摘要:

Clinical Pharmacology and Therapeutics(1986)39,239–244; doi:10.1038/clpt.1986.

ISSN:0009-9236    

DOI:10.1038/clpt.1986.33

年代:1986

数据来源: WILEY

摘要:

Tertatolol is a potent new β‐blocker with no intrinsic sympathomimetic activity or β1/β2‐receptor subtype selectivity. When given at therapeutic doses (5 mg/day) to human subjects it induced a reduction in the β‐adrenergic receptor number measured by3H‐CGP 12177 specific binding, without any change in the affinity on intact lymphocytes. This reduction was seen 7 hours (54%), 24 hours (35%), and 48 hours (30%) after a single drug dose. A similar receptor reduction was observed 7 hours (42%), 24 hours (37%), and 48 hours (15%) after 14 doses of the drug. In parallel, the pharmacologic efficacy of the drug was evident from the reduction in supine and upright heart rates and after submaximal exercise; heart rate was reduced to the same extent after single or repeated drug doses. The reduction of receptor number correlated well with the reduction in heart rate in the supine (P<0.001) and upright (P<0.01) positions and after exercise (P<0.02). In in vitro competitive binding experiments tertatolol was found to be a competitive inhibitor of β‐adrenergic receptors. However, on intact human lymphocytes preincubated with this drug, tertatolol reduced the density of β‐adrenergic receptors. We conclude that tertatolol, besides competitively inhibiting β‐adrenergic receptors, induced a marked and lasting decrease in the β‐adrenergic receptor number. This effect may be important for its β‐blocking effects.Clinical Pharmacology and Therapeutics(1986)39,245–

ISSN:0009-9236    

DOI:10.1038/clpt.1986.34

年代:1986

数据来源: WILEY

摘要:

The ingestion of food is known to affect blood pressure and heart rate, but food is often allowed in patients under observation for antihypertensive drug effects. Seventy‐seven patients with essential hypertension were observed for 8 hours after a 16‐hour fast. Thirty‐six continued to fast, 20 ate a high‐carbohydrate meal, and 21 ate a meal of their own choice. Blood pressure and heart rate did not change during fasting, but both meals lowered mean supine and standing diastolic blood pressures during the subsequent 4 hours by 3 to 7 mm Hg (P<0.001). The high‐carbohydrate meal reduced supine systolic blood pressure by 6 mm Hg (P<0.0001). Both meals increased supine and standing heart rates by 5 to 8 bpm (P<0.001). After the self‐selected meal, standing systolic blood pressure increased in younger patients but decreased in older patients. Food ingestion during antihypertensive drug studies may interfere with the interpretation of results and should be avoided whenever possible.Clinical Pharmacology and Therapeutics(1986)39,255–260; doi:10.103

ISSN:0009-9236    

DOI:10.1038/clpt.1986.35

年代:1986

数据来源: WILEY

摘要:

Intravenous dopamine has been shown to increase renal plasma flow in man. The role of endogenous dopamine in the maintenance of renal plasma flow has not been described. We speculated that if endogenous dopamine activity is important in the maintenance of renal plasma flow, then high doses of a potent dopamine blocking drug such as metoclopramide would decrease renal flow. To test this hypothesis, we measured renal plasma flow using a single‐injection technique with131I‐labeled orthoiodohippurate. Measurements were made before and after the administration of high doses of metoclopramide (1 to 2.5 mg/kg) to 20 patients receiving metoclopramide as an antiemetic before chemotherapy. Seven control subjects underwent sequential measurements of renal plasma flow without intervening metoclopramide dosing. Mean (±SD) renal plasma flow did not change in the control population (from 441 ± 198 to 437 ± 117 ml/min), but declined significantly in the patients who received metoclopramide (443 ± 115 ml/min before metoclopramide and 387 ± 137 ml/min after metoclopramide; P20% below baseline levels. The magnitude of the effect did not appear to correlate with the pretreatment creatinine clearance, age, or sex of the patients. We conclude that high doses of metoclopramide decrease renal plasma flow in man. These data suggest a role for dopamine in the maintenance of renal plasma flow in patients receiving intravenous hydration. Changes of the magnitude we observed may well be of clinical importance. These findings therefore also suggest the possibility of metoclopramide potentiation of cisplatin nephrotoxicity.Clinical Pharmacology and Therapeutics(1986)39,261–264; doi:10.1038/c

