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Biomedical subjects

S M Podos

Publications and source records attributed to S M Podos.

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

Selective alpha 2-adrenergic agonists B-HT 920 and UK14304-18. Effects on aqueous humor dynamics in monkeys.

Selective alpha 2-adrenergic agonists UK14304-18 and B-HT 920 were evaluated in the eyes of cynomolgus monkeys. In normal monkeys, unilateral topical application of 0.3%, 0.5%, or 1% UK14304-18 or B-HT 920 reduced (P less than .05) intraocular pressure bilaterally up to 9.9 +/- 1.2 mm Hg (mean +/- SEM) and 8.4 +/- 1.4 mm Hg in treated and contralateral eyes, respectively. Five-day twice-daily 0.5% UK14304-18 administration reduced (P less than .05) intraocular pressure up to 49% in eight glaucomatous monkeys. In eight normal monkeys, 0.5% B-HT 920 and 0.5% UK14304-18 produced no alterations in outflow facility. Following unilateral application of 0.5% B-HT 920 or 0.5% UK14304-18, fluorophotometrically measured aqueous humor production was reduced (P less than .05) bilaterally up to 67% compared with baseline values. Also, 0.5% UK14304-18 reduced (P less than .025) systolic and diastolic blood pressure. UK14304-18 and B-HT 920 seem to reduce intraocular pressure by decreasing aqueous production. They are potential new agents for the treatment of glaucoma.

Administration, Topical↗
PubMed1991

MK-507 (L-671,152), a topically active carbonic anhydrase inhibitor, reduces aqueous humor production in monkeys.

An investigation was carried out to determine the mechanism by which MK-507 (L-671,152), a water-soluble inhibitor of human carbonic anhydrase II in vitro, reduces intraocular pressure when applied topically to monkey eyes. Intraocular pressure, tonographically measured outflow facility, and fluorophotometrically determined aqueous humor flow were measured before and after therapy in eight normal cynomolgus monkeys. Fifty microliters of 2% MK-507 was instilled in one eye and diluent in the contralateral eye. Baseline values for intraocular pressure, outflow facility, and aqueous humor flow were similar in the drug-treated and diluent-treated control eyes. After therapy, intraocular pressure was significantly (P less than .05) reduced from 1 to 7 hours (eg, 14.0 +/- 1.0 and 15.9 +/- 0.9 mm Hg [mean +/- SEM], treated and control eyes, respectively, at 3 hours). Outflow facility was not significantly (P greater than .40) changed at 3 hours, and aqueous humor flow measured over 5 hours was significantly (P less than .05) reduced (38%) in treated (0.9 +/- 0.1 microL/min) as compared with control eyes (1.5 +/- 0.1 microL/min). The results suggest that MK-507 reduces intraocular pressure by decreasing aqueous humor production.

Administration, Topical↗
PubMed1991

Additivity of prostaglandin F2 alpha-1-isopropyl ester to timolol in glaucoma patients.

The effect on intraocular pressure (IOP) of adding prostaglandin F2 alpha-1-isopropyl ester (PGF2 alpha-IE) to timolol was studied in 21 eyes of 13 patients with newly diagnosed primary open-angle glaucoma that was inadequately controlled with timolol alone. After at least 2 weeks of twice daily timolol 0.5% therapy, PGF2 alpha-IE, 0.5 microgram in 30 microliters, was topically applied twice daily at 8 AM and 8 PM, 5 minutes before each timolol dose, for 7 days. Intraocular pressures were measured before timolol treatment, and at 8 AM, 8:30 AM, 12 PM, 2 PM, and 4 PM on the day before the addition of PGF2 alpha-IE, and on day 1 and on day 7 of combined therapy. Mean IOP was 39 +/- 2 mmHg (+/- standard error) before timolol therapy and 31 +/- 2 mmHg after at least 2 weeks of treatment with timolol alone. A significant (P = 0.004) further reduction of IOP was first observed 4 hours after the first dose of PGF2 alpha-IE, which was maintained throughout the duration of combined therapy. During the last day of combined treatment and at 12 hours after the final dose, IOP was reduced a mean of 6 to 9 mmHg (mean, 9.0 +/- 1.5 mmHg at 12 hours) below baseline values obtained with timolol alone. These results indicate that adding PGF2 alpha-IE in patients treated with timolol causes a further reduction of IOP that may prove to be clinically useful in glaucoma therapy.

