Effect of drug combination on tacrolimus target dose in renal transplant patients with different CYP3A5 genotypes.

Various factors, including genetic polymorphisms, drug-drug interactions, and patient characteristics influence the blood concentrations of tacrolimus in renal transplant patients. In the present study, we established a population pharmacokinetic model to explore the effect of combined use of Wuzhi capsules/echinocandins and the patients' biochemical parameters such as haematocrit on blood concentrations and target doses of tacrolimus in renal transplant patients with different CYP3A5 genotypes. The aim of the study was to propose an individualised tacrolimus administration regimen for early renal transplant recipients.In this retrospective cohort study, we included 240 renal transplant recipients within 21 days of surgery (174 males and 66 females, mean age 39.4 years), who received tacrolimus alone (n = 54), in combination with Wuzhi capsules (99) or caspofungin (57) or micafungin (30). We collected demographic characteristics, clinical indicators, CYP3A5 genotypes, and 1950 steady-state concentrations of tacrolimus and included them in population pharmacokinetic model. An additional 110 renal transplant recipients and 625 steady-state concentrations of tacrolimus were included for external validation of the model. The population pharmacokinetic model was established and Monte Carlo was used to simulate probabilities for achieving the target concentration for individual tacrolimus administration.A two-compartment model of first-order absorption and elimination was developed to describe the population pharmacokinetics of tacrolimus. CYP3A5 genotypes and co-administration of Wuzhi capsules, as well as time after renal transplantation and haematocrit, were important factors affecting the clearance of tacrolimus. We found no obvious change in trend in the scatter plot of tacrolimus clearance rate vs. haematocrit. The Monte Carlo simulation indicated the following recommended doses of tacrolimus alone: 0.14 mg⋅kg-1⋅d-1 for genotype CYP3A5*1*1, 0.12 mg⋅kg-1⋅d-1 for CYP3A5*1*3, and 0.10 mg⋅kg-1⋅d-1 for CYP3A5*3*3. For patients receiving the combination with Wuzhi capsules, the recommended doses of tacrolimus were 0.10 mg⋅kg-1⋅d-1 for CYP3A5*1*1, 0.08 mg⋅kg-1⋅d-1 for CYP3A5*1*3, and 0.06 mg⋅kg-1⋅d-1 for CYP3A5*3*3 genotypes. Caspofungin or micafungin had no effect on the clearance of tacrolimus in renal transplant recipients.The population pharmacokinetics of tacrolimus in renal transplant patients was evaluated and the individual administration regimen of tacrolimus was simulated. For early kidney transplant recipients receiving tacrolimus treatment, not only body weight, but also CYP3A5 genotypes and drugs used in combination should be considered when determining the target dose of tacrolimus.

Apoptosis induced by DICO, a novel non-aromatic B-ring flavonoid via a ROS-dependent mechanism in human colon cancer cells.

5,7-Dihydroxy-2-(1,2-isopropyldioxy-4-oxo-cyclohex-5-enyl)-chromen-4-one (DICO) is a novel non-aromatic B-ring flavonoid, isolated mainly from Macrothelypteris viridifrons and has anti-tumour properties. In this study, we investigated the cytotoxicity and underlying biochemical pathways leading to cell death, in response to DICO treatment of a human colon cancer cell line HT-29. Our results indicated that DICO induced apoptosis by elevating the generation of reactive oxygen species, which could be quenched by the antioxidants N-acetyl cysteine. In addition, activation of signal transducer and activator of transcription 3 and suppression of nuclear factor kappa B played a crucial role in DICO-induced apoptosis. Overall, our results provide mechanistic insights into the apoptotic action of a potential anti-tumour drug, DICO.

Direct versus conventional anticoagulants for treatment of cancer associated thrombosis: a pooled and interaction analysis between observational studies and randomized clinical trials.

