Gliclazide

Drug Evaluation

Drugs 27: 301 -327 (1984)0012-6667/84/0400-0301/$13.50/0© ADiS Press LimitedAll rights reserved.

GliclazideA Preliminary Review of its Pharmacodynamic Properties andTherapeutic Efficacy in Diabetes Mellitus

B. Holmes, R.C. Heel, R.N. Brogden, T.M. Speight andG.s. AveryADIS Drug Information Services, Auckland

Various sections of the manuscript reviewed by: A.L. Bloom, Department of Haernatology, Uni versity Hospital of Wales, Cardiff, Wales; R.B. Jones, Andover, England; K.Kobayashi, Department of Clinical Pathology and Clinical Laboratory, Hyogo College ofMedicine, Nish inomiya, Japan; F.X. Lesbre, Lyon , France; A. Marble, Joslin DiabetesCenter, Boston, Massachusetts, USA ; R.C. Paton, Department of Medicine, Un iversityof Leeds , Leeds , England; L./. Rose, Division of Endocrinology and Metabolism, Hahnemann University, Ph iladelphia, USA; C.Th. Smit Sibinga, Red Cross Blood BankGroningen-Drenthe, Groningen , The Netherlands; D.F. Vloli, Institute of Clinical Medicine, University of Rome, Rome, Ital y; I .R.B. Williams, Liste r Hospital , Ste verage, England.

Contents

Summa ry 302I . Pharmacodynamic Studies 303

1.1 Hypoglycaemic Activity 3041.2 Effect on Plasma Cholesterol , Triglycerides and Fatty Acids 3051.3 Effects on the Blood 307

1.3.1 Effect on Platelet Adhesiveness 3071.3.2 Effect on Platelet Aggregation 3081.3.3 Effect on Platelet Metabol ism 3081.3.4 Effect on Platelet Coagulant Factors 3091.3.5 Effect on Fibrinolytic Activity 3101.3.6 Effect on Prostaglandin 12 Formation 310

1.4 Mechanism of Action 3102. Toxicology 3 11

2.1 Acute Toxicity Studies 3112.2 Chron ic Toxicity Studies 3112.3 Effects on Reproduction 311

3. Pharmacok inetic Studies 3123.1 Absorption 3123.2 Distribut ion 3123.3- Eliminat ion 313

3.3.1 Metabol ism 3133.3.2 Excretion 3143.3.3 Half-Life 314

Gliclazide: A Preliminary Review 302

Summary

3.4 Plasma Concentration and Clinical Effects 3144. Therapeutic Trials 315

4.1 Open Studies 3154.2 Controlled Trials 315

4.2.1 Gliclazide Compared with Tolbutamide 3154.2.2 Glidazide Compared with Glibendamide 3164.2.3 Glidazide Compared with Chlorpropam ide 3164.2.4 Glidazide Compared with Various Other Oral Hypoglycaemic Agents 316

4.3 Studies in Patients with Diabetic Retinopathy 3184.4 Studies in Patients with Diabetic Nephropath y 320

5. Side Effects 3215.1 Hypoglycaemia 3215.2 Weight Change 3215.3 Laboratory Test Abnormalities 321

6. Drug Interactions 3227. Dosage and Administrat ion 3228. Place of Glidazide in Therapy 323

Synopsis: Gliclazide' is a 'second generation ' oral hypoglycaemic agent. The particularinterest with this drug is that it has shown certain effects on the blood fo r which it is hopedthere may be some clinical benefit in diabetic angiopath ies. Both in animal and humanstudies it has demonstrated a reduction in platelet adhesiveness and aggregation, whilstpossible enhancement of platelet metabolism , reduction of coagulant factors. as well asincreased fibrinolytic activity, are still being investigated. Initial trials have suggested thatgliclazide therapy may reverse or at least slow down the progression of diabetic retinopathy. However, a few additi onal well-designed long term controlled studies are neededto confirm these findings, and to clarify whether any beneficial effect on diabetic retinopathy is unique to gliclaz ide or also occurs with other oral hvpoglycaemic drugs.

Both newly diagnosed maturity onset diabetics as well as those previously treated withsulphonylureas respond well to gliclazide therapy. In the small comparative studies whichhave been reported, gliclazide was of comparable efficacy to other oral hypoglycaemicagents.

Gliclazide has been well tolerated by most patients. the most frequently reported sideeffects being gastrointestinal in nature which occurred in less than 2% of patients.

Pharmacodynamic Studies: The abil ity of glic\azide to lower blood glucose concentrati ons has been demonstrated in various animals, as well as in a small number ofhealth y subjects and in pat ients with maturity onset diabetes. On a weight basis , glic\azidewas man y times more potent than tolbutamide, the relative potency varying betweenspecies (e.g. potency rat io of about I : 8 in rabbits and I : 27 in rats). As with othersulphonylurea oral hypoglycaemic drugs , glic\azide was not act ive in panc reatectomisedanimals. suggesting it has a direct action on the pancreas (postulated to be mediated byincreased calcium uptake in pancreatic islet cells) to increase insulin secretion. Singledoses of glic\azide 80mg in diabetic patients have brought about significant decreases inboth fasting and postprandial blood glucose levels, the effect being slightly less prolongedthan that of glibenc\amide 5mg which produces more abrupt changes in blood glucoseconcentrations, whilst tolbutamide 500mg produces a milder and relatively less prolongedeffect. Therapy with gliclazide has produced decreases in plasma cholesterol , tr iglycerideand fatt y acid levels, with at least I of the decreased levels reaching a statisticall y significant value at some stage during the administration of the drug. Gliclazide has demonst rated some effects on the blood in both animal and human studies which it is pos-

I ' Diarnicron' (Servicr): 'Glimicron' (Da i Nippon).


tulated may limit the progression of diabetic or other angiopathies. They include areduction of platelet adhesiveness and aggregation, whilst possible enhancement of platelet metabolism and anticoagulant factors as well as increased fibrinolytic activity arebeing investigated.

Pharmacokinetics: Gliclazide has been consistently well absorbed after oral administration in animals, but peak plasma concentrations (2.8 and 3.9 rng/L) after a dose of80mg, as well as time to reach peak concentrations (0.4 and 4.8 hours), have showngreater variability in studies in man . Its relatively low volume of distribution (15.9 to17.4L) suggesting only limited tissue distribution may in part be explained by its extensive binding to plasma album in (85 to 97%). In common with other sulphonylureas,gliclazide is apparently metabolised to either hydroxylated metabolites or N-oxygenatedcompounds and the corresponding alcohol and carboxylic acid. 60 to 70% of a dose iseliminated in the urine, with less than 20% of this as unchanged drug, while a further10 to 20% of a dose is eliminated in the faeces. In contrast, 90% of all drug-relatedmaterial in the plasma is unchanged gliclazide. The elimination half-life ofgliclazide mayvary between sexes, with values for males of around 8 hours and for females of II hours.

Therapeutic Trials: In open trials, 60 to 100% of maturity onset non-ketosis-pronediabetes mellitus patients achieved satisfactory control of their blood glucose levels ongliclazide therapy . These patients included those who were newly diagnosed as well asthose previously treated with other sulphonylurea drugs. However, as would be expected ,gliclazide was not effective in insulin dependent diabetics, in whom substitution of insulin with gliclazide resulted in loss of blood glucose control while addition of gJiclazidetherapy conferred no additional benefit compared with insulin alone . Combined therapyinvolving gliclazide and a biguanide was sometimes effective in patients resistant to asulphonylurea alone. In mostly small comparative studies, gJiclazide was generally comparable to other oral hypoglycaemic drugs in terms of overall quality of control of bloodglucose levels. In patients with diabetic retinopathy, gliclazide therapy for periods up toseveral years resulted in a significantly lower rate of deterioration of disease comparedwith control groups treated with another hypoglycaemic agent, whilst overall stability inthe progress of the disease during gliclazide therapy was noted in shorter term openstudies. Gliclazide did not significantly alter renal funct ion in patients with diabeticnephropathy.

Side Effects: Gliclazide is well tolerated by most patients. The most frequently reported side effects have been gastrointestinal upset such as abdominal pain, nausea , vomiting, dizziness, skin reactions and symptoms of hypoglycaemia , the latter in most casesresulting from overdosage or inadequate diet rather than an adverse effect of the drug.

Dosage and Administration: The recommended adult dose in maturity onset nonketotic diabetes mellitus is from 80 to 240mg daily . Maximum doses of 320mg have beenadministered in an attempt to achieve control of blood sugar concentrations and shouldthis fail, addition of a biguanide may be successful in some cases, provided ketosis hasnot developed .

Gliclazide, like other sulphonylurea drugs, is indicated only where diet fails to controlhyperglycaemia and glycosuria. It has no place in the treatment of juvenile diabetes orwhere there is severe metabolic decompensation with acidosis .

1. Pharmacodynamic Studies

Gliclazide is a 'second generation' sulphonylurea oral hypoglycaemic agent. It belongs to the

same class ofhypoglycaemic agents as tolbutamideand glibenclamide (fig. I). Its hypoglycaemic activity has been demonstrated in animals, healthy subjects and diabetic patients.

