Biomedical subjects

T Kaila

Publications and source records attributed to T Kaila.

At least 37 records · Page 2Linked to original sources

PubMed1994

Alcohol, pancreatic muscarinic receptors and acute pancreatitis.

Recently, a new theory about the pathogenesis of acute alcoholic pancreatitis was proposed. The aim of the present work was to further study the basis of this cholinergic theory about the pathogenesis of acute alcoholic pancreatitis. The results indicated that already a short-term alcohol consumption induces in some rats a dramatic decrease in the number of pancreatic muscarinic receptors. This decrease may predispose to acute alcoholic pancreatitis by increasing the cholinergic tone, since excessive cholinergic tone invariably leads to acute pancreatitis both in experimental animals and in man. Thus, the pathogenetic mechanism triggering acute alcoholic pancreatitis might be similar to the mechanism triggering acute pancreatitis caused by the scorpion sting, intoxication with an antiacetylcholine-esterase-containing insecticides or after excessive cholinergic stimulation.

Alcoholism↗

PubMed1994

Controlled ocular timolol delivery: systemic absorption and intraocular pressure effects in humans.

Timolol eyedrops may cause systemic side-effects in glaucoma patients due to absorption of the drug into systemic circulation. In a previous study, timolol concentrations in plasma were reduced if timolol was administered in ocular inserts instead of eyedrops. We compared the intraocular pressure lowering effect and systemic absorption of timolol inserts to those of 0.5% timolol eyedrops in humans. Inserts of silicone tubing released 90.3 +/- 13.9 micrograms of timolol in 24 hours in vivo. Timolol inserts afforded similar decreases in intraocular pressure in open-angle glaucoma patients as did b.i.d. eyedrops, but produced lower peak timolol concentrations in plasma, 0.70 +/- 0.10 ng/ml and 0.24 +/- 0.05 ng/ml, respectively. After eyedrops, peak concentrations were achieved at 15.0 +/- 2.2 min, while application of an insert resulted in a delayed peak (tmax = 623 +/- 195 min). The insert resulted in a higher systemically absorbed fraction of the timolol dose than the eyedrop, but the peak timolol concentration and daily absorbed amount of timolol were decreased. The release rate of timolol from the inserts in vivo was only slightly less than that in vitro. Silicone devices are useful for clinical testing of controlled delivery properties of ocular drugs.

Absorption↗

PubMed1994

Systemic absorption and anticholinergic activity of topically applied tropicamide.

We studied the plasma levels and systemic anticholinergic activity of tropicamide after ocular administration in eight women. Two 40 microliters drops of 0.5% tropicamide were instilled into the lower cul-de-sac of one eye of the subjects and concentrations and respective muscarinic receptor occupancy of tropicamide in plasma were monitored using radioligand binding techniques. Tropicamide was rapidly absorbed systemically with the mean peak concentration in plasma being 2.8 +/- 1.7 ng/ml (mean +/- SD) at five minutes after instillation. Tropicamide disappeared rapidly from the systemic circulation: drug concentration in plasma was 0.46 +/- 0.51 ng/ml (mean +/- SD) at 60 minutes and below 240 pg/ml at 120 minutes after instillation. Tropicamide bound to muscarinic receptors of rat brain with an apparent equilibrium binding constant (Ki-value in plasma) 220 +/- 25 nM (mean +/- SD, n = 3). Tropicamide occupied maximally 8% of muscarinic receptors in plasma after ocular application. The low affinity of tropicamide for muscarinic receptors and its negligible receptor occupancy in plasma can explain the low incidence of systemic side-effects of tropicamide eyedrops.

Absorption↗

PubMed1994

Acute exercise- and drug-induced potassium shifts during pregnancy.

The exercise- and drug-induced potassium shifts in pregnant women was studied. Six healthy nonpregnant women, six healthy pregnant women and four hypertensive, pregnant women on labetalol performed a bicycle exercise test. Blood samples for plasma potassium concentrations were drawn before, during and after the exercise. The exercise-induced plasma potassium increase was 0.9 +/- 0.2 mmol/l in healthy control women and 0.8 +/- 0.1 mmol/l in healthy pregnant women. In hypertensive pregnant women on labetalol the increase was 0.3 +/- 0.3 mmol/l (P < 0.01). There was a negative correlation (r = 0.941, P = 0.05) between the plasma potassium and labetalol concentration. Our results suggest that the potassium exchange during normal pregnancy is not changed. Labetalol reduced the exercise-induced plasma potassium increase which contrasts to other beta-blocking agents which usually augment the plasma potassium increase caused by exercise.

