The clinical application of traditional Chinese medicine NRICM101 in hospitalized patients with COVID-19.

BACKGROUND: The aim of this study was to assess the efficacy and safety of NRICM101 in hospitalized patients with COVID-19. RESEARCH DESIGN AND METHODS: We conducted a retrospective study from 20 April 2021 to 8 July 2021, and evaluated the safety and outcomes (mortality, hospital stay, mechanical ventilation, oxygen support, diarrhea, serum potassium) in COVID-19 patients. Propensity score matching at a 1:2 ratio was performed to reduce confounding factors. RESULTS: A total of 201 patients were analyzed. The experimental group (n = 67) received NRICM101 and standard care, while the control group (n = 134) received standard care alone. No significant differences were observed in mortality (10.4% vs. 14.2%), intubation (13.8% vs. 11%), time to intubation (10 vs. 11 days), mechanical ventilation days (0 vs. 9 days), or oxygen support duration (6 vs. 5 days). However, the experimental group had a shorter length of hospitalization (odds ratio = 0.12, p = 0.043) and fewer mechanical ventilation days (odds ratio = 0.068, p = 0.008) in initially severe cases, along with an increased diarrhea risk (p = 0.035). CONCLUSION: NRICM101 did not reduce in-hospital mortality. However, it shortened the length of hospitalization and reduced mechanical ventilation days in initially severe cases. Further investigation is needed.

Biotransformation and brain distribution of the anti-COVID-19 drug molnupiravir and herb-drug pharmacokinetic interactions between the herbal extract Scutellaria formula-NRICM101.

The aim of this study was to explore the effects of herbal drug pharmacokinetic interactions on the biotransformation of molnupiravir and its metabolite ß-D-N4-hydroxycytidine (NHC) in the blood and brain. To investigate the biotransformation mechanism, a carboxylesterase inhibitor, bis(4-nitrophenyl)phosphate (BNPP), was administered. Not only molnupiravir but also the herbal medicine Scutellaria formula-NRICM101 is potentially affected by coadministration with molnupiravir. However, the herb-drug interaction between molnupiravir and the Scutellaria formula-NRICM101 has not yet been investigated. We hypothesized that the complex bioactive herbal ingredients in the extract of the Scutellaria formula-NRICM101, the biotransformation and penetration of the bloodbrain barrier of molnupiravir are altered by inhibition of carboxylesterase. To monitor the analytes, ultrahigh-performance liquid chromatography tandem mass spectrometry (UHPLCMS/MS) coupled with the microdialysis method was developed. Based on the dose transfer from humans to rats, a dose of molnupiravir (100 mg/kg, i.v.), molnupiravir (100 mg/kg, i.v.) + BNPP (50 mg/kg, i.v.), and molnupiravir (100 mg/kg, i.v.) + the Scutellaria formula-NRICM101 extract (1.27 g/kg, per day, for 5 consecutive days) were administered. The results showed that molnupiravir was rapidly metabolized to NHC and penetrated into the brain striatum. However, when concomitant with BNPP, NHC was suppressed, and molnupiravir was enhanced. The blood-to-brain penetration ratios were 2% and 6%, respectively. In summary, the extract of the Scutellaria formula-NRICM101 provides a pharmacological effect similar to that of the carboxylesterase inhibitor to suppress NHC in the blood, and the brain penetration ratio was increased, but the concentration is also higher than the effective concentration in the blood and brain.

Exploration of sodium homeostasis and pharmacokinetics in bile duct-ligated rats treated by anti-cirrhosis herbal formula plus spironolactone.

