RESUMO
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.
Assuntos
Interações Ervas-Drogas , Hypericum/química , Floroglucinol/análogos & derivados , Terpenos/administração & dosagem , Animais , Relação Dose-Resposta a Droga , Humanos , Farmacocinética , Floroglucinol/administração & dosagem , Floroglucinol/efeitos adversos , Floroglucinol/isolamento & purificação , Extratos Vegetais/administração & dosagem , Extratos Vegetais/efeitos adversos , Extratos Vegetais/química , Terpenos/efeitos adversos , Terpenos/isolamento & purificaçãoRESUMO
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.
Assuntos
Hypericum/química , Células Secretoras de Insulina/efeitos dos fármacos , Floroglucinol/análogos & derivados , Extratos Vegetais/farmacologia , Terpenos/farmacologia , Animais , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Citocinas/metabolismo , Relação Dose-Resposta a Droga , Ensaio de Desvio de Mobilidade Eletroforética , Regulação da Expressão Gênica/efeitos dos fármacos , Células Secretoras de Insulina/metabolismo , Floroglucinol/administração & dosagem , Floroglucinol/isolamento & purificação , Floroglucinol/farmacologia , Extratos Vegetais/administração & dosagem , Ratos , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Fator de Transcrição STAT1/antagonistas & inibidores , Fator de Transcrição STAT1/metabolismo , Terpenos/administração & dosagem , Terpenos/isolamento & purificação , Fatores de TempoRESUMO
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).
Assuntos
Adenocarcinoma/tratamento farmacológico , Neoplasias do Colo/tratamento farmacológico , Oxaliplatina/farmacologia , Perileno/análogos & derivados , Floroglucinol/análogos & derivados , Terpenos/farmacologia , Adenocarcinoma/patologia , Antracenos , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Adesão Celular/efeitos dos fármacos , Movimento Celular/efeitos dos fármacos , Neoplasias do Colo/patologia , Resistencia a Medicamentos Antineoplásicos , Células HT29 , Humanos , Metástase Neoplásica/prevenção & controle , Oxaliplatina/administração & dosagem , Perileno/administração & dosagem , Perileno/farmacologia , Floroglucinol/administração & dosagem , Floroglucinol/farmacologia , Terpenos/administração & dosagemRESUMO
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.
Assuntos
Córnea/metabolismo , Composição de Medicamentos/métodos , Modelos Biológicos , Pele/metabolismo , Engenharia Tecidual/métodos , Córnea/efeitos dos fármacos , Composição de Medicamentos/tendências , Avaliação Pré-Clínica de Medicamentos/métodos , Humanos , Floroglucinol/administração & dosagem , Floroglucinol/análogos & derivados , Floroglucinol/metabolismo , Pele/efeitos dos fármacos , Terpenos/administração & dosagem , Terpenos/metabolismo , Engenharia Tecidual/tendênciasRESUMO
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.
Assuntos
Dermatite Atópica/tratamento farmacológico , Pele/efeitos dos fármacos , Estresse Mecânico , Canais de Cátion TRPC/biossíntese , Cicatrização/efeitos dos fármacos , Trifosfato de Adenosina/metabolismo , Sinalização do Cálcio/efeitos dos fármacos , Células Cultivadas , Ciclodextrinas/administração & dosagem , Dermatite Atópica/patologia , Técnicas de Silenciamento de Genes , Humanos , Queratinócitos/efeitos dos fármacos , Queratinócitos/metabolismo , Floroglucinol/administração & dosagem , Floroglucinol/análogos & derivados , Receptores Purinérgicos P2Y/genética , Receptores Purinérgicos P2Y/metabolismo , Pele/lesões , Pele/metabolismo , Canais de Cátion TRPC/genética , Canal de Cátion TRPC6 , Terpenos/administração & dosagemRESUMO
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.
Assuntos
Indutores da Angiogênese/administração & dosagem , Isquemia Encefálica/metabolismo , Interleucina-17/metabolismo , Floroglucinol/análogos & derivados , Acidente Vascular Cerebral/metabolismo , Terpenos/administração & dosagem , Animais , Isquemia Encefálica/complicações , Interleucina-17/genética , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Floroglucinol/administração & dosagem , Recuperação de Função Fisiológica/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos , Acidente Vascular Cerebral/complicações , Fator A de Crescimento do Endotélio Vascular/metabolismoRESUMO
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 48ï¼72 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.
