survey it would appear that the melanotic lesion plus the is said to be a female predominance of 52% to 48% melanotic blush was often surrounded by grade 11 pig- male. Figures of the sex incidence h Rhodesia are not mentation. available but it would appear that it is in fact predomi- In the present survey it would appear that there is a nant in the male. higher incidence of pigmentation of the sole of the foot in the African patients seen at Harari Hospital but that the SUMMARY incidence of grade III corresponds closely to that found The incidence of pigmentation of the sole of the African foot by Lewis. This is particularly true of the age-group of as seen at Harari Hospital, Rhodesia, is studied. There is a 10 years and over and certainly if only the age-group higher incidence of pigmentation in the African foot com- 20 years and over is examined. pared with the figures given in Uganda but there is a close relationship between the grade lII pigmentation as quoted by The fact that malignant melanoma occurs more com- Lewis and as observed in the present survey. The occurrence monly on the sole of the foot in Uganda and Rhodesia of malignant melanoma in a foot with grade I1 pigmentation has been variously ascribed to trauma, to hot iron instru- is noted and the relative lack of pigmentation in the feet of ments used on the sole of the foot, to exposure within young children is confirmed. It was, however, noted that there was one foot with grade 111 pigmentation in an infant under smoky huts over many years, to crab yaws and even to one year of age. Possible causative factors are examined and possible action of ultraviolet light. Certainly trauma in it would appear that, whatever the initiating factors might be, those people who do not wear shoes particularly in youth Lewis's postulate of ectopic, potentially unstable collections of and adolescence would appear to be a factor in produc- melanocytes seen in the sole of the foot may be the basic tion of malignant melanoma. The lesion, however, usually reason for the incidence of malignant melanoma in this site. appears after the age of 30 and is most common in the We wish to thank the Secretary for Health for permission age-group 40 years and over. The incidence of malig- to publish this paper; and the Consultant Staff, Harari Hospital, nant melanoma in relation to other cancers as given by for permission to examine their cases. Ross4 is 2.9% of all tumours. He also states that it is 14.3% of all skin tumours on the sole of the foot and REFERENCES 3.6% of all skin tumours at other sites. Various figures 1. Lewis. M. G. (1967): Brit. J. Cancer. 21, 483. may be quoted in comparison, such as the South West of 2. Becker, quoted by Lewis, M. J. (1948): Ann. N.Y. Acad. Sci., 4, 82. England Cancer Registry where there is an incidence of 3. Butterworth, T. and Klauder, J. (1934): J. Amer. Med. Assoc., 102, 1.7 / 100 000 and Uganda where the incidence is 1-41100 000, 739. but in certain regions this may rise to 3-8/100 000. There 4. Ross. C. M. D. (1967): Cent. Afr. 1. Med.. 13. 107 and 139.

. . POSSIBILITIES OF MODERN ORAL DIABETES THERAPY* I PLATOY~TRJDE? D~partrnentof Internal Medicine, Bethesda-Hdspital, Duisburg, Germany

,-A ? 1- - The usefulness of oral antichabitis therapy in the aged 100 o,p,T.. diabetic is well known, and this form of therapy is indis- 0 1 / . HB &~~*-ronnn~rot~onm blood pensable if difficulties exist in connection with insulin P! .._ application; for example, due to defective vision, intellec- tual disturbances and manual clumsiness. This article deals with problems and possibilities of oral therapy, especially with the new sulphonylurea preparation gliben- clarnide (HB 419), and also with the combined therapy with biguanides in patients whose diabetes is refractory to treatment with either of the compounds alone. Bander and colleagues' in 1966 described the hypoglycaemic Glucose - concentration in blood r I effect of glibenclamide. We wish to point out the pecu- p------liarities in the mode of action and in the clinical effect - f of HB 419, as demonstrated by several investigators and by ourselves. t STUDIES ON THE SULPHONYLUREAS time (hl The correlation between blood level of sulphonylurea and Fig. I. HB 419* and glucose concentrations in blood after - 6l00d sugar decrease demonstrated earlier exists also for giving different doses and samples by mouth.2e glibenclamide, as Shnidt and Fa have shown. We deter- mined blood levels and urinary excretion of "C-labelled ing to the amount of HB 419 administered, the maximum HB 419 in healthy subjects after a single oral dose of HB 419 concentration in the blood was reached after different samples of the drug at various dose levels (Fig. 1). 4 or 6 hours, depending on the dose. The peak coincided Blood glucose was determined at the same time. Accord- with the minimum blood sugar concentration. The de- layed blood sugar fall in our experiments by comparison *Paper presented at the of the Society for Endocrinology. Meta- with that found by other investigators is explained by bolism and D~abetesof --Southern Afnca, Cape Town. 23 September 1970. S.A. MEDICAL JOURNAL 23 January 1971

