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Biomedical subjects

R Sheldon

Publications and source records attributed to R Sheldon.

At least 55 records · Page 3Linked to original sources
PubMed1995

Antiarrhythmic activity of quinine in humans.

BACKGROUND: Quinine is the diastereomer of quinidine. In dogs, it has similar effects on conduction time but does not prolong epicardial repolarization time or ventricular refractoriness. It has antiarrhythmic effects in both cats and dogs. We assessed the antiarrhythmic potential of quinine in suppressing ventricular arrhythmias in humans. METHODS AND RESULTS: Patients underwent open-label, dose-ranging trials of quinine with daily doses of 600, 1200, and 1800 mg in a twice-daily dosing regimen. In 17 patients with frequent spontaneous ventricular ectopy, oral quinine suppressed arrhythmia in 11 of 12 patients who finished the study and was not tolerated by 4 patients, and 1 patient withdrew from the study. The mean effective daily dosage was 927 mg, the mean effective trough serum level was 11 mumol/L (range, 4 to 17 mumol/L), and the half-life was 20 +/- 7 hours. In a second open-label, dose-ranging trial in 10 patients with inducible ventricular tachycardia and reduced left ventricular systolic function (left ventricular ejection fraction, 35 +/- 16%), quinine suppressed inducibility of ventricular tachycardia in 3 of 10 patients. At a basic pacing cycle length of 500 milliseconds, ventricular effective refractory period was prolonged (279 +/- 21 versus 247 +/- 10 milliseconds, quinine versus drug free, P = .003). In the remaining patients, ventricular tachycardia cycle length was prolonged (373 +/- 48 versus 253 +/- 30 milliseconds, quinine versus drug free, P < .001). The corrected QT interval was not prolonged. CONCLUSIONS: Quinine is an effective and convenient antiarrhythmic drug for the suppression of ventricular arrhythmias in humans.

Aged↗
PubMed1994

Effects of aging on responses to isoproterenol tilt-table testing in patients with syncope.

The diagnosis of neuromediated syncope is often established with isoproterenol head-up tilt-table testing. Previous work has demonstrated changes in autonomic nervous system function with progressive age, suggesting that responses to tilt-table testing may depend on the age of the patient. The purpose of this study was to assess the effects of age on the clinical and hemodynamic responses to isoproterenol tilt testing in patients with syncope of undetermined etiology. Accordingly, 85 patients with syncope of undetermined etiology underwent tilt testing with infusions of 0, 2, and 5 micrograms/min of isoproterenol in 3 successive stages. Of 85 patients tested, 66 had a positive outcome. The proportions of patients with a positive test and with tests ending in syncope declined significantly with age, with positive outcomes seen in 100%, 86%, 69%, and 61% of patients aged 12 to 20, 21 to 35, 36 to 60, and 61 to 88 years, respectively (p = 0.033, chi-square). Presyncope developed more slowly in patients aged 61 to 88 years (half-time to presyncope 2.5 minutes) than in younger patients (half-times to presyncope 0.7 to 0.9 minute). There were no significant age-related changes in peak and trough systolic blood pressures and rate-pressure products, but trough heart rate increased significantly with age (r = 0.40, p = 0.003). In conclusion, the likelihood of a positive outcome to isoproterenol tilt-table testing declines with age. Older patients take longer to develop presyncope, are less likely to develop syncope, and are less able to develop a relative bradycardia. These results guide interpretation of isoproterenol tilt-table testing.

Adolescent↗
PubMed1994

Interaction of drug metabolites with the class I antiarrhythmic drug receptor on rat cardiac myocytes.