Assuntos
Isoxazóis/uso terapêutico , Floroglucinol/uso terapêutico , Espasmo/tratamento farmacológico , Ressecção Transuretral da Próstata , Bexiga Urinária/efeitos dos fármacos , Idoso , Estudos de Casos e Controles , Quimioterapia Combinada , Humanos , Isoxazóis/administração & dosagem , Tempo de Internação , Masculino , Pessoa de Meia-Idade , Floroglucinol/administração & dosagem , Período Pós-Operatório , Estudos Prospectivos , Hiperplasia Prostática , Irrigação Terapêutica , Resultado do Tratamento , Bexiga Urinária/fisiopatologiaRESUMO
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 (â¼700 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 â¼1.5% (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.
Assuntos
Encéfalo/efeitos dos fármacos , Hypericum/química , Floroglucinol/análogos & derivados , Terpenos/farmacocinética , Doença de Alzheimer/tratamento farmacológico , Animais , Cromatografia Líquida de Alta Pressão , Modelos Animais de Doenças , Hipocampo/metabolismo , Camundongos , Microssomos Hepáticos , Estrutura Molecular , Floroglucinol/administração & dosagem , Floroglucinol/química , Floroglucinol/farmacocinética , Terpenos/administração & dosagem , Terpenos/químicaRESUMO
Two acyl phloroglucinol compounds namely; Sideroxylonal B (1) and Macrocarpal A (2) were isolated from the Sideroxylonal-Rich Extract (SRE) of the juvenile leaves of Eucalyptus cinerea; F. Muell. ex Benth cultivated in Egypt. Identification of the isolated compounds was established on the basis of physico-chemical properties and spectral analysis (1D & 2D NMR). The two compounds were isolated for the first time from this species. The SRE alongside with the isolated compounds were tested against three human cancer cell lines; MCF7 (breast carcinoma cell line), HEP2 (laryngeal carcinoma), CaCo (colonic adenocarcinoma) and one type of normal human cell line;10â FS (fibroblast cells). The SRE, (1), and (2) showed cytotoxic activity with IC50 13.6 ± 0.62, 7.2 ± 0.5, 14.8 ± 0.55â µg mL-1 against HEP2 respectively, 11.6 ± 0.47, 4 ± 0.36, 11.4 ± 0.45â µg mL-1 against CaCo, respectively, and 8.6 ± 0.29, 4.4 ± 0.25, and 7.8 ± 0.3â µg mL-1 against MCF7, respectively. Meanwhile, the (SRE) together with (1) and (2) exhibited low cytotoxicity against normal cell line 10â FS, with IC50 55.4 ± 1.4, 43 ± 0.8 and 50.1 ± 1.12â µg mL-1, respectively. The antiprofilerative activity of the tested compounds was evaluated. The cell cycle profile of cells treated with Sideroxylonal-B and Macrocarpal-A indicates possible S-phase specific effects.
Assuntos
Eucalyptus/química , Neoplasias Experimentais/tratamento farmacológico , Neoplasias Experimentais/patologia , Floroglucinol/administração & dosagem , Floroglucinol/isolamento & purificação , Extratos Vegetais/química , Acilação , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Relação Dose-Resposta a Droga , Egito , Eucalyptus/classificação , Humanos , Floroglucinol/análogos & derivados , Folhas de Planta/química , Especificidade da Espécie , Resultado do TratamentoRESUMO
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 Naâº, K⺠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 Naâº, K⺠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 Naâº, K⺠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⺠influx. HC1 increases hippocampal and cortical Naâº, K⺠ATPase activities possibly through long-term regulatory mechanisms.