the fact that we used the Gerritzen-method, giving two several /?-cells with concentration of secretory granules biscuits hourly from 7 a.m. to 4 p.m. along the plasma membrane. All these described altera- As in the treatment with carbutamide, tolbutamide and tions are morphological signs for release of insulin from chlorpropamide, the mechanism of action is based on the /?-ceus. influence on the P-cells of the islets of Langerhans with Much work has been done in order to study insulin the release of stored pancreatic insulin. This is demon- secretion following administration of tolbutamide and strated by the increase of plasma insulin following ad- glibenclamide and glucose in diabetic and non-diabetic ministration of sulphonylureas (Fig. 2), and by typical human subjects." Fig. 4 shows the differences between morphological changes with pronounced degranulation blood sugar decrease and the rise in insulin serum after of the cells. Bander et al.' have recorded convincing the administration of tolbutamide and glibenclamide. In light-optic-morphological pictures. These studies have re- contrast to the observations made with tolbutamide, HB cently been extended to ultramicroscopic investigation~" 419, injected three times within 3 hours (Fig. 5), has no and to studies on isolated islets." In the rat, diminishing effect on the insulin secretion after the i%st two injections; after, the third, the insulin secretion is Maturity-onset Juvenile reduced, but not significantly. The combined HB 419 - glu- Normals (6) cose injection leads to an enormous release of insulin.

1 g TOIBUTAMIDE I .V. -

% BG DECREASE

1 9 TOIBUTAMIDE I .V. - 0' 30' 60' 90'0' 30' 60' 90'0' 30' 60'time lmg HB 419 I.V. --- N/ml I Fig. 2. Mean of insulin-like activity levels in diEFerent groups of human subjects after tolbutamide (Orinase) 25 mg/kg intravenously. (Pfeiffer et al., 1959).

I rnin 0 5 15' 30. L5 60 90 120 Fig. 4. Effect of intravenous tolbuta- mide and HB 419 on blood glucose (BG) and serum insulin4 OMI) in normal subjects (n = 15).

Fig. 3. Left: Survey view of islet of Langerhans in a normal rabbit. Alpha- and pcells are in close relation to the capillaries. Right: Degranulation of several p-cells in an islet of a rabbit treated with HB 419. Note the concentration of secretory granules along the plasma membrane (arrows) magnification 4375 x .I4 degranulation of &cells and enlargement of Golgi com- plexes become apparent only after application of 10 or 20 times the minimal effective dose of HB 419. In the rabbit, the application of twice the minimal effective dose Fig. 5. Dynamics of insulin secretion after repeated ieads to &&cant degranulation, which becomes manifest intravenous doses of HB 419, glucose, and HB 419 f after 24 and 48 hours. Fig. 3 shows degranulation of glucose m normal subjects (n = 6)'' 23 Januarie 1971 S.-A. MEDIESE TYDSKRIF 93

Three patients, in whom tolbu:amide had practically no the first injection was seen after HB 419. It is worth effect on the insulin or on blood sugar levels, showed with while mentioning that thi new substance has also a HB 419 a release of insulin and a decrease of blood sugar marked effect in regard to the fat metabolism: we could (Fig. 6). An additional dose of 50 g carbohydrate given demonstrate (Figs. 8 and 9) after HB 419 administration a orally -f-hour before the HB 419 injection intensifies the significant reduction of free fatty acids and glycerol as insulino-tropic effect. Finally, the repeated injection of signs of an antilipo!ytic insulin effect. while the choleste­ tolbutamide at 4-hour intervals in diabetics (Fig. 7) causes rol did not show any changes.'" only a very slight increase in insulin and practically no The results on the dynamics of insulin secretion in decrease in b~ood sugar, whereas an increase in insulin diabetic and non-diabetic humans were extended by and decrease in b~ood sugar to the same extent as after Fussganger er al. of the Pfeiffer group.' These were also confirmed by comparative studies on the perfused isolated

