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The Role and Application of Biomarkers and Surrogate Endpoints for New Drug Development : Focused on Diabetes Mellitus and Osteoporosis  

Seong, Soo-Hyeon (College of Pharmacy, Chungnam National University)
Yun, Hwi-Yeol (College of Pharmacy, Chungnam National University)
Baek, In-Hwan (College of Pharmacy, Chungnam National University)
Kang, Won-Ku (College of Pharmacy, Catholic University of Daegu)
Chang, Jung-Yun (Gastrointestinal, Urinary and Metabolic Drug Team, Korea Food and Drug Administration)
Seo, Kyung-Won (Gastrointestinal, Urinary and Metabolic Drug Team, Korea Food and Drug Administration)
Kwon, Kwang-Il (College of Pharmacy, Chungnam National University)
Publication Information
YAKHAK HOEJI / v.52, no.5, 2008 , pp. 331-344 More about this Journal
Abstract
Recently, the FDA (Food and Drug Administration) of the United States and many advanced countries remark biomarkers and surrogate endpoints as a critical path tool on model based drug development. Economic, technical and social profit on model based drug development like a reduction of the length of research and development have been achieved. Therefore we summarize previous studies about biomarkers and surrogate endpoints and suggest a development direction of therapeutic agents. In diabetes mellitus (DM) and osteoporosis, there are remarkable increases in number of patients and most of patients take medicine during their whole lifetime. For this reason, many patients with DM and osteoporosis have a tolerance on their medicine. We expect that research and development on biomarkers and surrogate endpoints will contribute to new drug development on DM and osteoporosis. Biomarkers for DM are blood levels of glucose, insulin, ${HbA}_{1c}$, CRP, alpha-glucosidase, adiponectin and DPP-4. Among these, validated surrogate endpoints for DM are blood levels of glucose, insulin and ${HbA}_{1c}$ Biomarkers for osteoporosis are BMD, BMC, trabecular volume, ICTP, DPD, osteocalcin, the activity of osteoclast and production of osteoblast. The validated surrogate endpoints for osteoporosis are BMD only. This review summarizes all suggested biomarkers and surrogate endpoints in DM and osteoporosis. The biomarkers are classified by drugs, and the method of validation for surrogate endpoints is suggested. This information would contribute to suggest a direction of DM and osteoporosis therapeutic agent development.
Keywords
biomarker; surrogate endpoint; diabetes mellitus; osteoporosis; critical path;
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1 Wagner, J. A. : Overview of biomarkers and surrogate endpoints in drug development. Dis. Markers 18, 41 (2002)   DOI   PUBMED
2 Revision of Committee : Critical path opportunites reports. FDA (2006) : on-line service
3 Groop, L., Groop, P. H., Stenman, S., Saloranta, C., Totterman, K. J., Fyhrquist, F. and Melander, A. : Comparison of pharmacokinetics, metabolic effects and mechanisms of action of glyburide and glipizide during long-term treatment. Diabetes Care 10(6), 71 (1987)   DOI   ScienceOn
