srs 03.02.98 pU04227ENGO alate QU Elsevier 81 ORC onI91 Long-term comparison of oral hypoglycemic agents in diabetic retinopathy Gliclazide vs. other sulfonylureas Yasuo Akanuma', Kinori Kosaka®, Yasunori Kanazawa’, Masato Kasuga?, Masatoshi Fukudat and Shigenabuy Aoki* "The Inia for Dias Care and Research. Asahi Life Fondation, Toko, Japan, “Taran Hospital. Tokso, Japan. The Third Deparment often Sealine, Fray of Medicine. Unersty of Tokvo, Toko. Japan “Department of Ophthalmology. School of Medicine. Unsersiy ofthe Rub us, Okina Japan end ‘Deporiment of Public Heth. Scot of Medicine, Gunma livery Machash. Jpn Received 8 May 1987 revision received 5 Ocaber 1987, accepied 3 December 1987) ‘ey words Long-esm comparative sinial tal: Retinopathy, dabeic: Gilae; Progtesson to prolraive retinopathy. Slo vee Summary Gliciazide has been reported to possess the properties of preventing the progression of diabetic retinopathy and of controlling blood glucose levels, This report describes a long-term comparative clinical trial of this agent to assess its efficacy against diabetic retinopathy. ‘One hundred and fifty-nine NIDDM patients with no retinopathy or with simple retinopathy entered this trial. One hundred and nineteen patients receiving other sulfonylurea agente were randomly allocated ta two ‘roups (G: gliclazide, SU: other sulfonylureas). Forty patients continued to be treated with diet alone (D group). Finally a total of 60 patients. that is, 21 patients in the G group, 19 patients in the SU group, and 20 patients in the D group. were followed with funduscopic examinations for more than 4 years, The results are summarized as follows, (1) Distribution of background factors between the two drug therapy groups was balanced, but in the D group more male patients and relatively milder cases were involved than in the drug therapy groups. (2) Fasting blood glucose control in the three groups was not significantly different, (3) Funduscopie deterioration was observed less frequently, though not significantly. in the G group than in the other groups. (4) Progression to preproliferative retinopathy was significantly les frequent in the G group than in the SU group. ‘Thus, gliclazide seems to have additional properties compared with other sulfonylurea drugs in preventing deterioration of diabetic retinopathy. and particularly in preventing progression to proliferative retinopathy. Adres for correspondence: Yasuo Akanuma, MD, Institute for Diabeies Care and Research, Asahi Life Foundation, [61 Marunouchi, Chiyoda-ku, Tokyo 100, Japan. (0168-822788/50350 © 1988 Elevier Science Publishers BV. (Brmedial Division)82 Introduction Diabetic retinopathy is a problem of erucial impor- tance yet to be resolved inthe treatment of diabetes ‘mellitus, With the recent progress of ophthalmo- logical surgery including photocoagulation by laser ‘beams, it has become possible to prevent the pro ress of retinopathy, but itis still important to take appropriate measures to prevent progress of the disease before the retina becomes involved, Studies seeking effective measures, however. have only re- cently been undertaken. Blood and vascular factors have received increasing attention as factors re- sponsible for aggravation of diabetic retinopathy. Recently gliclazide (G), a new sulfonylurea, which acts on such factors 1.2} in addition w its hypugly- ccemic activity, has become of interest to investiga- tors. ‘The authors organized a Diabetic Retinopathy Program (DRP) Study Group and conducted 2- year comparative clinical trials of glilazide vs. ‘other sulfonylureas (SU) to assess its efficacy against diabetic retinopathy. Our previous report [B} indicated that treatment with gliclazide may be useful in preventing the progress of diabetic reti- rnopathy as well as in controlling blood glucose levels The present study was undertaken to continue the observation primarily of retinal changes in out- patients at the Third Department of Internal Med- icine, Tokyo University Hospital for a further 3 years (hence for a total of $ years since the start of the DRP study) among the patients who had been treated im the onginal DRP study. Patients undergoing diet therapy alone (D) were also followed as a control group. Materials and methods Subjects Patients with type 2 diabetes mellitus