摘要:

Clinical Pharmacology and Therapeutics(1984)35,1–11; doi:10.1038/clpt.1984

ISSN:0009-9236    

DOI:10.1038/clpt.1984.1

年代:1984

数据来源: WILEY

摘要:

The effects of selective β1‐ as compared to nonselective β‐adrenergic blocking drugs on the peripheral circulation have not been adequately investigated. Ten healthy subjects received placebo for 1 wk followed by 4 wk of either propranolol or metoprolol in equivalent but increasing doses each week. Subjects then crossed over to the other sequence of placebo and drug. Measurements of calf blood flow, mean blood pressure, and calculation of calf vascular resistance were obtained at rest, after three loads of supine exercise on a bicycle ergometer, and during isoproterenol infusion testing. At the doses chosen, both β‐adrenergic blocking drugs induced equivalent decreases in exercise heart rate. Metoprolol lowered resting and exercise mean blood pressure at most doses, whereas propranolol had less of an effect on this variable. Neither drug altered resting or exercise calf blood flow or vascular resistance. More isoproterenol was required to increase the heart rate and decrease the vascular resistance during treatment with propranolol than with metoprolol. We conclude that in normotensive subjects metoprolol is somewhat more effective than propranolol in lowering mean arterial pressure during exercise when the drugs are given at doses equivalent in effects on exercise heart rate. Neither drug has a deleterious effect on calf blood flow or vascular resistance. Despite this, a marked separation between the vascular β2‐adrenergie –blocking effects of these drugs can be demonstrated with an isoproterenol infusion indicating β2‐adrenergic–receptor sparing by metoprolol.Clinical Pharmacology and Therapeutics(1984)35,12–18; do

ISSN:0009-9236    

DOI:10.1038/clpt.1984.2

年代:1984

数据来源: WILEY

摘要:

One gram ceftriaxone was injected at a constant rate in an intravenous infusion over 30 min to eight elderly subjects (mean age, 70.5 yr) and eight young subjects (mean age, 28.9 yr); the latter served as body weight–matched controls. Plasma and urine samples were collected in serial order for 48 hr and assayed for unchanged drug. Selected plasma samples were subjected to protein binding determinations by equilibrium dialysis. Statistical comparison of data for the old and young indicated no significant changes in means of (1) maximum plasma concentration (140 and 133 µg/ml); (2) elimination rate constant (0.078 and 0.093 hr−1) and elimination t½ (8.9 and 7.5 hr); (3) apparent volume of distribution (10.69 and 11.01 l); (4) plasma clearance (833 and 1023 ml/hr); (5) nonrenal clearance (515 and 606 ml/hr); and (6) percent dose excreted unchanged in urine (39.6 and 41.4). There was, however, a significant decrease in the renal clearance (318 and 416 ml/hr) and a significant increase in the plasma free fractions (0.157 and 0.136 at 100 µg/ml and 0.146 and 0.114 at 60 to 70 µg/ml) of ceftriaxone in elderly subjects. The 24% decrease in renal clearance in the elderly subjects corresponded to the 19% decrease in their creatinine clearance. Since the age‐related changes in kinetics were relatively small, it is concluded that dosage adjustment is probably not necessary for elderly subjects requiring ceftriaxone.Clinical Pharmacology and Therapeutics(1984)35,19–25; doi:10.1038

ISSN:0009-9236    

DOI:10.1038/clpt.1984.3

年代:1984

数据来源: WILEY

摘要:

The bronchodilating activity of oral cannabinoids was evaluated in three double‐blind experiments that involved the study of dose‐response and interactive relationships and the potential development of tolerance. Data indicated that ▵8‐tetrahydrocannabinol (▵8‐THC), cannabinol (CBN), and cannabidiol (CBD) in maximal doses of 75 mg, 1200 mg, and 1200 mg, respectively, did not induce significant dose‐related physiologic effects in experienced marijuana smokers. ▵8‐THC (75 mg) was, however, associated with bronchodilation, tachycardia, and peak highs less than that after ▵9‐tetrahydrocannabinol (▵9‐THC). The combinations of CBN and CBD with low‐dose ▵9‐THC (5 mg) did not induce significant bronchodilation but did exert interactive effects on heart rate and “high.” A 20‐day study of daily ▵9‐THC (20 mg), CBN (600 mg), and CBD (1200 mg) did not indicate tolerance or reverse tolerance to any drug. We conclude that ▵9‐THC and, to a lesser extent, ▵8‐THC, have acute bronchodilator activity but that CBN, CBD, and their combinations do not provide effective bronchodilation. The daily use of ▵9‐THC was not associated with clinical tolerance.Clinical Pharmacology a

