Biomedical subjects

M Scheinin

Publications and source records attributed to M Scheinin.

At least 163 records · Page 9Linked to original sources

PubMed1988

Continuous positive airway pressure with and without high-frequency ventilation: hemodynamics, oxygenation, and endocrine response.

After 18 h of mechanical ventilation following open heart surgery, central hemodynamics, systemic oxygen delivery (DO2), and oxygen consumption were assessed in ten consecutive patients receiving continuous positive airway pressure (CPAP) therapy. Plasma vasopressin, norepinephrine, and epinephrine levels were analyzed. While maintaining the mean airway pressure, two CPAP methods were studied: a demand CPAP with continuous flow without (CPAP) and one with high-frequency ventilation (CPAP-HFV). The frequency used during CPAP-HFV was 300 cycle/min. The spontaneous ventilatory rate was found to be equal during CPAP and CPAP-HFV. The cardiac and stroke volume indices were slightly higher (p less than .05) during CPAP-HFV, which accounted for the finding that DO2 was also slightly higher (p less than .05) during CPAP-HFV. The epinephrine and norepinephrine levels did not differ, whereas the vasopressin level was somewhat higher during CPAP-HFV, which might indicate a higher level of vigilance. It is concluded that cardiac output was slightly higher during CPAP-HFV compared to that during CPAP. This may be due to an effect of the oscillations on circulation or to differences in the level of vigilance.

Aged↗

PubMed1988

Acute effects of medetomidine, a selective alpha 2-adrenoceptor agonist, on anterior pituitary hormone and cortisol secretion in man.

Single iv doses (25, 50 and 100 micrograms) of medetomidine, a selective alpha 2-adrenoceptor agonist of the imidazole type, were administered to 8 healthy male volunteers in a randomized, double-blind, placebo-controlled study. The concentration of hGH in plasma was powerfully and dose-dependently increased. The plasma level of cortisol was dose-dependently decreased, whereas TSH showed a slight but statistically significant increase. Plasma levels of PRL, FSH and LH were unaffected by the drug. Medetomidine appears to resemble other alpha 2-adrenoceptor agonists, notably clonidine, in its endocrine effects. Its high selectivity and short duration of action make it a suitable tool for studies of the physiology and pharmacology of alpha 2-adrenoceptors in man.

Adrenergic alpha-Agonists↗

PubMed1988

Therapeutic applications of drugs acting on alpha-adrenoceptors.

For over a decade it has been known that clonidine and alpha-methyldopa lower blood pressure by activating central and peripheral alpha-2-adrenoceptors and prazosin likewise by antagonizing alpha-1-adrenoceptors. During the 1980s, the number of therapeutic indications for drugs which act via these classes of alpha-adrenoceptors has expanded greatly, particularly the non-cardiovascular applications of drugs acting on alpha-2-adrenoceptors. Novel alpha-2-agonists such as detomidine and medetomidine have been introduced into veterinary medicine as sedative/analgesics. It is possible that these and other compounds with better alpha-2-adrenoceptor selectivity than clonidine may be used in human medicine to ease symptoms of anxiety in drug- and alcohol-related withdrawal syndromes, and as preanaesthetic agents. Several novel alpha-2-adrenoceptor antagonists, such as idazoxan and atipamezole, have been developed with improved selectivity compared to the traditional antagonist at these receptors, yohimbine. At present none of these new compounds are registered for use, but several are undergoing clinical trials for a variety of therapeutic applications such as depression (idazoxan), arousal of animals sedated with alpha-2-agonists (atipamezole), and adult-onset diabetes (DG-5128). The established use of yohimbine in the treatment of male sexual impotence has been reconfirmed and several of the above compounds may be evaluated in the future to treat this disorder.

Adrenergic alpha-Agonists↗

PubMed1988

Evaluation of the systemic anticholinergic activity of nasally administered ipratropium bromide.

Plasma concentrations of nasally inhaled ipratropium bromide were analyzed in eight healthy volunteers by using a sensitive radioreceptor assay (RRA). The rate of saliva secretion, heart rate and changes in visual accommodation were quantitated in order to measure possible systemic anticholinergic drug effects. 240 micrograms of ipratropium bromide (40 micrograms each nostril, repeated twice at 15 min intervals) were inhaled nasally in a double blind, randomized, placebo-controlled experiment. Ipratropium bromide absorbed fast, and peak plasma concentrations of the drug (257 +/- 55 pg/ml) were detected as soon as 5 min after the last inhalation (at 35 min from the beginning). The plasma levels of ipratropium bromide decreased rapidly, being only 86 +/- 7 pg/ml one hour after the last inhalation. These low concentrations of ipratropium bromide indicate that only a small portion of it absorbs after nasal application, which is consistent with the lack of any systemic anticholinergic drug effects in our subjects. It is concluded that nasally applied ipratropium bromide is not likely to cause systemic anticholinergic side-effects, even in doses exceeding the therapeutic recommendations.

