Topically applied novel TRPV1 receptor antagonist, ACD440 Gel, reduces evoked pain in healthy volunteers, a randomized, double-blind, placebo-controlled, crossover study.

BACKGROUND: The TRPV1 receptor is a key molecule in pain generation. Previous development of oral TRPV1-antagonists was halted due to systemic heat insensitivity and body temperature alterations. The present Phase 1b study investigated the efficacy, safety and plasma exposure of a topically administered TRPV1-antagonist (ACD440 Gel) in healthy subjects. METHODS: The study comprised two parts. In part 1, 24 healthy subjects were included in this randomized double-blind, placebo-controlled, crossover trial. ACD440 Gel or Placebo was applied once daily and wiped off after 1 h, for 5 consecutive days. Assessments were done in normal skin, skin optimized for penetration (by stripping and occlusive gel application) and UVB-irradiated skin. Pain induced by thermo-nociceptive CO2 laser impulses generated laser-evoked potentials (LEPs), with readouts of peak-to-peak (PtP) amplitude in vertex-EEG and pain assessments by VAS (0-100). Endpoints include effects at 1 hour post-dose, AUC(Days 1-5) and AUC(0-24, Day 4). In UVB-irradiated skin, also pain on pinprick and skin redness were assessed. Part 2 explored the plasma pharmacokinetics of ACD440. RESULTS: ACD440 Gel reduced LEP PtP amplitude and VAS pain, p < 0.001, in all skin conditions, versus placebo. In UVB-irradiated skin, pinprick pain was also reduced, p = 0.047. Effects were significant after 1 h, maintaining for at least 9 h. There were no adverse events or drug-induced erythema. Plasma exposures of ACD440 were too low to establish an elimination half-life of ACD400. CONCLUSIONS: Topical ACD440 Gel demonstrated a significant analgesic effect on LEP, VAS score and pinprick pain, with low systemic exposures, supporting further clinical development. SIGNIFICANCE: This study demonstrates that the topical administration of a TRPV1-antagonist, ACD440 Gel, has potential as a new treatment for painful conditions affecting the skin, such as chronic peripheral neuropathic pain, without any local or systemic side effects.

No benefit adding eleutherococcus senticosus to stress management training in stress-related fatigue/weakness, impaired work or concentration, a randomized controlled study.

INTRODUCTION: Plant adaptogens are traditionally used for stress-related symptoms, but clinical evidence is inconsistent. This trial explored the effects of 120 mg/day Eleutherococcus senticosus root extract (ES), 2-day professional stress management training (SMT) and a combination of both (COM). METHODS: 144 participants suffering from asthenia and reduced working capacity related to chronic stress were randomized to the treatments. Validated scales and tests were used to investigate cognitive performance; feeling stressed; fatigue and exhaustion; alertness, restlessness and mood; quality of life and sleep; physical complaints and activities; and physiological stress parameters including cortisol awakening response (CAR), at baseline, after 2 and 8 weeks of treatment (German Clinical Trials Register DRKS00000692). RESULTS: Almost all parameters improved significantly over time without group differences. Significant differences were found in mental fatigue and restlessness, both in favor of COM vs. ES. COM was not superior to SMT in any parameter at week 8. An attenuation of the CAR was seen at week 2 without group differences. All treatments were well tolerated. DISCUSSION: Effects of adding ES to SMT are, if any, negligible.

[Analgesic effect of the selective noradrenaline reuptake inhibitor reboxetine]. / Analgetische Wirkung des selektiven Noradrenalin-Wiederaufnahme-Hemmers Reboxetin. Objektive und subjektive Messung.