Glibenclamic1e

Gliclazidc: A Preliminary Review

CI

Q-CO-NH_CH,-H'cD-so, - NH-CO-NH-{H,OCH3

H3C-{)- S02 - NH - CO - NH - (CH2b - CH3

Tolbutamide

Fig. 1. Structural formulae of gliclazide. gfibenclamide and tolbutamide.

304

1.1 Hypoglycaemic Activity

Gliclazide proved to be about 7 to 10 times asactive as tolbutamide in decreasing blood glucosein rabbits (Duhault et aI., 1972; Maekawa et aI.,1978b; Schimizu et aI., 1976a) [25 mg/kg gliclazide= 200 rug/kg tolbutamide), whilst the potency ratioincreased in rats (3 mg/kg gliclazide == 80 mg/kgtolbutamide) to around 27 (Duhault et aI., 1972;Schimizu et aI., 1976). Gliclazide 10 and 25 mg/kg orally also reduced blood glucose concentrationsin guinea-pigs and dogs . Increasing the dosage ofgliclazide from 2.5 rug/kg to 25 mg/kg resulted inan increased duration of activity of up to 24 hours.Tolbutamide did not show a similar effect, the duration of action remaining at around 10 to 12 hoursdespite increased dosage . Gliclazide showed no activity in pancreatectomised dogs and alloxan diabetic rats (Duhault et aI., 1972). This would appearto indicate that, as with other drugs of this type,gliclazide has a direct action on the pancreas toincrease insulin secretion.

Gliclazide 200mg was found to lower blood glucose levels to a significantly greater extent than tolbutamide 2g at 2 and 3 hours after administrationto 12 healthy subjects (Duhault et aI., 1972).Administration of a single dose of gliclazide 80mgproduced a maximum reduction of 20% in bloodglucose levels after 2 hours, the levels returning tocontrol values 4 to 6 hours after administration of

the drug in 23 healthy subjects (see also section3.4) [Campbell et aI., 1980).

In patients with maturity onset diabetes mellitus , single doses of gliclazide (dose range 40 to320mg) have been shown to decrease hyperglycaemia in response to oral (Campbell et aI., 1980) andintravenous glucose (Stephan et aI., 1980), a standard meal (Charbonnel, 1980; Lagrue and Riveline,1980; Lesbre, 1977; Shaw et aI., 1980; Violi et al.,1982), after food given at 4 and II hours after drugadministration (Campbell et aI., 1980) and duringan arginine tolerance test (Brogard et aI., 1982). Investigating the effects of single doses of various oralsulphonylureas in 32 diabetic patients, Strata et aI.(1980) found the action of gliclazide 80mg on fasting blood sugar to be slightly less prolonged thanthat of glibenclamide 5mg, which also produced amore abrupt response, whilst tolbutamide 500mgproduced a less pronounced and less prolonged effect (fig. 2). Eight healthy subjects demonstrated asignificant decrease in blood glucose for 240 minutes after gliclazide 40,80 or 120mg, compared witha control group, whilst the higher doses of 80 and120mg produced significant rises in plasma insulinlevels (Ohneda et aI., 1977).

Treatment with gliclazide 80 to 240mg daily forup to 7 months resulted in a significant rise in the' insulinogenic index' [the ratio of the area underthe plasma insulin curve (~U/ml' hour) to the areaunder the blood glucose curve (g/L> houri] in 18


Fig. 2. Fasting blood sugar levels in 32 diabetics after a single

dose of placebo (6-6). tolbutamide 500mg (0-0). gli

benelamide 5mg (A-A) or gliclaz ide 60mg (e-e) [after

Strata et al., 1960).

Puglisi and Colli, 1980; Smit Sibinga and Wieringa, 1980). Gliclazide demonstrated a protectiveeffect on x-ray induced experimental atheromatosis in rabbits treated with 5, IO or 25 rug/kg,whereas glibenclamide 0.07 mg/kg had no effect(Smit Sibinga and Wieringa, 1980).

However, results of similar studies in patientswith diabetes were less consistent. Thus, significant

non-ketotic diabetics . Low values of the insulinogenic index were seen in 6 secondary treatmentfailures during long term treatment, and surprisinglyalso in some of the adequately controlled diabetics. Two months of gliclazide therapy (160mgdaily) in 8 subjects produced a significant decreasein fasting blood glucose but no change in insulinconcentration (Marchand et aI., 1983). While theseresults could suggest that the antidiabetic action ofgliclazide may be related to an extrapancreatic effect, since the insulotropic action is apparentlylacking in certain patients (Stephan et aI., 1980),this postulate is not supported by the findings inanimals described above. Any extrapancreatic effect of gliclazide is thought not to involve the receptors (De Meyts et aI., 1983; Dolais-Kitabgi etal., 1983; Marchand et al., 1983; Vigneri et aI., 1982)but may take place at the 'post-receptor' level (unpublished data on file, Servier; Ward et aI., 1983).

1.2 Effect on Plasma Cholesterol ,Triglycerides and Fatty Acids

Studies in rats and rabbits have revealed thatgliclazide reduces plasma concentrations of cholesterol, triglycerides and fatty acids (Marquie, 1977;

150

:g, 140OlE:- 1301OOl

~ 120'0

g 110:0

g' 100:;:;en~ 90

Base 2

Time (hours)

4 5 6 7 6

Table I. Effects of gliclazide on plasma cholesterol . triglycerides and fatty acid concentrations in patients with diabetes

Reference No. of Dosage Duration Results·

patients (mg/day) (months)cholesterol triglycerides fatty acids

Asmal et al. (1960) 11 220 (mean) 6 ++ ±

Berber and Tomkin (1962) 6 160 3 ± ±

King et al. (1977) 12 Not stated 3 + ±

Lagrue and Riveline (1980) 56 60-240 24.7 + +

Radic et al. (1980) 45 80-240 12 ++ + +

Sadayoshi et al. (1962) 41 20-240 12-60 ++

Stephan et al. (1960) 18 60-240 6-84 + +

Strata et al. (1980) 10 80 Not +5 160 stated +

Villiger (1962) 65 160 3 ++ ++

a ++ = significant decrease ; + = apparent decrease (not statistically significant); ± = no signif icant effect.

Gliclazidc: A Preliminary Review 306

8

7~oE.s

6 .9ecQlo

5 goo!en

4 ~s:o

"'Een

"'0::

----

84

....__-------L.... ................... ............. .......---- .......

o

...---11----....- -------

.... - - - -II Gliclazide (n = 13)

o 0 Chlorpropamide (n = 13)

1.58

"'Een

"'0:: 0.45 '-------.......-------'------"'-------...-4Time (months)

1.36~oE.s.Q 1.13

ecQlo5 0.90oQl:gQ;o>-0> 068'S

Fig. 3. Plasma cholesterol and triglyceride changes in 26 patients treated for a 3-month period with either gliclazide (mean dose 273

mg/day) or chlorpropamide (352 mg/day) [after Asmal et aI., 1980].

decreases in both plasma cholesterol (240 to 225mg/dl) and triglyceride (236 to 175 mgjdl) levelswere found in diabetics on gliclazide therapy byVilliger(1982), whilst studies by Radic et al. (1980),Fukui et al. (1982) and Asmal et al. (1980; table I)reported significant decreases in cholesterol levelsalone (2.59 to 2.3 g/dl and 5.2 to 4.33 mmol/L),

GlOlc'" 20s:0

~~ 10(/)

u·0

'" 0>..t:~ -10Q)

~

'" -20E(/)

'"0:: -30

Base 1 2 3 4 5 6 7 8 gTime (hours)

Fig. 4. Mean percentage changes in free fatty acids after pla

cebo (t.-t.) , tolbutamide 500mg (0----0) and gliclaz ide 80

(0-0) and 160mg (.-11) [after Strata et aI., 1980] .

Two other studies reported no significant changein either cholesterol or triglyceride concentrations(Lagrue and Riveline, 1980; Stephan et aI., 1980)[table I]. Berber and Tomkin (1982) noted an increase in high density lipoprotein cholesterol inpatients receiving gliclazide 160mg daily, and tolbutamide 1.5g daily (increased from 1.24 to 1.72mmol/L and 1.42 to 1.68 mrnol/L, respectively) butonly the increase caused by gliclazide was statistically significant. However, total cholesterol andtriglyceride levels showed no significant alterationwith either drug. No consistent alterations occurred in plasma cholesterol or triglyceride levelsin a 3-month study of patients receiving eitherchlorpropamide 352 mg/day or gliclazide 273 mgjday (fig. 3; Asmal et aI., 1980). Similarly , neitherglipizide nor gliclazide significantly altered bloodlipids including cholesterol and triglycerides duringa 3-month treatment period (Strata et aI., 1980).Since only the mean values for the levels of cholesterol and triglycerides are quoted in these studiesit is not possible to determine whether thosepatients with elevated pretreatment levels experienced a greater or lesser response to gliclazide thanthose without elevated pretreatment levels.


King et al. (1977) investigated the effect of singledoses of placebo, tolbutamide 500mg, and gliclazide 80 and 160mg, on levels of free fatty acids inpatients with diabetes (fig. 4). All drugs producedabout a 20 to 25% maximum decrease in free fattyacids, with the peak effect occurring 4 to 5 hoursafter administration.

