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Biomedical subjects

M Hammarlund-Udenaes

Publications and source records attributed to M Hammarlund-Udenaes.

At least 37 records · Page 2Linked to original sources
PubMed1995

Influence of the dosing interval on prolactin release after remoxipride.

1. The prolactin response following administration of the D2-dopamine receptor antagonist remoxipride was studied in eight healthy male volunteers. The purpose of the study was to investigate the duration of a refractory period of prolactin release following two doses of remoxipride. A further aim was to compare the prolactin response following remoxipride and thyrotropin release hormone (TRH) during the refractory period. The subjects received two 30 min intravenous (i.v.) infusions of remoxipride 50 mg with different time intervals between the two doses, in a randomized six period crossover design. The time intervals between the two remoxipride doses were 2, 8, 12, 24 and 48 h. On one occasion the remoxipride dose was followed by an i.v. injection of TRH after 2 h. 2. The plasma peak prolactin concentrations obtained after the first remoxipride dose correspond to a maximal release of prolactin according to earlier studies. A small second peak of prolactin was observed after 2 h. The release was gradually increased with longer time intervals between the consecutive doses. The refractory period for a second prolactin release similar to the first one after remoxipride was found to be 24 h for most of the subjects. 3. TRH resulted in a faster and higher increase in prolactin response of a shorter duration than after remoxipride administered 2 h after the first dose.

Adult↗
PubMed1995

Prolactin release after remoxipride by an integrated pharmacokinetic-pharmacodynamic model with intra- and interindividual aspects.

An integrated pharmacokinetic-pharmacodynamic model is suggested for remoxipride and its effect on prolactin (PRL) release acting by preventing the inhibitory effect of dopamine D2 receptors in the anterior pituitary. The model was implemented to describe the time course of PRL plasma levels after administration of two consecutive doses of remoxipride at 5 different time intervals, 2, 8, 12, 24 and 48 hr. The model used is an indirect response model. It consists of three parts: 1) the pharmacokinetics of remoxipride; 2) a physiological substance model for PRL, incorporating the synthesis of PRL and its release into and elimination from plasma; and 3) a pharmacodynamic model describing the influence of remoxipride on the PRL release from the pool. A linear pharmacodynamic model gave the best description of the time course of PRL. The limitation in the PRL release is the amount available in the pool, which takes 24 to 48 hr to fully restore, rather than a maximal effect of remoxipride. The intra- and interindividual variability of remoxipride as well as of the PRL response was low.

Adult↗
PubMed1994

Influence of rate of administration of raclopride on akathisia and prolactin response.

The D2-dopamine receptor antagonist raclopride was administered to eight healthy male subjects, who had previously experienced akathisia following antipsychotic drugs. The influence of administration rate on onset, severity and duration of akathisia and on prolactin response was studied. Raclopride 3, 5 or 9 mg or placebo (P) was administered as single IV infusions during 10 min (R10 min/3 mg), 1 h (R1h/5 mg) or 4 h (R4h/9 mg) according to a randomized double-blind design. Despite a 24-fold difference in administration rate a similar peak raclopride concentration of about 350 nmol/l was obtained after all three infusions. Three of the eight subjects experienced akathisia following R10 min/3 mg and R1h/5 mg, respectively. After R4h/9 mg seven subjects experienced akathisia of longer duration but not more severe than after the short infusions. The incidence and duration of akathisia seem to be mainly related to the plasma raclopride concentrations over time, whereas the rate of administration might be more important for the severity. A maximal prolactin response was induced which was not markedly affected by the rate of administration.

Adult↗
PubMed1993

Pharmacokinetics and pharmacodynamics of morphine-3-glucuronide in rats and its influence on the antinociceptive effect of morphine.

