Protective effects of new medicinal mushroom, Grifola gargal singer (higher Basidiomycetes), on induced DNA damage in somatic cells of Drosophila melanogaster.

Grifola gargal is an edible mushroom with attributed antioxidant properties. Different sources of G. gargal materials, i.e., fruit bodies and mycelia grown in liquid or solid media, were used to study its potential protective capacity when somatic mutation and recombination is induced in Drosophila melanogaster using DMBA (7-12-dimethyl-benz(α)anthracene) as promutagen. Heterozygote larvae (white/white+) were grown in media with different concentrations of DMBA. Grifola gargal fruit bodies (GgFB) or mycelia from liquid culture (GgLC) or from solid culture (GgWG), i.e., biotransformed wheat kernel flour, were added to the culture media in combined treatments with DMBA. Water, DMBA solvent, or wheat flour (WF) plus DMBA solvent were used as negative controls. Larval mortality increased from 9% to 11% in negative controls to 31% to 36% in DMBA treatments. The addition of GgFB, GgLC, or GgWG materials produced a protective effect on 25 µmol/vial DMBA-induced mortality. Mutations observed in SMART, as light spots per 100 eyes (LS/100 eyes), increased with increasing doses of DMBA; this was also true when considering the mutation incidence expressed as percentage of eyes exhibiting light spots (% eyes with LS). Interestingly, mycelia from GgFB, GgLC, or GgWG, in the presence of 25 µmol/vial DMBA, showed lower values in SMART of both the total LS/100 eyes and the percentage of eyes with LS. Thus, Grifola gargal materials were not only nontoxic, but in combination with 25 µmol/vial DMBA lowered the mortality induced by the promutagen and showed antimutagenic effects. Protective effects of G. gargal against DMBA are discussed in terms of the onset of desmutagenic and/or bioantimutagenic mechanisms of detoxification in the host organism, probably due to some bioactive compounds known to occur in higher mushrooms.

Eyelash growth from application of bimatoprost in gel suspension to the base of the eyelashes.

OBJECTIVE: To determine whether bimatoprost (Lumigan, Allergan Inc., Irvine, CA) causes increased lash length when used in gel suspension applied to the base of the eyelashes. DESIGN: Randomized controlled trial. PARTICIPANTS: Nineteen subjects were enrolled. METHODS: Subjects recruited from the Bascom Palmer Eye Institute were screened, and those who met inclusion criteria were enrolled. Each participant received 2 vials of gel suspension, which contained bimatoprost and normal saline, respectively, each mixed 1:1 with Gonak gel (Akorn Inc., Lake Forest, IL) and labeled "right eye" and "left eye" according to randomization. The suspension was applied to the upper eyelid eyelashes every evening on the designated eye for 6 weeks. MAIN OUTCOME MEASURES: Lash length was measured with a caliper at enrollment, at weekly intervals during the application of the gel, and at 1 and 3 months after discontinuation of its use. Visual acuity, ocular symptoms, intraocular pressure, and photographs were documented at these same intervals. RESULTS: The mean eyelash growth from baseline in the bimatoprost group was 2.0 mm versus a mean of 1.1 mm in the placebo group, which was a statistically significant difference (P=0.009). The average intraocular pressure decreased equally in both groups (2 mmHg). No change in visual acuity or iris discoloration was noted in any of the subjects. CONCLUSIONS: Our data showed an increase in eyelash length with the use of bimatoprost in gel suspension, suggesting the product's eyelash-lengthening properties.

Effect of Kynurenic Acid on Pupae Viability of Drosophila melanogaster cinnabar and cardinal Eye Color Mutants with Altered Tryptophan-Kynurenine Metabolism.

