PubMed Health⌕ Search

Biomedical subjects

P Sjöberg

Publications and source records attributed to P Sjöberg.

At least 19 recordsLinked to original sources
PubMed2000

First exposure in man: toxicological considerations.

The safety of a volunteer/patient who participate in the very first human trial relies on data from animal experimentation and on the design of the trial. Recommendations on the type and extent of preclinical safety studies that should be conducted prior to first dose in man have been developed by the International Conference on Harmonisation, and the European Committee for Proprietary Medicinal Products. These recommendations include studies designed to characterise local tolerance and general toxicity of the drug candidate as well as its genotoxic potential and ability to interfere with reproduction. For trials which can be categorised as low dose PK screening trials and trials with products where rodent and non-rodent (primarily dog) models do not show any biological response (e.g. some biotechnology-derived hormones and cytokines) other testing paradigms should be used. The present recommendations for preclinical testing have had an important impact on the documented impressive safety record of phase I clinical trials. In this spirit we extend our warmest and sincerest thanks to Professor Jens S. Schou for his long and deep engagement in European and International harmonisation of preclinical test recommendations. His efforts have had a substantial impact on the present testing recommendations, which are of obvious benefit to the safety of the patient.

Animals↗
PubMed1999

Quantitative autoradiography with short-lived positron emission tomography tracers: a study on muscarinic acetylcholine receptors with N-[(11)C]methyl-4-piperidylbenzilate.

The present work demonstrates quantitative autoradiography by using positron emission tomography tracers and storage phosphorimaging plates. The uptake and association of [(11)C]N-methyl-4-piperidylbenzilate was measured in rat brain tissue cryosections of various thicknesses. The signal increased with increasing section thickness, but only in 10-micrometer-thick sections did the binding reach the steady state during a 50-min observation time. This violation of the equilibrium condition, potentially combined with perfusion limitations, leads to erroneous increased binding-site density and decreased affinity in the 25- and 50-micrometer-thick sections. For better imaging of receptor distribution it is reasonable to use thicker sections. For quantitative analysis of receptor-binding parameters, the specific properties of ligands at different thicknesses of cryosections need to be considered. Evidence is provided that the nonselective muscarinic antagonist N-methyl-4-piperidylbenzilate binds preferentially to the M(4) subtype of muscarinic acetylcholine receptors.

Animals↗
PubMed1998

Dose selection for carcinogenicity studies of pharmaceuticals: systemic exposure to phenacetin at carcinogenic dosage in the rat.

A systemic exposure-based alternative to the MTD (maximally tolerated dose) for high-dose selection in carcinogenicity studies of pharmaceuticals has been accepted by the ICH (International Conference on Harmonisation of Technical Requirements for the Registration of Pharmaceuticals for Human Use). As a result of a retrospective analysis performed by the U.S. FDA (United States Food and Drug Administration), a rat/human relative systemic exposure ratio of 25 is proposed by the ICH as an acceptable pharmacokinetic endpoint for high-dose selection. For use as a dose selection criterion, it is particularly important that the magnitude of the relative systemic exposure ratio should be sufficient to detect human pharmaceuticals classified by IARC (International Agency for Research on Cancer, World Health Organization) as known (category 1) or probable (category 2A) human carcinogens. For one of these, phenacetin (an IARC 2A compound and a rat carcinogen), a systemic exposure ratio of 15 was calculated by the FDA. This calculation was based on a number of extrapolations. The present study reports the actual systemic exposure to phenacetin in the rat under conditions mimicking the conditions in the carcinogenicity study used by the FDA to calculate the relative systemic exposure ratio of 15. The ratio was found to be 7, indicating that the carcinogenic potential of this particular probable human carcinogen could be detected at a considerably lower systemic exposure ratio than that proposed by the ICH.

Animals↗
PubMed1998

Theoretical calculation and prediction of brain-blood partitioning of organic solutes using MolSurf parametrization and PLS statistics.

