Biomedical subjects

K Svensson

Publications and source records attributed to K Svensson.

At least 73 records · Page 4Linked to original sources

PubMed1994

Effects of carvedilol on the metabolic, hemodynamic, and electrocardiographic responses to increased plasma epinephrine in normal subjects.

To study the effects of the new vasodilating beta-blocking agent carvedilol on a variety of metabolic, hemodynamic, and ECG parameters of importance for the clinical outcome of acute myocardial infarction (AMI), we infused epinephrine (EPI) in healthy male volunteers on two separate occasions to serum concentrations of the same level reached in AMI. Before the EPI infusions, the volunteers were pretreated for 2 weeks with either carvedilol or placebo in randomized order. EPI caused significant decreases in serum levels: S-potassium (0.62 mM), S-magnesium (0.07 mM), S-calcium (0.12 mM), and S-phosphate (0.26 mM). After pretreatment with carvedilol, the decreases in S-calcium and S-phosphate were partly prevented and those in S-potassium and S-magnesium were completely inhibited. Short-term treatment with carvedilol significantly decreased S-insulin and serum C-peptide and significantly attenuated the EPI-induced increase in B-glucose observed after placebo. The EPI infusion significantly increased serum concentrations of free fatty acids and glycerol. These increases were significantly attenuated by carvedilol, whereas carvedilol had no significant affects of a variety of other lipid variables. EPI infusion caused a significant (p < 0.01) increase in systolic blood pressure (SBP) from 124.8 +/- 8.1 to 135.8 +/- 12.5 mm Hg and an increase in heart rate (HR) from 71.0 +/- 11.5 to 77.2 +/- 12.2, resulting in a significant increase in rate-pressure product (RPP). This estimate of cardiac work was significantly (p < 0.05) reduced by pretreatment with carvedilol.(ABSTRACT TRUNCATED AT 250 WORDS)

Adrenergic beta-Antagonists↗

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

Substituted 3-phenylpiperidines: new centrally acting dopamine autoreceptor antagonists.

The (+)-and (-)-enantiomer of compounds 4 and 5 were synthesized and tested for central dopamine (DA) receptor stimulating activity, using biochemical and behavioral tests in rats. Based on the available data the (-)-enantiomers of 4 and 5 are characterized as centrally acting DA autoreceptor antagonists with oral activity. They display a similar pharmacological profile as the prototype DA autoreceptor antagonists (+)-1 and (+)-2 and show a certain preference for the D3 DA receptor antagonist binding site.

Animals↗

PubMed1993

Antagonism of cocaine self-administration by the preferential dopamine autoreceptor antagonist, (+)-AJ 76.

(+)-AJ 76 is a presumed preferential dopamine (DA) autoreceptor antagonist which, in previous behavioral investigations, has displayed properties characteristic of both DA agonists and DA antagonists. In an attempt to test the hypothesis that (+)-AJ 76 might be an effective cocaine pharmacotherapy, the present experiments evaluated (+)-AJ 76's behavioral profile in 3 standard reinforcement paradigms. In the first experiment, (+)-AJ 76 paralleled a DA antagonist in that it failed to support self-administration behavior at all doses (0.1, 0.32, and 1.0 mg/kg/inj) tested. In the second experiment, (+)-AJ 76 (0.9, 3.5, and 14.0 mg/kg) closely resembled the DA agonist D-amphetamine (0.25, 1.0, and 4.0 mg/kg) in producing a clear dose-dependent conditioned place preference. In the third experiment, (+)-AJ 76 (1.88, 3.75, 7.5, 15.0, and 30.0 mg/kg) significantly reduced breaking points (BPs), increased rates of responding, and delayed the onset of responding for cocaine. While (+)-AJ 76 mimics a typical DA antagonist in its ability to reduce BPs and augment rates of responding for cocaine, recent evidence suggests that it more closely resembles a DA agonist in its ability to delay the onset of responding for cocaine. In summary, the present investigations have shown that (+)-AJ 76's profile in 3 reinforcement paradigms is unusual and not exclusively representative of either DA agonists or DA antagonists. The potential utility for such an agent in treating cocaine abuse is discussed.

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

Synthesis and biological activity of cis-(3aR)-(-)-2,3,3a,4,5,9b-hexahydro- 3-propyl-1H-benz[e]indole-9-carboxamide: a potent and selective 5-HT1A receptor agonist with good oral availability.

