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Biomedical subjects

J Lötsch

Publications and source records attributed to J Lötsch.

At least 19 recordsLinked to original sources
PubMed1999

Comparison of inhibitory effects of meloxicam and diclofenac on human thromboxane biosynthesis after single doses and at steady state.

OBJECTIVE: To evaluate the extent of human cyclooxygenase-1 (COX-1) inhibition by meloxicam, which has been reported to preferentially inhibit cyclooxygenase-2 (COX-2). The effects of meloxicam were compared with those of diclofenac, a nonselective COX inhibitor. METHODS: COX-1 inhibition was determined by measuring thromboxane B2 (TXB2)-generation from clotting whole blood ex vivo after single oral doses of 7.5 and 15 mg meloxicam and 75 mg diclofenac and at steady state (15 mg meloxicam daily and 150 mg diclofenac daily). The effect was expressed as percentage inhibition of serum TXB2 generation and was directly related to the serum drug concentration with use of a standard sigmoidal E(max) model. RESULTS: In terms of inhibition of TXB2 generation, diclofenac was about 1 order of magnitude more potent than meloxicam, indicated by a diclofenac EC50 (concentration of drug required to cause 50% of maximum effect) that was about 10 times lower than that of meloxicam (EC50 diclofenac single doses: 37.50+/-29.64; EC50 meloxicam single doses: 677.50+/-189.08). However, serum concentrations of meloxicam after administration of 15 mg were approximately 10-fold higher than those of diclofenac. Therefore there was no statistically significant difference in the area under the effect time curve (P = .115) and the mean effect (P = .424) between meloxicam and diclofenac. The EC50 of both drugs was significantly higher at steady state (diclofenac steady state: 87.07+/-55.24 ng/mL; meloxicam steady state: 1850.12+/-829.93 ng/mL) than after a single dose (P < .001). CONCLUSION: These data show that meloxicam inhibits TXB2 generation at clinically relevant doses, although less potently than diclofenac. Thus our data suggest that the COX-2 preference of meloxicam observed in vitro may not result in clinical advantages when the higher dose of 15 mg is needed. Because of the increase in EC50 at steady state, COX-1 is relatively spared when the lower dose of 7.5 mg is administered.

Administration, Oral↗
PubMed1999

Pharmacokinetics of meropenem in critically ill patients with acute renal failure undergoing continuous venovenous hemofiltration.

OBJECTIVE: Meropenem is a broad-spectrum antibiotic used for severe infections. In patients with chronic end-stage renal failure, meropenem clearance is reduced and doses must be adjusted according to the creatinine clearance. The aim of this study was to assess pharmacokinetic data of meropenem in patients with acute renal failure and to determine the amount of drug removed by continuous venovenous hemofiltration, an often-used renal replacement therapy in patients with acute renal failure. METHODS: Nine critically ill anuric patients with acute renal failure undergoing continuous venovenous hemofiltration received 500 mg meropenem 2 or 3 times daily. Plasma and hemofiltrate concentrations were determined during 1 dosing interval at steady state. Pharmacokinetic parameters were calculated for a 2-compartment open model and dose requirements were calculated. RESULTS: The total meropenem clearance was 52.0 +/- 8.4 mL/min, with a hemofiltration clearance of 22.0 +/- 4.7 mL/min and a nonrenal-nonhemofiltration clearance of 29.9 +/- 5.4 mL/min; 235.9 +/- 88.6 mg, or 47.2% +/- 17.7%, of the dose were removed through continuous venovenous hemofiltration. The terminal elimination half-life was 8.7 +/- 3.5 hours and the volume of distribution at steady state was 12.4 +/- 1.8 L. Peak and trough concentrations for a dosing interval of 12 hours were 38.9 +/- 9.7 mg/L and 7.3 +/- 1.3 mg/L, respectively. The corresponding concentrations for a dosing interval of 8 hours were 44.7 +/- 10.4 mg/L and 11.9 +/- 0.7 mg/L, respectively. CONCLUSION: Pharmacokinetic data of anuric patients with acute renal failure were similar to those of patients with end-stage renal failure. Because hemofiltration contributes significantly to meropenem elimination, the recommended dose for critically ill anuric patients receiving continuous venovenous hemofiltration should be increased by 100% to avoid potential underdosing.

Acute Kidney Injury↗
PubMed1999

Application of microdialysis for the determination of muscle and subcutaneous tissue concentrations after oral and topical ibuprofen administration.

