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Biomedical subjects

A Urtti

Publications and source records attributed to A Urtti.

88 records · Page 5Linked to original sources
PubMed1990

Effects of epinephrine pretreatment and solution pH on ocular and systemic absorption of ocularly applied timolol in rabbits.

The ratio between ocular and systemic drug concentrations describes the relative safety of ophthalmic dosage forms of the same drug in terms of its systemic side effects. In this study, we evaluated the effects of epinephrine pretreatment and solution pH on the aqueous humor:plasma and iris-ciliary body:plasma ratios of peak timolol concentrations after ocular application of timolol. Timolol eyedrops (5 mg/mL, 25 microL) were applied ocularly in pigmented rabbits. Raising pH of the eyedrops from 6.2 to 7.5 did not affect the ratio between ocular and systemic peak drug concentrations, since both ocular and systemic concentrations of timolol were increased. Administration of epinephrine (20 mg/mL, 50 microL) 5 min prior to timolol eyedrop administration reduced the peak timolol concentrations in plasma 65-80%. Epinephrine did not affect the ocular concentrations of timolol. The decreased peak concentrations in plasma were due to the conjunctival and nasal vasoconstricting effects of epinephrine and to the subsequent slower absorption of timolol. Our study demonstrates that compared with currently available eyedrops (pH 6.9), the ocular:systemic concentration ratio of ophthalmic timolol can be improved four- to sixfold in rabbits by combining epinephrine-induced conjunctival and nasal vasoconstriction and improved ocular absorption from pH 7.5 eyedrops.

Absorption↗
PubMed1990

Improved ocular: systemic absorption ratio of timolol by viscous vehicle and phenylephrine.

Increasing the ocular absorption of timolol relative to its systemic absorption is important clinically because ophthalmic timolol may cause serious respiratory, cardiac, and central nervous system side effects. The authors evaluated the effects of phenylephrine coadministration and solution viscosity on the aqueous humor:plasma and iris ciliary body:plasma ratios of peak timolol concentrations after ocular application. Timolol eye drops (5 mg/ml, 25 microliters) were administered to the eyes of pigmented rabbits. Coadministered phenylephrine (0.8-8.2 mg/ml) decreased the systemic peak concentrations of timolol significantly. Since ocular absorption of timolol was not affected by phenylephrine, the ocular:systemic concentration ratios were improved four- to fivefold. Phenylephrine slows down the systemic absorption of timolol by constricting the conjunctival and nasal capillaries. The ratios of the aqueous humor:plasma and iris ciliary body:plasma peak concentration of timolol were improved three- to ninefold in the presence of sodium carboxymethylcellulose compared with nonviscous eye drops. The improved ocular penetration is probably due to the longer corneal contact, and the decreased rate of systemic absorption may be caused by the slower spreading of the solution on the nasal mucosa. Compared with timolol eye drops, the ratio of the eye:plasma peak timolol concentrations was improved tenfold by using viscous eye drops with phenylephrine. Systemic concentrations of ophthalmic timolol and possibly related side effects can be decreased when timolol is instilled in a viscous vehicle with a low phenylephrine concentration.

Absorption↗
PubMed1989

Ophthalmic epinephrine, phenylephrine, and pilocarpine affect the systemic absorption of ocularly applied timolol.

Ocularly applied timolol eyedrops may cause serious systemic side-effects in some patients. In this study we evaluated the effects of pretreatment with epinephrine and pilocarpine eyedrops on systemic absorption of ophthalmic timolol. Epinephrine decreased the systemic absorption of timolol, while pilocarpine increased the peak concentrations of timolol in plasma. When applied in the same solution with timolol, pilocarpine had no effect and phenylephrine decreased the systemic absorption of timolol. The observed effects were due to the conjunctival and nasal vasoconstricting effects of epinephrine and phenylephrine and to the vasodilating effects of pilocarpine. These pharmacokinetic interactions demonstrate the importance of the conjunctival and nasal blood flow in the systemic absorption of timolol.

Absorption↗
PubMed1988

Application site dependent ocular absorption of timolol.