4 Yale, J. F., Valiquett, T. R., Ghazzi, M. N., Owens-Grillo, J. K., Whitcomb, R. W. and Foyt, H. L. : The effect of a thiazolidinedione drug, troglitazone, on glycemia in patients with type 2 diabetes mellitus poorly controlled with sulfonylurea and metformin. A multicenter, randomized, double-blind, placebo-controlled trial. Ann. Intern. Med. 134, 737 (2001)   DOI   PUBMED
5 Kolterman, O. G., Kim, D. D., Shen, L., Ruggles, J. A., Nielsen, L. L., Fineman, M. S. and Baron, A. D. : Pharmacokinetics, pharmacodynamics, and safety of exenatide in patients with type 2 diabetes mellitus. Am. J. Health-Syst. Ph. 62(2), 173 (2005)
6 Ellerington, M. C., Hillard, T. C., Whitcroft, S. I., Marsh, M. S., Lees, B., Banks, L. M., Whitehead, M. I. and Stevenson, J. C. : Intranasal salmon calcitonin for the prevention and treatment of postmenopausal osteoporosis. Calcif. Tissue. Int. 59, 6 (1996)   DOI   ScienceOn
7 Chesnut, C. H. 3rd., Majumdar, S., Newitt, D. C., Shields, A., Van Pelt, J., Laschansky, E., Azria, M., Kriegman, A., Olson, M., Eriksen, E. F. and Mindeholm, L. : Effects of salmon calcitonin on trabecular microarchitecture as determined by magnetic resonance imaging: Results from the QUEST study. J. Bone. Miner. Res. 20, 1548 (2005)   DOI   ScienceOn
8 Anderson, J., Bannister, D. W., Parsons, V. and Tomlinson, R. W. : Total urinary hydroxyproline excretion in osteomalacia. Calcif. Tissue Res. 1, 183 (1967)   DOI   ScienceOn
9 Sorva, A., Risteli, J., Risteli, L., Valimaki, M. and Tilvis, R. : Effects of vitamin D and calcium on markers of bone metabolism in geriatric patients with low serum 25- hydroxyvitamin D levels. Calcif. Tissue Int. 49(suppl), 88 (1991)   DOI
10 Edwards, C. J., Russell, R. G. and Spector, T. D. : Statins and Bone: Myth or Reality? Calcif. Tissue Int. 69, 63 (2001)   DOI   ScienceOn
11 Lee, J. W., Smith, W. C., Nordblom, G. D. and Bowsher, R. R. : Validation of assays for the bioanalysis of novel biomarkers: Practical recommendations for clinical investigation of new drug entities. Biomarkers in Clinical Drug Development 132, 119 (2003)
12 Rolan, P. : The contribution of clinical pharmacology surrogates and models to drug developoment-a critical appraisal. Brit. J. Clin. Pharmaco. 44, 219 (1997)   DOI   PUBMED   ScienceOn
13 Jorgensen, L. G. M., Petersen, P. H. and Brandslund, I. : Clinical outcome estimates based on treatment target limits of laboratory tests: proposal for a plot visualizing effects and differences of medical target setting exemplified by glycemic control in diabetes. Clin. Chem. Lab. Med. 44(3), 327 (2006)   DOI   PUBMED
14 Rosen, C. J. and Tenenhouse, A. : Biochemical markers of bone turnover. A look at laboratory tests that reflect bone status. Postgrad. Med. 104(4), p. 101-2, p. 107-10, p. 113-4 (1998)   PUBMED
15 Dailey, G. : Assessing glycemic control with self-monitoring of blood glucose and hemoglobin A(1c) measurements. Mayo. Clin. Proc. 82(2), 229 (2007)
16 Shultis, W. A., Leary, S. D., Ness, A. R., Scott, J., Martin, R. M., Whincup, P. H. and Smith, G. D. : Haemoglobin A1c is not a surrogate for glucose and insulin measures for investigating the early life and childhood determinants of insulin resistance and Type 2 diabetes in healthy children. An analysis from the Avon Longitudinal Study of Parents and Children (ALSPAC). Diabet. Med. 23(12), 1357 (2006)   DOI   ScienceOn
