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The treatment for Glioblastoma is limited due to the presence of the blood brain barrier, which restricts the entry of chemotherapeutic drugs into the brain. Local delivery into the tumor resection margin has the potential to improve efficacy of chemotherapy. We developed a safe and clinically translatable irinotecan implant for local delivery to increase its efficacy while minimizing systemic side effects. Irinotecan-loaded implants were manufactured using hot melt extrusion, gamma sterilized at 25 kGy, and characterized for their irinotecan content, release, and drug diffusion. Their therapeutic efficacy was evaluated in a patient-derived xenograft mouse resection model of glioblastoma. Their safety and translatability were evaluated using histological analysis of brain tissue and serum chemistry analysis. Implants containing 30% and 40% w/w irinotecan were manufactured without plasticizer. The 30% and 40% implants showed moderate local toxicity up to 2- and 6-day post-implantation. Histopathology of the implantation site showed signs of necrosis at days 45 and 14 for the 30% and 40% implants. Hematological analysis and clinical chemistry showed no signs of serious systemic toxicity for either implant. The 30% implants had an 80% survival at day 148, with no sign of tumor recurrence. Gamma sterilization and 12-month storage had no impact on the integrity of the 30% implants. This study demonstrates that the 30% implants are a promising novel treatment for glioblastoma that could be quickly translated into the clinic., (© 2024. The Author(s).)

Purpose: To analyse the morphological evolution of filtering blebs with anterior-segment OCT (AS-OCT) and its correlation with intraocular pressure after ab externo SIBS microshunt implantation with mitomycin C (MMC) during a 3-month follow-up period., Methods: Twenty-eight filtering blebs of 28 patients with open-angle glaucoma were measured horizontally and vertically in the sub-Tenon space with AS-OCT after ab externo SIBS microshunt implantation with MMC. The intraocular pressure (IOP) was monitored simultaneously at each visit. Maturation of and morphological changes in the blebs and correlations with the IOP were recorded., Results: The average median preoperative IOP of 20.7 (range, 12-30) mmHg decreased to 8.5 (range, 4-17), 8.9 (range, 5-17), 10.4 (range, 8-16) and 10.9 (range, 9-15) mmHg at 24 hr, 1 week, 1 month and 3 months, respectively (p < 0.001). A multiform morphology on AS-OCT prevailed at all time points, with a 3.5% rate of a uniform bleb morphology at the first week. The horizontal and vertical diameters of the blebs increased from baseline to the third month. The horizontal expansion (406 ± 127 μm on day 7, p = 0.04, 712 ± 211 μm on day 30, p = 0.02 and 952 ± 218 μm on day 90, p < 0.001) was greater than the vertical expansion (16 ± 18 μm, p = 0.3 on day 1, 63 ± 27 μm, p = 0.02 on day 30 and 137 ± 34 μm, p < 0.001 on day 90) without correlation with the IOP (r = -0.3, p = 0.2)., Conclusion: Anterior-segment OCT (AS-OCT) of the filtering blebs formed after ab externo SIBS microshunt implantation showed progressive horizontal and vertical expansion of the blebs in the sub-Tenon space, with a significant peak at the first month not significantly correlated with the decrease in the IOP., (© 2021 Acta Ophthalmologica Scandinavica Foundation. Published by John Wiley & Sons Ltd.)

There is a steady global rise in the use of progestin subdermal implants, where use has increased by more than 20 times in the past two decades. BC risk has been reported with the older progestin only methods such as oral pills, injectables, and intrauterine devices, however, little is known about the risk with subdermal implants. In this review, we aim to update clinicians and researchers on the current evidence to support patient counseling and to inform future research directions. The available evidence of the association between the use of progestin subdermal implants and BC risk is discussed. We provide an overview of the potential role of endogenous progesterone in BC development. The chemical structure and molecular targets of synthetic progestins of relevance are summarized together with the preclinical and clinical evidence on their association with BC risk. We review all studies that investigated the action of the specific progestins included in subdermal implants. As well, we discuss the potential effect of the use of subdermal implants in women at increased BC risk, including carriers of BC susceptibility genetic mutations., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Mohammed, Mousa, Talaat, Ibrahim and Saber-Ayad.)

Minocycline hydrochloride (MINO) has been one of the most frequently used antibiotics in the treatment of periodontitis due to its antibacterial activity and osteogenesis effects; however, high levels of MINO administered during the treatment halt the formation of new bone. Therefore, the purpose of the present study was to prepare a MINO-microsphere/sucrose acetate isobutyrate (SAIB) hybrid depot to reduce the burst release of MINO and ensure antibacterial and osteogenesis effects of MINO in the treatment of periodontitis. Uniform microspheres, approximately 5 µm size, with a slightly rough surface and different MINO loading (10, 12, and 14%) were prepared, and the microspheres were added into SAIB, after which the burst release significantly decreased from 66.18 to 2.92%, from 71.82 to 3.82%, and from 73.35 to 4.45%, respectively, and the release from all the MINO-microspheres/SAIB hybrid depots lasted for 77 days. In addition, cytotoxicity test showed that the MINO-microsphere with 12% drug loading promoted the proliferation of osteoblasts the most and was subsequently used in vivo experiments. Moreover, in the model of ligatured-induced periodontitis in SD rats, the MINO-microsphere/SAIB hybrid depot not only significantly increased the alveolar bone height and bone volume but also reduced the inflammation of the periodontal tissue. Additionally, it also inhibited the expression of the receptor activator of nuclear factor-kappa B ligand (RANKL) and promoted the expression of osteoprotegerin (OPG).. These results indicated that the MINO-microsphere/SAIB hybrid depot might be promising in the treatment of periodontitis.

Objective: To evaluate the intraocular pressure (IOP)-lowering efficacy and safety of 10 and 15 µg bimatoprost implant in patients with open-angle glaucoma (OAG) or ocular hypertension (OHT)., Methods: This randomized, 20-month, multicenter, masked, parallel-group, phase 3 trial enrolled 528 patients with OAG or OHT and an open iridocorneal angle inferiorly in the study eye. Study eyes were administered 10 or 15 µg bimatoprost implant on day 1, week 16, and week 32, or twice-daily topical timolol maleate 0.5%. Primary endpoints were IOP and IOP change from baseline through week 12. Safety measures included treatment-emergent adverse events (TEAEs) and corneal endothelial cell density (CECD)., Results: Both 10 and 15 µg bimatoprost implant met the primary endpoint of noninferiority to timolol in IOP lowering through 12 weeks. Mean IOP reductions from baseline ranged from 6.2-7.4, 6.5-7.8, and 6.1-6.7 mmHg through week 12 in the 10 µg implant, 15 µg implant, and timolol groups, respectively. IOP lowering was similar after the second and third implant administrations. Probabilities of requiring no IOP-lowering treatment for 1 year after the third administration were 77.5% (10 µg implant) and 79.0% (15 µg implant). The most common TEAE was conjunctival hyperemia, typically temporally associated with the administration procedure. Corneal TEAEs of interest (primarily corneal endothelial cell loss, corneal edema, and corneal touch) were more frequent with the 15 than the 10 µg implant and generally were reported after repeated administrations. Loss in mean CECD from baseline to month 20 was ~ 5% in 10 µg implant-treated eyes and ~ 1% in topical timolol-treated eyes. Visual field progression (change in the mean deviation from baseline) was reduced in the 10 µg implant group compared with the timolol group., Conclusions: The results corroborated the previous phase 3 study of the bimatoprost implant. The bimatoprost implant met the primary endpoint and effectively lowered IOP. The majority of patients required no additional treatment for 12 months after the third administration. The benefit-risk assessment favored the 10 over the 15 µg implant. Studies evaluating other administration regimens with reduced risk of corneal events are ongoing. The bimatoprost implant has the potential to improve adherence and reduce treatment burden in glaucoma. CLINICALTRIALS., Gov Identifier: NCT02250651., (© 2021. The Author(s).)

Background: Despite the positive characteristics of the levonorgestrel-releasing intrauterine device (IUD)-a long-acting, highly effective contraceptive with important non-contraceptive attributes-the method has not been widely available in low- and middle-income countries. This study of hormonal IUD, copper IUD, implant and injectable users in Nigeria compares their characteristics, reasons for method choice, and experiences obtaining their method., Methods: We conducted a phone survey with 888 women who received a hormonal IUD, copper IUD, contraceptive implant or injectable from 40 social franchise clinics across 18 states in Nigeria. We analyzed survey data descriptively by method and assessed factors associated with hormonal IUD use through multivariate logistic regression models. Follow-up in-depth interviews conducted with 32 women were analyzed thematically., Results: There were few differences by method used in the socio-demographic profiles and contraceptive history of participants. Among users choosing a long-acting, reversible method, the top reasons for method choice included perceptions that the method was "right for my body," long duration, recommended by provider, recommended by friends/family, few or manageable side effects, and high effectiveness. Among hormonal IUD users, 17% mentioned reduced bleeding (inclusive of lighter, shorter, or no period), and 16% mentioned treatment of heavy or painful periods. Qualitative data supported these findings. Among survey respondents, between 25% and 33% said they would have chosen no method if the method they received had not been available. Both quantitative and qualitative data indicated that partner support can affect contraceptive use, with in-depth interviews revealing that women typically needed partner permission to use contraception, but men were less influential in method choice., Conclusions: Expanding access to the hormonal IUD as part of a full method mix provides an opportunity to expand contraceptive choice for women in Nigeria. Findings are timely as the government is poised to introduce the method on a wider scale., Competing Interests: The authors have declared that no competing interests exist.

