Biomedical subjects

J Kanto

Publications and source records attributed to J Kanto.

At least 73 records · Page 4Linked to original sources

PubMed1989

Intramuscular atropine in elderly people: pharmacokinetic studies using the radioreceptor assay and some pharmacodynamic responses.

The pharmacokinetics (radioreceptor assay, RRA) and some clinical effects of atropine were studied in 7 elderly gynaecological surgery patients. The RRA measures only the pharmacologically active isomer of atropine, 1-hyoscyamine. Following a single 0.01 mg/kg intramuscular (M. deltoideus) injection, a very fast rate of absorption was found with mean peak serum concentration occurring after only 13 min. The reason for this could be either a preferential tissue uptake of the 1-form or the injection site or both. The elimination half-life was 2.27 hr. Only 23.1% of the given drug was excreted in urine in 24 hr as a pharmacologically active form. The clinical effects (heart rate rise, subjective sedation and antisialogogue effect) were seen after only 30 min. This somewhat faster appearance of clinical effects than in previous studies can be due to the injection site. The sedative effect of the drug is clear and long lasting in elderly people.

Aged↗

PubMed1989

Hormonal, haemodynamic, and subjective effects of intravenously infused indomethacin: no change in the physiological response to hypertonic saline challenge.

This double-blind, placebo-controlled human study was performed to determine the endocrine responses to intravenously administered indomethacin at two dose rates (0.36 or 0.72 mg/kg bolus followed by 0.071 or 0.143 mg/kg/hr for 150 min.). A 5% hypertonic saline infusion was used for further assess the hormonal systems regulating body fluid and electrolyte balance. Plasma renin activity (PRA) and concentrations of aldosterone and vasopressin (AVP) were unaffected by indomethacin. Hypertonic saline caused a 5% increase in plasma sodium and a 4.2% increase in serum osmolality, with a concomitant two-fold rise in plasma AVP levels and significant declines in PRA and aldosterone. Indomethacin had no effects on these responses, and did not affect plasma catecholamine concentrations, but the hypertonic saline infusion doubled the noradrenaline levels in plasma. Atrial natriuretic peptide (ANP)-like immunoreactivity in plasma was not affected by indomethacin nor by hypertonic saline. The higher dose rate of indomethacin resulted in significant stimulation of growth hormone release, but plasma prolactin levels were not influenced. Thus acute intravenous administration of indomethacin proved to be devoid of significant effects on the multihormonal system regulating fluid and electrolyte balance.

Adult↗

PubMed1989

Pharmacokinetic implications for the clinical use of propofol.

Propofol, the recently marketed intravenous induction agent for anaesthesia, is chemically unrelated to earlier anaesthetic drugs. This highly lipophilic agent has a fast onset and short, predictable duration of action due to its rapid penetration of the blood-brain barrier and distribution to the CNS, followed by redistribution to inactive tissue depots such as muscle and fat. On the basis of pharmacokinetic-pharmacodynamic modelling, a mean blood-brain equilibration half-life of only 2.9 minutes has been calculated. In most studies, the blood concentration curve of propofol has been best fitted to a 3-compartment open model, although in some patients only 2 exponential phases can be defined. The first exponential phase half-life of 2 to 3 minutes mirrors the rapid onset of action, the second (34 to 56 minutes) that of the high metabolic clearance, whereas the long third exponential phase half-life of 184 to 480 minutes describes the slow elimination of a small proportion of the drug remaining in poorly perfused tissues. Thus, after both a single intravenous injection and a continuous intravenous infusion, the blood concentrations rapidly decrease below those necessary to maintain sleep (around 1 mg/L), based on both the rapid distribution, redistribution and metabolism during the first and second exponential phases (more than 70% of the drug is eliminated during these 2 phases). During long term intravenous infusions cumulative drug concentrations and effects might be expected, but even then the recovery times do not appear to be much delayed. The liver is probably the main eliminating organ, and renal clearance appears to play little part in the total clearance of propofol. On the other hand, because the total body clearance may exceed liver blood flow, an extrahepatic metabolism or extrarenal elimination (e.g. via the lungs) has been suggested. Approximately 60% of a radiolabelled dose of propofol is excreted in the urine as 1- and 4-glucuronide and 4-sulphate conjugates of 2.6-diisopropyl 1,4-quinol, and the remainder consists of the propofol glucuronide. Thus for hepatic and renal diseases, co-medication, surgical procedure, gender and obesity do not appear to cause clinically significant changes in the pharmacokinetic profile of propofol, but the decrease in the clearance value in the elderly might produce higher concentrations during a long term infusion, with an increased drug effect. In addition, the lower induction dose observed in relation to increased age might be partly explained by a smaller central volume of distribution.(ABSTRACT TRUNCATED AT 400 WORDS)

