Effectiveness of oral phloroglucinol as a premedication for unsedated esophagogastroduodenoscopy: A prospective, double-blinded, placebo-controlled, randomized trial.

BACKGROUND: Anti-spasmodic agents are commonly injected during esophagogastroduodenoscopy (EGD) to improve visualization of the gastric mucosa by inhibiting gastrointestinal (GI) peristalsis. The availability of oral anti-spasmodic agents would increase convenience. In this study, we evaluated the effectiveness of oral phloroglucinol (Flospan®) as a premedication for unsedated EGD. METHODS: A prospective, double-blinded, placebo-controlled, randomized controlled trial was conducted in a tertiary hospital. Individuals scheduled to undergo unsedated EGD were randomly assigned to receive either oral phloroglucinol or matching placebo 15 min before EGD. The primary outcome was the rate of complete gastric peristalsis suppression. Outcomes were assessed by independent investigators according to the classification of gastric peristalsis and ease of intragastric observation at the beginning (Period A) and end (Period B) of EGD. RESULTS: Overall, 71 phloroglucinol-treated and 71 placebo-treated participants (n = 142 total) were included. The phloroglucinol group showed significantly higher proportions of participants with complete gastric peristalsis suppression than the placebo group (22.5% vs. 9.9%, P = 0.040). The ease of intragastric observation was significantly better in the phloroglucinol group than in the placebo group at Periods A (P < 0.001) and B (P = 0.005). Patients in both groups had comparable adverse events and showed willingness to take the premedication at their next examination. CONCLUSIONS: Oral phloroglucinol significantly suppressed gastrointestinal peristalsis during unsedated EGD compared with placebo (Clinical trial registration number: NCT03342118).

Influence of the external cephalic version attempt on the Cesarean section rate: experience of a type 3 maternity hospital in France.

PURPOSE: To define the effects of attempted external cephalic version (ECV) in a low-risk population for breech delivery in a maternity hospital where breech vaginal delivery is widely practiced. MATERIALS AND METHODS: Retrospective exposed-unexposed study including 204 patients presented with a live singleton fetus breech presentation on third-trimester ultrasound and who delivered at Reims University Hospital between January 1st, 2013 and July 1st, 2018. RESULTS: 121 patients received ECV. Cesarean section rate was lower (OR with no adjustment 0.42 [0.24-0.76] p = 0.004) but without significant difference in the exposed patients after adjustment. This difference was significant between exposed and unexposed patients in the subgroup of 51 primiparous (OR = 0.14 [0.04-0.52] p = 0.002) and 51 multiparous (OR = 0.26 [0.08-0.89] p = 0.028) but not in the subgroup of 102 nulliparous. There was no difference in fetal impact other than neonatal management in the delivery room, which is less needed in exposed primiparous women. Attempted ECV significantly decreased the breech rate (72.5 vs 100%, p < 0.001). There were 7 (5.79%) complications. Three factors favored success: high uterine height (p = 0.011), a non-elevated BMI (p = 0.006) and an earlier term at ECV (p = 0.003). CONCLUSION: The attempt of ECV in the Reims University Hospital does not significantly reduce the Cesarean section rate and has no effect on neonatal status.

Pharmacokinetics and Metabolism of Liposome-Encapsulated 2,4,6-Trihydroxygeranylacetophenone in Rats Using High-Resolution Orbitrap Liquid Chromatography Mass Spectrometry.

2,4,6-trihydroxy-3-geranylacetophenone (tHGA) is a bioactive compound that shows excellent anti-inflammatory properties. However, its pharmacokinetics and metabolism have yet to be evaluated. In this study, a sensitive LC-HRMS method was developed and validated to quantify tHGA in rat plasma. The method showed good linearity (0.5-80 ng/mL). The accuracy and precision were within 10%. Pharmacokinetic investigations were performed on three groups of six rats. The first two groups were given oral administrations of unformulated and liposome-encapsulated tHGA, respectively, while the third group received intraperitoneal administration of liposome-encapsulated tHGA. The maximum concentration (Cmax), the time required to reach Cmax (tmax), elimination half-life (t1/2) and area under curve (AUC0-24) values for intraperitoneal administration were 54.6 ng/mL, 1.5 h, 6.7 h, and 193.9 ng/mL·h, respectively. For the oral administration of unformulated and formulated tHGA, Cmax values were 5.4 and 14.5 ng/mL, tmax values were 0.25 h for both, t1/2 values were 6.9 and 6.6 h, and AUC0-24 values were 17.6 and 40.7 ng/mL·h, respectively. The liposomal formulation improved the relative oral bioavailability of tHGA from 9.1% to 21.0% which was a 2.3-fold increment. Further, a total of 12 metabolites were detected and structurally characterized. The metabolites were mainly products of oxidation and glucuronide conjugation.

