Liver function monitoring: a prospective nested case-control study of Salvia miltiorrhiza polyphenol injection.

Instructions for Salvia miltiorrhiza polyphenol injections indicate abnormal liver function as an occasional adverse reaction, but the incidence of this adverse drug reaction (ADR) has increased in recent years. We assessed S. miltiorrhiza polyphenol ADRs by performing a nested case-control study(NCCS) and meta-analysis. In the NCCS, 2633 patients receiving this treatment in the First Affiliated Hospital of Bengbu Medical College were enrolled. Logistic regression models found that in 58 (2.2%) patients experiencing abnormal liver function, the risk for liver dysfunction was associated with sulfa drug allergy (OR = 7.874, 95%CI (1.280, 48.447), P = 0.026), payment methods (OR = 0.106, 95%CI (0.012, 0.934), P = 0.043), duration of administration (OR = 0.922, 95%CI (0.862, 0.986), P = 0.017), cefathiamidine (OR = 0.441, 95%CI (0.216, 0.900), P = 0.025), human serum albumin (OR = 1.958, 95%CI (1.011, 3.789), P = 0.046), Dazhu Rhodiola injection (OR = 2.599, 95%CI (1.112, 6.070), P = 0.027), or reduced glutathione (OR = 0.394, 95%CI (0.188, 0.826), P = 0.014). Meta-analysis of reports on S. miltiorrhiza polyphenol ADRs in controlled trials and other observational studies included 676 patients, of which 17 (2.17%; 95%CI (0.0105, 0.0358)) presented with liver dysfunction; associated ADR risk factors included co-administration of other drugs. Our NCCS and meta-analysis had similar ADR incidence rates, which were higher than the rate in the drug instructions. This study provides guidance for assessing liver dysfunction risks associated with S. miltiorrhiza polyphenol injections.

Inhibitory effects of Danhong Injection and its major constituents on human cytochrome P450 enzymes in vitro.

Danhong Injection (DHI) as a Chinese patent medicine is mainly used to treat ischemic encephalopathy and coronary heart disease in combination with other chemotherapy. However, the information on DHI's potential drug interactions is limited. The goal of this work was to examine the potential P450-mediated metabolism drug interaction arising from DHI and its active components. The results showed that DHI inhibited CYP2C19, CYP2D6, CYP3A4, CYP2E1 and CYP2C9 with IC50 values of 1.26, 1.42, 1.63, 1.10 and 1.67% (v/v), respectively. Danshensu and rosmarinic acid inhibited CYP2E1 and CYP2C9 with IC50 values of 36.63 and 75.76 µm, and 34.42 and 76.89 µm, respectively. Salvianolic acid A and B inhibited CYP2D6, CYP2E1 and CYP2C9 with IC50 values of 33.79, 21.64 and 31.94 µm, and 45.47, 13.52 and 24.15 µm, respectively. The study provides some useful information for safe and effective use of DHI in clinical practice.

Lotus leaf alkaloid fraction can strongly inhibit CYP2D6 isoenzyme activity.

ETHNOPHARMACOLOGICAL RELEVANCE: The Chinese herbal medicine He-Ye, the leaves of the lotus (Nelumbo nucifera) plant, is traditionally used in China for the treatment of sunstroke, thirst, diarrhea, and fever. Currently, the leaf is used not only as an herbal tea to reduce lipid level and control body weight, but also as a major ingredient in some lipid-lowering Chinese patented medicines. Our previous study demonstrated that the alkaloid fraction (AF) of the herb has a strong inhibitory effect on CYP2D6 isoenzyme activity in vitro. The present study aims to further verify this activity using the in vivo rat model and to explore the inhibitory mechanism on CYP2D6 using human liver microsomes (HLMs). MATERIALS AND METHODS: After a continuous 7-d oral dose of AF (50mg/kg) or a vehicle, Sprague Dawley rats received a single intravenous dose of dextromethorphan or metoprolol. Blood samples were collected at various time points, and the plasma concentrations of the relevant metabolites dextrorphan and hydroxymetoprolol were assayed by LC-MS/MS for evaluating the effect of AF on their pharmacokinetics and CYP2D6 activity. Dextromethorphan as a probe at different concentrations was incubated with HLMs in an incubation buffer system, in the presence or absence of AF at different concentrations. After incubation, the produced metabolite was assayed. RESULTS: After being pretreated with AF in rats, the plasma concentrations of dextrorphan and hydroxymetoprolol significantly decreased, with Cmax going from 79.44 to 29.96 and 151.18 to 83.39hng/mL (P<0.05), AUCall from 167.27 to 62.25 and 347.68 to 223.24hng/mL (P<0.05), and AUCinf from 183.39 to 84.76 and 350.59 to 234.57hng/mL (P<0.05), respectively, in comparison with those of untreated rats. The t1/2 of hydroxymetoprolol significantly increased from 1.14 to 1.99h (P<0.05). The in vitro incubation test showed that AF competitively inhibited the CYP2D6, with apparent Ki value of 0.64µg/mL. CONCLUSIONS: AF can strongly inhibit the activity of CYP2D6 enzyme, as confirmed by in vivo and in vitro models. Possible drug interactions may occur between AF and other medications metabolized by CYP2D6. Thus, caution should be paid when the lotus leaf and its preparations are concurrently administered with conventional medicines.

