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Biomedical subjects

E Middleton

Publications and source records attributed to E Middleton.

At least 37 records · Page 2Linked to original sources
PubMed1991

Lack of pharmacokinetic and pharmacodynamic interactions between ketoconazole and prednisolone.

The effects of ketoconazole on the pharmacokinetics and pharmacodynamics of intravenous prednisolone (14.8 mg) were assessed in six healthy volunteers. Subjects were studied with and without receiving ketoconazole, 200 mg orally for 6 days. The addition of ketoconazole did not significantly change the clearance (96 +/- 11 versus 90 +/- 11 ml/hr/kg), mean residence time (4.29 +/- 0.43 versus 4.45 +/- 0.59 hours), volume of distribution (0.41 +/- 0.02 versus 0.40 +/- 0.02 L/kg), or plasma protein binding characteristics of prednisolone. The suppressive effects of prednisolone on serum cortisol, blood basophil, and helper T lymphocyte values, assessed by the ratio of the area under the curve (AUC) after prednisolone administration to the baseline AUC, was not altered significantly by ketoconazole. The 50% inhibitory concentration values derived from pharmacodynamic models developed to describe the direct suppressive effects of corticosteroids indicated no alteration in intrinsic sensitivity in the presence of ketoconazole. Ketoconazole does not appear to alter the pharmacokinetics or the pharmacodynamic response patterns of selected direct suppression effects of single low doses of prednisolone.

Adult↗
PubMed1990

Steroid dose sparing: pharmacodynamic responses to single versus divided doses of methylprednisolone in man.

Inhibitory drug interactions affecting the metabolism of methylprednisolone (MP) may produce either steroid sparing or adverse effects partly by increasing the exposure time to the steroid. This phenomenon can be mimicked by administering MP in divided doses. Two types of responses were compared after a single MP dose (40 mg bolus) and a divided regimen (20 mg bolus and a 5 mg bolus 8 hours later) in six healthy male volunteers. The suppression of basophils measured as whole blood histamine and plasma cortisol concentrations was assessed during 32 hours. The 37.5% reduction in dose produced a 23% overall decreased blood histamine response. A pharmacodynamic model for basophil cell distribution to and from an extravascular compartment describes the effects of MP after both regimens. A slower initial decline in blood histamine after the divided regimen may be related to incomplete suppression of basophil cell return to blood. The 50% inhibitory concentrations of MP of about 5 ng/ml were similar for both regimens. The decline and return of cortisol concentrations were similar between MP treatments with suppression continuing for 24 hours. The 50% inhibitory concentrations of MP values for adrenal suppression were about 1 ng/ml. Pharmacodynamic modeling is useful in quantitating corticosteroid responses and generally predicted the "dose-sparing" effects that were achieved by prolonging MP plasma concentrations. This study supports previous clinical observations that patients may require morning through evening exposure to MP to optimize efficacy while adrenal suppression is being minimized.

Adult↗
PubMed1990

The effect of forced expiration on the uniformity of 99Tcm-DTPA aerosol ventilation images in patients with excess sputum production.

This study examines the use of the forced expiratory technique (FET) as a means of improving the uniformity of radionuclide aerosol ventilation images in patients with excess sputum production. Ventilation images are objectively classified by two computer derived indices to characterize the degree of radioaerosol clumping and overall uniformity. In a series of twenty five patients with a long-standing history of daily sputum production, images acquired before and after forced expiration and again after a second ventilation immediately following FET showed no significant change in either index. The results obtained do not provide evidence to support the routine use of FET in conjunction with radioaerosol scintigraphy. The method of image classification correlates well with a visual assessment of image uniformity and has general application.

Aerosols↗
PubMed1989

Protein kinase C inhibition by plant flavonoids. Kinetic mechanisms and structure-activity relationships.