The use of class I antiarrhythmic drugs may be complicated by the presence of active metabolites. A simple technique to predict the clinical activity of these metabolites might help with the clinical use of these drugs. We tested the hypothesis that drug metabolites bind to the class I drug receptor, but that only clinically active metabolites bind appreciably at clinically observed concentrations. Using a radioligand assay, we determined whether 13 class I drug metabolites interacted with a receptor for class I drugs associated with the cardiac sodium channel. The radioligand was [3H]batrachotoxinin A20 benzoate. All 13 metabolites bound to the drug receptor with IC50 values of 2.7 to 375 microns, and a mean Hill number of 1.0 +/- 0.3. All of the seven active metabolites (N-acetylprocainamide, mono-N-dealkyldisopyramide, 5-hydroxypropafenone, N-desisopropylpropafenone, 0-demethylencainide, 3-methoxy-0-demethylencainide and desethylamiodarone) each bound to the receptor at concentrations approaching their clinical concentrations, whereas none of the six inactive metabolites (quinidine-N-oxide, 3-hydroxyquinidine, glycinexylidide, monoethylglycinexylidide, N-demethylencainide and N,0-demethylencainide) did. Using a relationship which correlates drug IC50 values and clinically observed drug concentrations we calculated predicted clinical concentrations if the metabolites were clinically active. A predicted/observed ratio < or = 10 correlates with 100% positive and negative accuracies whether a drug metabolite has clinical activity. Thus a simple radioligand assay predicts whether class I drugs have clinical activity.

Animals↗
PubMed1993

Evaluation of a single-stage isoproterenol-tilt table test in patients with syncope.

OBJECTIVES: The purpose of this study was to compare clinical outcomes and tilt test variables between a single-stage tilt test with an infusion of 5 micrograms/min of isoproterenol and a conventional multistage test with infusions of 0, 2 and 5 micrograms/min of isoproterenol in three successive stages. BACKGROUND: The diagnosis of neuromediated syncope is often established with isoproterenol--head-up tilt table testing. Previous work has suggested that a single infusion of 5 micrograms/min of isoproterenol during 80 degrees head-up tilt for < or = 10 min should be sufficient to establish the diagnosis. METHODS: Forty patients with recurrent syncope underwent both tests in a randomized crossover fashion. RESULTS: Of 24 patients with positive findings on a multistage test, 19 (79%) had positive findings on a single-stage test, whereas 13 (81%) of 16 patients with negative results on a multistage test had negative results on a single-stage test (p < 0.001, chi-square analysis). Presyncope developed monoexponentially with time at similar rates in both tests, with half-times to presyncope of 1.3 and 2 min for the single-stage and multistage test, respectively. Intertest intrapatient times to presyncope correlated well (r = 0.74, p = 0.001). Finally, peak and trough heart rates each were similar and correlated well between tests. The mean peak heart rate was 136 +/- 25 and 133 +/- 18 beats/min for the single-stage and multistage test, respectively (p = NS, t test; r = 0.50, p = 0.002, linear regression). The mean trough heart rate was 76 +/- 31 and 78 +/- 36 beats/min for the single-stage and multistage test, respectively (p = NS, t test; r = 0.86, p < 0.001, linear regression analysis). CONCLUSIONS: The single-stage and multistage tilt tests are equivalent with regard to clinical outcome and tilt test variables, although the single-stage test is considerably less time-consuming.

Adult↗
PubMed1993

Role of myosin light-chain phosphorylation in endothelial cell retraction.

Endothelial cells retract centripetally when they are exposed to histamine and when extracellular calcium is chelated. This centripetal retraction implies that a centripetal tension must be expressed in the cells. We asked whether phosphorylation of the light chain of myosin (MLC) was important for the retraction to occur, and, by inference, expression of the tension. In human umbilical vein endothelial (HUVE) cells and in porcine pulmonary artery endothelial (PPAE) cells tryptic peptide maps indicated that MLC was phosphorylated by myosin light-chain kinase (MLCK). Activity of MLCK is inhibited by ML-9, a kinase inhibitor with relative specificity for MLCK, and when MLCK is phosphorylated by the adenosine 3',5'-cyclic monophosphate (cAMP)-dependent kinase. Pretreatment of HUVE cells or PPAE cells with ML-9 or forskolin-aminophylline (to increase cell cAMP) reduced basal MLC phosphorylation and prevented an expected increase in MLC phosphorylation following exposure of HUVE cells to histamine. Pretreatment of HUVE cells with ML-9 or forskolin-aminophylline prevented HUVE cell retraction (measured as an increase in permeability of a monolayer of HUVE cells) in response to histamine. Pretreatment of PPAE cells with ML-9 or forskolin-aminophylline prevented PPAE cell retraction in response to chelation of extracellular calcium. These data support the hypothesis that phosphorylation of MLC is an important component of endothelial cell retraction.

