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Biomedical subjects

R V Lewis

Publications and source records attributed to R V Lewis.

At least 55 records · Page 3Linked to original sources
PubMed1989

Effects of atenolol, verapamil, and xamoterol on heart rate and exercise tolerance in digitalised patients with chronic atrial fibrillation.

The aim of the study was to compare the effects of atenolol (50 mg b.i.d.), verapamil (80 mg b.i.d.), xamoterol (200 mg b.i.d.), and matching placebo on heart rate (HR) and exercise tolerance in digitalised patients with chronic atrial fibrillation. Each treatment was taken for 4 weeks, and digoxin was continued throughout the study. During treatment with placebo (digoxin alone), the mean postexercise heart rate was 164 beats/min, and four subjects had rates of greater than or equal to 170 beats/min. Atenolol, verapamil, and xamoterol achieved significantly better control of exercise-induced tachycardia, mean postexercise heart rates being reduced to 120, 131, and 130 beats/min, respectively (p less than 0.01 for each). However, minimum HRs less than or equal to 45 beats/min occurred during treatment with placebo, atenolol, and verapamil, whereas treatment with xamoterol was associated with a minimum heart rate of 56 beats/min. Treatment with atenolol was associated with a marked reduction in maximum treadmill walking distance (mean 356 m) as compared both with placebo (mean 421 m, p less than 0.01) and verapamil (mean 439 m, p less than 0.01). Xamoterol reduced maximum walking distances as compared with verapamil (402 vs. 439 m; p less than 0.05) but not placebo (402 vs. 421 m; NSS). Thus, atenolol, verapamil, and xamoterol achieved better control of exercise-induced tachycardia than digoxin, but atenolol clearly impaired exercise tolerance whereas verapamil did not. Xamoterol achieved more even control of ventricular response rates and prevented the resting bradycardias that occurred with the other treatments. However, walking distances were significantly lower than those noted during treatment with verapamil.

Adrenergic beta-Agonists↗
PubMed1989

Timolol metabolism and debrisoquine oxidation polymorphism: a population study.

1. The metabolism of orally administered timolol (T) to its ring cleavage ethanolamine (TE) and glycine (TG) products was studied in 108 unrelated hypertensive patients. 2. Statistically significant correlations between the 0-8 h urinary debrisoquine/4-hydroxy-debrisoquine ratio and the T/TE (rs = 0.74, P less than 0.001), T/TG (rs = 0.42, P less than 0.001) and T/TE + TG (rs = 0.49, P less than 0.001) ratios were found. 3. The log10 T/TE, T/TG and T/TE + TG ratios from poor metabolisers of debrisoquine (PMs) were grouped at the upper end of a unimodal distribution. 4. These results indicate that timolol metabolism is partly under monogenic control of the debrisoquine-type. 5. The mean +/- s.d. plasma timolol concentration in PMs (82 +/- 43 ng ml-1) was double that in extensive metabolisers (45 +/- 19 ng ml-1) (P = 0.011). The clinical significance of this observation remains to be established.

Adult↗
PubMed1989

The effects of indomethacin and sulindac upon the blood pressures of individuals with untreated labile or mild hypertension.

Twelve patients (mean age 48.8 years, 5 females) with untreated labile or mild essential hypertension completed a randomised, double-blind crossover study comparing the effects of two-week courses of indomethacin, sulindac and matching placebo upon sitting and standing blood pressure. Both indomethacin and sulindac significantly increased systolic BP when compared with placebo; indomethacin tended to have a greater pressor effect than sulindac. During treatment with indomethacin, the mean BP rose from 136/86 to 149/92 (sitting), and from 136/93 to 150/99 standing. The extent of the pressor response was unrelated to baseline BP. The results indicate that both non-steroidal anti-inflammatory drugs (NSAIDs) have a significant pressor effect in individuals with untreated labile or mild hypertension. The fact that sulindac had a pressor effect implies that this response may be unrelated to inhibition of renal prostaglandins, or that the renal-sparing effect of sulindac is only relative. Extra-renal prostaglandins may play a role in the control of BP in this population. Individuals with labile or mild hypertension do not appear to exhibit exaggerated pressor responses during treatment with these NSAIDs, as similar increases in BP have been reported in normal subjects.