The second messengers, cGMP and Ca 2+ , have both been implicated in retinal degeneration; however, it is still unclear which of the two is most relevant for photoreceptor cell death. This problem is exacerbated by the close connections and crosstalk between cGMP-signalling and calcium (Ca 2+ )-signalling in photoreceptors. In this review, we summarize key aspects of cGMP-signalling and Ca 2+ -signalling relevant for hereditary photoreceptor degeneration. The topics covered include cGMP-signalling targets, the role of Ca 2+ permeable channels, relation to energy metabolism, calpain-type proteases, and how the related metabolic processes may trigger and execute photoreceptor cell death. A focus is then put on cGMP-dependent mechanisms and how exceedingly high photoreceptor cGMP levels set in motion cascades of Ca 2+ -dependent and independent processes that eventually bring about photoreceptor cell death. Finally, an outlook is given into mutation-independent therapeutic approaches that exploit specific features of cGMP-signalling. Such approaches might be combined with suitable drug delivery systems for translation into clinical applications., (© 2021. The Author(s).)

Poly (lactic-co-glycolic acid) (PLGA), a biocompatible and biodegradable polymer, is one of the most commonly used vehicles for controlled-release (CR) implantable dosage forms. Drug molecules formulated in such CR vehicles are released slowly over an extended period of time - often months to years - posing challenges for batch release and quality control testing. Thus, reliable and reproducible accelerated testing methods are required to bridge this gap during early formulation development. This work describes the development of an accelerated in vitro release testing method to predict the real-time in vitro release of a synthetic peptide from a 6-month CR PLGA implant formulation. While accelerated methods have been previously reported for PLGA-based formulations, this work describes a unique case of an aggregation-prone peptide, which required careful attention to the impact of different conditions on both release kinetics and peptide stability. This method describes a suitable combination of release conditions that could help in understanding the release profiles of such peptides prone to aggregation. Parameters including pH, buffer species, temperature, and addition of organic co-solvents and surfactants were evaluated separately and in combination for their ability to achieve complete peptide release within 2 weeks while accurately recapitulating release rate, profile and peptide stability. The accelerated release method that gave the best agreement with real-time release was a mixed media of co-solvent (5% tetrahydrofuran), surfactant (5% TritonX-100) and elevated temperature (50 °C) in a neutral buffer (PBS pH 7.4). This optimized accelerated release method achieved complete release of the peptide load within 14-21 days compared to 3- to 6-months of real-time release and could discriminate critical differences in release behavior between different CR formulations to guide formulation and process development., (Published by Elsevier B.V.)

Metallic materials are commonly used for load-bearing implants and as internal fixation devices. It is customary to use austenitic stainless steel, especially surgical grade type 316L SS as temporary and Ti alloys as permanent implants. However, long-term, poor bonding with bone, corrosion, and release of metal ions, such as chromium and nickel occur. These ions are powerful allergens and carcinogens and their uncontrolled leaching may be avoided by surface coatings. Therefore, bioactive glasses (BGs) became a vital biomedical material, which can form a biologically active phase of hydroxycarbonate apatite on their surface when in contact with physiological fluids. To reduce the high coefficient of friction and the brittle nature of BGs, polymers are normally incorporated to avoid the high-temperature sintering/densification of ceramic-only coatings. For medical application, electrophoretic deposition (EPD) is now used for polymer (organic) and ceramic (inorganic) components at room temperature due to its simplicity, control of coating thickness and uniformity, low cost of equipment, ability to coat substrates of intricate shape and to supply thick films in composite form, high purity of deposits as well as no phase transformation during coating. Although extensive research has been conducted on polymer/inorganic composite coatings, only some studies have reported multifunctional properties, such as biological antibacterial activity, enhanced cell adhesion, controlled drug release ability, and mechanical properties. This review will focus on biodegradable coatings, including zien, chitosan, gelatin, cellulose loaded with antibacterial drugs/metallic ions/natural herbs on biostable substrates (PEEK/PMMA/PCL/PLLA layers), which have the potential of multifunctional coating for metallic implants., (© 2021 The Authors. Cell Biology International published by John Wiley & Sons Ltd on behalf of International Federation of Cell Biology.)

Objectives: Gonadotropin-releasing hormone analogs are the treatment of choice for central precocious puberty (CPP). This study characterizes patients treated with histrelin implant or leuprolide injection., Methods: A US claims database was used to identify patients aged ≤20 years with ≥1 histrelin or leuprolide claim (index treatment) between April 2010 and November 2017 and continuous enrollment ≥3 months before and ≥12 months after the index treatment date., Results: Overall, 4,217 patients (histrelin, n=1,001; leuprolide, n=3,216) were identified. The percentage of patients with CPP diagnosis was greater in the histrelin (96.5%) vs. leuprolide (68.8%; p<0.0001) cohort. In patients with CPP (histrelin, n=966; leuprolide, n=2,214), mean age at treatment initiation was similar for histrelin (9.0 ± 2.0 years) and leuprolide (9.1 ± 2.3 years), with >50% of patients aged 6-9 years. Mean treatment duration was significantly longer for histrelin (26.7 ± 14.8 months) vs. leuprolide (14.1 ± 12.1 months; p<0.0001), and was longer in younger patient groups. More patients switched from leuprolide to histrelin (12.3%) than vice versa (3.6%; p<0.0001). Median annual total treatment costs were slightly lower for the histrelin cohort ($23,071 [interquartile range, $16,833-$31,050]) than the leuprolide cohort ($27,021 [interquartile range, $18,314-$34,995]; p<0.0001)., Conclusions: Patients with CPP treated with histrelin had a longer duration of treatment, lower rates of index treatment discontinuation, and lower annual treatment costs vs. those treated with leuprolide., (© 2021 Lawrence A. Silverman et al., published by De Gruyter, Berlin/Boston.)

Macular edema (ME) is the most frequent vision threatening consequence after retinal vein occlusion (RVO). In this study, we evaluate the effect of dexamethasone intravitreal implants (DII, Ozurdex) in a real-life cohort of 99 patients with ME due to RVO. All patients who received DII for ME following RVO between 2011 and 2016 at the University Eye Hospital Freiburg, Germany and who had fully accessible electronic medical records were eligible for this study. Most of the patients included in this study were not treatment-naïve: 61 eyes had received prior anti-VEGF drugs, 6 eyes had received intravitreal corticosteroids (triamcinolone) and 15 had been treated with both; 17 eyes were treatment-naïve. Mean follow-up was 312 ± 310 days. Mean visual acuity (VA) was maintained throughout the observation period (mean VA at baseline: 66.7 ± 23.5 letters; at last observation 64.9 ± 28.3). Central retinal thickness (CRT) decreased from 526 ± 179 µm at baseline to 431 ± 199 µm. Mean intraocular pressure (IOP) increased from 14.4 ± 3.1 mmHg at baseline to 17.1 ± 6.3 mmHg. Cataract surgery was performed in 22% of phakic eyes. DII was used as second-line treatment in the majority of cases in this cohort. The fact that mean VA remained unchanged while mean CRT decreased illustrates that morphologic improvement does not always translate into functional gain. Mean IOP was maintained within normal limits and cataract formation was as expected in this age group.

Background: Long-acting, reversible contraceptives (LARC; progestin only) are an increasingly common hormonal contraceptive choice in reproductive aged women looking to suppress ovarian function and menstrual cyclicity. The overall objective was to develop and validate a rodent model of implanted etonogestrel (ENG) LARC, at body size equivalent doses to the average dose received by women during each of the first 3 years of ENG subdermal rod LARC use., Methods: Intact, virgin, female Sprague-Dawley rats (16-wk-old) were randomized to 1 of 4 groups (n = 8/group) of ENG LARC (high-0.30μg/d, medium-0.17μg/d, low-0.09μg/d, placebo-0.00μg/d) via a slow-release pellet implanted subcutaneously. Animals were monitored for 21 days before and 29 days following pellet implantation using vaginal smears, ultrasound biomicroscopy (UBM), saphenous blood draws, food consumption, and body weights. Data were analyzed by chi-square, non-parametric, univariate, and repeated measures 2-way ANOVA., Results: Prior to pellet implantation there was no difference in time spent in estrus cycle phases among the treatment groups (p > 0.30). Following pellet implantation there was a dose-dependent impact on the time spent in diestrus and estrus (p < 0.05), with the high dose group spending more days in diestrus and fewer days in estrus. Prior to pellet insertion there was not an association between treatment group and estrus cycle classification (p = 0.57) but following pellet implantation there was a dose-dependent association with cycle classification (p < 0.02). Measurements from the UBM (ovarian volume, follicle count, corpora lutea count) indicate an alteration of ovarian function following pellet implantation., Conclusion: Assessment of estrus cyclicity indicated a dose-response relationship in the shift to a larger number of acyclic rats and longer in duration spent in the diestrus phase. Therefore, each dose in this model mimics some of the changes observed in the ovaries of women using ENG LARC and provides an opportunity for investigating the impacts on non-reproductive tissues in the future.

