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.

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.

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.

[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.

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.

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.

Study of antidepressant-like activity of an enriched phloroglucinol fraction obtained from Hypericum caprifoliatum.

CONTEXT: Hypericum caprifoliatum Cham & Schlecht (Guttiferae) extracts have a potential antidepressant-like effect in rodents. However, the molecular mechanisms by which these extracts exert this effect remain unclear. OBJECTIVE: This study evaluated the effect of HC1, a fraction obtained from H. caprifoliatum enriched in phloroglucinol derivatives, on the Na⁺, K⁺ ATPase activity in mouse brain and verified the influence of veratrine on the effect of HC1 in the forced swimming test (FST). MATERIALS AND METHODS: Veratrine (0.06 mg/kg) and HC1 (360 mg/kg) were given alone or combined i.p. 60 and p.o. 30 min, respectively, before FST. The effect of single and repeated administration (once a day for 3 consecutive days) of HC1 (360 mg/kg) on Na⁺, K⁺ ATPase activity was evaluated ex vivo in the cerebral cortex and hippocampus of mice subjected or not to FST. RESULTS: HC1 reduced the immobility time (103.15 ± 18.67 s), when compared to the control group (183.6 ± 9.51 s). This effect was prevented by veratrine (151.75 ± 22.19 s). Mice repeatedly treated with HC1 presented a significant increase in Na⁺, K⁺ ATPase activity, both in cerebral cortex (46 ± 2.41 nmol Pi/min·mg protein) and hippocampus (49.83 ± 2.31 nmol Pi/min·mg protein), in relation to the respective controls (30 ± 2.66 and 29.83 ± 2.31 nmol Pi/min·mg protein respectively). DISCUSSION AND CONCLUSION: The HC1 antidepressant-like effect on FST might be related to its capacity to inhibit Na⁺ influx. HC1 increases hippocampal and cortical Na⁺, K⁺ ATPase activities possibly through long-term regulatory mechanisms.

St. John's wort extract with a high hyperforin content does not induce P-glycoprotein activity at the human blood-brain barrier.

St. John's wort (SJW) extract, a herbal medicine with antidepressant effects, is a potent inducer of intestinal and/or hepatic cytochrome P450 (CYP) enzymes and P-glycoprotein (P-gp), which can cause clinically relevant drug interactions. It is currently not known whether SJW can also induce P-gp activity at the human blood-brain barrier (BBB), which may potentially lead to decreased brain exposure and efficacy of certain central nervous system (CNS)-targeted P-gp substrate drugs. In this study, we used a combination of positron emission tomography (PET) imaging and cocktail phenotyping to gain a comprehensive picture on the effect of SJW on central and peripheral P-gp and CYP activities. Before and after treatment of healthy volunteers (n = 10) with SJW extract with a high hyperforin content (3-6%) for 12-19 days (1800 mg/day), the activity of P-gp at the BBB was assessed by means of PET imaging with the P-gp substrate [11C]metoclopramide and the activity of peripheral P-gp and CYPs was assessed by administering a low-dose phenotyping cocktail (caffeine, omeprazole, dextromethorphan, and midazolam or fexofenadine). SJW significantly increased peripheral P-gp, CYP3A, and CYP2C19 activity. Conversely, no significant changes in the peripheral metabolism, brain distribution, and P-gp-mediated efflux of [11C]metoclopramide across the BBB were observed following the treatment with SJW extract. Our data suggest that SJW does not lead to significant P-gp induction at the human BBB despite its ability to induce peripheral P-gp and CYPs. Simultaneous intake of SJW with CNS-targeted P-gp substrate drugs is not expected to lead to P-gp-mediated drug interactions at the BBB.

Radical protection in the visible and infrared by a hyperforin-rich cream--in vivo versus ex vivo methods.

The formation of radicals plays an important role in the development of atopic eczema or barrier-disrupted skin. We evaluated the radical scavenging effect of a cream containing a Hypericum perforatum extract rich in hyperforin in a double-blind placebo-controlled study on 11 healthy volunteers. Electron paramagnetic resonance spectroscopy was applied to determine radical formation during VIS/NIR irradiation of the inner forearm. The results were compared to ex vivo investigations on excised porcine ear skin after a single application of the creams. The non-treated skin was measured as control. The absolute values and the kinetics are not comparable for ex vivo and in vivo radical formation. Whereas in vivo, the radical production decreases with time, it remains stable ex vivo over the investigated timescale. Nevertheless, ex vivo methods could be developed to estimate the protection efficiency of creams. In vivo as well as ex vivo, the radical formation could be reduced by almost 80% when applying the hyperforin-rich cream onto the skin, whereas placebo resulted in about 60%. In vivo, a daylong protection effect could be validated after a 4-week application time of the cream indicating that a regular application is necessary to obtain the full effect.

