A sterilizable platform based on crosslinked xanthan gum for controlled-release of polymeric micelles: Ocular application for the delivery of neuroprotective compounds to the posterior eye segment.

TPGS (D-α-tocopheryl polyethylene glycol 1000 succinate) polymeric micelles show interesting properties for ocular administration thanks to their solubilization capability, nanometric size and tissue penetration ability. However, micelles formulations are generally characterized by low viscosity, poor adhesion and very short retention time at the administration site. Therefore, the idea behind this work is the preparation and characterization of a crosslinked film based on xanthan gum that contains TPGS micelles and is capable of controlling their release. The system was loaded with melatonin and cyclosporin A, neuroprotective compounds to be delivered to the posterior eye segment. Citric acid and heating at different times and temperatures were exploited as crosslinking approach, giving the possibility to tune swelling, micelles release and drug release. The biocompatibility of the platform was confirmed by HET-CAM assay. Ex vivo studies on isolated porcine ocular tissues, conducted using Franz cells and two-photon microscopy, demonstrated the potential of the xanthan gum-based platform and enlightened micelles penetration mechanism. Finally, the sterilization step was approached, and a process to simultaneously crosslink and sterilize the platform was developed.

Effect of isoflurane anaesthetic time on ocular a-scan ultrasonography measures and their relationship to age and OCT measures in the Guinea pig.

A-scan ultrasonography enables precise measurement of internal ocular structures. Historically, its use has underpinned fundamental studies of eye development and aberrant eye growth in animal models of myopia; however, the procedure typically requires anaesthesia. Since anaesthesia affects intra-ocular pressure (IOP), we investigated changes in internal ocular structures with isoflurane exposure and compared measurements with those taken in awake animals using optical coherence tomography (OCT). Continuous A-scan ultrasonography was undertaken in tri-coloured guinea pigs aged 21 (n = 5), 90 (n = 5) or 160 (n = 5) days while anaesthetised (up to 36 min) with isoflurane (5% in 1.5L/min O2). Peaks were selected from ultrasound traces corresponding to the boundaries of the cornea, crystalline lens, retina, choroid and sclera. OCT scans (Zeiss Cirrus Photo 800) of the posterior eye layers were taken in 28-day-old animals (n = 19) and compared with ultrasound traces, with choroid and scleral thickness adjusted for the duration of anaesthesia based on the changes modelled in 21-day-old animals. Ultrasound traces recorded sequentially in left and right eyes in 14-day-old animals (n = 30) were compared, with each adjusted for anaesthesia duration. The thickness of the cornea was measured in enucleated eyes (n = 5) using OCT following the application of ultrasound gel (up to 20 min). Retinal thickness was the only ultrasound internal measure unaffected by anaesthesia. All other internal distances rapidly changed and were well fitted by exponential functions (either rise-to-max or decay). After 10 and 20 min of anaesthesia, the thickness of the cornea, crystalline lens and sclera increased by 17.1% and 23.3%, 0.4% and 0.6%, and 5.2% and 6.5% respectively, whilst the anterior chamber, vitreous chamber and choroid decreased by 4.4% and 6.1%, 0.7% and 1.1%, and 10.7% and 11.8% respectively. In enucleated eyes, prolonged contact of the cornea with ultrasound gel resulted in an increase in thickness of 9.3% after 10 min, accounting for approximately half of the expansion observed in live animals. At the back of the eye, ultrasound measurements of the thickness of the retina, choroid and sclera were highly correlated with those from posterior segment OCT images (R2 = 0.92, p = 1.2 × 10-13, R2 = 0.55, p = 4.0 × 10-4, R2 = 0.72, p = 5.0 × 10-6 respectively). Furthermore, ultrasound measures for all ocular components were highly correlated in left and right eyes measured sequentially, when each was adjusted for anaesthetic depth. This study shows that the depth of ocular components can change dramatically with anaesthesia. Researchers should therefore be wary of these concomitant effects and should employ adjustments to better render 'true' values.