Adult↗
PubMed1991

Free radical enhancer xenobiotic is an inducer of cataract in rabbit.

Free radical enhancers, diquat, paraquat, plumbagin and juglone were used to study the oxy radical-induced damage to the rabbit lens in vitro and in vivo. Each compound caused a 6-8 fold increase in malondialdehyde (MDA) and a 30-55% decrease in reduced glutathione of the lens in vitro. These peroxidative and oxidative changes were potentiated in the presence of 100% O2, abolished by N2 and prevented by desferal-Mn (III) (DF-Mn) or liposomal superoxide dismutase (LSOD) indicating the involvement of O2-. Diquat injected intravitreally as a single dose (300 nmole in 30 microliters of isotonic saline) in the right eye of a 5-wk-old Dutch belted rabbit, induced early cataract after 24-72 h. The lens of the contralateral control eye injected with isotonic saline had no change. In the right eye, O2-. and OH. productions were significantly (P less than 0.01) higher; O2-. was about 16 fold higher in the aqueous humor and vitreous humor, and 5 fold in the lens and retina, and OH. was 35 fold higher in the aqueous humor, 2 fold in vitreous humor and 5 fold in the lens and retina as compared to the respective tissues of the control eye. Enhanced lipid peroxidation in the lens was apparent from the higher levels of MDA and formation of aminophospholipid.MDA Schiff-base conjugates. We propose that cyclic oxidation-reduction of xenobiotics coupled to the endogenous redox systems in the eye, could generate oxy radicals in excessive amounts, triggering cataractogenesis.

Animals↗
PubMed1990

The ocular hypotensive effect of the topical carbonic anhydrase inhibitor L-671,152 in glaucomatous monkeys.

L-671,152, a new potent water-soluble inhibitor of human carbonic anhydrase II in vitro, was applied topically to cynomolgus monkey eyes in which glaucoma had been produced by argon laser photocoagulation of the trabecular mesh-work. Intraocular pressure was measured at 0 hours, 0.5 hours, and hourly for 8 hours in eight eyes for 2 baseline days, 1 day receiving the vehicle and 5 days receiving therapy with 2% L-671,152 twice a day, after initial single-dose trials of various concentrations. Intraocular pressure was not significantly different comparing baseline and vehicle-treated days. Significant intraocular pressure reductions occurred from 1 to 8 hours after the first dose, and lasted for at least 16 hours after the second dose. The reduction in intraocular pressure became more pronounced from day 1 to day 5 at each time interval. The mean (+/- SEM) maximum reduction in intraocular pressure was 7.8 +/- 2.1 mm Hg on day 1 and 10.1 +/- 2.4 mm Hg on day 5 at 3 hours after administration, comparing the intraocular pressure in drug-treated and vehicle-treated eyes. L-671,152 has a longer duration of action than does previously studied MK-927 in glaucomatous monkeys. It appears to have great clinical potential.

Administration, Topical↗
PubMed1990

MK-927, a topical carbonic anhydrase inhibitor. Dose response and reproducibility.

