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Biomedical subjects

T Kaila

Publications and source records attributed to T Kaila.

At least 55 records · Page 3Linked to original sources
PubMed1991

Systemic absorption of ocular timolol in poor and extensive metabolizers of debrisoquine.

The oxidation of timolol exhibits genetic polymorphism of debrisoquine type. After oral administration, poor metabolizers have high timolol concentrations in plasma and show an intensified systemic beta-blockade. Since the contribution of debrisoquine metabolizer status on timolol eyedrop therapy is not known we determined the systemic absorption of ocularly applied timolol in healthy subjects classified either extensive or poor metabolizers. Unlike after oral timolol ocular drug administration caused higher peak drug concentrations in plasma in extensive metabolizers. The variation in the systemic absorption of ocular timolol contributed more than the debrisoquine oxidation phenotype to timolol plasma levels after a single ocular timolol application.

Absorption↗
PubMed1991

Effects of glycopyrrolate and atropine on heart rate variability.

Analysis of heart rate variability, combined with physiological tests (deep breathing and tilt tests) was used to characterise the effects of atropine and glycopyrrolate on the parasympathetic nervous tone of the heart in healthy male volunteers. The low dose of atropine (120 micrograms) administered as a continuous infusion in 15 min was associated with parasympatomimetic effects estimated by the slowing of the heart rate and an increase of the mean and beat-to-beat heart rate variability. The bradycardia and increase of heart rate variability following infusion of glycopyrrolate (50 micrograms) was less marked and did not differ significantly from that of placebo. The higher doses of atropine (720 micrograms) and glycopyrrolate (300 micrograms) administered as a continuous infusion in 15 min produced an equal vagal cardiac blockade characterised by significant tachycardia and a decrease in overall and beat-to-beat heart rate variability. It is concluded that at low doses the parasympatomimetic action of glycopyrrolate is less marked than that of atropine; and at higher doses only small differences exist between these two muscarinic antagonists in their effects on cardiac vagal outflow, assessed by heart rate and heart rate variability.

Adult↗
PubMed1991

Pharmacokinetics and clinical response of hyoscine plus morphine premedication in connection with cardiopulmonary bypass surgery.

Plasma hyoscine and morphine levels and various pharmacodynamic responses have been examined in seven patients scheduled for a coronary-artery bypass graft. Hyoscine 0.006 mg kg-1 and morphine 0.20 mg kg-1 were administered intramuscularly as routine premedication. Surgery was performed using high-dose fentanyl anaesthesia (100 micrograms kg-1). The clinical responses followed were heart rate, blood pressure, subjective sedation and antisialogogue effect. The plasma hyoscine levels were determined by radioreceptor assay, and plasma morphine levels by liquid chromatography, both up to 24 h. The maximum levels of plasma hyoscine (6.6 micrograms l-1) and morphine (158 micrograms l-1) and the time they were reached (13.0 and 9.7 min, respectively) were comparable with the values obtained in earlier studies using young healthy subjects. After the start of cardiopulmonary bypass, significant decreases in plasma levels of both hyoscine and morphine were found. The elimination half-life of hyoscine in the plasma was 2.4 h, which is somewhat greater than obtained in earlier studies with young healthy patients under regional anaesthesia. Elimination of plasma morphine (t1/2el = 3.3 h) was not significantly altered by the procedure. The sedative and antisialogogue effects of the drugs appeared quickly and were significant, but no tachycardia or other side effects were observed. In conclusion, the kinetic properties of both hyoscine and morphine are suitable for routine use as premedicants before cardiac surgery.

Anesthesia, Intravenous↗
PubMed1990

Systemic absorption of ocular scopolamine in patients.

The systemic absorption of scopolamine 0.25% eyedrops given unilaterally was quantitated in eight patients following therapeutic drug application. Another set of eight patients received placebo drops to study the effect of scopolamine on heart rate, blood pressure and salivation. Scopolamine was rapidly and efficiently absorbed after its ocular administration. The peak plasma scopolamine concentration of 550 +/- 60 pg/ml was reached within 15 minutes in all but two patients. Ocular scopolamine did not affect patients blood pressure or heart rate when compared to patients in the placebo group. Thirty minutes after administration of scopolamine the salivary secretion was slightly but insignificantly reduced.

Absorption↗
PubMed1990

Pharmacokinetics of i.m. glycopyrronium.

