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Antti Haapalinna - One of the best experts on this subject based on the ideXlab platform.
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pharmacological properties central nervous system effects and potential therapeutic applications of Atipamezole a selective α2 adrenoceptor antagonist
Cns Drug Reviews, 2006Co-Authors: Antti Pertovaara, Antti Haapalinna, J Sirvio, Raimo VirtanenAbstract:Atipamezole is an alpha2-adrenoceptor antagonist with an imidazole structure. Receptor binding studies indicate that its affinity for alpha2-adrenoceptors and its alpha2/alpha1 selectivity ratio are considerably higher than those of yohimbine, the prototype alpha2-adrenoceptor antagonist. Atipamezole is not selective for subtypes of alpha2-adrenoceptors. Unlike many other alpha2-adrenoceptor antagonists, it has negligible affinity for 5-HT1A and I2 binding sites. Atipamezole is rapidly absorbed and distributed from the periphery to the central nervous system. In humans, Atipamezole at doses up to 30 mg/subject produced no cardiovascular or subjective side effects, while at a high dose (100 mg/subject) it produced subjective symptoms, such as motor restlessness, and an increase in blood pressure. Atipamezole rapidly reverses sedation/anesthesia induced by alpha2-adrenoceptor agonists. Due to this property, Atipamezole is commonly used by veterinarians to awaken animals from sedation/anesthesia induced by alpha2-adrenoceptor agonists alone or in combination with various anesthetics. Atipamezole increased sexual activity in rats and monkeys. In animals with sustained nociception, Atipamezole increased pain-related responses by blocking the noradrenergic feedback inhibition of pain. In tests assessing cognitive functions, Atipamezole at low doses has beneficial effects on alertness, selective attention, planning, learning, and recall in experimental animals, but not necessarily on short-term working memory. At higher doses Atipamezole impaired performance in tests of cognitive functions, probably due to noradrenergic overactivity. Recent experimental animal studies suggest that Atipamezole might have beneficial effects in the recovery from brain damage and might potentiate the anti-Parkinsonian effects of dopaminergic drugs. In phase I studies Atipamezole has been well tolerated by human subjects.
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Atipamezole an α2 adrenoceptor antagonist has disease modifying effects on epileptogenesis in rats
Epilepsy Research, 2004Co-Authors: Asla Pitkanen, Antti Haapalinna, Susanna Narkilahti, Zinayida Bezvenyuk, Jari NissinenAbstract:Abstract Stimulation of α 2 -adrenoceptors delays the development of kindling, a model of epileptogenesis in humans. Blocking α 2 -adrenoceptors is proconvulsant, but has beneficial effects on somatomotor recovery after experimental stroke. We investigated whether Atipamezole, a selective α 2 -adrenoceptor antagonist, affects the recovery process from status epilepticus (SE)-induced brain damage, which affects the risk of epileptogenesis. Vehicle or Atipamezole (100μg/kg/h) treatment was started 1 week after the induction of SE and continued for 9 weeks using Alzet minipumps ( n = 70). Development and severity of epilepsy, spatial and emotional learning, and histologic analysis were used as outcome measures. There were no differences in the percentage of animals with epilepsy in the different treatment groups. In the Atipamezole group, however, daily seizure frequency was lower ( P P P P
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the α2 adrenoceptor antagonist Atipamezole potentiates anti parkinsonian effects and can reduce the adverse cardiovascular effects of dopaminergic drugs in rats
Naunyn-schmiedebergs Archives of Pharmacology, 2003Co-Authors: Antti Haapalinna, Tiina Leino, Esa HeinonenAbstract:The present experiments investigated the effects of the specific α2-adrenoceptor antagonist Atipamezole, alone and in combination with a dopamine agonist, on motor function in rats with a unilateral 6-hydroxydopamine lesion of the nigro-striatal pathway and on exploratory behaviour and cardiovascular function in rats equipped with telemetry transmitters. Dexmedetomidine, an α2-adrenoceptor agonist and the α2-adrenoceptor antagonists idazoxan and yohimbine were used as reference compounds. In the unilaterally lesioned animals, direct dopamine agonists, such as apomorphine, induce contralateral turning behaviour. Indirect agonists, such as amphetamine, induce ipsilateral circling in the animals. Atipamezole (0.3 mg/kg s.c) potentiated and dexmedetomidine (10 µg/kg s.c.) decreased contralateral circling evoked by apomorphine (50 µg/kg s.c.) and by l-3,4-dihydroxyphenylalanine (L-DOPA, 5 mg/kg i.p.). Atipamezole also prolonged the duration of action of L-DOPA. Atipamezole dose-dependently induced ipsilateral turning behaviour and potentiated turning induced by amphetamine (1 mg/kg i.p.). The α1-adrenoceptor antagonist prazosin (0.1 mg/kg i.p.) partially antagonised the effect of amphetamine and had a strong inhibitory effect on the