Adult↗
PubMed1988

Purification and characterization of a family of high molecular weight surface-array proteins from Campylobacter fetus.

A variety of Gram-negative and Gram-positive bacteria possess crystalline surface layers, although little is known of their function. We previously have shown that the high molecular weight surface-array proteins of Campylobacter fetus are important in both the pathogenicity and antigenicity of this organism. For biochemical and immunological characterization, we purified high molecular weight (100,000, 127,000, 149,000) surface-array proteins from three C. fetus strains using sequential gel filtration and ion exchange high performance liquid chromatography. These proteins are acidic with pI values between 4.12 and 4.25 and contain large proportions of acidic amino acids (19.7%-22.0%) in addition to hydrophobic amino acids (37.3%-38.5%). They share a novel amino-terminal sequence through at least 19 residues. Carbohydrate analysis using periodic acid-Schiff staining and treatment with trifluoromethanesulfonic acid shows no evidence of glycosylation. Antiserum to a purified Mr = 100,000 protein from C. fetus 82-40 LP cross-reacts with three other purified C. fetus surface-array proteins by enzyme-linked immunosorbent assay with titers greater than 12,800. We conclude that: 1) there is a family of surface-array proteins of C. fetus with common structural and antigenic characteristics; 2) that these molecules have similar biochemical characteristics to surface-array proteins described for other bacteria; but however, 3) by amino-terminal sequence analysis these are unique.

Amino Acid Sequence↗
PubMed1988

Relationships between heart rate, exercise tolerance and cardiac output in atrial fibrillation: the effects of treatment with digoxin, verapamil and diltiazem.

Six patients with chronic atrial fibrillation (AF) took single doses of digoxin, verapamil and diltiazem, alone and in combination. Three hours after dosing, resting and post-exercise heart rate, exercise tolerance and resting and post-exercise cardiac output were measured. Post-exercise heart rates ranged from 167 bpm (after placebo) to 122 bpm (after digoxin plus diltiazem) (P less than 0.05). However, the lower ventricular rates seen after treatment with the calcium antagonists were not associated with improved exercise tolerance, which did not differ significantly between the various treatments. Reduction of the ventricular rate was associated with a small increase in stroke volume but the benefits of this were offset by a rate related reduction in cardiac output. Further reduction of the rapid ventricular rates seen in digitalized patients with AF does not appear to be of benefit in terms of improving either exercise tolerance or cardiac output.

Aged↗
PubMed1988

A comparison of digoxin, diltiazem and their combination in the treatment of atrial fibrillation.

Fourteen patients (four females) with chronic atrial fibrillation were entered into a randomized, double-blind crossover study to compare the effects of treatment with diltiazem alone, digoxin alone, and a combination of diltiazem plus digoxin. The dose of digoxin was adjusted so as to achieve serum concentrations within the range 1.3-2.6 nmol l-1 between six and eight hours after dosing. Four patients were withdrawn from the study; three patients experienced side effects while taking diltiazem and one reverted to sinus rhythm while taking digoxin. Among the remaining 10 patients, mean heart rates were significantly lower during treatment with the combination of digoxin and diltiazem than with digoxin alone both at rest, after exercise and during ambulatory ECG monitoring. Post-exercise heart rates were reduced by 15% with combination therapy when compared with digoxin alone (151.9 vs. 128.1 bpm), but there was no evidence that this reduction in ventricular rate was associated with improved exercise tolerance. The results suggest that further reduction of the rapid ventricular rates seen in digitalized patients with AF by the use of diltiazem does not appear to be of benefit in the majority of patients.