BACKGROUND: The topical administration of non-steroidal antiinflammatory drugs (NSAIDs) is widely used for the treatment of soft tissue pain. However, it is not known whether effective tissue concentrations are reached with the topical route. OBJECTIVE: To evaluate and compare unbound muscle and subcutaneous tissue ibuprofen concentrations with use of microdialysis after topical and oral administration. METHODS: In a 2-way crossover design, 11 healthy volunteers received either 800 mg oral ibuprofen or 16 g of 5% ibuprofen gel applied onto the skin of the thigh (defined area, 17 x 19 cm). Microdialysis catheters were inserted into the medial vastus muscle (25 to 30 mm) and into the subcutaneous adipose layer of the thigh (4 to 5 mm). Dialysate was collected in 20-minute intervals up to 5 hours. RESULTS: Essentially all of the orally administered dose was recovered in urine as ibuprofen or metabolites during 24 hours, but only about 0.55% of the topically administered dose was recovered. The relative systemic bioavailability of ibuprofen gel, based on urine recovery data, was (mean +/- SD) 0.57%+/-0.30%. Mean values of the dialysate areas under the drug concentration-time curves after topical and oral administration were 731.2+/-605.0 and 176.6+/-122.9 ng x h x mL(-1) for subcutaneous tissue and 63.5+/-90.3 and 213.4+/-117.2 ng x h x mL(-1) for muscle, respectively. Muscle dialysate concentrations after topical administration varied considerably among the subjects. CONCLUSION: These results suggest that, if target tissue concentrations correlate directly with the degree of pain relief, patients with pain caused by dermal or subcutaneous tissue damage will have greater pain relief after topical administration of ibuprofen accompanied with less systemic side effects. In addition, a proportion of patients with muscle pain may also experience pain relief from topical ibuprofen.

Administration, Cutaneous↗
PubMed1999

Visual evoked potentials in migraine patients: alterations depend on pattern spatial frequency.

Visual information is conducted by two parallel pathways (luminance- and contour-processing pathways) which are thought to be differentially affected in migraine and can be investigated by means of pattern-reversal visual evoked potentials (VEPs). Components and habituation of VEPs at four spatial frequencies were compared between 26 migraineurs (13 without aura, MO; 13 with aura, MA) and 28 healthy volunteers. Migraineurs were recorded in the headache-free interval (at least 72 h before and after an attack). Five blocks of 50 responses to chequerboards of 0.5, 1, 2 and 4 cycles per degree (c.p.d.) were sequentially averaged and analysed for latency and amplitude. Differences in VEPs were dependent on spatial frequency. Only when small checks were presented, i.e. at high spatial frequency (2 and 4 c.p.d.), was the latency of N2 significantly prolonged in MA and did it tend to be delayed in MO subjects. Habituation behaviour was not significantly different between groups under the stimulating conditions employed. Prolonged N2 latency might be explained by the lack or attenuation of a contour-specific component N130 in migraineurs, indicating an imbalance of the two visual pathways with relative predominance of the luminance-processing Y system. These results reflect an interictally persisting dysfunction of precortical visual processing which might be relevant in the pathophysiology of migraine.

Adult↗
PubMed1999

Pharmacokinetic modeling of M6G formation after oral administration of morphine in healthy volunteers.

BACKGROUND: Morphine is metabolized to two major metabolites, morphine-3-glucuronide and morphine-6-glucuronide (M6G). Under the conditions of long-term oral morphine administration, the accumulation of M6G may contribute to the analgesic effects, but it may also cause respiratory depression. METHODS: Five healthy male volunteers (ages 25-34 yr) received 90 mg MST (morphine sulfate 5H2O sustained-released tablet, equivalent to 67.8 mg oral morphine). Multiple plasma and urine samples were taken for as long as 14 and 36 h, respectively. Individual pharmacokinetics after intravenous administration of morphine and M6G were available from a previous investigation. A new model that considers the M6G-plasma profile as a sum of the input from the first-pass metabolism of morphine and the input from systemically available morphine was applied to the plasma concentration versus time curves of M6G. The concentrations of M6G at the effect site after long-term morphine administration were simulated. RESULTS: The fraction of morphine absorbed from the gut was 82+/-14%. Of this, 42+/-8% passed through the liver, resulting in an oral bioavailability of morphine of 34+/-9%. Of the total amount of M6G, 71+/-7% was formed during the first-pass metabolism, and 29+/-7% was formed by metabolism of systemic morphine. After 36 h, the amounts of M6G and morphine excreted in the urine were 92+/-17% and 9+/-3%, respectively. Simulation of effect-site concentrations of M6G indicated that after multiple oral dosing of morphine in patients with normal liver and renal function, M6G might reach concentrations two times greater than that of morphine. CONCLUSIONS: M6G may contribute to the analgesic and side effects seen with long-term morphine treatment. The current model of morphine and M6G pharmacokinetics after oral administration of morphine may serve as a pharmacokinetic basis for experiments evaluating the analgesic contribution of M6G with long-term oral dosing of morphine.

