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1 mg JAN Metformin HydrochlorideJAN

6 Goat s ruegalega officinalis L United Kingdom Prospective Diabetes StudyUKPDS mg SU in vivo

7 250mg Glycoran Tablets 250mg glycogen JAN Metformin HydrochlorideJAN C4H11N5HCl ,1-Dimethylbiguanide monohydrochloride LA

8 pka

9 mm mm mg PTP ph 250mg D- 4

10 4075%RH PTP rpm 80% 15 5

11 1 500mg mg 2, % 1,666/2,616 6

12 2 2 HDL VLDLLDL 7

13 n= mg mg1 n=21 Dose (mg/body) Tmax (hr) Cmax (ng/ml) AUC0-24hr (nghr/ml) t1/2 (hr) n=21 Cmax 40%AUC 25% 8

14 525% /hr mL/min./kg L/kg 9

15 % 10

16 11

17 12

19 3 14

20 2, % % % / ph - AST(GOT)ALT(GPT)Al-P-GTP 15

21 5% 0.15% 0.1% CK(CPK) 16

22 1,011 1,003 2, % 30.31% 26.66% (%)

23 18

24 100mg 2 B12 16) DNA DNA ATP DNA 19

25 50100mg/kg LD50mg/kg mg/kg 1 100mg/kg 50mg/kg 1 50mg/kg mg/kg

26 in vivo 21

27 3 PTP PTP 250mg 250mg 250mg 22

29 24

30 1) Lee, A. J.Pharmacotherapy, 16, 327(1996) 2) Zhou G. et al.j. Clin. Invest., 108, (2001) 3) Proske,G., et al.arzneim.-forsch., 12 (3), 314 (1962) 4) 5) Opitz, K., et al.dtsch. Med. Wschr., 87(2), 105 (1962) 6) Sterne, J.Thérapie, 13(4), 650 (1958) 7), 67, 12 (1971) 8) Kroneberg, G., et al.arzneim.-forsch., 8(7a), 470 (1958) 9) 10) USP DI, Drug Information for the Health Care Professional, 20 th ed., vol., 2086 (2000) 11) Brunton, L. L., et al.(ed.)goodman & Gilman's the pharmacological basis of therapeutics, 11 th ed., 1847 (2006) 12) Brunton, L. L., et al.(ed.)goodman & Gilman's the pharmacological basis of therapeutics, 11 th ed., 1638 (2006) 13) Hale, T. W., et al.diabetologia, 45, 1509 (2002) 14) Lalau, J. D., et al.int. J. Clin. Pharmacol. Ther. Toxicol., 27, 285 (1989) 15) UK Prospective Diabetes Study(UKPDS) GroupLancet, 352, 854 (1998) 16) ( 2 ),,, ) Sterne, J.Oral Hypoglycemic AgentsPharmacology and Therapeutics, 193, Academic Press (1969) 18) Tuchmann-Duplessis, H., et al.compt. Rend., 253(2), 321 (1961) 25

31 1 500mg mg Glucophage (Bristol-Myers Squibb) 2 500mg mg mg 850mg SU 2550mg/ 1000mg Glucophage (Merck Serono) Glucophage (Merck) Glucophage (Merck Lipha Sant) 2 500mg 850mg mg/ 500mg 850mg 500mg 850mg 1000mg

32 FDA FDAPregnancy Category An Australian categorisation of risk of drug use in pregnancy B C1999 FDAPregnancy Category BAnimal reproduction studies have failed to demonstrate a risk to the fetus and there are no adequate and well-controlled studies in pregnant women or Animal studies have shown an adverse effect, but adequate and well-controlled studies in pregnant women have failed to demonstrate a risk to the fetus in any trimester. An Australian categorisation of risk of drug use in pregnancy CDrugs which, owing to their pharmacological effects, have caused or may be suspected of causing, harmful effects on the human fetus or neonate without causing malformations. These effects may be reversible. Accompanying texts should be consulted for further details. 27

33 SPC Glucophage Pediatric Use The safety and effectiveness of GLUCOPHAGE for the treatment of type 2 diabetes have been established in pediatric patients ages 10 to 16 years (studies have not been conducted in pediatric patients below the age of 10 years). Use of GLUCOPHAGE in this age group is supported by evidence from adequate and well-controlled studies of GLUCOPHAGE in adults with additional data from a controlled clinical study in pediatric patients ages 10 to 16 years with type 2 diabetes, which demonstrated a similar response in glycemic control to that seen in adults. (See CLINICAL PHARMACOLOGY: Pediatric Clinical Studies.) In this study, adverse effects were similar to those described in adults. (See ADVERSE REACTIONS: Pediatric Patients.) A maximum daily dose of 2000 mg is recommended. (See DOSAGE AND ADMINISTRATION: Recommended Dosing Schedule: Pediatrics.) Recommended Dosing Schedule Pediatrics The usual starting dose of GLUCOPHAGE is 500 mg twice a day, given with meals. Dosage increases should be made in increments of 500 mg weekly up to a maximum of 2000 mg per day, given in divided doses. SPC Glucophage Therapeutic indications Treatment of type 2 diabetes mellitus, particularly in overweight patients, when dietary management and exercise alone does not result in adequate glycaemic control. In children from 10 years of age and adolescents, Glucophage film-coated tablets may be used as monotherapy or in combination with insulin. 4.2 Posology and method of administration Children and adolescents: Monotherapy and combination with insulin Glucophage film-coated tablets can be used in children from 10 years of age and adolescents. The usual starting dose is 500 mg or 850 mg metformin hydrochloride once daily, given during meals or after meals. After 10 to 15 days the dose should be adjusted on the basis of blood glucose measurements. A slow increase of dose may improve gastrointestinal tolerability. The maximum recommended dose of metformin hydrochloride is 2 g daily, taken as 2 or 3 divided doses. 28

34 4.4 Special warnings and precautions for use Children aged between 10 and 12 years: Only 15 subjects aged between 10 and 12 years were included in the controlled clinical studies conducted in children and adolescents. Although efficacy and safety of metformin hydrochloride in these children did not differ from efficacy and safety in older children and adolescents, particular caution is recommended when prescribing to children aged between 10 and 12 years. 29

35 30

Experimental and Clinical Studies of Pregnant Hypertension Takashi SHIMAZU Department of Obstetrics and Gynecology, Osaka City University Medical Scho

Experimental and Clinical Studies of Pregnant Hypertension Takashi SHIMAZU Department of Obstetrics and Gynecology, Osaka City University Medical School While the problem of late pregnant hypertension