摘要:

We have determined simultaneously the density of β‐adrenoceptors in human myometria (by (‐)‐[125I]iodopindolol binding) derived from 36 women undergoing cesarean section and in the corresponding circulating lymphocytes (by (‐)‐[125I]iodocyanopindolol binding). In myometrial membranes about 80% to 85% of the β‐adrenoceptors were of the β2‐subtype. The density of myometrial and lymphocyte β‐adrenoceptors in women treated with the β2‐ adrenoceptors agonist hexoprenaline to prevent preterm labor was about 65% to 70% lower than that in nontreated women. Concomitantly, in hexoprenaline‐treated women the 10 µmol/L isoproterenol‐evoked increase in lymphocyte cyclic adenosine monophosphate content (as index for lymphocyte β‐adrenoceptor responsiveness) was diminished to a similar extent. Combining all data resulted in a significant positive correlation between myometrial and lymphocyte β‐adrenoceptor densities (r= 0.7303;n= 36;p<0.001). It is possible that determination of β‐adrenoceptor function in circulating lymphocytes may be a useful model to monitor myometrial β‐adrenoceptor changes during tocolytic therapy.Clinical Pharmacology and Therapeut

ISSN:0009-9236    

DOI:10.1038/clpt.1989.1

年代:1989

数据来源: WILEY

摘要:

The pharmacokinetics and pharmacodynamics of the antipruritic H1‐receptor antagonist hydroxyzine hydrochloride were studied in nine healthy, fasting subjects (mean age 69.5 ± 3.7 years) who ingested a single dose of hydroxyzine syrup, 0.7 mg/kg (mean dose 49.0 ± 6.7 mg). Blood samples were collected hourly for 6 hours, every 2 hours from 6 to 12 hours, at 24 hours, and then every 24 hours for 144 hours. At these times an intradermal injection of 0.01 ml of a 0.1 mg/ml histamine phosphate solution was performed, and wheal and flare areas were computed. The serum elimination t½of hydroxyzine was 29.3 ± 10.1 hours; the volume of distribution was 22.5 ± 6.3 L/kg; the clearance rate was 9.6 ± 3.2 ml/min/kg, and the AUC was 1383.1 ± 1039.0 ng · hr/ml. The mean serum elimination t½of cetirizine, the active metabolite of hydroxyzine generated in vivo, was 24.8 ± 7.7 hours, not significantly different from that of the parent compound(p =0.05). After a single dose of hydroxyzine the mean wheal and flare areas were significantly suppressed from 1 to 144 hours, compared with the mean predose wheal and flare sizes(p<0.01). Maximum wheal suppression, compared with all other wheals measured during the study, occurred from 4 to 10 hours, inclusive, and maximum flare suppression occurred from 2 to 72 hours, inclusive(p<0.01). Hydroxyzine has a long t½and a large volume of distribution in the elderly. The suppressive effect on the wheal and flare after a single dose of hydroxyzine is also extremely prolonged, suggesting the possibility of enhanced H1‐receptor activity in old age.Clinical Pharmacology and Therapeutics(1989)45,9–14; doi:10

ISSN:0009-9236    

DOI:10.1038/clpt.1989.2

年代:1989

数据来源: WILEY

摘要:

The time course of diphenhydramine concentrations and effects on both mental performance and subjective feelings of drowsiness were assessed in 15 healthy men. Subjects received single oral doses of diphenhydramine, 50 mg, and placebo in this double‐blind crossover study. Diphenhydramine plasma concentrations and central nervous system actions were assessed for 24 hours after each treatment. Cognitive impairment was assessed with an automobile driving simulator and digit symbol substitution scores, whereas drowsiness was self‐assessed on a visual analog scale. Diphenhydramine produced significant feelings of drowsiness for up to 6 hours after the dose, whereas significant mental impairment was apparent for only 2 hours. Despite the difference in duration of these effects, drowsiness and mental impairment have parallel slopes when effects are related to diphenhydramine concentrations. These data suggest thatalthough the apparent diphenhydramine concentration thresholds to produce drowsiness are lower (30.4 to 41.5 ng/ml) than those needed to produce mental impairment (58.2 to 74.4 ng/ml), these effects have profiles consistent with their being manifestations of the same pharmacologic effect.Clinical Pharmacology and Therapeutics(1989)45,15–21; doi:10.1038/clpt.

