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Biomedical subjects

D Roy

Publications and source records attributed to D Roy.

At least 271 records · Page 15Linked to original sources

Sinus node dysfunction and sudden cardiac death following treatment with encainide.

Encainide, a class Ic drug, is generally thought of as having little effect on sinus node function. In this article, we present the clinical course and electrophysiological findings of a patient who had cardiac arrest after 1 week of encainide therapy for ventricular extrasystoles. No ventricular tachyarrhythmias were induced during programmed ventricular stimulation (baseline study and while receiving encainide therapy). Prior to encainide therapy, sinus node function was normal, but clinical observations after admission for cardiac arrest and subsequent electrophysiological study revealed that encainide had caused striking impairments in sinus node function. During a 6-month follow-up without antiarrhythmic drug treatment, this patient has had an uneventful course. We concluded that encainide can cause severe and life-threatening sinus node dysfunction.

Anilides↗

Amplification of flecainide-induced ventricular conduction slowing by exercise. A potentially significant clinical consequence of use-dependent sodium channel blockade.

Proarrhythmic effects of flecainide acetate have been reported during exercise, but the mechanism for the arrhythmogenic interaction between flecainide and exercise is unknown. We hypothesized that the sinus tachycardia of exercise may enhance flecainide-induced conduction slowing by increasing use-dependent sodium channel blockade, thereby facilitating the occurrence of ventricular reentry. To evaluate the modulation of flecainide's effects by exercise, we studied 19 patients who were receiving therapeutic doses of flecainide for the treatment of cardiac arrhythmias. Sixteen patients underwent treadmill exercise testing by a modified Bruce protocol. During exercise, QRS duration increased progressively from 94 +/- 22 msec (mean +/- SD) at rest to 116 +/- 25 msec (p less than 0.001) at a mean heart rate increase of 84 +/- 32 beats/min. The patient with the greatest QRS increase developed a monomorphic ventricular tachycardia at peak exercise. At rest, the QRS duration after treatment with flecainide increased 12.1 +/- 10.0% compared with the pretreatment value, and with exercise, the QRS duration increased by a further 28.1 +/- 17.0% compared with the predrug value. We found that the best predictor of further exercise-induced QRS slowing was the change in QRS duration produced by flecainide at rest (r = 0.76, p = 0.001). In an age- and disease-matched control group, the QRS duration did not change during exercise that caused a similar heart rate increase.(ABSTRACT TRUNCATED AT 250 WORDS)

Arrhythmias, Cardiac↗

Toxic effects of an anionic detergent on the lipid constituents of various cell types of the gill epithelium of Rita rita: a histochemical investigation.

Rita rita exposed to a concentration of 6.9 mg per liter (96-h LC50 of an anionic detergent, dodecylbenzene sodium sulfonate) exhibited a gradual decrease in the lipid moieties of the epithelial cells, club cells, and goblet mucous cells lining the gill arch and gill filament epithelium. However, in time, no reaction of any of the lipid moieties could be observed, indicating the absence of the same, using various histochemical techniques. The results are discussed in light of the mechanistic understanding of detergent action.

Animals↗

Characterization of drug metabolism enzymes in estrogen-induced kidney tumors in male Syrian hamsters.

In an attempt to characterize metabolism enzymes of the estrogen-induced kidney tumor in male Syrian hamsters, the activities of enzymes involved in drug and glutathione metabolism were determined in tumor tissue. Kidney tumors were induced in male Syrian hamsters by treatment with estradiol for 8 months. Cytochrome P-450 and cytochrome b5 concentrations in tumors were below detectable levels. However, when cytochrome P-450-mediated oxidation was analyzed by product formation assays, the oxidation of E-diethylstilbestrol to diethylstilbestrol-4',4"-quinone by tumor microsomes was 10-20% of the rate found in control microsomes. In kidney tissue surrounding estrogen-induced tumors, cytochrome P-450 and b5 contents were 50-60% less than those in untreated kidney. Activities of reducing enzymes of drug metabolism (cytochrome P-450, cytochrome b5 and NADH:cytochrome c reductases), glutathione metabolism enzymes (glutathione peroxidase, glutathione transferase, glutathione reductase, and gamma-glutamyl transpeptidase), and free radical scavenging enzymes (superoxide dismutase, catalase, and quinone reductase) in tumor were significantly lower than in untreated kidney tissue. The activities of these enzymes in renal tumor surrounding tissue were between those observed in tumor and control kidney. Glucose-6-phosphate dehydrogenase activity was increased by 50% in surrounding tissue and 430% in tumor compared to values in untreated controls. The decreased enzyme activity levels in hormone-exposed tissue surrounding tumors likely represented an adaptation of this tissue to the neoplastic environment induced by chronic estrogen treatment.