We investigated the dose-response and reproducibility of the intraocular pressure-lowering effect of MK-927 in ocular hypertensive patients. Patients were enrolled until at least 8 "marked responders" (peak reduction in intraocular pressure comparing the MK-927-treated eye with the placebo-treated eye greater than or equal to 6 mm Hg) and 7 "mild responders" (peak reduction in intraocular pressure comparing the MK-927-treated eye with the placebo-treated eye less than or equal to 3 mm Hg) were identified. In part A, 27 patients received one drop of 2% MK-927 in one eye (baseline mean +/- SEM intraocular pressure, 28.0 +/- 1.0 mm Hg) and placebo in the contralateral eye. Intraocular pressure was measured at baseline and 1, 2, 3, 4, and 6 hours. Maximum reduction in intraocular pressure was 4.0 +/- 0.8 mm Hg at 3 hours, with a duration of 4 hours. Ten patients were identified as marked responders and 7 as mild responders. In part B, 8 of the marked responders entered a four-period crossover study and received 2%, 0.5%, and 0.125% MK-927 and placebo in the same treated eye as in part A, and placebo in the contralateral eye. The 7 mild responders in part C received 2% MK-927 in a similar fashion as in part A. MK-927 in concentrations of 0.125% and 0.5% had little or no effect on intraocular pressure in patients with a marked response to 2% MK-927. Within-patient variability in peak response to single doses of 2% MK-927 was substantial (coefficient of variation of 0.3 and 0.5 for marked responder and mild responder groups, respectively.

Administration, Topical↗
PubMed1990

The effect of MK-927, a topical carbonic anhydrase inhibitor, on IOP in glaucomatous monkeys.

MK-927 is a water soluble, potent inhibitor of human carbonic anhydrase (CA) II in vitro. Topical administration of MK-927 reduces intraocular pressure (IOP) in rabbits. Elevated IOP was produced in cynomolgus monkey eyes by argon laser photocoagulation of the trabecular meshwork. IOP was measured at 0 hr, 0.5 hr and hourly for 8 hrs in 8 eyes for two baseline days, one day on vehicle and five days of therapy with 2% MK-927 b.i.d., after initial single-dose trials of various concentrations. IOP was not significantly different comparing baseline and vehicle treated days. Significant (p less than 0.05) reductions of IOP occurred for five days lasting at least 8 hrs after each dosing. At 3 hrs after treatment with vehicle the IOP was 31.6 +/- 3.4 (SE) mm Hg. Maximum reduction of IOP occurred at 3 hrs after application of MK-927, the IOP decreasing from day 1 (19.9 +/- 1.0 mm Hg) to day 5 (16.5 +/- 1.6 mm Hg). MK-927 appears to have great clinical potential.

Administration, Topical↗
PubMed1990

Effects of prostaglandins F2 alpha, A2, and their esters in glaucomatous monkey eyes.

The effect of prostaglandin (PG) F2 alpha-isopropyl ester (IE), PGA2, or PGA2-IE on intraocular pressure (IOP) was tested in eight cynomolgus monkey eyes with argon laser-induced glaucoma. Dose-response testing and baseline IOP measurements were done. For multiple dose testing, 5 micrograms in 25 microliters (0.02%) of each PG was topically applied twice daily for 5 days. The IOP was measured at 30- or 60-minute intervals for 6 hours after the morning dose each day. A significant (P less than 0.05) reduction of IOP peaked at 5-9 mm Hg below baseline values on the 5th day of treatment for each PG. The ocular hypotensive effect of these PGs progressively became more pronounced during the course of twice-daily dosing, with a significant reduction maintained at least 17 hours after some doses. No more than trace aqueous flare and no cells were observed in any eye during the course of treatment. These findings demonstrate that PGs other than F2 alpha are potent ocular hypotensive agents in primates.

Administration, Topical↗
PubMed1989

Maintained reduction of intraocular pressure by prostaglandin F2 alpha-1-isopropyl ester applied in multiple doses in ocular hypertensive and glaucoma patients.

