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Biomedical subjects

D Miura

Publications and source records attributed to D Miura.

At least 19 recordsLinked to original sources
PubMed1993

Decrease in deoxyribonucleotide triphosphate pools and induction of alkaline-labile sites in mouse bone marrow cells by multiple treatments with methotrexate.

Methotrexate (MTX), an inhibitor of dihydrofolate reductase (DHFR), slightly induced micronuclei in bone marrow and peripheral blood cells, and this induction was enhanced by multiple treatments with the drug. Furthermore, we have suggested that the multiple-dose effect on the induction of micronuclei by MTX might be explained by intracellular accumulation of the drug, resulting in an enhancement of DHFR inhibition. An imbalance or decrease in the deoxyribonucleotide (dNTP) pool would be generated by this enzyme inhibition. Therefore, we attempted to determine the level of the dNTP pool in mouse bone marrow cells. The levels of three dNTPs (dTTP, dATP, dGTP) as determined by HPLC were only 1/10-1/40 of the levels previously found in mammalian cell lines, but dCTP levels could not be determined precisely because they approached the limits of detectability. The levels of dTTP, dATP and dGTP in mouse bone marrow cells 3 h after four injections of MTX (4 mg/kg/day) decreased to 21.2%, 47.0% and 38.1%, respectively, of those in the control group. The level of dTTP 3 h after four injections of 100 mg/kg of the drug decreased to almost 0%. The results of alkaline elution assays suggested that alkaline-labile sites were generated in mouse bone marrow cells 6 h after four injections of MTX (4 mg/kg). These findings suggest that the multiple-dose effects of MTX on micronucleus induction in mouse bone marrow cells may be explained by the decrease in the dNTP pool and subsequent generation of alkaline-labile sites (possibly apurinic/apyrimidinic sites).

Animals↗
PubMed1992

Mechanism of induction of micronuclei and chromosome aberrations in mouse bone marrow by multiple treatments of methotrexate.

Methotrexate (MTX), an inhibitor of dihydrofolate reductase (DHFR), slightly induced micronuclei and this induction of micronuclei was enhanced by multiple treatments with the drug (Yamamoto et al., 1981; Hayashi et al., 1984; CSGMT/JEM.MMS, 1990). More micronuclei and chromosomal aberrations in mouse bone marrow cells were induced by multiple than by single treatment. The MTX level in mouse plasma and bone marrow showed little (or no) differences between single and quadruple treatments several hours after the injection(s). On the other hand, the DHFR activity in bone marrow cells 3 h after one and four injections was decreased to approximately 38 and 0%, respectively, of that in non-treated mice. Furthermore, the intracellular MTX level in the bone marrow cells (but not in total bone marrow) after four injections was about 10-fold higher than that after one injection. The amount of MTX bound to protein 3 h after four injections, as assayed by gel filtration (Sephadex G-25), was approximately 8-fold greater than after one injection. Therefore, the multiple-dose effects of MTX on the induction of micronuclei and chromosomal aberrations may be explained by the intracellular accumulation of MTX resulting in an enhancement of enzyme inhibition.

Animals↗
PubMed1986

Antiarrhythmic drug efficacy at electrophysiology testing: predictive effectiveness of procainamide and flecainide.

In an effort to assess the ability of procainamide to predict effectiveness of antiarrhythmic agents at programmed electrical stimulation (PES) testing, we compared the result of procainamide at PES testing with that of all of the other agents studied. One hundred fifty-three patients underwent PES studies because of either sustained or nonsustained ventricular tachycardia (VT). Procainamide prevented VT induction in 79 of 153 patients. Seventy-four of the remaining 153 were inducible for VT on procainamide, with 55 of these being protected by another antiarrhythmic agent (p less than 0.001). If procainamide failed to prevent VT induction, other conventional and experimental agents were equally as likely to be effective in preventing VT induction. Analysis of flecainide acetate as a predictor of efficacy was also evaluated. Fifty-five patients received flecainide and 29 of these were protected at PES testing; 26 of these patients were also protected with another agent. When VT was inducible in patients who received flecainide, 15 of these 26 patients were protected by another agent, either conventional or experimental (p less than 0.01). Thus, if procainamide or flecainide prevented VT induction they accurately predicted effectiveness of other drugs; however, when they did not prevent VT induction, they served as a poor predictor of the possible effectiveness of other drugs. Serial drug testing at PES studies with multiple conventional and experimental drugs increases the likelihood of finding an effective antiarrhythmic agent.

Anti-Arrhythmia Agents↗
PubMed1986

Atrial contraction is an important determinant of pulmonary venous flow.