Animals↗

Doppler echocardiographic predictors of recurrence of atrial fibrillation after cardioversion.

To determine if the return of atrial contraction as evidenced by progressive return of the A wave on the Doppler atrial profile could better predict long-term success of cardioversion than other clinical and echocardiographic parameters, 50 patients were studied 4 hours, 24 hours and, if sinus rhythm persisted, up to 180 days after cardioversion. Recurrence of atrial fibrillation (AF) was 64% at 6 months. Age, sex, prior episodes of AF, presence of mitral valve disease or magnitude of mitral valve gradient did not predict recurrence, but duration of AF was significantly longer in the failure group (p less than 0.01). Left atrial dimension greater than or equal to 45 mm had a positive predictive value of 66%, with a sensitivity of 59% and a specificity of 61%. Presence or magnitude of the A wave at 4 hours did not predict long-term success of cardioversion. Percent increase of the A wave from 4 to 24 hours less than 10% had the highest positive predictive value (80%) for recurrence of AF (sensitivity 71% and specificity 71%) and can be obtained in the immediate post-cardioversion period to better establish prognosis and adjust therapeutic regimens.

Adult↗

Temporary decrease in renal quinone reductase activity induced by chronic administration of estradiol to male Syrian hamsters. Increased superoxide formation by redox cycling of estrogen.

Cytochrome P-450-mediated redox cycling between the synthetic estrogen diethylstilbestrol (DES) and diethylstilbestrol-4',4"-quinone (DES Q) has previously been demonstrated. Cytochrome P-450 reductase catalyzes the reduction of DES Q presumably via a semiquinone formed by one-electron reduction. A reducing action of NAD(P)H quinone reductase (EC 1.6.99.2) mediating two-electron reduction of DES Q has been investigated in the present work. Quinone reductase catalyzed the conversion in the presence of NADH or NADPH of DES Q to 53-65% Z-DES, a marker product of reduction. Dicumarol (15 microM), a known specific inhibitor of quinone reductase, inhibited this reduction almost completely. Using microsomes from Syrian hamster kidney, a target organ of estrogen-induced carcinogenesis, the reduction of DES Q was only partially inhibited by dicumarol. Apparent Km values of quinone reductase and cytochrome P-450 reductase were 17.25 and 11.9 microM, respectively. These data demonstrate that in hamster kidney, quinone reductase and cytochrome P-450 reductase compete for the reduction of DES Q. Microsomal 02-. radical generation was stimulated 10-fold over base levels by the addition of 100 microM DES Q. The formation of 02-. radicals was inhibited by addition of superoxide dismutase (0.2 mg/ml) or by 2'-AMP or NADP, known inhibitors of cytochrome P-450 reductase. In contrast, dicumarol enhanced microsome-mediated 02-. formation. It is concluded that cytochrome P-450 reductase in hamster kidney microsomes mediates one-electron reduction of estrogen quinones to free radicals (semiquinones), which may subsequently enter redox cycling with molecular oxygen to form 02-.. Moreover, quinone reductase reduces DES Q directly to E- and Z-DES, and thus may prevent the formation of toxic intermediates during redox cycling of estrogens. Measurements of quinone reductase activity in liver and kidney of hamsters treated with estrogen for various lengths of time revealed a temporary decrease in activity by 80% specifically in the kidney after 1 month of chronic treatment with estradiol. Thus, a temporary decrease in quinone reductase activity, which occurred specifically in estrogen-exposed hamster kidney, may enhance the formation of free radical intermediates generated during biotransformation of estrogens.