Antiplatelet effect of phloroglucinol is related to inhibition of cyclooxygenase, reactive oxygen species, ERK/p38 signaling and thromboxane A2 production.

Platelet dysfunction is a major risk factor of cardiovascular diseases such as atherosclerosis, stroke and myocardial infarction. Many antiplatelet agents are used for prevention and treatment of these diseases. In this study, phloroglucinol (2.5-25 µM) suppressed AA-induced platelet aggregation and thromboxane B(2) (TXB(2)) production, but not U46619-induced platelet aggregation. Phloroglucinol (100-250 µM) showed little cytotoxicity to platelets. Phloroglucinol inhibited the COX-1 and COX-2 activities by 45-74% and 49-72% respectively at concentrations of 10-50 µM. At concentrations of 1 and 5 µM, phloroglucinol attenuated the AA-induced ROS production in platelets by 30% and 53%, with an IC(50) of 13.8 µM. Phloroglucinol also inhibited the PMA-stimulated ROS production in PMN. Preincubation of platelets by phloroglucinol (10-25 µM) markedly attenuated the AA-induced ERK and p38 phosphorylation. Intravenous administration of phloroglucinol (2.5 and 5 µmol/mouse) suppressed the ex vivo AA-induced platelet aggregation by 57-71%. Phloroglucinol administration also elevated the mice tail bleeding time. Moreover, phloroglucinol inhibited the IL-1ß-induced PGE(2) production in pulp fibroblasts. These results indicate that antiplatelet and anti-inflammatory effects of phloroglucinol are related to inhibition of COX, ROS and TXA2 production as well as ERK/p38 phosphorylation in platelets. Phloroglucinol further suppress PMA-induced ROS production in PMN. The antiplatelet effect of phloroglucinol was confirmed by ex vivo study. Clinically, the consumption of phloroglucinol-containing food/natural products as nutritional supplement may be helpful to cardiovascular health. Phloroglucinol has potential pharmacological use.

Myrtucommulone from Myrtus communis: metabolism, permeability, and systemic exposure in rats.

Nonsteroidal anti-inflammatory drug intake is associated with a high prevalence of gastrointestinal side effects, and severe cardiovascular adverse reactions challenged the initial enthusiasm in cyclooxygenase-2 inhibitors. Recently, it was shown that myrtucommulone, the active ingredient of the Mediterranean shrub Myrtus communis, dually and potently inhibits microsomal prostaglandin E2 synthase-1 and 5-lipoxygenase, suggesting a substantial anti-inflammatory potential. However, one of the most important prerequisites for the anti-inflammatory effects in vivo is sufficient bioavailability of myrtucommulone. Therefore, the present study was aimed to determine the permeability and metabolic stability in vitro as well as the systemic exposure of myrtucommulone in rats. Permeation studies in the Caco-2 model revealed apparent permeability coefficient values of 35.9 ·â€Š10⁻6 cm/s at 37 °C in the apical to basolateral direction, indicating a high absorption of myrtucommulone. In a pilot rat study, average plasma levels of 258.67 ng/mL were reached 1 h after oral administration of 4 mg/kg myrtucommulone. We found that myrtucommulone undergoes extensive phase I metabolism in human and rat liver microsomes, yielding hydroxylated and bihydroxylated as well as demethylated metabolites. Physiologically-based pharmacokinetic modeling of myrtucommulone in the rat revealed rapid and extensive distribution of myrtucommulone in target tissues including plasma, skin, muscle, and brain. As the development of selective microsomal prostaglandin E2 synthase-1 inhibitors represents an interesting alternative strategy to traditional nonsteroidal anti-inflammatory drugs and cyclooxygenase-2 inhibitors for the treatment of chronic inflammation, the present study encourages further detailed pharmacokinetic investigations on myrtucommulone.