were followed during continued treatment in this investigation Patients receiving concomitant biguanide medi- cation or high doses 2 7.5 mg/day) of glibenclamide as oral hypoglycemic agents at the start of the fol Jow-up were excluded from the study. Only those who had simple retinopathy on funduscapic exam ination were recruited to the study while patients with preproliferative retinopathy were excluded, Patients whose funduscopic findings were within ‘normal limits were also included in the study if they had been diabetie for not less than 5 yeurs or if they presented slight degrees of retinal vascular changes. ‘on fluorescein angiography. Markedly obese sub- jects (relative body weight 2 120%) were excluded from the study, ‘As a control group. patients with as long a dur- ation of illness as in the drug-treated groups were selected from those undergoing treatment by diet therapy alone, Test drugs Patients in the G group received 40-mg tablets of Bliclazide, beginning at a dose level of 40 mg (one tablet) gid. asa rule. The dosage was increased to ‘@ maximum of 240 mg (6 tablets) q.id. according to the condition of the patient. Patients in the SU group were continued on the sulfonylureas which they had previously been receiving. Observations (1) Parameters and periods. Each patient was fo: lowed by monthly measurements of body weight, blood pressure and fasting blood glucose (FBG), and observations for subjective symptoms, adverse drug reactions and signs of hypoglycemia. Plasma lipid determination, urinalysis, hematological examination, liver function tests, renal function tests, electrocardiograms (ECG) and glucose toler- ance tests (GTT) were performed at 6- or 12-month intervals. Funduscopy and fluorescein angiography were performed at the beginning of the DRP study and subsequently at half-year or longer intervals during the ria In order to eliminate technical variations the ophthalmoscopic photography was performed by a single specialist (Yuichi Komuro, Photographer of the Department of Ophthalmology, Tokyo Uni- versity Hospital, using an Olympus GRC-6 fundusChromoretinograms were taken at four different sites on each side (optic disk, macula, and primary branches of the superior and inferior arteries and veins). Fluorescein angiograms were recorded at ten different sites, ie. the optic disk with the posterior pole at the center, the macula. primary branches of the superior and inferior arteries and veins, and up- per nasal, nasal, lower nasal, upper temporal, tem poral and lower temporal portions, beginning with the right eye followed by the left eye with care being taken to photograph the same areas as far as prac- ticable at every examination Evaluation Although the’ study could not be designed in a double-blind manner, attempts were made to adopt objective assessment procedures, ¢g.. random al- location of patients to the oral hypoglycemic med- ication groups (G group vs. SU group) and single blind evaluation of funduscopic findings. (1) Control of blood glucose. FBG values were rated as follows [4]: good control, less than 140 gidl on 80% or more ofall FBG tests performed during the S-year period: poor control, not iess than 170 mgidl on $0% or more of all FBG tests; and otherwise, fair contro} (2) Evaluation of funduscopie findings. The degree of retinal changes wat assessed as follows [5} ‘ophthalmoscopic findings were rated in each case ‘ona 4-grade scale of severity of (1) hemorchage, (2) soft exudates, (3) hard exudates, (4) neovascular: zation, and (5) tissue proliferation, and fluorescein angiographic findings were rated similarly as (1) leakage, (2) vascular occlusion, (3) microaneu- rysms, and (4) neovascularization, Based on these assessments, each patient was classified according to the overall degree of severity in each eye into the 0-4-point scale as follows © (within normal limits): virtually free From reti- nopathy (corresponds to Scott 0}; 1 (ald): simple retinopathy (corresponds to Scott fa oF 1); 2 (moderate): advanced simple retinopathy (cor- responds to Scott IIIa); 83 3 (severe): preproliferative retinopathy (corre sponds to Scott IIIb, mild degree of Scott Ib or IV), 4 (very severe): overt proliferative retinopathy (corresponds to Scott Tb, IV, Va. Vb oF VI). ‘The investigator (Dr. M. Fukuda) in charge