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Biomedical subjects

M H Chandler

Publications and source records attributed to M H Chandler.

At least 37 records · Page 2Linked to original sources
PubMed1992

Multiple dose pharmacokinetics of four different doses of nisoldipine in hypertensive patients.

This randomized double-blind parallel group study characterized the pharmacokinetics of the calcium channel antagonist, nisoldipine (core-coat tablets), administered once daily for 7 days in doses of 5 mg (n = 12), 10 mg (n = 13), 20 mg (n = 12), and 30 mg (n = 11) to patients with mild to moderate hypertension. Serial blood samples were obtained from 0 to 24 hours and from 0 to 48 hours after nisoldipine administration on days 1 and 7, respectively. Nisoldipine plasma concentrations were determined by gas chromatography with electron capture detection. No statistically significant difference was found in dose-normalized area under the curve between the four groups. Area under the curve (standardized to body weight) correlated to dose (r = .74, P less than .05). No significant difference existed in oral clearance (L/h/kg) when analyzed for equivalence across the four doses: 8.21 +/- 3.47 (5 mg), 11.84 +/- 13.85 (10 mg), 11.48 +/- 7.49 (20 mg), and 10.36 +/- 5.49 (30 mg). The present investigation characterizes the pharmacokinetics of nisoldipine core-coat tablets in hypertensive patients and demonstrates the dose proportionality or linearity of nisoldipine plasma concentrations and area under the curve, measured over a dose range of 5 to 30 mg.

Adult↗
PubMed1992

In vivo and in vitro beta 2-adrenergic receptor responsiveness in young and elderly asthmatics.

This pilot study was undertaken to characterize age-related alterations in airway and metabolic beta 2-adrenergic receptor response using terbutaline as a probe. A single dose of terbutaline 0.007 mg/kg was administered subcutaneously to 10 young (range 20-35 yrs) and 10 elderly (range 60-73 yrs) men and women with asthma. beta-Receptor function was assessed by serial pulmonary function tests, heart rate, blood pressure, plasma potassium, glucose, insulin, and catecholamine levels, and in vitro 3', 5'-cyclic adenosine monophosphate (cAMP) production of pure T lymphocytes. The trend was for lung beta 2-receptor response (bronchodilation) and T lymphocyte cAMP production to be lower in elderly than in young asthmatics, but differences did not reach statistical significance. Elderly subjects' beta 1-adrenergic receptor responsiveness (systolic blood pressure) was also dampened. These data suggest that T lymphocyte stimulation does reflect pulmonary beta 2-receptor response. Whether elderly asthmatics require and tolerate higher dosages of parenteral terbutaline than younger asthmatics deserves further study.

Adult↗
PubMed1991

Age-dependent stereoselective increase in the oral clearance of hexobarbitone isomers caused by rifampicin.

1. The disposition of hexobarbitone enantiomers before and after rifampicin treatment (600 mg daily for 14 days) was investigated in six young (29 +/- 3 years old) and six elderly (71 +/- 4 years old) healthy male volunteers. Hexobarbitone was given as a single 500 mg oral dose of the racemate. 2. The mean (+/- s.d.) oral clearance of S-(+) hexobarbitone was 1.9 +/- 0.3 and 1.8 +/- 0.2 ml min-1 kg-1, respectively, in young and elderly subjects and increased approximately six fold following 14 days of rifampicin treatment in both young (to 11.9 +/- 2.2 ml min-1 kg-1) and elderly (to 10.7 +/- 2.8 ml min-1 kg-1) subjects. 3. In contrast, rifampicin treatment produced a larger and a differential increase in the oral clearance of R-(-) hexobarbitone in young and elderly subjects; an 89 fold change in the young (15.6 +/- 16.4 to 1146.7 +/- 1478.0 ml min-1 kg-1) and a 19 fold change (10.3 +/- 3.0 to 199.9 +/- 98.1 ml min-1 kg-1) in the elderly.

Administration, Oral↗
PubMed1990

Pulmonary function in the elderly: response to theophylline bronchodilation.

