Effects of isolation housing and timing of drug administration on amikacin kinetics in mice.
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AIM: To study the influences of social condition and drug administration time on amikacin metabolism in mice. METHODS: Forty Male ICR mice were randomly assigned into 4 groups according to 1) housing condition: individual housing (I, one mouse in a cage) or aggregated housing (A, 10 mice in a cage) and 2) drug administration time: at midday (D) or at midnight (N), i.e. I-D, I-N, A-D, and A-N groups. Amikacin was injected s.c. 15 mg.kg-1 after 4 wk of raising at D or N. Blood samples were taken at 5, 10, 15, 20, 30, and 60 min after medication in each mouse. Plasma amikacin was measured by enzyme immunoassay. The concentration-time data were fitted with one-compartment open model in each mouse and data were analyzed with group t test. RESULTS: The clearance (Cl) of amikacin was larger and the half-life (T1/2) was shorter in A-N group than in A-D or I-N groups respectively. AUC(0-1) in A-N group was less than in I-N group. No differences of kinetic parameters between 2 isolated housing (I-D and I-N) groups were found. CONCLUSION: Aggregated housing and midnight drug administration increased the disposition of amikacin. (+info)
Pharmacokinetic-pharmacodynamic modeling of metoprolol stereoisomers in spontaneously hypertensive rat.
(18/6505)
AIM: To study the combined pharmacokinetic-pharmacodynamic (PK-PD) model of metoprolol stereoisomers, and compare their inhibitory effects on cardiovascular system in the spontaneously hypertensive rats (SHR). METHODS: The drug concentration in plasma was measured by the reversed phase HPLC and the drug effects were recorded by polygraph. The pharmacokinetic parameters and the PK-PD model parameters were calculated. RESULTS: The plasma concentration-time profiles were adequately described by two-compartment model. Differences of Vd between (+)-Met and (-)-Met were found. The relationships between effects and concentration of effect compartment were represented by the sigmoid-Emax model. The Css50 of Vmax, dp/dtmax, and HR inhibitory effects of (+)-Met were larger than those of (-)-Met. CONCLUSION: Stereo-selective drug distribution and different potencies of the inhibitory effects of (+)-Met and (-)-Met existed in SHR. (+info)
Pharmacokinetics of bendazac lysine in 10 Chinese young men.
(19/6505)
AIM: To compare the pharmacokinetics of domestic and imported tablets of bendazao lysine (BL). METHODS: A single oral dose of 500 mg BL of this 2 kinds of tablets was given to 10 Chinese volunteers of Han nationality in a randomized crossover study. Plasma levels were determined with HPLC-UV method. Data were analyzed automatically by using a CAPP program on microcomputer. RESULTS: The plasma concentration-time curve was fitted to 2-compartment open model, and the major pharmacokinetic parameters of domestic and imported BL tablets were shown respectively as following: Cmax 66 +/- 16 and 65 +/- 8 mg.L-1; Tmax 0.98 +/- 0.22 and 0.98 +/- 0.21 h; T1/2 beta 6.2 +/- 1.8 and 6.2 +/- 1.7 h; AUC 335 +/- 47 and 337 +/- 58 mg.h.L-1. There was no significant difference between domestic and imported tablets. The bioavailability of the domestic vs that of the imported tablet was 99 +/- 12%. The unchanged BL in urine were about 5.4% and 5.6% respectively of the dosage in 24 h after a single oral dose. CONCLUSION: The two kinds of tablets had the same biological effects. (+info)
Pharmacokinetics of flutamide in patients with renal insufficiency.
(20/6505)
AIMS: The aim of this study was to determine the pharmacokinetic parameters of flutamide, a nonsteroidal antiandrogenic compound, and its pharmacologically active metabolite, hydroxyflutamide, in renal insufficiency. Haemodialysis (HD) clearance of flutamide and hydroxyflutamide was also determined. METHODS: Pharmacokinetic parameters were assessed for flutamide and hydroxyflutamide in 26 male subjects with normal renal function (creatinine clearance by 24 h urine collection, CLcr, greater than 80 ml min(-1) 1.73 m(-2); n=6) or reduced renal function; CLcr=50-80 (n=7), 30-49 (n=3), 5-29 (n=4), and <5 ml min(-1) 1.73 m(-2)-HD (n=6), following a single, oral 250 mg flutamide dose. Subjects undergoing HD received a second 250 mg dose of flutamide 4 h prior to HD; blood and dialysate were collected during HD to determine dialysability of flutamide and hydroxyflutamide. RESULTS: Cmax, tmax, AUC, t1/2, and renal clearance of flutamide and hydroxyflutamide did not differ between groups. Less than 1% of the dose appeared in dialysate as hydroxyflutamide. No serious adverse events were observed. CONCLUSIONS: Renal function did not affect flutamide nor hydroxyflutamide disposition. HD did not alter hydroxyflutamide pharmacokinetics. Dosing adjustments for renal impairment or HD are not indicated for flutamide. (+info)
Rapidly available glucose in foods: an in vitro measurement that reflects the glycemic response.
