Efficacy, tolerability and side-effect profile of fluvoxamine for major depression: meta-analysis.

Fluvoxamine, one of the oldest selective serotonin reuptaking inhibitors, is commonly prescribed to patients with major depression. Several studies have reviewed the efficacy and tolerability of fluvoxamine for the treatment of major depression. However, these reviews are outdated, have not been systematic and/or suffered from several methodological weaknesses. We conducted a systematic review to synthesize the best available evidence on the efficacy of fluvoxamine for adult patients suffering from major depression in comparison with other active antidepressive agents. Relevant randomized controlled trials were identified through a comprehensive search. The primary outcome was a relative risk of response, and the secondary outcome was a relative risk of remission. Tolerability and side-effect profile were also examined. Fifty-three trials were included. There were no large differences between fluvoxamine and any other antidepressants in terms of efficacy and tolerability. There is evidence of differing side effect profiles, especially when comparing gastrointestinal side effects between fluvoxamine and tricyclics. Clinicians should focus on practically or clinically relevant differences including those in side-effect profiles.

Plasma des-acyl and acyl ghrelin in patients with eating disorders.

A recently recognized peptide, ghrelin, increases appetite and energy retention in human. Previous reports have shown higher plasma level in eating disorder (ED) patients and correlations with body mass index (BMI). This study examined these findings by measuring active (N-RIA) and total (C-RIA) levels of plasma ghrelin. Multipurpose assessments of symptoms were conducted for 11 ED patients and 5 control females. Results revealed significant differences of C-RIA between the groups. The BMI did not correlate with ghrelin, but demonstrated reversal correlation with the ratio of N-RIA and C-RIA (NC ratio) according to the ED or control group. The NC ratio also tended to be associated with a self-rating score. The NC ratio might be related to specific characteristics of ghrelin secretion or clearance in ED patients. Further basic and clinical investigations are necessary.

Acute effects of doxorubicin on skinned cardiac muscle fibres of guinea pigs.

OBJECTIVE: The aim was to examine the effect of doxorubicin on spontaneous cyclic Ca2+ release from the sarcoplasmic reticulum of skinned fibres, as measured by isometric tension development in EGTA free, Ca2+ free solution. METHODS: Experiments were done on fragments of papillary muscles from the right ventricles of guinea pigs. Skinned fibres were prepared by treatment with saponin. The effects of doxorubicin in concentrations of 2 x 10(-9) to 2 x 10(-5) M on cyclic contractions were evaluated in 20 muscles. The effects of doxorubicin in concentrations of 2 x 10(-7) and 2 x 10(-5) M on pCa-tension relation were examined in 14 muscles treated with Brij-58. RESULTS: Doxorubicin (2 x 10(-9) to 2 x 10(-5) M) increased the frequency of cyclic contractions and induced an incomplete muscle relaxation in a dose dependent manner. Doxorubicin 2 x 10(-7) M had no effect on pCa-tension relation. Doxorubicin 2 x 10(-5) M shifted the pCa-tension curve slightly to the left. CONCLUSIONS: An incomplete muscle relaxation is considered to be due to an increase in Ca2+ release from the sarcoplasmic reticulum and a slight increase in the sensitivity of the contractile proteins to Ca2+. These observations suggest that one cause of the intracellular Ca2+ overload induced by doxorubicin, a putative mechanism of the doxorubicin induced cardiomyopathy, is attributable to the direct effects of doxorubicin on the sarcoplasmic reticulum, impairing its ability to sequester Ca2+.

Tachyarrhythmia provoked by coughing and other stimuli.

A rare case of cough-induced tachyarrhythmia is described. The effectiveness of atropine sulfate, and worsening of the arrhythmia resulting from administration of digitalis, suggests that vagal reflex might be the mechanism responsible for the tachyarrhythmia.

Effect of diltiazem on spontaneous cyclic Ca2+ release from sarcoplasmic reticulum.

We used saponin-treated skinned fibers isolated from papillary muscles of the right ventricle of guinea pigs to compare the effects of diltiazem on the spontaneous cyclic Ca2+ release from the sarcoplasmic reticulum (SR) of cardiac muscle with the effects of caffeine. Both diltiazem and caffeine increased the frequency of cyclic contractions in EGTA (ethyleneglycol-bis-(beta-aminoethylether) N,N,N',N'-tetra-acetate)-free solution and induced an incomplete, concentration-dependent relaxation of the muscle. The results suggest that the spectrum of the pharmacological effects of diltiazem on the SR is similar to that for caffeine, that is diltiazem accelerates the spontaneous Ca2+ release from the SR and suppresses Ca2+ reuptake by the SR, and that diltiazem as well as caffeine may act on the SR in vivo in a specific condition.

