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Recently, several new drugs including lubiprostone, linaclotide and prucalopride have been approved for treatment of chronic constipation. However, a significant unmet medical need still remains, particularly among those patients achieving poor results by current therapies. The 5-HT4 receptor modulators velusetrag and naronapride, the guanylate cyclase C agonist plecanatide and the ileal bile acid transporter inhibitor elobixibat are recognized as the most promising drugs under investigation.

Herein, we give a comprehensive review on the pharmacological therapeutics for the treatment of chronic constipation, with the purpose of reflecting the drug development trends in this field. Open in a separate window 1. It was estimated that constipation has a prevalence range from 8. Constipation in women occurs twice as frequently as in men. Severe constipation e. In addition to the direct economic burden caused by treatment, patients may face hardships such as missing school or work 5.

Spiller, and D. Tidd, An- tisense Res. Wang, R. Lee, G. Cauchon, D. Low, Proc. USA, 92, Iversen, Anticancer Drug Des. Geary, J. Leeds, T. Watanabe, M. Moore, J. Fitchett, J. Burckin, M. Templin, and A. Cossum, L. Truong, S. Owens, P. Shea, and S. Crooke, J. Crooke, I. Grillone, A. Tendolkar, A. Gar- rett, M. Leeds, and W. Barr, Clin.

Leeds, S. Henry, R. Geary, T. Antisense Nucleic Acid Drug Dev. Cossum, H. Sasmor, D. Dellinger, L. Truong, L. Cummins, S. Rappaport, B. Hanss, J. Kopp, T. Bruggeman, T. Coffman, and P. Kidney 47, Iverson, Anticancer Drug Des. Iversen, M. Bishop, J. Sharp, H. Tewary, M. Arneson, S. Ruddon, A. Kessinger, and G.

Zon, Antisense Res. Zhang, J. Shahinian, G. Lu, T. Liu, M. Jiang, J. Temsamani, R. Martin, P. Schechter, S. Diasio, Clin. Takakura, R. Yoshida, T. Butler, K. Stecker, and C. Bennett, Lab. Graham, S. Crooke, D.

Monteith, S. Cooper, K. Lemonidis, K. Stecker, M. Martin, and R. Crooke, Pharmacol. Oligonucleotide Therapeutics Nyce, Expert Opin. Drugs, 6, Templin, A. Graham, P. Aberg, B. Butler, R. Nyce and W. Metzger, Nature, , Hardee, S. Weinbach, and L. Bennett and S. Wagner, M. Matteucci, G. Lewis, A. Gutierrez, C.

Moulds, and B. Froehler, Science, , Barton and N. Lemoine, Br. Cancer, 71, Burgess, E. Fisher, S. Ross, V. Bready, Y. Qian, L. Bayewitch, A. Cohen, C. Herrera, S. Hu, T. Lott, F. Martin, G. Pierce, L. Simonet, and C. Hertl, L.

Neckers, and S. In- vest. Holstad, and K. Isenberg, Pharrnacotherapy, 13, Simons, E. Edelman, R. Langer, and R. Rosenberg, Nature, , Abe, W. Zhou, J. Taguchi, N. Takuwa, K. Kurokawa, M. Kumada, and Y. Takuwa, Biochern. Whitesell, A. Rosolen, and L. Neckers, Antisense Res. Wahlestedt, E. Koob, F. Yee, and M.

Heilig, Science, , Zhang, L. Zhou, and B. Weiss, J. Gyurko, and M. Phillips, Regul. Nielsen, and D. Osen-Sand, M. Catsicas, K. Staple, K. Jones, G. Ayala, J. Knowles, G. Grenningloh, and S. Nature, , Burch and L. Mahan, J. Lima and S. Crooke, Biochemistry, 36, Perez, T. Coleman, K. Dorshkind, W. Sarmiento, C. Rosen, and R. Narayan, Proc. USA, 90, Hijiya, J. Zhang, M. Kant, K. Herlyn, G. Zon, and A. USA, Dean and R. McKay, Proc. USA, 91, Dean, R. McKay, L. Miraglia, R. Howard, S. Cooper, Giddings, P.

Nicklin, L. Meister, R. Ziel, T. Geiger, M. Muller, and D. Fabbro, Can- cer Res. Monia, F. Johnston, T. Fabbro, Med. Johnston, H. Cummins, J. Nesterova and Y. Cho-Chung, Med. Maksymowych, W. Blackburn, E. Williams, Tami, K. Wagner, and W. Shanahan, Arthritis Rheum. Fredriksson and U. Pettersson, , Yacyshyn, M. Jewell, A. Tami, C. Bennett, D. Shanahan, Jr. Yacyshyn, B. Woloschuk, M. Yacyshyn, D. Martini, K.

Tami, F. Yuen, R. Advani, G. Fisher, J. Halsey, B. Lum, R. Kwoh, J. Holmlund, A. Dorr, and B. Waters, A. Webb, D. Cunningham, P. Clarke, F. Cot- ter, J. Jansen, V. Proceedings o f Stevenson, M. Gallagher, A. Cassella, I. Vasilevskaya, B. Monia, J. Holm- lund, F. Dorr, and K. Yao, Clin. Nemunaitis, J. Holmlund, M. Richards, J. Bruce, N. Kwoh, R. Geary, A. Dorr, D. V o n Hoff, and S. Yuen, J. Halsey, G. Holmlund, R. Kwoh, A. Cancer Res. Stevenson, K.

Yao, M. Gallagher, D. Friedland, E. Mitchell, A. Cassella, B. Holmlund, F. Dorr, and P. Dwyer, J. Holm- lund, A. Cunningham, J. Holmlund, J. Schiller, R. Dorr, and J.

