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1.
Yoon K Loke Shiva Pradhan Jessica Ka-yan Yeong Chun Shing Kwok 《British journal of clinical pharmacology》2014,78(4):707-717
Aims
There are concerns regarding increased risk of acute coronary syndrome with dabigatran. We aimed to assess whether alternative treatment options such as rivaroxaban or apixaban carry a similar risk as compared with dabigatran.Methods
We searched MEDLINE and EMBASE for randomized controlled trials of apixaban, dabigatran or rivaroxaban against control (placebo, heparin or vitamin K antagonist). We pooled odds ratios (OR) for adverse coronary events (acute coronary syndrome or myocardial infarction) using fixed effect meta-analysis and assessed heterogeneity with I2. We conducted adjusted indirect comparisons to compare risk of adverse coronary events with apixaban or rivaroxaban vs. dabigatran.Results
Twenty-seven randomized controlled trials met the inclusion criteria. Dabigatran was associated with a significantly increased risk of adverse coronary events in pooled analysis of nine trials (OR 1.45, 95% CI 1.14, 1.86). There was no signal for coronary risk with apixaban from nine trials (pooled OR 0.89, 95% CI 0.78, 1.03) or rivaroxaban from nine trials (pooled OR 0.81, 95% CI 0.72, 0.93). Overall, adjusted indirect comparison suggested that both apixaban (OR 0.61, 95% CI 0.44, 0.85) and rivaroxaban (OR 0.54; 95% CI 0.39, 0.76) were associated with lower coronary risk than dabigatran.Restricting the indirect comparison to a vitamin K antagonist as a common control, yielded similar findings, OR 0.57 (95% CI 0.39, 0.85) for apixaban vs. dabigatran and 0.53 (95% CI 0.37, 0.77) for rivaroxaban vs. dabigatran.Conclusions
There are significant differences in the comparative safety of apixaban, rivaroxaban and dabigatran with regards to acute coronary adverse events. 相似文献2.
Härtter S Koenen-Bergmann M Sharma A Nehmiz G Lemke U Timmer W Reilly PA 《British journal of clinical pharmacology》2012,74(3):490-500
AIMS
This study examined the effects of the CYP3A/P-glycoprotein inducer, rifampicin, on the pharmacokinetics of dabigatran following oral administration of the prodrug, dabigatran etexilate.METHODS
This was an open-label, fixed-sequence, four-period study in healthy volunteers. Subjects received a single dose of dabigatran etexilate 150 mg on day 1, rifampicin 600 mg once daily on days 2–8, and single doses of dabigatran etexilate on days 9, 16 and 23.RESULTS
Twenty-four subjects were treated, of whom 22 received all treatments. Relative to the reference (single dose of dabigatran etexilate alone; treatment A), administration of dabigatran etexilate following 7 days of rifampicin (treatment B) decreased the geometric mean (gMean) area under the concentration–time curve (AUC0–∞) and maximal plasma concentration (Cmax) of total dabigatran by 67 and 65.5%, respectively. The time to peak and the terminal half-life were not affected. The gMean ratio for the primary comparison (treatment B vs. treatment A) was 33.0% (90% confidence interval 26.5, 41.2%) for AUC0–∞ and 34.5% (90% confidence interval 26.9, 44.1%) for Cmax, indicating a significant effect on total dabigatran exposure (total pharmacologically active dabigatran represents the sum of nonconjugated dabigatran and dabigatran glucuronide). After a 7 day (treatment C) or 14 day washout (treatment D), the AUC0–∞ and Cmax of dabigatran were reduced by 18 and 20%, and by 15 and 20%, respectively, compared with treatment A, which was considered not clinically relevant. The overall safety profile of all treatments was good.CONCLUSIONS
Administration of rifampicin for 7 days resulted in a significant reduction in the bioavailability of dabigatran, which returned almost to baseline after 7 days washout. 相似文献3.