% sG DECREASE rat pancreas and the perfused isolated pieces and islets ~j(JNaCI FOLLOWIN~ of rat pancreas (Fig. 10). Perfusion with low glucose ° SOLUT.I.V. concentration, to which sulphonylureas were added. re­ -'------,J"'iLBC~T:;.~DE -10 .,...:::::::::::.:::<:_ I.V. sponded to tolbutamide with a rapidly occurring peak in insulin secretion, subsiding despite addition of tolbuta­ " " mide to the perfusion medium; HB 419, on the other -20 " ". hand, induced a more sluggish and lower but persisting ", ". lt1 and increasing enhancement of insulin liberation. These -30 ..... -···.HB 4191.V. '- findings were interpreted as indicating a qualitatively ". rather than quantitatively different ,B-cytotropic action of "'. j(J tolbutamide and HB 419. They are similar to the diffc- '·... HB 419 I.V. FOLLOWING -so 50g CH p.a. IMI ° 5 15 3 ~U/ml Glucose FFA 30

20 ~ With HB419 10~--" TOLBUTAMIDE Hs 419 I.V. HB 419 I.V. NaCl SOLUTION IT2J Without HB419 I.V. FOLLOWING I.V. FOLLOWING 50g CH p.a. 50g CH p.a. Fig. 6. Blood. glucose (BG) and serum insulin OMl) in adult-onset diabetics (n = 3) after intravenous injection of tolbutamide, HE 419, and HE 419 preceded by oral intake of 50 g of carbohydrates."

1 9 tolbutamide Lv. ­ i ::: l 1mg HB 419 i_ v_ •••... j ":;: Blood sugar reduction (%) } :~: ::11 o -- fl .. ~ 14 I l--·r·_~. 16 17 19thrsl -10 ~ Fig. 8. Changes in the metabolites, glucose and free -- 1\ ,0_005 fatty acids, before and after administration of HB 419." -20

-30 \{ Cholesterol Triglycerides F-Glycerol

" , , I , , I ! min 0 S 15' 30' 4S 50' go'o S' 15' 30' 4S 50' 00' ~ ~ ;;-: with HB419 E ~ Without HB419 300 300 1 5 IMI pUlml I=SEM 1 9 tolbutamide i. v. ­ 1mg HB 419 i. v. - ZOO

~Il .J--• .-1-. -_ 1.---f ···f-'-'1- -1---. :1 ------I :~ ::~.:i~J ,i I~ lal j 1 '-·-·f Jo' 100 .: ::1 r1J ~~u 100 ~_!: ~: ~ 0,5 ~.! ~ j ) ~::: ~::: ~::I ra::; ~::! ~::; ~::; %: ~% ~% ~J ~ ~::i ~::i ~::; ~::: ~::: ~::: %0::; %:: ~::; ~::; ~::l min 0s,,s. 30' ~ 60- gQ'~ s,s. 30· ~ So' go' ~::I ~::! ~::j ~::[ ~::: ~':: ~:j ~:[ ~::: ~::: ~··i Fig. 7. Changes in blood sugar and serum insulin after 14 16 17 19 14 16 17 19 14 16 17 two intravenous injections of tolbutamide or HE 419. 4 hours apart, given to IO maturity-onset diabetics of Fig. 9. Changes in cholesterol, triglycerides and glycerol normal body-weight." before and after administration of HB 419." 94 S.A. MEDICAL JOURNAL n January 1971

rences seen with the two sulphonylureas on both plasma 1,0g tolbutamide i.v. 2,Omg HB 419 i.v. insulin and blood glucose as mentioned before. , 100 100

11011 100mg/l00ml glucose 15.5 mM) 15 (u U/mln) 'll!lillunnrrnuulmmm nmm1111I mnITIllHi IIIUJIDTI mUlJ> 15 500 TolbutamIde 500 Llg/min 50 50 .A H8419 2.1 "g/mon 400 I\ 15 \ 15 ~ I~ '-. )00 "U/m I "U/m ~ IMI IMI -150 60 110 110 -15 0 60 120 1III mir,utes minutes 10 tests 10 tests 100 Fig. 12. Serum insulin curve after intravenous injection of I g tolbutamide and 2 mg HB 419."