Administration, Oral↗
PubMed1999

Pharmacokinetics of opioids in liver disease.

The liver is the major site of biotransformation for most opioids. Thus, the disposition of these drugs may be affected in patients with liver insufficiency. The major metabolic pathway for most opioids is oxidation. The exceptions are morphine and buprenorphine, which primarily undergo glucuronidation, and remifentanil, which is cleared by ester hydrolysis. Oxidation of opioids is reduced in patients with hepatic cirrhosis, resulting in decreased drug clearance [for pethidine (meperidine), dextropropoxyphene, pentazocine, tramadol and alfentanil] and/or increased oral bioavailability caused by a reduced first-pass metabolism (for pethidine, dextropropoxyphene, pentazocine and dihydrocodeine). Although glucuronidation is thought to be less affected in liver cirrhosis, and clearance of morphine was found to be decreased and oral bioavailability increased. The consequence of reduced drug metabolism is the risk of accumulation in the body, especially with repeated administration. Lower doses or longer administration intervals should be used to remedy this risk. Special risks are known for pethidine, with the potential for the accumulation of norpethidine, a metabolite that can cause seizures, and for dextropropoxyphene, for which several cases of hepatotoxicity have been reported. On the other hand, the analgesic activity of codeine and tilidine depends on transformation into the active metabolites, morphine and nortilidine, respectively. If metabolism is decreased in patients with chronic liver disease, the analgesic action of these drugs may be compromised. Finally, the disposition of a few opioids, such as fentanyl, sufentanil and remifentanil, appears to be unaffected in liver disease.

Administration, Oral↗
PubMed1998

Effects of nasal-airway volume and body temperature on intranasal chemosensitivity.

Interrelations between intranasal detection sensitivity for odor (H2S) and pain (CO2), nasal-airway volume (acoustic rhinometry), and body temperature were studied in young, healthy men across the diurnal cycle. The results showed a weak but statistically significant negative correlation between nasal volume and odor threshold and a weak but positive correlation between body temperature and odor threshold.

Adult↗
PubMed1998

Factors affecting pain intensity in a pain model based upon tonic intranasal stimulation in humans.

OBJECTIVE: The present publication describes an inflammatory pain model based on an air-stream introduced in the nasal cavity. The aim of the present study was to investigate the influence of flow, humidity and temperature of the air-stream on the intensity of the evoked pain sensations. METHODS: Six healthy volunteers participated in the study. Pain was produced by a stream of air introduced to the nasal cavity at different flow rates (5, 6 and 81/min), humidity (20 and 80% relative humidity) and temperature (16, 24, and 32 degrees C). The evoked pain was quantified by means of visual analogue scales. RESULTS: The air-stream induced a dull and burning painful sensation. The intensity of pain was found to be related to the air-stream's humidity and temperature. Specifically, a dry air-stream (20% relative humidity) evoked significantly stronger pain than a humidified air-stream (80% relative humidity). Pain was significantly greater at a temperature of 32 degrees C than at 24 degrees and 16 degrees C, while the temperatures of 16 and 24 degrees C did not differ with respect to pain intensity. In contrast, a tendency towards stronger pain produced by a flow of 81 compared to that with 51 could not be statistically justified within the present study. CONCLUSIONS: The non-invasive pain stimulus was found to be easily applicable and the evoked pain sensation could be modified by variation of humidity and temperature of the air-stream.

Adult↗
PubMed1998

Pharmacokinetics of morphine-6-glucuronide and its formation from morphine after intravenous administration.