Renal sodium retention is an essential indicator that is used for the prognosis of cirrhosis with ascites that requires diuretic treatment to restore sodium homeostasis. The diuretic effects of Yin-Chen-Hao-Tang (YCHT) alone or in combination with diuretics for sodium retention in patients with cirrhosis have not been investigated. This study aimed to investigate the diuretic effects and sodium retention caused by YCHT with spironolactone, from both the pharmacokinetic and pharmacodynamic perspective, in bile duct-ligated rats. The HPLC method was validated and utilized for the pharmacokinetic analysis of rat urine. Urine samples were collected and analyzed every 4 hours for 32 h after oral administration of YCHT at 1 or 3 g/kg daily for 5 days in bile duct-ligated rats. A dose of 20 mg/kg spironolactone was also administered to pretreat the YCHT 1 g/kg or the 3 g/kg group on the 5th day to explore the interaction of the two treatments. Urine sodium, potassium, weight, volume, and spironolactone and canrenone levels were measured to investigate fluid homeostasis after the coadministration. The linearity, precision, and accuracy of the HPLC method were suitable for subsequent urinary pharmacokinetic analyses. The pharmacokinetic parameters in the 1 g/kg YCHT with spironolactone group revealed that the elimination half-life of the spironolactone metabolite, canrenone, was prolonged. In addition, the cumulative excretion amount, the area under the rate curve (AURC), and the maximum rate of excretion (Rmax) were significantly decreased when the spironolactone group was pretreated with 3 g/kg YCHT. Urinary sodium excretion elicited by spironolactone was suppressed by pretreatment with 1 or 3 g/kg YCHT. The 32-hour urine output was not altered by the administration of YCHT alone, but it was significantly decreased by 64.9% after the coadministration of YCHT with spironolactone. The interaction of spironolactone and YCHT was found to decrease urine sodium-potassium and water excretion, and this change was attributed to the decreased level of spironolactone metabolites and possibly the regulation of the renin-angiotensin-aldosterone system by obstructed cirrhosis. The dose adjustment of YCHT or diuresis monitoring should be noted when co-administering YCHT and spironolactone to treat hepatic diseases clinically.

Pharmacokinetic and pharmacodynamic herb-drug interactions of common over-the-counter pain medications.

Pain is one of the most common reasons for seeking medical intervention, and self-medication with over-the-counter medications and/or traditional herbal remedies has become increasingly popular. In this review, original articles on understanding possible herb-drug interactions between traditional herbs and four major pain medications-acetaminophen, aspirin, ibuprofen and naproxen-are compiled and analyzed. In terms of analytical methods, high-performance liquid chromatography using an isocratic eluent system coupled to biological sample clean-up is the most common, while a wide variety of detectors have been observed, including a photodiode array, variable wavelength detector, electrochemical detector and tandem mass spectrometer. Both synergistic and anti-synergistic effects were observed for acetaminophen and aspirin, while only synergistic effects have been found for naproxen. Currently, no interactions have been reported for ibuprofen.

Neuroprotective effect and herbal-drug pharmacokinetic interaction of Gastrodia elata extract on valproic acid.

Valproic acid (VPA) is a widely used antiepileptic drug, and the herbal extract of Gastrodia elata exerts an anticonvulsant effect. However, few studies have investigated the pharmacokinetic and pharmacodynamic interactions between G. elata extract and VPA. We hypothesize that G. elata extract increases the VPA levels in the brain and enhances the antiepileptic effects of VPA, and this synergistic effect is mediated by transporters at the bloodbrain barrier (BBB). We performed microdialysis on pilocarpine-induced epileptic model rats in vivo to investigate this hypothesis. The results demonstrated that cotreatment with G. elata extract and VPA ameliorated drug-resistant epilepsy by increasing the VPA levels in the brain. In addition, G. elata extract and VPA exerted synergistic anticonvulsive effects to decrease the seizure severity by protecting neurons in the hippocampus and altering the DOPAC and 5-HT levels. However, these phenomena were partially blocked by the organic anion transporter peptide (OATP) inhibitor cyclosporine A (CsA; 20 mg/kg, i.p.), which demonstrated that the increase in the VPA level in the brain was modulated by the transporter OATP. This study provides a comprehensive strategy for assessing the interaction between traditional medicines and conventional antiepileptic drugs in a status epilepticus animal model.

Pharmacokinetics and transplacental transfer of codeine and codeine metabolites from Papaver somniferum L.