)0 40 SO 60 70l lin secretion following glucose loads was studied by Chan­ time/min dalia and co-workers' in 4 maturity-onset diabetics (Fig. Fig. la. Effect of tolbutamide 500 Ilg/min and HB 419 13). The 'lag phase' of insulin secretion was not corrected (glibenclamide) 2·5 Ilg/min on insulin secretion by the isolated perfused rat pancreas. Basal glucose concentration 100 mgflOO ml, 5·5 mM! rzlJ BEFORE HB 419 (4 PTS.) CJ 4th wk. of HB 419 (4 PTS.) Otto" has compared blood glucose and plasma insulin _ 4th moo of HB 419 (2 PTS.) (lM!) levels in 10 healthy subjects after oral or intra­ E 3- 150 venous administration of HB 419 and tolbutamide. In ~ Z Fig. 11 the two values are shown after oral administration :; ::::l 100 of HB 419 solution: the fall in blood sugar follows 10 - 20 VI minutes after the changes in insulin level. After intra­ ~ venous injection of 2 mg HB 419 or 1 g tolbutamide the ~ 50 blood sugar fall is the same as before; only the action ""w of glibenclamide is slower and more prolonged. The serum VI t.~ curves after intravenous application of 1 g tolbutamide BLOOD lIt! 207 351 359 335 308 and after 2 mg glibenclamide (Fig. 12) show striking GLUCOSE 110 145 245 249 227 182 (mg %) 90 233 299 311 283 157

