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H Scheinin

Publications and source records attributed to H Scheinin.

At least 19 recordsLinked to original sources
PubMed1992

Pharmacodynamics and pharmacokinetics of intramuscular dexmedetomidine.

The pharmacodynamics and pharmacokinetics of intramuscular dexmedetomidine--a novel alpha 2-adrenergic receptor agonist under development for preanesthetic use--were studied in healthy male volunteers. Single intramuscular doses of dexmedetomidine (0.5, 1.0, and 1.5 microgram/kg) and placebo were administered to six subjects in a single-blind, multiple crossover study. Dexmedetomidine induced dose-related impairment of vigilance assessed both objectively and subjectively. The drug also caused moderate decreases in blood pressure and heart rate. Plasma norepinephrine was dose-dependently (maximum 89%) decreased. The intramuscular doses resulted in linearly dose-related plasma concentrations of dexmedetomidine. Pharmacokinetic calculations revealed a time to maximum concentration from 1.6 to 1.7 hours, an elimination half-life of 1.6 to 2.4 hours, an apparent total plasma clearance of 0.7 to 0.9 L/hr/kg, and apparent volume of distribution of 2.1 to 2.6 L/kg. The sedative effect of dexmedetomidine dissipated during the 6-hour observation time, but all other effects were still evident 6 hours after administration of the higher doses, paralleling the plasma concentration curves. The relationship of plasma concentrations of dexmedetomidine to pharmacodynamic variables was consistent with a linear pharmacodynamic model. The pharmacodynamic-pharmacokinetic profile of intramuscular dexmedetomidine may be suited to the proposed preanesthetic clinical use of this alpha 2-agonist.

Adrenergic alpha-Agonists↗
PubMed1992

Dexmedetomidine attenuates sympathoadrenal responses to tracheal intubation and reduces the need for thiopentone and peroperative fentanyl.

The effects of the new, highly selective alpha 2-adrenergic agonist, dexmedetomidine, were studied in a randomized, placebo-controlled, double-blind trial in 24 ASA I patients. Dexmedetomidine 0.6 micrograms kg-1 or saline was given i.v. 10 min before induction of anaesthesia. The required dose of thiopentone was significantly (P less than 0.001) smaller in the dexmedetomidine group (mean 4.4 (sd 0.9) mg kg-1) than in the control group (6.9 (1.6) mg kg-1), and the drug attenuated the cardiovascular responses to laryngoscopy and tracheal intubation. The concentration of noradrenaline in mixed venous plasma was smaller in the dexmedetomidine group during all phases of induction (P less than 0.01). During surgery, fentanyl was required in a dose of 0.5 (0.6) mg kg-1 and 2.8 (2.6) mg kg-1 in the dexmedetomidine and control groups, respectively (P less than 0.001). During 2 h postoperative follow-up, oxycodone 0.06 (0.06) mg kg-1 and 0.16 (0.1) mg kg-1 (P less than 0.05) was given to the two groups respectively.

Adrenergic alpha-Agonists↗
PubMed1992

Dexmedetomidine reduces intraocular pressure, intubation responses and anaesthetic requirements in patients undergoing ophthalmic surgery.

We studied the effects of a single i.v. dose of dexmedetomidine, a highly selective and specific alpha 2 adrenoceptor agonist, on intraocular pressure (IOP), haemodynamic and sympathoadrenal responses to laryngoscopy and tracheal intubation, and on anaesthetic requirements in ophthalmic surgery. Thirty ASA I-II patients undergoing cataract surgery were allocated randomly to receive either dexmedetomidine 0.6 microgram kg-1 or saline placebo i.v. 10 min before induction of anaesthesia in a double-blind design. After dexmedetomidine there was a 34% (95% confidence interval (CI) 27-43%) reduction in IOP (P less than 0.001) and 62% (CI 57-68%) decrease in plasma noradrenaline concentrations (P less than 0.001). After intubation, maximum heart rate was 18% (CI 3-33%, P = 0.036) and the maximum IOP 27% (CI 11-43%, P = 0.005) less in the dexmedetomidine group compared with the patients treated with placebo. Within 10 min after intubation, maximum systolic and diastolic arterial pressures were also significantly (P = 0.013 and P = 0.020) smaller in the dexmedetomidine group. The induction dose of thiopentone was smaller (23% (CI 20-26%) P = 0.012), and the use of isoflurane or fentanyl supplements during anaesthesia was less frequent in the dexmedetomidine group. The patients premedicated with dexmedetomidine recovered faster from anaesthesia (P = 0.042). These results suggest that dexmedetomidine may be a useful anaesthetic adjunct in ophthalmic surgery.

