Desvenlafaxine Succinate: Is it a New Promise and Hope for
Management of Vasomotor Symptoms in Postmenopausal
Women?
Review Article
Desvenlafaxine succinate: Is it a new promise and hope for
management of vasomotor symptoms in postmenopaus...
1. Introduction
Natural menopause, specifically, is confirmed after 12
consecutive months of amenorrhea in the absence of an...
Fig. 1 e Search strategy adopted for the review.
Table 1 e Characteristics of trials using desvenlafaxine succinate (DVS) ...
appeared to reduce hot flushes, possibly through an effect on
attenuation of central opioid peptide withdrawal or through
n...
bleeding (23% vs 12%, p  0.024). Nausea was the most com-
mon adverse event observed in DVS group.18
A 12-week multicenter...
15. Archer DF, Seidman L, Constantine GD, Pickar JH, Olivier S. A
double-blind, randomly assigned, placebo-controlled stud...
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Desvenlafaxine Succinate: Is it a New Promise and Hope for Management of Vasomotor Symptoms in Postmenopausal Women?

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Natural menopause, specifically, is confirmed after 12
consecutive months of amenorrhea in the absence of any
obvious, pathologic cause.1 These 12 months of amenorrhea and beyond, characterize a woman as postmenopausal. This can further be divided into early postmenopause (4 years after the FMP) and late postmenopause (>5 years since the FMP)

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Desvenlafaxine Succinate: Is it a New Promise and Hope for Management of Vasomotor Symptoms in Postmenopausal Women?

  1. 1. Desvenlafaxine Succinate: Is it a New Promise and Hope for Management of Vasomotor Symptoms in Postmenopausal Women?
  2. 2. Review Article Desvenlafaxine succinate: Is it a new promise and hope for management of vasomotor symptoms in postmenopausal women? Kavita Krishna a, *, Vandana Nimbargi b , Bijoy Panda c a Professor, Department of Medicine, Bharati Vidyapeeth Deemed University Medical College and Hospital, Pune, Maharashtra, India b Associate Professor, Department of Obstetrics & Gynaecology, Bharati Vidyapeeth Deemed University Medical College and Hospital, Pune, Maharashtra, India c Assistant Professor, PharmD Program, Poona College of Pharmacy, Bharati Vidyapeeth Deemed University, Pune, Maharashtra, India a r t i c l e i n f o Article history: Received 13 August 2012 Accepted 18 February 2013 Available online 21 April 2013 Keywords: Menopause Vasomotor symptoms treatment Hot flushes and night sweats Desvenlafaxine succinate a b s t r a c t Background: Desvenlafaxine succinate (DVS) is one of several serotoninenorepinephrine reuptake inhibitors (SNRIs) and has been approved by the US Food and Drug Administra- tion (FDA) for the treatment of major depressive disorder (MDD) and trials are being per- formed further to extend its approval in management of vasomotor symptoms in postmenopausal women. Objective: To review the published trials that evaluated the role of serotoninenorepinephrine reuptake inhibitors (SNRIs), especially desvenlafaxine succinate, on vasomotor symptoms (VMS). Methods: PubMed (the web-based version of MEDLINE) was searched using term “desven- lafaxine succinate AND vasomotor symptoms”. Trials examining the efficacy and safety of desvenlafaxine succinate in VMS were considered for critical review. Results: Recently, a program of clinical trials with desvenlafaxine (a salt from the major metabolite of venlafaxine) has been developed for VMS. Currently, there are seven ran- domized, double blind clinical trials published, showing a significantly higher efficacy of desvenlafaxine versus placebo on VMS. There were also increased minor side effects with desvenlafaxine, especially nausea, at the beginning of the treatment. Conclusions: A non-hormonal alternativeddesvenlafaxine succinate may be useful and is indicated for VMS in some but not most, cases. There was also an increase in minor side effects, especially nausea, at the beginning of the treatment. Studies comparing des- venlafaxine to other available treatment options relative to efficacy and safety are lacking, with the exception of only one trial