MINUTES 0 15 30 60 90 120 HB 419 or tolbutcmide i.v. 180 I Fig. 13. Mean blood glucose and serum insulin levels during oral GIT befor<: ::nj after HB 419 therapy.T "i'1'I . ~ I i r following HB 419 therapy. The highest insulin levels were I tolbutamide I attained at 90 or 120 minutes during oral glucose-tolerance tests before as well as after HB 419 therapy. The glucose "I tolerance improved in all patients following therapy. The J,lU/ml mg/l00 ml"HE'jI insulin levels after oral GTT increased during the fourth IMI glucos. week and fourth month of therapy. Jackson13 has shown 1\ 0 110 lao -1~ 0 50 110 181 minutes " minutes similar results with chlorpropamide. 10 ;rsh 10 tests t!Oc:n 1ndications Fig. lJ. Blood glucose and plasma insulin after oral and Having discussed this interesting new substance from intravenous administration of tolbutamide or HB 419." the pharmacological and clinical point of view, we are now going to deal with some special therapeutic pro­ differences between the substances: the peak rise in insu­ blems connected with sulphonylurea therapy. First of all lin concentration after tolbutamide is reached 1 minute the question arises, of course, under what circumstances after the end of the intravenous injection; after HB 419 the application of the new sulphonylurea substance is the insulin discharge is slow, sustained and plateau-shaped, indicated. We feel that some failures' and disappointments closely corresponding to the fall in blood sHgar. Also, experienced initially were due to wrong indication and the two substances cause vigorous discharge of insulin premature application. In view of our own experience from the pancreas, but there are clear-cut differences in of It years and the general opinion held today, the dia­ the timing of the response. betic who is in good control with the conventional sul­ The effect of prolonged glibenclamide therapy on insu- phonylureas should be left for the time being on this 23 Januarie 1971 treatment. The decisive factor is that the criteria demanded TABLE 11. DRUGS PROLONGING HALF-LIFEOF TOLBUTAMIDE' for oral therapy--excellent or good controlare attained Half-life (Table I)." before Half-life drug prolonged to (hours) Drug combined with tolbutamide (hours) References 8 SulDhanhenazolc 1 eldav 24 1 TABLE I. CRITERIA FOR DEGREE OF CONTROL 5-6 Sulihaihenazole 2 g/d& 4 Sulphadimethoxine 2 g /day 2 1Dubach ef UL 7 Sulfisoxamle 2 glday 7 Blood sugar 4 Sulphaphenazole 2 g/day 17 Christensen (true glucose) 6h Dicoumarol (olasma level 1-2 UE /ml) 18 1 Control (mg/100mI) Glucosuria/24 h d Dicoumarol hasma level 1.2 10 I 3'3 Dicoumarol &asG level 1-2 Lilmlj 10 Christensen & Excellent 4t Dicoumarol (plasma level 1.2 pglml) 17 M@lholm Fasting 100 5 Dicoumarol (plasma level 108 wz/ml) 24 Hansen 1st hour postprandial 150 Neg. 6+ Dicoumarol Cplasma level 10.8. iglml) 25 2-8 Dicoumarol (plasma level 10.8 pglml) 17-6 1 2nd hour postprandial 130 11.6 Dicoumarol 50 meldav 2 1 Good -.- Fasting - - - 100 mg 3 X day E6 }Solomon I st hour postprandial g 3 X day 17 2nd hour postprandial g 3 X day 22 Fair Fasting TABLE 111. TOLBUTAMIDE HALF-LIFE IN BLOOD BEFORE AND AFTER 1st hour postprandial TREATMENT wm~DIFFEREM DRUGS= 2nd hour postprandial Poor Half-life of tolbutamide (hours) Fasting 220 No. of - 1st hour postprandial 280 Up to 30 g persons Before During 2nd hour postprandial 250 Drug tested tested treatment treatment Sulphaphenazole 4 33 22 In view of what you have heard to date about the Methylsulphaphenazole 5 43 37+ Ethylsulphaphenazole 5 43 3% pharmacology of glibenclamide, it is justifiable, however, Phenylbutazone 6 44 to carry out a therapeutic trial with this substance