Sixty-three structurally diverse compounds were investigated to statistically model the brain-blood partitioning of organic solutes using theoretically computed molecular descriptors and multivariate statistics. The program MolSurf was used to compute theoretical molecular descriptors related to physicochemical properties such as lipophilicity, polarity, polarizability, and hydrogen bonding. The multivariate Partial Least Squares Projections to Latent Structures (PLS) method was used to delineate the relationship between the brain-blood partitioning of organic solutes and the theoretically computed molecular descriptors. Good statistical models were derived. Properties associated with polarity and Lewis base strength had the largest impact on the blood-brain partitioning and should be kept to a minimum to promote high partitioning. The absence of atoms capable of hydrogen bonding interactions as well as high lipophilicity and the presence of polarizable surface electrons, i.e., valence electrons, were also found to promote high brain-blood partitioning. The results indicate that theoretically computed molecular MolSurf descriptors in conjunction with multivariate statistics of PLS type can be used to successfully model the brain-blood partitioning of organic solutes and hence differentiate drugs with poor partitioning from those with acceptable partitioning at an early stage of the preclinical drug-discovery process.

Blood-Brain Barrier↗
PubMed1996

Chromatographic fractionation and analysis by mass spectrometry of conjugated metabolites of bis(2-ethylhexyl)phthalate in urine.

Mono(2-ethylhexyl)phthalate (MEHP), the primary metabolite of the plasticizer bis(2-ethylhexyl)phthalate (DEHP), was given to guinea pigs and mice and the methods for the isolation, separation and analysis of its metabolites in urine were developed. Following solid-phase extraction with octadecylsilane-bonded silica, individual metabolites were purified and separated using a combination of ion-exchange chromatography on lipophilic gels and reversed-phase high-performance liquid chromatography. Analysis of intact conjugates, as well as nonconjugated metabolites, was performed by fast atom bombardment mass spectrometry (FAB-MS) and, after derivatization, by gas chromatography-mass spectrometry. Enzymatic methods were used for further characterization. The study confirms glucuronidation as the major conjugation pathway for MEHP in the investigated species. Although less important quantitatively, glucosidation is shown to be an alternative conjugation pathway in mice. The methods developed were applied to a sample of urine from a hyperbilirubinemic newborn infant subjected to DEHP-exposure in conjunction with an exchange transfusion. It was demonstrated that metabolites of DEHP were excreted in amounts which could be analyzed by FAB-MS.

Animals↗
PubMed1995

Enantioselective assay of beta-receptor antagonists present in microdialysis and plasma samples of rats.

The enantiomers of alprenolol, metoprolol, and propranolol have been separated on an enantioselective cellulase column and analysed using a fully automated HPLC system involving coupled column chromatography and fluorescence detection. The assays had sufficient selectivity and sensitivity to investigate the disposition of these beta 2-receptor antagonists in blood and brain extracellular fluid of rats. A cellulase column was used as the first column to separate the enantiomers giving separation factors between 2.9 and 4.3. After the separation, the enantiomers were trapped on two small precolumns by the use of a switching valve and were then introduced on an achiral C18 analytical column by eluting the small columns backward. The enantiomers in blood and brain tissue dialysates were analysed by direct injection of 8 microliters samples. The limit of quantitation was 0.025-0.4 micrograms/ml of the different enantiomers. Plasma samples were analysed after a simple extraction procedure. The intraassay precision of the lowest quality control plasma samples (0.2-0.8 micrograms rac-drug/ml) was 4-8% for the different enantiomers.

Adrenergic beta-Antagonists↗
PubMed1993

Two-year carcinogenicity study with sennosides in the rat: emphasis on gastro-intestinal alterations.

A carcinogenicity study was conducted by administering a purified senna extract via the drinking water to Sprague-Dawley rats of each sex for 2 years. The daily doses received were 0, 5, 15 and 25 mg/kg. Histopathological examination was restricted to tissues from the gastro-intestinal tract, liver, kidneys, adrenals and from tissues with any observed abnormalities or masses. A laxative effect was observed in high-dose females, and in mid- and high-dose males. No significant differences in survival were found between treated and control groups. Mean body weight gain was significantly decreased in high-dose males. Increased kidney weights were noted in mid-dose males and females, and high-dose females. Histopathological examination of control and high-dose rats did not indicate any difference in the incidence of neoplastic lesions. As regards non-neoplastic lesions, a treatment- but not dose-related increase in reactive mesenteric lymph node hyperplasia was observed in preterminally sacrificed rats. However, a corresponding increase was not noted in the terminally sacrificed rats or when preterminal and terminal animals were combined. No ultrastructural changes in the myenteric nerve plexus of the colon and jejunum could be detected in the small number of investigated tissue samples. In conclusion, results from the present investigation do not indicate any relationship between long-term administration of purified senna extract and gastrointestinal, liver, kidney or adrenal tumors in the rat.