Paul K. L. Chin Daniel F. B. Wright Mei Zhang Mary C. Wallace Rebecca L. Roberts David M. Patterson Berit P. Jensen Murray L. Barclay Evan J. Begg 《Drugs in R&D》2014,14(2):113-123
Aims
Dabigatran is largely cleared by renal excretion. Renal function is thus a major determinant of trough dabigatran concentrations, which correlate with the risk of thromboembolic and haemorrhagic outcomes. Current dabigatran dosing guidelines use the Cockcroft–Gault (CG) equation to gauge renal function, instead of contemporary equations including the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equations employing creatinine (CKD-EPI_Cr), cystatin C (CKD-EPI_Cys) and both renal biomarkers (CKD-EPI_CrCys).Methods
A linear regression model including the dabigatran etexilate maintenance dose rate, relevant interacting drugs and genetic polymorphisms (including CES1), was used to analyse the relationship between the values from each renal function equation and trough steady-state plasma dabigatran concentrations.Results
The median dose-corrected trough steady-state plasma dabigatran concentration in 52 patients (38–94 years) taking dabigatran etexilate was 60 µg/L (range 9–279). The dose-corrected trough concentration in a patient on phenytoin and phenobarbitone was >3 standard deviations below the cohort mean. The CG, CKD-EPI_Cr, CKD-EPI_Cys and CKD-EPI_CrCys equations explained (R2, 95 % CI) 32 % (9–55), 37 % (12–60), 41 % (16–64) and 47 % (20–69) of the variability in dabigatran concentrations between patients, respectively. One-way analysis of variance (ANOVA) comparing the R2 values for each equation was not statistically significant (p = 0.74).Discussion
Estimates of renal function using the four equations accounted for 32–47 % of the variability in dabigatran concentrations between patients. We are the first to provide evidence that co-administration of phenytoin/phenobarbitone with dabigatran etexilate is associated with significantly reduced dabigatran exposure.Electronic supplementary material
The online version of this article (doi:10.1007/s40268-014-0045-9) contains supplementary material, which is available to authorized users. 相似文献4.
What is already known about this subject.
- The antibiotic clindamycin has a bitter taste when it is used orally.
What this study adds
- A case series on oral as well as i.v. use of clindamycin associated with taste disorders is presented.
- After corrections in a case-by-case analysis for several possible confounders such as indication, clindamycin is disproportionally associated with taste disorders.
- Serum and hence saliva and sputum clindamycin levels seem to be responsible for this reversible adverse drug reaction.
Aims
Topical use of clindamycin has been associated with taste disorders in the literature, but little is known about the nature of this adverse drug reaction. The aim of this article was to describe reports of clindamycin-induced taste disorders and to analyse the factors involved.Methods
The adverse drug reaction database of the Netherlands Pharmacovigilance Centre was searched for reports concerning taste disorders with antibiotics. Clinical review of the cases and statistical analysis with logistic regression were performed. Characteristics of patients who reported taste disorders were compared for age, gender and formulation in clindamycin vs. other antibiotic users.Results
Taste disorders were reported in seven (18%) of the clindamycin cases. In five reports an oral formulation was involved, in one report intravenous (i.v.) administration and in one report both formulations were used. Latency was <1 day after start and in one case taste disorders were present repeatedly at 10 min after every i.v. application. The adjusted reporting odds ratio was 7.0 (95% confidence interval 2.8, 17.3) and supports a possible causal relationship.Conclusions
The association of clindamycin and taste disorders is supported by disproportionality analysis and seems to be independent of possible confounders such as age, gender and infections. The case reports suggest a role for clindamycin concentrations excreted in body fluids like saliva. 相似文献5.
