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Biomedical subjects

L Paalzow

Publications and source records attributed to L Paalzow.

At least 19 recordsLinked to original sources
PubMed1998

Long-term intraduodenal infusion of a water based levodopa-carbidopa dispersion in very advanced Parkinson's disease.

OBJECTIVE: To evaluate the effects of continuous duodenal infusion of levodopa over time on the disabling fluctuations in motor performance in advanced parkinsonian patients. It has earlier been demonstrated that these fluctuations can be reduced by keeping the plasma concentration of levodopa constant. MATERIAL AND METHODS: In view of the low water solubility of levodopa a stable dispersion of the drug was developed and used for continuous intraduodenal infusion in patients with advanced Parkinson's disease. Nine patients were evaluated with respect to an optimal oral treatment, during nasoduodenal infusion by a portable pump and then followed for 6 months to 2 1/2 years when treated via transabdominal infusion. Upon each test occasion, over 2 non-consecutive days, objective movement analysis by means of an opto-electronic system was applied every 15-20 min and video recordings performed twice every h. On several test occasions plasma levodopa concentrations were analysed every 15 min. RESULTS: The patients showed improvement and decreased variance of their motor function. In the 2 patients followed over a period of 2 1/2 years levodopa plasma concentration showed reduced fluctuations on infusion and the levodopa consumption as well as mean levodopa plasma concentration decreased. CONCLUSION: Continuous duodenal infusion of levodopa is an alternative treatment strategy for patients with advanced Parkinson's disease when conventional therapy has failed.

Activities of Daily Living↗
PubMed1995

Malnutrition and pharmacokinetics of penicillin in Ethiopian children.

Penicillin was given to 104 children with different nutritional status, normal, underweight, marasmus and kwashiorkor. Penicillin was given either intravenously, intramuscularly or orally and the plasma concentration was followed at regular times after administration. There was a significantly decreased plasma clearance of penicillin in all malnourished groups compared to the normal weight-for-age group. The half-lives of penicillin were, however, not significantly different between the nutritional groups. This was explained by the fact that also the volume of distribution was decreased in the malnourished group with a net result that the half-life was unchanged. The bioavailability was decreased if penicillin was given to non-fasting individuals. The greatest difference between fasting and non-fasting was seen in the severely malnourished children with marasmus and kwashiorkor. Therefore, it is advised that, if penicillin is given orally to very sick and undernourished children, the dose should be increased and preferably be given in the fasting state.

Absorption↗
PubMed1994

Pharmacokinetics of levodopa and carbidopa in rats following different routes of administration.

This study examined the pharmacokinetics of levodopa and carbidopa in the rat after different modes of administration. The drugs were given simultaneously by the intravenous, intraarterial, oral, duodenal, and intraperitoneal routes, as single doses. The ratio of levodopa to carbidopa given was always 4:1. Two iv doses (5 and 15 mg/kg of levodopa) were given to test for nonlinearity. Three ip doses of levodopa were given (5, 7.5, and 15 mg/kg), and the 15 mg/kg dose was given in three volumes (2, 4, and 20 mL/kg). One oral dose and two intraduodenal doses of 15 mg/kg were given. The drugs were dissolved in saline in one of the intraduodenal doses and suspended in 1.8% methylcellulose in the other. The elimination of levodopa was nonlinear. There was a comparatively high degree of interindividual variability in absorption with the oral route, but this was substantially reduced when levodopa was given intraduodenally. There was also much less variability with the intraperitoneal route compared to the oral, and the degree of absorption was generally high. There was a significantly higher extent and slower rate of absorption when levodopa was administered ip in a large volume of vehicle. These results suggest that the oral route may not be the optimal method of delivering levodopa to patients who have a fluctuating response and that a continuous delivery system via the intraperitoneal or intraduodenal routes might be a better alternative.

Absorption↗
PubMed1993

Intraduodenal infusion of a water-based levodopa dispersion for optimisation of the therapeutic effect in severe Parkinson's disease.

