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Cytidine 5’-diphosphocholine has been widely studied in systemic neurodegenerative diseases, like Alzheimer’s disease, Parkinson’s disease, and brain ischemia. The rationale for the use of citicoline in ophthalmological neurodegenerative diseases, including glaucoma, anterior ischemic optic neuropathy, and diabetic retinopathy, is founded on its multifactorial mechanism of action and the involvement in several metabolic pathways, including phospholipid homeostasis, mitochondrial dynamics, as well as cholinergic and dopaminergic transmission, all being involved in the complexity of the visual transmission. This narrative review is aimed at reporting both pre-clinical data regarding the involvement of citicoline in such metabolic pathways (including new insights about its role in the intracellular proteostasis through an interaction with the proteasome) and its effects on clinical psychophysical, electrophysiological, and morphological outcomes following its use in ophthalmological neurodegenerative diseases (including the results of the most recent prospective randomized clinical trials).

IntroductionKnee osteoarthritis (KOA) represents a widespread degenerative disease that causes pain and motor disability. Conservative treatments mainly focus on relieving symptoms, improving joint function, and trying to delay surgery. Safety and efficacy of hybrid cooperative complexes (2.4% sodium hyaluronate and 1.6% sodium chondroitin; HA-SC) for symptomatic KOA were investigated in a single-arm, prospective, pilot study.MethodsPatients with a visual analogue scale (VAS) pain score ≥ 4 and Kellgren–Lawrence Grade < 4 received a single intraarticular HA-SC injection. Patients with a VAS score change from baseline ≤ 1 received a second injection at day 30. Device-related adverse events (DR-AEs)/adverse events (AEs) were primary endpoints. Secondary endpoints included Western Ontario and McMaster Universities Osteoarthritis Index LK 3.1 (WOMAC LK 3.1), VAS, patient global assessment of disease status (PtGA), and patient proportion needing a second injection.ResultsOf 83 patients with KOA (Kellgren–Lawrence Grade, 2–3), 34.9% had DR-AEs at day 7. No serious DR-AEs/AEs were reported. A significant (P < 0.0001) reduction over time in VAS pain score plus WOMAC pain, stiffness, physical function limitation, and total scores was reported. Median PtGA scores indicated a ‘slight improvement’ at most follow-up visits. Only 18.1% of patients required a second injection.ConclusionsA single intraarticular HA-SC injection was safe, well-tolerated, and did not lead to major deterioration in terms of reducing knee pain, stiffness, and physical function limitation in patients with symptomatic KOA.

A network of nanofibers is formed in situ through solid-state deformation of disentangled ultra-high molecular weight polyethylene (dis-UHMWPE) during compounding with a polyolefin elastomer below the melting temperature of dis-UHMWPE crystals. Dis-UHMWPE was prepared in the form of powder particles larger than 50 μm by polymerization at low temperatures, which favored the crystallization and prevention of macromolecules from entangling. Shearing the blend for different durations and at different temperatures affects the extent to which the grains of dis-UHMWPE powder deform into nanofibers. Disentangled powder particles could deform into a network of nanofibers with diameters between 110 and 340 nm. The nanocomposite can be further sheared for a longer time to decrease the diameter of dis-UHMWPE nanofibers below 40 nm, being still composed of ≈70 wt.% of crystalline and ≈30 wt.% of amorphous components. Subsequently, these thinner fibers begin to melt and fragment because they are thinner and also because the amorphous defects locally decrease the nanofibers’ melting temperature, which results in their fragmentation and partial loss of nanofibers. These phenomena limit the thickness of dis-UHMWPE nanofibers, and this explains why prolonged or more intense shearing does not lead to thinner nanofibers of dis-UHMWPE when compounded in a polymeric matrix.

Quercetin is a hydrophobic molecule with short blood circulation times and instability. The development of a nano-delivery system formulation of quercetin may increase its bioavailability, resulting in greater tumor suppressing effects. Triblock ABA type polycaprolactone-polyethylenglycol- polycaprolactone (PCL-PEG-PCL) copolymers have been synthetized using ring-opening polymerization of caprolactone from PEG diol. The copolymers were characterized by nuclear magnetic resonance (NMR), diffusion-ordered NMR spectroscopy (DOSY), and gel permeation chromatography (GPC). The triblock copolymers self-assembled in water forming micelles consisting of a core of biodegradable polycaprolactone (PCL) and a corona of polyethylenglycol (PEG). The core-shell PCL-PEG-PCL nanoparticles were able to incorporate quercetin into the core. They were characterized by dynamic light scattering (DLS) and NMR. The cellular uptake efficiency of human colorectal carcinoma cells was quantitatively determined by flow cytometry using nanoparticles loaded with Nile Red as hydrophobic model drug. The cytotoxic effect of quercetin-loaded nanoparticles was evaluated on HCT 116 cells, showing promising results.

