摘要:

Clinical Pharmacology and Therapeutics(1988)44, 251–253; doi:10.1038/clpt.1988.1

ISSN:0009-9236    

DOI:10.1038/clpt.1988.146

年代:1988

数据来源: WILEY

摘要:

Theophylline disposition (5.5 mg/kg administered intravenously) was studied in 12 patients with cystic fibrosis (CF) and 16 healthy control volunteers. Dietary controls and logs were used to minimize the influence of food on theophylline metabolism. Control subjects were restudied in random order on two subsequent occasions after 2 weeks of either pancreatic enzymes or placebo. Theophylline and its three main metabolites, 1‐methyluric acid, 3‐methylxanthine, and 1,3‐dimethyluric acid, were analyzed in serum and urine by HPLC. The total body clearance, renal clearance, nonrenal clearance, and volume of distribution of theophylline were significantly greater (p<0.05) in patients with CF than in control subjects. The increased nonrenal clearance was the result of increased biotransformation to each of the three main metabolites. Patients with CF exhibited enhancedN‐demethylation and 8‐hydroxylation of theophylline, pathways that appear to be mediated by two different families of P‐450 enzymes. Theophylline clearance after 2 weeks of pancreatic enzyme administration in the control subjects was the same as with placebo. Possible reasons for enhanced theophylline biotransformation in CF are discussed.Clinical Pharmacology and Therapeutics(1988)44, 254–264; doi:10.1038

ISSN:0009-9236    

DOI:10.1038/clpt.1988.147

年代:1988

数据来源: WILEY

摘要:

The effect of clonidine on smoking cessation was studied by randomly assigning 186 smokers in a double‐blind fashion to either placebo or clonidine. Abstinence from smoking was reported more frequently by subjects receiving clonidine, but the difference was statistically significant only at the end of the first week (34.4% vs 21.5%;p<0.05). Bothersome side effects were common and resulted in the early discontinuation of the study medication by 23 of the subjects taking clonidine and eight taking placebo (p<0.05). Although this study did not demonstrate a significant effect of clonidine on smoking cessation, a beneficial trend was detected and therefore further trials with transcutaneous delivery of this agent in combination with behavior modification techniques are warranted.Clinical Pharmacology and Therapeutics(1988)44, 265–267; doi:10.1038/clpt.1988

ISSN:0009-9236    

DOI:10.1038/clpt.1988.148

年代:1988

数据来源: WILEY

摘要:

Several research groups have reported that the oral administration of propranolol with protein‐rich food leads to a marked increase (mean + 60%) in the area under the drug plasma concentration‐time curve (AUCoral) of this highly metabolized and well‐absorbed drug. It has been postulated that this “food effect” is caused at least in part by a transient increase in hepatic blood flow (QH) with its associated decrease in first‐pass metabolism (hepatic extraction is a monotonic decreasing function of QH). A randomized crossover study using postural manipulations to produce changes in QHof the magnitude observed after food consumption (20% to 50%) was performed in an attempt to isolate the contribution of transient changes in QHto the food effect phenomenon. A solution of 80 mg propranolol HC1 was taken orally and subjects were randomly assigned to postural manipulation protocols that should change QHsuch that AUCoralwould be minimized (phase 1) or maximized (phase 2). Estimated QH(indocyanine green total body clearance from blood) was determined before and at three time points during each phase. It was observed that indocyanine green total body clearance during periods of standing was 15% to 40% below that observed during periods of seating (significant atp<0.05 for many of the appropriate comparisons). However, AUCoralfor propranolol was not affected (mean ± 1 SD; AUCphase2/AUCphase 1= 0.98 ± 0.28) by these changes in QH, which are comparable to those encountered after food consumption. Thus the food effect on propranolol bioavailability is apparently not principally the result of a change in QHand must be due to other mechanisms such as a decrease in apparent intrinsic metabolic clearance (e.g., caused by inhibition of the mixed‐function oxidase or glucuronyl‐transferase systems), alterations in the plasma protein binding of drug in hepatic sinusoidal blood, or inhibition of slowly reversible intrahepatic drug binding.Clinical Pharmacology and Therapeutics(1988)44, 268–274; doi:1

ISSN:0009-9236    

DOI:10.1038/clpt.1988.149

年代:1988

数据来源: WILEY

摘要:

Nafarelin, a potent gonadotropin—releasing hormone (GnRH) agonist, was absorbed rapidly into systemic circulation (time to reach peak concentration, 20 to 40 minutes) after intranasal but not after sublingual or vaginal administration. Serum elimination half‐life was about 2 hours. Nasal absorption of nafarelin was increased by increasing the concentration of the drug in the dose solution and incorporating sodium glycocholate into the nasal formulation. An optimal formulation providing maximum nasal absorption of nafarelin was one containing 1.75 mg nafarelin per ml and 2% sodium glycocholate. Bioavailability of this nasal formulation relative to a single subcutaneous dose averaged 21%. The metabolism and excretion of nafarelin were determined in three subjects after subcutaneous administration of [14C]‐nafarelin. Radioactivity was excreted in approximately equal amounts in urine and stool. Six metabolites accounted for most of the radioactivity in urine. Four metabolites were short peptide fragments of nafarelin and the other metabolites were naphthylalanine and 2‐naphthylacetic acid.Clinical Pharmacology and Therapeutics(1988)44, 275–282; doi:10.1038/clp

ISSN:0009-9236    

DOI:10.1038/clpt.1988.150

年代:1988

数据来源: WILEY

摘要:

We describe the relationship of 2‐hydroxydesipramine (OH‐DMI) plasma levels and response in a prospective DMI study in which dosage was rapidly adjusted to achieve a relatively uniform DMI plasma level. In prior studies, OH‐DMI plasma levels were not related to response, but in these fixed‐dose protocols the effects of OH‐DMI are easily obscured by the higher concentrations of the parent drug. We hypothesized that in this study a contribution of OH‐DMI to response might become apparent because DMI levels were relatively constant. Inpatients with nonpsychotic, unipolar DSM‐III major depression who remained depressed (Hamilton score>18) after 1 week of hospitalization without medication received a 4‐week DMI trial. Twenty‐four‐hour drug plasma levels were used to adjust dose to reach a target DMI steady‐state plasma level. Twenty‐seven patients completed the trial. On every measure of response, total drug levels (DMI + OH‐DMI) were more strongly correlated with outcome than were DMI levels alone. With multiple regression, both DMI and OH‐DMI levels were independently and significantly associated with response. These findings suggest that OH‐DMI has antidepressant activity.Clinical Pharmacology and Therapeutics(1988)44, 283

ISSN:0009-9236    

DOI:10.1038/clpt.1988.151

年代:1988

数据来源: WILEY

摘要:

After 20 mg sublingual nifedipine in 12 men with clinically stable chronic cor pulmonale the mean arterial pressure and systemic vascular resistance fell, cardiac index rose, and mean pulmonary arterial (Ppa) and wedge (Ppaw) pressures, right atrial pressure, and PaO2remained unchanged. After 20 mg orally every 6 hours for 24 hours in 11 patients, the mean arterial pressure fell further, systemic vascular resistance remained low, and the cardiac index returned to baseline, whereas the Ppa and Ppaw decreased, but the pulmonary vascular driving pressure (Ppa ‐ Ppaw), right atrial pressure, PaO2, and spirometry and ejection fractions remained unchanged. Of eight patients receiving maintenance therapy four developed untoward side effects in 1 to 3 weeks and one was noncompliant. The remaining three patients evaluated at 6 weeks failed to improve and had unchanged resting hemodynamics. Thus in the absence of a potentially reversible hypoxic pulmonary hypertension, nifedipine may not improve pulmonary arterial pressure and cardiac function in clinically stable patients with cor pulmonale.Clinical Pharmacology and Therapeutics(1988)44, 289–296; doi:10.1038/clpt.1988

ISSN:0009-9236    

DOI:10.1038/clpt.1988.152

年代:1988

数据来源: WILEY

摘要:

The effects of hydrochlorothiazide (HCTZ) and guanabenz monotherapy on blood pressure and serum lipoprotein levels were compared in a 14‐week, randomized, parallel, double‐blind multicenter study of 218 outpatients with mild hypertension. Mean supine blood pressure decreased 13/9 mm Hg in the guanabenz group and 17/11 mm Hg in the HCTZ group, changes that were significantly (p<0.01) different from baseline but not significantly different between the two treatment groups. Significant (p<0.01) mean decreases in total cholesterol and low‐density lipoprotein (LDL) cholesterol levels (of 9 mg/dl and 4 mg/dl from baseline values) occurred during guanabenz treatment; HDL cholesterol levels fell by an average of 4 mg/dl. In the HCTZ group, triglyceride levels were significantly (p<0.01) increased by 13 mg/dl, and HDL cholesterol levels fell by 2 mg/dl. The change in LDL cholesterol levels, but not HDL cholesterol levels, was significantly different between guanabenz and HCTZ periods. The results show that guanabenz, although providing effective blood pressure control that is comparable to that of HCTZ, has more favorable effects on lipoproteins.Clinical Pharmacology and Therapeutics(1988)44, 297–302; doi:10.1038/clpt.

ISSN:0009-9236    

DOI:10.1038/clpt.1988.153

年代:1988

数据来源: WILEY

摘要:

The effects of renal disease on the steady‐state kinetics of oxaprozin were assessed in eight patients on hemodialysis with normal serum albumin levels and eight normal subjects who received six doses. A larger clearance and volume of distribution at steady state for total and unbound oxaprozin occurred in the patients on hemodialysis. The elimination half‐lifes were not different. The mean total AUC, peak concentration, average steady‐state plasma concentration, and trough concentration for total and unbound oxaprozin were decreased in the patients on hemodialysis. These differences are consistent with impaired absorption of oxaprozin in patients on hemodialysis. The higher dose—averaged unbound fraction of oxaprozin in plasma in patients on hemodialysis may be caused by endogenous binding inhibitors. Because clearance was not reduced in patients on hemodialysis, the dose of oxaprozin may not need to be reduced when albumin levels are normal.Clinical Pharmacology and Therapeutics(1988)44, 303–309; doi:10.1038/clp

ISSN:0009-9236    

DOI:10.1038/clpt.1988.154

年代:1988

数据来源: WILEY

摘要:

We quantitated atropine plasma levels and monitored blood pressure, heart rate, and salivary secretion after ocular application. Eight patients received 40 μl 1% atropine in the lower cul‐de‐sac of one eye in connection with ocular surgery. Atropine plasma levels were determined for 90 minutes by radioreceptor assay. The peak plasma atropine concentration of 860 ± 402 pg/ml was reached within 8 minutes in all patients. The ocular absorption of atropine was at least as rapid as that reported for intramuscular administration. Ocular atropine did not affect patients' blood pressure or heart rate when compared with those of the placebo group. Thirty minutes after administration of atropine eyedrops, the salivary secretion in the experimental group was reduced, but was statistically insignificant from the placebo group.Clinical Pharmacology and Therapeutics(1988)44, 310–314; doi:10.1038/clpt.

ISSN:0009-9236    

DOI:10.1038/clpt.1988.155

年代:1988

数据来源: WILEY