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Baloxavir Marboxil for Uncomplicated Influenza in Adults and Adolescents.
N Engl J Med 2018; 379(10):913-923NEJM

Abstract

BACKGROUND

Baloxavir marboxil is a selective inhibitor of influenza cap-dependent endonuclease. It has shown therapeutic activity in preclinical models of influenza A and B virus infections, including strains resistant to current antiviral agents.

METHODS

We conducted two randomized, double-blind, controlled trials involving otherwise healthy outpatients with acute uncomplicated influenza. After a dose-ranging (10 to 40 mg) placebo-controlled trial, we undertook a placebo- and oseltamivir-controlled trial of single, weight-based doses of baloxavir (40 or 80 mg) in patients 12 to 64 years of age during the 2016-2017 season. The dose of oseltamivir was 75 mg twice daily for 5 days. The primary efficacy end point was the time to alleviation of influenza symptoms in the intention-to-treat infected population.

RESULTS

In the phase 2 trial, the median time to alleviation of influenza symptoms was 23.4 to 28.2 hours shorter in the baloxavir groups than in the placebo group (P<0.05). In the phase 3 trial, the intention-to-treat infected population included 1064 patients; 84.8 to 88.1% of patients in each group had influenza A(H3N2) infection. The median time to alleviation of symptoms was 53.7 hours (95% confidence interval [CI], 49.5 to 58.5) with baloxavir, as compared with 80.2 hours (95% CI, 72.6 to 87.1) with placebo (P<0.001). The time to alleviation of symptoms was similar with baloxavir and oseltamivir. Baloxavir was associated with greater reductions in viral load 1 day after initiation of the regimen than placebo or oseltamivir. Adverse events were reported in 20.7% of baloxavir recipients, 24.6% of placebo recipients, and 24.8% of oseltamivir recipients. The emergence of polymerase acidic protein variants with I38T/M/F substitutions conferring reduced susceptibility to baloxavir occurred in 2.2% and 9.7% of baloxavir recipients in the phase 2 trial and phase 3 trial, respectively.

CONCLUSIONS

Single-dose baloxavir was without evident safety concerns, was superior to placebo in alleviating influenza symptoms, and was superior to both oseltamivir and placebo in reducing the viral load 1 day after initiation of the trial regimen in patients with uncomplicated influenza. Evidence for the development of decreased susceptibility to baloxavir after treatment was also observed. (Funded by Shionogi; JapicCTI number, 153090, and CAPSTONE-1 ClinicalTrials.gov number, NCT02954354 .).