Motor performance of five patients with advanced Parkinson's disease was investigated during their optimum oral therapy (conventional tablets and/or depot capsules) and during a continuous duodenal infusion of levodopa. Due to the low water solubility of the drug, conventional tablets of levodopa+carbidopa (Sinemet) were milled and dispersed in a 1.8% aqueous methylcellulose solution. The dispersion was delivered nasoduodenally by a portable pump. The effect of levodopa in the two dosing regimens was estimated optico-electronically every 15 min and was also evaluated from videorecordings every 30 min and plasma levels of levodopa was regularly measured. Each dosage regimen the was studied twice, at a 2-4 day interval. Duodenal infusion improved motor function in all five patients and the fluctuations were reduced when compared to the oral therapy. Variation in plasma levodopa concentrations was 3-10 fold during oral therapy, while during the infusion a stable concentration was obtained. The therapeutic concentration varied from 0.3-3 ml-1 between patients. The relative bioavailability of levodopa in the solid preparation compared to the dispersion was in all patients 100%. Our results encourage further development of a duodenal infusion system with a levodopa dispersion for clinical use in parkinsonian patients who show severe fluctuation.

Administration, Oral↗
PubMed1993

Decreased chloramphenicol clearance in malnourished Ethiopian children.

The disposition of chloramphenicol and chloramphenicol monosuccinate has been studied in thirty-four Ethiopian children of varying nutritional status. After a single intravenous dose corresponding to chloramphenicol 25 mg per kg bodyweight, the plasma clearance of chloramphenicol monosuccinate was decreased only in severely malnourished children with kwashiorkor. Seventeen % of the dose (range 0-51%) was recovered in urine as intact prodrug, indicating incomplete and variable bioavailability of chloramphenicol. Compared to underweight children, on average marasmic and kwashiorkor subjects exhibited a 2- and 3-fold increase, respectively, in the AUC of chloramphenicol. Elevated AUCs could be traced to reduced hepatic clearance of the drug. The unbound fraction both of chloramphenicol and its prodrug were slightly elevated in serum from kwashiorkor subjects. The possibility of using a single point measurement of plasma chloramphenicol as a guide to individualized dosage are discussed.

Biological Availability↗
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↗
PubMed1990

Pharmacokinetics and effects of levodopa in advanced Parkinson's disease.

Five patients with severe Parkinson's disease were characterized with respect to their pharmacokinetic and pharmacodynamic responses to levodopa given: orally, intravenously (three different infusion rates) and intraduodenally. The best therapeutic infusion rate in the intravenous study was used for the intraduodenal infusion of levodopa. A lag time between plasma concentration and effect following oral administration was seen in three of the five patients and this disequilibrium was estimated as the rate constant Ke0 using model-independent analysis. The plasma concentration-effect relationship was similar for the three modes of administration and in all patients the therapeutic plasma concentration for full mobility was greater than 4-5 micrograms.ml-1. The disequilibrium half-life for development of effect after oral administration was calculated to be about 30 min. The patients remained clinically stable during the period of the intraduodenal infusion.

Administration, Oral↗
PubMed1990

Pharmacokinetics of methylergometrine in the rat: evidence for enterohepatic recirculation by a linked-rat model.

The pharmacokinetics of methylergometrine were investigated in the rat, with emphasis on the role of biliary excretion and enterohepatic recirculation in the overall disposition of the drug. A linked-rat model, where the bile from a rat receiving a constant rate of iv infusion of methylergometrine was allowed to flow into the duodenum of another rat, was used for the estimation of the degree of enterohepatic recirculation (EHC). The excretion of unchanged methylergometrine in the bile was estimated separately. Plasma protein binding and plasma-to-whole blood partitioning were also determined. Plasma clearance in control rats was 17.4 +/- 0.7 ml/min x kg for iv bolus and 15.4 +/- 0.7 ml/min x kg for iv infusion. The corresponding values in the bile-cannulated rats were significantly lower, 7.7 +/- 0.4 and 8.7 +/- 0.1 ml/min x kg, respectively. The lower clearance in the bile-cannulated rats was caused mainly by a lower free fraction in plasma, fu (0.11 +/- 0.01), in this group compared with the control group (0.19 +/- 0.0.03). The unbound volume of distribution at steady state (Vssu) was only 6.5 liters/kg in the bile-cannulated rats, compared to 14.7 liters/kg in control rats, suggesting that under steady-state conditions, more than 50% of the methylergometrine is conjugated or residues in the hepatobiliary loop, either as a conjugate or unchanged. The fraction of unchanged methylergometrine excreted in the bile was less than 0.3% of the given dose, while the fraction of the dose being reabsorbed during one cycle (freabs) was 8.4 +/- 6.3%.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1988

Pharmacokinetics of streptomycin in Ethiopian children with tuberculosis and of different nutritional status.