17 Gangji, A. S., Cukierman, T., Gerstein, H. C., Goldsmith, C. H. and Clase, C. M. : A systematic review and meta-analysis of hypoglycemia and cardiovascular events: a comparison of glyburide with other secretagogues and with insulin. Diabetes Care 30(2), 389 (2007)   DOI   ScienceOn
18 Schwartz, S., Raskin, P., Fonseca, V. and Graveline, J. F. : Effect of troglitazone in insulin-treated patients with type 2 diabetes mellitus. Troglitazone and exogenous insulin study group. New Engl. J. Med. 338(13), 861 (1998)   DOI   ScienceOn
19 Roberts, V. L., Stewart, J., Issa, M., Lake, B. and Melis, R. : Triple therapy with glimepiride in patients with type 2 diabetes mellitus inadequately controlled by metformin and a thiazolidinedione: results of a 30-week, randomized, double-blind, placebo-controlled, parallel-group study. Clin. Ther. 27(10), 1535 (2005)   DOI   ScienceOn
20 Lesko, L. J. and Atkinson, A. J. : Use of biomarkers and surrogate endpoints in drug development and regulatory decision making: criteria, validation, strategies. Annu. Rev. Pharmacol. 41, 347 (2001)   DOI   ScienceOn
21 Bernaoe, M., Czech, A. and Taton, J. : Relative effectiveness of tolbutamide, chlorpropamide and gliclazide. Pol. Tyg. Lek. 47(1-2), 35 (1992)   PUBMED
22 Fernandez-Real, J. M., Lopez-Bermejo, A., Casamitjana, R. and Ricart, W. : Novel interactions of adiponectin with the endocrine system and inflammatory parameters. J. Clin. Endocrinol. Metab. 88, 2714 (2003)   DOI   ScienceOn
23 Abildgaard, N., Brixen, K., Eriksen, E. F., Kristensen, J. E., Nielsen, J. L. and Heickendorff, L. : Sequential analysis of biochemical markers of bone resorption and bone densitometry in multiple myeloma. Haematologica 89(5), 567 (2004)   PUBMED
24 Colburn, W. A. : Biomarkers in drug discovery and development: From target identification through drug marketing. J. Clin. Pharmacol. 43, 329 (2003)   DOI   ScienceOn
25 Wagner, J. A. : Overview of biomarkers and surrogate endpoints in drug development. Dis. Markers 18, 41 (2002)   DOI   PUBMED
26 Okabe, R., Inaba, M., Nakatsuka, K., Miki, T., Naka, H., Moriguchi, A. and Nishizawa, Y. : Significance of serum CrossLaps as a predictor of changes in bone mineral density during estrogen replacement therapy; comparison with serum carboxyterminal telopeptide of type I collagen and urinary deoxypyridinoline. J. Bone Miner. Metab. 22, 127 (2004)   DOI   ScienceOn
27 Kanauchi, M., Kanauchi, K., Inoue, T., Kimura, K. and Saito, Y. : Surrogate markers of insulin resistence in assessing individuals with new categories "prehypertention" and "prediabetes". Clin. Chem. Lab. Med. 45(1), 35 (2007)   DOI   ScienceOn
28 Matsunaga, S., Ito, H. and Sakou, T. : The effect of vitamin K and D supplementation on ovariectomy-induced bone loss. Calcif. Tissue Int. 65, 285 (1999)   DOI   ScienceOn
29 Kradjan, W. A., Takeuchi, K. Y., Opheim, K. E. and Wood, F. C. Jr. : Pharmacokinetics and pharmacodynamics of glipizide after once daily and divided dose. Pharmacotherapy 15(4), 465 (1995)   PUBMED
30 Bischoff, H. : Pharmacology of alpha-glucosidase inhibition. Eur. J. Clin. Invest. 24, 3 (1994)   DOI   PUBMED