Ocular absorption of timolol in rabbits was studied after topical ocular administration of 3H-timolol in an eyedrop or in silicone cylindrical devices that released timolol at 7.2 micrograms/h. The devices were applied in either the inferior or superior conjunctival sac. Timolol concentrations were nearly equal in the inferior and superior portions of ocular tissues when the drug was administered in an eyedrop. Administration in the devices resulted in unequal timolol distribution in the cornea, conjunctiva, sclera, and iris-ciliary body. Timolol concentrations were higher in the part of each tissue that was closer to the site of the device application. Unequal concentrations of timolol in the superior and inferior part of the eye and very low timolol concentrations in the aqueous humor indicated that timolol was absorbed mainly via a noncorneal route from the device placed in the inferior conjunctival sac. Induced blinking at one minute intervals did not change ocular absorption of timolol. Compared with inferior conjunctival sac applications, placement of the devices in the superior conjunctival sac resulted in increased corneal and total ocular absorption of timolol as indicated by higher timolol concentrations in the aqueous humor and by a smaller difference between concentrations in the superior and inferior portions of the examined tissues. The application site dependent ocular absorption indicated that controlled release of timolol in the tear fluid did not result in a uniform timolol distribution in the preocular tear fluid of rabbit eyes.

Absorption↗
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↗
PubMed1985

A comparison between iris-ciliary body concentration and receptor affinity of timolol.

Topical unilateral application of timolol reduces the IOP (intraocular pressure) of both the treated and the untreated eye. For this reason, a cental mechanism of action, in addition to the local one, has been suggested for the reduction of IOP by this drug. In this study timolol concentrations in the iris-ciliary body of the treated and untreated rabbit eyes were compared with pharmacologically active in vitro timolol concentrations. The drug concentration in the untreated eye too was found to be high enough to exert a local action.

Animals↗
PubMed1985

Concentration-dependent precorneal loss of pilocarpine in rabbit eyes.

Precorneal loss of pilocarpine was studied in pigmented and albino rabbits. We instilled 25 microliter of isotonic pilocarpine solution, pH 6.4, into rabbit eyes and monitored drug concentration in the precorneal tear film. Increased concentration (0.2% - 2.0%) of pilocarpine accelerated precorneal drug loss from the tear film from 0.686 min-1 to 1.064 min-1. This increase was mainly due to induced lacrimation. Polyvinyl alcohol (1.4%) retarded precorneal loss of pilocarpine. The rate of loss was the same in pigmented and albino rabbits. The effects of the changed precorneal loss of pilocarpine on corneal drug absorption are discussed.

Animals↗
PubMed1984

Ocular distribution of topically applied adrenaline in albino and pigmented rabbits.

Systemic absorption, ocular distribution and ocular metabolism in albino and pigmented rabbit of topically applied 1% [3H]l-adrenaline eye drops was studied by liquid scintillation counting and thin layer chromatography. The effect of adrenaline on the pupillary diameter was also registered. The peak plasma level of adrenaline was reached at 150 min. The corneal adrenaline metabolism was substantial, but did not vary with the rabbit strain. At 30 min after instillation, the total adrenaline concentration of pigmented iris and ciliary body exceeded that of corresponding albino tissues. At 180 min the drug concentration of the iris and ciliary body did not differ between the rabbit strains. The time course of adrenaline induced mydriasis was equal in both rabbit strains. Since neither total adrenaline concentration at 180 min nor the time course of adrenaline induced mydriasis differed between the rabbit strains, the higher initial adrenaline uptake by pigmented tissues is not explained by pigment binding. It is proposed that the increased initial binding of adrenaline by pigmented tissues is caused by a difference between pigmented and albino tissues in the number of adrenergic neurones; this is also supported by the literature.

Albinism↗
PubMed1983

Prolonged pulse-entry of pilocarpine with a soluble drug insert.

Apparent biophase availability of pilocarpine was studied in the eyes of albino rabbits. Pilocarpine doses of 0.85 and 2.30 mg in aqueous solutions, 1.00 mg in oil and 0.85 mg in a solid insert, were applied ocularly. The insert was a water soluble polyvinylpyrrolidone (PVP) matrix, which released 80% of its pilocarpine content in 35 min in vitro. In the inferior fornix of the eye this insert gelled in about 5 min and dissolved in 1 h. Pupillary diameters were measured and converted to values for the response parameter (RP). Time delay and magnitude of peak response, apparent biophasic availability (area under the curve of RP vs time), and a constant for the apparent rate of elimination were calculated from RP values. The time delay for the peak response was 16.l3-24.0 min, and the constant for apparent rate of elimination was 0.69-0.81 h-1. Neither time delay nor this constant was affected by the dose or the dosage form. Magnitude of the peak response and apparent biophasic availability were influenced by the vehicle and the dose: insert (0.85 mg) greater than oily solution (1.00 mg) greater than aqueous solution (2.30 mg) greater than aqueous solution (0.85 mg). The insert and oily solution did not show vehicle-controlled drug absorption and can be regarded as prolonged pulse-entry medication.