BACKGROUND: Reboxetine is a selective noradrenaline reuptake inhibitor (NARI). As noradrenaline plays a relevant role in antinociceptive mechanisms, the hypothesis was investigated in this study whether reboxetine has analgetic efficacy. METHODS: Twenty-four healthy volunteers were investigated in a crossover design. Reboxetine (2 x 2 mg) or placebo were given for 5 days with the "crossover" following a one-day washout in between. The primary end-points were the N1 and P2 amplitudes of laser evoked somatosensory potentials (laser SEP) of vertex EEG. In addition, visual analogue scales (VAS, 100 mm) were used. RESULTS: Reboxetine showed a higher analgesic potency than placebo, with a statistically significant superiority in capsaicinirritated skin--in the objective tests (laser SEP, P < 0.0001 for N1 and P = 0.0002 for P2) as well as in the subjective pain measurements (VAS, P < 0.0003). Besides pain, the subjective feelings of burning and itching were lower with reboxetine than with the placebo. CONCLUSIONS: The hypothesis that a selective noradrenergic substance could be of analgesic efficacy was proven the first time experimentally. Reboxetine reduced the N1 and the P2 components of the laser SEP, which speaks for central and peripheral mechanisms of action.

Dimethindene maleate in the treatment of sunburn. A double-blind, placebo-controlled pilot study.

The efficacy of topical dimethindene maleate (DMM, CAS 31614-69-5, Fenistil Gel) in the treatment of sunburn was evaluated in a placebo-controlled, 1-period crossover trial in 24 healthy volunteers. An UV-erythema (sunburn) of a well-defined intensity and extent was experimentally induced on three different skin test-areas by means of UV-A/B irradiation with three times the minimal erythema dose (MED). About 24 h after irradiation, one skin test-area was subjected to a 1-h occlusive treatment with DMM gel, the second test area was subjected to treatment with a placebo gel and the third one remained untreated. As objective-quantitative indicators of tenderness, a key symptom of sunburn, sensory and pain thresholds to CO2-Laser stimulation and laser somatosensory evoked potentials (SEPs) in Vertex-EEG were assessed about 1.5 h postdose. The reaction times (RTs) to painless and painful CO2-laser stimulation (sensory and pain threshold level, respectively) on the DMM-treated area were significantly longer than RTs to stimulation on the placebo-treated area. Thresholds in terms of laser energy showed no differences between the treatments. The SEP N1-amplitude on the DMM-area was markedly decreased in comparison to placebo. With regard to subjective sensations of pain, itching and tenderness assessed by means of visual analogue scales (VAS), no clinically relevant differences between treatments were observed after sole UV-irradiation. After additional laser stimulation tenderness was--objectively but not subjectively--decreased on the DMM-area versus placebo. Both gel preparations were well tolerated.

Bioavailability of escin after administration of two oral formulations containing aesculus extract.

In a steady-state cross-over study in 18 healthy volunteers, the relative bioavailability of beta-escin (CAS 11072-93-8) after oral administration of a new immediate release enteric-coated test formulation containing aesculus extract was evaluated in comparison with a prolonged-release reference preparation. The subject received the test and the reference preparation in randomised sequence for 7 days each with no washout period in between. The daily dose was 50 mg escin b.i.d. Blood samples for pharmacokinetic profiling were taken on the 7th treatment day of each period over a full 24-h cycle of two successive dosing intervals. For the determination of beta-escin serum concentrations, a highly specific radioimmunoassay (RIA) was used. Generally, escin serum concentrations were lower during the second dosing interval (night) than during the first interval, probably indicating a drug by food interaction. (The morning dose was given after overnight fasting whereas the evening dose was given between meals). Test and reference demonstrated bioequivalence with regard to the extent of absorption; for the AUC (0-24 h p.a.), the 90% confidence interval ranged from 84% to 114% (point estimate: 98%). The differences observed for rate parameters can be disregarded due to the generally slow elimination and the wide therapeutic concentration range of escin.

Dose-effect relationship of idebenone in an experimental cerebral deficit model. Pilot study in healthy young volunteers with piracetam as reference drug.

