Tomasz Żarnowski

Influence of combined treatment with NMDA and non-NMDA receptor antagonists on electroconvulsions in mice

alpha-Amino-3-hydroxy-5-methyl-isoxazole-4-propionate/kainate (AMPA/kainate) receptor antagonists (at subthreshold doses against electroconvulsions), 1-(4-aminophenyl)-4-methyl-7,8-methylenedioxy-5H-2,3-benzodiazepine (GYKI 52466 at maximally 5 mg/kg) and 2,3-dihydroxy-6-nitro-7-sulfamoylbenzo(F)quinoxaline (NBQX at maximally 20 mg/kg) enhanced the protective effects of NMDA receptor antagonists, MK-801 (dizocilpine) or 2-(2-carboxypiperazine-4-yl)-1-propenyl-1-phosphonic acid (D-CPP-ene), against electroconvulsions. Similarly, MK-801 or D-CPP-ene reduced the ED50 values of both NBQX and GYKI 52466 against maximal electroshock. The adverse effects of D-CPP-ene, evaluated in the chimney and rotorod tests, were potentiated by both GYKI 52466 (2.5 mg/kg) and NBQX (10 mg/kg). Also, D-CPP-ene (0.1 mg/kg) worsened the motor performance of mice pretreated with GYKI 52466 in the rotorod test. Neither MK-801 (0.025 mg/kg) nor D-CPP-ene (0.1 mg/kg) affected the NBQX-induced impairment of motor coordination. Similarly, GYKI 52466 (2.5 mg/kg) or NBQX (10 mg/kg) did not influence the performance of mice treated with MK-801 (0.2 mg/kg). It may be concluded that the blockade of more than one subtype of glutamate receptors leads to a more pronounced anticonvulsive effect when compared with the effect of blockade of an individual receptor subtype. In some cases more efficient seizure protection was not associated with increased adverse effects.

The competitive NMDA antagonist, D-CPP-ene, potentiates the anticonvulsant activity of conventional antiepileptics against maximal electroshock-induced seizures in mice

D-CPP-ene[3-(2-carboxy-piperazine-4-yl)-1-propenyl-1-phosphonic acid; a competitive antagonist of N-methyl-D-aspartic acid] in a dose of 2 mg/kg (i.p.) significantly increased the threshold for electroconvulsions. When given in a dose half that affecting the electroconvulsive threshold, D-CPP-ene potentiated the anticonvulsant activity of carbamazepine, diazepam, diphenylhydantoin, phenobarbital and valproate against maximal electroshock (50 mA)-induced seizures in mice. However, this NMDA antagonist did not influence the plasma levels of the antiepileptic drugs studied, so a pharmacokinetic interaction, in terms of total plasma levels at least, is not probable. The chimney test and retention test in mice revealed that the combined treatment of D-CPP-ene at 1.0 mg/kg (i.p.) with either diazepam, diphenylhydantoin, phenobarbital or valproate (providing a 50% protection against maximal electroshock convulsions) resulted in motor impairment and caused impairment of long-term memory. On the other hand, a combination of D-CPP-ene and carbamazepine was devoid of adverse effects. It can be concluded that the potential utility of D-CPP-ene in combination with conventional antiepileptic drugs does not seem promising, except for carbamazepine.

Comparison of the use of 5‐fluorouracil and bevacizumab in primary trabeculectomy: results at 1 year

Background:  The present study compared the effects of adjuvant bevacizumab and 5‐fluorouracil on the efficacy and safety of trabeculectomy.