In a randomized, double-masked, placebo-controlled study, 0.25 microgram (n = 11) or 0.5 microgram (n = 13) of prostaglandin F2 alpha-1-isopropyl ester (PGF2 alpha-IE) was applied topically twice daily for 8 days to one eye of ocular hypertensive or chronic open-angle glaucoma patients. Compared with contralateral, vehicle-treated eyes, PGF2 alpha-IE significantly (P less than 0.05) reduced intraocular pressure (IOP), beginning 4 hours after the first 0.5-microgram dose and lasting at least 12 hours after the fourteenth dose, with a significant (P less than 0.005) mean reduction of 4 to 6 mmHg maintained throughout the last day of therapy with either dose. A contralateral effect was not observed. Mean tonographic outflow facility was significantly (P less than 0.05) higher in PG-treated compared with vehicle-treated eyes (0.17 +/- 0.02 versus 0.12 +/- 0.01 microliter/minute/mmHg, respectively; +/- standard error of the mean) for the 0.5 microgram dose. Conjunctival hyperemia reached a maximum at 30 to 60 minutes after PGF2 alpha-IE application. Some patients reported mild irritation lasting several minutes after some doses. Visual acuity, accommodative amplitude, pupillary diameter, aqueous humor flare, anterior chamber cellular response, Schirmer's test, pulse rate, and blood pressure were not significantly altered. Our findings show that PGF2 alpha-IE is a potent ocular hypotensive agent and a promising drug for glaucoma therapy.

Aged↗
PubMed1989

Experimental compounds to lower intraocular pressure.

A need exists for new ocular hypotensive agents that are more efficacious and that have fewer side effects than those now clinically used. Laser-induced glaucoma in monkeys is an excellent model to test potential new drugs that lower intraocular pressure (IOP). A variety of agents that act through secondary messenger systems or via enzymes to lower IOP are being investigated in primates. Several alpha-adrenergic agonists and antagonists are effective ocular hypotensive agents in monkeys and humans. Para-aminoclonidine, an alpha2 agonist, inhibits the transient post-laser rise of IOP in humans. Prostaglandin F2 alpha-1-isopropyl ester significantly reduces IOP when tested in multiple dose fashion in glaucomatous monkey eyes and glaucoma patients. Modified carbonic anhydrase inhibitors, designed to enhance intraocular penetration, reduce IOP in the monkey model and in ocular hypertensive patients in single-dose studies when given topically. Studies show that forskolin and vanadate are less promising agents for glaucoma therapy.

Adrenergic alpha-Agonists↗
PubMed1989

The role of endogenous prostaglandins in clinically-used and investigational glaucoma therapy.

A review of the relevant literature strongly suggests that several medical and laser treatments presently used in glaucoma therapy, and other potential treatments under investigation, reduce IOP, at least, in part, by stimulating endogenous PG synthesis. There are four lines of evidence leading to this conclusion. (1) PGs are potent ocular hypotensive agents. (2) Adrenergic and cholinergic agonists stimulate PG synthesis by ocular tissues in vitro. (3) Epinephrine and ALT cause elevation of PG levels in the aqueous humor in vivo. (4) PG synthesis inhibitors such as indomethacin or flurbiprofen block, or partially inhibit, the reduction of IOP produced by epinephrine, para-aminoclonidine, forskolin, vanadate, verapamil, arachidonic acid, and ALT in rabbits, cats, monkeys, and/or humans. This last finding has great clinical importance with regard to the efficacy of such treatment modalities as epinephrine and ALT, since it indicates that these modalities may be less effective in reducing IOP in glaucoma patients who are taking systemic PG synthesis inhibitors - such as aspirin or indomethacin - for arthritis, cerebrovascular disease, arteriosclerotic coronary vascular disease, headache, or the common cold. Other surgical procedures for glaucoma such as cyclocryotherapy or other cyclodestructive procedures may also reduce IOP in part by stimulating local PG synthesis. Since PGs are produced in various ocular tissues and some of these PGs are highly potent ocular hypotensive agents, their potential role in mediating the reduction of IOP produced by medical or surgical modalities of glaucoma therapy must always be considered. Furthermore, these considerations support the concept that topical application of an appropriately selected PG, or its derivative, may provide a more direct means of lowering IOP than some of the currently used procedures or therapeutic agents.

