Hypericum extract reverses S-ketamine-induced changes in auditory evoked potentials in humans - possible implications for the treatment of schizophrenia.

BACKGROUND: Auditory evoked potentials (AEP) provide a correlate of cognitive dysfunction in schizophrenia. Both cognitive dysfunction and AEP-characteristics might be related to reduced glutamatergic neurotransmission as induced by glutamate-antagonist like ketamine. Hypericum extract LI160 has demonstrated a ketamine-antagonising effect. We examined whether LI160 reverses changes of a low dose ketamine on AEP in healthy subjects. METHODS: We performed a double-blind randomized treatment with either 2 x 750 mg LI 160 or placebo given one week, using a crossover design, in 16 health subjects. A test-battery including AEPs, the oculodynamic test (ODT) and a cognitive test were performed before and after an infusion with 4 mg of S-ketamine over a period of 1 hour. RESULTS: S-ketamine lead to a significant decrease in the N100-P200 peak to peak (ptp) amplitude after the placebo treatment, whereas ptp was significantly increased by S-ketamine infusion in the LI160 treated subjects. The ODT and the cognitive testing revealed no significant effect of ketamine-infusion and therefore no interaction between treatment groups. CONCLUSIONS: AEP measures are sensitive means to assess the effect of low dose ketamine. Provided that ketamine mimics cognitive deficits in schizophrenia, LI160 might be effective to treat these symptoms.

Comparison of the analgesic effects of a fixed-dose combination of orphenadrine and diclofenac (Neodolpasse) with its single active ingredients diclofenac and orphenadrine: a placebo-controlled study using laser-induced somatosensory-evoked potentials from capsaicin-induced hyperalgesic human skin.

OBJECTIVE: The aim of this study was to investigate the analgesic efficacy of Neodolpasse, a fixed-dose combination of orphenadrine and diclofenac, compared with those of its single active ingredients in a human pain model. METHODS: The study was designed as a randomised, double-blind, placebo-controlled, four-period crossover study. Twenty-four healthy female and male subjects received single infusions of Neodolpasse, orphenadrine, diclofenac or saline solution over 60 minutes. Infusions were separated by a 1-week washout period. Neurogenic inflammation and hyperalgesia were induced by topical occlusive application of a 1% capsaicin solution for 30 minutes on defined skin areas on the back. The pain response to CO2 laser pulses applied to the capsaicin-pretreated skin was measured by event-related vertex EEG recordings. This allowed us to study the influence of a single infusion on the central P2- and peripheral N1-components of laser-induced somatosensory-evoked potentials (LSEP) as a measure of pain response. RESULTS: Although none of the active treatments had a significant effect on the peripheral N1-component, all active treatments reduced the P2-component of the LSEP, reflecting central/spinal analgesic (anti-hyperalgesic) effects. These effects were statistically significant for orphenadrine (p < 0.0001) and for the combination of orphenadrine and diclofenac (p < 0.0013). The single ingredient diclofenac reduced the P2-component by a value just below clinical relevance (p < 0.0848). CONCLUSION: This study demonstrated the efficacy of Neodolpasse in a human pain model. The observed effect was mainly caused by central mechanisms and was found to be superior for the fixed-dose combination of orphenadrine and diclofenac compared with the individual ingredients. Both components contributed to the effect of the combination in an additive fashion, which can be explained by the different molecular mechanisms of action of each drug.

Effects of Hypericum extract (LI160) on the change of auditory evoked potentials by cortisol administration.

Target symptoms treated with Hypericum extract, i.e. somatisation, fatigue and depression could be related to an increased activity of glucocorticoids in the brain. One potential mechanism is the increased permeability of the blood-brain barrier for glucocorticoids. Hypericum extract LI160 reduces intracerebral glucocorticoid concentration possibly by its action to induce the expression of the transport protein P-glycoprotein (P-gp). To test this hypothesis directly, we performed a randomised double-blind crossover study to examine the effect of intravenously administered cortisol on auditory evoked potentials (AEPs) and salivary cortisol concentration. Nineteen healthy subjects were treated for 2 weeks with 300 mg LI160 twice a day or placebo. On the 14th day, AEPs were recorded every 30 min, at times -60, -30 and 0 min before the start of the infusion and at +30, +60 and +90 min after starting the infusion. The rate of infusion was 20 mg cortisol/h. No changes in the AEP, especially the N1-P2 component, could be observed under cortisol infusion and consequently no modification with the treatment of Hypericum extract. The salivary concentration of cortisol under cortisol infusion was slightly but significantly decreased in the Hypericum condition compared to placebo. The results of the present study are therefore inconclusive with respect to the influence of LI160 treatment on the expected cortisol-induced AEP changes, but support the concept of an action of Hypericum on P-gp function by the observed changes in salivary cortisol.

Effect of the new H1-antagonist ReN1869 on capsaicin-induced hyperalgesia in human skin/Human phase-I trial using somatosensory evoked potentials induced by a CO2 laser.

Extensive pre-clinical investigations have shown that the tricyclic compound ReN1869 ((R)-1-(3-(10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-ylidene)-1-propyl)-3-piperidine carboxylic acid, CAS 170149-99-2) is a potent H1-antagonist with pronounced antinociceptive properties. In this human phase-I trial the effect of different acute and multiple doses of ReN1869 on capsaicin induced neurogenic inflammation and hyperalgesia was investigated. Twenty-one healthy male subjects were enrolled in this randomised, double-blind, three-period, crossover trial design--consisting of acute and one week b.i.d. oral administration of 25 and 50 mg doses of ReN1869 and matching placebo--separated by 3 week washout periods. Capsaicin solution (1%) (INCI: Capsicum frutescens--containing capsaicinoides from Capsicum annuum annuum, CAS 84603-55-4) was applied in an occlusive mode for 30 min on the skin of the back in all three acute and subchronic medication periods to induce neurogenic inflammation. When the nociceptive laser pulses were applied to the capsaicin pre-treated skin, ReN1869 exerted a highly significant reduction of the pain response--as predominantly detected by suppression of the (central) P2-component in the laser-induced somatosensory evoked potentials (LSEPs) from Vertex-EEG. The primary efficacy endpoint, the N1/P2 peak to peak amplitude, was significantly reduced with the administration of ReN1869--primarily by a suppression of the P2-component of the LSEP. This suppression was dose-dependent and was more pronounced after a one week treatment (subchronic mode) with ReN1869 than after the first dose (acute mode). In contrast to the (central) P2-component there was no significant effect on the (peripheral) N1-component of the LSEPs taken from capsaicin-treated skin. As ReN1869 had no significant effect when the laser pulses were applied to normal skin, and the compound's effect was mainly restricted to the (central) P2-component, when LSEPs were taken from capsaicin treated skin, it can be concluded that ReN1869 exerts its positive effect to reduce capsaicin-induced hyperalgesia by a primarily central mechanism.