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1.
Rhinology ; 55(2): 142-151, 2017 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-28214913

RESUMO

BACKGROUND: The objective of this clinical trial (CRS-02) was to assess the efficacy, safety and tolerability of two dosages of the herbal medicinal product BNO 1016 (Sinupret extract) in patients with chronic rhinosinusitis (CRS). METHODOLOGY: 929 patients suffering from CRS were enrolled in this randomised placebo-controlled trial with a treatment period of 12 weeks. The primary endpoint was the mean Major Symptom Score (MSS) in week 8 and week 12 compared to placebo. Secondary endpoints included further MSS related parameters and responder rates over time. Pharmacoeconomic endpoints were also analysed. Finally, safety and tolerability were evaluated. RESULTS: Sinupret extract was not superior over placebo regarding the primary endpoint. However, the results of the secondary endpoints showed a clear trend towards superior efficacy. Therefore, additional post-hoc sensitivity analyses were performed in patients with a baseline MSS over 9 and persistence of disease more than 1 year diagnosed by specialists in otorhinolaryngology. Those patients significantly benefited from Sinupret extract. Therapy was superior for the primary endpoint analysis. Patients were less impaired with respect to work and daily activities. A good safety and tolerability of Sinupret extract was assured in all patients. CONCLUSIONS: Sinupret extract can safely be administered in patients with CRS. Although the primary endpoint of the study was not significant, a post-hoc subgroup analysis in patients whose disease was diagnosed by a specialist revealed a pronounced treatment effect. Effects in that subgroup were even stronger with longer disease persistence and stronger severity.


Assuntos
Extratos Vegetais/uso terapêutico , Rinite/tratamento farmacológico , Sinusite/tratamento farmacológico , Adolescente , Adulto , Idoso , Doença Crônica , Método Duplo-Cego , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Rinite/virologia , Sinusite/virologia , Inquéritos e Questionários , Resultado do Tratamento
2.
J Pharm Pharmacol ; 54(11): 1507-14, 2002 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-12495553

RESUMO

To be effective, herbal medicinal products are expected to meet comparable standards concerning the assessment of efficacy, safety and biopharmaceutical quality as chemically defined synthetic drugs as food supplements. However, these requirements are often not fulfilled, particularly regarding the characterization of biopharmaceutical properties such as in-vitro dissolution and in-vivo bioavailability. With respect to the relevance of biopharmaceutical quality of herbal medicinal products, two different Ginkgo biloba brands (test product: Ginkgo biloba capsules; reference product: Ginkgold) were analysed for dissolution rates and bioavailability of the most relevant active ingredients. Dissolution rates at pH 1 and 4.5 were determined according to the USP 23. The relative bioavailability of ginkgolide A, ginkgolide B and bilobalide was investigated after single oral administration of 120 mg Ginkgo biloba extract as tablets or capsules. Bioavailability data (area under the curve and peak concentration in plasma) were clearly different and did not show bioequivalence of test and reference products. The slow in-vitro dissolution of the test product resulted in a large decrease in bioavailability. These results indicate for the first time that the pharmaceutical properties of a herbal medicinal product have a significant impact on the rate and extent of drug absorption, and very likely on efficacy in humans.


Assuntos
Diterpenos , Ginkgo biloba/química , Extratos Vegetais/farmacocinética , Administração Oral , Adulto , Área Sob a Curva , Disponibilidade Biológica , Ciclopentanos/sangue , Furanos/sangue , Cromatografia Gasosa-Espectrometria de Massas , Ginkgolídeos , Humanos , Concentração de Íons de Hidrogênio , Lactonas/sangue , Masculino , Pessoa de Meia-Idade , Extratos Vegetais/química , Solubilidade , Tecnologia Farmacêutica , Equivalência Terapêutica
3.
Pharmacopsychiatry ; 34 Suppl 1: S148-51, 2001 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-11518066

RESUMO

In our previous investigations, we could demonstrate that extract preparations of Hypericum perforatum (St. John's wort, SJW) inhibit the uptake of several neurotransmitters (serotonin, norepinephrine, dopamine, GABA, L-glutamate) in synaptosomal preparations of rodent brain. Hyperforin, the lipophilic constituent, was identified as the main component responsible for these effects. The properties seen for hyperforin in these and other pharmacological models present a plausible and logical explanation for the well documented antidepressive effects of SJW extract preparations in clinical studies. However, evidence for other active principles in SJW extract have been reported (See also communications by Misane & Ogren and Philippu in this issue). Accordingly, we tested various SJW extract preparations and all relevant constituents as possible inhibitors of synaptosomal uptake of neurotransmitters. Two further components were found to be active in those models. Adhyperforin, like hyperforin, showed a strong inhibiting profile in all uptake systems investigated. Moreover, we could observe a weak to moderate inhibiting profile for the oligomeric procyanidins fraction (OPC). Further investigations would have to clarify any possible contribution of these two constituents to the antidepressive effects of SJW extract seen in animal experiments and clinical trials.