Adolescent↗
PubMed1992

Dexmedetomidine infusion for maintenance of anesthesia in patients undergoing abdominal hysterectomy.

The usefulness of intravenous dexmedetomidine infusion for maintenance of anesthesia was studied in patients anesthetized with thiopental, fentanyl, nitrous oxide, and oxygen. Isoflurane was added as needed. The study was conducted in two parts, the first of which was an open dose-response study that comprised 14 women undergoing abdominal hysterectomy. After a suitable infusion regimen of dexmedetomidine was determined according to hemodynamic criteria, 20 patients were included in a double-blind, randomized placebo-controlled trial (10 receiving dexmedetomidine, 10 saline solution). Dexmedetomidine was administered as a two-step infusion to rapidly achieve a steady-state plasma concentration. The infusion was started with an initial dose given over 10 min before the induction of anesthesia; at induction the maintenance rate was begun and continued until closure of the abdominal fascia. The infusion regimens of dexmedetomidine tested in the dose-response study ranged from 120 ng.kg-1 x min-1, followed by 6 ng.kg-1 x min-1, to 270 + 13.5 ng.kg-1 x min-1. In the second part of the study, an initial infusion of 170 ng.kg-1 x min-1 was chosen, followed by 10 ng.kg-1 x min-1 for maintenance. Anesthesia was induced with thiopental (4.0 mg/kg) and maintained with isoflurane in 70% nitrous oxide and oxygen. Isoflurane was administered according to predetermined hemodynamic criteria. Dexmedetomidine infusion did not completely abolish the need for isoflurane but diminished its requirement by > 90% (P = 0.02). The heart rate response to endotracheal intubation was significantly blunted.

Adrenergic alpha-Agonists↗
PubMed1991

Effect of dexmedetomidine and midazolam on human performance and mood.

The effects of dexmedetomidine (DXM), a novel alpha 2-adrenoceptor agonist, on human performance and mood were studied in a double-blind randomized crossover study in 12 healthy student volunteers. Single IM doses of dexmedetomidine, 0.6 microgram/kg (DXM1) and 1.2 micrograms/kg (DXM2), 80 micrograms/kg midazolam (MID) and saline placebo, were given at one-week intervals. Performance was measured objectively and mood was assessed subjectively with visual analogue scales (VAS) at baseline and 40 min, 2 h, 4 h and 6 h after each injection. Blood pressure and heart rate in the sitting position were measured and venous blood was sampled during each testing round. DXM1 did not significantly impair cognitive (digit symbol substitution), coordinative (tracking) or reactive skills, and at 6 h it shortened reaction time and reduced errors in complex tracking. It produced exophoria, increased body sway with the eyes open and impaired subjective performance on VAS. The higher dose dexmedetomidine also caused impaired cognitive, coordinative and reactive skills (although a trend towards improved coordination was found at 6 h), reduced attention, produced exophoria, increased body sway with the eyes open and caused drowsiness, clumsiness, passiveness and mental slowness on the appropriate VAS scales. MID resembled DXM2 in impaired objective and subjective measures of skilled performance, although the objective effects of MID were of speedier onset and shorter duration. In contrast to MID, DXM caused a significant and dose-dependent decrease in systolic and diastolic blood pressure still detectable 6 h after injection.(ABSTRACT TRUNCATED AT 250 WORDS)

Adrenergic alpha-Agonists↗
PubMed1991

Effect of intravenously administered dexmedetomidine on pain after laparoscopic tubal ligation.

Ninety-six women undergoing laparoscopic tubal ligation were randomized to receive intravenously either 0.2 or 0.4 microgram/kg of dexmedetomidine, 60 micrograms/kg of oxycodone, or 250 micrograms/kg of diclofenac for postoperative pain in a double-blind study design. The study drugs were administered in the recovery room for moderate or severe pain and were repeated until pain subsided or disappeared. In the group receiving diclofenac, 83% of the patients required analgesic supplementation with morphine. This contrasted (P less than 0.01) with 33% of the patients receiving either oxycodone or the higher dose of dexmedetomidine. After the first dose of oxycodone was injected, the visual analogue scale for pain (0%-100%) was reduced from 58% to 33%, whereas corresponding pain relief was only achieved after the third injection of 0.4 microgram/kg of dexmedetomidine. Repeated doses of 0.2 microgram/kg of diclofenac or dexmedetomidine did not reduce the visual analogue scale value by more than 17%. More sedation was seen with the higher dose of dexmedetomidine than with either diclofenac or oxycodone (P less than 0.001). Both doses of dexmedetomidine decreased heart rate when compared with diclofenac (P less than 0.001). In the group given 0.4 microgram/kg of dexmedetomidine, 33% of the patients required atropine for bradycardia. The authors conclude that after laparoscopic tubal ligation, intravenously administered dexmedetomidine relieves pain and reduces opioid drug requirement but is attended by sedation and a high incidence of bradycardia.