Phloroglucinol-conjugated gold nanoparticles targeting mitochondrial membrane potential of human cervical (HeLa) cancer cell lines.

In recent, targeting mitochondria in cancer is considered to be a challenging task. This report illustrates preliminary findings from an investigation of the conjugation of gold nanoparticles with a bioactive natural compound, phloroglucinol targeting mitochondrial transmembrane potential of HeLa cancer cells. We systematically investigated the formation of gold-nano conjugates over precisely controlled reaction conditions. Their sharp features enable superior surface plasmon resonance, morphology, surface charge, and stability. We show that gold-nano conjugates scavenging free radicals and persuade cell death in HeLa cancer cells. We also show that gold-nano conjugates induce apoptosis by promoting mitochondrial transmembrane permeation via fluorescent microscopic studies. This work gives new insights into bridging metabolomics and nanotechnology into developing novel lead therapeutic molecules.

Persistence of STAT-1 inhibition and induction of cytokine resistance in pancreatic ß cells treated with St John's wort and its component hyperforin.

OBJECTIVES: St John's wort extract (SJW) and its component hyperforin (HPF) were shown to potently inhibit cytokine-induced STAT-1 and NF-κB activation in pancreatic ß cells and protect them against injury. This study aimed at exploring the time course of STAT-1 inhibition afforded by these natural compounds in the ß-cell line INS-1E. METHODS: INS-1E cells were pre-incubated with SJW extract (2-5 µg/ml) or HPF (0.5-2 µm) and then exposed to a cytokine mixture. In some experiments, these compounds were added after or removed before cytokine exposure. STAT-1 activation was assessed by electrophoretic mobility shift assay, apoptosis by caspase-3 activity assay, mRNA gene expression by RT-qPCR. KEY FINDINGS: Pre-incubation with SJW/HPF for 1-2 h exerted a remarkable STAT-1 downregulation, which was maintained upon removal of the compounds before early or delayed cytokine addition. When the protective compounds were added after cell exposure to cytokines, between 15 and 90 min, STAT-1 inhibition also occurred at a progressively decreasing extent. Upon 24-h incubation, SJW and HPF counteracted cytokine-induced ß-cell dysfunction, apoptosis and target gene expression. CONCLUSIONS: SJW and HPF confer to ß cells a state of 'cytokine resistance', which can be elicited both before and after cytokine exposure and safeguards these cells from deleterious cytokine effects.

Understanding drug interactions with St John's wort (Hypericum perforatum L.): impact of hyperforin content.

OBJECTIVE: The aim of this study was to review herb-drug interaction studies with St John's wort (Hypericum perforatum L.) with a focus on the hyperforin content of the extracts used in these studies. METHODS: PUBMED was systematically searched to identify studies describing pharmacokinetic interactions involving St John's wort. Data on study design and the St John's wort extract or product were gathered to extract hyperforin content and daily dose used in interaction studies. KEY FINDINGS: This analysis demonstrates that significant herb-drug interactions (resulting in a substantial change in systemic exposure) with St John's wort products were associated with hyperforin daily dosage. Products that had a daily dose of <1 mg hyperforin were less likely to be associated with major interaction for drugs that were CYP3A4 or p-glycoprotein substrates. Although a risk of interactions cannot be excluded even for low-dose hyperforin St. John's wort extracts, the use of products that result in a dose of not more than 1 mg hyperforin per day is recommended to minimise the risk of interactions. CONCLUSIONS: This review highlights that the significance of herb-drug interactions with St John's wort is influenced by the nature of the herbal medicines product, particularly the hyperforin content.

Effects of phloroglucinol on the active phase of labour (EPAL trial): a single blinded randomised controlled trial in a tertiary hospital in sub-Sahara Africa.

