Mass spectrometric identification of amiodarone N-monodesethyl metabolite and application of an HPLC method to a pharmacokinetic study.

Identification of an amiodarone metabolite in the plasma of patients receiving a single dose of the drug was carried out by mass-spectrometry following extraction and HPLC separation. The kinetics of the plasma concentrations of unchanged compound and its identified metabolite (N-monodesthyl-amiodarone) were studied in six patients after a single administration of amiodarone by oral or intravenous routes, using a sensitive and specific high-performance liquid chromatographic method. The observed plasma clearance rate for the drug varied from 0.2 to 0.5 1.h-1.kg-1 of body weight; and the elimination half-life of the unchanged compound was found to be approximately 21 hours. Oral bioavailability, as determined in one patient, was about 60%. The proportion of the metabolite found in the plasma following a single oral administration was significantly higher than that observed after infusion. The ratio of areas under the curves for metabolite-to-unchanged compound was 0.55 and 0.13 for oral and intravenous doses respectively. During a circumscribed study carried out in five patients receiving oral doses of the drug (daily dose varied from 2.6 to 9.3 mg/kg) accumulation of the metabolite was observed. The mean of the plasma level ratios (metabolite to-unaltered drug) obtained in five patients was approximately 0.97.

[Detection of left intraventricular thrombi in the acute phase of myocardial infarction by 2-dimensional echocardiography. Apropos of 103 cases]. / Détection des caillots intra-ventriculaires gauches à la phase aiguë de l'infarctus du myocarde par l'échocardiographie bidimensionnelle. A propos de 103 cas.

Two-dimensional echocardiography (2D echo) was performed in 103 patients (94 men, 9 women, aged 35 to 76 years; mean 55,4 years) during the acute phase of primary myocardial infarction in order to detect left ventricular thrombi (LVT). This investigation was carried out between the 7th and 30th days with an 84 degrees phased array sector scanner. A total of 17 LVT were visualised, all at the apex of the left ventricle. There factors seemed to predispose to this condition: --the site of infarction: LVT were more common in anterior (16/56) than inferior infarcts (1/47) (p less than 0,001); --the extent of the necrosis: LVT occurred in 13/30 antérior infarcts when the akinesia involved at least two antero-apical segments, compared to only 3/26 when the necrosis was less extensive (p less than 0,05); --cardiac failure in anterior myocardial infarction: LVT were found in 11/21 cases with cardiac failure and in only 5/35 without cardiac failure (p less than 0,01). The outcome of 45 patients was assessed by 2D echo 3 to 12 months after the acute episode (mean 7,6 months). Control echo was unchanged in 35 patients (15 inferior, 20 anterior infarcts) without LVT. In 10 patients with LVT treated by oral VitK antagonists, the thrombus disappeared in 5 cases without embolism; it decreased in volume in 3 cases and persisted unchanged in 2 cases.(ABSTRACT TRUNCATED AT 250 WORDS)

[Comparative study of quinidine and disopyramide in the treatment of stable ventricular extrasystole]. / Etude comparée de la quinidine et du disopyramide dans le traitement des extrasystoles ventriculaires stables.

The antiarrhythmic efficiency of quinidine arabogalactan-sulphate (QAGS) and disopyramide were determined in 38 patients showing chronic, stable frequency premature ventricular beats (PVB). The study which was carried out in 4 medical Centers, used a longitudinal cross-over design. After a baseline evaluation which consisted of two 24 hours electrocardiograms, the patients were randomised to one of the two drugs during a period of 6 or 7 days. The drug sequence were followed by a placebo sequence. A 24 hours electrocardiogram was performed at the end of each sequence. The daily doses were equivalent to 660 mg of quinidine base for QAGS and 600 mg for disopyramide. Among the 38 patients who entered in the study, 32 went through each sequence of the test. The average number of PVB was significantly reduced by QAGS and disopyramide (p less than 0.0001). With QAGS 18 patients had more than 65 p. 100 reduction of PVB and 12 of them more than 80 p. 100. With disopyramide, 14 patients had more than 65 p. 100 reduction of PVB and 12 of them more than 80 p. 100. There was no statistical difference in the overall efficiency of the two drugs. Three patients died, one from myocardial reinfarction, one from ventricular fibrillation; in one other case, the cause of the death remained undetermined. QAGS was better tolerated than disopyramide; adverse effects occurred in 6 patients with QAGS and in 10 with disopyramide. The responsibility of disopyramide in the occurrence of two severe ventricular arrhythmia may be questioned.