Caillet C Chauvelot-Moachon L Montastruc JL Bagheri H;French Association of Regional Pharmacovigilance Centers 《British journal of clinical pharmacology》2012,74(5):886-889
AIMS
The objective was to investigate the safety profile of four drugs marketed as racemic and enantiomeric forms in France.METHODS
Data from the French PharmacoVigilance Data Base (January 2005 to June 2010) were analysed for four pairs of racemic/isomeric drugs. A case–noncase approach was used to measure the disproportionality of combination between adverse drug reaction (ADR) and exposure to drug.RESULTS
No significant difference in the number of ADRs was observed between Rac-cetirizine/(R)-cetirizine or Rac-citalopram/(S)-citalopram pairs. (S)-Omeprazole induced more haematological effects than Rac-omeprazole. Rac-Ofloxacin induced more haematological, renal and neuropsychiatric ADRs than (S)-ofloxacin, whereas levofloxacin was associated with more reports of musculoskeletal ADRs.CONCLUSIONS
The profile of ADRs could differ for some drugs marketed as racemic and enantiomeric forms. Further studies would be necessary to confirm these data. 相似文献6.
7.
Dagmar Kubitza Angelika Roth Michael Becka Abir Alatrach Atef Halabi Holger Hinrichsen Wolfgang Mueck 《British journal of clinical pharmacology》2013,76(1):89-98
Aim
This study investigated the effects of hepatic impairment on the pharmacokinetics and pharmacodynamics of a single dose of rivaroxaban (10 mg), an oral, direct Factor Xa inhibitor.Method
This single centre, non-randomized, non-blinded study included subjects with mild (n = 8) or moderate hepatic impairment (n = 8), according to the Child–Pugh classification, and gender-matched healthy subjects (n = 16).Results
Rivaroxaban was well tolerated irrespective of hepatic function. Mild hepatic impairment did not significantly affect the pharmacokinetics or pharmacodynamics of rivaroxaban, compared with healthy subjects. However, in subjects with moderate hepatic impairment, total body clearance was decreased, leading to a significant increase in the area under the plasma concentration–time curve (AUC). The least-squares (LS)-mean values for AUC were 1.15-fold [90% confidence interval (CI) 0.85, 1.57] and 2.27-fold (90% CI 1.68, 3.07) higher in subjects with mild and moderate hepatic impairment, respectively, than in healthy subjects. Consequently, the pharmacodynamic responses were significantly enhanced in subjects with moderate hepatic impairment. For inhibition of Factor Xa, increases in the area under the effect–time curve and the maximum effect were observed, with LS-mean ratios of 2.59 and 1.24, respectively, vs. healthy subjects. Prolongation of prothrombin time was similar in healthy subjects and those with mild hepatic impairment, but was significantly enhanced in those with moderate hepatic impairment.Conclusion
Moderate (but not mild) hepatic impairment reduced total body clearance of rivaroxaban after a single 10 mg dose, leading to increased rivaroxaban exposure and pharmacodynamic effects. 相似文献8.
Kenneth Todd Moore William Byra Seema Vaidyanathan Jaya Natarajan Jay Ariyawansa Hiba Salih Kenneth C Turner 《British journal of clinical pharmacology》2015,79(6):907-917
Aims
The primary objective was to explore the pharmacodynamic changes during transition from rivaroxaban to warfarin in healthy subjects. Safety, tolerability and pharmacokinetics were assessed as secondary objectives.Methods
An open label, non-randomized, sequential two period study. In treatment period 1 (TP1), subjects received rivaroxaban 20 mg once daily (5 days), followed by co-administration with a warfarin loading dose regimen of 5 or 10 mg (for the 10 mg regimen, the dose could be uptitrated to attain target international normalized ratio [INR] ≥2.0) once daily (2–4 days). When trough INR values ≥2.0 were attained, rivaroxaban was discontinued and warfarin treatment continued as monotherapy (INR 2.0–3.0). During treatment period 2, subjects received the same warfarin regimen as in TP1, but without rivaroxaban.Results
During co-administration, maximum INR and prothrombin time (PT) values were higher than with rivaroxaban or warfarin monotherapy. The mean maximum effect (Emax) for INR after co-administration was 2.79–4.15 (mean PT Emax 41.0–62.7 s), compared with 1.41–1.74 (mean PT Emax 20.1–25.2 s) for warfarin alone. However, rivaroxaban had the smallest effect on INR at trough rivaroxaban concentrations. Neither rivaroxaban nor warfarin significantly affected maximum plasma concentrations of the other drug.Conclusions
The combined pharmacodynamic effects during co-administration of rivaroxaban and warfarin were greater than additive, but the pharmacokinetics of both drugs were unaffected. Co-administration was well tolerated. When transitioning from rivaroxaban to warfarin, INR monitoring during co-administration should be performed at the trough rivaroxaban concentration to minimize the effect of rivaroxaban on INR. 相似文献9.