Eucalyptus increases ceramide levels in keratinocytes and improves stratum corneum function.

The objectives of this study were to identify a plant extract that would improve stratum corneum functions and to elucidate the mechanism(s) involved. Based on the information that stratum corneum functions depend on the level of ceramide in the stratum corneum, we identified a Eucalyptus extract that was able to increase the level of ceramide in human keratinocytes in culture and in human stratum corneum and that improves the stratum corneum water holding and barrier functions. Addition of the Eucalyptus extract to human keratinocytes in culture increased the level of ceramide in a dose-dependent manner and also increased the biosynthesis of ceramide, glucosylceramide and sphingomyelin. Topical application of the Eucalyptus extract on the dry skin of human subjects induced by acetone and diethylether treatment resulted in a significant increase in ceramide level in the stratum corneum, a significant improvement in its water-holding function and an improvement in its barrier function. The addition of macrocarpal A, one of the main components of the Eucalyptus extract, to human keratinocytes in culture increased the level of ceramide and the mRNA expression of serine palmitoyltransferase, acid sphingomyelinase, neutral sphingomyelinase, glucosylceramide synthase and glucocerebrosidase in a dose-dependent manner. Our results indicate that the increased content of ceramides in the stratum corneum may underlie the therapeutic effect of the Eucalyptus extract. Our results also indicate the possibility that macrocarpal A is the key component that stimulates the synthesis of ceramide in the stratum corneum.

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).

Phloroglucinol as an adjuvant analgesic to treat renal colic.

PURPOSE: We tested whether the addition of phloroglucinol to piroxicam could improve pain relief in patients with acute renal colic visiting the emergency department. MATERIALS AND METHODS: Patients with a diagnosis of acute renal colic were prospectively randomized to receive intravenous phloroglucinol (200 mg) or placebo combined with intramuscular piroxicam (20 mg). We monitored the visual analogic scale (VAS), heart rate, arterial blood pressure, need for rescue therapy, and adverse events at different time points for 1 hour. We recorded admission requirement and new visit at 72 hours for renal colic. The primary end point was to assess pain relief at 1 hour, defined as a decrease of 50% or more as compared with the initial VAS. The secondary objectives were to compare the 2 groups for VAS at any time points, the need for rescue therapy, and the occurrence of adverse events. RESULTS: Of the 309 eligible patients, 253 entered the study. A total of 126 patients received phloroglucinol and 127 patients received placebo. Pain relief at 1 hour was obtained in 89 patients (71%) receiving phloroglucinol and 89 patients (70%) receiving placebo (P = .89). There were no differences in VAS between the 2 groups at any time points. Rescue therapy was required in 37 patients (29%) receiving phloroglucinol and 38 patients (30%) receiving placebo (P = .51). Number of adverse events was similar with phloroglucinol and placebo: 20 (16%) and 16 (13%), respectively (P = .44). CONCLUSIONS: There was no evidence that the addition of phloroglucinol improved the efficiency of piroxicam to relieve pain in acute renal colic.

No clinically relevant CYP3A induction after St. John's wort with low hyperforin content in healthy volunteers.

OBJECTIVE: Induction of CYP3A by St. John's wort (SJW) products with high hyperforin content is well described. Since CYP3A induction is mediated by hyperforin in a concentration-dependent manner, and SJW preparations differ significantly in hyperforin content, the aim of the study was to evaluate the effect of an SJW powder with low hyperforin content on CYP3A function. METHODS: Twenty healthy male volunteers received an SJW powder with low hyperforin content for 2 weeks. Midazolam plasma concentration time profiles were characterized after a single oral dose of 7.5 mg midazolam on the day before and on the 14th day of SJW medication. RESULTS: Midazolam AUC(0-infinity) slightly decreased from 124.0 +/- 62.5 ng/ml.h at baseline to 105.6 +/- 53.2 ng/ml.h after SJW (P < 0.05), representing a mean 11.3% decrease (95% CI: -22.8 to 0.21). No significant change in midazolam C(max), t(1/2) and t(max) was observed. For all pharmacokinetic parameters, the 90% CI for the geometric mean ratio of treatment over baseline were within the no-effect boundaries of 0.70-1.43. CONCLUSION: Administration of an SJW product with low hyperforin content resulted in a mild induction of CYP3A not considered clinically relevant.

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.

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.

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.