摘要:

Clinical Pharmacology and Therapeutics(1986)40, 599–603; doi:10.1038/clpt.1986.2

ISSN:0009-9236    

DOI:10.1038/clpt.1986.232

年代:1986

数据来源: WILEY

摘要:

The pharmacokinetics of oral 6‐mercaptopurine (6MP) was assessed in 20 children with acute lymphoblastic leukemia during maintenance therapy. The AUC was between 0 and 6 × 10 ng · min/ml, and AUC normalized to 1 mg/m2of 6MP was between 0 and 815 ng · min/ml. Good correlation existed between peak concentrations and AUC (r = 0.866; P<0.001). In more than half of the cases there was evidence of prolonged elimination t½or rebound of a serum concentration during the elimination phase corresponding to either an additional compartment or enterohepatic circulation of 6MP. One child did not achieve detectable concentrations on 2 different study days and was switched to a different protocol. The two children who had severe myelotoxicity achieved the largest AUC values per milligram per square meter of 6MP. Our results indicate that pharmacokinetic variability may contribute to either severe myelotoxicity or therapeutic failures. This suggests that monitoring of this drug in children with acute lymphoblastic leukemia may be helpful.Clinical Pharmacology and Therapeutics(1986)40, 604–609; doi:10.1038/clpt.

ISSN:0009-9236    

DOI:10.1038/clpt.1986.233

年代:1986

数据来源: WILEY

摘要:

The purpose of the study was to compare the renal effects of low doses of exogenous dopamine to assess the responsiveness of renal dopaminergic receptors in normotensive and hypertensive subjects. Eight hypertensive patients and seven normotensive volunteer subjects were studied. Inulin and para‐aminohippuric (PAH) clearances, natriuresis, and fractional excretion of sodium increased significantly after intravenous dosing with dopamine (2 µg/min/kg) in both groups. These increases were significantly higher in hypertensive than in normotensive subjects: 31.8% ± 3.7% vs. 16.2% ± 1.2% for inulin clearance (P<0.01), 83.3% ± 10.5% vs. 41.1% ± 3.4% for PAH clearance (P<0.01), and 331% ± 38% vs. 216% ± 26% for natriuresis (P<0.01). These findings suggest hyperresponsiveness to dopamine during hypertension. This enhanced response to exogenous dopamine can be considered as a further argument favoring the existence of a deficit in dopaminergic activity during hypertension. Dopamine also induced a significant reduction in blood pressure and increased heart rate in hypertensive subjects but no significant change in blood pressure and heart rate occurred in normotensive subjects.Clinical Pharmacology and Therapeutics(1986)40, 610–614; doi:10.1038/cl

ISSN:0009-9236    

DOI:10.1038/clpt.1986.234

年代:1986

数据来源: WILEY

摘要:

Ten healthy male subjects were phenotyped with isoniazid for their acetylator status and then received intravenous amrinone at a dose of 75 mg during a period of 10 minutes. Blood samples were drawn at specified times during a 24‐hour period after dosing. Plasma concentrations of amrinone were determined by a specific HPLC method. The plasma concentration data were fitted to a biexponential model by nonlinear regression. The mean apparent first‐order elimination t½for amrinone in the slow acetylators was 4.4 hours, whereas it was 2.0 hours in the fast acetylators (P<0.05). There was little difference in the volume of distribution at steady state. Clearance was lower in the slow acetylators, 16.6 L/hr, than in the fast acetylators, 37.2 L/hr (P<0.05). The AUC was higher for the slow acetylators, 4.96 µg · hr · ml−1, than for the fast acetylators, 2.20 µg · hr · ml−1(P<0.01). Concentrations of amrinone and itsN‐acetyl metabolite in the urine from each volunteer were determined. The ratio ofN‐acetylamrinone to amrinone was calculated and, as expected, the fast acetylators had a higher ratio than did the slow acetylators (P<0.01).Clinical Pharmacology and Therapeutics(1986)40, 615–619; doi:

ISSN:0009-9236    

DOI:10.1038/clpt.1986.235

年代:1986

数据来源: WILEY

摘要:

The combined effects on performance of two anxiolytics with different mechanisms of action were evaluated double‐blind and crossover in 12 healthy students. Objective (tracking, divided attention, Maddox wing, etc.) and subjective (visual analogue scales and questionnaires) tests were done before and twice after single oral doses. Diazepam (0.15 and 0.30 mg/kg) impaired performance dose relatedly and rendered the subjects drowsy, calm, mentally slow, and clumsy. Buspirone (15 mg) proved inactive in objective tests but matched diazepam (0.30 mg/kg) subjectively. In combinations, buspirone added to the effects of diazepam in Maddox wing and letter cancellation but tended to counteract diazepam effects on divided attention and learning acquisition. Subjectively buspirone prolonged diazepam‐induced sedation. Increased calmness caused by diazepam was not affected by concomitant buspirone. It is suggested that combining small doses of buspirone to diazepam does not cause any additional decrement in psychomotor performance. Possible advantages of the diazepam‐buspirone combination in therapeutic use are discussed.Clinical Pharmacology and Therapeutics(1986)40, 620–626; doi:10.1038/clpt.

ISSN:0009-9236    

DOI:10.1038/clpt.1986.236

年代:1986

数据来源: WILEY

摘要:

A 29 amino acid analog of growth hormone releasing hormone (GH‐RH)‐40 was given intravenously, subcutaneously, and intranasally to normal men to determine its effectiveness in stimulating growth hormone (GH) release. The GH‐RH analog, [Nle27]GH‐RH(l‐29)‐NH2, is an amidated 29 amino acid peptide that has one amino acid substitution at position 27. This peptide stimulates GH secretion when given by the intravenous, subcutaneous, and intranasal routes without adverse effect. The degree of GH stimulation was variable among subjects and the greatest amount of stimulation occurred with the highest doses. GH stimulation occurred in a dose‐responsive manner after all three routes of administration. A tenfold higher subcutaneous dose was required to stimulate a comparable amount of GH secretion as compared with intravenous administration, and a thirtyfold higher intranasal than intravenous dose was required to stimulate approximately one fifth the amount of GH release. For comparison, one dose of GH‐RH‐40, 1 µg/kg, was administered intravenously. GH secretion after 1 µg/kg GH‐RH‐40 and 1 µg/kg Nle27GH‐RH was comparable between the two groups of subjects. Stimulation of GH secretion by Nle27GH‐RH occurred within 5 minutes of intravenous and within 10 minutes of subcutaneous and intranasal administration; peak GH levels were observed within 30 minutes. GH levels declined and returned to near baseline levels 2 hours after administration of the analog. Since GH‐RH‐40 has been demonstrated to be effective in stimulating GH release and promoting acceleration of linear growth in GH‐deficient children, it is likely that a shorter peptide with full biologic activity such as Nle27GH‐RH may also be effective in the treatment of some children with GH deficiency.Clinical Pharmacology and Therapeutics(1986)4

ISSN:0009-9236    

DOI:10.1038/clpt.1986.237

年代:1986

数据来源: WILEY

摘要:

SQ 28,668 is a structural analog of thromboxane A2. It inhibits the effects of thromboxane in vitro. Fifty‐six healthy male subjects were given either placebo or three equal daily doses of SQ 28,668 ranging from 25 to 1200 mg. Plasma drug concentrations increased in a dose‐dependent manner. The shape of the plasma drug concentration‐time curve was consistent with enterohepatic recirculation. The effects of SQ 28,668 on ex vivo platelet aggregation suggested that SQ 28,668 is a specific competitive antagonist of thromboxane A2with a platelet receptor dissociation constant (estimated by Schild analysis) of about 19 nmol/L. Approximately 94% occupation of thromboxane receptors by SQ 28,668 was required to produce a small but measurable increase of the template bleeding time. Dose‐ranging studies of antithrombotic drugs are difficult and expensive. For this reason, a method was developed that allows estimation of the dose of a thromboxane receptor antagonist that would be expected to be therapeutically equivalent to a given dose of aspirin.Clinical Pharmacology and Therapeutics(1986)40, 634–642; doi:10.1038/clp

