Biomedical subjects

T Kaila

Publications and source records attributed to T Kaila.

67 records · Page 4Linked to original sources

PubMed1989

Beta-adrenoceptor antagonist activities and binding affinities of timolol enantiomers in rat atria.

S-Timolol is an effective anti-glaucoma drug, but has potentially hazardous side effects. Recently, R-timolol, also, has been reported to be effective in lowering elevated intraocular pressure. In the present study, the beta-adrenoceptor antagonist activities and binding of R- and S-enantiomers of timolol have been examined on rat atrial preparations. The beta-antagonistic activities were investigated using spontaneously beating rat heart atria. Both timolol enantiomers inhibited (-)-isoprenaline-induced chronotropic action competitively. S-Timolol was about 54 times more potent than R-timolol. The apparent binding affinities of timolol enantiomers to beta 1- and beta 2-adrenoceptors were determined by a radioligand binding assay using (-)-[125I]iodocyanopindolol (ICYP) as a marker and CGP 20712 A as a beta 1- and ICI 118,551 as a beta 2-adrenoceptor antagonist. Both enantiomers of timolol inhibited ICYP binding in nanomolar concentrations with Hill coefficients near unity. Neither enantiomer showed selectivity between beta 1- and beta 2-adrenoceptors, but R-timolol was approximately 30 times less active than S-timolol. It is concluded that R-timolol is a relatively potent non-selective beta-adrenoceptor blocking agent, but may possibly exert a more localized beta-adrenoceptor action in the eye than S-timolol, thus improving the safety of ocular timolol therapy.

Adrenergic beta-Antagonists↗

PubMed1988

Systemic absorption of topically applied ocular atropine.

We quantitated atropine plasma levels and monitored blood pressure, heart rate, and salivary secretion after ocular application. Eight patients received 40 microliters 1% atropine in the lower cul-de-sac of one eye in connection with ocular surgery. Atropine plasma levels were determined for 90 minutes by radioreceptor assay. The peak plasma atropine concentration of 860 +/- 402 pg/ml was reached within 8 minutes in all patients. The ocular absorption of atropine was at least as rapid as that reported for intramuscular administration. Ocular atropine did not affect patients' blood pressure or heart rate when compared with those of the placebo group. Thirty minutes after administration of atropine eyedrops, the salivary secretion in the experimental group was reduced, but was statistically insignificant from the placebo group.

Adult↗

PubMed1988

Timolol binding to bovine ocular melanin in vitro.

The binding characteristics of 3H-timolol to bovine iris melanin were determined by using a ligand binding assay. The association and dissociation kinetics were performed using 100 nM 3H-timolol and 0.5 mg/ml melanin at 37 degrees C. The effects of pH, ethanol, 2.5 microM isoxuprine and 1 microM d- and 1-propranolol on 100 nM 3H-timolol binding were also determined. In saturation experiments 3H-timolol (from 1.25 nM to 5 microM) was equilibrated with 0.5 mg/ml melanin. The binding was saturable with the binding maximum of about 1 microM timolol/g melanin. The binding of 100 nM 3H-timolol to melanin increased up to 5 hours and amounted 24% of the added radioactivity. The best fit of the association constants was obtained by using a two fit model. The association rate constants were 4.92 x 10(5) M-1 min-1 and 5.95 x 10(6) M-1 min-1. The dissociation was rapid in vitro and uniphasic with a dissociation rate constant of 5.08 x 10(-3) min-1. The pH, ethanol and both enantiomers of propranolol did not appreciably alter the timolol binding, while isoxuprine diminished it.

Animals↗

PubMed1988

Effects of a beta-blocking agent, timolol maleate, on saliva in healthy volunteers.