INTRODUCTION: One of the most recognized factors of maternal and neonatal outcome pertaining to the peripartum period is the duration of labour. Finding a drug that will decrease the duration of labour with no effects on mother and foetus will be welcomed. Thereby in this study we aimed to evaluate the effects of phloroglucinol on the duration of the active phase of labour. METHODS: We did a single blinded placebo controlled randomised 1:1 parallel designed superiority trial between January and June 2017 in Douala general hospital. Participants greater than 18 years with singleton uncomplicated pregnancy who consented following randomisation, were administered either 80mg/8ml intravenous phloroglucinol or 8ml of sterile water when in active labour. The primary outcome was the duration of labour. Modified intention to treat analysis was done with the level of significance set at a p value of 0.05. RESULTS: 122 participants received the intervention. The mean total duration labour in the treatment and placebo group were 216.8 ± 38.7 and 358.5 ± 65.8 respectively (p value = 0.243). The mean duration of the active phase of labour in the treatment and placebo group were 183.0±35.6 and 316.0±52.2 respectively (p value = 0.046). The mean rate of cervical dilatation in the treatment and placebo group were 2.1 ± 0.4 and 1.3 ± 0.4 respectively (p value = 0.322). There was no difference in maternal and foetal outcomes between the two groups. CONCLUSION: Phloroglucinol shortens the duration of active phase of labour by about 2 hours (42%). It is safe to mother and baby and does not cause adverse foetal or maternal outcomes.

Phloroglucinol ameliorates cognitive impairments by reducing the amyloid ß peptide burden and pro-inflammatory cytokines in the hippocampus of 5XFAD mice.

Among the various causative factors involved in the pathogenesis of Alzheimer's disease (AD), oxidative stress has emerged as an important factor. Phloroglucinol is a polyphenol component of phlorotannin, which is found at sufficient levels in Ecklonia cava (E. cava). Phloroglucinol has been reported to exert antioxidant activities in various tissues. Previously, we reported that the stereotaxic injection of phloroglucinol regulated synaptic plasticity in an AD mouse model. In this study, we aimed to investigate the effects of oral administration of phloroglucinol in AD. The oral administration of phloroglucinol for 2 months attenuated the impairments in cognitive function observed in 6-month-old 5X familial AD (5XFAD) mice, as assessed with the T-maze and Y-maze tests. The administration of phloroglucinol for 2 months in 5XFAD mice caused a reduction in the number of amyloid plaques and in the protein level of BACE1, a major amyloid precursor protein cleavage enzyme, together with γ-secretase. Phloroglucinol also restored the reduction in dendritic spine density and the number of mature spines in the hippocampi of 5XFAD mice. In addition, phloroglucinol-administered 5XFAD mice displayed lower protein levels of GFAP and Iba-1 and mRNA levels of TNF-α and IL-6 compared with vehicle-administered 5XFAD mice. These results demonstrated that phloroglucinol alleviated the neuropathological features and behavioral phenotypes in the 5XFAD mouse model. Taken together, our results suggest that phloroglucinol has therapeutic potential for AD treatment.

The potential of hypericin and hyperforin for antiadhesion therapy to prevent metastasis of parental and oxaliplatin-resistant human adenocarcinoma cells (HT-29).

Cancer cells disseminate to other parts of the body during metastasis through the process of intravasation. The hypericin and hyperforin effect has been described to understand the signal mechanisms that stimulate or stunt cancer cell sprouting to metastasis on colon adenocarcinoma cells HT-29 and its resistant form HT-29-OxR. We focused on the key points of adhesion proteins (cadherin, integrin, selectin and syndecan) and also proteins participating in or contributing to the process of cancer cell migration and adhesion through genes expression and proteins levels. Treatment effects were identified as a consequence of decreased cell adhesion, changes of expression in the adhesive proteins as well as basal membrane degradation associated with changes in the expression of matrix proteinases and in their activity. Finally, the cells affected by hypericin or hyperforin were evaluated by monitoring the cancer cell adhesion properties and proliferation processes. Supplementary Fig. (Supplemental digital content 1, http://links.lww.com/ACD/A267).

Triphlorethol A, a Dietary Polyphenol from Seaweed, Decreases Sleep Latency and Increases Non-Rapid Eye Movement Sleep in Mice.