Acute anticonvulsant effects of capric acid in seizure tests in mice

Capric acid (CA10) is a 10-carbon medium-chain fatty acid abundant in the medium-chain triglyceride ketogenic diet (MCT KD). The purpose of this study was to characterize acute anticonvulsant effects of CA10 across several seizure tests in mice. Anticonvulsant effects of orally (p.o.) administered CA10 were assessed in the maximal electroshock seizure threshold (MEST), 6-Hz seizure threshold, and intravenous pentylenetetrazole (i.v. PTZ) seizure tests in mice. Acute effects of CA10 on motor coordination were assessed in the grip and chimney tests. Plasma and brain concentrations of CA10 were measured. Co-administration studies with CA10 and another abundant medium-chain fatty acid, caprylic acid (CA8) were performed. CA10 showed significant and dose-dependent anticonvulsant properties by increasing seizure thresholds in the 6-Hz and MEST seizure tests; it was ineffective in the i.v. PTZ seizure test. At higher doses than those effective in the 6-Hz and MEST seizure tests, CA10 impaired motor performance in the grip and chimney tests. An enhanced anticonvulsant response in the 6-Hz seizure test was produced when CA8 and CA10 were co-administered. An acute p.o. administration of CA10 resulted in dose-proportional increases in its plasma and brain concentrations. CA10 exerted acute anticonvulsant effects at doses that produce plasma exposures comparable to those reported in epileptic patients on the MCT KD. An enhanced anticonvulsant effect is observed when CA10 and the other main constituent of the MCT KD, CA8, were co-administered. Thus, acute anticonvulsant properties of CA10 and CA8 may influence the overall clinical efficacy of the MCT KD.

Elevated Concentrations of Kynurenic Acid, a Tryptophan Derivative, in Dense Nuclear Cataracts

Purpose: Kynurenines and their glycoside derivatives in the ocular lens absorb ultraviolet radiation and thus possibly help protect the retina from ultraviolet light. The current study analysed kynurenine aminotransferase I (KAT I) activity and kynurenic acid (KYNA) concentrations in human senile cataractous lenses and in experimentally induced cataracts in diabetic rats treated with streptozotocin (STZ). Methods: KYNA levels and KAT I activity were investigated with HPLC and detected fluorimetrically in the nuclei of 91 human cataractous lenses collected during planned extracapsular extraction. The lenses were classified on the Lens Opacity Classification System III scale and compared with clear lenses regarding KYNA concentrations. Cataractous lenses from STZ-treated rats were compared with control lenses. Results: KYNA concentration was 0.95 ± 0.22 in human NC0 (nuclear color) control lenses, 0.8 ± 0.72 in NC1, 1.18 ± 0.88 in NC2, 1.31 ± 0.70 in NC3, 1.78 ± 0.92 in NC4, 8.80 ± 8.28 (p < 0.05 vs. NC0) in NC5, and 14.0 ± 11.1 (p < 0.05 vs. NC0) in NC6. A correlation was found between KYNA concentrations and the grade of cataract (r = 0.047, p < 0.001). KAT I activity in human cataracts was 0.44 ± 0.16 pmol/mg protein− 1 hr− 1. Elevated KYNA concentrations in rat cataractous lenses were also observed (p < 0.05). Conclusions: KYNA levels are elevated in senile nuclear human cataracts and in cataractous lenses of rats with experimentally induced diabetes.

Occurrence of human papillomavirus in pterygia.

Purpose:  The aim of the study was to assess the occurrence of human papillomavirus (HPV) DNA in pterygium.

Evaluation of the Effectiveness of Surgical Treatment of Malignant Glaucoma in Pseudophakic Eyes through Partial PPV with Establishment of Communication between the Anterior Chamber and the Vitreous Cavity

Purpose. Determination of partial posterior vitrectomy (PPV) in the proposed modification for treatment of malignant glaucoma. Methods. The prospective, consecutive, single-center case series study involved patients in whom symptoms of malignant glaucoma occurred after combined cataract and glaucoma surgery or after glaucoma surgery in pseudophakic eye. When medical and laser treatment were not successful, partial PPV with establishment of communication between the anterior chamber and the vitreous cavity was performed. Efficacy measures were intraocular pressure (IOP) reduction, corrected distance visual acuity (CDVA), AND the number of antiglaucoma medications. Surgical success and occurring complications were also evaluated. Results. The study enrolled 20 eyes of 17 patients. Average IOP was reduced from 30.4 ± 14.2 (SD) mmHg to 14.6 ± 3.2 (SD) mmHg one year after surgery (P < 0.00001). A statistically significant reduction of the number of antiglaucoma medications was obtained from 3.3 ± 1.1 (SD) preoperatively to 1.2 ± 1.1 (SD) at the end of follow-up. Statistically significant improvement of CDVA was observed 3, 6, and 12 months after surgery. Conclusions. Partial PPV with establishment of communication between the anterior chamber and the vitreous cavity enables effective IOP control over a 12-month observation; however, in most cases, it is necessary to use antiglaucoma medications for IOP control.