Animals↗
PubMed1989

Calcium-dependent phosphorylation of proteins in rabbit ciliary processes.

Calcium-dependent phosphorylation of endogenous substrate proteins in albino rabbit ciliary processes was studied by SDS-polyacrylamide gel electrophoresis and autoradiography. In the soluble fraction, a modest augmentation of phosphorylation was observed by Ca2+ alone and together with the additional activators, calmodulin (CAM) or phorbol myristate acetate (PMA). However, there was a greater enhancement of protein phosphorylation by Ca2+ and activators in the particulate fraction. The degree of Ca2+-CAM-dependent protein phosphorylation was greater than that of Ca2+-PMA-dependent phosphorylation. Endogenous substrate proteins for Ca2+-CAM-dependent protein kinases had apparent molecular sizes of 205,170,150,130,77,58,40,32 and 18 kDa. Phosphorylation of the 58 kDa protein band was strongest. This protein was identified as vimentin on the basis of its behavior with Triton-X100 treatment, and by Western blotting using anti-vimentin antibody. Endogenous substrates of protein kinase C (Ca2+-PMA-dependent) were located at 87 kDa and possibly in the 56 and 54 kDa protein bands. A 50 kDa protein was found to be phosphorylated in the presence of Ca2+ alone, and was not affected by the presence of other activators (CAM or PMA). A Ca2+-dependent dephosphorylation of a 43 kDa protein was observed, and some proteins rapidly phosphorylated by Ca2+-CAM kinase were also relatively quickly dephosphorylated at incubation times greater than 1 min.

Animals↗
PubMed1989

Cyclic nucleotide-dependent phosphorylation of proteins in rabbit ciliary processes.

Cyclic nucleotide-dependent protein phosphorylation in albino rabbit ciliary processes was studied in particulate and soluble fractions of the tissue by the technique of SDS-polyacrylamide gel electrophoresis and autoradiography. In the presence of gamma-32P-ATP, the soluble fraction showed increased phosphorylation of proteins of 200, 32 and 16 kDa molecular weight when 10 microM cAMP was added. Protein phosphorylation increased with time up to 5 min. No significant augmentation of phosphorylation was observed in the presence of 10 microM cGMP compared to control. In the particulate fraction, proteins with molecular weights of 200, 160, 105, 72, 58, 32 and 16 kDa showed increased phosphorylation in the presence of 10 microM cAMP. Phosphorylation caused by the addition of cAMP was maximal between 30 sec and 1 min for the particulate membrane fraction, but with longer incubation times the incorporation of phosphate residues decreased. The same molecular weight proteins of the membrane fraction that were phosphorylated in a cAMP-dependent manner were phosphorylated in the absence of exogenous cAMP by addition of either the catalytic subunit of cAMP-dependent protein kinase or activators of membrane-bound adenylate cyclase such as l-isoproterenol, vasoactive intestinal peptide, aluminum fluoride or forskolin. A cAMP-dependent dephosphorylation of a 56 kDa protein was observed in the membrane fraction. Cyclic GMP did not cause observable changes in the pattern of protein phosphorylation in the particulate fraction of rabbit ciliary processes.(ABSTRACT TRUNCATED AT 250 WORDS)

Adenylyl Cyclases↗
PubMed1988

Long-term reduction of intraocular pressure after repeat argon laser trabeculoplasty.

