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Background: The role of pulmonary veins (PVs) in persistent atrial fibrillation (AF) perpetuation appears less important than in paroxysmal AF. Electrogram-based substrate ablation is not widely performed as a stand-alone strategy., Objective: To evaluate PV activity in AF perpetuation and efficacy of our patient-tailored ablation strategy (electrogram-based substrate ablation with or without pulmonary vein isolation [PVI])., Methods: One hundred twenty-one patients with paroxysmal (n = 19; 15.7%), persistent (n = 77; 63.6%), or long-standing persistent (n = 25; 20.7%) AF underwent electrogram-based substrate ablation with AF termination end point: sinus rhythm or atrial tachycardia conversion. Before ablation, we classified PVs as "passive" if silent PV or if PV cycle length is greater than left atrial appendage cycle length. No PVI was performed in such cases., Results: Passive PVs were observed in 52 of 121 patients (paroxysmal AF = 0%, persistent AF = 40%, and long-standing persistent AF = 76%; P < .0001]). Substrate ablation terminated AF in 95.6% (sinus rhythm conversion in 80.2%). Compared with patients with active PVs, patients with passive PVs had longer AF sustained duration (19.1 ± 29.7 months vs 4.9 ± 11.1 months; P < .0001), larger left atrial diameter (46.9 ± 7.3 mm vs 41.9 ± 6.0 mm; P = .0014), lower left ventricular ejection fraction (45.4% ± 13.5% vs 55.1% ± 9.4%; P < .0001), and more often structural heart disease (57% vs 33%; P = .02). After a follow-up of 20.39 ± 11.23 months (1.6 procedures per patient), 82% were arrhythmia free with this strategy., Conclusions: PV activity during AF decreases with AF chronicity, left atrial dilatation, and left ventricular ejection fraction. Our patient-tailored ablation strategy without systematic PVI provides good results., (Copyright © 2014 Heart Rhythm Society. Published by Elsevier Inc. All rights reserved.)

Background and purpose: Up until recently complex fractionated atrial electrogram (CFAE) ablation has been considered as time consuming and its achievement as challenging, especially for non experimented operators. Moreover, results of substrate ablation based on CFAE detection in atrial fibrillation (AF) are very disparate, mainly because of the operator's subjective electrogram visual analysis and the difficult distinction between CFAEs really involved in AF perpetuation from other CFAE. Automatic detection provided by 3D mapping system (CARTO® algorithm) can be helpful but is not selective enough, drawing too wide CFAE areas. We sought to demonstrate a better selectivity of a new CFAE algorithm setting in order to better discriminate CFAEs really involved in AF perpetuation from other CFAE. Methods and subjects: A population of 32 patients (60.4±12.7 years) with paroxysmal (n=3) AF (PAF), persistent (n=16) AF (PeAF) or long-standing persistent (n=13) AF (LSPeAF), and AF history =56±65 months, underwent CFAE ablation based on visual analysis. Before ablation, left atrium CFAE mapping was performed on CARTO® shortest complex interval (SCI) algorithm and reanalyzed after ablation with the two different settings: nominal (SCI 60-120ms/0.05-0.15mV) vs. customized setting (SCI 30-40ms/0,04-0.15mV). CFAE areas automatically detected by both settings (CFAE-CARTO® areas) were respectively measured. The decision to ablate CFAE was only based upon the operator's electrogram visual analysis taken as reference because of high AF termination rate (93.7%) due to operator's CFAE selection experience. These ablation points drawn reference-CFAE areas involved in AF perpetuation (ablation point=60mm 2 ) allowing to compare the selectivity of the two previous automatic maps. Results: With the customized CARTO® SCI setting, we observed a significant reduction of CFAE areas detected by CARTO® (CFAE-CARTO® areas) and of the ablated CFAE surface inside non-CFAE CARTO® areas, (30.6±20.5cm2 vs. 68.8±24.5cm2, p<0.0001, and 1.86±1.82% vs. 3±3%, p=0.003). Furthermore the proportion of ablated areas/detected CFAE-CARTO® areas were higher with customized setting (38.2±19.6% vs. 20.4±17.5%, p=0.008). Conclusions: This new customized CFAE algorithm setting is significantly more selective than the nominal one and allows an automated detection of CFAE really involved in AF perpetuation truer to an efficient experienced operator's electrogram visual analysis.