Animals↗
PubMed1982

Tofizopam modulates the affinity of benzodiazepine receptors in the rat brain.

Tofizopam, a 3,4-benzodiazepine, lacks the sedative action common to 1,4-benzodiazepines, but has anxiolytic activity. In this study we administered tofizopam (50 mg/kg) to rats perorally twice a day for six days, and analyzed the binding of [3H]flunitrazepam to benzodiazepine receptors of these drug-treated rats. The effect of tofizopam treatment was compared to that brought about by treatment with diazepam (12 mg/kg twice a day for six days) and to binding in controls treated with vehicle. Compared to the controls, the diazepam group had a marked decrease in binding of [3H]flunitrazepam to benzodiazepine receptors both in the forebrain and in the hindbrain. As a result of the increased affinity of the receptors tofizopam slightly, but statistically significantly, enhanced binding. With both drugs the number of receptors was unaltered. The effect of tofizopam in the hindbrain was similar to that in the forebrain. The results of this study support our earlier finding from single-dose studies that tofizopam acts indirectly on benzodiazepine receptors.

Animals↗
PubMedDate not supplied

Minimizing systemic absorption of topically administered ophthalmic drugs.

Due to absorption several ocularly applied medications give rise to systemic side-effects. The problem of systemic drug absorption should be taken into account in designing ocular drug and dosage forms so that oculospecificity of the medications is optimized. In this review we summarize the current knowledge about the systemic absorption of ocularly applied topical drugs. Special emphasis is directed to the methods that can be used to minimize systemic absorption and increase the oculospecificity of drugs, e.g., reducing volume and increasing viscosity of eyedrops, controlling drug release from depot preparations, prodrug-derivatization, and addition of vasoconstrictive agents.

Absorption↗
PubMedDate not supplied

Synthesis and analysis of O,O'-dicarboxylate (dibenzyl) bispilocarpates as possible prodrugs of pilocarpine.

As a part of a series of studies to develop prodrug derivatives of pilocarpine, the O,O'-succinyl (dibenzyl), O,O-adipoyl (dibenzyl), O,O-fumaryl (dibenzyl), and O,O-terephthaloyl (dibenzyl) bispilocarpate fumarates were synthesized as a new class of pilocarpine prodrugs. The compounds were prepared from pilocarpic acid benzyl monoester by coupling two pilocarpic acid benzyl monoesters together with spacer chains by usual esterification methods. Liquid chromatography, thermospray liquid chromatography-mass spectrometry, high-resolution mass spectrometry, and NMR spectroscopy were applied to the identification and the purity evaluation of the synthetic products.

Chromatography, Liquid↗
PubMedDate not supplied

Peptide-oligonucleotide phosphorothioate conjugates with membrane translocation and nuclear localization properties.

Eighteen peptide-oligonucleotide phosphorothioate conjugates were prepared in good yield and thoroughly characterized with electrospray ionization mass spectra. When applied to the living cells, conjugates exhibiting membrane translocation and nuclear localization properties displayed efficient intracellular penetration but failed to show any serious antisense effect. Studies on the intracellular distribution of the fluorescein-labeled conjugates revealed their trapping in endosomes.

Cell Membrane↗
PubMedDate not supplied

The uptake of clodronate (dichloromethylene bisphosphonate) by macrophages in vivo and in vitro.

Clodronate (dichloromethylene bisphosphonate) accumualtes extensively in the bone by binding to apatite crystals. We found recently that the drug also accumulates in the spleen and, to a lesser extent, in the liver of mice and rats. In the present study, the role of macrophages in soft tissue accumulation was studied in mice by autoradiography and macrophage-depleting techniques, and also by isolated rat peritoneal macrophages. The localization of [14C]clodronate in mouse spleen showed that the drug concentrates in the marginal zone between the white and red pulp, which is known to be rich in macrophages. Pretreatment of mice with pure clodronate did not change the accumulation of [14C]clodronate in the spleen. However, when splenic and hepatic macrophages were eliminated by the liposome-encapsulated clodronate, only a weak [14C]clodronate accumulation occurred in these organs. Isolated macrophages did not take up free [14C]clodronate, but the addition of ferrous iron to the incubate resulted in the uptake of 14C activity by macrophages. They were probably stimulated by the insoluble clodronate-iron complex. The results suggest that 1) macrophages are involved in the accumulation of clodronate in the spleen and liver, and 2) combination of clodronate with extracellular iron is a prerequisite for the activation of macrophages to take up the drug complex. Since the spleen and, to a lesser extent, the liver are rich in iron released from destroyed red cells, accumulation of clodronate takes place in these organs.

Animals↗