Authors+Show Affiliations

From the Department of Medicine, University of Virginia School of Medicine, Charlottesville (F.G.H.); the Department of Pediatrics, Keiyu Hospital, Yokohama (N.S.), Hirotsu Clinic, Kawasaki (N.H.), the Department of Respiratory Medicine, Kurashiki Central Hospital, Kurashiki (T.I.), Sekino Hospital, Tokyo (H.S.), Tsuchiura Beryl Clinic, Tsuchiura (K.Y.), Shionogi, Osaka (K.K., T.S., M.A., K.T., T.U.), and the Research Division for Development of Anti-Infective Agents, Institute of Development, Aging, and Cancer, Tohoku University, Sendai (A.W.) - all in Japan; the Division of Infectious Diseases, Department of Medicine, University of Alberta, Edmonton, Canada (N.L.); the Department of Medical Microbiology, Academic Medical Center, University of Amsterdam, Amsterdam (M.D.J.); the Department of Microbiology and Immunology, University of Melbourne, at the Peter Doherty Institute for Infection and Immunity, Melbourne, VIC, Australia (A.C.H.); and Shionogi, Florham Park, NJ (S.P.).From the Department of Medicine, University of Virginia School of Medicine, Charlottesville (F.G.H.); the Department of Pediatrics, Keiyu Hospital, Yokohama (N.S.), Hirotsu Clinic, Kawasaki (N.H.), the Department of Respiratory Medicine, Kurashiki Central Hospital, Kurashiki (T.I.), Sekino Hospital, Tokyo (H.S.), Tsuchiura Beryl Clinic, Tsuchiura (K.Y.), Shionogi, Osaka (K.K., T.S., M.A., K.T., T.U.), and the Research Division for Development of Anti-Infective Agents, Institute of Development, Aging, and Cancer, Tohoku University, Sendai (A.W.) - all in Japan; the Division of Infectious Diseases, Department of Medicine, University of Alberta, Edmonton, Canada (N.L.); the Department of Medical Microbiology, Academic Medical Center, University of Amsterdam, Amsterdam (M.D.J.); the Department of Microbiology and Immunology, University of Melbourne, at the Peter Doherty Institute for Infection and Immunity, Melbourne, VIC, Australia (A.C.H.); and Shionogi, Florham Park, NJ (S.P.).From the Department of Medicine, University of Virginia School of Medicine, Charlottesville (F.G.H.); the Department of Pediatrics, Keiyu Hospital, Yokohama (N.S.), Hirotsu Clinic, Kawasaki (N.H.), the Department of Respiratory Medicine, Kurashiki Central Hospital, Kurashiki (T.I.), Sekino Hospital, Tokyo (H.S.), Tsuchiura Beryl Clinic, Tsuchiura (K.Y.), Shionogi, Osaka (K.K., T.S., M.A., K.T., T.U.), and the Research Division for Development of Anti-Infective Agents, Institute of Development, Aging, and Cancer, Tohoku University, Sendai (A.W.) - all in Japan; the Division of Infectious Diseases, Department of Medicine, University of Alberta, Edmonton, Canada (N.L.); the Department of Medical Microbiology, Academic Medical Center, University of Amsterdam, Amsterdam (M.D.J.); the Department of Microbiology and Immunology, University of Melbourne, at the Peter Doherty Institute for Infection and Immunity, Melbourne, VIC, Australia (A.C.H.); and Shionogi, Florham Park, NJ (S.P.).From the Department of Medicine, University of Virginia School of Medicine, Charlottesville (F.G.H.); the Department of Pediatrics, Keiyu Hospital, Yokohama (N.S.), Hirotsu Clinic, Kawasaki (N.H.), the Department of Respiratory Medicine, Kurashiki Central Hospital, Kurashiki (T.I.), Sekino Hospital, Tokyo (H.S.), Tsuchiura Beryl Clinic, Tsuchiura (K.Y.), Shionogi, Osaka (K.K., T.S., M.A., K.T., T.U.), and the Research Division for Development of Anti-Infective Agents, Institute of Development, Aging, and Cancer, Tohoku University, Sendai (A.W.) - all in Japan; the Division of Infectious Diseases, Department of Medicine, University of Alberta, Edmonton, Canada (N.L.); the Department of Medical Microbiology, Academic Medical Center, University of Amsterdam, Amsterdam (M.D.J.); the Department of Microbiology and Immunology, University of Melbourne, at the Peter Doherty Institute for Infection and Immunity, Melbourne, VIC, Australia (A.C.H.); and Shionogi, Florham