This clinical investigation was designed to characterize the pharmacologic response to theophylline in elderly individuals. Incremental theophylline plasma concentrations (0, 5, 10, 15, and 20 mcg/mL), achieved through dose escalation of intravenous aminophylline, were correlated with pulmonary airway responses in ten young and ten elderly male asthmatic volunteers. The older group had lower baseline pulmonary function values, suggestive of a greater degree of baseline airways obstruction. Despite wide intersubject variability, the elderly subjects demonstrated a lower absolute change in bronchodilator response to equal concentrations of theophylline than did their younger counterparts (P less than .05). A progressive increase in heart rate was noted with increasing theophylline concentrations, but no significant difference in heart rate change between groups was detected (P greater than .05). Whether the difference in theophylline induced bronchodilator response observed in the young and elderly groups is due to a difference in age or in severity of airway obstruction is yet unknown.

Adult↗
PubMed1990

Using clinical data to determine vancomycin dosing parameters.

The serum concentrations and pharmacokinetic parameters produced from standard doses of vancomycin were evaluated in 22 patients. The mean (+/- SD) half-life, clearance (Cl), and volume of distribution, respectively, were 6.2 (+/- 1.9) h, 79.2 (+/- 34.3) ml/min, and 0.54 (+/- 0.23) L/kg. Geometric regression analysis was used to determine significant correlations between Cl and creatinine clearance (CrCl) (p less than 0.001). The dosing method developed is based on the pharmacokinetic parameters of vancomycin derived from our patient data and the relationship between Cl and CrCl described by the following equation, Cl = (0.674) (CrCl) + 13.45 (r = 0.703). Predictive performance measures were used to compare our dosing method with that of the Matzke nomogram. Our method was found to be less biased and more precise in regards to predicted half-life and volume of distribution, while less biased with no difference in precision in regard to predicting clearance. We plan to use this dosing method at our institution to provide a more individualized initial dosing regimen for vancomycin. Other institutions may wish to use a similar approach to design a dosing nomogram specific for their patient population.

Adult↗
PubMed1990

Multiple-dose pharmacokinetics of concurrent oral ciprofloxacin and rifampin therapy in elderly patients.

The purpose of this clinical study was to investigate the influence of concomitant drug therapy with ciprofloxacin and rifampin on the individual pharmacokinetic profile of each agent in elderly patients. Twelve nursing home patients (age, 74 +/- 7 years), colonized with methicillin-resistant Staphylococcus aureus, were randomized to receive 14-day therapy with oral ciprofloxacin (750 mg every 12 h) (group A; n = 6) or ciprofloxacin (750 mg every 12 h) and oral rifampin (300 mg every 12 h) (group B; n = 6). Serial blood samples were obtained from 0 to 12 h following ciprofloxacin doses 1 and 13 and from 0 to 36 h after the last ciprofloxacin dose. No significant differences (P greater than 0.05) were found between or within groups in any pharmacokinetic parameter. The mean ciprofloxacin oral clearance values were 0.35 +/- 0.06, 0.41 +/- 0.15, and 0.38 +/- 0.11 liter/h per kg for doses 1, 13, and 28, respectively, in group A patients. The mean oral clearance values in group B patients for the respective doses were 0.53 +/- 0.36, 0.32 +/- 0.13, and 0.36 +/- 0.17 liter/h per kg. Likewise, no significant differences (P greater than 0.05) in rifampin pharmacokinetic parameters were found when compared with historical controls. These data suggest that ciprofloxacin and rifampin may be given concomitantly in standard clinical dosing regimens. The combination results in therapeutic levels of both drugs and appears to be safe for administration to elderly nursing home patients.

Administration, Oral↗
PubMed1990

Home monitoring of theophylline levels: a novel therapeutic approach.