Animals↗

Toxicity of an anionic detergent, dodecylbenzene sodium sulfonate, to a freshwater fish, Rita rita: determination of LC50 values by different methods.

LC50 values and their 95% confidence limits for various intervals of exposure to an anionic detergent, dodecylbenzene sodium sulfonate, have been determined using recommended methods. The advantages and disadvantages of these methods are discussed in light of the variations in the values. Different visible behaviors of the fish under the influence of the detergent have also been explained.

Animals↗

Impact of detergents on the protein histochemistry of various cell types of the gill epithelium of Rita rita.

Fish, Rita rita, were exposed to an anionic detergent, dodecylbenzene sodium sulfonate, 6.9 mg per litre of tap water (96-hr LC50 of the detergent). A gradual decrease in the protein constituents of the major cell types, viz, the epithelial cells and the goblet mucous cells in the epithelium lining the gill arch, gill filament, and club cells present only in the gill arch epithelium has been observed by using a series of histochemical techniques.

Animals↗

Statistical analysis of anionic detergent-induced changes in the goblet mucous cells of opercular epidermis and gill epithelium of Rita rita (Ham.) (Bagridae: Pisces).

Rita rita exposed to 96-hr LC50 (6.9 mg/liter) of an anionic detergent, dodecylbenzene sodium sulfonate, show significant changes in the number and size of goblet mucous cells in the opercular epidermis as well as in the lining epithelium of the gill arch and the gill filament at different time intervals of treatment. A shift in the staining nature of these cells from acidic glycoprotein to neutral glycoprotein, acidic glycosaminoglycans in the opercular epidermis and acidic glycoprotein to neutral glycoprotein and then again to acidic glycoprotein + acidic glycosaminoglycans in the gill filament epithelium reflects a change in the physiological status of fish.

Animals↗

Age-related change in the multiple unit activity of the rat brain parietal cortex and the effect of centrophenoxine.

In this study, spontaneous multiple unit activity (MUA, action potentials derived simultaneously from a number of neurons in a given brain region) was recorded through electrodes chronically implanted in the parietal cerebral cortex of the rats of 1, 3, 6, 9, 12, and 26 months of age (cross-sectional study). Electrophysiological recordings were obtained from unrestrained conscious rats using standard techniques. The results indicated that multiple unit activity was decreased with aging (senescence). Maximum firing rate (MUA counts) was found at the age of 3 months. At 6 months of age, the MUA was decreased by about 30%, while during 6 to 12 months of age the activity seemed to remain unchanged. At 26 months of age the firing rate was, however, further decreased (about 40%). Centrophenoxine administration led to an increase in MUA in the rats of 12 and 26 months of age. The results, thus, further showed that centrophenoxine, a nootropic drug known for its antiaging effects in experimental animals as well as in humans, also manifested beneficial effects electrophysiologically. The data presented in this work are new and significant, since although age effects on gross electrophysiological signals (EEG, evoked potentials, etc.) are known, the aging changes in cellular level electrophysiological signals (action potentials) have not been generally studied particularly in conscious animals.

Aging↗

Long-term prognosis after myocardial infarction in patients with previous coronary artery bypass surgery.

