Explore the vast range of titles available.

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.

There is no treatment available for vision loss associated with advanced dry age-related macular degeneration (AMD) or geographic atrophy (GA). In a pilot, proof of concept phase 2 study, we evaluated ciliary neurotrophic factor (CNTF) delivered via an intraocular encapsulated cell technology implant for the treatment of GA. We designed a multicenter, 1-y, double-masked, sham-controlled dose-ranging study. Patients with GA were randomly assigned to receive a high-or low-dose implant or sham surgery. The primary endpoint was the change in best corrected visual acuity (BCVA) at 12 mo. CNTF treatment resulted in a dose-dependent increase in retinal thickness. This change was followed by visual acuity stabilization (loss of less than 15 letters) in the high-dose group (96.3%) compared with low-dose (83.3%) and sham (75%) group. A subgroup analysis of those with baseline BCVA at 20/63 or better revealed that 100% of patients in the high-dose group lost <15 letters compared with 55.6% in the combined low-dose/sham group (P = 0.033). There was a 0.8 mean letter gain in the high-dose group compared with a 9.7 mean letter loss in the combined low-dose/sham group (P = 0.0315). Both the implant and the implant procedure were well-tolerated. These findings suggest that CNTF delivered by the encapsulated cell technology implant appears to slow the progression of vision loss in GA, especially in eyes with 20/63 or better vision at baseline.

Nitric oxide (NO) is a short-lived signaling molecule that plays a pivotal role in cardiovascular system. Organic nitrates represent a class of NO-donating drugs for treating coronary artery diseases, acting through the vasodilation of systemic vasculature that often leads to adverse effects. Herein, we design a nitrate-functionalized patch, wherein the nitrate pharmacological functional groups are covalently bound to biodegradable polymers, thus transforming small-molecule drugs into therapeutic biomaterials. When implanted onto the myocardium, the patch releases NO locally through a stepwise biotransformation, and NO generation is remarkably enhanced in infarcted myocardium because of the ischemic microenvironment, which gives rise to mitochondrial-targeted cardioprotection as well as enhanced cardiac repair. The therapeutic efficacy is further confirmed in a clinically relevant porcine model of myocardial infarction. All these results support the translational potential of this functional patch for treating ischemic heart disease by therapeutic mechanisms different from conventional organic nitrate drugs. Nitric oxide (NO) is an important gaseous signaling molecule with multiple physiological roles in cardiovascular system. Here the authors develop a cardiac patch with NO releasing function that favors heart repair after myocardial infarction.

Bimatoprost implant 10 µg is an intracameral, biodegradable implant that slowly releases bimatoprost to lower intraocular pressure (IOP). This study was designed to evaluate safety and the duration of the IOP-lowering effect after single and as-needed repeat administration of the bimatoprost implant in patients with open-angle glaucoma (OAG) and ocular hypertension (OHT). This study is an interim analysis of an ongoing, prospective, open-label, multicenter study in patients with OAG or OHT who are inadequately managed with topical IOP-lowering medication for reasons other than efficacy. IOP-lowering rescue treatment is allowed if implant retreatment criteria are not met. The primary endpoint is time to retreatment/rescue after the initial implant administration analyzed with the Kaplan-Meier method. Key safety measures include treatment-emergent adverse events (TEAEs) and reading-center evaluation of central corneal endothelial cell density (CECD). Analysis of data collected through 15 September 2023 focused on outcomes after a single or two implants. In total, 441 patients received the 10-µg bimatoprost implant in the study eye on day 1 (cycle 1), 179 patients received a second administration (cycle 2), and 378 patients had at least 12 months of follow-up data available. The median time (95% confidence interval) from the first administration to a second administration or rescue was 392 (369, 485) days; the probability of not requiring retreatment or rescue by day 360 was 57.5%. A second implant administration similarly provided a long duration of IOP control. The baseline mean (standard error, SE) IOP was 25.6 (0.14) mmHg; the mean (SE) change from baseline IOP in unrescued eyes after a single administration was - 7.5 (0.21) mmHg at week 24 and - 6.4 (0.28) mmHg at month 12. Conjunctival hyperemia, typically associated with the administration procedure, was the most common ocular TEAE (cycle 1, 14.3%; cycle 2, 12.8%). Mean (SE) percentage change in CECD from baseline at 12 months after administration was - 4.3 (0.81)% in cycle 1 and - 8.5 (2.22)% in cycle 2. The cycle 1 implant was no longer visible or ≤ 25% of initial size in 66.3% and 94.3% of study eyes at months 12 and 24, respectively. In this interim analysis based on available data, the IOP-lowering effect of the initial administration of the 10-µg bimatoprost implant was well maintained for > 1 year in most patients. Results after a second administration were comparable. The safety profile of initial and repeat administration was acceptable. ClinicalTrials.gov identifier NCT03850782; registered 20 February 2019.