Kynurenic acid (KYNA) is one of the metabolites of evolutionary conserved tryptophan (Trp)/kynurenine (Kyn) metabolic pathway. Elevation of KYNA contributes to development of psychosis in schizophrenia but attenuates neurodegeneration in Drosophila model of Huntington's disease. We have reported that KYNA increased lethality of pupae of wild-type flies, but not of vermilion (v) mutants with impaired formation of Kyn from Trp, suggesting that KYNA toxicity depends on its interaction with downstream Kyn metabolites [i.e., 3-hydroxykynurenine (3-HK) and/or xanthurenic acid (XA)]. The present study aimed to further explore the mechanisms of KYNA-induced lethality by the assessment of KYNA effect on pupae of two Drosophila mutants: cinnabar (cn), characterized by higher KYNA and lower 3-HK production, and cardinal (cd), characterized by higher 3-HK and XA levels compared to wild-type flies. Our microarray datamining revealed that the gene expression pattern of enzymes forming Trp/Kyn pathway stands in line with previously reported developmental changes in KYNA, 3-HK, and XA concentrations in wild-type and mutant flies. Administration of KYNA increased pupae lethality in cd, but not in cn mutants. Present data suggest that toxic effect of exogenous KYNA depends on the presence of 3-HK and/or XA. This is further supported by our finding that early stages of Drosophila development are associated with a positive expression pattern of genes encoding sulfotransferases, enzymes that are inhibited by KYNA and are involved in detoxification of XA. Alternatively, the toxic effect of KYNA might depend on anti-proliferative effects of KYNA.

Effect of age on the development of a latanoprost-induced increase in iris pigmentation.

PURPOSE: To study the effect of patient age on the incidence of latanoprost-induced increases in iris pigmentation. DESIGN: Prospective observational observer-masked study. PARTICIPANTS: Thirty-six patients younger than 60 years (group 1) and 36 patients older than 75 years (group 2) with primary open-angle glaucoma. METHODS: We photographed both irises of each patient before and 6 months after unilateral latanoprost therapy. The basal iris colors were matched in both groups. MAIN OUTCOME MEASURES: Iris heterochromia identification at the 6-month evaluation of the photographs. RESULTS: Twenty-eight patients (77.78%) in group 2 developed an increase in iris pigmentation compared with eight patients (22.22%) in group 1 (P = 0.0001, chi-square test). CONCLUSIONS: Age seems to be an important risk factor for latanoprost-induced iris color change.

The clinical impact and incidence of periocular pigmentation associated with either latanoprost or bimatoprost therapy.

PURPOSE: To evaluate the incidence and characteristics of periocular pigmentation with latanoprost versus bimatoprost. METHODS: A retrospective, active-controlled comparison of consecutive patients treated with latanoprost or bimatoprost for 12 months evaluating patients to determine the incidence, characteristics, and reversibility of periocular pigmentation. RESULTS: Periocular pigmentation was found in 1% patients treated with latanoprost and 6% patients treated with bimatoprost within 12 months of beginning treatment (p = 0.004). CONCLUSIONS: This study suggests that periocular pigmentation may develop after treatment with latanoprost or bimatoprost.

Monte Carlo simulation of latanoprost induced iris darkening.

The aim of this study was to provide numerical evidence that latanoprost induced iris darkening (LIID) can be caused by changes to the melanin granule size distribution in the anterior segment of the iris. Iridectomies from two patients were used, where both had undergone unilateral treatment with latanoprost and had exhibited LIID. The untreated eye provided the comparative control. Micrographs from the iris samples were analysed to determine the number and size of the mature melanin granules. Monte Carlo (MC) simulation of light propagation in the iris was performed to examine the changes in reflectance and absorption with varying particle size and density. The reflected intensity of light was obtained as a function of wavelength. CIE colour theory was employed in order to estimate a perceived colour from the reflectance data. MC simulations showed that the reflectance was reduced for the LIID irises compared to the control irises for both subjects and for all wavelengths of light. The MC simulated colours were in good agreement with the in vivo photography of the eye colour. Hence, we have demonstrated that increases in melanin granule size causes iris darkening, and can explain LIID.

Incidence of a latanoprost-induced increase in iris pigmentation in Japanese eyes.