Thirty-eight eyes (in 31 patients with glaucoma) that had shown a favorable response to an initial argon laser trabeculoplasty had a repeat laser trabeculoplasty four to 81 months (mean +/- S.E.M., 23 +/- 3 months) later because of inadequately controlled intraocular pressures. A mean (+/- S.E.M.) of 65 +/- 3 burns (range, 50 to 115) were given during the initial laser trabeculoplasty, and 58 +/- 2 burns (range, 36 to 100) were given during the first repeat treatment. Three months after the first repeat laser trabeculoplasty, one eye (3%) had undergone filtering surgery and 30 eyes (78%) were considered successes. Of the 30 eyes that were followed up for 12 months after the first repeat laser trabeculoplasty, two (7%) had undergone filtering surgery, three (10%) had received a second repeat laser trabeculoplasty, and 22 (73%) were successes. Fifteen eyes underwent a second repeat laser trabeculoplasty at six to 47 months (mean +/- S.E.M., 21 +/- 3 months) after the first repeat laser trabeculoplasty. Seven (47%) of these eyes required filtering surgery within three to 12 months after the second repeat laser trabeculoplasty. Four of 38 (11%) of the initial, two of 38 (5%) of the first repeat, and zero of 15 of the second repeat laser trabeculoplasty treatments resulted in a one- to two-hour rise in intraocular pressure of at least 10 mm Hg.

Adult↗
PubMed1988

Manganous chloride stimulation of adenylate cyclase responsiveness in ocular ciliary process membranes.

Manganous chloride was compared with magnesium chloride in supporting maximal stimulations of the adenylate cyclase system in ocular ciliary process membranes by isoproterenol, vasoactive intestinal peptide, sodium fluoride, guanosine 5'-(beta, gamma-imino) triphosphate (GppNHp), or forskolin, and in supporting synergism between isoproterenol and forskolin. The primary effect of Mn2+ (2 mM) was due to an interaction at the catalytic unit. Mn2+ had no significant effect on the function of the GTP-binding stimulatory G-protein (Gs) which couples beta-adrenergic receptors to the catalytic unit of adenylate cyclase. However, Gs-protein function was impaired by Mn2+ relative to Mg2+ when GppNHp was used instead of GTP as the ligand for the Gs-protein. Compared with Mg2+, Mn2+ caused a 4-5.5-fold increase in adenylate cyclase responsiveness to all the activators tested (except GppNHp, where the increase was 2.5-3.5-fold). Thus Mn2+ ions appeared to be intrinsically more effective at divalent cation binding sites on the catalytic unit that control its enzymatic activity. Ciliary process membranes differ from erythrocyte and S49 lymphoma cell membranes where 2 mM Mn2+ strongly inhibits hormone-Gs-protein-mediated stimulations of adenylate cyclase. Divalent cations bound to the catalytic unit also affected the degree of synergism between hormone-activated Gs and forskolin to stimulate adenylate cyclase activity. In the presence of MgCl2 all effective doses of isoproterenol and forskolin in combination showed marked synergism. In contrast, with MnCl2 there was no synergism with high-dose isoproterenol-forskolin combinations, which gave only additive responses.

Adenylyl Cyclases↗
PubMed1988

Signs of early damage in glaucomatous monkey eyes: low spatial frequency losses in the pattern ERG and VEP.

Experimental glaucoma was created in one eye of three cynomolgus monkeys by argon laser application to the mid-trabecular meshwork. Simultaneous pattern electroretinograms (PERG) and pattern visual evoked potentials (PVEP) were measured in both control and glaucoma eyes to spatial frequencies of 0.5, 1.25, 2.5, and 3.5 cpd which were counterphase modulated at 6 Hz. The transient flash electroretinogram was also measured. While normal flash electroretinograms were recorded in all eyes both before and after the unilateral production of elevated intraocular pressure (IOP), reductions in PERG and PVEP amplitude were seen in the eyes with glaucoma as early as two weeks following a sustained increase of IOP, despite the absence of cupping of the optic nervehead judged by ophthalmoscopic examination and analysis of photograph by two observers. Optic nervehead abnormalities occurred subsequently. In glaucomatous monkey eyes, the earliest PERG and PVEP changes were most evident with lower spatial frequencies of stimulation. Our data suggest that the optimal stimulus parameters for the detection of early glaucoma are low spatial frequency patterns presented at a rapid rate of temporal modulation.

Animals↗