Xia Zhao Peihong Sun Ying Zhou Yuwang Liu Huilin Zhang Wolfgang Mueck Dagmar Kubitza Richard J Bauer Hong Zhang Yimin Cui 《British journal of clinical pharmacology》2009,68(1):77-88
AIMS
To investigate the safety, pharmacokinetics and pharmacodynamics of rivaroxaban, an oral, direct Factor Xa (FXa) inhibitor, in healthy, male Chinese subjects.METHODS
Two randomized, single-blind, placebo-controlled, dose-escalation studies were conducted in healthy Chinese men aged 18–45 years. In the single-dose study, subjects received single, oral doses of rivaroxaban 2.5, 5, 10, 20 and 40 mg. In the multiple-dose study, oral rivaroxaban was administered in doses of 5, 10, 20 and 30 mg twice daily for 6 days.RESULTS
Rivaroxaban, in single and multiple doses up to 60 mg, was well tolerated. Rapid absorption was observed in both studies (time to Cmax 1.25–2.5 h). In the multiple-dose study, rivaroxaban exposure increased dose-proportionally after the first dose and at steady state (for the 5–20-mg doses). The half-life of rivaroxaban was up to 7.9 h in the single-dose study. Maximal inhibition of FXa activity was achieved within 1–3 h of dosing in the single-dose study [at 20 mg FXa inhibition as a median percentage change from baseline, 45.92; 95% confidence interval (CI) 44.64, 50.70] and 2–3 h after administration at steady state in the multiple-dose study (at 20 mg median FXa inhibition as a median percentage change from baseline, 60.25; 95% CI 56.16, 63.05), in line with maximum rivaroxaban plasma concentrations.CONCLUSIONS
Rivaroxaban demonstrated predictable pharmacokinetics and pharmacodynamics in healthy Chinese subjects, in line with findings observed previously in White subjects. This suggests that fixed doses of rivaroxaban may be administered to all patients, regardless of their ethnic origin. 相似文献10.
Wei-Yu Kao Chien-Wei Su Yi-Shin Huang Yueh-Ching Chou Yi-Chih Chen Wen-Hung Chung Ming-Chih Hou Han-Chieh Lin Fa-Yauh Lee Jaw-Ching Wu 《British journal of clinical pharmacology》2014,77(1):180-189
Aim
Oral antifungal agent-induced liver injury is a common safety concern that may lead to patients'' hesitation in treating fungal infections such as onychomycosis. This study evaluated risk of drug-induced liver injury (DILI) caused by oral antifungal agents in Taiwanese populations.Methods
A population-based study was conducted by analyzing who used oral antifungal agents from 2002 to 2008 from the Taiwan National Health Insurance Database. A comparison control group was randomly extracted from the remainder of the original cohort.Results
Of the 90 847 oral antifungal agents users, 52 patients had DILI. Twenty-eight DILI cases used ketoconazole, 12 fluconazole, eight griseofulvin, three itraconazole and two terbinafine. The incidence rates (IR) of DILI per 10 000 persons were 31.6, 4.9, 4.3, 3.6 and 1.6 for fluconazole, ketoconazole, griseofulvin, itraconazole and terbinafine, respectively. Longer exposure duration increased the risk of DILI, with IR for exposure duration ≥ 60 defined daily dose (DDD) of 170.9, 62.5, and 36.1 per 10 000 persons for ketoconazole, itraconazole and terbinafine, respectively. Patients taking antifungal agents had higher incidences of developing DILI compared with those in the control group after adjusting for age, gender and co-morbidities (relative risk 2.38, P < 0.001). All of the six patients with fatal DILI used fluconazole. Old age and fluconazole increased the risk of oral antifungal-induced fatal DILI.Conclusions
Oral antifungal agents are associated with low incidence of acute liver injury, but which may be fatal, especially for the elderly. Longer treatment duration may increase the risk of antifungal agent-induced liver injury, especially ketoconazole. 相似文献11.