of the severity rating was informed of the time of photographic recording but was unaware of the control state of diabetes or the therapy regimens of individual eases; hence there was a single-blind evaluation Withdrawals and drop-outs Patients were withdrawn from the study for circum: stances such as: serious adverse reaction, serious complication, change to insulin therapy. ete Patients were recorded as drop-outs for failure to visit the clinic, irregular attendance at the clinic, change (o other treatment than the oral hypogly- ccemic drug before completion of the study. Statistical analysis of data All statistical analyses of data were carried out at the Department of Public Health, School of Med- icine, Gunma University. using the SPSS program package Statistical procedures employed were: chi-square test, Fisher's exact probability test. Mann-Whitney U-test, Spearman’s rank correlation and T-test ‘The 5% level (two-tailed) was adopted for statisti- cal significance of difference, and the 10% level (two-tailed) for a trend to difference. Results Withdrawals and exclusions from statistical analysis A total of 159 patients were admitted 10 the DRP study. During the S-year study period, 71 patients (44.7%) wore withdrawn or dropped out within 4 years of study. The commonest reason was the transfer of patients to other hospitals or clinics (25 ceases, 35.2%), because of the transfer of their at- tending physicians (investigators) to other institu- tions before completion of the study. The next was exacerbation of the diabetic state (16 cases, 22.5%); the medication being subsequently replaced with84 insulin therapy in all these cases. There were seven patients (9.9%) who were studied for less than 4 years because of delayed admission to the study. ‘Other reasons included withdrawal at the pauent’s ‘own request and reluctance to undergo funduscopie examination, especially fuorescein angiography. ‘The drop-outs and withdrawals were generally more frequent in the SU group, due simply to a high incidence of transter to other institutions but not for any other particular reason. ‘There were 88 patients (55.3%) who were fol- lowed for not less than 4 years, OF these. 21 patients failed to undergo funduscopic examination later than 48 months into the study. Sixteen (76.2 %) of the 21 patients were not examined for various reasons such as irregular clinic attendance and poor treatment compliance within the whole study period. Four patients refused the examination, and funduscopy was impracticable in one patient be- cause of complicating glaucoma, ‘Thus a total of 67 patients (42.1%) could be fol- lowed by observations of the diabetic condition and ‘by funduscopic examinations for not less than 4 TABLE | DISTRIBUTION OF BACKGROUND FACTORS. Al entry patients (159 cases: percentages ae sven in preathees years. In order to make the study conditions uni form in the three groups. seven of the 26 patients in the SU group were excluded from the present comparative evaluation because they had received several kinds of sulfonylurea preparations during the 5-year study period. There were ultimately 60 cases eligible for statistical analysis ie., 21 cases in the G group, 19 in the SU group and 20 in the D ‘group. Background characteristics of patients Allentry patients (159 cases) admitted to the study were assessed as to distribution of patient back- {ground characteristics among the three groups. As Table 1 shows, male patients were more frequent and there were significantly more patients with low inital FBG values in the D group as compared with the drug therapy groups (G and SU), There was no significant difference between the G and SU groups ‘The distribution of background characteristics of those patients who were followed for atleast $ years ‘was essentially the same as that in the present series, of 60 case (Table 2) Factor 6 su D Stats significance Unbalanced forrs Sex male 18400) 3700) 8D) O05 by Few sera 7000 7600), GD) FG aft visi cy Mid 12% se Poms ‘mean ¢ SD (by Fes (wd) Um.) Mean FBG tefore isl 119 mugs 2kans) 38675) P< 00001 ‘aid 9139 ee) san) S029 thy tet Ho W227 ane) 060) Gu GUD) Boland fctors Age. duration of DM, family histor of DM, complications, ECG findings before trial. reaive body weight fist vis relatve body sigh at the beginning