In our previous studies, we have demonstrated that marine polyphenol phlorotannins promote sleep through the benzodiazepine site of the gamma-aminobutyric acid type A (GABAA) receptors. In this follow-up study, the sleep-promoting effects of triphlorethol A, one of the major phlorotannin constituents, were investigated. The effect of triphlorethol A on sleep-wake architecture and profiles was evaluated based on electroencephalogram and electromyogram data from C57BL/6N mice and compared with the well-known hypnotic drug zolpidem. Oral administration of triphlorethol A (5, 10, 25, and 50 mg/kg) dose-dependently decreased sleep latency and increased sleep duration during pentobarbital-induced sleep in imprinting control region mice. Triphlorethol A (50 mg/kg) significantly decreased sleep latency and increased the amount of non-rapid eye movement sleep (NREMS) in C57BL/6N mice, without affecting rapid eye movement sleep (REMS). There was no significant difference between the effects of triphlorethol A at 50 mg/kg and zolpidem at 10 mg/kg. Triphlorethol A had no effect on delta activity (0.5⁻4 Hz) of NREMS, whereas zolpidem significantly decreased it. These results not only support the sleep-promoting effects of marine polyphenol phlorotannins, but also suggest that the marine polyphenol compound triphlorethol A is a promising structure for developing novel sedative hypnotics.

Improved in vitro models for preclinical drug and formulation screening focusing on 2D and 3D skin and cornea constructs.

The present overview deals with current approaches for the improvement of in vitro models for preclinical drug and formulation screening which were elaborated in a joint project at the Center of Pharmaceutical Engineering of the TU Braunschweig. Within this project a special focus was laid on the enhancement of skin and cornea models. For this reason, first, a computation-based approach for in silico modeling of dermal cell proliferation and differentiation was developed. The simulation should for example enhance the understanding of the performed 2D in vitro tests on the antiproliferative effect of hyperforin. A second approach aimed at establishing in vivo-like dynamic conditions in in vitro drug absorption studies in contrast to the commonly used static conditions. The reported Dynamic Micro Tissue Engineering System (DynaMiTES) combines the advantages of in vitro cell culture models and microfluidic systems for the emulation of dynamic drug absorption at different physiological barriers and, later, for the investigation of dynamic culture conditions. Finally, cryopreserved shipping was investigated for a human hemicornea construct. As the implementation of a tissue-engineering laboratory is time-consuming and cost-intensive, commercial availability of advanced 3D human tissue is preferred from a variety of companies. However, for shipping purposes cryopreservation is a challenge to maintain the same quality and performance of the tissue in the laboratory of both, the provider and the customer.

Anticancer effects of seaweed compounds fucoxanthin and phloroglucinol, alone and in combination with 5-fluorouracil in colon cells.

Colorectal cancer therapy with 5-fluorouracil (5-Fu) frequently become ineffective due to resistance to this drug; and thus other effective compounds are essential for therapy. It is well-known marine brown seaweeds contain antioxidant compounds the carotenoid fucoxanthin (Fx) and polyphenolic compound phloroglucinol (Ph) which exerted diverse biological activities including antioxidant and anticancer. The aim of this study was to determine the anticancer activities of Fx or Ph alone as well as combination of each chemical with 5-Fu on two human colorectal cancer cell lines (HCT116 and HT29), with comparison to responses in a normal colon cell line (CCD-18Co). Effects of these compounds on cell viability, induction of DNA damage, and cell death were evaluated using MTT assay, comet assay, nuclear condensation assay, and Western blot. 5-Fu decreased cell viability in a concentration-dependent manner in HCT116 and HT29 cells but was not cytotoxic in CCD-18Co cells. 5-Fu induced DNA damage in HCT116 cells with induction of cell death, while no marked effects on DNA damage and cell death were observed in HT29 cells. Fx or Ph alone also reduced cell viability in both cancer cell lines but no apparent cytotoxic effect in CCD-18Co cells, except for Fx at 50 and 100 µM. Diminished cell viability was accompanied by induction of DNA damage (by Fx) and induction of cell death (by Ph). In combination with 5-Fu, Fx at 10 µM (in HCT116 and HT29 cells), and Ph at 300 µM (in HT29 cells) enhanced the cytotoxic effect of 5-Fu; however, no marked cytotoxicity was noted in CCD-18Co cells. Since Fx and Ph alone reduced cancer cell line viability without an effect on normal cells and when in combination enhanced the cytotoxic effect of 5-Fu only in colon cancer cells, these compounds seem promising as anticancer agents.

