Biomedical subjects

L Molander

Publications and source records attributed to L Molander.

At least 19 recordsLinked to original sources

PubMed2001

Pharmacokinetics of nicotine in healthy elderly people.

BACKGROUND: Mortality hazards of smoking extend well into later life; this suggests that smoking cessation will continue to improve life expectancy in older people. The pharmacology and pharmacokinetics of nicotine have not been studied in elderly subjects. Drug disposition and pharmacodynamic responsiveness to nicotine may change with age, and conclusions founded on data from studies of younger populations may not apply to elderly populations. Our aim was to assess the pharmacokinetics of nicotine in healthy elderly subjects compared with healthy adults. METHODS: Twenty healthy elderly subjects (age, 65-76 years) and 20 healthy adult subjects (age, 22-43 years) were given an intravenous infusion of 0.028 mg/kg of nicotine over 10 minutes. Nicotine and cotinine concentrations were measured in plasma and urine. Heart rate and blood pressure were monitored. RESULTS: For most adult and elderly subjects nicotine distributed according to a two-compartment system. Even though there was a large interindividual variation within and overlap between groups, nicotine total clearance (-23%), nonrenal clearance (-21%), renal clearance (-49%), volume of central compartment (-37%), volume of distribution at steady state (-17%), and cotinine renal clearance (-18%) were statistically significantly decreased in elderly subjects compared with adults. Maximal heart rate response to nicotine was decreased in the elderly subjects (-29%). CONCLUSION: Even though statistically significant differences were observed, the disposition of nicotine does not seem to be changed to a clinically important extent in elderly subjects compared with younger adults.

Adult↗

PubMed2000

Site of nicotine absorption from a vapour inhaler--comparison with cigarette smoking.

OBJECTIVE: The aim of the study was to assess the site of nicotine absorption during and after use of a nicotine-vapour inhaler compared with that after cigarette smoking. METHODS: Using a catheterisation technique, the nicotine plasma concentration-time profiles in arterial and jugular venous blood after using a nicotine inhaler were compared with those achieved after cigarette smoking a in seven healthy habitual smokers. RESULTS: After use of the inhaler, arterial nicotine concentrations rose slowly to a maximum level of 5. 9 +/- 1.5 ng/ml at a mean time to reach peak concentration (t(max)) of 9.0 +/- 1.1 min, whereas jugular venous nicotine levels peaked at 25.4 +/- 5.4 ng/ml at 6.7 +/- 0.3 min. The concentration-time curves indicate that the absorption occurs mainly via the mucosa of the oral cavity and the pharynx, and that there is minimal absorption via the lungs. In contrast, after smoking a cigarette, arterial nicotine plasma concentrations rose quickly to a maximum level of 49. 2 +/- 9.7 ng/ml after 4.0 +/- 0.6 min, while the maximum concentration of nicotine in the jugular vein was 22.4 +/- 3.9 ng/ml after 6.4 +/- 0.4 min, indicating primarily pulmonary absorption of nicotine. CONCLUSION: Nicotine absorption after use of the vapour inhaler occurs primarily via the mucosa of the oral cavity; the absorption occurs slowly and the arterial nicotine concentration spike, typical of cigarette smoking, is avoided. Thus, the likelihood for abuse of the nicotine inhaler is probably small.

Absorption↗

PubMed2000

Pharmacokinetics of nicotine in kidney failure.