Animals↗
PubMed1992

Validation of different microdialysis methods for the determination of unbound steady-state concentrations of theophylline in blood and brain tissue.

Three microdialysis methods, the "tritium" method, the "point-of-no-net-flux" method, and a method using the low perfusion rate of 0.1 microliter/min, were compared with respect to their ability to generate estimates of unbound steady-state concentrations (Cu(ss)) of the antiasthmatic drug theophylline in blood and brain tissue in anesthetized rats. Concomitantly, the influence of the perfusion flow rate on the estimated extracellular Cu(ss) obtained with the point-of-no-net-flux method was investigated. Theophylline was administered as a rapid intravenous bolus dose followed by constant intravenous infusion. Changes in perfusion flow rate from 2.0 to 0.75 microliter/min and, finally, to 0.25 microliter/min, using the point-of-no-net-flux method, had no significant effect on the estimated Cu(ss) of theophylline in blood and striatum. This observation, particularly in the case of brain tissue, is not consistent with the theory that the process of dialysis drains a significant amount of substance from the immediate vicinity of the dialysis probe. Similar estimates of Cu(ss) in blood as well as in brain tissue were obtained with all three methods. Their accuracy in estimating Cu(ss) in blood was further strengthened by observations of unbound fractions similar to those reported in the literature. Furthermore, all three methods gave striatum/blood ratios at steady state of approximately 0.5, indicating that there is active transport of theophylline from brain tissue. It is concluded that the tritium method, when validated, can be used to study the time course of unbound drug concentrations in blood and tissues.

Animals↗
PubMed1991

Glucuronidation of mono(2-ethylhexyl)phthalate. Some enzyme characteristics and inhibition by bilirubin.

A method for assaying mono(2-ethylhexyl)phthalate (MEHP) uridine diphosphate (UDP) glucuronyl transferase activity in microsomal preparations from guinea pig liver is described. The quantitation of the MEHP-glucuronide was performed by HPLC after direct injection of a sample of deproteinized incubation mixture. Solubilization of microsomal UDP-glucuronyltransferase activity was achieved by use of Lubrol, and optimal conditions for glucuronidation of MEHP were established. To investigate whether there is competition between MEHP and bilirubin for glucuronidation, inhibition experiments were performed with solubilized enzyme preparations. In these incubations addition of bilirubin decreased the formation of MEHP-glucuronide. No change in the maximal conversion rate (Vmax) was observed, indicating the occurrence of competitive inhibition. This observation may have implications in clinical situations where patients with hyperbilirubinemia are exposed to MEHP, e.g. in exchange transfusions in newborn infants.

Animals↗
PubMed1988

Analysis by fast atom bombardment mass spectrometry of conjugated metabolites of bis(2-ethylhexyl) phthalate.

Mono(2-ethylhexyl) phthalate was given to guinea pigs and mice and its metabolites were isolated from urine. A procedure consisting of sorbent extraction, ion-exchange chromatography and reversed-phase high-performance liquid chromatography was used in the purification scheme. The metabolites were analysed by fast atom bombardment mass spectrometry. It is concluded that the purification procedure is very mild and that fast atom bombardment is a useful ionization technique for intact conjugates of metabolites of bis(2-ethylhexyl) phthalate.

Animals↗
PubMed1988

Dose and sex-dependent disposition of ketoconazole in rats.