Rationale: An intravitreal dexamethasone (IV-DEX) implant is safe and effective for the treatment of macular edemas; however, the efficacy of IV-DEX implants in silicone oil (SO)-filled eyes remains controversial. There is no previous study comparing an IV-DEX implant in the same eye with and without intravitreal SO., Patient Concerns: A 72-year-old man with proliferative diabetic retinopathy, macular edema, and rhegmatogenous retinal detachment, treated with pars plana vitrectomy with SO tamponade had refractory macular edema., Diagnosis: Refractory macular edema., Intervention: Subtenon triamcinolone injection, intravitreal anti-vascular endothelial growth factor injection, and IV-DEX implantation were performed; this was followed by intravitreal SO removal combined with IV-DEX implantation., Outcomes: The macular edema did not decrease significantly with posterior subtenon triamcinolone injection, intravitreal anti-vascular endothelial growth factor injection, and IV-DEX implantation; however, the edema was relieved after SO removal and a new IV-DEX implantation., Lessons: IV-DEX implant may be less efficacious in the treatment of macular edema in an SO-filled eye than that in a normal vitreous cavity., Competing Interests: The authors have no conflicts of interests to disclose., (Copyright © 2021 the Author(s). Published by Wolters Kluwer Health, Inc.)

Study Objective: To identify why adolescents with polycystic ovary syndrome (PCOS) chose the etonogestrel (ENG) contraceptive implant, to determine the 12-month continuation rate, and to characterize factors related to discontinuation., Design, Setting, and Participants: Retrospective chart review of adolescents seen at a tertiary care children's hospital between July 1, 2008, and August 30, 2019, with PCOS diagnosis confirmed per National Institutes of Health criteria and ≥12-month ENG follow-up., Interventions and Main Outcome Measures: Demographic characteristics, reasons for ENG insertion and removal, and information on other hormonal/contraceptive therapies were collected. Patients were categorized as ENG continuers (use ≥12 months) or discontinuers (removal at <12 months), and groups were compared., Results: A total of 96 patients met inclusion criteria (age 17.7 ± 2.2 years, body mass index 34.8 ± 8 kg/m 2 ). Reasons for ENG were documented in 74% (51% contraception, 32% ease of use, 15% other, 13% estrogen avoidance). In all, 27% had never been sexually active, and 67% had had prior sexual activity. Treatments prior to ENG placement included 74% combined hormonal contraception, 20% medroxyprogesterone acetate withdrawal, and 17% depot medroxyprogesterone. A total of 77% continued ENG at 12 months. The main reasons for discontinuation were bleeding (41%), concern about weight gain (23%), and mood changes (18%). No preimplantation characteristics were independently predictive of continuation, although 100% of patients with type 2 diabetes (n = 11) continued. Patients who sought additional care, including telephone calls (41% vs 12%, P = .006) and clinic visits (64% vs 20%, P < .001) were more likely to discontinue., Conclusions: The ENG implant was well tolerated in adolescents with PCOS and similar to published 12-month continuation rates., (Copyright © 2021 North American Society for Pediatric and Adolescent Gynecology. Published by Elsevier Inc. All rights reserved.)

In the field of drug delivery, the most commonly used treatments have traditionally been systemically delivered using oral or intravenous administration. The problems associated with this type of delivery is that the drug concentration is controlled by first pass metabolism, and therefore may not always remain within the therapeutic window. Implantable drug delivery systems (IDDSs) are an excellent alternative to traditional delivery because they offer the ability to precisely control the drug release, deliver drugs locally to the target tissue, and avoid the toxic side effects often experienced with systemic administration. Since the creation of the first FDA-approved IDDS in 1990, there has been a surge in research devoted to fabricating and testing novel IDDS formulations. The versatility of these systems is evident when looking at the various biomedical applications that utilize IDDSs. This review provides an overview of the history of IDDSs, with examples of the different types of IDDS formulations, as well as looking at current and future biomedical applications for such systems. Though there are still obstacles that need to be overcome, ever-emerging new technologies are making the manufacturing of IDDSs a rewarding therapeutic endeavor with potential for further improvements., (Copyright © 2020 Elsevier B.V. All rights reserved.)

The initial drug release from in situ forming implants is affected by factors such as the physicochemical properties of the active pharmaceutical ingredient, the type of the excipients utilized, and the surrounding environment. The feasibility of UV-vis imaging for characterization of the initial behavior of poly(d,l-lactide- co -glycolide) (PLGA)/1-methyl-2-pyrrolidinone (NMP) in situ forming implants was investigated. The in vitro release of leuprolide acetate (LA) and implant formation in real time were monitored using dual-wavelength imaging at 280 and 525 nm, respectively, in matrices based on agarose gel and hyaluronic acid (HA) solution emulating the subcutaneous matrix. Three hours upon injection of the pre-formulation, approximately 15% of the total amount of LA administered was found in the agarose gel, while 5% was released from the implant into the HA solution. Concurrently, more extensive swelling of the implants in the HA solution as compared to implants in the agarose gel was observed. Transport of both LA and the solvent NMP was investigated using UV-vis imaging in a small-scale cell where the geometry of the formulation was controlled, showing a linear correlation between drug release and solvent escape. Light microscopy showed that the microstructures of the resulting implants in agarose gel and HA solution were different, which may be attributed to the different solvent exchange rates. UV imaging was also used to examine the interaction of LA with the release medium by characterizing the diffusion of LA in agarose gel, HA solution, and phosphate buffered saline. The reduced LA diffusivity in HA solution as compared to agarose gel and the LA distribution coefficient in the agarose gel-HA system indicated the presence of interactions between LA and HA. Our findings show that the external environment affects the solvent exchange kinetics for in situ forming implants in vitro , resulting in different types of initial release behavior. UV-vis imaging in combination with biorelevant matrices may offer an interesting approach in the development of in situ forming implant delivery systems.

Objective: To compare plasma etonogestrel concentrations sampled from the contralateral- versus ipsilateral-to-implant arm., Study Design: Sub-analysis of a cross-sectional study in Botswana in 33 participants who provided contralateral and ipsilateral blood samples., Results: Plasma etonogestrel concentrations in contralateral and ipsilateral specimens were highly correlated (correlation coefficient = 0.99; p < 0.0001). Bland-Altman analysis of agreement showed that etonogestrel levels were on average 5.9 pg/mL higher (2.1%) in ipsilateral compared to contralateral specimens (95% confidence interval: -4.1, 15.9 pg/mL)., Conclusions: We found no meaningful differences in plasma etonogestrel concentrations between samples taken from the contralateral- versus ipsilateral-to-implant arm., Implications: Our data suggest that etonogestrel plasma concentrations are unlikely to be meaningfully different between samples drawn from the ipsilateral- versus the contralateral-to-implant arms in etonogestrel contraceptive implant users., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Poly (lactic-co-glycolic acid) (PLGA) in situ-forming implants are well-established drug delivery systems for controlled drug release over weeks up to months. To prevent initial burst release, which is still a major issue associated with PLGA-based implants, drugs attached to particulate carriers have been encapsulated. Unfortunately, former studies only investigated the resulting release of the soluble drugs and hence missed the potential offered by particulate drug release. In this study, we developed a system capable of releasing functional drug-carrying particles over a prolonged time. First, we evaluated the feasibility of our approach by encapsulating silica particles of different sizes (500 nm and 1 μm) and surface properties (OH or NH 2 groups) into in situ-forming PLGA implants. In this way, we achieved sustained release of particles over periods ranging from 30 to 70 days. OH-carrying particles were released much more quickly when compared to NH 2 -modified particles. We demonstrated that the underlying release mechanisms involve size-dependent diffusion and polymer-particle interactions. Second, particles that carried covalently-attached ovalbumin (OVA) on their surfaces were incorporated into the implant. We demonstrated that OVA was released in association with the particles as functional entities over a period of 30 days. The released particle-drug conjugates maintained their colloidal stability and were efficiently taken up by antigen presenting cells. This system consisting of particles incorporated into PLGA-based in situ-forming implants offers the dual advantage of sustained and particulate release of drugs as a functional unit and has potential for future use in many applications, particularly in single-dose vaccines., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Purpose: This study aims to compare subfoveal choroidal thicknesses (SFCTs) after intravitreal dexamethasone (IVD) or intravitreal aflibercept (IVA) treatment in patients with persistent diabetic macular edema (DME) unresponsive to intravitreal ranibizumab (IVR). Methods: The study consisted of patients with DME unresponsive to IVR treatment in which 37 were administered 1 dose IVD (group A) and 34 patients who were administered 3 doses of IVA (group B), as well as 35 healthy individuals (group C). Detailed ophthalmological examination and optical coherence tomography parameters of group A and group B, including central retinal thickness and SFCT, were retrospectively evaluated before and after treatment. Results from preinjection, and 1, 2, and 3 months after injection were analyzed. Results of group A and group B were compared within themselves and also compared with group C. Results: SFCT measurements were compared within group A and group B (1 = preinjection; 2 = 1 month postinjection; 3 = 2 months postinjection; 4 = 3 months postinjection). There was significant thinning in SFCT between 1-2, 1-3, 1-4, 2-3, 2-4, and 3-4 time intervals within both group A and group B (both P  < 0.001). Comparison of SFCT measurements showed preinjection, 1-, and 2-month values of group A were significantly thicker than those of group C ( P  < 0.001), whereas there was no significant difference between 3-month values ( P  = 0.09). Preinjection, 1-, and 2-month values of group B were significantly thicker than those of group C ( P  < 0.001), whereas there was no significant difference between 3-month values ( P  = 0.06). Conclusions: Three month follow-up showed thinning in SFCT measurements in patients with persistent DME unresponsive to IVR who were applied IVD or IVA treatment.