ISSN:0009-9236    

DOI:10.1038/clpt.1989.3

年代:1989

数据来源: WILEY

摘要:

The pathogenesis of aminoglycoside nephrotoxicity is intimately related to the extent of drug accumulated in the renal cortex. In the framework of searching for preventive measures of aminoglycoside‐induced nephrotoxicity, we investigated the influence of dosage regimen on the renal cortical accumulation of gentamicin and netilmicin in humans. Patients with a tumor partly involving one kidney, with normal renal function, and scheduled for nephrectomy received one dose of either gentamicin (4.5 mg/kg) or netilmicin (5 mg/kg) as a single short‐term infusion or as 24‐hour continuous infusion. Treatment started 24 hours before surgery. Serum aminoglycoside pharmacokinetics were examined during treatment and renal cortical tissue was sampled at the moment of operation for drug determination. The short‐term infusion schedule yielded cortical concentrations of 103.2 ± 36.3 and 137.4 ± 34.6 µg/gm for gentamicin and netilmicin, respectively. Tissue levels after continuous infusion were 158.1 ± 52.9 and 178.5 ± 21.8 µg/gm for gentamicin and netilmicin, respectively. For each aminoglycoside, a single short‐term infusion resulted in significantly lower renal drug levels than did a continuous infusion of the same dose. From the nephrotoxicity point of view, these data support the administration of gentamicin and netilmicin as once‐daily injections. This also supports the appropriateness of further studies to determine clinical efficacy of once‐a‐day dosing for aminoglycosides.Clinical Pharmacology and Therapeutics(1989)45,22–27;

ISSN:0009-9236    

DOI:10.1038/clpt.1989.4

年代:1989

数据来源: WILEY

摘要:

Propafenone is a new class 1 antiarrhythmic agent. The drug is extensively metabolized. 5‐Hydroxylation andN‐dealkylation constitute major metabolic pathways. Recently it has been demonstrated that the in vivo metabolism of propafenone is controlled by the debrisoquin/sparteine polymorphism. To elucidate which of the above metabolic reactions is catalyzed by cytochrome P‐450db1, the formation of 5‐hydroxypropafenone andN‐desalkylpropafenone was studied in the microsomal fraction of four human kidney donor livers previously characterized with regard to their ability to hydroxylate the β‐adrenergic antagonist bufuralol. The l'hydroxylation of bufuralol is catalyzed by the P‐450db1responsible for polymorphic debrisoquin/sparteine oxidation. The formation of 5‐hydroxypropafenone but notN‐desalkylpropafenone was closely related to bufuralol l'hydroxylation. Incubation with LKM1 antibodies, which selectively recognize P‐450db1, inhibited 5‐hydroxypropafenone formation completely whereas N‐dealkylation was unimpaired. Propafenone was a strong competitive inhibitor of bufuralol l'hydroxylation. Thus it can be concluded that 5‐hydroxypropafenone is formed by the cytochrome P‐450 isozyme involved in polymorphic bufuralol oxidation.Clinical Pharmacology and Therapeutics(1989)45,2

ISSN:0009-9236    

DOI:10.1038/clpt.1989.5

年代:1989

数据来源: WILEY

摘要:

Liver dextromethorphanO‐demethylation to dextrorphan is associated with the debrisoquin type of oxidation phenotype in humans. We studied dextromethorphan oxidation in vitro using human liver microsomes to investigate the kinetics of the polymorphic monooxygenase (cytochrome P‐450 db1) and factors that may influence its activity. In microsomal preparations from six extensive metabolizers the reaction parameters were: Michaelis‐Menten constant = 3.4 ± SD 1.0 µmol/L and maximum rate of metabolism = 10.2 ± 5.3 nmol × mg P−1× hr−1, vs 48 µmol/L and 2.2 nmol × mg P−1× hr−1, respectively in microsomes prepared from the hver of one poor metabolizer. The reaction was inhibited by nonspecific monooxygenase inhibitors such as SKF 525‐A (Ki = 100 nmol/L) and cimetidine (Ki = 40 µmol/L), by known substrates of the polymorphic isozyme such as [+]‐bufuralol (Ki = 7.5 µmol/L), debrisoquin (Ki = 25 µmol/L), and sparteine (Ki = 45 µmol/L), and by the selective cytochrome P‐450 db1inhibitor quinidine (Ki = 15 nmol/L). This assay permits in vitro screening for candidate substrates or inhibitors of the polymorphic isozyme.Clinical Pharmacology and Therapeutics(1989)4

ISSN:0009-9236    

DOI:10.1038/clpt.1989.6

年代:1989

数据来源: WILEY

摘要:

Sequential changes in the pharmacokinetics of cyclosporine (CsA) and metabolites M1, M17, and M21 were determined, 1, 3, and 12 weeks after initiation of CsA therapy in 21 renal transplant recipients. Concentrations of CsA and its metabolites were measured by HPLC. The dose‐adjusted AUC (AUCsst) and 24‐hour trough (C24trough) level of CsA and the metabolites increased significantly during the study period. However, there was no change in the AUCsstratio of each of the metabolites to that of CsA, suggesting that CsA metabolism did not change. However, the factors that alter the binding and distribution of CsA (i.e., hematocrit, plasma proteins, and lipoproteins) showed a significant rise during the study period, and the rise correlated well with the observed changes in AUCsstand C24trough. Thus alterations in the distribution and binding of CsA and its metabolites in blood, rather than reduction in the metabolism of CsA, may explain changes in CsA pharmacokinetics over time.Clinical Pharmacology and Therapeutics(1989)45,41–48; doi:10.1038/clpt.

ISSN:0009-9236    

DOI:10.1038/clpt.1989.7

年代:1989

数据来源: WILEY

摘要:

Etoposide plasma protein binding (PB) is reported to be 94% based on in vitro studies using normal human serum albumin (SA). Etoposide PB in 17 patients with cancer receiving etoposide (50 to 100 mg/m2) and in plasma of 14 volunteers was determined by equilibrium dialysis with3H‐etoposide. The unbound fraction (Fu) in patients with cancer was 0.139 ± 0.099 compared with 0.043 ± 0.0036 in plasma from normal volunteers(p<0.0009;ttest). Etoposide binding ratio (BR) was correlated directly with SA (r2= 0.83;p<0.05). In the population with cancer Fuwas significantly correlated with bilirubin (r2= 0.837;p<0.05). In a multivariate analysis, SA and bilirubin were significant predictors of Fu(r2= 0.93;p<0.05). This study corroborates previous reports of etoposide PB in normal human serum and demonstrates altered PB in patients with abnormal serum albumin or bilirubin levels.Clinical Pharmacology and Therapeutics(1989)45,49–55; doi:10.1038/clpt.

ISSN:0009-9236    

DOI:10.1038/clpt.1989.8

年代:1989

数据来源: WILEY

摘要:

The dispositions of concomitantly administered indocyanine green (ICG) and thiopental were determined in 12 patients undergoing general anesthesia and surgery. These were best characterized by a two‐compartment ICG model and a four‐compartment thiopental model, chiefly because of data obtained from frequent early arterial blood samples. The models had a common central volume (V1), and the peripheral ICG compartment was the subset of a peripheral thiopental compartment. The two‐compartment ICG model described its mixing within the intravascular space. The traditional Vcof three‐compartment models of thiopental disposition is described by the present four‐compartment model as an initial distribution volume, V1, codetermined by ICG as central blood volume, and a rapidly equilibrating peripheral volume, V4. The combined simultaneous ICG‐thiopental model more clearly reflects physiology than do the results of earlier curve‐fitting techniques and may be useful in studying the pharmacokinetic basis of altered reactivity to thiopental.Clinical Pharmacology and Therapeutics(1989)45,56–65; doi:10.

ISSN:0009-9236    

DOI:10.1038/clpt.1989.9

年代:1989

数据来源: WILEY

摘要:

In a placebo‐controlled, single‐blind study we evaluated the ability of three large doses of naloxone (1.0, 5.0, and 10 mg) to antagonize the established respiratory‐depressant effects of a common analgesic dose of intravenous buprenorphine (0.3 mg/70 kg). This dose of buprenorphine consistently reduce d indexes of CO2responsiveness to about one half of their control values, much like comparable doses of other opioid analgesics. One milligram of naloxone had little effect on this respiratory depression. Both 5 and 10 mg produced consistent reversal, which was more complete with the larger dose. The reversal effect of naloxone did not occur immediately as is characteristic with morphine and other opiods but rather appeared to reach a maximum 3 hours after reversal. These findings indicate that high doses of naloxone are required to antagonize buprenorphine and naloxone's limited efficacy results not from' its short duration of action but rather its relative inability to displace buprenorphine already bound to opioid receptors.Clinical Pharmacology and Therapeutics(1989)45,66–71; doi:10.1038/clpt

ISSN:0009-9236    

DOI:10.1038/clpt.1989.10

年代:1989

数据来源: WILEY