Effects of direct-acting antiviral therapy for patients with advanced hepatocellular carcinoma and concomitant hepatitis C-A population-based cohort study.

OBJECTIVE: We analyzed real-world data to elucidate the effects of anti-Hepatitis C virus (HCV) direct-acting antiviral (DAA) therapy on survival in patients with advanced hepatocellular carcinoma (HCC) and concomitant HCV infection treated with sorafenib. MATERIALS AND METHODS: This population-based retrospective cohort study used the Taiwan National Health Insurance Research Database and the Registration System for Patients Treated with Oral Hepatitis C Antivirals to identify patients with advanced HCC and concomitant HCV infection who received initial targeted therapy (sorafenib) in 2018-2019. The overall survival (OS) of the DAA and non-DAA groups were compared using the Kaplan-Meier survival analysis. Propensity score matching was performed using a ratio of 1:4 to reduce confounding between the DAA and non-DAA groups. RESULTS: The study included 1,684 patients (122 DAA and 1,562 non-DAA users) with HCC and concomitant HCV infection who used sorafenib for the first time in 2018-2019. The Kaplan-Meier survival analysis indicated that advanced HCC patients who used DAAs had longer OS compared to non-DAA patients. The mean survival times were 20.7 months for DAA and 12.5 months for non-DAA. Results obtained after propensity matching indicated a significant difference in OS between the DAA and non-DAA groups. CONCLUSIONS: The analysis of big data from the Taiwan National Health Insurance Research Database revealed that advanced HCC patients on sorafenib benefited from DAAs as a treatment for HCV infection. Patients whose HCV infection was cured had better OS.

Evaluation of documented drug interactions and contraindications associated with herbs and dietary supplements: a systematic literature review.

BACKGROUND AND AIMS: The use of herbs and dietary supplements (HDS) alone or concomitantly with medications can potentially increase the risk of adverse events experienced by the patients. This review aims to evaluate the documented HDS-drug interactions and contraindications. METHODS: A structured literature review was conducted on PubMed, EMBASE, Cochrane Library, tertiary literature and Internet. RESULTS: While 85 primary literatures, six books and two web sites were reviewed for a total of 1,491 unique pairs of HDS-drug interactions, 213 HDS entities and 509 medications were involved. HDS products containing St. John's Wort, magnesium, calcium, iron, ginkgo had the greatest number of documented interactions with medications. Warfarin, insulin, aspirin, digoxin, and ticlopidine had the greatest number of reported interactions with HDS. Medications affecting the central nervous system or cardiovascular system had more documented interactions with HDS. Of the 882 HDS-drug interactions being described its mechanism and severity, 42.3% were due to altered pharmacokinetics and 240 were described as major interactions. Of the 152 identified HDS contraindications, the most frequent involved gastrointestinal (16.4%), neurological (14.5%), and renal/genitourinary diseases (12.5%). Flaxseed, echinacea, and yohimbe had the largest number of documented contraindications. CONCLUSIONS: Although HDS-drug interactions and contraindications primarily concerned a relatively small subset of commonly used medications and HDS entities, this review provides the summary to identify patients, HDS products, and medications that are more susceptible to HDS-drug interactions and contraindications. The findings would facilitate the health-care professionals to communicate these documented interactions and contraindications to their patients and/or caregivers thereby preventing serious adverse events and improving desired therapeutic outcomes.

What is the effective component in suanzaoren decoction for curing insomnia? Discovery by virtual screening and molecular dynamic simulation.

The reliable structure of gamma aminobutyric acid type A (GABA-A) receptor was built based on several criteria. According to zolpidem and GABA binding conformations, the key residues that were indicated to be the determination of binding were consistent with our simulation. Investigation of the major effective constituents from suanzaoren to modulate the GABA-A was the aim of the study. Jujuboside A, which was indicated to be the effective constituent from suanzaoren, had no blood-brain barrier (BBB) penetration and was unable to bind at both binding sites due to its large volume. In addition, the glycoside groups on jujuboside A were easily to be hydrolyzed. In contrast, jujubogenin, which was hydrolyzed from jujuboside A, had the most compatible binding conformation. In addition, jujubogenin formed two HBs with the key residue beta(2)-Thr226 and beta(2)-Tyr229 at the GABA binding site. Moreover, it gained the comparably highest scoring values among suanzaoren constituents. Furthermore, the Adsorption, Distribution, Metabolism, Excretion, and Toxicity (ADMET) descriptor predicted that jujubogenin have good BBB penetration. Consequently, we suggested jujubogenin to be the effective suanzaoren constituent to mediate the GABA-A receptor.