Park, NJ (S.P.).From the Department of Medicine, University of Virginia School of Medicine, Charlottesville (F.G.H.); the Department of Pediatrics, Keiyu Hospital, Yokohama (N.S.), Hirotsu Clinic, Kawasaki (N.H.), the Department of Respiratory Medicine, Kurashiki Central Hospital, Kurashiki (T.I.), Sekino Hospital, Tokyo (H.S.), Tsuchiura Beryl Clinic, Tsuchiura (K.Y.), Shionogi, Osaka (K.K., T.S., M.A., K.T., T.U.), and the Research Division for Development of Anti-Infective Agents, Institute of Development, Aging, and Cancer, Tohoku University, Sendai (A.W.) - all in Japan; the Division of Infectious Diseases, Department of Medicine, University of Alberta, Edmonton, Canada (N.L.); the Department of Medical Microbiology, Academic Medical Center, University of Amsterdam, Amsterdam (M.D.J.); the Department of Microbiology and Immunology, University of Melbourne, at the Peter Doherty Institute for Infection and Immunity, Melbourne, VIC, Australia (A.C.H.); and Shionogi, Florham Park, NJ (S.P.).From the Department of Medicine, University of Virginia School of Medicine, Charlottesville (F.G.H.); the Department of Pediatrics, Keiyu Hospital, Yokohama (N.S.), Hirotsu Clinic, Kawasaki (N.H.), the Department of Respiratory Medicine, Kurashiki Central Hospital, Kurashiki (T.I.), Sekino Hospital, Tokyo (H.S.), Tsuchiura Beryl Clinic, Tsuchiura (K.Y.), Shionogi, Osaka (K.K., T.S., M.A., K.T., T.U.), and the Research Division for Development of Anti-Infective Agents, Institute of Development, Aging, and Cancer, Tohoku University, Sendai (A.W.) - all in Japan; the Division of Infectious Diseases, Department of Medicine, University of Alberta, Edmonton, Canada (N.L.); the Department of Medical Microbiology, Academic Medical Center, University of Amsterdam, Amsterdam (M.D.J.); the Department of Microbiology and Immunology, University of Melbourne, at the Peter Doherty Institute for Infection and Immunity, Melbourne, VIC, Australia (A.C.H.); and Shionogi, Florham Park, NJ (S.P.).From the Department of Medicine, University of Virginia School of Medicine, Charlottesville (F.G.H.); the Department of Pediatrics, Keiyu Hospital, Yokohama (N.S.), Hirotsu Clinic, Kawasaki (N.H.), the Department of Respiratory Medicine, Kurashiki Central Hospital, Kurashiki (T.I.), Sekino Hospital, Tokyo (H.S.), Tsuchiura Beryl Clinic, Tsuchiura (K.Y.), Shionogi, Osaka (K.K., T.S., M.A., K.T., T.U.), and the Research Division for Development of Anti-Infective Agents, Institute of Development, Aging, and Cancer, Tohoku University, Sendai (A.W.) - all in Japan; the Division of Infectious Diseases, Department of Medicine, University of Alberta, Edmonton, Canada (N.L.); the Department of Medical Microbiology, Academic Medical Center, University of Amsterdam, Amsterdam (M.D.J.); the Department of Microbiology and Immunology, University of Melbourne, at the Peter Doherty Institute for Infection and Immunity, Melbourne, VIC, Australia (A.C.H.); and Shionogi, Florham Park, NJ (S.P.).From the Department of Medicine, University of Virginia School of Medicine, Charlottesville (F.G.H.); the Department of Pediatrics, Keiyu Hospital, Yokohama (N.S.), Hirotsu Clinic, Kawasaki (N.H.), the Department of Respiratory Medicine, Kurashiki Central Hospital, Kurashiki (T.I.), Sekino Hospital, Tokyo (H.S.), Tsuchiura Beryl Clinic, Tsuchiura (K.Y.), Shionogi, Osaka (K.K., T.S., M.A., K.T., T.U.), and the Research Division for Development of Anti-Infective Agents, Institute of Development, Aging, and Cancer, Tohoku University, Sendai (A.W.) - all in Japan; the Division of Infectious Diseases, Department of Medicine, University of Alberta, Edmonton, Canada (N.L.); the Department of Medical Microbiology, Academic Medical Center, University of Amsterdam, Amsterdam (M.D.J.); the Department of Microbiology and Immunology, University of Melbourne, at the Peter Doherty Institute for Infection and Immunity, Melbourne, VIC, Australia (A.C.H.); and Shionogi, Florham Park, NJ (S.P.).From