1.3 Effects on the Blood

The relevance of platelet function, as measuredin the laboratory, to the clinical situation in diabetes is not yet known (Butterfield, 1980). However. it is known that both microangiopathy andatherosclerosis involve interaction of blood vessel,platelet and plasma factors which may be alteredin diabetes . Elevation of lipids and of coagulationfactors, particularly procoagulant factor VIII andfibrinogen, have been reported in patients withdiabetes, and may playa part in influencing blood

307

rheology. Platelets may influence the developmentof angiopathy by 2 distinct but interrelated properties - adhesion and aggregation (Bloom, 1980).Aggregation and adhesion (in in vitro systems), andcertain of their mediating mechanisms, are reported as being increased in diabetes (Colwell etal., 1978). Agents which inhibit or reduce these reactions or lower the concentrations of the relevantreactants may thus reasonably be postulated to limitthe progression of diabetic or other angiopathies.However, this expectation is subject to the constraint that some of the platelet changes seen insuch patients may be secondary to the angiopathy(Mustard and Packham, 1977), with consequentincreased platelet turnover and the presence ofyoung reactive platelets .

1.3.1 Effect on Platelet AdhesivenessPlatelet adhesiveness has been shown to be in

creased in diabetes when measured by a number

Table II. Effect of gliclazide on platelet adhesiveness in patients with diabetes

Reference No. of Dosage Duration Decrease in adhesiveness'patients (mg/day) (months)

Bobillo et at. (1975) 25 Not stated 3 ++ P < 0.001

Dettori (1980) 14 80-240 3 +6 ++ P < 0.02

12 ++ P < 0.001

Jones et al. (1980) 12 80 3 ++ P < 0.025

6 ++ P < 0.001

Nakayama et al. (1979) 30 20-240 22 Maintained at medium to low level

Paton et at, (1981) 11 Adjusted for control 10 ++ P < 0.05b

Radic et al. (1980) 50 80-240 12 ++ Not stated

Shaw et al. (1980) 9 80-320 1 +3 +

Thouverez (1972) 40 20 3 ++ P < 0.00140 ++ (all doses)

80 ++160 ++

Verry et al. (1974) 150 Not stated 3-24 +

Yamada et al. (1977) 9 Not stated 12-24 Maintained at normal to low level

a Retention index measured by method of Salzmann; ++ =significant decrease ; + =apparent decrease (not statistically significant).b Significant at 2 months only.


of techniques, including the Salzman glass bead retention index method (Colwell et aI., 1978). Intravenous and oral administration of gliclazide 10 to50 mg/kg in rabbits (Desnoyers et aI., 1972) and100 mg/kg orally in alloxan diabetic rabbits(Kuwashima et al. , 1979), as well as oral administration of 5 to 25 rug/kg/day in dogs, resulted ina marked decrease in the retention index (Desnoyers et aI., 1972). Schimizu et al. (1976b) carried outa similar study in animals which confirmed thesefindings with gliclazide, but which also demonstrated that tolbutamide had no effect on plateletadhesiveness. As a result of these early studies, further investigations of the effects of gliclazide onplatelet adhesiveness in diabetic patients were carried out. As can be seen from table II, gliclazide20 to 320 mg/day administered for periods rangingfrom I month to 2 years has in most trials broughtabout a significant decrease in platelet adhesiveness. However the design of these studies has notdistinguished between an effect due to improvement of hyperglycaemia and an effect of the drugper se. In the only comparative study of this type,gliclazide (80 to 240 rug/day) was similar to aspirin(I to 3 g/day) and dipyridamole (150 to 500 mg/day) in inhibiting the adhesiveness of human platelets (Deguchi et al., 1978).

1.3.2 Effect on Platelet AggregationIn diabetics there may be increased platelet ag

gregation induced by adenosine diphosphate (ADP),as indicated by both the primary aggregation response and the release reaction (Colwell et aI.,1978). Studies in rabbits have demonstrated significant inhibition of ADP-induced aggregation bygliclazide given as an infusion (3 or 10 rug/kg/minfor 4 to 8 min before administration of ADP), asa single oral dose (30 to 100 mg/kg) or as continuous therapy (20 rug/kg) for 7 days . Using the sameroutes of administration, tolbutamide (10 to 30 mg/kg/min, as an infusion; 50 to 150 mg/kg as a singledose; and 100 rug/kg as continuous oral therapy)had no effect on aggregation (Desnoyers and SaintDizier, 1980; Schimizu et aI., 1976b). Kuwashimaet al. (1979) reported a significant reduction inplatelet aggregation induced by collagen (2 Ilg/ml)

308

in alloxan diabetic rabbits given gliclazide 100 mg/kg orally for 4 weeks compared to a diabetic control group. Similarly, Arfors and Tangen (1977) reported marked and highly significant inhibition ofADP-induced platelet aggregation of human platelets in vitro, using gliclazide concentrations of I and2 mg/rnl.

However, studies in diabetics have been lessconclusive (table III), and the variability of findings in such studies prevent meaningful conclusions. Only 3 trials have reported a significant decrease in ADP-induced platelet aggregation forgliclazide at some stage in the trial (Chan et aI.,1982; Dettori, 1980; Violi et al., 1982), whilst othershave reported only a tendency toward inhibition(Kato et al. , 1976; Yamada et aI., 1977) or no effectat all. In a comparative study, both glibenclamide5 to 10mg and gliclazide 80 to 240mg resulted ina return to normal in the aggregation values produced by ADP I umol/L, In this study, gliclazidehad no effect on aggregation induced by higherconcentrations (10 and 100 umol/L) of ADP, collagen or adrenaline, while glibenclamide significantly decreased the aggregation induced by collagen (750 Ilg/ml) and adrenaline (10 urnol/L) [Klaffet al., 1979]. In contrast, Chan et al. (1982) reported a significant decrease in ADP-inducedplatelet aggregation in patients receiving gliclazidebut not in those receiving glibenclamide.

1.3.3 Effect on Platelet MetabolismStudies on platelet metabolism have examined

the thromboxane metabolic pathway and levels of.B-thromboglobulin, which are believed to reflect thelevel of platelet activity (Tsuboi et aI., 1981; Violiet aI., 1982). Only one significant finding of a decreased level of .B-thromboglobulin (33%) in diabetic patients receiving gliclazide 80 to 160mg overa 30-day period has been reported (Violi et al .,1982). Tsuboi's investigation of the effect of gliclazide on prostaglandin and thromboxane synthesisin guinea-pig platelets revealed an in vitro and exvivo inhibition of arachidonate release from platelet phospholipids. Gliclazide has induced a decrease in the heavy (large and very metabolicallyactive) populations of platelets C and D frequently


Table III. Effect of gliclazide (GI) and some other sulphonylureas on platelet aggregat ion in blood of diabetic patients

Reference No. of Dosage Duration Method of stimulating Inhibition of aggregation· ·b

patients (mg/day) (months) aggregationADP adrenaline collagen

Non-comperetiv« trials

Dettor i (1980) 14 80-240 3 ADP 1 " g/ml + + + +

6 Adrenaline 5 " g/ml + + ++12 ++ ++

Shaw et al. (1980) 4 80-320 ADP 1, 2.5, 5 "g/ml +

Verry et al. (1974) 150 Not stated 3-24 Collagen

Violi et al. (1982) 18 80-160 15 days ADP 1.2 "mol/L +30 days ++

Comparative stud ies

Chan et at, (1982) 35 GI20 ADP 1, 4 "mol/L GI + +

Gb15 Gb ±

King et al. (1977) 12 GI 3 ADP 10 "mol/L GI + +

Gp 3 Collagen 750 " g Gp + +

GI Gb

Klaff et al. (1979) 10 G180-240 ADP 1 " mol/L + +Gb 5-10 10 Ilmol/L ± ±

100 "mol/L ± ±

Collagen 750 Ilg/ml GI ± Gb ++

Adrenaline 1 "mol/L GI ± Gb ±

10 " mol/L ± ++

a Method of evaluation of inhibition of aggregation used in most studies was that of Born (1962).b + + = significant inhibition: + = apparent inhibition (not statist ically significant): ± = no effect.Abbreviations : Gb = glibenclamide: Gp = glipizide (doses not stated): ADP = adenosine diphosphate.

present in diabetic patients, together with an increase in light populations B and A (Desnoyers andSaint-Dizier, 1980; Vainer and Verry, 1974). Interference with platelet synthetic activity whichmainta ins platelet glycogen storage has also beenclaimed (Desnoyers and Saint-Dizier, 1980; Vainerand Verry, 1974), but further studies are requiredto substantiate these initial observations.

1.3.4 Effect on Platelet CoagulantFactorsStudies using blood samples from rabbits showed

that gliclazide 10 to 20 rug/kg intravenously couldproduce from 25 to 55% inhibition of the activation of coagulant factor XI by collagen. Oral

admin istration of 10 to 20 mg/kg resulted in 30 to35%inhibition. Under the same experimental conditions, tolbutamide 125 and 250 mg/kg orally andglibenclamide 5 mg/kg orally had no inhibitory activity. Gliclazide 20 and 40 ~g/ml was associatedwith a significant decrease (63% and 50%, respectively) in the activation of 'contact product-forming activity' when incubated with human plateletsin the presence of adenosine diphosphate (Desnoyers and Saint-Dizier, 1980).