In this study the pharmacokinetics and pharmacodynamics of morphine-3-glucuronide (M3G) were investigated in rats after i.v. administration as a bolus dose (86.7 mumol kg-1) and as a constant rate infusion (2.9 mumol h-1) over 5 days. After the bolus dose, the clearance (Cl) was 12.1 +/- 0.6 ml min-1*kg, the volume of distribution at steady state (Vss) 1.68 +/- 0.89 l kg-1, the half-life of the first phase 13.2 +/- 1.8 min and the half-life of the second phase 11.6 +/- 7.7 h. After the constant rate infusion, Cl was 10.5 +/- 1.7 ml min-1*kg. The antagonistic effect of M3G on the antinociceptive effect of a bolus dose of morphine (35 mumol kg-1) was tested during steady state concentrations of M3G on day 4 and to M3G naïve rats. No antinociceptive, hyperalgesic or withdrawal effects were observed as a result of M3G administration, but a significantly lower antinociceptive effect of morphine was found in the M3G infusion group compared to the control group. Systemically administered M3G antagonized the antinociceptive effect of morphine, but this cannot be the only explanation to the tolerance development observed after morphine administration.

Animals↗
PubMed1993

The pharmacokinetics of remoxipride and metabolites in patients with various degrees of renal function.

1. The pharmacokinetics of remoxipride, a new neuroleptic, were investigated in an open study with three parallel groups. Twenty-one patients with severely impaired (ClCr < 25 ml min-1), moderately impaired (ClCr 25-50 ml min-1) and normal (ClCr > 65 ml min-1) renal function were evaluated. A single oral dose of remoxipride hydrochloride 100 mg was administered, and blood and urine were collected over 48 h. Concentrations of remoxipride and metabolites were measured by h.p.l.c. 2. In patients with severely decreased renal function, the AUC and Cmax of remoxipride were increased significantly, and t1/2 was prolonged, as compared with the control patients. The renal clearance and urinary recovery of the unchanged drug were significantly diminished. 3. The unbound fraction of remoxipride in plasma was decreased in patients with renal failure, in association with a disease-related increase in alpha 1-acid glycoprotein. In spite of a 25% recovery of unchanged drug in the urine in patients with normal renal function, the AUC of unbound drug was twice as high in patients with severely impaired renal function. 4. A strong correlation between creatinine clearance and renal drug clearance was observed indicating a direct relationship between kidney function and the renal clearance of remoxipride. 5. Remoxipride was the predominant compound in plasma as well as in urine in patients with severely decreased as well as normal renal function. In patients with severely decrease renal function, remoxipride and all five pharmacologically inactive metabolites showed increased peak plasma concentrations, delayed tmax, increased AUC, prolonged half-lives and decreased renal clearance.

Adult↗
PubMed1993

Quantification of effect delay and acute tolerance development to morphine in the rat.

In this study the effect delay and the development of acute tolerance to morphine's antinociceptive effect were investigated in the rat. The antinociceptive response induced after three different short infusions of morphine was measured by using the electrical stimulation vocalization method. Three treatment groups received morphine hydrochloride over 10, 60 and 180 min, targeting maximal plasma concentrations of 25 microM at the end of the infusion. The maximal concentrations of morphine obtained for the three groups were 29.4 +/- 3.7, 26.7 +/- 4.7 and 28.9 +/- 7.3 microM, respectively. Both an effect delay and acute tolerance were observed. For each group, the peak effects were 248 +/- 82, 337 +/- 116 and 303 +/- 49% above base line, at 35, 65 and 90 min after the start of the infusions. A pharmacokinetic-pharmacodynamic model with separate effect and tolerance compartments (the ET-model) well described the antinociceptive response over time. The antinociceptive effect was best described by using a linear model, whereas acute tolerance was best described by using an Emax model. The rates of drug equilibration between the plasma and the effect compartment (ke0) and the plasma and the tolerance compartment (kt0), expressed as half-lives, were 34 +/- 2 and 48 +/- 4 min, respectively. High concentrations were required for the acute tolerance to develop (TC50 of 17 microM).

Animals↗
PubMed1993

Modeling of tolerance development and rebound effect during different intravenous administrations of morphine to rats.

