Bank, S.

Groll, A.

Marks, I.N.

van Eldik, E.

English

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THE EFFECT OF GLYCOPYRROLATE AND A COMBINED OXYPHENCYCLIMINE·HYDROXIZINE PREPARATION ON GASTRIC ACID SECRETIONI. MARKS, B.Sc., M.B., F.R.C.P. (EDlN.), S. BANK, M.B., M.R.C.P. (LOND.), A. GROLL,* M.B., M.R.C.P. (LOND.)AND E. VAN ELDIK, M.B., CH.B.; From The Gas;ro-lnTesTinal Service, GrooTe Schuur HospiTal, Cape Town2OOSAGE LEvEL15 Oktober 1966702DOSAGE LEVEL:!9. \\'ood. P. (1956): Diseases of the Heart and Circulation. London:Eyre & Spouiswoode.30. Goodwin, l. F., Hunter. l. D., Cleland, W. P., Davies, L. G. andSteiner, R. E. (1955): Brit. Med. J., 2, 573.31. \\liI500, M. G. (1962): Advances in Rheumatic Fever, 1940-1961. lewYork: Harper & Row.32. Bland, E. F. and Jones, T. D. (1951): Circulation. 4. 836.33. Jhaveri, S.. Czoniczer, G., Reider, R. B. and MasselJ. B. F. (1960):Ibid., 22, 39.34. Wilson, M. G. (1962): Progr. Cardiovasc. Dis., 5, 145.35. Wood, P. (1956): Op. cit ..'" p. 504.36. Linde. L. M., Harper, J. A., Chuang, K. A. and Mulder. D. G.(1965): J. Thorac. Cardiovasc. Surg., 3, 49.37. Effler, D. B. (1962): Cleveland Clin. Quart.. 29, 167.38. Braunwald, N. S., Cooper, T. and Morrow, A. G. (1960): J. Thorac.Cardiovasc. Surg., 40, 1.39. Levy. J.. Varco, R. L., Lillehei. C. W. and Edwards. J. L. (1963):Ibid., 45, 434.40. Spencer, F. C. (1963): Ann. Surg.. 158, 595.41. SrarnJer, J. (1962): Amer. J. Cardiol., 10, 319.42. Stam!er. R. and Stamler, J. (1962): Ibid., 10, 319.43. Paul, J. R. (1957): The Epidemiology of Rheumatic Fever. ewYork: American Heart Association.44. Logan, A. and Turner, R. (1953): Lancet. 1, 1007 and 1057.45. Bailey. C. P. and Bolton, H. E. (1956): N.Y. Med. J., 56, 825.46. Angelino, P. F., Levi, V., Brusca, A. and Actis-Dato. A. (1956):Amer. Heat! J., 51, 916.47. Glover. R. P. (1959): Amer. J. Cardiol., 4, 132.Fig. I. Effect of varying doses of glycopyrrolate (Robinul)on basal secretion and the MAO. The dose was adminis-tered twice daily (I dose = 1·0 mg.).RESULTSoutput was calculated from the output of 'total' acid duringthe hour preceding the injection of histamine and the maximalacid output (MAO) from the output of 'total' acid during thehour following the injection of histamine. Only these mea-sures of acid secretion were employed in the present paper.Subsequent augmented histamine tests were carried out afterthe administration of a given dosage of one of the anticholi-nergic preparations for a period of 3 days. The preparationwas given orally at 8 a.m. and 8 p.m., except on the morningof the test when it was given 3 hours before the test was dueto start. Ten of the 30 patients were tested with 2 or 3 anti-cholinergic preparations and a further 2 were tested on 2occasions with the same preparation. The remaining 18patients were tested on only one occasion with either Robinulor Enarax.Glycopyrrola;e (Robinul)Robinul was tested in 15 patients, six of whom wereinvestigated on more than one occasion. The dose ofRobinul employed in these patients ranged from 1 to 3mg. b.d. The results of the 22 tests carried out in the 16patients are illustrated in Fig. I and the mean reduction inbasal secretion and the MAO with the different dosagelevels of Robinul presented ID Table I.S.A. TVDSKRIF V[R GE 'EESKUNDE10. Becker. B. J. P. (1946): S. Afr. J. Med. Sei .. 11. 1 .11. Sehwartz. M. B.. Sehamroth. L. and Seftel, H. C. (1958): ied. Proc..4, 275.12. Sehrire. V. (195 ): Amer. Heart l .. 56, 742.13. Jones. T. D. (1944): J. Amer. Med. Assoc., 126, 4 I.14. Joint UK and US Report on the Treatment of Acute Rheumatic Feverin Children (1955): Circulation, 11, 343.15. Keith. J. D.. Rowe. R. D. and Vlad, P. (195 ): Heart Disease ill Ill'jallcy alld Childhood, p. 6!2. New York: Macmillan.16. Ritchie. W. T. (1935): Edinb. Med. l., 42, 11.17. Vaishnava. S., Webb, J. K. G. and Jo eph, C. (1960): Indian J. ChildHlth, 9, 290.Barman. J. B.o Stern. S.. Shapiro, T .