Animal studies showed decreased levels of factor V and VIII as well as platelet factor 4 afteradministrat ion of gliclazide to rabbits (Hoshiyama1980). Gliclazide (0.1 to 1.0 mmol/L) markedly inhibited the release of factor VIII from washed hu-

Gliclazide: A Preliminary Review

man platelets (Kajikawa et aI., 1978). Similarly asignificant decrease in factor VIII coagulant activity and factor VIII antigen was found in 10 diabeticpatients given 10 months' treatment with gliclazide(Paton et aI., 1981), though again some of theseeffects may have been due to an effect on bloodglucose levels. Antithrombin III activity remainednormal in 20 diabetics given gliclazide, but showeda significant decrease in 15 diabetics on glibenclam ide (Chan et aI., 1982).

/.3.5 Effect on Fibrinolytic ActivityVascular plasminogen activator levels are

thought to be decreased in 20% of diabetics. Desnoyers and Saint-Dizier (1980) found that gliclazide 10 mg/kg given orally to rats significantly increased plasminogen activator levels . In diabeticpatients, however, while 6 months' therapy withgliclazide resulted in a trend towards increased levels, these changes failed to reach statistical significance (Chan et aI., 1982). When other oral hypoglycaemic agents were tested in the rat preparation,tolbutamide 250mg, chlorpropamide 100mg anddimethylbiguanide 500mg all produced apparentincreases in plasminogen activator levels , but againthese changes were not statistically significant(Desnoyers and Saint Dizier 1980). However, Chanet al. (1982) found that 6 months of glibenclamidetherapy in 15 diabetic patients significantly decreased plasminogen activator levels .

Further animal studies (Arfors and Tangen,1977) reported a significant increase in primary andhaemostatic plug formation time after single dosesof gliclazide 100 rug/kg, as well as after continuousdosing of 25 mg/kg for 7 days in rabbits. Almer(1980) noted a return to normal in the vascularfibrinolytic activity in 6 diabetics over a 6-monthtreatment period with gliclazide, which was stillpresent at follow-up 4 years later (Almer et aI.,1983), whilst Paton et al. (1981) monitoring 10 diabetics over a 6-month period found no significantalteration of euglobulinysis nor of any of the otherfactors used to assess fibrinolytic activity.

While such studies invite interesting speculation. findings have not been conclusive. Thus, theseobservations can only be considered a foundation

310

for further studies involving monitoring offibrinolytic activ ity during gliclazide therapy III

diabetics.

1.3.6 Effect on Prostaglandin 12 FormationAs prostaglandin 12 is a potent inhibitor of

platelet functions produced by vessel walls (Higgset aI., 1978; Moncada et aI., 1976), it has been postulated that the restoration of reduced prostaglandin 12 formation may prevent the tendency tothrombus formation and microangiopathy in diabetic patients. Gliclazide (100 to 300 /lg/ml) enhanced the spontaneous prostaglandin 12 formation in the aorta of guinea-pigs and rats in vitro. Asimilar effect was observed with tolazamide andacetohexamide, but not with chlorpropamide, tolbutamide and glibenclamide. In vivo. oral administration of gliclazide 100 to 300 mg/kg to streptozin-diabetic rats restored the reduced formationof prostaglandin 12 (Fujitani et aI., 1983).

1.4 Mechanism of Action

Like other hypoglycaemic sulphonylureas, glic1azide appears to act directly on the pancreas toincrease insulin secretion (see section 1.1). Thereis some evidence that changes in calcium transportmay be involved in this action. Thus gliclazide, likeother drugs in its class, has been shown to affectthe movement of calcium in isolated pancreaticislet cells. The stimulant action of gliclazide upon45Ca net uptake, and subsequent insulin release bythe endocrine pancreas, is inhibited by organic calcium antagonists, e.g. verapamil. Hypoglycaemicsulphonylureas and organic calcium antagonists alsoexert opposite effects upon A23187-ionophore mediated calcium translocation in an artificial system.It is postulated that ionophores located in the {3

cell plasma membrane represent the target for theprimary action of gliclazide upon calcium transport into islet cells (Malaisse et aI., 1980), and thatthe mechanism of action could be related to a facilitated transport of cations across the cell plasmamembrane (Deleers et al. , 1983).

While there is some evidence suggesting that gliclazide may also act at extrapancreatic sites (see


2.3 Effects on Reproduction

Fig. 5. Plasma concentration of gliclazide in a 'fast' and 'slow'absorber after administrat ion of 80mg on separate occas ions[after Campbell et al. 19801.

48322416

Time (hours)

8

5

4

3

E2Oi

.3cQ

~CQ)oc0o

48'" 8 16 24 32EVI

'"C. 3 'Slow'Q)

"0'N

'":§ 2a

Pregnant mice and rats given gliclazide at da ilydose levels up to 500 and 480 mg/kg orall y, respectively, showed no adverse effects on the courseor outcome of pregnancy. However , pregnant rabbits given doses of 10 to 50 mg/kg orally showedevidence of maternal and embryo toxic ity but noteratogen icity. Fetal tissue drug concentrations inthe mouse were similar to those in the parentalbody mass. Distribution of gliclazide was similarin pregnant and non-pregnant mice. Postnatal development in rats and mice was unaffected byadministration of gliclazide to the dams throughout the entire gestation period. Gliclazide had noadverse effects on fertility, gestation or postnatal

Single-dose toxicity studies revealed a low orderof acute oral toxicity with few adverse effects apparent at dose levels up to 4 g/kg in mice, rats anddogs. Gliclazide at doses of 30 and 100 rug/kgintravenously caused a sustained hypertension anda slight increase in heart rate in cats, whilst urinaryvolume and electrolyte excretion (K+ and CI-) werereduced in rats treated with large doses of gliclazide (1000 mg/kg orally) . The median lethal oraldose in guinea-pigs was 1599 to 2068 mg/kg . Subacute stud ies in dogs revealed a max imum tolerated dose of 150 mg/kg orally and good toleranceto dose levels up to 100 mg/kg orall y for 3 weeks(unpublished data on file, Servier) .

2. Toxicology2.1 Acute Toxicity Studies

2.2 Chronic Toxicity Studies

section 1.1), further studies are needed to confirmthese prelim inary find ings.

Six months' administration of gliclazide 25, 100or 200 mg/kg orall y to rats revealed no significantchanges in haematological and biological parameters, or in results of urinal ysis. No tissue changeswere observed. Female rats appeared more susceptible to toxicity and showed slight increases in liverenzymes together with slight decreases in erythrocyte counts, haematocrit values and haemoglobulin concentrations at dosages of 200 mg/kg andhigher. Doses up to 100 mg/kg orally for up to 2months failed to produce any signs of toxicity inguinea-pigs. Similarly, administration of gliclazideat dose levels up to 24 mg/kg orally for 12 monthsor up to 29 mg/kg for 6 months in dogs producedno evidence of toxicity. 12 months of repeated dosesof 20, 60 and 180 mg/kg orall y in the rhesus monkey failed to reveal any significant toxic effect ofgliclazide on the clinical condition, bodyweight , andfood and fluid intake, or du ring detailed laboratoryinvestigations, ophthalmological examination andcomprehensive histopathological evaluations (unpublished data on file, Servier ; Matsuoka et aI.,1980),

Gliclazidc: A Preliminary Review 312

mortality in the first generat ion of rats after dosesup to 200 mg/kg orally (unpublished data on file,Servier ). Similarly , in a published report evenhigher doses (up to 800 mg/kg/day) did not alterfertility of either male or female rats and rabbits,or produce fetal abnormalities, although inhibition

3.0

E0;

2.5..=,c0

~C 2.0Q)oc0o

1.5Ql"0'Nto~ 1.0e;,toEU>to 0.51l:

of weight gain was noted with higher doses (Kawanishi et al., 1981 ).

3. Pharmacokinetic Studies3.1 Absorption

Gliclazide has been well absorbed in animalstudies in several species, consistentl y reaching peakplasma levels within 2 to 3 hours (Campbell et aI.,1980; Miyazaki et al., 1983). In a stud y in healthyvolunteers, 7 subjects attained mean maximum gliclazide plasma concentrations of 3.9 gil within 4hours of an 80mg dose, whilst 6 subjects attaineda lower peak concentration of 2.8 gil, which wasdelayed for up to a further 4 hours (Campbell etal., 1980) [fig. 5]. However, it is not clear whetherthis represents different rates of absorption , orwhether it is due to differences in the rates of metabolism of the drug. In another study in 6 healthysubjects, peak plasma concentrations occurredwithin 2 to 4 hours after administration of gliclazide 40mg, although a secondary increase in plasmaconcentration occurred in I subject 10 hours afteradm inistration (Kobayashi et aI., 1981; fig. 6).Plasma concentration-time curves for a single doseof gliclazide were found to have a similar profilein healthy subjects and diabetic patients , bearingin mind the different doses adm inistered (fig. 6a).Oral administrat ion of gliclazide 80 rug/day for 7days resulted in a slightly longer time to maximumconcentration with the last dose administered, together with an increased maximum plasma concentration and area under the curve from 0 to 24hours (table IV; fig. 6b) [Kobayashi et aI., 1981].