PurposeSexual transmission of HIV has been clinically proven to be preventable with a once-daily oral tablet; however, missed doses dramatically increase the risk of HIV infection. Long-acting subcutaneous implants do not allow the user to miss a dose. A desirable long-acting drug-eluting implant can deliver a constant amount of drug, adjust the delivered dose, and be readily manufactured. We present a long-acting, subcutaneous implant design composed of tenofovir alafenamide hemifumarate (TAF) pellets loaded in a sealed polyether urethane tube for the prevention of HIV transmission.MethodsImplants were prepared with pressed drug pellets and extruded polyurethane tubing. In vitro release rate of implants using different pellet formulations, rate-controlling membranes, and geometries were measured.ResultsTenofovir alafenamide release appeared to be governed by a pseudo-steady state and followed a mass transport model of release from a cylindrical drug reservoir. Implant seal integrity was tested and confirmed using mechanical testing. The inclusion of sodium chloride in the pellet increased the release rate and reduced initial lag. The release was sustained for 100 days.ConclusionsThe release rate of tenofovir alafenamide mechanistically varied with geometry and rate controlling membrane composition. The polyether urethane implant presented herein is modular and tunable to adjust the release rate and duration of the TAF release.

The poor transport of molecular and nanoscale agents through the blood–brain barrier together with tumour heterogeneity contribute to the dismal prognosis in patients with glioblastoma multiforme. Here, a biodegradable implant (μMESH) is engineered in the form of a micrometre-sized poly(lactic-co-glycolic acid) mesh laid over a water-soluble poly(vinyl alcohol) layer. Upon poly(vinyl alcohol) dissolution, the flexible poly(lactic-co-glycolic acid) mesh conforms to the resected tumour cavity as docetaxel-loaded nanomedicines and diclofenac molecules are continuously and directly released into the adjacent tumour bed. In orthotopic brain cancer models, generated with a conventional, reference cell line and patient-derived cells, a single μMESH application, carrying 0.75 mg kg −1 of docetaxel and diclofenac, abrogates disease recurrence up to eight months after tumour resection, with no appreciable adverse effects. Without tumour resection, the μMESH increases the median overall survival (∼30 d) as compared with the one-time intracranial deposition of docetaxel-loaded nanomedicines (15 d) or 10 cycles of systemically administered temozolomide (12 d). The μMESH modular structure, for the independent coloading of different molecules and nanomedicines, together with its mechanical flexibility, can be exploited to treat a variety of cancers, realizing patient-specific dosing and interventions. Surgical resection is the primary treatment strategy for glioblastoma multiforme, but the infiltrating nature of the tumour, coupled with its heterogeneity and the presence of the blood–brain barrier that hampers drug delivery, contributes to recurrence and poor prognosis. Here the authors engineer a mechanically flexible mesh that can adhere to the tumour resected cavity and release a combination of nanomedicines and small molecules in a controlled and sustained manner for tumour therapy.

The second messengers, cGMP and Ca2+, 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 (Ca2+)-signalling in photoreceptors. In this review, we summarize key aspects of cGMP-signalling and Ca2+-signalling relevant for hereditary photoreceptor degeneration. The topics covered include cGMP-signalling targets, the role of Ca2+ 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 Ca2+-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.

Carmustine wafers (CW; Gliadel ® wafers) are approved to treat newly-diagnosed high-grade glioma (HGG) and recurrent glioblastoma. Widespread use has been limited for several reasons, including concern that their use may preclude enrollment in subsequent clinical trials due to uncertainty about confounding of results and potential toxicities. This meta-analysis estimated survival following treatment with CW for HGG. A literature search identified relevant studies. Overall survival (OS), median survival, and adverse events (AEs) were summarized. Analysis of variance evaluated effects of treatment (CW vs non-CW) and diagnosis (new vs recurrent) on median survival. The analysis included 62 publications, which reported data for 60 studies (CW: n = 3,162; non-CW: n = 1,736). For newly-diagnosed HGG, 1-year OS was 67 % with CW and 48 % without; 2-year OS was 26 and 15 %, respectively; median survival was 16.4 ± 21.6 months and 13.1 ± 29.9 months, respectively. For recurrent HGG, 1-year OS was 37 % with CW and 34 % without; 2-year OS was 15 and 12 %, respectively; median survival was 9.7 ± 20.9 months and 8.6 ± 22.6 months, respectively. Effects of treatment (longer median survival with CW than without; P  = 0.043) and diagnosis (longer median survival for newly-diagnosed HGG than recurrent; P  < 0.001) on median survival were significant, with no significant treatment-by-diagnosis interaction ( P  = 0.620). The most common AE associated with wafer removal was surgical site infection (SSI); the most common AEs for repeat surgery were mass effect, SSI, hydrocephalus, cysts in resection cavity, acute hematoma, wound healing complications, and brain necrosis. These data may be useful in the context of utilizing CW in HGG management, and in designing future clinical trials to allow CW-treated patients to participate in experimental protocols.

