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Biomedical subjects

A Sundwall

Publications and source records attributed to A Sundwall.

At least 19 recordsLinked to original sources
PubMed2000

Quantitative whole-body radioluminography-future strategy for balance and tissue distribution studies.

The present routine to conduct balance and/or tissue dissection distribution studies has now and then been questioned, because the way they are generally conducted does not produce information in proportion to the spending of animal and personnel resources. Usually only total radioactivity is measured and due considerations are not always taken to the metabolic fate of the label. In this study a different strategy is presented-integrating quantitative whole-body radioluminography and different chromatographic methods on extracts of tissue pieces punched from the whole-body sections. In addition to the saving in cost and time, the proposed integrated whole-body radioluminographic/metabolic profile protocol will provide (i) a detailed picture of the distribution of radioactivity at selected dose levels and time points in male, female, and pregnant animals; (ii) the time course of radioactivity in blood/plasma and tissues selected from the images (approximate half-life and AUC); (iii) accumulated urinary and fecal excretion of radioactivity and an estimate of the proportion of radioactive metabolites; (iv) tissue information about the proportion of parent drug versus metabolites of pieces punched from the whole-body sections; and (v) indications of possible tissue binding.

Animals↗
PubMed1996

Oxazolidonylethyl adducts to hemoglobin and DNA following nornitrogen mustard exposure.

Formation of adducts to hemoglobin (Hb) and DNA of nornitrogen mustard (NNM) was studied with the aim of developing a method for monitoring exposure to NNM. Adducts to N-terminal valines in Hb were studied by the N-alkyl Edman method using pentafluorophenyl isothiocyanate (PFPITC) as the derivatizing reagent. In preliminary studies five major Hb adducts were shown to be formed in reaction of NNM with red cell hemolysate in vitro. Following treatment with PFPITC three of these were found to be pentafluorophenylthiohydantoins (PFPTHs) of N-alkylated valines and the fourth probably originates from NNM esters in which PFPITC had reacted with the nitrogen of N-chloroethylaminoethyl. A PFPTH was found to originate from N-2-(3-oxazolidonyl)ethylvaline, Val-OZ. Val-OZ is formed in reaction, with ring closure to oxazolidone, of CO2 with the 2-chloroethylamino group in the primary valine-N adduct. Besides a few other adducts, Val-OZ was also observed in mouse Hb following injection of NNM, and also after injection of cyclophosphamide. Following reaction in vitro of NNM with DNA, three major adducts to guanine-N-7 were observed; one of them, 7-(N'-(2-chloroethyl)-2-aminoethyl]-guanine (NNMCl), was converted by carbonate to 7-(2-3-oxazolidonyl)ethyl]guanine (Gua-OZ). In mice treated with NNM, Gua-Oz was the only DNA adduct observed. Val-Oz is a chemically stable Hb adduct, potentially useful for monitoring exposures to NNM and cyclophosphamide.

Animals↗
PubMed1989

Effect of acute and subchronic nicotine treatment on cortical acetylcholine release and on nicotinic receptors in rats and guinea-pigs.

1. The effect of acute and chronic (16 days) administration of nicotine on cortical acetylcholine (ACh) release, gross behaviour and brain nicotinic binding sites was investigated in rats and guinea-pigs. 2. The drug, injected either subcutaneously (0.45-0.90 mg kg-1) or intracerebroventricularly (1, 3 and 5 micrograms) increased the cortical ACh release, in a dose-dependent manner, through mecamylamine-sensitive receptors for 1-2 h in both species. 3. Chronic treatment significantly increased basal ACh release in the rat and slightly lowered it in the guinea-pig, but the response to a challenging dose of nicotine was proportionally maintained in both species. 4. The number of nicotinic receptors was four times higher in the rat than in the guinea-pig and was not dependent on the radioligand used ([3H]-nicotine or [3H]-ACh, in the presence of atropine) to determine this. The nicotinic binding sites showed an apparent increase in chronically treated rats but no change in guinea-pigs. 5. Tolerance to the inhibitory effect of the drug, assessed with the T maze test, was found in the rat. No apparent change in gross behaviour was detected in the guinea-pig. 6. It is concluded that chronic nicotine treatment causes evident tolerance to its inhibitory effect on behaviour in the rat, but no adaptation to its excitatory properties on the cholinergic brain structures in rats and guinea-pigs.