Adult↗

PubMed1988

Anaesthesia for cardioversion: a comparison of propofol and thiopentone.

Propofol (2,6-diisopropylphenol) 2.5 mg.kg-1 IV was compared with thiopentone 5 mg.kg-1 IV as an induction agent in anaesthesia for elective cardioversion. Thirty-five patients (ASA physical status II-III) with atrial fibrillation were included. Thirty patients were randomized to receive propofol or thiopentone. Five patients were treated twice during the study period and anaesthetized with both agents (the first treatment according to the random order and the second with the agent not used on the first occasion). The induction characteristics and the haemodynamic response for propofol and thiopentone were similar. The success rate of cardioversion did not differ between the groups. Recovery times were shorter after propofol than after thiopentone with respect to ocular muscle balance, central integration and subjective sedation of patients. The incidence of side-effects did not differ between the groups. None of the patients reported any awareness during the procedure. All five patients treated twice (with both agents) assessed the anaesthetic procedure with propofol as being more pleasant than that with thiopentone.

Anesthesia, Intravenous↗

PubMed1988

Comparison between propofol and thiopentone for induction of anaesthesia in children.

Propofol 2.5 mg/kg was compared with thiopentone 5 mg/kg in a randomised open study, as an induction agent in paediatric anaesthesia. One hundred and twenty children who were to undergo elective surgery were included in the study. Both propofol and thiopentone produced a rapid and smooth induction with a low incidence of side effects. A similar decrease (10%) in mean arterial pressure was observed with both agents, but propofol showed better suppression of the haemodynamic response to tracheal intubation. Respiratory upsets occurred less frequently with propofol than with thiopentone, but propofol frequently induced discomfort on injection. Both agents provided satisfactory and controllable induction of anesthesia and no major adverse reactions occurred during or after anaesthesia. We conclude that propofol is a useful alternative as an induction agent in children.

Adolescent↗

PubMed1988

Pharmacokinetic implications for the clinical use of atropine, scopolamine and glycopyrrolate.

Several specific and sensitive new methods for determining atropine and its metabolites in biological fluids have increased the possibility to characterise the pharmacokinetic properties of this antimuscarinic agent. Following i.v. injection, atropine disappears very quickly from the circulation, resembling its fast onset of action. Age, but not sex, appears to have a clear effect on its kinetics, explaining at least partly the higher sensitivity of very young and very old patients to this anticholinergic agent. Following i.m. or oral atropine administration, typical anticholinergic effects coincide quite well with the absorption rate of the drug, indicating that the premedication should be given about 1 and 2 h before induction of anaesthesia. A sufficient absorption after rectal administration offers an alternative treatment, especially in children. Differing from its placental transfer, atropine has a delayed and incomplete lumbar cerebrospinal fluid penetration, indicating a fundamental difference between these two biological membranes. Oropharyngeally administered atropine has a very variable absorption, but inhaled or intratracheally given drug has produced interesting new results, e.g. pulmonary atropine administration appears to have clinical significance in special situations, such as cardiac arrest and organophosphate poisoning (military personnel). Depending on the method used, different data on the metabolism and excretion for atropine have been reported and therefore further studies are needed in this respect. The pharmacokinetics of scopolamine and glycopyrrolate and their relation to clinical response are poorly understood.