Objectives: Deslorelin 4.7 mg and melatonin 18 mg subcutaneous implants were studied in purebred male and female cats, via questionnaires sent to French cat breeders, to assess breed, age, duration of the contraceptive effect, fertility after use, changes in behaviour and side effects., Methods: Reproductive data were collected in 57 tom cats and 41 queens implanted with deslorelin 4.7 mg, and 42 queens implanted with melatonin 18 mg, for a total of 140 purebred cats, from 38 different catteries, representing 18 breeds., Results: Using deslorelin (Suprelorin 4.7 mg; Virbac), sexual behaviour in males was inhibited for a mean ± SD of 13.4 ± 3.2 (range 8-21) months in 37/57 cats. Of these, 24/37 mated successfully and produced litters at a mean of 15.5 ± 3.6 (range 9-20) months. Inhibition lasted 11 ± 1.1 (range 9-12; n = 6), 13.2 ± 2.4 (range 12-18; n = 6) and 15 ± 3.5 (range 9-18; n = 6) months in Norwegian Forest Cat, Singapura and Ragdoll males, respectively. In 26/41 females implanted with deslorelin 4.7 mg, oestrus was inhibited for a mean of 16.0 ± 5.7 (8-38) months; 12/26 went on to produce a litter. Of the side effects specific to females: two presented persistent oestrus, leading to the removal of the implant; two developed lactation; one had fibroadenomatosis; and one was sterilised owing to cystic endometrial hyperplasia. Using melatonin (Melovine 18 mg; Ceva), 33/42 females had oestrus inhibited for a mean of 86 ± 50 (range 21-277) days after implantation with a peak return to oestrus in March, and 12/33 had a subsequent litter. No side effects were reported., Conclusions and Relevance: This study is the first to collect a large amount of field data, in 140 purebred male and female cats where a deslorelin 4.7 mg or a melatonin 18 mg implant was used. These field results may allow for more accurate clinical advice and open up new avenues of research.

Among young persons, ease of use, high efficacy, and high acceptability makes the etonogestrel contraceptive implant an important choice for this age group. Adolescent-friendly, patient-centered counseling considers the patient's cognitive development, the influence of friends and family, as well as their own preferences and values. Age-appropriate language, graphics, and models are useful to explain contraceptive options and relevant side effects. Effectiveness, reversibility, safety, noncontraceptive benefits, and side effects are important attributes and should be discussed when teens are choosing a contraceptive method. In this review we describe suggested best practices for counseling adolescents about the etonogestrel implant so they can make informed, prudent decisions about using this contraceptive method., (Copyright © 2020 North American Society for Pediatric and Adolescent Gynecology. Published by Elsevier Inc. All rights reserved.)

Background: In 2009, the Government of Ethiopia initiated the implant scale-up initiative, which expanded contraceptive access by training health extension workers (HEWs) to insert single-rod etonogestrel contraceptive implants (Implanon) at rural health posts. Removals were provided by referrals to higher levels of the health system. However, little was known about whether women were getting their implants removed at the recommended 3-year postinsertion date or what barriers they faced to removal., Methods: Between June and July 2016, 1,860 Ethiopian women, who had a 1-rod etonogestrel implant inserted by either an HEW or another health care provider between 3 and 6 years prior, were surveyed. We describe the characteristics of the sample and use multivariable logistic regression to predict factors associated with keeping implants inserted beyond 3 years., Results: Women who had received their implants from HEWs were significantly more likely to report keeping them inserted for more than 3 years (adjusted odds ratio=2.50; 95% confidence interval=1.19, 5.24), compared with those who got their implant from another health care provider. Women who reported distance to the facility or transportation as a barrier were also significantly more likely to keep their implant for more than 3 years. Married and educated women were less likely to keep their implants for an extended duration. Among women who had their implant for 3 years or less, women who had had it inserted by an HEW were significantly more likely to report that the provider was unable or refused to provide removal as a barrier., Discussion: Efforts to expand lower level and community-based access to contraceptive implants that do not ensure reliable access to removals at the same level as insertions may lead to women using implants beyond the recommended duration., (© Costenbader et al.)

Objective: To evaluate whether a short course of tamoxifen decreases bothersome bleeding in etonogestrel contraceptive implant users., Methods: In a 90-day, double-blind randomized control trial, we enrolled etonogestrel implant users with frequent or prolonged bleeding or spotting. A sample size of 40 per group (N=80) was planned to compare 10 mg tamoxifen or placebo twice daily for 7 days after 3 consecutive days of bleeding or spotting no more than once per 30 days (maximum three treatments). Participants then entered a 90-day open-label study where all received tamoxifen if needed every 30 days (maximum three treatments). Participants used text messages to record daily bleeding patterns. Our primary outcome was the total number of consecutive amenorrhea days after the first treatment. Secondary outcomes included time to bleeding or spotting cessation and restart after first treatment, overall bleeding patterns, and satisfaction., Results: From January 2017 to November 2018, 112 women enrolled in the study; 88 (79%) completed 90 days, and 79 (71%) completed 180 days. Participant characteristics did not differ between groups; mean age 24, majority identified as white not Hispanic with at least some college education. After the first treatment, the tamoxifen group reported an average of 9.8 (95% CI 4.6-15.0) more consecutive days of amenorrhea and more total days of no bleeding (amenorrhea or spotting) in the first 90 days (median 73.5 [range 24-89] vs 68 [range 11-81], P=.001). The placebo group showed a similar treatment benefit after first active use of tamoxifen in the open-label phase. At the end of the randomized study (first 90 days), women who received tamoxifen reported higher satisfaction (median 62 mm [range 16-100]) than those treated with placebo (46 mm [range 0-100]; P=.023)., Conclusion: A short course of tamoxifen reduces problematic bleeding and improves satisfaction in users of etonogestrel implants., Clinical Trial Registration: ClinicalTrials.gov, NCT02903121.

Aims: To evaluate the timing and spectral-domain optical coherence tomography (SD-OCT) features of diabetic macular oedema (DME) recurrence according to baseline OCT patterns in patients treated with dexamethasone implant (DEX-I)., Methods: This is a retrospective observational study (72 eyes/65 patients). Best-corrected visual acuity, timing of DME recurrence, and SD-OCT pattern [intraretinal cysts (IRC), IRC plus subretinal fluid (mixed), external limiting membrane (ELM), ellipsoid (IS/OS) layer integrity] were assessed at baseline and monthly until first DME recurrence., Results: Forty-two (58.3%) and 30 (41.6%) DME eyes had an IRC and mixed DME pattern at baseline, respectively. Twenty-four out of thirty mixed eyes (80%) relapsed without subretinal fluid. At baseline, mixed eyes showed similar changes in ELM and IS/OS (60 and 76.6% of eyes, respectively) versus IRC eyes (42.8 and 80.9% of eyes). After DME recurrence, more mixed eyes at baseline showed ELM and IS/OS changes (63.3 and 86.6%) than IRC eyes (50 and 76.2%). 33.3% of mixed eyes had DME recurrence at ≥ 6 months from first DEX-I implant versus 19% of IRC eyes., Conclusions: Mixed DME eyes were treated with DEX-I relapse later and more frequently without subretinal fluid than IRC eyes. SD-OCT characteristics of different DME patterns at baseline can predict morphological features and timing of DME recurrence.