Atipamezole-induced potentiation of the amphetamine response. Prazosin did not have any major effect on either the apomorphine response itself or on the potentiation of the apomorphine response by Atipamezole. This suggests that Atipamezole can modulate motor function both indirectly, by stimulating the release of noradrenaline and directly, by blocking postsynaptic α2-adrenoceptors in neurones other than noradrenergic nerves. The α2-adrenoceptor antagonists, when tested at comparably effective central α2-adrenoceptor antagonising doses in a rat mydriasis model: Atipamezole 0.3 mg/kg s.c., idazoxan 1 mg/kg s.c. and yohimbine 3 mg/kg s.c., all induced ipsilateral turning behaviour and potentiated apomorphine-induced contralateral circling. The effects of the α2-adrenoceptor antagonists were in general similar in these experiments. In habituated non-lesioned rats equipped with telemetry transmitters, apomorphine (50 µg/kg s.c.) decreased blood pressure in the home cage and in an open-field test. It also decreased spontaneous motor activity in the open field. Neither Atipamezole (0.3 mg/kg s.c.) nor idazoxan (1 mg/kg s.c.) had any effect on blood pressure when given alone, but reversed the apomorphine-induced decrease in blood pressure. Atipamezole also diminished apomorphine-induced sedation in the open-field test. In conclusion, Atipamezole improved the efficacy of L-DOPA and apomorphine in an animal model of Parkinson’s disease and also reduced adverse dopaminergic effects on vigilance and on cardiovascular function. These results suggest that an investigation of the effects of specific α2-adrenoceptor antagonists in Parkinson’s disease patients is warranted.
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an α2 adrenergic antagonist Atipamezole facilitates behavioral recovery after focal cerebral ischemia in rats
Neuropharmacology, 2001Co-Authors: Kirsi Puurunen, Antti Haapalinna, Jukka Jolkkonen, J Sirvio, Juhani SiveniusAbstract:Abstract Previous studies suggest that enhanced noradrenergic neurotransmission promotes functional recovery following cerebral lesions. The present study investigated whether systemic administration of an α 2 -adrenergic antagonist, Atipamezole, facilitates recovery following transient focal cerebral ischemia in rats. The effect of Atipamezole therapy on recovery from ischemia was compared with the effect of enriched-environment housing in rats. Ischemia was induced by occlusion of the right middle cerebral artery (MCA) for 120 min using the intraluminal filament model. Daily Atipamezole treatment (1 mg/kg, subcutaneously) was started on day 2 after ischemia induction and drug administration stopped after 10 days. Another group of rats was housed in an enriched environment from day 2 following ischemia induction until the end of the experiment. Several different behavioral tests were used to measure functional recovery during the 26 days following the induction of focal cerebral ischemia. There was improved performance in the limb-placing test from the beginning of Atipamezole treatment to day 8, and in wheel-running in the foot-slip test on days 2 and 4. Enriched-environment housing facilitated recovery in the foot-slip test in a later phase of the test period (days 8 to 10). Discovery of a hidden platform in a water-maze task was also facilitated in rats housed in the enriched environment, but this was probably due to the increased swimming speed of these rats. The present data suggest that the α 2 -adrenergic antagonist, Atipamezole, facilitates sensorimotor recovery after focal ischemia, but has no effect on subsequent water-maze tests assessing spatial learning and memory, when assessed 11 days after the cessation of drug administration.
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behavioral effects of the α2 adrenoceptor antagonist Atipamezole after focal cerebral ischemia in rats
European Journal of Pharmacology, 2000Co-Authors: Jukka Jolkkonen, Antti Haapalinna, Kirsi Puurunen, Sanna Rantakomi, Anu Harkonen, Juhani SiveniusAbstract:The present study characterized the behavioral effects of the selective α2-adrenoceptor antagonist, Atipamezole, in a rat model of focal cerebral ischemia. Atipamezole (1 mg/kg, s.c.) or desipramine (5 mg/kg, i.p.), a noradrenaline reuptake blocker, was administered either as a single injection 2 days after ischemia induction or for 10 days thereafter (subacute administration). A subacute Atipamezole treatment given 30 min before behavioral assessment improved performance in the limb-placing test (days 5, 7, 9, and 11) and in the foot-slip test (days 3 and 7), but not in the beam-walking test. There was no difference between experimental groups in behavioral performance following a single administration of Atipamezole or following single or subacute administration of desipramine. The drug treatments did not attenuate the impairment of spatial cognitive performance of ischemic rats in the Morris water-maze test. These results suggest that repeated use-dependent release of noradrenaline by Atipamezole facilitates the sensorimotor recovery following focal cerebral ischemia in rats.