Peak plasma levels were significantly lower andoccurred significantly later, with overall absorptionbeing decreased by 20% in a group of 5 elderly females (mean age 77 years) compared with a groupof 5 younger females (mean age 26 years) [Foretteet al., 1982].

24

241234 6 10

1 2 4 6 8 12

Time after admin istration (hours)

3.5

8

7

6

5

4

3

21

E0;..=,c.Q'§CQlUCooQ)"0'Nto:§e;,toEU>to1l:

b

a

Fig. 6. (a) Plasma concentration-time curves for gliclazide in 6heal thy sub jects given a single 40mg dose (after Kobayashi et

al., 1981).

(b) Plasma concentration-time curves for 7 diabetic patients who

took a single dose of gliclazide 80mg (e-e). and for the last

dose in 4 patients who were administered gliclazide 80 mg/dayfor 7 days (0 - 0).

3.2 Distribut ion

The volume of distribution of gliclazide inhealthy and diabetic subjects was 15.9 to 17.4L(Kobayashi et al., 1981 ), or 20 to 40% of body-


Table IV. Some pharmacok inetic parameters for gliclazide after oral administration

Reference Number and type Duration Dose Cp malit Tmax AUCO_24 Vd tYa,1

of subject of study (I'g/ml) (h) (I'g/ml · h) (h)

Campbell et al. 7 healthy 1 dose 80mg 3.9 4(1980) ' 6 healthy 1 dose 80mg 2.8 4-8

4 healthy Not 3 mg/kg 36.3% of 10.4stated bodyweight

23 healthy 3 days 80mg 0.7-4.9144 diabetic 80mg 0.3-8.2

Kobayashi et al. 12 healthy 1 dose 40mg 2.8 2.8 37.2 17.4L 12.3(1981) 7 diabetic 7 days. 80mg 6.8 2.3 72 16L 12.6

4/7 diabetic 80mg 7.6 3.0 91.4 15.9L 12.3

Abbreviations: Cp max = maximum plasma concentration; Tmax = time to maximum plasma concentration; AUCO_24 = area underplasma concentration-time curve from 0 to 24 hours ; Vd = volume of distribution; tv." = elimination half-life .

weight (Campbel1 et al., 1980)[table IV], there beinglarge intersubject variations. The volume of distribution was found to increase with age, values ofaround 24L being found in elderly patients (Foretteet aI., 1982). These relati vely low values suggestonly limited tissue distribution, which could in partbe explained by the extent of protein binding. In15 healthy volunteers, gliclazide, in common withother sulphonylureas, was extensively bound (85 to97%) to plasma protein, but again there was a considerable variability in the extent of binding between individuals (Campbel1 et aI., 1980). Koba yashi et al. (1981) exam ined the distribution ofgliclazide-bound blood proteins in 2 healthy subjects, and reported that fractionated serum proteinsof macroglobul in (M), "Y-globulin (lgG), albuminand smal1 molecular substances contained gliclazide at an average of 3.7,0.7,82.3 and 13.2%, respectively, during the 24 hours after administration.

Benakis and Glasson (1980), using carbonyl 14C_gliclazide 15 rng/kg and whole body autoradiography in the rat, showed a rapid and high degreeoflocalisation of radioacti vity in the liver and kidneys. The drug and its metabolites were identifiedin 15 organs and tissues such as pancreas, adrenalglands, lung, intestine, muscle and skin tissue. Smal1quantities were found in the brain and eye. Similar

results were found by Miyazaki et al. (1983) afteradministrat ion of 3H-gliclazide 10 rug/kg to rats .

3.3 Eliminat ion

3.3.1 MetabolismExamination of radioactive metabolic products

of gliclazide in urine and plasma after administration of label1ed drug has led to proposals for themajor metabol ic pathways in man. As with othersulphonylureas, gliclazide is oxidised to produceeither hydroxylated metabolites or N-oxygenatedcompounds, and the corresponding alcohol andcarboxylic acid. Gliclazide is extens ively metabolised, less than 20% of the dose being excretedunchanged in the urine. However, in plasma, gliclazide represents over 90% of all drug-related material, the most important metabolite (an N-oxygenated derivative) being present only to the extentof I%. Th is metabol ite has not demonstrated anyhypoglycaemic action but claims have been madethat it possesses effects on platelet aggregation andmicrothrombi format ion. The othe r metabol itesseen in urine are only present in trace quantities(less than 20 ng/m l) in plasma. The extensive protein binding of gliclazide and its lipid solubil ity,which would inhibit glomerular filtration as wellas enhancing reabsorption offiltered material from


the tubules, might help explain the extreme differences between the amounts of gliclazide found inplasma and urine (Campbell et aI., 1980).

carbutamide, chlorpropamide and metahexamide(25 to 50 hours). Mean elimination half-life increases with age (20.5 hours) in the elderly subject(Forette et aI., 1982).

3.4 Plasma Concentration and Clinical Effects

t Meals

4 8 12 16 20 24

Time (hours)

0-----0----U p' ----------0 40mg

''0 ' 80mg

",. - - -I ' ~,

I"I ' -- 80mg

I ---I ---- 40mg

4 8 12 16 20 24Q)

en 1108::l 1000> 90~ '680~ c; 700:: .s 60

'-'----,r-'----r----'--,--,---,---r-

Fig.7. Relationship between the estimated curve for plasma gliclazide concentrat ion and plasma glucose concentration in

healthy subjects (each plot represents the mean value aftersingle-dose oral administration for 3 volunteers) [after Sadayoshi et aI., 1982).

c:o~ 4CQ)oc: 38OJ't:l'N 2'":§0>",_1EEen _"'0>0:: 3 0

A study in healthy volunteers fasted overnightbefore being given gliclazide 80mg demonstrated amaximum reduction in plasma glucose levels (20%)at 2 hours (Campbell et aI., 1980). Glucose concentrations returned to control values 4 to 6 hoursafter administration, but ingestion of a meal at 4hours made analysis of the data more difficult. Nocorrelation between percentage drop in glucose andgliclazide plasma concentrations was shown to exist over the whole 24-hour period , but if only theconcentrations from 0 to 4 hours were consideredthen the correlation was significant. There appeared to be a 'threshold' gliclazide concentrationof 0.25 gIL required for hypoglycaemic action . Sa-

3.3.2 ExcretionStudies with 14C-gliclazide in animals and man

have reported 60 to 70% of the dose to be excretedin the urine and 10 to 20% in the faeces (Campbellet aI., 1980; Miyazaki et aI., 1983). Elimination inhuman faeces was slower than with other species,activity still being present in the 96-hour collectionperiod (Campbell et aI., 1980). The extent of protein binding in man would hinder the glomerularfiltration process, whilst gliclazide lipid solubilitywould enhance reabsorption from the tubules. Thesame value for plasma clearance (13.5 ml/min) wasfound in a group of elderly subjects (mean age 77years) as in a group of younger subjects (mean age26 years) [Forette et aI., 1982].

Rats given 14C-gliclazide 10 mg/kg intravenously demonstrated a maximum concentration inthe bile after 2 to 5 hours, and during the 8-hourmonitoring period 20% of the dose was circulatingin the bile (Benakis and Glasson , 1980). Similarly ,biliary excretion of radioactivity amounted to 40%of the dose of 3H-gliclazide 10 mg/kg given to rats(Miyazaki et aI., 1983). Since the radioactivity inhuman faeces after administration of labelled drugis not thought to be due to unchanged drug, it ispostulated that biliary excretion also takes place inman (Campbell et aI., 1980).

3.3.3 Half-LifePlasma concentrations of gliclazide in healthy

subjects and diabetic patients have been shown todecline exponentially as a single phase [Campbellet aI., 1980; Kobayashi et aI., 1981; Sadayoshi etal., 1982]. Campbell et al. (1980) reported considerable variation in the elimination half-lives (6.1to 14.3 hours), with healthy male subjects havinga significantly shorter mean half-life (8 hours) compared with females (11 hours). Gliclazide is therefore eliminated in man at an intermediate ratecompared with other sulphonylureas, not as rapidly as tolbutamide, glibenclamide or tolazamide(half-lives 4 to 9 hours) , but faster than occurs with


dayoshi et al. (1982) reported a significant 'mirrorimage' relationship between glucose blood concentrations and plasma concentrations of the drug in3 healthy volunteers (fig. 7). Similarly, in a placebo-controlled study, diabetics given gliclazide 40to 240mg as a single dose and a glucose load of 50gat time-zero followed by a meal at 4 hours, demonstrated a maximum fall in glucose levels at 2hours, a positive correlation between gliclazideplasma and plasma glucose reduction during theperiod 0 to 4 hours, and a 'threshold' concentrationof glicJazide for hypoglycaemic activity . But in diabetics this minimum effective concentration washigher (1.5 g/L), possibly reflecting the decreasedsensitivity of the pancreatic tl-cell to respond toglicJazide stimulation (Campbell et al., 1980).