Adult↗
PubMed1991

Comparison of the behavioral and neurochemical effects of the two optical enantiomers of medetomidine, a selective alpha-2-adrenoceptor agonist.

Medetomidine (MED) is a veterinary sedative whose mode of action is activation of alpha-2 adrenoceptors. Because the carbon atom which separates the two ring systems is methylated, there is a center of stereochemical asymmetry in the molecule. The resulting enantiomers, d-MED and l-MED have recently become available for study. The biological activity of MED, as is now demonstrated in rats in vivo, seems to reside almost exclusively in the d-MED form. Only at extremely high doses (e.g., 10 mg/kg) does l-MED exert any effects, interpreted as alpha-2 adrenoceptor antagonism. In contrast, doses of d-MED as low as 30 micrograms/kg cause sedation, hypothermia and induce neurochemical changes in norepinephrine and 5-hydroxytryptamine metabolism in brain characteristic of alpha-2-agonists (decreases in concentrations of biogenic amine metabolites, turnover and increases in concentration of parent amine). The most sensitive neurochemical indicator of the alpha-2-agonist action of d-MED was the concentration of unconjugated 3-methoxy-4-hydroxy-phenyethylene glycol in rat cerebral spinal fluid, doses of d-MED as low as 10 micrograms/kg caused a significant reduction in this norepinephrine metabolite. Simultaneous administration of the specific alpha-2 adrenoceptor antagonist, atipamezole (1 mg/kg), effectively inhibited the behavioral and most of the neurochemical actions of d-MED (100 micrograms/kg). It is concluded that the enantiomers of MED may be extremely useful in elucidating structure action relationships at alpha-2 adrenoceptors.

Adrenergic alpha-Agonists↗
PubMed1990

No involvement of alpha 2-adrenoceptors in the regulation of basal prolactin secretion in healthy men.

The role of alpha 2-adrenoceptors in the regulation of basal prolactin secretion was investigated in healthy male volunteers. Two independent, placebo-controlled, double-blind experiments were performed. In the first experiment, 50 micrograms dexmedetomidine (MPV-1440), a selective alpha 2-adrenoceptor agonist, and saline placebo were infused (IV) in five subjects. In the second experiment, 100 mg atipamezole (MPV-1248), a selective alpha 2-adrenoceptor antagonist, and saline placebo were infused in six volunteers. The concentrations of prolactin in plasma were not affected by the drugs. These results suggest that alpha 2-adrenoceptors do not a play significant role in the control of basal prolactin secretion in healthy men.

Adrenergic alpha-Agonists↗
PubMed1990

Dexmedetomidine, an alpha 2-adrenoceptor agonist, reduces anesthetic requirements for patients undergoing minor gynecologic surgery.

The effects of dexmedetomidine, an alpha 2-adrenoceptor agonist, on vigilance, thiopental anesthetic requirements, and the hemodynamic, catecholamine, and hormonal responses to surgery were investigated in healthy (ASA physical status 1) women scheduled for dilatation and curettage (D & C) of the uterus. Fifteen minutes before induction they received single iv doses of either dexmedetomidine (0.5 micrograms/kg; n = 19) or saline (n = 20) in a double-blind fashion. Anesthesia was induced with thiopental and maintained with N2O/O2 (70/30%) and thiopental. Dexmedetomidine was well tolerated and no serious drug-related subjective side-effects or adverse events were observed. The most prominent subjective effects were fatigue and decreased salivation. The total amount of thiopental needed to perform D & C of the uterus was reduced approximately 30% (from 456 +/- 141 mg [mean +/- SD] after saline to 316 +/- 79 mg after dexmedetomidine). This was mostly due to a smaller induction dose in the group receiving dexmedetomidine. Dexmedetomidine appeared to improve the recovery from anesthesia as measured by visual analogue scales (VAS) on fatigue and nausea. The plasma concentration of norepinephrine was decreased by 56% after dexmedetomidine implying decreased sympathetic nervous activity. Systolic and diastolic blood pressure were moderately reduced after dexmedetomidine administration. The authors conclude that dexmedetomidine preanesthetic medication decreases thiopental anesthetic requirements and improves the recuperation from anesthesia with no serious hemodynamic or other adverse effects. Further studies in patients undergoing more stressful surgery are indicated.