12.
Parijat Sen Amartya Kundu Partha Sardar Saurav Chatterjee Ramez Nairooz Hossam Amin Wilbert S. Aronow 《Am J Cardiovasc Drugs》2016,16(1):33-41
Background
There are limited data on outcomes following cardioversion in atrial fibrillation (AF) patients treated with non-vitamin K antagonist oral anticoagulants (NOACs). A meta-analysis was performed to evaluate the efficacy and safety of NOACs in patients with AF undergoing cardioversion.Methods
PubMed, Cochrane Library, EMBASE, Web of Science and CINAHL databases were searched from January 1, 2001 through to October 30, 2014. Randomized controlled trials (RCTs) comparing NOACs (apixaban, rivaroxaban and dabigatran) with warfarin in AF patients undergoing cardioversion were selected. The primary efficacy outcome was stroke and systemic embolism, and the primary safety outcome was major or clinically relevant non-major (CRNM) bleeding. We used random-effects models.Results
Four RCTs were included, involving a total of 3635 randomized participants who underwent a total of 4257 cardioversions. A total of 12 events of stroke and systemic embolism were found in the NOAC group and ten events in the warfarin group [odds ratio (OR) 0.73, 95 % confidence interval (CI) 0.31–1.72]. Risk of major or CRNM bleeding was not different with NOACs, when compared with warfarin (OR 1.41, 95 % CI 0.87–2.28).Conclusions
Data from patients enrolled in RCTs, showed that NOACs are effective and safe for AF patients undergoing cardioversion.13.
Sebastian H?rtter Regina Sennewald Gerhard Nehmiz Paul Reilly 《British journal of clinical pharmacology》2013,75(4):1053-1062
Aim
To investigate the effect of the P-glycoprotein inhibitor verapamil on the pharmacokinetics and pharmacodynamics of dabigatran etexilate (DE).Method
In this two part multiple crossover trial in 40 healthy subjects, DE 150 mg was given alone or with verapamil at different doses, duration of treatment (single vs. multiple dosing), formulations, and timings (before, concurrently or after DE). Primary pharmacokinetic endpoints were determined from concentrations of total dabigatran (unconjugated plus conjugated). Pharmacodynamic endpoints were determined from clotting time.Results
The greatest effect was observed with single dose verapamil 120 mg immediate release given 1 h before single dose DE. Geometric mean area under the plasma concentration curve [AUC(0,∞)] and maximum analyte concentration in the plasma (Cmax) were increased by 143% [90% confidence interval (CI) 91, 208] and 179% (90% CI 115, 262), respectively. The effect was reduced to a 71% and 91% increase in AUC and Cmax, respectively, when DE was administered with verapamil 240 mg extended release. After multiple verapamil dosing, DE AUC(0,∞) and Cmax increases were 54% and 63%, respectively. However, DE given 2 h before verapamil increased DE AUC(0,∞) and Cmax by <20%. With regard to clotting prolongation, the dabigatran plasma concentration–effect relationship was generally not affected by the co-administration of verapamil. Concomitant administration of DE and verapamil did not reveal any unexpected safety findings.Conclusion
Verapamil increased DE bioavailability, likely due to inhibition of P-glycoprotein. Our results suggest that an interaction between verapamil and DE can be minimized if DE is administered 2 h prior to verapamil. 相似文献14.