The synthesis and biological activity of cis-(3aR)-(-)-2,3,3a,4,5,9b- hexahydro-3-propyl-1H-benz[e]indole-9-carboxamide ((-)-3a), U93385, is described. The cis racemate and its enantiomer as well as the corresponding trans enantiomers were also synthesized and evaluated. The synthesis of these analogs was achieved via either a four-step conversion of the 9-hydroxy precursor into 9-carboxamide or an alternative synthesis using the (R)-alpha-methylbenzyl group as the chiral auxiliary. The cis racemate (+/-)-3a, was found to be a selective and potent 5-HT1A receptor agonist with the activity residing in the cis-(3aR)-enantiomer, (-)-3a. The cis-(3aS)-enantiomer (+)-3a and trans-(3aR)-enantiomer (-)-3b displayed partial 5-HT1A agonist activity whereas the other trans-(3aS)-enantiomer (+)-3b showed no activity. The enantiomer (-)-3a was found to be selective in both in vitro and in vivo biochemical/behavioral assays. This compound potently reduced rectal temperature in mice, decreased the firing rate of rat midbrain serotonergic neurons, and suppressed rat brain 5-HT synthesis. This compound also reduced sympathetic nerve discharge and blood pressure in the anesthetized cat and showed activity in the forced swim assay in mice. It exhibited good oral activity in behavioral and biochemical assays and, in fact, had a 46% oral availability in the rat when comparing blood levels of parent drug after iv and po administration. This compound has demonstrated a potential for anxiolytic and antidepressant activity and is currently undergoing clinical evaluation.

Administration, Oral↗

PubMed1993

The dopamine D3-receptor: a postsynaptic receptor inhibitory on rat locomotor activity.

We report on the pharmacological effects of the 20 fold D3 vs. D2 dopamine receptor preferring compound U99194A. It is shown that U99194A increases rat locomotor activity at doses that do not increase release or utilisation of dopamine in the striatum or the nucleus accumbens significantly. The data do not support any direct agonist action of U99194A at dopamine receptors. It is suggested that U99194A can antagonise a population of postsynaptic dopamine receptors involved in the suppression of some aspects of psychomotor activity. These postsynaptic receptors presumably belong to the D3 receptor subtype.

Aminoquinolines↗

PubMed1993

Partial dopamine receptor agonists reverse behavioral, biochemical and neuroendocrine effects of neuroleptics in the rat: potential treatment of extrapyramidal side effects.

The partial DA receptor agonist preclamol, (-)-3-PPP (50-200 mumol/kg, s.c.) partially reversed the catalepsy induced by the dopamine (DA) receptor antagonists haloperidol (5.3 mumol/kg, i.p.) and raclopride (20.1 mumol/kg, i.p.) in rats. Terguride (transdihydrolisuride), a partial DA receptor agonist with an efficacy lower than that of preclamol, blocked haloperidol (10.6 mumol/kg, i.p.) induced catalepsy at 5 mumol/kg, s.c., but not at 20 mumol/kg, s.c. The effects of terguride in this assay are possibly related to the compound's mixed partial DA agonist/5-HT1A receptor agonist properties. The high efficacy agonist, pramipexole (SND 919) also blocked haloperidol induced catalepsy at 50 mumol/kg, s.c. Haloperidol (0.33-1.3 mumol/kg, i.p.) reduced the locomotor activity down to 5% of saline controls and elevated limbic and striatal DOPA accumulation. When combined with haloperidol, preclamol (100-200 mumol/kg, s.c.) antagonized both the strong hypomotility and increase in DOPA accumulation. Finally, the elevation of serum prolactin in rats induced by haloperidol (0.25 mumol/kg, i.p.) was significantly antagonized by co-administration of preclamol (39 mumol/kg, s.c.). These results show that partial DA agonists can reverse both behavioral, biochemical and neuroendocrine effects of neuroleptics. It also suggests the utility of partial DA receptor agonists in combination with classical neuroleptics in order to minimize the appearance of extrapyramidal side-effects and hyperprolactinemia.

Animals↗

PubMed1993

A simple computer-based method for performing and analyzing intracranial self-stimulation experiments in rats.

Intracranial self-stimulation (ICSS) in the rat is a useful tool for studying the importance of various brain monoamines in positive reinforcement. The effects of compounds interacting with dopaminergic neurotransmission is measurable by studying the changes of reward thresholds. By computerisation of the analysis of these thresholds, standardisation and reproducibility is greatly enhanced. The use of an object-oriented programming language simplifies the programming of a specific application and it provides scientists without formal training in computer programming the means to create their own software. A system for the acquisition, execution, analysis and storage of ICSS experiments is described. The hardware is based on Apple Macintosh computers, interfaced to the test chambers and physiological stimulators using a plug-in card supporting A/D, D/A, digital I/O and timer functions. The software written in G (LabVIEW) provides the user with a graphically based 'Virtual Instrument' performing all aspect of the ICSS experiment. The software performs threshold analysis immediately after completion of the ICSS experiment, thereby greatly reducing the total time previously needed to evaluate these experiments. The graphical approach used in LabVIEW allows the programmer to make fast and simple alterations to suit different experimental problems.