Purpose: Reliable drug therapy with injectable intravitreal implants requires implants of consistent quality. The purpose of this study was to prepare dexamethasone-poly(d,l-lactide-co-glycolide) (PLGA) biodegradable implants and assess implant quality within and between batches for different polymer compositions. Methods: Implants containing 20% w/w dexamethasone with 3 theoretical rates of release (fast, intermediate, and slow) were manufactured with decreasing proportion of acid-terminated PLGA (50:50) and increasing proportion of ester-terminated PLGA (50:50) in a batch process using hot-melt extrusion. The implants were manufactured without and with in-process modification of extrusion/conveyor speed in the late phase of each batch. Implant samples collected at early, middle, and late phases of each batch were analyzed for diameter, drug loading, mechanical properties (strength and toughness), and drug release. Results: With a fixed process, unlike a modified process with an increase in extrusion speed and reduction of conveyor speed in the late phase, all implant formulations tended to decrease in diameter and mechanical properties in the late phase. Drug release profiles for the intermediate and slow release compositions were similar with or without process modification, unlike the fast release composition. Addition of ester-terminated PLGA resulted in a slower drug release. When all formulations are grouped together, the implant diameter exhibited a moderate correlation with mechanical properties, but no correlation was observed with drug release. Conclusions: Within a hot-melt extrusion batch process, the dexamethasone-PLGA implant diameter and hence toughness and strength tend to decline in the latter phase. In-process adjustment of extrusion and conveyor speeds can improve batch consistency and, potentially, implant integrity or performance during or after injection. Process changes did not affect drug release for 2 of the 3 implant compositions.

Purpose: To evaluate the effects of a coexisting epiretinal membrane (ERM) on the treatment outcomes of a dexamethasone implant (DI) in diabetic macular edema (DME) patients. Methods: One hundred five eyes of 78 DME patients (44 F, 34 M; mean age: 65.7) treated with minimum 2 DIs were enrolled into this retrospective study. The study population was divided into the ERM (+) study group and the ERM (-) control group. The best corrected visual acuity (BCVA), intraocular pressure, and central macular thicknesses (CMTs) were evaluated at baseline and months 1, 2, and 3 after each DI treatment. Results: Both groups were comparable in baseline BCVA, CMT, HbA1c levels, and age. In the study group ( n : 49), BCVA changed following the first DI from 0.83 to 0.76 and from 0.97 to 0.80 following the second DI. CMT decreased after the first DI from 465 to 377 μ ( P  < 0.001) and from 477 to 356 μ ( P  < 0.001) after the second DI. In the control group ( n : 56), BCVA changed following the first DI from 0.81 to 0.77 and from 0.86 to 0.83 following the second DI. After the first DI, CMT decreased from 483 to 280 μ ( P  < 0.001) and from 468 to 301 μ ( P  < 0.001) after the second DI. The inter-group comparison revealed no significant difference in visual or anatomical gain ( P  = 0.46, P  = 0.05, respectively). Conclusion: The presence of an epiretinal membrane did not change the treatment response to DI therapy.

In-situ forming implants receive great attention for repairing serious bone injuries. The aim of the present study was to prepare novel chitosan in-situ forming implants (CIFI) loaded with bioactive glass nanoparticles and/or raloxifene hydrochloride (RLX). Incorporating raloxifene hydrochloride (RLX) as a selective estrogen receptor modulator was essential to make use of its anti-resorptive properties. The prepared formulae were tested for their in-vitro gelation time, drug release, injectability, rheological properties, erosion rate and morphological properties. Results revealed that the formulation composed of 1% (w/v) chitosan with 2% (w/v) NaHCO 3 and 1% (w/v) bioactive glass nanoparticles (CIFI-BG) possessed the most sustained drug release profile which extended over four months with low burst release effect compared to the same formulation lacking bioactive glass nanoparticles (CIFI). Selected formulations were tested for their ability to enhance bone regeneration in induced puncture in rate tibia. Results declared that these formulations were able to enhance bone regeneration after 12 weeks in comparison to the untreated tibial punctures and that containing bioactive glass could be considered as novel approach for treatment of serious bone injuries which require long term treatment and internal mechanical bone support during healing., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Purpose: To compare the clinical outcome of intravitreal dexamethasone implant versus oral acetazolamide in patients with cystoid macular edema (CME) secondary to retinitis pigmentosa (RP). Design: Multicenter, prospective, propensity-score-matched, comparative study. Methods: Eyes with RP and CME were treated either with intravitreal dexamethasone implant or with oral acetazolamide (500 mg/day). Patients were evaluated monthly and followed up for 12 months. Primary outcome measures were changes in central retinal thickness and best corrected visual acuity (BCVA). Adverse events were recorded. Results: Propensity score matching resulted in 2 groups of 30 eyes each. All patients completed 12 months of follow-up. Mean central retinal thickness decreased from 535 μm at baseline to 208 μm at month 12 in the dexamethasone implant group and from 519 to 339 μm in the oral acetazolamide group ( P  < 0.001, Student's t -test). Mean BCVA average change from baseline during the study (area-under-the-curve approach) was -0.084 logarithm of the minimum angle of resolution (logMAR) (+4.2 letters) in the dexamethasone implant group and -0.032 (+1.6 letters) in the oral acetazolamide group ( P  < 0.05, Mann-Whitney U test). Patients in the dexamethasone implant group required on average 1.7 treatments during 1 year of therapy. Conclusions: In this study, intravitreal dexamethasone implant produced better anatomic and functional improvements over oral acetazolamide in patients affected by CME secondary to RP. Larger, randomized clinical trials with longer follow-up are warranted to confirm these data.

Background: While prior epidemiologic studies have suggested that injectable progestin-based contraceptive depot medroxyprogesterone acetate (DMPA) use may increase a woman's risk of acquiring HIV, recent data have suggested that DMPA users may be at a similar risk for HIV acquisition as users of the copper intrauterine device and levonorgestrel implant. Use of the etonogestrel Implant (Eng-Implant) is increasing but there are currently no studies evaluating its effect on HIV acquisition risk., Objective: Evaluate the potential effect of the Eng-Implant use on HIV acquisition risk by analyzing HIV target cells and cytokine profiles in the lower genital tract and blood of adult premenopausal HIV-negative women using the Eng-Implant., Methods: We prospectively obtained paired cervicovaginal lavage (CVL) and blood samples at 4 study visits over 16 weeks from women between ages 18-45, with normal menses (22-35 day intervals), HIV uninfected with no recent hormonal contraceptive or copper intrauterine device (IUD) use, no clinical signs of a sexually transmitted infection at enrollment and who were medically eligible to initiate Eng-Implant. Participants attended pre-Eng-Implant study visits (week -2, week 0) with the Eng-Implant inserted at the end of the week 0 study visit and returned for study visits at weeks 12 and 14. Genital tract leukocytes (enriched from CVL) and peripheral blood mononuclear cells (PBMC) from the study visits were evaluated for markers of activation (CD38, HLA-DR), retention (CD103) and trafficking (CCR7) on HIV target cells (CCR5+CD4+ T cells) using multicolor flow cytometry. Cytokines and chemokines in the CVL supernatant and blood plasma were measured in a Luminex assay. We estimated and compared study endpoints among the samples collected before and after contraception initiation with repeated-measures analyses using linear mixed models., Results: Fifteen of 18 women who received an Eng-Implant completed all 4 study visits. The percentage of CD4+ T cells in CVL was not increased after implant placement but the percentage of CD4+ T cells expressing the HIV co-receptor CCR5 did increase after implant placement (p = 0.02). In addition, the percentage of central memory CD4+ T-cells (CCR7+) in CVL increased after implant placement (p = 0.004). The percentage of CVL CD4+, CCR5+ HIV target cells expressing activation markers after implant placement was either reduced (HLA-DR+, p = 0.01) or unchanged (CD38+, p = 0.45). Most CVL cytokine and chemokine concentrations were not significantly different after implant placement except for a higher level of the soluble lymphocyte activation marker (sCD40L; p = 0.04) and lower levels of IL12p70 (p = 0.02) and G-CSF (p<0.001). In systemic blood, none of the changes noted in CVL after implant placement occurred except for decreases in the percentage CD4 T-cells expressing HLA-DR+ T cells (p = 0.006) and G-CSF (p = 0.02)., Conclusions: Eng-Implant use was associated with a moderate increase in the availability of HIV target cells in the genital tract, however the percentage of these cells that were activated did not increase and there were minimal shifts in the overall immune environment. Given the mixed nature of these findings, it is unclear if these implant-induced changes alter HIV risk., Competing Interests: no authors have competing interests.