Janus kinase-signal transducer and activator of transcription signaling pathway in the ocular cells of rat fetuses exposed to maternal saturated fat ingestion.

OBJECTIVE: The aim of this study was to analyze possible alterations (morphological and inflammatory) in the ocular cells of fetuses from mothers with insulin resistance exposed to saturated fatty acids through the period of pregnancy. METHODS: Wistar female rats were induced to develop insulin resistance before pregnancy. Fetuses' skulls were collected on the 20th day of intrauterine life. The rats were separated on the first day of management into two groups according to the diet applied: control group (C): diet containing soybean oil as a source of fat; and saturated fatty acid group (S): diet containing butter as a source of fat. RESULTS: Histological and immunohistochemical analyses have been conducted. The immunohistochemical analyses of interleukin 6, suppressor of cytokine signaling, 3 and signal transducer and activator of transcription 3 did not demonstrate alterations in the expression of proteins in the fetuses of mothers fed with a saturated fatty diet. Moreover, no histopathological changes were noticed between groups. CONCLUSION: The saturated fatty diet does not induce tissue changes or activate the Janus kinase/signal transducer and activator of transcription signaling pathway during eye development in the fetuses of mothers with insulin resistance.

In silico prediction of ocular toxicity of compounds using explainable machine learning and deep learning approaches.

The accurate identification of chemicals with ocular toxicity is of paramount importance in health hazard assessment. In contemporary chemical toxicology, there is a growing emphasis on refining, reducing, and replacing animal testing in safety evaluations. Therefore, the development of robust computational tools is crucial for regulatory applications. The performance of predictive models is heavily reliant on the quality and quantity of data. In this investigation, we amalgamated the most extensive dataset (4901 compounds) sourced from governmental GHS-compliant databases and literature to develop binary classification models of chemical ocular toxicity. We employed 12 molecular representations in conjunction with six machine learning algorithms and two deep learning algorithms to create a series of binary classification models. The findings indicated that the deep learning method GCN outperformed the machine learning models in cross-validation, achieving an impressive AUC of 0.915. However, the top-performing machine learning model (RF-Descriptor) demonstrated excellent performance with an AUC of 0.869 on the test set and was therefore selected as the best model. To enhance model interpretability, we conducted the SHAP method and attention weights analysis. The two approaches offered visual depictions of the relevance of key descriptors and substructures in predicting ocular toxicity of chemicals. Thus, we successfully struck a delicate balance between data quality and model interpretability, rendering our model valuable for predicting and comprehending potential ocular-toxic compounds in the early stages of drug discovery.

Biochemical and histopathological evaluation of systemic and ocular toxicity of favipiravir in rats.

Purpose: Favipiravir (FAV) used against COVID-19 is an antiviral drug that causes adverse reactions, such as hyperuricaemia, liver damage, and hematopoetic toxicity. The aim of the study was to investigate the systemic and ocular side-effects of FAV in rats, for the first time.Materials and methods: A total of 18 albino male Wistar rats were used in the study. The rats were divided into 3 groups as the healthy group (HG), the group given 50 mg/kg/day favipiravir (FAV50), and the group given 200 mg/kg/d favipiravir (FAV200). These doses were given to the experimental groups for one week. At the end of the experiment histopathological examinations were performed on the conjunctiva and sclera of the eye. In addition, malondialdehyde (MDA), total glutathione (tGSH), superoxide dismutase (SOD), interleukin-1ß (IL-1ß), and tumor necrosis factor alpha (TNF-α) levels were measured in blood samples taken from rats. Results: Compared to HG, the MDA (1.37 ± 0.61 vs. 4.82 ± 1.40 µmol/mL), IL-1ß (2.52 ± 1.14 vs. 6.67 ± 1.99 pg/mL), and TNF-α levels (3.28 ± 1.42 vs. 8.53 ± 3.06 pg/mL) of the FAV200 group were higher. The levels of tGSH (7.58 ± 1.98 vs. 2.50 ± 0.98 nmol/mL) and SOD (13.63 ± 3.43 vs. 3.81 ± 1.43 U/mL) the FAV200 group were lower than the HG (p < 0.05, for all). The degree of damage to the cornea and sclera of the FAV200 group was quite high according to HG (p < 0.001). Conclusions: FAV can cause damage to rat conjunctiva and sclera by increasing oxidant stress and inflammation at high dose.