where the comparative option was tibolone. The lack of head-to-head trials with the nonhormonal treatments, in particular, leaves practitioners with numerous choices. Larger and longer studies are warranted to prove its long-term efficacy and safety. Copyright ª 2013, Indraprastha Medical Corporation Ltd. All rights reserved. * Corresponding author. E-mail address: kavitakrishna2006@gmail.com (K. Krishna). Available online at www.sciencedirect.com journal homepage: www.elsevier.com/locate/apme a p o l l o m e d i c i n e 1 0 ( 2 0 1 3 ) 1 4 6 e1 5 1 0976-0016/$ e see front matter Copyright ª 2013, Indraprastha Medical Corporation Ltd. All rights reserved. http://dx.doi.org/10.1016/j.apme.2013.02.010
  3. 3. 1. Introduction Natural menopause, specifically, is confirmed after 12 consecutive months of amenorrhea in the absence of any obvious, pathologic cause.1 These 12 months of amenorrhea and beyond, characterize a woman as postmenopausal. This can further be divided into early postmenopause (1e4 years after the FMP) and late postmenopause (>5 years since the FMP).2,3 Surgical menopause results following surgical removal of the ovaries. In either instance, one result of the declining estrogen concentrations is the occurrence of vasomotor symptoms (VMS) that include hot flushes and night sweats, which occurs in, as many as 68.5% of women as a result of menopause. While the median duration of these symptoms is 4 years, approximately 10% of women continue to experience VMS as many as 12 years after their final menstrual period. As such, VMS have a significant impact on the quality of life and overall physical health of women experiencing VMS, leading to their pursuance of treatment to alleviate these symptoms.4 Management of VMS includes lifestyle modifications, some herbal and vitamin supplements, hormonal therapies including estrogen and tibolone,5e9 and nonhormonal thera- pies including clonidine, gabapentin, and some of the sero- tonin and serotoninenorepinephrine reuptake inhibitors.10,11 The latter agents, including desvenlafaxine, have been the focus of increased research as more is discovered about the roles of serotonin and norepinephrine in the thermoregula- tory control system. Desvenlafaxine succinate (DVS) is one of several serotoninenorepinephrine reuptake inhibitors (SNRIs). Others are venlafaxine hydrochloride, milnacipran, and duloxetine. DVS has been approved by the US Food and Drug Administration (FDA) for the treatment of major depressive disorder (MDD) based on a number of randomized, placebo controlled clinical trials. This critical review of various published data in a standard scientific database will focus on the role of desvenlafaxine as a treatment option for vasomotor symptoms (VMS) management in postmenopausal women. 2. Materials and method 2.1. Search strategy The following database was used to identify studies for this review: PubMed (the web-based version of MEDLINE) using term “desvenlafaxine succinate AND vasomotor symptoms” with certain limits (“O-desmethylvenlafaxine”[Supple- mentary Concept] OR “O-desmethylvenlafaxine”[All Fields] OR “desvenlafaxine succinate”[All Fields]) AND (vasomotor[All Fields] AND (“diagnosis”[Subheading] OR “diagnosis”[All Fields] OR “symptoms”[All Fields] OR “diagnosis”[MeSH Terms] OR “symptoms”[All Fields])) AND (“humans”[MeSH Terms] AND (Randomized Controlled Trial[ptyp] OR Clinical Trial[ptyp] OR Meta-Analysis[ptyp] OR Comparative Study [ptyp] OR Review[ptyp] OR Case Reports[ptyp] OR Clinical Conference[ptyp] OR systematic[sb] OR Editorial[ptyp]) AND English[lang]). This search strategy was developed according to Biondi-Zoccai.12 The language restriction was enforced to English and the search strategy was set to an end on month of July 2012. 2.2. Inclusion criteria Study design criteria for inclusion in this review were: Clinical Trial, Comparative Study, Controlled Clinical Trial, Evaluation Studies, Multicenter Study, Randomized Controlled Trials (RCTs). 