Aging↗

PubMed1988

Ritodrine infusion at term: effects on maternal and fetal prostacyclin, thromboxane and prostaglandin precursor fatty acids.

A prospective randomized study was performed to investigate the effect of a short-term ritodrine infusion on the concentrations of maternal and fetal prostaglandins and their precursor fatty acids. Mothers gave birth by an elective cesarean section at term, and either ritodrine (study group) or physiological saline (controls) was infused 2 h prior to the operation. Ritodrine decreased the levels of thromboxane A2 significantly in the mother, while the concentration of prostacyclin remained unchanged. In the umbilical arterial plasma concentrations of prostacyclin or thromboxane A2 there were no differences between ritodrine-treated and control subjects. Ritodrine had no effect on the prostaglandin precursor fatty acids and other fatty acids of plasma phospholipids of the mother or her fetus. It is concluded that ritodrine may suppress the maternal prostaglandin production, but has no effect on the levels of vasoactive prostaglandins or their precursor fatty acids in the fetus.

6-Ketoprostaglandin F1 alpha↗

PubMed1988

Pharmacokinetics and clinical use of flumazenil (Ro 15-1788).

Flumazenil (Ro 15-1788) is a specific benzodiazepine antagonist which can prevent or abolish selectively at the receptor level all centrally mediated effects of benzodiazepines. Following oral administration flumazenil is rapidly absorbed (peak concentrations are achieved after 20 to 90 minutes), but bioavailability is low (16%) due to significant presystemic elimination. As less than 0.2% of an intravenous dose was recovered as unchanged drug in the urine, extensive metabolism must occur and so far 3 metabolites of flumazenil (N-demethylated and/or hydrolysed products) have been identified. For the clinical value of flumazenil a rapid onset of action is mandatory, which is facilitated by its fast uptake and regional brain distribution as verified by positron emission tomography. The limited duration of benzodiazepine-antagonistic action of flumazenil (2 to 3 hours) is due to its rapid hepatic elimination. This can be characterised either by the short half-life (0.7 to 1.3 hours) or better by the high plasma or blood clearance of 520 to 1300 ml/min (31 to 78 L/h). The low plasma protein binding of flumazenil (about 40%) will not limit its wide distribution (apparent distribution volume 0.6 to 1.6 L/kg) or its partly flow-dependent hepatic elimination. Whereas in first trials flumazenil appeared to be without its own pharmacological effects, there is now increasing evidence that flumazenil is not devoid of intrinsic actions. Dependent on the dose, the basal clinical conditions and experimental tests, flumazenil has both weak agonist-like and inverse agonist-like properties which might be explained by a modulation of GABA-ergic activity. In several clinical studies intravenous doses down to 0.2mg of flumazenil initiated a rapid and reliable reversal of benzodiazepine-induced sedation, hypnosis or coma. Small incremental intravenous doses of 0.1 to 0.2mg of flumazenil are useful in benzodiazepine intoxications, in differential diagnosis of coma, excessive postoperative sedation and possibly in reversing paradoxical reactions of benzodiazepines. Because flumazenil is short acting, careful clinical observation is crucial. To maintain its antagonistic action repeated administrations will be necessary. At present, the therapeutic indications are restricted to some special situations. However, flumazenil is an interesting agent, which might contribute also to a better understanding and future development of more specific benzodiazepines, hopefully without the potential for dependence seen with existing compounds.

Anesthesia↗

PubMed1988

Allergic reaction to an amide local anesthetic in segmental epidural analgesia.

A very serious case of anaphylactoid reaction to bupivacaine occurred during epidural analgesia. A rise in complement 3 activation products and a decrease in immunoglobulin E were observed, while bupivacaine toxicity was ruled out by normal serum concentration. Severe maternal hypotension, and a sudden decrease in the fetal heart rate were detected clinically. By a cesarean section, a baby girl was delivered, who at the age of 1 year appears normal.

