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Biomedical subjects

A Carlsson

Publications and source records attributed to A Carlsson.

At least 127 records · Page 7Linked to original sources
PubMed1993

The dopamine D3 receptor and autoreceptor preferring antagonists (+)-AJ76 and (+)-UH232; a microdialysis study.

The in vivo neurochemical profiles of haloperidol, raclopride and the dopamine D3 and autoreceptor preferring dopamine receptor antagonists (+)-UH232 and (+)-AJ76 on dopamine release and metabolism in the dorsal striatum and in the nucleus accumbens are described. It is shown that both (+)-UH232 and especially (+)-AJ76 have different effects on brain dialysate dopamine and 3,4-dihydroxyphenylacetic acid (DOPAC) as compared to haloperidol or raclopride. It is suggested that the relative increase in dialysate dopamine over the relative increase in DOPAC is a neurochemical fingerprint, unique for different dopamine receptor antagonists. As a consequence the increased release and metabolism of dopamine after systemic administration of dopamine receptor antagonists may be controlled by different receptors and different dopamine antagonists can partly distinguish between these receptors. This may be due to their different interactions with different dopamine D2 type receptors. It is finally concluded that (+)-UH232 and especially (+)-AJ76 seem to prefer release regulating autoreceptors at the level of the axon terminals.

3,4-Dihydroxyphenylacetic Acid↗
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

Evidence for an increased catecholamine synthesis in rat adrenal glands following stimulation of peripheral dopamine receptors.

In studies on peripheral dopamine (DA) turnover in our department evidence has accumulated that changes in adrenal DA levels induced by varying degrees of neurogenic stimulation roughly reflect changes in the catecholamine (CA) synthesis rate. The question arises if changes in DA levels in rat adrenals induced by different DA D-2 receptor agonists and previously reported from our laboratory, also indicate changes in CA synthesis. After various periods of drug administration rats were killed by decapitation and tissue CA levels in adrenals and forebrain were determined by HPLC-EC. The potent inhibitor of DA-beta-hydroxylase FLA 63 (40 mg/kg i.p.) increased adrenal DA by 186% after 1 h and by 423% after 3 h. The DA D-2 agonist quinpirole (0.2 mg/kg s.c., 30 min) itself increased adrenal DA by 55-60% compared to control. In FLA 63 pretreated rats quinpirole increased adrenal DA levels by further 127% (FLA 63-1 h), resp. 122% (FLA 63-3 h) than did FLA 63 itself. The DA D-2 receptor antagonist domperidone (3 mg/kg s.c., 150 min) blocked the quinpirole effect both in saline and FLA 63 (3 h) pretreated rats. Adrenal DOPAC was changed in similar manner as adrenal DA in FLA 63 pretreated rats. No significant changes either in adrenal NA or A were observed after FLA 63 pretreatment. Under the present experimental conditions adrenal DA may thus mainly be looked upon as an intermediate in the synthesis of NA and A, and the elevation of DA induced by DA D-2 receptor stimulation as a consequence of increased catecholamine synthesis.

3,4-Dihydroxyphenylacetic Acid↗
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

Pravastatin and gemfibrozil alone and in combination for the treatment of hypercholesterolemia.

