Myocardial region (right or left ventricle) and aetiology of heart failure can influence the inotropic effect of ouabain in failing human myocardium.

AIMS: To investigate whether the inotropic effect of ouabain in failing human myocardium varies according to the heart chamber tested (right or left ventricle) or the aetiology of the heart disease, i.e. ischaemic or idiopathic. METHODS: The inotropic effect of ouabain was measured, as the percentage change in baseline tension, in myocardial strips isolated from right (RV; n=21) and left ventricles (LV; n=21) of hearts explanted from patients with idiopathic (IDC; n=11) and ischaemic cardiomyopathy (CAD; n=10). Concentration-effect curves obtained with ouabain (0.05-1.6 micromol l-1 ) were analysed using the Emax sigmoidal model, and the following parameters were calculated: Emax, EC50, n and EC10 (threshold concentration). The influence of ventricular chamber and heart failure aetiology on these parameters was evaluated by means of a two-way anova. RESULTS: Age and baseline haemodynamic parameters did not differ between IDC and CAD patients. Baseline strip contractility was highly variable (range: 0.48-10.0 mN), but neither ventricular chamber nor aetiology could explain such variability. A two-way anova showed that EC10 was greater in CAD than in IDC preparations (0.097+/-0.013 micromol l-1 vs 0.059+/-0. 009 micromol l-1; 95% C.I. for difference 0.043, 0.071) and Emax was lower in RV than in LV (121+/-21% vs 250+/-38%; 95% C.I. -221, -36), while EC50 and n were not significantly different between groups. CONCLUSIONS: The inotropic effect of ouabain in human myocardium may vary according to aetiology of heart failure and the ventricle being tested. Although our results do not support the hypothesis of increased sensitivity to cardiac glycosides in CAD patients, they may explain the diminished effect observed in patients with RV failure.

Intraocular penetration of topical lidocaine 4%.

PURPOSE: To evaluate the intraocular penetration of lidocaine 4% topically applied before phacoemulsification. SETTINGS: Institute of Ophthalmology, University of Verona, and Department of Medical Pharmacology, University of Padua, Italy. METHODS: Thirty eyes having phacoemulsification for senile cataract were anesthetized by topical application of lidocaine 4%. The drug was applied 3 times in 30 minutes in 15 eyes and 6 times in 60 minutes in 15 eyes. At the beginning of surgery, aqueous humor samples were obtained to measure the lidocaine levels. Blood samples were obtained in 6 patients 30 and 60 minutes after aqueous humor collection. The aqueous humor levels were compared with the amount of pain perceived by patients during surgery. RESULTS: Mean aqueous humor lidocaine concentration was 8.68 micrograms/mL +/- 2.43 (SD) after 3 instillations and 23.21 +/- 8.87 micrograms/mL after 6 instillations. Blood levels of lidocaine were negligible. Patients whose intraocular level was below 12 micrograms/mL perceived more pain during surgery. Only 2 eyes had these low levels after 6 instillations. CONCLUSIONS: Topically applied lidocaine 4% effectively penetrates the eye, providing analgesia for phacoemulsification. We suggest at least 6 instillations in the hour preceding surgery. In this study, pain during surgery was primarily related to poor intraocular levels of the anesthetic agent.

Tolerance to the repolarization effects of rac-sotalol during long-term treatment.

AIMS: To establish whether tolerance to the QT effect could ensue during maintenance treatment with rac-sotalol. METHODS: The effect of rac-sotalol on QT interval duration was studied in 10 patients after single oral administration (160 mg) and after 6-day multiple oral dosing (80 mg two or three times daily). In order to separate the pure Class III effect from the bradycardia-related QT prolongation, heart rate/QT relationship was preliminarly assessed in each patient after the administration of a pure beta-adrenoceptor blocker (propranolol, 80 mg orally). Repolarization changes were quantified as percent difference between the measured QT and the expected QT on the basis of the individual heart rate/QT relationship. RESULTS: In all patients QT interval prolongation was linearly correlated with rac-sotalol log plasma concentration. The maximal QT prolongation and peak plasma concentration were not significantly different following acute and chronic administrations (QT effect: +18.1+/-6.3% vs +14.2+/-3.3%; peak concentration: 1.64+/-0.49 mg l(-1) vs 1.83+/-0.66 mg l(-1)). Line slopes were also unchanged following chronic treatment (21.8+/-8.9 vs 21.1+/-9.2). In four cases a significant rightward shift of the line occurred during repeated administrations, consistent with the appearance of pharmacodynamic tolerance. The inconstancy of this change in responsiveness may either be ascribed to a genetically determined individual susceptibility or to a variable interplay between Class III effect, gradual QT prolongation due to long-term beta-adrenoceptor blockade and tolerance development. CONCLUSIONS: During maintenance treatment with rac-solatol, partial loss of repolarization effects occurred in some patients suggesting pharmacological tolerance.