the Department of Medicine, University of Virginia School of Medicine, Charlottesville (F.G.H.); the Department of Pediatrics, Keiyu Hospital, Yokohama (N.S.), Hirotsu Clinic, Kawasaki (N.H.), the Department of Respiratory Medicine, Kurashiki Central Hospital, Kurashiki (T.I.), Sekino Hospital, Tokyo (H.S.), Tsuchiura Beryl Clinic, Tsuchiura (K.Y.), Shionogi, Osaka (K.K., T.S., M.A., K.T., T.U.), and the Research Division for Development of Anti-Infective Agents, Institute of Development, Aging, and Cancer, Tohoku University, Sendai (A.W.) - all in Japan; the Division of Infectious Diseases, Department of Medicine, University of Alberta, Edmonton, Canada (N.L.); the Department of Medical Microbiology, Academic Medical Center, University of Amsterdam, Amsterdam (M.D.J.); the Department of Microbiology and Immunology, University of Melbourne, at the Peter Doherty Institute for Infection and Immunity, Melbourne, VIC, Australia (A.C.H.); and Shionogi, Florham Park, NJ (S.P.).From the Department of Medicine, University of Virginia School of Medicine, Charlottesville (F.G.H.); the Department of Pediatrics, Keiyu Hospital, Yokohama (N.S.), Hirotsu Clinic, Kawasaki (N.H.), the Department of Respiratory Medicine, Kurashiki Central Hospital, Kurashiki (T.I.), Sekino Hospital, Tokyo (H.S.), Tsuchiura Beryl Clinic, Tsuchiura (K.Y.), Shionogi, Osaka (K.K., T.S., M.A., K.T., T.U.), and the Research Division for Development of Anti-Infective Agents, Institute of Development, Aging, and Cancer, Tohoku University, Sendai (A.W.) - all in Japan; the Division of Infectious Diseases, Department of Medicine, University of Alberta, Edmonton, Canada (N.L.); the Department of Medical Microbiology, Academic Medical Center, University of Amsterdam, Amsterdam (M.D.J.); the Department of Microbiology and Immunology, University of Melbourne, at the Peter Doherty Institute for Infection and Immunity, Melbourne, VIC, Australia (A.C.H.); and Shionogi, Florham Park, NJ (S.P.).From the Department of Medicine, University of Virginia School of Medicine, Charlottesville (F.G.H.); the Department of Pediatrics, Keiyu Hospital, Yokohama (N.S.), Hirotsu Clinic, Kawasaki (N.H.), the Department of Respiratory Medicine, Kurashiki Central Hospital, Kurashiki (T.I.), Sekino Hospital, Tokyo (H.S.), Tsuchiura Beryl Clinic, Tsuchiura (K.Y.), Shionogi, Osaka (K.K., T.S., M.A., K.T., T.U.), and the Research Division for Development of Anti-Infective Agents, Institute of Development, Aging, and Cancer, Tohoku University, Sendai (A.W.) - all in Japan; the Division of Infectious Diseases, Department of Medicine, University of Alberta, Edmonton, Canada (N.L.); the Department of Medical Microbiology, Academic Medical Center, University of Amsterdam, Amsterdam (M.D.J.); the Department of Microbiology and Immunology, University of Melbourne, at the Peter Doherty Institute for Infection and Immunity, Melbourne, VIC, Australia (A.C.H.); and Shionogi, Florham Park, NJ (S.P.).From the Department of Medicine, University of Virginia School of Medicine, Charlottesville (F.G.H.); the Department of Pediatrics, Keiyu Hospital, Yokohama (N.S.), Hirotsu Clinic, Kawasaki (N.H.), the Department of Respiratory Medicine, Kurashiki Central Hospital, Kurashiki (T.I.), Sekino Hospital, Tokyo (H.S.), Tsuchiura Beryl Clinic, Tsuchiura (K.Y.), Shionogi, Osaka (K.K., T.S., M.A., K.T., T.U.), and the Research Division for Development of Anti-Infective Agents, Institute of Development, Aging, and Cancer, Tohoku University, Sendai (A.W.) - all in Japan; the Division of Infectious Diseases, Department of Medicine, University of Alberta, Edmonton, Canada (N.L.); the Department of Medical Microbiology, Academic Medical Center, University of Amsterdam, Amsterdam (M.D.J.); the Department of Microbiology and Immunology, University of Melbourne, at the Peter Doherty Institute for Infection and Immunity, Melbourne, VIC, Australia (A.C.H.); and Shionogi, Florham Park, NJ (S.P.).From the Department