Prediction of serious eye damage or eye irritation potential of compounds via consensus labelling models and active learning models based on uncertainty strategies.

Serious eye damage and eye irritation have been authenticated to be significant human health issues in various fields such as ophthalmic pharmaceuticals. Due to the shortcomings of traditional animal testing methods, in silico methods have advanced to study eye toxicity. The models for predicting serious eye damage and eye irritation potential of compounds were developed using 2299 and 5214 compounds, respectively. The 40 global single models and 40 local models were developed by combining 5 molecular description methods and 4 machine learning methods. The 40 active learning models were developed by adopting uncertainty-based active learning strategies and taking local models as initial models. The 110 global consensus models based on 40 global single models were developed using a consensus strategy. Active learning models and global consensus models performed high prediction accuracy. The test accuracy of the best serious eye damage model and eye irritation model reached 0.972 and 0.959, respectively. The applicability domains for all models were calculated to verify the rationality of prediction effect. In addition, 8 structural alerts probably causing serious eye damage or eye irritation were sought out. The prediction models and structural alerts contributed to providing hazard identification and assessing chemical safety.

Long-Acting Protective Ocular Surface by Instilling Adhesive Dual-Antiviral Nanoparticles.

The eye is susceptible to viral infections, causing severe ocular symptoms or even respiratory diseases. Methods capable of protecting the eye from external viral invasion in a long-term and highly effective way are urgently needed but have been proved to be extremely challenging. Here, a strategy of forming a long-acting protective ocular surface is described by instilling adhesive dual-antiviral nanoparticles. Taking pseudotyped severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) as a model virus, antiviral agent-loaded nanoparticles are coated with a "double-lock" hybrid cell membrane abundant with integrin-ß1 and angiotensin converting enzyme II (ACE2). After instillation, the presence of integrin-ß1 endows coated nanoparticles with steady adhesion via specific binding to Arg-Gly-Asp sequence on the fibronectin of ocular epithelium, achieving durable retention on the ocular surface. In addition to loaded inhibitors, the exposure of ACE2 can trap SARS-CoV-2 and subsequently neutralize the associated spike protein, playing a dual antiviral effect of the resulting nanoparticles. Adhesive dual-antiviral nanoparticles enabled by coating with a "double-lock" hybrid cell membrane could be a versatile platform for topical long-acting protection against viral infection of the eye.

Exploration of the Plausible Mechanism of Ethambutol Induced Ocular Toxicity by Using Proteomics Informed Physiologically Based Pharmacokinetic (PBPK) Modeling.

PURPOSE: Ethambutol (EMB) is a first-line anti-tubercular drug that is known to cause optic neuropathy. The exact mechanism of its eye toxicity is unknown; however, proposition is metal chelating effect of both EMB and its metabolite 2,2'-(ethylenediamino)-dibutyric acid (EDBA). The latter is formed by sequential metabolism of EMB by alcohol dehydrogenases (ADHs) and aldehyde dehydrogenases (ALDHs). The purpose of this study was to predict the levels of drug and EDBA in the eye using physiologically based pharmacokinetic (PBPK) modeling. METHODS: The PBPK model of EMB was developed using GastroPlus. The intrinsic hepatic clearance of ALDH, calculated by the model, was scaled down using proteomics data to estimate the rate of formation of EDBA in the eye. Additionally, the comparative permeability of EMB and EDBA was assessed by employing in silico and in vitro approaches. The rate of formation of EDBA in the eye and permeability data were then incorporated in a compartmental model to predict the ocular levels of EMB and EDBA. RESULTS: The simulation results of compartmental model highlighted that there was an on-site formation of EDBA upon metabolism of EMB. Furthermore, in silico and in vitro studies revealed that EDBA possessed much lower permeability than EMB. These observations meant that once EDBA was formed in the eye, it was not permeated out and hence achieved higher ocular concentration. CONCLUSION: The on-site formation of EDBA in the eye, its higher local concentration due to lower ocular clearance and its pre-known characteristic to chelate metal species better explains the ocular toxicity shown by EMB.