This pilot clinical investigation was conducted to compare a home therapeutic drug-monitoring (TDM) method for theophylline blood levels and a traditional TDM method with respect to various patient outcome factors. Outpatients with chronic obstructive pulmonary diseases (COPD) or asthma who were receiving long-term theophylline therapy were randomized to one of two groups: home TDM or traditional TDM (controls). Patients in the former group monitored their serum theophylline levels at home over 6 months. Patients in both groups completed survey instruments, including questionnaires, visual analog scales, and other psychosocial measures, at designated times throughout the study period. Pulmonary function tests and dyspnea index scores were evaluated at each clinic visit. Results indicated a significantly lower (p less than 0.05) number of changes in concomitant drug therapy in the home TDM group compared with controls. Other indicators that showed a trend toward more favorable outcomes in the home TDM group included symptomology, percentage of levels within the therapeutic range, patient attitudes regarding participation in health care management, and pulmonary function test results. Home monitoring prevented unnecessary clinic visits in several instances when theophylline dosage adjustments were based on telephone reports from patients. The utility of a home TDM method for theophylline has not been reported previously despite potential for broad applications. Findings from this preliminary study may support the use and feasibility of state-of-the-art methodologies in carefully selected subpopulations outside the confines of the hospital or clinic setting.

Ambulatory Care↗
PubMed1988

The effects of renal function on the disposition of isradipine.

The effect of renal function on isradipine kinetics was examined in four groups of subjects (N = 55) who had normal or impaired renal function. Each subject received isradipine orally as a 10-mg capsule. Serial blood samples were obtained from 0 to 48 hours postdose and the isradipine plasma concentrations determined by radioimmunoassay. Kinetic parameters, Cmax, lambda 3, t 1/2, AUC, CL'o (oral clearance), and CLo (oral clearance standardized to body weight) were determined. Marked intersubject variability of the pharmacokinetic parameters was observed. No statistically significant differences (P greater than .05) were found for AUC, Cl'o, and Clo parameters when renal impairment groups were compared with controls. AUC values were lower (P less than .05), however, for the group with severe renal function impairment than for groups with mild or moderate renal function impairment. No significant correlations (r = -.23, P greater than .05; and r = .13, P greater than .05, respectively) were found between creatinine clearance (CLCR) and CLo and between age and CLo. Considering the interpatient variability in isradipine disposition and the lack of significant differences in CLo between groups, no clear-cut dosing regimen alterations, based on single-dose data, are warranted in renal impairment.

Adult↗
PubMed1988

Age-associated stereoselective alterations in hexobarbital metabolism.

This clinical investigation was designed to study the influence of age on stereoselective drug disposition using hexobarbital as a model marker. The disposition of hexobarbital enantiomers was investigated in 10 young and 10 elderly, healthy male volunteers. Mean oral clearance (+/- SD) of d-hexobarbital (1.9 +/- 0.5 vs. 1.7 +/- 0.3 ml/min/kg; P greater than 0.05) did not differ significantly between the young and elderly subjects, respectively. However, despite wide intersubject variability, l-hexobarbital mean oral clearance (+/- SD) was approximately twofold greater in the young than in the elderly subjects (16.9 +/- 11.9 vs. 8.2 +/- 3.2 ml/min/kg; P less than 0.05). This resulted in a significantly greater enantiomeric oral clearance ratio in the young when compared with the elderly subjects (8.3 +/- 3.4 vs. 4.7 +/- 1.4; P less than 0.01). No significant difference (P greater than 0.05) in pharmacologic response after hexobarbital administration was found between the two groups. Demonstration of an age-related preferential decline in metabolism of one enantiomer over another has not been reported previously for any racemic drug in animals or humans.

Administration, Oral↗
PubMedDate not supplied

Severe phenytoin intoxication as a result of altered protein binding in AIDS.

Alterations in plasma protein binding may alter patient response to pharmaceutical agents because only free drug is considered to be pharmacologically active. Such alterations appear to be more significant with highly bound agents such as phenytoin. Traditionally, most drug assays monitor total drug concentrations and do not quantitate free drug. When binding alterations are present, total drug concentrations may mislead clinicians in evaluating patient response. We describe a case in which profound hypoalbuminemia (0.2 g/dL), associated with focal segmental glomerulosclerosis, produced toxic free phenytoin concentrations (4.9 micrograms/mL) in an HIV-positive 25-year-old black woman. At such a high serum concentration of free phenytoin, the patient exhibited seizure-like effects. Renal abnormalities and hypoalbuminemia associated with acquired immunodeficiency syndrome (AIDS) may place patients at risk for elevated free fractions of phenytoin and subsequent toxicity.

Acquired Immunodeficiency Syndrome↗