BACKGROUND: Morphine-6-beta-glucuronide is a primary morphine metabolite with potent opioid action. However, its low and slow brain permeability eventually prevents its central opioid effects after short-term intravenous administration. Research is needed to establish whether morphine-6-beta-glucuronide qualifies as an analgesic; this study provides the pharmacokinetic bases for such studies. METHODS: Plasma concentration-time data of morphine-6-beta-glucuronide and morphine obtained from 20 healthy volunteers after short-term intravenous administration of either morphine-6-beta-glucuronide or morphine were described by a biexponential disposition curve. Disposition parameters of morphine-6-beta-glucuronide and morphine were estimated by nonlinear regression, and basic pharmacokinetic parameters (clearance, volume of distribution at steady state, and mean disposition residence time) were derived. A new model of metabolite kinetics was applied, and the disposition parameters of morphine and morphine-6-beta-glucuronide were then used to fit the plasma concentration-time profile of morphine-6-beta-glucuronide formed from morphine. Thereby the fraction of morphine metabolized to morphine-6-beta-glucuronide and the mean transit time of morphine across the site of metabolism were estimated. RESULTS: The extent and time course of morphine-6-beta-glucuronide formation from morphine could be well described by a parametric model, with a fraction of morphine metabolized to morphine-6-beta-glucuronide of 7.55% +/- 1.24% and a mean metabolic transit time for morphine to morphine-6-beta-glucuronide of 0.28 +/- 0.21 hour. The underlying disposition of morphine and morphine-6-beta-glucuronide was characterized by clearance (morphine clearance, 32.7 +/- 6 ml.min-1.kg-1, morphine-6-beta-glucuronide clearance, 2.2 +/- 0.4 ml.min-1.kg-1), volume of distribution at steady state (morphine, 1.8 +/- 0.3 L.hr-1; morphine-6-beta-glucuronide, 0.12 +/- 0.02 L.hr-1), and mean disposition residence time (morphine, 1.8 +/- 0.4 hours; morphine-6-beta-glucuronide, 1.7 +/- 0.4 hours). CONCLUSIONS: The time course of morphine-6-beta-glucuronide formation kinetics was analyzed with use of the information on the disposition kinetics of both morphine and preformed morphine-6-beta-glucuronide, which was obtained by separate data fits. The transformation of morphine to morphine-6-beta-glucuronide could be described by two parameters characterizing the extent and delay of metabolite formation. The results of this study will serve as pharmacokinetic bases of future investigations of morphine-6-beta-glucuronide in human beings.

Adult↗
PubMed1998

Trigeminal chemosensitivity: Differences in relation to the time of the day.

Day-night differences of trigeminal chemosensitivity were investigated in 18 healthy volunteers employing both pain-related cortical potentials and pain ratings in response to stimulation of the nasal mucosa with CO2. Day-night differences were found with N 1 P2 amplitudes, P2 latencies and pain ratings. It is concluded that the time of the day must not be ignored when human chemosensitivity is investigated at suprathreshold levels.

Adult↗
PubMed1997

The negative mucosal potential: separating central and peripheral effects of NSAIDs in man.

OBJECTIVE: We wanted to test whether assessment of both a central pain-related signal (chemo-somatosensory evoked potential, CSSEP) and a concomitantly recorded peripheral signal (negative mucosal potential, NMP) allows for separation of central and peripheral effects of NSAIDs. For this purpose, experimental conditions were created in which NSAIDs had previously been observed to produce effects on phasic and tonic pain by either central or peripheral mechanisms. METHODS: According to a double-blind, randomised, controlled, threefold cross-over design, 18 healthy subjects (11 males, 7 females; mean age 26 years) received either placebo, 400 mg ibuprofen, or 800 mg ibuprofen. Phasic pain was applied by means of short pulses of CO2 to the nasal mucosa (stimulus duration 500 ms, interval approximately 60 s), and tonic pain was induced in the nasal cavity by means of dry air of controlled temperature, humidity and flow rate (22 degrees C, 0% relative humidity, 145 ml.s-1). Both CSSEPs as central and NMPs as peripheral correlates of pain were obtained in response to the CO2 stimuli. Additionally, the subjects rated the intensity of both phasic and tonic pain by means of visual analogue scales. RESULTS: As described earlier, administration of ibuprofen was followed by a decrease in tonic pain but-relative to placebo-an increase in correlates of phasic pain, indicating a specific effect of ibuprofen on the interaction between the pain stimuli under these special experimental conditions. Based on the similar behaviour of CSSEP and NMP, it was concluded that the pharmacological process underlying this phenomenon was localised in the periphery. By means of the simultaneous recording of interrelated peripheral and central electrophysiologic correlates of nociception, it was possible to separate central and peripheral effects of an NSAID. The major advantage of this pain model is the possibility of obtaining peripheral pain-related activity directly using a non-invasive technique in humans.

Adult↗
PubMed1997

Chronobiology of nasal chemosensitivity: do odor or trigeminal pain thresholds follow a circadian rhythm?