A sensitive radioreceptor assay was used to determine the pharmacokinetics of glycopyrronium following a single i.m. injection of 8 micrograms kg-1 in nine surgical patients. Rapid absorption was found, with a mean peak plasma concentration after 16.1 min and mean elimination half-life of 75.4 min. Almost half (49.3%) of the drug was excreted in pharmacologically active form in the urine within 3 h. A significant increase in heart rate (P less than 0.05) occurred in 15 min, lasting up to 60 min, and an antisialagogue effect in 10 min, lasting up to 8 h (P less than 0.05). There was no measurable glycopyrronium in lumbar cerebrospinal fluid samples (n = 9) taken 40 min after administration of drug.

Blood Pressure↗
PubMed1990

Pharmacokinetics of glycopyrronium in parturients.

A sensitive radioreceptor assay was used to determine the pharmacokinetics of glycopyrronium 6 micrograms/kg after intramuscular (deltoid muscle) administration in eight Caesarean section patients. A fast absorption rate was found with a mean maximum plasma concentration (Cmax) of 6.3 (SD 1.5) ng/ml, a mean time to Cmax (Tmax) of 10.0 (3.8) minutes and the elimination half-life (t1) of 33.4 (1.92). The respective AUC0-8 h value was 5.61 (1.27) hours ng/ml. This dose produced a significant increase in the maternal heart rate after 10 minutes (p less than 0.05) and an antisialogogue effect after 30 minutes (p less than 0.05) of the drug injection. Almost half of drug (48.3%) was excreted into the urine within 3 hours. There were no measurable levels of glycopyrronium in the lumbar cerebrospinal fluid (CSF) after 60 minutes of drug injection. The concentrations of glycopyrronium in the umbilical venous (0.28 (0.25) ng/ml) and in the umbilical arterial (0.18 (0.11) ng/ml) plasma after 86 minutes of drug injection were low and clinically insignificant, as was the case in the amniotic fluid (0.15 (0.08) ng/ml).

Adult↗
PubMed1990

Radioreceptor assay for pharmacokinetic studies of glycopyrrolate.

A sensitive radioreceptor assay for the determination of glycopyrrolate concentrations in human plasma, urine and cerebrospinal fluid (CSF) is described. The applicability of the assay for kinetic studies in human was studied by determining the plasma concentrations and the renal excretion in three gynaecological surgical patients, who received 8 micrograms/kg of glycopyrrolate as a premedication intramuscularly. Tritiated N-methyl scopolamine was used to label the muscarinic cholinergic receptors in the membrane preparation obtained from the rat brain. The limit of detection of the assay was 70 ng/l in plasma, 2 micrograms/l in urine and 140 ng/l in CSF. There was no evidence of cross-reactivity of glycopyrrolate derivatives in clinical concentrations. A very rapid absorption was found with a mean maximum plasma concentration (Cmax) of 14.26 (range 12.02-16.97) micrograms/l and mean Tmax (time to Cmax) of 13.3 (range 10-15) min. and almost 50% of the dose administered was excreted into the urine within 3 hr. The CSF levels of glycopyrrolate were under detection limit. It is concluded that the sensitivity of the method is sufficient for pharmacokinetic studies of glycopyrrolate after therapeutic dosing.

Aged↗
PubMed1990

Vasomotor rhinitis and the systemic absorption of ipratropium bromide.

Plasma concentrations of nasally administered ipratropium bromide were analyzed in 10 subjects suffering from severe vasomotor rhinitis and 10 age-sex matched control subjects. The rate of salivary secretion and heart rate were monitored in order to measure systemic anticholinergic effects. A total dose of 360 micrograms of ipratropium bromide (60 micrograms into each nostril, repeated twice at 15 min intervals) were administered nasally to the subjects in randomized order. Ipratropium bromide was rapidly absorbed from the nasal mucosa into the systemic circulation in both groups. The peak plasma concentrations were detected within 10 min after the last drug administration. The peak concentrations were about 50% higher (380 +/- 153 pg/ml) in patients than in control subjects (245 +/- 134 pg/ml). The AUCs/0-15 min (1970 +/- 1140 pg/ml X min) in patients were about 100% higher than in the control subjects (960 +/- 560 pg/ml X min). During the experiment there was a small decrease in the heart rate (8 bpm) and salivary secretion (10%) in both groups. In conclusion, the vasomotor rhinitis increases the systemic absorption of nasally administered ipratropium bromide, but the small increase in the absorption is not likely to have any clinical consequences.

Administration, Intranasal↗
PubMed1990

Intramuscular atropine in healthy volunteers: a pharmacokinetic and pharmacodynamic study.