Wolfgang Mueck Dagmar Kubitza Michael Becka 《British journal of clinical pharmacology》2013,76(3):455-466
Aims
The anticoagulant rivaroxaban is an oral, direct Factor Xa inhibitor for the management of thromboembolic disorders. Metabolism and excretion involve cytochrome P450 3A4 (CYP3A4) and 2J2 (CYP2J2), CYP-independent mechanisms, and P-glycoprotein (P-gp) and breast cancer resistance protein (Bcrp) (ABCG2).Methods
The pharmacokinetic effects of substrates or inhibitors of CYP3A4, P-gp and Bcrp (ABCG2) on rivaroxaban were studied in healthy volunteers.Results
Rivaroxaban did not interact with midazolam (CYP3A4 probe substrate). Exposure to rivaroxaban when co-administered with midazolam was slightly decreased by 11% (95% confidence interval [CI] −28%, 7%) compared with rivaroxaban alone. The following drugs moderately affected rivaroxaban exposure, but not to a clinically relevant extent: erythromycin (moderate CYP3A4/P-gp inhibitor; 34% increase [95% CI 23%, 46%]), clarithromycin (strong CYP3A4/moderate P-gp inhibitor; 54% increase [95% CI 44%, 64%]) and fluconazole (moderate CYP3A4, possible Bcrp [ABCG2] inhibitor; 42% increase [95% CI 29%, 56%]). A significant increase in rivaroxaban exposure was demonstrated with the strong CYP3A4, P-gp/Bcrp (ABCG2) inhibitors (and potential CYP2J2 inhibitors) ketoconazole (158% increase [95% CI 136%, 182%] for a 400 mg once daily dose) and ritonavir (153% increase [95% CI 134%, 174%]).Conclusions
Results suggest that rivaroxaban may be co-administered with CYP3A4 and/or P-gp substrates/moderate inhibitors, but not with strong combined CYP3A4, P-gp and Bcrp (ABCG2) inhibitors (mainly comprising azole-antimycotics, apart from fluconazole, and HIV protease inhibitors), which are multi-pathway inhibitors of rivaroxaban clearance and elimination. 相似文献15.
Jan Beyer-Westendorf Vera Gelbricht Kati F?rster Franziska Ebertz Denise R?llig Thomas Schreier Luise Tittl Christoph Thieme Ulrike H?nsel Christina K?hler Sebastian Werth Eberhard Kuhlisch Thoralf Stange Ingolf R?der Norbert Weiss 《British journal of clinical pharmacology》2014,78(4):908-917
Aim
Vitamin-K antagonists (VKA) and non-vitamin-K dependent oral anticoagulants (NOAC) have been approved for anticoagulation in venous thromboembolism (VTE) and atrial fibrillation and patients previously treated with VKA are switched to NOAC therapy. Safety data for this switching are urgently needed.Methods
Using data from a large regional prospective registry of daily care NOAC patients, we evaluated the safety of switching anticoagulation from VKA to dabigatran or rivaroxaban. Switching procedures and cardiovascular and bleeding events occurring within 30 days after switching were centrally adjudicated.Results
Between 1 October 2011 and 18 June 2013, 2231 patients were enrolled. Of these, 716 patients were switched from VKA to NOAC. Only 410 of the 546 evaluable patients (75.1%) had a recorded INR measurement within the 10 days preceding or following the end of VKA treatment (mean INR 2.4). As of day 30, major bleeding complications were rare (0.3%; 95% CI 0.0, 1.0) with an overall bleeding rate of 12.2% (95% CI 9.8, 14.8). Major cardiovascular events occurred in 0.8% (95% CI 0.3, 1.8). There was no significant difference in outcome event rates between the subgroups of patients with or without INR testing.Conclusion
In daily care, only 75% of VKA patients have an INR measurement documented before NOAC are started. On average, NOAC are started within 2 to 5 days after the last intake of VKA. However, at 30 days follow-up cardiovascular events or major bleedings were rare both in patients with and without INR testing. However, switching procedures need to be further evaluated in larger cohorts of patients. 相似文献16.