ETHNOPHARMACOLOGICAL RELEVANCE: Papaveris Pericarpium, which is the dried husk of Papaver somniferum L., has been used as a phytomedicine to relieve cough, diarrhea and pain. The alkaloid codeine contained therein via biotransformation converts to morphine and potentially produces addictive and toxic effects. Due to the healthy concern for a pregnant woman, our hypothesis is that codeine and its metabolites can penetrate the placental barrier to reach the foetus and amniotic fluid, and these processes may be modulated by the transporter. AIM OF THE STUDY: Because codeine is also considered a prodrug of morphine, it has a good analgesic effect. It is often used by pregnant women but may expose the foetus to the risk of morphine harm. The aim of this study is to investigate the metabolic rate, distribution and transplacental transfer mechanism of codeine and its metabolites morphine and morphine-3-glucuronide (M3G) in pregnant rats and to assess the risk of medication for pregnant women. MATERIALS AND METHODS: Ultrahigh-performance liquid chromatography-tandem mass spectrometry (UHPLC-MS/MS) combined with a microdialysis system was developed to monitor codeine, morphine and M3G in multiple sites of maternal blood, placenta, foetus and amniotic fluid after codeine administration. A compartmental model was used to calculate the pharmacokinetic parameters of codeine in blood after codeine administration (10 mg/kg, i.v.). The area under the concentration (AUC) ratio of AUCmetabolite/AUCcodeine and AUCtissue/AUCblood was used to represent the metabolic biotransformation ratio and the drug from blood-to-tissue transfer ratio, respectively. RESULTS: The pharmacokinetic results demonstrated that codeine fit well with a two-compartment model and went through rapid metabolism to morphine and M3G in pregnant rats after codeine administration (10 mg/kg, i.v.). The biotransformation ratios of AUCmorphine/AUCcodeine, AUCM3G/AUCmorphine and AUCM3G/AUCcodeine were 0.12 ± 0.03, 54.45 ± 20.61 and 6.53 ± 2.47, respectively, after codeine administration (10 mg/kg, i.v.), which suggested that codeine was easily metabolized into M3G through morphine. The tissue distribution results demonstrated that all of the analytes penetrated into the foetus through the placenta; however, the blood-to-tissue transfer ratio (AUCtissue/AUCblood) of morphine and M3G was relatively lower than that of codeine after codeine administration (10 mg/kg, i.v.), which suggested that the blood-placenta barrier blocks the penetration of morphine and M3G into the foetus. Thus, the tissue transfer of morphine in the placenta and foetus was significantly enhanced by treatment with corticosterone, an inhibitor of organic cation transporter (OCT). CONCLUSION: Based on microdialysis coupled to a validated UHPLC-MS/MS system, the pharmacokinetics and metabolic biotransformation of codeine and its metabolites were analyzed and clarified. The potential mechanism of morphine placental transfer was modulated by OCT transporters.

Borneol and Tetrandrine Modulate the Blood-Brain Barrier and Blood-Tumor Barrier to Improve the Therapeutic Efficacy of 5-Fluorouracil in Brain Metastasis.

The efficacy of chemotherapeutic drugs for the treatment of brain metastasis may be compromised by the blood-brain barrier (BBB) and blood-tumor barrier (BTB). P-glycoprotein (P-gp) is a multidrug resistance protein that potentially limits the penetration of chemotherapeutics through the BBB and BTB. 5-Fluorouracil (5-FU) is widely used to treat cancer. Bioactive constituents of medicinal herbs, such as borneol and tetrandrine, potentially improve drug penetration through the BBB and BTB. We hypothesized that borneol and tetrandrine might modulate the BBB and BTB to enhance 5-FU penetration into the brain. To investigate this, in vitro and in vivo models were developed to explore the modulatory effects of borneol and tetrandrine on 5-FU penetration through the BBB and BTB. In the in vitro models, barrier integrity, cell viability, barrier penetration, P-gp activity, and NF-κB expression were assessed. In the in vivo brain metastasis models, cancer cells were injected into the internal carotid artery to evaluate tumor growth. The experimental results demonstrated that borneol and borneol + tetrandrine reduced BBB integrity. The efflux pump function of P-gp was partially inhibited by tetrandrine and borneol + tetrandrine. In the in vivo experiment, borneol + tetrandrine effectively prolonged survival without compromising body weight. In conclusion, BBB and BTB integrity was modulated by borneol and borneol + tetrandrine. The combination of borneol and tetrandrine could be used to improve the chemotherapeutic control of brain metastasis.