In a randomized, double-blind, placebo controlled crossover study, the pharmacokinetics and some clinically important pharmacodynamic effects of intramuscular atropine (dl-hyoscyamine) were studied in 6 healthy male volunteers. The plasma concentrations of l-hyoscyamine were analyzed by radioreceptor assay (RRA) and the plasma concentrations of dl-hyoscyamine by radioimmunoassay (RIA). The absorption rate and the elimination rate of dl-hyoscyamine and l-hyoscyamine were comparable (tmax = 8.40 vs 8.67 min, t1/2el = 2.95 vs 2.43 h, dose 0.02 mg/kg) but the mean maximum plasma concentration of dl-hyoscyamine was 2.9 times and the mean AUC value 6.0 times higher than that of l-hyoscyamine which indicates a kinetic difference between the enantiomers. The concentrations of d-hyoscyamine calculated from the dl- and l-hyoscyamine concentrations reached maximum between 1 and 2 h after drug injection. The renal excretion of l-hyoscyamine occurred mostly in 6 h (34% of the dose) and no conjugated drug forms were detected. The increase in heart rate was observed only after the higher dose (0.02 mg/kg) and it was significant between 30 min and 2 h. The plasma concentrations of l-hyoscyamine and the change in heart rate expressed as percentages showed a linear correlation: concentrations under 0.5 micrograms/l caused slowing of rate, higher concentrations caused acceleration. Also, the antisialagogue effect (30 min-3 h) correlated with plasma concentrations.

Adult↗
PubMed1990

beta-Glucuronide and sulfate conjugation of scopolamine and glycopyrrolate.

The metabolism of scopolamine and glycopyrrolate was studied in 11 healthy parturients undergoing cesarean section. After a single intramuscular injection of scopolamine (5 micrograms/kg, n = 7) or glycopyrrolate (6 micrograms/kg, n = 4), the concentrations of the drugs in the urine were determined up to 8-12 h using a radioreceptor assay. This assay measures scopolamine and glycopyrrolate with their possible active metabolites. The effect of beta-glucuronidase and sulfatase incubation on the drug concentrations was also studied. The concentrations of scopolamine and/or its active metabolites were on the average 7 times higher after incubation indicating that beta-glucuronide or sulfate conjugation is an important metabolic pathway for scopolamine. On the contrary, the glycopyrrolate concentrations increased only slightly between 1 and 3 hours after the drug injection. Thus, beta-glucuronide or sulfate conjugation plays only a minor part in the metabolism of glycopyrrolate.

Female↗
PubMed1989

Prevalence of debrisoquine oxidation phenotypes in glaucoma patients.

The oxidation of debrisoquine, a sympatholytic antihypertensive agent, exhibits genetic polymorphism. The debrisoquine/4-OH-debrisoquine metabolic ratio (MR) separates the population to poor (PM, MR greater than 12.6) and extensive (EM, MR less than 12.6) metabolizers. 5-10% of the caucasians belong to the PM phenotype. The oxidation of many other drugs, like timolol, correlates with the debrisoquine phenotype. We determined the debrisoquine phenotype in 102 glaucoma patients. The majority of the patients was treated with ophthalmic timolol. Five patients were classified as PMs. However, two of them were on quinidine, a well known inhibitor of debrisoquine oxidation. The prevalence of debrisoquine PM phenotype in glaucoma patients was 2.9% (excluding patients on quinidine) or 4.9% (with patients on quinidine). The figures are slightly lower than the mean value reported for the normal Finnish population. However, both figures lay within the 95% confidence limits of the prevalence of PM phenotype in the normal Finnish population. The beta-blocking activity of oral timolol is increased in PMs. The significance of timolol oxidation phenotype during ocular timolol therapy warrants further investigation.

Cross-Sectional Studies↗
PubMed1989

A comparison of two sedative premedications for minor oral surgery under local anaesthesia.

Two commonly used drug combinations were studied as premedications before surgical 3rd molar removal under local anaesthesia. The study was randomized, crossover and double-blind in 12 patients. Our routine premedication for lengthy operations, consisting of diazepam 10 mg p.o. plus i.m. scopolamine 0.006 mg/kg and morphine 0.2 mg/kg, was compared with a combination of diazepam 10 mg p.o. plus metoprolol 50 mg p.o. The latter combination was expected to cause fewer central nervous system side effects and be more suitable for out-patient surgery. Drug levels in blood, physiological and biochemical indicators of operation-related stress, CNS side effects, and the patients' subjective preferences were monitored. Both combinations were equally accepted by the patients, but the diazepam/scopolamine/morphine combination caused clearly more side effects after discharge than diazepam/metoprolol. The operation-related haemodynamic changes and plasma catecholamine responses were similar after both premedications.

Adult↗
PubMed1989

Pharmacokinetics of scopolamine during caesarean section: relationship between serum concentration and effect.

