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Biomedical subjects

R Lammintausta

Publications and source records attributed to R Lammintausta.

At least 19 recordsLinked to original sources
PubMed2004

Effects of ospemifene, a novel SERM, on biochemical markers of bone turnover in healthy postmenopausal women.

Ospemifene is a novel selective estrogen receptor modulator (SERM). Here we studied the effects of ospemifene on bone turnover in postmenopausal women. This was a randomized, double-blind study in which 159 healthy postmenopausal women received 30 (n = 40), 60 (n = 40) or 90 mg (n = 40) of ospemifene or placebo (n = 39) for 3 months. Bone resorption was assessed by measuring the urinary outputs of N- and C-terminal crosslinking telopeptides of type I collagen (NTX and CTX, respectively). Bone formation was assessed by measuring the levels of procollagen type I N propeptide (PINP), procollagen type I C propeptide (PICP), and bone-specific alkaline phosphatase (bone ALP) in serum. All markers were studied at baseline, 3 months, and 2-4 weeks after cessation of the medication. Ospemifene decreased bone resorption dose-dependently, as seen from falls in NTX by 6.1, 9.4 and 12.9% in the 30, 60 and 90 mg ospemifene groups, respectively (p < 0.05 for all dose levels when compared to placebo). CTX values decreased in the 90 mg ospemifene group by 4.8% (p < 0.05). A dose-dependent decrease was also observed in the bone formation markers: PINP values decreased by 9.8 (p < 0.05) and 15.3% (p < 0.01), and PICP values by 12.0 and 11.9% in the 60 and 90 mg ospemifene groups, respectively. Bone ALP decreased in 60 and 90 mg ospemifene groups by 1.9 and 2.6%, respectively (p < 0.05 for both dose levels when compared to placebo). These results show that ospemifene is effective in reducing bone turnover in postmenopausal women.

Alkaline Phosphatase↗
PubMed2000

Synthesis of new potent and selective aromatase inhibitors based on long-chained diarylalkylimidazole and diarylalkyltriazole molecule skeletons.

A series of long-chained diarylalkylimidazoles and diarylalkyltriazoles were synthesized and evaluated for the inhibitory potency for aromatase (estrogen synthetase) activity in human placental microsomes. The relative specificity of inhibition was evaluated by measuring the inhibition of cholesterol side-chain cleavage enzyme (desmolase) in human placental mitochondria and the inhibition of 7-ethoxycoumarin O-deethylase (a typical drug-metabolizing enzyme activity) in rat liver microsomes. The structural requirements including substituent effects for the strongest potency and for the highest specificity were delineated. alpha,omega-Diarylalkyltriazoles and imidazoles were the most interesting molecules, in which the geometric and optical isomerism displayed remarkable selectivity for aromatase inhibition.

Animals↗
PubMed1998

Facilitation of cognitive functions by a specific alpha2-adrenoceptor antagonist, atipamezole.

The present experiments investigated the effects of a specific and potent alpha2-adrenoceptor antagonist, atipamezole (as a stimulator of the noradrenergic system) on cognitive performance in rats. Atipamezole enhanced the acquisition of a linear-arm maze test and also improved the choice accuracy of poorly performing rats in a delayed (20 min) three-choice maze test. Furthermore, atipamezole improved the achievement of a one-trial appetite-maze when injected immediately after teaching, thus having an effect on consolidation. Atipamezole clearly impaired the acquisition of the active avoidance test. The present results indicate that stimulation of noradrenergic system by atipamezole improves the performance of animals in tasks assessing relational learning and memory, possibly affecting attention, short-term memory and the speed of information processing. It has also an effect on a consolidation process unrelated to attentional or motivational mechanisms. In a stressful test. stimulation of noradrenaline release leads to impairment of performance.

Adrenergic alpha-2 Receptor Antagonists↗
PubMed1998

Endocrine mechanism of action of toremifene at the level of the central nervous system in advanced breast cancer patients.

