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Biomedical subjects

A Urtti

Publications and source records attributed to A Urtti.

At least 73 records · Page 4Linked to original sources
PubMed1994

Effect of some penetration enhancers on epithelial membrane lipid domains: evidence from fluorescence spectroscopy studies.

The effect of the penetration enhancers Azone, oleic acid, 1-dodecanol, dodecyl N,N-dimethylaminoacetate (DDAA), and dodecyl N,N-dimethylaminoisopropionate (DDAIP) on epithelial membrane lipids was examined using human buccal cell membranes as a model for epithelial lipid bilayer. Buccal epithelial cells (BEC) were labeled with 1,6-diphenyl-1,3,5-hexatriene (DPH), 1-(4-(trimethylammonio)phenyl)-6- phenyl-1,3,5-hexatriene (TMA-DPH), and 8-anilino-1-naphthalene sulphonic acid (ANS) fluorophores to characterize enhancer-induced changes in the hydrophobic core, in the superficial polar head region, and on the exterior surface, respectively, with fluorescence anisotropy and fluorescence lifetimes. All the enhancers studied were found to decrease the BEC membrane lipid packing order in a concentration-dependent and time-dependent manner in the deep bilayer region, as shown by a 37-66% decrease in anisotropy. Oleic acid was also found to disrupt membrane lipids strongly in the polar head region, causing at least a 34% decrease in anisotropy values. Azone and DDAA were shown to alter molecular movement on the surface of the bilayers (24 and 19% decrease in anisotropy, respectively). The results suggest that interaction with membrane lipid domains is an important, but not the only, mode of action for the penetration enhancers studied.

Alanine↗
PubMed1994

Comparison of cell proliferation and toxicity assays using two cationic liposomes.

The present study compares different cytotoxicity and cell proliferation assays including cell morphology, mitochondrial activity, DNA synthesis, and cell viability and toxicity assays. CaSki cells were exposed to two cationic liposomal preparations containing dimethyldioctadecyl-ammonium bromide (DDAB), dioleoylphosphatidylethanolamine (DOPE) and a commercial transfection-reagent DOTAP (N[1-(2,3-dioleoyloxy)propyl]-N,N,N-trimethylammonium-methylsulfat e). The results provided by these assays were similar. However, the lactate dehydrogenase assay was more sensitive in measuring early damages of cell membranes than the Trypan blue assay. Also, cell morphology showed early toxic changes, such as cytoplasmic vacuolization and cell shrinking, and it should be included with such toxicity evaluations. DDAB:DOPE was more toxic than DOTAP. The cells treated with DOTAP at 10 microM were surviving as well as the control cells, while DOTAP at 40 uM and DDAB:DOPE at 10 microM had slight toxic effects on CaSki cells. The most toxic effects were seen in CaSki cells after treatment with DDAB:DOPE at 40 microM.

Bromodeoxyuridine↗
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

Delivery of antiglaucoma drugs: ocular vs systemic absorption.

In order to reduce the intraocular pressure antiglaucoma drugs must penetrate into the inner eye. Ocular bioavailability is determined by the ability of drug to penetrate through the cornea and conjunctiva/sclera, and on the other hand, by its elimination from the conjunctival sac. Major part of this elimination is by systemic drug absorption via conjunctiva. Typically conjunctival systemic absorption of drugs is an order of magnitude greater than their ocular absorption. In addition substantial systemic absorption of ophthalmic drugs takes place via nasal mucosa. Systemic absorption of antiglaucoma drugs like beta blocking agents may cause systemic side-effects. The risk of systemic side-effects might be decreased by increasing the ocular/systemic ratio of drug absorption. Several approaches can be used to improve ocular/systemic drug absorption ratio. Firstly, corneal drug permeability is improved. This can be done using different formulations or prodrug derivatives. Secondly, systemic absorption can be decreased e.g. with kinetic drug interactions or drug formulations. Thirdly, the rate of drug delivery can be changed thereby affecting especially the peak concentrations of drug in systemic circulation. Different methods for improvement of ocular delivery relative to the systemic absorption of antiglaucoma drugs are summarized and the impact of systemic pharmacokinetics on the viability of each approach is discussed.

