Boardman, R.

Farber, S.

Gazidis, C.

Goldberg, B.

Levin, N.W.

English

AJOL - African Journals Online

4 Maart 1961 S.A. TYDSKRIF VIR GENEESKUNDE 175ciated with tylosis. The only reported association of clino-dactyly is that with webbing of the toes.s In the familywe studied there were 10 members with clinodactyly-6 female and 4 male. In 8 cases the curving of the littlefinger was bilateral but in 2 this curving was only presentin the left hand. Of those with clinodactyly, 6 wereaffected with tylosis as well. Clinodactyly is transmittedas an autosomal dominant. Lack of complete penetrance.was shown by the fact that in 6 cases the parents did nothave the condition. In 1 case (N24) neither the parentsnor the grandparents had clinodactyly. These features ofdominant transmission with incomplete penetrance havebeen reported by others.sIs there a genetic linkage between clinodactyly andtylosis, or is the association purely one of chance? Wewere unable to obtain statistically significant results infavour of genetic linkage, using the sibling pair methodof PenroseY·lS However, assuming that the incidence oftylosis and clinodactyly in South Africa is 1 in 40,()()()24and 1 in I,OOOS respectively, the probability of these 2co~Oitions occurring together is in the region of 1 in 40miJ1fon.SUMMARYIn a family affected with tylosis palmaris et plantaris 59members were studied. The family tree and the mode' ofgenetic transmission are outlined. The incidence, histo-pathology, clinical features, differential diagnosis and treat-ment of tylosis are discussed. The association of tylosisand clinodactyly is noted. In addition some of the reportedabnormalities occurring with tylosis are revi"ewed.We wish to thank Profs. G. A. Elliott, B. J. P. Becker, andP. V. Tobias for encouragement and a i lance in the pre-paration of this article; the Photographic Unit of the Depart-ment of Medicine and Mr. S. Dry of the Anatomy Depart-ment, Univer ity of the Witwater rand, for reproduction ofthe figures; and Dr. K. F. Mills, Superintendent, Johanne-burg General Hospital, for perrni sion to publish.REFERE CES1. Anderson, J. (1951): Brit. J. Deem., 63, 127.2. Bureau, G., Horeau, M., Barriere, H. and DuFage, C. (1958): Bull.Soc. rran9. Derm. Syph., 65, 32 .3. Cockayne, E. A. (1933): The Inherited Abnormaliries of the Skin anditS Appendages. London: Oxford University Press.4. Dencer, D. (1953): Brit. Plast. Surg., 6, 130.5. Heffner, R. A. (1924): J. Hered., IS, 323.6. Idem (1929): Ibid., 20, 395.7. Idem (1941): Ibid., 32, 37.8. Hersh, A. H., De Marinis, F. snd Stecher, R. M. (1953): Amer. J.Hum. Genet., 5, 257.9. Howel-Evans, W., McConnell, R. B., Clarke, C. A. and Sheppard, P. M.(1958): Quart. J. Med., 27, 413.10. Ingram, J. T. and Brain, R. T. (1957): Sequeira's Diseases of rhe Skin,6th ed. London: Churchill.11. Knenner, D. M. (1934): J. Hered.. 25. 329.J2. Kumer, L. and Loos, H. O. (1935): Wien. kJin. Wschr., 48, 174.13. Landazuri, H. F. (195 ): Plast. Reconstr. Susg., 22, 557.14. Lawler, S. D. and Renwick, J. H. (1957): Personal communication toHowel·Evans et al. loco cil.915. Ormshy, O. J. and Montgomery, H. (1948): Diseases of rhe Skin,7th ed. Philadelphia: Lea and Febiger.16. Porter, A. D. (1951): Brit. J. Derm., 63, 123.17. Penrose, L. S. (1935): Ann. Eugen., 6, 133.18. Idem (1938): Ibid., 8, 233.19. Pupa, J. A. and Farina, R. (1953): Plast. Reconstr. Surg., 12, 446.20. SeOlt, O. L. S. In Sorsby, A. ed. (1953): Clinical Genetics. u.ndon:Buttesworth.21. SeOlt, M. J., Costello, M. J. and Simuangco, S. (1951): Arch. Derm.Syph., 64, 301.22. Semon, H. C. G. (1953): An Atlas of rhe Commoner Skin Diseases,4th ed. Baltimore: Williams and Wilkin.<.23. Sulton, R. L. and Sulton, R. L., jun. (1939): Handbook of Diseases ofrhe Skin, 10th ed. St. Louis: C. V. Mosby.. 