BACKGROUND: Smoking is an important risk factor for cardiovascular and cerebrovascular complications in patients with chronic kidney failure. Very high plasma nicotine concentrations have been reported in patients with severe kidney failure, indicating that the disposition of nicotine in these patients may be different. The purpose of this study was to assess the pharmacokinetics of intravenously administered nicotine in healthy subjects and in patients with kidney failure. METHODS: Nine healthy subjects (glomerular filtration rate [GFR], 84 to 143 mL/min/1.73 m2), four patients with mild kidney failure (GFR, 63 to 73 mL/min/1.73 m2), five patients with moderate kidney failure (GFR, 18 to 36 mL/min/1.73 m2), and six patients with severe kidney failure (GFR, 1 to 10 mL/min/1.73 m2) were recruited. Three patients were treated with continuous ambulatory peritoneal dialysis. An intravenous infusion of nicotine (0.028 mg/kg) was given for 10 minutes. Nicotine and cotinine concentrations were measured in plasma, urine, and peritoneal dialysate from 0 to 24 hours after start of infusion RESULTS: There were significant correlations between GFR and total clearance, nonrenal and renal clearance of nicotine, area under the plasma concentration-time curve extrapolated to infinity, terminal elimination half-life, and mean residence time. Nonrenal clearance was 1303 mL/min and 661 mL/min in healthy subjects and patients with severe kidney failure, respectively. Only 1% to 2% of the nicotine dose was excreted unchanged in a 24-hour collection of peritoneal dialysate. The elimination of cotinine was also decreased in patients with kidney failure. CONCLUSION: Progressive kidney failure is associated with a gradual decrease of renal and nonrenal elimination of nicotine.

Adult↗

PubMed2000

Reduction of tobacco withdrawal symptoms with a sublingual nicotine tablet: a placebo controlled study.

Many smokers are unable to use gum as a cessation aid due to fillings, bridgework and dyspepsia or they reject it for esthetic reasons. The nicotine sublingual tablet is a new alternative to the nicotine polacrilex chewing gum that does not necessitate chewing. Twenty subjects used 2-mg sublingual nicotine tablets and placebo in a double-blind randomized crossover study of 2-day smoke-free periods. Craving and other withdrawal symptoms were rated on 100-mm visual analog scales (VAS) nine times over each 2-day period. Plasma nicotine concentrations in the afternoon of each study day were determined. A blood sample was also taken in the afternoon of a 2-day period with normal smoking. The mean number of nicotine tablets was 10 and seven on days 1 and 2, respectively. The corresponding number for placebo tablets was six and five. No subject used less than five tablets on any study day. The degree of nicotine substitution, defined as the quotient between the plasma levels achieved with the sublingual tablet and smoking, was 43, 30 and 23% for smokers with FTQ < or = 6, FTQ = 7 and FTQ > or = 8 (Fagerström Tolerance Questionnaire), respectively. Active treatment was significantly superior in decreasing craving and other withdrawal symptom scores compared to placebo treatment. Mean total scores were reduced by approximately 50%. Adverse events were mainly symptoms of local irritation such as a burning sensation in the throat or under the tongue, a lump in the throat and heartburn. These results demonstrate partial relief of the tobacco withdrawal syndrome with use of the sublingual tablet similar to that achieved from other forms of nicotine replacement.

Administration, Sublingual↗

PubMed1999

Electroencephalographic effects of intravenous nicotine--a dose-response study.

RATIONALE: It has often been demonstrated that both tobacco abstinence and nicotine have effects on the EEG power spectrum and components of the event-related potentials. In contrast, few attempts have been made to establish the dose-response relationship between nicotine and EEG parameters. OBJECTIVES: The aim of this study was to investigate the dose-response relationship for EEG and auditory oddball P300 parameters over a wide range of intravenously infused nicotine doses. METHOD: Fourteen regular smokers who had abstained from nicotine for at least 12 h were given intravenous infusions of 0, 3.5, 7, 14 and 28 micrograms/kg nicotine over 10 min in a single-blind randomised cross-over design. Parallel recordings of spontaneous EEG, auditory P300 and heart rate, as well as venous blood sampling were made before, during and after nicotine administration. RESULTS: Linear dose-related decreases of delta and theta power were found, along with increases in alpha2 power and alpha peak frequency. Alpha1, beta and P300 parameters were unaffected. CONCLUSION: Our results are consistent with nicotine-dependent changes in EEG measures indicative of arousal.

Cross-Over Studies↗

PubMed1997

Temperature dependency of the release and bioavailability of nicotine from a nicotine vapour inhaler; in vitro/in vivo correlation.