4. Therapeutic Trials

As with other sulphonylureas, the frequency withwhich blood glucose concentrations are well controlled by glicJazide may be influenced by severalfactors; for example, the quality of response to previous oral hypoglycaemicdrugs, the duration of thediabetes, and whether or not patients have beentreated previously. Many trials have documentedpatients' previous therapy and the duration of thediabetes, but few have related these factors to bloodglucosecontrol on gliclazide (Baba et al., 1983; Fukui et al., 1976; Plauchu and Pousset, 1972).

4.1 Open Studies

Many workers have recorded an overall significant decrease in blood sugar concentrations duringopen trials with glicJazide (Bodansky et al., 1982;Brogard et al., 1982; Gibson et al., 1982; Iunes etal., 1983; Lagrue and Riveline, 1980; Lesbre andCanicave, 1977; Medbak et al., 1980; Mukaino etal., 1977; Paton et al., 1980; Ponari et al., 1979;Rubinjoni et al., 1978; Sakamoto et al., 1976; Waiters and McCarthy, 1980). Others, on the basis ofvarying criteria, have evaluated gliclazide therapyas producing 'satisfactory' control of hyperglycaemia in 60 to 100% of patients with maturity onsetdiabetes mellitus (Cabezas-Cerrato and Fernandez-

315

Cruz, 1975;Canivet, 1972; Fukui et al., 1976; Nakayama et al., 1979; Oli, 1980; Sadayoshi et al.,1982; Strata et al., 1980; Villegas Cinco and Fernando, 1978) [table V]. The dosage of gliclazide insuch studies has ranged from 40 to 320mg daily,but 80 to 240mg has been sufficient in mostpatients. In addition to those studies tabulated,several others reported a decrease in glycosylatedhaemoglobin during treatment with gliclazide(Gibson et al., 1983;Guillausseau et al., 1983; Jadzinski et al., 1983).

In a 6-month study (Charbonnel , 1980) involving 156 patients who had not been previouslytreated with hypoglycaemic agents, both the meanfasting and postprandial blood sugar levels fell significantly 2.05 to 1.17 and 2,48 to 1.43 g/L, respectively). Patients previously treated with sulphonylureas (114) and biguanides (29) alone alsoexperienced significant decreases in fasting andpostprandial blood sugar levels on gliclazide compared with previous therapy, but those previouslytaking a combination of sulphonylurea and biguanide did not develop a significant improvementin blood sugar control during gliclazide therapy .Thus, in this as in other studies (Fukui et al., 1976;Plauchu and Pousset, 1972), the percentage decreases in blood sugar levels were much greater inthe previously untreated patients (43%)when compared with those previously treated with suiphonylureas (9.6%), biguanides (18.4%) or combinationtherapy (3.6%). In a large multicentre study (Strataet aI., 1980) involving patients previously treatedwith oral hypoglycaemic agents and in a few caseswith insulin, together with previously untreatedpatients, gliclazide was able to establish control ofblood glucosebelow a level of J.3g/L (fasting bloodsugar) in 45 to 77% of diabetics.

4.2 Controlled Trials (Table VI)

4.2.1 Gliclazide Compared with TolbutamideA 3-month study was conducted by Berber and

Tomk in (1982) on 12 insulin-dependent diabetics ,6 of whom received glicJazide 160mg daily in addition to their insulin therapy . Mean fasting bloodsugar levels in the glicJazide group increased slightly


from 10 to 11 .2 mmol/L whilst in the insulin-onlygroup fasting blood sugar decreased from 12 to 7.1mmol/L, Clearly, gliclazide therapy had no beneficial effect in these insulin-dependent diabetics. Inthe same study, 6 maturity onset insulin-independent diabetics received gliclazide 160mg dailyand another 6 were given tolbutamide 1.5g dailyfor the duration of the trial. Mean fasting bloodsugar levels fell significantly (7.4 to 4.95 mmol/L)in the tolbutamide group, but the fall in the gliclazide group did not reach statistical significance (7.6to 6.0 mmol/L) ,

4.2.2 G/ic/azide Compared with G/ibenc/amideSeveral studies involving comparisons of glicla

zide therapy with that of glibenclamide found nosignificant difference in the quality of blood sugarcontrol produced by the 2 drugs (table VI). Onlyone study (Balabolkin et aI., 1983), reported a significantly greater decrease in blood glucose levelswith gliclazide compared with treatment with glibenclamide after 2 months' therapy. Fagerberg andGamstedt (1980) found no differences in fastingblood glucose levels or 2-hour postprandial levelsafter I, 6 and 12 months of therapy. They concluded that their 16 maturity onset non-insulin-dependent diabetics previously controlled on glibenclamide could be equally well controlled withglicazide in equipotent dosages. Klaff et al. (1979),studying 10 newly diagnosed maturity onset diabetics, reported a significant lowering of postprandial blood glucose levels after both glibenclamide(12.2 to 9.3 mmol/L) and gliclazide (12.2 to 7.8mmol/L) were added to their diet, and the difference between the groups was not significant. Thelarger double-blind multicentre trial by Baba et al.(1983) involving 277 patients also found no significant difference in control of fasting blood sugarlevels by both drugs. Gliclazide produced goodcontrol (fasting blood sugar l.l to 1.39 gIL) in 49%of patients whilst glibenclamide did the same in51%.

4.2.3 Glic/azide Compared withChlorpropamideIn 26.maturity onset diabetics, 3 months' therapy

316

with either gliclazide or chlorpropamide resulted insignificant decreases in mean fasting blood glucoselevels when compared with pretreatment levels.However, once again the difference in degree ofcontrol effected by the 2 drugs was not significant.The dosage of chlorpropamide (352 rug/day) wasgreater than that of gliclazide (273 mg/day) at allintervals during the study period. Considering thepercentage reduction of pre-therapy blood glucoselevels, I of the 13 patients on chlorpropamideachieved a greater than 50% reduction, with 3 inthe range 30 to 50%, while none of the 13 gliclazidepatients achieved greater than 50% reduction, Ishowed a response in the range 30 to 50%, and themajority (9 patients) fell in the 10 to 30% range(Asmal et aI., 1980) [fig. 8].

When substituted for acetohexamide or chlorpropamide in 17 patients , gliclazide in daily dosesranging from 160 to 240mg was shown to producea significantly better degree of diabetic control. 64%of patients achieved a superior degree (reductionin blood glucose exceeding 2.0 gIL) of control offasting blood glucose, with 79%also showing a superior reduction in postprandial blood glucose levels. The efficacy of gliclazide was maintained overthe 9-month study period (unpublished report onfile, Servier).

4.2.4 G/ic/azide Compared with Various OtherOral Hypoglycaemic AgentsGliclazide has been found to be both at least as

effective (Cabral et aI., 1982; Regnault, 1980) andmore effective (Kosaka et aI., 1983b) than otheroral hypoglycaemic agents in maintaining bloodsugar control. No significant difference in thechanges in fasting blood sugar was seen betweenthe patients receiving gliclazide (alone or in combination with a biguanide or insulin) and a 'controlgroup' (taking another sulphonylurea, alone or incombination with a biguanide or insulin alone) ina study of 140 maturity onset diabetics over an 18month period (Regnault, 1980) [table VI]. Patientsreceiving gliclazide (80 rug/day) over a 2-year period had better control offasting blood sugar levelsthan a similar group of patients who received othersulphonylurea therapy over the same period. Con-

Tab

leV

.S

ome

open

stud

ies

ofgl

icla

zid

ein

patie

nts

with

mat

urity

onse

td

iabe

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me

llitu

so ;:S

'

Ref

eren

ceN

umbe

ran

dD

osag

eD

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ion

Res

pons

e(%

ofpa

tien

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Crit

eria

for

resp

on

see;- N 0:

type

of(m

g/da

y)(m

onth

s)ex

celle

ntgo

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ir(f

ast

ing

bloo

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gar)

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tsp

oo

r);

> "tl

Cab

ezas

-Cer

rato

and

803-

639

4015

Exc

elle

nt<

1.2

gIL

2F

erna

ndez

Cru

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<1.

4gI

L3'

(197

5)P

oor

<1.

5gI

L::s ., ..,

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lure

>1

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L(6

%of

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Can

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42(P

T)

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201-

863

1720

Goo

d<

1.5

gIL

'"-<(1

972)

9(N

PT

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air

1.5-

2.0

gIL

iii'

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>20

0mg

Fuk

uiet

at.

3240

-240

6-12

6816

16G

ood

<1.

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Fai

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>1.

7gI

L

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ayam

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al.

3020

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(197

9)

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(198

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209

3833

9.5

Exc

elle

nt<

7.2

mm

ol/L

(RB

S)

Goo

d7

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.3m

mol

/LF

air

8.3

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mm

ol/L

Pla

uchu

and

Pou

sset

23(P

T)

160

Not

stat

ed47

2621

No

tst

ated

(197

2)9

(NP

T)

4444

Sad

ayos

hi

etal

.(1

982)

4120

-240

12-6

053

24N

otst

ated

Sha

wet

al.

(198

0)50

(NP

T)

80-3

202-

2246

1618

20E

xce

llen

t<

7.5

rnrn

olrt

,(P

PS

)G

ood

<8

.5m

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l/L

Fai

r<

10rn

mol

/t,P

oor

>10

rnm

oljt

,

Str

ata

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.(1

980)

d20

(PT

):22

(NP

T)

160-

240

1-6

4547

8E

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t<

1.3

gIL

30(P

T):

1(N

PT

)80

-240

Not

stat

ed77

176

Goo

d1.