Absorption↗

PubMed1988

Comparison of the effects of metoclopramide on sympathetic and muscarinic responses after pretreatment with atropine and pirenzepine.

Metoclopramide (0.15 mg/kg i.v.) was administered to seven healthy volunteers after pretreatment with either atropine, pirenzepine or saline. With the i.v. doses of atropine (0.020 mg/kg) and pirenzepine (0.20 mg/kg) used in the study, antimuscarinic activities in serum were comparable for the most part of the study. Atropine induced a pronounced rise in heart rate and a hypotensive blood pressure response in the orthostatic test, whereas heart rate was significantly lower after pretreatment with pirenzepine than after saline, without any significant effects on systolic blood pressure. Plasma noradrenaline but not plasma adrenaline response to upright posture was increased after metoclopramide following saline but it was reduced following pirenzepine pretreatment, atropine having no significant effect on plasma noradrenaline response in the orthostatic test. Saliva secretion was lower after atropine than after pirenzepine or saline. Pirenzepine seems to diverge from classical anticholinergic drugs, and it reduces the metoclopramide-induced increase in sympathetic responsivity under conditions where cardiac function is not appreciably affected.

Adult↗

PubMed1987

Noradrenergic and dopaminergic effects of nomifensine in healthy volunteers.

Intravenous doses (100 mg in 20 minutes) of the antidepressant drug nomifensine, administered to male volunteers, increased heart rate and blood pressure, elevated the plasma levels of norepinephrine and its metabolite 3-methoxy-4-hydroxyphenylglycol (MHPG), and powerfully stimulated growth hormone release and inhibited the secretion of prolactin. Oral nomifensine, either as a single 100 mg dose or as a similar dose after 2 weeks' treatment with the drug (150 mg/day), caused none of the above effects. This was in line with the limited (less than 30%) oral bioavailability of the active, unconjugated form of the drug, estimated in the same subjects. MHPG in plasma was slightly but consistently reduced by the 2 weeks' treatment, suggesting reduced turnover of norepinephrine. The observed clinical effects of nomifensine are compatible with uptake inhibition and augmented release of norepinephrine and dopamine and possibly direct agonistic effects on dopamine receptors. Although nomifensine was withdrawn from the market because of immunologic complications, it serves as a model compound of a new pharmacologic class of antidepressants, devoid of many of the disturbing side effects of the tricyclic drugs.

Adult↗

PubMed1987

Sedative and cardiovascular effects of medetomidine, a novel selective alpha 2-adrenoceptor agonist, in healthy volunteers.

1. Single intravenous doses (25, 50 and 100 micrograms) of medetomidine (MPV-785, an imidazole derivative), a selective alpha 2-adrenoceptor agonist, were administered to eight healthy male volunteers in a double-blind, placebo-controlled study. 2. The following dose-related effects, all of which were compatible with an agonistic action of the drug at alpha 2-adrenoceptors, were noted: reductions of systolic and diastolic blood pressure (maximum 18/11 mm Hg), heart rate (maximum 10 beats min-1), saliva secretion (maximum 84%) and noradrenaline levels in plasma (maximum 70%). 3. Dose-dependent sedation or impairment of vigilance was also observed, both by subjective and objective (critical flicker fusion threshold) assessments, with the highest dose actually inducing sleep in five of the subjects. 4. The observed effects were in general agreement with those previously seen after intravenous administration of the centrally acting antihypertensive alpha 2-adrenoceptor activating drug, clonidine, but of a shorter duration. 5. The relative importance of alpha 2-adrenoceptors located in peripheral tissues and in the central nervous system for the drug's cardiovascular effects could not be determined, but the high lipid solubility of the compound and the rapid onset of sedation are in favour of a major central component. 6. Medetomidine may be a useful tool for the investigation of the physiology and pharmacology of alpha 2-adrenoceptors in man. In addition, the therapeutic and diagnostic uses of the compound should be investigated in pathological conditions related to increased sympathetic neuronal activity.