We describe the in vitro and in vivo evaluation of a subcutaneous reservoir implant delivering tenofovir alafenamide hemifumarate (TAF) for the prevention of HIV infection. These long-acting reservoir implants were able to deliver antiretroviral drug for over 90 days in vitro and in vivo We evaluated the implants for implantation site histopathology and pharmacokinetics in plasma and tissues for up to 12 weeks in New Zealand White rabbit and rhesus macaque models. A dose-ranging study in rabbits demonstrated dose-dependent pharmacokinetics and local inflammation up to severe necrosis around the active implants. The matched placebos showed normal wound healing and fibrous tissue encapsulation of the implant. We designed a second implant with a lower release rate and flux of TAF and achieved a median cellular level of tenofovir diphosphate of 42 fmol per 10 6 rhesus macaque peripheral blood mononuclear cells at a TAF dose of 10 μg/kg/day. This dose and flux of TAF also resulted in adverse local inflammation and necrosis near the implant in rhesus macaques. The level of inflammation in the primates was markedly lower in the placebo group than in the active-implant group. The histological inflammatory response to the TAF implant at 4 and 12 weeks in primates was graded as a severe reaction. Thus, while we were able to achieve a sustained target dose, we observed an unacceptable inflammatory response locally at the implant tissue interface., (Copyright © 2020 Su et al.)

Background: Whether they are injected peri- or intraocularly, corticosteroids are still essential tools in the therapeutic arsenal for treating inflammatory macular oedema. A few years ago, however, only triamcinolone acetonide was available to ophthalmologists. While this compound was initially developed for rheumatological or dermatological use, it has been increasingly deployed in ophthalmology, despite still being off-label. In 2011, the system for delivery of dexamethasone from a biodegradable, injectable implant into the vitreous cavity obtained approval for use in inflammatory macular oedema. While the efficacy and safety of triamcinolone in macular oedema, including inflammatory oedema, have already been studied, there are currently no publications on subconjunctival triamcinolone injections, which are simple, effective and well tolerated. To date, the dexamethasone 700 μg implant has been authorized for the treatment of noninfectious intermediate and posterior uveitis, but there have been no studies to evaluate the efficacy and safety of the different peri- and intraocular strategies, including the treatment of inflammatory macular oedema., Methods: This protocol is therefore designed to compare the efficacy and safety of peri- and intraocular corticosteroid injections in the treatment of inflammatory macular oedema. In this ongoing study, 142 patients will be included, and the oedematous eye will be randomised to treatment with either subconjunctival triamcinolone injection or an intravitreal implant containing 700 μg dexamethasone. Follow-up is planned for 6 months with monthly visits. Each visit will include visual acuity measurement, a slit lamp examination, fundoscopy, intraocular pressure measurement, laser flare measurement (if available) and spectral domain optical coherence tomography., Discussion: The results of this trial will have a real impact on public health if it is shown that a Kenacort retard® (i.e. triamcinolone) injection costing just €2.84 and performed in the physician's office (with no additional overhead costs) is at least as effective as the dexamethasone 700 μg implant (Ozurdex®; costing approximately €960 with the injection performed in a dedicated room), with no increased side effects., Trial Registration: ClinicalTrials.gov, NCT02556424. Registered on 22 September 2015.

Purpose: To observe the rate of hypotony and intraocular pressure (IOP) fluctuations immediately following intravitreal dexamethasone implantation in vitrectomized eyes., Methods: The study included previously vitrectomized eyes scheduled to receive intravitreal dexamethasone implants. IOP measurements were performed at minute 1, minute 10, hour 1, hour 2, hour 3 and day 1. The primary outcome measure of the study was the rate of hypotony at the various time points, while the secondary outcome measure was the IOP profile over time., Results: A total of 26 eyes were enrolled in the study. Immediately following the injection, 11 (42.3%) of the eyes exhibited an IOP<6mm Hg. Hypotony was observed in one eye (3.8%) at hour 3 and day 1. After the immediate IOP reduction, IOP recovered rapidly and showed a peak at hour 1, with 5 eyes (19.2%) exhibiting IOP levels ≥25mmHg and 1 eye (3.8%) ≥30mm Hg. Aside from the eye with persistent hypotony resulting in a choroidal effusion, no other complication was observed., Conclusions: Injection of dexamethasone implants in vitrectomized eyes resulted in immediate IOP reduction. Hypotony showed a short, self-limited course in the majority of eyes. In the presence of additional risk factors for wound incompetency, regular follow-up in the early post-injection period appears to be needed., (Copyright © 2020 Elsevier Masson SAS. All rights reserved.)

Purpose: To describe intravitreal anti-VEGF drug and dexamethasone use in four Italian regions., Methods: Four regional claims databases were used to measure drug prevalence, compare dosing intervals to those recommended in the summary of product characteristics (SPC), and identify switchers. Bilateral treatment and diabetic macular edema (DME) coding algorithms were validated, linking claims with a sample of prospectively collected ophthalmological data., Results: Overall, 41,836 patients received ≥1 study drug in 2010-2016 (4.8 per 10,000 persons). In 2016, anti-VEGF drug use ranged from 0.8 (Basilicata) to 5.7 (Lombardy) per 10,000 persons while intravitreal dexamethasone use ranged from 0.2 (Basilicata) to 1.4 (Lombardy) per 10,000 persons. Overall, 40,815 persons were incident users of study drugs. Among incident users with ≥1 year of follow-up ( N  = 30,745), 16.0% ( N  = 30,745), 16.0% ( N  = 30,745), 16.0% (., Conclusion: Study drug use increased over time in Lombardy, Basilicata, Calabria, and Sicily, despite a large heterogeneity in prevalence of use across regions. Drug treatment appeared to be partly in line with SPC, suggesting that improvement in clinical practice may be needed to maximize drug benefits., Competing Interests: Giulia Scondotto, Janet Sultana, Valentina Ientile, Ylenia Ingrasciotta, Andrea Fontana, Massimiliano Copetti, Eliana Mirabelli, Costantino J. Trombetta, Carlo Rapisarda, Teresio Avitabile, Antonio Longo, Patricia Ibanez Toro, Maria Vadalà, Salvatore Cillino, Gianni Virgili, Olivia Leoni, Sebastiano Walter Pollina Addario, Pasquale Cananzi, Claudia La Cavera, Maria Rosalia Puzo, Giovambattista De Sarro, Adele De Francesco have no conflicts of interest to declare. Gianluca Trifirò participated in advisory boards within the last five years on topics not related to this manuscript and organized by Sandoz, Hospira, Sanofi, Biogen, Ipsen, and Shire and is a consultant for Otsuka. He is the principal investigator of observational studies funded by several pharmaceutical companies (e.g., Amgen, AstraZeneca, Daiichi Sankyo, IBSA) to the University of Messina as well as scientific coordinator of the master's program “Pharmacovigilance, pharmacoepidemiology and pharmacoeconomics: real world data evaluations” at the University of Messina which receives unconditional funding from several pharmaceutical companies., (Copyright © 2020 Giulia Scondotto et al.)

Background: At present, the controlled local drug delivery is a very promising approach compared to systemic administration, since it mostly targets the affected tissue. In fact, various drug carriers for local delivery have been prepared with improved therapeutic efficacy., Objective: in situ polymer gels are drug delivery systems that not only present liquid characteristics before their administration in body, but once they are administered, form gels due to gelation. Their gelation mechanism is due to factors such as pH alteration, temperature change, ion activation or ultraviolet irradiation. in situ gels offer various advantages compared to conventional formulations due to their ability to release drugs in a sustainable and controllable manner. Most importantly, in situ gels can be used in local drug delivery applications for various diseases., Methods: This review includes the basic knowledge and theory of in situ gels as well as their various applications according to their administration route., Results: Various natural, semisynthetic, and synthetic polymers can produce in situ polymeric gels. For example, natural polysaccharides such as alginic acid, chitosan, gellan gum, carrageenan etc . have been utilized as in situ gels for topical delivery. Besides the polysaccharides, poloxamers, poly(Nisopropylacrylamide), poly(ethyleneoxide)/ (lactic-co-glycolic acid), and thermosensitive liposome systems can be applied as in situ gels. In most cases, in situ polymeric gels could be applied via various administration routes such as oral, vaginal, ocular, intranasal and injectable., Conclusion: To conclude, it can be revealed that in situ gels could be a promising alternative carrier for both chronic and immediate diseases., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Purpose of Review: Outline some regulatory considerations and scientific challenges related to the development of long-acting antiretrovirals (ARVs) for the treatment and prevention of HIV-1 infection., Recent Findings: Poor adherence to oral ARV regimens continues to pose challenges for effective treatment and prevention of HIV-1 infection. The development of long-acting ARV modalities for treatment and prevention of HIV-1 infection is emerging as a promising alternative to the current treatment and prevention paradigm and has gained considerable interest., Summary: The development of long-acting ARVs can present some unique drug development challenges. Advance planning and prioritization of studies early in development can facilitate the development of long-acting ARVs for the prevention and treatment of HIV-1 infection for all populations, including pediatric patients and pregnant women.

