Biomedical subjects

A Ekman

Publications and source records attributed to A Ekman.

At least 37 records · Page 2Linked to original sources

PubMed1996

Inverse agonism at dopamine D2 receptors. Haloperidol-induced prolactin release from GH4C1 cells transfected with the human D2 receptor is antagonized by R(-)-n-propylnorapomorphine, raclopride, and phenoxybenzamine.

Our earlier observation that the antipsychotic drug haloperidol in the absence of dopamine increases cAMP formation and prolactin release in two prolactin-producing cell lines expressing rat dopamine D2 receptors (GH3, GH4ZR7), but not in similar cells devoid of D2 receptors (GH4C1), prompted us to suggest that haloperidol may act as an inverse (or negative) agonist, rather than as a neutral antagonist, at the D2 receptor (Nilsson and Eriksson 1993). In the present study it is shown that haloperidol elicits a dose-dependent increase in prolactin release also in prolactin-producing GH4C1 cells transfected with the human dopamine D2 receptor (short isoform) (GH4C1-hD2s); in addition, it is shown that another antipsychotic drug, flupenthixol, also causes prolactin release per se in this cell line. The effect of haloperidol on prolactin release in GH4C1-hD2s is calcium dependent and counteracted by pretreatment either with the D2 receptor agonist R(-)-n-propylnorapomorphine or with a D2 receptor antagonist that does not affect prolactin release per se (raclopride). In addition, pretreatment with the alkylating compound phenoxybenzamine at a concentration causing a marked reduction of D2 receptor density in GH4C1-hD2s cells significantly counteracted haloperidol-induced prolactin release.

Animals↗

PubMed1995

Dopamine D3 receptor antisense influences dopamine synthesis in rat brain.

Intracerebroventricular infusion of an all-phosphorothioate antisense oligodeoxynucleotide targeted at the rat dopamine D3 receptor mRNA (10 micrograms h-1, 5 days) resulted in a significant reduction (19%) of the binding of the [D2 + D3] ligand [3H]spiperone in the limbic forebrain, where D3 receptors are relatively abundant, but not in caudate-putamen, where D3 receptors are sparse. In nucleus accumbens antisense treatment also caused an increase in dopamine synthesis; in contrast, antisense administration did not counteract the effect of apomorphine on dopamine formation. No effect of antisense administration on dopamine synthesis was observed in caudate-putamen. The results support the usefulness of the antisense strategy for the study of D3 receptors and suggest that D3 receptors may influence dopamine synthesis.

Animals↗

PubMed1995

Neutrophil and asbestos fiber-induced cytotoxicity in cultured human mesothelial and bronchial epithelial cells.

This study investigates reactive oxygen species generation and oxidant-related cytotoxicity induced by amosite asbestos fibers and polymorphonuclear leucocytes (PMNs) in human mesothelial cells and human bronchial epithelial cells in vitro. Transformed human pleural mesothelial cells (MET 5A) and bronchial epithelial cells (BEAS 2B) were treated with amosite (2 micrograms/cm2) for 48 h. After 24 h of incubation, the cells were exposed for 1 h to nonactivated or amosite (50 micrograms) activated PMNs, washed, and incubated for another 23 h. Reactive oxygen species generation by the PMNs and the target cells was measured by chemiluminescence. Cell injury was assessed by cellular adenine nucleotide depletion, extracellular release of nucleotides, and lactate dehydrogenase (LDH). Amosite-activated (but also to a lesser degree nonactivated) PMNs released substantial amounts of reactive oxygen metabolites, whereas the chemiluminescence of amosite-exposed mesothelial cells and epithelial cells did not differ from the background. Amosite treatment (48 h) of the target cells did not change intracellular adenine nucleotides (ATP, ADP, AMP) or nucleotide catabolite products (xanthine, hypoxanthine, and uric acid). When the target cells were exposed to nonactivated PMNs, significant adenine nucleotide depletion and nucleotide catabolite accumulation was observed in mesothelial cells only. In separate experiments, when the target cells were exposed to amosite-activated PMNs, the target cell injury was further potentiated compared with the amosite treatment alone or exposure to nonactivated PMNs. In conclusion, this study suggests the importance of inflammatory cell-derived free radicals in the development of amosite-induced mesothelial cell injury.