Sakari Karhuvaara - One of the best experts on this subject based on the ideXlab platform.
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reversal of the sedative and sympatholytic effects of dexmedetomidine with a specific α2 adrenoceptor antagonist Atipamezole a pharmacodynamic and kinetic study in healthy volunteers
Anesthesiology, 1998Co-Authors: Harry Scheinin, Riku Aantaa, Markku Anttila, Pasi Hakola, Antti Helminen, Sakari KarhuvaaraAbstract:BACKGROUND Specific and selective alpha2-adrenergic drugs are widely exploited in veterinary anesthesiology. Because alpha2-agonists are also being introduced to human practice, the authors studied reversal of a clinically relevant dexmedetomidine dose with Atipamezole, an alpha2-antagonist, in healthy persons. METHODS The study consisted of two parts. In an open dose-finding study (part 1), the intravenous dose of Atipamezole to reverse the sedative effects of 2.5 microg/kg of dexmedetomidine given intramuscularly was determined (n = 6). Part 2 was a placebo-controlled, double-blinded, randomized cross-over study in which three doses of Atipamezole (15, 50, and 150 microg/kg given intravenously in 2 min) or saline were administered 1 h after dexmedetomidine at 1-week intervals (n = 8). Subjective vigilance and anxiety, psychomotor performance, hemodynamics, and saliva secretion were determined, and plasma catecholamines and serum drug concentrations were measured for 7 h. RESULTS The mean +/- SD Atipamezole dose needed in part 1 was 104+/-44 microg/kg. In part 2, dexmedetomidine induced clear impairments of vigilance and psychomotor performance that were dose dependently reversed by Atipamezole (P < 0.001). Complete resolution of sedation was evident after the highest (150 microg/kg) dose, and the degree of vigilance remained high for 7 h. Atipamezole dose dependently reversed the reductions in blood pressure (P < 0.001) and heart rate (P = 0.009). Changes in saliva secretion and plasma catecholamines were similarly biphasic (i.e., they decreased after dexmedetomidine followed by dose-dependent restoration after Atipamezole). Plasma norepinephrine levels were, however, increased considerably after the 150 microg/kg dose of Atipamezole. The pharmacokinetics of Atipamezole were linear, and elimination half-lives for both drugs were approximately 2 h. Atipamezole did not affect the disposition of dexmedetomidine. One person had symptomatic sinus arrest, and another had transient bradycardia approximately 3 h after receiving dexmedetomidine. CONCLUSIONS The sedative and sympatholytic effects of intramuscular dexmedetomidine were dose dependently antagonized by intravenous Atipamezole. The applied infusion rate (75 microg x kg(-1) x min(-1)) for the highest Atipamezole dose was, however, too fast, as evident by transient sympathoactivation. Similar elimination half-lives of these two drugs are a clear advantage considering the possible clinical applications.
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rapid reversal of alpha 2 adrenoceptor agonist effects by Atipamezole in human volunteers
British Journal of Clinical Pharmacology, 1991Co-Authors: Sakari Karhuvaara, Antero Kallio, M Salonen, J Tuominen, Mika ScheininAbstract:1. The ability of Atipamezole, a specific and selective alpha 2-adrenoceptor antagonist, to reverse the pharmacological effects induced by the alpha 2-adrenoceptor agonist dexmedetomidine was studied in six healthy male volunteers. Each volunteer received in four sessions in a randomized and single-blind manner three different doses (6.7 micrograms kg-1, 27 micrograms kg-1 and 67 micrograms kg-1) of Atipamezole or saline placebo as 5 min i.v. infusions preceded by a fixed i.v. dose of dexmedetomidine (0.67 micrograms kg-1). 2. Dexmedetomidine caused profound sedation, with the subjects actually falling asleep. This was effectively reversed by the two highest doses of antipamezole. 3. Dexmedetomidine reduced salivary flow on average by 70%. A rapid and full reversal of this effect was seen after the highest dose of antipamezole. 4. Hypotension induced by dexmedetomidine was also effectively antagonized by Atipamezole. Bradycardia was very modest after dexmedetomidine in this study, and thus no reversal of alpha 2-adrenoceptor agonist-induced bradycardia could be demonstrated. 5. Plasma noradrenaline concentrations were reduced by 80% by dexmedetomidine. This was effectively antagonized by Atipamezole, and the highest dose caused a 50% overshoot in plasma noradrenaline concentrations over the basal levels. 6. It is concluded that the effects of dexmedetomidine are effectively reversible by Atipamezole. A dose ratio of 10:1 for Atipamezole:dexmedetomidine was clearly insufficient for this purpose, but ratios in the range of 40:1 to 100:1 were found to be effective in the current experimental situation.