Within a general cerebral deficit model--inspiratory hypoxia-the dose--effect relationship of idebenone (CAS 58186-27-9), an antioxidant, was studied with regard to selected electrophysiological and psychometric parameters. Seventeen healthy male volunteers (mean age = 32 years, mean BW = 75 kg) received three different oral medications: placebo, idebenone and piracetam (CAS 7491-74-9) as reference. The test drug idebenone was administered in five different dosages, ranging--in 60 mg steps--from 60 to 300 mg t.id. Piracetam was given at a dose level of 800 mg t.i.d. A strict dose-regimen was used in idebenone for safety reasons. Each dosage/medication--except idebenone 300 mg t.i.d.--was given for one week without washouts in between. On each 7th treatment day, pharmacodynamic assessments comprising electroretinography (ERG), auditory evoked potentials (AEP) and visual analogue scales (VAS) were run. Immediately after the phases with the lower dosages, the study was continued with the highest dosage of idebenone (300 mg t.i.d.) for a period of four weeks with pharmacodynamic assessments on the 7th, 14th and 28th day. In this pilot study, the target variable, the amplitude of the ERG b-wave indicated a definite antihypoxidotic effect after the highest dosage of idebenone. With 300 mg idebenone t.i.d., ERG b-wave amplitudes increased linearily with increasing duration of treatment. The 'central' AEP P2-amplitude demonstrated a different dose-effect relationship. AEP P2-amplitudes increased with increasing dosages of idebenone. The prolongation of treatment with 300 mg t.i.d. resulted in no further improvement of this parameter (ceiling effect). Subjective ratings (VAS) by the volunteers confirmed the results seen in electrophysiological variables. The findings, however, remain to be confirmed within an adequate double-blind, crossover study design.

The comparative effects of single and multiple doses of RS-8359, moclobemide and placebo on psychomotor function in healthy subjects.

Electro-oculogram (including saccadic eye movements), auditory-evoked potentials and visual analogue scales for a subjective impression of effects were used to evaluate some pharmacodynamic properties of RS-8359. In the electro-oculogram, administration of central nervous system-stimulating drugs is expected to decrease latency and fixation time and to increase angular velocity. As no significant effect on these parameters was found after any dose of RS-8359, within the limitations of the methods used, it seems unlikely that any appreciable direct stimulation of the central nervous system occurs with this agent, and significant central nervous system side effects also seem unlikely. Moreover, the data on auditory-evoked potentials suggest that RS-8359 may improve cognitive performance, which is often impaired in major depressive disorders. However, the doses used in these studies were associated with nausea and vomiting, possibly caused by increased serotonergic activity secondary to monoamine oxidase A inhibition. The results indicate that RS-8359 has no apparent sedative liability, which should benefit patients who need to remain in work, to drive or to continue other activities requiring a normal level of alertness.

A cohort study with children living in an air-polluted region--a model for public health.

Regions with heavy industry are in many ways regions of crisis. The health of the population is primarily affected by the different air pollutants. Dust, with all its organic (dioxins and furans) and inorganic (heavy metals) contents, makes up the greatest part of the air-borne pollutants. The influence on health of environmental pollution was ascertained through the determination of different parameters (functional methods and determination of physiological parameters). This influence could be observed in children over a period of 8 years with regular investigations (e.g. determination of pulmonary function by spirometry and immunological parameters). Besides this exogenous load the persons are exposed to other environmental stresses-shift work, unemployment, alcoholism and divorce-which have a particular influence on the attitude and the upbringing of the children. Sixty per cent of the children in this polluted region ate no breakfast in the morning. Consequently it could be shown that the blood sugar in 70% of the children was below 70 mg/dl. Additionally, a relatively high amount of COHb (2.5% to 3%), and an increased concentration of serum IgE (47% of children with a concentration over 100 IU/ml), could be detected. Through a change in the environmental awareness of the children and their consequent influence, an effort should be made to achieve a positive effect on the health of the whole population. The children were given a chance to participate in various sports for the whole day during a week in the mountains at 1200 m. The teachers exercised with the children for at least 8 h per day. Besides gymnastics the program consisted of downhill and cross-country skiing. In addition, the children were offered a balanced and natural diet and they were instructed accordingly. This week of activity led to a clear reduction of the concentration of COHb, but to a far less clear improvement in the concentration of blood sugar and the pulmonary function.

Total serum IgE concentration of children from air-polluted regions.

Distributions of IgE levels were determined from 312 children (divided into three age groups), living in small Austrian towns with different levels of air pollution. The spread of IgE concentration was extremely wide; the mean value was 124 kU/I with a standard deviation of 240. An increase of concentration was found in the group aged 6 to 11 years. No significant difference was found according to sex and the higher rates of IgE. The reference rates were then used to compare children living in an industrial region with heavy metal production. A significant difference was found in the lower IgE concentrations (25th and 50th percentiles).

