Biomedical subjects
Publications and source records attributed to G Kobal.
The presented computer model reconstructs the ECG with 500 myocardium cells based on seven ionic channels. The low hardware-requirement and the exact demonstration of physiological and pathophysiological coherence make this simulation model very useful for medical scientific education.
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The overall aim of the present study was to investigate a new method for the screening of taste function in a clinical context. Instead of dripping liquids onto the tongue, thin edible wavers were used. One-hundred healthy subjects participated in the study (41 male, 59 female; mean age: 52 years; age range: 20-89 years). Supra-threshold taste stimuli were presented as flavoured wavers made from flour and water. Sequential testing was performed regionally on the anterior one-third of the tongue and as whole mouth testing. When comparing ratings for the 5 different wavers separately for regional and whole mouth testing, differences between qualities only emerged for regional testing. Women were found to have less difficulty in taste identification which was most pronounced for regional testing. No effects of the subjects' age were observed. In conclusion, the wavers were found to be easy to use; they have a shelf-life of 2 to 3 years and can be carried in the pocket. The results indicate that the wavers may be suited for the screening of gustatory function, especially in a clinical setting.
The study aimed to investigate the relation of both negative mucosal potentials (NMP) obtained from respiratory epithelium, and pain ratings to repetitive stimulation with CO2 (21 subjects). Trains of four stimuli of identical intensity (70% v/v) were applied at a constant interseries interval (approximately 60 s) but different interstimulus intervals (ISI) of 2 s or 6 s. At an ISI of 6 s, ratings decreased while they increased at an interval of 2 s (P < 0.01). This change was accompanied by the buildup of burning pain probably relating to the 'wind-up' of spinal neurons. In contrast, the decrease of NMP amplitudes was stronger the shorter the ISI (P < 0.01). These findings are in line with the view that the NMP reflects activation of epithelial nociceptors (C-fibers and/or A delta-fibers).
After chemical stimulation of the human olfactory epithelium it is possible to record a negative response (electro-olfactogram, EOG) which is interpreted as the summated receptor potentials of the olfactory nerve. The aim of the present investigation was to test the EOG's changes in relation to pairs of stimuli. Stimulation was performed with vanillin (0.8 ppm) regarded to exclusively excite fibers of the olfactory nerve. Ten healthy volunteers participated in the experiments. Pairs of stimuli were applied at different interstimulus intervals ISIs (2-8 s). EOG could be recorded in 6 out of 10 subjects. After olfactory stimulation the responses' peak amplitude was found to range from 0.15 to 1.8 mV. When pairs of olfactory stimuli were applied responses obtained at an ISI of 8 s were clearly separated whereas at an ISI of 2 s responses were superimposed on each other. As with an ISI of 8 s, the amplitude produced by the second stimulus was nearly as great as the first responses' amplitude (decrease by approximately 20%). In contrast, intensity estimates obtained in an additional experiment (n = 10) decreased by 40-60%. Based on the present data peripheral encoding in the olfactory system appears to be less subject to desensitization compared to the decrease of intensity estimates.
The human olfactory pathways are well defined up to the level of the prepiriform cortex but the neocortical projections and their functional organization are still largely unknown. We recorded whole-scalp neuromagnetic signals to olfactory stimulation with boluses of phenylethyl alcohol, hydrogen sulphide, and vanillin. The main magnetic response peaked about 700 ms after the stimulus onset. The three odorants activated overlapping cortical areas around the superior temporal sulci of both hemispheres, revealing a neocortical area involved in olfactory processing.
Multiple chemical sensitivities (MCS) has become an increasingly frequent diagnosis assigned to patients with symptoms associated with exposures to environmental chemicals. Since the characteristic symptoms of MCS are triggered by very low concentrations of chemicals, in the range of olfactory thresholds, it is widely believed that the intranasal chemoreceptive senses are involved in the pathophysiology of MCS. Thus, the present study addressed both the olfactory and trigeminal systems: using a double-blind approach we investigated whether MCS patients show differences in responses after exposure to either room air or low concentrations of a widely used chemical agent (2-propanol). A total of 23 patients participated in the experiments (mean age 47 years; 13 female, 10 male). MCS was diagnosed according to Cullen's criteria Performance of the nasal chemical senses was established by means of chemosensory event-related potentials (CSERP) and subjective measures of olfactory function (odor discrimination, phenylethyl alcohol odor thresholds). CSERP were recorded in response to olfactory (H2S), and trigeminal (CO2) stimuli. The study provided three major results: (1) Approximately 20% of patients diagnosed with MCS presented symptoms regardless of the type of challenge, suggesting the susceptibility of MCS patients to unspecific experimental manipulations. (2) Changes in CSERP latencies indicated a change in the processing of both olfactory and trigeminal stimuli. (3) While odor threshold remained unchanged, the patients' ability to discriminate odors decreased after exposure to room air. In contrast, this decrease was less pronounced after exposure to 2-prop. Summarily, MCS patients respond to challenge with 2-prop with changes of chemosensory perception which might increase their susceptibility to environmentally volatile chemicals. Changes in the pattern of event-related potentials are interpreted as the possible change of the orientation of cortical generators, i.e., neuronal populations that were involved in the processing of chemosensory information. However, investigations in healthy controls are needed in order to draw further conclusions.