A group of 205 patients hospitalized with myocardial infarction 2 to 162 months (mean 66) after bypass surgery and 205 control patients with myocardial infarction were compared and followed up for 34 +/- 25 months after hospital discharge. At baseline the postbypass group contained more men (p less than 0.03) and more patients with previous myocardial infarction (p less than 0.06), but the groups were otherwise comparable. Indexes of infarct size were lower in postbypass patients: sum of ST elevation, QRS score, peak serum creatine kinase (CK) (1,115 +/- 994 versus 1,780 +/- 1,647 IU/liter) and peak MB CK (all p less than or equal to 0.001). Postmyocardial infarction ejection fraction was 45 +/- 15% in the postbypass group and 43 +/- 15% in the control group (p = NS); in-hospital mortality rate was 4 and 5%, respectively (p = NS). When patent grafts were taken into account, the two groups were comparable in extent of coronary artery disease. At 5 years after discharge, cumulative mortality was similar in the postbypass and control groups (30 versus 25%, respectively, p = NS). However, postbypass patients had more reinfarctions (40 versus 23%, p = 0.007), more admissions for unstable angina (23 versus 18%, p = 0.04) and more revascularization procedures (34 versus 20%, p = 0.04) than did control patients. The total for these events at 5 years was 70% in the postbypass group and 49% in the control group (p = 0.001). Thus, although patients with previous bypass surgery who develop acute myocardial infarction have a smaller infarct, their subsequent survival is no better than that of other patients with acute myocardial infarction. They experience more reinfarctions and unstable angina. Previous bypass surgery is an important clinical marker for recurrent cardiac events after myocardial infarction.

Angiography↗

A comparative clinical trial of fluoxetine, mianserin and placebo in depressed outpatients.

Fluoxetine, a selective serotonin reuptake inhibitor, was compared with mianserin and placebo in a double-blind study. In total, 81 depressed patients were included. Patients were rated weekly on the Hamilton Depression Rating Scale (HDRS) and the Montgomery & Asberg Depression Rating Scale (MADRS). The duration was 6 weeks, and 52 patients completed the study. Significantly more patients on fluoxetine improved than patients on placebo. For mianserin no significant differences were found with either fluoxetine or placebo. Mean HDRS at the end of the study was also statistically significantly lower for fluoxetine, but not for mianserin, than placebo. Subscores of the MADRS showed improved sleep on mianserin at weeks 2 and 3. Suicidal feelings were reduced to a greater degree on fluoxetine than on mianserin and placebo at weeks 6 and 7. Fluoxetine induced weight loss, while patients on mianserin gained weight. Side effects were present in most patients on the two active drugs; those on fluoxetine experienced nausea and vomiting, and those on mianserin drowsiness.

Adolescent↗

Effects of a cysteine precursor, L-2-oxothiazolidine-carboxylate, nutritional status, and sex on tissue glutathione and hepatic GSH-utilizing enzymes of CD-1 mice.

Objectives of this study were to compare the effects of sex, nutritional status and L-2-oxothiazolidine carboxylate (OTC) treatment on tissue constituents frequently involved in responses to chemical toxins. Four groups of adult CD-1 mice were studied: fed females, fed males, fasted males, and fasted males three hours after treatment with OTC (10 mmoles/kg, sc). Female fed mice were found to differ from male fed mice as follows: lower tissue GSH in liver and kidney but not lung; lower hepatic microsomal cytochrome P-450 content and cytosolic GSH transferase activities, particularly using CDNB as substrate; and higher hepatic GSH peroxidase but similar GSSG reductase activities. Overnight fasting was associated with a decrease in hepatic and renal GSH and hepatic cytochrome P-450. OTC treatment was only found to increase hepatic GSH and decrease renal GSH. Thus in fasted CD-1 male mice, the intracellular cysteine precursor, OTC, has an apparently selective effect on tissue GSH contents without confounding effects on hepatic GSH utilizing or restoring activities.

Animals↗

Phenytoin metabolic activation: role of cytochrome P-450, glutathione, age, and sex in rats and mice.