Introduction Long‐acting HIV pre‐exposure prophylaxis promises to improve uptake, adherence and persistence challenges experienced with daily oral tablets. We assessed the acceptability of an annual tenofovir alafenamide (TAF) implant in South African women enrolled from 9 July 2020 until 31 May 2022 in a Phase I trial. Methods Six women received one TAF implant for 4 weeks (Group 1), after which 30 women were randomized (4:1, TAF to placebo ratio) to receive 1 or 2 TAF or placebo implants for 48 weeks (Group 2), before trial discontinuation. Acceptability assessments were conducted pre‐ and post‐implant removal. Implant attributes (size, quantity, insertion site, palpability, visibility) and physical experiences (insertion/removal procedures, implant site reactions [ISRs]) were rated on a scale of 1 (highly unacceptable) to 6 (highly acceptable), with 4 being the acceptability threshold. The mean (range) of the mean acceptability scores across all pre‐removal visits were calculated, including stratification by removal timing (early vs. scheduled). Implant likes and dislikes were also assessed. Results The median participant age was 26 years. Prior to implant removal, the mean (range) acceptability scores were 5.4 (3.6–6.0) for product attributes and 5.1 (1.7–6.0) for physical experiences. Eleven (31%) participants had early implant removals, occurring on average 19 weeks (range 2–27 weeks) after insertion. The proportion of study visits reporting adherence measure as unacceptable in early versus scheduled removals: ISRs (50% vs. 19%), visibility (30% vs. 15%), palpability (14% vs. 8%), pain (16% vs. 4%) and implant quantity (13% vs. 1%). Pre‐removal acceptability scores for ISRs (p = 0.003) and physical experiences (p = 0.05) were significantly associated with early removal. Overall, mean (range) acceptability scores were 5.8 (4.0–6.0) and 5.9 (4.7–6.0) for lifestyle compatibility and likelihood of recommendation, respectively. After removal, 39% of participants found ISRs unacceptable, followed by 22% citing implant visibility. Potential for long‐term HIV protection, followed by discreet and convenient use, were most liked, while ISRs were the most disliked aspect. Conclusions While implant attributes, physical experiences and insertion/removal procedures were largely acceptable, local ISRs significantly reduced tolerability and acceptability, resulting in higher‐than‐expected early removals. The potential benefits of an annual TAF implant may be undermined unless tolerability is improved.

Background Bacterial proliferation on the endosseous implants surface presents a new threat to the using of the bone implants. Unfortunately, there is no effective constructed antibacterial coating which is bacterial anti-adhesion substrate-independent or have long-term biofilm inhibition functions. Methods Drug release effect was tested in Chymotrypsin (CMS) solution and S. aureus . We used bacterial inhibition rate assays and protein leakage experiment to analyze the in vitro antibacterial effect of (Montmorillonite/Poly- l -lysine-Chlorhexidine) 10 [(MMT/PLL-CHX) 10 ] multilayer film. We used the CCK-8 assay to analyze the effect of (MMT/PLL-CHX) 10 multilayer films on the growth and proliferation of rat osteoblasts. Rat orthopaedic implant-related infections model was constructed to test the antimicrobial activity effect of (MMT/PLL-CHX) 10 multilayer films in vivo. Results In this study, the (MMT/PLL-CHX) 10 multilayer films structure were progressively degraded and showed well concentration-dependent degradation characteristics following incubation with Staphylococcus aureus and CMS solution. Bacterial inhibition rate assays and protein leakage experiment showed high levels of bactericidal activity. While the CCK-8 analysis proved that the (MMT/PLL-CHX) 10 multilayer films possess perfect biocompatibility. It is somewhat encouraging that in the in vivo antibacterial tests, the K-wires coated with (MMT/PLL-CHX) 10 multilayer films showed lower infections incidence and inflammation than the unmodified group, and all parameters are close to SHAM group. Conclusion (MMT/PLL-CHX) 10 multilayer films provides a potential therapeutic method for orthopaedic implant-related infections.