PURPOSE: To compare the efficacy and safety of pravastatin, gemfibrozil, combined therapy, and placebo in the treatment of hypercholesterolemia. PATIENTS AND METHODS: At 5 centers in Sweden and 2 in Finland, 290 ambulatory patients were randomized to active treatment or placebo for 12 weeks following a single-blind placebo lead-in period. The study was double-blind and placebo-controlled. Patients has plasma total cholesterol levels of at least 6.0 mmol/L or in the 90th percentile by age and sex and triglycerides less than 4.0 mmol/L. Concentrations of lipids, lipoproteins, and apolipoproteins were measured, and clinical laboratory tests included liver function and creatine kinase determinations. RESULTS: Pravastatin reduced total cholesterol (26.3% versus 15.2%, p < or = 0.01), low-density lipoprotein cholesterol (LDL-C) (33.5% versus 16.8%, p < or = 0.01), and apolipoprotein B (28.8% versus 15.3%, p < or = 0.01) more than gemfibrozil. Gemfibrozil reduced very-low-density lipoprotein cholesterol (VLDL-C) (49.1% versus 21.9%, p < or = 0.01) and triglycerides (42.2% versus 14.2%, p < or = 0.01) and increased high-density lipoprotein cholesterol (HDL-C) (15.2% versus 5.9%, p < or = 0.01) more than pravastatin. Pravastatin and gemfibrozil increased apolipoprotein A-I comparably (3.3% versus 5.0%, p = NS). The combination significantly (p < or = 0.01) reduced total cholesterol (29.0%), LDL-C (37.1%), VLDL-C (49.4%), and apolipoprotein B (31.6%), and increased HDL-C (16.8%). The combination reduced the total cholesterol/HDL-C (39.3%) and LDL-C/HDL-C (45.8%) ratios significantly (p < 0.01). Adverse events and clinical laboratory abnormalities were generally mild and transient in all groups, although creatine kinase tended to be higher with combination therapy. Study drugs were withdrawn from two patients with asymptomatic creatine kinase elevations. Severe myopathy was not observed; however, the presence of subclinical musculoskeletal effects cannot be excluded. CONCLUSIONS: Co-administration of pravastatin and gemfibrozil combined the specific effects of the two drugs on lipoprotein concentrations and ratios. The incidence of side effects was low; severe myopathy did not occur. The combination may be useful in selected cases of combined hyperlipidemia; however, since myopathy at a low incidence or after long-term therapy cannot be excluded, the routine use of combination therapy is not advisable.

Adult↗
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

Objective and subjective efficacy evaluation of various polymer-based saliva substitutes.

Various polymer solutions with and without surfactants were evaluated regarding their lubricating properties on the oral mucosa. After rinsing with the solutions, the oral mucosal friction value was registered with a probe (objective effect). After each rinsing occasion at home, the patients answered a questionnaire (subjective effect). None of the tested polymers showed a longer, clinically significant effect than the other ones. Some of them had the same effect as substitutes available on the Swedish market.

Cellulose↗
PubMed1993

The effect of liquid fibre on gastric emptying in the rat and humans and the distribution of small intestinal contents in the rat.

A combination of the polysaccharide ethyl-hydroxyethyl-cellulose (EHEC) and the surfactant sodium-dodecylsulphate (SDS) has the extraordinary physical property of being liquid at room temperature but gelling firmly at 37 degrees C. It has been named 'liquid fibre' and its effect on gastric emptying has been tested in rats and humans, as well as its effect on intestinal distribution in rats. Rats were gavaged with 5 ml of radiolabelled liquid fibre, SDS in water, or water control. Subgroups were killed after 25, 50, 100, 200, and 300 minutes, the gut removed, and the distribution of radioactivity measured scintigraphically. Liquid fibre gelled in the stomach and spread exponentially down the small intestine before 25 minutes. This distribution was maintained for 200 minutes after which the stomach began to empty again. In the human study, 10 healthy men drank 250 ml liquid fibre and placebo labelled with 1.85 MBq technetium tin colloid on separate occasions. Gastric emptying was measured by gamma-camera. Half emptying time significantly increased from 17.7 to 55.8 minutes (means, p < 0.05). The time for 10% to empty (which includes any lag time) increased from 7.0 to 19.4 minutes (p < 0.05). Average emptying rate decreased from 4.49%/min for placebo to 1.60%/min for liquid fibre (p < 0.01). The dramatic delay in gastric emptying suggests liquid fibre may have clinical applications while its liquid formulation should improve acceptability.

Adult↗
PubMed1993

Blood pressure after stroke. A one-year follow-up study.

BACKGROUND AND PURPOSE: Blood pressure changes in the year after acute stroke have been poorly documented. METHODS: We therefore studied blood pressure for 1 year after discharge from the hospital in 226 consecutive patients (mean age, 73 years) surviving an acute stroke. RESULTS: Marked increases (p < 0.001) in mean systolic and mean diastolic blood pressures were seen in two thirds (69%) of the patients 1 month after discharge, and blood pressure remained stable at this level during the remainder of the follow-up year. Similar blood pressure changes were seen irrespective of sex, final stroke diagnosis, or whether the patient had a history of hypertension before the stroke. Patients with a history of hypertension had significantly higher blood pressures (p < 0.001) throughout the follow-up year than previously normotensive patients. One month after discharge blood pressure was found to have decreased in 31% of the patients; these were older and had a higher mortality during the follow-up year than patients with blood pressure increases. About 20% of all patients suffered from orthostatism (defined as a decrease in systolic blood pressure of > or = 20 mm Hg when rising from the supine position to standing). CONCLUSIONS: We conclude that antihypertensive treatment should not be reduced before discharge from the hospital and that blood pressure should be checked about 1 month after discharge. We suggest that standing blood pressure also be measured to make an appropriate treatment decision.