The development of tolerance and the rebound effect to the antinociceptive effect of morphine were investigated and correlated with morphine pharmacokinetics. Five i.v. regimens, including a bolus dose (35 mumol/kg), 2 constant rate infusions (2.5 and 4.2 mumol/hr) over 4 days, 1 saline bolus dose and 1 glucose infusion were followed for 8 days. Clearance (CL) was estimated as 148 +/- 58 ml/min*kg after the bolus dose and 108 +/- 32 ml/min*kg during infusion (N.S.). Tolerance developed during the first day of morphine infusion and no antinociceptive effect could be measured from the third day. After cessation of the infusions, rebound hyperalgesia, significant for the higher infusion rate (P < .05), was observed. No hyperalgesia was detected after the bolus dose. A pharmacodynamic model with separate effect and tolerance compartments was used to describe the antinociceptive effect over time. The rates of equilibration of drug between the blood and effect compartment and the blood and tolerance compartment, expressed in half-lives, were estimated as 25 +/- 8 min and 26 +/- 6 hr, respectively. It is apparent from these results that an i.v. bolus dose of morphine causes less tolerance than constant rate infusions of morphine. With the presented model it is possible to quantify the rate and extent of tolerance development of morphine.

Animals↗
PubMed1992

The postoperative pharmacokinetics of codeine.

The metabolism and systemic availability of codeine have been studied in 12 patients after cholecystectomy. They were given 20 mg codeine as an IV bolus dose on the first day after surgery and 50 mg codeine as a single oral on the fourth day after surgery. Codeine had a medium to high extraction ratio and a total plasma clearance of 10.8 (4.3) ml.min-1.kg-1. The clearance varied four-fold between subjects. All the patients were extensive metabolizers with regard to the debrisoquine/sparteine polymorphism, as tested using dextromethorphan as the probe drug. Nevertheless, the formation of morphine from codeine was very small and plasma morphine concentrations were below the detection limit of 3.3 nmol.l-1 (1 ng.ml-1). As a corollary, the morphine/codeine ratio in the the concentration-time curves was less than 3% in all the patients. The systemic availability of codeine varied extensively between subjects (range 12-84%). This might partly explain differences in the dose of codeine required as an analgesic.

Adult↗
PubMed1992

Estimation of unbound concentrations of morphine from microdialysate concentrations by use of nonlinear regression analysis in vivo and in vitro during steady state conditions.

The unbound concentration of morphine in striatum of rats was estimated during a constant rate infusion of morphine 14 mumol/h*kg, by use of the microdialysis technique and nonlinear regression analysis. The concentrations in plasma of morphine and its metabolite, morphine-3-glucuronide, were 4.2 +/- 1.4 microM and 7.7 +/- 4.0 microM, respectively, during the constant rate infusion. The corresponding estimated unbound concentrations of morphine in striatum varied between 0.06 and 0.11 microM. No morphine-3-glucuronide was detected in the brain dialysates. The unbound concentration in striatum was lower than expected based on unbound plasma concentrations and could be an indication of active transport from the brain. Five different equations were tested to find the best empirical description of the relationship between microdialysate concentration and perfusion rate by nonlinear regression analysis. The equations were validated by a serum in vitro study, where three unbound concentrations of morphine estimated from microdialyis were compared to estimates obtained from equilibrium dialysis. The precision of the parameter estimates obtained from the five equations was tested by Monte Carlo simulations. One of the equations (Eq. 4) was selected in preference to the others, because of the good agreement with the estimated unbound concentration obtained by equilibrium dialysis in vitro, and good precision of the parameter estimates. The method described in this paper is valuable when estimating the unbound concentration of drug from microdialysate concentrations during steady state conditions. Furthermore, the method is easily accessible when working in the pharmacokinetic and pharmacodynamic field.

Animals↗
PubMed1992

Pharmacokinetics of raclopride formulations. Influence of prolactin and tolerability in healthy male volunteers.