Adrenergic alpha-Agonists↗

PubMed1987

Hypokalaemia and other non-bronchial effects of inhaled fenoterol and salbutamol: a placebo-controlled dose-response study in healthy volunteers.

1. The hypokalaemia-inducing effects of two widely used inhaled antiasthmatic beta 2-adrenoceptor agonists, fenoterol and salbutamol, were compared in six healthy male volunteers. 2. Each drug was administered in three different doses, 400, 600 and 800 micrograms, which were repeated three times with 30 min intervals (total doses 1200, 1800 and 2400 micrograms in 1 h). The treatments were given at 1 week intervals in random order in a single-blind fashion. 3. The concentration of potassium in plasma was dose-dependently reduced by both drugs with peak effects 75-90 min after the first inhalations. The hypokalaemic effect of fenoterol was significantly greater than that of equal doses of salbutamol (average +/- s.d. reductions of 1.13 +/- 0.32 and 0.67 +/- 0.25 mEq l-1, respectively, after the highest doses, P less than 0.05). Concomitantly, decreases were noted in the amplitude of the T-wave on the ECG. 4. The concentration of cyclic AMP in plasma was measured and used as an indicator of systemic beta 2-adrenoceptor agonistic effects of the drugs. Increases in cAMP were a close mirror image of the drugs' effects on potassium in plasma. 5. Plasma renin activity, noradrenaline in plasma and heart rate were also dose-dependently increased by the treatments, whereas blood pressure remained unaltered. 6. While the clinical significance of hypokalaemia induced by inhaled beta 2-adrenoceptor sympathomimetics still is a matter of debate, our results point to possible differences between therapeutically equipotent doses of fenoterol and salbutamol in their propensity to cause hypokalaemia and other acute non-bronchial effects.

Administration, Inhalation↗

PubMed1987

Meptazinol and pentazocine: plasma catecholamines and other effects in healthy volunteers.

1. This double-blind, random-order study was designed to compare the clinical effects and the plasma catecholamine responses after i.v. administration of meptazinol at doses 0.7 and 1.4 mg kg-1, pentazocine at doses 0.3 and 0.6 mg kg-1 and saline placebo to six healthy volunteers. 2. Mean arterial pressure was not affected by either drug. Heart rate showed slight drug-related changes. Respiratory rate fell slightly with both drugs, but independently of dose. 3. The critical flicker fusion threshold-test and Maddox wing readings could both clearly differentiate active drugs from placebo. Meptazinol caused more nausea and dysphoria as expressed with visual analogue scales. Both analgesics caused short-lived feelings of euphoria. 4. After pentazocine plasma noradrenaline increased almost two-fold in 10-20 min. The effect of meptazinol was slightly smaller, whereas meptazinol caused a pronounced increase in plasma adrenaline concentrations in two of six subjects. Pentazocine had a smaller, but significant effect on plasma adrenaline. 5. We conclude that the effects of meptazinol in healthy volunteers do not differ markedly from those of pentazocine, although it may cause more nausea and dysphoria. The pronounced increase in plasma adrenaline concentrations in two of six subjects calls for caution in its use in patients with cardiac diseases.

Adult↗

PubMed1987

Oral premedication with clonidine: effects on stress responses during general anaesthesia.

The effect of clonidine (4.5 micrograms kg-1) on haemodynamics and hormonal stress responses was evaluated in 21 female patients undergoing breast surgery. The standardized general anaesthesia included diazepam as premedicant, thiopentone, enflurane, N2O, fentanyl and vecuronium. Venous plasma concentrations of noradrenaline, adrenaline, growth hormone, vasopressin, and cortisol were assayed at various times before, during and after surgery. Clonidine attenuated the sympathoadrenal response; arterial blood pressure and heart rate increases in association with intubation were lower in clonidine-premedicated patients. Noradrenaline levels were lower throughout and 3 h after surgery in the clonidine group (P less than 0.05). Adrenaline levels were lower in this group 2 min after intubation (P less than 0.05). Growth hormone, vasopressin and cortisol plasma levels were increased at the end of and after surgery, with no differences between the groups. In spite of the effect on sympathoadrenal response, clonidine did not have any significant additive anxiolytic effect. Statistically significant differences were not found as to need for postoperative analgesics.

Administration, Oral↗

PubMed1987

Reduction of pain at venous cannulation in children with a eutectic mixture of lidocaine and prilocaine (EMLA cream): comparison with placebo cream and no local premedication.