• MilwilSky. H. and Braun. K.(1961): Amer. Heart J., 61, 763.19. Ash. R. (1936); Amer. J. Dis. Child .. 52, 280.20. Coburn. A. F. (1931): The FaCeD,. of Infection in the Rheumatic State.Baltimore: \Villiams & \\firkins.21. Coombs. C. F. (1924): Rheumatic Heart Disease. ew York: WilliamWood & Co.~2. Poynton. F. J. (1925): Btit. Med. J., 2, 7 .23. Friedberg, C. K. (1956): op cit.,' p. 848.24. Padmavati, S. (1962): Citculation, 25, 703.25. Calcerom, C. B. (1960): S. Tomiis J. Med., 15, 396.26. Atwater. R. M. (1927): Amer. J. Hyg.. 7, 343.~7. Bland. E. F. and lones, T. D. (1939): J. Amer. Med. Assoc .. 13, 1380.2 . Cherian, G._ VytiJingam. K. 1.. Sukumar. I. P. and Gopinath. N.(1964): Brit. Heart J., 26. 157.904METHODTwenty-seven patients were used for the present study.Twenty-four of these had duodenal ulcers, I a gastric ulcerand 2 a functional dyspepsia. Their ages ranged between 17and 55 years.Each patient underwent 2 - 5 augmented histamine tests,which included a control test and tests carried out during acourse of treatment with one or more of the following anti-cholinergic agents: Glycopyrrolate (Robinul) in a I, 2 or 3 mg.b.d. dosage level, a combination preparation of 5 mg. oxy-phencyclimine and 10 mg. hydroxizine (Enarax) in a I, 2 or 3tabs. b.d. dosage level and propantheline (Pro-banthine P.A.)in a 30 mg. b.d. dosage level. A total of 81 tests were carriedout in the 30 patients.The augmented histamine test was carried out as previouslydescribed.' After an overnight fast, a tube was introducedthrough the nose and passed into the stomach. Under fluoro-scopic control, the tip of the tube was adjusted to lie in themost dependent part of the stomach. The fasting contents wereaspirated and the patient allowed to lie comfortably on hisback or on his left side. Throughout the test a vacuum of30 - 50 mm.Hg was applied to the tube, in order to maintaincontinuous aspiration, interrupted only by occasional manualaspiration of gastric contents with a syringe to ensure com-plete collections. The patient was urged to expectorate anysaliva accumulating in the mouth. Gastric contents wereaspirated for I hour before and I hour following the adminis-tration of histamine acid phosphate (0·04 mg.jkg. body-weight, given subcutaneously). Fifty mg. of mepyraminemaleate (Anthisan) was given by intramuscular injection, 30minutes before the injection of histamine. Aliquots of thebasal and post-histami ne collections were titrated with N j 10TaOH using Topfers reagent and phenolphthalein as indica-tors for 'free' and 'total' acid, respectively. The basal acidIn the medical management of peptic ulcer, great empha-sis is placed on the neutralization or inhibition of gastricacid secretion. Antacid preparations are of unquestionablevalue in the transient reduction of gastric acidity, but it isgenerally agreed that anticholinergic drugs are requiredto achieve a more uniform suppression of the acidity ofthe gastric contents. The present study was undertaken toinvestigate the antisecretory effect of two recently availableanticholinergic preparations on gastric secretIOn."Present address: University of Alabama. Birmingham. Alabama, USA.IS October 1966 S.A. MEDICAL JOUR AL 905TABLE I. EFFECT OF VARIOUS ANTICHOLINERGIC PREPARATIONS ONGASTRIC SECRETIO EXPRESSED I' TERMS OF MEAN PERCENTAGEREDUCTION OF BASAL SECRETION AND MAOFig. 2. Effect of varying doses of oxypbencyclimine-hy-droxizine (Enarax) on basal secretion and the MAO. Thedose was administered twice daily (1 dose = 5 mg. oxy-phencyclimine + 10 mg. hydroxizine).