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pharmacological effects and pharmacokinetics of Atipamezole a novel alpha 2 adrenoceptor antagonist a randomized double blind cross over study in healthy male volunteers
British Journal of Clinical Pharmacology, 1990Co-Authors: Sakari Karhuvaara, Antero Kallio, Mika Scheinin, Markku Anttila, J S Salonen, Harry ScheininAbstract:1. Single doses (10, 30 and 100 mg) of Atipamezole (MPV-1248), a new potent and selective imidazole-type alpha 2-adrenoceptor antagonist, and saline placebo were administered as 20 min intravenous infusions to six healthy male volunteers in a randomized double-blind, cross-over phase I study. Later, 100 mg Atipamezole was given orally to the same subjects in an open fashion. 2. The i.v. doses resulted in linearly dose-related concentrations of Atipamezole in plasma. Pharmacokinetic calculations revealed an elimination half-life of 1.7-2.0 h, an apparent volume of distribution of 3.0-3.5 l kg-1 and a total plasma clearance of 1.1-1.5 l h-1 kg-1. No Atipamezole could be detected in plasma after oral dosing. 3. Subjective drug effects were seen mainly after the largest i.v. dose and included increased alertness and nervousness, coldness and sweating of hands and feet, tremor and shivering, motor restlessness, and increased salivation. Salivation was also quantitated using dental cotton rolls, with dose-related increases produced by the i.v. doses. 4. The 100 mg i.v. dose increased plasma noradrenaline concentrations on average by 484 +/- 269 (s.d.)%, and also elevated both systolic and diastolic blood pressure (mean increases 17 +/- 7/14 +/- 2 mm Hg). The 30 mg dose had minor and the 10 mg dose no effects on these variables. Adrenaline and cyclic AMP levels in plasma were increased only after the largest dose. No drug effects were observed after oral dosing. 4. Plasma C-peptide and blood glucose levels were not markedly influenced by the drug, and cortisol secretion was not stimulated. 5. The observed effects are compatible with the presumed alpha 2-adrenoceptor antagonistic action of Atipamezole and are in general concordance with the reported results of other alpha 2-adrenoceptor antagonists (yohimbine and idazoxan). 6. Although not orally active, Atipamezole may prove to be a useful agent in studies of alpha 2-adrenoceptor function in man.
Harry Scheinin - One of the best experts on this subject based on the ideXlab platform.
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effects of Atipamezole a selective alpha adrenoceptor antagonist on cardiac parasympathetic regulation in human subjects
Autonomic and Autacoid Pharmacology, 2004Co-Authors: Jani Penttila, Harry Scheinin, Markku Anttila, T Kaila, A Helminen, S Karhuvaara, S HuhtalaAbstract:1 This double-blind, cross-over, placebo-controlled study on six healthy male volunteers was designed to evaluate the effects of alpha2-adrenoceptor antagonism on cardiac parasympathetic regulation. 2 The subjects received Atipamezole intravenously as a three-step infusion, which aimed at steady-state serum concentrations of 10, 30 and 90 ng ml(-1) at 50-min intervals. 3 Drug effects were assessed with repeated recordings of blood pressure and electrocardiogram, in which the high-frequency (0.15-0.40 Hz) R-R interval variation is supposed to reflect cardiac parasympathetic efferent neuronal activity. 4 At the end of the three steps of the infusion, the mean (+/-SD) concentrations of Atipamezole were 10.5 (3.9), 26.8 (5.6) and 81.3 (21.1) ng ml(-1). 5 Within this concentration range, Atipamezole appeared to reduce slightly the high-frequency R-R interval fluctuations, indicating a minor vagolytic effect in the heart. 6 Atipamezole increased systolic and diastolic arterial pressure, on average by 20 and 14 mmHg (maxima at the second step of the infusion), which evidently reflects an overall sympathetic augmentation.