Animals↗

PubMed1993

Predicting results of rehabilitation after hip fracture. A ten-year follow-up study.

Data influencing the outcome of rehabilitation after hip fracture were obtained from 103 consecutive patients. All were admitted from their own homes and were observed at the time of discharge from the hospital and at three weeks, four months, one year, five years, and ten years postfracture. Background and functional variables were recorded and analyzed by means of multivariate discriminant statistical techniques. The three most important variables for discharge to home were (1) the ability to walk two weeks after surgery, (2) living with someone, and (3) good general health. From four months until ten years postfracture, the most persistent positive variable for returning to and living at home was an active prefracture lifestyle. The most persistent negative variable was old age. By means of prognostic schemes, it is possible, as early as the time of fracture or a few days after surgery, to make a reliable prediction as to whether the patient will return home. Both the patient and society benefit from early rehabilitation at home in cooperation with primary care personnel and social workers, as it reduces the cost of the injury by avoiding a lengthy hospital stay and unnecessary institutional aftercare.

Activities of Daily Living↗

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

Antagonism of cocaine's pharmacological effects by the stimulant dopaminergic antagonists, (+)-AJ76 and (+)-UH232.

The aminotetralins (+)-AJ76 and (+)-UH232 are stimulant dopaminergic antagonists, which may preferentially antagonize autoreceptors of dopamine nerve terminals. Both agents antagonized cocaine's depressant effects on firing rates of ventral tegmental dopaminergic neurons, but (+)-UH232 was much more potent. When injected simultaneously with cocaine, (+)-UH232 inhibited and (+)-AJ76 enhanced the locomotor stimulation observed during the first 30 min following s.c. cocaine administration. However, (+)-AJ76 antagonized cocaine-induced stereotypies as well as the later more intense cocaine locomotor stimulation. It is suggested that preferential dopamine autoreceptor antagonists may provide a novel approach to a pharmacotherapy for treating cocaine abuse.

3,4-Dihydroxyphenylacetic Acid↗

PubMed1992

Effects of the preferential dopamine autoreceptor antagonist (+)-AJ76 in the intracranial self-stimulation paradigm.

As revealed by locomotor activity experiments in rodents, cis-(1S,2R)-5-methoxy-1-methyl-(2-n-propylamino)tetralin [(+)-AJ76] is a preferential dopamine autoreceptor antagonist that produces stimulatory or weak inhibitory behavioral effects in animals that display low or high baseline activity, respectively. In the present study, the possible positive reinforcing properties of (+)-AJ76 were studied by means of the intracranial (median forebrain bundle) self-stimulation (ICSS) technique in rats. The current intensity of the electrical stimuli was used as the independent variable. The resulting rate/intensity curves were analyzed by computer, and the half-maximal response (called EC50) was calculated for each animal. When starting on a suprathreshold current intensity, (+)-AJ76 dose dependently (3.1-52.0 microM/kg, SC) increased the EC50 without producing any apparent motor deficits like muscular rigidity or catalepsy. A clear-cut and more potent inhibitory action was also noted for haloperidol (0.033-0.133 microM/kg, SC) and the di-N-methyl analog of (+)-AJ76 called (+)-AJ118 (0.8-3.5 microM/kg, SC), while d-amphetamine (1.4 or 5.4 microM/kg, SC) decreased the EC50 values. In the second experiment, animals were subjected to a subthreshold current intensity for 30 min. The intensity was set to produce a response of 15% or less of maximal, shaping response rate for the respective animals. Of these 22 animals, 10 responded with a stimulation, while the ICSS response was inhibited in the others. We did not, however, get consistent results in all rats tested. In summary, this study shows that (+)-AJ76 appears to lack positive reinforcing properties comparable to those produced by classical stimulants such as d-amphetamine.

Animals↗

PubMed1992

Pit and fissure sealing and mutans streptococci levels in saliva.