PURPOSE: To prospectively determine the incidence of a latanoprost-induced increase in iris pigmentation in Japanese brown iris eyes by identifying changes in iris pigmentation on a series of iris color photographs. METHODS: In a cohort study, we prospectively and consecutively enrolled 104 patients (104 eyes) with primary open-angle glaucoma or normal-tension glaucoma who began treatment with latanoprost eye drops for the first time. None of the enrolled patients had a history of previous intraocular surgery or laser surgery. Patients comprised 51 men and 53 women. Their ages ranged from 23 to 80 years (mean +/- SD, 63.8 +/- 10.4 years). Before and every 3 months after starting latanoprost treatment, iris photographs were taken using a slit-lamp biomicroscope with an attached camera. To identify an increase in iris pigmentation, seven glaucoma specialists independently read the series of photographs. If five of the seven observers agreed that iris pigmentation had increased, we determined that the iris pigmentation had increased from the time the previous photograph was taken. Ten normal volunteers served as controls, and photographs of their eyes were used in the evaluation of iris pigmentation. The Kaplan-Meier life table analysis was adopted to evaluate the incidence of increase in iris pigmentation during treatment with latanoprost. RESULTS: The Kaplan-Meier life table analysis indicated that the incidence of increased iris pigmentation at 3, 6, 9, 12, and 15 months after the start of latanoprost treatment was 16.3%, 34.2%, 49.5%, 58.2%, and 58.2%, respectively. CONCLUSIONS: Latanoprost instillation for at least 1 year induced increased iris pigmentation in approximately 50% of the treated Japanese eyes, which is a considerably higher percentage than that reported in Caucasians.

A Clinical Randomized Trial Comparing the Cycloplegic Effect of Cyclopentolate Drops Applied to Closed Eyelids Versus Open Eyelids.

BACKGROUND AND PURPOSE: Adequate cycloplegia and dilation are required for refraction and fundus exam in children. Standard practice is to instill cycloplegic drops in the inferior cul-de-sac, and this is often traumatic for children. Our study assesses the use of cyclopentolate on closed lids as a method of instillation for ensuring complete cycloplegia. PATIENTS AND METHOD: Ninety children presenting for annual refraction were enrolled. Three were excluded as they did not finish the testing. One drop of Alcaine® and one drop of cyclopentolate HCL 1% were used in each eye. Cyclopentolate drops were placed on the inner canthus near the lid margin on the closed eye and directly onto the conjunctiva of the fellow eye. RESULTS: Overall, 145/174 eyes (83%) were fully cyclopleged with one drop. The methods of instillation were equally successful (seventy-two indirect vs. seventy-three direct). Age, eye color, spherical refractive error, astigmatic refractive error, and presence of amblyopia on the study visit played no role in the success of either method. Dark irises where the pupil margin was clinically indistinguishable had the largest number of failures (n = 17/44) in comparison to light irises (12/130), but had an equal amount of failures for both direct and indirect methods. CONCLUSION: Placing one drop of cyclopentolate HCL 1% on a closed eyelid had a success rate for complete cycloplegia that was equivalent to placing one drop directly on the cornea.

Comparison of mydriatic regimens used in screening for retinopathy of prematurity in preterm infants with dark irides.

PURPOSE: To determine the mydriatic regimen that provides optimal dilation of the pupil with minimal systemic side effects for screening of retinopathy of prematurity. METHODS: This cross-sectional, randomized, double-masked clinical trial compared cyclopentolate 1% + phenylephrine 2.5%, tropicamide 1% + phenylephrine 2.5%, and a prepared combination of cyclopentolate 0.2% with phenylephrine 1% for pupillary dilation in preterm infants with dark irides. Thirteen infants were randomized to each regimen. Outcomes measured were pupillary dilation, heart rate, blood pressure, abdominal girth, and intolerance to feeds. RESULTS: All three mydriatic regimens provided adequate pupillary dilation at 45 minutes, with dilation sustained at 60 minutes. There was a significant increase in mean blood pressure in the cyclopentolate 1% + phenylephrine 2.5% and the tropicamide 1% + phenylephrine 2.5% groups. Although there was no significant change of abdominal girth in any of the three groups, a total of eight patients developed intolerance to feeds; four (50%) of these infants were from the cyclopentolate 1% + phenylephrine 2.5% group. CONCLUSION: The prepared combination of cyclopentolate 0.2% + phenylephrine 1% appears to be the mydriatic of choice for preterm infants with dark irides as it provided adequate pupillary dilation with the least systemic side effects.

Propofol: del blanco al verde / Propofol: From white to green

No disponible

Loxapine as an alternative to phenothiazines in a case of oculocutaneous skin pigmentation.

The authors describe a patient with changes in oculocutaneous pigmentation that cleared after chlorpromazine was discontinued. They suggest that loxapine may be a suitable alternative to phenothiazines when skin pigmentation and ocular involvement occur, although the patient must be carefully monitored for ocular problems.