24. Swan, H. P. (1956): Ulstes Med. J., 25, 27.25. Thost (18 0): Dissertation, Heidelherg. (Quoted by Cockayne, E. A.loc. cir.3).26. Touraine, A. (1954): Brit. J. Derm., 66, 294.27. Unoa, P. G. (1886): Histoparhology. Edinburgh: Walker. (Quoted byCockayne, E. A. loc. cit.3).28. Vickers, H. R. (1960): Practitioner, 184. 350.29. Wynn-Williams, D. 11953): Brit. J. Plast. Surg., 6, 123.OBSERVATIONS ON A NEW BENZOTHIADIAZlNEDIURETIC-TRICHLORMETHIAZIDE*N. W. LEVIN, M.B., B.CH. (RAND), B. GOLDBERG, M.D. (RAND), M.R.e.p. (LOND.), R. BOARDMA! ,** S. FARBER** andC. GAZIDIS**Department of Medicine, University of the Witwatersrand, and Johannesburg General Hospitalthe weight of each subject. During the next 7 days,trichlormethiazide was given in doses of 4 mg. b.d. Threegrams of potassium chloride were administered in divideddoses daily during the last 3 days of this period. Measure-ments of weight, urine volume, and electrolyte contentTABLE 1. EFFECT OF TREATMENT IN HEALTHYlSUBJECTS*Subject 1mEqDays Urinaryvol. ml. Na K Cl1,345 164 85 1872,800 338 986 3801,810 236 131·9 2401,770 159 126·6 206800 65·4 75'5 88'5940 71'5 110'1 831,670 210 266 2661,960 160 115 225* Effect of 4 mg. of trichlormethiazide twice daily on urinaryvolume, sodium, potassium and chloride excretion in 3 healthysubjects after a control period of 4 days. Three g. of potassiumchloride were given daily for the last 3 days.I - 4 contro5678910IIThe introduction of the benzothiadiazine djuretics has hada marked influence on the treatment of patients withoedema. Modifications of the original molecule haveresulted in preparations which, in the main, vary quantita-tively in potency but not qualitatively. This paper presentsthe effects observed of a recently developed derivative,trichlormethiazide (3-dichloro-methy1-6-chloro-7-sulfamyl-3, 4-dihydro-l, 2, 4-benzothiadiazine-I, I-dioxide) (Fig. 1),on urinary electrolyte excretion in normal subjects and onpatients with fluid retention.Normal SubjectsThree healthy male medical students were studied. Theywere phiced on a standard hQspital diet for 11 days.During the first 4 days (control period) the 24-hourexcretion of water, sodium, potassium, chloride, bicar-bonate, and the pH of the urine was measured as well as'~TricblOI'Illethiazide ('fluitran') was made available forstudy Ihrough Dr. M. Tonkin, Medical Director, Scherag(Pty.) Ltd.~"~ Final year medical students.176 S.A. MEDICAL JOURNAL 4 March 1961DAYS.--3 NORMAL SUBJECTSELECTROLYTE EXCRETION INTRICHLORMETHIAZIDElf,(. \I \I '. \I ', \I .-2ISOUTPUTMLKGMS-I4 5 7 8 IQ 11 DAYSMEAN o......~.._....i ....__..WT.2pH 6Fig. 2. The effect of 4 mg. of trichlormethiazide twicedaily on body weight, bicarbonate excretion, and urinaryvolume is shown.In 2 other 'healthy subjects the time of onset andduration of action of trichlormethiazide were studied.Urine was collected as above in periods from 8 a.m. - 2p.m., 2 p.m. - 8 p.m. and 8 p.m. - 8 a.m. over 3 days whileon a standard hospital diet. Trichlormethiazide (8 mg.)was then given and the effect on urine volume and electro-lyte excretion observed for a further 60 hours. The resultsare shown in Figs. 3 and 4.11 DAYSo ~-_--",,-_--..-~__......_,..+__,...,were continued throughout the study, the urine beingcollected and preserved with toluene and thymol. Theresults are shown in Tables I and 11 and Fig. 2.ChlorothiazideHydroClumethiazideTABLE I. (CONTO.) EffECT Of TREATME I HEALTHY SUBJECTSubject 2mEqDays Urinaryvol. ml. a K Cl1 - 4 comrol J,51O J50 82 1765 1,700 J85 136 1786 1,650 152 118 207 2,220 J82 134 2291,830 209 75 21 J9 1,680 147 88·5 188JO 1,140 1 t I 83 J63Jl 870 121 78 J66 .Subject 3mEqDays UrinaryNavol. ml. K ClJ - 4 omrol J,251 180 76 2365 J,530 345·1 8J·5 3066 1,000 J38·6 80·6 J867 J,770 7J ·3 112·7 2048 J,050 106·3 109·2 1319 1,050 43'5 61 64·210 730 93'5 74·5 93·5Jl 900 J33 65 151TABLE D. EFFECT OF TREATMENT I HEALTHY SUBJEcrs--(CONTD.)