Aged↗
PubMed1988

Factors affecting the clinical response to treatment with digoxin and two calcium antagonists in patients with atrial fibrillation.

It has been suggested that patients in whom atrial fibrillation (AF) is associated with poor exercise tolerance respond better to treatment with xamoterol plus digoxin than to digoxin alone; this may be attributable to better control of exercise induced tachycardia. We have examined data obtained during studies comparing digoxin and two calcium antagonists in the treatment of AF to see whether subgroups of patients with particularly poor exercise tolerance, rheumatic heart disease or rapid post-exercise heart rates might derive particular benefit from one modality of treatment as opposed to another. The results do not indicate that calcium antagonists improve exercise tolerance compared with digoxin in any of these subgroups despite achieving consistently better control of exercise induced tachycardia.

Atrial Fibrillation↗
PubMed1988

Central effects of beta-adrenoceptor antagonists. I--Performance and subjective assessments of mood.

1. Central effects of the beta-adrenoceptor antagonists, propranolol (40, 80 and 160 mg) and atenolol (50 and 100 mg) were studied in 12 healthy male subjects. Two placebo ingestions and an active control (oxazepam 15 mg) were included. Single doses were administered double-blind at 11.00 h, and assessments of performance and subjective feelings were made before, 2 h and 4 h after ingestion. 2. Performance was measured using letter cancellation, digit symbol substitution, continuous attention, choice reaction time, finger tapping, short term and immediate memory, critical flicker fusion and two flash fusion. Subjective feelings were assessed using twelve visual-analogue scales. 3. Oxazepam impaired performance at letter cancellation (P less than 0.001), digit symbol substitution (P less than 0.05), continuous attention (P less than 0.001), immediate recall (P less than 0.05) and finger tapping (P less than 0.05), but neither of the beta-adrenoceptor antagonists affected these measures. Propranolol (40 and 160 mg) also impaired short term memory (P less than 0.05), though it was not possible to establish this effect with atenolol. 4. Subjective alertness was reduced by oxazepam (P less than 0.01) and atenolol (P less than 0.05), while propranolol (40 mg) reduced anxiety (P less than 0.01) and propranolol (80 mg) impaired ability to concentrate (P less than 0.05). 5. The results suggest that both lipophilic and hydrophilic antagonists modify the central nervous system, though impairment may be difficult to establish with conventional tests. The observations on memory and alertness suggest that the central effect of beta-adrenoceptor antagonists may be subtle.

Adrenergic beta-Antagonists↗
PubMed1988

The relative effects of digoxin and diltiazem upon ventricular ectopic activity in patients with chronic atrial fibrillation.

In eight patients with chronic atrial fibrillation, treatment with digoxin (plasma drug concentration 1.3 to 2.0 nmol l-1) was associated with a significantly higher incidence of ventricular premature beats (VPBs) (mean 22.8 h-1) than diltiazem 120 mg three times daily (mean 6.8 h-1) (P less than 0.05). Seven out of the eight patients showed an increase in numbers of VPBs recorded over 24 h during treatment with digoxin when compared with diltiazem. The clinical importance of these results is unclear, but atrial fibrillation and ischaemic heart disease frequently co-exist, and increases in ventricular ectopy may predispose to serious ventricular arrhythmias following myocardial infarction.

Aged↗
PubMed1987

Target tissue distribution of the proenkephalin peptides F, E, and B.

The adrenal medulla is a rich source of endogenous opioid peptides. These peptides exist predominantly in the form of larger (25-34 amino acid long) enkephalin containing peptides, whose biological roles have yet to be elucidated. We report here the tissue binding distribution of three iodinated enkephalin containing peptides, Peptides F, E, and B, in rats, rabbits, and guinea pigs following intravenous injection. Each [125I]peptide has a unique distribution profile but all three are found to bind to the pituitary in each species of animal examined. A number of lines of evidence point toward the enkephalin containing peptides, Peptides F, E, and B, having physiological roles distinct from the enkephalins. The distribution profile of these [125I]peptides reported here gives insight into their potential effector sites.