BACKGROUND: There are emerging observational studies (OSs) to assess real-world comparative effectiveness and safety of direct oral anticoagulants (DOACs) in cancer associated thrombosis (CAT). We conducted a pooled and interaction analysis to compare the treatment effect estimates of DOACs between OSs and randomized controlled trials (RCTs). METHODS: We systematically searched PUBMED, EMBASE and Cochrane Library for OSs and RCTs that reported recurrent venous thromboembolism (VTE) and/or major bleeding events in CAT patients receiving DOACs and conventional anticoagulants [warfarin or low molecular-weight heparins (LMWHs)]. Relative risks (RRs) for OSs and RCTs were calculated using random-effects models separately, and interaction analyses were afterward applied to assess the comparability between OSs and RCTs. RESULTS: Baseline characteristic was comparable between identified 10 OSs (35,142 patients) and 8 RCTs (2,602 patients). Overall, no significant difference of treatment effect estimates between OSs and RCTs was detected (Pinteraction: 0.42 for recurrent VTE; Pinteraction: 0.38 for major bleeding). DOACs significantly decreased the risk of recurrent VTE compared with conventional anticoagulants in CAT patients (RR: 0.74, 95% CI: 0.63-0.86, I2: 0% for OSs; RR: 0.65, 95% CI: 0.49-0.86; I2: 0% for RCTs), without increasing major bleeding risk (RR: 0.90, 95% CI: 0.76-1.07, I2: 24.0% for OSs; RR: 1.17, 95% CI: 0.72-1.88, I2: 26.2% for RCTs). Whereas, increased risk of gastrointestinal bleeding (GIB) was found with DOACs versus conventional anticoagulants in CAT patients (RR: 2.77, 95% CI: 1.35-5.68, I2: 0% for RCTs). Analyses of subgroups, based on comparators and follow-up duration, did not significantly affect results. CONCLUSIONS: In this study, effectiveness and safety of DOACs versus conventional anticoagulants in CAT from OSs are in agreement with those from RCTs, confirming a low risk of recurrent VTE and similar risk of major bleeding in CAT patients receiving DOACs.

HPLC analysis, optimization of extraction and purification conditions, biological evaluation of total protoflavones from Macrothelypteris viridifrons.

The present study aims to evaluate phytochemical and pharmacological potential of total protoflavones from Macrothelypteris viridifrons. In the phytochemical study, an HPLC analysis method was established, and the optimal extraction and purification conditions were analyzed. The extractive condition was optimized as follows: the backflow extraction with 20 folds of 70% ethanol at 80◦C for 1 h twice. Moreover, by combining the alkali-extraction and acid-precipitation method with the macroporous resin purification technology, the final purity rate of total protoflavones was no less than 54.85%. In the pharmacological study, the total protoflavones from M. viridifrons showed a significant tumor-inhibitory effect in the H22 hepatoma cells transplantation model with a higher inhibitory rate of 55.76% in high dosage (100mg/kg) treatment group compared with the positive control group (20 mg/kg cyclophosphamide). Taken of all, these results support that protoflavones are the material basis of M. viridifrons as an anticancer folk medicine.

Characterisation of phenols and antioxidant and hypolipidaemic activities of Lethariella cladonioides.

BACKGROUND: This study aimed to investigate the antioxidant and hypolipidaemic activities of an ethanol extract of Lethariella cladonioides (Nyl.) Krog (EE) and to characterise its chemical constituents. RESULTS: Nine phenols were identified as canarione, thamnolic acid, squamatic acid, vermicularin, norstictic acid, baeomycesis acid, lecanoric acid, barbatinic acid and usnic acid from analysis of EE by using high-performance liquid chromatography with a diode array detector-mass spectrometry. In antioxidant analysis in vitro, the highest scavenging rate of EEs on the 2,2'-azinobis-(3-ethylbenzothiazoline-6-sulfonic acid) (ABTS) radicals, superoxide anion, hydroxyl radicals and hydrogen peroxide was 81.55 ± 1.95%, 81.84 ± 4.00%, 74.28 ± 3.71% and 74.28 ± 3.71%, respectively. Meanwhile, after administration of EE for 6 weeks in high fat/cholesterol diet mice, the most significant reduction in levels of serum triglyceride, serum total cholesterol, serum low density lipoprotein cholesterol and liver malondialdehyde were 24%, 20%, 15% and 35%, respectively. The most significant increase in levels of serum high density lipoprotein cholesterol and liver superoxide dismutase was 35% and 88%, respectively. CONCLUSION: L. cladonioides possesses strong antioxidant and hypolipidaemic activities.