A case of left ventricular aneurysm of uncertain etiology presenting as ventricular tachycardia.

A case of a 59-year-old Asian male with several episodes of syncope and palpitation is reported. Electrophysiologic study disclosed that sustained ventricular tachycardia was induced by programmed electrical stimulation at the right ventricular apex. The electrogram in the left ventricular aneurysm showed delayed activities and the fastest depolarization. Entrainment was observed by faster pacing. Left ventriculography showed a large aneurysm and normal coronary arteries. Congenital left ventricular aneurysm is the most likely clinical diagnosis given the lack of past history of chest pain, myocarditis, cardiomyopathy, etc. Congenital aneurysm which presents as ventricular tachycardia is very rare, and has never been reported in an Asian. Medical management has thus far been successful.

Swallowing-induced arrhythmia.

Deglutition tachyarrhythmia, first reported in 1926 by Sakai and Mori, is a rare clinical entity. Vagal reflex has been supposed to be responsible for the induction of the arrhythmia. We have recently studied a patient with swallowing-induced premature atrial contractions. Atropine sulfate and catecholamine infusion increased the frequency of the arrhythmia, while beta blockade suppressed it. It is suggested that the mechanism of the swallowing-induced arrhythmia might be related to a sympathetic reflex. As far as we know, there have been few reports in which the sympathetic reflex was proposed to be responsible for the arrhythmia.

[Evaluation of right ventricular systolic and diastolic properties using 81mKr scintigraphy with continuous infusion].

To evaluate right ventricular (RV) systolic and diastolic properties in patients with various heart diseases, RV volume curves obtained from 81mKr scintigraphy with continuous infusion were analyzed. The data were acquired in right anterior oblique position for five minutes, and from RV time activity curve and its first derivative curve, ejection fraction and peak ejection rate as systolic indices, and peak filling rate, time to peak filling and 1/3 mean normalized diastolic filling rate as diastolic indices were calculated. Ejection fraction in patients with dilated cardiomyopathy was lower than that in controls, but there was no difference in systolic indices among controls and patients with the other heart diseases. However, diastolic indices in patients with hypertrophic cardiomyopathy, patients with hypertensive heart disease, patients with dilated cardiomyopathy, patients with inferior myocardial infarction, and some patients with anteroseptal myocardial infarction were lower than those in controls. In conclusion, analysis of RV time activity curve by 81mKr scintigraphy with continuous infusion provides RV systolic and diastolic indices, which may permit evaluation of RV systolic and diastolic properties in various heart diseases.

[An attempt of thallium-201 myocardial perfusion imaging during transient coronary arterial occlusion by PTCA].

To evaluate the myocardial perfusion during transient coronary occlusion, we attempted to obtain the myocardial scintigraphy during percutaneous transluminal coronary angioplasty (PTCA). Tl-201 was injected at the last inflation of angioplastic balloon and occlusion was kept on for 60 sec. Planar images or SPECT were obtained immediately after PTCA. With this protocol, myocardial perfusion defects were observed during PTCA and fully redistributed 3 hours after Tl injection. Extent of ischemic lesions were almost same as that observed during exercise in two cases without collateral vessels. In a case with well visualized collateral vessels, perfusion defect was smaller in PTCA images than that in exercise stressed images. We conclude that intravenous injection of Tl-201 during PTCA is useful to assess the alteration of myocardial perfusion due to transient coronary occlusion without increasing the risk of angioplastic procedure.

[Complete remission obtained in refractory acute lymphocytic leukemia using high-dose cytosine arabinoside combined with low-dose L-asparaginase].