The local analgesic efficacy of a cream formulation of lidocaine and prilocaine (EMLA) in reducing pain at venous cannulation was investigated in children scheduled for elective surgery. Forty children participated in a double-blind, randomized comparison between EMLA and inactive placebo cream. Another group of 18 children without any local treatment was studied as an additional control material. Subjective pain scores, expressed with a visual analogue scale, were significantly lower in the EMLA group compared with both the group treated with placebo cream (P less than 0.001) and the open control group (no cream; P less than 0.01). Local pallor and slight oedema were the only side-effects, registered in both cream-treated groups. A preliminary study was also carried out with 10 children (five with EMLA and five without) in order to determine whether catecholamine and vasopressin levels in venous blood are affected by the stress and anxiety associated with venepuncture in children premedicated with oral flunitrazepam. No significant hormone responses were, however, detected. The lidocaine concentrations measured in venous blood taken from the application site of EMLA cream were low, and there were no measurable levels of lidocaine in simultaneous blood samples from the opposite extremity. In our opinion EMLA cream is safe and alleviates effectively the pain associated with venepuncture, and thus deserves a place in the routine premedication of children.

Administration, Cutaneous↗

PubMed1987

Sympatho-adrenal and pituitary hormone responses during and immediately after thoracic surgery--modulation by four different pain treatments.

Four different pain treatments (single intercostal block with bupivacaine, repeated intercostal block, epidural morphine and epidural bupivacaine infusions) were compared in 39 patients subjected to lung surgery under general anaesthesia. The patients' own estimate of the postoperative pain was not significantly different between the groups, but the epidurally treated patients required fewer doses of supplementary analgesic than those given just a single dose of intercostal bupivacaine. Bupivacaine levels in blood were below the toxic range in all groups. The concentration of antidiuretic hormone in blood was increased early during the operation, and had only partly returned to normal on the first postoperative morning. Growth hormone in plasma was increased only at the end of the operation. Catecholamine levels in blood increased gradually, reaching their peak postoperatively. There were only slight differences between the groups in these posterior and anterior pituitary and sympatho-adrenal responses to surgical stress. Thus, neither repeated intercostal blockade nor epidural administration of morphine or bupivacaine could prevent the endocrine responses to thoracic surgery, in spite of significant, albeit incomplete, pain relief. This was probably caused in part by residual pain, and also by poor access of the extradural medications to the autonomic afferent pathways mediating nociceptive signals from thoracic organs and tissues.

Aged↗

PubMed1987

Placental and blood-CSF transfer of intramuscularly administered atropine in the same person.

Both placental and blood-CSF transfer of atropine (0.01 mg/kg intramuscularly) was measured (by RIA) in 11 parturients undergoing Caesarean section under spinal analgesia. In the foeto-placental unit a significant penetration into amniotic fluid was found, whereas in CSF there was a measurable level of the drug (greater than 1.5 ng/ml) in only one mother. Our results show that there is a fundamental difference in the penetrability of tertiary ammonium alkaloids like atropine through these two biological membranes. However, our results concern penetration into human lumbar CSF and do not necessarily reflect potential penetration into the ventricular CSF, choroid plexus or brain ventricular ependyma.

Amniotic Fluid↗

PubMed1987

Alterations in peripheral and central dopamine receptor sensitivity after subchronic treatment with fluphenazine and sulpiride.

The effects of subchronic treatment with the antipsychotic drugs fluphenazine and sulpiride on the sensitivity of peripheral neuronal dopamine receptors and central dopamine autoreceptors were evaluated. The ability of apomorphine, a dopamine agonist, to inhibit electrically induced sympathetic vasoconstriction in pithed rats, and apomorphine-induced inhibition of spontaneous locomotor activity in awake rats were used as indices of peripheral and central dopamine receptor sensitivity, respectively. A single injection of fluphenazine decanoate, a long-acting preparation of fluphenazine, enhanced the central locomotor inhibitory effect of low doses of apomorphine 4 and 6 weeks after drug administration, whereas the antidopaminergic effect on peripheral dopamine receptors was prolonged and persisted at least up to 6 weeks. In another set of experiments rats were treated with fluphenazine hydrochloride and sulpiride for 10 days and subsequently challenged with apomorphine after various withdrawal times. Both antipsychotic drugs augmented the inhibitory effect of apomorphine in the periphery, although the time courses of the potentiation were different. Both treatments also enhanced the locomotor inhibitory effect of apomorphine. These results are in line with our previous finding that long-term treatment with dopamine antagonists can induce neuronal dopamine receptor up-regulation also outside the central nervous system. Peripheral neuronal dopamine receptors thus show similar adaptive responses to long-term blockade as central dopamine autoreceptors, and may serve as a useful experimental model in studies concerned with mechanisms of dopaminergic autoregulation in the central nervous system.