OBJECTIVE: To investigate the temperature dependency of the dose released and the plasma levels of nicotine from a vapour inhaler. METHODS: In an open, randomised, three-way cross-over pharmacokinetic study 18 healthy subjects inhaled nicotine for 20 min (80 inhalations) every hour for 10 h (11 administrations) at three different environmental temperatures: 20 degrees, 30 degrees and 40 degrees C. In the in vitro experiment, 5, 10, 15 and 20 l air were forced through the inhaler. With a 15 l air volume, the average amount of nicotine released was 1.44, 3.49, 4.80 and 6.99 mg at 10 degrees C, 22 degrees C, 29 degrees C and 40 degrees C, respectively. The maximum dose released at the highest temperature (40 degrees C) and the largest air volume investigated (20 l) was approximately 7.5 mg. RESULTS: In vivo peak plasma levels obtained at 30 degrees and 40 degrees C were 29.7 and 34.0 ng.ml-1, compared with 22.5 ng.ml-1 at ambient room temperature (20 degrees C). At 20 degrees C, the area under the plasma concentration-time curve (AUC) of the last dosing interval was 20.5 ng.ml-1.h. At 30 degrees C and 40 degrees C, the AUCs were 26.5 and 30.3 ng.ml-1.h, respectively. The results thus showed a mean increase of the in vivo AUC by 29% at 30 degrees C and by 48% at 40 degrees C compared with the AUC at 20 degrees C. These increases should be compared to the in vitro results, showing a mean increase of 59% and 122% respectively, at 30 degrees and 40 degrees C. The in vitro results also showed that a relatively larger fraction of the dose was released into the first 5 l of air at the higher temperatures, at 40 degrees C, about 50% of the total amount released into 20 l. CONCLUSION: It was concluded that the in vitro/in vivo discrepancy was most probably due to increased aversive effects at elevated temperatures, causing the subjects to inhale smaller puff volumes. Further, the inhaler would not produce nicotine plasma levels exceeding those achieved following cigarette smoking, even in a hot climate.

Administration, Inhalation↗

PubMed1996

Dose released and absolute bioavailability of nicotine from a nicotine vapor inhaler.

In an open, randomized, three-way crossover study, 14 healthy smokers used one type of nicotine vapor inhaler intensely for 20 minutes every hour for 11 hours (12 administrations). Two different inhalation techniques were applied, shallow frequent sucking (buccal mode) and deep inhalations (pulmonary mode). The determination of nicotine was performed by capillary gas chromatography after single-step liquid-liquid extraction of the plasma sample. Nicotine was detected by means of a nitrogen-sensitive detector, giving high selectivity and sensitivity. The mean (+/- SD) nicotine dose released from each nicotine vapor inhaler unit was estimated at 4.00 +/- 0.60 mg (buccal mode) and 3.87 +/- 0.75 mg (pulmonary mode), inhaled with approximately 15 L of air. Mean (+/- SD) peak plasma level of the last dosing interval was 32.0 +/- 8.7 ng/ml and 34.2 +/- 8.9 ng/ml for the buccal and the pulmonary technique, respectively, achieved after 0.33 and 0.50 (median) hour, respectively. The mean (95% confidence interval [CI]) absolute bioavailability of nicotine was 51 (95% CI, 40 to 65) and 56 (95% CI, 47 to 67) when the buccal and pulmonary techniques were used, respectively. A significant correlation was found between systemically available dose and average steady-state nicotine plasma concentration. Based on the achievement of similar nicotine plasma levels, it may be concluded that the two modes of inhalation appear to be clinically equivalent.

Administration, Inhalation↗

PubMed1995

Effect of nicotine vapour inhalation on the relief of tobacco withdrawal symptoms.

Fifteen subjects participated in a randomised, placebo-controlled cross-over study to assess the effect of a nicotine vapour inhaler on craving and other withdrawal symptoms during a two-day smoking-free period. Craving and withdrawal symptoms were rated nine times over the two-day period on 10 cm visual analogue scales. Plasma nicotine concentrations in the afternoon of each study day were determined. The results show that active treatment was significantly superior to placebo in decreasing craving and other withdrawal symptom scores. No difference was found between two inhalation techniques, one with shallow, frequent inhalations (buccal technique), and the other with deep inhalations (pulmonary technique). The average number of active nicotine vapour inhalers and placebo inhalers used during the two-day sessions was 12 and 11, respectively. Afternoon plasma nicotine levels of approximately 7 ng/ml were obtained with both inhalation techniques. A strong correlation was found between the afternoon plasma nicotine levels and craving, a high nicotine level being associated with a low craving score. The study has provided information about how to use the nicotine vapour inhaler that could have important implications if it were to be approved for the treatment of tobacco dependence. The use of withdrawal symptom reduction as a surrogate end-point is discussed.

