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Biomedical subjects

B B Kitchell

Publications and source records attributed to B B Kitchell.

At least 19 recordsLinked to original sources
PubMed1985

The effects of age and smoking on the plasma protein binding of lignocaine and diazepam.

In 63 healthy ambulant subjects 18 to 88 years of age, the plasma protein binding of diazepam (principally bound to albumin) decreased with age. Diazepam binding in plasma correlated positively with plasma albumin concentration which also decreased with age. In contrast, the plasma protein binding of the basic drug, lignocaine (predominantly bound to alpha 1-acid glycoprotein [AAG]), tended to increase slightly with age. Lignocaine binding in plasma correlated positively with plasma AAG concentration which also increased slightly with age. Smoking did not affect the plasma protein binding of diazepam or lignocaine or the plasma concentrations of albumin, AAG or nonesterified fatty acids. These results suggest that age-related changes in plasma protein binding of lignocaine and diazepam are determined in part by age-related changes in the concentrations of the binding proteins in plasma. The ageing process alone causes only small changes in the plasma protein binding of these drugs compared with the effect of disease states, however.

Adolescent↗
PubMed1984

Heart and liver lipid fatty acid and behavior changes in mice after a diet change.

270-Day old, male Ham/ICR mice were subjected to a diet change from high protein and carbohydrate and low fat to a diet higher in fat and lower in carbohydrate and protein. Age matched mice were maintained on laboratory rodent chow as controls. The diet change was not defined so the observed differences could not necessarily be ascribed to altered protein, carbohydrate, or fat intake. Comparison of the controls with the experimental mice revealed the " junk food" mice differed in lipid fatty acid profiles of the heart and liver and in percentage of lipid palmitic and oleic acids in these organs and also in plasma. Appearance was altered in the experimental mice which had dull, greasy coats. In addition, the experimental animals were less active, slept singly, and were slower in negotiating a three-choice maze than their comparably housed counterparts, indicating altered activity/curiosity behavior.

Animals↗
PubMed1984

Hemodynamic and metabolic responses to exercise after alpha 1-, beta 1-, and nonselective beta-adrenoceptor blockade in man.

The effects of acute alpha 1-adrenoceptor blockade with prazosin, beta 1-adrenoceptor blockade with atenolol, and nonselective beta-adrenoceptor blockade with propranolol were compared in a placebo-controlled crossover study. The study involved measurement of the hemodynamic and metabolic responses to exercise after heavy exercise in order to induce skeletal muscle glycogen depletion and thus enhance the dependence on hepatic glucose output and circulating free fatty acids. Catecholamine responses to exercise were enhanced by glycogen depletion and by both beta-blocking drugs. Catecholamine levels were highest with propranolol; as a consequence, at high work loads, propranolol failed to produce a significant reduction in systolic blood pressure and elevated diastolic blood pressure. At high work loads, atenolol reduced systolic blood pressure but did not change diastolic blood pressure. Both beta blockers reduced free fatty acid levels, but only propranolol accelerated the fall of plasma glucose levels during "glycogen-depleted" exercise. In contrast, during exercise prazosin reduced systolic and diastolic blood pressures, and elevated heart rate and plasma catecholamines, particularly noradrenaline. Concomitantly, prazosin raised free fatty acid and lactate levels, and increased the plasma glucose level at a time when placebo therapy resulted in a steady fall in glucose levels. The results indicate important differences in the hemodynamic effects of cardioselective versus nonselective beta-blockade during long-term (or glycogen-depleted) exercise. The importance of beta 2-mediated hepatic glycogenolysis in man is confirmed. Acute alpha 1-blockade with prazosin induces reflex elevation of catecholamine levels. There is no indication of an important role for an alpha 1-mediated mechanism in hepatic glucose production in man.

Adult↗
PubMed1984

Hemodynamic and metabolic responses to exercise after adrenoceptor blockade in humans.