Assuntos
Hypericum , Neurotransmissores/metabolismo , Perileno/análogos & derivados , Extratos Vegetais/farmacologia , Sinaptossomos/efeitos dos fármacos , Sinaptossomos/metabolismo , Animais , Antracenos , Antidepressivos/farmacologia , Compostos Bicíclicos com Pontes , Dopamina/metabolismo , Relação Dose-Resposta a Droga , Ácido Glutâmico/metabolismo , Masculino , Norepinefrina/metabolismo , Perileno/farmacologia , Floroglucinol/análogos & derivados , Ratos , Ratos Wistar , Serotonina/metabolismo , Terpenos/farmacologia , Ácido gama-Aminobutírico/metabolismo
4.
Pharmacopsychiatry ; 34 Suppl 1: S98-102, 2001 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-11518085

RESUMO

Hyperforin represents a major antidepressive constituent of St. John's wort (SJW) extract. It not only inhibits the neuronal uptake of serotonin, norepinephrine and dopamine like many other antidepressants, but also inhibits GABA and L-glutamate uptake. This broad-spectrum effect is obtained by an elevation of the intracellular Na+ concentration, probably due to activation of sodium conductive pathways not yet finally identified but most likely ionic channels. This makes hyperforin the first member of a new class of compounds with a preclinical antidepressant profile due to a completely novel mechanism of action.


Assuntos
Antidepressivos/farmacologia , Hypericum , Extratos Vegetais/farmacologia , Sinaptossomos/efeitos dos fármacos , Terpenos/farmacologia , Animais , Ligação Competitiva , Compostos Bicíclicos com Pontes , Concentração de Íons de Hidrogênio/efeitos dos fármacos , Camundongos , Floroglucinol/análogos & derivados , Serotonina/farmacocinética , Sódio/metabolismo , Canais de Sódio/metabolismo , Trocadores de Sódio-Hidrogênio/metabolismo , Sinaptossomos/metabolismo , Trítio
5.
Neuropsychopharmacology ; 23(2): 188-97, 2000 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-10882845

RESUMO

Extracts of St. John's Wort are widely used for the treatment of depressive disorders. The active principles have not yet been finally elucidated. We have recently shown that hyperforin, a major active constituent of St. John's Wort, not only inhibits the neuronal uptake of serotonin, norepinephrine and dopamine, but also that of L-glutamate and GABA. No other antidepressant compound exhibits a similar broad uptake inhibiting profile. To investigate this unique kind of property, kinetic analyses were performed regarding the uptake of 3H-L-glutamate and 3H-GABA into synaptosomal preparations of mouse brain. Michaelis-Menten kinetics revealed a reduction of Vmax (8.27 to 1.80 pmol/mg/min for 3H-L-glutamate, 2.76 to 0.77 pmol/mg/min for 3H-GABA) while Km was nearly unchanged in both cases, suggesting non-competitive inhibition. The unselective uptake inhibition by hyperforin could be mimicked by the Na+-ionophore monensin and by the Na+-K+-ATPase inhibitor ouabain. However, both mechanisms can be discarded for hyperforin. Several amiloride derivatives known to affect sodium conductance significantly enhance 3H-GABA and 3H-L-glutamate uptake and inhibit the uptake inhibition by hyperforin, while monensin or ouabain inhibition were not influenced. Selective concentrations of benzamil for amiloride sensitive Na+-channels and selective concentrations of 5'-ethylisopropylamiloride (EIPA) for the Na+-H+-exchangers both had an attenuating effect on the hyperforin inhibition of L-glutamate uptake, suggesting a possible role of amiloride sensitive Na+-channels and Na+-H+-exchangers in the mechanism of action of hyperforin.