ISSN:0009-9236    

DOI:10.1038/clpt.1986.36

年代:1986

数据来源: WILEY

摘要:

The kinetics of caffeine elimination were investigated in 10 normal male subjects and in 11 recovering alcoholics before and during disulfiram dosing. In normal subjects the total body clearance of caffeine declined 30% (142 to 99 ml/min) at the maintenance dose of disulfiram, 250 mg/day, and 29% (161 to 114 ml/min) at the loading dose of 500 mg/day. In recovering alcoholics, the total body clearance decreased from 333 to 253 ml/min, a 24% change. The mean caffeine t½increased 39% and 34% in normal subjects after 250 and 500 mg disulfiram, respectively, and 29% in recovering alcoholics. The inhibition of caffeine elimination was moderate in most subjects. However, the clearance of caffeine decreased by ≥50% after disulfiram in three of the 11 recovering alcoholics. These patients may have an increased risk of cardiovascular and cerebral excitation associated with higher concentrations of caffeine, which could complicate withdrawal from alcohol.Clinical Pharmacology and Therapeutics(1986)39,265–270; doi:10.1038/clpt.19

ISSN:0009-9236    

DOI:10.1038/clpt.1986.37

年代:1986

数据来源: WILEY

摘要:

We conducted an analysis of 37 patients with the acquired immune deficiency syndrome (AIDS) who received pentamidine for the treatment ofPneumocystis cariniipneumonia to quantitate the incidence and severity of pentamidine‐induced hypoglycemia. Ten of these patients (27%), nine of whom were symptomatic, developed hypoglycemia during or shortly after pentamidine therapy. The mean nadir blood glucose concentration in those who developed hypoglycemia during or shortly after pentamidine therapy was 38 mg/dl (range 20 to 55 mg/dl). The hypoglycemia frequently persisted after the end of pentamidine therapy. The incidence of nephrotoxicity in patients who developed hypoglycemia was 100%, as compared with 38% in the group who remained euglycemic (P<0.01). The overall incidence of pentamidine‐induced hypoglycemia with AIDS is several‐fold higher than previously reported for patients with other immunocompromising diseases who receive pentamidine. We conclude that pentamidine‐induced hypoglycemia is a frequent adverse reaction in patients with AIDS and is potentially life‐threatening if not recognized.Clinical Pharmacology and Therapeutics(1986)39,271–275; doi:10.1038/

ISSN:0009-9236    

DOI:10.1038/clpt.1986.38

年代:1986

数据来源: WILEY

摘要:

Cetiedil citrate is an antisickling agent shown to be effective in reducing the severity and duration of acute sickle cell crisis. With the use of a sensitive GC/MS assay, the pharmacokinetic profile of cetiedil was studied in normal men and in men with sickle cell anemia who were not in crisis at the time of study. A peak cetiedil concentration of 70 to 200 ng/ml was found immediately after a 30‐minute drug infusion. The plasma level then gradually declined to approximately 10 ng/ml during a 3‐hour distributive phase. Computer analysis of the data was most consistent with a three‐compartment model. No pharmacokinetic differences were found between the normal men and the subjects with sickle cell. Because the cetiedil plasma levels achieved during this in vivo study are well below concentrations that exhibit antisickling activity in vitro, additional clinical studies will be necessary before an optimal dosing regimen can be established.Clinical Pharmacology and Therapeutics(1986)39,276–281; doi:10.1038/clpt

ISSN:0009-9236    

DOI:10.1038/clpt.1986.39

年代:1986

数据来源: WILEY

摘要:

O‐demethylation of the investigational antiarrhythmic encainide was found to be correlated with the genetically determined hydroxylation of debrisoquin in 20 randomly selected and unrelated subjects and in five members of one family. Extensive metabolizers of debrisoquin had a mean (± SD) encainide elimination t½of 1.19 ± 0.98 hours (range 0.25 to 3.4 hours). Poor metabolizers of debrisoquin (two normal subjects and three family members) had a mean t½of 13.2 ± 0.73 hours (range 7.8 to 22.4 hours). The elimination rate constant of encainide and the fractional excretion ofO‐desmethyl encainide in urine were linearly related to the fractional urinary excretion of 4‐hydroxy‐debrisoquin. Poor metabolizers could be identified after a 50 mg dose of encainide by the fractional excretion ofO‐desmethyl encainide in urine or the absence of (1) measurable ECG changes or (2)O‐desmethyl encainide in plasma. The correlation between excretion ofO‐desmethyl encainide and 4‐hydroxy‐debrisoquin suggests that significant numbers of the Caucasian population (7% to 9%) are likely to be poor metabolizers of encainide and to have markedly different pharmacokinetics and plasma concentration‐response relationships than extensive metabolizers.Clinical Pharmacology and Therapeutics(1986)39,282–28

ISSN:0009-9236    

DOI:10.1038/clpt.1986.40

年代:1986

数据来源: WILEY

摘要:

Quinidine has been reported to increase digoxin plasma concentrations, which increases the risk of digoxin overdose. The effect of quinidine on digitoxin pharmacokinetics is still controversial because most studies were not performed with subjects achieving definite steady‐state conditions. To determine whether quinidine affects digitoxin kinetics and cardiac efficacy, we measured glycoside plasma concentrations and renal excretion as well as ECG parameters and systolic time intervals before and during quinidine dosing in eight healthy subjects at steady state. Mean (± SD) digitoxin plasma concentrations and renal excretion increased from 13.6 ± 2.2 ng/ml and 16.1 ± 5.8 μg/24 hours before dosing to 19.7 ± 3.1 ng/ml and 23.4 ± 4.9 μg/24 hours, respectively, during quinidine dosing for 32 days. While renal digitoxin clearance was not noticeably changed by quinidine, total digitoxin clearance and extrarenal digitoxin clearance decreased by an average of 32% and 40.5%, respectively. The elimination t½was prolonged from 150.3 ± 20.6 to 202.6 ± 37.5 hours. The increased digitoxin plasma level is pharmacodynamically active. We conclude that there is a clinically important interaction between digitoxin and quinidine, but it is to a lesser extent and is caused by different mechanism, in part, than the interaction between digoxin and quinidine.Clinical Pharmacology and Therapeutics(1986)39,288–294; doi:10.103

ISSN:0009-9236    

DOI:10.1038/clpt.1986.41

年代:1986

数据来源: WILEY

摘要:

This double‐blind, randomized, parallel, placebo‐controlled study evaluated the analgesic effects of single oral doses of 30 mg nalbuphine, 650 mg acetaminophen, and the contribution of each to the efficacy of their combination in 128 hospitalized patients with postoperative pain. Subjective reports of patients evaluated each hour for 6 hours were used as indices of analgesic response. Both nalbuphine and acetaminophen were significantly superior to placebo for most measures of total and peak analgesia. The interaction contrast between nalbuphine and acetaminophen was not significant for any analgesic measurements, indicating an additive effect of the components. The combination was the most effective treatment, followed by nalbuphine, acetaminophen, and placebo. Effects of the combination were significantly different from those of acetaminophen at 4, 5, and 6 hours and from those of placebo at 1 to 6 hours. There was no significant difference in the frequency or intensity of side effects among the groups. The combination of nalbuphine and acetaminophen appears to be a therapeutically useful combination.Clinical Pharmacology and Therapeutics(1986)39,295–299; doi:10.1038/clpt.1

ISSN:0009-9236    

DOI:10.1038/clpt.1986.42

年代:1986

数据来源: WILEY