Objective: Etifoxine is approved for the treatment of psychosomatic manifestations of anxiety. Several cases of acute hepatitis have been recently notified to the French pharmacovigilance centres. Our aim was to review all relevant cases of etifoxine hepatitis., Methods: All cases of liver disorders involving etifoxine and reported since November 1995 were extracted from the French pharmacovigilance database. Only cases with suggestive chronological events, no other drug-related or non-drug causes, and sufficient information, were included., Results: Of the 30 selected cases, 18 were retained for further analysis. The median duration of treatment before the onset of symptoms was 18 days (11 to 61 days). The results of liver tests evidenced cytolytic hepatitis in 15 cases and mixed-type hepatitis in 3. One patient also exposed to lisinopril/hydrochlorothiazide developed a fulminant hepatitis that required liver transplantation and six other patients had biological signs of severity. Except for the transplanted patient, 15 patients fully recovered within 3 months, and two clearly improved (further outcome unknown) after etifoxine withdrawal., Conclusion: One previously published case and our series confirm that etifoxine can cause acute liver injury with a possibly severe outcome. This adverse effect is not mentioned in the summary of the product characteristics., (Copyright © 2012 Elsevier Masson SAS. All rights reserved.)

Background: Studies have shown that the presence of left atrial (LA) fibrosis can be assessed by LA delayed-enhancement cardiac magnetic resonance (LA DE-CMR) and may be predictive of outcome after ablation for atrial fibrillation (AF). We sought to test the hypothesis that the amount of LA fibrosis evaluated by DE-CMR correlates with the difficulty of complex fractionated atrial electrograms (CFAE) ablation., Methods: Twenty-two consecutive patients (86.4% nonparoxysmal AF) underwent substrate CFAE radiofrequency (RF) ablation (±Pulmonary veins isolation) with AF termination as the endpoint. LA DE-CMR was performed prior to ablation. A global index of DE was defined by an average of six LA segmental scores based on a four-grade scale (no enhancement to maximum enhancement). Time between first RF application and AF termination, and RF duration until AF termination, was recorded. CFAE area/total LA surface was also measured on CARTO maps (Biosense Webster, Diamond Bar, CA, USA). These measures served to evaluate ablation difficulty, and were correlated with CMR images by double-blinded analysis., Results: Ablation restored sinus rhythm in 20 of 22 patients (91%), with a time to terminate AF of 140 ± 91 minutes. There was a significant correlation between the global averaged DE-CMR fibrosis grade and the electrophysiological substrate indexes such as "time to terminate AF" (Rho = 0.70, P = 0.0003), "RF duration until AF termination" (Rho = 0.65, P = 0.001), and a trend toward correlation with "CFAE area/LA surface" (Rho = 0.47, P = 0.03)., Conclusions:  LA DE-CMR can predict increased difficulty of CFAE ablation in AF. This tool may be beneficial in both selection of patients and ablation strategy., (©2011, The Authors. Journal compilation ©2011 Wiley Periodicals, Inc.)

We report the case of a 30-year-old man with situs inversus totalis, recurrent orthodromic reciprocal tachycardia, and the Wolff-Parkinson-White syndrome. He underwent, in our department, radiofrequency ablation of an accessory pathway (AP) located in the lateral mitral atrioventricular ring. Ablation of the AP was carried out successfully through a patent foramen ovale under fluoroscopic guidance, in a right anterior oblique projection with a 30° tilt and in anteroposterior views. We also used a mirror reversal of electrocardiogram (ECG) leads to better judge the site of the AP by using existing ECG algorithms. Complete situs inversus is a rare disorder, which has no consequence for the patient in the absence of cardiac or extracardiac involvement. Ablation of APs in situs inversus has been previously reported in only three cases of complete situs inversus and one case of situs ambiguous. In patients with mirror-image dextrocardia, APs seem more often located on the 'left' free wall (mitral annulus), as in the normal population. Radiofrequency ablation is feasible and safe after mirror reversion of the ECG electrodes and fluoroscopy.