Eosinophil chemotaxis and anterior uveitis from topical dimaprit and nordimaprit.

Topical application of the H2-histamine receptor agonist, dimaprit (S-[4-N,N-dimethylaminopropyl]isothiourea), produced eosinophil chemotaxis into the anterior segment of rabbit eyes only when an H2-antagonist was co-administered. Nordimaprit (S-[4-N,N-dimethylaminoethyl]isothiourea), a structural homologue of dimaprit that lacked activity at histamine receptors, produced eosinophil chemotaxis whether or not an H2-antagonist was co-administered. Onset of eosinophil chemotaxis began after 2 or more days of treatment, and was accompanied by corneal edema, opacification, and ocular inflammation. There was no concurrent eosinophilia in the peripheral blood or in the conjunctiva. The response occurred in pigmented and albino rabbit eyes, and was facilitated by prior co-administration of proparacaine eye drops. Another dimaprit homologue without activity at histamine receptors, homodimaprit (S-[4-N,N-dimethylaminobutyl]isothiourea), did not produce eosinophil chemotaxis when applied topically, nor did the H2-agonists impromidine, histamine, or 4-methylhistamine, whether co-administered with an H2-antagonist or not. It was concluded that dimaprit and nordimaprit produced a selective eosinophil chemotaxis unrelated to H1- and H2-histamine receptor activity. However, the H2-agonist activity of dimaprit appeared to inhibit this response unless neutralized by an H2-antagonist. Topical application of dimaprit with an H2-antagonist or nordimaprit alone may allow large numbers of non-degranulated eosinophils, free of other cell types, to be harvested from the aqueous humor.

Prostaglandin-induced iris color darkening. An experimental model.

OBJECTIVES: To determine the role of sympathetic innervation and the effect of topical prostaglandin therapy on iris color in pigmented rabbits. METHODS: Twelve Dutch-belted rabbits underwent unilateral superior cervical ganglionectomy (SCGx) at age 1 to 3 months. A second group of 11 rabbits underwent bilateral SCGx at age 1 month and were treated once or twice daily for 6 to 9 months with 1 drop (about 20 microL) of latanoprost, 0.005%, to one eye and its vehicle to the contralateral eye. Standardized color photographs of the iris of each eye were taken at 1- to 2-month intervals for 6 to 10 months and evaluated by 4 to 6 observers in a masked fashion. RESULTS: At 8 to 10 months after unilateral SCGx, 11 of 12 rabbits showed definite heterochromia, with the lighter-colored iris on the SCGx side. Of the 11 rabbits that underwent bilateral SCGx and unilateral latanoprost treatment, 9 showed heterochromia at 6 to 9 months, with the darker-colored iris on the latanoprost-treated side. CONCLUSIONS: These results demonstrate that sympathetic innervation is required for age-related, physiologic darkening of iris color in rabbits, that prostaglandins may compensate for sympathetic denervation to produce darkening in SCGx eyes, and that this model may be useful to study prostaglandin-induced iris color change.

A 5-year, multicenter, open-label, safety study of adjunctive latanoprost therapy for glaucoma.

OBJECTIVE: To evaluate the 5-year safety and efficacy of adjunctive 0.005% latanoprost once daily. METHODS: Patients with primary open-angle or exfoliation glaucoma who completed a 3-year, open-label, uncontrolled, prospective trial could enter a 2-year extension phase. High-resolution color photographs of irides were taken at baseline and at 14 subsequent visits. Photographs were assessed for change in iris pigmentation compared with baseline. Intraocular pressures and adverse events were recorded. MAIN OUTCOME MEASURE: Development and progression of increased iris pigmentation over 5 years. RESULTS: Of the 519 original patients, 380 enrolled in the extension phase with approximately 89% having an eye color known to be susceptible to color change. After 5 years, most patients had no increase in iris pigmentation, but certain colored irides exhibited notably greater susceptibility than others. For those whose irides did change, onset occurred during the first 8 months in 74% and during the first 24 months in 94%. No patient developed an increase in pigmentation after month 36; the rate of progression decreased over time. Adverse event profiles were similar for patients with and without increased pigmentation. The overall mean intraocular pressure reduction from baseline of 25% was sustained with no need for change in intraocular pressure-lowering treatment in 70% of the eyes. CONCLUSION: Latanoprost therapy is safe and well tolerated for long-term treatment of open-angle glaucoma.