Effects of dimethindene maleate on psychomotor performance in the oculodynamic test compared with placebo and loratadine.

The effects of dimethindene maleate (CAS 3614-69-5) on the central nervous system-as sustained release pellets (Fenistil OAD; OAD = once a day) and sustained release tablets (Fenistil retard) with an immediate release fraction-were investigated by means of the oculodynamic test (ODT) and visual analogue scales and compared to loratadine (CAS 79794-75-5) and placebo. In the confirmatory part of the study 18 healthy volunteers were included in a single-blind, randomised, 3-way change-over design with Fenistil OAD, loratadine, and placebo. An additional, fourth exploratory arm with Fenistil retard was run in 6 (out of the 18) subjects after completing the main part of the study. The ODT includes electro-oculography, choice reaction task, and cardiologic parameters under workload. Visual analogue scales were used for subjective ratings on well-being and drug effects concerning wakefulness (sedation), excitation, dizziness, performance, effort, and dry mouth. The results show no relevant differences between either of the active drugs and placebo. Therefore it can be stated that after a single dose there is no sedating effect of dimethindene maleate compared to loratadine or placebo.

[Clinical pilot study of the myogenic effects of flupirtine in comparison to tetrazepam and placebo]. / Klinische Pilotstudie zur myogenen Wirkung von Flupirtin im Vergleich zu Tetrazepam und Plazebo.

The effects of flupirtine (CAS 56995-20-1, D-9998, Katadolon) on muscle force and related electromyographic (EMG) activity has been assessed in comparison to tetrazepam and placebo in 12 healthy male volunteers after oral single-dose administration and under steady-state conditions. Muscle functions primarily reflecting dynamic daily demands remained unaffected under flupirtine in contrast to tetrazepam, the latter exhibiting the typical signs of increased (co-)innervation which can be interpreted as a compensation of a decrease of muscle force. Under conditions that serve as a model for static-spastic situations, flupirtine showed a decrease, tetrazepam a typical increase in the force parameter. Under the same conditions, a decrease of the EMG-amplitude was observed for flupirtine and, to a lesser extent, for tetrazepam as well. With respect to its muscle relaxing property, flupirtine differs both, quantitatively and qualitatively from tetrazepam, which has shown effects common for benzodiazepines.

Influences of dimethindene maleate in a new formulation on oculo and psychomotor performance using the oculodynamic test (ODT) in volunteers.

Most antihistamines are assumed to possess a more or less pronounced sedative potential in addition to their antihistaminic properties. Therefore, a single-blind three-way crossover study was designed to assess the influence of single-dose dimethindene maleate (new "once a day formulation") on vigilance and performance vs. loratadine as reference and vs. placebo. Drug effects on performance were tested in 18 healthy volunteers by the oculodynamic test [ODT, i.e. choice reaction task (CRT), combined with recording of electrooculography (EOG) and cardiovascular parameters] and effects on subjective well-being by visual analogue scales (VAS). Main target parameters for evaluation of CNS-effects are latency and subjective perception of sedation (VAS). Neither statistically significant nor clinically relevant differences in all objective and subjective target variables (ODT and VAS) between active drugs and placebo, after single-dose administration were found. The same holds for accessory EOG, CRT and vital parameters under workload.

Evaluation of the local anaesthetic activity of dimetindene maleate by means of laser algesimetry in healthy volunteers.