Cisplatin is the most commonly used antitumor drug in the chemotherapy of a variety of malignancies. However, the severe side effects and drug resistance limit its clinical application. The aim of this study was to develop PLGA-based cisplatin-loaded implants and evaluate the antitumor efficacy of continuous intratumoral chemotherapy with the implants. The cisplatin-loaded implants were prepared by the direct compression method and characterized regarding drug content, micromorphology, in vitro and in vivo drug release profiles. Furthermore, the antitumor activity of the implants was conducted in sarcoma 180 tumor-bearing mice. The SEM images showed smooth surface of the implants and the mean drug content of the tested implants was (37.7% ± 0.5%, w/w). Both in vitro and in vivo release profiles of the implants were characterized by initial burst release followed by the sustained-release of cisplatin. Intratumoral implantation of the cisplatin-loaded implants could effectively inhibit the tumor growth. Additionally, intratumoral chemotherapy with the implants significantly reduced the systemic toxicity compared with intravenous injection of cisplatin. It is worth noting that an increase in the dose of the implants led to a higher tumor suppression rate without additional systemic toxicity. These results demonstrated that cisplatin-loaded implants enhanced the antitumor efficacy and reduced the dose-related side effects in sarcoma 180 tumor-bearing mice.

Introduction: Cataract surgery is the most commonly performed surgery in the world, and its success depends in part on the quality of mydriasis., Purpose: To compare, for the same eye, the pupillary dilation obtained with Mydrane® (standardized intracameral solution of 0.02% tropicamide, combined with 0.31% phenylephrine and 1% lidocaine) intraoperatively versus Mydriasert® (0.28mg tropicamide insert and 5.4mg phenylephrine) with a contact time between 45 and 60 minutes in the preoperative period., Methods: Single center prospective study from November 2016 to January 2018 at the Laveran Army Instructional Hospital in Marseille. Patients referred for surgery were dilated at the preoperative consultation with Mydriasert®. The pupillary diameter after 45-60 minutes of contact with the insert was manually measured, by two different examiners, through the "iris image" tab of the Pentacam® elevation topography. Patients were dilated on the day of their cataract surgery with 0.2cc of Mydrane® injected in the anterior chamber through a paracentesis. Thirty seconds later, prior to injection of viscoelastic, an eye photograph was taken by screen capture. The pupillary diameter was evaluated by two different examiners with to the Piximeter 5.9 metrology software. The difference in pupil dilation between Mydriasert® and Mydrane® was tested with the paired series Student t-test., Results: In total, 111 eyes of 82 patients were included. Mydriasert® achieved a mean pupillary dilation of 7.21±0.79mm. The mydriasis obtained with Mydrane® averaged 6.35±0.8mm. This difference of 0.86mm was statistically significant (P<0.001) with a confidence interval of 95% [-0.97; -0.74]., Conclusion: On average, Mydrane® dilates the pupil less than Mydriasert®. However, the mydriasis obtained with Mydrane® remains comfortable for the performance of the capsulorhexis. It helps save preoperative time and affords additional anesthetic to the cataract surgery. Nevertheless, the use of Mydriasert® is beneficial when extra mydriasis is required., (Copyright © 2019 Elsevier Masson SAS. All rights reserved.)

Objective: To evaluate the mid-long-term efficacy and safety of the dexamethasone intravitreal (DEX) implant (Ozurdex 1 ) in naïve patients with diabetic macular edema (DME). Methods: Prospective and single-center study conducted on consecutive patients with a diagnosis of DME, who received a DEX implant and were followed up for at least 12 months. The main outcomes measurements were the mean change in best corrected visual acuity (BCVA) and in foveal thickness (FT) as compared to the baseline values. Results: Of the 84 screened patients 50 were included in the study. The BCVA significantly improved from 52.4 (20.4) letters at baseline to 62.6 (15.6), 61.2 (18.4), 61.6 (18.6), 60.6 (19.0), and 60.6 (18.8) at 2, 4, 6, 12 months and end of follow-up period, respectively (repeated measures ANOVA and the Greenhouse-Geisser correction; p =  .0008). At the end of the follow-up period, a gain of BCVA of ≥5, ≥10, and ≥15 letters were observed in 26 (52.0%), 18 (36.0%), and 16 (32.0%) patients, respectively. The mean FT was significantly reduced from 446.0 (139.9) µm at baseline to 327.2 (103.6) at the end of follow-up (repeated measures ANOVA and the Greenhouse-Geisser correction; p =  .0008). During the study follow-up, the patients receive a mean of 3.4 (2.9-3.9) implants. Of the 32 phakic eyes at baseline, 17 (53.1%) either developed new lens opacity or progression of an existing opacity. Conclusion: In eyes with DME not previously treated with intravitreal drugs, DEX implants provide meaningful functional and anatomical benefits, and these results are sustained mid-long-term.

Bone injury is very serious in elder people or osteoporotic patients. In-situ forming implants (IFI) for bone rebuilding are usually poly-lactic-co-glycolic acid (PLGA)-based, which have a burst release effect. This study aimed to prepare novel liquid lipid-based PLGA-IFI loaded with raloxifene hydrochloride for prolonged non-surgical treatment of bone injuries by applying solvent-induced phase inversion technique. Labrasol® and Maisine® were added to the selected IFI forming long lasting lipid-based IFI (LLL-IFI). The formulations were characterized by analysing their in-vitro drug release, solidification time, injectability, rheological properties, and DSC in addition to their morphological properties. Results revealed that the LLL-IFI composed of 10%w/v PLGA with a lactide to glycolide ratio of 75:25 with ester terminal and 10% Maisine® possessed the most sustained drug release and lowest burst effect, as well as delayed pore formation compared to its counterpart lacking Maisine®. The selected LLL-IFI and PLGA-IFI formulations were tested for their capability to enhance bone regeneration in bone injuries induced in rats. Both formulations succeeded in healing the bones completely with the superiority of LLL-IFI in the formation of well-organized bone structures lacking fibrous tissues. The results suggest that LLL-IFI and PLGA-IFI are innovative approaches for treating critical and non-critical sized bone injuries., (Copyright © 2019. Published by Elsevier B.V.)

Purpose of Review: The aim of this review is to summarize the development of the photoactivated depot (PAD) approach for the minimally invasive and continuously variable delivery of insulin., Recent Findings: Using an insulin PAD, we have demonstrated that we can release native, bioactive insulin into diabetic animals in response to light signals from a small external LED light source. We have further shown that this released insulin retains bioactivity and reduces blood glucose. In addition, we have designed and constructed second generation materials that have high insulin densities, with the potential for multiple day delivery. The PAD approach for insulin therapy holds promise for addressing the pressing need for continuously variable delivery methods that do not rely on pumps, and their myriad associated problems.

Predominately Angus steers (n = 24; initial BW = 435 ± 28.3 kg) were used to evaluate non-coated (NC) and coated implants (CI) containing equal amounts of trenbolone acetate (TBA; 200 mg) and estradiol benzoate (EB; 28 mg) in finishing steers on sera metabolite responses, gene expression, and immunohistochemical analyses of the Longissimus muscle (LM). Performance data were analyzed as a randomized complete block design, and all other data were analyzed as repeated measures for a completely randomized design. Treatments were no implant (NI), NC (Synovex-PLUS; Zoetis, Parsippany, NJ), and CI (Synovex-One Feedlot) implant. There were 2 pen replicates per treatment (n = 4 steers/pen). LM biopsies, blood, and BW were collected before feeding on days 0, 14, 28, 56, 84, 112, and 133, with final BW being captured on day 140. Genes of interest were determined by RT-qPCR using two housekeeping genes. Sera was analyzed for estradiol-17β (E2),17β-trenbolone (TbOH), insulin-like growth factor 1 (IGF-I), NEFA, and urea-N (SUN). An α of 0.10 determined significance for performance and sera data; α of 0.05 was used for gene and histology data. No performance differences (P ≥ 0.10) were detected. An implant × day interaction (P ≤ 0.10) for E2, IGF-I, and SUN was detected; implants elevated (P ≤ 0.10) E2, 17β-TbOH, and IGF-I; and decreased SUN across day of the study, meaning sera metabolites are not altered with time on feed. An implant × day interaction was detected for myogenic factor 5 (MYF-5) positive cells and proportions of MHCIIX. In LM, CI had greater (P < 0.10) IGF-I in LM over NI. CI increased (P < 0.05) G protein-coupled estrogen receptor 1 (GPER1) expression, as well as, GPER1 semi-quantitative scores over NI and NC. An implant × day interaction (P ≤ 0.05) for estrogen and androgen receptor-positive nuclei was detected; implants had increased (P ≤ 0.05) estrogen and androgen receptor-positive nuclei compared to NI. CIs increase genes associated with muscle tissue growth., (© The Author(s) 2019. Published by Oxford University Press on behalf of the American Society of Animal Science. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

To minimize the gastric and esophageal injury effect, a system to deliver doxycycline hyclate (DOXY) to the duodenum area is needed. DOXY-containing modified-release oral pellets (DMOP) coated with hydroxypropyl methylcellulose phthalate HP-55 (HPMCP HP-55) and hydroxypropyl methylcellulose E15 (HPMC E15) appear to be a reasonable choice. This coating layer dissolves at pH 5.5, which is the pH of the duodenum, but not at a gastric pH (1.2). The formulation and preparation of DMOP were optimized, and a scale-up test was performed. The results showed that the production reproducibility was acceptable, and the quality of DMOP well met the standards of Chinese Pharmacopeia (Ch.P, 2015 edition). Notably, the accumulated DOXY release was lower than 50% at pH 1.2 (20 min) and higher than 85% at pH 5.5, which met the USP40-NF35 standard for DOXY modified-release formulations. Moreover, the storage stability of DMOP with different packages was investigated by stress testing, accelerated and long-term testings. The stability of DMOP was maintained up to 12 months, in terms of DOXY content and in vitro release behavior. The results seem to suggest that DMOP could be a promising duodenum delivery system., (© 2019 Wiley Periodicals, Inc.)