PURPOSE: To differentiate the antagonistic and agonistic effect of toremifene at the level of the hypothalamus-hypophysis axis a leutinizing hormone-releasing hormone (LHRH) test was performed during a phase II clinical trial. METHODS: In 15 postmenopausal patients with advanced breast cancer, follicle-stimulating hormone (FSH) and LH release--induced by an LHRH agonist (Suprefact injection, 0.5 mg s.c.)--was monitored during a 16-week period of toremifene treatment (60 mg/day p.o.). Prolactin, estradiol, and sex hormone-binding globulin (SHBG) levels were also measured. The functional test was carried out prior to toremifene therapy and then 4, 8, 12, and 16 weeks afterward. RESULTS: The drug sensitized the pituitary to the action of the gonadotrophins; the LHRH-induced FSH and LH release showed a considerably increasing tendency during the toremifene therapy. Estradiol levels decreased statistically significantly and SHBG levels showed a statistically significant increase. A decreased level of prolactin is the sign of an antiestrogenic effect of toremifene on the hypophysis and, as a result, provides evidence for a direct influence of toremifene upon the pituitary. An increase in LH and prolactin release in response to the LHRH test was characteristic in the responders. CONCLUSION: According to the LHRH test, the antagonistic effect of toremifene seems to be more dominant than the concomitantly existing agonistic property. Neither clinical nor endocrinological side effects could be observed at the level of the CNS during a prolonged period of toremifene administration.

Antineoplastic Agents, Hormonal↗
PubMed1998

Effect of selegiline on mortality in patients with Parkinson's disease: a meta-analysis.

INTRODUCTION: The Parkinson's Disease Research Group of the United Kingdom (PDRG-UK) reported increased mortality in PD patients treated with levodopa plus selegiline compared with those treated with levodopa alone. METHODS: We performed a meta-analysis on five long-term, prospective, randomized trials of selegiline in patients with untreated PD. Included in the analysis were four randomized, double-blind, placebo-controlled studies and one randomized, double-blind, placebo-controlled study of 2 years' duration followed by long-term, open follow-up. RESULTS: The mean duration of follow-up was 4.1 +/- 1.8 years. There were 14 deaths in 297 selegiline-treated patients (4.7%) and 17 deaths in 292 non-selegiline-treated patients (5.8%). The hazard ratio for mortality was 1.02 (95% CI 0.44 to 2.37; p = 0.96). An analysis restricted to patients receiving only levodopa with or without selegiline noted 11 deaths in 257 levodopa/selegiline-treated patients (4.3%) and 11 deaths in 254 patients treated with levodopa alone (4.3%). The hazard ratio was 1.06 (95% CI 0.44 to 2.55; p = 0.90). Death rate per 1,000 patient years was 11.4 in the selegiline group and 14.2 in the nonselegiline group. Kaplan-Meier survival curves reflecting pooled survival data showed no significant difference in duration of survival. The hazard ratio was 0.84 (95% CI 0.41 to 1.70; p = 0.63) for selegiline- versus non-selegiline-treated patients and 1.05 (95% CI 0.46 to 2.43; p = 0.91) for selegiline/levodopa- versus levodopa-treated patients. CONCLUSION: These results contrast with those of the PDRG-UK study and demonstrate no increase in mortality associated with selegiline treatment whether or not patients also received levodopa.

Aged↗
PubMed1993

The effects of alpha 2-adrenoceptor stimulation on neocortical EEG activity in control and 6-hydroxydopamine dorsal noradrenergic bundle-lesioned rats.

The present study investigated the effects of a alpha 2-adrenoceptor agonist, D-medetomidine (0.3, 3.0, 30.0 and 300.0 micrograms/kg, s.c.), on neocortical EEG activity in control and 6-hydroxydopamine dorsal noradrenergic bundle-lesioned rats. D-Medetomidine at 0.3, 3.0, and 30.0 micrograms/kg dose dependently increased waking-immobility-related high-voltage spike and wave spindles. Movement and waking-immobility-related slow wave activity was increased at doses of 3.0, 30.0 and 300.0 micrograms/kg. D-Medetomidine at 300.0 micrograms/kg produced continuous 1-2 Hz slow wave activity and the animals were markedly sedated. In rats injected with D-medetomidine at 0.3, 3.0 and 30.0, micrograms/kg EEG activity could be desynchronized (block of high-voltage spindles and slow waves) by pinching the tail. However, rats injected with D-medetomidine at 300.0 micrograms/kg showed no change in EEG activity or behavior following tail pinching. D-Medetomidine induced similar EEG activity (high-voltage spindles and slow waves) and behavioral changes (sedation) in 6-hydroxydopamine dorsal noradrenergic bundle-lesioned rats. Atipamezole, an alpha 2-adrenoceptor antagonist, blocked D-medetomidine-induced EEG and behavioral changes in control and 6-hydroxydopamine dorsal noradrenergic bundle-lesioned rats. Based on the present results we suggest that stimulation of presynaptic noradrenergic fibers is not a prerequisite for the increase of high-voltage spindle and slow wave activity induced by an alpha 2-adrenoceptor agonist and that the magnitude of EEG slowing induced by D-medetomidine correlates with the decreased behavioral response to sensory stimulation.