Administration, Inhalation↗

PubMed1995

Relative bioavailability of nicotine from a nasal spray in infectious rhinitis and after use of a topical decongestant.

The relative bioavailability of nicotine from a nasal spray was assessed in 15 smokers suffering a common cold and rhinitis according to generally accepted criteria. The patients were given a single dose of 2 mg nicotine from the nasal spray with and without concurrent administration of a nasal vasoconstrictor decongestant, xylometazoline, in randomised order. Control session measurements were made in the disease-free state. Applying strict bioequivalence criteria, we found that common cold/rhinitis slightly reduced the bioavailability of nicotine, both in its rate and extent; the geometric mean of the ratio of Cmax, AUC and tmax were 0.81, 0.93 and 1.36, respectively. The nasal vasoconstrictor, xylometazoline, normalised the extent of the bioavailability of nicotine, but further prolonged the time for absorption to almost twice that measured in the disease-free state, increasing the tmax ratio to 1.72. The results suggest that a minor proportion of people stopping smoking with the help of a nicotine nasal spray may experience a minor reduction in the effect of the spray during common cold/rhinitis. However, the nicotine self-titration behaviour found with most smoking cessation products (except the nicotine patch) will automatically lead to an adjustment of the dosage to achieve the desired effect.

Administration, Intranasal↗

PubMed1983

Relationship between plasma concentration and arousal in normal subjects after single oral and parenteral doses of melperone, a butyrophenone neuroleptic.

The relationship between plasma concentration and effect on arousal was studied in normal subjects after single oral and parenteral doses of melperone. A strong correlation between plasma concentration and effect was found when the effector compartment and central compartment were in equilibrium. The relationship was independent of the route of administration.

Administration, Oral↗

PubMed1983

Sedative effects and prolactin response to single oral doses of melperone.

The pharmacokinetics of melperone and the relationship between plasma concentration and the effect on arousal and prolactin secretion after single oral doses (10, 25, 50 and 100 mg) was studied in normal subjects. Dose-dependent kinetics were indicated by the fact that higher plasma concentrations than expected were demonstrated after the 100-mg dose. Melperone decreased arousal and increased prolactin secretion in a dose-dependent manner. The level of arousal was correlated to melperone plasma concentration over the entire dose range. Prolactin secretion was also correlated to melperone plasma concentration, provided the relationship was studied separately for the individual melperone doses. Thus at higher doses, higher plasma concentrations are needed to elicit the same prolactin outflow. The possibility that reduced arousal reactions might contribute in the antipsychotic action of neuroleptic drugs was discussed.

Adult↗

PubMed1982

Effect of melperone, chlorpromazine, haloperidol, and diazepam on experimental anxiety in normal subjects.

An attempt was made to evaluate tranquilizing effects of three neuroleptic drugs (10 and 50 mg melperone, 1 mg haloperidol, and 50 mg chlorpromazine) and diazepam (10 mg) on experimental anxiety in normal subjects. This was done by studying the effects of the drugs on the anticipatory autonomic (skin conductance) response evoked during aversive classical conditioning. Diazepam, 50 mg melperone, and chlorpromazine completely abolished the anticipatory response, decreased the number of conditioned and unconditioned responses, and decreased skin conductance level. Treatment with 10 mg melperone and haloperidol had no effect on the conditioned and unconditioned responses.

Acoustic Stimulation↗

PubMed1982

Pharmacokinetics of parenteral and oral melperone in man.