The effects of acute alpha 1-adrenoceptor blockade with prazosin, beta 1-adrenoceptor blockade with atenolol, and nonselective beta-adrenoceptor blockade with propranolol were compared in a placebo-controlled crossover study of the hemodynamic and metabolic responses to acute exercise 2 h after prolonged prior exercise to induce skeletal muscle glycogen depletion, enhancing the dependence on hepatic glucose output and circulating free fatty acids (FFA). Plasma catecholamines were higher during exercise after, as opposed to before, glycogen depletion and were elevated further by all three drugs. Propranolol failed to produce a significant reduction in systolic blood pressure and elevated diastolic blood pressure. Atenolol reduced systolic blood pressure and did not change diastolic blood pressure. Both beta-blockers reduced FFA levels, but only propranolol lowered plasma glucose relative to placebo during exercise after glycogen depletion. In contrast, prazosin reduced systolic and diastolic blood pressures and resulted in elevated FFA and glucose levels. The results indicate important differences in the hemodynamic effects of beta 1-selective vs. nonselective beta-blockade during exercise after skeletal muscle glycogen depletion. Furthermore they confirm the importance of beta 2-mediated hepatic glucose production in maintaining plasma glucose levels during exercise. Acute alpha 1-blockade with prazosin induces reflex elevation of catecholamines, which in the absence of blockade of hepatic beta 2-receptors produces elevation of plasma glucose. The results suggest there is little role for alpha 1-mediated hepatic glucose production during exercise in humans.

Adrenergic alpha-Antagonists↗
PubMed1983

Differentiation of hemodynamic, humoral and metabolic responses to beta 1- and beta 2-adrenergic stimulation in man using atenolol and propranolol.

The respective contributions of beta-adrenoceptor subtypes to the hemodynamic, humoral and metabolic consequences of adrenergic stimulation during graded exercise in man were investigated using nonselective beta-adrenoceptor blockade with propranolol and beta 1-adrenoceptor blockade with atenolol. Doses of these agents that produced comparable suppression of beta 1 response as measured by antagonism of cardioacceleration during exercise were selected. Six healthy, nonsmoking males received these drugs in a placebo-controlled, Latin-square, randomized manner using a double-blind protocol. Both drugs produced comparable reductions of systolic blood pressure and elevation of diastolic blood pressure compared with placebo as exercise load increased. Propranolol produced higher peak epinephrine levels than atenolol or placebo (808 +/- 162, 640 +/- 190 and 584 +/- 153 pg/ml, respectively, p = 0.03), but norepinephrine levels did not show significant differences. Plasma renin activity was similarly suppressed both at rest and during all grades of exercise by both drugs. Lactate levels during moderate exercise were significantly lower after propranolol than after either atenolol or placebo (p = 0.03), but were similar at heavy work loads. Plasma glucose values rose on placebo (from 96.5 +/- 2.1 to 97.7 +/- 2.7 mg/dl) and on atenolol (from 99.7 +/- 2.2 to 102.1 +/- 4.8 mg/dl), but fell on propranolol (from 96.4 +/- 1.9 mg/dl to 87.2 +/- 2.5 mg/dl, p less than 0.01). These results indicate that blockade of vascular smooth muscle beta 2 receptors does not substantially alter hemodynamics during intense short-term exercise. Stimulation of renin release and lipolysis are produced through beta 1-adrenoceptor mechanisms, whereas beta 2 adrenoceptors are important in the provision of carbohydrate as an energy substrate for exercising muscle.

Adult↗
PubMed1983

Facial hair barbering in rats.

Facial alopecia was observed in three of four adult, female, Fischer 344 rats sharing the same cage for 2 months. Alopecia was characterized by irregular areas of hair loss between the eyes, which occasionally extended below the eyes and between the ears. These areas were nonpruritic and were not associated with dermatophytes, pathogenic skin bacteria, or ectoparasites. When the unaffected rat was removed and allowed to cohabit with new cagemates, facial alopecia became apparent in those animals within 6 days, and the hair of the original cagemates grew back within 3 weeks. The alopecia was caused by hair barbering by a dominant female rat.

Alopecia↗
PubMed1982

Detection and characterization using circular dichroism and fluorescence spectroscopy of a stable intermediate conformation formed in the denaturation of bovine carbonic anhydrase with guanidinium chloride.

Particularly stable elements of noncovalent structure in bovine carbonic anhydrase have been detected and studied. These are present in a highly populated intermediate state formed during denaturation of the enzyme with guanidinium chloride. The intermediate has been detected by analysis of the denaturation profiles, and some of its structural properties have been characterized by CD and fluorescence spectroscopy, including fluorescence polarization and lifetime measurements. Measurements have been made on the Zn2+-enzyme, Co2+-enzyme, and apoenzyme to ascertain the structural effects of the active-site Zn2+. Kinetic measurements indicate that this intermediate is on the folding pathway from the random coil to the native state.

Apoenzymes↗
PubMed1982

Heparin kinetics determined by three assay methods.