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Open in a separate window 1. It was estimated that constipation has a prevalence range from 8. Constipation in women occurs twice as frequently as in men. Severe constipation e. In addition to the direct economic burden caused by treatment, patients may face hardships such as missing school or work 5.

Inadequate intake of dietary fiber, lack of exercise, intestinal dysfunction, etc. However, chronic primary or chronic idiopathic constipation CIC , which is typically classified into three categories: outlet obstruction, normal-transit constipation and slow colonic transit 6 , has no definitive cause. For the initial treatment of chronic constipation, increasing fiber intake or using lavatives is commonly recommended.

Although clinical trials show that most lavatives achieve poor results, new pharmacological therapies with different mechanisms of action have been developed over the last decade for the treatment of chronic constipation. Tidd, An- tisense Res. Wang, R. Lee, G. Cauchon, D. Low, Proc. USA, 92, Iversen, Anticancer Drug Des.

Geary, J. Leeds, T. Watanabe, M. Moore, J. Fitchett, J. Burckin, M. Templin, and A. Cossum, L. Truong, S. Owens, P. Shea, and S. Crooke, J. Crooke, I. Grillone, A. Tendolkar, A. Gar- rett, M. Leeds, and W. Barr, Clin. Leeds, S. Henry, R. Geary, T. Antisense Nucleic Acid Drug Dev. Cossum, H. Sasmor, D. Dellinger, L. Truong, L. Cummins, S. Rappaport, B. Hanss, J. Kopp, T. Bruggeman, T. Coffman, and P. Kidney 47, Iverson, Anticancer Drug Des.

Iversen, M. Bishop, J. Sharp, H. Tewary, M. Arneson, S. Ruddon, A. Kessinger, and G. Zon, Antisense Res. Zhang, J. Shahinian, G. Lu, T. Liu, M. Jiang, J. Temsamani, R. Martin, P. Schechter, S. Diasio, Clin. Takakura, R. Yoshida, T. Butler, K. Stecker, and C. Bennett, Lab. Graham, S. Crooke, D. Monteith, S.

Cooper, K. Lemonidis, K. Stecker, M. Martin, and R. Crooke, Pharmacol. Oligonucleotide Therapeutics Nyce, Expert Opin. Drugs, 6, Templin, A. Graham, P. Aberg, B. Butler, R. Nyce and W. Metzger, Nature, , Hardee, S. Weinbach, and L. Bennett and S. Wagner, M. Matteucci, G. Lewis, A. Gutierrez, C. Moulds, and B. Froehler, Science, , Barton and N. Lemoine, Br. Cancer, 71, Burgess, E. Fisher, S. Ross, V.

Bready, Y. Qian, L. Bayewitch, A. Cohen, C. Herrera, S. Hu, T. Lott, F. Martin, G. Pierce, L. Simonet, and C. Hertl, L. Neckers, and S. In- vest. Holstad, and K. Isenberg, Pharrnacotherapy, 13, Simons, E. Edelman, R. Langer, and R. Rosenberg, Nature, , Abe, W. Zhou, J. Taguchi, N. Takuwa, K. Kurokawa, M. Kumada, and Y. Takuwa, Biochern. Whitesell, A. Rosolen, and L. Neckers, Antisense Res. Wahlestedt, E. Koob, F. Yee, and M. Heilig, Science, , Zhang, L. Zhou, and B. Weiss, J. Gyurko, and M.

Phillips, Regul. Nielsen, and D. Osen-Sand, M. Catsicas, K. Staple, K. Jones, G. Ayala, J. Knowles, G. Grenningloh, and S. Nature, , Burch and L. Mahan, J. Lima and S. Crooke, Biochemistry, 36, Perez, T. Coleman, K. Dorshkind, W. Sarmiento, C. Rosen, and R. Narayan, Proc. USA, 90, Hijiya, J. Zhang, M. Kant, K.

Herlyn, G. Zon, and A. USA, Dean and R. McKay, Proc. USA, 91, Dean, R. McKay, L. Miraglia, R. Howard, S. Cooper, Giddings, P. Nicklin, L. Meister, R. Ziel, T. Geiger, M. Muller, and D. Fabbro, Can- cer Res. Monia, F. Johnston, T. Fabbro, Med. Johnston, H. Cummins, J. Nesterova and Y. Cho-Chung, Med. Maksymowych, W. Blackburn, E. Williams, Tami, K. Wagner, and W.

Shanahan, Arthritis Rheum. Fredriksson and U. Pettersson, , Yacyshyn, M. Jewell, A. Tami, C. Bennett, D. Shanahan, Jr. Yacyshyn, B. Woloschuk, M. Yacyshyn, D. Martini, K. Tami, F. Yuen, R. Advani, G. Fisher, J. Halsey, B. Lum, R. Kwoh, J. Holmlund, A. Dorr, and B. Waters, A. Webb, D. Cunningham, P. Clarke, F. Cot- ter, J. Jansen, V. Proceedings o f Stevenson, M. Gallagher, A. Cassella, I. Vasilevskaya, B. Monia, J.

Holm- lund, F. Dorr, and K. Yao, Clin. Nemunaitis, J. Holmlund, M. Richards, J. Bruce, N. Kwoh, R. Geary, A. Dorr, D. V o n Hoff, and S. Yuen, J. Halsey, G. Holmlund, R. Kwoh, A. Cancer Res. Stevenson, K. Yao, M. Gallagher, D. Friedland, E. Mitchell, A. Cassella, B. Holmlund, F. Dorr, and P. Dwyer, J. Holm- lund, A. Cunningham, J. Holmlund, J. Schiller, R. Dorr, and J. Nemunaitis, Clin Cancer Res.