% redu<·tion ill MAO% reduction ill basal secrnionPro- Pro-banthine Robillul Enarax banchine Robillu{ EnaraxP.A. P.A.No. of tabletsglrell h.d. I I 2 3 I 2 3 I I 3 I 2 374 0 78 10 30 3448 25 85 I 49 4791 62 100 100 76 61 67 6780 75 16 036 74 91 20 52 540 43 74 22 65 58 24 53 60 5825 60 40 34 27 3457 66 48 390 50 38 2536 32 19 32TABLE 11. COMPARISON OF PERCENTAGE REDUCTION IN BASALSECRETION A D MAO IN GROUP OF PATIENTS GIVE' MORE THAN IANTICHOLI ERGIC PREPARATIONdose levels of Robinul and En-arax was comparable withthat of the Pro-banthine P.A. and that the larger dosestended to be more effective than the 30 mg. Pro-ban thinepreparation. This was supported by the data in Table 1regarding the mean reduction in acid secretion on the 7patients tested with Pro-banthine P.A. The mean reductionin basal secretion in this small group was 51 0 0 and themean reduction in MAO, 31 0 0. Two of these 7 patientsadmitted to dryness of the mouth while on Pro-banthine.The data in Table 11 show, in addition, that the anti-secretory effect of Robinul and Enarax was comparableon a tablet-for-tablet basis. However, the number ofpatients in :his sub-group was too small to permit of adefinite conclusion.The mean reduction in basal secretion ranged from 43'\,with the tabs. 1 b.d. dose to 66 0 0 with the tabs. 3 b.d.dose and the mean reduction in MAO ranged from about40 0 0 with the smaller dose to 4ro with the larger dose.Dryness of the mouth was troublesome in 1 of the 4patients on the tabs. 3 b.d. dose but in none of the patientson the maller do es and was present to a lesser degree in2 of the remaining 18 patients. The tranquillizing effectof the hydroxizine (Aterax) was difficult to assess becauseof the shortness of the trial periods but none of thepatient complained of undue lassitude or tiredness.Comparison 'J! Robinul, Enarax and Pro-balllhine P.A.The antisecretory effect of different doses of Robinuland Enarax was compared with the effect of propantheline(Pro-ban thine P.A., 30 mg.) in 7 patients and a further 3patients were investigated with both Robinul and Enarax.Table II shows that the antisecretory effect of the singleDISCUSSiONThe present study confirmed the efficacy of glycopyrrolate(Robinul) and a combined oxyphencyclimine-hydroxizinepreparation (Enarax) in the reduction of gastric acidsecretion.'·' Tt showed, in addition, that both basal secre-tion and the response to maximal histamine stimulationwere affected. Basal secretion was reduced to a greaterextent than was the MAO in the majority of patients andthe antisecretory effect of even the lower dosage levels ofthese preparations was comparable to that found followingthe administration of a 30 mg. dose of a prolonged-actionpreparation of propantheline. Side-effects were minimal orabsent with effective antisecretory dosages of glycopyrro-late or Enarax, but it should be noted that no elderlymales were included in the series.IDOSI.GE LEV8.1 ZDO~-€ LEVElNumber Mean % reduCTionPreparaTion Dose of paTients and rangeBasal MAOr 1 b.d. 7 49 (0-75) 38 (0-71)Robinul ~ 2 b.d. 13 59 (0-85) 45 (19-73)~ 3 b.d. 2 61 (22-100) 64 (60-67)1 b.d. 5 42 (7-75) 40 (0-79)Enarax ~ 2 b.d. 13 46 (0-76) 38 (0-66)l 3 b.d. 4 66 (46--91) 47 (39-54)Pro-banthine P.A.