Assuntos
Antidepressivos/farmacologia , Depressão/tratamento farmacológico , Floroglucinol/farmacologia , Extratos Vegetais/farmacologia , Animais , Antidepressivos/administração & dosagem , Antidepressivos/isolamento & purificação , Córtex Cerebral/efeitos dos fármacos , Córtex Cerebral/metabolismo , Modelos Animais de Doenças , Hipocampo/efeitos dos fármacos , Hipocampo/metabolismo , Hypericum , Masculino , Camundongos , Floroglucinol/administração & dosagem , Floroglucinol/isolamento & purificação , Extratos Vegetais/administração & dosagem , Sódio/metabolismo , ATPase Trocadora de Sódio-Potássio/metabolismo , Natação , Veratrina/administração & dosagem , Veratrina/farmacologiaRESUMO
Hyperforin is well-known for its anti-inflammatory, anti-tumor, anti-bacterial, and antioxidant properties. The application of a hyperforin-rich verum cream could strengthen the skin barrier function by reducing radical formation and stabilizing stratum corneum lipids. Here, it was investigated whether topical treatment with a hyperforin-rich cream increases the radical protection of the skin during VIS/NIR irradiation. Skin lipid profile was investigated applying HPTLC on skin lipid extracts. Furthermore, the absorption- and scattering coefficients, which influence radical formation, were determined. 11 volunteers were included in this study. After a single cream application, VIS/NIR-induced radical formation could be completely inhibited by both verum and placebo showing an immediate protection. After an application period of 4weeks, radical formation could be significantly reduced by 45% following placebo application and 78% after verum application showing a long-term protection. Furthermore, the skin lipids in both verum and placebo groups increased directly after a single cream application but only significantly for ceramide [AP], [NP1], and squalene. After long-term cream application, concentration of cholesterol and the ceramides increased, but no significance was observed. These results indicate that regular application of the hyperforin-rich cream can reduce radical formation and can stabilize skin lipids, which are responsible for the barrier function.
Assuntos
Anti-Inflamatórios/administração & dosagem , Sequestradores de Radicais Livres/administração & dosagem , Floroglucinol/análogos & derivados , Creme para a Pele/uso terapêutico , Pele/efeitos dos fármacos , Terpenos/administração & dosagem , Adulto , Anti-Inflamatórios/metabolismo , Ceramidas/metabolismo , Feminino , Sequestradores de Radicais Livres/metabolismo , Humanos , Lipídeos , Masculino , Floroglucinol/administração & dosagem , Floroglucinol/metabolismo , Pele/metabolismo , Absorção Cutânea , Creme para a Pele/metabolismo , Terpenos/metabolismo , Adulto JovemRESUMO
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.
Assuntos
Hypericum/química , Raios Infravermelhos/efeitos adversos , Luz/efeitos adversos , Floroglucinol/análogos & derivados , Creme para a Pele/administração & dosagem , Terpenos/administração & dosagem , Administração Tópica , Adulto , Animais , Antioxidantes/administração & dosagem , Método Duplo-Cego , Espectroscopia de Ressonância de Spin Eletrônica , Feminino , Humanos , Masculino , Floroglucinol/administração & dosagem , Placebos , Suínos , Adulto JovemRESUMO
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 35.9â·â10â»6 cm/s at 37â°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.
Assuntos
Anti-Inflamatórios não Esteroides/administração & dosagem , Inibidores de Lipoxigenase/administração & dosagem , Inibidores de Lipoxigenase/farmacocinética , Microssomos Hepáticos/metabolismo , Myrtus/química , Floroglucinol/análogos & derivados , Administração Oral , Animais , Anti-Inflamatórios não Esteroides/química , Anti-Inflamatórios não Esteroides/metabolismo , Anti-Inflamatórios não Esteroides/farmacocinética , Araquidonato 5-Lipoxigenase/efeitos dos fármacos , Disponibilidade Biológica , Células CACO-2 , Estabilidade de Medicamentos , Humanos , Oxirredutases Intramoleculares/antagonistas & inibidores , Inibidores de Lipoxigenase/química , Masculino , Estrutura Molecular , Permeabilidade , Floroglucinol/administração & dosagem , Floroglucinol/química , Floroglucinol/metabolismo , Floroglucinol/farmacocinética , Prostaglandina-E Sintases , Ratos , Ratos WistarRESUMO
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.