Pulmonary venous flow has two phases (systolic and diastolic) in normal subjects when studied by pulsed Doppler echocardiography. Only one phase of pulmonary venous flow (diastolic) was observed in six patients without synchronous atrial contraction (four patients with atrial fibrillation and two with complete atrioventricular [AV] block). This pattern reversed to normal (biphasic) when AV synchrony was reestablished by cardioversion to sinus rhythm in patients with atrial fibrillation and by AV sequential pacing in patients with complete AV block. Thus, both atrial and ventricular contraction and relaxation are important determinants of pulmonary venous flow.

Adult↗
PubMed1986

N-acetylprocainamide's antiarrhythmic action in patients with ventricular tachycardia.

Antiarrhythmic properties of N-acetylprocainamide, an active metabolite of procainamide, were studied in 15 patients who presented with a cardiac arrest or documented sustained ventricular tachycardia. Programmed electrical stimulation studies were performed. All patients tested had inducible ventricular tachycardia by programmed electrical stimulation techniques while off all antiarrhythmic therapy. Patients were then tested on procainamide 1000 mg administered intravenously, and ventricular tachycardia could be provoked in 8 of 10 patients. Twenty-four to 36 hours later, N-acetylprocainamide was administered, intravenously, and programmed stimulation was performed after 20 minutes. N-acetylprocainamide did not significantly change heart rate, mean arterial blood pressure, electrocardiographic intervals, A-H or H-V conduction times. N-acetylprocainamide prevented ventricular tachycardia induction in 6 of 15 patients. The mean serum N-acetylprocainamide levels in the group protected was 15.7 +/- 4 micrograms/ml and 16.2 +/- 4 micrograms/ml in the group not protected. These 6 patients were discharged on N-acetylprocainamide 1.5 grams orally every 8 hours. Three patients have been maintained on chronic N-acetylprocainamide every 8 hours. Three patients have been maintained on chronic N-acetylprocainamide therapy (6 +/- 2 months), two patients had breakthrough ventricular tachycardia on follow-up Holter monitoring and alternative therapy was given. N-acetylprocainamide has antiarrhythmic efficacy in preventing induction of ventricular tachycardia by programmed electrical stimulation in a high risk group of patients. On chronic oral therapy, N-acetylprocainamide appears to be well tolerated with antiarrhythmic efficacy that may be enhanced with further upward dose titration.

Acecainide↗
PubMed1985

Flecainide: long-term treatment using a reduced dosing schedule.

Flecainide was initially prescribed at a dose of 200 mg twice daily, but after early toxicity in patients with ventricular tachycardia (VT), the dosage was reduced to 100 mg twice daily. The effects of flecainide were studied in 40 patients (29 men and 11 women, mean age 62 +/- 2 years, ejection fraction 45 +/- 3%) who underwent programmed electrical stimulation to determine the efficacy of flecainide in preventing VT chronically at the reduced dose. Sustained VT was induced in 21 patients and nonsustained VT in 19. Flecainide prevented VT induction in 26 patients (65%). At a mean dose of 1.5 +/- 0.1 mg/kg, prolongation occurred in the effective refractory period of the first (280 +/- 5 vs 249 +/- 5 ms) and second (254 +/- 6 vs 209 +/- 9 ms) extrastimuli (p less than 0.01). In the patients protected by flecainide, the effective refractory periods increased by a 17 +/- 2% and 21 +/- 3%, in contrast to only a 7 +/- 3% and 6 +/- 4% increase in the nonprotected group (p less than 0.05), despite a higher mean dose (1.9 +/- 0.1 vs 1.35 +/- 0.1 mg/kg). Twenty-one patients were discharged on flecainide therapy, 100 mg twice daily, and were followed for a mean of 11 months. Sixteen patients are alive and well, 1 died suddenly, 1 died from a noncardiac cause and 1 had a "breakthrough" arrhythmia. Two were switched to quinidine therapy by their referring physicians, but were without problems while receiving flecainide.(ABSTRACT TRUNCATED AT 250 WORDS)

Anti-Arrhythmia Agents↗
PubMed1985

Prolongation of QT interval and antiarrhythmic action of bepridil.

Studies were undertaken with bepridil, a new calcium blocker that prolongs the QT interval, to determine the antiarrhythmic and possible arrhythmogenic properties of this agent. The technique of programmed electrical stimulation was employed to evaluate bepridil in 15 patients with symptomatic ventricular tachycardia (VT). Bepridil prevented VT induction in 7 of 15 patients. Bepridil prolonged the QT and refractoriness and a linear correlation could be demonstrated between the percent change in QTc and refractory period prolongation for the bepridil-protected group. Bepridil in one patient reduced by one the number of stimuli required to induce VT, but no spontaneous arrhythmias were noted. Bepridil thus possesses antiarrhythmic properties with a minimal proarrhythmic effect.

Aged↗
PubMed1985

Long-term lorcainide therapy in patients with ventricular tachycardia.