Solid-phase microextraction coupled with liquid chromatography for determination of beta-carotene in food.

Beta-carotene in vegetables and nutritional products is analyzed using solid-phase microextraction (SPME) coupled with liquid chromatography (LC) to improve the speed of analysis and to reduce the consumption of organic solvents. The relative standard deviations (RSDs) of this analytical method for beta-carotene determinations in vegetables and nutritional products are approximately 10% and 5%, respectively. The amount of beta-carotene was found to vary from 0.35 +/- 0.05 ppm to 76.5 +/- 6.9 ppm for several vegetables in Taiwan. This method was linear over the range of 0.4-40 ppm with correlation coefficients higher than 0.997. The experimentally determined level of beta-carotene in nutritional products varied from 3.8 +/- 0.2 ppm to 24.6 +/- 1.1 ppm following SPME-LC. The recoveries of beta-carotene for these measurements following SPME were all higher than 97% +/- 2% (n = 3). The detection limits of beta-carotene for this method were from 0.027 to 0.054 ppm. Conventional solvent extractions take approximately 4-6 h for extraction and reconcentration but SPME takes approximately 1 h. From several tens to hundreds of milliliters, organic solvents can be saved using SPME. SPME provides better analyses on beta-carotene than conventional solvent extraction for nutritional products in terms of speed, precision, simplicity, and solvent consumption.

Effects of veratrine and paeoniflorin on isolated mouse vas deferens.

In this study, we attempted to identify the interactions and mechanisms between veratrine and paeoniflorin on isolated mouse vas deferens. Paeoniflorin had no effect on isolated mouse vas deferens. Veratrine (1 x 10(-5) approximately 1 x 10(-3) g/ml) could directly induce contraction of isolated rat and mouse vas deferens. The concentration induced by veratrine (1 x 10(-5) g/ml) was completely inhibited by Ca2+-free solution and verapamil (1 x 10(-5) M), in both the epididymal and the prostatic portions of isolated mouse vas deferens. Naloxone (1 x 10(-5) M) did not alter the contraction induced by veratrine (1 x 10(-5) g/ml) in either the epididymal or the prostatic portions of isolated mouse vas deferens. Paeoniflorin (4.8 x 10(-5) g/ml) inhibited the contraction induced by veratrine (1 x 10(-5) g/ml) in both the epididymal and the prostatic portions of isolated mouse vas deferens. Paeoniflorin (4.8 x 10(-5) g/ml) potentiated norepinephrine (1 x 10(-5) M)-induced phasic contraction in the epididymal portion, but decreased contractions in the prostatic portion. Paeoniflorin (4.8 x 10(-5) g/ml) increased KCI (56 mM)-induced phasic contraction in the epididymal portion, but decreased the tonic contraction in either the epididymal or the prostatic portion. Veratrine (1 x 10(-5) g/ml)-induced contractions could be decreased by pretreatment with ryanodine (1 x 10(-5) M) in both the epididymal and the prostatic portions. Pretreatment with the combination of paeoniflorin (4.8 x 10(-5) g/ml) and ryanodine (1 x 10(-5) M) did not potentiate the inhibition of paeoniflorin in the veratrine-induced contraction in both the epididymal and the prostatic portions of isolated mouse vas deferens.

Effects of paeoniflorin on the formalin-induced nociceptive behaviour in mice.

In this study, we attempted to identify the mechanisms of paeoniflorin on antinociceptive effects in mice. Paeoniflorin (48, 96, 240, 480 microg, i.c.v.) showed dose-related antinociception both on the early and late phases of formalin test in mice. Moreover, paeoniflorin (48 microg, i.c.v.) could potentiate the antinociception of morphrine (0.5, 1.0 mg/kg, s.c.) in the formalin test. However, the antinociceptive effects of paeoniflorin were not potentiated by L-arginine (600 mg/kg, i.p.) or antagonized by beta-funaltrexamine (beta-FNA) (10 microg, i.c.v.), ICI-174,864 (1 microg, i.c.v.) and ryanodine (10 ng, i.c.v.) on both the early and late phases of formalin test. L-NAME (75 mg/kg, i.p.) could reverse the effect of paeoniflorin on the late phase of formalin test. Naloxone (1 mg/kg, i.p.) and nor-binaltorphimine (nor-BNI) (1 microg, i.c.v.) could block the paeoniflorin-induced antinociception on the early phase of formalin test. These results suggested that the central antinociceptive effects of paeoniflorin on formalin test in mice were mediated by the activation of kappa-opioid receptor and not related to the increase of intracellular calcium.