A 41-year-old male was diagnosed as acute lymphocytic leukemia (ALL) in November, 1982 and partial remission was obtained by a combination chemotherapy of LVP, DVP ABOP and VAMP. In January, 1983, peripheral blood showed an increasing number of leukemic cells and he was readmitted to our hospital. WBC count in the peripheral blood was 13,200/mm3 and an 82% ratio of leukemic cells was observed. Bone marrow aspiration showed a hypercellularity of 89.4% leukemic cells. High-dose Ara-C therapy was started at a dose of 3 g/m2 i.v. every 12 hours for 6 days. Leukemic cells in peripheral blood were rapidly decreased in number, and the nucleated cell count of bone marrow was also reduced after 3 weeks of treatment, however 95% of leukemic cells remained. Low-dose L-asparaginase was then supplemented at a dose of 2000 U for 3 days, and 2 months later complete remission was achieved. The side effects associated with this high-dose Ara-C therapy were nausea, vomiting, diarrhea, fever and conjunctivitis, although these were tolerable. These observations suggest that high-dose Ara-C combined with L-asparaginase should be added to the treatment of leukemia which is refractory to conventional chemotherapy.

[Effects of propafenone on the parameters of body surface electrocardiogram in comparison with those of disopyramide].

The purpose of this study is to investigate the clinical effects of propafenone on the QT(QTc), QRS, PQ and RR interval of body surface electrocardiogram (ECG) in comparison with the effects of disopyramide. In 10 patients (5 with paroxysmal atrial fibrillation and 5 with ventricular premature complex: ages 48-77), after 4 days' observation without any cardioactive drugs, disopyramide (300mg/day) was administered orally for 7 days. After discontinuing the administration of disopyramide, 4 more days were allowed to wash out the drug, and propafenone (450mg/day) was administered orally for 7 days. 12-lead ECG was taken twice before the administration of disopyramide (Pre-1 and -2), on the 1st, 3rd, 5th and 7th days after the administration of disopyramide. Then it was also taken on the day before the beginning of propafenone administration and on the 1st, 3rd, 5th and 7th days after the administration of propafenone. The corrected QT (QTc = QT/square root of RR), QRS, PQ and RR intervals in lead II or V2 of each ECG were measured as the mean value of 5 consecutive sinus beats. The control values of QTc, QRS, PQ and RR intervals were calculated as the mean values of Pre-1 and -2, and the other values were expressed as the % ratio to the control values. Propafenone hardly altered the QTc interval but prolonged QRS interval after the 5th day of administration (110 +/- 12%, p < 0.05), while disopyramide significantly prolonged the QTc interval after the 3rd day of administration (109 +/- 5%, p < 0.001) without affecting the QRS interval.(ABSTRACT TRUNCATED AT 250 WORDS)

[Frequency dependent prolongation of inter-atrial conduction time by mexiletine in human atrium].

To investigate frequency dependent conduction slowing by mexiletine in the human atrium, we examined inter-atrial conduction time (IACT) at different stimulation frequencies (100/min to 220/min) in 13 patients with paroxysmal atrial fibrillation (Paf) and 7 patients without Paf. IACT was prolonged as the stimulation frequency was increased, and either before or after mexiletine administration IACT was longer in the Paf group (max 114 +/- 9 msec, p < 0.01, mean +/- SD) at any stimulation frequency than in the non-Paf group (max 100 +/- 8 msec). The change in IACT induced by mexiletine administration (% delta IACT) was larger in the Paf group (max 14.8 +/- 5.4%, p < 0.05) than in the non-Paf group (max 5.5 +/- 2.2%) at stimulation frequency over 140/min. Effective refractory period measured at the high right atrium was slightly decreased due to mexiletine in both the non-Paf and the Paf group. In conclusion, mexiletine showed frequency dependent suppression of conduction in the human atrial myocardium especially in patients with Paf.

[Electrophysiologic study of cibenzoline in patients with paroxysmal atrial fibrillation with special reference to atrial fibrillation threshold].

Electrophysiologic effects of cibenzoline were studied in 7 patients (6 males and one female) aged from 40 to 69 years (mean +/- SD; 52 +/- 10) with paroxysmal atrial fibrillation which was documented by 12 leads ECG or by 24 hours Holter monitoring. No organic heart diseases were found except in one patient with dilated cardiomyopathy and sick sinus syndrome (SSS). Cibenzoline (200mg) given orally increased P wave duration, PR interval and QRS duration significantly. The duration of P wave was gradually increased as the pacing frequency was increased. Neither sinus cycle length, nor sinus node recovery time (SRT), nor Wenkebach cycle length, nor atrial effective refractory period, nor QT interval was changed by the drug. One patient with SSS showed increase in SRT from 2,303 msec to 5,150 msec. The minimum current which was required to induce atrial fibrillation by rapid atrial stimulation (50 Hz, 1 sec) lasting more than 30 sec was defined as atrial fibrillation threshold (AFT). The AFT was 4.0 +/- 2.2 mA at the baseline state in 7 patients. After the oral administration of cibenzoline, 5 patients showed increase in AFT, while 1 patient showed decrease and another patient showed no change in AFT. Statistically, AFT was significantly increased to 7.3 +/- 3.4 mA in 7 patients. The results suggest that cibenzoline might be effective to prevent paroxysmal atrial fibrillation in patients without organic heart diseases.