One hundred patients inducible at electrophysiologic studies underwent serial drug testing with procainamide, lidocaine, and lorcainide to determine comparative efficacy. Acute intravenous administration was followed by repeat programmed electrical stimulation (PES) studies on separate days for each antiarrhythmic drug. Lorcainide prevented ventricular tachycardia (VT) induction in 69% of the 100 patients studied, procainamide was effective in 50% of the 75 patients studied, and lidocaine prevented VT induction in 30% of 53 patients. Following PES and serial drug testing, 46 patients were started on lorcainide, nine patients on procainamide, and 45 patients were started on other antiarrhythmic drug regimens. Seventy percent of the patients have remained on lorcainide therapy, while 47% have continued on other drug therapies started over a 20.5 +/- 3.2-month mean follow-up period. Despite sleep-wake disturbances and a need for sedation at night, lorcainide therapy was tolerated well in this population and remained an effective antiarrhythmic with prolonged administration.

Benzeneacetamides↗
PubMed1984

Evaluation of lorcainide in patients with symptomatic ventricular tachycardia.

One hundred patients with inducible ventricular tachycardia (VT) on electrophysiologic studies underwent serial drug testing with procainamide, lidocaine and lorcainide to determine comparative efficacy. Acute intravenous administration was followed by repeat programmed electrical stimulation (PES) studies on separate days for each antiarrhythmic agent. Lorcainide prevented VT induction in 69% of the 100 patients studied, procainamide in 50% of the 75 patients studied and lidocaine in 30% of 53 patients. After PES and serial drug testing, 46 patients were started on lorcainide, 9 on procainamide and 45 on other antiarrhythmic drug regimens. Eighty percent of the patients have remained on lorcainide therapy, whereas 47% have continued on other drug therapies started over 17.5-month mean follow-up period. Despite sleep-wake disturbances and a need for sedation at night, lorcainide therapy was well tolerated in this population and remained an effective antiarrhythmic agent with prolonged administration.

Anti-Arrhythmia Agents↗
PubMed1984

Comparison of noninvasive arrhythmia induction techniques with electrophysiologic studies and evaluation of lorcainide in patients with symptomatic ventricular tachycardia.

Twenty-six patients (19 men and 7 women) with symptomatic ventricular tachycardia (VT) were studied using invasive and noninvasive techniques to induce VT. Of the study population, 12% had syncope and VT on Holter monitoring, 30% had cardiac arrest and 58% had symptomatic VT. All patients had antiarrhythmic agents stopped 5 half-lives before evaluation and then had autonomic profile (upright tilt, cold pressor test, exercise testing and hand grip) as well as programmed electrical stimulation studies performed. Autonomic profile testing induced VT in 5 of 26 patients (19%) and in only 1 patient was the arrhythmia reproducibly induced. All 26 patients had VT induced on electrophysiologic testing; 9 patients had nonsustained and 17 had sustained VT. Lorcainide administered intravenously prevented VT induction in 20 of 26 patients tested, whereas procainamide was effective in 11 of 24 patients. Ten of the 13 not protected by procainamide were protected by lorcainide. Twenty patients were started on long-term lorcainide therapy and followed up for 29 +/- 3.4 months. Five patients have discontinued therapy, 2 because of breakthrough arrhythmias, 2 because of severe sleep-wake disturbances and 1 because of private physician preference. An additional 3 patients died during therapy because of myocardial infarction in 1, progressive myopathy in 1 and sudden death in 1. Sixty percent of patients started on lorcainide therapy have continued. In this patient population, noninvasive induction of VT is not a sensitive or reproducible technique in assessing antiarrhythmic therapy. Furthermore, when selected on the basis of electrophysiologic testing, lorcainide is a well-tolerated and effective antiarrhythmic agent.

Aged↗
PubMed1984

The efficacy of cibenzoline in preventing PES induction of ventricular tachycardia in the dog.

The electrophysiologic effects of cibenzoline were studied using programmed electrical stimulation (PES) techniques and were compared to those of quinidine. Cibenzoline, like the conventional class 1 agent quinidine, was effective in preventing arrhythmia induction. Twelve dogs were given 0.02 mg/kg digoxin intravenously for seven days to achieve a steady-state digoxin level. On the eighth day, cibenzoline was administered in incremental doses (0.5 to 10.5 mg/kg) and PES was performed at 30-minute intervals. A mean dose of 2.6 +/- 0.8 mg/kg cibenzoline prevented ventricular tachycardia induction. At this dose, cibenzoline had no significant effect on mean arterial blood pressure, but PR interval increased by 17 +/- 9 per cent, QRS duration by 27 +/- 14 per cent, and the ventricular refractory period (ERP) for the first extra stimulus increased by 35 +/- 9 per cent. A gradual decrease in heart rate and an increase in PR interval and QRS duration was caused by incremental doses of cibenzoline. In six additional animals, quinidine was administered in incremental doses (1 to 30 mg/kg) and PES performed at 30-minute intervals. A mean of 15 +/- 5 mg/kg prevented induction of ventricular tachycardia in five animals. No significant change in heart rate, PR, QRS, and ERP was found at the effective dose.