ISSN:0009-9236    

DOI:10.1038/clpt.1984.4

年代:1984

数据来源: WILEY

摘要:

Deficient aromatic hydroxylation ofS‐mephenytoin was observed in an index subject during a kinetic study of stereoselective metabolism of mephenytoin. A genetic basis for this defect was suggested by decreased urinary recovery of 3‐methyl‐5‐(4‐hydroxyphenyl)‐5‐ethylhydantoin (4‐OH‐M) in the 24 hr after oral racemic mephenytoin in two brothers of the propositus. The parents and a third brother had urinary recoveries of 4‐OH‐M of the same order as in a group of 20 normal subjects. The kinetic implications of this defect were studied in the index subject and compared with four normal subjects after a single oral dose of differentially radiolabeled pseudoracemic mephenytoin (5 µCi of14C‐S‐mephenytoin, 45 µCi of H3‐R‐mephenytoin, and 11.5 µmol/kg of both S‐ and R‐mephenytoin) followed by single oral doses of 1.4 mmol of unlabeled racemic mephenytoin daily the next 4 days. In normal subjects, there was substrate stereoselective metabolism with the S‐enantiomer rapidly excreted as 4‐OH‐M and the R‐enantiomer slowly excreted as 5‐phenyl‐5‐ethylhydantoin (PEH). Stereoselective metabolism persisted during repeated dosing. In the hydroxylation‐deficient subject, there was no evidence of stereoselective metabolism, recovery of 4‐OH‐M was low, and both enantiomers were slowly excreted, predominantly as PEH. Plasma PEH concentrations and urinary PEH excretion rates were approximately twice that in normal subjects. Thus a genetic deficiency in ability to hydroxylate S‐mephenytoin results in the S‐enantiomer metabolization by the alternate route of demethylation to PEH that cumulates, thereby, in comparison to the normal, effectively doubling the dose of total hydantoin.Clinical Pharmac

ISSN:0009-9236    

DOI:10.1038/clpt.1984.5

年代:1984

数据来源: WILEY

摘要:

Nine patients undergoing cardiopulmonary bypass surgery were given either 2 mg diamorphine or 2.5 mg morphine by intrathecal injection. Spinal fluid (sf) samples were collected over 25 min and drug concentrations measured by HPLC. Concentrations in sf were about 4000 times as great as after 1 mg/kg IV morphine. The kinetic properties of morphine and heroin in sf differed; diamorphine was removed from sf much more rapidly than morphine. Lipophilic opiates may be safer for intrathecal use because of the shorter life of substantial drug concentrations in the mobile sf phase.Clinical Pharmacology and Therapeutics(1984)35,40–45; doi:10.1038/clpt.1984

ISSN:0009-9236    

DOI:10.1038/clpt.1984.6

年代:1984

数据来源: WILEY

摘要:

One hundred twenty‐one patients with postpartum pain caused by uterine cramp or episiotomy pain were the subjects of a randomized, double‐blind, single‐dose study of oral nalbuphine (N), 15 mg (N = 39); codeine (C), 60 mg (N = 42); and placebo (N = 40) for analgesia. Observations were made over 6 hr. There were significant differences for sum of pain intensity differences and total pain relief between the active drugs and placebo but not between N and C. Time to onset of analgesia favored N (mean = 0.65 min) over C (mean = 0.74 min), but the analgetic effect of N diminished more rapidly at this dose. Results were the same for both uterine cramp and episiotomy pain. Adverse effects were of the narcotic type and of the same incidence for the two active drugs. Two new parameters for determining analgetic effect are introduced: number of dropouts per dose and number of subjects with zero analgetic effect.Clinical Pharmacology and Therapeutics(1984)35,46–49; doi:10.1038/clp