2.3. Data extraction and analysis All titles and abstracts were screened independently by the reviewers and irrelevant studies were discarded. The full text of the remaining studies ware assessed to determine if the inclusion criteria were met. The included studies were assessed for trial characteristics and outcome, by the re- viewers, without blinding to author or source. Any discrep- ancies in outcome assessment were resolved in discussion. 3. Results 3.1. Literature search Nearly, 7 randomized controlled trials (RCTs) having followed up data was included. There was no disagreement between the reviewers regarding inclusion of trials. All the trials were double blinded and placebo controlled. Out of which 4 trials were multicentric and amongst that, one trial was a compar- ative trial where standard drug was tibolone. Fig. 1 briefly mentions the search strategy through the database. 3.2. Study characteristics and outcome assessment The characteristics and outcome assessment of the 7 RCTs are shown in Tables 1 and 2 respectively. All the trials were double blinded and healthy postmenopausal women with 50 moderate-to-severe hot flushes per week were enrolled as the main criteria. Nearly, 3295 participants were followed for atleast 12 weeks and the efficacy and safety of the drug was evaluated with primary end point such as average number of reductions in hot flushes and reduction in nighttime awak- enings. Few of the trials utilized standardized scoring tools like Profile of Mood States (POMS), Greene Climacteric Scales (GCS), Discontinuation-Emergent Signs and Symptoms (DESS) Score and Menopausal Symptom Treatment Satisfaction Questionnaire (MS-TSQ) scores. Safety parameters were pre- dicted in terms of incidences of uterine bleeding, laboratory values, vital signs and any adverse events reported during the trial period. 4. Discussion In nonhormonal prescription therapy, neuroactive agents have been studied mostly in women with breast cancer or who are at risk for breast cancer for their effectiveness at relieving VMS. Increased serotonergic activity within the CNS a p o l l o m e d i c i n e 1 0 ( 2 0 1 3 ) 1 4 6 e1 5 1 147
  4. 4. Fig. 1 e Search strategy adopted for the review. Table 1 e Characteristics of trials using desvenlafaxine succinate (DVS) in postmenopausal women with vasomotor symptoms (VMS). (Ref) Study Population No. of patients (n) Drug and doses given to respective groups (mg) Follow up 19 Cheng Multicentre 2012 Postmenopausal women with 50 moderate or severe hot flushes per week 458 Desvenlafaxine: 100 mg/day, 150 mg/day or placebo 12 weeks 18 Bouchard Multicentre, comparative 2012 Postmenopausal women with 50 moderate or severe hot flushes per week 485 Desvenlafaxine: 100 mg/day, Tibolone: 2.5 mg/day or placebo 12 weeks 14 Archer 2009 Postmenopausal women with 50 moderate or severe hot flushes per week 567 Desvenlafaxine: 100 mg/day, 150 mg/day or placebo 26 weeks 15 Archer Multicenter 2009 Postmenopausal women with 50 moderate or severe hot flushes per week 458 Desvenlafaxine: 100 mg/day, 150 mg/day or placebo 12 weeks 16 Speroff Multicenter 2008 Postmenopausal women with 50 moderate or severe hot flushes per week 707 Desvenlafaxine: 50 mg/day, 100 mg/day, 150 mg/day and 200 mg/day or placebo 52 weeks 17 Wyrwich Multicenter 2008 Postmenopausal women with 50 moderate or severe hot flushes per week 620 Desvenlafaxine: 50 mg/day, 100 mg/day, 150 mg/day and 200 mg/day or placebo 12 weeks 20 Gallagher 2012 [Abstract] Postmenopausal women with 50 moderate or severe hot flushes per week e Desvenlafaxine 100 mg/d (no titration), 50 mg/d, 25 mg/d (4 days) then 50 mg/d (3 days), or desvenlafaxine 25 mg/d. Participants then received open-label desvenlafaxine 100 mg/d for 15 weeks. In the 2-week taper phase, participants received placebo, desvenlafaxine 50 mg/d then placebo (7 days each), desvenlafaxine 50 mg/d then 25 mg/d (7 days each), or desvenlafaxine 50 mg/d every other day 2 weeks a p o l l o m e d i c i n e 1 0 ( 2 0 1 3 ) 1 4 6 e1 5 1148