Animals↗
PubMed1984

Intravenous quinidine by intermittent bolus for electrophysiologic studies in patients with ventricular tachycardia.

The safety and efficacy of intravenous quinidine gluconate, using intermittent boluses of 80 mg/cc every 5 minutes to a total dose of 800 mg, was evaluated in 61 patients referred for electrophysiologic studies (EPS). Patients were referred because of out-of-hospital cardiac arrest (12), symptomatic ventricular tachycardia (VT) (24), asymptomatic VT (18), syncope of unknown origin (6), and supraventricular arrhythmias (1). Clinical heart failure was present in 74% of patients, with a mean ejection fraction of 45 +/- 3 for all patients. Quinidine prevented VT induction in 78% of patients at a mean dose of 9.6 mg/kg and facilitated VT induction in 7% of patients. Quinidine failed to decrease mean arterial pressure in 14 patients, and in the remaining 47 patients arterial pressure decreased by 16%. Six patients had hemodynamically significant hypotension. Two patients had hypotension severe enough to require saline administration, while four had hypotension not needing fluid replacement. Sixteen percent of patients experienced other side effects. Quinidine can be administered safely by intermittent infusion and is effective in preventing programmed stimulation induction of VT. Carefully monitored, intravenous intermittent bolus administration of quinidine should be utilized more frequently in EPS, since significant adverse side effects are infrequent.

Adult↗
PubMed1984

Studies on the possible mechanisms of lidoflazine arrhythmogenicity.

Lidoflazine is a calcium channel blocking agent that is effective and safe in the treatment of angina pectoris, but has been reported to be associated with sudden death when administered for the treatment of supraventricular arrhythmias. Studies were performed in dogs to determine if lidoflazine caused a rise in serum digoxin concentration that could cause arrhythmias or if it was directly arrhythmogenic. Dogs received chronic injections of digoxin and then digoxin in combination with lidoflazine. No increase in digoxin concentration was found. Dogs also underwent programmed electrical stimulation while not receiving medications and then after incremental doses of lidoflazine administered intravenously. Lidoflazine did not cause spontaneous ventricular tachycardia and did not lower the threshold of ventricular tachycardia induction. Combined administration of lidoflazine and digoxin did not facilitate arrhythmia induction. These studies do not support a digoxin-lidoflazine interaction or a direct arrhythmogenic action of lidoflazine.

Animals↗
PubMed1980

[Adriamycin-cardiomyopathy induced by an increment of (Ca2+) (author's transl)].

As compared to the metabolic inhibitor 2,4-Dinitrophenol, the cytostatic drug Adriamycin influences the isolated embryo ventricular cells of the chicken, thus causing a decrease in the contraction amplitude, an increase in the heart-rate, and the occurrence of "after-contractions". With radioactive measurements it could be demonstrated, that the reason therefore is an increment of Ca2+i. This may be explained by a decreased Ca-uptake by the sarcoplasmic reticulum and the mitochondria. This increment of Ca2+i brought about a change in the action potential and the refractory-period, as well as the occurrence of "'after-contractions" by control of the potassium flux.

Action Potentials↗
PubMed1980

[Experimental study on elucidating pathogenesis of adriamycin induced cardiomyopathy (author's transl)].

For the determination of the pathophysiological mechanisms responsible for the adriamycin-induced cardiomyopathy we investigated the acute myocardial effects of this drug on contractile behavior in cultured embryonic ventricular cells in comparison to metabolic inhibitors, e.g., 2,4-dinitrophenol. There could be demonstrated a fall in contraction amplitude due to exposure to adriamycin, an increase in heart rate and the occurrence of "after-contractions". The fall in contraction could be explained by a decreased Ca-uptake by the sarcoplasmic reticulum (SR) and/or the mitochondria, leading to a rise in [Ca2+]i. This would tend to reduce spontaneous rate in pacemaker cells, to increase gK (conductance of potassium) and to influence the conduction. 10 microgram/ml adriamycin showed a 25% increment of K-flux above rest. A similar result was obtained by use of 10(-4) mmol/l 2,4-DNP which also caused cessation of spontaneous activity. This increment in K-flux, a parameter for K-permeability, might be caused by an increase in [Ca2+]i. The possible origin of this increment of [Ca2+]i might be of mitochondrial nature.l Thus an acute perturbance of mitochondrial function might give rise to [Ca2+]i, since mitochondria are known as Ca-buffering compartment. The pathophysiological mechanisms of the adriamycin cardiomyopathy therefore can be seen in the increase of [Ca2+]i.

Animals↗