Heparin kinetics were determined in four normal subjects, each of whom received three different doses (25, 50, and 75 units/kg body weight) by intravenous injection. Multiple blood samples were collected after each dose and each plasma sample was assayed for heparin activity using three different assay methods. Two of these assays are based on coagulation tests, i.e., activated partial thromboplastin time and thrombin time, while the third is based on chemical neutralization of heparin using hexadimethrine bromide. Heparin kinetics showed pronounced dose-dependent changes, irrespective of the assay method used, which were characterized by increasing biologic half-life and decreasing total clearance (Cl) with increasing dose. No changes were noted in apparent volume of distribution (Vd). This data also showed that there were differences in kinetic parameters of heparin depending on the assay method. In general, values for total Cl and apparent Vd based on chemical neutralization were approximately 1.5 to 2.0 times these parameters based on coagulation tests. We conclude that the immediate mechanism of the dose-dependent heparin kinetics is decreasing total clearance with increasing dose and suggest that in vivo activation of the anticoagulant properties of heparin may explain the assay-dependent kinetics.

Adult↗
PubMed1982

Diazepam and lidocaine plasma protein binding in renal disease.

The plasma protein binding of diazepam and lidocaine was measured in patients with renal disease (those with uremia, nephrotic syndrome, or who had received a transplant) and in age- and sex- matched control subjects. Percentage unbound diazepam in plasma was increased over control in all three groups of patients as follows: uremic patients 3.23%, control, 1.64% (P less than 0.001), nephrotic patients, 3.55%, control, 1.63% (P less than 0.001); and transplant recipients, 2.11%, control 1.50% (P less than 0.001). The binding ratio (molar concentration of bound to unbound drug) in patients was related to albumin concentration (r = 0.609, P less than 0.001). Percentage of unbound lidocaine did not differ substantially from control in nephrotic patients (34.2%, control 30.8%), but was reduced in the uremic patients (20.8%, control 30.7%, P less than 0.001) and transplant recipients (24.6%, control 33.7%, P less than 0.005). These increases were associated with increases in alpha 1-acid glycoprotein (AAG) concentration (uremic patients 134.9 mg/dl, control 66.3, P less than 0.001; transplant recipients 106.5, control 65.6, P less than 0.001). The binding ratio of lidocaine was closely related to the AAG concentration in patients (r = 0.933, P less than 0.001) and controls (r = 0.719, P less than 0.001). Thus, the binding of basic drugs may be increased or decreased in patients with renal disease, depending on the relative contribution of the individual plasma to the total binding and the type of disease.

Adult↗
PubMed1981

The ability of vascular tissue to produce prostacyclin decreases with age.

The ability of aortae from young and mature swine to produce prostacyclin (PGI2) has been determined. PGI2 was measured as its hydration product, 6-keto-PGF1 alpha and assayed by stable isotope dilution GCMS. There was no significant difference in 6-keto-PGF1 alpha production between intimal strips from young and mature aortae in the basal state. In the presence of saturating concentrations of arachidonic acid, however, intimal strips from young aortae synthesized twice as much 6-keto-PFG1 alpha as did older tissues. Fatty acid compositions of young and mature aortae were virtually identical, making dietary difference an unlikely explanation for the age-related decrease in PGI2 synthesis. Both young and mature vascular tissues produced essentially only PGI2; insignificant amounts of PGE2 and PGF2 alpha were found.

6-Ketoprostaglandin F1 alpha↗
PubMed1981

The artifactual nature of heparin-induced drug protein-binding alterations.

Our purpose was to determine whether the reported alteration of protein drug binding after heparin administration in man was artifactual as a result of continued in vitro activity of triglyceride lipases. The lipoprotein lipase inhibitors protamine (14 mg/ml) and ethylenediaminetetraacetic acid (10 mg/ml) were added to blood samples from 11 healthy subjects before and 15 min after 100 USP units of intravenous heparin. Heparin elevated total nonesterified fatty acid (NEFA) concentration (P less than 0.001) and free fractions of lidocaine, diazepam, and propranolol (P less than 0.001 for all). The presence of the lipase inhibitors diminished the heparin-induced elevation of NEFA (P less than 0.001) and free fractions of lidocaine (P less than 0.001) and diazepam (P less than 0.001), but these values were still greater than control. The inhibitors reduced propranolol binding in control samples and did not diminish the effects of heparin. The change in NEFA concentrations correlated with the free fraction changes of all three ligands (r = 0.739 to 0.849). These data suggest that the heparin-induced protein binding changes are to, a large extent, in vitro artifacts.