Aminophylline↗
PubMed1993

Modulation of flecainide's cardiac sodium channel blocking actions by extracellular sodium: a possible cellular mechanism for the action of sodium salts in flecainide cardiotoxicity.

Sodium salts reverse the clinical cardiotoxicity of class 1c antiarrhythmic agents, but the underlying mechanisms are unknown. We studied the modulation of flecainide's action by changes in extracellular sodium concentration ([Na+]e) produced by isotonic substitution of choline for sodium. Increasing [Na+]e by 25 mM attenuated the depressant effects of 3.2 microM flecainide of Vmax in canine cardiac Purkinje fibers, whereas decreasing [Na+]e enhanced drug action. The voltage dependence of Vmax was shifted by flecainide (activation potential for 50% decrease in Vmax, V50: -77.4 +/- 3.5 mV at 3.2 microM flecainide) compared to control (V50: -73.7 +/- 2.8 mV, mean +/- S.D., P < .05). Increasing [Na+]e in the presence of flecainide returned V50 toward control (-75.8 +/- 3.1 mV, P < .05 vs. flecainide at normal [Na+]e). Increased [Na+]e shifted the flecainide concentration-response curve to the right (EC50 19.0 microM) compared to normal (EC50 14.6 microM) and low (EC50 10.8 microM) [Na+]e. [Na+]e modulated the concentration-dependent displacement by flecainide of [3H]batrachotoxin-A-benzoate, with increased [Na+]e shifting the binding curve to the right and decreased [Na+]e shifting it to the left compared to normal [Na+]e. There was a strong linear correlation (r = 0.99) between flecainide's EC50 for Vmax depression and its IC50 for [3H]batrachotoxin-A-benzoate displacement at various [Na+]e. We conclude that [Na+]e modulates flecainide's interaction with the sodium channel. Sodium's ability to displace blocking drug from the sodium channel may underlie the efficacy of sodium salts in treating flecainide toxicity, and could play a similar role in antagonizing cardiotoxicity of other class 1 compounds.

Action Potentials↗
PubMed1992

Reproducibility of isoproterenol tilt-table tests in patients with syncope.

To assess the reproducibility of head-up tilt-table testing 46 patients each underwent 2 isoproterenol tilt-table tests 1 to 6 weeks apart. Of 20 patients with an initially asymptomatic negative test result, 17 (85%) had a second negative test result. Of 20 patients whose initial test ended in syncope, 18 had a second test ending in syncope (n = 12) or presyncope (n = 6). Five of 6 patients whose first test ended in presyncope had a second test that ended in presyncope, and 1 had a second test that was asymptomatic. Finally, a total of 14 patients had at least 1 test (either the first or second) ending in presyncope, and 11 of these (79%) had another test ending in presyncope or syncope. The dose-dependence of isoproterenol was irreproducible. The reproducibility of the duration of head-up tilt necessary to elicit symptoms of presyncope or syncope was determined in the 23 patients who had these symptoms on both tests. Symptoms developed monoexponentially with duration of head-up tilt with half-times of 1.4 to 2.6 minutes, but these times did not correlate significantly between tests. In a selected subgroup of 12 patients who developed syncope in the first test and either presyncope or syncope in the second test during administration of isoproterenol (5 micrograms/min), the time of onset of presyncope correlated well (r = 0.73, p = 0.007) as did that of syncope (r = 0.86, p = 0.012). Finally, hemodynamic changes during symptoms were compared between the 2 tests.(ABSTRACT TRUNCATED AT 250 WORDS)

Adolescent↗
PubMed1992

Methodology of isoproterenol-tilt table testing in patients with syncope.