Hyperforin/HP-ß-Cyclodextrin Enhances Mechanosensitive Ca2+ Signaling in HaCaT Keratinocytes and in Atopic Skin Ex Vivo Which Accelerates Wound Healing.

Cutaneous wound healing is accelerated by mechanical stretching, and treatment with hyperforin, a major component of a traditional herbal medicine and a known TRPC6 activator, further enhances the acceleration. We recently revealed that this was due to the enhancement of ATP-Ca2+ signaling in keratinocytes by hyperforin treatment. However, the low aqueous solubility and easy photodegradation impede the topical application of hyperforin for therapeutic purposes. We designed a compound hydroxypropyl-ß-cyclodextrin- (HP-ß-CD-) tetracapped hyperforin, which had increased aqueous solubility and improved photoprotection. We assessed the physiological effects of hyperforin/HP-ß-CD on wound healing in HaCaT keratinocytes using live imaging to observe the ATP release and the intracellular Ca2+ increase. In response to stretching (20%), ATP was released only from the foremost cells at the wound edge; it then diffused to the cells behind the wound edge and activated the P2Y receptors, which caused propagating Ca2+ waves via TRPC6. This process might facilitate wound closure, because the Ca2+ response and wound healing were inhibited in parallel by various inhibitors of ATP-Ca2+ signaling. We also applied hyperforin/HP-ß-CD on an ex vivo skin model of atopic dermatitis and found that hyperforin/HP-ß-CD treatment for 24 h improved the stretch-induced Ca2+ responses and oscillations which failed in atopic skin.

An orally active geranyl acetophenone attenuates airway remodeling in a murine model of chronic asthma.

2,4,6-Trihydroxy-3-geranyl acetophenone (tHGA) is a synthetic compound that is naturally found in Melicope ptelefolia. We had previously demonstrated that parenteral administration of tHGA reduces pulmonary inflammation in OVA-sensitized mice. In this study, we evaluated the effect of orally administered tHGA upon airway remodeling in a murine model of chronic asthma. Female BALB/C mice were sensitized intraperitoneally with ovalbumin (OVA) on day 0, 7 and 14, followed by aerosolized 1% OVA 3 times per week for 6 weeks. Control groups were sensitized with saline. OVA sensitized animals were either treated orally with vehicle (saline with 1% DMSO and Tween 80), tHGA (80, 40, 20mg/kg) or zileuton (30mg/kg) 1h prior to each aerosolized OVA sensitization. On day 61, mice underwent methacholine challenge to determine airway hyperresponsiveness prior to collection of bronchoalveolar lavage (BAL) fluid and lung samples. BAL fluid inflammatory cell counts and cytokine concentrations were evaluated while histological analysis and extracellular matrix protein concentrations were determined on collected lung samples. Oral tHGA treatment attenuated airway hyperresponsiveness and inhibited airway remodeling in a dose-dependent fashion. tHGA's effect on airway remodeling could be attributed to the reduction of inflammatory cell infiltration and decreased expression of cytokines associated with airway remodeling. Oral administration of tHGA attenuates airway hyperresponsiveness and remodeling in OVA-induced BALB/c mice. tHGA is an interesting compound that should be evaluated further for its possible role as an alternative non-steroidal pharmacological approach in the management of asthma.

Hyperforin promotes post-stroke functional recovery through interleukin (IL)-17A-mediated angiogenesis.

Hyperforin, the main active ingredient of the medicinal plant Hypericum perforatum, has been shown to be neuroprotective against acute ischemic stroke. However, the long-term actions of hyperforin on the post-stroke functional recovery and underlying mechanisms have not been investigated. C57BL/6 wild-type mice or interleukin (IL)-17A knock-out mice underwent middle cerebral artery occlusion (60min) followed by reperfusion for 28 days. Here, we found that delayed treatment with hyperforin significantly promoted functional recovery and increased IL-17A expression in the ischemic hemisphere at 28 days post-ischemia (dpi). IL-17A knock-out or anti-IL-17A monoclonal antibody (mAb) treatment significantly attenuated the promoting effects of hyperforin on functional recovery. After screening for neurotrophic factors, we revealed that blocking IL-17A significantly decreased, whereas recombinant mouse IL-17A (rIL-17A) treatment significantly increased vascular endothelial growth factor (VEGF) expression. Our data also showed that rIL-17A treatment significantly increased CD34 expression and promoted functional recovery at 28dpi, and the promoting effects were attenuated by VEGF neutralizing antibody treatment. Furthermore, hyperforin treatment significantly increased the expression of VEGF and CD34 in the ischemic hemisphere at 28dpi, and the effects were attenuated by blocking IL-17A. Furthermore, VEGF neutralizing antibody significantly attenuated the promoting role of hyperforin on the cerebral CD34 expression. Thus, our results suggest that, in addition to the acute neuroprotection when delivered immediately after ischemic stroke, hyperforin could also promote functional recovery when delivered in the later phases of stroke recovery. Our results also reveal a previously uncharacterized property of IL-17A/VEGF signaling-induced angiogenesis in hyperforin-mediated functional recovery.