Absorption↗
PubMed1994

Growth inhibition of macrophage-like and other cell types by liposome-encapsulated, calcium-bound, and free bisphosphonates in vitro.

Bisphosphonates effectively inhibit osteoclastic bone resorption in diseases characterized by excessive bone loss. Liposome-encapsulated clodronate (dichloromethylene bisphosphonate) also is known to inactivate phagocytic cells in vivo, and inhibit the growth of macrophage-like RAW 264 cells in vitro. The macrophage suppressive effect of liposomal clodronate is of interest in autoimmune diseases, like rheumatoid arthritis, in which phagocytic cells are involved in inflammatory processes. Earlier in vivo studies suggested that liposomal clodronate is a far more potent inactivator of macrophages than liposomal forms of two other bisphosphonate compounds, pamidronate (3-amino-1-hydroxypropylidene bisphosphonate), and etidronate (1-hydroxyethylidene-1,1-bisphosphonate). We examined the growth inhibitory properties of these three bisphosphonates with macrophage-like RAW 264 cells and with other types of cells in vitro. All three bisphosphonates encapsulated in liposomes effectively inhibited the growth of RAW 264 and CV1-P cells, while free drugs were 20-1000 times less potent growth inhibitors. Also, high extracellular calcium concentrations enhanced the potency of bisphosphonates for RAW 264 cells, indicating that, in addition to liposomes, the uptake of bisphosphonates by macrophages is mediated also by calcium. In all formulations, pamidronate was the most potent compound for the cells, with the exception of CV1-P cells, for which liposomal clodronate was the most potent. The effects of liposomal drugs were selective for highly endocytotic cells. The results suggest that liposome-encapsulated bisphosphonates could provide a specific tool to affect the function of macrophages and all three of these bisphosphonates are potentially effective as macrophage suppressors in autoimmune diseases.

Animals↗
PubMed1993

Electrochemical characterization of human skin by impedance spectroscopy: the effect of penetration enhancers.

The electrochemical properties of human cadaver skin were studied in a diffusion cell with impedance spectroscopy as a function of time in the absence and presence of penetration enhancers dodecyl N,N-dimethylamino acetate and Azone. An improved electrochemical model of skin is presented, and combining the novel model with modern fractal mathematics, the effect of enhancers on the surface of skin is demonstrated. The enhancers appeared to open new penetration routes and increase the ohmic resistance, capacitive properties, and fractal dimension of skin, which means a rougher or more heterogeneous surface.

Administration, Cutaneous↗
PubMed1993

Intraocular pressure reduction and systemic absorption of timolol after administration of one side-coated inserts in rabbits.

The object of this study was to test whether flat, circular ophthalmic inserts releasing drug only from one side, would show improved activity parameters and reduced systemic absorption. To this purpose, uncoated and one-side coated hydroxypropylcellulose inserts containing timolol were prepared and evaluated. An acrylic copolymer (Eudragit RS) was used as coating material. Timolol release from inserts was studied both in vitro and in vivo. Timolol release in vitro from the coated inserts was much slower than from the uncoated ones, due to the smaller releasing surface area. Compared with timolol eyedrops (0.5%, 50 microliters), administration of 250 micrograms of timolol in uncoated or coated inserts produced a significantly greater hypotensive effect at 6 and 8 hr post instillation in rabbits with artificially increased intraocular pressure. The coated inserts containing 62.5 micrograms of timolol antagonised isoproterenol-induced ocular hypotension significantly more than timolol eyedrops (0.5%, 12.5 microliters) and uncoated inserts containing 62.5 micrograms of timolol. Both uncoated and coated inserts provided a significant sustaining of timolol release in tear fluid and decreased systemic peak concentrations of timolol with respect to the eyedrop control. However, one-side coated inserts failed to show significant improvements with respect to the uncoated samples.

Absorption↗
PubMed1993

Systemic absorption and systemic effects of ocularly administered dexmedetomidine in rabbits.