Adult↗

PubMed1993

Selectivity of acebutolol, atenolol, and metoprolol in healthy volunteers estimated by the extent the drugs occupy beta 2-receptors in the circulating plasma.

The selectivity of acebutolol, atenolol, and metoprolol in healthy volunteers was estimated by determining the extent to which the drugs occupied beta 1-receptors of rabbit lung and beta 2-receptors of rat reticulocytes in the circulating plasma after drug intake. This ex vivo method had the advantage of including all drug components contributing to the drug-receptor equilibrium in vivo and of excluding the factors regulating organ sensitivity to catecholamine stimulation. The oral doses of 400 mg acebutolol, 100 mg atenolol, and 100 mg metoprolol were administered to six healthy male volunteers using a double-blind, randomized, and cross-over study design. The three drugs occupied beta 1-receptors to a similar extent at 2 hours after drug intake. The receptor fraction occupied by metoprolol at 3 to 8 hours after drug intake was usually smaller, however (analysis of variance for repeated measures, P < .05) than that of the other drugs. Acebutolol occupied significantly larger fractions of beta 2-receptors (analysis of variance for repeated measures, P < .05) than did atenolol and metoprolol. Therefore, at an identical beta 1-receptor occupancy, the beta 2-receptor occupancy of acebutolol was larger than that of the other agents. Apparently, active metabolites decreased markedly the selectivity of acebutolol, but not that of metoprolol. The receptor occupancy of the agents was well in agreement with the literature concerning the selectivity, intensity, and time-course of drug actions after identical doses.(ABSTRACT TRUNCATED AT 250 WORDS)

Acebutolol↗

PubMed1993

Extent of beta 1- and beta 2-receptor occupancy in plasma assesses the antagonist activity of metoprolol, pindolol, and propranolol in the elderly.

We estimated antagonist activity of metoprolol, pindolol, and propranolol in elderly cardiovascular patients by determining the extent to which the drugs occupied rabbit lung beta 1- and rat reticulocyte beta 2-adrenoceptors in plasma samples during drug treatment. The randomized, double-blind, crossover study was carried out by administering twice daily 100 mg metoprolol, 5 mg pindolol, and 80 mg propranolol for 7 days to 20 hypertensive subjects with a mean age of about 70 years. A 2-week interval was kept between administration of the different regimens. Receptor occupancy was measured at 1 hour before and 2 hours after administration of the last dose of each regimen by adding rabbit lung beta 1- and rat reticulocyte beta 2-receptors to plasma samples and by labeling the receptors with a radiolabeled beta-antagonist, (-)-[3H]CGP-12177. The results and conclusions were the following: (a) The extent to which metoprolol, pindolol, and propranolol occupied rabbit lung beta 1- and rat reticulocyte beta 2-adrenoceptors in plasma samples estimated accurately the intensity of beta-receptor antagonism in the patients who did not tolerate physiological and pharmacological tests measuring the degree of beta 1- and beta 2-adrenoceptor blockade. (b) The mean beta 1- and beta 2-receptor occupancy of pindolol and propranolol varied between 76% and 99% during the treatments. The mean beta 1-receptor occupancy of the metoprolol regimen varied between 54% and 92%, and its beta 2-receptor occupancy varied between 6% and 38%. Thus the antagonist activity of the metoprolol regimen differed significantly from that of the other regimens (ANOVA for repeated measures, p < 0.05 and 0.001, for the beta 1- and beta 2-occupancy, respectively). (c) The extent of beta 1- and beta 2-receptor occupancy in plasma samples was in conformity with the literature on the intensity, selectivity, and duration of beta-blockade after similar drug doses. (d) The data on the receptor occupancy of beta-blocking drugs in plasma samples appear to be valuable in analyzing their effects, and it may be a method for optimizing drug therapy for aged cardiovascular patients.

Adrenergic beta-Antagonists↗

PubMed1993

Pharmacokinetics of glycopyrronium in uraemic patients.

We studied the pharmacokinetics of glycopyrronium in 11 uraemic patients undergoing cadaveric renal transplantation and in seven ASA I control patients undergoing general surgery. Glycopyrronium 4 micrograms kg-1 was given i.v. before induction of anaesthesia. Blood and urine samples were collected for up to 24 h for measurement of glycopyrronium concentrations using a radioreceptor assay. Volume of distribution in the elimination phase (V beta) was similar in both groups, the elimination half-life (T1/2 beta) was longer (P < 0.05), area under the plasma concentration-time curve (AUC) larger (P < 0.01) and plasma clearance (CI) smaller (P < 0.01) in the uraemic patients. In 3 h, mean 0.7 (range 0-3)% and 50 (21-82)% of glycopyrronium was excreted in the urine in the uraemic and healthy patients, respectively (P < 0.001). The 24-h renal excretion was 7 (0-25)% in uraemic and 65 (30-99)% in control patients (P < 0.001). We conclude that the elimination of glycopyrronium is severely impaired in uraemic patients.