[Provocation tests for coronary spasm. Methods, value and indications]. / Les tests de provocation du spasme coronarien. Méthodes, valeur et indications.

Five methods are currently used to demonstrate coronary spasm: they use derivatives of ergotamine, alkalinisation, cold, adenosine triphosphate and exercise stress test. The criteria used to confirm spasm are either direct visualisation at coronary angiography or indirect electrocardiographic changes. The value of these test is beginning to be established: --their specificity is excellent with all methods (a positive test is diagnostic); --their sensitivity is mediocre (a negative test does not exclude the diagnosis). This depends on three factors: the choice of criteria of positivity: angiographic appearances is the most reliable; the timing of the test: it is more likely to be positive when the test is carried out close to episodes of chest pain; the method of provocation: the most sensitive tests use either the ergotamine derivatives or alkalinisation; --reproductibility is satisfactory at short and long term. These tests have diagnostic and therapeutic indications. It is preferable to perform diagnostic tests during coronary angiography in patients with normal coronary arteries and unexplained episodes of chest pain. However, in patients with fixed coronary lesions (except triple vessel and left main stem disease) when coronary bypass surgery is planned, the results of the test can help in the choice of associated therapy, such as plexectomy and calcium antagonist drugs. The repetition of the test is useful in the evaluation of antispastic therapy: when the test becomes negative the drug used is probably effective. In conclusion, with equal patient comfort and MSR, provocation tests using the ergotamine derivatives would seem to be the method of choice: alkalinisation is a good alternative.

[Outcome of vasospastic angina with normal or near-normal coronary arteries (author's transl)]. / Dvenir de l'angor spastique à coronaires normales ou peu altérées.

The outcome of vasospastic angina with normal or near-normal coronary arteries was investigated in 48 patients followed up for periods of 3 to 55 months (mean : 19.1 months). The course of the disease was unfavorable in 13 patients, of whom 3 died, 5 developed myocardial infarction and 5 refractory angina. It was favourable in 16 patients who remained asymptomatic for at least 6 months, and intermediate in 16 patients whose anginal attacks became less frequent. Three patients were lost sight of. Calcium antagonists were administered to 32 patients; they proved superior to beta-blockers but imperfectly controlled the course of the disease : the anginal attacks completely ceased in 12 patients, became less frequent in 11 and persisted or became worse in 5. A close correlation was found between long-term outcome and the results of provocation tests performed at the beginning of treatment, and it is proposed that these tests should be used as therapeutic guide-lines.

[Block of the autonomic nervous system in the study of sinus function]. / Blocage du système nerveux autonome dans l'exploration de la fonction sinusale.

Blockade of the autonomic nervous system by injection of propranolol (0,2 mg/Kg) and atropine (0,04 mg/Kg) was carried out in a series of 48 patients classified in 3 groups:--Group I:sinus bradycardia (22 cases)--Group II:suspected tachycardia-bradycardia syndrome (14 cases)--Group III:suspected sinus node dysfunction (12 cases). Two parameters were studied after autonomic blockade: observed intrinsic sinus node frequency (OIF) and corrected "adjusted" sinus node recovery time (CASRT). The results were compared with those obtained during basal electrophysiological investigation. The OIF was abnormal in 26 cases (54%) and junctional rhythm was observed 9 times (19%). Prolongation of the post-stimulation pause occurred in 32 cases (67%), transformation from a normal to a pathological pause in 15 cases and normalisation of a pathological pause in 4 cases (8%). Sinus node recovery time did not change significantly in the other cases. There was a good correlation between OIF and CASRT when the OIF was abnormal and mediocre (48%), when the OIF was normal. The following conclusions were made:--CASRT improves diagnosis of organic sinus node dysfunction which may escape detection by basal electrophysiological investigation and excludes functional abnormalities.--OIF is of good diagnostic value when pathological. However, the integrity of sinus node function cannot be affirmed when this parameter is normal.

[Disappearance of coronary collateral circulation during a crisis of spontaneous angina. The role of spasm]. / Disparition de la circulation collatérale coronarienne au cours d'une crise d'angor spontané. Rôle du spasme.