in all Oxyphenylbutazone 5 43 14 cases where the patients are no longer optimally con- Sulphadiazine 4 5t trolled on the therapy currently applied. In such cases, Sulphadimethoxine 5 ? Phenazone 3 43 ;* one should start with a dose of 5 mg. The impression Aminophenazone 2 43 53 that has been gained is that more maturity-onset diabetics, Dicoumarol 8 5 12 whose management is the domain of the sulphonylureas, Phenindione 3 5t - can be successfully treated with the new product than with earlier sulphonylureas. Generally, we prescribed UP the half-life times, which is in part quite considerable to 10 mg glibenclamide (2 tablets) to be taken in a single when tolbutanide is used. dose in the morning. Only if a dosage of 15 mg was Shock symptoms do not diier from those arising from necessary for the control and compensation of diabetes, the use of long-acting insulin, but the hypoglycaemic was a third tablet administered in the evening. effect is considerably longer in duration and can vary _Y from hours to several days. Hence a condition of shock Side-Effects may occur even after sulphonylurea treatment has been Let us now take a look at the problem of the side- withdrawn and patients must be kept under careful obser- effects af sulphonylurea therapy. We know that with the vation for several days after the first shock event. The substances formerly used these amounted to between 2 hypoglycaemic reaction is very frequently associated with and 3%, and consisted in the main of allergic skin reac- neurological focal symptoms, sometimes arising as a tions, and, less frequently, of intestinal complaints. Some- transient hemiparesis which at first resembles that of a times there may be considerable and prolonged hypogly- cerebrovascular attack, and causes delay in the initiation caemias, for instance in patients with renal insufficiency of correct therapy. that results from delayed excretion and accumulation of For the study of the side-effects following glibencla- the substance in the organism.= Also serious consuming mide administration, Retiene et aZ.= from the Schoffling Processes with glycogen depletion of the liver, such as clinic carried out extensive investigations basec! on blood her cirrhosis, adrenal insufficiency and ~ostoperative picture controls, etc., effected during an 18-month period. stress, encourage the development of hypoglycaemia. None of the patients developed incompatibility or toxic Moreover, alcohol can have the effect of promoting hypo- side-effects due to the drug (Fig. 14). glycaemia if sulphonylureas are taken at the same time, which, in connection with tra0ic accidents, for instance, Secondary Failures may be of great significance. The principal reason for their occurrence is, as is known, One extremely important factor is to be found in the that the insulin content of the pancreas diminishes in the fact that serious hypo&caemias during sulphonylnrea course of life, and hence also the possibility of stimula- therapy may occur as a result of other medicaments ting the secretion of insulin by means of the sulphonyl- being administered simultaneously. These in turn have ureas. In connection with this, Balodimos et al.' have a hypoglycaemia-promoting action due to the fact that made an interesting contribution (Fig. 15). On the basis they considerably prolong the half-life time of the sdph* of a 9-year study with tolbutamide, they found that the nylureas (Tables II and m). These tables list a number proportion of secondary failures averaged 19.6%, and, of such substances and demonstrate a prolongation of from the second year on, accounted for approximately 96 S.A. MEDICAL JOURNAL 23 January 1971