Glycopyrrolate↗

PubMed1993

Plasma concentrations and ocular effects of cyclopentolate after ocular application of three formulations.

1. Eight volunteers received in randomized order two 30 microliters drops of either 1% w/v cyclopentolate hydrochloride or a corresponding amount of cyclopentolate polygalacturonate in saline or in acetate buffer in one eye. Cyclopentolate concentrations in plasma were measured by a radioreceptor assay. 2. Peak plasma drug concentrations of about 3 ng ml-1 occurred within 30 min after all formulations. Occasionally, a second concentration peak in plasma, probably reflecting drug absorption from the gastrointestinal tract, was seen after 2 h. The mean elimination half-life of cyclopentolate was 111 min when all subjects and formulations were considered together. There were no statistically significant differences between the formulations with respect to the time-course of plasma drug concentration. 3. The maximal mydriatic effect was reached within about 15 min and was maintained for several hours, often being 1/3 of its peak value after 30 h. Similarly, an intense cycloplegic response was achieved within a few minutes, the peak changes in the near-point of vision being 9 to 10 dioptres. The cycloplegic response was more intense after one of the polygalacturonate complexes, especially at later time points.

Adult↗

PubMed1993

Receptor occupancy in lumbar CSF as a measure of the antagonist activity of atenolol, metoprolol and propranolol in the CNS.

1. The antagonist activity of atenolol, metoprolol and propranolol in the CNS was estimated by determining the extent to which the drugs occupy animal beta 1- and beta 2-receptors in CSF ex vivo at the time of lumbar puncture. 2. Five CSF and plasma samples were obtained 4 h after drug intake from subjects treated for hypertension with atenolol, 100 mg once daily and five from subjects treated with metoprolol, 50 mg three times daily. Twenty-four samples were obtained 1, 2, 4 or 12 h after drug intake from subjects receiving a single 40 mg dose of propranolol. 3. The receptor occupancy in the samples was determined by adding beta 1-receptors of rabbit lung and beta 2-receptors of rat reticulocytes into the samples and labeling the receptors with a nonselective beta-adrenoceptor antagonist, (-)-[3H]-CGP-12177. 4. Atenolol and metoprolol occupied, as expected, larger fractions of beta 1- than beta 2-receptors in CSF and plasma samples. The receptor fraction occupied by atenolol in CSF was significantly (P < 0.05) lower than that occupied by metoprolol. The differences in occupancy between the drugs in plasma, however, were not statistically significant. 5. Propranolol occupied larger fractions of beta 2- than beta 1-receptors in the samples. Although propranolol concentrations in CSF were only 1/20-1/40 of those in plasma, the receptor occupancy of propranolol in CSF was similar to that in plasma.(ABSTRACT TRUNCATED AT 250 WORDS)

Adrenergic alpha-Antagonists↗

PubMed1993

Absorption of ocular timolol: drug concentrations and beta-receptor binding activity in the aqueous humour of the treated and contralateral eye.

We studied the ocular and systemic absorption of 40 microliters of topical 0.5% timolol in 57 patients using radioligand binding techniques. The mean concentration of timolol in aqueous humour of the treated eye was 1.9 +/- 0.8 micrograms/ml 74 minutes after instillation of the drug. About 18 h after drug instillation the aqueous humour concentration of timolol was 105.5 +/- 60.9 ng/ml. Timolol was found in 15 (42%) contralateral eyes. Concentration of timolol in the contralateral eye increased from 0.04 +/- 0.08 ng/ml at 50 min to 0.3 +/- 0.2 ng/ml at 134 min and was 0.2 +/- 0.4 ng/ml at 18 h after instillation. Timolol concentrations in the aqueous humour of the treated eye appeared to be high enough to occupy beta 1- and beta 2-receptors completely (100%) at 74 min and at 18 h after drug instillation. Timolol concentrations in the contralateral eye were high enough to occupy up to 33.0 +/- 24.7% of the beta 2-receptors and up to 51.7 +/- 35.1% of beta 2-receptors. High drug concentrations and complete beta-receptor occupancy in the aqueous humour of the treated eye after topical timolol are in agreement with the long-lasting ocular hypotensive effects. The low drug concentrations and partial receptor occupancy in the contralateral eye may also be of some clinical significance.

Absorption↗

PubMed1993

Concentrations and antagonist activity of topically applied betaxolol in aqueous humour.