Protein kinase C (PKC) from rat brain was inhibited by plant flavonoids in a concentration-dependent manner depending on flavonoid structure. Of the fifteen flavonoids studied, fisetin, quercetin and luteolin were the most potent, while hesperetin, taxifolin and rutin were among the least potent. The flavonol fisetin was almost 100% inhibitory at a concentration of 100 microM. The extent of inhibition was the same whether diacylglycerol or 12-O-tetradecanoylphorbol-13-acetate was used as enzyme activator. Inhibition was independent of Ca2+, phospholipid, and enzyme activator, as shown by inhibition of protamine phosphorylation in the absence of the regulatory components. Fisetin was a competitive inhibitor with respect to ATP binding and noncompetitive with respect to protein substrate. The X-ray crystal structure analysis of hesperetin monohydrate showed that the molecule is essentially planar despite the sofa conformation of the gamma-pyran ring and the 27 degrees twist of the 2-phenyl ring. Comparison of this inactive flavanone with those of the active flavones showed that, although hesperetin can adopt a planar profile similar to those of fisetin and quercetin, the 4'-methoxy substituent blocks an essential structural feature required for inhibitory activity. Analysis of these structure-activity data revealed a model of the minimal essential features required for PKC inhibition by flavonoids: a coplanar flavone structure with free hydroxyl substituents at the 3', 4' and 7-positions.

Animals↗
PubMed1989

The effect of azelastine and some other antiasthmatic and antiallergic drugs on calmodulin and protein kinase C.

The antiallergic and antiasthmatic drug, azelastine, interacts strongly with calmodulin (but not bovine serum albumin) as determined by an indirect assay; it also moderately inhibited the Ca2+-calmodulin-dependent enzyme bovine brain phosphodiesterase. Ketotifen was less active than azelastine in both assays of calmodulin reactivity and both drugs were less active than the recognized calmodulin inhibitor, W-7. Neither azelastine nor ketotifen had any inhibitory effect on the Ca2+- and phospholipid-dependent protein kinase C. A number of other commonly employed antiallergic and antiasthmatic drugs were essentially inactive in the calmodulin assays and had no or marginal inhibitory effect on protein kinase C.

3',5'-Cyclic-AMP Phosphodiesterases↗
PubMed1989

The effects of the bioflavonoid quercetin on squamous cell carcinoma of head and neck origin.

Quercetin exhibits antitumor activity. We investigated the effect of quercetin on the in vitro and in vivo growth of two squamous cell carcinoma cell lines and a normal human lung fibroblast-like cell line. The in vivo effect was evaluated using implantable cell growth chambers implanted subcutaneously in immunocompetent rats. Quercetin was injected intraperitoneally, and multiple dosages were tested. Cells were counted on days 1, 3, 5, and 7, and growth curves were constructed. Quercetin caused inhibition of growth in both squamous cell carcinoma lines. Effect on the fibroblast-like human lung cells was noted only at the maximum concentration. Significant growth inhibition of squamous cell carcinoma was observed in implantable cell growth chambers retrieved 3 days after quercetin treatment. Quercetin appears to possess a cytotoxic effect on squamous cell carcinoma of head and neck origin both in vivo and in vitro. The inhibitory effect on malignant cells appears to be selective and dose-dependent.

Animals↗
PubMed1989

Inhibition of reverse transcriptases by flavonoids.

Selected naturally occurring flavonoids were shown to inhibit three reverse transcriptases (RT): avian myeloblastosis (AMV) RT, Rous-associated virus-2 (RAV-2) RT and Maloney murine leukemia virus (MMLV) RT when poly (rA)oligo(dT)12-18 or rabbit globin mRNA were used as template. Amentoflavone, scutellarein and quercetin were the most active compounds and their effect was concentration-dependent. The enzymes exhibited differential sensitivity to the inhibitory effects of the flavonoids. The compounds also inhibited rabbit globin mRNA-directed, MMLV RT-catalyzed DNA synthesis. Amentoflavone and scutellarein inhibited ongoing new DNA synthesis catalyzed by RAV-2 RT. Kinetic studies were performed in an attempt to elucidate the mechanism of action of amentoflavone and scutellarein. A model is proposed for the mechanism of action of the flavonoids on RT activity.