Adrenergic alpha-Agonists↗
PubMed1990

Acute hemodynamic effects of medetomidine and clonidine in healthy volunteers: a noninvasive echocardiographic study.

Single intravenous (i.v.) doses of 4(5)-[1-(2,3-dimethylphenyl)ethyl]imidazole, medetomidine (MED), (25, 50, and 100 micrograms) and clonidine (CLO 200 micrograms) were administered to five healthy male volunteers in a randomized, double-blind, placebo-controlled, multiple cross-over study. The hemodynamic effects of the drugs were determined by a two-dimension Doppler-echocardiographic method. Blood pressure (BP) and heart rate (HR) were monitored noninvasively. Cardiac output (CO) was maximally reduced by 23% after 100 micrograms MED and 200 micrograms CLO. Dose-related decreases were observed in systolic BP (SBP) and diastolic BP (DBP) and HR. Maximal reductions were 18 and 11 mm Hg and 11 beats/min after 100 micrograms MED, and 18 and 13 mm Hg and 12 beats/min after CLO. Calculated total peripheral resistance (TPR) and the PR interval on ECG remained unchanged. Ejection fraction (EF) and stroke volume (SV) were not significantly affected by either drug, but mean circumferential fiber shortening velocity (VCF) and the preejection period/left ventricular ejection time (PEP/LVET) ratio indicated a tendency to slightly decreased myocardial performance. We conclude that the new selective alpha 2-adrenoceptor agonist, MED, resembles CLO in its acute hemodynamic actions in healthy humans.

Adrenergic alpha-Agonists↗
PubMed1990

Pharmacological effects and pharmacokinetics of atipamezole, a novel alpha 2-adrenoceptor antagonist--a randomized, double-blind cross-over study in healthy male volunteers.

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.

Adrenergic alpha-Antagonists↗
PubMed1990

Medetomidine premedication in dental surgery--a double-blind cross-over study with a new alpha 2-adrenoceptor agonist.

A single 50-micrograms dose of medetomidine, a highly selective alpha 2-adrenoceptor agonist, was administered intravenously as premedication 30 min before surgical third molar extraction under local anaesthesia to ten healthy male subjects in a double-blind, placebo-controlled, cross-over study. Blood pressure, heart rate, plasma catecholamines and cortisol were measured as indicators of operation-related stress. Apprehension and pain were assessed with repeated Visual Analogue Scales. The dental surgeon rated the overall effectiveness of the premedications, and the patients reported their subjective preference. Drug-induced sedation was determined with the Critical Flicker Frequency (CFF) test. The dental surgeon rated medetomidine as significantly more effective premedication than saline placebo. Apprehension was significantly reduced by medetomidine. The patients clearly preferred medetomidine premedication. Blood pressure was lower in the medetomidine session, whereas no significant differences were seen in heart rate. Plasma noradrenaline was lower after medetomidine, but adrenaline and cortisol levels were not affected. In conclusion, medetomidine may offer a useful alternative to traditional premedications in out-patient surgery, and its clinical usefulness should also be studied in other anaesthetic paradigms.

Adrenergic alpha-Agonists↗
PubMed1990

Biological correlates of mental stress related to anticipated caesarean section.

The relationships between self-reported assessments of acute anxiety and several biochemical and physiological indicators of stress reaction were investigated in pregnant women at term in connection with spinal analgesia for caesarean section. Fear and apprehension were statistically significantly associated only with blood pressure and with an increase in heart rate from the previous day. The subjective estimate of the quality of the preoperative night's sleep was negatively associated with biochemical plasma and cerebrospinal fluid (CSF) measures of sympatho-adrenal activity. The previously reported negative correlation between body height and 5-hydroxyindoleacetic acid (5-HIAA, an indicator of serotonin metabolism) in lumbar CSF was confirmed. The concentration of 5-HIAA in CSF was positively correlated with the levels of other acidic monoamine metabolites and cortisol in CSF. It is concluded that hormone and monoamine metabolite measurements in CSF and plasma have only limited usefulness as quantitative indicators of the intensity of preoperative fear and anxiety.

3,4-Dihydroxyphenylacetic Acid↗
PubMed1990

Dexmedetomidine premedication for minor gynecologic surgery.