Identification and characterization of potent CYP2D6 inhibitors in lotus leaves.

ETHNOPHARMACOLOGICAL RELEVANCE: The herb of lotus (Nelumbo nucifera) leaves is a commonly used traditional Chinese herbal medicine that is utilized for the treatment of sunstroke, to assuage thirst, and to cure both diarrhea and fever in China. Modern pharmacological studies have demonstrated that the herb exhibits various pharmacological effects, such as anti-hyperlipidemia, anti-obesity, anti-oxidant, anti-HIV, anti-microbial, and anti-hypoglycemic activities. Currently, the herb is becoming more popular in China as a "tea drink" or as a main ingredient of some herbal formulations, which implies that the herb and/or its products are now more likely to be concurrently administered with conventional medicines for losing body weight and reducing blood lipids. However, its potential inhibitory effect on human cytochrome P450 (CYP) has not been systemically investigated to date. The present study was performed to assess the potential inhibitory effects of lotus leaf alcoholic extract (LAE), its major fractions, and its main compounds on five CYP isoenzymes (CYP2C9, CYP2C19, CYP2D6, CYP2E1, and CYP3A4) in vitro. MATERIAL AND METHODS: Five probe substrates were incubated with human liver microsomes in the presence or absence of the LAE, the alkaloid fraction (AF), the flavonoid fraction (FF), or the individual aporphine alkaloids, namely, nuciferine (NF), N-nornuciferine (N-NF), and 2-hydroxy-1-methoxyaporphine (HMA). After the incubation, the relative metabolites of the substrates were analyzed using LC-MS/MS. RESULTS: The results showed that the LAE strongly inhibited CYP2D6 with an IC50 value of 12.05µg/mL and weakly inhibited other isoenzymes. In addition, FF was found to weakly inhibit CYP2D6, whereas AF exerted a markedly higher inhibitory effect on CYP2D6 activity with an IC50 value of 0.96µg/mL. The three aporphine alkaloids isolated from the AF (NF, N-NF, and HMA) significantly inhibited CYP2D6 with IC50 values of 3.78, 3.76, and 3.15µM, respectively. Their Lineweaver-Burk plots and Dixon plots showed that NF, N-NF, and HMA competitively inhibited CYP2D6 activity with Ki values of 1.88, 2.34, and 1.56µM, respectively. CONCLUSION: The study revealed that the alkaloid compounds in lotus leaves exert a potent inhibitory effect on CYP2D6 isoenzyme. The possible drug interactions of the leaves and their preparations with conventional medicines should thus be taken into account.

Pharmacokinetic mechanism of enhancement by Radix Pueraria flavonoids on the hyperglycemic effects of Cortex Mori extract in rats.