Dose-dependent effects of Hedyotis diffusa extract on the pharmacokinetics of tamoxifen, 4-hydroxytamoxifen, and N-desmethyltamoxifen.

Tamoxifen, a widely prescribed medication in premenopausal women diagnosed with hormone-dependent breast cancer, is potentially co-prescribed with Hedyotis diffusa (H. diffusa), particularly in Taiwan. However, no related report has investigated the drug-herb interaction of H. diffusa on the pharmacokinetics of tamoxifen and its metabolites. In the present study, male Sprague-Dawley rats were administered different doses of H. diffusa extract for 5 consecutive days prior to the administration of tamoxifen (10 mg/kg). A validated ultra-liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) system was developed to monitor tamoxifen, 4-hydroxytamoxifen, N-desmethyltamoxifen, and endoxifen in rat plasma. Pharmacokinetic results demonstrated that the area under curves (AUCs) of tamoxifen and the relative bioavailability (%) of tamoxifen were dose-dependently decreased (31-68%) by pre-treatment with H. diffusa extract (3 g/kg and 6 g/kg). In addition, the conversion ratio of 4-hydroxytamoxifen was downregulated (0.5-fold change) and the N-desmethyltamoxifen conversion ratio was upregulated (2-fold change) by high-dose H. diffusa extract. As a result, the relative bioavailability and biotransformation changes affect the clinical efficacy of tamoxifen treatment. These preclinical findings reveal a hitherto unreported interaction between tamoxifen and H. diffusa extract that has implications for their therapeutic efficacy in treating breast cancer.

The Pharmacological Effects and Pharmacokinetics of Active Compounds of Artemisia capillaris.

Artemisia capillaris Thunb. (A.capillaris, Yin-Chen in Chinese) is a traditional medicinal herb with a wide spectrum of pharmacological properties ranging from effects against liver dysfunction to treatments of severe cirrhosis and cancer. We used relevant keywords to search electronic databases, including PubMed, Medline, and Google Scholar, for scientific contributions related to this medicinal herb and the pharmacokinetics of its components. The pharmaceutical effects of A.capillaris contribute to the treatment not only of viral hepatitis, cirrhosis, and hepatocellular hepatoma, but also metabolic syndrome, psoriasis, and enterovirus in the clinic. The bioactive compounds, including scoparone, capillarisin, scopoletin, and chlorogenic acid, exhibit antioxidant, anti-inflammatory, antisteatotic, antiviral, and antitumor properties, reflecting the pharmacological effects of A.capillaris. The pharmacokinetics of the main bioactive compounds in A. capillaris can achieve a maximum concentration within 1 hour, but only chlorogenic acid has a relatively long half-life. Regarding the use of the A. capillaris herb by health professionals to treat various diseases, the dosing schedule of this herb should be carefully considered to maximize therapeutic outcomes while lessening possible side effects.

Modulation of the transport of valproic acid through the blood-brain barrier in rats by the Gastrodia elata extracts.

HEADINGS ETHNOPHARMACOLOGICAL RELEVANCE: Valproic acid (VPA) is primarily used as a medicine for the treatment of seizures. Gastrodia elata (G. elata) extract has been used as an alternative medicine for epilepsy patients. Cotreatment with VPA and G. elata extract is commonly prescribed in Taiwan and mainland China. Nevertheless, the mechanism of the blood-brain barrier (BBB) transportation effect of G. elata extract on VPA has not been characterized. AIM OF STUDY: Our hypothesis is that G. elata extract modulates the BBB penetration of VPA through specific transporter transfer. MATERIALS AND METHODS: A validated liquid chromatography-tandem mass spectrometry and multiple microdialysis method was developed to simultaneously monitor VPA in the blood and brain of rats. To investigate the mechanism of BBB modulation by the G. elata extract on VPA in the brain, cyclosporin A, a P-glycoprotein (P-gp) inhibitor and organic anion transporting polypeptide (OATP) inhibitor, was coadministered with the G. elata extract and VPA. RESULTS: The pharmacokinetic results demonstrated that the VPA penetration ratio of the BBB, determined by the area under the concentration curve (AUC) ratio of VPA (AUCbrain/AUCblood), was approximately 0.36. After treatment with the G. elata extract (1 and 3 g/kg, p.o. for 5 consecutive days), the VPA penetration ratios were significantly enhanced to 1.47 and 1.02, respectively. However, in the experimental group coadministered cyclosporin A, the G. elata extract was unable to enhance the BBB transportation of VPA. Instead, the VPA penetration ratio in the brain was suppressed back to 0.38. CONCLUSIONS: The present study reveals that the enhancement effect of the transporter mechanism of G. elata extract on VPA transport into the brain occurs through the OATP transporter but not the P-gp transporter.