Odor and trigeminal pain thresholds were studied four times each at 24:00, 04:00, 08:00, 12:00, 16:00 and 20:00 h in randomized order on different days in five healthy male volunteers. No circadian rhythm of olfactory or trigeminal thresholds were observed. However, the variability of odor, but not pain thresholds, increased from 04:00 h (thresholds between 0.4 and 1.2 p.p.m.) to 16:00 h (thresholds between 0.1 and 2 p.p.m.). It is hypothesized that environmental influences contribute to this increase in variance.

Adult↗
PubMed1997

Lack of analgesic activity of morphine-6-glucuronide after short-term intravenous administration in healthy volunteers.

BACKGROUND: The analgesic activity of morphine-6-glucuronide (M-6-G) is well recognized for its contribution to the effects of morphine and its possible use as an opioid analgesic with a wider therapeutic range than morphine. The present study attempted to quantify the relative contribution of M-6-G to analgesia observed after systemic administration of morphine. METHODS: In a placebo-controlled, sixfold crossover study in 20 healthy men, the effects of M-6-G were assessed at steady-state plasma concentrations of M-6-G identical to and two and three times higher than those measured after administration of morphine. Morphine and M-6-G were administered as an intravenous bolus followed by infusion over 4 h. Dosage A was M-6-G-bolus of 0.015 mg/kg plus infusion of 0.0072 mg x kg(-1) x h(-1). Dosage B was M-6-G-bolus of 0.029 mg/kg plus infusion of 0.014 mg x kg(-1) x h(-1). Dosage C was M-6-G-bolus of 0.044 mg/kg plus infusion of 0.022 mg x kg(-1) x h(-1). Dosage D was a morphine bolus of 0.14 mg/kg plus infusion of 0.05 mg x kg(-1) x h(-1) for 4 h. Dosage E was M-6-G combined with morphine (doses A + D). Dosage F was a placebo. The analgesic effects of M-6-G and morphine were measured before administration of the bolus and after 3.5 h using an experimental pain model based on pain-related cortical potentials and pain ratings after specific stimulation of the nasal nociceptor with short pulses of gaseous carbon dioxide. RESULTS: Morphine significantly reduced subjective and objective pain correlates compared with placebo. In contrast, M-6-G produced no statistically significant effects. The addition of M-6-G to morphine did not increase the effects of morphine. Morphine produced significantly more side effects than M-6-G. CONCLUSION: After short-term intravenous administration at doses that produce plasma concentrations of M-6-G similar to those seen after administration of morphine, M-6-G had no analgesic effects in the present placebo-controlled study in healthy volunteers.

Adult↗
PubMed1997

Antinociceptive effects of the kappa-opioid receptor agonist RP 60180 compared with pentazocine in an experimental human pain model.

Agonists at kappa-opioid receptors may preserve the analgesic properties of mu-opioidergic agonists while avoiding their major adverse effects. The present study was aimed to investigate the antinociceptive effects of the new kappa-opioid receptor agonist RP 60180. An experimental pain model was used based on specific pain stimuli and event-related potentials. Effects of RP 60180 were compared to placebo and to pentazocine that served as positive control. Twenty healthy male volunteers participated in a placebo-controlled, randomized, double-blind, five-way cross-over study. Single peroral doses of RP 60180 (0.1, 0.5, and 1.0 mg), pentazocine (50 mg), and placebo were administered. Pain was induced by means of short pulses of gaseous CO2 applied to the nasal mucosa. In response to these stimuli, chemo-somatosensory event-related potentials (CSSERP) and pain ratings were recorded. Maximum antinociceptive effects were observed 2 h after the administration of 1.0 mg of RP 60180 and 50 mg of pentazocine. This was shortly after RP 60180 had reached the maximum plasma concentration and when highest plasma concentrations of pentazocine were measured. Both RP 60180 and pentazocine reduced pain-related CSSERP amplitudes by approximately 40% at this time. Pentazocine tended to produce more side effects. These results indicate the potential therapeutic value of kappa-agonist analgesics.

Adult↗
PubMed1996

Analgesic effects of propyphenazone in comparison to its combination with caffeine.

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.

Administration, Oral↗
PubMed1996

Pharmacokinetics of morphine and its glucuronides after intravenous infusion of morphine and morphine-6-glucuronide in healthy volunteers.

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.

Adult↗
PubMed1996

Loss of olfactory function leads to a decrease of trigeminal sensitivity.

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.

Action Potentials↗