of Medicine, University of Virginia School of Medicine, Charlottesville (F.G.H.); the Department of Pediatrics, Keiyu Hospital, Yokohama (N.S.), Hirotsu Clinic, Kawasaki (N.H.), the Department of Respiratory Medicine, Kurashiki Central Hospital, Kurashiki (T.I.), Sekino Hospital, Tokyo (H.S.), Tsuchiura Beryl Clinic, Tsuchiura (K.Y.), Shionogi, Osaka (K.K., T.S., M.A., K.T., T.U.), and the Research Division for Development of Anti-Infective Agents, Institute of Development, Aging, and Cancer, Tohoku University, Sendai (A.W.) - all in Japan; the Division of Infectious Diseases, Department of Medicine, University of Alberta, Edmonton, Canada (N.L.); the Department of Medical Microbiology, Academic Medical Center, University of Amsterdam, Amsterdam (M.D.J.); the Department of Microbiology and Immunology, University of Melbourne, at the Peter Doherty Institute for Infection and Immunity, Melbourne, VIC, Australia (A.C.H.); and Shionogi, Florham Park, NJ (S.P.).From the Department of Medicine, University of Virginia School of Medicine, Charlottesville (F.G.H.); the Department of Pediatrics, Keiyu Hospital, Yokohama (N.S.), Hirotsu Clinic, Kawasaki (N.H.), the Department of Respiratory Medicine, Kurashiki Central Hospital, Kurashiki (T.I.), Sekino Hospital, Tokyo (H.S.), Tsuchiura Beryl Clinic, Tsuchiura (K.Y.), Shionogi, Osaka (K.K., T.S., M.A., K.T., T.U.), and the Research Division for Development of Anti-Infective Agents, Institute of Development, Aging, and Cancer, Tohoku University, Sendai (A.W.) - all in Japan; the Division of Infectious Diseases, Department of Medicine, University of Alberta, Edmonton, Canada (N.L.); the Department of Medical Microbiology, Academic Medical Center, University of Amsterdam, Amsterdam (M.D.J.); the Department of Microbiology and Immunology, University of Melbourne, at the Peter Doherty Institute for Infection and Immunity, Melbourne, VIC, Australia (A.C.H.); and Shionogi, Florham Park, NJ (S.P.).From the Department of Medicine, University of Virginia School of Medicine, Charlottesville (F.G.H.); the Department of Pediatrics, Keiyu Hospital, Yokohama (N.S.), Hirotsu Clinic, Kawasaki (N.H.), the Department of Respiratory Medicine, Kurashiki Central Hospital, Kurashiki (T.I.), Sekino Hospital, Tokyo (H.S.), Tsuchiura Beryl Clinic, Tsuchiura (K.Y.), Shionogi, Osaka (K.K., T.S., M.A., K.T., T.U.), and the Research Division for Development of Anti-Infective Agents, Institute of Development, Aging, and Cancer, Tohoku University, Sendai (A.W.) - all in Japan; the Division of Infectious Diseases, Department of Medicine, University of Alberta, Edmonton, Canada (N.L.); the Department of Medical Microbiology, Academic Medical Center, University of Amsterdam, Amsterdam (M.D.J.); the Department of Microbiology and Immunology, University of Melbourne, at the Peter Doherty Institute for Infection and Immunity, Melbourne, VIC, Australia (A.C.H.); and Shionogi, Florham Park, NJ (S.P.).From the Department of Medicine, University of Virginia School of Medicine, Charlottesville (F.G.H.); the Department of Pediatrics, Keiyu Hospital, Yokohama (N.S.), Hirotsu Clinic, Kawasaki (N.H.), the Department of Respiratory Medicine, Kurashiki Central Hospital, Kurashiki (T.I.), Sekino Hospital, Tokyo (H.S.), Tsuchiura Beryl Clinic, Tsuchiura (K.Y.), Shionogi, Osaka (K.K., T.S., M.A., K.T., T.U.), and the Research Division for Development of Anti-Infective Agents, Institute of Development, Aging, and Cancer, Tohoku University, Sendai (A.W.) - all in Japan; the Division of Infectious Diseases, Department of Medicine, University of Alberta, Edmonton, Canada (N.L.); the Department of Medical Microbiology, Academic Medical Center, University of Amsterdam, Amsterdam (M.D.J.); the Department of Microbiology and Immunology, University of Melbourne, at the Peter Doherty Institute for Infection and Immunity, Melbourne, VIC, Australia (A.C.H.); and Shionogi, Florham Park, NJ (S.P.).No affiliation info available