31 Lee, J. W., Devanarayan, V., Barrett, Y. C., Weiner, R., Allinson, J., Fountain, S., Keller, S., Weinryb, I., Green, M., Duan, L., Rogers, J. A., Millham, R., O'Brien, P. J., Sailstad, J., Khan, M., Ray, C. and Wagner, J. A. : Fit-for-purpose method development and validation for successful biomarker measurement. Pharm. Res. 23(2), 312 (2006)   DOI   ScienceOn
32 Herman, G. A., Stevens, C., Van Dyck, K., Bergman, A., Yi, B., De Smet, M., Snyder, K., Hilliard, D., Tanen, M., Tanaka, W., Wang, A. Q., Zeng, W., Musson, D., Winchell, G., Davies, M. J., Ramael, S., Gottesdiener, K. M. and Wagner, J. A. : Pharmacokinetics and pharmacodynamics of sitagliptin, an inhibitor of dipeptidyl peptidase 4, in healthy subjects: results from two randomized, double-blind, placebo-controlled studies with single oral doses. Clin. Pharmacol. Ther. 78(6), 675 (2005)   DOI   ScienceOn
33 Biomarkers Definition working group (BDWG) : Biomarkers and surrogate endpoints: Preferred definitions and conceptual framework. Clin. Pharmacol. Ther. 69(3), 89 (2001)   DOI   ScienceOn
34 Revision of Committee : Post-genomic biomarker. Bioview 12(3), (2004)
35 Rydberg, T., Jonsson, A., Karlsson, M. O. and Melander, A. : Concentration-effect relations of glibenclamide and its active metabolites in man: modelling of pharmacokinetics and pharmacodynamics. Brit. J. Clin. Pharmaco. 43(4), 373 (1997)   DOI   ScienceOn
36 el-Sayed, Y. M., Suleiman, M. S., Hasan, M. M., Abdel-Hamid, M. E., Najib, N. M., Sallam, E. S. and Shubair, M. S. : Comparison of the pharmacokinetics and pharmacodynamics of two commercial products containing glibenclamide. Int. J. Clin. Pharmacol. Ther. Toxicol. 27(11), 551 (1989)   PUBMED
37 Fonseca, V., Rosenstock, J., Patwardhan, R. and Salzman, A. : Effect of metformin and rosiglitazone combination therapy in patients with type 2 diabetes mellitus: a randomized controlled trial. JAMA 283(13), 1695 (2000)   DOI   ScienceOn
38 Bischoff, H. : The mechanism of alpha-glucosidase inhibitor in the management of diabetes. Clin. Invest. Med. 18(4), 303 (1995)
39 Stanski, D. R. : Model-based drug development : A critical path opportunity. FDA (2006)
40 De Gruttola, V. G., Clax, P., DeMets, D. L., Downing, G. J., Ellenberg, S. S., Friedman, L., Gail, M. H., Prentice, R., Wittes, J. and Zeger, S. L. : Considerations in the Evaluation of Surrogate endpoints in clinical trials: Summary of national institutes of health workshop. Control. Clin. Trials. 22, 485 (2001)
41 Colburn, W. A. : Optimiziing the use of biomarkers, surrogate endpoints, and clinical endpoints for more efficient drug development. J. Clin. Pharmacol. 40, 1419 (2000)   PUBMED
42 Basu, S., Larsson, A., Vessby, J., Vessby, B. and Berne, C. : Type 1 diabetes is associated with increased cyclooxygenaseand cytokine-mediated inflammation. Diabetes Care 28, 1371 (2005)   DOI   ScienceOn
43 Kim, H., Yun, M. and Kwon, K. I. : Pharmacokinetic and pharmacodynamic characterization of gliclazide in healthy volunteers. Arch. Pharm. Res. 26(7), 564 (2003)   DOI   ScienceOn
44 Wagner, J. A. : Early clinical development of pharmaceuticals for type 2 diabetes mellitus: from preclinical models to human investigation. J. Clin. Endocrinol. Metab. 87(12), 5362 (2002)   DOI   ScienceOn