The pharmacokinetics (radioreceptor assay, RRA) and some of the clinical effects of the anticholinergic agent, scopolamine, were studied in 16 parturients during caesarean section. Following a single 0.005 mg/kg intramuscular injection (deltoid muscle), a very fast rate of absorption was found with mean peak serum concentrations occurring after only 10 min (n = 6). Due to severe bradycardia, 0.5 mg of atropine i.v. had to be given in addition to the i.m. scopolamine treatment to one parturient. The RRA measured the total concentration produced by the two anticholinergic agents in both serum and urine. There was a fundamental difference in the diffusion of scopolamine through the placenta and the blood-lumbar (CSF-barrier (n = 15). There was significant drug penetration in the foeto-placental unit, indicating an efficient drug transfer to the child, but there were measurable levels of the drug in the lumbar CSF in only three cases. The apparent elimination phase half-life of scopolamine in serum was only around 1 h. The urinary excretion of scopolamine and/or its antimuscarinic metabolites lasted only for 6 h (2.63 +/- 1.14% of the dose). The onset of the clinical effects of scopolamine appeared to be delayed, but long-lasting in contrast to the rapid absorption and quick disappearance from the serum. Both the heart rate changes, sedative and antisialogogue effects and serum concentrations did not show any correlation. There appears to be a surprisingly great difference between the pharmacokinetic parameters and the clinical effects of scopolamine.

Absorption↗
PubMed1989

Glycopyrrolate: pharmacokinetics and some pharmacodynamic findings.

In the present study, a sensitive and reproducible radioreceptor assay (RRA) was used to evaluate the basic pharmacokinetic properties of glycopyrrolate, a quaternary amine with peripheral antimuscarinic activity. Based on the plasma levels after a single intravenous injection, 6 micrograms/kg (n = 6), the distribution phase half-life (2.22 +/- 1.26 s.d. min) and the elimination phase half-life (0.83 +/- 0.29 h) of glycopyrrolate were short due to the low distribution volume during the elimination phase (0.64 +/- 0.29 l/kg) and to the respectively high total plasma clearance value (0.54 +/- 0.14 l/kg/h). An intramuscular injection, 8 micrograms/kg (n = 6), was followed by a fast and predictable systemic drug absorption and clinical effects (heart rate increase, dry mouth). In this group the time to maximum plasma concentration (tmax) was 27.48 +/- 6.12 min and the maximum plasma concentration (Cmax) was 3.47 +/- 1.48 micrograms/l. After oral drug intake, 4 mg (n = 6), an apparently low and variable gastrointestinal absorption was found (tmax = 300.0 +/- 197.2 min, Cmax = 0.76 +/- 0.35 microgram/l), thus indicating that the oral route of drug administration is of no value as a routine premedication. The correlation between the plasma concentration of glycopyrrolate and the drug effects appears to be variable. Because of its sensitivity, the RRA method proved to be quite useful in evaluating the kinetics of glycopyrrolate and its relationship to various clinical effects.

Absorption↗
PubMed1989

Decrease in the number of muscarinic receptors in rat pancreas after chronic alcohol intake.

The effect of eight months of alcohol intake on the number and affinity of muscarinic receptor sites in the rat pancreatic tissue were measured by using N-3H-methylscopolamine (NMS) as a radioligand. There were no differences in the receptor affinities for NMS between the alcohol-exposed and age-matched control animals, but the number of muscarinic receptor sites was 60 percent lower in the alcoholic animals. The present experimental model is consistent with altered food and water intake as consequences of chronic alcoholism and thus changes in food and water consumption may participate in mediating the effects of chronic alcohol intake on NMS binding sites. We suggest that the previously reported marked alcohol-induced increase in pancreatic acetylcholine levels, which has been proposed to play a crucial role in the pathogenesis of acute alcoholic pancreatitis, may be a secondary phenomenon induced by increased resistance at the muscarinic receptor level.

Animals↗
PubMed1989

Prostaglandin F2 alpha binding to bovine ocular and synthetic melanins in vitro.

The binding of 3H-prostaglandin F2 alpha to bovine iris and synthetic melanin was studied in vitro using a ligand binding assay. Prostaglandin F2 alpha was reversibly bound to both types of melanin. The binding was saturable and the Scatchard analysis revealed the existence of at least two binding sites with the corresponding K(D) values of 3.71 nM and 1.99 microM for natural and 4.99 nM and 0.19 microM for synthetic melanin, respectively. The high affinity Bmax values were 3.4 nM/g for natural and 2.5 nM/g for synthetic melanin. The dissociation of prostaglandin F2 alpha from melanin after dilution of the complex was rapid and uniform.

Animals↗
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↗