Acetylcholine↗
PubMed1988

Relationship between gastric emptying and serum concentrations of emepronium in dogs and human volunteers.

Clinical trials with increased dosages, relative to the standard regimen, of the anticholinergic drug emepronium (Cetiprin Novum) resulted in a clear improvement in micturition- and urodynamic parameters in urinary incontinent patients. In the present study possible effects on the gastric emptying were tested in dogs and in human volunteers. In dogs a wide dose range of emepronium (5-100 mg/kg p.o.) was used to establish a relationship between serum concentration and effect on the gastric emptying. Gastric emptying was slightly decreased after 25 mg/kg (peak conc. of emepronium about 100 micrograms/l) and markedly decreased after 50 mg/kg (500 micrograms/l) and 100 mg/kg (5000 micrograms/l). In the volunteers no effect of emepronium on gastric emptying was observed, either after 200 mg q.i.d. or after 400 mg q.i.d. (about 3 and 6 mg/kg q.i.d.), which resulted in peak serum concentrations of 100-300 micrograms/l).

Adult↗
PubMed1987

Gastrointestinal transit rate-related absorption of emepronium: a study in mice.

The gastrointestinal (GI) absorption in mice of the anticholinergic quaternary ammonium compound emepronium, assessed by the urinary excretion of radioactivity and unchanged drug, increased from 1% to 7% and from 0.5% to 5%, respectively, in the dose range 0.1 to 40 mg/kg, whereafter a plateau was reached. Changes in the metabolism were evident at doses exceeding 80 mg/kg when 80% of the radioactivity was excreted as unchanged emepronium, as compared to 50% at lower doses. No dose-dependent urinary excretion of radioactivity was detected following intravenous injection. The increase in the fraction of the dose excreted in the urine after oral administration therefore cannot be easily explained by a dose-dependent metabolism or renal excretion. However, a relationship was seen between the reduced gastrointestinal motility, produced by increasing doses of the drug, and the increased bioavailability. Atropine sulphate given subcutaneously (1-50 mg/kg) more than doubled the urinary recovery of a small pharmacologically inactive oral dose of emepronium (5 mg/kg) and thus confirmed the transit rate-dependent absorption of emepronium. The superimposed effect of the pharmacological action on the GI transit rate, derived from the inherent property of an anticholinergic drug, may be of special significance for a drug with a low degree of absorption and a high variability, such as has been observed in clinical trials with the quaternary drug emepronium (Cetiprin).

Animals↗
PubMed1985

Ion pair formation and gastrointestinal absorption of emepronium.

Ion pair forming agents were evaluated in vitro for their ability to form lipophilic ion pairs with the quaternary ammonium compound emepronium and in vivo to enhance its gastrointestinal absorption. A 5- to 100-fold excess of trichloroacetate (TCA), diethylhexylphosphate (DEHPA), heptafluorobutyrate (HFBA), sodium lauryl sulphate (SLS), bromide or chloride all increased the extractability of the emepronium ion into methylene chloride. The additive with the most marked effect on the apparent partition coefficient of emepronium (Kapp) was SLS. At emepronium 10(-4) M, Kapp increased from a basal value of 0.1 to 368 with a 100-fold molar excess. However, the increased partitioning to methylene chloride was not reflected in an increased gastrointestinal absorption of the emepronium ion when this was given orally to mice. When intestinal juice, instead of distilled water or buffer, was used as the aqueous phase, the partition coefficient was markedly higher (Kapp approximately 2) but it was significantly less influenced by addition of sodium lauryl sulphate (Kapp approximately 6). The preexisting positive influence of the intestinal juice on the lipophilic character of emepronium and the rather limited additive effect of agents that form lipophilic complexes with emepronium, lead to the conclusion that the ion pair concept is not a suitable approach to enhance the gastrointestinal absorption of this drug.