of wr, unduscopi Beings before tah.There was no significant difference in the case numbers of any of these background factors be- tween the two drug therapy groups (G and SU) al- though cases with high mean FBG values at the inception of the sindy were slightly more frequent in the SU group than in the G group. In the D TABLE? ES group which served as a control, male patients were slightly more frequent and patients with low initial FBG values were significantly more frequent (P < 0.05) than in the drug therapy groups (G and su) ‘The patients had an average age of ST + 11 years BACKGROUND FACTORS ON THE S-YEAR FOLLOW-UP PATIENTS (n = 601 Figures in parentheses are percentages Factor su D Toual Siaseal sass 4 Sex male 10476) 106526) 16 (600) 36H) female (24) 9aTa) 8200) 40.0) Age ears) mmean # SD. Sab at at Stet NS Duration of diabetes (months) mean + SD Bie 1se 6 DE] IDL! NS. Family history of diabetes no 08 218s) 708) 78) QS ws 13619) 171893) Bes) BLD ‘Complications none 1(24) 130684) 12400) 36,600 bypentension B68) 421 6G 180) bypertesion tas 20008) 2400) 5) hers others 148 0( 00) (00) 1 1) CG finding before tat normal BEI NET — 9480-338) abnormal BGRI) BER SS) 27450) 8 FBG at fist vst (mpid) mean & SD. i439 usa ea urea NS. Relative body weight ‘mean # SD Nseie 15413 eet See NS. 1a Bist vit (4) Mean FBG before trial 14662) 5263) 18,900) 376) P< 005 (eit) 51238) 101826) 2100174283) oy Pees 2693) €21) 0100) too) SU DY US216 216 WE SIS P< O00! (by Fes) (SU Dp Relative body weight atthe 89 148 of 00) 1y 8) 2.33) ‘beginning of tal (%) 90 109 LEY 129 1570) 37D Ho~ 119 4090 $0283) -341S0) 12200) 10 409942 1450) 9180) mean & SD W217 WS oes 9 tes NS. Fundoscopic fing normal RU2G 74S) 18 46.2)——ST ABS) before trl (yes) slighe Wa wus) St) og moderate 2(48) 2034) 1439) undetermined 0400 0 00) 2017) Tovervl between the inal mean + SD 925 wes Bes NS. ‘and the Sina! Funduscopic ‘xamination (moaths) NS. = nor significanta6 TABLED EVALUATION OF GLYCEMIC CONTROL OF FASTING BLOOD GLUCOSE For the evita of glycemic contra ee teat, Figures in pacntheis ate percentages Fair G 16762) sia 900) su 12632) 71368) 0100) b 600) 41200) 0100) and a mean duration of diabetes mellitus of 122 + 69 months, ‘They underwent the final funduscopic examina tion in this study after 59 S months of treatment, the average period being very similar among the three groups. Controt of blood glucose Blood glucose control during the S-year period of study in each of the three groups is shown in Table 3. No significant difference was observed between the two drug therapy groups in this respect. Patients were satisfactorily controlled in the diet therapy group and there were no significant differences con- ‘cerning blood glucose control among the three groups. Overall evaluation of funduscopic findings Fig. | illustrates the distribution of retinopathic se- verity before and after the study in all three groups. TATA Wh i! So, Fig Progress of diabetic retinopathy duting follow-up for ‘more than 4 years. (N: number of 55) Toul ‘States analysis 2 NS. 9 by Crest 2 The incidence of retinopathy increased during the study in the G group (before 47.7%, after 54.8%), though to a lesser extent than in the SU group (be- fore 54.0%, after 67.6%). In the G group, the num- ber of eyes with moderate retinopathy did not in- crease (before and after 4.8%), whereas in the SU Bioup, cases of mild (before 48.6%, afler $4.1%), moderate (before 5.4%, after 8.1%). and advanced (ie. preproliferative) retinopathy (before 0%, after 4%) all increased. The sum of retinopathic eyes in= creased in the D group (before 51.3%, after 73.0%) but there were no additional cases of moderate re- tinopathy (before 8.1%, after 5.4%). Preprolifera TABLE 4 OVERALL EVALUATION OF FUNDUSCOFIC FIND. INGS IN PATIENTS FOLLOWED FOR MORE THAN 4 ‘YEARS Figures reer to numbers of eyes, percentages are given in par centheses, Group Improved Not Worsered Total changed s » 3 Sais wt 2 Py " Ss ws) 7 2 2 10 re en en 6 Zo = 13546 su = 008 NS, NSTABLES a7 ‘CORRELATION BETWEEN THE CHANGE IN FUNDUSCOPIC FINDINGS AND BLOOD GLUCOSE CONTROL IN DIA. BETIC PATIENTS FOLLOWED FOR MORE THAN 4 YEARS. Figues in parentheses are percentages. Fundusopic Improved Not changed findings FBG control Good 4 a Faie 4 ° Tova! 3033) 294483) y= ~00%08 (Spearmae's rank