The disposition of the antifungal drug ketoconazole was studied in mature (60-day-old) male and female rats given single intravenous doses of 10, 20 or 40 mg/kg body weight. The plasma profiles of ketoconazole were characterized by an initial rapid decline, followed by an apparent zero-order decline and a subsequent first-order elimination phase. In male animals the zero-order phase was less pronounced, resulting in a 3-5 times higher overall rate of elimination. A consequence of the dose-dependent disposition was that a 4-fold increase in dose resulted in a 9- and 17-fold increase in the area under the plasma concentration-time curve (AUC) of females and males, respectively. Terminal half-lives were independent of dose in both sexes. The disproportionate increase in AUC with dose, together with the observation that no intact ketoconazole was excreted in urine and only very small amounts in bile (less than 1% of given dose), suggest that the dose-dependent disposition is caused by saturation of metabolizing enzymes. These enzymes are most likely under the influence of androgens, since the capacity of males to eliminate ketoconazole was reduced by castration and in females this capacity was increased by testosterone treatment.

Animals↗
PubMed1988

Pigmentation of kidneys and lymph nodes of mesocolon in rats fed diets containing the laxative danthron.

The tumor-promoting activity of the anthraquinone laxative danthron was studied by giving 3 groups of male rats a single subcutaneous injection of the colon tumor-inducing agent 1,2-dimethylhydrazine (DMH). After 1 week, the animals were fed diets containing 0, 600 or 2400 ppm of danthron for 26 weeks. Two other groups of rats were included in the study; one received no treatment while the other was given danthron only. Altogether 9 tumors were observed among animals given DMA with or without danthron. The incidence of colon tumors was higher in animals receiving DMH and danthron than in those given DMH only (5/60 vs. 0/30), but this difference was not statistically significant. The kidneys and lymph nodes of mesocolon were enlarged and showed a yellowish-red and brown discoloration, respectively. The pigment mostly displayed a PAS-positive reaction but contained no lipid as determined by several staining procedures. The available evidence suggests that the pigment is drug-derived.

1,2-Dimethylhydrazine↗
PubMed1988

Metabolism of mono-(2-ethylhexyl)phthalate in fetal, neonatal and adult rat liver.

The aim of the investigation was to study to what extent maturity influences the metabolism of mono-(2-ethylhexyl)phthalate (MEHP), the primary metabolite of the plasticizer di-(2-ethylhexyl)phthalate. The conversion of MEHP to its (omega-1)-hydroxylated product was determined in liver microsomes from fetal, neonatal (1- and 5-day-old) and adult rats. Product formation was determined by gas chromatography-mass spectrometry. The results show that fetal and neonatal as well as adult rat livers are capable of metabolizing MEHP by (omega-1)-hydroxylation. Preparations from 1- and 5-day-old rats were much more efficient than those from fetal rats. The transition into adult life gave no further increase in hydroxylase activity as compared to that in 5-day-old rats. The work shows that there is a rapid postnatal development of MEHP (omega-1)-hydroxylase activity in the rat.

Aging↗
PubMed1986

Effects of di-(2-ethylhexyl) phthalate and five of its metabolites on rat testis in vivo and in in vitro.

In an attempt to establish which compound or compounds are responsible for the testicular damage observed after administration of di-(2-ethylhexyl) phthalate (DEHP) in rats, the effects of the parent compound and five of its major metabolites (mono-(2-ethylhexyl) phthalate (MEHP), 2-ethylhexanol (2-EH), mono-(5-carboxy-2-ethylpentyl) phthalate, mono-(2-ethyl-5-oxohexyl) phthalate and mono-(2-ethyl-5-hydroxyhexyl) phthalate) were investigated in vivo and in vitro. The concentrations of MEHP and the three MEHP-derived metabolites in plasma were determined after single and multiple oral doses of DEHP. The plasma concentrations and areas under the plasma concentration-time curves (AUC's) of each of the MEHP-derived metabolites were considerably lower than those of MEHP both after single and after repeated administration of 2.7 mmol of DEHP/kg body weight. The mean elimination half-life of MEHP was significantly shorter in animals given repetitive doses than in those given a single dose, but there was no statistically significant difference between the mean AUC values. No testicular damage was observed in young rats given oral doses of 2.7 mmol of DEHP or 2-EH/kg body weight daily for five days. In animals which received corresponding doses of MEHP the number of degenerated spermatocytes and spermatids was increased, whereas no such effects were found in animals given the MEHP-derived metabolites. MEHP was also the only compound that enhanced germ cell detachment from mixed primary cultures of Sertoli and germ cells.

Animals↗