Adenine Nucleotides↗

PubMed1994

6,7,8,9-Tetrahydro-N,N-di-n-propyl-3H-benzindol-8-amines. Derivatives as potent and orally active serotonin 5-HT1A receptor agonists.

Derivatives and isosteric derivatives of the potent 5-HT1A agonist 8-(di-n-propylamino)-6,7,8,9- tetrahydro-3H-benz[e]indole-1-carbaldehyde (5) were prepared and evaluated in vivo and in vitro for serotonergic and dopaminergic activity. The 1-cyano analog 8 was found to be almost equipotent to 5 and the previously described 2-cyano derivative 6, while a 1-chloro and 1-(1,1,1-trifluoroethyl) substituent (9 and 10, respectively) formed less potent derivatives. The isosteric 6,7,8,9-tetrahydro-1H-benz[g]indoles 4 and 12-15 showed surprisingly low affinity or activity at both serotonergic and dopaminergic systems. The interpretations of these results by means of drug-receptor interactions at the 5-HT1A subtype are discussed. Compounds 6 and 8 were found to have high oral bioavailability in the rat (63% and 54%, respectively).

Animals↗

PubMed1993

Orally active central dopamine and serotonin receptor ligands: 5-, 6-, 7-, and 8-[[trifluoromethyl)sulfonyl]oxy]-2-(di-n-propylamino)tetralins and the formation of active metabolites in vivo.

The racemic triflate derivatives 5-8 of the 5-, 6-, 7-, and 8-hydroxylated 2-(di-n-propylamino)-teralins 1-4 were shown to possess similar pharmacological profiles to their phenolic counterparts in in vitro binding and in vivo biochemical and behavioral assays in rats. Consequently, subcutaneous administration of the 5-, 6-, and 7-triflates displayed essentially dopaminergic agonist properties, while the 8-triflate was shown to be a selective 5-HT1A receptor agonist. With respect to their agonist activities, the triflates were less potent than their phenolic analogs. The absolute oral bioavailability of compound 8 (8-triflate) was 4-5 times greater than the corresponding hydroxylated compound. Interestingly, in the in vivo biochemical assay compound 8 was found to be more potent after oral than after subcutaneous administration, indicating formation of one or more active metabolites. Following a study of the metabolism of compound 8 in rat hepatocytes, the monopropyl analog 9 was identified as the major metabolite and was surprisingly found to be more potent than compound 8. Oral administration of compound 5 (5-triflate) resulted in behavioral and biochemical effects indicative of mixed DA/5-HT1A agonist properties not seen after subcutaneous administration. These results may also be indicative of the formation of active metabolites.

8-Hydroxy-2-(di-n-propylamino)tetralin↗

PubMed1993

A high dose of EEDQ reduces pituitary dopamine D2 receptor density and the prolactin suppressive potency of agonists.

In male rats, a high dose of the alkylating compound N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (EEDQ, 30 mg/kg s.c., 24 h) caused a reduction of pituitary dopamine D2 receptor density by 27% as measured by means of in vivo radioligand binding (using a single dose of the ligand [3H]spiperone). The same dose of EEDQ reduced the potency, but not the maximal response, of the dopamine D2 receptor agonists R-(-)-N-n-propylnorapomorphine (NPA), (+)-3-(3-hydroxyphenyl)-N-n-propylpiperidine ((+)-3-PPP), and 6-allyl-2-amino-5,6,7,8-tetrahydro-4H-thiazolo[4,5]azepine (B-HT 920) with respect to suppression of prolactin release after pretreatment with gamma-butyrolactone. The measured reduction in dopamine D2 receptor density after EEDQ was of the same magnitude as the reduction in receptor number predicted from the EEDQ induced shift in the dose-response curve of the full dopamine D2 receptor agonist NPA. The findings are discussed in relation to our previous observation that a somewhat lower dose of EEDQ (20 mg/kg s.c., 24 h) effectively reduces the efficacy of partial dopamine D2 receptor agonists while affecting neither the prolactin response to full dopamine D2 receptor agonists nor the density of pituitary dopamine D2 receptors.