[Elucidation of reversibility in myocardial injury during hypoxia and reoxygenation in papillary muscles of rats].

We reported the calcium release of sarcoplasmic reticulum (SR) is the major source of activator calcium to postrest contraction (PRC), and that the transsarcolemmal calcium influx is (the major source of activator calcium) to regular contraction in rats. In this study we investigated the combined effects of hypoxia and glucose elimination on PRC and regular contraction. In other words, using papillary muscles of rats, to elucidate the characteristics of reversible or irreversible myocardial injury after ischemia, we investigated the effects of hypoxia on both SR and sarcolemmal functions. After 90 min hypoxia (the first hypoxia-90 min), regular contraction was significantly more reduced than PRC (p less than 0.001; n = 16). With 90 min of reoxygenation, the recovery from hypoxic injury of PRC was better than recovery from injury of regular contraction (p less than 0.01; n = 16). After either 30 min hypoxia (the second hypoxia-30 min) or 60 min hypoxia (the second hypoxia-60 min), regular contraction was also more reduced than PRC, respectively (p less than 0.001; n = 8). However, the recovery from both the second hypoxic injury-30 min and the second hypoxic injury-60 min of PRC was not significantly different from that of regular contraction, respectively (NS; n = 8). Percentages of diastolic tension, which were normalized by baseline regular contraction, increased during hypoxia and decreased incompletely after reoxygenation. After the first reoxygenation of 90 min, 1 microM noradrenaline significantly augmented the magnitude of regular contraction (p less than 0.05; n = 5).(ABSTRACT TRUNCATED AT 250 WORDS)

[Electrophysiological effect of verapamil on human atrium].

To investigate the effect of verapamil on atrial vulnerability, the following measurements were performed before and after the intravenous administration of verapamil (0.15 mg/kg) in 10 subjects with paroxysmal atrial fibrillation (Paf), and 10 subjects without Paf (non-Paf). During the sinus rhythm, 1) intra-/interatrial conduction time (Intra-/Inter- ACT); the initial deflection of high right atrium (HRA) to that of His bundel/coronary sinus were measured. After 8 consecutive HRA stimuli (A1), premature stimulus (A2) was introduced by shortening the coupling interval (A1A2) and we measured 2) conduction delay zone (CDZ); the zone of A1A2 with the prolongation of Inter-ACT, 3) % maximum atrial fragmentation (%MAF); % maximum value of the ratio of HRA activity width at A2 (Awt) against that at A1 (Awc), 4) fragmented atrial activity zone (FAZ); the zone of A1A2 with % value of Awt/Awc more than 150%,5) repetitive atrial response (RAR); more than 2 atrial activities which occur in response to A2. (6) right atrial effective refractory period (RAERP). Verapamil significantly shortened CDZ and %MFA, slightly lengthened RAERP, and had RAR disappear in Paf, while it did not effect any indices significantly in non-Paf. We concluded that verapamil could reduce atrial vulnerability in Paf due to blocking of atrial conduction delay mediated by slow response fibers.

[Electrophysiological effects of flecainide acetate on guinea-pig left atrial cells].

Using conventional glass microelectrode technique, electrophysiological effects of flecainide acetate on guinea-pig left atrial muscle fibers were examined. Resting membrane potential was not affected by flecainide at any concentrations tested (10(-7) M-3 X 10(-5) M), although overshoot potential was significantly decreased at the concentration over 3 X 10(-6) M. Effective refractory period significantly increased at 10(-5) M. The reduction of Vmax was about 25% and 50% by 3 X 10(-6) M and 10(-5) M, respectively at 1 Hz. At 3 X 10(-6) M, Vmax decreased by about 10%, 15%, 22%, 33%, and 34% at 0.2, 0.5, 1, 2, and 3 Hz respectively. Flecainide, decreased Vmax of atrial muscle fibers in a dose and frequency dependent manner. It is suggested that flecainide might be effective in the treatment of atrial tachyarrhythmias.