Animals↗
PubMed1985

Modulation of choline transport and acetylcholine synthesis in synaptosomes from different brain regions.

Uptake and biotransformation of radioactive choline (3H-Ch) have been studied in P2 fractions from different brain regions of mice treated with different doses of sodium pentobarbital (45-120 mg/kg intraperitoneally) or saline. Sodium dependent uptake (SDU) has been measured as the difference between results of incubations with Na+ in the incubation medium and when the sodium salts were replaced by Trisphosphate and sucrose. The uptake of radioactivity increased during the incubation with 3H-Ch but the proportion of 3H-ACh was the same at all time points. The proportion of 3H-ACh to 3H-Ch in the P2 pellet was 86, 81 and 69 per cent in hippocampus, striatum and cortex, respectively. Omission of sodium ions in the incubation medium reduced uptake of 3H-Ch by about 90 per cent at 1 microM Ch in the incubation medium and the proportion of 3H-ACh to 3H-Ch was only 10 to 20 per cent while the proportion of 3H-PhCh increased from insignificant amounts to between 20 to 30 per cent. There were quantitative regional differences in SDU, a two times greater uptake was obtained in the striatum compared with cortex and hippocampus. Apparent Km and Vmax were 0.9 X 10(-6)M and 71 pmol/mg, respectively, for the cortex of untreated animals. The contribution of endogenous Ch from the P2 fraction to the incubation medium gave a final concentration of 0.5 microM Ch in the standard uptake experiments. The 3H-Ch uptake was significantly reduced in P2 fraction from cortex and hippocampus prepared from mice anaesthetized with sodium pentobarbital while the uptake in P2 fractions from the striatum was unaffected. Sodium pentobarbital treatment did not affect the proportion of 3H-ACh in the pellets.

Acetylcholine↗
PubMed1983

Pharmacodynamic effects of nicotine and acetylcholine biosynthesis in mouse brain.

Nicotine (4; 8 mg/kg) given intraperitoneally to mice had a marked hypothermic effect with a duration of more than 2 hours. Mecamylamine (0.5; 2.5 mg/kg) prevented the hypothermic effect of 2 mg/kg nicotine but had no effect on 4 mg/kg nicotine. Atropine (5 mg/kg) did not affect the hypothermia produced by nicotine. Other symptoms induced by nicotine (0.5-4 mg/kg) were convulsions, rigidity, tremor and decrease in motor activity. Pretreatment with mecamylamine (0.5 mg/kg) prevented convulsions but had only a slight effect on the decreased motor activity. Atropine pretreatment was ineffective. It thus seems as if the effects of nicotine at least to some part are mediated by nicotine-like receptors. When a tracer dose of labelled choline (3H-Ch) was given to mice treated with nicotine (4 mg/kg) a marked increase (+100%) in the biosynthesis of labelled acetylcholine (ACh) in the striatum was found when the animals were killed by decapitation. If the mice were killed by a more rapid technique, microwave irradiation of the head, no change in 3H-ACh formation was observed in comparison to controls. The findings indicate that nicotine can preserve a very labile pool of newly synthesized ACh in the striatum.

Acetylcholine↗
PubMed1980

Melatonin administration to dogs.

Melatonin concentrations in serum and urine were examined following oral administration of melatonin to dogs. Four different doses of melatonin ranging from 10 to 80 mg per kg of body weight were given. Melatonin was rapidly absorbed and reached a maximum serum level after 20--30 min, with a distribution phase of 3.5 hours and elimination half life (t1/2) of 5 hours. The fraction excreted in the urine was 0.25% of the administrated dose during the first 5 hours. These results as well as the diurnal rhythm of serum melatonin in the dogs are similar to corresponding data reported in the human.

Administration, Oral↗
PubMed1980

Assessment of cholinergic neuronal activity in the brain.