Assuntos
Plaquetas/efeitos dos fármacos , Floroglucinol/farmacologia , Espécies Reativas de Oxigênio/metabolismo , Tromboxano A2/biossíntese , Ácido 15-Hidroxi-11 alfa,9 alfa-(epoximetano)prosta-5,13-dienoico/farmacologia , Animais , Ácido Araquidônico/farmacologia , Plaquetas/metabolismo , Ciclo-Oxigenase 1/efeitos dos fármacos , Ciclo-Oxigenase 1/metabolismo , Ciclo-Oxigenase 2/efeitos dos fármacos , Ciclo-Oxigenase 2/metabolismo , Relação Dose-Resposta a Droga , Humanos , Concentração Inibidora 50 , Interleucina-1beta/administração & dosagem , Masculino , Camundongos , Camundongos Endogâmicos ICR , Floroglucinol/administração & dosagem , Fosforilação/efeitos dos fármacos , Agregação Plaquetária/efeitos dos fármacos , Inibidores da Agregação Plaquetária/administração & dosagem , Inibidores da Agregação Plaquetária/farmacologia , Coelhos , Transdução de Sinais/efeitos dos fármacos , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismoRESUMO
Hyperforin, a major constituent of St. John's Wort (Hypericum perforatum, HP), provides anti-inflammatory, anti-tumor, and anti-bacterial properties. Previous studies have shown anti-oxidative properties of St. John's Wort extracts; however, its free radical scavenging activity in skin cells or skin has not been assessed in detail so far. Therefore, the free radical scavenging activity of hyperforin was tested in the H(2)DCFDA-assay in vitro in HaCaT keratinocytes irradiated with solar simulated radiation. Hyperforin (EC(50) 0.7 µM corresponding to 0.42 µg/ml) was much more effective compared to Trolox (EC(50) 12 µg/ml) and N-acetylcysteine (EC(50) 847 µg/ml) without showing phototoxicity. The radical protection factor of a cream containing 1.5%w/w of a hyperforin-rich HP extract was determined to be 200 × 10(14) radicals/mg, indicating a high radical scavenging activity. The cream was further applied ex vivo on porcine ear skin and significantly reduced radical formation after infrared irradiation. Finally, the UV-protective effect of the HP cream was tested on 20 volunteers in a randomized, double-blind, vehicle-controlled study. HP cream significantly reduced UVB-induced erythema as opposed to the vehicle. Occlusive application of HP cream on non-irradiated test sites did not cause any skin irritation. Taken together, these results demonstrate that hyperforin is a powerful free radical scavenger.
Assuntos
Anti-Inflamatórios/farmacologia , Antioxidantes/farmacologia , Eritema/prevenção & controle , Floroglucinol/análogos & derivados , Terpenos/farmacologia , Administração Tópica , Adulto , Animais , Antioxidantes/administração & dosagem , Método Duplo-Cego , Feminino , Sequestradores de Radicais Livres/farmacologia , Humanos , Hypericum/química , Inflamação/tratamento farmacológico , Queratinócitos/efeitos dos fármacos , Masculino , Pessoa de Meia-Idade , Floroglucinol/administração & dosagem , Floroglucinol/farmacologia , Extratos Vegetais/farmacologia , Pele/efeitos dos fármacos , Pele/efeitos da radiação , Suínos , Terpenos/administração & dosagem , Raios Ultravioleta/efeitos adversos , Adulto JovemRESUMO
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.
Assuntos
Ceramidas/biossíntese , Eucalyptus/química , Queratinócitos/efeitos dos fármacos , Floroglucinol/análogos & derivados , Extratos Vegetais/administração & dosagem , Sesquiterpenos/administração & dosagem , Pele/efeitos dos fármacos , Administração Tópica , Adulto , Ceramidas/genética , Método Duplo-Cego , Feminino , Humanos , Queratinócitos/metabolismo , Masculino , Floroglucinol/administração & dosagem , Extratos Vegetais/isolamento & purificação , RNA Mensageiro/biossíntese , RNA Mensageiro/genética , Reação em Cadeia da Polimerase em Tempo Real , Pele/metabolismo , Perda Insensível de Água/efeitos dos fármacos , Adulto JovemRESUMO
OBJECTIVES: To analyze the evolution of drug prescriptions during pregnancy from 2004 to 2008 in Haute-Garonne (France) and the impact of recommendations concerning drugs in pregnancy sent by French health authorities (AFSSAPS) and French college of gynaecologists and obstetricians to health professionals during the period. PATIENTS AND METHODS: This descriptive study of reimbursed drug prescriptions during pregnancy concerns women included in the EFEMERIS database who have given birth from July 1st, 2004 to June 30th, 2008. The health insurance service records of Haute-Garonne were used. RESULTS: Taking into account 2 subsequent delistings of drugs for reimbursement during the period, we observed a significant increase of reimbursed drug prescriptions dispensed to pregnant women (8.7 different substances for women who have given birth in 2004 and 9.4 in 2008). Vitamins, immunserums, immunoglobulins and homeopathy prescriptions have especially increased. Paracetamol, iron, folic acid and phloroglucinol were the most prescribed drugs during all the periods. DISCUSSION AND CONCLUSION: Since 2004, EFEMERIS represents a monitoring centre for the prescription of reimbursed drugs to pregnant women. This analysis allowed to exhibit trends in prescription patterns. Most of the alerts or recommendations had a positive but limited impact.