45 Lachin, J. M., Genuth, S., Nathan, D. M. and Rutledge, B. N. : The hemoglobin glycation index is not an independent predictor of the risk of microvascular complications in the diabetes control and complications trial. Diabetes 56, 1913 (2007)   DOI   ScienceOn
46 Frey, N., Laveille, C., Paraire, M., Francillard, M., Holford, N. H. and Jochemsen, R. : Population PKPD modelling of the long-term hypoglycaemic effect of gliclazide given as a once-aday modified release (MR) formulation. Brit. J. Clin. Pharmaco. 55(2), 147 (2003)   DOI   ScienceOn
47 Badian, M., Korn, A., Lehr, K. H., Malerczyk, V. and Waldhausl, W. : Pharmacokinetics and pharmacodynamics of the hydroxymtabolite of glimepiride (Amaryl) after intravenous administration. Drug Metabol. Drug Interact. 13(1), 69 (1996)   PUBMED
48 Bruno, R. : Impact of PK/PD modeling and simulation in drug development. 13th NA ISSX/20th JSSX meeting in Maui Hawaii. (2005)
49 Nyholm, B., Brock, B., Orskov, L. and Schmitz, O. : Amylin receptor agonists: a novel pharmacological approach in the management of insulin-treated diabetes mellitus. Expert. Opin. Inv. Drug. 10(9), 1641 (2001)   DOI   ScienceOn
50 Lee, P. E., Gill, S. S., Freedman, M., Bronskill, S. E., Hillmer, M. P. and Rochon, P. A. : Atypical antipsychotic drugs in the treatment of behavioural and psychological symptoms of dementia: systematic review. Brit. Med. J. 329, 75 (2004)   DOI   ScienceOn
51 Waugh, J., Keating, G. M., Plosker, G. L., Easthope, S. and Robinson, D. M. : Pioglitazone: a review of its use in type 2 diabetes mellitus. Drugs 66(1), 85 (2006)   DOI   ScienceOn
52 Haidar, S. H., Johnson, S. B., Fossler, M. J. and Hussain, A. S. : Modeling the pharmacokinetics and pharmacodynamics of a unique oral hypoglycemic agent using neural networks. Pharm. Res. 19(1), 87 (2002)   DOI   ScienceOn
53 Jonsson, A., Chan, J. C., Rydberg, T., Vaaler, S., Hallengren, B., Cockram, C. S., Critchley, J. A. and Melander, A. : Pharmacodynamics and pharmacokinetics of intravenous glibenclamide in Caucasian and Chinese patients with type-2 diabetes. Eur. J. Clin. Pharmacol. 55(10), 721 (2000)   DOI   ScienceOn
54 Meigs, J. B., Panhuysen, C. I., Myers, R. H., Wilson, P. W. and Cupples, L. A. : A genome-wide scan for Loci linked to plasma levels of glucose and $HbA_{1c}$ in a community-based sample of caucasian pedigrees. Diabetes 51, 833 (2002)   DOI   ScienceOn
55 Lane, N. E., Haupt, D., Kimmel, D. B., Modin, G. and Kinney, J. H. : Early estrogen replacement therapy reverses the rapid loss of trabecular bone volume and prevents further deterioration of connectivity in the rat. J. Bone Miner. Res. 14, 206 (1999)   DOI   ScienceOn
56 Adachi, J. D., Saag, K. G., Delmas, P. D., Liberman, U. A., Emkey, R. D., Seeman, E., Lane, N. E., Kaufman, J. M., Poubelle, P. E., Hawkins, F., Correa-Rotter, R., Menkes, C. J., Rodriguez-Portales, J. A., Schnitzer, T. J., Block, J. A., Wing, J., McIlwain, H. H., Westhovens, R., Brown, J., Melo-Gomes, J. A., Gruber, B. L., Yanover, M. J., Leite, M. O., Siminoski, K. G., Nevitt, M. C., Sharp, J. T., Malice, M. P., Dumortier, T., Czachur, M., Carofano, W. and Daifotis, A. : Two-year effects of alendronate on bone mineral density and vertebral fracture in patients receiving glucocorticoids. Arthritis Rheum. 44, 202 (2001)   DOI   ScienceOn
