Jackson, W.P.U.

Vinik, A.I.

English

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1002 S.A. TYDSKRIF VIR GE EESKU DE 9 Augustu 1969-power: weight ratio to run a 4-minute mile at Johannesburg'saltitude of 5,784 feet above sea-level. In deciding whether theathlete is capable of running at the speed required for asufficient time, the extent of anaerobic metabolism he may incurmust also be considered. Details of such findings are given.At sea-level the maximum oxygen intake would increaseby about 12% on average and oxygen consumption at thedifferent speeds would decrease so that the percentage of themaximum the athlete would use when running at 15 m.p.h. atthe coast would be reduced markedly and he would run inles anaerobic metabolism.The results how how a scientific assessment can be madeof an athlete's ability to achieve world-class times in endurancerunning and are suggested as an aid in the selection of athletesfor competition in international events. This would be con-iderably less expensive than sending large teams of athletesthat are selected on the present hit-and-miss basis.We wish to tbank Dr C. G. Williams, now of the Universityof Cape Town, and Mrs M. J. von Rahden for their assi tancein carrying out these studies; and the athletes concerned fortheir willing co-operation. The Sugar Association of SouthAfrica defrayed certain expenses through its research funds.REFERENCES1. Strydom, N. B., Cooke, H. M., Miller, H. D. and Weiner, P. (1965):Int. Z. angew. Pbysiol., 21, 13.2. Wyndham, C. H., Strydom, '. B., Leary, W. L. and Williams, C. G.(1966): Ibid., 22,2 5.3. Wyndham, C. H., Strydom, . B., Von Rahden, M. J. E. andWilliams, C. G. (1962): ature (Lond.), 195, 1210.4. Wyndham, C. H. and Heyns, A. J. A. (196 ): Int. Z. angew. Physiol.,27, 51.5. Wyndham, C. H. and Ward, J. S. (1956): S. Afr. J. Med. Sci., 21,142.6. Benade, A. J. S.: Unpublished data.7. Holmgren, A., Mossfeldt, F., Sjostrand, T. and Strom, G. (1960):Acta physiol. scand., 50, 72.Leary, W. P. and Wyndham, C. H. (1965): S. Air. Med. J., 39, 651.9. Tanner, J. M. (1964): The Physique of rhe Olympic Arhlere. London:Allan & Vnwin.10. WilIiams, C. G., Wyndham, C. H., Kok, R. and Von Rahden, M. J.E. (1967): Int. Z. angew. Physiol., 24, 18.11. Wyndham, C. H. and Strydom, . B. (1969): S. Afr. Med. J., 43,893.12. Abrahams, A. ill RoUeston, H., ed. (1950): British Encyclopaediaof Medical Pracrice, 2nd ed., vol. 2, p. 302. London: Butterworth.PRELIMINARY TRIAL OF A POWERFUL NEW SULPHONYLUREA IN MATURITY·ONSETDIABETES-HB419 (GLffiENCLAMIDE)*W. P. u. JACKSO , M.A., M.D., ER.C.P. AND A. 1. VINIK, M.B., B.CH., F.c.P. (S.A.), Diabetes Clinic, GrooteSchwu Hospital and the Department of Medicine, University of Cape TownWe have several sulphonylureas from which to choose inthe treatment of maturity-onset diabetes. They all act bystimulating insulin output from the subjects' own pan-creatic beta cells. It is thus extremely unlikely that a newsulphonylurea will be found to be effective in a largeproportion of patients when others have failed, thoughcertainly some are more powerful than others--chlorpropa-mide is more effective than tolbutamide in some indi-viduals-and the reason for even this limited difference ineffectiveness is incompletely resolved. For a new sul-phonylurea to be justifiably placed on the market it musttherefore fulfil several criteria:1. It must be at least as effective as the most powerfulexisting drugs.2. It must be virtually non-toxic.3. It must be acceptable by reason of few and minorside-effects.4. It should not be liable to produce serious hypogly-caemia when correctly used.The compound HB419, glibenclamide, is a sulphonyl-urea with a long side-chain. Chemically, it is - { 4-(,8[2-methoxy-5-chlorobenzamidoJ-ethyl)-benzosulfonyl } -N'-cy-clohexyl urea. Its structural formula is shown in Fig. 1.ClQO_NH_OH,_OH,O ",-NH_OO_NHOOCHJFig. 1. Structural formula of glibenclamide.This drug is quite remarkably powerful on a weightbasis, being approximately 500 times as potent as tolbuta-'Date received: 19 February 1969.mide and at least 50 times as potent as chlorpropa-mide.'" This does not necessarily mean that it will bemore effective in the treatment of diabetes, but certainlya far smaller dose is required, and this fact might reason-ably be expected to reduce or abolish some of the toxiceffects pertaining to standard doses of other sulphonyl-ureas. In fact, toxicity studies by the makers have indi-cated that although the new side-chain has rendered thissulphonylurea much more potent it has not rendered itmore toxic, weight for weight, than previous drugs of thesame class.'" In view of the very much smaller dose re-quired, HB419 should therefore prove to be virtually safe,except of course that it will occasionally produce hypo-glycaemia. It has no antibacterial properties.The duration of effective action of HB419 is reportedas being longer than that of tolbutamide, about 8 hoursafter a 5-mg. dose, or over 12 hours with larger doses.'