Comparative biotransformation of luteolin and apigenin from the flower extract and the stem-and-leaf extract of Dendranthema morifolium Ramat. Tzvel. in rats.

BACKGROUND: The flower of Dendranthema morifolium Ramat Tzvel has been widely used as a nutritional health supplement worldwide. However, most of the studies have focused on the flower and the rest of the plant was neglected. Our hypothesis is that similar flavonoids may be present at different parts of D. morifolium, and the flavonoids may undergo a similar biotransformation pathway within the body. To investigate this hypothesis, an in vivo pharmacokinetic experimental model was developed to explore the comparative biotransformation of luteolin and apigenin after administration of D. morifolium extracts (10 g kg-1 , p.o.) in freely moving rats. Because luteolin and apigenin mainly underwent phase II metabolism, the metabolic enzymes of ß-glucuronidase/sulfatase or ß-glucuronidase were used to hydrolyze the plasma sample, depending on the biotransformation pathway involved. RESULTS: The results revealed that luteolin and apigenin mainly went through glucuronide and sulfate conjugations, respectively, in both the extract of flowers and the stem-and-leaf group. In addition, the area under the concentration curve (AUClast ) of luteolin glucuronides and sulfates in the group administered the stem-and-leaf extract was approximately 4.6 times higher than that of the flower extract group. The dominant products of biotransformation for apigenin were sulfates. CONCLUSION: These findings support our hypothesis that not only the flower parts of D. morifolium, but also the stem-and-leaf parts contain rich flavones, including glycosides and aglycone, and they undergo similar biotransformation pathways. © 2021 Society of Chemical Industry.

Preclinical Pharmacokinetic Interaction and Histopathological Analyses of Hedyotis diffusa on Sorafenib in Rats.

Sorafenib is one of the most effective target therapeutic agents for patients with late-stage hepatocellular carcinoma. To seek possible alternative adjuvant agents to enhance the efficacy and improve the side effect of sorafenib, Hedyotis diffusa, one of the most prescribed phytomedicines for treating liver cancer patients in Taiwan, was evaluated in this work. We hypothesized that H. diffusa extract is a safety herb combination on the pharmacokinetic and pharmacodynamic effects of sorafenib. We designed treatments of sorafenib in combination with or without H. diffusa extract to examine its pharmacokinetic properties and effects on liver inflammation. The HPLC-photodiode-array method was designed for monitoring the plasma level and pharmacokinetic parameter of sorafenib in rat plasma. The pharmacokinetic results demonstrated that the area under the curve of sorafenib (10 mg/kg, p.o.) in combination with various doses of H. diffusa formulation (1, 3, and 10 g/kg, p.o.) for 5 consecutive days were 5560 ± 1392, 7965 ± 2055, 7271 ± 1371, and 8821 ± 1705 min µg/mL, respectively, no significant difference when compared with sorafenib treatment alone. Furthermore, the hepatic activity in rats administered with sorafenib with/without H. diffusa extract was quantitatively scored by modified hepatic activity index grading. H. diffusa extract in the range of 1 to 10 g/kg per day did not elicit significant herb-induced hepatotoxicity in rats, based on the histopathological study. Consequently, our findings provided positive safety outcomes for the administration of sorafenib in combination with the phytomedicine H. diffusa.

Anti-inflammatory effects of Radix Aucklandiae herbal preparation ameliorate intestinal mucositis induced by 5-fluorouracil in mice.

