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M I Nilsson

Publications and source records attributed to M I Nilsson.

16 recordsLinked to original sources
PubMed1991

Pharmacokinetics and effects on prolactin of remoxipride in patients with tardive dyskinesia.

The pharmacokinetics of remoxipride, a new selective dopamine-D2 receptor antagonist with antipsychotic action, was evaluated in eight elderly psychiatric patients with tardive dyskinesia (TD). The daily oral doses of remoxipride were gradually increased from 50 mg per day to 200 mg t.i.d. over 2 weeks. The pharmacokinetics following the initial 50 mg dose (day 1) and the last 200 mg dose (day 15) of the drug were compared in serial samples. Plasma prolactin concentrations were assessed at the same time points. The area under the total plasma concentration versus time curves (AUC) of remoxipride increased proportionally with dose from day 1 to 15. The mean "dose corrected" AUC values for the total concentrations were 96.8 at day 1 (4 X 24.2, 50 mg single oral dose) and 92.2 mumol.h/l at day 15 (200 mg). The unbound fraction of remoxipride calculated on AUC was slightly higher on day 15 (20%) than on day 1 (15%) (P less than 0.05), indicating slightly concentration-dependent protein binding of the drug. The mean elimination half-life of total remoxipride was slightly longer on day 15 than day 1 (7.5 versus 5.3 h, P less than 0.01) The corresponding half-lives for the unbound concentrations were 6.4 and 3.9 h, respectively (P less than 0.01). The pharmacokinetics of remoxipride is similar in these TD patients and in non-TD patients in previous studies. Following repeated administration of remoxipride, tolerance to the prolactin-releasing action of remoxipride is observed.(ABSTRACT TRUNCATED AT 250 WORDS)

Aged↗
PubMed1990

Plasma concentrations of remoxipride and the gastrointestinal transit of 111In-marked extended-release coated spheres.

To explore the oral absorption of remoxipride, spheres of remoxipride were labeled with indium-111 colloid before coating with a release-controlling ethylcellulose membrane. Since the labeling remained inside the coating, it was suitable as a marker. Eight healthy volunteers were given a single dose of 100 mg remoxipride in 111In-marked spheres as a multiple-unit capsule. The radioactivity and the position of the spheres (microcapsules) were followed externally for 30 hr by gamma scintigraphy. Parallel to this, plasma concentrations were drawn for 48 hr to confirm the extended dissolution and absorption of remoxipride. The hard gelatin, multiple-unit capsule released the microcapsules within the stomach. These were then rapidly emptied into the small intestine, within 0.5-1 hr. There was then an immediate distribution in the upper small intestine before collection in the lower portion, within 2-5 hr. After passing into the large intestine, there was again extended distribution of the microcapsules. A mean Cmax of 2.7 microM remoxipride was achieved 4 hr after drug administration and a mean AUC of 26.1 mumol.L-1.hr was achieved. Judging from the absorption versus time profile, calculated according to the Wagner-Nelson method, and the scintigraphic images, it is concluded that the main absorption occurs from the small intestine. Data from four volunteers, however, indicated a comparatively good absorption also from the large intestine. Due to the good absorption properties, it is reasonable to expect a low variation in the extent of bioavailability of remoxipride after administration in an extended-release, multiple-unit capsule formulation.

Administration, Oral↗
PubMed1989

Remoxipride--a new potential antipsychotic compound. Tolerability and pharmacokinetics after single oral and intravenous administration in healthy male volunteers.

The tolerability and pharmacokinetics of remoxipride were studied in 18 healthy normal male volunteers. Increasing oral doses of 0.5-100 mg were given to eight male volunteers in one study (study I). In addition, an intravenous (IV) infusion of 20 mg remoxipride and a 20 mg oral dose were given in an open crossover study to ten males (study II). Remoxipride was well tolerated with respect to cardiovascular effects, clinical chemistry, body temperature and adverse effects in all subjects. Following IV administration, remoxipride plasma concentrations declined exponentially in five subjects and biexponentially in the remaining five. The mean apparent volume of distribution was 0.5 l/kg (SD = 0.10) and the mean half-life 4.1 h (range 2.6-6.6). The recovery of unchanged remoxipride in urine was 10-36%, and the mean renal clearance was 32 ml/min (SD = 13). Remoxipride was a low clearance drug with a total plasma clearance of about 120 ml/min (SD = 41). The mean oral bioavailability was 96%. There was a linear relationship between the peak plasma concentration as well as the area under the concentration versus time curve and the administered dose. A transient increase in plasma prolactin concentrations occurred but there were no effects on plasma growth hormone levels.