Assuntos
Ácido Glutâmico/farmacocinética , Canais de Sódio/metabolismo , Sinaptossomos/metabolismo , Terpenos/farmacologia , Ácido gama-Aminobutírico/farmacocinética , Animais , Transporte Biológico/efeitos dos fármacos , Compostos Bicíclicos com Pontes , Relação Dose-Resposta a Droga , Antagonistas de Aminoácidos Excitatórios/farmacologia , Feminino , Antagonistas GABAérgicos/farmacologia , Hypericum , Ionóforos/farmacologia , Camundongos , Camundongos Endogâmicos , Monensin/farmacologia , Inibidores da Captação de Neurotransmissores/farmacologia , Ouabaína/farmacologia , Floroglucinol/análogos & derivados , Plantas Medicinais , Canais de Sódio/efeitos dos fármacos , Sinaptossomos/efeitos dos fármacos
6.
Praxis (Bern 1994) ; 89(50): 2111-21, 2000 Dec 14.
Artigo em Alemão | MEDLINE | ID: mdl-11155494

RESUMO

Over the last few years St-John's wort preparations have been used in large quantities in Germany for treating mild to moderate depression. In the meantime the antidepressive action of these extracts has been proved in numerous placebo-controlled studies. Furthermore, a considerably lower adverse effect rate compared with classic antidepressants has been established. Analogously to other antidepressants, subchronic St-John's wort treatment of rats showed significant down-regulation of beta receptor density and a significant increase in 5HT2 receptors. The extract also exhibited antidepressant activity in animal pharmacological models of depression. Interest is now focused on identifying the underlying pharmacological mechanisms of action of this phytotherapeutic agent. Like other working parties, we were only able to identify a weak inhibitory effect of the extract and the pure substance hypericin on the monoamine oxidases A and B. Similarly to synthetic antidepressants, St-John's wort exerts marked inhibitory effects on synaptosomal uptake of serotonin and noradrenaline. However, dopamine and uptake and neuronal uptake of GABA and L-glutamate are also inhibited. These effects may mainly be attributed to the substance hyperforin contained in the extract. An additional, as yet unknown, pharmacological mechanism of action of St-John's wort extracts is beginning to emerge. Although hyperforin shows similar properties to classical antidepressants, there are indications of a novel mechanism of action. Our laboratory is currently investigating the means by which St-John's wort extract, or its constituent hyperforin, develops its antidepressant action.


Assuntos
Encéfalo/efeitos dos fármacos , Transtorno Depressivo/tratamento farmacológico , Hypericum , Extratos Vegetais/uso terapêutico , Plantas Medicinais , Animais , Encéfalo/fisiopatologia , Transtorno Depressivo/fisiopatologia , Humanos , Receptores de Neurotransmissores/efeitos dos fármacos , Receptores de Neurotransmissores/fisiologia
7.
J Pharmacol Exp Ther ; 290(3): 1363-8, 1999 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-10454515

RESUMO

Extracts of Hypericum perforatum (St. John's Wort) are widely used for the treatment of depressive disorders and are unspecific inhibitors of the neuronal uptake of several neurotransmitters. Previous studies have shown that hyperforin represents the reuptake inhibiting constituent. To characterize the mechanism of serotonin reuptake inhibition, kinetic analyses in synaptosomes of mouse brain were performed. Michaelis-Menten kinetics revealed that hyperforin (2 microM) induces a decrease in V(max) by more than 50% while only slightly decreasing K(m), indicating mainly noncompetitive inhibition. By contrast, citalopram (1 nM) leads to an elevation of K(m) without changing V(max). Monensin, a Na(+)/H(+) exchanger, showed similar properties as hyperforin (decrease of V(max) without changing K(m)). Compared with classical antidepressants, such as selective serotonin reuptake inhibitors and tricyclic antidepressants, hyperforin is only a weak inhibitor of [(3)H]paroxetine binding relative to its effects on serotonin uptake. As monensin decreases serotonin uptake by increasing Na(+)/H(+) exchange, we compared the effects of hyperforin and monensin on the free intracellular sodium concentration ([Na(+)](i)) in platelets by measuring 1,3-benzenedicarboxylic acid, 4,4'-[1,4,10-trioxa-7, 13-diazacyclopentadecan-7,13-diylbis(5-methoxy-6, 2-benzofurandiyl)]bis-, tetraammonium salt (SBFI/AM) fluorescence. Both drugs elevated [Na(+)](i) over basal levels, with a maximal [Na(+)](i) of 69 +/- 16.1 mM (50 microM hyperforin) and 140 +/- 9.1 mM (10 microM monensin). Citalopram at concentrations relevant for [(3)H]serotonin uptake inhibition had no effect on [Na(+)](i). Although the mode of action of hyperforin seems to be associated with elevated [Na(+)](i) similar to those levels found with monensin, the molecular mechanism might be different, as even at high concentrations, hyperforin does not elevate free intracellular sodium concentration ([Na(+)](i)) up to the extracellular level, as monensin does. Hyperforin represents the first substance with a known preclinical antidepressant profile that inhibits serotonin uptake by elevating [Na(+)](i).