Pub Type(s)

Clinical Trial, Phase II
Clinical Trial, Phase III
Journal Article
Multicenter Study
Randomized Controlled Trial
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

30184455

Citation

Hayden, Frederick G., et al. "Baloxavir Marboxil for Uncomplicated Influenza in Adults and Adolescents." The New England Journal of Medicine, vol. 379, no. 10, 2018, pp. 913-923.
Hayden FG, Sugaya N, Hirotsu N, et al. Baloxavir Marboxil for Uncomplicated Influenza in Adults and Adolescents. N Engl J Med. 2018;379(10):913-923.
Hayden, F. G., Sugaya, N., Hirotsu, N., Lee, N., de Jong, M. D., Hurt, A. C., ... Watanabe, A. (2018). Baloxavir Marboxil for Uncomplicated Influenza in Adults and Adolescents. The New England Journal of Medicine, 379(10), pp. 913-923. doi:10.1056/NEJMoa1716197.
Hayden FG, et al. Baloxavir Marboxil for Uncomplicated Influenza in Adults and Adolescents. N Engl J Med. 2018 09 6;379(10):913-923. PubMed PMID: 30184455.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Baloxavir Marboxil for Uncomplicated Influenza in Adults and Adolescents. AU - Hayden,Frederick G, AU - Sugaya,Norio, AU - Hirotsu,Nobuo, AU - Lee,Nelson, AU - de Jong,Menno D, AU - Hurt,Aeron C, AU - Ishida,Tadashi, AU - Sekino,Hisakuni, AU - Yamada,Kota, AU - Portsmouth,Simon, AU - Kawaguchi,Keiko, AU - Shishido,Takao, AU - Arai,Masatsugu, AU - Tsuchiya,Kenji, AU - Uehara,Takeki, AU - Watanabe,Akira, AU - ,, PY - 2018/9/6/entrez PY - 2018/9/6/pubmed PY - 2018/10/3/medline SP - 913 EP - 923 JF - The New England journal of medicine JO - N. Engl. J. Med. VL - 379 IS - 10 N2 - BACKGROUND: Baloxavir marboxil is a selective inhibitor of influenza cap-dependent endonuclease. It has shown therapeutic activity in preclinical models of influenza A and B virus infections, including strains resistant to current antiviral agents. METHODS: We conducted two randomized, double-blind, controlled trials involving otherwise healthy outpatients with acute uncomplicated influenza. After a dose-ranging (10 to 40 mg) placebo-controlled trial, we undertook a placebo- and oseltamivir-controlled trial of single, weight-based doses of baloxavir (40 or 80 mg) in patients 12 to 64 years of age during the 2016-2017 season. The dose of oseltamivir was 75 mg twice daily for 5 days. The primary efficacy end point was the time to alleviation of influenza symptoms in the intention-to-treat infected population. RESULTS: In the phase 2 trial, the median time to alleviation of influenza symptoms was 23.4 to 28.2 hours shorter in the baloxavir groups than in the placebo group (P<0.05). In the phase 3 trial, the intention-to-treat infected population included 1064 patients; 84.8 to 88.1% of patients in each group had influenza A(H3N2) infection. The median time to alleviation of symptoms was 53.7 hours (95% confidence interval [CI], 49.5 to 58.5) with baloxavir, as compared with 80.2 hours (95% CI, 72.6 to 87.1) with placebo (P<0.001). The time to alleviation of symptoms was similar with baloxavir and oseltamivir. Baloxavir was associated with greater reductions in viral load 1 day after initiation of the regimen than placebo or oseltamivir. Adverse events were reported in 20.7% of baloxavir recipients, 24.6% of placebo recipients, and 24.8% of oseltamivir recipients. The emergence of polymerase acidic protein variants with I38T/M/F substitutions conferring reduced susceptibility to baloxavir occurred in 2.2% and 9.7% of baloxavir recipients in the phase 2 trial and phase 3 trial, respectively. CONCLUSIONS: Single-dose baloxavir was without evident safety concerns, was superior to placebo in alleviating influenza symptoms, and was superior to both oseltamivir and placebo in reducing the viral load 1 day after initiation of the trial regimen in patients with uncomplicated influenza. Evidence for the development of decreased susceptibility to baloxavir after treatment was also observed. (Funded by Shionogi; JapicCTI number, 153090, and CAPSTONE-1 ClinicalTrials.gov number, NCT02954354 .). SN - 1533-4406 UR - https://www.unboundmedicine.com/medline/citation/30184455/Baloxavir_Marboxil_for_Uncomplicated_Influenza_in_Adults_and_Adolescents_ L2 - http://www.nejm.org/doi/full/10.1056/NEJMoa1716197?url_ver=Z39.88-2003&amp;rfr_id=ori:rid:crossref.org&amp;rfr_dat=cr_pub=pubmed DB - PRIME DP - Unbound Medicine ER -