The pharmacokinetic and pharmacodynamic properties of raclopride, a new antipsychotic, were investigated in 16 healthy men. Single 4 mg doses were administered as intravenous infusion, oral solution and 2 extended release (ER) formulations. Total plasma clearance was about 100 ml/min (6.0 L/h), of which renal clearance accounted for 0.2 ml/min, indicating extensive metabolism. The volume of distribution was 1.5 L/kg; mean absolute bioavailability was 65 to 67% following the oral solution and the ER formulations. A transient increase in plasma prolactin levels followed both the intravenous infusion and the oral solution. The ER formulations resulted in a lower increase, which appeared later. However, the area under the prolactin level curve was similar after administration of all dosage forms. The frequency and severity of the most commonly reported side effects (tiredness and restlessness) were higher after the intravenous infusion than after the ER capsules. These findings indicate that such capsules may be advantageous for clinical antipsychotic treatment with raclopride.

Administration, Oral↗
PubMed1991

Response to furosemide during dehydration with and without naproxen pretreatment of kidney donors and renal transplant recipients.

The response to 40 mg furosemide p.o. in 6 healthy kidney donors and 6 renal transplant recipients with and without naproxen pretreatment has been studied. No volume replacement was given in order to study the development of tolerance. The subjects showed an average dehydration of 1.5 kg.6 h-1. While mean creatinine clearance was equal in patients and donors (76 vs 80 ml/min), renal furosemide clearance was significantly lower in the patients (47 vs 81 ml min; P less than 0.05). The patients also excreted a smaller fraction of the dose in the urine (5.7 vs 7.8 mg/6 h; P less than 0.05). As the overall renal sensitivity was similar in the two groups, the natriuretic response was correspondingly smaller in transplant recipients as compared to donors. Within the observation period of 6 h after dosing, acute tolerance developed in the donors and in 4 of the 6 patients, as shown by clockwise hysteresis in the dose (urine furosemide excretion rate)-response (natriuresis) curves. Pretreatment with naproxen reduced renal sensitivity to furosemide (right shift of the dose response curve) in all the donors but in only 2 of the patients. In both groups acute tolerance was less pronounced after naproxen, which may indicate involvement of the prostaglandin system in the development of acute tolerance. The results may also indicate regeneration of sympathetic nerves with functional capacity in at least some renal transplants, or that other mechanisms of salt regulation compensate for loss of sympathetic nerve activity.

Administration, Oral↗
PubMed1991

Plasma levels of thioridazine and metabolites are influenced by the debrisoquin hydroxylation phenotype.

The pharmacokinetics of thioridazine and its metabolites were studied in 19 healthy male subjects: 6 slow and 13 rapid hydroxylators of debrisoquin. The subjects received a single 25 mg oral dose of thioridazine, and blood samples were collected during 48 hours. Concentrations of thioridazine and metabolites in serum were measured by HPLC. Slow hydroxylators of debrisoquin obtained higher serum levels of thioridazine with a 2.4-fold higher Cmax and a 4.5-fold larger AUC(0-infinity) associated with a twofold longer half-life compared with that of rapid hydroxylators. The side-chain sulphoxide (mesoridazine) and sulphone (sulphoridazine), which are active metabolites, appeared more slowly in serum and had lower Cmax values, but comparable AUC. The thioridazine ring-sulphoxide attained higher Cmax and 3.3-fold higher AUC in slow hydroxylators than in rapid hydroxylators of debrisoquin. Thus the formation of mesoridazine from thioridazine and the 4-hydroxylation of debrisoquin seem to be catalyzed by the same enzyme, whereas the formation of thioridazine ring-sulphoxide is probably formed mainly by another enzyme.

Adult↗
PubMed1991

Remoxipride: pharmacokinetics and effect on plasma prolactin.