*a: K Na: ClSubjeCTs SubjectsJ 2 3 J 2 31·92 1·83 2·36 ·88 ·88 ·763·43 J'36 4·24 ·89 ·671·16J'79 1·30 J·71 ·99 ·74 ·731 ·26 1. 36 ·64 ·78·80·35·86 2·79 ·98 ·74 1·00 ·81·66 1·66 ·72 ·87 ·78 ·68·791·33 ]·26 ·79 ·681·00]']5 ],55 2·04 ·75 ·73 ·88* la: K and a :CI urinary excretion ralios before andduring the administration of 4 mg. of trichlormethiazide twicedailY to 3 healthy subjects.R?O*....... HF-~ V I ~:ll:2NOlS ~ SOlYDays1 - 4 comrol5678910]JTrichlormethiazide 1A Flumethiazide 18Fig. J. The chemical formulae of some of the benzo-tbiadiazine diuretics are shown. These are all substitutesat po ilion 3 of chlorothiazide or flumelhiazide.BenzydroflumethiazideBCI0~N'~P~1I 'ClH~C'.!S ~ ~N-HHydrochlorothiazidePatients with Fluid Retention17 patients with fluid retention (9 with cardiac failure.1 with the nephrotic syndrome, and 1 with steroid-inducedoedema) were treated with 4 mg. of trichlormethiazidetwice daily. Two patients had gross oedema, 9 mild oedema,and 6 had left ventricular failure without manifestoedema. Potassium supplements were not given duringthe 10 or 11 days of observation. In the patients withcardiac failure, specific treatment, excluding otherdiuretics, was given if indicated. Daily weight and frequentblood-electrolyte level were recorded in each patient4 Maart 1961 S.A. TYDSKRIF VIR GENEESKUNDE 177TABLE m. EFFECT OF TREATMEl\'T T A PATIE T WITH OEDEMA*DAYSo-4-3-2LBS-IWT. CHANGEO-l_---~----------+0.5+ 1-6-5K+ CHANGEMEO- 0.5 2 4 6 8 10 5Fig. 5. The mean cumulative weight change and the meanserum potassium level is shown over 11 day of treatmentwith trich10rmethiazjde in 17 palien with fluid retention.from the inhibition of carbonic anhydra e. The morerecent derivative have, howe er, Little carbonic-anhydra e-inhibiting effect. A the molecule of chlorothiazide habeen manipulated, so has the effective do e of thederivatives decrea ed and it ha been uggested that tillincreased activity may be due to an increased olubiLityof the drug in the lipoid of the cell membrane.' A morespecific interference with energy production in the cellis not, however, excluded, and po ible differences inelectrolyte excretion produced by the different prepara-tions may result from thi .The admini tration of 4 mg. of trichlormethiazide twicedaily to 3 normal ubjects re ulted in an increa e inurine volume, odium, and chloride excretion and, to ale er extent, pota sium. rinary pH and bicarbonateexcretion were not altered to any considerable extent. In2 ubjects the ratio of odium to chloride excretion in theurine increased temporarily and then decrea ed when com-pared with control level. In the same ubjects imilarchange were noted in the odium: pota ium ratio. There ults are con i tent with a primary action on odiumreabsorption and econdary 0 motic diure i . The ab enceof an increa e in urine pH or bicarbonate excretionugge ts little if any carbonic-anhydra e-inhibiting effect ofthe drug and i imilar to that reported a occurring withrTR'CHLORM(HUoUIOE8 MGMSt-RIO!LQliWETH>;1oZIQE8,\fG!lilSm.Eq.UrinaryDays vol. ml. Na K Cl, pHI - 2 control 1,205 180 33 ·164 6·33 1,840 200 34·8 214 6·44 1,190 212 40·2 214 6·45 1,410 184 38·4 190 6·067 1,430 105 58·5 177 4·92,290 284 91·6 334 5·79 1,280 174 67·5 200 5·210 1,430 124 89·3 183 5·2* Effect of 4 mg. of trichlormethiazide twice daily on urinaryvolume, sodium, potassium, chloride and pH in a patient withfluid retention.';.L..JlJ t...LUiJ":~ 1a..uu.JTRIOtLO;lM£Tloll.AI,O£ TRIOfl,~E··l~lJ.LU~ - ~ - ~ - ~ ~ ~ ~Fig. 3. The effect of an 8 mg. dose of trich10rmethiazideon