Adrenergic Fibers↗
PubMed1993

Alpha 1-adrenoceptor antagonist decreases alpha 2-adrenoceptor antagonist-induced high voltage spindle suppression in adult and aged rats.

The present experiments were undertaken to study whether blockade of alpha 1-adrenoceptors would prevent the high-voltage spindle suppressing effect of atipamezole, an alpha 2-adrenoceptor antagonist. In adult rats, an alpha 1-adrenoceptor antagonist, prazosin, increased dose dependently the high voltage spindles in saline and atipamezole-pretreated rats. In addition, in aged rats prazosin blocked the high-voltage spindle suppressing action of atipamezole. Prazosin produced a smaller increase in high-voltage spindle values in aged than in adult rats. According to the present results, alpha 2-adrenoceptor antagonists may suppress high-voltage spindles indirectly by activating alpha 1-adrenoceptors in young and aged rats.

Adrenergic alpha-Agonists↗
PubMed1992

The effects of alpha-2 adrenoceptor antagonist, atipamezole, on spatial learning in scopolamine-treated and aged rats.

In order to study whether noradrenergic drugs improve age-related cognitive dysfunctions the present experiments investigated whether atipamezole, a selective and specific alpha-2 antagonist, improves spatial learning impairment due to cholinergic blockade (scopolamine 0.8 mg/kg) or aging in rats. Previously, it has been shown that atipamezole dose-dependently (0.03-3.0 mg/kg) increases the turnover of noradrenaline in rat brain. According to the present results, atipamezole (0.1, 0.3, 0.6 mg/kg) did not affect spatial learning/memory when assessed in a free swim trial of the water maze task in control rats. Furthermore, atipamezole (0.1, 0.6 mg/kg) did not improve learning deficit in scopolamine treated young rats. Higher doses (greater than or equal to 1.0 mg/kg) of atipamezole could not be tested, because they induce floating behaviour in rats. In aged rats, which were screened to be impaired in the initial acquisition of the water maze task, 0.3 mg/kg atipamezole impaired further learning of this task. Because previous studies suggest that age-related learning impairment in the water maze may be, at least partly, due to a cholinergic deficit, the present results suggest that atipamezole which increases the release of noradrenaline in brain does not alleviate this learning deficit.

Adrenergic alpha-Antagonists↗
PubMed1992

The effects of dexmedetomidine, an alpha 2 agonist, on learning and memory, assessed using passive avoidance and water maze tasks in rats.

The effects of dexmedetomidine, a specific and potent alpha 2 agonist, on the performance of rats in passive avoidance and water maze tasks were studied. Pre-training administration of subanaesthetic dose (9.0 micrograms/kg) of dexmedetomidine impaired the retention of the passive avoidance task (assessed 24 hr after training) but it did not affect the training of this task. Smaller doses (0.3, 0.9 and 3.0 micrograms/kg) did not affect the training or retention of this aversively motivated task. On the other hand, pre-training administration of 0.3 and 0.9 microgram/kg dexmedetomidine impaired the acquisition of the water maze task, whereas larger doses (3.0 and 9.0 micrograms/kg) had no significant effect on spatial learning. Pre-training administration of dexmedetomidine (0.3-9.0 micrograms/kg) increased swimming speed in rats. Only a large dose (300 micrograms/kg) of dexmedetomidine, administered immediately after training, impaired the retention of the passive avoidance task and the acquisition of the water maze task. These data agree with previous findings that pharmacological manipulation of the noradrenergic system affects the retention of aversively-motivated (passive avoidance) tasks. The present results suggest that the dose-response curve of dexmedetomidine for impairment of learning/memory differs between the passive avoidance and water maze tasks.

Adrenergic alpha-Agonists↗
PubMed1992

Atipamezole, an alpha 2 antagonist, stabilizes age-related high-voltage spindle and passive avoidance defects.

The present study investigates the effects of an alpha 2 antagonist, atipamezole (Ati), on the high-voltage spindle (HVS; Ati at 0.1, 1.0, and 3.0 mg/kg) activity, passive avoidance retention (PA; Ati at 3 mg/kg; injected before retention trial), and water maze (WM; Ati at 3 mg/kg; injected after daily training trials) acquisition of young and aged rats. PA retention trial performance defect of aged rats was partially alleviated by Ati at a 3-mg/kg dose. Ati at 3 mg/kg had no effect on the PA performance of young rats. Retention trial performance of nonshocked young or aged rats was not altered by a 3-mg/kg Ati dose. WM acquisition was not affected by posttraining Ati injections. Age-related increase of HVS was stabilized by Ati at 1 or 3 mg/kg. Ati at 1 and 3 mg/kg completely suppressed HVS of young rats. Ati at 0.1 mg/kg had no effect on HVS of young or aged rats. The results suggest that alpha 2-antagonist-administration-induced increase in noradrenergic activity may stabilize age-related HVS activity increase and PA performance defect.