Animals↗

PubMed1993

(S)- and (R)-8-(di-n-propylamino)-6,7,8,9-tetrahydro-3H-benz[e]indole-1- carbaldehyde: a new class of orally active 5-HT1A-receptor agonists.

The enantiomers of 6,7,8,9-tetrahydro-N,N-di-n-propyl-3H-benz[e]indol-8- amine (S-(-)-2b and R-(+)-2b) and their corresponding 1-formyl analogs (S-(-)-6 and R-(+)-6) were prepared and evaluated pharmacologically for serotonergic and dopaminergic activity. The introduction of a formyl group in the 1-position shifted the pharmacological profile of 2b from a mixed D2/5-HT1A agonists to a selective 5-HT1A agonist (6). The enantiomers of 6 were agonists with full intrinsic activity and had an affinity comparable to that of 8-hydroxy-2-(di-n-propylamino)tetrahydronaphthalene (8-OH-DPAT). In contrast to 8-OH-DPAT, the enantiomers of compound 6 were found to have good oral availability.

8-Hydroxy-2-(di-n-propylamino)tetralin↗

PubMed1993

Interferon-alpha and interferon-gamma combined with chemotherapy: in vitro sensitivity studies in non-small cell lung cancer cell lines.

Non-small cell lung cancers (NSCLC) are often resistant to chemotherapy. Cisplatin has shown the most activity against all the histological subtypes and is now used in most combined treatment programmes. Interferon (IFN)-alpha has been shown to potentiate cisplatin and other drugs experimentally and in clinical trials involving NSCLC. We are looking at the responses of different NSCLC cell lines to cisplatin (P), etoposide (VP-16) and IFN [recombinant human IFN-alpha 2c (IFN-alpha) and IFN-gamma 1b (IFN-gamma)], individually and in combination. We then compare the results with those from a clinical trial of etoposide and cisplatin with interferon in advanced NSCLC. We report here the results from the first of our cell lines, established from a large cell anaplastic carcinoma. We have confirmed earlier findings that NSCLC cell lines are not sensitive to either IFN-alpha or IFN-gamma alone. However a combination of IFN-alpha and IFN-gamma does reduce cell proliferation in our cell lines. This IFN combination potentiates the response of the cells to etoposide far more than to cisplatin. There is a trend towards greater activity when a combination of cisplatin and etoposide is used, compared with the activity of either drug alone. This effect is further increased by the interferon combination.

Adenocarcinoma↗

PubMed1992

6-Hydroxy-3-n-propyl-2,3,4,5-tetrahydro-1H-3-benzazepine and analogs: new centrally acting 5-HT1A receptor agonists.

The ring-closed phenylethylamine analogue 6-hydroxy-3-n-propyl-2,3,4,5-tetrahydro-1H-3-benzazepine (1) is a 5-HT1A receptor agonist of moderate potency, according to both in vivo biochemical data and in vitro binding data. The active compounds of this series also induce the 5-HT behavioral syndrome. Molecular modeling studies were performed with molecular mechanics calculations, and a tentative explanation for the relatively low potency of these serotonergic benzazepines is provided.

Animals↗

PubMed1992

Effects of N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline on the prolactin suppression induced by a series of full and partial dopamine D2 receptor agonists in male rats.

The effect of pretreatment with a high dose of the alkylating agent N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (EEDQ) (20 mg/kg, 24 h) on the intrinsic activity displayed by a series of full and partial dopamine D2 receptor agonists on prolactin regulating pituitary D2 receptors in male rats was studied. To increase baseline prolactin levels, gamma-butyrolactone in a dose inhibiting brain dopamine neurotransmission was given to all animals. In controls, i.e. rats not given EEDQ, supramaximal doses of all full and partial D2 receptor agonists tested decreased serum prolactin levels with greater than 80%. While the intrinsic activities of the dopamine precursor 1-DOPA and of the full agonists (+)-3-PPP, 5-OH-DPAT, B-HT 920 (talipexole), apomorphine, and NPA (R-(-)-N-n-propylnorapomorphine) were not affected by pretreatment with EEDQ, the effects of supramaximal doses of the partial agonists (-)-HW-165, TDHL (terguride), SDZ208-911, (-)-3-PP) (preclamol), and SDZ 208-912 were reduced to 66%, 74%, 59%, 100%, and 100%, respectively. The effect of EEDQ on the intrinsic activity displayed by the various agonists corresponds inversely to the intrinsic efficacy displayed by the drugs in other models of D2 receptor function with one exception only; thus, the prolactin suppressive effect of (-)-3-PPP was more effectively antagonized by EEDQ than would have been predicted from the intrinsic efficacy usually attributed to the drug. Since the dose of EEDQ used in the present study has previously been shown not to decrease D2 receptor density in the pituitary as measured using in vivo radioligand binding, it is suggested that alkylation of D2 receptors may change the conformation of the individual receptor complexes in a way that decreases the responsiveness to partial but not full agonists.