Dexmedetomidine is a selective alpha 2-adrenoceptor agonist which has previously been shown to reduce the ocular pressure of normotensive rabbits as well as those with pressures artificially elevated by laser irradiation. In this study instillation of an equivalent hypotensive dose (12.5 micrograms) did not cause changes in heart rate, blood pressure, blood glucose or plasma catecholamine content even though dexmedetomidine could be detected in plasma. However, this dose given intravenously (i.v.) was also without effect. Higher ocular doses resulted in equivalent bradycardia and changes in blood glucose levels as when the dose was given i.v. These two parameters proved to be most sensitive indicators of systemic alpha 2-agonism, blood pressure did not change and plasma catecholamine levels were too low to be reliably assayed. It is concluded that when hypotensive doses of dexmedetomidine are instilled into the eye, intraocular concentrations are sufficiently high to exert pharmacological effects. As it is absorbed into the general circulation, it is diluted such that its systemic effects are minimal.

Absorption↗
PubMed1992

Duration and long-term efficacy of phenylephrine-induced reduction in the systemic absorption of ophthalmic timolol in rabbits.

Co-administration of phenylephrine decreases systemic timolol absorption after a single topical ocular dose of timolol in rabbits. This is probably due to vasoconstriction in the conjunctiva of the eye and nasal mucosa. In this study, we evaluated the duration of action and long-term efficacy of phenylephrine in reducing the systemic absorption of ophthalmic timolol in pigmented rabbits. Although co-administered phenylephrine had a short duration of interaction with systemic timolol absorption (20-60 min), its effect on systemic timolol absorption was substantial. The long-term vasoconstrictive effect of phenylephrine was studied by administering timolol-phenylephrine eyedrops into the eyes of rabbits once a day for two months. Systemic peak concentrations of timolol following timolol-phenylephrine eyedrop administration remained unchanged throughout the study. Phenylephrine may be useful additive in decreasing the systemic concentrations of ophthalmic drugs.

Absorption↗
PubMed1992

Cardiac effects of different eyedrop preparations of timolol in rabbits.

Coadministration of phenylephrine and increasing solution viscosity can decrease systemic timolol absorption after eyedrop application. In this study, changes in the heart rate of rabbits after non-viscous (1 cP) and viscous timolol-phenylephrine (330 cP) solution were compared with those after control timolol eyedrops. The resting heart rate of rabbits was not influenced by control timolol eyedrops (0.6 mg/ml, 25 microliters in both eyes). In contrast, control timolol eyedrops antagonized greatly isoproterenol-induced tachycardia for 120 min. Timolol (0.6 mg/ml)-phenylephrine (0.8 mg/ml) eyedrops (25 microliters in both eyes) antagonized the chronotropic effect of isoproterenol less than control timolol eyedrops for the first 10 min. Compared to control timolol eyedrops, administration of viscous timolol (0.3 mg/ml)-phenylephrine (0.8 mg/ml) solution (25 microliters in both eyes) lowered systemic beta-blocking activity of timolol for 120 min. Previously we have shown that compared to non-viscous (1 cP) timolol (5.0 mg/ml) eyedrop (25 microliters), viscous (330 cP) timolol (2.5 mg/ml)-phenylephrine (0.8 mg/ml) solution (25 microliters) results in equal or increased timolol concentrations in the ocular tissues. All three timolol eyedrops antagonized the isoproterenol-induced tachycardia more than buffer solution but the onset of significant beta-blocking effect induced by eyedrops varied from 3 min (control eyedrop) to 40 min (viscous eyedrop). Our results indicate that possible cardiac effects of ophthalmic timolol can be diminished by phenylephrine coadministration and increased solution viscosity.

Animals↗
PubMed1992

Dexmedetomidine-induced ocular hypotension in rabbits with normal or elevated intraocular pressures.