(30 mg.) J b.d. 7 51 (0-80) 31 (1-76)There were marked VariatIOns in the magnitude of thereduction of basal secretion and the MAO with all dosagelevels employed, but the data in Table I indicate that thelarger dosage levels suppressed both basal secretion andthe MAO more effectively than did the smaller doses. Themean reduction in basal secretion ranged from 49~0 withthe I mg. dose to 61 0 " with the 3 mg. dose and the meanreduction in MAO varied between 38 0 0 with the smallerand 64 0 0 with the larger dose.Side-effects were experienced in patients during 4 of the22 tests. One of the 7 patients on a I mg. b.d. dosage level,2 of the 13 patients on a 2 mg. b.d. dosage level and 1 ofthe 2 on a 3 mg. b.d. dosage level had slight dryness ofthe mouth. More serious side-effects were not encountered.Oxyphencyclimine-Hydroxizine (Enarax)Twenty-two tests with Enarax were carried out in 19patients. The dose of Enarax employed ranged from I to 3tablets b.d. The data on these and the respective controltests are illustrated in Fig. 2 and the mean reduction inbasal secretion and the MAO with the different dosagelevels of Enarax are presented in Table 1.Marked variations in the percentage reduction in basalsecretion and MAO were again noted for each of the 3dosage levels, the larger doses tending to suppress basalecretion and MAO more effectively than the smaller ones.--906 S.A. TYDSKRIF V1R GENEESKU 'DE 15 Oktober 1966The antisecretory effect of Robinul was perhaps slightlygreater than that of Enarax on a tablet-for-tablet basis.Enarax. however, has the advantage of having a longduration of action'" and in addition, of containing a 10mg. dose of Aterax. The latter, with its central sedative.antisecretory and antispasmodic action has been claimedto be a useful adjunct to anticholinergic therapy in thetreatment of peptic ulceration and functional bowel dis-order.'·loIt should be stressed that the dosage schedule of one ormore tablet administered twice daily was an arbitraryone, employed only for purposes of the present trial, andthat the data regarding suppression of gastric secretionwere derived from tests commenced exactly 3 hoursfollowing a given dose of one of the preparations. Thepresent paper does not provide information on the numberof doses required to produce adequate suppression ofacid secretion over a 24-hour period, but available datasuggest that this may be achieved with Enarax adminis-tered every 8 or 12 hours or with Robinul given at 6 to-hourly intervals.The marked variations in the effect of a given dose ofan anticholinergic preparation observed in differentpatients lends support to the concept, championed by Sunand Shay," regarding the importance of the optimumeffective dose (QED) in the management of peptic ulcera-tion. They suggest that the QED be determined for eachpatient by gradually increasing the dose of drug to a levelof one increment below that which produces uncomfort-able symptoms of parasympathetic inhibition. The relativeabsence of these side-effects in the majority of patients inthe present study suggested that the dosages employedwere generally below the QED and that at least some ofthe patients would have tolerated a larger dose of theanticholinergic preparation than that employed. Since thedegree of inhibition in acid secretion increased with anincrease in the dose of drug, this would have allowed thepatients to have been given an even more effective doseof anticholinergic preparation.SUMMARYGlycopyrrolate (Robinul) and oxyphencyciirnine HCI-hydroxi-zine (Enarax), 2 recently available anticholinergic prepara-tions, have been shown to result in an appreciable reductionin basal and histamine-induced acid secretion, with dose levelsproducing little or no side-effects.This study was supported by the South African Council forScientific and Industrial Research and by the Ben MayGastroenterology Research Fund. We wish to thank Or. J. G.Burger, Medical Superintendent of Groote Schuur Hospital,for permission to publish. Glycopyrrolate (Robinul) was sup-plied by A. H. Robins Co., Inc., Richmond, Va., and oxyphen-cyciimine-hydroxizine (Enarax) by nc.B., Brussels.REFERE CES1. Marks. I. . (1961): Gastroenterology. 41, 599.2. Sun, D. C. H. (1962): Ann. N. Y. Aead. Sci .. 