4-Butyrolactone↗

PubMed1992

Interferon-alpha and -gamma in combination with chemotherapeutic drugs: in vitro sensitivity studies in four human mesothelioma cell lines.

Mesothelioma is a tumor of the serous surfaces in the thorax and abdomen. This tumor has proved to be exceptionally resistant to treatment, although a variety of multi-modality therapies have been tried. We have used four human mesothelioma cell lines, originating from diffuse asbestos-related malignant (pleural) mesothelioma, to assess in vitro sensitivity to five chemotherapeutic drugs, to recombinant human interferon (IFN)-alpha and -gamma and to combined immuno-chemotherapy. The cytotoxic effects were assayed by vital dye exclusion. The drugs tested were etoposide, cisplatin, mitoxantrone, 4-epirubicin and vindesine. The combinations tested were etoposide+cisplatin, and etoposide+cisplatin+mitoxantrone. All the drugs and combinations were also tested with recombinant human (rHu) IFN-alpha 2C (rHuIFN-alpha), rHuIFN-gamma, and rHuIFN-alpha+rHuIFN-gamma. The cell lines were most sensitive to mitoxantrone, 4-epirubicin and vindesine (TC50 < or = 0.001 micrograms/ml), and least sensitive to etoposide and cisplatin (TC50 > or = 0.1 micrograms/ml) used singly. There was no improvement in sensitivity when the drugs were combined. To further investigate the lack of response to cisplatin treatment, we examined the binding of cisplatin to the mesothelioma cell DNA. The tumor cell DNA bound markedly less cisplatin than human fetal fibroblast DNA. Three cell lines were tested with rHuIFN-alpha and rHuIFN-gamma on their own or rHuIFN-alpha+rHuIFN-gamma. They were consistently sensitive to rHuIFN-alpha, but the sensitivity to rHuIFN-gamma varied with the cell lines. Finally, we tested two cell lines with the drugs singly and in combination, together with 0.01 micrograms/ml each of rHuIFN-alpha and rHuIFN-gamma.(ABSTRACT TRUNCATED AT 250 WORDS)

Antineoplastic Agents↗

PubMed1991

Effects of the partial dopamine receptor agonists SDZ 208-911, SDZ 208-912 and terguride on central monoamine receptors. A behavioral, biochemical and electrophysiological study.