The pharmacokinetics of melperone (Buronil, Ferrosan, Sweden) was studied after administration of various parenteral and oral doses to man. After parenteral administration, the data could be fitted to a two-compartment model, but after oral dosing the distribution phase could not be separated from the elimination phase, and so an one-compartment model gave the best fit. The half-lives were about 3-4 h, except after intramuscular injection, when the half-life was about 6 h. The bioavailability of oral doses was about 60% of the intravenous injection. After the highest oral dose of 100 mg, the pharmacokinetics, expressed as AUC or Cmax, showed non-linearity, possibly due to saturation of the hepatic elimination system.

Administration, Oral↗

PubMed1981

Effect of single oral doses of various neuroleptic drugs on salivary secretion rate, pH, and buffer capacity in healthy subjects.

The effects of melperone, thioridazine, levomepromazine, and chlorprotixene on salivary secretion rate, pH, and buffer capacity was studied in eight healthy volunteers given single oral doses of placebo or 10, 25, and 50 mg of the drugs in a single-blind crossover design. Both resting and stimulated saliva samples were collected before and every hour for 6h after administration. All drugs reduced secretion rate and lowered pH and buffer capacity, mostly in a dose-dependent manner. The effects of levomepromazine and chlorprotixene were more pronounced than those of melperone and thioridazine.

Adult↗

PubMed1979

Interferon production by mammalian cells grown in a serum-free medium.

Interferon, produced by rabbit heart cells grown in a serum-free medium, failed to protect rabbit heart serum-free cells, but protected rabbit heart serum-containing-medium cells against vaccinia and vesicular stomatitis virus. Interferon produced in serum-free cells had a greater species specificity than that produced in serum-containing media. The difference in activity was shown to be due to lack of adsorption by serum-free-medium cells.

Animals↗

PubMed1979

Pharmacokinetics of femoxetine in man.

The pharmacokinetics of a structurally new 5HT-uptake inhibitor, femoxetine (FG 4963), with antidepressant properties have been investigated in man using a radioactive as well as a non-labelled substance. A two compartment open model gives a good description of the data, both after oral and intravenous administration. The substance was almost completely absorbed after an oral dose, but only 5-10% reached the systemic circulation due to extensive first pass metabolism. The metabolites had distribution and excretion rates similar to the parent compound. Only a small part (less than 2%) was excreted as femoxetine in the urine. The urinary excretion of the parent compound varied more than a 100-fold depending on the pH of the urine. The urine pH, however, did not influence the plasma concentration of femoxetine. Most of the substance (up to 80%) was eliminated by urinary excretion of metabolites, and only a small part of the radioactive dose was excreted in the faeces (up to 11%). The pharmacokinetic parameters were not found to be dose dependent in the range investigated, but it was not possible to decide whether the bioavailability was dependent on the dose. The variation between subjects was rather large, giving only a limited possibility for prediction of the plasma concentration from one subject to another.

Administration, Oral↗

PubMed1976

Effects of thymoleptics on behavior associated with changes in brain dopamine. II. Modification and potentiation of apomorphine-induced stimulation of mice.

The thymoleptics potentiate and modify the behavioral effects of apomorphine (probably the most specific dopaminergic agonist) as well as those of Dopa. The effect of the thymoleptics is not abolished by emptying of amine stores, and this together with other evidence suggests that these drugs facilitate the access of apomorphine to the dopamine receptors. The effects of thymoleptics on elements of animal behavior that can be associated with brain dopamine appear interesting on the background of a considerable body of evidence indicating an association of brain dopamine with depression and mania (references).

Animals↗

PubMed1976

Effects of thymoleptics on behaviour associated with changes in brain dopamine. I. Potentiation of dopa-induced gnawing of mice.

The thymoleptics imipramine, desipramine, protriptyline, nortriiptyline, chlorimipramine and amitriptyline all potentiate gnawing of mice induced by Dopa following decarboxylase inhibitior Ro 4-4602. The gnawing behavior is probably associated with the increase in brain dopamine resulting from this treatment. Thymoleptics also affect other types of behaviour associated with brain dopamine. The relevance of these effects to clinical antidepressive effect and their possible utilization for preclinical screening tests is discussed.

Animals↗