99, 158.3. Moeller, H. C. (1962): Ibid., 99, 158.4. Abbot!. W. E., Sourial, A. S., Krieger, H. and Levey. S. (1962):Ibid., 99, 163.5. Winkelstein. A. (1959): Amer. J. Gastroent., 23, 66.6.. 1eHardy, G., MeHardy, R., Ward, S. and Cradie. H. (1959): J. l.aMed. Soc., 111, 290.7. Hock, C. W. (1960): Amer. J. Gastroent.. 34. 293.8. Piper, D. W., ElIiot!. F. M., Sietsma, A. S. and Pryor, A. W. (1960):Med. J. Aust .. I, 236.9. Strub, I. H. and Carballo. A. (1959): Chn. Med .. 6. 10.10. Rider. J. A., Moeller. H. C. and Olivares·Ageaoili. 1.. (1962): Amer.Praetit.. 13, 591.11. Sun. D. C. H. and Shay, H. (1956): Arch. Intern. Med .. 97. 442.SEPTIC ARTHRITISc. S. B. GALASKO,* M.B., B.CH. (RAND), Department of Onhopaedic Surgery, Johannesburg Hospiratand University of the Witwatersrand, JohannesburgThe incidence of septic arthritis is no less today than inthe pre-antibiotic era, but that of chronic arthritis is less:In the pre-antibiotic era the development of a painless,ankylosed joint was considered a good result. Very few re-tained a fully functional painless joint. Destruction of thejoint, pathological dislocation and a painful fibrous anky-losis were common sequelae.Today two-thirds of cases have a satisfactory outcomewith simple measures such as rest and antibiotics.' In theother cases the infection becomes suppressed by the anti-biotics and a subacute arthritis develops which may flareup into an acute attack as soon as antibiotic therapy is dis·continued. The eau ative organisms eventually tend to be-come in ensitive to the antibiotics used.In an attempt to avoid this long drawn-out course withfrequent exacerbations, a number of procedures have beenused. The joint may be aspirated. This relieves tension onthe joint ligaments and hence reduces pain. It also enablesone to culture the causative organism and to ascertain itsantibiotic sensitivity. At the same time one may instil anti-biotics, usually penicillin, into the joint. It has been shownthat most antibiotic. with the exception of crystalline·Present address: Royal College of .. urgeons of England, Lincoln's InnFields. London.penicillin, do not cross the normal or traumatized jointlining.' As the causative organism is lying within the joint'ssynovial fluid, it is exposed to a much higher concentra-tion of antibiotics by direct instillation into the joint.Soto-Hall el at.' have shown that increasing the intra-articular pressure in the hip, possibly because of its ratherunique arterial blood supply, may cause an avascular ne-crosis of the head of the femur. Aspiration will relieve thetension in the affected joint and hence avoid this possiblecompi ication.Repeated aspirations, with or without simultaneous in-stillation of antibiotics, have also been used, especial1y ifthe effusion tends to recur. Jergeson and Jawitz' insert atube via a trocar into the affected joint and then instilantibiotics 12-hourly into the joint. This is left undisturbedfor 3 hours and then the tube is connected to suctiondrainage until the next instillation.Watkins' prefers open operation and incision and drain-age of the affected joint. If there is a lot of purulent fluidpresent, he finds no contraindications to maintaining anintra-articular drain for up to 4 - 7 days.In the past few months we have used continuous per-fusion of joints in 3 cases. all 3 affecting the knee, withvery gratifying results.

The effect of glycopyrrolate and a combined oxyphencyclimine-hydroxizine preparation on gastric acid secrection

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The effect of glycopyrrolate and a combined oxyphencyclimine-hydroxizine preparation on gastric acid secrection

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