3-1.

7gI

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(PT

);21

(NP

T)

40-2

406-

1275

916

Poo

r>

1.7

gIL

37(P

T);

16(N

PT

)40

-240

32-4

453

425

14(P

T):

23(N

PT

)80

-240

1-38

6722

11

Vill

egas

-Cin

coan

d17

(PT

)80

-240

2-3

7426

Goo

d<

1.1

gIL

Fern

ando

(197

8)34

(NP

T)

Fai

r<

1.3

gIL

aM

ultic

entr

est

udy.

Res

ults

show

nar

efr

om

the

indi

vid

ual

cent

res

.A

bbre

viat

ions

:P

T=

prev

ious

lytr

ea

ted

;N

PT

=no

tpr

evio

usly

trea

ted

:R

BS

=ra

ndo

mbl

ood

suga

r;P

PS

=p

ost

pra

nd

ial

bloo

dsu

gar.

I:: .....

.


trol in both these groups was not as good as thatproduced in the group treated by diet alone, butthe severity of diabetes in these patients would havebeen much less than in the dru g-treated groups(Kosaka et aI., 1983b).

4.3 Studies in Patients with DiabeticRetinopathy

Diabetic retinopathy has a variable natu ral history. In order to study the evolution oflesions andthe effects of any therapeutic intervention, qua ntitative evaluatio n is important. There are a nu mber of methods available. Photographic grading willon ly indicate major changes, while point countingmethods are valid and repeatable but time consuming. Fluorescein angiograms are most accuratein early and mild retinopathy, and vitreous fluorescence gives an accurate numerical value .

Treatment of diabetic retinopathy has consistedof correcting only I of the many factors involvedin its development - that of dist urbed glucose metabolism . Correction of haemobiological abnor-

14

12!:......-:~------

~ 10'0E.s

318

malities (such as increased blood viscosity, agglutination of the red cells or formation of plateletaggregates which constitute intracapillary microthrombi) has yet to be addressed .

Examinati on of serial photographs taken duringthe passage of fluorescein through the retina innormal or pancreatomised dogs revealed a protective effect of gliclazide (10 rug/kg intravenously)against capillary obstruction induced by a constantadenine diphosphate infusion (Duhau lt et aI., 1980).This finding, together with its already demonstrated effects on platelets, has led to studies of gliclazide in patients with diabetic retinopathy.

Several auth ors (Canivet, 1972; Fukui et aI.,1976; Plauchu and Pousset, 1972) reported no significant change in fundoscopic or other examinations of the eye during 'open' treat ment with gliclazide, but the period of treatment (maximum of12 months) was too short to conclude that the drughad prevented the development or progression ofdiabetic retinopathy. A longer open stud y reportedstabilit y in the progress of the disease in 47 of the60 eyes examined, whilst II of the 13 with reti-

* p < 0.023

'""'-..(>-_----u *

c 8Q~C

400Q) 40 C>c0 .s0 300Q) Q)III III0 00 2 200 -c:::l en0> :::lt'Cl 100 0E'"t'Cl

0n: 0- 4 -2 0 2 4 6 8 10 12

Time (weeks)

Fig. 8. Mean blood glucose concentrations during administration 01gliclazide (e and . ) or chlorpropamide (0 and 0 ) in 26 diabetics(alter Asmal et al.. 1979).


Table VI. some controlled trials of gliclazide in patients with maturity onset diabetes

Reference Design Number of Drug and dosage" Duration Resultsb

patients (mg/day) (months) (quality of control offasting blood sugar)

Glic/azide compared with various other oral hypoglycaemic drugs

Cabral et al. (1982) non-blind G 19 40-160 37 Gliclazide group =

14 Control group 'control" group

Kosaka et al. db G 81 G 80 24 Diet ~G ~5

(1983a.b) 5116 578 diet Diet alone

Regnault (1980) db 140 Gliclazide group 18.5 Gliclazide group =

(G. G + B. G + I) 'control' group

'Control' group

(5.5+ B.I)

G/ic/azide compared with tolbutamide

Berber and Tomkin 6c G 160 + I 3 G < I(1982) 6c I

6 G 160 + diet6 T 1.5g + diet T >G

Glic/azide compared with glibenc lamideBaba et al. (1983) db Gb 131 Gb 2.5-10 6 Gb = G

multicentre G 146 G 40-160

Balabolkin et al. Gb 20 Not stated 6·8 weeks G > Gb

(1983) G 27

Fagerberg and co 16 Gb 2.5-15 6 up to 12 Gb = GGamstedt (1980) G 120·400

Klatt et at, (1979) co 10 Gb 5-10 4-6 weeks on Gb = Gd

G 80-240 each drug

Minami et al. (1981) Not stated G 12 G 40-120 36 Gb = G

Gb 13 Gb 2.5-7.5

Gliclazide compared with chlorpropamide

Asmal et al. (1980) 1 month washout 26 G 273 mean 3 G=Cthen ra C 352 mean

Unpublished report co 17 G 80·240 5-9 G >Con file. 5ervier 14 C 250 G >A

3 A 500

319

a Dosage was adjusted to obtain optimum contro l of blood sugar unless otherwise stated.

b > significantly better control of blood sugar; ~ better control of blood glucose; = equivalent control; < significantly poorer controlof blood sugar.

c Insulin-dependent diabetic patients.d Postprandial blood sugar.e Control group were taking other oral hypoglycaemic agents.

Abbreviations: db = double-blind; co = crossover; ra = random allocation; G = gliclazide; B = biguanide; I = insulin; 5 = sulphonylurea;P = placebo; T = tolbutamide; Gb = glibenclamide; C = chlorpropamide; A = acetohexamide.

Gli clazidc: A Preliminary Review 320

Fig. 9. Change in urinary protein excretion before and during

therapy with gliclazide 80mg daily in 10 diabetics with pre-existing constant proteinuria over a 9-month treatment period. The

data points indicate means of all values before treatment andall values during treatment for each patient (after Jones et aI.,1980).

c:.Qa;13xQ)

c'iiioa.~

'"c§

3

2

Beforegliclazide

During

gliclazide

with the control group (19%), after 18 to 32 monthsof therapy. In another small controlled study, retinopathy improved or remained stable in 11/12patients receiving g1iclazide 80mg daily for a 3-yearperiod and in 9/13 patients receiving glibenclamide 5mg daily (Minami et aI., 1981).

Kosaka et al. (1983c,d), using 3 methods ofevaluation of diabetic retinopathy in a 2-yeardouble-blind trial, found that the results of evaluation varied with the method employed, furtherillustrating the difficulties inherent in evaluatingthe effects of treatment on this condition. Thus,the rate of worsening of retinopathy was lower inthe gliclazide group (109 assessments) than in agroup receiving other sulphonylureas (177 assessments), or in a group treated with diet alone (120assessments) when estimated according to the severity of the disease, whereas no difference existedamong the groups when evaluation was by a pairedcomparison method. However , the rate of worsening of retinopathy as estimated by ranking ofphotofluorographic findings was higher in the gliclazide group.

4.4 Studies in Patients with DiabeticNephropathy

nopathy present at entry into the trial did not experience a deterioration of the disease over the 2.5year monitoring period (Lesbre et aI., 1977). Several recent controlled studies, some against othersulphonylureas, using multiple methods of assessment (e.g. retinopathy and fluorescein angiography) suggest a lesser progression of retinopathywith gliclazide in the short term (6 months) [Babaet aI., 1983; Chan et aI., 1982], and medium term(Cabral et aI., 1982; Charbonnel et aI., 1977; Kosaka et al., 1983; Lesbre and Canicave, 1977; Minami et aI., 1981 ; Regnault et aI., 1980). Charbonnel(1977) reported a significantly lower rate of deterioration in the gliclazide group (24%) comparedwith a control group receiving other hypoglycaemics (55%), as well as a significantly greater numberof gliclazide patients (43%) showing an impro vement in the status of their retinopathy compared

Diabetic nephropathy is a serious disorder carrying a high mortality. The earliest clinical indication is interm ittent proteinuria, which later becomes continuous and gradually increases inamount. Decline of renal function may not occurfor several years, but once it begins, end-stage renalfailure may occur rapidly. Gliclazide has not yetbeen studied widely in renal patients, initial studieshave been in patients with type I diabetes mellitus,but, since it is extensively metabolised and the metabolites have not shown any hypoglycaemic activ ity, it may be an appropriate choice if an oral hypoglycaemic drug is to be used in diabetic patientswith proteinuria or other early indications of renaldysfunction.

Mean urinary prote in excretion in 12 diabeticswith pre-existing constant proteinuria was not significantly altered during 9 months of treatm ent withgliclazide 80mg daily (Jones et aI., 1980) [fig. 9].


Similarly, in 15 patients with pre-existing mild proteinuria « 3g every 24 hours), who received glic1azide 80 to 240mg daily for 24 months, a significant reduction in proteinuria occurred (p <0.0I), whilst in those with higher levels of proteinuria no significant worsening was observed duringthe treatment period (Lagrue and Riveline , 1980).