The effects of timolol maleate on the secretion and composition of human saliva were studied in vivo. Eight healthy volunteers received orally 10 mg timolol maleate. Stimulated parotid saliva samples, resting whole saliva samples, and blood samples were collected immediately before and four times after the drug intake at intervals of 1 h. The levels of total protein, lysozyme, IgA, IgG and IgM, salivary peroxidase, myeloperoxidase, lactoferrin, amylase, thiocyanate (SCN-), and hypothiocyanite (OSCN-) were analyzed from saliva samples. Drug levels were measured both from parotid saliva and blood samples. Results were compared to the analyses of the samples collected in a similar way but without administration of any drugs. Decreased levels of total protein, lactoferrin, amylase, and salivary peroxidase were observed in parotid saliva after a single oral dose of timolol maleate. No such decrease was found in lysozyme, myeloperoxidase, SCN-, OSCN-, or immunoglobulins. Salivary flow rate was not significantly changed after drug intake. The results suggest that the beta-blocking drug may cause qualitative changes in the composition of saliva by inhibiting the synthesis and/or release of acinar proteins.

Amylases↗

PubMed1988

Cultured neurofibromatosis tumor fibroblasts lack beta-adrenergic receptors.

Beta-adrenergic receptors on cultured neurofibromatosis (NF) skin and tumor fibroblasts were characterized by a radioligand binding assay using (-)-125I-iodocyanopindolol (ICYP), a potent beta-antagonist. NF tumor fibroblasts had a very low density of beta-adrenergic receptors (0-450 binding sites/cell) when compared to fibroblasts obtained from a healthy skin area of NF patients or from healthy controls (average 1,800 binding sites/cell). The apparently low binding of ICYP to the NF tumor fibroblasts can be an expression of an alteration in the structure or function of the plasma membrane.

Fibroblasts↗

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

Radioreceptor assay of anticholinergic drugs.

The radioreceptor assay (RRA) of anticholinergic drugs in plasma and other biological fluids presents methodological difficulties. The specificity is not comparable with some pure chemical methods because drug metabolites which are active in binding to muscarinic receptors participate in the assay. There are also problems with serum dilution, with the lipophilicity of the radioligands and drugs, and with the protein binding of the drugs. However, the RRA of anticholinergic drugs is rapid and sensitive. In racemic drugs, only active stereoisomers show affinity for the muscarinic receptors. Results with RRA have been shown to correlate with anticholinergic effects, both desired and side effects. A careful familiarization with the method used for each individual drug analysis allows its useful clinical application.

Animals↗

PubMed1987

The pharmacokinetics of ocularly applied timolol in rabbits.

[3H]timolol derived radioactivity and beta-antagonistic activity in the aqueous humour, iris, ciliary body and blood in rabbits were analyzed by liquid scintillation counting (LSC) and radioreceptor assay (RRA) after ocular timolol. After ocular application of tracer labelled timolol, the radioactivity decreased slowly in the iris (Kel = 0.05 h-1) and ciliary body (Kel = 0.02 h-1). In the aqueous humour the elimination rate was faster (Kel = 0.57 h-1). The beta-antagonistic activities of the aqueous humour and plasma decreased rapidly when compared to LSC values. The ethanol extractable pool of the beta-antagonistic activity from the iris and ciliary body was only a few percent of the corresponding LSC estimates. The kinetics of beta-antagonistic activity extractable from iris and ciliary body was identical with that in the aqueous humour. Timolol concentrations in the untreated rabbit eye were sufficiently high to lower the intraocular pressure.

Animals↗

PubMed1987

The effect of a short-term ritodrine treatment on the concentration of beta-adrenergic receptors in human myometrium.

The concentration of beta-adrenoceptors in human myometrium has been studied of women giving birth by elective cesarean section at term. Eight of the woman were treated with intravenous ritodrine two hours prior to the operation. In the control group seven women received physiological saline with the same infusion rate as ritodrine in the study group. The concentration of beta-receptors in the myometrium of the lower uterine segment was determined with radioligand binding assay. Ritodrine treatment decreased the available beta-receptors significantly.

Female↗

PubMed1986

Effects of eyelid closure and nasolacrimal duct occlusion on the systemic absorption of ocular timolol in human subjects.