Design of Nanotechnological Carriers for Ocular Delivery of Mangiferin: Preformulation Study.

(1) Background: Mangiferin (MGN) is a natural compound, showing anti-inflammatory and antioxidant activities for the potential treatment of eye diseases. The poor physicochemical features of MGN (low solubility and high instability) justify its nanoencapsulation into nanostructured lipid carriers (NLC) to improve its ocular bioavailability. (2) Methods: Firstly, MGN-NLC were prepared by the high shear homogenization coupled with the ultrasound (HSH-US) method. Finally, unloaded and MGN-loaded NLC were analyzed in terms of ocular tolerance. (3) Results: MGN-NLC showed good technological parameters suitable for ocular administration (particle size below 200 nm). The ORAC assay was performed to quantify the antioxidant activity of MGN, showing that the antioxidant activity of MGN-NLC (6494 ± 186 µM TE/g) was higher than that of the free compound (3521 ± 271 µM TE/g). This confirmed that the encapsulation of the drug was able to preserve and increase its activity. In ovo studies (HET-CAM) revealed that the formulation can be considered nonirritant. (4) Conclusions: Therefore, NLC systems are a promising approach for the ocular delivery of MGN.

Neovascular age-related macular degeneration in which exudation predominantly occurs as a subretinal fluid during anti-vascular endothelial growth factor treatment.

We investigated the characteristics of neovascular age-related macular degeneration (AMD) in which exudation predominantly occurs as a subretinal fluid (SRF) during anti-vascular endothelial growth factor (VEGF) treatment. A total of 509 treatment-naïve neovascular AMD patients treated with anti-VEGF for 24 months were retrospectively analyzed. The baseline characteristics to determine the odds of occurrence of SRF alone were evaluated using multivariate modeling. SRF was the sole manifestation of lesion activity in 209 (40.9%) eyes during follow-up. The visual outcome of eyes with only SRF occurrence during follow-up was comparable to that of eyes without exudative recurrence. In addition, the incidence of macular atrophy was significantly lower in eyes with only SRF occurrence (9.6%, 20 of 208 eyes) than in eyes without exudative recurrence (16.7%, 9 of 54 eyes, P = 0.018). Multivariate analysis revealed that better best-corrected visual acuity (BCVA) at baseline (odds ratio [OR], 0.306; P = 0.001), presence of SRF alone at baseline (OR, 5.256; P < 0.001), lower pigment epithelial detachment (PED) height (less than 100 µm; OR, 4.113; P = 0.025), and aneurysmal type 1 macular neovascularization (MNV) (OR, 2.594; P = 0.002) were associated with an increased likelihood of SRF occurrence during follow-up. In conclusion, the eyes with only SRF occurrence during anti-VEGF treatment showed more favorable visual outcomes and a lower incidence of macular atrophy. The baseline characteristics, including better baseline BCVA, presence of SRF alone at baseline, lower PED height, and MNV subtype, might influence the predominant development of SRF during anti-VEGF treatment.

The fabrication and assessment of mosquito repellent cream for outdoor protection.