correlation ceticient (NS) tive retinopathy appeared among patients in this group (before 0%, after 2.7%). Table 4 summarizes the changes in severity of funduscopic findings following the study. Eyes showing improvement in funduscopic findings were ‘most frequent in the G group while those showing aggravation were most frequent in the SU group. Although not significant, there was a tendeney (0 wards aggravation of funduscopic findings in the SU group compared to the G group (Utest, P < 0.10). Correlation between FBG con duscopic evaluation Results of data analysis for correlation of FBG and retinal changes are presented in Table 5. There was ‘no significant correlation between blood glucose control and the progression of retinopathy: pro- gression of retinopathy occurred in 38.7% and 37.5% in cases of good and fair FBG control sub- jects respectively al and overall fun- Incidence of preprolifecative retinopathy Preproliferative retinopathy occurred in 15 eyes (5.7%) during the 5-year period of study. There fol- Tows calculation of its incidence in the three groups, among the total of 262 eyes which were examined both ophthalmologically and with fluorescein an- giography at least twice during the study, as shown in Table 6. The condition occurred in two (2.6%) of 77 eyes Worsened Total 0 aaa 6 1608) nae o ‘of patients receiving G and in 12 (10.3%) of 117 ‘eyes of patients receiving SU; hence there was a sig- nificantly higher incidence in the SU group, com- pared to the G group (P = 0.05) ‘The incidence rate was 1.5% (one out of 68 eyes) in the D group. This was significantly lower than that in the SU group (P = 0.03). TABLE6 INCIDENCE OF PREPROLIFERATIVE RETINOPATHY DURING THE S-YEAR INVESTIGATION PERIOD. Figures refer numbers of ees, percentages ae given in pa renthees Group Normal and Preprolifrai Tout simple retinopathy retinopathy 1s 2 7 ory eo su 0s 2 0 aon 03 > sr ' « (os) as, Toul 107 15 2 43 67 alysis by Fisher's direst probability test, G su P< 00s > P00 NS.88 Safet of drug treatment ‘Among the patients who were followed with period- ic checkups for 5 yeurs there were no adverse re actions, signs of hypoglycemia or laboratory find- ings to suggest any clinical problem. There were no significant abnormal ECG findings Discussion In the study of retinal changes in diabetics it is es- sential to perform carefully programmed, long- term clinical observations. We previously reported results of a 2-year controlled clinical trial of glicla- ide vs. other sulfonylurcas and diet therapy to evaluate the effectiveness of the drug in the treat- ‘ment of diabetic retinopathy [3] This study showed that gliclazide and the other sulfonylureas were comparable both with respect 10 hypoglycemic effect and safety and suggested the potential efficacy of gliclazide for preventing the progress of diabetic retinopathy. Gliclazide has been demonstrated in laboratory studies to exert effects on the blood and vascular systems besides its hypoglycemic effect as a sulfo nylurea, i¢., suppression of platelet function (6, an: tithrombotic action (7-9]. stimulation of prosta glandin I, synthesis in the vascular wall (10) and en= hancement of fibrinolytic activity [11]. {t was of ‘great interest, therefore. to ascertain whether the ‘drug might be effective in preventing the develop- ‘ment and/or deterioration of diabetic retinopathy in a tong-term study, It is unquestioned that strict management and treatment of diabetes are effective in preventing the progress of diabetic retinopathy {19}. yet during the S-year study period progress of retinopathy was still noted in 3.6% of patients whose blood glucose level was satisfactorily controlled. This fact suggests other factors than blood glucose control may be involved in the progress of retinopathy. In the evaluation of drug efficacy against diabetic retinopathy. it is important to determine whether and to what extent the above-described rate of pro: ares of retinopathy (3.6%) is reduced by (reutment with the drug under investigation. In this study, we ormmulated a rating scale for the assessment of the degree of severity of retinopathy based on new cri teria {5] to be used in this investigation, so that changes from the initial stage of retinopathy could be fully reflected in the assessment. Consequently, ‘ur proportion