OBJECTIVE: The aim of the study was to investigate whether the analgesic effect of propyphenazone (PROP) was increased when it was administered in combination with caffeine (CAFF). METHODS: For assessment of analgesia a model was chosen based on chemo-somatosensory event-related potentials (CSSERP) elicited by stimulation of the nasal mucosa. Twenty healthy volunteers participated in the experiments. The study followed a placebo-controlled, randomised, double-blind, 5-fold cross-over design. Each of the 5 medications (400 mg PROP, 600 mg PROP, 400 mg PROP + 100 mg CAFF, 600 mg PROP + 150 mg CAFF, placebo) was orally administered. Experiments were separated by at least 5 days. In addition to assessment of CSSERP, subjects estimated the intensity of the stimulus. Drug effects unrelated to nociception were monitored, and in addition, the plasma levels of PROP were also analysed. RESULTS: While 400 mg PROP did not significantly reduce the amplitude of CSSERP in comparison to placebo, all other medications produced a significant decrease in amplitudes. For both dosages of PROP, there was a significant amplification of the antinociceptive effect of PROP by CAFF, as indicated by the decrease in CSSERP amplitude. A significant effect of the factor "drug" was also found in the spontaneous EEG, indicating an arousal reaction after CAFF. No significant differences between plasma levels of PROP were found when applied either alone or in combination with CAFF. CONCLUSION: The significant increase in the antinociceptive effect of PROP when administered together with caffeine appears to be related either to amplification of PROP's antinociceptive actions by CAFF or an atinociceptive effect of CAFF itself.
OBJECTIVE: The present study tested analgesia produced by a new controlled release formulation of tramadol. The investigation employed an experimental pain model based on chemo-somatosensory event-related potentials (CSSERP) in response to painful chemical stimuli applied to the nasal mucosa. STUDY: Twenty healthy volunteers participated in the experiments, which followed a controlled, randomised, double-blind, 3-way cross-over design. Each of the three medications (tramadol 100 mg [T100], tramadol controlled release 100 mg [TCR100] and tramadol controlled release 150 mg [TCR150]) was administered orally to fasting subjects. There was at least a 6 day washout period between tests. Each experiment was divided into five sessions, which took place before and 2, 4, 6, and 12 h after drug administration. In addition to the assessment of CSSERP, subjects rated the intensity of both the tonic and phasic painful stimuli. Nonspecific drug effects were also monitored by means of frequency analysis of the spontaneous EEG, ratings of adverse effects, and the subjects' performance in a tracking task. RESULTS: The significant reduction of amplitude N1 at central recording positions indicated that TCR 150 was the most effective analgesic 12 h after administration. Both 6 and 12 h after administration TCR 100 was more effective in terms of analgesia compared to T100. In addition, TCR100 appeared to produce fewer adverse effects than the standard formulation of tramadol. CONCLUSIONS: The controlled release formulation can be expected to become a valuable tool in peroral therapeutic regimens for chronic pain.
Steady-state pharmacokinetics of morphine and morphine-6-glucuronide (M-6-G) after intravenous administration of either morphine or M-6-G were determined in healthy volunteers. With a dosing regimen calculated on the basis of data obtained in a first series of experiments in four subjects (morphine: intravenous loading dose of 0.24 mg/kg for 5 minutes and an intravenous infusion of 0.069 mg.kg-1.hr-1 for 4 hours; M-6-G: loading dose of 0.011 mg/kg for 5 minutes and an infusion of 0.006 mg.kg-1.hr-1 for 4 hours), it was possible to yield plasma concentrations of morphine and M-6-G in another four subjects close to predefined targeted levels (35 and 45.5 ng/ml morphine and M-6-G, respectively). This dosing regimen may be used in further pharmacodynamic studies to compare the analgesic effects of morphine and M-6-G. In addition, metabolite kinetics of M-6-G were calculated as a function of time with use of a linear systems approach to the estimation of rate and fraction of morphine glucuronidation to M-6-G.