Administration, Oral↗
PubMed1989

Effect of urinary pH on the plasma and urinary kinetics of remoxipride in man.

The influence of urinary pH on the plasma and urinary kinetics of remoxipride in man has been studied in an open crossover trial in ten healthy male volunteers. Ammonium chloride (urinary pH 5.2) and sodium hydrogen carbonate (urinary pH 7.8) were used as pretreatments on two occasions in randomized order. On each occasion remoxipride 50 mg solution was administered orally and plasma and urinary concentrations of the drug were determined by HPLC and plasma prolactin concentrations by RIA. Remoxipride was rapidly distributed in the body according to a one-compartment model. The mean plasma elimination half-life (t1/2) was 3.6 h in the ammonium chloride experiment and 6.2 h in the sodium hydrogen carbonate experiment. The mean plasma clearance of remoxipride was 141 and 89.9 ml.min-1 in the acidic and alkaline conditions, respectively, and the corresponding mean renal clearances were 58.5 ml.min-1 and 11.7 ml.min-1. The urinary excretion of remoxipride up to 72 h after drug administration was 43.1% and 12.3% following acidification and alkalinization, respectively. Remoxipride induced a similar rapid, transient elevation of plasma prolactin under both conditions. Thus, the urinary pH has a marked effect on the elimination kinetics of remoxipride. After an overdose, treatment with ammonium chloride might be valuable in hastening elimination of remoxipride from the body.

Adult↗
PubMed1988

Remoxipride--a new potential antipsychotic drug. Pharmacological effects and pharmacokinetics following repeated oral administration in male volunteers.

Remoxipride, a new potential antipsychotic drug, was administered over 4 days at two dose levels, 70 and 140 mg t.i.d., to eight healthy male volunteers. Pharmacokinetics, safety, tolerability, and effect on plasma prolactin levels were evaluated. Remoxipride exhibited essentially linear pharmacokinetics. Only minor deviations in biochemical and physiological safety parameters were found. The drug was well tolerated by all subjects at the 70 mg dose level. At 140 mg akathisia appeared in seven subjects. The drug induced a rapid and transient increase in plasma prolactin concentrations at both dose levels after single doses. During steady state, a significant reduction in the prolactin response was observed as compared to after the first dose.

Administration, Oral↗
PubMed1988

Remoxipride, a selective dopamine D2 receptor antagonist, in tardive dyskinesia.

Remoxipride in a dose range of 150-600 mg/day was evaluated in a single-blind placebo controlled study in eight patients with persistent tardive dyskinesia (TD). Dyskinesia score was significantly reduced without an increase in parkinsonism. The maximum mean reduction in dyskinesia rating score was 44%. After withdrawal of remoxipride TD scores returned to baseline levels without rebound deterioration. A negative correlation between remoxipride concentrations and the dyskinesia scores were found. Adverse effects were few and mild and no clinically relevant changes were seen in clinical chemistry, haematology or cardiovascular assessments. It is concluded that remoxipride in the dose range used has anti-dyskinetic effects but does not induce parkinsonism.

Aged↗
PubMed1983

Pharmacokinetics of methadone in methadone maintenance treatment: characterization of therapeutic failures.

Deuterated methadone (M-d3) and GC-MS analysis were used to study the steady state pharmacokinetics of methadone (M) in eight patients reported as therapeutic failures in a methadone maintenance treatment programme. The patients were compared to an unselected group of 12 patients stabilized on M for 25 days. During one dosage interval a pulse dose of M-d3 was administered intravenously instead of the oral M-dose (M-d0). The pharmacokinetic parameters, half-life in the beta-phase (t1/2 beta), volume of distribution during the postdistributive phase (Vd beta) and during steady state (Vdss) were determined as well as the body (ClS) and renal (ClR) clearances of M. Pronounced differences in Vd beta and Vdss were found between the two groups. The therapeutic failures had a smaller Vd beta and Vdss 3.09 +/- 0.96 1/kg and 2.74 +/- 0.96 1/kg vs 4.56 +/- 1.00 1/kg and 4.20 +/- 0.78 1/kg in the control group. The differences were due to changes between the groups in the volume of the central compartment. Differences between the groups were also found in t1/2 beta - 24.5 +/- 2.6 h in the therapeutic failures and 34.0 +/- 7.0 h (p less than 0.001) in the comparison group. However, the change in t1/2 beta was probably a consequence of the change in Vd beta, as the body clearance of M was similar in the two groups - 104 +/- 36 ml/min vs 111 +/- 36 ml/min. The smaller volume of distribution could lead to unacceptably high fluctuation of M in the central compartment, and withdrawal symptoms during the latter part of the dosage interval.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1982