This study covered the ocular hypotensive effects of the stereoisomers of the alpha 2-adrenoceptor agonist medetomidine. The dextro-isomer, dexmedetomidine, is known from pharmacologic experiments to be a specific, potent, and selective full agonist at alpha 2-adrenoceptors, whereas the levo-enantiomer seems to be almost inactive. Thus, the levo-isomer (0.5 mg/ml, 25 microliters) had no significant effect on intraocular pressure. After unilateral topical administration, dexmedetomidine (0.5 mg/ml, 25 microliters) lowered intraocular pressure bilaterally in normal rabbits and in rabbits with intraocular pressure elevated after laser irradiation of the pigmented trabecular band of the anterior chamber angle. In the treated (ipsilateral) eye of normal rabbits, a maximum decrease of 4.6 +/- 0.6 mmHg was observed at 2 hr post treatment. In the contralateral eye, the maximum decrease was 4.1 +/- 0.5 mmHg at 1 hr after treatment. In rabbits with laser-induced elevation of intraocular pressure, the maximum decrease in treated hypertensive eyes was 13.5 +/- 0.3 mmHg 1 hr after dexmedetomidine administration. These results indicate that the selective alpha 2-adrenoceptor agonist, dexmedetomidine, is a potent and effective drug for decreasing intraocular pressure in rabbits.

Administration, Topical↗
PubMed1991

Timolol release from matrices of monoesters of poly(vinyl methyl ether-maleic anhydride): effects of polymer molecular weight and a basic additive.

Alkyl monoesters of poly(vinyl methyl ether-maleic anhydride) (PVM-MA) are acidic bioerodible polymers that have been used in cosmetics and tablet film coatings. They may be suitable for topical controlled-release applications since the polymeric backbone is not cleaved to smaller fragments that could be absorbed into the systemic circulation. The dissolution of these polymers depends on the length of the alkyl ester chain of the polymer and on the pH on the polymer surface. We studied the effect of the molecular weight of the polymer on in vitro release of timolol from matrices of n-propyl, n-butyl, and n-hexyl monoesters of PVM-MA. The effect of a basic additive, disodium phosphate, on timolol release from the polymers was also evaluated. The rate of timolol release decreased with increasing length of the alkyl side chain in the polymer. Drug release from the n-propyl and n-butyl monoesters followed zero-order release kinetics, but that from the n-hexyl monoester followed square root-of-time release kinetics. The molecular weight of the polymer did not affect drug release from the matrices without disodium phosphate. With the basic additive, the rate of timolol release increased with increasing molecular weight from the matrices of n-propyl and n-butyl monoesters of PVM-MA, but had only a very small effect on drug release from the n-hexyl monoester. Release of timolol from the n-propyl and n-butyl monoesters was controlled by polymer dissolution and, thus, it was affected by the basic additive in the matrix. Diffusion-controlled drug release from the n-hexyl ester was not affected by disodium phosphate.

Delayed-Action Preparations↗
PubMed1991

Determination of physicochemical properties, stability in aqueous solutions and serum hydrolysis of pilocarpic acid diesters.

New alkyl and aralkyl pilocarpic acid diesters, prodrugs of pilocarpine, were synthesized with the aim of improving the bioavailability of pilocarpine by increasing its corneal permeability. These esters were several orders of magnitude more lipophilic than pilocarpine as determined by their apparent partition coefficients between 1-octanol and phosphate buffer (pH 7.40) (log P). Good correlation between log P and HPLC capacity factors of the compounds was observed. All the compounds are stable in acidic aqueous solution; in serum, however, pilocarpic acid diesters are hydrolysed enzymatically to pilocarpic acid monoester, which undergoes spontaneous cyclization to active pilocarpine and inactive isopilocarpine. The half-lives of the diesters in serum varied from 6-232 min. In addition to the direct effects of the R2, R1 moiety had a remarkable effect on the rate of enzyme-catalysed hydrolysis taking place in moiety R2. The formed pilocarpine was analysed with a new HPLC method which allowed good resolution of pilocarpine, isopilocarpine, pilocarpic acid and isopilocarpic acid. Rates for pilocarpine formation were both determined by experiment and calculated using the STELLA simulation programme with known degradation rate constants of pilocarpic acid diesters and monoesters. Since the simulations were in good agreement with the experimental results, it is concluded that STELLA simulation programme is useful in predicting pilocarpine formation.