ETHNOPHARMACOLOGICAL RELEVANCE: 5-Fluorouracil (5-FU) is a chemotherapy agent that is widely used in clinical oncologic practice. However, intestinal mucositis is the most frequently occurring side effect of cancer therapy with 5-FU. Based on a literature survey, Radix Aucklandiae herbal preparation potentially ameliorates intestinal mucositis in 5-FU-treated mice. AIM OF THE STUDY: The aim of this study was to investigate the inflammation and gastrointestinal regulation of intestinal mucositis induced by 5-FU, including the intestinal morphology, as well as the reduction in food intake, body weight loss, and diarrhea. MATERIALS AND METHODS: Intestinal mucositis was induced in mice by 5-FU (30 mg/kg, i.p., for 5 consecutive days). The dose-dependent Radix Aucklandiae herbal preparation (0.3, 1, and 3 g/kg/day, p.o.), loperamide (3 mg/kg/day, p.o.) or celecoxib (40 mg/kg/day, p.o.) was concurrently administered until the 7th day. Physical status observation, diarrhea assessment, serum proinflammatory cytokine levels, intestinal villus height and crypt depth, and total goblet cells from tissues were assessed. RESULTS: The dosage regimen of 5-FU administration caused severe intestinal mucositis in mice, including damage to the intestinal morphology, accompanied by a reduction in food intake, body weight loss, and diarrhea. The high-dose Radix Aucklandiae herbal preparation significantly relieves 5-FU-induced intestinal mucositis by enhancing proliferative activity in epithelial crypts; improving anepithymia, body weight loss, and diarrhea; and displaying protective effects on goblet cells in intestinal mucosal epithelia. Activation of NF-κB in the intestinal mucositis model was also suppressed by the Radix Aucklandiae herbal preparation, suggesting that it is a potent inhibitor of NF-κB and proinflammatory cytokines, such as IL-1ß, IL-6, TNF-α, and COX-2. CONCLUSIONS: Our data support the conclusion that the Radix Aucklandiae herbal preparation could effectively ameliorate 5-FU-induced gastrointestinal toxicity and be applied clinically for the prevention of intestinal mucositis during chemotherapy.

Protein unbound pharmacokinetics of ambroxol in the blood and brains of rats and the interaction of ambroxol with Polygala tenuifolia by multiple microdialysis.

ETHNOPHARMACOLOGICAL RELEVANCE: Ambroxol elevates glucocerebrosidase (GCase) activity and reduces nigrostriatal alpha-synuclein burden to better ameliorate motor function in Parkinson's disease (PD). Polygala tenuifolia is a potential alternative botanical medicine for the treatment of many nonmotor symptoms of PD commonly used in Taiwanese patients. Co-administration of these two medicines pose potential herb-drug interaction. AIM OF THE STUDY: Our hypothesis is that ambroxol and P. tenuifolia may potentially possess herbal drug synergetic effects in the blood and brain. MATERIALS AND METHODS: To investigate this hypothesis, a multiple microdialysis system coupled with validated ultra-high performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) method was developed for rat blood and brain samples. Experimental rats were divided into three groups: low-dose and high-dose ambroxol alone (10 mg/kg, i.v. and 30 mg/kg, i.v., respectively) and ambroxol (10 mg/kg, i.v.) pretreated with P. tenuifolia extract (1 g/kg, p.o. for 5 consecutive days). RESULTS: Ambroxol easily penetrated into the brain and reached a maximum concentration in the striatum at approximately 60 min after low- and high-dose treatment. The area under the concentration curve (AUC) ratio increased proportionally at the doses of 10 and 30 mg/kg, which suggested a linear pharmacokinetic manner of ambroxol. The brain penetration of ambroxol was approximately 30-34%, which was defined as the ambroxol AUC blood-to-brain distribution ratio (AUCbrain/AUCblood). The P. tenuifolia extract did not significantly alter the pharmacokinetics of ambroxol in the blood and brain of rats. CONCLUSION: The present study suggests that it is safety without pharmacokinetic interactions for this dosing regimen to use P. tenuifolia extract and ambroxol together.

Low-frequency electroacupuncture at acupoints guanyuan (CV4) and zhongji (CV3) lengthen ejaculatory latency and improves sexual behavior in male rats.