Effect of urinary pH on the disposition of methadone in man.

The influence of urinary pH on the acute disposition of methadone in man was studied in five healthy volunteers. A cross-over experiment was performed in each subject. In the first experiment the subjects were treated with ammonium chloride (urinary pH approximately 5.2) and in the other the urine was made alkaline (pH approximately 7.8) by treatment with sodium hydrogen carbonate. d, l-Methadone-HCl 10 mg (M) was administered intramuscularly on each occasion and blood, saliva and urine levels of M were determined by mass fragmentography. Plasma half-lives, volumes of distribution and body clearances of M were calculated in both experiments. The plasma half-lives in the beta-phase were 19.5 +/- 3.6 h (acidic urine) and 42.1 +/- 8.8h (alkaline urine), respectively (p less than 0.001). The volumes of distribution were increased when the pretreatment was changed from ammonium chloride to sodium bicarbonate, namely from 3.51 +/- 0.41 l/kg to 5.24 +/- 0.83 l/kg (p less than 0.01). The body clearance decreased from 134 +/- 21 ml/min (acidic) to 91.9 +/- 9.1 ml/min (alkaline urine) (p less than 0.01). The ration M plasma/M RBC was about 2.3 and the elimination of M from RBCs was good agreement with the plasma kinetics of M under both experimental conditions. The salivary levels of M did not reflect the plasma kinetics and considerable variation was seen in the ratio M saliva/ M plasma (0.26-2.98). Thus, the present experiments demonstrate that pretreatment either with ammonium chloride or bicarbonate had profound effects on both the distribution and elimination kinetics of methadone.

Adult↗
PubMed1982

Pharmacokinetics of methadone during maintenance treatment: adaptive changes during the induction phase.

Deuterated methadone (M-d3) and GCMS were used to study the pharmacokinetics of methadone (M) during the induction stage of methadone maintenance treatment (MMT). A pulse dose of M-d3 was given on Days 1 and 25 of two dosage regimens, one with a continuous 30 mg dose (n = 6), and the other with 30 mg for 10 days, followed by 60 mg as the maintenance dose (n = 6). Plasma and urinary levels of M and M-d3 were measured throughout and plasma half-lives, oral bioavailabilities and volumes of distribution were calculated from the data of Days 1-2 and 24-26. The oral bioavailability of a methadone solution was found to be between 81 and 95%: elimination half-life in the beta-phase varied between 19 and 58 h; the volume of distribution was 4.1 +/- 0.65 l/kg; and total body clearance of M was 54-195 ml/min and its renal clearance 3.4-34 ml/min. A consistent finding was a lower urinary pH and increased renal clearance during the first month of treatment. The shorter elimination half-lives in those patients probably caused unacceptably high fluctuation in the body content of M during the 24 h dosage interval, and may have interfered therefore, with its therapeutic effectiveness.

Adaptation, Physiological↗
PubMed1982

Clinical pharmacokinetics of methadone.

Studies with single doses of methadone have shown that the oral biological availability is 79 +/- 21%, range 41-99%. The rate of elimination is mostly due to metabolic clearance. Below a urinary pH of 6, renal clearance becomes of quantitative importance. In five subjects treated with ammonium chloride (acidic urine), the plasma half-life of methadone was found to be 19.5 +/- 3.6 h. When treated with sodium bicarbonate the same subjects had plasma half-lives of 42.1 +/- 8.8 h. During continuous treatment with methadone, cellular tolerance may occur and in some subjects also metabolic tolerance. In treatment of severe cancer pain such adaptive changes in methadone pharmacodynamics and pharmacokinetics are best managed by a regimen involving a fixed dose but a flexible and patient-controlled dosage interval.