Adrenergic alpha-Antagonists↗
PubMed1991

Effects of alpha 2-drugs and pilocarpine on the high-voltage spindle activity of young and aged control and DSP4-lesioned rats.

The present study investigates the effects of alpha 2-drugs and pilocarpine on the neocortical high-voltage spindle (HVS) activity in young and aged control and DSP4-lesioned rats. DSP4 partially decreased cortical and thalamic noradrenaline levels, but had no effect on HVS activity. The alpha 2-adrenoceptor agonist guanfacine (0.004, 0.02, 0.1 mg/kg) increased HVS activity in young and aged control and DSP4-lesioned rats. Guanfacine produced a significantly smaller increase in HVS activity in aged rats. A combination of pilocarpine (3 mg/kg), a muscarinic agonist, and atipamezole (1 mg/kg), an alpha 2-adrenoceptor antagonist, suppressed HVS activity more effectively than either of the drugs alone in young or aged control and DSP4-lesioned rats. The present results demonstrate that 1) the alpha 2-adrenoceptor antagonist and muscarinic agonist interact in suppressing HVSs in noradrenergically lesioned young and aged rats; 2) alpha 2-adrenoceptor agonists produce a greater increase in HVS activity in young than aged rats; and 3) partial noradrenergic lesions do not affect the HVS-modulating effects of alpha 2-adrenoceptor active drugs in young or aged rats.

Adrenergic alpha-Antagonists↗
PubMed1991

Effects of atipamezole and tetrahydroaminoacridine on nucleus basalis lesion-induced EEG changes.

In the present study the effect of combined anticholinesterase [tetrahydroaminoacridine (THA)] and alpha2-antagonist (antipamezole) treatment were evaluated on nucleus basalis (NB, quisqualic acid) lesion-induced EEG activity changes. THA (1, 3 and 6 mg/kg; an anticholinesterase) and atipamezole (Ati: 3 and 10 mg/kg; an alpha2-antagonist) suppressed dose-dependently NB lesion-induced high-voltage spindle activity and increase in slow/fast activity ratio. A combination of THA (3 mg/kg) and Ati (3 or 10 mg/kg) more effectively suppressed NB lesion-induced HVS activity than either of the drugs alone did. The present results suggest that alpha2-noradrenergic and NB cholinergic systems interact in the regulation of slow wave and HVS activity and that combined stimulation of these systems more effectively stabilize NB lesion-induced EEG changes.

Adrenergic alpha-Antagonists↗
PubMed1991

Combination of atipamezole and tetrahydroaminoacridine/pilocarpine treatment suppresses high voltage spindle activity in aged rats.

The present study evaluated the effects of combined alpha2-antagonist (atipamezole) and anticholinesterase (tetrahydroaminoacridine, THA) or muscarinic agonist (pilocarpine) treatments on the high voltage spindle (HVS) activity in aged rats. On their own, high doses of THA (3 mg/kg), pilocarpine (3 mg/kg) and atipamezole (3 mg/kg) suppressed HVS activity. Low doses of THA (1 mg/kg), pilocarpine (1 mg/kg) and atipamezole (1 mg/kg) did not suppress HVS activity. Combinations of low doses of atipamezole and THA or pilocarpine suppressed HVS activity. Our results suggest that 1) the administration of alpha2-antagonist blocked the age-related deficit of thalamocortical activation, 2) a combination of alpha2-antagonist and a cholinergic drug may more effectively stabilize age-related HVS activity than either of the treatments alone.

Adrenergic alpha-Antagonists↗
PubMed1991

Evoked field responses, recurrent inhibition, long-term potentiation and immobility-related nonrhythmical EEG in the dentate gyrus of fimbria-fornix-lesioned and control rats.