PurposeThis study aims to evaluate whether the use of citicoline oral solution could improve quality of life in patients with chronic open-angle glaucoma (OAG).DesignRandomized, double-masked, placebo-controlled, cross-over study was used. Patients were randomized to one of the two sequences: either citicoline 500 mg/day oral solution-placebo or placebo-citicoline 500 mg/day oral solution. Switch of treatments was done after 3 months; patients were then followed for other 6 months. Follow-up included 3-month, 6-month, and 9-month visits.OutcomesThe primary outcome was the mean change of “intra-patient” composite score of the Visual Function Questionnaire-25 (VFQ-25). after citicoline oral solution vs placebo at 6-month visit as compared with baseline.MethodsThe trial was multicenter, conducted at 5 European Eye Clinics. OAG patients with bilateral visual field damage, a mean deviation (MD) ranging from − 5 to − 13 dB in the better eye, and controlled IOP were included. VFQ-25 and SF-36 questionnaires were administered at baseline and at 3-, 6-, and 9-month visits. A mixed effect model, with a random effect on the intercept, accounted for correlations among serial measurements on each subject.ResultsThe primary pre-specified outcome of the analysis reached statistical significance (p = 0.0413), showing greater improvement after citicoline oral solution. There was an increase in the composite score in both arms compared to baseline, but it was significant only for the placebo-citicoline arm (p = 0.0096, p = 0.0007, and p = 0.0006 for the three time-points compared to baseline). The effect of citicoline was stronger in patients with vision-related quality of life more affected by glaucoma at baseline.ConclusionsThis is the first placebo-controlled clinical study evaluating the effect of a medical treatment aiming at improving vision-related quality of life in glaucomatous patients.

PurposeTo evaluate the penetration of levofloxacin and dexamethasone sodium phosphate into the aqueous humour (AH) after administration in combination and as single molecules. Evaluation of the penetration of those agents in the site of action and their pharmacodynamic potential activity in view of the intended clinical use after cataract surgery.MethodsRandomised, assessor-blinded, parallel-group. Patients scheduled for cataract surgery were assigned in a 1:1:1 ratio to: levofloxacin + dexamethasone sodium phosphate (L-DSP), Levofloxacin (L) or Dexamethasone sodium phosphate (DSP) eye drops. Either test or reference drugs were instilled in the cul-de-sac twice, 90 and 60 min before paracentesis.ResultsA total of 125 patients completed the study. Fraction of dose absorbed in the anterior chamber was 3.8–4.2 · 10−4 for levofloxacin and 0.3–0.4 · 10−4 for dexamethasone, respectively. No notable differences in concentration of levofloxacin were found between L-DSP arm (1.970 nmol/ml) and L arm (2.151 nmol/ml). The concentrations of levofloxacin were well above the MICs for the most frequent Gram-positive and Gram-negative eye pathogens. Dexamethasone concentrations were slightly lower in L-DSP arm (0.030 nmol/ml) than in DSP arm (0.042 nmol/ml), but still in the pharmacodynamically active range in the site of action. The difference was not clinically relevant. DSP was not detected in any HA sample, suggesting its full hydrolysis to free dexamethasone.ConclusionOur results confirm that no interaction is evident on the corneal penetration of levofloxacin and dexamethasone which reach pharmacologically active concentrations when instilled as fixed combination eye drops to patients undergoing cataract surgery.Trial registrationClinicalTrials.gov Identifier: NCT03740659

Purpose To analyze the prospectively collected data in a series of patients treated with single- or multilevel ACDF with a stand-alone, zero-profile device, focusing on clinico-radiological outcome, complications and technical hints, and to review the literature on such new devices. Methods Eighty-five patients harboring symptomatic DDD underwent ACDF with the Zero-P cage-plate: 29 at 1-level and 56 at 2–4 levels (total 162 devices). In the multilevel group, 9 patients received a combination of Zero-P and stand-alone cages (hybrid implants). This study focuses on 32 patients with follow-up ranging from 20 to 48 months. NDI, SF-36 and arm pain VAS scores were registered preoperatively and at follow-up visits. Dysphagia was assessed using the Bazaz score. Imaging included X-rays, CT and MRI, also to assess the presence of vertebral body fractures in multilevel cases. Paired Student t test was used for statistical analysis. Results SF-36 and NDI showed a statistically significant improvement ( p  < 0.01) and mean arm pain VAS score decreased from 79 to 41. X-rays and CT demonstrated, respectively, a 94.5 % and a 92 % fusion rate. Three patients complained of moderate and two of mild transient dysphagia (15.5 %). No device-related complications occurred and no fractures, secondary to four screws insertion in one vertebral body (i.e., swiss cheese effect), were detected in multilevel cases. In patients with extensive anterior osteophytes only a “focal spondylectomy” was required. Conclusion The Zero-P device is safe and efficient, even in multilevel cases. Dysphagia is minimal, extensive anterior osteophytectomy is unnecessary and technical hints may ease the surgical workflow. This is the largest series, with the longest follow-up, reported.