urinary output and sodium excretion in respect of itsonset and duration of action is shown.Fig. 4. The effect of an 8 mg. dose of trichlormethiazideon potassium, chloride, and urinary pH in respect of itsonset and duration of action is shown.DISCUSSIONThe benzothiadiazines exert their effect, to a large extent,at the proximal convoluted tubule where they inhibit thereabsorption of a portion of the filtered sodium. Thisresults in an osmotic diuresis. Moreover, there i an effecton the distal convoluted tubule of variable degree resultingduring the course of treatment. The mean cumulativeweight change and the mean serum-potassium change areshown in Fig. 5. There was no demonstrable alteration inthe other blood electrolytes or urea. Table III showsthe effects of trichlormethiazide on the urinary excretionof electrolytes in a patient with oedema.178 S.A. MEDICAL JOURNAL 4 March 1961the 3-benzyl derivative' and to a le er extent withhydroflumethiazide.· The econdary retention of odiumob erved after a few day uggests that a compen atorymechanism to restore body odium began to exert aneffect. This may be due to increa ed ecretion of aldo te-rone as evidenced by a decrea e in the odium-pota iumratio and i to be expected in normal ubjects depletedof water and odium.' It is unlikely that other diureticswith similar modes of action would differ in this respect.There wa no marked increase in the ab olute amountof pota ium excreted, except in one subject in which agreater urinary excretion was seen to follow the admini-tration of pota ium upplements. Similar ob ervation ,that trichlorrnethiazide and bendroflumethiazide tend tocau e les pota ium 10 than chlorothiazide, hydrochlor-thiazide, flumethiazide and hydroflumethiazide, havebeen made by Bern tein.· A greater carbonic-anhydra e-inhibiting effect of the latter ub tances may account forthis.A single dose of 8 mg. of trichlormethiazide was foundto exert an action within 6 hour of administration. Theeffect continued for 24 - 36 hour and wa observed toabolish the normal diurnal rhythm of water and electrolyteexcretion in the urine (subject 2, Figs. 2 and 3). It hasal 0 been stated that there is a continued water diure iswithout electrolyte 10 s following cessation of continuoustherapy of 7 days duration." Thi ha been a sociated witha decrease in serum osmolarity produced by the previoustreatment. It would appear then that trichlorrnethiazidehas a long duration of action and may be better given inintermittent cour es with contioued diuretic effect bothduring and for a period after stopping the drug. Ifadministered in this manner, hyponatraemia, which pre-umably may develop on continuous therapy, would notoccur.Sati factory diuresis was observed in the 17 patientstreated with trichlormethiazide. There was a mean cumu-lative weight loss of St lb. in the e patients in 1 week.Comparisons with other diuretics cannot be madeaccurately with this heterogenous group of patients. Thediuresis observed was atisfactory while the rate of clinicalimprovement was similar to the expected results with otherdiuretics, and Ford7 has shown that S mg. of trichlor-methiazide i equivalent to 2 m!. meralluride in natriureticeffect. In some patients the weight increased after a week,and was una ociated with signs of fluid retention. It isconsidered likely that this resulted from an increase infood intake and consequent increase in actual body solids.Although during the period of treatment there wa nodrop in the mean serum-potassium level, in some patientsa small decre:;.se was ob erved. Thus, although potassiumdepletion may be less likely to occur with this than withpre ious preparation , as judged by comparative urinaryexcretion, it may still be neces ary to