Eyelid closure and nasolacrimal occlusion may decrease the systemic absorption of topically applied drugs. We studied the absorption kinetics of 20 microliter 0.5% timolol eyedrops in eight healthy volunteers. Each subject was supine for 30 minutes after the drug application. In randomized order, the volunteers kept their eyelids closed (ELC), or applied nasolacrimal occlusion (NLO) or blinked normally. Blood samples were drawn up to 90 minutes and analyzed for timolol with a radioreceptor assay. There was great interindividual variation in the timolol absorption. NLO reduced the total timolol absorption, but in some subjects the initial absorption was also enhanced by this procedure.

Absorption↗

PubMed1985

Systemic absorption of topically applied ocular timolol.

Symptoms and findings arising from the systemic beta blockade caused by topical ocularly applied timolol appear shortly after drug application. We studied the systemic absorption of 20 microliters of 0.5% timolol instilled unilaterally in the lower conjunctival cul-de-sac in 6 volunteers. At 3 min one subject, at 5 min three and at 8 min all but one showed measurable (greater than or equal to 215 pg/ml) timolol concentrations in the plasma. The rapid systemic absorption of topically applied ocular timolol observed in our study is consistent with the rapid appearance of the cardiovascular and pulmonary side effects reported in connection with timolol eye drop therapy.

Adult↗

PubMedDate not supplied

Kinetics of propiverine as assessed by radioreceptor assay in poor and extensive metabolizers of debrisoquine.

A pharmacokinetic study with 30 mg propiverine p.o. was performed in healthy volunteers (10 males, 6 females, age 36-56 years, body weight 55-100 kg, body height 162-184 cm, Broca index 0.96-1.19). 8 of them were poor and 8 extensive metabolizers of the debrisoquine type hydroxylation polymorphism. The total anticholinergic activity of the parent compound and active metabolites was measured with a radioreceptor assay calibrated with the metabolite M2. The affinity of this metabolite to the muscarinic receptors was similar to that of atropine. The urinary excretion of 3 major metabolites was determined with TLC and densitometry. Arterial blood pressure, heart rate, diameter of pupils, accommodation and parotic salivary flow were also measured. The concentrations of anticholinergic equivalents of propiverine were below 1 ng/ml of M2. 1.4-6.0% of the dose were excreted as N-oxidized metabolites into the urine. The poor and extensive metabolizers of debrisoquine did not differ significantly with regard to the concentration time behaviour of the active drug components, pattern of major metabolites, adverse drug reactions or any pharmacodynamic parameters measured.

Adult↗

PubMedDate not supplied

Pharmacokinetics of glycopyrrolate in children.

STUDY OBJECTIVE: To investigate the pharmacokinetics of glycopyrrolate in children. DESIGN: Open study with three parallel groups. SETTING: Pediatric surgery department at a university hospital. PATIENTS: 26 healthy ASA physical status I children undergoing minor surgery. INTERVENTIONS: Patients were assigned to 1 of 3 groups: under 1 year of age (Group 1, n = 8), between 1 and 3 years of age (Group 2, n = 7), and over 3 years of age (Group 3, n = 11). Glycopyrrolate 5 micrograms/kg was given as a single intravenous (i.v.) injection before induction of general anesthesia. Blood samples (for determination of drug concentrations in plasma) were collected via venous cannula inserted into the contralateral antecubital vein. MEASUREMENTS AND MAIN RESULTS: ECG was observed continuously, blood pressure was measured with an automatic noninvasive device, and blood samples were taken just before and at 2, 4, 6, 10, 15, 30, 60, 120, 180, 240, 360, and 480 minutes after injection of glycopyrrolate. Glycopyrrolate concentrations in plasma were determined with a radioreceptor assay. The only significant difference in the pharmacokinetic parameters was the shortened elimination half-life in patients between 1 and 3 years of age. Glycopyrrolate 5 micrograms/kg i.v. did not cause any significant alterations in heart rate. CONCLUSIONS: There were no significant changes in the distribution volume or clearance of glycopyrrolate in children of different ages. The shortened elimination half-life in children between 1 and 3 years of age is of minor clinical importance.

Anesthesia, Intravenous↗