Adult↗

PubMed1988

The effect of flunitrazepam on acoustic reflex--a methodological pilot study.

Four healthy volunteers took part in this study in four sessions at one week intervals minimum. Three intravenous dose levels of flunitrazepam as well as placebo (saline) were investigated. The sessions were randomized and the study was double blind. The results show that a significant correlation exists between the serum concentrations of flunitrazepam and acoustic reflex amplitude, latency, Maddox wing readings and subjective sedation. Critical flicker fusion frequency test was insensitive in this respect. We conclude that acoustic reflex may be a new method for determination of benzodiazepine effects in man.

Double-Blind Method↗

PubMed1987

Simple devices in differentiating the effects of buprenorphine and fentanyl in healthy volunteers.

We have tested the usefulness of the critical flicker fusion threshold-test (CFF), Maddox wing readings (MW), and visual analogue scale scores (VAS) in a double-blind, random-order study designed to evaluate the clinical effects of two different kinds of opiates, buprenorphine and fentanyl in comparison with those of placebo. The results were compared with the so-called postanaesthetic recovery score (PARS). In 7 healthy volunteers MW and VAS differentiated the effects of buprenorphine 7.5 micrograms/kg i.v. from those of fentanyl 2.5 micrograms/kg i.v. and placebo. CFF was very insensitive in this respect and PARS completely useless. Our results show that, in addition to the known usefulness of VAS, MW is also able to differentiate the effects of these opiates.

Adult↗

PubMed1987

Use of simple tests to determine the residual effects of the analgesic component of balanced anaesthesia.

In order to evaluate simple means of determining the rate of recovery after general anaesthesia, the usefulness of the critical flicker fusion threshold test, the Maddox wing apparatus and the visual analogue scale were compared. The postanaesthetic recovery score was used as a reference. Two patient groups (n = 15 in each) received, in a randomized double-blind study, a similar balanced anaesthesia for Caesarean section, except that the analgesic component was either fentanyl 2.5 micrograms kg-1 i.v. or buprenorphine 7.5 micrograms kg-1 i.v. Maddox wing apparatus and visual analogue scale were sensitive enough to differentiate between the postanaesthetic residual effects of the two opioids, but critical flicker fusion threshold and, especially, postanaesthetic recovery score were insensitive in this respect. There was no difference between the two patient groups in mean arterial pressure and heart rate. Our results show that the residual effects of different kinds of opioids as an analgesic component of balanced anaesthesia can be differentiated using simple means like Maddox wing apparatus and visual analogue scales.

Adult↗

PubMed1987

Placental transfer of flunitrazepam following intramuscular administration during labour.

After a single intramuscular dose of flunitrazepam 0.015 mg kg-1 (n = 14) in women 37 to 41 weeks pregnant, the concentrations in the umbilical artery and amniotic fluid were significantly lower than in maternal venous plasma. Although the difference between the maternal venous and umbilical venous plasma concentrations was not significant, the mean fetomaternal ratio was 0.7. The plasma protein binding of flunitrazepam was 80 +/- 4% in the mother and 79 +/- 5% in the umbilical circulation. Both mothers and midwives subjectively estimated intramuscular flunitrazepam as a valuable sedative-anxiolytic agent during the first stage of labour.

Adult↗

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

Elimination of and heart rate response to atropine in the elderly are independent of sex.

Sex-related changes in the pharmacokinetics and pharmacodynamics (heart rate) of atropine were studied in female (n = 9) and male (n = 9) elderly patients after a single 0.02 mg/kg i.v. injection of the drug at the beginning of a combination anaesthesia. No significant differences were found between the sexes, which indicates that there are no sex-related alterations in the response to this anticholinergic agent.

Aged↗

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

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

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↗