ETHNOPHARMACOLOGICAL RELEVANCE: Diabetes mellitus, characterized by abnormal blood glucose evaluation, is a serious chronic disease. In the treatment of the disease, α-glycosidase inhibitors play an important role for controlling the postprandial blood glucose level. Cortex Mori, a traditional Chinese herbal medicine, has a long history of use for the treatment of headaches, cough, edema and diabetes. Modern pharmacological studies have shown that the herb has beneficial effects on the suppression of postprandial blood glucose levels by inhibiting α-glycosidase activity in the small intestine. 1-Deoxynojirimycin (DNJ), the main active ingredient of this herb, is recognized as a potent α-glycosidase inhibitor. Our previous studies have shown that the hypoglycemic effect of Cortex Mori extract (CME) was significantly improved when giving CME in combination with Radix Pueraria flavonoids (RPF). In the present study, the pharmacokinetics and intestinal permeability of DNJ were comparatively investigated in rats after being given orally or by intestinal perfusion with CME alone or in CME-RPF pairs, to explore the mechanism of this synergistic effect. MATERIALS AND METHODS: The role of RPF on the plasma and urine concentrations of DNJ from CME orally administered was investigated. Four groups of rats received a single oral dose of either CME or CME-RPF, at DNJ equivalent doses of 20 and 40mg/kg, respectively. After dosing, plasma and urine were collected and assayed by LC/MS/MS. In addition, another two groups of rats were used for small intestinal perfusion with CME or CME-RPF at DNJ concentration of 10µM. RESULTS: Compared to the data when dosing with CME alone, the Cmax of DNJ were decreased from 5.78 to 2.94µg/ml (p<0.05) and 10.66 to 5.35µg/ml (p<0.01); Tmax were delayed from 0.40 to 0.55h and 0.35 to 0.50h (p<0.05); and MRT were significantly prolonged from 1.14 to 1.72h (p<0.05) and 0.95 to 1.62h (p<0.01), after dosing with CME-RPF at DNJ doses of 20 and 40mg/kg, respectively. In addition, the urinary recovery of DNJ over the first 4h after dosing significantly decreased from 48.76% to 33.86%. Effective permeability (Peff) of DNJ was decreased from 7.53×10(-3) to 3.09×10(-3)cm/s (p<0.05) when RPF was added to CME, when it was evaluated using the rat intestinal perfusion model. CONCLUSIONS: All the above results demonstrate that RPF was able to suspend and delay the absorption of DNJ, but did not affect the total amount of DNJ in the body. The resulting higher concentration of DNJ in the small intestine produced a relatively stronger effect of depressing the elevation of the postprandial blood glucose level. These findings support the important role of RPF in the application of CME on blood glucose control.

Different pharmacokinetics of the two structurally similar dammarane sapogenins, protopanaxatriol and protopanaxadiol, in rats.

Dammarane Sapogenins (DS), with main ingredients of protopanaxatriol (PPT, 33%) and protopanaxadiol (PPD, 16%), is an alkaline hydrolyzed product of ginsenosides and had significant activities in improving learning and memory and decreasing chemotherapy-induced myelosuppression. In the present study, the pharmacokinetics and oral bioavailabilities of PPT and PPD were investigated when a single dose of DS was administrated orally (75 mg/kg) and intravenously (i.v., 30 mg/kg) to rats. Their in vitro stabilities in the GI tract were also investigated. PPT and PPD concentrations were measured by LC-MS. The results showed that PPT was eliminated rapidly from the body with an average t1/2, λz value of 0.80 h and CL of 4.27 l/h/kg after i.v. administration, while PPD was eliminated relatively slowly with a t1/2, λz of 6.25 h and CL of 0.98l/h/kg. After oral administration, both PPD and PPT could be absorbed into the body, but their systemic exposures were quite different. PPT was absorbed into the body quickly, with a Tmax of 0.58 h and a Cmax of 0.13 µg/ml, while PPD was absorbed relatively slowly with a Tmax of 1.82 h and a Cmax of 1.04 µg/ml. The absolute bioavailabilities of PPT and PPD were estimated as 3.69% and 48.12%, respectively. The stability test found that PPT was instable in the stomach with 40% degradation after 4h incubation at 37°C, both in pH1.2 buffer and in the stomach content solution. The instability in the stomach might be one of the reasons for PPT's poor bioavailability.

Non-bonded force field for the interaction between metals and organic molecules: a case study of olefins on aluminum.

In this work, we parameterize an empirical potential for the interaction between organic molecules and metal surfaces via force matching. This is done by pursuing a self-consistent approach similar to the ones used for equilibrium simulations; however, special attention is paid to the suitability of the resulting potential for tribological (non-equilibrium) situations. Specifically, we study olefin molecules confined between two aluminum surfaces under realistic pressures and shear rates. We find that the Buckingham potential produces better agreement with the first principle data than other force fields. While our training set only contains hexene molecules, we find that the standard error in the fitted olefin-aluminum interaction increases only by a factor of 1.15 when the force field is applied to butene, octene, and decene. Including mirror charges into the treatment only marginally improves fits. While olefins on aluminum is merely a special case, the proposed methodology can be used to parameterize any other interaction between polymers and metal surfaces for use in tribological simulations.