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reversal of the sedative and sympatholytic effects of dexmedetomidine with a specific α2 adrenoceptor antagonist Atipamezole a pharmacodynamic and kinetic study in healthy volunteers
Anesthesiology, 1998Co-Authors: Harry Scheinin, Riku Aantaa, Markku Anttila, Pasi Hakola, Antti Helminen, Sakari KarhuvaaraAbstract:BACKGROUND Specific and selective alpha2-adrenergic drugs are widely exploited in veterinary anesthesiology. Because alpha2-agonists are also being introduced to human practice, the authors studied reversal of a clinically relevant dexmedetomidine dose with Atipamezole, an alpha2-antagonist, in healthy persons. METHODS The study consisted of two parts. In an open dose-finding study (part 1), the intravenous dose of Atipamezole to reverse the sedative effects of 2.5 microg/kg of dexmedetomidine given intramuscularly was determined (n = 6). Part 2 was a placebo-controlled, double-blinded, randomized cross-over study in which three doses of Atipamezole (15, 50, and 150 microg/kg given intravenously in 2 min) or saline were administered 1 h after dexmedetomidine at 1-week intervals (n = 8). Subjective vigilance and anxiety, psychomotor performance, hemodynamics, and saliva secretion were determined, and plasma catecholamines and serum drug concentrations were measured for 7 h. RESULTS The mean +/- SD Atipamezole dose needed in part 1 was 104+/-44 microg/kg. In part 2, dexmedetomidine induced clear impairments of vigilance and psychomotor performance that were dose dependently reversed by Atipamezole (P < 0.001). Complete resolution of sedation was evident after the highest (150 microg/kg) dose, and the degree of vigilance remained high for 7 h. Atipamezole dose dependently reversed the reductions in blood pressure (P < 0.001) and heart rate (P = 0.009). Changes in saliva secretion and plasma catecholamines were similarly biphasic (i.e., they decreased after dexmedetomidine followed by dose-dependent restoration after Atipamezole). Plasma norepinephrine levels were, however, increased considerably after the 150 microg/kg dose of Atipamezole. The pharmacokinetics of Atipamezole were linear, and elimination half-lives for both drugs were approximately 2 h. Atipamezole did not affect the disposition of dexmedetomidine. One person had symptomatic sinus arrest, and another had transient bradycardia approximately 3 h after receiving dexmedetomidine. CONCLUSIONS The sedative and sympatholytic effects of intramuscular dexmedetomidine were dose dependently antagonized by intravenous Atipamezole. The applied infusion rate (75 microg x kg(-1) x min(-1)) for the highest Atipamezole dose was, however, too fast, as evident by transient sympathoactivation. Similar elimination half-lives of these two drugs are a clear advantage considering the possible clinical applications.
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comparison of dexmedetomidine and midazolam sedation and antagonism of dexmedetomidine with Atipamezole
Journal of Clinical Anesthesia, 1993Co-Authors: Harry Scheinin, M Aho, Olli Erkola, A Kallio, Kari KorttilaAbstract:Abstract Study Objective : To evaluate the effects of dexmedetomidine, an alpha-2 agonist, as an intravenous sedative drug and the effects of Atipamezole, an alpha.-2 antagonist, on recovery. Design : Randomized, double-blind study with three parallel groups. An open dose-finding study preceded it to optimize the Atipamezole dose. Setting : Outpatient operating room at the gynecologic and obstetric university hospital in Helsinki, Finland. Patients : Seventy-two healthy women scheduled for legal termination of pregnancy. Interventions : Patients were assigned to one of three groups of 24 patients each to receive either dexmedetomidine 2 μg/kg and Atipamezole 50 μg/kg; dexmedetomidine 2 μg/kg and saline; or midazolam 0.15 mg/kg and saline. In addition to paracervical block, each patient received two different study drugs: study drug 1 was a sedative agent (either dexmedetomidine or midazolam), administered before the procedure. If the sedation was not deep enough and the patient reacted to the procedure, a low dose of propofol was administered. Study drug 2 was a reversing agent or a placebo, administered following the procedure. Measurements and Main Results : The mean time to regain consciousness was shorter in the dexmedetomidine-Atipamezole and the dexmedetomidine-saline groups compared with the midazolam group. Postoperative sedation, tested both by subjective and objective assessments, decreased more quickly in the dexmedetomidine-Atipamezole group compared with the dexmedetomidine-saline and the midazolam groups. Conclusion : Atipamezole is an effective antagonist for reversing psychomotor impairment following dexmedetomidine sedation.