Dimetindene maleate (DMM, Fenistil, CAS 3614-69-5) a specific H1-receptor antagonist, is therapeutically used for the treatment of respiratory allergies, urticaria, itching dermatoses and generally pruritic sensations occurring with various diseases. As it exhibits local anaesthetic activity in the rabbit cornea and the local anaesthetic activity of a couple of H1-antagonists was found to be linearly correlated to the H1-potency represented by the pA2-values--and dimethindene maleate demonstrates a high pA2-value--it seemed worth investigating the local anaesthetic potency in man making use of an objective and well validated pain model, the Laser algesimetry. The study was carried out with 24 healthy volunteers in a double-blind placebo- and reference-controlled, randomized, cross-over design. Three different medications were applied with occlusive dressing: DMM, lidocaine, and placebo. Selective thermo-noxious stimulation of A-delta- and C-fibers was induced by a CO2-laser. Somato-sensory evoked vertex potentials (SEPs) were simultaneously recorded. Both verum treatments showed a remarkable analgesic potency compared to placebo. Effects were preferably concentrated on the peripheral N1-component of the SEPs. The overall means of the N1-amplitudes were suppressed compared to placebo by both active drugs, with the effects being more pronounced for DMM.

Bioavailability of vinpocetine and interference of the time of application with food intake.

In a pilot study based on an open cross-over design involving four phases, the relative bioavailability of the eburnamenine derivative vinpocetine (CAS 42971-09-5) was investigated in 8 healthy volunteers in relation to different times of drug administration relative to food intake. The substance was applied orally as 10 mg film tablets. The areas under the plasma concentration-time curves (AUC) amounted to 27.3 +/- 18.1 ng.h/ml (fasting) and 42.8 +/- 27.4 up to 54.3 +/- 38.4 ng.h/ml (non-fasting, intake before and after meal, resp.). The relative bioavailability under non-fasting conditions was found to be approx. 60 to 100% higher than under fasting conditions.

Study to evaluate the encephalotropic potency of a hemodialysate. Controlled study using electro-retinography and visual evoked potentials under hypoxic conditions in human volunteers (preliminary communication).

Twelve healthy young males volunteered in this pilot-study to test the encephalotropic potency of a deproteinized hemodialysate of calf blood (Actovegin). This compound contains peptides, oligosaccharides and nucleinic acid derivatives, which are supposed to improve transport of glucose and oxygen into cells. The study is based on a placebo-controlled, partially double-blind, 3-way crossover design. The subjects received single administrations of the hemodialysate as injection (10 ml, 400 mg), as infusion (500 ml, 4 g) and a placebo injection (saline) in randomized sequence. Drug effects on visual evoked potentials (VEP) and electro-retinography (ERG) were tested--in the context of a hypoxia based model of dementia (10.5% O2 inspiratory)--1, 2, and 4 h post administration. The main target variables were the amplitudes of the VEP-P2-component and of the ERG-b-wave. The hemodialysate--as an encephalotropic drug--was expected to counteract the hypoxia-induced reduction of both amplitudes. On a descriptive/exploratory level the restitution of the (hypoxia-suppressed) target variables was found. The combined application of visual evoked potentials (VEP) and of electroretinography (ERG) was able to consistently reveal central and peripheral sites of hypoxia-antagonistic action of the drug in study, which might not be restricted solely to neuronal structures, but seems to be extended to glial structures too. The predominant effects form a pattern of clinically relevant changes, which should be confirmed in a larger number of subjects. The preferable form of administration--featuring positive effects in hypoxia antagonism--seems to be the infusion with its higher dosage.(ABSTRACT TRUNCATED AT 250 WORDS)

[Comparative studies on the bioavailability of nicergoline from two different steady-state preparations]. / Vergleichende Untersuchungen zur Bioverfügbarkeit von Nicergolin aus zwei unterschiedlichen Darreichungsformen im Steady State.

Comparative Studies on the Bioavailability of Nicergoline from Two Different Preparations in Steady State The bioavailability of nicergoline (CAS 27848-84-6) in a new 30 mg tablet and a 10 mg dragee formulation (Sermion) was evaluated under steady state conditions in 18 healthy male volunteers between the age of 21 and 37 years. During the run-in phase, the volunteers received on 7 consecutive days 30 mg nicergoline either 1 x 30 mg/d tablet (test substance) or 3 x 10 mg dragees (reference). On day 8, after intake of 1 x 30 mg in a 24 h interval or 1 x 10 mg in a 8 h interval respectively, the plasma concentrations of the nicergoline metabolite 10-methoxy-6-methyl-ergoline-8 beta-methanol (MDL) were measured. The area under the plasma concentrations in the 24 h interval after administering the 30 mg tablet was not 3 times greater as to be expected; it was by a factor of 4 significantly greater than the area under the curve of the 10 mg dragee in the 8 h interval. Therefore, nicergoline has a higher availability in the 30 mg tablet than in the 10 mg dragee form. Both formulations were equally well tolerated.