-3It is reasonable to suppose that a single daily dose willprove adequate to control the majority of sensitive dia-betics.Each tablet of HB4l9 contains 5 mg. Because of theinherent safety of the drug there is no particular maxi-mum dose level, but more than 4 tablets a day are be-lieved to be wasteful, while it is probable that more than2 will seldom be necessary.A small preliminary trial of this drug, ending April1968, wa carried out in Cape Town.MATERIAL AND METHODSSubjectsIn the Diabetes Clinic of Groote Sehuur Hospital weused HB419 in 34 diabetics on an outpatient basis. Wechose only maturity-onset diabetics, who had all failedto be controlled on diet alone, and who were all re-ceiving other tablets or insulin (one case) at the start ofthe trial. There were no 'new' cases-most had had dia-In a few cases it was possible to test the effect of takingthe daily requirement of tablets together in one dose. Therecommended time for single-dose therapy was midday,because breakfast is generally a small meal. In 2 instancestablets taken together did not produce as good a controlas when taken separately. .There were 9 patients whose diabetes was of over 10years' duration. Two achieved excellent control withHB419-in one case only after the addition of metformin:2 achieved good control and 4 failed.Combination with Diguanides'In 17 cases-i.e. exactly one-half the total subjects-it was necessary to add a diguanide to the HB419 in anattempt to improve control. The diguanide used was phen-formin (Insoral TD) in 15 cases, 2 or 3 capsules daily,and metformin (Glucophage) in 2 cases. Final results ofcombined therapy were 4 failed, 5 fair, 4 good and4 excellent.One White woman, aged 65 years, had mild ischaemicheart disease and diabetes that had been present for morethan 10 years. Five different sulphonylureas, includingHB419, produced no more than a poor 'fair' response.The addition of metformin, 3 tablets daily, to 4 HB419tablets led to an 'excellent' response.Toxic EfJectsThere were no toxic effects to HB419. Side-effects werefew. One patient complained of headache, and one offatigue and abdominal pain which did not necessitatestopping the HB419~the relationship of these complaintsto the tablets was considered doubtful. (See case 2, below.)No significant effect in 34 cases was noted on haemo-globin, total white cell count, platelet count, serum bili-rubin levels, alkaline phosphatase, SGOT or cholesterol.In 8 cases no effect was seen on blood-urea levels, serumsodium, potassium, chloride, uric acid, thymol turbidity,zinc sulphate test, total proteins or albumin level. In 3cases the serum amylase levels remained virtually un-changed.In addition no significant change was seen in body-weight. Hypoglycaemic symptoms were not encountered.Proteinuria was not seen unless already present.S.A. MEDICAL JOURNAL 10031.'III3I27III101067No. of cases4I2I4HB419TABLE J. CONTROL OF PATIENTS 0Degree of cOIl/ro/'Good' after tolbutamide failed .'Excellent' after tolbutamide failed.'Excellent' equal to tolbutamide .'Fair' equal to tolbutamide'Excellent' equal to cWorpropamide'Good' equal to chlorpropamide .'Excellent' better than chlorpropamide .'Good' better than chlorpropamide'Fair' better than chlorpropamide'Fair' equal to chlorpropamide'Excellent' after glymidine failed'Good' better than glyrnidine ......'Failed' equal to cWorpropamide'Fair' better than diguanide alone ...'ExceIlent' after poor on insulin'Excellent' also on no tabletsTotal 'ExceIlent' on HB419Total 'Good' on HB4l9 ....Total 'Fair' on HB4l9Total 'Failed' on HB4199 August 1969betes between 5 and 10 years. We also tried to avoidobese subjects; although 12 of our 34 were more than 5%overweight by Broca's index, only 2 were more than15% overweight. No patients with severe complicating di-sease were included, though a few had well-compensatedheart disease.Our 34 subjects included 10 men and 24 women; therewere 21 White and 13 non-White patients, with an agerange of 30 - 80 years.MethodsPatients already taking tolbutamide or glymidine werefirst tried on I tablet of HB419 daily; patients on chlor-propamide were started on the same number of tabletsthat they were already taking. Patients already taking adiguanide in addition to sulphonylurea were usually kepton the diguanide. A few patients who had been on com-bined therapy were initially tried on HB419 alone, but inno case was this successful, and so it was decided there-after to continue with the diguanide at the same dose.Patients were seen 2 - 4 weeks after starting HB419 