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pharmacological effects and pharmacokinetics of Atipamezole a novel alpha 2 adrenoceptor antagonist a randomized double blind cross over study in healthy male volunteers
British Journal of Clinical Pharmacology, 1990Co-Authors: Sakari Karhuvaara, Antero Kallio, Mika Scheinin, Markku Anttila, J S Salonen, Harry ScheininAbstract:1. Single doses (10, 30 and 100 mg) of Atipamezole (MPV-1248), a new potent and selective imidazole-type alpha 2-adrenoceptor antagonist, and saline placebo were administered as 20 min intravenous infusions to six healthy male volunteers in a randomized double-blind, cross-over phase I study. Later, 100 mg Atipamezole was given orally to the same subjects in an open fashion. 2. The i.v. doses resulted in linearly dose-related concentrations of Atipamezole in plasma. Pharmacokinetic calculations revealed an elimination half-life of 1.7-2.0 h, an apparent volume of distribution of 3.0-3.5 l kg-1 and a total plasma clearance of 1.1-1.5 l h-1 kg-1. No Atipamezole could be detected in plasma after oral dosing. 3. Subjective drug effects were seen mainly after the largest i.v. dose and included increased alertness and nervousness, coldness and sweating of hands and feet, tremor and shivering, motor restlessness, and increased salivation. Salivation was also quantitated using dental cotton rolls, with dose-related increases produced by the i.v. doses. 4. The 100 mg i.v. dose increased plasma noradrenaline concentrations on average by 484 +/- 269 (s.d.)%, and also elevated both systolic and diastolic blood pressure (mean increases 17 +/- 7/14 +/- 2 mm Hg). The 30 mg dose had minor and the 10 mg dose no effects on these variables. Adrenaline and cyclic AMP levels in plasma were increased only after the largest dose. No drug effects were observed after oral dosing. 4. Plasma C-peptide and blood glucose levels were not markedly influenced by the drug, and cortisol secretion was not stimulated. 5. The observed effects are compatible with the presumed alpha 2-adrenoceptor antagonistic action of Atipamezole and are in general concordance with the reported results of other alpha 2-adrenoceptor antagonists (yohimbine and idazoxan). 6. Although not orally active, Atipamezole may prove to be a useful agent in studies of alpha 2-adrenoceptor function in man.
Esa Heinonen - One of the best experts on this subject based on the ideXlab platform.
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the α2 adrenoceptor antagonist Atipamezole potentiates anti parkinsonian effects and can reduce the adverse cardiovascular effects of dopaminergic drugs in rats
Naunyn-schmiedebergs Archives of Pharmacology, 2003Co-Authors: Antti Haapalinna, Tiina Leino, Esa HeinonenAbstract:The present experiments investigated the effects of the specific α2-adrenoceptor antagonist Atipamezole, alone and in combination with a dopamine agonist, on motor function in rats with a unilateral 6-hydroxydopamine lesion of the nigro-striatal pathway and on exploratory behaviour and cardiovascular function in rats equipped with telemetry transmitters. Dexmedetomidine, an α2-adrenoceptor agonist and the α2-adrenoceptor antagonists idazoxan and yohimbine were used as reference compounds. In the unilaterally lesioned animals, direct dopamine agonists, such as apomorphine, induce contralateral turning behaviour. Indirect agonists, such as amphetamine, induce ipsilateral circling in the animals. Atipamezole (0.3 mg/kg s.c) potentiated and dexmedetomidine (10 µg/kg s.c.) decreased contralateral circling evoked by apomorphine (50 µg/kg s.c.) and by l-3,4-dihydroxyphenylalanine (L-DOPA, 5 mg/kg i.p.). Atipamezole also prolonged the duration of action of L-DOPA. Atipamezole dose-dependently induced ipsilateral turning behaviour and potentiated turning induced by amphetamine (1 mg/kg i.p.). The α1-adrenoceptor antagonist prazosin (0.1 mg/kg i.p.) partially antagonised the effect of amphetamine and had a strong inhibitory effect on the Atipamezole-induced potentiation of the amphetamine response. Prazosin did not have any major effect on either the apomorphine response itself or on the potentiation of the apomorphine response by Atipamezole. This suggests that Atipamezole can modulate motor function both indirectly, by stimulating the release of noradrenaline and directly, by blocking postsynaptic α2-adrenoceptors in neurones other than noradrenergic nerves. The α2-adrenoceptor antagonists, when tested at comparably effective central α2-adrenoceptor antagonising doses in a rat mydriasis model: Atipamezole 0.3 mg/kg s.c., idazoxan 1 mg/kg s.c. and yohimbine 3 mg/kg s.c., all induced ipsilateral turning behaviour and potentiated apomorphine-induced contralateral circling. The effects of the α2-adrenoceptor antagonists were in general similar in these experiments. In habituated non-lesioned rats equipped with telemetry transmitters, apomorphine (50 µg/kg s.c.) decreased blood pressure in the home cage and in an open-field test. It also decreased spontaneous motor activity in the open field. Neither Atipamezole (0.3 mg/kg s.c.) nor idazoxan (1 mg/kg s.c.) had any effect on blood pressure when given alone, but reversed the apomorphine-induced decrease in blood pressure. Atipamezole also diminished apomorphine-induced sedation in the open-field test. In conclusion, Atipamezole improved the efficacy of L-DOPA and apomorphine in an animal model of Parkinson’s disease and also reduced adverse dopaminergic effects on vigilance and on cardiovascular function. These results suggest that an investigation of the effects of specific α2-adrenoceptor antagonists in Parkinson’s disease patients is warranted.