5. Side Effects

At dosages used in the treatment of maturityonset diabetes mel1itus, gliclazide is well toleratedby the majority of patients. The most frequentlyreported side effects have been gastrointestinal upset, such as abdominal pain, nausea or vomiting,dizziness, skin reactions , and symptoms of hypoglycaemia which in most cases have been the resultof overdosage or inadequate diet rather than an adverse effect of the drug.

Of 727 patients included in studies of metabolicand haemodynamic effects (unpublished data onfile, Servier), adverse effects occurred in 7.6% ofpatients. Gastrointestinal disturbances accountedfor 1.7% of adverse effects and necessitated withdrawal in 5 cases, while skin reactions occurred in0.7% of patients and required withdrawal in 3 cases.

9

8

7

6

</l 5EQl 4iiia.'0 3;;;

2DE:JZ 1

+20 + 15 + 10 +5 0 -5 - 10 - 15 - 20

Fig. 10. Distribution of percentage change in weight after 1 year

of gliclazide therapy in 50 diabetics (0 = females; • = males)[after Radic et aI., 1980).

321

5.1 Hypoglycaemia

Symptoms of hypoglycaemia have been reported by several investigators (Charbonnel, 1980;Forette, 1977; Lagrue and Riveline, 1980; Masbernard and Portal, 1972; Shaw et aI., 1980; VillegasCinco and Fernando , 1978; unpublished data onfile, Servier). Of the 727 patients included in studies of metabolic and haemodynamic effects (unpublished data on file, Servier), hypoglycaemia or'apparent hypoglycaemia' occurred in 5.2% (38) ofpatients, but in most cases was corrected by dosagereduction. Only 3 patients required termination ofthe drug due to hypoglycaemia.

5.2 Weight Change

Most studies reported no significant overallchange in weight of patients whilst taking g1iclazide(Asmal et aI., 1980; Baba et aI., 1983; Bodansky etaI., 1982; King et aI., 1977; Lagrue and Riveline ,1980; Lesbre and Canicave, 1977; Stephan et aI.,1980). However, some authors (Almer et aI., 1983;Charbonnel , 1980; Donnet et aI., 1982; Forette ,1977; Oli, 1980) have reported a significant weightloss in obese patients after treatment with g1iclazide for periods from 6 months to 4 years. Normalweight patients did not experience a significantchange in weight (Charbonnel , 1980), whilst thosebelow average were shown to gain weight after 10months of gliclazide therapy (Forette, 1977). Thedistribution of percentage change in weight after Iyear of gliclazide treatment in 50 diabetics is shownin figure 10.

5.3 Laboratory Test Abnormalities

Apart from I or 2 isolated cases of raised concentrations of AST and/or ALT (Asmal et aI., 1980;Masbernard and Portal , 1972) no significant alteration of hepatic function has been reported. Bloodurea nitrogen levels have been reported to be bothincreased (Villegas-Cinco and Fernando, 1978) anddecreased (unpublished data on file, Servier). Similarly, both significant increases and significant decreases in eosinophils have been documented as


well as decreased red and white blood cell countsin different trials (Baba et al., 1983; unpublisheddata on file, Servier). However, the clinical importance of these changes is questionable as theyhave not yet been supported by other studies . It isbelieved that in some of the studies the haematological values were distorted on entry into the trialby subjects with unusually high or low counts, sothe significant changes brought the values to withinthe normal range of these subjects. Gliclazide wasshown to have no effect on thyroid function in 15diabet ic patients given 160mg for 6 months (Tourniaire and Orgiazzi, 1980).

6. Drug Interactions

Although drug interactions with gliclazide havenot been systematically studied, many drugs havebeen co-administered without the need to altertherapy (Campbell et al., 1980; Charbonnel, 1980).As gliclazide is highly protein bound and has arelatively small volume of distribution, drugs thatdisplace gliclazide from its binding sites on plasmaprotein may temporarily increase the concentration of unbound drug and theoretically could causehypoglycaemia. Therapeutic concentrations of aspirin, phenylbutazone, and sulphafurazole (sulfisoxazole) displace gliclazide from human plasmaand increase the free drug concentration from 3%to 5-8%, but other highly bound drugs includingwarfarin, chlorthiazide, clofibrate and chlorpropamide do not significantly alter the extent ofbinding of gliclazide (Campbell et al., 1980).

Drugs which may inhibit the metabolism of gliclazide in the liver could result inhypoglycaemicepisodes as has occurred with other sulphonylureasadministered with drugs such as chloramphenicol,dicoumarol ,sulphaphenazole, phenylbutazone, oxyphenbutazone or clofibrate. As monoamine oxidase inhibitors have been shown to stimulate insulin secretion in animals, hypoglycaemia could result from their concomitant administration withgliclazide. Aspirin (200 rug/kg orally), phenelzine(15 mg/kg intramuscularly) and phenylbutazone(100 rng/kg orally) all prolonged the hypoglycaemic effect of gliclazide (25 rug/kg), but did not

322

significantly alter the magnitude of the responsewhen studied in rabbits for 24 hours (unpublisheddata on file, Servier). On the other hand , a druginteraction with imidazole type antifungal drugs(miconazole, econazole, clotrimazole and ketoconazole) was reported with sulphonylureas and gliclazide (Niemegeers et al., 1981; Loupi et al., 1982;Meurice et al., 1983). Intolerance to alcohol mayoccur in some sulphonylurea-treated patients. Thiseffect has been reported in 1 patient taking gliclazide (Canivet, 1972).

{j-Adrenoceptor blocking drugs may mask thesigns of hypoglycaemia and possibly inhibit gluconeogenesis and may be a problem particularly inpoorly controlled cases. Propranolol (1.0 rug/kg)promoted the recovery from the lowered blood glucose induced by gliclazide (1.0 mg/kg) in rabbits(Maekawa et al., 1978a).

Diminution of the hypoglycaemic action of thedrug may occur with the concomitant administration of thiazide diuretics, corticosteroids and oestrogens.

7. Dosage and Administration

Gliclazide, as with other sulphonylurea drugs,is indicated only in maturity onset stable diabetes,where dietary modifications fail to control hyperglycaemia and glycosuria. Gliclazide is not effective in insulin-dependent diabetics, and so is notindicated in juvenile diabetes mellitus.

The recommended dose in newly diagnosed diabetics is to begin with 80mg daily with breakfast,and increase by 40 to 80mg as required in singleor divided dosage to a maximum of 240 rug/day.However, in therapeutic trials, therapy was oftenstarted at a lower level of 40mg daily, and in somecases a total daily dose of 320mg (as a single ortwice daily dose) was needed before patientsachieved satisfactory control (see section 3.1). Nosignificant differences in blood sugar levels, andquality of blood sugar balance, were seen in 21 diabetics given gliclazide either once or twice a day(Schrub et al., 1972), suggesting that a convenientonce daily dose schedule may be appropriate in atleast some patients .


Dose titration starting from 80 to l60mg daily,depending on the severity of the diabetes, is recommended when substituting gliclazide for otheroral hypoglycaemic agents.

If adequate control of hyperglycaemia is notachieved with dietary measures and maximumdosage of gliclazide, the response has been improved in a number of patients by the concomitantadministration of a biguanide. The dosage of thebiguanide should be adjusted gradually until control is achieved .

8. Place of Gliclazide in Therapy

In open trials, glicazide reduced blood sugarlevels to normal in newly diagnosed patients withmaturity onset diabetes failing to respond to dietary measures alone, and maintained or improvedcontrol in patients previously managed on othersulphonylureas or biguanides. Gliclazide has beengenerally well tolerated, the most frequently reported side effects being gastrointestinal in nature.Although there were differing reports, and reportedexperience in formal studies is limited, most observers noted that gliclazide did not seem to giverise to an increase in weight, did not alter renalfunction when administered to a small number ofpatients with diabetic nephropathy and generallydid not change or in a few cases significantly decreased plasma levels of cholesterol, triglyceridesor free fatty acids, thus seemingly avoiding whatcan sometimes be undes irable effects with otherhypoglycaemic agents.

Comparative trials, not surprisingly, suggest thatgliclazide likely controls blood glucose levels in appropriately selected patients as effectively as otheroral hypoglycaemic drugs. Thus, particular interestwith gliclazide is related primarily to its effects onthe blood. Some data from animal studies , andstudies in patients with diabetic retinopathy, suggest that the effects of this drug on platelet aggregation and haemostasis may possibly be beneficial,reversing or at least slowing progression of retinopathy . In the cases where other hypoglycaemicagents were also tested for these properties theywere generally found to be less active , or in some

323

cases inactive. Quite clearly, any oral hypoglycaemic drug which could be shown with certaintyto halt or reverse diabetic retinopathy would be amajor advance. However, further evidence is required to confirm any clinical benefits of the effects of gliclazide on the blood in the long term,and to show more clearly whether any such clinicalbenefits are unique to gliclazide or also occur withother oral hypoglycaemic drugs.

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Auth ors' address: Barbara l lohnes. ADIS Drug Information Serv

ices. P.O. Hox 34-030. Birkcnh cad, Auckland 10 (New Zealand).

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