To assess the impact of isoproterenol, duration of tilt, symptom development and hemodynamic changes on the outcome of tilt table tests, 100 patients with syncope underwent successive 80 degrees head-up tilt for 10 min during infusions of 0, 2 and 5 micrograms/min of isoproterenol. All 15 patients with another cause of syncope had a normal test result and 66 (78%) of the 85 patients with syncope of unknown origin had a test that resulted in syncope or presyncope. Isoproterenol was required to produce syncope or presyncope in greater than 90% of positive tests and 66% to 80% of positive tests required a dose of 5 micrograms/min of isoproterenol. Without isoproterenol, symptoms did not develop until after greater than or equal to 4 min of head-up tilt. With either 2 or 5 micrograms/min of isoproterenol, the half-time of symptom onset was 0.7 to 1.9 min and the rate of symptom development did not depend on the dose of isoproterenol. During syncope, the mean heart rate, systolic blood pressure and rate-pressure product each decreased significantly from 132 +/- 21 to 67 +/- 25 beats/min, 117 +/- 19 to 60 +/- 16 mm Hg and 15.3 +/- 2.9 to 4.2 +/- 2.2 x 10(3) mm Hg/min, respectively. During presyncope, mean trough rate-pressure product (5.5 +/- 2 x 10(3) mm Hg/min) was significantly higher (p = 0.027) than during syncope.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1986

A syndrome of microangiopathic hemolytic anemia, renal impairment, and pulmonary edema in chemotherapy-treated patients with adenocarcinoma.

Chemotherapy is frequently used to treat adenocarcinoma. Thirty-nine cases are reviewed in which the patients developed a hemolytic-uremic-like syndrome, apparently in response to chemotherapy. About 44% of the patients had gastric adenocarcinoma, and 82% had received mitomycin C. Most patients (75%) developed the syndrome 6 to 12 months after starting chemotherapy, and 60% were in remission. Severe microangiopathic hemolytic anemia, thrombocytopenia, and renal impairment were each noted in about 90% of the cases. Neurologic symptoms were usually absent, but 49% of the patients developed adult respiratory distress syndrome (ARDS). The overall case fatality rate was 72%; those patients with ARDS had a 95% mortality rate, while 50% of those without ARDS survived. The half-life of survival of those who ultimately died was 2 months. Treatment is unsatisfactory, although steroids and plasmapheresis may prolong survival.

Adenocarcinoma↗
PubMed1984

Identification of hearing loss in the neonatal intensive care unit population.

A protocol was designed to evaluate babies in neonatal intensive care units by means of the auditory brain stem response (ABR) audiometric technique during their hospitalization. This article presents the results obtained from 200 babies. Twenty-three infants failed the ABR test. Fifteen babies were followed. Ten of these infants had significant sensorineural hearing loss. Three had unilateral involvement and seven had bilateral impairment. The seven bilaterally affected infants were fitted with appropriate hearing aid amplification and enrolled in audiologic habilitation programs. Continued follow-up of these babies has confirmed the hearing loss diagnosis. These data estimate that 5 percent of babies in neonatal intensive care units have some degree of hearing loss. The findings encourage the use of the ABR technique as a means of identifying hearing loss in the neonatal intensive care unit population.

Audiometry↗
PubMed1977

Altered dihydrofolate reductase in fol regulatroy mutants of Escherichia coli K12.

Three spontaneous fol regulatory mutants contain dihydrofolate reductase molecules which differ in physical properties from enzymes of their parent strains. The enzymes were purified over 100-fold by affinity chromatography and were shown to differ in vitro in thermolability and in affinity for trimethoprim, a competitive inhibitor of the enzyme. These results indicate that some fol regulatroy mutations occur in the structural gene for dihydrofolate reductase.

Chromatography, Affinity↗
PubMed1976

Regulatory mutants of dihydrofolate reductase in Escherichia coli K12.

Trimethoprim inhibits dihydrofolate reductase. Mutations conferring trimethorpim-resistance on E coli K12 result in either an altered reductase with decreased affinity for the drug, or in 2-30 fold higher levels of the enzyme. Studies of the latter class of mutants indicate that dihydrofolate reductase is regulatdd by a diffusible molecule, and is probably under negative control. The regulatrory mutants, some of which are temperature-sensitive, act cis.

Drug Resistance, Microbial↗