57 Shah, H. D. : Novel agents in osteoporosis. Indian J. Pharmacol. 36, 48 (2004)
58 Wagner, J. A. : Biomarker validation and qualification: Fitness for use. Biomarker World Congress (2007)
59 Smirnakis, K. V., Plati, A., Wolf, M., Thadhani, R. and Ecker, J. L. : Predicting gestational diabetes: choosing the optimal early serum marker. Am. J. Obstet. Gynecol. 196(4), 410.e1-410.e7 (2007)   DOI   PUBMED
60 Herman, G. A., Bergman, A., Liu, F., Stevens, C., Wang, A. Q., Zeng, W., Chen, L., Snyder, K., Hilliard, D., Tanen, M., Tanaka, W., Meehan, A. G., Lasseter, K., Dilzer, S., Blum, R. and Wagner, J. A. : Pharmacokinetics and pharmacodynamic effects of the oral DPP-4 inhibitor sitagliptin in middle-aged obese subjects. J. Clin. Pharmacol. 46(8), 876 (2006)   DOI   ScienceOn
61 Culy, C. R. and Jarvis, B. : Repaglinide: a review of its therapeutic use in type 2 diabetes mellitus. Drugs 61(11), 1625 (2001)   DOI   ScienceOn
62 von Nicolai, H., Brickl, R., Eschey, H., Greischel, A., Heinzel, G., Konig, E., Limmer, J. and Rupprecht, E. : Duration of action and pharmacokinetics of the oral antidiabetic drug gliquidone in patients with non-insulin-dependent (type 2) diabetes mellitus. Arzneimittelforschung 47(3), 247 (1997)   PUBMED
63 Yun, H. Y., Park, H. C., Kang, W. and Kwon, K. I. : Pharmacokinetic and pharmacodynamic modelling of the effects of glimepiride on insulin secretion and glucose lowering in healthy humans. J. Clin. Pharm. Ther. 31(5), 469 (2006)   DOI   ScienceOn
64 Chung, M. : Pharmacokinetics and pharmacodynamics of extended-release glipizide GITS compared with immediaterelease glipizide in patients with type 2 diabetes mellitus. J. Clin. Pharmacol. 42(6), 651 (2002)   DOI   ScienceOn
65 Coppack, S. W., Lant, A. F., McIntosh, C. S. and Rodgers, A. V. : Pharmacokinetic and pharmacodynamic studies of glibenclamide in non-insulin dependent diabetes mellitus. Brit. J. Clin. Pharmaco. 29(6), 673 (1990)   DOI   ScienceOn
66 Meigs, J. B., O'donnell, C. J., Tofler, G. H., Benjamin, E. J., Fox, C. S., Lipinska, I., Nathan, D. M., Sullivan, L. M., D'Agostino, R. B. and Wilson, P. W. : Hemostatic markers of endothelial dysfunction and risk of incident type 2 diabetes. Diabetes 55, 530 (2006)   DOI   ScienceOn
67 Gungor, N., Saad, R., Janosky, J. and Arslanian, S. : Validation of surrogate estimates of insulin sensitivity and insulin secretion in children and adolescents. J. Pediatr. 144, 47 (2004)   DOI   ScienceOn
68 Kruse, K. and Kracht, U. : Evaluation of serum osteocalcin as an index of altered bone metabolism. Eur. J. Pediatr. 145, 27 (1986)   DOI   ScienceOn
69 Revision of Committee : Challenge and Opportunity on the critical path to new medical product. FDA (2004)
70 Heikinheimo, R. J., Inkovaara, J. A., Harju, E. J., Haavisto, M. V., Kaarela, R. H., Kataja, J. M., Kokko, A. M., Kolho, L. A. and Rajala, S. A. : Annual injection of vitamin D and fractures of aged bones. Calcif. Tissue Int. 51, 105 (1992)   DOI   ScienceOn