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evaluation of the effects of a specific α2 adrenoceptor antagonist Atipamezole on α1 and α2 adrenoceptor subtype binding brain neurochemistry and behaviour in comparison with yohimbine
Naunyn-schmiedebergs Archives of Pharmacology, 1997Co-Authors: Antti Haapalinna, Raimo Virtanen, Juhamatti Savola, Timo Viitamaa, Ewen Macdonald, Leena Tuomisto, Esa HeinonenAbstract:In the present study we evaluated the α1- and α2-adrenoceptor subtype binding, central α2-adrenoceptor antagonist potency, as well as effects on brain neurochemistry and behavioural pharmacology of two α2-adrenoceptor antagonists, Atipamezole and yohimbine. Atipamezole had higher selectivity for α2- vs. α1-adrenoceptors than yohimbine regardless of the subtypes studied. Both compounds had comparable affinity for the α2A-, α2C- and α2B-adrenoceptors, but yohimbine had significantly lower affinity for the α2D-subtype. This may account for the fact that significantly higher doses of yohimbine than Atipamezole were needed for reversal of α2-agonist (medetomidine) -induced effects in rats (mydriasis) and mice (sedation and hypothermia). The effect on central monoaminergic activity was estimated by measuring the concentrations of transmitters and their main metabolites in whole brain homogenate. At equally effective α2-antagonising doses in the rat mydriasis model, both drugs stimulated central noradrenaline turnover (as reflected by increase in metabolite levels) to the same extent. Atipamezole increased dopaminergic activity only slightly, whereas yohimbine elevated central dopamine but decreased central 5-hydroxytryptamine turnover rates. In behavioural tests, Atipamezole (0.1–10 mg/kg) did not affect motor activity but stimulated food rewarded operant (FR-10) responding (0.03–3 mg/kg) whereas yohimbine both stimulated (1 mg/kg) and decreased (≥ 3 mg/kg) behaviour in a narrow dose range in these tests. In the staircase test, both antagonists increased neophobia, but in the two compartment test only yohimbine (≥ 3 mg/kg) decreased exploratory behaviour. The dissimilar effects of the antagonists on neurochemistry and behaviour are thought to be caused by non α2-adrenoceptor properties of yohimbine. In conclusion, the α2-antagonist Atipamezole blocked all α2-adrenoceptor subtypes at low doses, stimulated central noradrenergic activity and had only slight effects on behaviour under familiar conditions, but increased neophobia. The low affinity for the α2D-adrenoceptor combined with its unspecific effects complicates the use of yohimbine as pharmacological tool to study α2-adrenoceptor physiology and pharmacology.
Mika Scheinin - One of the best experts on this subject based on the ideXlab platform.
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cardiovascular and sedation reversal effects of intramuscular administration of Atipamezole in dogs treated with medetomidine hydrochloride with or without the peripheral α2 adrenoceptor antagonist vatinoxan hydrochloride
American Journal of Veterinary Research, 2019Co-Authors: Heta Turunen, Mika Scheinin, Juhana Honkavaara, Magdy Adam, Marja Raekallio, Flavia Restitutti, Ira Janika Kalliokujala, Katri Nevanpera, Sofia Mannikko, Heidi HautajarviAbstract:OBJECTIVE To investigate the cardiovascular and sedation reversal effects of IM administration of Atipamezole (AA) in dogs treated with medetomidine hydrochloride (MED) or MED and vatinoxan (MK-467...
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characterization of 3h Atipamezole as a radioligand for α2 adrenoceptors
European Journal of Pharmacology, 1992Co-Authors: Birgitta Sjoholm, Ritva Voutilainen, Kirsti Luomala, Juhamatti Savola, Mika ScheininAbstract:Atipamezole (MPV-1248, 4-(2-ethyl-2,3-dihydro-1H-inden-2-yl)-1H-imidazole), a potent alpha 2-adrenoceptor antagonist, was tritiated to high specific activity. We then compared [3H]Atipamezole and [3H]rauwolscine as radioligands for alpha 2-adrenoceptors in rat cerebral cortex, neonatal rat lung, and human platelets. (-)-Noradrenaline and phentolamine were used to define specific alpha 2-adrenergic binding. Unlabelled Atipamezole was used in a similar manner to define saturable, high-affinity non-adrenergic binding. [3H]Atipamezole binding to human platelets (Kd 1.3 nM) and rat brain membranes (Kd 0.5 nM) equilibrated rapidly and was displaced in the expected manner by alpha 2-adrenergic ligands. In contrast, [3H]Atipamezole binding in neonatal rat lung membranes was only effectively inhibited by unlabelled Atipamezole, and by high concentrations of idazoxan. The total density of binding sites for [3H]Atipamezole was clearly in excess of the density of alpha 2-adrenoceptors in this tissue, as defined by [3H]rauwolscine binding. We conclude that [3H]Atipamezole binds with high affinity to alpha 2-adrenoceptors in human platelets and rat cerebral cortex, and that the compound can be used to investigate alpha 2-adrenoceptor properties and drug actions in these tissues. In neonatal rat lung, [3H]Atipamezole identified an additional population of binding sites, distinct from both classical alpha 2-adrenoceptors and idazoxan-defined imidazoline receptors. The pharmacological identity of these binding sites remains to be elucidated. This non-adrenergic component in the binding characteristics of [3H]Atipamezole complicates its use as a general alpha 2-adrenoceptor radioligand.