andthen at monthly intervals. At each attendance the patientwas weighed with coat removed and was questioned aboutsymptoms and about urine tests performed at home.Several of the more intelligent kept home records onspecially printed sheets. Blood was drawn for sugar esti-mation and several other tests. All subjects had repeatedestimations of haemoglobin, total white cells and plate-lets, blood urea, serum bilirubin, SGOT and alkalinephosphatase. Early morning urine specimens brought toclinics at' each visit were tested for sugar and protein byourselves.Most patients were observed on HB419 for 5 - 6months, some up to 10 months. In 3 cases failure wasevident after one month and insulin had to be started.The maximum or final number of tablets of HB419 usedwas as follows: 1 daily in 5 cases; 2 daily in 20 cases;3 daily in 3 cases and 4 daily in 5 cases. One patient re-quired none.Patients were not considered 'failed' until a diguanidehad been used in conjunction with sulphonylurea (exceptin one case when severe symptoms including weaknessand drowsiness developed).RESULTSControl was judged by the urine tests done by thepatients themselves and at the clinics, together with blood-sugar readings taken in the clinic. 'Excellent', 'good' and'fair' control are terms used as on the maker's test sheets.Thus 'excellent' implies fasting blood-sugar levels below120 mg./ lOO m!' (Autoanalyzer, Hoffman method) orpostprandial levels below 160 mg./ lOO ml. with no, oralmost no, glycosuria. 'Fair' indicates fasting levels be-tween 150 and 200 mg. / 100 ml. with frequent glycosuriaof moderate degree. 'Good' is between these two.It should be noted that, especially in older diabetics,the blood-sugar level may be high when glycosuria isabsent, because of a high renal threshold. In such caseswe have estimated control' rather on the basis of theblood-sugar levels, though to maintain really good con-trol with high renal threshold is usually quite impossibleor at least impracticable.The final judgement as regards control is shown inTable I.)1004 S.A. TYDSKRIF VIR GE EESKU DE 9 Augustus 1969CASE REPORTSCaselA White woman aged 66 years, who had been diabetic for8 years and had been on sulphonylureas since diagnosis, waswell controlled on chlorpropamide plus phenformin, but com-plained of severe flushing and palpitation after taking a smalltot of alcohol." On substituting HB4l9 for the chlorpropamidethis complaint was abolished.Case 2A thin White woman aged 55 years, recently diagnosed asdiabetic, initially required one tablet (250 mg.) of chlorpropa-mide for control, and showed glycosuria after discontinuingthis. She was equally well controlled on a tablet of HB4l9,though she said she felt queer and had to draw a deep breath4 hours after taking it (? mild hypoglycaemia). The dose wasreduced to half a tablet and eventually the HB4l9 was with-drawn, with a continuation of excellent control.This patient illustrates the fact that recent diabetes mayinitially need sulphonylurea for control, but subsequently maybe controlled quite well without any therapy except a diabetic-type diet, even if the patient is not overweight."CaselA White woman aged 39 years, of normal weight and adiabetic for 3 years, was taking lente insulin up to 60 unitsdaily and was irregularly controlled, going frequently fromhypoglycaemic reactions to gross glycosuria. Control became'excellent' on only one tablet of HB419 daily, with no insulin.Case 4A Bantu man, aged 45 years and of normal weight, wasadmitted to hospital in hyperosmolar, non-ketotic diabeticcoma.' After recovery he was controlled very well onchlorpropamide 2 tablets plus phenformin 3 capsules daily. Heremained equally well controlled ('excellent') when 2 tabletsof HB4l9 were taken in place of the chlorpropamide.DISCUSSIONHB419 appears to be a well-tolerated drug, approximatelyequal to chlorpropamide in its ability to control diabetes,tablet for tablet (i.e. 250 mg. chlorpropamide and 5 mg.HB419). Because of the lack of toxicity of the compara-tively minute dose of HB419, more than 2 tablets can begiven with impunity, and occasionally with improved re-sults. Thus we thought that in 2 subjects the larger doseof 4 tablets produced a distinctly better response than 2tablets a day. Three cases seemed better controlled onHB4l9 than on chlorpropamide, and in one the reversewas the case. HB419 appeared to be distinctly morepowerful than tolbutamide or glymidine (Glycodiazine).8HB419 combines well with the diguanides. It was pos-sible to save about half the patients who were 'failing' onsulphonylurea alone, including HB4l9, by adding a di-guanide. Thus 8 of 17 cases became 'good' or 'excellent'and another 5 became 'fair'.'Excellent plus good' results were obtained in 60% ofthe patients (20 