Background: IL-10 knockout (KO) mice are protected from experimental autoimmune encephalomyelitis (EAE) with low-dose estrogen (E2) treatment similar to wild-type (WT) mice. Previous studies have demonstrated a decrease in tumor necrosis factor in all E2-treated groups, which led to the protection of the mice., Methods: This study used IL-10 KO mice and WT mice treated either with E2 or sham pellets 7 days prior to induction of EAE. Mice were observed for 21 days post-immunization. The spleen, inguinal lymph nodes, and brain were evaluated by flow cytometry. Spinal cords were evaluated using a cytokine/chemokine array, RT-PCR, and histology., Results: This study demonstrates that E2 treatment induced three heightened regulatory mechanisms that potentially protect IL-10 KO mice from EAE: (1) an increase in programmed death-ligands 1 and 2 on monocytes and macrophages in the periphery and within the CNS; (2) an increase in CD73 in the inflamed CNS, which can increase the production of the anti-inflammatory molecule adenosine; and (3) a decrease in CD4 + CD25 + FoxP3 + regulatory T cells in the spleen. Together, these factors comprise an alternative compensatory mechanism that significantly downregulates key pro-inflammatory cytokine, chemokine, and chemokine receptor genes which are enhanced in the spinal cord of IL-10 KO mice. This group of E2-treated mice remained asymptomatic after EAE challenge similar to E2-treated WT mice, despite their having more T and B lymphocytes in the brain, and modestly increased demyelination in the spinal cord., Conclusion: These results indicate that previously unrecognized compensatory mechanisms of EAE protection are stimulated by E2 in the absence of IL-10, which can provide disease protection comparable to the IL-10-dependent effects induced by E2 in WT mice.

Aim: Main failure of diabetic tractional retinal detachment (TRD) surgery is the development of proliferative vitreoretinopathy (PVR), causing higher re-detachment rates. We investigated whether the use of dexamethasone (DEX) implant at the end of pars plana vitrectomy (PPV) with silicone oil tamponade might have an impact on these outcomes., Design: Comparative, nonrandomized, retrospective study., Participants: A total of 148 eyes from 148 patients that underwent PPV with silicone oil tamponade for diabetic TRD (with DEX implant, n = 52; without DEX implant, n = 96)., Methods: Consecutive patients' records were reviewed for time between TRD diagnosis and surgery; lens status before surgery and after 6, 12, and 24 months; retina attachment rate after primary PPV; change in postoperative PVR severity; rate of re-detachment at 6, 12, and 24 months; use of IOP lowering treatment after 6, 12, and 24 months; surgery details; intra- and postoperative complications. Correlations between outcome measures, postoperative PVR severity, and re-detachment rates were analyzed., Main Outcome Measures: Change in postoperative PVR severity and retinal re-detachment rates with and without the adjuvant use of DEX implant., Results: Retinal re-detachment rates were significantly higher in the group of patients that did not receive DEX implant [11/96 (11.5%) vs. 0/52 (0%), p = 0.049; 11/84 (12.9%) vs. 4/52 (7.7%), p = 0.007; 14/71 (19.7%) vs. 5/52 (10%) p < 0.001 at 6, 12, and 24 months, respectively]. PVR severity correlated with retinal status at 12 and 24 months (p = 0.018 and p = 0.027, respectively). The difference in PVR severity between the two groups was statistically significant at 6, 12, and 24 months (p < 0.001)., Conclusions: DEX implant at the end of PPV in patients with diabetic TRD improves PVR severity and decreases re-detachment rates. This should be considered as an option in the customized treatment of TRD.

Uveitis is a major cause of ocular morbidity, potentially leading to significant visual impairment. The recent adoption of alternative drug delivery options has led to the development of new sustained-delivery corticosteroid systems, able to manage successfully chronic noninfectious posterior uveitis. The treatment goal is to target the site of inflammation with low dose of corticosteroids, delivered over an extended period of time, to minimize the cumulative damage resulting from repeated recurrences, reducing both injections frequency and ocular side effects. This article will review the pharmacology and preliminary clinical data of the 0.18 mg fluocinolone acetonide intravitreal implant (YUTIQ™), to show its efficacy and safety in the treatment of noninfectious posterior uveitis.

Background: Evidence-informed priority setting is vital to improved investment in public health interventions. This is particularly important as South Africa (SA) makes the shift to universal health coverage and institution of National Health Insurance., Objectives: To measure the financial impact of increasing the demand for modern contraceptive methods in the SA public health sector. We estimated the total cost of providing contraceptives, and specifically the budgetary impact of premature removals of long-acting reversible contraceptives., Methods: We created a deterministic model in Microsoft Excel to estimate the costs of contraception provision over a 5-year time horizon (2018 - 2023) from a healthcare provider perspective. Only direct costs of service provision were considered, including drugs, supplies and personnel time. Costs were not discounted owing to the short time horizon. Scenario analyses were conducted to test uncertainty., Results: The base-case cost of current contraceptive use in 2018 was estimated to be ZAR1.64 billion (ZAR29 per capita). Injectable contraceptives accounted for ~47% of total costs. To meet the total demand for family planning, SA would have to spend ~30% more than the estimate for current contraceptive use. In the year 2023, the 'current use' of modern contraceptives would increase to ZAR2.2 billion, and fulfilling the total demand for family planning would require ZAR2.9 billion. The base-case cost of implantable contraceptives was estimated at ZAR54 million. Assuming a normal removal rate, the use of implants is projected to increase by 20% during the 5-year period between 2019 and 2023, with an estimated 46% increase in costs. The cost of early removal of Implanon NXT is estimated at ZAR75 million, with total contraception costs estimated at ZAR102 million in 2019, compared with ZAR56 million when a normal removal rate is applied., Conclusions: The costs of scaling up modern contraceptives in SA are substantial. Early and premature removals of implantable contraceptives are costly to the nation and must be minimised. The government should consider conducting appropriate health technology assessments to inform the introduction of new public health interventions as SA makes the shift to universal health coverage by means of National Health Insurance.

Implantable drug delivery systems, such as drug pumps and polymeric drug depots, have emerged as means of providing predetermined drug release profiles at the desired site of action. While initial implants aimed at providing an enduring drug supply, developments in polymer chemistry and pharmaceutical technology and the growing need for refined drug delivery patterns have prompted the design of sophisticated drug delivery implants such as on-demand drug-eluting implants and personalized 3D printed implants. The types of cargo loaded into these implants range from small drug molecules to hormones and even therapeutic cells. This review will shed light upon recent advances in materials and composites used for polymeric implant fabrication, highlight select approaches employed in polymeric implant fabrication, feature medical applications where polymeric implants have a significant impact, and report recent advances made in these areas.

Objective: Over the last two decades, optical control of neuronal activity in the central nervous system has seen rapid development, demonstrating the utility of optogenetics as both an experimental and therapeutic tool. Conversely, applications of optogenetics in the peripheral nervous system have been relatively constrained by the challenges of temporally variable opsin expression, light penetration and immune attack of non-native opsins. Whilst opsin expression can be increased significantly through high-concentration viral induction, subsequent attack by the immune system causes temporal decay and high variability in electrophysiological response., Approach: In this study, we present a method to circumvent the aforementioned challenges by locally supplementing all-trans-retinal (ATR) (via a slow release pellet) to increase tissue photosensitivity in transgenic mice expressing channelrhodopsin 2 (ChR2) in nerves., Main Results: In mice supplemented with ATR, we demonstrate enhanced electrophysiological activation and fatigue tolerance in response to optical stimulation for six weeks., Significance: Local supplementation of ATR enables improved optogenetic stimulation efficacy in peripheral nerves. This method enables greater exploration of neurophysiology and development of clinically-viable optogenetic treatments in the peripheral nervous system.