Effects of veratrine and paeoniflorin on the isolated rat aorta.

The interactions and mechanisms between veratrine and paeoniflorin on the isolated rat aorta were studied. Veratrine (1x10(-6) to 1x10(-4) g/ml) could induce contraction on the isolated rat aorta in a concentration-related manner. Paeoniflorin had no effect on the isolated rat aorta. Pretreatment with prazosin (1x10(-6) M) and nifedipine (1x10(-6) M) but not yohimbine (1x10(-5) M) could decrease the tension of contraction induced by veratrine (1x10(-4) g/ml). Sodium nitroprusside (1x10(-4) M) could inhibit the contraction induced by veratrine (1x10(-4) g/ml) with or without endothelium, whereas methylene blue (5x10(-5) M) could increase the contraction induced by veratrine (1x10(-4) g/ml). Treatment with veratrine (1x10(-4) g/ml) could decrease the tension of contraction induced by norepinephrine (1x10(-6) M) or phenylephrine (1x10(-4) M). The inhibition of veratrine on norepinephrine-induced contraction was potentiated by L-arginine (1x10(-4) M) and reversed by L-NAME (1x10(-5) M). Paeoniflorin (1x10(-4) M) could decrease the tension of contraction induced by veratrine (1x10(-4) g/ml) and methylene blue (5x10(-5) M). The inhibition of paeoniflorin on veratrine was more potent on rat isolated aorta with endothelium than without endothelium. Ryanodine (1x10(-5) M) and Ca2+ -free medium could inhibit methylene blue-induced contraction. From the above results, the relaxation of veratrine on the norepinephrine-induced contraction might be related to the increase of NO and cGMP. The contraction of veratrine on the isolated rat aorta was via the increase of intracellular calcium which was inhibited by paeoniflorin.

The interactions of paeoniflorin and veratrine on isolated rat atria.

In this study, we attempted to identify the interactions and mechanisms between veratrine and paeoniflorin on isolated rat atria. Paeoniflorin alone showed no effect on the rat atria. Veratrine increased the atrial contraction and induced arrhythmia at 1 x 10(-5) g/ml. Veratrine could directly induce contraction and elicit tetanic contraction at 1 x 10(-4) g/ml in the left atria with or without electric stimulation. Paeoniflorin (4.8 x 10(-6) to 4.8 x 10(-3) g/ml), verapamil (2.2 x 10(-6) g/ml), tetrodotoxin (TTX) (3.2 x 10(-8) g/ml) and quinidine (7.5 x 10(-6) g/ml) inhibited the increase of contraction and delayed the onset of contraction induced by veratrine (1 x 10(-5) g/ml). The inhibitory effect of paeoniflorin combined with verapamil on the contraction induced by veratrine was more potent than that of paeoniflorin or verapamil alone. However, the inhibitory effect of paeoniflorin was not potentiated by TTX or quinidine. From the above results, the contraction evoked by veratrine in the rat atria may be concluded to be caused by the stimulation of Na(+)- and Ca(2+)-ion channels. The inhibition of paeoniflorin on the contraction induced by veratrine may primarily be related to the blockade of Ca2+ channels.

Anti-inflammatory and analgesic activities from roots of Angelica pubescens.

In the present study, we extracted Angelica pubescens (AP) with various solvents in order to find the bioactive constituents that demonstrated analgesic and anti-inflammatory effects. The results were obtained as follows: (1) Methanol-, chloroform-, and ethyl acetate-extracts effectively reduced the pain that was induced by 1% acetic acid and a hot plate. (2) Methanol-, chloroform-, and ethyl acetate-extracts reduced the edema that was induced by 3% formalin or 1.5% carrageenan. (3) Sixteen compounds have been isolated and identified from the roots of AP. Among these compounds, columbianadin, columbianetin acetate, bergapten, umbelliferone, and caffeic acid significantly demonstrated anti-inflammatory and analgesic activities at 10 mg/kg. However, only osthole and xanthotoxin revealed anti-inflammatory activity. Isoimperatorin only demonstrated an analgesic effect. These results revealed that the anti-inflammatory and analgesic constituents from roots of AP were related to peripheral inhibition of inflammatory substances and to the influence on the central nervous system.