1. The pharmacokinetics of remoxipride, a new neuroleptic, were investigated in 15 healthy subjects after an intravenous infusion of 50 mg, an intramuscular injection of 100 mg and after administration of two immediate release capsules (A and B), each of 100 mg, in a cross-over study. The effect of the different remoxipride formulations on plasma prolactin concentrations was also studied. 2. The volume of distribution of remoxipride was 0.65 +/- 0.11 kg-1 (mean +/- s.d.). Total plasma clearance was 119 +/- 39 ml min-1, of which 31 +/- 13 ml min-1 was due to renal clearance. The absolute bioavailability after the i.m. and oral formulations was greater than 90%, indicating a small extent of first-pass metabolism. The mean elimination half-life was 4.8 +/- 1.4 h. The unbound fraction of remoxipride and the blood/plasma ratio were 0.19 +/- 0.03 and 0.64 +/- 0.06, respectively. 3. The transient increase in plasma prolactin was similar after all four remoxipride administrations and independent of the given dose.

Adult↗
PubMed1991

Studies of meclofenamic acid and two metabolites in horses--pharmacokinetics and effects on exercise tolerance.

The pharmacokinetics and the effects on treadmill exercise of the anti-inflammatory drug meclofenamic acid were studied in seven Standardbred horses after single intravenous and/or oral doses. The decline in plasma concentration after a single intravenous dose of meclofenamic acid (2.2 mg/kg b.wt) was described by a two-compartment open model. The average elimination half-life was 1.4 h, the apparent volume of distribution 0.14 l/kg and the plasma clearance 0.12 l/h kg. Absorption was the rate-limiting step after oral administration. Non-compartmental analysis showed a mean absorption time of 4.3 h. The pharmacokinetics of two metabolites of meclofenamic acid were also studied in two of the horses. The elimination half-lives of the two metabolites were virtually the same in each horse (3.0 h and 3.4 h). The blood lactate response to exercise was significantly decreased after treatment with meclofenamic acid, indicating a lower utilization of the glycolytic ('anaerobic') energy contribution during exercise. Circulatory capacity was apparently unaffected with an unchanged heart rate response to exercise.

Absorption↗
PubMed1989

Furosemide pharmacokinetics and pharmacodynamics in health and disease--an update.

The literature on furosemide pharmacokinetics and pharmacodynamics is critically reviewed, concentrating on those papers published subsequent to the 1979 reviews of this topic. Intravenous and oral data are presented for healthy volunteers and for patients with various disease states. It is the latter populations about which the majority of the studies have been published since 1979. Inter- and intraindividual variations in bioavailability are discussed, as are data on the metabolism of furosemide to its glucuronide conjugate. Published studies examining the relationship between furosemide pharmacodynamics and pharmacokinetics are also evaluated. The literature is reviewed through June 1988.

Disease↗
PubMed1988

On the mechanism of acute tolerance to furosemide diuresis.

The renal response to continuous furosemide infusion (8 mg/h) and subsequent ECV changes was studied in 8 healthy volunteers. Furosemide increased urine flow from a basal flow of 4.3 ml/min to a maximum of 15.4 ml/min. During dehydration (-1.8 kg) the diuresis decreased to 8.4 ml/min. The sodium, chloride and potassium excretion likewise decreased. This reduction in diuretic effect (acute tolerance) was accompanied by significantly increased plasma levels of norepinephrine (1.38 to 2.14 nmol/l), PRA (0.52 to 1.13 ng/ml/h) and aldosterone (0.29 to 0.45 nmol/l). After rehydration the urine flow increased to 23.1 ml/min. The changes in diuretic response from initial effect to the dehydrated state and after rehydration were mainly a consequence of changed renal sensitivity to furosemide (urinary excretion of 21 to 14 to 35 mumol Na+ per microgram furosemide excreted). It is proposed that activation of the sympathetic nervous system and/or the renin-angiotensin-aldosterone system may play a role in mediating the acute tolerance to furosemide diuresis. The relative importance of each remains to be clarified.

Adult↗