treatment. Treatment regimens are described in Table 1 (2RHZ +4RH, 2 mo. RHZ + 4 mo. RH).

The same relationships were evident after 4 months of treatment. CFU counts among mice treated with 2 mo. RIF-INH-PZA-PA-824 + 2 mo. RIF-INH-PA-824 were not different from those of mice treated with 2 mo. RIF-INH-PZA + 2 mo. RIF-INH (0.72 ± 0.58 versus 0.45 ± 0.16 log₁₀ CFU, respectively). None of the mice in these two groups was culture negative. On the other hand, all mice treated with 2 mo. RIF-PA-824-PZA + 2 mo. RIF-PA-824 were culture negative, although the difference in CFU counts was not statistically significant.

After 6 months of treatment, the five mice receiving 2 mo. RIF-INH-PZA + 4 mo. RIF-INH and 2 mo. RIF-INH-PZA-PA-824 + 4 mo. RIF-INH-PA-824 were all culture negative except for two mice and one mouse with 1 CFU detected in the entire lung homogenate, respectively. Mice receiving 6 mo. RIF-INH-PA-824 were also culture negative with the exception of two mice with 1 and 4 CFU detected. Mice receiving 2 mo. PA-824-INH-PZA + 4 mo. PA-824-INH were uniformly culture positive with a mean of nearly 2 log₁₀ CFU per lung. Among mice treated with PA-824 alone, the CFU count did not change appreciably from the 2-month to the 6-month time point. At the 6-month point, the CFU counts on PA-824-containing plates (both 2 and 10 µg/ml) equaled those on non-PA-824-containing plates, indicating that the PA-824-susceptible bacillary population had been replaced by a uniformly PA-824-resistant population as a result of the selective bactericidal activity of PA-824.

When assessed 3 months after completion of treatment, 0%, 5%, and 11% of mice relapsed in groups treated with the standard RIF-INH-PZA-based regimen, the same regimen with PA-824 added, and the same regimen with PA-824 substituted for INH, respectively (Table 3). These differences were not statistically significant. When PA-824 was substituted for PZA, relapse was significantly more common (79%) (P < 0.001 versus RIF-INH-PZA control).

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TABLE 3. Relapse after completion of 6 months of treatment

Top Abstract Introduction Materials and Methods Results Discussion References

 
In this study, as in our previous study (14), treatment with PA-824 alone resulted in significant bactericidal activity as demonstrated by a 2 log₁₀ reduction in CFU counts over the first 2 months and by selection of PA-824-resistant mutants. Moreover, the substitution of PA-824 for INH had a beneficial effect on two secondary outcomes, lowering lung CFU counts after 2 months of treatment and accelerating the time to culture conversion, compared to the standard regimen. In the end, however, the two regimens were not statistically different on the primary outcome of interest, the proportion of mice relapsing after completing 6 months of treatment, leaving us unable to conclude that this PA-824-containing regimen was superior to the standard regimen. Additional studies that assess the proportion of mice relapsing after shorter durations of treatment will be necessary to determine conclusively whether the substitution of PA-824 for INH has the potential to substantially shorten the duration of treatment in the murine model.