The effect of preventive pit and fissure sealants with a resin-based material on the number of salivary mutans streptococci was evaluated in 46 healthy 12-year-old school children (F group) with medium or high counts during a 1-year study period. As controls served 33 children of the same age with the same bacterial levels at baseline (C group) and 55 children with low levels (L group). Caries prevalence and incidence were registered clinically and radiographically. Sealing of all accessible pit and fissures was carried out in the F group with a light-cured Bis-GMA sealant. Bacterial levels at baseline and 3, 6, 12 and 52 weeks after treatment were estimated with a chairside method. The results disclosed a significant (P < 0.05) drop in the number of salivary mutans streptococci in the F and C groups at all sampling occasions compared to baseline. There were however no differences between the groups during the study period. Both the caries prevalence and incidence were significantly (P < 0.05) higher in F and C groups when compared to the L group. The results suggest that preventive pit and fissure sealing with a resin based material does not affect salivary mutans streptococci levels.

Child↗

PubMed1992

New method of evaluating patient preference for different inhalation delivery systems.

In order to assess patients' preferences for different inhalation devices a questionnaire has been developed. The questionnaire consisted of items covering various aspects considered important for patients who regularly use inhalation devices. The questions were designed to be of a general character so any inhalation device could be evaluated. We evaluated the questionnaire in a multicenter, open crossover study comparing patients' opinions of MDI with and without spacer and of a dry powder inhaler, Turbuhaler. One hundred twenty-three patients with stable asthma confirmed by daily peak expiratory flow rate (PEF) measurements used for 2 weeks MDI only and MDI with spacer and for 2 weeks Turbuhaler. The order was randomized. The drugs were terbutaline inhaled via MDI and Turbuhaler and budesonide inhaled via MDI with spacer and turbuhaler. At the end of each evaluation period the patients answered a number of questions about their opinion by marking on a visual analogue scale. A factor analysis revealed that the different questions represent a few common factors important for evaluating opinion about inhalation devices. These factors are handling of the device, use, time to learn how to use the device properly, how confident the patients feel about the use of it, and taste/irritation. A standardized questionnaire of reduced size seems to be a suitable method for evaluating patient preference for different inhalation devices.

Administration, Inhalation↗

PubMed1991

Effects of repeated administration of the preferential dopamine autoreceptor antagonist, (+)-AJ76, on locomotor activity and brain DA metabolism in the rat.

AJ76, the cis-(+)-(1S,2R) enantiomer of 5-methoxy-1-methyl-2-(n-propyl-amino) tetralin is a dopamine autoreceptor antagonist which has shown locomotor stimulatory properties, especially in habituated rats. AJ76 was given repeatedly to male rats at different time intervals and different doses to investigate if tachyphylaxis/tolerance would develop. Tolerance did not occur if AJ76 (300 mumol/kg p.o.) was administered once daily for 7 days, (regarding both stimulation of locomotor activity and increase in brain DOPAC levels). Tolerance occurred after a single dose of 52 mumol/kg s.c. given in the morning followed by the same challenge dose 4 but not 24 h later. When the first dose was decreased to 13 mumol/kg s.c. no tachyphylaxis could be demonstrated regarding stimulation of locomotor activity. It is concluded that AJ76 induces a dose-dependent and short lasting tachyphylaxis, while no tolerance is observed after one week repeated administration. The possible mechanism behind these effects are discussed.

3,4-Dihydroxyphenylacetic Acid↗

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

Dopamine receptors, controlling dopamine levels in rat adrenal glands-comparison with central dopaminergic autoreceptors.

Previous work in this laboratory, as well as observations reported in the literature, indicate that the adrenal medulla contains dopamine (DA) receptors of the D-2 subtype, which among other things are capable of controlling the DA level in rat adrenal glands. To further characterize the DA receptors involved in the control of the adrenal DA level, the effects of 9 DA receptor agonists with various intrinsic activities were compared. After various periods of drug administration the rats were killed by decapitation and the DA content of the adrenal glands and the DOPAC content of the forebrain were measured by high-performance liquid chromatography with electrochemical detection. All the investigated DA receptors agonists caused an increase in adrenal DA level, although statistical significance was not reached in one case [(-)-HW 165]. Domperidone, a DA D-2 receptor antagonist which does not readily cross the blood brain barrier, blocked the DA-elevating effects of apomorphine, quinpirole, B-HT 920 and both enantiomers of 3-PPP. For the two ergolines terguride and SDZ 208-920 the blockade by domperidone was not complete, suggesting that their effects are mediated not only through DA, but also through other receptor systems. The dose of domperidone used (3 mg/kg) had but a marginal influence on brain DOPAC levels, supporting the almost exclusively peripheral effect of this agent. Our data indicate that the DA D-2 receptors which control the DA level in the adrenal medulla in rats, have characteristics similar to, though not identical with the autoreceptors in the forebrain.

3,4-Dihydroxyphenylacetic Acid↗