ISSN:0009-9236    

DOI:10.1038/clpt.1984.7

年代:1984

数据来源: WILEY

摘要:

Cimetidine dynamics were studied in six multiple‐trauma patients receiving 300 to 600 mg every 6 hr for prevention of stress ulceration. Patients received cimetidine intravenously for a mean duration of 7.8 days. There was a positive correlation between cimetidine serum concentration and gastric pH; the correlation between intragastric cimetidine concentration and gastric pH was stronger. The association between therapeutic efficacy (pH>4) and serum concentration over 1 mcg/ml was significant. The association with gastric cimetidine concentration above 2 mcg/ml was significant.Clinical Pharmacology and Therapeutics(1984)35,50–54; doi:10.1038/clpt.19

ISSN:0009-9236    

DOI:10.1038/clpt.1984.8

年代:1984

数据来源: WILEY

摘要:

Methyldopa is metabolized by sulfate conjugation catalyzed by phenol sulfotransferase (PST), O‐methylation catalyzed by catechol‐O‐methyltransferase (COMT), and decarboxylation catalyzed by aromatic L‐amino acid decarboxylase. These experiments were performed to determine whether individual variations in red blood cell (RBC) COMT and platelet PST activities might reflect variations in the metabolism of methyldopa in man. Methyldopa, 3.5 mg/kg, was taken orally by 28 subjects. Blood samples were obtained from these subjects for the assay of platelet PST and RBC COMT activities, and a 24‐hr urine sample was collected for the measurement of methyldopa and its major metabolites. Human platelets contain two independently regulated forms of PST. One form is thermolabile (TL), and the other is thermostable (TS). Methyldopa and α‐methyldopamine are substrates for the TL but not for the TS form of PST. The results of the experiment showed significant correlations between TL platelet PST activity and the proportion of α‐methyldopamine excreted as a sulfate conjugate, and between RBC COMT activity and the proportion of methyldopa excreted as an O‐methyl metabolite. There was no significant correlation, however, between TL platelet PST activity, and the proportion of methyldopa itself excreted as a sulfate conjugate. These results are compatible with the conclusion that differences among subjects in drug metabolizing enzyme activities are one factor responsible for wide individual variations in methyldopa metabolism in man.Clinical Pharmacology and Therapeutics(1984)35,55–63; doi

ISSN:0009-9236    

DOI:10.1038/clpt.1984.9

年代:1984

数据来源: WILEY

摘要:

The effect of protein binding on cefmenoxime steady‐state kinetics was studied in 20 critical patients with gram‐negative pneumonia. Sixteen patients were given 1 gm cefmenoxime every 6 hr, two received 2 gm every 6 hr, and two received 2 gm every 8 hr. Serum protein binding was measured by equilibrium dialysis. Assays were by HPLC. Serum cefmenoxime concentration‐time data were characterized by a model‐independent method based on statistical moment theory. Despite varying renal function in patients, mean cefmenoxime serum concentration‐time curves for all three dosing regimens were closely aligned, reflecting successful empiric dosage adjustment. Terminal phase t½ ranged from 0.8 to 2.9 hr and was significantly related to creatinine clearance. Cefmenoxime total clearance was significantly related to both λz(2.303 times the slope of the terminal portion of the log‐concentration–time curve) and creatinine clearance (CCr). Plasma clearance of free cefmenoxime was more strongly correlated with CCr than the clearance of total cefmenoxime. Drug recovery from 24‐hr urine collections at steady state was 76.9 ± 19.8% of the daily dose (mean ± SD, n = 13). Cefmenoxime protein binding in patients differed markedly from normal values. A regression equation derived from data on 11 cephalosporins appeared to predict total volume of distribution in the steady state (Vdss‐Total) from the fraction of unbound drug accurately. Since cefmenoxime has a high therapeutic index, no clinical consequences are expected to result from variation in protein binding. Observed differences in protein binding between patients and normal subjects could have clinical consequences for highly bound acidic drugs that, unlike cefmenoxime, have narrow therapeutic indices.Clinical Pharmacology and Therapeutics(1984)35,64–73;

ISSN:0009-9236    

DOI:10.1038/clpt.1984.10

年代:1984

数据来源: WILEY