The partial dopamine receptor agonists SDZ 208-911 (N-[(8-alpha)-2,6-dimethylergoline-8-yl]-2,2-dimethylpropanamid e), SDZ 208-912 (N-[8-alpha)-2-chloro-6-methylergoline-8-yl]-2,2- dimethylpropanamide) and terguride (transdihydrolisuride; TDHL) were tested in biochemical, behavioral (locomotor activity) and electrophysiological assays in male rats. In reserpine-pretreated rats, SDZ 208-911 and terguride dose-dependently reduced striatal DOPA formation (NSD 1015 treatment) with similar efficacy (-80%) and potency as the selective D2 receptor agonist quinpirole (LY 171555). SDZ 208-912 only produced a partial reduction (-32%) at the highest dose tested. SDZ 208-911 and terguride partially reversed (by approximately 50%) the gamma-butyrolactone (GBL)-induced increase in striatal DOPA accumulation. Quinpirole produced a 100% reversal while SDZ208-912, per se, was inactive. While quinpirole decreased DOPA accumulation, all three partial agonists elevated striatal DOPA accumulation in non-pretreated rats with SDZ 208-912 being as potent and efficacious as haloperidol. The three partial agonists displayed comparatively high affinities in vitro for the dopamine D2 (3H-spiperone) receptor site and somewhat lower affinity for the 5-HT1A (3H-8-OH-DPAT) receptor site. SDZ 208-911 and SDZ 208-912 also showed high affinities for central alpha 2 (3H-idazoxane) receptors. In line with these findings, the partial ergoline agonists dose-dependently elevated the DOPA accumulation in the noradrenaline-rich cortical brain region and decreased the 5-HT synthesis rate (5-HTP accumulation) in the limbic brain region. Furthermore, high doses of SDZ 208-911 and terguride produced weak signs of the 5-HT behavioral syndrome (flat body posture) in reserpinized rats. In the locomotor activity studies in non-pretreated rats, SDZ 208-911, SDZ 208-912 and terguride reduced the activity to 10-20% of controls with SDZ 208-912 being approximately ten times less potent than the other two compounds. Weak postsynaptic dopamine receptor agonist effects of the partial agonists were demonstrated only in reserpine-pretreated rats; all three partial agonists tested produced occasional forward locomotion and the so-called "jerking" behavior. Extracellular single unit recordings were carried out in chloral hydrate-anesthetized rats to investigate the effects on firing rates of dopamine neurons located in the substantia nigra pars compacta. Intravenous administration of SDZ 208-911 and terguride depressed the firing rate by 42 and 53%, respectively, while apomorphine completely inhibited the cells. SDZ 208-912 only reduced the firing by 16% and some cells displayed a biphasic response with a weak depression at low doses that disappeared at high doses.(ABSTRACT TRUNCATED AT 400 WORDS)

4-Butyrolactone↗

PubMed1991

Effects of the two partial D2 agonists (+)- and (-)-3-PPP on prolactin release in EEDQ treated male rats.

The effects of pretreatment with the irreversible inactivator of brain D2 receptors N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (EEDQ) on the suppression of prolactin (PRL) release induced by the two partial D2 agonists (+)- and (-)-3-(3-hydroxyphenyl)-N-n-propyl-piperidine [(+)-3-PPP, (-)-3-PPP] were investigated in gamma-butyrolactone (GBL) treated male rats. Pretreatment with a high dose of EEDQ (20 mg/kg, 24 h) did not influence the PRL response to (+)-3-PPP. In contrast, the effect of (-)-3-PPP was dose-dependently antagonized by EEDQ administration; thus, while pretreatment with EEDQ 2 mg/kg (24 h) failed to influence the efficacy of (-)-3-PPP, a complete antagonism of the PRL suppressive effect of the (-) enantiomer was obtained by administration of EEDQ 16 or 20 mg/kg (24 h). Moreover, in EEDQ (20 mg/kg, 24 h) treated rats (-)-3-PPP effectively antagonized the PRL inhibiting effect of the (+) enantiomer. Also, in EEDQ (20 mg/kg, 24 h) treated animals not receiving GBL (-)-3-PPP induced a dose-dependent increase in plasma levels of PRL. The data indicate that higher doses of EEDQ are required in order to reduce the responsiveness of lactotroph D2 receptors than that of various populations of brain D2 receptors. Also, the data lend support for the assumption that an altered receptor responsiveness may dramatically modify the response to a partial agonist with low intrinsic efficacy without affecting the response to a partial agonist with higher intrinsic efficacy.

4-Butyrolactone↗

PubMed1991

Pituitary and brain D2 receptor density measured in vitro and in vivo in EEDQ treated male rats.

The effect of the alkylating compound N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (EEDQ) (20 mg/kg, 24 h) on dopamine D2 receptor density in rat pituitary and brain was measured using in vitro and in vivo radioligand binding techniques. In the in vitro radioligand binding experiments EEDQ was found to reduce the density (Bmax) of [3H]-spiperone binding sites in the striatum by 86% while in the pituitary the corresponding decrease was only 37%. The affinity (KD) of the remaining striatal and pituitary D2 receptors was not different in EEDQ treated animals as compared to controls. When D2 receptor density was measured in vivo the effect of EEDQ was less pronounced. Thus, in rats given EEDQ the specific binding of either of the two D2 ligands [3H]-raclopride or [3H]-spiperone (administered in a single dose) in striatum and in the limbic forebrain was reduced by 45-62%; moreover, no significant decrease in pituitary D2 receptor density was observed. The data are discussed in relation to the finding (presented in a separate paper) that the same dose of EEDQ that failed to influence pituitary D2 receptor density as measured in vivo effectively antagonizes the prolactin decreasing effect of the partial D2 agonist (-)-3-(3-hydroxyphenyl)-N-n-propyl-piperidine [(-)-3-PPP].