Data are reported demonstrating a role for glutathione and age in the metabolic activation of phenytoin to a reactive metabolite. The in vitro liver microsomal covalent binding of [14C]-phenytoin (DPH) was examined in mice and rats. After incubation with 25-300 microM DPH, covalent binding was dose dependent and linear with time. Incubation in an atmosphere of carbon monoxide or nitrogen markedly decreased covalent binding. Comparison of covalent binding in male rats and mice pretreated with inducers of drug metabolism (phenobarbital, 3-methylcholanthrene) showed significantly greater enhancement following phenobarbital induction compared to controls. In vitro addition of inhibitors of drug metabolism (piperonyl butoxide, alpha-naphthylisothiocyanate, cobaltous chloride, SKF-525A) all significantly decreased covalent binding. Binding studies with subcellular fractions showed maximal covalent binding in microsomes. Addition of thiols, i.e., glutathione, cysteine and cysteamine, significantly decreased covalent binding to 9-36% of control. Addition of butylated hydroxyanisole and butylated hydroxytoluene decreased covalent binding to 10-22% of control. In vivo pretreatment with diethyl maleate and in vitro preincubation with trichloropropene oxide resulted in a significant increase in covalent binding. Rats of ages 8 weeks, 24 weeks and 72 weeks showed a decrease both in covalent binding and in inducibility of covalent binding with increasing age. There was no significant difference in covalent binding between male and female rats of similar ages. These findings are consistent with a cytochrome P-450 dependent generation of a phenytoin arene oxide electrophilic arylating reactive intermediate.

Aging↗

Single and fractionated whole body hyperthermia in murine fibrosarcoma.

The effects of single and multiple fractionated whole body hyperthermia (WBH) 41.5 degrees C on benzo(a) pyrene induced fibrosarcoma of mice were evaluated in terms of tumour response and systemic alterations of the host. While single exposure of WBH(S) 2 hrs, caused moderate inhibition of tumours and increase in the median survival time, multiple fractionated exposures [WBH(M)] caused significant enhancement of tumours with decrease in mean survival time. Tumoricidal effects associated with increased acid phosphatase and beta-glucuronidase activity were observed in both the regimes of WBH. In WBH(M) the development of thermotolerance was indicated by decreased activity of these enzymes in subsequent treatments. Elevation of plasma corticosterone and significant lymphocytopenia occurred in both the regimes. The alterations were transient in WBH(S) but persisted for more than two weeks in WBH(M), indicating that tumour enhancement is possibly influenced by corticosterone-mediated immunosuppression. In the WBH(M), the tumoricidal effects were counteracted and surpassed by the growth stimulatory physiological alterations of the host. Therefore the mode of application of WBH and the systemic responses of the host are critical factors that should be considered in designing therapeutic regimes with WBH.

Acid Phosphatase↗

Electrophysiologic effects and long-term efficacy of bepridil for recurrent supraventricular tachycardias.

Thirteen patients underwent electrophysiologic evaluation for recurrent supraventricular tachycardia (SVT). The effects of intravenous bepridil (4 mg/kg) were evaluated during the initial study in 5 patients, and 12 patients underwent repeat study 7 to 10 days later taking oral bepridil, 300 to 400 mg/day. Intravenous bepridil increased the pacing cycle length inducing atrioventricular (AV) (276 +/- 43 vs 334 +/- 31 ms, p less than 0.01) and ventriculoatrial (VA) block (268 +/- 34 vs 310 +/- 35 ms, p less than 0.001), the retrograde refractory period of the accessory pathway (251 +/- 17 vs 295 +/- 25 ms, p less than 0.05) and the ventricular refractory period (216 +/- 17 vs 226 +/- 11 ms, p less than 0.05), and prevented induction of sustained SVT in 3 patients. Oral bepridil increased the sinus cycle length (723 +/- 64 vs 800 +/- 118 ms, p less than 0.05), corrected QT (403 +/- 14 vs 431 +/- 21 ms, p less than 0.05) and the pacing cycle inducing AV (288 +/- 63 vs 353 +/- 78 ms, p less than 0.01) and VA block (271 +/- 31 vs 408 +/- 124 ms, p less than 0.01). It prolonged the refractory period of the atrium (195 +/- 29 vs 233 +/- 36 ms, p less than 0.05), AV node (264 +/- 35 vs 303 +/- 22 ms, p less than 0.05), ventricle (221 +/- 16 vs 245 +/- 21 ms, p less than 0.01), accessory pathway in the AV (290 +/- 47 vs 329 +/- 54 ms, p less than 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)

Administration, Oral↗