The effects of complete fimbria-fornix (FF) lesioning, bilateral medial-FF lesioning and systemic administration of a novel noradrenergic alpha 2-antagonist, atipamezole, on electrophysiological properties of the hippocampal formation were studied in the rat. In the hilus of the dentate gyrus (DG) complete FF lesioning abolished the long-term potentiation (LTP) of the population spike (PS), which in control rats could be induced by the application of high-frequency stimulus trains on the medial perforant pathway (PP). Several other electrophysiological properties examined in the medial-FF-lesioned rats changed as well. These changes included a decrease in the efficacy of recurrent inhibition and slight differences in granular cell population response evoked by perforant path stimulation. Also, in the DG the power of awake immobility-related nonrhythmical electroencephalogram (EEG) was significantly lower in FF-lesioned rats than in controls. In the DG of control rats systemic administration of atipamezole (1 mg/kg) shifted the population spike-field postsynaptic potential response curve towards the left. In FF-lesioned rats this drug had no effects. The slight effects of atipamezole would be in line with earlier studies, which have shown that noradrenergic activation facilitates neuronal transmission in the DG. Possible explanations for the changes seen in FF-lesioned rats include deafferentation of different subcortical projections and increased epileptic activity. These established changes in synaptic plasticity, recurrent inhibition, nonrhythmical EEG and evoked responses would indicate that information processing is severely hampered in the first stage of the hippocampal trisynaptic circuit after fimbria-fornix lesioning. Thus, the results show that aminergic/cholinergic projections have a significant role in information processing in the dentate gyrus of hippocampal formation.

Adrenergic beta-Antagonists↗
PubMed1991

Modulation of EEG rhythmicity and spike activity in the rat hippocampus by systemically administered tetrahydroaminoacridine, scopolamine and atipamezole.

The hippocampal EEG recording electrodes were implanted bilaterally in the hilus of the dentate gyrus (DG) and the stratum radiatum layer of the CA1 area in young (2-3-month-old) and aged (17-20-month-old) rats. In the subgroups of rats, brain noradrenaline (NA) was depleted by DSP-4 neurotoxin (50 mg/kg, IP). The aged animals were included in DSP-4-lesioned group in order to diminish the plastic regeneration of the noradrenergic system which may be more effective in young subjects. All the EEG recordings, after the administration of different agents or vehicle, were made while rats were awake and immobile. Approximately 40% decrease of brain NA had no noticeable effects on the nonrhythmical hippocampal EEG in either age group. In all the rats, compared to the baseline recordings, scopolamine hydrobromide (2 mg/kg, IP, a muscarinic antagonist) increased the incidence of spontaneous EEG spikes, while tetrahydroaminoacridine (THA, 12.5 mg/kg, IP, an acetylcholine esterase inhibitor) decreased the spike activity and induced theta rhythm. Atipamezole (3 mg/kg, SC), a noradrenergic alpha 2-antagonist, increased the baseline amplitude of the nonrhythmical EEG in the DG and increased slightly the spike activity in the CA1 area. The combined blockade of muscarinic receptors by scopolamine (2 mg/kg) and noradrenergic alpha 2-receptors by atipamezole (3 mg/kg) resulted in irregular EEG pattern and corresponding power spectra differed from the scopolamine spectra. The last combination treatment suggests that the effect of atipamezole was not mediated by the secondary cholinergic activation. In the DG, the spectral power increase caused by atipamezole may be related to the increased excitability/bursting liability of granular cells because NA turnover is increased by this agent and NA increases the excitability of granular cells.(ABSTRACT TRUNCATED AT 250 WORDS)

Adrenergic alpha-Antagonists↗
PubMed1991

A review of the pharmacology of selegiline.

Selegiline (1-deprenyl) is an irreversible inhibitor of monoamine oxidase (MAO) type B. Because in the human brain, dopamine is metabolised mainly by MAO-B, selegiline increases dopamine content in the central nervous system. Besides the inhibition of MAO-B, selegiline also inhibits the uptake of dopamine and noradrenaline into presynaptic nerve and increases the turnover of dopamine. Thanks to these properties, selegiline significantly potentiates the pharmacological effects of levodopa. These favourable characteristics have been applied in the treatment of Parkinson's disease using selegiline both with levodopa and alone. Unlike earlier MAO-inhibitors, selegiline does not potentiate the hypertensive effects of tyramine. This is due to the selectivity to MAO-B, leaving intestinal MAO-A intact, and also due to the fact that selegiline inhibits the uptake of tyramine into neurons. Selegiline can prevent the parkinsonism caused by MPTP in animals; similar findings have been reported with other toxins like 6-OHDA and DSP-4, that destroys noradrenergic nuclei. Furthermore, selegiline reduces oxidative stress caused by degradation of dopamine and increases free radical elimination by enhancing superoxide dismutase and catalase activity. These findings may be important when considering the possible neuroprotective effects of selegiline. Besides the basic pharmacology also the interactions and pharmacokinetics of selegiline are reviewed in this article.

Animals↗