Introduction: Management of recurrent ventricular tachycardia (VT) remains difficult. Neither medical treatments nor conventional endocardial radiofrequency (RF) ablation are efficient to prevent some recurrences. In these cases, a percutaneous pericardial approach may be required., Methods: Among all the patients referred to our center between 1998 and 2007 for a VT ablation, 276 endocardial and 35 epicardial procedures were performed, the latter in case of failure of the conventional approach. We report in this study the efficacy and the safety of these 35 interventions analyzed retrospectively., Results: Thirty-five epicardial procedures were attempted in 32 patients. An electric storm was present in 5 of 32 (16%) patients, with other individuals presenting with a recurrent VT despite drug therapy and a previous endocardial ablation. Pericardial space was reached in 28 of 32 patients by a xyphoidian puncture. An immediate success of RF on clinical VT was obtained in 22 of 29 (76%) cases. During a mean follow-up of 384 +/- 405 days, only 9 patients (26%) experienced a recurrence of a sustained VT. One patient died from tamponade during the procedure despite surgical drainage. Other complications had no significant consequences., Conclusion: Percutaneous epicardial puncture is feasible and relatively safe in patients with recurrent VT in whom conventional endocardial RF ablation failed. Epicardial RF ablation offers a high success rate in these challenging patients with only few severe complications.

Aims: The study aimed at evaluating the long-term effects of transient atrioventricular (AV) block on clinical outcomes during atrioventricular nodal re-entrant tachycardia (AVNRT) cryoablation., Methods and Results: In 150 consecutive patients (39 +/- 14 years, ineffective anti-arrhythmic drugs 1.9 +/- 1.3), slow-pathway cryoablation for AVNRT was performed. A 7 Fr 6 mm-tip cryocatheter was used. After successful cryomapping (-30 degrees C), defined as jump abolition or AV nodal refractory period prolongation, cryoablation (-80 degrees C for 4 min) was applied if no AV block occurred. Atrioventricular nodal re-entrant tachycardia inducibility was checked after 30 min. Acute success (AVNRT non-inducibility) was achieved in 142 patients (95%). Overall, after a follow-up of 18 +/- 10 months, 118 of 150 patients (79%) were recurrence-free (including 2 patients for whom the procedure was unsuccessful). Among successful procedures, 116 of 142 (82%) patients were recurrence-free. During cryoablation, inadvertent transient AV block of varying degrees occurred in 34 patients (22.7%), namely, increased PR in 17 patients and a 2nd-3rd AV block in the remaining 17. In 24 patients, AV block occurred at the last effective site (increased PR in 13 patients and a 2nd-3rd AV block in 11). In the study population as a whole, univariate predictors of recurrence in the follow-up were AVNRT inducibility (P < 0.001), increased PR at the last effective site (P < 0.001), residual jump (P < 0.02), and small Koch's triangle (X-ray distance < 11 mm between the His and coronary sinus ostium catheters; P < 0.02). Atrioventricular nodal re-entrant tachycardia inducibility (P < 0.03), increased PR (P < 0.01), and small Koch's triangle (P< 0.04) were independently significant. For attempts at the last effective site, 3 groups of patients were compared: 13 patients with increased PR duration (Group A), 11 with a 2nd-3rd AV block (Group B), and 126 without AV block (Group C). Cryo-application time was 277 +/- 203 s in Group A, 75 +/- 87 s in Group B, and 253 +/- 135 s in Group C (A vs. B, P < 0.01; B vs. C, P < 0.001; and C vs. A, P= NS). There was no statistical difference among groups in the atriogram/ventriculogram amplitude ratio at the site of the last attempt, unsuccessful acute procedure, small Koch's triangle, and residual jump. Actuarial incidence of recurrence-free status at 12 months was 38% in A, 82% in B, and 82% in C (A vs. B, P < 0.05; B vs. C, P = NS; and C vs. A, P < 0.001)., Conclusion: All AV blocks occurring during cryoablation were transient, confirming the safety of this method. An increased PR duration at the last effective site is associated with a higher recurrence rate, whereas a 2nd-3rd degree AV block has a recurrence rate similar to that of patients without AV block despite a shorter cryo-application time at the last site.