Animals↗
PubMed1989

Pharmacokinetics and pharmacodynamic modeling of direct suppression effects of methylprednisolone on serum cortisol and blood histamine in human subjects.

Pharmacodynamic models for "directly suppressive" effects of methylprednisolone are based on the premise that receptor interactions of steroids are followed by immediate suppression of either the circadian secretion of cortisol or the constant rate recirculation of histamine-containing basophils that persists until inhibitory concentrations of methylprednisolone disappear. Methylprednisolone doses of 0, 10, 20, and 40 mg were given as the 21-succinate sodium salt in a balanced crossover study to six normal men. Plasma steroid concentrations and blood histamine were measured simultaneously. Both forms of methylprednisolone exhibited linear kinetic parameters. One dynamic model quantitates the baseline circadian pattern and the decline and return of cortisol with similar parameter estimates for all three dose levels. A similar model describes the monoexponential decline and the log-linear return to steady-state baseline of blood histamine. Similar inhibitory concentration values for both effects approximated the equilibrium dissociation constant of in vitro steroid receptor binding. The new models are more physiologically appropriate for these steroid effects than three other models that are commonly employed in pharmacodynamics. Steroid effects generally appear to be receptor mediated with either nongene immediate responses or gene-mediated delayed effects. These models allow quantitation of the rapid effects of steroids with simple equations and common fitted parameters for all steroid dose levels.

Adult↗
PubMed1989

A specific LTD4/LTE4-receptor antagonist improves pulmonary function in patients with mild, chronic asthma.

LY171883 is a new selective LTD4/LTE4-receptor antagonist. To evaluate the efficacy of LY171883, we studied 138 nonsmoking asthmatic patients, 18 to 65 yr old, in a double-blind, randomized block-design study. All patients were required to demonstrate a greater than or equal to 15% increase in FEV1 after inhaled bronchodilator use and were then randomly assigned to either LY171883 (600 mg) or placebo twice daily for 6 weeks. Assessment of efficacy was measured by inhaled metaproterenol use (mg/wk), symptoms, twice-daily peak expiratory flow, and weekly FEV1 measurements. LY171883-treated patients had improved FEV1 values upon completion of the treatment period compared with placebo recipients (p = 0.003). Metaproterenol use decreased in both groups, but treatment differences, though not statistically significant, favored LY171883 (p = 0.089). Of patients who used at least 23 mg/wk of metaproterenol (36 inhalations) at initiation of the study, those who received LY171883 used significantly less metaproterenol than those who received placebo (p = 0.007). LY171883 was well tolerated and reduced the need for a bronchodilator drug while improving pulmonary function. Results of this study support the hypothesis that leukotrienes LTD4 and/or LTE4 may be important in the pathogenesis of asthma in humans.

Acetophenones↗
PubMed1988

Chronic rhinitis in adults.

Chronic rhinitis afflicts many American adults; the exact number is unknown because of the difficulty in establishing an exact diagnosis and because of the likely presence of overlap syndromes, including perennial allergic rhinitis, perennial nonallergic rhinitis with eosinophilia, and so-called vasomotor rhinitis. Nasal allergic reactions with release of pharmacologically active chemical mediators can participate in the pathogenesis of chronic rhinitis. In addition, reflex mechanisms probably play an important role in the initiation and maintenance of chronic nasal symptoms. Diagnosis is best achieved by a detailed history, with special attention to home, environmental, and occupation-related exposures and to selective epicutaneous skin tests and repeated smears of nasal secretions for detection of eosinophils. Therapy includes avoidance of all sorts of dust, fumes, sprays, and the like and appropriate attention to minimizing home environmental and occupational exposures. Pharmacotherapy is discussed elsewhere in this supplement.

Adult↗
PubMed1988

Lack of effect of atenolol on the pharmacokinetics of theophylline.