Mosquito-borne infections like dengue, malaria, chikungunya, etc. are a nuisance and can cause profound discomfort to people. Due to the objectional side effects and toxicity associated with synthetic pyrethroids, N,N-diethyl-3-methylbenzamide (DEET), N,N-diethyl phenylacetamide (DEPA), and N,N-di ethyl benzamide (DEBA) based mosquito repellent products, we developed an essential oil (EO) based mosquito repellent cream (EO-MRC) using clove, citronella and lemongrass oil. Subsequently, a formulation characterization, bio-efficacy, and safety study of EO-MRC were carried out. Expression of Anti-OBP2A and TRPV1 proteins on mosquito head parts were studied by western blotting. In-silico screening was also conducted for the specific proteins. An FT-IR study confirmed the chemical compatibility of the EOs and excipients used in EO-MRC. The thermal behaviour of the best EOs and their mixture was characterized by thermogravimetric analysis (TGA). GC-MS examination revealed various chemical components present in EOs. Efficacy of EO-MRC was correlated with 12% N,N-diethyl benzamide (DEBA) based marketed cream (DBMC). Complete protection time (CPT) of EO-MRC was determined as 228 min. Cytotoxicity study on L-132 cell line confirmed the non-toxic nature of EO-MRC upon inhalation. Acute dermal irritation study, acute dermal dose toxicity study, and acute eye irritation study revealed the non-toxic nature of EO-MRC. Non-target toxicity study on Danio rerio confirmed EO-MRC as safer for aquatic non-target animals. A decrease in the concentration of acetylcholinesterase (AChE) was observed in transfluthrin (TNSF) exposed Wistar rats. While EO-MRC did not alter the AChE concentrations in the exposed animals. Results from western blotting confirmed that Anti-OBP2A and TRPV1 proteins were inhibited in TNSF exposed mosquitoes. Mosquitoes exposed to EO-MRC showed a similar expression pattern for Anti-OBP2A and TRPV1 as the control group. In silico study revealed eight identified compounds of the EOs play significant roles in the overall repellency property of the developed product. The study emphasizes the mosquito repellent activity of EO-MRC, which could be an effective, eco-friendly, and safer alternative to the existing synthetic repellents for personal protection against mosquitoes during field conditions.

Enhancing Ocular Bioavailability of Ciprofloxacin Using Colloidal Lipid-Based Carrier for the Management of Post-Surgical Infection.

Conjunctivitis and endogenous bacterial endophthalmitis mostly occurred after ophthalmic surgery. Therefore, the present study aimed to maximize the ocular delivery of ciprofloxacin (CPX) using colloidal lipid-based carrier to control the post-surgical infection. In this study, CPX was formulated as ophthalmic liposomal drops. Two different phospholipids in different ratios were utilized, including phosphatidylcholine (PC) and dimyrestoyl phosphatidylcholine (DMPC). The physiochemical properties of the prepared ophthalmic liposomes were evaluated in terms of particle size, entrapment efficiency, polydispersity index, zeta potential, and cumulative CPX in-vitro release. In addition, the effect of sonication time on particle size and entrapment efficiency of CPX ophthalmic drops was also evaluated. The results revealed that most of the prepared formulations showed particle size in nanometer size range (460-1047 nm) and entrapment efficiency ranging from 36.4-44.7%. The antibacterial activity and minimum inhibitory concentration (MIC) were investigated. Ex vivo antimicrobial effect of promising formulations was carried out against the most common causes of endophthalmitis microorganisms. The pharmacokinetics of the prepared ophthalmic drops were tested in rabbit aqueous humor and compared with commercial CPX ophthalmic drops (Ciloxan®). Observed bacterial suppression was detected in rabbit's eyes conjunctivitis with an optimized formulation A3 compared with the commercial ophthalmic drops. CPX concentration in the aqueous humor was above MIC against tested bacterial strains. The in vivo data revealed that the tested CPX drops showed superiority over the commercial ones with respect to peak aqueous humor concentration, time to reach peak aqueous humor concentration, elimination rate constant, half-life, and relative bioavailability. Based on these results, it was concluded that the prepared ophthalmic formulations significantly enhanced CPX bioavailability compared with the commercial one.

Metformin promotes histone deacetylation of optineurin and suppresses tumour growth through autophagy inhibition in ocular melanoma.