[Phloroglucinol combined with parecoxib for cystospasm after transurethral resection of the prostate].

Objective: To evaluate the effect and safety of phloroglucinol combined with parecoxib on cystospasm after transurethral resection of the prostate (TURP). METHODS: We conducted a prospective randomized case-control study on 98 patients treated by TURP. After operation, the patients were randomly assigned to a treatment (n=50) and a control group (n=48), the former treated by intravenous injection of 80 mg phloroglucinol qd plus 40 mg parecoxib bid while the latter given 80 mg phloroglucinol only, both for 3 successive days. Then we recorded the frequency and duration of cystospasm, visual analogue scales (VAS), adverse reactions, post-operative bladder irrigation time, catheter-indwelling time, and hospital stay and compared them between the two groups of patients. RESULTS: Compared with the controls, the patients in the treatment group showed a significantly lower frequency of cystospasm (ï¼»1.95±0.14ï¼½ vs ï¼»0.70±0.65ï¼½ times, P<0.01), duration of cystospasm (ï¼»0.44±0.21ï¼½ vs ï¼»0.12±0.14ï¼½ min, P<0.01), and VAS score (2.70±1.80 vs 1.90±1.30, P<0.01) at 48－72 hours after TURP, but no statistically significant differences were found between the control and treatment groups in the post-operative bladder irrigation time (ï¼»2.75±0.87ï¼½ vs ï¼»2.64±0.83ï¼½ d, P>0.05), catheter-indwelling time (ï¼»3.52±0.32ï¼½ vs ï¼»3.44±0.42ï¼½ d, P>0.05), and hospital stay (ï¼»5.23±0.81ï¼½ vs ï¼»5.10±0.73ï¼½ d, P>0.05), and no obvious adverse reactions were observed in either of the two groups. CONCLUSIONS: Phloroglucinol combined with parecoxib is more effective and safer than phloroglucinol alone in relieving postoperative cystospasm after TURP.

Development of a highly reproducible system to evaluate inhibition of cytochrome P450 3A4 activity by natural medicines.

PURPOSE: In recent years, a number of natural medicines have been reported to have inductive or inhibitive effects on the activity of drug metabolizing enzymes, upon co-administration with prescribed medicines. However, information regarding natural medicine-drug interactions that influence drug metabolism is limited owing to the lack of efficient screening method for such interactions. Therefore, to understand whether P450 activity is affected by natural medicine in small intestines, we have established frozen recombinant P450-expressing cells infected with human CYP3A4 expressing adenovirus (Ad-CYP3A4) to evaluate the effect of natural medicines on CYP3A4 activity. METHODS: Ad-CYP3A4 cells were created by infecting HepG2 cells with Ad-CYP3A4 at 10 multiplicity of infection (MOI) and these cells were stored using cryopreservation medium (fAd-CYP3A4 cells) to obtain long-term consistent data and stable supplies of cells expressing a constant level of CYP3A4 activity. RESULTS: The CYP3A4 activity in fAd-CYP3A4 cells remained unaffected at the end of each frozen period (0, 1, 2, and 6 months). Inhibitory effect on CYP3A4 activity by typical inhibitors (ketoconazole, hyperforin) and natural medicines (Cat's Claw, Devil's Claw, Feverfew, Peppermint Oil, Red Clover, and Siberian Eleuthero) were evaluated. The inhibitors had nearly equal IC50 values in fAd-CYP3A4 cells, Ad-CYP3A4 cells and recombinant CYP3A4 microsomes. Cat's Claw, Peppermint Oil and Siberian Eleuthero inhibited CYP3A4 activity more potently than 0.1 µM ketoconazole in fAd-CYP3A4 cells. CONCLUSIONS: In the present study, we have successfully developed a highly reproducible system to evaluate CYP3A4 inhibition in small intestines by natural medicines.