This study was designed to inform future clinical investigations of PA-824, and its results demonstrate the importance of evaluating promising new anti-TB drug candidates in combination with other drugs. Because it is the first study of PA-824-containing regimens to include an assessment of relapse after completion of therapy as a measure of sterilizing activity, several additional points are worth making. First, despite the significant bactericidal activity of PA-824 against both actively multiplying tubercle bacilli and drug-induced persisters when given alone, its addition to the standard RIF-INH-PZA regimen did not improve the standard regimen's sterilizing activity. Potential explanations for this finding include (i) lack of additive activity of PA-824 when combined with the drugs in the RIF-INH-PZA regimen, (ii) limited sterilizing activity of PA-824, and (iii) a negative interaction (i.e., antagonism) between PA-824 and one or more drugs in the RIF-INH-PZA regimen. While the findings presented here would appear to exclude an adverse pharmacokinetic interaction between PA-824 and the other drugs, they do not permit any further explanation. Second, the substitution of PA-824 for RIF or PZA was detrimental to the activity of the standard regimen. These results suggest that, at least within the context of the other first-line drugs, PA-824 does not have the sterilizing activity of RIF or PZA. Finally, the substitution of PA-824 for INH, like the substitution of moxifloxacin for INH in a previous study (11), resulted in lower CFU counts after 2 months of therapy and more rapid culture conversion. To determine whether moxifloxacin or PA-824 provides the more potent substitute for INH will require a head-to-head comparison. The fact that both drugs improve the activity of the standard regimen when substituted for INH, despite having activity that is no better than INH when the drugs are given alone, suggests that INH may have an antagonistic effect on regimens that include RIF and PZA.

Because of its significant anti-TB activity, unique mechanism of action, and lack of cross-resistance with existing anti-TB drugs, PA-824 may also have the potential to contribute to entirely novel regimens when combined with other new investigational drugs. Such regimens may or may not require existing first-line drugs and may substantially improve the treatment of multidrug-resistant or even drug-susceptible TB. Thus, it will be important to fully characterize the sterilizing activity of PA-824 and its interactions with both new and existing anti-TB drugs.

There are two important caveats to bear in mind when interpreting our results and attempting to extrapolate them to the treatment of human disease. The first involves the dose of PA-824 used in these experiments. PA-824 has dose-dependent activity in both the initial and continuation phases of treatment in the murine model (14). Although PA-824 is currently in phase I testing, the dose in the mouse that will be equipotent to the ultimate human dose remains unknown. It is therefore possible that the results of the present study either underestimate or overestimate the potential contribution of PA-824 to combination chemotherapy. The second caveat involves the assessment of new drug candidates in the murine model. It is well-known that mice infected with M. tuberculosis do not develop caseation, the pathological hallmark of TB in humans. Despite this, the results of experiments evaluating combination chemotherapeutic regimens in this model have been consistent with clinical results for existing first-line anti-TB drugs (6) as well as for the recent substitution of moxifloxacin for ethambutol (2, 11). However, it is possible that the potential efficacy of a new drug candidate will not be well represented in the murine model. In the case of PA-824, recent findings suggest that the drug undergoes nitroreductive activation to its active moiety and that this reaction is enhanced under conditions of low redox potential (1, 8). Because such hypoxic conditions may be more prevalent in the caseous lesions that are found in human disease than in the cellular lesions observed in mice, it is possible that the results of treatment with PA-824 in the murine model underestimate its activity in humans. Investigation of PA-824's activity in other models that exhibit caseation (e.g., guinea pig or rabbit) could shed light on this speculation, but these models have not previously been utilized for the study of combination chemotherapy regimens and the kind of study described herein would likely be prohibitively expensive to perform.

 
This work was supported by the Global Alliance for Tuberculosis Drug Development and the National Institute of Allergy and Infectious Disease (grant AI58993 and supplement to grant AI43846).

 
* Corresponding author. Mailing address: Department of Medicine, Johns Hopkins University School of Medicine, 1550 Orleans Street, Baltimore, MD 21231. Phone: (410) 502-0580. Fax: (410) 614-8173. E-mail: enuermb{at}jhmi.edu.

Supplemental material for this article may be found at http://aac.asm.org/.

Top Abstract Introduction Materials and Methods Results Discussion References

 

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Antimicrobial Agents and Chemotherapy, August 2006, p. 2621-2625, Vol. 50, No. 8
0066-4804/06/$08.00+0     doi:10.1128/AAC.00451-06
Copyright © 2006, American Society for Microbiology. All Rights Reserved.

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• Guy, E. S., Mallampalli, A. (2008). Review: Managing TB in the 21st century: existing and novel drug therapies. Ther Adv Respir Dis 2: 401-408 [Abstract]  
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