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1.
Summary— The pharmacokinetics of penticainide, a class Ic antiarrhythmic drug, was studied in 16 healthy adults (eight males and eight females) after a single 300-mg oral dose in fasting conditions and with a standard meal. Penticainide concentrations in plasma and urine were measured by hplc. The pharmacokinetic parameters of penticainide including Cmax, tmax, AUC and t1/2 were not significantly altered in the presence of food. AUC values (mean ± sd) were 50.68 ± 10.8 mg·h·l−1 and 49.52 ± 9.87 mg·h·l−1 in the absence and presence of food, respectively. However, a significant difference was observed between males and females in both fasting and fed conditions with a higher value of the apparent oral clearance in the second group. The values of apparent oral clearance, expressed in weight-normalized units were 1.33 ± 0.35 ml·mn−1·kg−1 (male) and 1.93 ± 0.34 ml·mn−1·kg−1 (female) in fast conditions ( P < 0.01) and 1.38 ± 0.28 ml·mn−1·kg−1 (male) and 1.93 ± 0.49 ml·mn−1·kg−1 (female) in fed conditions ( P < 0.02), respectively. The pharmacokinetics of penticainide is not modified by the presence of food, but an influence of body weight may be considered.  相似文献   

2.
Summary— This study was undertaken to evaluate the influence of the cyclooxygenase inhibitor indomethacin on the time course of the haemodynamic effects of lipopolysaccharide (LPS) intravenous infusion (10 mg·kg−1·h−1) in anaesthetized rats. LPS infusion produced a rapid (within 10 min) and prolonged (over the 90 min observation period) fall in mean arterial blood pressure (MABP) and a decrease in the pressor responses to noradrenaline (NA, 0.1, 0.3 and 1 μg·kg−1, intravenously [iv]) elicited 60 and 90 min after the onset of LPS infusion. Indomethacin (7 mg·kg−1 iv 30 min prior to the onset of saline or LPS infusion), which by itself did not affect basal MABP nor reactivity to NA in control rats, significantly attenuated the fall in MABP observed within 20 min after the onset of LPS infusion (but did not significantly modify the hypotension observed between 30 and 90 min). Indomethacin also completely prevented the hyporeactivity to NA observed 60 min after the onset of LPS infusion, but it did so only partially at 90 min. Aortic rings removed from LPS or LPS + indomethacin-treated rats showed an identical profile of contractile reactivity (hyporesponsiveness to NA, relaxation to L-arginine, and restoration of the contractile response by methylene blue). These results suggest that in this model, cyclooxygenase products are involved in the early haemodynamic effects of LPS. However, they do not seem to play an obligatory role in the onset of longer term haemodynamic changes.  相似文献   

3.
Summary.  Background: The pharmacological effect of rFVIIa occurs at the surface of activated platelets by enhancing thrombin generation at the site of vascular damage. It is therefore important to study the effects of rFVIIa in platelet-related bleeding situations. We examined the effect of rFVIIa and an rFVIIa-analogue, NN1731, on clopidogrel-induced and thrombocytopenic bleeding in rats. Methods and results: Clopidogrel [10 mg kg−1; per oral (p.o.)] severely inhibited platelet aggregation and increased blood loss after tail-transection four hours after administration. Treatment with rFVIIa (5, 10, 20 mg kg−1) or NN1731 (1, 5, 10 mg  kg−1), administered five minutes after induction of bleeding, reduced blood loss significantly and dose-dependently. NN1731 had an increased hemostatic potential compared with rFVIIa, reducing blood loss to the control level, whereas this was not even achieved with the highest dose of rFVIIa. Antibody-induced thrombocytopenia reduced platelet numbers by more than 90% and increased the blood loss after tail-transection. Treatment with 10 and 20 mg kg−1 rFVIIa significantly reduced blood loss, whereas 10 mg kg−1 NN1731 reduced the bleeding to control levels. Conclusions: The hemostatic effect of rFVIIa and NN1731 was demonstrated in thrombocytopenic and clopidogrel-treated rats, showing efficacy in situations with decreased platelet number or functionality. Our findings are consistent with the hypothesis that rFVIIa/NN1731 contribute to hemostasis by thrombin generation even in situations with platelet disorders. Furthermore, NN1731 demonstrated a higher hemostatic potential than rFVIIa.  相似文献   