Brain Uptake of Tetrahydrohyperforin and Potential Metabolites after Repeated Dosing in Mice.

Tetrahydrohyperforin (IDN-5706) is a semisynthetic derivative of hyperforin, one of the main active components of Hypericum perforatum extracts. It showed remarkable positive effects on memory and cognitive performances in wild-type mice and in a transgenic mouse model of Alzheimer's disease, but little was known about the concentrations it can reach in the brain. The investigations reported herein show that repeated treatment of mice with tetrahydrohyperforin (20 mg/kg intraperitoneally, twice daily for 4 days and once on the fifth day) results in measurable concentrations in the brain, up to 367 ng/g brain (∼700 nM) 6 h after the last dose; these concentrations have significant effects on synaptic function in hippocampal slices. The other main finding was the identification and semiquantitative analysis of tetrahydrohyperforin metabolites. In plasma, three hydroxylated/dehydrogenated metabolites were the largest (M1-3) and were also formed in vitro on incubation of tetrahydrohyperforin with mouse liver microsomes; the fourth metabolite in abundance was a hydroxylated/deisopropylated derivative (M13), which was not predicted in vitro. These metabolites were all detected in the brain, with peak areas from 10% (M1) to ∼1.5% (M2, M3, and M13) of the parent compound. In summary, repeated treatment of mice with tetrahydrohyperforin gave brain concentrations that might well underlie its central pharmacological effects. We also provide the first metabolic profile of this compound.

A Prospective, Randomized Comparison of Intramuscular Phloroglucinol Versus Oral Misoprostol for Cervix Pretreatment Before Diagnostic Hysteroscopy.

The aim of this study was to compare the effectiveness and safety of intramuscular phloroglucinol and oral misoprostol for cervix pretreatment before diagnostic hysteroscopy. Several modalities for cervical priming and pain reduction have been adopted to reduce the complications related to cervical dilatation before hysteroscopy. Among them, the prostaglandin analog misoprostol is the most frequently used agent. Phloroglucinol, a spasmolytic, has also been showed to have an effect in inducing cervical dilatation but is rarely used before hysteroscopy. One hundred twenty outpatients undergoing anesthesia-free diagnostic hysteroscopy were randomly assigned to receive 80 mg intramuscular phloroglucinol and 400 mg oral misoprostol before diagnostic hysteroscopy. The main outcome measures were preoperative cervical width, visual analog scales (VAS) for pain, cervical passage time, and adverse reactions. Intramuscular phloroglucinol resulted in a significantly wider cervical width, lower VAS pain score, shorter cervical passage time, and a lower adverse effects rate compared with oral misoprostol. Intramuscular phloroglucinol is more effective and safer than oral misoprostol in inducing proper cervical priming and may be the optimal choice for cervical pretreatment before diagnostic hysteroscopy.

Identification of a novel polyprenylated acylphloroglucinol­derived SIRT1 inhibitor with cancer­specific anti-proliferative and invasion-suppressing activities.

SIRT1, a class III histone deacetylase, plays a critical role in regulating cancer cell growth, migration and invasion, which makes it a potential target for cancer therapeutics. In this study, we screened derivatives of several groups of natural products and identified a novel SIRT1 inhibitor JQ-101, a synthetic derivative of the polyprenylated acylphloroglucinol (PPAP) natural products, with an IC(50) for SIRT1 of 30 µM in vitro, with 5-fold higher activity for SIRT1 vs. SIRT2. Exposure of tumor cells to JQ-101 significantly enhanced acetylation of p53 and histone H4K16 at known sites of SIRT1 deacetylation, validating SIRT1 as its cellular target. JQ-101 suppressed cancer cell growth and survival by targeting SIRT1, and also exhibited selective cytotoxicity towards a panel of human tumor cell lines, while producing no toxicity in two normal human cell types at comparable concentrations. JQ-101 induced both apoptosis and cell senescence, and suppressed cancer cell invasion in vitro. In summary, we have identified JQ-101 as a new SIRT1 inhibitor which may have potential application in cancer treatment through its ability to induce tumor cell apoptosis and senescence and suppress cancer cell invasion.