OBJECTIVE: To explore the therapeutic potential and the underlying mechanism of metformin, an adenosine monophosphate-activated kinase (AMPK) activator, in ocular melanoma. METHODS: CCK8, transwell, and colony formation assays were performed to detect the proliferation and migration ability of ocular melanoma cells. A mouse orthotopic xenograft model was built to detect ocular tumor growth in vivo. Western blot, immunofluorescence, and electron microscopy were adopted to evaluate the autophagy levels of ocular melanoma cells, and high-throughput proteomics and CUT & Tag assays were performed to analyze the candidate for autophagy alteration. RESULTS: Here, we revealed for the first time that a relatively low dose of metformin induced significant tumorspecific inhibition of the proliferation and migration of ocular melanoma cells both in vitro and in vivo. Intriguingly, we found that metformin significantly attenuated autophagic influx in ocular melanoma cells. Through high-throughput proteomics analysis, we revealed that optineurin (OPTN), which is a key candidate for autophagosome formation and maturation, was significantly downregulated after metformin treatment. Moreover, excessive OPTN expression was associated with an unfavorable prognosis of patients. Most importantly, we found that a histone deacetylase, SIRT1, was significantly upregulated after AMPK activation, resulting in histone deacetylation in the OPTN promoter. CONCLUSIONS: Overall, we revealed for the first time that metformin significantly inhibited the progression of ocular melanoma, and verified that metformin acted as an autophagy inhibitor through histone deacetylation of OPTN. This study provides novel insights into metformin - guided suppression of ocular melanoma and the potential mechanism underlying the dual role of metformin in autophagy regulation.

Ascorbic acid specifically reduces the misclassification of nonirritating reactive chemicals in the OptiSafe™ macromolecular eye irritation test.

Recently, we showed that the addition of physiological concentrations of ascorbic acid, a tear antioxidant, to the OptiSafe™ macromolecular eye irritation test reduced the false-positive (FP) rate for chemicals that had reactive chemistries, leading to the formation of reactive oxygen species (ROS) and molecular crosslinking. The purpose of the current study was to 1) increase the number of chemicals tested to comprehensibly determine whether the antioxidant-associated reduction in OD is specific to FP chemicals associated with ROS chemistries and 2) determine whether the addition of antioxidants interferes with the detection of true positive (TP) and true negative (TN) ocular irritants. We report that when ascorbic acid is added to the test reagents, retesting of FP chemicals with reactive chemistries show significantly reduced OD values (P < 0.05). Importantly, ascorbic acid had no significant effect on the OD values of TP or TN chemicals regardless of chemical reactivity. These findings suggest that supplementation of ascorbic acid in alternative ocular irritation tests may help improve the detection of TN for those commonly misclassified reactive chemicals.

Safety assessment of Asterarcys quadricellulare, a microalga, with applications in poultry and livestock feed.

Asterarcys quadricellulare (AQ) is a microalgal species with potential applications in improving the quality of animal feed, and safety studies on this species are lacking. Therefore, this study presents safety data on an industrially cultivated strain of AQ tested using the following Organisation for Economic Co-operation and Development (OECD) guidelines: acute skin irritation in rabbits; skin sensitisation in guinea pigs; acute eye irritation in rabbits; acute oral fixed-dose procedure in rats; and bacterial reverse mutation using the B.N. Ames technique. Results showed that AQ is non-irritant and non-sensitising to skin. AQ caused transient conjunctival lacrimation and redness; however, the scores for these clinical signs translated into low ocular irritation indices and classification of AQ as non-irritant to the eyes. An acute oral dose of AQ (2000 mg/kg) did not cause mortality, change in body weight gain, or any general, functional, and neurobehavioral clinical signs. In five strains of Salmonella typhimurium bacteria, treatment with AQ did not cause biologically or statistically significant changes in the number of revertant colonies, indicating that AQ does not cause mutagenic toxicity. This study demonstrates the safety of a heterotrophically-produced strain of AQ and supports its use as a safe and non-toxic feed ingredient.

Toxicological profile of bisphenol F via comprehensive and extensive toxicity evaluations following dermal exposure.