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rapid reversal of alpha 2 adrenoceptor agonist effects by Atipamezole in human volunteers
British Journal of Clinical Pharmacology, 1991Co-Authors: Sakari Karhuvaara, Antero Kallio, M Salonen, J Tuominen, Mika ScheininAbstract:1. The ability of Atipamezole, a specific and selective alpha 2-adrenoceptor antagonist, to reverse the pharmacological effects induced by the alpha 2-adrenoceptor agonist dexmedetomidine was studied in six healthy male volunteers. Each volunteer received in four sessions in a randomized and single-blind manner three different doses (6.7 micrograms kg-1, 27 micrograms kg-1 and 67 micrograms kg-1) of Atipamezole or saline placebo as 5 min i.v. infusions preceded by a fixed i.v. dose of dexmedetomidine (0.67 micrograms kg-1). 2. Dexmedetomidine caused profound sedation, with the subjects actually falling asleep. This was effectively reversed by the two highest doses of antipamezole. 3. Dexmedetomidine reduced salivary flow on average by 70%. A rapid and full reversal of this effect was seen after the highest dose of antipamezole. 4. Hypotension induced by dexmedetomidine was also effectively antagonized by Atipamezole. Bradycardia was very modest after dexmedetomidine in this study, and thus no reversal of alpha 2-adrenoceptor agonist-induced bradycardia could be demonstrated. 5. Plasma noradrenaline concentrations were reduced by 80% by dexmedetomidine. This was effectively antagonized by Atipamezole, and the highest dose caused a 50% overshoot in plasma noradrenaline concentrations over the basal levels. 6. It is concluded that the effects of dexmedetomidine are effectively reversible by Atipamezole. A dose ratio of 10:1 for Atipamezole:dexmedetomidine was clearly insufficient for this purpose, but ratios in the range of 40:1 to 100:1 were found to be effective in the current experimental situation.
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pharmacological effects and pharmacokinetics of Atipamezole a novel alpha 2 adrenoceptor antagonist a randomized double blind cross over study in healthy male volunteers
British Journal of Clinical Pharmacology, 1990Co-Authors: Sakari Karhuvaara, Antero Kallio, Mika Scheinin, Markku Anttila, J S Salonen, Harry ScheininAbstract:1. Single doses (10, 30 and 100 mg) of Atipamezole (MPV-1248), a new potent and selective imidazole-type alpha 2-adrenoceptor antagonist, and saline placebo were administered as 20 min intravenous infusions to six healthy male volunteers in a randomized double-blind, cross-over phase I study. Later, 100 mg Atipamezole was given orally to the same subjects in an open fashion. 2. The i.v. doses resulted in linearly dose-related concentrations of Atipamezole in plasma. Pharmacokinetic calculations revealed an elimination half-life of 1.7-2.0 h, an apparent volume of distribution of 3.0-3.5 l kg-1 and a total plasma clearance of 1.1-1.5 l h-1 kg-1. No Atipamezole could be detected in plasma after oral dosing. 3. Subjective drug effects were seen mainly after the largest i.v. dose and included increased alertness and nervousness, coldness and sweating of hands and feet, tremor and shivering, motor restlessness, and increased salivation. Salivation was also quantitated using dental cotton rolls, with dose-related increases produced by the i.v. doses. 4. The 100 mg i.v. dose increased plasma noradrenaline concentrations on average by 484 +/- 269 (s.d.)%, and also elevated both systolic and diastolic blood pressure (mean increases 17 +/- 7/14 +/- 2 mm Hg). The 30 mg dose had minor and the 10 mg dose no effects on these variables. Adrenaline and cyclic AMP levels in plasma were increased only after the largest dose. No drug effects were observed after oral dosing. 4. Plasma C-peptide and blood glucose levels were not markedly influenced by the drug, and cortisol secretion was not stimulated. 5. The observed effects are compatible with the presumed alpha 2-adrenoceptor antagonistic action of Atipamezole and are in general concordance with the reported results of other alpha 2-adrenoceptor antagonists (yohimbine and idazoxan). 6. Although not orally active, Atipamezole may prove to be a useful agent in studies of alpha 2-adrenoceptor function in man.