Animals↗
PubMed1987

Quantifying side-effects of beta-blockers: the role of visual analogue scales.

Beta-blockers are often prescribed for patients who are asymptomatic and for whom the benefits of therapy are likely to be small. Side-effects are therefore of great importance. Symptoms such as muscle fatigue and peripheral coldness are commonly associated with treatment with beta-blockers but these subjective phenomena are difficult to detect and quantify so that their prevalence and severity are uncertain. Conventional symptom questionnaires may be relatively insensitive and visual analogue scales (VAS), which permit interval quantification of subjective phenomena, may have some advantages. They appear to be able to detect the presence of tiredness of the legs and peripheral coldness among hypertensive patients taking beta-blockers and are more sensitive than descriptive or 'category' questionnaires. However, some patients find VAS hard to understand and a minority of patients score erratically for all symptoms. A most detailed explanation is of paramount importance. Scores derived from VAS surveys are not normally distributed and should be examined using non-parametric statistical methods; normalising transformations do not improve the sensitivity of the method.

Adrenergic beta-Antagonists↗
PubMed1986

A single amino acid substitution in an ectopic alpha subunit of a human carcinoma choriogonadotropin.

Human choriogonadotropin [hCG] has two dissimilar noncovalently associated subunits, designated alpha and beta. An ectopically secreted hCG alpha subunit that fails to associate with the beta subunit and displays an anomalously high molecular weight on molecular sieve chromatography but not on sodium dodecyl sulfate-polyacrylamide gel electrophoresis has been sequenced. A single substitution of Glu56 by Ala56 has been found in the altered subunit. No evidence for conformational differences between normal and ectopic alpha could be found using circular dichroism or intrinsic fluorescence as measures of secondary and tertiary structure, respectively. Hydrophobicity profiles as determined by the method of Kyte and Doolittle (Kyte, J., and Doolittle, R. F. (1982) J. Mol. Biol. 157, 105-132) predicted, however, that the hydrophilic segment, Thr54-Ser55-Glu56-Ser57-Thr58, becomes an extension of the preceding hydrophobic segment when Glu56 is substituted with Ala. This solitary hemoglobin S-like mutation may lead to an altered tertiary structure, self dimerization, or an alteration in glycosylation that could be responsible for the ectopic alpha subunit's failure to associate with the beta subunit.

Alanine↗
PubMed1986

Photoaffinity labelling of carnitine acetyltransferase with S-(p-azidophenacyl)thiocarnitine.

A photolabile reagent, p-azidophenacyl-DL-thiocarnitine, was synthesized and tested as a photoaffinity label for carnitine acetyltransferase (EC 2.3.1.7) from pigeon breast. p-Azidophenacyl-DL-thiocarnitine is an active-site-directed reagent for this acetyltransferase, since it is a competitive inhibitor (Ki 10 microM) versus carnitine. U.v. irradiation of a mixture of p-azidophenacyl-DL-thiocarnitine and enzyme produces irreversible inhibition. Acetyl-DL-carnitine protects the enzyme from inhibition by photoactivated p-azidophenacyl-DL-thiocarnitine. In the presence of 30 mM-2-mercaptoethanol as a scavenger, the relationship between loss of activity and photoincorporation of reagent suggests that one molecule of reagent is incorporated per molecule of inhibited enzyme. However, peptide maps of enzyme labelled with p-azidophenacyl[14C]thiocarnitine indicate that several (about six) tryptic peptides (of a possible 60-65) are modified. The presence of 5 mM-acetyl-DL-carnitine significantly decreases the incorporation of reagent in each labelled tryptic peptide.

Acetyltransferases↗
PubMed1986

S-(4-bromo-2,3-dioxobutyl)-CoA labels two distinct sites on citrate synthase.