Fifty-six malnourished Ethiopian children with tuberculosis classified in four nutritional groups (normal, underweight, marasmus and kwashiorkor), were given streptomycin 20 or 30 mg.kg-1 i.m. The plasma concentration-time data revealed an increased apparent volume of distribution in children with kwashiorkor compared to normals. The total plasma clearance was low and did not differ between the nutritional groups. Thus, the half-life was prolonged only in kwashiorkor. The results could be explained by decreased protein binding in plasma and decreased renal clearance by glomerular filtration.

Child↗
PubMed1988

Pulmonary disposition of pethidine in postoperative patients.

1. Two methods of pethidine administration, namely constant-rate infusion and single i.v. injection, were used to assess the pulmonary disposition of the drug in 10 postoperative patients. Using two sites of blood sampling, the pulmonary extraction ratio was determined. 2. Pronounced pulmonary uptake of pethidine was found in all patients (n = 10). On the other hand, there was no significant evidence of pulmonary clearance. 3. The mean total plasma clearance was 810 ml min-1 and the volume of distribution was 3.11 kg-1. 4. A flow model was used to describe the disposition of pethidine in man. The concentration-time profiles calculated by the model were in accordance with observed data. The data showed that both pulmonary uptake and pulmonary release of pethidine were rapid. 5. Constant-rate infusion was found advantageous in the determination of pulmonary extraction, with respect to the accuracy and precision of the results. The extraction obtained after a single injection may be overestimated on account of uptake of the drug by the lungs.

Aged↗
PubMed1988

Respiratory and cardiovascular effects in relation to plasma levels of midazolam and diazepam.

1. In the present study possible relationships between cardiovascular and respiratory effects and plasma concentrations were investigated after administration of midazolam and diazepam. Eight healthy volunteers were given three injections at 20 min intervals of equipotent sedative doses of midazolam (0.05 mg kg-1) and diazepam (0.15 mg kg-1) in a randomized double-blind cross-over design. Blood pressure, blood-gases and respiration measured nonivasively, were monitored throughout the experimental session of 160 min, and frequent blood samples were collected during the session. 2. Correlations between the blood pressure reduction, the increase of PaCO2 in blood, and plasma concentrations were found for both drugs. A maximal reduction of blood pressure and PaCO2 was produced after sedative doses of midazolam and diazepam. 3. A possible acute tolerance development towards the blood pressure reduction was found after the repeated administration of diazepam but not after the midazolam administration. 4. The plasma concentrations producing half the maximal effects after administration of midazolam was 50-60 ng ml-1, indicating that the influence on blood pressure and PaCO2 after drug administration is evoked at lower plasma concentrations than sedation. 5. No correlation between the respiratory effects and plasma concentrations was found for either drug.

Adult↗
PubMed1988

INH and streptomycin in Ethiopian children with tuberculosis and different nutritional status.

The plasma concentration of INH and streptomycin was followed in 45 Ethiopian children with tuberculosis. The children were grouped according to their nutritional status as normal, underweight, marasm and kwashiorkor. INH was well absorbed in all nutritional groups to give therapeutically active plasma levels. When terminal half life (t1/2) of INH was calculated for individual patients there were more children in all nutritional groups with t1/2 greater than or equal to 2 hours than less than 2 hours, indicating a slow acetylation of INH. Streptomycin was well absorbed in all nutritional groups and therapeutic levels were obtained with 20 mg/kg i.m. After 30 mg/kg i.m. of streptomycin kwashiorkor children had an increased t1/2 of streptomycin indicating a decreased renal excretion of the drug in kwashiorkor. The clinical follow-up of the children indicated that serious tuberculosis could be successfully treated with INH and streptomycin in the doses used.

Child↗
PubMed1987

Interaction of mixed micelles formed from glycocholic acid and lecithin with the protein binding of various drugs.