Adult↗
PubMed1981

Sex-related differences in the plasma protein binding of lignocaine and diazepam.

1 The percentage of lignocaine free in the plasma of ten females receiving oral contraceptive medication was significantly greater than in 17 males of similar age (18--42 years). 2 In the same subjects the percentage of diazepam free in plasma was significantly greater in the contraceptive treated group than in 11 contraceptive-free females and significantly greater in contraceptive-free females than in males. 3 The differences in lignocaine binding were almost completely attributable to changes in alpha 1-acid glycoprotein concentration, which is reduced by oestrogens. The binding of diazepam was significantly related to albumin, alpha 1-acid glycoprotein and non-esterified fatty acid concentrations which together were related to 55% of the variation in the binding of this basic compound.

Adult↗
PubMed1980

Lidocaine plasma protein binding.

The percent of unbound lidocaine in the plasma of 24 healthy subjects was measured by equilibrium dialysis after addition of 3 microgram/ml C14 lidocaine hydrochloride. The percentage of unbound lidocaine varied from 19.9 to 38.8 (30.2 +/- 5, mean +/- SD) was inversely related to the concentration of alpha 1-acid glycoprotein (AAG) in the plasma (r = -0.931, p less than 0.001). The binding ratio (number of moles bound divided by number of moles unbound) of lidocaine was directly related to the plasma AAG concentration (r = 0.960, p less than 0.001). The binding ratio of lidocaine in solutions containing AAG but no albumin, prepared from the plasma of subjects in the study, was also directly related to the concentration of this acute-phase protein (r = 0.909, p less than 0.001). Human serum albumin solution (4 gm/100 ml) bound lidocaine to the extent of 20% under the same conditions. There was no relationship between the binding ratio of lidocaine and the albumin concentration in the plasma of the 24 subjects. In 7 normal subjects variation in AAG between 2 samples collected at least 1 mo apart was associated with a concomitant change in plasma lidocaine binding (r = 0.943, p less than 0.01). Thus even in normal subjects there is considerable interindividual and intraindividual variation in lidocaine binding, and measurements of AAG concentration in plasma may be a useful predictor of the extent of lidocaine plasma binding.

Adult↗
PubMed1980

Diazepam and N-desmethyldiazepam redistribution after heparin.

The effects of heparin, 1,000 U intravenously, on the blood, plasma, and free concentrations of diazepam and its metabolite, N-desmethyldiazepam, have been investigated 3 hr after oral administration of 10 mg diazepam to 5 normal subjects. The percent free diazepam and N-desmethyldiazepam increased 15 min after heparin from 1.66 +/- 0.35 to 3.99 +/- 1.88 (mean +/- SD; p less than 0.05) in the case of diazepam anolite. The actual free concentration of diazepam rose from 3.6 +/- 1.04 to 6.9 +/- 1.33 ng/ml (p less than 0.05) 15 min after heparin while total blood concentration was unchanged (144 +/- 54 vs 130 +/- 57 ng/ml). Free concentrations of N-desmethyldiazepam rose from 0.62 +/- 0.17 to 1.01 +/- 0.34 but the effect, though consistent, was not statistically significant. Blood concentrations did not change (15 +/- 3.2 vs 14 +/- 3.9 ng/ml). That free drug level rose without a change in blood or total plasma levels suggests that factors other than simple plasma binding displacement are involved in this drug interaction.

Adult↗
PubMed1979

Urea and guanidine hydrochloride induced dissociation and denaturation of bacteriophage F2 capsid.

A single, low molecular weight protein is found after urea or guanidine hydrochloride (Gdn.HCl) treatment of empty capsids derived from bacteriophage f2. The final product of denaturation is apparently a monomer, existing as a random coil in larger than or equal to 4.0 M Gdn.HCl but in a less extended form in 8.0 M urea. In contrast, an 11 S protein component is isolated after treatment of the intact virus with 4.0 M Gdn.HCl (Zelazo & Haschemeyer, 1969), indicating that RNA plays a role in stabilizing larger subunits. Denaturation by Gdn.HCl occurs in two stages as measured by changes in CD and Stokes radius: dissociation that involves a structural perturbation of aromatic side chains, followed by a major, cooperative transition that evidently results in the loss of all noncovalent structure. Denaturation by urea appears to be a much less cooperative process that occurs in several steps over a wide range of urea concentration (1--7 M). In both urea and Gdn.HCl, dissociation into subunits begins at a lower concentration of denaturant than the major changes in conformation.

Bacteriophages↗