Healthy controls were compared to patients with decreased olfactory sensitivity (n = 32) to investigate interactions between the olfactory and trigeminal systems. Amplitudes of chemo-somatosensory event-related potentials in response to suprathreshold trigeminal stimuli (CO2) were found to be smaller in patients (P < 0.05) indicating a decrease of trigeminally mediated sensations.
1. The aim of this study was to investigate the analgesic effect and its duration of a new sustained-release preparation of tramadol in an experimental pain model based on pain-related chemosomatosensory evoked potentials (CSSEPs) and subjective intensity estimates of painful phasic and tonic stimuli. 2. Twenty volunteers participated in a randomised, double-blind, three-fold cross-over study. Measurements were obtained before and 0.5, 1, 4, 6, and 12 h after administration of the drug (100 mg, 200 mg and placebo orally). CSSEPs were recorded after stimulation of one nostril with phasic, painful CO2 pulses. The other nostril was stimulated with a constant stream of dry air, which produced a tonic painful sensation. Subjects rated the perceived intensity of phasic and tonic stimuli via visual analogue scales. In order to test for nonspecific effects, acoustic evoked potentials (AEPs) were recorded, the spontaneous EEG was analysed in the frequency domain, the subject's vigilance was assessed in a tracking task, and the side effects of the drug were monitored. 3. The sustained-release preparation of tramadol produced a significant dose-related decrease in CSSEP amplitudes when compared with placebo. The reduction in amplitudes outlasted the observation period of 12 h, demonstrating the prolonged duration of the analgesic effect. 4. A dose-related significant decrease could be observed for the estimates of tonic pain. Similar to the decrease of amplitudes of the CSSEP, the reduction of the ratings of tonic pain outlasted the observation period of 12 h. The observed slight decrease in the estimates of phasic pain under medication did not reach a statistically significant level when compared with placebo. No significant effect could be demonstrated for the perception of the phasic and the tonic pain as determined by the McGill-Questionnaire. 5. A significant dose-related increase in the estimates of the side effects 'drowsiness', 'vertigo' and 'sickness' but not for 'tiredness' could be demonstrated.
Patch-clamp recordings revealed the presence of a non-desensitizing cyclic nucleotide-gated channel on human olfactory receptor neurons and a fast-desensitizing non-specific cation channel activated by nucleotides on human supporting cells. Cyclic nucleotide-gated channels on olfactory receptor neurons showed selective channel activation by cAMP (K1/2 = 5 microM) and cGMP (K1/2 = 2 microM), a unitary conductance of approximately 20 pS, a reversal potential of single-channel currents close to 0 mV, a linear current-voltage relationship over the range of -80 to 80 mV and a strong extracellular but a weaker intracellular blocking effect of Ca2+. The channel activity outlasted the cyclic nucleotide pulses for hundreds of milliseconds when higher agonist concentrations (> 50 microM cAMP) were applied. The duration of the response was longer than in cyclic nucleotide-gated channels from other species studied so far. The plateau duration and the decay remained constant for pulses with a length of 50-150 ms, whereas pulses shorter than 50 ms successively reduced the time required by shortening the plateau phase. A larger difference for the K1/2 values of cAMP (K1/2 = 22 microM) and cGMP (K1/2 = 2.5 microM) were found for a small group (n = 3) of cyclic nucleotide-gated channels, pointing to the selective expression of the alpha-subunit in a small subgroup of olfactory receptor neurons.
"Sniffin' Sticks" is a new test of nasal chemosensory performance based on pen-like odour-dispensing devices. This portable test is suited for repetitive, inexpensive screening of odour identification. The test includes a forced odour-identification task for seven odours performed by means of a list of four items (multiple-choice). In 146 subjects the basic screening test was compared to a down-scaled version of the UPSIT (CC-SIT). Sniffin' Sticks exhibited a relatively higher coefficient of correlation with the subjects' age; they also demonstrated the women's superior olfactory sensitivity more pronounced when compared to men. In addition, the coefficient of correlation between age and olfactory performance was slightly higher when the sticks were used. Preliminary investigations in nine patients with impaired olfactory function (i.e., anosmic or hyposmic patients) revealed significantly lower scores in patients compared to healthy controls matched for age and sex (p < 0.001). It is concluded that Sniffin' Sticks may be useful in the routine clinical assessment of olfactory performance where both time and costs matter.
