In a single-blind study lasting 6 months an entirely new anti-anginal preparation, perhexiline maleate (Pexid), was prescribed in a dose of 200 mg b.d. to 21 patients suffering from angina pectoris. There was a statistically significant reduction in the average number of anginal attacks over the 6-month period in each subgroup studied. Half the cases studied were asymptomatic at the end of the period. Side-effects were reported in 16 patients; dizziness, headache, weakness, loss of weight and decreased libido being the commonest symptoms. No patient withdrew from the trial because of these symptoms, which disappeared within 4 weeks of continued therapy.S. Afr. Med. J., 48, 904 (1974)

Gitlin, N.

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904 S.-A. MEDIESE TYDSKRIF 4 Mei 1974Perhexiline Maleate in the Management ofPatients with Angina PectorisA LONG-TERM ASSESSMENTN. GITLINSUMMARYIn a single-blind study lasting 6 months an entirely newanti-anginal preparation, perhexiline maleate (Pexid), wasprescribed in a dose of 200 mg b.d. to 21 patients suf-fering from angina pectoris.There was a statistically significant reduction in theaverage number of anginal attacks over the 6-monthperiod in each subgroup studied. Half the cases studiedwere asymptomatic at the end of the period. Side-effectswere reported in 16 patients; dizziness, headache, weak-ness, loss of weight and decreased libido being the com-monest symptoms. No patient withdrew from th~ trialbecause of these symptoms, which disappeared within 4weeks of continued therapy.S. Afr. Med. l., 48, 904 (1974).Perhexiline maleate (Pexid) is an entirely new cardio-vascular drug with the chemical formula:2-(2,2 dicyclohexylethyl)-piperidine maleate.It is not a beta-blocking agent and its actions inexperimental work appear to be vasodilatation of thesystemic and coronary arterial systems, with increasedcoronary blood flow; a reduction of left ventricular work;slowing of the exercise-induced tachycardia only; and asustained bronchodilatation and diuretic effect.'" The ac-tion of the drug is not fully understood but is not due tobeta blockade or the inhibition of adenosine deaminaseactivity. It is unrelated chemically to any drug at presentused in the management of angina pectoris.Slowing of the exercise-induced heart rate by perhexilineis due to a direct action on the sino-atrial node. Animalstudies indicate that this preparatIon has a quinidine-likeaction on the cardiac membrane and causes prolongationof both depolarisation and repolarisation times.3The effects of the preparation on left ventricular func-tion in man were recently determined and, usingcatheter techniques in patients with angma pectoris, towhom perhexiline had been orally administered for 2weeks, it was found to cause a slight decrease in cardiacindex without depressing left ventricul:tr function. Bothat rest and during tachycardia, there was improvedoxygen extraction as well as improved lactate extraction.'Department of Medicine, Groote Schuur Hospital, -Cape TownN. GITLIN, M.B. CH.B., M.R.C.?, Consultant PhysicianDate received: 19 November 1973.Several clinical studies of the effects of perhexiline havebeen reported;" and this preparation was shown toconsiderably reduce the incidence of anginal symptoms.Recent work also suggests that this preparation mayhave anti-arrhythmic effects in the human, particularlyin relation to ventricular extrasystoles'Following an earlier assessment of a double-blindcrossover trial with perhexiline maleate' in the manage-ment of angina,' referred to in the text as Trial 1, a long-term continuous perhexiline maleate administration studywas embarked upon. The main aim of this trial was toevaluate long-term effectiveness of perhexiline in anginapectoris, as well as to establish any side-effects orcomplications.PATIENTS AND METHODSTwenty-two patients with a history of angina pectorisof at least 6 months' duration were studied. There were 15males (12 White, 2 Coloured and 1 Indian) and 7females (5 White and 2 Coloured). One patient diedafter 4 months due to congestive cardiac failure andis not included in the analysis. Ages ranged from 46 to78 years (Table I).No patient had had a myocardial infarction in the3 months preceding the study. No patient suffered severehypertension, anaemia, hypothyroidism or any otherapparent system disorder. All forms of treatment, apartfrom digoxin, diuretics and glyceryl trinitrate (when re-quired), were discontinued for a period of 2 weeks beforethe commencement of the trial. The patients were givenperhexiJine 200 mg b.d. for the entire 6-month period ofassessment. Twelve of the patients had taken part in theprevious crossover trial and'will be