The effects of 3 days of pretreatment with cardioselective doses of atenolol on theophylline pharmacokinetics were determined. Nine healthy nonsmoking male volunteers received 6 mg kg-1 i.v. aminophylline under baseline conditions and after both 50 mg day-1 and 100 mg day-1 atenolol. Theophylline clearance, volume of distribution and half-life were not influenced by atenolol pretreatment. These data indicate that cardioselective doses of atenolol do not alter the pharmacokinetics of theophylline.

Adult↗
PubMed1988

Some biological properties of plant flavonoids.

The flavonoids are a large group of naturally occurring low molecular weight substances found in fruits, vegetables, nuts, seeds, flowers, and roots as well as wine and teas. They are consumed in the Western diet to the extent of about 1 gram per day. Flavonoids affect many mammalian cellular functions and enzyme systems. Their role in health and disease as natural biologic response modifiers remains to be determined.

Animals↗
PubMed1987

The effects of a beta-2 selective adrenergic agonist and a beta-nonselective antagonist on theophylline clearance.

Beta-adrenergic agonists and antagonists have been shown to alter theophylline pharmacokinetics. It was the purpose of this study to characterize further the effects that terbutaline and propranolol have on theophylline disposition. In nine healthy male volunteers, mean parameters for theophylline disposition did not change after four days of terbutaline (5 mg q8h). Theophylline clearance, however, did change within the subjects. Clearance increased in five subjects, decreased in three, and remained unchanged in one volunteer. Pretreatment with four days of terbutaline (5 mg q8h) and propranolol (60 mg q8h) significantly decreased mean theophylline clearance (60.1 +/- 12.9 vs 40.6 +/- 9.9 mL/min/1.73m2; P less than .01) increased half-life (8.37 +/- 1.77 vs 12.32 +/- 2.70 hours; P less than .05), and increased postinfusion theophylline concentration (13.5 +/- 2.7 vs 18.95 +/- 2.5 micrograms/mL; P less than .001). In five subjects theophylline clearance increased after terbutaline pretreatment (64.6 +/- 13.0 vs 75.0 +/- 13.9 mL/min/1.73m2). The percentage increase ranged from 3.9 to 28.5%. These subjects were restudied after receiving propranolol alone (60 mg q8h). Comparison between the propranolol and terbutaline study and the propranolol alone study indicated no mean change in clearance in these five subjects (41.8 +/- 12.7 vs 36.1 +/- 5.1 mL/min/1.73m2). Thus it appears that the changes observed in these five subjects after terbutaline pretreatment may have been random in occurrence as has been shown to occur with theophylline disposition and are not related to terbutaline pretreatment. It is concluded that beta-2 adrenergic stimulation does not alter theophylline pharmacokinetics, whereas nonselective beta-adrenergic antagonism profoundly affected theophylline disposition. This is an additional reason not to use propranolol in patients who receive theophylline.

Adrenergic beta-Agonists↗
PubMed1987

Longitudinal effects of pregnancy on the pharmacokinetics of theophylline.

The effects of pregnancy on the disposition of theophylline were assessed in 10 patients throughout pregnancy and post-partum. The clearance relative to total theophylline concentrations was only slightly affected during the first two trimesters (2.61 +/- 0.63 l/h and 2.85 +/- 1.05 l/h), while a statistically significant reduction was evident late in pregnancy (2.05 +/- 0.49 l/h). Post-partum clearance values (2.16 +/- 2.81 l/h) suggest an ongoing suppression relative to pre-pregnancy levels. A similar pattern was evident with clearance values based on free theophylline plasma concentrations (p = 0.12). Absolute volume of distribution increased in concert with gestation, suggesting that theophylline partitions into the enlarged tissue spaces. In addition, theophylline binding to plasma proteins decreased, albeit insignificantly, during the second (fraction bound = 29%) and third (32%) trimesters compared to post-partum values (41%). Increases in half-life during the third trimester (13.00 +/- 2.31 h vs 9.53 +/- 3.53 h post-partum) were highly significant. This change reflects the net effect of reduced clearance and increased distribution. Breast feeding had no effect on the disposition of theophylline, although the transfer of this compound into breast milk was confirmed.

Asthma↗