  5. 5. appeared to reduce hot flushes, possibly through an effect on attenuation of central opioid peptide withdrawal or through noradrenergic activity. Studies have included selective sero- tonin reuptake inhibitors and serotoninenorepinephrine re- uptake inhibitors (venlafaxine and desvenlafaxine).10,11,13 Most studies of non-hormonal prescription therapies have required women to have 2 hot flushes for the day or 14/week at baseline prior to study enrollment, which differ from the FDA industry requirement of 50 or more hot flushes per week. In our critical review of various RCTs focusing manage- ment of vasomotor symptoms by desvenlafaxine found have enrolled healthy postmenopausal women experiencing 50 moderate-to-severe hot flushes/week. Few studies have considered nighttime awakening and climacteric conditions. This confirms all the RCTs have enrolled participants ac- cording to the FDA industry requirements. Desvenlafaxine, a metabolite of venlafaxine was demon- strated in RCTs14e16 at 100 mg and 150 mg per day to signifi- cantly reduce the number of hot flushes compared with placebo at weeks 4 and 12 (all p 0.012) with 65.4 and 66.6% reduction from baseline at 12 weeks respectively, compared with placebo at 50.8%. Hot flushes severity and number of nighttime awakenings were significantly reduced at both time points ( p 0.048). More adverse events were reported during week 1 than placebo, with no difference in discontinuations. Dose titration appears to improve initial tolerability and decrease adverse event reporting. Another placebo controlled trial utilized the criteria of efficacy and treatment satisfaction design, where the in- vestigators first identified the treatment satisfaction thresholds for interpreting treatment related changes in VMS and then determined the doses of DVS that effectively provide relief VMS. The tool used to assess this was a Menopause Symptom Treatment Satisfaction Question- naire. Greater percentages of participants in DVS group re- ported being “satisfied” or “extremely satisfied” with daytime and nighttime control of hot flushes compared with placebo. Amongst the various doses the 100 and 150 mg/day dose of DVS met both the important VMS change thresholds.17 A recent randomized placebo and active controlled study evaluated the safety and efficacy of DVS vs. Tibolone (2.5 mg/ day) or placebo. Reduction of the average daily number of moderate and severe hot flushes at week 12 was found to be non-significant where as time to 50% reduction was achieved at week 4 ( p ¼ 0.006). Adverse drug events were consistent with the known safety profile of DVS and significantly more women who received tibolone experienced episodes of Table 2 e Outcome assessment of trials using desvenlafaxine succinate (DVS) in postmenopausal women with vasomotor symptoms (VMS). (Ref) Study Blinding? Measurement of outcome Outcome 19 Cheng Multicentre 2012 Double blind Secondary outcomes of mood, climacteric symptoms, and treatment satisfaction change from baseline in Profile of Mood States (POMS) total mood disturbance, Greene Climacteric Scale (GCS), and Menopausal Symptoms Treatment Satisfaction Questionnaire (MS-TSQ) scores Desvenlafaxine treatment improved mood and climacteric symptoms and participants were satisfied with this compared to placebo. 18 Bouchard Multicentre, comparative 2012 Double blind Primary endpoints: Reduction in the average daily number of moderate-to-severe hot flushes at weeks 4 and 12 Safety Assessments: Incidence of uterine bleeding, adverse events, laboratory values, and vital signs Participants achieved 50% reduction of hot flushes than placebo and tibolone. Tibolone group experienced episodes of bleeding compared with women who received desvenlafaxine or placebo. 14 Archer 2009 Double blind Primary endpoints: Change from baseline in average daily number of moderate-to-severe HFs and average daily HF severity were compared with placebo at weeks 4, 12, and 26 Desvenlafaxine (DVS) is an effective treatment for menopausal hot flushes 15 Archer Multicenter 2009 Double blind Primary endpoints: Hot flush number and severity were assessed at weeks 4 and 12 Safety Assessments: Adverse events, laboratory values, and vital signs Desvenlafaxine (DVS) is an effective treatment for menopausal hot flushes Dose titration improves initial tolerability 16 Speroff Multicenter 2008 Double blind Primary endpoints: Change from baseline in average daily number of moderate-to-severe hot flushes and in daily hot flush severity score at weeks 4 and 12 Desvenlafaxine (DVS) is an effective