(21/6505)
BACKGROUND: A chemically based classification of dietary carbohydrates that takes into account the likely site, rate, and extent of digestion is presented. The classification divides dietary carbohydrates into sugars, starch fractions, and nonstarch polysaccharides, and groups them into rapidly available glucose (RAG) and slowly available glucose (SAG) as to the amounts of glucose (from sugar and starch, including maltodextrins) likely to be available for rapid and slow absorption, respectively, in the human small intestine. OBJECTIVE: We hypothesize that RAG is an important food-related determinant of the glycemic response. DESIGN: The measurement of RAG, SAG, and starch fractions by an in vitro technique is described, based on the measurement by HPLC of the glucose released from a test food during timed incubation with digestive enzymes under standardized conditions. Eight healthy adult subjects consumed 8 separate test meals ranging in RAG content from 11 to 49 g. RESULTS: The correlation between glycemic response and RAG was highly significant (P < 0.0001) and a given percentage increase in RAG was associated with the same percentage increase in glycemic response. After subject variation was accounted for, RAG explained 70% of the remaining variance in glycemic response. CONCLUSIONS: We show the significance of in vitro measurements of RAG in relation to glycemic response in human studies. The simple in vitro measurement of RAG and SAG is of physiologic relevance and could serve as a tool for investigating the importance of the amount, type, and form of dietary carbohydrates for health. (+info)
Inhibition of carbohydrate-mediated glucagon-like peptide-1 (7-36)amide secretion by circulating non-esterified fatty acids.
(22/6505)
Two studies were performed to assess the entero-insular axis in simple obesity and the possible effect of variations in the level of circulating non-esterified fatty acids (NEFA) on one of the components of the entero-insular axis, glucagon-like peptide-1 [(7-36) amide]. In the first study, we compared the entero-pancreatic hormone response to oral carbohydrate in obese and lean women. Obese subjects demonstrated hyperinsulinaemia and impaired glucose tolerance but this was not associated with an increased secretion of either glucose-dependent insulinotropic polypeptide or glucagon-like peptide-1 (GLP-1). These findings therefore provide no support for the hypothesis that overactivity of the entero-insular axis contributes to the hyperinsulinaemia seen in obesity. Indeed, the plasma GLP-1 response to carbohydrate was markedly attenuated in obese subjects, confirming previous observations. In the second study, in which carbohydrate-stimulated GLP-1 responses were again evaluated in obese and lean women, circulating NEFA levels were modulated using either heparin (to increase serum NEFA) or acipimox (to reduce serum NEFA). Treatment with acipimox resulted in complete suppression of NEFA levels and in a markedly higher GLP-1 response than the response to carbohydrate alone or to carbohydrate plus heparin. We suggest that higher fasting and postprandial NEFA levels in obesity may tonically inhibit nutrient-mediated GLP-1 secretion, and that this results in attenuation of the GLP-1 response to carbohydrate. However, although serum NEFA levels post-acipimox were similarly suppressed in both lean and obese subjects, the GLP-1 response was again significantly lower in obese subjects, suggesting the possibility of an intrinsic defect of GLP-1 secretion in obesity. The reduction of GLP-1 levels in obesity may be important both in relation to its insulinotropic effect and to its postulated role as a satiety factor. (+info)
Endometrial evaluation is not predictive for in vitro fertilization treatment.
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PURPOSE: The main purpose of this study was to evaluate ovarian function by clomiphene citrate (CC) challenge test in a group of tubal infertile women and to study endometrial morphological maturation in the early luteal phase of CC-stimulated cycles as compared to in vitro fertilization (IVF) treatment outcome. METHODS AND RESULTS: Four women presented with strongly retarded, proliferative endometrium in the luteal phase. Of these, three presented with impaired ovarian function, high basal follicle-stimulating hormone, and high follicle-stimulating hormone levels after clomiphene stimulation on cycle day 10. In the remaining 30 women, showing an in-phase endometrium after CC stimulation, a comparison of six morphological characteristics did not reveal any significant differences between the 14 women who did become pregnant and the 16 who did not. No significant differences in endometrial thickness were observed between the groups. Significant differences were found when comparing estradiol and progesterone area under the curve during the luteal phase (P < 0.001 and P < 0.01, respectively) between those who did and those who did not become pregnant. CONCLUSIONS: Luteal endometrium morphology was not a sharp instrument to detect differences between women who did and women who did not become pregnant following IVF treatment, while ovarian function, as measured by hormonal markers, seemed to be a more reliable prognostic factor for IVF treatment outcome. (+info)
Dual mechanism of daunorubicin-induced cell death in both sensitive and MDR-resistant HL-60 cells.
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Exposure of some acute myeloid leukaemia (AML) cells to daunorubicin leads to rapid cell death, whereas other AML cells show natural drug resistance. This has been attributed to expression of functional P-glycoprotein resulting in reduced drug accumulation. However, it has also been proposed that P-glycoprotein-expressing multidrug-resistant (MDR) cells are inherently defective for apoptosis. To distinguish between these different possibilities, we have compared the cell death process in a human AML cell line (HL-60) with a MDR subline (HL-60/Vinc) at doses that yield either similar intracellular daunorubicin concentrations or comparable cytotoxicity. Adjustment of the dose to obtain the same intracellular drug accumulation in the two cell lines did not result in equal cytotoxicity, suggesting the presence of additional resistance mechanisms in the P-glycoprotein-expressing HL-60/Vinc cells. However, at equitoxic doses, similar cell death pathways were observed. In HL-60 cells, daunorubicin induced rapid apoptosis at 0.5-1 microM and delayed mitotic cell death at 0.1 microM. These concentrations are within the clinical dose range. Similarly, HL-60/Vinc cells underwent apoptosis at 50-100 microM daunorubicin and mitotic cell death at 10 microM. These results show, for the first time, that anthracyclines can induce cell death by a dual mechanism in both sensitive and MDR cells. Our results also show that not only the cytotoxicity, but also the kinetics and mechanism of cell death, are dose dependent. Interestingly, regrowth was observed only in association with delayed cell death and the formation of enlarged, often polyploid, cells with micronucleation, suggesting that morphological criteria may be useful to evaluate treatment efficacy in patients with myeloid leukaemias. (+info)