Bisphenol F (BPF) is classified as a harmful substance by the U.S. Environmental Protection Agency. Although previous studies focused on human exposure to BPF via direct consumption or inhalation, few investigators assessed potential toxicological effects following skin contact. The aim of this study was to examine (1) the degree and pattern by which BPF is absorbed onto the skin in vivo, and (2) determination of toxicity and safety using the following tests: acute dermal; a 28-day repeat dermal; a skin irritation; an eye irritation; and a skin sensitization. As indicated by the amount of BPF remaining in the epidermis or dermis, data demonstrated that BPF was absorbed through the skin at a 26.5% rate. BPF penetrated the subcutaneous layer at a "fast rate" (Kp: 2.2E-02). Although no toxicological changes or local irritation were observed following skin exposure, BPF induced potent sensitization. In summary, the findings of this study showed that BPF penetrated and was absorbed into the skin at a high rate which was associated with enhanced chemical-induced skin sensitization and this may have significant implications following exposure of skin to BPF.

Annexin A1 Mimetic Peptide and Piperlongumine: Anti-Inflammatory Profiles in Endotoxin-Induced Uveitis.

Uveitis is one of the main causes of blindness worldwide, and therapeutic alternatives are worthy of study. We investigated the effects of piperlongumine (PL) and/or annexin A1 (AnxA1) mimetic peptide Ac2-26 on endotoxin-induced uveitis (EIU). Rats were inoculated with lipopolysaccharide (LPS) and intraperitoneally treated with Ac2-26 (200 µg), PL (200 and 400 µg), or Ac2-26 + PL after 15 min. Then, 24 h after LPS inoculation, leukocytes in aqueous humor, mononuclear cells, AnxA1, formyl peptide receptor (fpr)1, fpr2, and cyclooxygenase (COX)-2 were evaluated in the ocular tissues, along with inflammatory mediators in the blood and macerated supernatant. Decreased leukocyte influx, levels of inflammatory mediators, and COX-2 expression confirmed the anti-inflammatory actions of the peptide and pointed to the protective effects of PL at higher dosage. However, when PL and Ac2-26 were administered in combination, the inflammatory potential was lost. AnxA1 expression was elevated among groups treated with PL or Ac2-26 + PL but reduced after treatment with Ac2-26. Fpr2 expression was increased only in untreated EIU and Ac2-26 groups. The interaction between Ac2-26 and PL negatively affected the anti-inflammatory action of Ac2-26 or PL. We emphasize that the anti-inflammatory effects of PL can be used as a therapeutic strategy to protect against uveitis.

A Reevaluation of the Tolerability and Effects of Single-Dose Ivermectin Treatment on Onchocerca volvulus Microfilariae in the Skin and Eyes in Eastern Ghana.

Mass administration of ivermectin (IVM) has significantly reduced onchocerciasis prevalence, intensity, and morbidity in most endemic areas. Most IVM clinical trials were performed long ago in persons with high-intensity infections that are uncommon in West Africa today. This cohort treatment study recruited participants from a hypoendemic area in eastern Ghana to reevaluate the efficacy and tolerability of IVM with a special focus on the kinetics of microfilaria (Mf) clearance. Mf in the skin and anterior chambers (AC) were assessed by skin snip and slit lamp examinations at baseline and at 3 and 6 months after treatment with IVM 150 µg/kg. Most participants (184-231, 79.7%) enrolled were treatment-naïve. The baseline geometric mean skin Mf count was 12.67/mg (range 3-86). Although persons with MfAC at baseline (64/231, 27%) had significantly higher skin Mf counts than people without MfAC, 7 of 39 (15%) of persons with skin Mf counts in the range of 3-5 Mf/mg had MfAC. Skin Mf were detected in 14% (31/218) and 45% (96/216) of participants 3 and 6 months after IVM treatment, respectively. MfAC were detected in 12 of 212 (5.7%) study participants at 6 months. 81% (187 of 231) of participants experienced 439 adverse events within 7 days after treatment; all adverse events were mild (96.1%) or moderate. This study has provided new data on the kinetics of Mf in the skin and eyes after IVM treatment of persons with light to moderate intensity Onchocerca volvulus infections that are common in Africa at this time.