~ so BIGUANIDES Biguanides differ completely in -their mode of action from sulphonylureas and certainly represent a true extension to I I I I the scope of diabetes therapy (Fig. 16). Beckmann" has

2-3 4-6 7-12 13-18 months 126 /_3 147 133 97 CH)- CHZ- CHZ- CHrNH- C- NH - C- NH 600~ 'h.....bocyt.. Z ~ooo I I I I 11 11 ::zoo 000 I NH NH ":"'be":"'r.,-,...., tr-eot-men-'~2~-3---4""-6---7--1-2---1"'3:""18-mon-th. "=141 112 126 125 101 NL (n- Butyl) biguonide ( Buformin) -~ '0"' 0- CHrCHz-NH-C-NH-C-NHZ I I I 11 11 j ~~- ,~ NH NH 4-6 7-12 13-18 fTCInths mu/ml... n=]54 128 133 140 105 NL 10 - Phenethyl) biguonide j.~"- (Phenformin) 1 T 1 1 r CH) _~~,--, ~ N- C-NH-C-NHZ : :, 4-6 13-18 mont~ CH) "=151 131 131 105 a 11 Fig. 14. Mean values of leucocytes, thrombocytes, alkaline NH NH phosphatase and SGPT throughout an 18-month clinical study with glibenclamide.'" Nl, NL Dimethylbiguonide (Metformin ) Fig. 16. The formulae of buformin, phenformin and ~ SECONDARY FAI LURE metformin. • CONTINUOUSLY en 500 shown that the effective dose of buformin is 2 mg/kg I- SATISFACTORY CONTROL Z that of phenformin is 1 mg/kg and that of metformin i­ w 20 mg/kg. He also demonstrated that the hypoglycaemi. ~ 400 « action of these substances differs widely between differen a- animals and that the dose that reduces the blood suga u.. 300 0 by 50% in animals is almost identical with the LD. Suicide attempts have indicated that humans can, in COD­ Cl<:w cc 200 trast with animals, tolerate more than 20 times the ther<>­ ~ peutic dose and this is yet another instance where th." ::::> results of animal trials do not correlate well with resuJ', Z 100 achieved in man. The essential difference between the metabolical" o healthy subject and the diabetic is set out in an artic~ 2 345 678 9 by Madison and Unger,'· in which the effect of phenfc ­ NUMBER OF YEARS OF TREATMENT min on the glucose concentration in the arterial ar:l Fig. 15. Number of patients with continuously satisfactory venous blood of diabetics and healthy persons is COl ­ control and secondary failure in each year of tolbutamide pared and no effect is seen in healthy persons (Fig. 1 ). therapy.' It is of particular interest that biguanides improve gluc._ c utilization, i.e. increase sensitivity to insulin, despite a one-quarter of all patients treated. The statistics further­ reduced plasma insulin concentration; this is in dir·;t more very clearly show the progressive decline in the contrast with sulphonylureas. Evidence of this is gi\ n number of optimally controlled diabetics in the course in the next two illustrations. In Fig. 18 Grodsky <. d of the years. co-workers" have demonstrated the effect of phenfon 'n The combination of sulphonylureas with insulin should on _the blood glucose level and immuno-reactive ins' n be restricted to individual cases. Additional doses of in 4 obese maturity-onset diabetics after an oral glue ;e sulphonylureas may undoubtedly give rise to an increased load of 50 g. Before the second load the patients recei :d endogenous release of insulin, also in the case of diabetics 10 times 50 mg phenformin-retard at 8-hourIy intervals: le treated with insulin, so that the exogenous administration blood glucose and the IRI declined during biguanide th a· of insulin can be reduced. The combined therapy of sul­ py. In a subject with a strong family history of diab es phonylureas and biguanides will be discussed later. (Fig. 19) levels of circulating insulin were noted , er 23 Januarie 1971 administration of glucose by mouth, despite the presence of glucose administration were all loweied. a normal glucose-tolerance curve. After treatment with Berger et aL6 showed that 11 patients who had received phenformin, levels of serum 'insulin subsequent to oral a 7-day preliminary treatment with phenformin ~erformed better in a glucose-tolerance test after a 100-g glucose -ortrry load des~itea lower plasma insulin concentration. Thus c----o vein biguanid& improve glkose utilization through increased sensitivity to insulin. Other explanations of the mode of action of the biguanides are an impairment of intestinal glucose absorption8 and inhibition of glu~oneogenesisby \03 the liver. 5 11D- -.L diabetic subjects I The importance of biguanides in monotherapy and com- W 'v I bined therapy is largely due to the work of Mehnert.".'" 2 110- U Monotherapy with biguanides can occasionally bring good 2a * ID$- metabolic control in overweight maturity-onset diabetics. 0 Additional biguanide therapy should, however, certainly 0 & so- be attempted particularly for those patients in whom sulphonylureas are no longer achieving adequate meta- ID- bolic compensation. Biguanides extend the scope of tw:, , I I , 1 I therapy quite considerably, and have spared many patients - 20 0 20 68 128 180 ZLO 300 360 min temporarily or permanently from the necessity of insulin Fig. 17. Effect of phenformin on the glucose concentration therapy. This has been recognized by the various phar- in arterial and venous blood of 7 diabetic and 5 healthy subjects." maceutical manufacturers who have developed drugs con- taining fixed combinations of both active substances. We 7 BEFORE PHEllFORMll AFTER PHEIFORUlY ourselves are now working with a combination of both glibenclarnide and phenformin as was described in 1969 by Schfieider at the International Tegernsee Conference.'' The great disadvantage of earlier biguanide preparations -their poor intestinal compatibility-has been largely removed through the development of long-acting prepara- tions and reduction of the single dose. Fig. 20 from the work of Mehnert and Krall" demori-. . strates the value of combination therapy in patients for whom diet or tolbutamide or Silubin alone were unsuc- cessful, the optimal result being only achieved with a combination of these three. Finally, two other opportuni- ties to use biguanides are worthy of note: in insulin resistance and labile diabetes, especially in young diabetics. Fig. 21 shows a case history of a patient receiving twice 60 units insulin per day and who had a urinary excretion of glucose of over 100 g/day and a b!ood sugar between