Analgesic potency of a new anticonvulsant drug versus acetylsalicylic acid via laser somatosensory evoked potentials. Randomized placebo-controlled double-blind (5-way) crossover study.

A randomized, double-blind crossover study was performed with three different acute oral dosages of CM 40907 (3-(4-hydroxypiperidyl)-6-(2'-chlorophenyl)-pyridazine) (600, 900 and 1200 mg), a newly developed anticonvulsant drug, vs acetylsalicylic acid (ASA, 1000 mg) and placebo in 12 male healthy volunteers to check analgesic potency. Objective algesimetry was done by Laser Somatosensory Evoked Potentials (LSEP). Subjective pain intensities were measured by retrospective visual analog scale ratings (VAS). Effects on objective vigilance were checked by Auditory Evoked Potentials (AEP). For both types of evoked potentials there was a simultaneous control of alterations in vigilance by means of the adaptive pursuit tracking task (APTT). A vigilance-controlled EEG (V-EEG) and a resting (R-EEG), visual analog scales (VAS) on sedation, excitation and anxiety as well as vital parameters (blood pressure and heart rate under supine and upright conditions) and adverse event scales were included in this trial as well. CM 40907 showed distinct analgesic effects on objective and subjective algesimetric parameters, which for the highest dosage (1200 mg) were superior in ("central") P2-amplitude suppression of LSEPs to those of ASA in ("peripheral") N1-amplitudes suppression and ongoing for more than 6 h. Subjective sedation was decreased, however, AEP-findings indicated a decreased vigilance after CM 40907. Some EEG-patterns, specifically related with CM 40907--although being ambiguous in classification terms--resembled features of benzodiazepines. Blood pressure and heart rate were raised in a clinically irrelevant manner.

Early clinical testing of cognition enhancers: prediction of efficacy.

The major problem in predicting clinical efficacy from animal experimental results and phase I data is the lack of resemblance between the models used and the clinical condition. This problem is complicated by the diversity of the potential mechanisms of action of new compounds. A further question is whether Phase I studies should be used as predictors of clinical efficacy at all. Should they be used simply for determining pharmacologically active dose ranges and tolerance? If used as predictors should drug development stop if negative results are obtained? These questions were not resolved. It was nonetheless suggested that some human models (e.g. scopolamine-induced amnesia, hypoxia-induced performance deficits) were indeed potential predictors of clinical response and, in addition, were analogous to similar models in animals. On the other hand characterisation of quantified EEG (QEEG) profiles remained controversial.

Acute effects of two dosages of orally administered midazolam on psychomotor performance in healthy volunteers.

The acute effects of two doses of orally administered midazolam (Dormicum, 10 and 30 mg) which as a putative anaesthetic premedicant is clinically expected to provide valid effects already after acute dosing on sedation parameters, were evaluated vs placebo within a randomized double-blind 3-period crossover design in 12 healthy male volunteers. The washout period was 7 days. Objective sedation measures were obtained with the oculodynamic test (ODT), which is a multidimensional computerized psychological testing device. Cardiorespiratory parameters were simultaneously sampled throughout the ODT-sessions. Intradiurnal assessments were done at -30, +30, +90 and +180 min post-dose. Subjective side effects were recorded by spontaneous recall and by means of a symptom check list. With midazolam there was a dose-dependent increase of sedation in the ODT, which persisted for at least 3 h after intake. The subjective side effects fitted a sedative pattern with mild (10 mg) and marked (30 mg) impairment of vigilance. Cardiovascular and respiratory parameters were changed vs placebo. All subjects reported an anterograde amnesia after the 30-mg dose at about 3 or 5 h post-dose, which depicts a double-peaking time course in some subjects. The subjects ability to cooperate in the psychomotor test regimen was distinctly impaired after 30 mg of midazolam during daytime administration.