Background: Pericicatricial right intra-atrial reentrant tachycardias occur frequently in patients who have undergone surgical correction of an interatrial defect., Aim: To characterize the tachycardia circuits using three-dimensional electroanatomical mapping., Methods: Twelve tachycardias were analysed in 11 patients who had undergone surgical correction of an interatrial defect. Patients were divided into two groups: atrial flutter with typical sawtooth flutter waves in inferior leads, atrial tachycardia with clearly delimited P waves separated by an isoelectric line., Results: Seven tachycardias were classified as atrial flutter; three-dimensional mapping identified a peritricuspid circuit with inferior vena cava-tricuspid annulus isthmus involvement in all cases. All atrial flutters were terminated by linear ablation of this isthmus. Five tachycardias were classified as atrial tachycardia; three-dimensional mapping identified periatriotomy loops. All atrial tachycardias were ablated successfully between two scars or between a scar and an anatomical barrier., Conclusion: Periatriotomy loops were always associated with an atrial tachycardia electrocardiogram pattern. Three-dimensional electroanatomical mapping appeared to be particularly useful for circuit identification and for ablation of these complex arrhythmias.

Aims: Although all races are concerned with the Brugada syndrome, no case has ever been reported among black Africans. We describe five different cases in this specific group of populations., Methods and Results: In all patients, Brugada syndrome was identified after detailed noninvasive and invasive evaluations. Sex ratio was four males for one female. Convulsive syncope was noticed in 1 patient with a family history of sudden death. Diagnostic coved-type pattern was observed spontaneously in the normal position of right precordial leads in 3 patients and in a higher position of leads in 3 patients. Sixty percent had first-degree atrioventricular block. An ajmaline test was performed in 4 patients and was positive either in normal position of leads or in superior position in all of them. Sustained ventricular tachycardia (VT) or ventricular fibrillation (VF) was inducible during programmed ventricular stimulation in 3 patients. Right ventricular cineangiography found localized apical hypokinesia with preserved systolic function in 1 patient. Automatic cardioverter defibrillator was implanted in 2 patients. SCN5A was not found in any of the patients., Conclusion: These observations demonstrate that Brugada syndrome is also present in black African populations, and increasingly reported cases of apparent sudden death in the sub-Saharan part of the world need to rule out cardiac electrical disturbance such as Brugada syndrome.

Aims: Within the last several years, transvenous cryo-ablation has become an alternative method to perform ablation of the slow-pathway. This study evaluated the acute and long-term safety and effectiveness of atrio-ventricular nodal re-entrant tachycardia (AVNRT) cryo-ablation., Methods and Results: The first 69 consecutive patients with AVNRT (60 slow-fast, 4 fast-slow, and 5 slow-slow) who underwent slow-pathway cryo-ablation were included. Mean age was 37 +/- 15, body weight 68 +/- 14 kg, symptom duration 125 +/- 104 months, and number of ineffective antiarrhythmic (AA) drugs 1.8 +/- 1.4. A 7 Fr cryo-catheter (Cryocath(A)) was used, with initially 4-mm-tip and later with 6-mm-tip electrode. Cryo-mapping (n = 7.9 +/- 8.4 per pt) was performed at the temperature of -30 degrees C to test the effect on the target ablation site. Successful cryo-mapping was defined as abolition of nodal conduction jump or AV nodal refractory period prolongation. Cryo-ablation (n = 5.1 +/- 4.9 per pt) was then applied by freezing to -75 degrees C for 4 min in duration if no AV-block occurred. Acute procedural success (defined as AVNRT non-inducibility) after the first cryo-ablation attempt was achieved in 60/69 patients (87%). During cryo-ablation, inadvertent transient AV-block was encountered in 14 patients (five I AV-block and nine II-III AV-block). A mid-septal target site was the only variable correlated with inadvertent AV-block occurrence during cryo-ablation (P < 0.02). Long-term clinical success after cryo-ablation was globally achieved in 56/66 (85%) with a mean follow-up of 18 +/- 9 months (3 pts dropped-out). After the first procedure, 41/66 (62%) had no relapse, eight had a dramatic reduction in AVNRT duration-frequency and considered themselves cured, and five needed previously ineffective AA (with no relapse in three, drastic reduction in AVNRT duration-frequency in two). The five last patients needed one or more procedures, after which one had no recurrence and one had reduction in duration-frequency. Absence of recurrence after the first procedure was positively correlated with 6-mm-tip cryo-catheter use (<0.001) and negatively with acute procedural success (<0.001). At multivariate analysis, both were independently significant (<0.04 and <0.008, respectively). Long-term clinical success was correlated only with 6-mm-tip cryo-catheter use (<0.001)., Conclusions: Slow pathway cryo-ablation is associated with an acute success but a higher recurrence rate. A 6-mm-tip cryo-catheter seems to assure during cryo-ablation a large acute and long-term success. AV-block seems non-guaranteed by a negative cryo-mapping, stressing on need of a careful surveillance. Nevertheless, the theoretical advantage of avoiding the risk of permanent AV-block when compared with radiofrequency needs larger series to be demonstrated.