referred to as the groupfrom Trial I. The variables measured in the studyincluded body weight, pulse rate, blood pressure, numberof anginal attacks per week, nitroglycerin intake per week.resting and effort ECG, haemoglobin, white blood' cellcount, platelet count, prothrombin index, blood glucose,blood-urea, uric acid, alkaline phosphatase, urine analysisand serum glutamic oxalo-acetic transaminase (SGOT).These studies were performed each month, and at thesame time the patients were given a 28-day diary to recordtheir daily intake of nitroglycerin tablets and their daily.number of anginal attacks. The patients were also given theexact number of perhexiline tablets to last for 28 days andhad to report back and account for any unused tablets.For statistical analysis as shown in Table I, 3 subgroupsof the 2 I patients were considered.4 May 1974 S.A. MEDICAL JOURNALTABLE I. AGE OF PATIENTS STUDIEDPatient groupTrial 1 (D-P) Trial (P-D) New TotalSexMales 5 3 7 15Females 0 4 2 6Age - Mean 55,0 yrs 59,8' yrs 60,4 yrs 58,9' yrs40 - 49 2 0 1 350 - 59 1 3 4 860 - 69 2 3 1 670 - 79 0 0 3 3905D-P (Patients from Trial 1 who were on perhexiline first and then placebo); P-D (Patients from Trial 1 who were on placebo first andthen perhexiline) ... One patient's age was not certain.Electrocardiogram ChangesFig. 1. Frequency of angina attacks during 6-monthperhexiline maleate therapy.542-NEW PATJENTS-9---EX OOUBLE'BUND TRIAL(PEXID"PLACEBQ SEQUENCEJ 5 PATIENTS...... EX DOUBLE-BLIND TRIAL(PLACEBQ'PEXID'SEQUENCEJ 7 PATIENTS6 MONTHPERHEXIUNE MALEATE STUDYo-..l----' .-1lr-------,-----_--=-- - ----3monthsof perhexiline maleate therapyPRETREATMENT BASELINE PRIOR TO CHRONiC STUDYPRETREATMENT BASELINE PRIOR TO DOUBLE·BLlND STUDY·PERHEXll1~jEr.lAliATE IS COVERED BY niE rRAOE-'.'tAID. ?f),;O'~..........I~in I, and oxprenolol (20 mg t.ds.) in a further case.In all these patients improvement in anginal symptomsand reduction in nitroglycerin consumption were obtainedwithin one month of treatment, and this effect wasmaintained during the 6 months of therapy.At the initial visit ECG abnormalities were detected in20 of the 21 patients. ST-segment depre"s;on after e50rtwas recorded in 11 and frequent ventricular prematureextrasystoles in 2 patients. At the end of the study therewas less ST-segment depression on effort in 2 patients, andin a further 4 patients the inverted T waves at restbecame upright. In the 2 patients with ventricular extra-systoles the arrhythmia disappeared in one and wasreduced in the other.RESULTSAnginal AttacksFintly there was the group of 5 patients from Trial 1who had been on the perhexiline-placebo sequence in theearlier study (D-P). Secondly, there were 7 patients alsofrom Trial I who had been on the placebo-perhexili!l~·sequence (P-D), and finally 9 new patients who receivedperhexiline for the fiEt time. The main reason forsubdividing the patients was to distinguish any carry-overeffect of perhexiline.Fou:-teen patients were referred to an ophthalmologistfor full ophthalmological examination including visualacuity, visual fields, lens examination and ocular tensionstudies, before and at the conclusion of the 6-monthperiod.Before commencing the 6-month study the 9 newpatients had had an average of 22,2 attacks, group D-Pan average of 16,7, and group P-D 13 attacks of anginaper week.At the end of the 6 months the new patients wereexperiencing only 1,4 attacks of angina per week.(significance in reduction of attacks P<O,OOI accordingto the paired t-test), D-P group 5,2 (significance P<O,OI),and the P-D group 0,9 (significance P<O,OOl) attack5(Fig. I).No significant differences were observed between themonths of treatment. As noted in the previous double-blind crossover study a decrease in the frequency ofanginal symptoms occurred in the majority of cases andII of the 21 patient3 were totally asymptomatic. In 9others the angina was of less severity and only onereported a deterioration of anginal symptoms. Anginadecubitus was present in 6 of the present series and thenumber of their anginal attacks dropped from an averageof 28 to an average of 3 attacks per week. There was ;:tnassociated decrease in nitreglycerin intake and they wereable to return to their normal daily activities.Of the patients in the present study, 6 had previouslybeen on beta-adrenergic blocking agents with an inade-quate response. These agents included propranolol (300-400 mg daily) in 4 instances, practolol (400 mg b.d.)12906Ophthalmological AssessmentS.