Mixed micelles (MM) formed from glycocholic acid and lecithin are suited to solubilize lipophilic drugs for intravenous use. To test for possible drug-drug interactions, the protein binding of a series of agents known to bind to different sites on albumin (diazepam, warfarin, ketoprofen, frusemide, probenecid) and additionally (prazosin, quinidine, propranolol) or exclusively (disopyramide) to alpha 1-acid glycoprotein or to transcortin (prednisolone) was determined in the presence and absence of MM. Concentrations of MM, corresponding to the maximum possible plasma concentration achieved by injecting the highest clinical doses of MM into the systemic circulation, had little or no effect on the unbound fractions of drugs known to bind exclusively to albumin. Only at five times higher MM concentrations were the free fractions substantially increased (by up to 45%). Unbound fractions of drugs bound with high affinity but low capacity to alpha 1-acid glycoprotein were increased between 50-85% even at 'therapeutic' doses of MM. The present study suggests that drugs solubilized by MM should be given by slow injection or infusion to patients already receiving drugs which are highly bound to alpha 1-acid glycoprotein.

Glycocholic Acid↗
PubMed1987

Probenecid-induced accumulation of 5-hydroxyindoleacetic acid and homovanillic acid in rat brain.

The accumulation of 5-hydroxyindoleacetic acid (5-HIAA) and homovanillic acid (HVA) in rat brain has been examined after probenecid infusion over 8 h. At plasma probenecid concentrations of 200-400 micrograms mL-1 a steady state level in the accumulation of 5-HIAA and HVA was achieved, the increase above the endogenous levels being 135% and 65%, respectively. When the plasma concentration of probenecid rose above 400 micrograms mL-1 there was further accumulation of both 5-HIAA and HVA probably induced by increased neuronal activity or toxicity due to probenecid. The explanation for the plateau of 5-HIAA and HVA obtained over the plasma probenecid concentration interval of 200-400 micrograms mL-1 could be that the levels were reached when there was complete inhibition of active transport, and when the rate of formation of the metabolites equalled the rate of elimination by alternative routes i.e. bulk flow and diffusion. Therefore when probenecid is used to inhibit the active transport of acid monoamine metabolites across the blood-brain barrier, its plasma concentration should be within the range of 200-400 micrograms mL-1.

Animals↗
PubMed1986

Potential pulmonary uptake and clearance of morphine in postoperative patients.

The influence of lung uptake and lung clearance on the disposition of morphine was studied in surgical patients. In the postoperative period morphine was given intravenously by a two-rate infusion regimen. Under steady-state conditions samples of mixed central venous blood (pulmonary artery) and peripheral arterial blood (radial artery) were taken simultaneously and at the same time cardiac output was measured. The concentration differences between venous and arterial blood were used to calculate the extraction ratio of morphine across the lung. In all patients there was marked pulmonary uptake, but the concentration differences in most of them were small under steady-state conditions. The extraction ratio (mean +/- SD) across the lung was 0.06 +/- 0.10, implying insignificant lung clearance. However, in two patients, both with diabetes mellitus, there was a significant concentration gradient, indicating that the lung could contribute to the total body elimination of morphine. On the other hand, the total clearance was similar in diabetic and nondiabetic patients (1190 and 1150 ml/min, respectively), implying that pulmonary clearance would have no significant influence on the kinetics of morphine. A physiologically based pharmacokinetic model was used to describe the disposition of morphine in post-operative patients. The model allowed simulation of pulmonary diffusion, uptake and elimination and supported conclusions based on model-independent experimental data.

Adult↗
PubMed1986

Pharmacokinetics of methysergide and its metabolite methylergometrine in man.

Five healthy men were given 1.0 mg methysergide maleate intravenously and 2.7 mg methysergide maleate orally in a cross-over study. The systemic availability of methysergide was only 13%, most probably due to a high degree of first-pass metabolism to methylergometrine. We also found evidence of extrahepatic clearance of methysergide. After oral administration the plasma concentrations of the metabolite were considerably higher than those of the parent drug and the area under the plasma concentration curve (AUC) for methylergometrine was more than ten times greater than for methysergide. Our findings may be relevant to the treatment of migraine if methylergometrine contributes to the effect of methysergide. Methylergometrine had a significantly longer elimination half-life than methysergide (223 +/- 43 min vs 62.0 +/- 8.3 min and 174 +/- 35 min vs 44.8 +/- 8.1 min in the oral and intravenous studies respectively).

Administration, Oral↗
PubMed1985

Constant rate of infusion--improvement of tests for teratogenicity and embryotoxicity.

Sodium salicylate was used as a model substance to investigate whether the embryotoxic effects on rat fetuses varies between two modes of administration. A marked increase in fetal adverse effects was observed at analgetic doses with the once-a-day bolus regimen compared to the constant rate input. The difference was less marked at antirheumatic levels.

Abnormalities, Drug-Induced↗