Disappearance of the collateral coronary circulation was observed during an attack of spontaneous angina. During coronary angiography, the patient developed precordial pain, ST depression in Leads I, II, III, AVL, AVF, and V2 to V6. The two coronary arteries were opacified: there was no change in the left coronary tree but the collateral circulation arising from the right coronary artery and revascularising the obstructed left anterior descending artery the ECG reverted to its previous state and the collateral circulation reappeared. This case suggests that coronary artery spasm may lead to disappearance of the collateral circulation. It raises problems of methodology in the demonstration of spastic phenomena and emphasises the role of the collateral circulation in the genesis of ischaemia. It is another illustration of coronary artery spasm accompanied by ST depression.

[Angiography imaging in pulmonary embolism (author's transl)]. / L'angiographie dans l'embolie pulmonaire.

The principal angiography images found in cases of recent pulmonary embolism include intravascular lacunae, dome-shaped obstructions, a "dead tree" appearance and an avascular region. The first two are specific, but are mainly observed during the few days following the embolism. Highest quality images are obtained by selective angiography of the pulmonary artery, but this technique, which involves transfer of the patient to a specialized unit and catheterization of the pulmonary artery, is not without risk and, more particularly, does not explore the veins of the lower limbs. However, in a series of 110 cases of recent pulmonary embolism, venous thrombosis, usually femoroiliocaval, was present in 102 patients. A new technique is therefore proposed, ascending venous angiopneumography, which has two advantages: --It can be performed in any radiological department as a catheter does not have to be inserted. --It explores both pulmonary and venous systems. Though pulmonary images are less specific (false positives occur more frequently), the simultaneous exploration of the veins allows logical determination of therapy based on the size and site of the embolus and possible associated extension of the venous thrombosis.

[Phlebography in venous thrombosis of the lower limbs (author's transl)]. / La phlébographie dans les thromboses veineuses des membres inférieurs.

Phlebography is the best diagnostic technique for deep venous thromboses of the lower limbs. The authors use the "free flow" technique which they have modified by visualisation of the I. V. C. and I. V. A lacunar appearance or cupola-shaped interruption are indicative of a recent thrombosis, whilst the absence of a main venous trunk and a collateral circulation are more common in the presence of an old thrombosis. They emphasise the possible sources of error in interpretation and the difficulty in determining how long the thrombosis has been present. Despite its disadvantages, phlebography remains the essential examination in order to select treatment in patients in whom there is a suspicion of venous thrombosis or pulmonary embolism. Venous Doppler and rheoplethysmography, less sensitive and less specific, have a place in routine detection and the surveillance of treatment.

[Ascending venous angiopneumography. A new method of exploration in pulmonary embolism]. / L'angiopneumographie veineuse ascendante. Une nouvelle méthode d'exploration de l'embolie pulmonaire.

Selective angiopneumography is considered to be the best diagnostic investigation for pulmonary embolism. However, the technique has to be performed in a specialised unit, is associated with a certain degree of risk and does not explore the lower limb veins which are the usual site of migratory thrombi. The authors have therefore developed a new angiographic technique, ascending venous angiopneumography (AVAP) which successively opacifies the lower limb veins, inferior vena cava (IVC) and pulmonary arteries. It was used in 180 patients suspected of having a recent pulmonary embolism. It has three main advantages: 1) TECHNIQUE: this only involves injection of a vein on the dorsum of the foot, may be carried out in any radiological centre and is repeatable. 2) DIAGNOSIS: the investigation is more sensitive but less specific than selective angiopneumography when compared in a series of 25 cases: it was never normal in the 16 cases of pulmonary embolism, but in its absence there were 4 doubtful cases out of 8. This lack of specificity is compensated by the data obtained during the initial phlebocavographic times. The diagnosis of pulmonary embolism may be made when the context is suggestive and radiological evidence of venous thrombosis is obtained (124 cases). The diagnosis is very improbable when all phases of AVAP are normal (45 cases). 3) THERAPY: treatment should take the initial venous thrombosis into account, especially with regards to the choice of thrombolytic agents and surgical clipping of the IVC. Finally, this is a low-risk procedure.

[Use of intramuscular lidocaine in the acute stage of myocardial infarction]. / Utilisation de la lidocaïne intra-musculaire à la phase aiguë de l'infarctus du myocarde.