treatment for menopausal hot flushes 17 Wyrwich Multicenter 2008 Double blind Primary endpoints: Number and severity of hot flushes and number of nighttime awakenings were recorded in daily diaries for 12 weeks of treatment. At week 12, responses to the Menopause Symptoms Treatment Satisfaction Questionnaire Significant satisfaction thresholds were achieved in participants with desvenlafaxine (DVS) 100 mg/day 20 Gallagher 2012 [Abstract] Double blind Primary endpoints: Nausea incidence during the first 2 weeks of treatment and Discontinuation-Emergent Signs and Symptoms (DESS) Checklist total scores after taper weeks 1 and 2 Taper regimens of desvenlafaxine (DVS) 50 mg/d-placebo or 50/25-mg/d, were better tolerated than abrupt discontinuation a p o l l o m e d i c i n e 1 0 ( 2 0 1 3 ) 1 4 6 e1 5 1 149
  6. 6. bleeding (23% vs 12%, p 0.024). Nausea was the most com- mon adverse event observed in DVS group.18 A 12-week multicenter, double blind and placebo controlled trial was performed to assess the effects of DVS in secondary outcomes of mood, climacteric symptoms and treatment and treatment satisfaction in postmenopausal women with moderate-to-severe VMS. Change from baseline in Profile of Mood States (POMS)-total mood disturbance (POMS-TMD) and Green Climacteric Scale (GSC) scores re- flected significant improvement ( p 0.001) respectively at a dose of DVS 100 mg/day. Even all the sub-domains of the POMS-TMD and GCS were significant ( p 0.05). Additionally, the elements of Menopausal Symptoms Treatment Satisfac- tion Questionnaire (MS-TSQ) score was significant (all p 0.042) which finally stated that more women were satisfied with DVS treatment than with placebo.19 A placebo controlled trial was performed to predict its tolerability by titrating up and tailoring down desvenlafax- ine succinate in postmenopausal women with vasomotor symptoms (VMS). In the 1-week titration phase, participants received desvenlafaxine 100 mg/d (no titration), desvenla- faxine 50 mg/d, desvenlafaxine 25 mg/d (4 days) then 50 mg/ d (3 days), or desvenlafaxine 25 mg/d. Participants then received open-label desvenlafaxine 100 mg/d for 15 weeks. In the 2-week taper phase, participants received placebo, desvenlafaxine 50 mg/d then placebo (7 days each), des- venlafaxine 50 mg/d then 25 mg/d (7 days each), or des- venlafaxine 50 mg/d every other day. Primary endpoints included nausea incidence during the first 2 weeks of treatment and Discontinuation-Emergent Signs and Symp- toms (DESS) Checklist total scores after taper weeks 1 and 2. Titration regimens improved tolerability of desvenlafaxine 100 mg/d in postmenopausal women with VMS. Taper reg- imens of desvenlafaxine 50 mg/d-placebo or 50/25 mg/d, were better tolerated than abrupt discontinuation or des- venlafaxine 50 mg given every other day taper regimen.20 Limitations of the trials include the study duration, the lack of ethnic diversity, and neglecting to evaluate the pres- ence of VMS risk factors among the study participants. The efficacy endpoints used in all of the trials were evaluated at 12 weeks and 26 weeks, which is a rather short duration. Trials evaluating the efficacy and safety of desvenlafaxine over an extended time are warranted. 5. Conclusion Desvenlafaxine is a viable option for the treatment of VMS in postmenopausal women where 100 and 150 mg/day regimen can effectively reduce the frequency of moderate-to-severe hot flushes and number of nighttime awakenings. Individu- alized dose titration may improve initial tolerability and decrease adverse events. Studies comparing desvenlafaxine to other available treatment options relative to efficacy and safety are lacking, with the exception of the one trial comparing it to tibolone. The lack of head-to-head trials with the nonhormonal treatments, in particular, leave practi- tioners with numerous choices, as one medication has not been shown to be superior. Larger studies with longer dura- tions, inclusive of more diversity among subject ethnicity, and with a focus that includes reporting the impact on overall QOL, are warranted to evaluate the long-term safety and ef- ficacy of desvenlafaxine for VMS treatment and improve the generalizability of the results. Conflicts of interest All authors have none to declare. r e f e r e n c e s 1. Freedman RR. Pathophysiology and treatment of menopausal hot flashes. Semin Reprod Med. 2005;23(2):117e125. 