4.
Summary— The population pharmacokinetics of amikacin was studied in 40 intensive care unit patients (212 plasma concentrations) by NPEM algorithm using a one-compartment model. The population was best characterized by the following pharmacokinetic parameters: renal clearance relative to creatinine clearance (Cs = 0.96 ± 0.33), and either the total volume of distribution (Vd = 23.9 ± 7.0 I) or the volume of distribution relative to body weight (Vs = 0.36 ± 0.10 1·kg−1. The volume of distribution was increased with respect to the usual value of 0.25 1·kg−1. The statistical distribution of these pharmacokinetic parameters was approximately gaussian, with no significant correlation between volume of distribution and clearance. The medians and standard deviations of Cs and Vs were used as reference population values to estimate the pharmacokinetics of amikacin in a second group of 29 patients by the bayesian method, with two blood samples per patient. For each patient, the fitted parameters were able to predict the plasma concentrations of amikacin during the next 72 h with no significant bias and good precision (2.9 mg·1−1 for peaks and 0.5 mg·1−1 for troughs). This study confirms the ability of the NPEM algorithm to provide reference population values for use in bayesian monitoring of aminoglycoside therapy.  相似文献   

5.
Summary.  Background:  Heparin and low molecular weight heparin (LMWH) are widely used for prevention and treatment of thromboemobolic events, but may occasionally cause uncontrollable bleeding. Heparin can readily be antagonized with protamine, but this is less effective against LMWH. Objectives:  To test the effects of rFVIIa or an analogue of rFVIIa, NN1731, on heparin- and LMWH-induced bleeding in rats. Methods:  Initially the doses of heparin and tinzaparin (a LMWH) were determined by dose-titration. Following pretreatment with heparin or tinzaparin in rats, tail-transection was performed, and the effect of rFVIIa and NN1731 on the bleeding was observed. Results:  rFVIIa (5, 10 and 20 mg kg−1) reduced bleeding time and blood loss caused by heparin- and tinzaparin-induced bleeding, using doses of 200 IU kg−1 ( n  = 8) and 500 IU kg−1 ( n  = 9), respectively. Similarly, 10 mg kg−1 NN1731 significantly reduced both heparin- and tinzaparin-induced bleeding to the normal level. Following severe anticoagulation with 1800 IU kg−1 tinzaparin, 10 mg kg−1 NN1731 reduced and normalized the bleeding, while the effect of 20 mg kg−1 rFVIIa failed to reach statistical significance. These data are consistent with the hypothesis that rFVIIa/NN1731 are capable of generating sufficient thrombin locally on the surface of activated platelets to induce hemostasis in the presence of heparin/LMWH. Conclusions:  This study suggests that rFVIIa and NN1731 may have the potential to control bleedings caused by heparin or LMWH.  相似文献   

6.
Colchiceine and ursodeoxycholic acid (UDCA) are drugs currently in use as therapy for different types of liver damage. We evaluated their ability to reverse the damage induced by carbon tetrachloride (CCl4) in rats. Six groups were analysed: (1) CCl4 (0.4 g kg−1, i.p., three times a week) for 13 weeks; (2) CCl4 for 8 weeks followed by colchiceine (60 μg kg−1) + CCl4 for 5 weeks; (3) CCl4 for 8 weeks and thereafter UDCA (25 mg kg−1) + CCl4 for 5 weeks. Groups 4, 5 and 6 were appropriate controls of colchiceine, UDCA and vehicles respectively. Na+,K+- and Ca2+-ATPase activities and the cholesterol–phospholipid (CH/PL) ratio from erythrocyte and hepatocyte membranes were quantified. Membrane enzymatic activities and CH/PL ratios were affected more in group 1 than groups 2 and 3. We concluded that colchiceine and UDCA were effective drugs in this model of liver damage.  相似文献   