Methods of using intramuscular lignocaine and its relay with an intravenous infusion were studied in 34 patients with reference to serum levels. A first group of 9 patients with myocardial infarction received an intramuscular injection of 300 mg lignocaine into the deltoid or gluteral muscles at five day intervals. The deltoid appears to be the better site of injection in patients confined to bed because of its quick absorption, higher serum levels between the 15th and 90th minute (+47%), and longer duration of action (180 compared to 120 minutes). The difference is not observed in ambulatory patients and seems to be related to sluggish circulation in the gluteral muscles during bed rest. Its relay with intravenous infusion was studied in 14 patients. In the first 6 patients, intradeltoid injection was immediately followed by an infusion of 2.5 mg/mn, giving an average plasma lignocaine level between the 15th and 60th minute greater than 5 mu/ml. In the 8 other patients, a period of I hour was allowed to elapse before starting the infusion. The plasma levels were found to be within the therapeutic range in all patients and no side effects were observed. The administration of an intravenous infusion of 150 mg/hr of lignocaine for 48 hours led to excessively high plasma levels in 8 patients at the 24th hour, 3 of whom had side effects. Reducing the dosage to 100 mg/hr from the 12th hour onwards in II patients avoided this complication. A 300 mg intradeltoid injection of lignocaine is easy to give in the patient's home and therefore, is the best adapted method for the pre hospital treatment of myocardial infarction. When necessary, it may be relayed with an intravenous infusion one hour later, in the coronary care unit.

[The intravenous nitroglycerin test during coronary angiography]. / Le test à la nitroglycérine injectable au cours de la coronarographie.

The effects of intravenous nitroglycerin (Lenitral) on the calibre of coronary arteries and their lesions was studied in 100 consecutive patients undergoing coronary angiography. The coronary arteries were divided into segments (3 for the right coronary, 2 for the left anterior descending, and 2 for the circumflex artery). 510 segments were assessed (279 normal, and 231 pathological). The diameter of each was measured through the mid point before and after injection of a bolus of 0.3 mg nitroglycerin. The calibre of the coronary segments increased in 325 cases (63.7%). In 49 cases, the increase was greater than 50%. It remained the same in 151 cases (29,6%) and decreased in 84 cases (6,7%). The average increase in calibre was 16% (p less than 0.01). This had little relation to the artery under study, the location of the segment or whether the segment was pathological or normal. However, two findings were of interest: - the percentage of segments which increased their calibre was significantly higher in the normal segments (191 out of 279 cases, 68%) than in the pathological segments (134 out of 231 cases, 58%) (p less than 0.01). - Coronary lesions may change in appearance: images of stenosis or obstruction completely regressed in 4 cases, the degree of stenosis seemed to increase in 11 cases because of dilatation of the coronary vessel proximal and distal to the narrowing, and distal vessels appeared much more dilated in 5 cases. The factors which seem to affect the vasomotor response are multiple, and include the state of the arterial wall, the presence of vasodilatation or vasoconstriction prior to injection and the mode of administration of the nitroglycerin. The test should be performed by intravenous or intracoronary injection at the end of coronary angiography so as not to mask spastic phenomena. Some errors in the interpretation of the degree of stenosis or the quality of the distal post-stenotic coronary bed could thus be avoided.

[Medical treatment of ilio-caval venous thrombosis]. / Traitement médical des thromboses veineuses ilio-caves.

120 patients with ilio-caval thrombosis were managed medically. 55 patients were given heparin (5 mg/Kg/day for 15 days), 50 patients received streptokinase (loading dose 250,000 u; maintenance dose 100,000 m/h for 48 hours) and 15 patients had urokinase (112,500 u/h for 44 hours). Thrombolytic therapy was prescribed, in the absence of contraindications, for patients below 70 year of age: other patients were treated with heparin. The results were assessed by venography performed before and after treatment: success was defined as the complete disappearance of the thrombus of disobliteration of the ilio-caval axis. The overall success rate was 32%, with 68% failures. Success was higher with streptokinase (50%) than with heparin (20%) or urokinase (13%). The site, extension ans aetiology of the thrombosis did not affect the results. On the other hand, two other factors seemed to play an important role: - the duration of thrombosis: this only affected the streptokinase group; 23 of the 25 successes were obtained in patients treated before the tenth day. The results were unaffected by the duration of the thrombosis in the heparin group; - the biological effectiveness of therapy: 7 out of the 11 successes in the heparin group had been constantly well anticoagulated; there were only 4 successes out of 38 patients in whom the biological effectiveness had been intermittent. There were 21 successes out of 32 patients treated by streptokinase with serum fibrin levels of less than 1 g. There were only 4 successes in the 18 other cases. The incidence of haemorrhage was identical in the 3 groups. Embolism was slightly commoner in the streptokinase (3) than in the heparin group (2).