Xu XS Moore K Burton P Stuyckens K Mueck W Rossenu S Plotnikov A Gibson M Vermeulen A 《British journal of clinical pharmacology》2012,74(1):86-97
AIMS
The aim of this analysis was to use a population approach to facilitate the understanding of the pharmacokinetics and pharmacodynamics of rivaroxaban in patients with acute coronary syndrome (ACS) and to evaluate the influence of patient covariates on the exposure of rivaroxaban in patients with ACS.METHODS
A population pharmacokinetic model was developed using pharmacokinetic samples from 2290 patients in Anti-Xa Therapy to Lower Cardiovascular Events in Addition to Standard Therapy in Subjects with Acute Coronary Syndrome Thrombolysis in Myocardial Infarction 46. The relationship between pharmacokinetics and the primary pharmacodynamic end point, prothrombin time, was evaluated.RESULTS
The pharmacokinetics of rivaroxaban in patients with ACS was adequately described by an oral one-compartment model. The estimated absorption rate, apparent clearance and volume of distribution were 1.24 h−1 (interindividual variability, 139%), 6.48 l h−1 (31%) and 57.9 l (10%), respectively. Simulations indicate that the influences of renal function, age and bodyweight on exposure in ACS patients are consistent with the findings in previous Phase 1 studies. Rivaroxaban plasma concentrations exhibit a close-to-linear relationship with prothrombin time in the ACS population, with little interindividual variability. The estimated pharmacokinetic and pharmacodynamic parameters for the ACS patients were comparable to those for venous thromboembolism prevention, deep vein thrombosis and atrial fibrillation patients.CONCLUSIONS
The similarity in pharmacokinetics/pharmacodynamics of rivaroxaban among different patient populations and the low interindividual variability in the exposure–prothrombin time relationship indicate that the anticoagulant effect of rivaroxaban is highly predictable and consistent across all the patient populations studied. 相似文献17.
Background and Purpose
Acute liver failure (ALF) is a severe and potentially lethal clinical syndrome. 3,3′-Diindolylmethane (DIM) is a natural plant-derived compound with anti-cancer activities. Recently, DIM has also been shown to have anti-inflammatory properties. Here, we tested the hypothesis that DIM would suppress endotoxin-induced ALF.Experimental Approach
We investigated the therapeutic potential of DIM in a mouse model of D-galactosamine/Lipopolysaccharide (GalN/LPS)-induced ALF. The efficacy of DIM treatment was assessed by survival, liver histopathology, serum levels of alanine transaminase, pro-inflammatory cytokines and number of activated liver macrophages. Effects of DIM on the expression of two miRNAs, 106a and 20b, and their predicted target gene were measured by qRT-PCR and Western blotting. Effects of DIM on the release of TNF-α from RAW264.7 macrophages transfected with mimics of these miRNAs and activated by LPS was assessed by elisa.Key Results
DIM treatment protected mice from ALF symptoms and reduced the number of activated liver macrophages. DIM increased expression of miR-106a and miR-20b in liver mononuclear cells and decreased expression of their predicted target gene IL-1 receptor-associated kinase 4 (IRAK4), involved in signalling from Toll-like receptor 4 (TLR4). In vitro transfection of RAW264.7 cells using miRNA mimics of miR-106a and 20b decreased expression of IRAK4 and of TNF-α secretion, following LPS stimulation.Conclusions and Implications
DIM attenuated GalN/LPS-induced ALF by regulating the expression of unique miRNAs that target key molecules in the TLR4 inflammatory pathway. DIM may represent a potential novel hepatoprotective agent. 相似文献18.