Administration, Oral↗
PubMed1982

Clinical evaluation of oral methadone in treatment of cancer pain.

A dose-adjustment program for oral methadone and the long-term effects of the analgesic therapy have been evaluated in 15 patients with incurable cancer. Rapid and continuous pain relief without serious side-effects was achieved by "ad libitum" dosage in the first 3-5 days. Thereafter, a dosage based on each patients's subjective need was instituted. The mean daily dose was 44 during the first day and it decreased to 22 mg daily at the end of the dose-adjustment week. Three patients did not complete the program because of insufficient effect or severe nausea. Among the 12 patients who chose to continue the methadone treatment after the initial dose-adjustment period, four continued the therapy to their death, three discontinued the therapy due to insufficient effect, and three due to adverse reactions. In one case it was possible to stop the treatment due to decreased pain. The treatment period in these 12 patients varied between 8 and 270 days. Oral methadone offers good pain relief for long periods of time in this group of patients and has obvious advantages as compared to long term parenteral therapy with narcotic analgesics.

Administration, Oral↗
PubMed1981

Patient-controlled dose regimen of methadone for chronic cancer pain.

Fourteen patients with severe cancer pain participated in a trial of methadone given in a fixed dose (10 mg) but at intervals selected by the patients themselves during the loading phase. The aim was to achieve rapid pain relief while avoiding the risk of toxicity from accumulation of methadone. As expected, the dosage intervals increased gradually over the first few days of treatment, the daily dose decreasing from 30-80 mg on the first day to 10-40 mg at the end of the week. Plasma concentrations of methadone varied sevenfold after four to five days (0.24 to 1.75 mumol/1; 7.4 to 54.2 microgram/100 ml). Eleven patients reported complete or almost complete pain relief and elected to continue with methadone after the study. In no case was treatment withdrawn because of intoxication. From these findings a patient-controlled dosage regimen of oral methadone may be an effective and safe alternative to parenteral narcotic medication, adjusting both for individual variation in pain intensity and for pharmacokinetics.

Adult↗
PubMed1981

Single dose pharmacokinetics and bioavailability of methadone in man studied with a stable isotope method.

The disposition of methadone was studied in eight opiate dependent subjects during detoxification. Plasma concentrations were determined by mass fragmentography of 48 hours after administration of methadone 20 mg as tablets and simultaneous intravenous injection of deuterium-labelled methadone 20 mg. Pharmacokinetic parameters were calculated for the intravenous dose assuming a two compartment of open model. Bioavailability was determined by comprising the areas under the plasma concentration versus time curves of unlabelled and labelled methadone. The beta-phase plasma half-lives varied five-fold, with a range from 8.5 to 47 h. The apparent volumes of distribution varied from 2.1 to 5.6 l/kg. Five patients had a bioavailability exceeding 90%, and three had lower bioavailabilities of between 41 and 76%. The unlabelled and labelled drug appeared to be pharmacokinetically equivalent. The data show that for a majority of these subjects the bioavailability was higher than 45%, the previously reported value. The marked individual variation in methadone pharmacodynamics and kinetics, and the possibilities both of cellular and metabolic tolerance, require an individually optimized dosage regimen.

Administration, Oral↗
PubMed1979

Pharmacokinetics of methadone during maintenance therapy: pulse labeling with deuterated methadone in the steady state.

A technique is presented for study of steady state kinetics of methadone using pulse labeling with deuterated methadone (d3) and mass fragmentography to measure both unlabeled and labeled methadone in blood. Seven subjects maintained on methadone for at least 10 months were admitted to a closed metabolic ward. The daily dose of unlabeled methadone (d0) was substituted by one dose of methoadone-d3 and plasma levels of methadone-d0 and methadone-d3 were followed for 48 h using a precise (SD +/- 5%) and sensitive (30 pmol/ml) mass fragmentographic technique. Plasma half-lives (T1/2) for both methadone-do and methadone-d3 were calculated from samples obtained 8--24 H following the dose of methadone-d3. The t1/2 of oral methadone-d3 was shorter (22 +/- 2 h) than that of methadone-d0 (52 +/- 20 h). The same pattern was observed after intravenous administration. The results indicate multiple pools of methadone in the body.

Administration, Oral↗