Chromatography, High Pressure Liquid↗
PubMed1991

Synthesis and identification of pilocarpic acid diesters, prodrugs of pilocarpine.

A series of new pilocarpic acid diesters were synthesized to obtain prodrugs for pilocarpine with varying physico-chemical properties. Thermospray liquid chromatography-mass spectrometry (TSP-LC-MS), liquid chromatography with UV-detection (LC-UV) and NMR-spectroscopy were used for the identification of the synthetic products and for evaluation of their purity including typical impurities (pilocarpic acid monoester, pilocarpine). TSP-LC-MS-analysis was performed in the reversed-phase mode using acetonitrile (60%)-0.2 M ammonium acetate (40%) as mobile phase. In LC-UV-analysis chromatographic separation was carried out on a reversed-phase column and the mobile phase consisted of methanol (71%) and 0.02 M potassium dihydrogen phosphate, pH 4.5 (29%). Electron ionization-mass spectrometry (EI-MS) was used for elucidation of structures. Elemental compositions of the substances were verified with high resolution-mass spectrometry (HR-MS). The complete establishment of structures presented was based on 1H-, and COSY-NMR-spectroscopy joined to TSP-LC-MS-analysis.

Chromatography, Liquid↗
PubMed1991

Improved corneal pilocarpine permeability with O,O'-(1,4-xylylene) bispilocarpic acid ester double prodrugs.

O,O'-(1,4-Xylylene) bispilocarpic acid esters are pilocarpine prodrugs containing two pilocarpic acid monoesters linked with one pro-moiety. Each mole of prodrug forms two pilocarpine moles in the presence of esterases. Corneal uptake and permeability of various bispilocarpic acid diesters were investigated in vitro using isolated albino rabbit corneas. The permeability coefficient of pilocarpine was 2.8 x 10(-6) cm/sec, whereas for bispilocarpic acid diesters, despite their large molecular weights (between 638 and 722), permeability coefficients were 6.5-20.2 x 10(-6) cm/sec. Only pilocarpine, and no intact prodrug, was observed at the endothelial side. Corneal uptake was increased with increasing lipophilicity, but a parabolic relationship between the logarithm of the apparent partition coefficient (1-octanol-pH 7.4 phosphate buffer) (log PC) and the corneal permeability was noticed. Corneal permeability and the rate of enzymatic hydrolysis of the compounds correlated well. The corneal permeability of pilocarpine given as lipophilic bispilocarpic acid diester (log PC greater than or equal to 3) prodrugs seems to be controlled by the formation of pilocarpine in the corneal epithelium rather than by the absorption of prodrugs into the epithelium or their epithelium-stroma transport rate.

Animals↗
PubMed1991

Dodecyl N,N-dimethylamino acetate and azone enhance drug penetration across human, snake, and rabbit skin.

The effectiveness of the penetration enhancers, dodecyl N,N-dimethylamino acetate (DDAA) and Azone, on pretreated human epidermis for the permeation of model drugs, indomethacin, 5-fluorouracil, and propranolol-HCl, was studied in in vitro diffusion cells. Snakeskin (Elaphe obsoleta) and rabbit pinna skin were compared as possible models for human skin. The drug concentrations were analyzed by HPLC. With all skins and all model drugs, DDAA increased drug permeability at least as well as Azone, and in most cases it was a more effective permeation enhancer. The relative permeation improvements in human skin, snakeskin, and rabbit skin were 10- to 20-, 5- to 50-, and 20- to 120-fold, respectively. Tritiated water served as an indicator of skin condition. Its penetration in the skin samples was independent of the drugs used, and both penetration enhancers significantly increased the flux of tritiated water through all skins. Thus, DDAA and Azone significantly increased the permeation of lipophilic and hydrophilic model compounds. Rabbit pinna skin was a poor model for human skin in vitro, while snakeskin was much closer to human skin in terms of transdermal permeability. In most cases drug permeability decreased in the order rabbit much greater than human greater than or less than snake.

Aged↗
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↗