Assuntos
Prescrições de Medicamentos/estatística & dados numéricos , Complicações na Gravidez/tratamento farmacológico , Acetaminofen/administração & dosagem , Bases de Dados Factuais/estatística & dados numéricos , Feminino , Ácido Fólico/administração & dosagem , Humanos , Soros Imunes/administração & dosagem , Imunoglobulinas/administração & dosagem , Seguro Saúde/estatística & dados numéricos , Ferro/administração & dosagem , Materia Medica/administração & dosagem , Floroglucinol/administração & dosagem , Guias de Prática Clínica como Assunto , Gravidez , Vitaminas/administração & dosagemRESUMO
Upon activation, microglia, the immunocompetent cells in the brain, get highly phagocytic and release pro-inflammatory mediators like nitric oxide (NO). Excessive NO production is pivotal in neurodegenerative disorders, and there is evidence that abnormalities in NO production and inflammatory responses may at least support a range of neuropsychiatric disorders, including depression. Although extracts of St. John's wort (Hypericum perforatum L.) have been used for centuries in traditional medicine, notably for the treatment of depression, there is still considerable lack in scientific knowledge about the impact on microglia. We used N11 and BV2 mouse microglia, as well as RAW 264.7 macrophages to investigate the effects of St. John's wort extract and constituents thereof on NO production Moreover, flow cytometry and fluorescence microscopy were employed to analyze the influence on phagocytosis, transcription factor activation states, and cell motility. We found that extracts of St. John's wort efficiently suppress lipopolysaccharide-induced NO release and identified hyperforin as the responsible compound, being effective at concentrations between 0.25 and 0.75 microM. The reduced NO production was mediated by diminished inducible nitric oxide synthase expression on the mRNA and protein level. In addition, at similar concentrations, hyperforin reduced zymosan phygocytosis to 20-40% and putatively acted by downregulating the CD206 macrophage mannose receptor and modulation of cell motility. We found that the observed effects correlate with a suppression of the activated state of Nf-kappaB and phospho-CREB, while c-JUN, STAT1, and HIF-1alpha activity and cyclooxygenase-2 expression remained unaffected by hyperforin. These results reveal that hyperforin influences pro-inflammatory and immunological responses of microglia that are involved in the progression of neuropathologic disorders.
Assuntos
Hypericum/química , Óxido Nítrico Sintase Tipo II/efeitos dos fármacos , Fagocitose/efeitos dos fármacos , Floroglucinol/análogos & derivados , Terpenos/farmacologia , Animais , Compostos Bicíclicos com Pontes/administração & dosagem , Compostos Bicíclicos com Pontes/isolamento & purificação , Compostos Bicíclicos com Pontes/farmacologia , Linhagem Celular , Relação Dose-Resposta a Droga , Citometria de Fluxo , Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo , Camundongos , Microglia/efeitos dos fármacos , Microglia/metabolismo , Microscopia de Fluorescência , Óxido Nítrico/metabolismo , Óxido Nítrico Sintase Tipo II/metabolismo , Floroglucinol/administração & dosagem , Floroglucinol/isolamento & purificação , Floroglucinol/farmacologia , Extratos Vegetais/administração & dosagem , Extratos Vegetais/farmacologia , Terpenos/administração & dosagem , Terpenos/isolamento & purificaçãoRESUMO
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.
Assuntos
Citocromo P-450 CYP3A/biossíntese , Hypericum , Floroglucinol/análogos & derivados , Preparações de Plantas/farmacologia , Terpenos/farmacologia , Administração Oral , Adulto , Compostos Bicíclicos com Pontes/administração & dosagem , Compostos Bicíclicos com Pontes/análise , Compostos Bicíclicos com Pontes/farmacologia , Estudos Cross-Over , Indução Enzimática , Interações Ervas-Drogas , Humanos , Masculino , Midazolam/administração & dosagem , Midazolam/farmacocinética , Floroglucinol/administração & dosagem , Floroglucinol/análise , Floroglucinol/farmacologia , Preparações de Plantas/administração & dosagem , Preparações de Plantas/química , Pós , Especificidade por Substrato , Terpenos/administração & dosagem , Terpenos/análise , Adulto JovemRESUMO
The recent clinical studies on hypericum extract support the present indications for its use in mild to moderate depression and depressive episodes. The effectiveness is superior to placebo and comparable with synthetic antidepressive drugs. The rate of unwanted events is explicitly lower and their severity in general only mild. A further indication for hypericum could be somatoform disorders, but further clinical studies are recommended. The main compound responsible for interactions is presumably hyperforin, but further ingredients could contribute according to the specific composition of the particular extract.