Introduction: The Brugada syndrome is a rare genetic disease that can lead to death. Its diagnosis requires electrocardiography., Case: A 36-year-old man was admitted with syncope. Brugada syndrome was diagnosed by the typical ECG pattern. The interaction between lithium therapy and ECG was shown clearly by the alternating type 1 and type 3 Brugada ECG patterns, depending on lithium status., Discussion: The Brugada syndrome may be unmasked by lithium therapy, due to its properties as a Na+ channel blocker, even at low doses. This case also demonstrated the usefulness of ECG in detecting the Brugada syndrome before and during lithium prescription.

Unlabelled: A survey into the implantation of cardiac pacemakers during 2001 in the Ile-de-France area was carried out by the French National Insurance Medical Service in order to evaluate performance in all centres performing more than 10 primary implantations per year., Methods and Results: In 2001, 12 centres out of a total of 49 performed less than 50 primary implantations per year, representing 5% of the total regional activity, which was estimated to be 6414 procedures. The remaining 95% of procedures were spread evenly among 8 high-throughput centres (> 200 primary implantations per year) and 29 medium-throughput centres (50 to 200 primary implantations per year). Indications for pacing were analysed retrospectively by a team of regulatory doctors on a sample of 2176 patients with reference to the ACC/AHA/NASPE guidelines. After examination of the medical records, the indication was ranked as being class I, II or Ill (absence of indication). A valid indication was lacking in 8.2% of cases. Sinus node dysfunction represented 74.6% of the non-indications, and this classification had the predictive factors of asymptomatic dysfunction, and treatment with anti-arrhythmic or bradycardic medication. The proportion of class III interventions was significantly lower in the high-throughput centres (5.8 vs 9.9%, p < 0.05)., Conclusion: 8.2% of primary pacing procedures were not indicated and resulted principally from asymptomatic sinus node dysfunction.

Atrial flutter with 1/1 nodo-ventricular conduction is a classical complication of Vaughan-Williams's Class I antiarrhythmic drugs. The increase of the flutter cycle and weak action of the antiarrhythmic on the atrioventricular node leads to 1/1 conduction of atrial depolarisation to the ventricles. In view of their marked action on the atrioventricular node, this type of pro-arrhythmic effect is very unexpected with Class III antiarrhythmics. The authors report 7 cases of 1/1 atrial flutter with oral amiodarone observed between 1994 and 2001. The patients were 6 men and 1 woman with an average age of 58 +/- 14 years. Four of them had underlying cardiac disease; none were hyperthyroid. The initial arrhythmia was 2/1 atrial flutter (n = 4), 1/1 atrial flutter (n = 2) and atrial fibrillation (n = 1). Treatment was preventive with doses of 400 mg/day associated with carvedilol in one patient and 200 mg/day in another. The other five patients all received loading doses of 9200 +/- 2400 mg over 10 +/- 4 days. The symptoms were palpitations (n = 2) associated in one patient with hypotension, one syncope, one near syncope and one cardiogenic shock. The ventricular cycle of the 1/1 flutter was 287 +/- 33 ms. The QRS duration was 136 +/- 35 ms with ventricular tachycardia-like appearances in 3 cases. An adrenergic trigger factor was noted in 5 patients. One patient required emergency cardioversion. The authors discuss the physiopathology of 1/1 flutter and theoretical diagnostic methods are proposed. In conclusion, amiodarone does not always prevent the occurrence of 1/1 nodo-ventricular conduction in atrial flutter.