The mechanism of timolol in lowering intraocular pressure. In the normal eye.

A single-drop, double-masked, randomized, placebo-controlled study of the mechanism of the ocular-pressure lowering property of timolol maleate, a beta-adrenergic blocker, was carried out in 23 normal subjects, using fluorophotometry. Timolol suppressed aqueous formation in all subjects. The range of suppression was 13% to 48%, with a mean +/- SD of 34% +/- 9%. The drug had no effect on anterior chamber volume or endothelial permeability to fluorescein and, apparently, had no effect on outflow resistance. No differences were observed between its effect on men and women or between eyes with light and dark irides.

Prostaglandins: a new approach to glaucoma management with a new, intriguing side effect.

This introductory overview considers the advantages of a class of local hormones-the prostaglandins (PGs)-for the management of intraocular pressure (IOP) in glaucoma, over agonists and antagonists of neurotransmitters that dominated this field in the 20th century. PGs and PG analogues, in particular esterified prodrug forms of PGF2 alpha, are effective ocular hypotensive agents, but cause some conjunctival hyperemia and corneal sensory irritation at higher concentrations. Based on structure-activity studies, a 17-phenyl PGF2 alpha prodrug, latanoprost (PhXA41), was found to have a greatly improved therapeutic index, without compromising the ocular hypotensive potency of PGF2 alpha prodrugs. The IOP lowering mechanism of such PGF2 alpha s, increased uveoscleral outflow, can be expected to have great physiologic advantages, especially with respect to normal tension glaucoma, over most currently used ocular hypotensive drugs. The introduction of this new approach has already led to a new insight into the control and clinical significance of this outflow route. Similarly, the newly discovered ocular side effect, PG-induced increase in iridial pigmentation, can be expected to provide insight into the oculo-protective role of iridial melanocytes and into the punative association between a decline in the ocular melanin system and the vulnerability of the eye to some age-related diseases.

Prostaglandin-induced hair growth.

Latanoprost, used clinically in the treatment of glaucoma, induces growth of lashes and ancillary hairs around the eyelids. Manifestations include greater thickness and length of lashes, additional lash rows, conversion of vellus to terminal hairs in canthal areas as well as in regions adjacent to lash rows. In conjunction with increased growth, increased pigmentation occurs. Vellus hairs of the lower eyelids also undergo increased growth and pigmentation. Brief latanoprost therapy for 2-17 days (3-25.5 microg total dosage) induced findings comparable to chronic therapy in five patients. Latanoprost reversed alopecia of the eyelashes in one patient. Laboratory experiments with latanoprost have demonstrated stimulation of hair growth in mice and in the balding scalp of the stumptailed macaque, a primate that demonstrates androgenetic alopecia. The increased number of visible lashes is consistent with the ability of latanoprost to induce anagen (the growth phase) in telogen (resting) follicles while inducing hypertrophic changes in the involved follicles. The increased length of lashes is consistent with the ability of latanoprost to prolong the anagen phase of the hair cycle. Correlation with laboratory studies suggests that initiation and completion of latanoprost hair growth effects occur very early in anagen and the likely target is the dermal papilla.

Prostaglandin-induced iridial pigmentation in primates.

Latanoprost, a new ocular hypotensive prostaglandin F2 alpha analogue prodrug, was found to induce increased pigmentation of monkey irides in chronic toxicity studies. This prompted us to investigate the effect of naturally occurring prostaglandins on the monkey iris to determine whether this pigmentary effect is unique for latanoprost or whether it is a class effect of prostaglandins. PGF2 alpha-isopropyl ester (IE), PGE2-IE and latanoprost were applied topically to cynomolgus monkey eyes for 18-44 weeks. One eye of each animal was treated, while the other served as control. In addition, latanoprost was applied to sympathectomized monkey eyes. PGF2 alpha-IE, PGE2-IE, as well as latanoprost, induced increased pigmentation in the monkey eye. The first signs of this effect were seen after about two months of treatment. Latanoprost also induced increased pigmentation in sympathectomized eyes. It is concluded that both naturally occurring prostaglandins and their synthetic analogues can induce increased iridial pigmentation in cynomolgus monkeys, and that the effect does not require the presence of sympathetic nerves.