-A. MEDIESE TYDSKRIFLaboratory Investigations4 Mei 1974IIIn these 14 patients no ophthalmological differenceswere noted at the end of the period, with the exceptionof one, where posterior cortical changes of the lens inkeeping with the patient's age were observed.Side-EffectsSide-effects were similar to those previously reported,and no new side-effects were detected. Sixteen patientshad one or more side-effects. In none were the side-effectsof such intensity as to cause withdrawal from the trial.Dizziness was most frequent and usually occurred withinthe first 7 - 10 days of therapy, passing off in all patientswithin 4 weeks. Less frequent side-effects were headacheand weakness, which lasted for a few days. In 3 patients(out of a total of 5), where decreased libido had occurred,this improved towards the end of the study. In I of 3patients with impotence, this may have been due toassociated diabetes. Other rare side-effects of a transientnature included arthralgia, frequency of micturition andconstipation (Table lI).TABLE 11. SIDE-EFFECTS ENCOUNTERED IN 21 PATIENTSSymptom No. %Dizziness 11 52Weight loss <>2 kg) 11 52Decreased libido 5 24Headache 4 19Weakness ... 4 19Impotence 3 14Frequency 2 10Constipation 2 10Arthralgia ... 1 5No symptoms 5 24During the 6-month study there was a mean loss ofwei'~ht of 2,9 kg. Six patients lost less than 5 kg, 5 patientslost between 5 and 10 kg, and 1 exceptional patientwith marked oedema lost 17,7 kg. Approximately two-thirds of this loss occurred within the first 2 monthsHowever, a weight gain ranging from 0,5 to 3,2 kg occurr-ed in 7 patients. In 2 patients weight remained unchanged.On 4 separate oc::as:om, including an initial base lineassessment, haematological evaluations were performedand no abnormal effects on haemoglobin concentration,platelet count, white cell count and differential count werenoted.The prothrombin incex remained unchanged, with theexception of one case where it dropped to 86~~. Noabnormal change was detected in blood-urea, uric acid,alkaline phosphatase and blood glucose levels. Urin~analysis showed no abnormalities.In 15 patients the SGOT levels remained within normallim:ts. However, in 4 patients values rose to between20 and 40 units (normal less than 20 units), and in 2the maximum values reached 120 and 90 units respectivelv.Subsequent to this trial, full liver function te~ts, includingalbumin-globulin rat;03, protein electrophoresis, bilirubin,alkaline phosphatase, creatinine phosphokinase and lactic• dehydrogenase estimations, as well as liver biopsies, wereall normal and the impression was that the raised SGOTlevels settled in mmt patients and dropped cons'derablyin the others.CONCLUSIONStatistically significant reductions in the average numberof anginal attacks were recorded over the 6-month periodin all three subgroups studied, half the cases being totallyasymptomatic at the end of the period.No new side-effects were detected, and the same side-effects previously recorded' were encountered again. Inonly one patient of the group studied were the anginalattacks not reduced. In no patient was the trial discontinuedbecause of side-effects or intolerance to the drug.REFERENCESI. Hudak, W. J., Lewis, R. E. and Kuhn, W. L. (1970); J. Pharmacol.Exp Ther., 173, 371.2. Feinsilver, I., Cho, Y. W. and Aviado, D. M. (l97U); Chest, 58, 558.3. Matsuo, S., Cho, Y. W. and Aviado, D. M. (1970); Ibid., 58, 581.4. Pepine, C. J., Schang, S. J. and Bemiller, C. R. (1973): Postgrad.Med. J .. suppl. 3, 49, 43. .5. Winsor, T. (1969): Clin. Pharmacol. Ther., 11, 85.6. Bums-Cox, C. J., Chandrasekhar, K. P., Ikram, H., Pierce, T. H.,Pilcher, J., Quinlan, C. D. M. and Russell-Rees, J. (1971): Brit.Med. J., 4, 586.7. Gitlin, N. and Nellen, M. (1973): Postgrad. Med. J., suppl. 3, 49, 100.8. Sukerman, M. W., Hemandez, P. O. and De Hemandez, M. (1973):Postgrad. Med. J., suppl. 3, 49, 46.

Perhexiline maleate in the management of patients with angina pectoris

In a single-blind study lasting 6 months an entirely new anti-anginal preparation, perhexiline maleate (Pexid), was prescribed in a dose of 200 mg b.d. to 21 patients suffering from angina pectoris. There was a statistically significant reduction in the average number of anginal attacks over the 6-month period in each subgroup studied. Half the cases studied were asymptomatic at the end of the period. Side-effects were reported in 16 patients; dizziness, headache, weakness, loss of weight and decreased libido being the commonest symptoms. No patient withdrew from th~ trial because of these symptoms, which disappeared within 4 weeks of continued therapy.S. Afr. Med. J., 48, 904 (1974)

Gitlin, N

Perhexiline Maleate in the Management of Patients with Angina Pectoris

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Perhexiline maleate in the management of patients with angina pectoris

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