Aqueous humour concentrations and antagonist activity of betaxolol were studied after ocular administration in forty-five patients scheduled for cataract surgery. The patients were randomly divided into five groups and received 40 microliters of 0.5% betaxolol into the lower cul-de-sac of one eye. In groups I, II, III and IV the drug was instilled 5-6, 12, 24 and 48 h, respectively, before surgery, into the eye to be operated, and in group V 4 h before surgery into the contralateral eye. Aqueous humour samples were aspirated at the beginning of the operation. Aqueous humour concentrations of betaxolol were analyzed using a radioreceptor assay, and the ex-vivo-beta 1- and beta 2-receptor occupancies of betaxolol were calculated. The highest concentration of betaxolol in aqueous humour was found 5-6 hours after instillation of the drug. Topical betaxolol was found to stay in aqueous humour for 48 h, a much longer time than the recommended interval of dosage. Betaxolol beta 1-receptor occupancy was 99-95% during the study, but also beta 2-receptor occupancy was significant (52%) 24 h after instillation of the drug. Because receptor occupancy is the basis of antagonist activity, the role of beta 2-receptor blocking effect of betaxolol in lowering intraocular pressure cannot be excluded.

Absorption↗

PubMed1993

Beta 1- and beta 2-antagonist activity of topically applied betaxolol and timolol in the systemic circulation.

The beta 1- and beta 2-antagonist activity of betaxolol and timolol in the systemic circulation was studied ex-vivo after their ocular administration in thirty patients during cataract surgery. The patients received 40 microliters of 0.5% betaxolol or 0.25% timolol into the lower cul-de-sacs of both eyes. Blood samples were collected up to four h after instillation of the doses. Plasma concentrations of betaxolol and timolol were analyzed using a radioreceptor assay. The ex-vivo-beta 1-and beta 2-receptor occupancies corresponding drug plasma levels were calculated using radioligand binding techniques. The extent of beta 1-receptor occupancy of betaxolol in the systemic circulation was less than 20% and its beta 2-receptor occupancy was negligible. The extent of beta 1-receptor occupancy of timolol was about 65% and its beta 2-receptor occupancy about 80%. Because receptor occupancy is the basis of antagonist activity of beta-blocking agents, this study shows that the beta 1-antagonist activity of betaxolol in the systemic circulation is much less than that of timolol, and that its beta 2-antagonist activity is negligible. The study suggests that the reported side effects of betaxolol in patients with obstructive pulmonary diseases are not mediated via its beta 2-receptor blocking properties.

Administration, Topical↗

PubMed1993

Plasma and aqueous humour concentrations and systemic effects of topical betaxolol and timolol in man.

Plasma and aqueous humour concentrations and systemic effects of timolol and betaxolol were studied after ocular administration in 45 patients scheduled for extracapsular cataract extraction and intraocular lens implantation. The patients were divided randomly into three groups and received 40 microliters of either 0.5% betaxolol, 0.25% timolol or placebo into the lower cul-de-sacs of both eyes. Blood samples were collected over a period of 4 h and blood pressure and heart rate were monitored during the study. Aqueous humour samples were aspirated at the beginning of the operation. Plasma and aqueous humour concentrations of timolol and betaxolol were analyzed using a sensitive radioreceptor assay. The mean plasma concentrations of betaxolol were lower than those of timolol. The concentration of betaxolol in the aqueous humour was twice as high as the concentration of timolol. Both drugs produced a significant decrease in heart rate. In the timolol group a decrease in heart rate was found 15 min after drug administration, and in the betaxolol group after one hour.

Absorption↗

PubMed1993

The analysis of plasma kinetics and beta-receptor binding and -blocking activity of timolol following its small intravenous dose.

Plasma kinetics and beta-receptor blocking and -binding activity of timolol was studied in six healthy volunteers following its intravenous 0.25 mg dose. Timolol concentrations were measured using radioreceptor assay (RRA), blocking activity by comparing the dose ratios (DRs) of the infusion rates of isoprenaline required to increase heart rate by 25 bpm (I25) and binding activity by determining the extent to which timolol occupied beta 1-receptors of rabbit lung and beta 2-receptors of rat reticulocytes in undiluted plasma samples. Timolol was eliminated from plasma with a mean half-life for the elimination phase of 2.6 hours. The dose antagonized potently isoprenaline-induced tachycardia at least for four hours. The effect was excellently correlated with the estimated beta 2-receptor binding activity of timolol in the circulating plasma. In conclusion, the small intravenous timolol dose was eliminated from plasma by a fashion, which was very similar to its eighty-fold higher oral doses reported earlier in the literature. The 0.25 mg dose was of considerable systemic beta-receptor blocking and -binding activity, that may help to explain its reported side-effects following ocular drug administration. The extent to which beta-blocking agents occupy rabbit lung beta 1- and rat reticulocyte beta 2-receptors in the circulation appears to predict the intensity and selectivity of their beta-blocking effects in healthy volunteers.