2. Blumel JE, Chedraui P, Baron G, et al. A large multinational study of vasomotor symptom prevalence, duration, and impact on quality of life in middle-age women. Menopause. 2011;18(7):778e785. 3. Politi MC, Schleinitz MD, Col NF. Revisiting the duration of vasomotor symptoms of menopause: a meta-analysis. J Gen Intern Med. 2008;23(9):1507e1513. 4. Thurston RC, Joffe H. Vasomotor symptoms and menopause: findings from the study of women’s health across the nation. Obstet Gynecol. 2011;38:489e501. 5. Elkins G, Marcus J, Stearns V, et al. Randomized trial of a hypnosis intervention for treatment of hot flashes among breast cancer survivors. J Clin Oncol. 2008;26(31):5022e5026. 6. Daley A, MacArthur C, Mutrie N, et al. Exercise for vasomotor menopausal symptoms. Cochrane Database Syst Rev. 2007;4: CD006108. 7. Kronenberg F, Fugh-Berman A. Complementary and alternative medicine for menopausal symptoms: a review of randomized, controlled trials. Ann Intern Med. 2002;137(10):805e813. 8. Li S, Holm K. Physical activity alone and in combination with hormone replacement therapy on vasomotor symptoms in postmenopausal women. West J Nurs Res. 2003;25(3): 274e288. 9. MacLennan AH, Broadbent JL, Lester S, Moore V. Oral oestrogen and combined oestrogen/progestogen therapy versus placebo for hot flushes. Cochrane Database Syst Rev. 2004;4: CD002978. 10. Pachman DR, Jones JM, Loprinzi CL, et al. Management of menopause-associated vasomotor symptoms: current treatment options, challenges and future directions. Int J Women’s Health. 2010;2:123e135. 11. Thacker HL. Assessing risks and benefits of nonhormonal treatments for vasomotor symptoms in perimenopausal and postmenopausal women. J Womens Health. 2011;20(7):1007e1016. 12. Biondi-Zoccai GG, Agostoni P, Abbate A, Testa L, Burzotta F. A simple hint to improve Robinson and Dickersin’s highly sensitive PubMed search strategy for controlled clinical trials. Int J Epidemiol. 2005;34:224e225. 13. Loprinzi CL, Kugler JW, Sloan JA, et al. Venlafaxine in management of hot flashes in survivors of breast cancer: a randomised controlled trial. Lancet. 2000;356(9247): 2059e2063. 14. Archer DF, Dupont CM, Constantine GD, Pickar JH, Olivier S, Study 319 Investigators. Desvenlafaxine for the treatment of vasomotor symptoms associated with menopause: a double- blind, randomized, placebo-controlled trial of efficacy and safety. Am J Obstet Gynecol. 2009;200(3):238. e1e238.e10. Epub 2009 Jan 24. a p o l l o m e d i c i n e 1 0 ( 2 0 1 3 ) 1 4 6 e1 5 1150
  7. 7. 15. Archer DF, Seidman L, Constantine GD, Pickar JH, Olivier S. A double-blind, randomly assigned, placebo-controlled study of desvenlafaxine efficacy and safety for the treatment of vasomotor symptoms associated with menopause. Am J Obstet Gynecol. 2009;200(2):172. e1e10. Epub 2008 Dec 25. 16. Speroff L, Gass M, Constantine G, Olivier S, Study 315 Investigators. Efficacy and tolerability of desvenlafaxine succinate treatment for menopausal vasomotor symptoms: a randomized controlled trial. Obstet Gynecol. 2008;111(1):77e87. 17. Wyrwich KW, Spratt DI, Gass M, Yu H, Bobula JD. Identifying meaningful differences in vasomotor symptoms among menopausal women. Menopause. 2008;4(Pt 1):698e705. 18. Bouchard P, Panay N, de Villiers TJ, et al. Randomized placebo- and active-controlled study of desvenlafaxine for menopausal vasomotor symptoms. Climacteric. 2012;15(1): 12e20. 19. Cheng RJ, Dupont C, Archer DF, et al. Effect of desvenlafaxine on mood and climacteric symptoms in menopausal women with moderate to severe vasomotor symptoms. Climacteric. 2013;16(1):17e27. 20. Gallagher JC, Strzinek RA, Cheng RF, Ausmanas MK, Astl D, Seljan P. The effect of dose titration and dose tapering on the tolerability of desvenlafaxine in women with vasomotor symptoms associated with menopause. J Womens Health (Larchmt). 2012;21(2):188e198 [Abstract]. a p o l l o m e d i c i n e 1 0 ( 2 0 1 3 ) 1 4 6 e1 5 1 151
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