4-Butyrolactone↗

PubMed1990

Environment-dependent effects of ethanol on DOPAC and HVA in various brain regions of ethanol-tolerant rats.

The development of tolerance to the behavioral and biochemical effects of ethanol was studied. Rats were made tolerant to ethanol by the administration of daily ethanol injections (3 g/kg, IP) for 7 and 28 days. Tolerance developed both to the behavioral (hypothermic, sedative) and biochemical (accumulation of dopamine metabolites in various brain areas) actions of ethanol. However, it was found that this tolerance to both the behavioral and biochemical effects of ethanol was no longer present when previously ethanol-tolerant animals were moved from their home environment and given a challenge dose of ethanol (2.5 g/kg; IP) in a new, unfamiliar environment. Our findings confirm that ethanol tolerance cannot be explained on the basis of a singular neurochemical event. The development of ethanol tolerance is due to a complex interaction between environmental, learning, and biochemical factors.

3,4-Dihydroxyphenylacetic Acid↗

PubMed1990

Effect of early dental health education for Finnish immigrant families.

The aim of the study was to evaluate whether or not the dental health of Finnish immigrant children would benefit from an extra session of information to the parents at the Child Health Centre, and whether this information, to be effective, should be given in Finnish. A further aim was to study the effect of this information on the parent's dental health knowledge and behaviour. Three groups of Finnish children, two test groups (FF and FS) and one control group (FC), and one control group of Swedish children (SC) took part in the study in Norrbotten and Stockholm county respectively. When the children were 6, 18 and 27 months of age, the parents of the Finnish test groups received information, the FF-groups in Finnish, and the FS-groups in Swedish. The parents of the Finnish and Swedish control groups were informed when the children were 6 and 18 months of age in Swedish. The various programmes were evaluated by comparing prevalence of dental caries of the children at the age of 3, as well as parents' attitudes to and knowledge of dental health and dental health behaviour. In Norrbotten 71% of the children in the FF-group were caries free compared to 53% in the FS-, 30% in the FC- and 80% in the SC-groups, and dfs averaged 1.7, 2.7, 6.0 and 0.9 for the groups respectively. The percentages of caries free children in Stockholm were 71, 58, 32 and 82 for the groups respectively and the mean dfs values 1.2, 2.1, 4.6 and 0.7. The data from the 36-month appointment showed equally good dental health knowledge and behaviour for the FF-groups as for the Swedish control groups.

Attitude to Health↗

PubMed1990

Dental caries and related factors--a longitudinal study of Finnish immigrant children in the north of Sweden.

In this study the development of dental caries was observed in Finnish immigrant children between 5 and 8 years of age. Baseline variables that could predict caries were identified. Dental health in this group of Finnish immigrant children was already very poor at the age of 5 and deteriorated further up to 8 years of age, when only 4% of the children were caries free. In the last three years, 48% had participated in an individualized prevention programme (average 0.6 hours). Using the parents' dental status as a predictor gave a higher percentage of correct classifications than the use of dmfs.

Attitude to Health↗

PubMed1989

Resolved 6,7,8,9-tetrahydro-N,N-dimethyl-3H-benz[e]indol-8-amine: central dopamine and serotonin receptor stimulating properties.

The enantiomers of 6,7,8,9-tetrahydro-N,N-dimethyl-3H-benz[e]indol-8- amine (1a) were prepared and tested for their actions on central dopamine and serotonin (5-HT) receptors. The dopaminergic effects were shown to reside in the (1)-R enantiomer. It was shown that compound 1a and its (+)-R enantiomer possess potent central 5-HT1A receptor stimulating properties.

Animals↗