Chelerythrine, a potent inhibitor of protein kinase C (PKC), was evaluated for its effect on inositol phosphate (IP) metabolism in newborn rat cardiomyocytes in culture. In a first step, we evaluated the effect of chelerythrine on IP accumulation in basal conditions. For a 10(-4) M dose, 5-phosphatase activity (which dephosphorylates IP3 into IP2) was completely blocked and we observed a large increase in IP accumulation limited to IP2 without any increase in IP3, strongly suggesting that chelerythrine at this dose modifies IP metabolism. At a lower dose (10(-5) M) of chelerythrine, which did not modify IP accumulation and 5-phosphatase activity in basal conditions, the response to angiotensin II stimulation was completely abolished by the addition of chelerythrine. We conclude thus that chelerythrine, even at 10(-5) M, interacts markedly with IP metabolism, and caution should be exerted when interpreting the results obtained with this drug, which is still currently used at this dose.

Background: The steroidal treatment used to prevent bronchopulmonary dysplasia (BD) in the preterm babies may be the cause of several complications, one of them being hypertrophic cardiomyopathy., Case Report: Four infants developed hypertrophic cardiomyopathy during glucocorticoid (dexamethasone and/or betamethasone) treatment for bronchopulmonary dysplasia. In one of them, septal hypertrophy led to left ventricular outflow tract obstruction and congestive heart failure. All four were premature infants born after 2 weeks of gestation and weighing 780 to 1,080 g. The first echocardiographic changes appeared between the 4th and 15th day of the glucocorticoid course when the cumulated dose was respectively 1.82-1.87-3.51 and 3.86 mg/kg. Hypertrophic cardiomyopathy resolved completely between 2 and 4 weeks after cessation of the treatment., Conclusion: The glucocorticoid dosage to prevent BD should be reduced to 0.3 mg/kg/j and the myocardial function should be monitored by repeated echocardiograms during the first 15 days of treatment.

Ten patients with orthotopic liver transplants were investigated during routine therapeutic monitoring to study the relationship between the concentrations of cyclosporin and its metabolites in blood, bile and urine, and whether this information can provide early signs of severe hepatic disorders post-transplantation. Cyclosporin (Sandimmun®) was administered by continuous infusion at a constant rate of 5 mg/kg/day, modified to keep the blood cyclosporin concentration within the target range (400 to 500 μg/L). The concentrations of cyclosporin and combined cyclosporin-metabolites in blood, bile and urine were assayed daily during the 3 post-transplantation weeks that the patients spent in intensive care.All patients developed cholestatis and cytolysis during the first week. The severity of these liver transplant disorders increased in 5 patients and decreased in the other 5 in the second week. The pharmacokinetics of cyclosporin differed in the 2 groups: in patients without severe hepatic disorders, the blood metabolites/cyclosporin ratio (M/C) stabilised at 1.2 ± 0.4 in week 2 and at 0.8 ± 0.2 in week 3, bile cyclosporin/blood cyclosporin (bile C/blood C) fluctuated around 13.5 (13.5 ± 9.5 in week 2 and 13.5 ± 9.0 in week 3) and the bile metabolite/blood metabolite (bile M/blood M) ratio was very high and variable (131 ± 86 in week 2 and 159 ± 116 in week 3). Metabolites significantly accumulated in the blood of patients with severe hepatic disorders (M/C = 2.8 ± 0.6 in week 2 and 3.5 ± 1.0 in week 3); bile C/blood C (2.6 ± 2.1 in week 2 and 3.4 ± 1.1 in week 3) and bile M/blood M (11.9 ± 7.8 in week 2 and 12.5 ± 7.9 in week 3) significantly decreased and showed less interindividual variability.Blood cyclosporin is usually monitored to help optimise the dosage. However, if this was extended to include the monitoring of metabolites in the blood, and cyclosporin and metabolites in the bile, it could provide an early indication of severe hepatic disorders in patients with transplanted livers.