Studies on the anticonvulsive, sedative and hypothermic effects of Periostracum Cicadae extracts.

The anticonvulsive, sedative and hypothermic effects of water and ethanol extracts of Periostracum Cicadae (PC), the cast off skin of Cryptotympana atrata were studied. The water-extract of whole Periostracum Cicadae (PCws) had anticonvulsive, sedative and hypothermic effects in rats. Orally, it decreased carrageenin-induced hyperthermia. The hypothermic effect of PCws was potentiated by 5-hydroxytryptophan and antagonized by p-chlorophenylalanine. PCws enhanced the decrease in locomotor activity induced by alpha-methyl-p-tyrosine or 5-hydroxytryptophan and reduced the increase in locomotor activity produced by levodopa plus benserazide or p-chlorophenylalanine. From these results, it was concluded that the sedative and hypothermic effect of PCws may be due to an increase in central serotonergic activity.

Further evidence for possible analgesic mechanism of electroacupuncture: effects on neuropeptides and serotonergic neurons in rat spinal cord.

The possible mechanism of electroacupuncture (EAc) in reference to the effects of neuropeptides on serotonergic neurons in rat spinal cord was studied. The tested drugs were administered by intrathecal injection or spinal push-pull perfusion. The results showed that baclofen, substance P (SP) and naloxone administered intrathecally could reduce the tail pressure pain threshold. The pain threshold was increased by met-enkephalin (EK) and EAc. The action of EAc was antagonized by naloxone. The release of 5-HT in the spinal cord evoked by tail pressure pain stimulation (TP) was inhibited by EK, baclofen and EAc. However, naloxone could potentiate the 5-HT release evoked by TP. EAc reversed the naloxone potentiation of TP-evoked 5-HT release. The 5-HT release evoked by exogenous SP, however, was potentiated by EK and EAc. From these results, it is suggested that the influence of EAc on 5-HT release may be due to activation of enkephalin-interneurons, which presynaptically inhibit the primary sensory neurons in the spinal cord.

The effects of vandellia cordifolia on renal functions and arterial blood pressure.

Vandellia cordifolia (COLSM) G. DON of Scrophulariaceae (V. cordifolia) is an annual wild herb indigenous to Taiwan. It can be found in plains, low altitudes, swampy places, and paddy fields. Taiwanese folk physicians use it in "nephritis, uremia, furnucle, carbuncle." The LD50 (95% confidence limit) of the crude extract of V. codifolia given by the oral route was more than 10 g/kg in rats. By the intraperitoneal route, it was 4.6 g/kg (4.35-4.93). The extraction rate was 16.6%. We studied its effects on renal functions and blood pressure and found that (1) it had diuretic effect on normal rats, (2) it decreased glomerular filtration rate and renal blood flow on normal kidneys in rabbits, (3) it had no effects on glomerular filtration rate and renal blood flow on glycerin-induced insufficient kidneys in rabbits, (4) it had diuretic effects on both normal and glycerin-induced insufficient kidneys in rabbits, (5) it could inhibit Na+ and K+ reabsorption on normal and glycerin-induced insufficient kidneys in rabbits, (6) it had hypertensive effect and this effect could be blocked by phenoxybenzamine. From the above facts, we conclude that V. cordifolia has diuretic effect and it may act on renal tubules to inhibit Na+ and K+ reabsorption.

The pharmacological studies in central nervous system on the interaction of Taiwanese Veratri Formosani Rhizoma and Sophorae Radix.

The eighteen opposing drugs were to be recognized as absolute incompatibility of Chinese herbs. Ku-Shen (Sophorae Radix) opposed Li-Lu (Veratri Rhizoma) is one of these incompatible drugs. In this study, we attempted to investigate and identify the interactions of these two drugs in the CNS by means of modern pharmacological technics. The results elucidate that toxicity, number of retching movements, change of locomotor activity and the concentration of monoamines' metabolites of Li-Lu can be changed by Ku-Shen. From these results, further evidence was provided that the involvement of Li-Lu and Ku-Shen in the eighteen opposing drugs of Chinese ancient Pentsao are deemed to be significant.