Adrenergic beta-Antagonists↗

PubMed1992

The effect of some macromolecular ionic complexes on the pharmacokinetics and -dynamics of ocular cyclopentolate in rabbits.

The effect of mucoadhesive polymeric vehicles on the mydriatic efficacy, and on the systemic and ocular absorption of cyclopentolate from eyedrops was studied in albino rabbits. Combining cyclopentolate base to polygalacturonic (CY-PGA) or hyaluronic (CY-HA) acid resulted in an increased mydriatic effect when compared with cyclopentolate hydrochloride (CY-HCl). During the first half an hour, the systemic absorption of cyclopentolate was lower after CY-PGA than after CY-HCl. The ocular penetration of cyclopentolate, based on drug concentrations in aqueous humor 30 minutes after the eyedrop instillation, was increased 3 fold when the polygalacturonate complex was used. CY-PGA, as well as other polymeric salts, might offer a possibility to increase the therapeutic index of cyclopentolate.

Absorption↗

PubMed1992

Systemic absorption of ocular cyclopentolate in children.

Cyclopentolate plasma levels were quantitated and heart rate and pupil size were monitored after ocular application of the drug to juveniles. In all, 12 children were given one 35-microliters eyedrop of either 1% cyclopentolate (n = 6) or placebo (n = 6) in randomized order in the lower cul-de-sac of one eye. A sensitive radioreceptor assay was used to determine the systemic drug absorption. With the exception of one child, detectable cyclopentolate concentrations were seen in plasma at as early as 3 min after the ocular drug application. There was a marked interindividual variation in peak plasma cyclopentolate concentrations ranging from undetectably low to 5.8 ng/ml (median, 2.9 ng/ml). In some children a second drug concentration peak was detected. Cyclopentolate increased the pupillary diameter from 4.8 +/- 1 mm before drug application to 8 +/- 0.9 mm at 30 min after administration, but the children's heart rate did not alter.

Absorption↗

PubMed1991

A sensitive radioligand binding assay for timolol in plasma.

A sensitive and reproducible radioreceptor assay (RRA) is described for the determination of low picogram levels of timolol in plasma. The plasma or serum samples (1 mL) are prepared by selectively extracting timolol with lipophilic solvents or, alternatively, only plasma (serum) proteins are precipitated prior to binding assay. The recovery of timolol is at least 90% during the sample preparation. In the radioligand binding assay, timolol and the nonselective beta-antagonist [3H](-)-CGP-12177 compete for the binding sites present in the rat reticulocyte membranes. The detection limit for timolol (30 pg/mL) exceeds 50 times the sensitivity of the GC-MS techniques for timolol. The RRA results and GC results obtained from the same clinical samples correlate excellently (r = 0.99). There was no evidence for interference caused by timolol metabolites in the RRA. Timolol concentrations in plasma following its oral and even ocular administration were possible to monitor using the RRA. The method can be modified to also measure several other beta-antagonist drugs in picogram per milliliter quantities.

Adrenergic beta-Antagonists↗

PubMed1991

Beta-blocking effects of timolol at low plasma concentrations.

The concentration-effect relationship of 0.25 mg intravenous timolol with and without pretreatment with 100 mg quinidine was studied in six healthy young volunteers with a randomized, double-blind, crossover study design. Blockade of cardiac beta-adrenoceptors was assessed by determining the dose ratios (DR) of isoproterenol infusions required to increase heart rate by 25 beats/min before and after timolol infusion. The logarithm of timolol concentration in plasma was linearly related to the logarithm (DR-1) of isoproterenol infusion, with a mean Pearson correlation coefficient of 0.89 +/- 0.11 (+/- SD; n = 24) at timolol concentrations well below 1 ng/ml. The increases in cyclic adenosine monophosphate (cAMP) and norepinephrine plasma levels caused by isoproterenol infusions were attenuated after timolol. Quinidine administration increased timolol plasma levels and cardiac beta-blocking effects by 10% to 40%. It was concluded that timolol at concentrations below 1 ng/ml in plasma competitively antagonizes cardiac and noncardiac effects of isoproterenol infusions. Timolol effects are augmented after quinidine administration. The beta-blockade occurring at low plasma levels can explain side effects and actions of ocularly applied timolol.

Adult↗