Quercetin is a hydrophobic molecule with short blood circulation times and instability. The development of a nano-delivery system formulation of quercetin may increase its bioavailability, resulting in greater tumor suppressing effects. Triblock ABA type polycaprolactone-polyethylenglycol- polycaprolactone (PCL-PEG-PCL) copolymers have been synthetized using ring-opening polymerization of caprolactone from PEG diol. The copolymers were characterized by nuclear magnetic resonance (NMR), diffusion-ordered NMR spectroscopy (DOSY), and gel permeation chromatography (GPC). The triblock copolymers self-assembled in water forming micelles consisting of a core of biodegradable polycaprolactone (PCL) and a corona of polyethylenglycol (PEG). The core-shell PCL-PEG-PCL nanoparticles were able to incorporate quercetin into the core. They were characterized by dynamic light scattering (DLS) and NMR. The cellular uptake efficiency of human colorectal carcinoma cells was quantitatively determined by flow cytometry using nanoparticles loaded with Nile Red as hydrophobic model drug. The cytotoxic effect of quercetin-loaded nanoparticles was evaluated on HCT 116 cells, showing promising results.

Background: Ocular surface frequently affects glaucoma patients. In this paper we aimed at evaluating the impact of glaucoma surgery on the ocular surface of patients who received unilateral trabeculectomy. Methods: 26 consecutive patients successfully treated with trabeculectomy on one eye (Trab Eye) and under control with topical treatments on the fellow eye (Med Eye) were included in this observational study. They received IDEEL and OSDI questionnaires, Tear Film Osmolarity (TFO), grading of conjunctival hyperemia, fluorescein tear break-up time (tBUT), grading of corneal staining and Schirmer test. Results: IDEEL and OSDI scores were 48 ± 38 and 11 ± 12, respectively, with moderate correlation (r = 0.50, p = 0.03). Compared with Med eyes, Trab Eyes had higher tBUT (6.5 ± 3.5 vs. 5.1 ± 2.7 s, p = 0.004), lower conjunctival hyperemia (0.8 ± 0.9 and 1.7 ± 1.1 respectively, p < 0.001) and lower corneal staining (0.3 ± 0.5 and 0.6 ± 0.5, respectively, p = 0.03). Correlation between corneal staining and conjunctival hyperemia was 0.55 in Trab Eyes (p = 0.01) and 0.44 in Med Eyes (p > 0.05). Patients with bilateral corneal staining had had threefold worse questionnaire scores (p < 0.05). The duration of treatment and the daily exposure to preservatives did not directly affect OS parameters in this cohort of patients. Conclusions: Patients receiving successful trabeculectomy showed better OS homeostasis (higher TBUT, lower grading of conjunctival hyperemia and corneal staining) than fellow medically treated eyes. Presence of corneal epithelial damage in both eyes is the factor more consistently affecting questionnaire scores.

Screening programs may be useful to reduce the rate of undetected glaucoma. Compass (CMP, CenterVue, Padova, Italy) Standard Suprathreshold strategy (SST) analyses the visual function at 52 retinal locations. A new Quick Suprathreshold strategy (QST) reduces the number of tested locations to 24. With both tests, the CMP also provides an image of the central retina and a detail of the optic nerve head. The aim of this paper is to measure the performances of SST and QST compared with clinical diagnosis. 63 consecutive healthy subjects and 60 consecutive patients with perimetric defects from glaucoma in both eyes were recruited. They received one test per eye (SST or QST in randomized order); results were classified into normal, suspect and abnormal according to a global index provided in the report and called SupraThreshold Response (STR). Agreement between clinical diagnosis and test output were calculated, and test time was also measured. The agreement with the clinical diagnosis was 95.7% for SST and 95.1% for QST. When two suspect tests were excluded, agreement for QST increased to 96.7%. Test duration was 164 ± 82 s for SST and 71 ± 41 s for QST (p < 0.0001). Such a difference was similar in both glaucoma patients (respectively 231 ± 65 s vs. 105 ± 33 s, p < 0.0001) and normal subjects (98 ± 17 and 39 ± 9 s, p < 0.0001). In conclusion, SST and QST showed similar, high agreement with clinical judgement. Morphological analysis is potentially helpful in further improving the clinical usefulness of suprathreshold tests. QST is characterized by a strong time saving compared with SST.