Deterioration of filtering bleb morphology and function after phacoemulsification

BackgroundTrabeculectomy remains the most efficient method of lowering he IOP applied for the treatment of glaucoma refractory to pharmacological treatment. Cataract is concerned as the most frequent late complication of trabeculectomy. The aim of the study was to analyse the effect of phacoemulsification with posterior chamber lens implantation on the morphology and function of filtering bleb in patients after previous successful trabeculectomy.MethodsThe retrospective study included 122 eyes treated for primary open angle glaucoma, 50 eyes (study group) in which, after a successful trabeculectomy with5-Fluorouracil, phacoemulsification with posterior chamber lens implantation was performed, and 72 eyes (control group), in which only a successful trabeculectomy was conducted. The surgical success of the trabeculectomy was expressed as IOP < 17 mmHg.ResultsIn the group of patients subjected to both trabeculectomy and phacoemulsification, mean IOP was significantly higher than in the group of patients who underwent trabeculectomy after 6 months (p = 0.003), 12 months (p = 0.01) and 18 months (p = 0.007) of observation. The filtering blebs after phacoemulsification in the study group were characterized by a greater reduction, compared to those in the control group. Cox regression survival success was 75% (SE = 5.9; 95% CI: 63.4 – 86.6), 75% (SE = 5.9; 95% CI: 63.4 – 86.6), 71% (SE = 5.4; 95% CI: 60.4 – 81.6) in study group and 92% (SE = 1.8; 95% CI: 91.5 – 98.5), 92% (SE = 1.9; 95% CI: 88.3 – 95.7), 91% (SE = 2.0; 95% CI: 87.1 – 94.9) in control group after 6, 12 and 18 months, respectively.ConclusionsPhacoemulsification causes a significant elevation of IOP in the eyes after previous successful trabeculectomy and deterioration of filtering bleb morphology.

Evidence for Intraocular Synthesis of Kynurenic Acid, a Putative Endogenous Neuroprotectant

Kynurenic acid (KYNA), an excitatory amino acid antagonist preferentially active at glycine binding site of the NMDA receptor, has been previously identified in the brain. This study was designed to examine its presence in the rabbit vitreous humor. Mean (± SD) level of KYNA in the vitreous was 22.3 ± 3.9 pmol/ml as determined by HPLC. Intravitreal administration of 10 mmol aminooxyacetic acid (AOAA), a KYNA synthesis inhibitor, diminished its production by 9.6% after 2 h, 47.8% after 24 h and 21.5% after 48 h. It can be concluded that AOAA decreases the intravitreal concentration of KYNA, providing evidence of its intraocular origin.

Risk Factors in Normal-Tension Glaucoma and High-Tension Glaucoma in relation to Polymorphisms of Endothelin-1 Gene and Endothelin-1 Receptor Type A Gene

The aim of the research is to analyse the influence of polymorphisms of endothelin-1 gene and endothelin-1 receptor type A gene on the clinical condition of patients with primary open angle glaucoma. Methods. 285 Polish patients took part in the research (160 normal-tension glaucoma and 125 high-tension glaucoma). DNA was isolated by standard methods and genotype distributions of four polymorphisms in genes encoding endothelin-1 (K198N) and endothelin-1 receptor type A polymorphisms (C1222T, C70G, and G231A) were determined. Genotype distributions were compared between NTG and HTG groups. The clinical condition of participants was examined for association with polymorphisms. Results. A similar frequency of occurrence of the polymorphic varieties of the studied genes was observed in patients with NTG and HTG. There is no relation between NTG risk factors and examined polymorphisms. NTG patients with TT genotype of K198N polymorphism presented with the lowest intraocular pressure in comparison to GG + GT genotype (p = 0.03). In NTG patients with CC genotype of C1222T polymorphism (p = 0.028) and GG of C70G polymorphism (p = 0.03) the lowest values of mean blood pressure were observed. Conclusions. The studied polymorphic varieties (K198N, C1222T) do have an influence on intraocular pressure as well as arterial blood pressure in NTG patients.