The effects of four different doses (0.167, 0.33, 0.67, and 1.0 microgram/kg) of dexmedetomidine, a novel alpha 2-adrenoceptor agonist, on anesthetic requirements, hemodynamics, and plasma catecholamine levels were investigated in a single-blind fashion in 20 healthy (ASA physical status I) women scheduled for uterine dilatation and curettage. The drug was administered intravenously 15 min before anesthesia induction with thiopental. Nitrous oxide/oxygen (70%/30%) was used for maintenance. Dexmedetomidine was well tolerated, and no serious drug-related subjective side effects or adverse events were observed. The most prominent subjective effects were tiredness and decreased salivation. The total amount of thiopental needed to perform uterine dilatation and curettage was decreased dose-dependently from 400 +/- 166 mg (mean +/- SD) after 0.167 microgram/kg of dexmedetomidine to 180 +/- 65 mg after 1.0 micrograms/kg of dexmedetomidine (P = 0.028). Blood pressure, heart rate, and plasma norepinephrine levels were reduced after dexmedetomidine. The optimal dose of dexmedetomidine for single-dose intravenous premedication studies in minor surgery appears to be in the range of 0.33-0.67 micrograms/kg.

Adrenergic alpha-Agonists↗
PubMed1989

Medetomidine--a novel alpha 2-adrenoceptor agonist: a review of its pharmacodynamic effects.

1. The pharmacodynamic effects of medetomidine, a novel alpha 2-adrenoceptor agonist, are reviewed. 2. In receptor binding experiments, and in isolated organ preparations medetomidine shows high specificity and selectivity to alpha 2-adrenoceptors. Its alpha 2/alpha 1 selectivity ratio is 1620 compared to 220 of clonidine. It is a highly potent full agonist at alpha 2-adrenoceptors, a fact that also distinguishes it from clonidine. 3. Medetomidine induces a dose-dependent decrease in the central release and turnover of norepinephrine (NE) measured as changes in metabolite concentrations or using pharmacological intervention techniques. 4. The selectivity, specificity and potency of medetomidine is further supported by various in vivo experiments showing dose-dependent hypotensive, bradycardic, sedative, anxiolytic mydriatic, hypothermic and analgesic effects. 5. The pharmacological, neurochemical and behavioral effects of medetomidine can be inhibited by prior, simultaneous or subsequent administration of selective and specific alpha 2-antagonists. 6. In humans medetomidine is well-tolerated and pharmacodynamic effects including e.g. dose-dependent decrease of vigilance, blood pressure, heart rate, salivary secretion and plasma NE are compatible with an agonistic action at alpha 2-adrenoceptors.

Adrenergic alpha-Agonists↗
PubMed1989

Effects of dexmedetomidine, a selective alpha 2-adrenoceptor agonist, on hemodynamic control mechanisms.

Dexmedetomidine, a selective alpha 2-adrenoceptor agonist, was administered to five healthy male volunteers in single intravenous doses of 12.5, 25, 50, and 75 micrograms as part of a placebo-controlled study. The drug caused dose-dependent decreases in systolic and diastolic blood pressure. A small initial hypertensive response was observed after injection of the two highest doses. Heart rate was decreased. The concentration of norepinephrine in plasma was decreased significantly (by up to 92%), and the decrease was dose-dependent. No significant drug-induced alterations were observed in plasma renin activity or in the concentrations of atrial natriuretic peptide and arginine vasopressin in plasma. Other drug effects included dose-dependent impairment of vigilance and stimulation of growth hormone secretion. Plasma cortisol levels were unaffected. Dexmedetomidine is a potentially useful tool for studies of the physiology and pharmacology of alpha 2-adrenoceptors in human beings and may have therapeutic applications in clinical conditions in which sedative and sympatholytic effects are considered beneficial, such as premedication for anesthesia and surgery.

Adrenergic alpha-Agonists↗
PubMed1989

Pharmacological effects of medetomidine in humans.

Single i.v. doses of medetomidine have been administered to healthy male volunteers in three clinical phase I studies. After an initial open dose-finding study, double-blind, placebocontrolled designs were used. The highest dose tested was 120 micrograms. Medetomidine was well tolerated. It caused dose-dependent decreases of blood pressure (max 22/14 mmHg), heart rate (max 14/min) and cardiac output (max 21%) without subjective sensations of hemodynamic changes or other unexpected side-effects. However, a clear dose-dependent sedative effect, both subjective and objective, and a decrease in salivation was seen after single i.v. doses. Medetomidine had a powerful and dose-dependent effect in reducing noradrenaline (by a maximum of 75%) and increasing human growth hormone levels in plasma. All the observed pharmacological effects are well compatible with an alpha 2-agonistic action of the drug and resemble those seen after i.v. administration of clonidine. However, medetomidine appeared to be more potent and short-acting than clonidine.

Adrenergic alpha-Agonists↗