7.
Background  Previous reports have indicated that statins could prevent bone loss in ovariectomized (OVX) rats and increase the expressions of osteogenic genes in cultured osteoblasts. In this study, we hypothesized that simvastatin might increase osteoblast number and protein expressions of osteogenic markers localized in bones in concomitance with the prevention of bone loss in OVX rats.
Materials and methods  Fifty-four 3-month-old OVX and sham-operated (SHAM) female Sprague–Dawley rats were used. Simvastatin (10–20 mg kg−1 day−1) was administrated orally for 6 weeks. Trabecular volume, osteoblast number and osteogenic proteins including BMP2, collagen type I and osteocalcin on bone sections obtained from lumbar vertebral body, distal femur and proximal tibia were measured.
Results  The results showed that SHAM rats had significantly less trabecular bone volume and osteoblast number than that of OVX rats 6 weeks after operation. Oral simvastatin treatment (10–20 mg kg−1 day−1) increased bone volume and osteoblast number in the distal femurs, proximal tibiae and vertebrae of OVX rats. Furthermore, the osteoblastic cells with immuno-stained BMP2, collagen type I and osteocalcin in vertebral bones were significantly increased by simvastatin treatment (20 mg kg−1 day−1) in OVX rats.
Conclusions  This study demonstrates that simvastatin enhances the production of osteogenic proteins in bone and this effect may contribute to the prevention of bone loss in OVX rats.  相似文献   

8.
Summary— In anaesthetized animals, systemic injection of ET1 at doses from 3 to 100 ng·kg−1 provoked only a transient hypotensive effect. At 300 ng·kg−1 we observed the classical biphasic effect, consisting of a transient lowering of the arterial pressure followed by a long-lasting hypertensive effect. Direct injection of the peptide into the vertebral artery of anaesthetized animals only affected arterial pressure (AP) when the blood-brain barrier was permeabilised. Under these conditions, a dose-dependent decrease in AP was observed, which was not associated with a significant effect on the heart rate. Micro-injections of the peptide in the medullary nucleus reticularis lateralis area (NRL), a medullary vasopressive centre, at doses of 30 to 60 ng·kg−1 led to a significant reduction in mean arterial pressure (MAP) (17 ± 4% and 36.5 ± 6%) respectively without a significant change in heart rate. These effects lasted less than 2 hours. These results suggest a possible role of ET1 as a neuromodulator involved in the central regulation of vasomotor tone, in the NRL region.  相似文献   

9.
Summary.  Recombinant activated factor VII (rFVIIa, NovoSeven®) represents an effective treatment for hemophilia patients with inhibitors, but no consensus as to the best dosing regimen exists. We assessed the efficacy and safety of a rFVIIa 'megadose' (300 µg kg−1 bolus) as treatment for bleeds in three young inhibitor patients. Of 114 bleeds, 95 responded to a single dose. Pain relief was faster and therapy duration significantly shorter than with continuous infusion (CI) regimens or standard boluses (90 µg kg−1 every 3 h). Rebleeding occurred in 9.6% of cases and 19/114 episodes required a second bolus injection. Although rFVIIa consumption per bleed (median: 300 µg kg−1) was higher than with standard boluses (180–270 µg kg−1), patients found single bolus administration more convenient than recurrent injections or CI. With two exceptions, no complications occurred within 3 h of treatment, despite high FVII:C levels (median: 27.4 U mL−1; range: 19.8–54 U mL−1). Treatment of bleeds with a rFVIIa megadose in young inhibitor patients is effective and well tolerated.  相似文献   

10.
Summary— The two diastereoisomers dexamethasone (DXM) and betamethasone (BTM) were infused at two different doses (2, 10 mg·kg−1) in anesthetized rabbits. Samples of plasma and cerebrospinal fluid were collected over a 180-min period. Steroid concentrations were measured by high performance liquid chromatography. The terminal half life (85.7 ± 20.8 min and 102.2 ± 29.6 min for DXM; 117.6 ± 19.8 min and 118.5 ± 15.8 min for BTM) and the mean residence time (121.4 ± 27.7 min and 146.1 ± 41.3 min for DXM; 168.6 ± 28.1 min and 172.2 ± 20.6 min for BTM) were unchanged between the doses. Dose-dependent changes in the area under the curve normalized by the dose, then volume distribution and clearance were observed. The average percentage of DXM and BTM bound to plasma proteins were 78.1 ± 11.5% and 88.3 ± 5.1% respectively at the lower dose, and decreased significantly with 10 mg·kg−1. DXM appeared more rapidly in the CSF, the highest concentrations of DXM were obtained within 15 min after the end of the injection. The CSF levels were lower than that of plasma unbound and the passage through the blood-brain barrier was saturable. These results will complicate pharmacokinetic and pharmacodynamic analysis.  相似文献   

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