ISSN:0009-9236    

DOI:10.1038/clpt.1986.238

年代:1986

数据来源: WILEY

摘要:

On 3 consecutive days, 4‐demethoxydaunomycin (D‐DNM) was administered orally (30 mg/m2) as bolus injection and 4‐ or 24‐hour infusion to seven patients with acute leukemia. Cellular (nucleated blood and bone marrow cells) and plasma drug concentrations were studied. After bolus injection, peak plasma D‐DNM concentrations were about 50 mg/ml. D‐DNM plasma t½s were 0.4 ± 0.3 hours (T½α) and 16.4 ± 4.7 hours (T½β). D‐DNM concentrations in nucleated blood and bone marrow cells were on the same order of magnitude and amounted to more than 400 times the plasma concentration, whereas 4‐demethoxydaunomycinol (D‐DNMol) concentrations were about 200 times higher. Cellular D‐DNM concentrations were maximal at the end of intravenous dosing and at 2 to 4 hours after D‐DNM ingestion. D‐DNMol concentrations increased more slowly and accumulated on subsequent treatment days in cells and plasma; D‐DNM and D‐DNMol cellular t½times were 42 and 72 hours, respectively. Antileukemic activity was observed.Clinical Pharmacology and Therapeutics(1986)40

ISSN:0009-9236    

DOI:10.1038/clpt.1986.239

年代:1986

数据来源: WILEY

摘要:

Pinacidil is an investigational vasodilator currently undergoing clinical trials as an antihypertensive agent. It is metabolized in humans to pinacidilN‐oxide. To determine whether pinacidil's metabolism or effects were influenced by either liver disease or the subject's debrisoquin phenotype, eight patients with chronic stable cirrhosis and 13 healthy subjects were studied. Seven of the healthy volunteers were extensive metabolizers of debrisoquin, whereas six were of the poor metabolizer phenotype. Neither the clearance of pinacidil nor the production of theN‐oxide was altered by the subjects' debrisoquin phenotype. Cirrhosis produced a 50% reduction in pinacidil's clearance (20.7 ± 1.4 vs. 42.1 ± 5.1 L/hr; P<0.0005) and a prolongation in the elimination t½from 3.9 ± 0.3 to 6.1 ± 0.6 hours (P<0.01). Less pinacidil was metabolized to theN‐oxide metabolite in the patients with cirrhosis than in the normal individuals. Thus pinacidil's metabolism and clearance are reduced in patients with cirrhosis but are independent of debrisoquin phenotype.Clinical Pharmacology and Therapeutics(1986)40, 650–655; doi:10.1038/

ISSN:0009-9236    

DOI:10.1038/clpt.1986.240

年代:1986

数据来源: WILEY

摘要:

The purpose of this study was to add to the limited information available regarding the pharmacology of ritodrine in the peripartum period when treatment fails and labor is not inhibited. Plasma or urine samples from eight parturients and 13 infants were studied; in addition plasma samples at delivery were obtained from a total of 26 mothers and infants. All the mothers received ritodrine in the 24 hours before delivery. Plasma and urine ritodrine (free and conjugated) were determined with HPLC by electrochemical detection. In maternal plasma, an apparent rapid distribution phase with a t½of 32 ± 21 minutes was followed by a prolonged equilibrium phase with a t½of 17 ± 10 hours. Seventy‐six percent of the ritodrine excreted by the mother was in the form of a conjugate. Ninety percent of the ritodrine excreted by the neonate was also excreted in the form of a conjugate.Clinical Pharmacology and Therapeutics(1986)40, 656–664; doi:10.1038/clpt.

ISSN:0009-9236    

DOI:10.1038/clpt.1986.241

年代:1986

数据来源: WILEY