of diabetic retinopathic progression. is higher than that usually reported inthe literature Responses to treatment of diabetes mellitus were assessed according (0 the control of FBG. The gly ccemie controt was rated as fair or better in patients followed for § years, and. in fact, the majority of cases were categorized as well contralled Among the 67 patients followed in this study, there were seven patients in the SU group whose FBG levels were not well controlled with tolbuta- imide replaced by chlorpropamide or glibenclamide. In contrast, diabetes was well conirolled with gli clazide or diet therapy atone over the period of S -years in all patients in the G and D groups. Patients ‘whose treatment was replaced by another therapy were withdrawn from the study. Thus the present patients subjected to final statistical analysis in the SU group were all those who had been receiving the same drug (sulfonylurea) throughout the 5-year ob- servation period: the most frequent drug was gl benclamide (11 cases), followed in order by tolbu- tamide (6 cases) and chlorpropamide (? cases) The frequency of cases with good glycemic con- trol was a slightly lower percentage in the SU group as compared with the other groups (G and D group). This may be due to the fact that patients with high FBG values were slightly more common in the SU group at the start of the study. In the D group, on the other hand, the FBG level was best controlled, possibly due to the greater proportion fof cases of mild diabetes. The intergroup differ ences. however, did not reach statistical significance in any of these respects. ‘Changes in funduscopic findings were assessed by ‘examining the degree of severity of retinopathy. All three groups showed an increase in incidence of ret- inopathy. toa slighily lesser extent in the G group. This would indicate that gliclazide was not notice- ably effective in preventing the development of dis betic retinopathy. However, the fact that the G group. as well as the D group, showed no increasein the incidence of moderate diabetie retinopathy suggests that the drug may be superior to other sul- fonylurea drugs with regard to delaying the pro- ‘gress of diabetic retinopathy. No patient developed preproliferative retinopathy among the patients re- ceiving gliclazide. whereas this retinal change oc- curred in the D group. In view of the lack of uniformity in the distri bution of patients by initial FBG value among the three groups and of the slightly poorer control of FBG in the SU group, we investigated the relation ship between the funduscopic findings and the state of FBG control, The analysis failed to demonstrate any significant correlation between these param eters ‘A further assessment was made of the retinal changes in the groups of patients in the study. No ‘one with preproliferative retinopathy had been ii tially admitted to this S-year study: here we com- pare its appearance among the three groups. Since photocoagulation andjor replacement with other drug therapy (insulin) were undertaken in cases showing progression to preproliferative retinopa- thy. thus often leading to withdrawal from the study, it was necessary to make the assessment of this parameter by including such withdrawals in the patient population treated during the 5-year period ‘of study. The proportion of drop-out cases was not significantly different among the three treatment ‘groups. The G group showed a significantly lower incidence of progression to preproliferative retinop- athy as compared with the SU group (P < 0.05). ‘The D group ako displayed a significantly lower incidence than the SU group (P = 0.03), The results ‘would indicate the efficacy of gliclazide as a treat ment to limit the increase in severity of diabetic ret- inopathy. Neither hypoglyvemia nor any significant adverse reactions that would create clinical problems were encountered among the cases treated in the S-year observation period. No significant abnormal labo- ratory data were noted. The results thus indicate that gliclazide isa safe drug which may be used over an extended period. 89 Acknowledgements, We wish to extend our gratitude to the following physicians snd technicians whose cooperation made this investigation possible: Drs. 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