Craig DG Bates CM Davidson JS Martin KG Hayes PC Simpson KJ 《British journal of clinical pharmacology》2011,71(2):273-282
AIMS
Paracetamol (acetaminophen) hepatotoxicity is the commonest cause of acute liver failure (ALF) in the UK. Conflicting data regarding the outcomes of paracetamol-induced ALF resulting from different overdose patterns are reported.METHODS
Using prospectively defined criteria, we have analysed the impact of overdose pattern upon outcome in a cohort of 938 acute severe liver injury patients admitted to the Scottish Liver Transplantation Unit.RESULTS
Between 1992 and 2008, 663 patients were admitted with paracetamol-induced acute severe liver injury. Of these patients, 500 (75.4%) had taken an intentional paracetamol overdose, whilst 110 (16.6%) had taken an unintentional overdose. No clear overdose pattern could be determined in 53 (8.0%). Unintentional overdose patients were significantly older, more likely to abuse alcohol, and more commonly overdosed on compound narcotic/paracetamol analgesics compared with intentional overdose patients. Unintentional overdoses had significantly lower admission paracetamol and alanine aminotransferase concentrations compared with intentional overdoses. However, unintentional overdoses had greater organ dysfunction at admission, and subsequently higher mortality (unintentional 42/110 (38.2%), intentional 128/500 (25.6%), P < 0.001). The King''s College poor prognostic criteria had reduced sensitivity in unintentional overdoses (77.8%, 95% confidence intervals (CI) 62.9, 88.8) compared with intentional overdoses (89.9%, 95% CI 83.4, 94.5). Unintentional overdose was independently predictive of death or liver transplantation on multivariate analysis (odds ratio 1.91 (95% CI 1.07, 3.43), P= 0.032).CONCLUSIONS
Unintentional paracetamol overdose is associated with increased mortality compared with intentional paracetamol overdose, despite lower admission paracetamol concentrations. Alternative prognostic criteria may be required for unintentional paracetamol overdoses. 相似文献19.
Xavier Delavenne Edouard Ollier Thierry Basset Laurent Bertoletti Sandrine Accassat Arnauld Garcin Silvy Laporte Paul Zufferey Patrick Mismetti 《British journal of clinical pharmacology》2013,76(1):107-113
Aim
The aim of this study was to develop a PK/PD model to assess drug–drug interactions between dabigatran and P-gp modulators, using the example of clarithromycin, a strong inhibitor of P-gp.Methods
Ten healthy male volunteers were randomized to receive in the first treatment period a single 300 mg dose of dabigatran etexilate (DE) and in the second treatment period 500 mg clarithromycin twice daily during 3 days and then 300 mg DE plus 500 mg clarithromycin on the fourth day, or the same treatments in the reverse sequence. Dabigatran plasma concentration and ecarin clotting time (ECT) were measured on 11 blood samples. Models were built using a non-linear mixed effect modelling approach.Results
The best PK model was based on an inverse Gaussian absorption process with two compartments. The relationship between dabigatran concentration and ECT was implemented as a linear function. No continuous covariate was associated with a significant decrease in the objective function. The concomitant administration of clarithromycin induced a significant change only in DE bioavailability, which increased from 6.5% to 10.1% in the presence of clarithromycin. Clarithromycin increased peak concentration and AUC by 60.2% and 49.1% respectively.Conclusion
The model proposed effectively describes the complex PK of dabigatran and takes into account drug–drug interactions with P-gp activity modulators, such as clarithromycin. 相似文献20.
Johanna Strandell rew Bate Staffan Hägg & I Ralph Edwards 《British journal of clinical pharmacology》2009,68(3):427-434