Animals↗

PubMed1987

Placental and blood-CSF transfer of orally administered diazepam in the same person.

Both placental and blood-lumbar CSF transfer of diazepam (5 mg orally) and its two metabolites, N-desmethyldiazepam and unconjugated oxazepam, was measured (by GLC) in 15 patients undergoing Caesarean section under spinal analgesia. Differing from our earlier studies with atropine (Virtanen et al. 1982; Kanto et al. 1981 & 1987), a reasonably fast penetration of diazepam and its two metabolites through the two biological membranes was found. Diazepam, N-desmethyldiazepam and to a lesser extent unconjugated oxazepam accumulated on the foetal side of the placenta, apparently due to a higher degree of plasma protein binding in the foetus. No accumulation was found in CSF, probably due to the lack of binding proteins in this tissue compartment. Concerning atropine, lumbar CSF with an incomplete drug penetration was found to be a "deeper" compartment than amniotic fluid, but in the present study with diazepam there was no clear difference between these two tissue compartments.

Adult↗

PubMed1987

Monoamine metabolite levels in rat CSF: kinetic studies.

The kinetics of monoamine metabolites, 3-methoxy-4-hydroxyphenylglycol (MHPG), 5-hydroxyindoleacetic acid (5-HIAA) and homovanillic acid (HVA), in cisternal CSF were determined after monoamine oxidase (MAO) inhibition (pargyline, 100 mg/kg) and tyrosine hydroxylase inhibition (alpha-methyl-p-tyrosine, alpha-MPT, 250 mg/kg) in awake rats. In addition, the possibility of a peripheral contribution to CSF MHPG levels was investigated by infusing large amounts of the metabolite into vena jugularis. Pargyline induced an exponential decrease of CSF MHPG, 5-HIAA and HVA, with respective half-lives of 51, 86 and 46 min. alpha-MPT caused a slower decline of MHPG and HVA, while 5-HIAA was unaffected. Results from the MHPG-infusion experiments indicate minor peripheral contribution to CSF MHPG levels in acute pharmacological studies. The present paper gives further support for the validity of our new animal model in detecting acute changes in central monoaminergic activity.

Animals↗

PubMed1987

Meptazinol and pentazocine: effects on prolactin, growth hormone and vasopressin levels in plasma.

The effects of two partial agonist opioid analgesics, meptazinol (at doses 0.7 and 1.4 mg/kg intravenously) and pentazocine (at doses 0.3 and 0.6 mg/kg), on anterior and posterior pituitary hormone secretion were studied in six normal human volunteers. Both drugs stimulated the secretion of prolactin dose-dependently, as expected. This effect was seen in all subjects, although two of the six subjects reacted more sensitively to both drugs. Plasma growth hormone concentrations were increased only after the higher dose of meptazinol. This was also seen in all subjects suggesting a specific pharmacological effect. Vasopressin (AVP) in plasma was greatly increased (up to 76 pg/ml) in three of the six subjects after the higher dose of meptazinol, but remained on a low level in the other three and after all other drug doses. The increase in AVP occurred only in those individuals who reported nausea after meptazinol. It was concluded that the augmented AVP release following meptazinol administration was likely to be a non-specific response induced by nausea and not an effect mediated by opiate receptors.

Adult↗

PubMed1987

Effects of nortriptyline and its 10-hydroxy metabolite on plasma noradrenaline (NA) concentrations, heart rate and blood pressure during intravenous NA infusion.

Eight healthy subjects were randomly given placebo and equimolar doses of nortriptyline (NT) and E-10-hydroxy-NT (E-10-OH-NT). Two hours after oral intake of drug, noradrenaline (NA) was infused intravenously at three consecutive rates. Before infusion of NA, E-10-OH-NT significantly increased heart rate compared to NT (p less than 0.05) and placebo (p less than 0.01). During NA infusion, the active drugs caused non-significant tendencies to augmented increase of blood pressure and decrease of heart rate. Plasma NA concentrations increased significantly due to the infused NA but were not influenced by NT or E-10-OH-NT. This absence of drug effect may have been due to several simultaneously operating factors affecting plasma NA concentrations, e.g., modification of the rates of NA release and clearance by exogenous NA or drugs and competing elimination pathways for infused NA. After stopping the NA infusion, a non-significant tendency to a slower elimination of NA was found after both active drugs.

Adult↗