Evaluation of the regional responsivity to ryanodine of human myocardium from patients with idiopathic dilated cardiomyopathy and secondary cardiomyopathies.

The aim of the study was to compare the contractile response to ryanodine of human heart preparations taken from right and left ventricles of patients affected by idiopathic (IDCM) and secondary (SCM) end-stage dilated cardiomyopathies. Right and left ventricle myocardial strips were obtained from hearts of patients undergoing orthotopic heart transplantation and suspended in an oxygenated bath (T = 35 degrees C; stimulation frequency = 0.5 Hz). After an equilibration period, a cumulative dose-response curve for contractility (peak tension) was obtained with ryanodine (0.5, 1, 2, 4, 8, 16, 32, 64 microM). Basal contractility was not significantly different between right and left ventricles or between IDCM and SCM preparations. Ryanodine reduced peak myocardial tension but failed to completely suppress it, even at concentrations which achieved maximum effect. Ryanodine effect still persisted after a 45'-60' washout. The concentration-effect curves from IDCM right ventricle, IDCM left ventricle, SCM right ventricle and SCM left ventricle were compared: IDCM left ventricle was less sensitive to ryanodine than IDCM right ventricle and SCM left ventricle, while no difference was detectable between SCM left ventricle and SCM right ventricle. Thus, the overall sensitivity ranking was: IDCM left ventricle < IDCM right ventricle = SCM right ventricle = SCM left ventricle. IDCM left ventricle showed, in addition, a biphasic response with a shift from negative to positive inotropic effect at concentrations higher than approximately 10 microM. These findings indicate that the cardio-depressant effect of ryanodine, a drug which interferes with intracellular Ca release from the sarcoplasmic reticulum, differs quantitatively and qualitatively in IDCM left ventricle from both IDCM right ventricle and SCM left ventricle. This suggests that some specific alteration in the intracellular Ca signalling in IDCM exists and, from a methodological point of view, stresses the need for a "bi-ventricular" approach to studying biochemical and functional abnormalities of advanced congestive heart failure.

Electrocardiographic interactions between pinacidil, a potassium channel opener and class I antiarrhythmic agents in guinea-pig isolated perfused heart.

1. Drugs that shorten action potential duration could decrease the Na-channel blocking effect of class I antiarrhythmic agents by reducing the availability of Na channel in the inactivated state. 2. This hypothesis was tested in guinea-pig perfused heart, measuring the surface ECG effects of three class I drugs endowed with different binding kinetics (15 microM mexiletine, 10 microM quinidine and 3 microM flecainide) in the presence of increasing concentrations of pinacidil (10 microM, 30 microM, 50 microM), a potassium channel opener that shortens action potential duration. 3. The ECG parameters measured were: the QRS interval, i.e. the intraventricular conduction time; the JT interval, which reflects the duration of ventricular repolarization; the ratio between JT peak (the time from the end of QRS and the peak of T wave) and JT interval, which quantifies changes in the morphology of the T wave. 4. At the concentrations tested all the antiarrhythmic drugs widened the QRS complex by 55-60%. Flecainide did not significantly change JT interval, but quinidine prolonged and mexiletine shortened it. Mexiletine also decreased the JT peak/JT ratio. Pinacidil by itself decreased the JT interval and the JT peak/JT ratio in a dose-dependent way, but did not affect QRS duration. 5. In the presence of fixed antiarrhythmic drug concentrations, however, pinacidil decreased the QRS prolongation induced by mexiletine (-17%) and quinidine (-8%), but not that induced by flecainide: this effect was already maximal at the lower concentration tested (10 microM) and there was no relationship between pinacidil-induced JT shortening and QRS changes. To explain this unexpected result it has been supposed that, at the driving frequency used (4 Hz), myocardial cells were partially depolarized and that pinacidil could repolarize them, thus decreasing the number of inactivated Na channels and the effects of drugs that (mainly or partly) block the channels in the inactivated state. In agreement with this hypothesis, an additional series of experiments carried out with 15 microM mexiletine at a lower stimulation rate (2 Hz) showed only a negligible loss of QRS effect (- 2.3%) at any pinacidil concentration.6. Flecainide, but not quinidine and mexiletine, antagonized the JT shortening induced by pinacidil;furthermore, no drug modified the JTp/JT decrease induced by pinacidil.7. These results indicate that: (a) an antagonism between class I antiarrhythmic drugs and pinacidil is possible; (b) mexiletine is the most involved among the drugs tested; (c) the interaction is not related to pinacidil-induced repolarization shortening, but probably to changes in membrane resting potential. The possible clinical implications need to be defined.