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Only recently has a new experimental technique been developed which combines tonic and phasic painful stimulation. By means of this technique the non-steroidal anti-inflammatory drug (NSAID) ibuprofen has been shown to produce a dose-related decrease in heterotopically applied phasic and tonic pain. The present study aimed to investigate the dose-related effects of the NSAID ketoprofen (50, 100, and 150 mg i.v.) when tonic and phasic stimuli were applied homotopically. Eighteen healthy volunteers participated in the double-blind, randomized, placebo-controlled study. After an initial training session subjects took part in four experiments, each of which was divided into three sessions (before, 30, and 120 min after drug administration). During each session 45 painful phasic CO2 stimuli of three concentrations were presented to the left nostril in randomized order (duration 200 ms; interval 40 s; 45%, 52%, and 59% v/v CO2). The left nostril was additionally stimulated with a constant stream of dry air, which produced a tonic painful sensation described as dull and burning. Subjects rated the intensity of the painful stimuli by means of visual analogue scales. Chemosomatosensory event-related potentials (CSSERPs) were recorded in response to phasic painful CO2 stimuli. Ketoprofen reduced the subjects' estimates of tonic pain in a dose-related manner. In contrast, given the special conditions of homotopic application of tonic and phasic painful stimuli, estimates of phasic pain increased significantly, corresponding to a significant increase in CSSERP amplitudes. An explanation of this inverse effect of the drug on responses to tonic and phasic pain may be a lateralized interaction between both C-fiber and A delta-fiber systems at a spinal or peripheral level.
The aim of this study was to determine whether the olfactory system is responsible for the discriminability of the stereoisomers of nicotine. The EOG was recorded after stimulation with different concentrations of undistilled S(-)-, distilled S(-)- and distilled R(-)-nicotine separately in three groups of frogs (Xenopus laevis). The responses to all types of nicotine used in the experiments increased with increasing stimulus concentration. The responses to undistilled S(-)-nicotine were significantly lower compared to responses to distilled S(-)- and R(+)-nicotine, whereas no significant differences could be found when the purified stereoisomers of nicotine [distilled S(-)-nicotine, distilled R(+)-nicotine] were compared. Control measurements of time course and peak concentration employing a UV-detection method demonstrated that the differences between distilled and undistilled S(-)-nicotine could not be explained by different nicotine concentrations. The fact that no differences between the pure nicotine stereoisomers could be found for all concentrations used in our experiments and that experiments in humans revealed similar detection thresholds for both stereoisomers points to a similar receptor affinity of R(+)- and S(-)-nicotine within the olfactory system. At this point, it cannot be determined whether the observed differences in the perception of nicotine enantiomers in humans are due to differences in quality coding by stereospecific receptors on the olfactory sensory cells or by specific receptors on the trigeminal nerve endings.
1. The aim of the study was to investigate the analgesic effects of flurbiprofen enantiomers using an experimental pain model based on both chemo-somatosensory event-related potentials (CSSERP) and subjective pain ratings. 2. Healthy female volunteers (n = 16, age 23-36 years) participated in a placebo-controlled, randomised, double-blind, four-way crossover study. Single doses of (S)-flurbiprofen (50 mg), (R)-flurbiprofen (50 and 100 mg) and placebo were administered orally. Measurements were taken before and 2 h after administration of the medications. During each measurement, 32 painful stimuli of gaseous carbon dioxide (200 ms duration, interval approximately 30 s) of two concentrations (60 and 65% CO2 v/v) were applied to the right nostril. EEG was recorded from five positions and CSSERP were obtained in response to the painful CO2- stimuli. Additionally, subjects rated the perceived intensity of the painful stimuli by means of a visual analogue scale (VAS). 3. The CSSERP-amplitude P2, a measure of analgesic effect, decreased after administration of both (R)- and (S)-flurbiprofen, while it increased after placebo. This was statistically significant at recording positions C4 (P < 0.01) and Fz (P < 0.05). The analgesia-related decreases in evoked potential produced by (R)-flurbiprofen were dose-dependent. Comparing similar doses of (R)- and (S)-flurbiprofen, the decrease in CSSERP-amplitudes produced by the (S)-enantiomer was somewhat more pronounced, indicating a higher analgesic potency. 4. The present data indicate that both enantiomers of flurbiprofen produce analgesic effects. Since (R)-flurbiprofen caused only little toxicity in rats as compared with the (S)-enantiomer or the racemic compound, a reduction of the quantitatively most important side effects in the gastrointestinal tract might be achieved by employing (R)-flurbiprofen in pain therapy.