Silubin 300ma/dav

TlME AFTER GLUCOSE ADWIRISTRATIOII IRII) Fig. 18. The effect of phenformin on levels of serum insulin and blood glucose after oral ad- ministration of 50 g glucose to 4 obese maturity- onset diabetic subject^.'^

0 30 61 91 121 1 38 68 30 120 TlME AFftE GL8COSEA~~IIISTIATiOYlYlP I Fig. 19. The effect of phenformin on levels of serum insulin and blood glucost after oral administration of 50 g glucose to a non-obese, non-diabetic 'normal' male Fig. 20. Typical metabolism diagram of a patient on with a strong family history ol diabetes mellitus." combined therzpy with tolbutamide and biguanide." S.A. MEDICALJOURNAL 23 January 1971

REFERENCES 1. Ariens, E. J. (1969): Acta diabet. lat., 6, suppl. 1, 143. 2tabl. 3tabl. 3tobl. 2. Aumiiller V. W. B;inder A. Heerdt, R., Muth, K., Pfatf, .W., Silubin Silubin Silubin Schmidt,'F. H., 'weher. H. And Weyer, R. (1966): Arzneimxttel- Forsch.. 12, 1640. 3. Bander, A., Pfaff, W. and Schesmer, G. (1969): Ibid., 19, 1448. 4. Balodimos, M. C., Camerini-Davalos, R. A. and Marble, A. (1966): Metabolism. 15. 957. 5. Beckmam. R. (1968): Proceedings of the 2nd International Biguanide Sjmposium, pp. 3 - 12. Stuttgart: Georg Theme. 6. Berger, S:, Downey, J. L. and Traismau, H. S. (1968): Ann. N.Y. Acad. Sci.. 148, 859. 7. Chandalia. H. B.. Hollobaugh, S. L., Pennington, L. F. and Bosheli, B. R. (1969): Horm. Metab. Res., 1, suppl., 73. 8. Czyzyk, A. (1969): Acta diabet. lat., 6, suppl. 1, 636. 9. Fussganger, R. D. Gobema R., Him, M., Jaros, P., Karsten. C., Pfeiffer, E. F. and' Raptir, S'. (1969): Horm. Metab. Res., 1, suppl., 34. 10. Grodsky, G. M.. Karam, J. H., Pavlatos, F. C. and Forsham, P. H. (1963): Metabolism, 12, 278. 11. Hellman, B. and Hellerstrom, C. in Pfeiffer, 5. F. (1969): Handbook of Diabetes Mellitus, vol. I, pp. 89 - 118. Munich: J. F. Lehmanns Verlag. 12. Jackson, W. P. U. (1964): On Diabetes Me1Iitu.s. Springfield, 111.: Fig. 21. The effect of combining insulin and bdormin in Charles C. Thomas. insulin-resistant patients." 13. Jackson, W. P. U. in Campbell, G. D. (1969): Orat Hypoglycxemt 200 and 300 mg/ 100 ml. The additional administration Agents: Phmn~acologyand Therapeutics. London: Academic Press. of Silubin den normalized the metabolic condition, and 14. Kern, H. F., Kern, D., Schmidt, F. H. and Stork, H. (1%9): Horm. the insulin requirement fell back to 60 units per day." Metab. Res., 1. suppl., 11. 15. Kristensen, M. and Christensen, L. K. (1969): Acta diabet, lat., 6, Opinions are divided regarding the management of suppl. 1, 116. labile diabetics, but the smoothing effect of biguanides on the fluctuating blood sugar of such patients is very fre- 16. Madison, L. L. and Unger, R. H. (1960): Diabetes, 9, 202. quently observed, particularly in the early stages of treat- 17. Mehnert, H. (1963): 'Experimentelle und klinische Untersuchungen zum Wirkungsmechanismus und Indiationsbereich hlutzuckersenkender ment."*= Biguamddenvate', Habilitirtionsschrift, Miinchen. SUMMARY 18. Idem (1968): Proceedings of the 2nd International Biguanide Sym- The new sulphonylurea substance glibenclamide (HB 419) posium, pp. 173 - 180. Stuttgart: Georg Thieme. exhibits differences in its mode of action and its clinical effect 19. Mehnert, H. and Krall, L. P. (1960): Dtsch. med. Wschr., 85, 577. in comparison with the conventional sulphonylureas. A stimu- lation of the insulin secretion is even possible in healthy 20. Mu:ler, R., Bauer, G., Schriider, R. and Sato, S. (1969): Horm. subjects and diabetics in whom tolbutamide was found to have Metab. Res., 1, suppl., 88. a significantly diminished effect on blood sugar decrease and 21. Otto, H. (1969): In Tegerm-Konferenz iiber dm neue orde Anti- plasma insulin. Studies on perfused isolated pancreas and islets diabetikum HB 419. Frankfurt. Farbwerke Hoeshst AG and Boehringer in the rat, stimulated by tolbutamide or glibenclamide, showed Mannheim GMBH. different insulin release, and must be interpreted as indicating a 22. Petrides, P. (1966): Dtsch. med. Wschr., 91, 689. qualitatively rather than quantitatively different fi-cytotropic 23. Idem (1969); ,Diabetes Meltitus, pp. 229 - 232. Vienna: Ver!ag der action of these substances. Wiener Med~unischenAkadernie. The mode of application is discussed and reference made to side-effects, and, in particular, to factors that promote hypo- 24. Raptis, S., Rau, R. M., Schriider K. E. Faulhaber, J. D. and glycaemia; the significance of drugs which influence and pro- Pfeiffer. E. F. (1969): Horm. ~etad.Res., i, suppl. 65. long the half-life times of sulphonylureas is also mentioned. 25. Retiene, K., Petzoldt. R., Althoff-Zucker, C., Beyer, 1. and Schiiffling, Tha biguanides have a completely different mode of action to K. (1969): Ibid., 1, suppl., 55. that of the sulphonylureas, and certainly represent a true ex- 26. Schmidt H. A. E. and Petrides P. (1969): In ~e~ernsee-Konferen~ tension to the scope of diabetes therapy. The biguanides im- iiber d& neue orde ~ntidiabetkumHB 419. Frankfurt: Farbwerke prove the glucose utilization and increase sensitivity to insulin, Hoechst AG and Boehringer Mannheim GMBH. despite a reduced plasma insulin concentration. Other explana- 27. Schneider, T. (1969): Ibid. tions of the mode of action are an impairment of intestinal glucose absorption and inhibition of gluconeogenesis by the 28. Schrap:er, P.. Petrides. P. and Yazdanfar. A. (1969): Med. u. liver. The combined therapy of biguanides with sulphonylureas Emahr., 10. 120. extends the possibilities of oral diabetes therapy. 29. Schricker, K. T. (1964): Med. Bild., 6. 187

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