The chemical nature of the inactivation of citrate synthase by S-(4-bromo-2,3-dioxobutyl)-CoA, an active site-directed irreversible inhibitor, has been investigated. Active site-directed inactivation leads to derivatization of either Lys22 by epsilon-amino Schiff base formation or Glu363 by apparent alkylation of the gamma-carboxyl group, respectively. Lys22 is labeled in the tight (catalytic) form of the enzyme while Glu363 is labeled in the open (product release) form. Glu363 and Lys22 are both located at or near the entrance to an active site in the crystal structure of citrate synthase (Remington, S., Wiegand, G., and Huber, R. (1982) J. Mol. Biol. 158, 111-152). Glu363 is in the sequence of the protomer forming the active site while Lys22 is in the sequence of the other polypeptide in the homodimer. Labeling in this region appears to inactivate the enzyme by preventing access of substrates to the active site. A distinct and separate labeling process involves derivatization of Asn192 in the tight (catalytic) form and Ser198 and/or Ser199 in the open (product release) form at a locus far removed from the active site. Labeling at the second site may simply identify chemically reactive residues, or it may identify the binding site for long chain acyl-CoA, which has been identified as a possible allosteric negative effector of citrate synthase (Caggiano, A. V., and Powell, G. L. (1979) J. Biol. Chem. 254, 2800-2806). This second labeling process apparently inactivates the enzyme by interfering with catalytically essential conformational changes.

Affinity Labels↗
PubMed1986

A complete amino acid sequence for the basic subunit of crotoxin.

The complete amino acid sequence of the basic subunit of crotoxin from the venom of Crotalus durissus terrificus has been determined. Fragmentation of the protein was achieved by using cyanogen bromide and arginine- and lysine-specific endoproteases. Sixteen Glx and Asx residues reported by Fraenkel-Conrat et al. (1980) in Natural Toxins (D. Eaker and T. Wadstrom, eds.), pp. 561-567, Pergamon, Oxford.) have been resolved as Glu or Gln and Asp or Asn residues, respectively. Most of the remaining sequence is identical to that reported by the foregoing authors although several significant differences were evident in our protein. Tyr-61 was not present; thus the correct sequence is Lys-60, Trp-61. The latter sequence aligns with sequences of all other known viperid and crotalid phospholipases A2 (S. D. Aird, I. I. Kaiser, R. V. Lewis, and W. G. Kruggel (1985) Biochemistry 24, 7054-7058). Other differences include Asx-99, which is Ser, and Asx-105, which is Tyr. Some positions display allelic variation. In some lots of venom Glx-33 is Gln, while in others it is Arg. Positions 37 and 69 occur as mixtures of both Lys and Arg. Amino acid sequence comparisons between the basic and acidic subunits of crotoxin and between the basic subunit and other phospholipase A2 molecules indicate that the basic subunit is structurally most similar to the monomers of nontoxic, dimeric phospholipases A2 from the venoms of Crotalus adamanteus, Crotalus atrox, and Trimeresurus okinavensis, and to the toxic monomeric phospholipase A2 from the venom of Bitis caudalis.

Amino Acid Sequence↗
PubMed1986

Role of conformational changes in the elution of proteins from reversed-phase HPLC columns.

To test the hypothesis that conformational alterations might be involved in the elution of proteins from reversed-phase HPLC columns, the conformations of proteins bound onto a C-8 alkyl-bonded silica surface have been examined in the presence of increasing concentrations of the commonly employed eluent, 1-propanol. Using a combination of photoacoustic, diffuse reflectance deconvolution Fourier transform infrared and front face fluorescence spectroscopic techniques (to minimize interference from light scattering), the existence of surface-associated protein conformational changes induced by propanol is unequivocally demonstrated. The linear relationship found between the amount of propanol needed to elute proteins from C-8 columns and the midpoint of spectrally observed structural transitions is consistent with a role for conformational changes in the elution process.

1-Propanol↗