Assuntos
Antidepressivos/farmacologia , Inibidores Seletivos de Recaptação de Serotonina/farmacologia , Sódio/metabolismo , Animais , Sítios de Ligação , Ligação Competitiva , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Compostos Bicíclicos com Pontes , Ericales/química , Feminino , Humanos , Líquido Intracelular/metabolismo , Cinética , Camundongos , Paroxetina/metabolismo , Floroglucinol/análogos & derivados , Extratos Vegetais/farmacologia , Serotonina/metabolismo , Sinaptossomos/efeitos dos fármacos , Sinaptossomos/metabolismo , Terpenos/farmacologia , Trítio
8.
Life Sci ; 63(6): 499-510, 1998.
Artigo em Inglês | MEDLINE | ID: mdl-9718074

RESUMO

We demonstrate that the phloroglucinol derivative hyperforin is not only the major lipophilic chemical constituent of the medicinal plant Hypericum perforatum (St. John's wort) but also a potent uptake inhibitor of serotonin (5-HT), dopamine (DA), noradrenaline (NA), GABA and L-Glutamate with IC50 values of about 0.05-0.10 microg/ml (5-HT, NA, DA, GABA) and about 0.5 microg/ml (L-glutamate) in synaptosomal preparations. Furthermore, potencies of two different hypericum extracts in two conventional pharmacological paradigms useful for the detection of antidepressants (behavioral despair, learned helplessness), closely correlate with their hyperforin contents. In addition, most till now known neuropharmacological properties of the clinically used hypericum extracts can also be demonstrated with pure hyperforin. It appears, therefore, that this non-nitrogenous constituent is a possible major active principle responsible for the observed clinical efficacies of the extract as an antidepressant and that it could also be a starting point for drug discovery projects engaged in the search of psychoactive drugs with novel mode of action.


Assuntos
Antidepressivos/química , Perileno/análogos & derivados , Extratos Vegetais/química , Quercetina/análogos & derivados , Xantenos/química , Animais , Antidepressivos/farmacologia , Comportamento Animal/efeitos dos fármacos , Compostos Bicíclicos com Pontes , Desamparo Aprendido , Hypericum , Masculino , Modelos Químicos , Monoaminoxidase/metabolismo , Inibidores da Monoaminoxidase/farmacologia , Inibidores da Captação de Neurotransmissores/isolamento & purificação , Inibidores da Captação de Neurotransmissores/farmacologia , Perileno/química , Perileno/farmacologia , Floroglucinol/análogos & derivados , Extratos Vegetais/farmacologia , Plantas Medicinais , Quercetina/química , Quercetina/farmacologia , Ratos , Sinaptossomos/metabolismo , Terpenos/isolamento & purificação , Terpenos/farmacologia , Xantenos/farmacologia
9.
Pharmacopsychiatry ; 31 Suppl 1: 16-21, 1998 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-9684943

RESUMO

Hydroalcoholic hypericum extract inhibits the synaptosomal uptake of serotonin, norepinephrine, and dopamine with about similar affinities and leads to a significant down-regulation of cortical beta-adrenoceptors and 5-HT2-receptors after subchronic treatment of rats. While neither hypericine nor kaempferol did show any reuptake inhibiting properties, hyperforin was identified as the unspecific reuptake inhibitor of hypericum extracts with half-maximal inhibitory concentrations for the three synaptosomal uptake systems mentioned above between 80 and 200 nmol/l. Moreover, a hyperforin-enriched (38%) CO2 extract also leads to a significant beta-receptor down-regulation after subchronic treatment. The data suggest hyperforin as the active principle of hypericum extracts in biochemical models of antidepressant activity.


Assuntos
Encéfalo/efeitos dos fármacos , Inibidores da Captação de Neurotransmissores/farmacologia , Perileno/análogos & derivados , Quercetina/análogos & derivados , Sinaptossomos/efeitos dos fármacos , Xantenos/química , Xantenos/farmacologia , Animais , Encéfalo/enzimologia , Compostos Bicíclicos com Pontes , Dopamina/metabolismo , Feminino , Hypericum , Masculino , Camundongos , Monoaminoxidase/metabolismo , Inibidores da Captação de Neurotransmissores/química , Inibidores da Captação de Neurotransmissores/metabolismo , Norepinefrina/metabolismo , Perileno/química , Perileno/farmacologia , Floroglucinol/análogos & derivados , Extratos Vegetais/química , Extratos Vegetais/farmacologia , Plantas Medicinais , Quercetina/química , Quercetina/farmacologia , Ratos , Ratos Wistar , Receptores Adrenérgicos beta/metabolismo , Receptores de Serotonina/metabolismo , Serotonina/metabolismo , Sinaptossomos/metabolismo , Terpenos/análise , Terpenos/farmacologia
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