[Effects of ouabain, caffeine, and diltiazem, on spontaneous cyclic Ca2+ release from sarcoplasmic reticulum in the skinned papillary muscles of guinea pigs].

The aim of this study was to assess whether ouabain has a direct action on the sarcoplasmic reticulum (SR) sufficient to be responsible for the mechanism of the inotropic action, and whether caffeine and diltiazem, which inhibit ouabain-induced afterpotential and after-contraction, can inhibit the effects of ouabain on the SR. As one of the functions of SR, spontaneous cyclic contractions (cyclic Ca2+ release from the SR) in saponin-treated skinned fibers of guinea pig papillary muscles were used. Ouabain 10(-9)-10(-7) M increased the frequency of cyclic contractions and induced an incomplete muscle relaxation. Caffeine 1-5 mM and diltiazem 1-5 mM induced a sustained tension. In the fibers treated with ouabain, caffeine and diltiazem induced a sustained tension. In Brij-58 treated skinned fibers, 10(-9) M ouabain did not change the Ca2+ sensitivity of the contractile system. It is now known that ouabain increases intracellular calcium transients. An incomplete muscle relaxation of cyclic contractions seems to be due to both increased SR Ca2+ release and decreased Ca2+ reuptake by SR. Thus, we suppose that ouabain-induced increase in intracellular calcium transients is due to increased intracellular Ca2+, which may be one of the mechanisms in the inotropic action. The masking effects of caffeine and diltiazem on the ouabain-induced increase in cyclic contractions seem to be responsible for the inhibitory effects of drugs on digitalis-induced afterpotential and after contraction.

[Effect of pilsicainide hydrochloride on atrial fibrillation threshold].

To inventigate the electrophysiologic effects of pilsicainide hydrochloride on atrial fibrillation, we compared atrial fibrillation threshold (AFT), right atrial effective refractory period (RAERP), and inter-atrial conduction time (Inter-ACT) before and after the administration of pilsicainide in 12 patients with lone paroxysmal atrial fibrillation. The following electrophysiologic study was performed before and after the administration of the drug as the paced cycle length of 500msec. First, RAERP was measured. Secondly, Inter-ACT from the stimulating artifact to the initial deflection in the elecrocardiograms of the coronary sinus was measured. Thirdly, high-frequency (50Hz) stimulation was given at right atrial appendage continuously for one second just after the eighth basic paced beat. The stimulation current was increased by 1mA in a stepwise fashion from 2mA until atrial fibrillation ensued. AFT was defined as the lowest intensity of the current that induced atrial fibrillation or flutter of more than 30 seconds. Pilsicanide significantly increased AFT and Inter-ACT, but did not change RAERP. In conclusion, it is suggested that pilsicainide might decrease atrial vulnerability mainly by its effect on inter-atrial conduction delay and by the resulting increase in AFT.

[Electrophysiologic effects of flecainide on guinea pig atrium].

We investigated the effects of flecainide on guinea pig atrial muscle. Using Langendorff's method, the whole heart of a guinea pig was perfused with Tyrode's solution containing acetylcholine (3 x 10(-7) M). Then, with right atrial extrastimulus and high frequency pacing method, the following values were measured before and after administration of flecainide (10(-7)-10(-5) M). A) Effective refractory period (ERP); the longest coupling interval which failed to produce right atrial activity at premature stimulus. B) Interatrial conduction time (ACT); After right atrial stimuli by trains at PCL 200 ms for 5 min the interval from the stimulation to the first deflection of the left atrial activity. C) Atrial fibrillation threshold (AFT); the minimal amount of current required to induce atrial fibrillation lasting for more than 30 sec by 50 Hz high frequency stimulation. Flecainide lengthened ERP (> or = 3 x 10(-5) M) and ACT (> or = 10(-7) M). Flecainide (10(-5) M) significantly increased AFT which correlated well with ERP (r = 0.81, p < 0.002) and ACT (r = 0.84, p < 0.002). In conclusion these effects of flecainide on guinea pig atrium might explain in part the clinical effectiveness of the drug on paroxysmal atrial fibrillation.