71 Bergman, A. J., Stevens, C., Zhou, Y., Yi, B., Laethem, M., De Smet, M., Snyder, K., Hilliard, D., Tanaka, W., Zeng, W., Tanen, M., Wang, A. Q., Chen, L., Winchell, G., Davies, M. J., Ramael, S., Wagner, J. A. and Herman, G. A. : Pharmacokinetic and pharmacodynamic properties of multiple oral dose of sitagliptin, a dipeptidyl peptidase-4 inhibitor: a double-blind, randomized, placebo-controlled study in healthy male volunteers. Clin. Ther. 28(1), 55 (2006)   DOI   ScienceOn
72 Herman, G. A., Bergman, A., Stevens, C., Kotey, P., Yi, B., Zhao, P., Dietrich, B., Golor, G., Schrodter, A., Keymeulen, B., Lasseter, K. C., Kipnes, M. S., Snyder, K., Hilliard, D., Tanen, M., Cilissen, C., De Smet, M., de Lepeleire, I., Van Dyck, K., Wang, A. Q., Zeng, W., Davies, M. J., Tanaka, W., Holst, J. J., Deacon, C. F., Gottesdiener, K. M. and Wagner, J. A. : Effect of single oral doses of sitagliptin, a dipeptidyl peptidase-4 inhibitor, on incretin and plasma glucose levels after an oral glucose tolerance test in patients with type 2 diabetes. J. Clin. Endocr. Metab. 91(11), 4612 (2006)   DOI   ScienceOn
73 de Winter, W., DeJongh, J., Post, T., Ploeger, B., Urquhart, R., Moules, I., Eckland, D. and Danhof, M. : A mechanism-based disease progression model for comparison of long-term effects of pioglitazone, metformin and gliclazide on disease processes underlying Type 2 Diabetes Mellitus. J. Pharmacokinet. Phar. 33(3), 313 (2006)   DOI   ScienceOn
74 Jaber, L. A., Antal, E. J., Slaughter, R. L. and Welshman, I. R. : Comparison of pharmacokinetics and pharmacodynamics of short- and long-term glyburide therapy in NIDDM. Diabetes Care 17(11), 1300 (1994)   DOI   ScienceOn
75 Rosenstock, J., Brazg, R., Andryuk, P. J., Lu, K. and Stein, P. : Efficacy and safety of the dipeptidyl peptidase-4 inhibitor sitagliptin added to ongoing pioglitazone therapy in patients with type 2 diabetes: a 24-week, multicenter, randomized, double-blind, placebo-controlled, parallel-group study. Clin. Ther. 28(10), 1556 (2006)   DOI   ScienceOn
76 Jaber, L. A., Antal, E. J. and Welshman, I. R. : Pharmacokinetics and pharmacodynamics of glyburide in young and elderly patients with non-insulin-dependent diabetes mellitus. Ann. Pharmacother. 30(5), 472 (1996)   DOI   PUBMED
77 Ofluoglu, D., Akyuz, G., Unay, O. and Kayhan, O. : The effect of calcitonin on beta-endorphin levels in postmenopausal osteoporotic patients with back pain. Clin. Rheumatol. 26, 44 (2007)   DOI   ScienceOn
78 Hu, F. B., Meigs, J. B., Li, T. Y., Rifai, N. and Manson, J. E. : Inflammatory markers and risk of developing type 2 diabetes in women. Diabetes 53, 693 (2004)   DOI   ScienceOn
79 Agerso, H. and Vicini, P. : Pharmacodynamics of NN2211, a novel long acting GLP-1 derivative. Eur. J. Pharm. Sci. 19(2-3), 141 (2003)   DOI   PUBMED   ScienceOn
80 Stepensky, D., Friedman, M., Raz, I. and Hoffman, A. : Pharmacokinetic-pharmacodynamic analysis of the glucoselowering effect of metformin in diabetic rats reveals first-pass pharmacodynamic effect. Drug Metab. Dispos. 30(8), 861 (2002)   DOI   ScienceOn
81 Woosley, R. L. and Cossman, J. : Drug development and the FDA's critical path initiative. Clin. Pharmacol. Ther. 81(1), 129 (2007)   DOI   ScienceOn