out of 33). This seems quite reasonablein view of the type of subjects selected for the trial. Theresults were not markedly poorer in patients whose dia-betes had been present for over 10 years, though therewere 4 failures out of 9 in this group.The very small dose of HB419 required for controlwould seem to be an advantage and hould reduce orentirely eliminate the serious toxic effects that have beenoccasionally described with other oral sulphonylureas.In one of our cases sensitivity to alcohol was abolished onchanging from chlorpropamide to HB419; another patientvomited when put on chlorpropamide but was able totolerate HB419 without any side-effects.Some side-effects must, however, be expected, incethey occur al 0 with placebos. Similarly it must be realizedthat a placebo will lead to 'good control' of diabetes insome 25% of new cases,'· but that this placebo effect iseliminated when one drug is compared against another.as in this present trial.It must be understood that this report is concerned withshort-term therapy and no mention is made of secondaryfailure of HB419. This has not yet been encountered,though it is presumably to be expected later. On the otherhand, a longer trial may produce better results, sincesome patients still in the trial may obtain improved con-trol on higher doses of HB419 and/ or on combinationwith diguanides where this has not yet been attempted.SUMMARYHB4l9 is a remarkably potent sulphonylurea, of which only afew milligrams are effective in sensitive maturity-onset diabetics.In a preliminary trial with 34 patients it appeared readilyacceptable, non-toxic and at least as potent as chlorpropamide.It combined well with a diguanide where this was necessary.Other workers have found that hypoglycaemia is a risk thatmust be taken into account.We should like to thank the Department of ChemicalPathology, University of Cape Town (Pro!. J. Kench), whoperformed the biochemical estimations; Mr M. S. Conradie ofthe Haematology Service, Groote Schuur Hospital, who per-formed the haematological studies (with kind permission ofOr R. S. Mibashan); Or J. G. Burger, Medical Superintendentof Groote Schuur Hospital, for facilities; and our patients andthe nursing and secretarial staff for making this study possible.We also wish to thank Messrs Hoechst Pharmaceuticals (Pty)Ltd for financial support and for supplies of HB419 andpharmacological data concerning it, and in particular Or R.Muller and Mr G. Wintemitz.This work was supported by the South African Council forScientific and Industrial Research and forms part of thework of the joint University/CSIR Endocrine Research Group.ADDENDUMSecondary failure of HB4l9 occurred in one Coloured femaleafter one year's successful therapy, but good control was againachieved by the addition of phenformin (Insoral TO).A White female of 55 years was found to require only ttablet of HB4l9 to produce good control, glycosuria recurringif this was omitted.At a conference on this drug (Tegemsee-Konferenz iiber dasneue orale Antidiabetikum HB4l9), held in January 1969, atwhich results in some 6,000 cases were reported, it becameclear that the danger of hypoglycaemia is quite considerable.Great care must be taken in starting treatment in very milddiabetics, particularly in elderly patients.Apart from hypoglycaemia and various side-effects that mayalso be seen with placebos, the only adverse reaction definitelyattributable to the drug was a very occasional skin rash ofsensitivity type.It was generally agreed that, apart from the natural risk ofhypoglycaemia, HB4l9 is a very safe and well-tolerated drug,with approximately the same power as chlorpropamide for con-trolling maturity-onset diabetics.REFERE CESl. Farbwerke Hoechst AG (1967): HB419 Expose.2. Aumiiller, v., Blinder. A .. Heerdt. R., Muth, K., Pfalf, W., Sehmidt.F. H .. Weber, H. and. Weyer, R. (1966): Arzneimittel-Forsch ..16, 1640.3. Loubatit:res. A. (1967): C. R. Acad. Sei. (Paris). 265, 643.4. Clarke. B. P. and Duncan, L. S. P. (1965): Lancet, I, 1248.5. Fitzgerald. M. G., Gaddie, R., Malins, J. W. and O'Sullivan. D. J.(1962): Diabetes, 11. 40.6. Bloom. A. (1959): Brit. Med. I., 2, 73l.7. Iackson, W. P. U. and Forman, R. (1966): Diabetes, IS, 714.Bank. S.. Herman. M. and Jackson, W. P. U. (1965): S. Afr. Med.J., 39. 1117.9. Iackson, W. P. U. in Campbell, G. D., ed. (1969): Oral HypoglycaemicAgents. London: Academic Press.10. Katz, H. M. and Bissel, G. (1965): Diabetes, 14, 650..

Preliminary trial of a powerful new sulphonylurea in maturity-onset diabetes-HB419 (Glibenclamide)

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Preliminary trial of a powerful new sulphonylurea in maturity-onset diabetes-HB419 (Glibenclamide)

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