Acupuncture is a key component of Traditional Chinese Medicine in which needles are inserted into specific areas in the body to stimulate certain physiological reactions of the body. Clinical research shows that acupuncture is beneficial in treating a variety of illnesses, such as erectile dysfunction. Therefore, we investigated the effect of electroacupuncture (EA) stimulation of both low- and high frequencies at Guanyuan (CV4) and Zhongji (CV3) acupoints on male copulatory behavior in sexually experienced male rats. The animals were randomly divided into four groups: control, sham EA, EA, and only acupuncture. The administered low and high EA were 2 Hz and 80 Hz, respectively, for which the respective intensities were 1.5 mA (30 min/day for 5 days) and 1.5 mA (30 min once). The only acupuncture-administered group received acupunctures at CV4 and CV3 without electrical stimulation. Following the acupuncture treatments, copulatory behavior test was conducted. Eventually, animals were sacrificed and blood samples were collected for testing the serum hormonal profile including luteinizing hormone (LH), testosterone (T), and serotonin (5-HT). Results showed that low-frequency EA-treated rats exhibited increasing intromissions and ejaculation latency compared to control, sham EA, and acupuncture groups, while high-frequency EA-treated rats displayed lower intromissions and ejaculation frequency when compared with those in controls. Furthermore, serum levels of 5-HT and LH in low-frequency EA-treated rats were higher than all the other groups. These results indicate that compared to high-frequency EA, the low-frequency EA might be efficacious in the treatment of premature ejaculation, thereby improving sexual behavior.

Preclinical study of simultaneous pharmacokinetic and pharmacodynamic herb-drug interactions between Yin-Chen-Hao-Tang and spironolactone.

BACKGROUND: The prevalence and therapeutic effects of the use of herbal remedies for chronic liver diseases make the combined administration of herbal products with conventional treatment unable to be ignored. This study investigated the pharmacokinetic and pharmacodynamic herb-drug interactions between the herbal formula Yin-Chen-Hao-Tang (YCHT) and spironolactone. METHODS: A selective high-performance liquid chromatography (HPLC) method was developed and validated for the detection of spironolactone and its metabolite canrenone in rat urine. The interaction study was conducted by collecting urine samples after oral administration of spironolactone alone or in combination with YCHT for 5 days. Urine pharmacokinetic parameters and urinary sodium, potassium, volume, and weight were analyzed. RESULTS: The results revealed significant increases in the cumulative amount and the area under the rate curve (AURC) of the metabolite canrenone after pretreatment with the high dose of YCHT. The urine weight and volume were significantly reduced dose-dependently as a result of pretreatment with YCHT. The urinary sodium-to-potassium ratio, which indicates diuretic effects, was also reduced in the high-dose YCHT condition. CONCLUSIONS: Herb-drug pharmacokinetic and pharmacodynamic interactions between YCHT and spironolactone were observed in the study. The herb-drug interaction that appeared with a single dose of spironolactone should be considered when patients are being treated with a continuous administration of this drug.

Scanning Electron Microscopy and Liquid Chromatography for Physical and Chemical Inspection of Industrial Pharmaceutical Traditional Chinese Herbal Medicine.

Multiherbal preparation of Coptidis rhizoma, Scutellariae radix, and Rhei rhizoma is a well-known herbal formula, which is widely used in the prescription for relieving heat toxicity, inflammation of the intestine, and eczema. However, little is known about the characteristics of the physical and chemical qualities of industrial pharmaceutical products. The aim of the study is to develop a liquid chromatography system to examine the quality and quantity of pharmaceutical products. Besides scanning electron microscopy, light microscopy photographs with Congo red staining and iodine-KI staining were used for physical examination of the quality of the pharmaceutical products. A reverse-phase C18 column was used to separate the analytes of baicalin, berberine, rhein, and p-hydroxybenzoate (internal standard) with a gradient eluent mobile phase of acetonitrile and 10 mM NaH2PO4 (pH 3.0, adjusted by orthophosphoric acid). The results demonstrated that a large variety of content range presents among the testing herbal pharmaceutical products. The contents of rhein, baicalin, and berberine were around 0.22-22.46, 0.44-50.79, and 0.41-2.48 mg/g, respectively. The physical examination data demonstrated that different brands of industrial pharmaceutical products have different shapes of granules or rods. In summary, to ensure the clinical efficacy of complicated herbal medicine, both quality and quantity controls are all very important. This study provides a reference standard operating procedure guide for the quality control (QC) with chemical and physical examination for the Chinese herbal pharmaceutical products of San-Huang-Xie-Xin-Tang (SHXXT).