A gas chromatographic method using a short, high-resolution capillary column connected to a specific thermoionic detector and requiring a simple and short extraction step without evaporation was developed for the rapid and precise determination of two new hypnotics, zolpidem and zopiclone, in serum at concentrations greater than 5 ng/mL. The assay was linear between 5 and 200 ng/mL, with coefficients of intra- and interassay variation less than 5% for both. The method was validated and then used to analyze zolpidem serum concentrations in nine rabbits after oral administration of 0.5 mg/kg and zopiclone serum concentrations in six patients treated orally with a 7.5-g dose.

The symptoms of acute poisoning after accidental administration of ten times the usually prescribed dosage of caffeine in a premature infant included the following neurological signs: incessant tremors, hypertonia, continuous opisthotonos posture, whining and crying and digestive disturbances. The very high serum caffeine levels, 160 mg/l, determined 66 hours after the first administration was confirmed by the very high cerebrospinal fluid caffeine concentration 115 mg/l. Two exchange transfusions performed at an interval of 16 hours produced a large decrease in serum caffeine levels of approximately 40 mg/l each time, and a similar decrease in the cerebrospinal fluid concentration. The clinical status of the infant improved very rapidly and the child's psychomotor development was normal at 3 months of age.

Single dose disposition of oral quinidine (400 mg sulfate) was studied in a control group of subjects (No. = 6) and in hospitalized alcoholic patients involving one group with (No. = 6) and one group without (No. = 11) hepatic cirrhosis. All subjects also underwent an antipyrine and a debrisoquine test. Patients with cirrhosis had a prolonged elimination half-life (29.5 +/- 5.9 h) and low clearance (24 +/- 7 ml.kg-1.h-1) of antipyrine and also a considerably higher debrisoquine metabolic ratio (18.8 +/- 3.3) than the controls, whereas the alcoholics without cirrhosis had metabolic patterns for these two test compounds comparable to those seen in the controls (antipyrine half-life: 8.8 +/- 1.1 h and 9.8 +/- 2.0 h; debrisoquine metabolic ratio: 3.6 +/- 0.7 and 3.8 +/- 1.2 for alcoholics and controls respectively). In patients with cirrhosis the apparent elimination half-life of quinidine was longer (12.8 +/- 1.8 h) whereas after oral administration clearance of quinidine (15.6 +/- 3.5 l.h-1) and quinidine/3-hydroxyquinidine ratio (9.9 +/- 2.1) were not different from controls (quinidine clearance: 13.45 +/- 1.9 l.h-1; quinidine/3-hydroxyquinidine: 10.3 +/- 2.7). A possible change in distribution patterns of quinidine in cirrhotics may explain these findings.

A sparteine test was carried out in 14 patients suffering from acute schizophrenic psychoses before and 1-2 times during oral haloperidol treatment in doses of 10-40 mg day-1. In patients classified as extensive metabolisers (sparteine MR less than 20 before treatment), haloperidol treatment resulted in a rise in sparteine MR that correlated with the serum-haloperidol concentration both within and between patients. At the highest serum haloperidol concentrations (60-80 nM) an increase in sparteine MR by a factor 15-50 was seen, but no patients were transformed into phenotypically poor metabolisers. The steady state concentration of haloperidol on the initial standard dose of 10 mg day-1 was the same in one patient classified as a sparteine poor metaboliser (MR = 112) as in eleven patients classified as extensive metabolisers (MR:0.22-1.47).