supplement pota -sium intake. During the period of observation no signifi-cant change in other blood electrolytes or the blood ureawas observed, although in subsequent patients on highdo age a rise in blood urea has been observed in some.with the other benzothiadiazine derivatives, it i likelythat in patient with renal insufficiency, worsening ofkidney function may occur with vigorous sodium deple-tion. Care should be exercised in these cases. Similarly,an increase in the serum uric-acid level may occur withtrichlormethiazide as with any of the benzothiadiazines.The LDs. dose of trichlorrnethiazide is given as 2·g g./kg.in mice. Hydrochlorothiazide has a similar LD•• dose, but,because of the larger dose necessary to produce a diuretieffect, the therapeutic ratio is not as high as for trichlor-methiazide." This may be of advantage in that toxic effectswould be less likely to occur with the smaller dose requiredwhen using trichlorrnethiazide. However, the therapeuticratio is still considerable with the other benzothiadiazinesand well within the toxic dose. Idiosyncrasies are inde-pendent of dose and may occur with either. In this seriesof subjects and in other patients treated concomitantly,no side-effects, toxic effects, or idiosyncrasies \ ereob erved.SUMMARY AND CONCLUSIONSThe effects of trichlormethiazide, a benzothiadiazinederivative, were observed in S normal subjects and in 17patients with fluid retention.Increased excretion of sodium, chloride, water, and toa lesser extent potassium, was observed after administra-tion of 4 mg. twice daily to normal subjects. The effectwas measurable within 6 bours and persisted for 24 - 36hours.In the patients with fluid retention a satisfactory diureticresponse was observed. Potassium depletion was slight andmay be less than that reported for Qther benzothiadiazinederivatives.o side-effects, toxic effects, or idiosyncrasies to thedrug were noted.We wish to thank Prof. G. A. Elliott for his encouragementand criticism, Messrs. V. oble, M. Brooks and . We tonfor technical as istance, and the Photograpbic Unit of theDepartment of Medicine for the illustrations.REFERE 'CESI. Annotation (1960): Brit Med. J .. 2, 923.2. Kennedy, . C., Bucbanan. K. D. and Cunaingham, C. (1960): Lancet.J. 1267.3. Deonis. E. W. and Ford. R. V. (1960): Amer. J. Cardiol., S, 402.4. Pins, R. F. (1959): The Physiologicol Basis of Diuretic Therapy. Spring-field: Charles C. Thomas.5. Bernstein. R. E. (1960): S Afr. J. Med. ScL, 25, 104.6. Hutcbeon, D. E. i196O): Doctor to Doctor (8). Discussion on diureticand antihypenensive therapy. San Fransic;co.7. Ford, R. V. (1960): Amer. J. Cardiol., 4. 407.. cberag (Pty.) Ltd. Per onal communication.THE SECOND WORLD CONFERE CE 0 IJEDICAL EDUCATIO *B. J. KAPLA , M.B., B.Ch., Senior Lecturer in Social Medicine, University of Cape TownThe .econd World Conferen.ce on Medical Education was McMurray of Cape Town, Dr. B. Kaminer of Johannesburg.held ID Palmer House, Chicago, from 30 August to 4 and my elf. Delegates came from 65 of the 98 medi aJeptember 1959. About 650 delegates attended from 66 chools in the USA and and it is estimated that aboutcou~tries, more than half the de~egates being from countries 60,000 students graduate annually from tbe 555 medicaloutSide the USA. Three South AfrIcans were pre ent, Mr. T. B. schools which were represented. One example of the progresof medical education is the fact that there are now 6• Received for publication on 13 January 1961. medical schools in India.

Observations on a new benzothiadiazine diuretic - trichlormethiazide

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Observations on a new benzothiadiazine diuretic - trichlormethiazide

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