Preclinical Herb-Drug Pharmacokinetic Interaction of Panax ginseng Extract and Selegiline in Freely Moving Rats.

Selegiline, an inhibitor of monoamine oxidase B, is prescribed during the early stages of Parkinson's disease. The nutritional herbal medicine Panax ginseng C.A. Meyer has been reported to show potential neuroprotective activity; however, the herb-drug pharmacokinetic interaction between selegiline and P. ginseng extract has not been characterized. Our hypothesis is that the ginseng extract and selegiline produce pharmacokinetic interactions at certain doses. To investigate this hypothesis, a validated ultraperformance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) method was developed to monitor selegiline in rat plasma. Experimental rats were divided into groups treated with selegiline alone (10 mg/kg, i.v.; 30 mg/kg, p.o.), with the low-dose ginseng extract (1 g/kg, p.o., for 5 consecutive days) or with the high-dose ginseng extract (3 g/kg, p.o., for 5 consecutive days). The pharmacokinetic results demonstrated that the oral bioavailability of selegiline alone was approximately 18%; however, when rats were pretreated with low and high doses of the ginseng extract, the bioavailability of selegiline was 7.2 and 29%, respectively. These results suggested that the ginseng extract may produce a biphasic pharmacokinetic phenomenon. In summary, ginseng alters the oral bioavailability of selegiline, and these observations might provide preclinical information concerning the pharmacokinetic interactions between selegiline and herbal supplements.

Bioactivity Evaluation of a Novel Formulated Curcumin.

Curcumin has been used as a traditional medicine and/or functional food in several cultures because of its health benefits including anticancer properties. However, poor oral bioavailability of curcumin has limited its oral usage as a food supplement and medical food. Here we formulated curcumin pellets using a solid dispersion technique. The pellets had the advantages of reduced particle size, improved water solubility, and particle porosity. This pellet form led to an improvement in curcumin's oral bioavailability. Additionally, we used the C-Map and Library of Integrated Network-Based Cellular Signatures (LINCS) Unified Environment (CLUE) gene expression database to determine the potential biological functions of formulated curcumin. The results indicated that, similar to conventional curcumin, the formulated curcumin acted as an NF-κB pathway inhibitor. Moreover, ConsensusPathDB database analysis was used to predict possible targets and it revealed that both forms of curcumin exhibit similar biological functions, including apoptosis. Biochemical characterization revealed that both the forms indeed induced apoptosis of hepatocellular carcinoma (HCC) cell lines. We concluded that the formulated curcumin increases the oral bioavailability in animals, and, as expected, retains characteristics similar to conventional curcumin at the cellular level. Our screening platform using big data not only confirms that both the forms of curcumin have similar mechanisms but also predicts the novel mechanism of the formulated curcumin.

Development of a Validated UPLC-MS/MS Method for Analyzing Major Ginseng Saponins from Various Ginseng Species.

Ginsenosides, which contain one triterpene and one or more sugar moieties, are the major bioactive compounds of ginseng. The aim of this study was to develop and optimize a specific and reliable ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) method for the analysis of twelve different resources of ginseng. The six marker compounds of ginsenoside Rb1, ginsenoside Rb2, ginsenoside Rc, ginsenoside Rd, ginsenoside Re, and ginsenoside Rg1, as well as an internal standard, were separated by a reversed-phase C-18 column with a gradient elution of water and methanol-acetonitrile. The multiple-reaction monitoring (MRM) mode was used to quantify and identify twelve market products. The results demonstrated that not only is the logarithm of its partition coefficient (cLog P; octanol-water partition coefficient) one of the factors, but also the number of sugars, position of sugars, and position of the hydroxyl groups are involved in the complicated separation factors for the analytes in the analytical system. If the amount of ginsenoside Rb1 was higher than 40 mg/g, then the species might be Panax quinquefolius, based on the results of the marker ginsenoside contents of various varieties. In summary, this study provides a rapid and precise analytical method for identifying the various ginsenosides from different species, geographic environments, and cultivation cultures.