Verapamil and norverapamil plasma levels in infants and children during chronic oral treatment.

Verapamil and norverapamil trough plasma levels were measured in 22 children, aged from 15 days to 17 years, under chronic oral treatment with the drug (mean daily dose +/- SD: 4.9 +/- 1.4 mg/kg) for supraventricular tachyarrhythmias (n = 20) or hypertrophic cardiomyopathy (n = 2). Overall, 67 determinations were available (1 to 11 per patient) and the mean concentration values (+/- SD) were 43.3 +/- 36.4 ng/ml for verapamil and 41.7 +/- 28.9 ng/ml for norverapamil. Verapamil and norverapamil trough concentrations were correlated with the daily dose (p < 0.05) but a wide intersubject variability was present at any given dose and the regression line did not pass through the origin of axes (x-axis intercept: 1.2 mg/kg for verapamil, 0.9 mg/kg for norverapamil). To study the influence of age on drug kinetics, verapamil plasma concentrations corrected by daily dose/kg ([V]/D) and norverapamil to verapamil concentration ratios (N/V) (taken as an index of metabolic clearance) were divided according to age quartiles. The median [V]/D was higher in the first and in the fourth age quartile than in the other two age groups. On the contrary, median N/V ratio increased with age, suggesting that drug metabolism was improving during the first year of life. Four children developed typical adverse reactions to the drug (bradycardia, AV block, hypotension). In one case verapamil plasma levels were definitely high (294 ng/ml). In the other three cases, concomitant factors (such as very young age and heart disease) seem to have contributed to drug toxicity.

A combination of hypothalamic phospholipid liposomes with trazodone for treatment of depression. An open controlled study.

In an open controlled trial of 48 patients with major depression illness (according to DSM-III), the patients were randomly assigned to 2 groups. One group of 25 patients was treated with 200-300 mg/day of trazodone and a second group of 23 patients was treated with 200-300 mg/day trazodone plus 1 ampoule (corresponding to 1000 gamma of lipidic phosphorous) twice daily of hypothalamic phospholipids (HPL). The effectiveness of treatment was evaluated by the Hamilton Rating Scale for Depression (HRSD). Side effects of treatment with trazodone were looked for by measuring systolic and diastolic blood pressure and heart rate and from EEG made before and on the 7th and 30th days of treatment. Combination with HPL shortened the typical latency of action of the antidepressant trazodone, definitely improved the subjective symptoms, especially the psychosomatic symptoms, on the HRDS and decreased the incidence of such side effects of trazodone as hypertension, reflex tachycardia and asthenia.

Effects of 6,6'-dithiodinicotinic acid (CPDS) and its metabolite 6-mercaptonicotinic acid (6-MNA) on murine and hamster fibroblasts (3T3 and BHK) and murine metastatic melanoma cells (F10).

We investigated the action of 6,6'-dithiodinicotinic acid (CPDS) and its metabolite 6-mercaptonicotinic acid (6-MNA) in vitro on murine (3T3) and baby hamster kidney (BHK) fibroblasts and an in vivo highly metastatic subline of murine B16 melanoma (F10). CPDS determined an inhibition of cell growth and a decrease in cell adhesion, while 6-MNA had no effect. When combined with data of the mitotic index and endogenous purine ribonucleotides (on which the drugs seem to have no effect), these observations are conceivable with the hypothesis that the primary target of CPDS is cell membrane.