Endogenous acetylcholine (ACh), ACh turnover and high affinity choline uptake (H.A. Ch uptake) have all been considered valuable markers for cholinergic neural activity. The present communication compare the markers regarding regional differences in the brain of normal mice as well as in mice treated with oxotremorine (OT), nicotine and sodium pentabarbital. A relationship is obtained between in vivo turnover values for 5 different brain regions and in vitro H.A. Ch uptake. Pretreatment with OT and sodium pentobarbital produces specific regional changes in both turnover and H.A. Ch uptake. However, both drugs produce shifts of the correlation lines due to uptake being less affected than turnover. Atropine completely prevented the effects of OT regarding turnover and H.A. Ch uptake. A convulsant dose of nicotine did not produce significant changes in any of the brain regions studied neither on turnover nor on H.A. Ch uptake.

Acetylcholine↗
PubMed1978

Metrifonate. Summary of toxicological and pharmacological information available.

The organophosphorus compound 0,0-dimethyl-(1-hydroxy-2,2,2-trichloroethyl)-phosphonate was introduced as an insecticide, trichlorfon, in 1952 (Lorenz et al., 1955) and as a drug, metrifonate, in the treatment of schistosomiasis in 1960 (Lebrun and Cerf, 1960). This organophosphorus compound is unique in that it has been claimed not to be a direct acting cholinesterase inhibitor but being transformed nonenzymatically into an active component dichlorvos, 2, 2-dichlorovinyl dimethyl phosphate (DDVP). The evidence for this transformation has mostly been indirect. Recently it has been proved chemically and quantitatively that this transformation occurs in the animal body (Nordgren et al., 1978). Metrifonate is the sole organophosphorus compound currently studied clinically in schistosomiasis. A substantial therapeutic effect is obtained only in Schistosoma haematobium infections. In this review on available data of metrifonate it is suggested that further more detailed studies of both S. haematobium and S. mansoni are necessary. This should include studies of the enzymic properties of the worms and the reaction of their esterases towards both metrifonate and DDVP as well as the pharmacokinetics of these compounds in man. In addition there are still unsolved discrepancies reported regarding organ toxicity of the compound which may, however, be due to different grades of parity of the test material.

Animals↗
PubMed1978

Pharmacokinetics of oxazepam given during labour.

The transfer across the placenta and the maternal and neonatal kinetics of oxazepam and its conjugate was studied in 12 patients and their newborns. Oxazepam was readily absorbed and peak plasma concentrations were similar to those in healthy non-pregnant volunteers. When meperidine was given within one hour of the dose of oxazepam the absorption was delayed but the bioavailability did not decrease. In the newborns the umbilical vein plasma concentration of oxazepam usually exceeded that of the conjugate. The reverse was true for all subsequent plasma samples from the newborn. The half-life of oxazepam in the newborn averaged 22 hours as compared to 6.5 hours in the mothers. A significant rise of the plasma concentration of oxazepam conjugate was noted in three newborns during the first 6-10 hours of extrauterine life. This shows that the newborn is able to conjugate oxazepam. The Apgar score values were normal.

Administration, Oral↗
PubMed1977

Effect of sodium pentobarbital on the apparent turnover of acetylcholine in different brain regions.

The turnover rate of acetylcholine(ACh)was measured in six different brain regions in the mouse following pulse injection of radioactive choline (Ch) and killing of the animals by microwave irradiation of the head (0.25 s, 5 kW). The time course of the change in 3H-ACh/3H-Ch ratio was linear 0-06 s in all brain regions after administration of 3H-Ch. Plots of the specific radioactivities (SA) of ACh and Ch versus time indicate a precursor-product relationship in all brain regions except the cerebellum both in control and sodium pentobarbital anesthesized animals. The turnover was highest in the striatum (55 nmol-g-1-min-1), while in the cortex and hippocampus this value was approximately half (27 and 21 nmol-g-1-min-1). In the midbrain and medulla oblongata the turnover rates were only 11 and 10 nmol-g-1-min-1. Sodium pentobarbital anesthesia reduced specifically the turnover in the cortex and hippocampus to about 60 to 70 percent.

Acetylcholine↗