Age Factors↗
PubMed1993

Screening for neuroborreliosis in patients with stroke.

BACKGROUND AND PURPOSE: Borrelia burgdorferi, the etiologic agent of Lyme disease, can cause different neurological manifestations. We studied the prevalence of Lyme neuroborreliosis in patients with stroke. METHODS: During a 1-year period, sera from patients with cerebral thrombosis or transient ischemic attack without cardioembolism were investigated for antibodies against B burgdorferi. RESULTS: One of 281 patients had a positive serum immunoglobulin M titer and 23 of 281 (8%) had positive serum immunoglobulin G titers against B burgdorferi. One of the 24 seropositive patients, with a diagnosis of transient ischemic attack due to dysphasia, had a lymphocytic pleocytosis and intrathecal antibody production against B burgdorferi. The medical history revealed a 9-month period of general and neurological symptoms compatible with Lyme neuroborreliosis before the strokelike incidents. CONCLUSIONS: We conclude that Lyme neuroborreliosis may imitate stroke, but screening for antibodies against B burgdorferi seems to be of little value and may be replaced by a careful medical history.

Adult↗
PubMed1993

On the neuronal circuitries and neurotransmitters involved in the control of locomotor activity.

Research on the role of dopamine and other neurotransmitters in the control of motor functions has made considerable progress in recent years. The neuronal circuitries involving especially the basal ganglia have been extensively explored, and evidence has been presented that dopamine does not play a quite as dominant role for the initiation of movement as was formerly believed. Among several other neurotransmitters involved, special attention has recently been directed to glutamate, which seems to be able to stimulate as well as inhibit motility via different pathways. However, powerful interactions involving other neurotransmitters as well, have been discovered. Another area of intensive research deals with the role of the different subtypes of dopamine receptors. Whereas D-1 and D-2 receptors cooperate in the initiation of movement, evidence is emerging that they serve partly differential functions and interact differently with, for example, glutamatergic mechanisms. Moreover, the possible role of the various newly discovered dopamine receptor subtypes is being intensively explored.

Animals↗
PubMed1993

Preclamol and parkinsonian fluctuations.

Preclamol, the (-)enantiomer of 3-PPP (= 3(3-hydroxyphenyl)-N-n-propyl piperidine), has a selective dopamine autoreceptor- and postsynaptic mixed agonist-antagonist profile. Its action on patients with disabling on-off parkinsonian fluctuations has been studied and compared with those of placebo and subcutaneous apomorphine. Preclamol had a mild but unequivocal antiakinetic effect, less than that caused by subcutaneous apomorphine, but it provoked less dyskinesia. Further studies to explore the therapeutic potential of preclamol seem justified.

Antiparkinson Agents↗
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

Pharmacologic properties of (-)-3PPP (preclamol) in man.

The dopamine (DA) autoreceptor agonist (-)-3PPP (preclamol) was tested in male schizophrenic volunteers for safety. The drug was administered intramuscularly in a single rising dose design, crossed with a similar "rising dose" placebo period; all evaluations and raters were blind to drug or placebo administration. Pharmacokinetic, endocrine, safety, and mental status outcome measures were completed before and after each single dose of drug or placebo. Pharmacokinetic analysis showed blood levels between 200-500 pmoles/ml after the intramuscular drug doses of 30-40 mg. Drug half life is 2-2.5 hrs. Growth hormone (GH) levels were elevated in a linear fashion to the 30 mg dose; whereafter, the drug failed to affect GH at all. All safety evaluations were negative, including any untoward effects on the major organ systems. After single dose drug administration, evidence of antipsychotic action occurred in two of the four subjects. This study suggests that (-)-3PPP/preclamol is a safe drug for study in the treatment of schizophrenia and may have antipsychotic efficacy.

Administration, Oral↗