PROteolysis-Targeting Chimeras (PROTACs) in leukemia: overview and future perspectives.

Leukemia is a heterogeneous group of life-threatening malignant disorders of the hematopoietic system. Immunotherapy, radiotherapy, stem cell transplantation, targeted therapy, and chemotherapy are among the approved leukemia treatments. Unfortunately, therapeutic resistance, side effects, relapses, and long-term sequelae occur in a significant proportion of patients and severely compromise the treatment efficacy. The development of novel approaches to improve outcomes is therefore an unmet need. Recently, novel leukemia drug discovery strategies, including targeted protein degradation, have shown potential to advance the field of personalized medicine for leukemia patients. Specifically, PROteolysis-TArgeting Chimeras (PROTACs) are revolutionary compounds that allow the selective degradation of a protein by the ubiquitin-proteasome system. Developed against a wide range of cancer targets, they show promising potential in overcoming many of the drawbacks associated with conventional therapies. Following the exponential growth of antileukemic PROTACs, this article reviews PROTAC-mediated degradation of leukemia-associated targets. Chemical structures, in vitro and in vivo activities, pharmacokinetics, pharmacodynamics, and clinical trials of PROTACs are critically discussed. Furthermore, advantages, challenges, and future perspectives of PROTACs in leukemia are covered, in order to understand the potential that these novel compounds may have as future drugs for leukemia treatment.

Photoaged polystyrene nanoplastics exposure results in reproductive toxicity due to oxidative damage in Caenorhabditis elegans.

The increase of plastic production together with the incipient reuse/recycling system has resulted in massive discards into the environment. This has facilitated the formation of micro- and nanoplastics (MNPs) which poses major risk for environmental health. Although some studies have investigated the effects of pristine MNPs on reproductive health, the effects of weathered MNPs have been poorly investigated. Here we show in Caenorhabditis elegans that exposure to photoaged polystyrene nanoplastics (PSNP-UV) results in worse reproductive performance than pristine PSNP (i.e., embryonic/larval lethality plus a decrease in the brood size, accompanied by a high number of unfertilized eggs), besides it affects size and locomotion behavior. Those effects were potentially generated by reactive products formed during UV-irradiation, since we found higher levels of reactive oxygen species and increased expression of GST-4 in worms exposed to PSNP-UV. Those results are supported by physical-chemical characterization analyses which indicate significant formation of oxidative degradation products from PSNP under UV-C irradiation. Our study also demonstrates that PSNP accumulate predominantly in the gastrointestinal tract of C. elegans (with no accumulation in the gonads), being completely eliminated at 96 h post-exposure. We complemented the toxicological analysis of PSNP/PSNP-UV by showing that the activation of the stress response via DAF-16 is dependent of the nanoplastics accumulation. Our data suggest that exposure to the wild PSNP, i.e., polystyrene nanoplastics more similar to those actually found in the environment, results in more important reprotoxic effects. This is associated with the presence of degradation products formed during UV-C irradiation and their interaction with biological targets.

Proteolysis-Targeting Chimeras (PROTACs) targeting the BCR-ABL for the treatment of chronic myeloid leukemia - a patent review.

INTRODUCTION: PROteolysis-TArgeting Chimeras (PROTACs) allow the selective degradation of a protein of interest (POI) by the ubiquitin-proteasome system (UPS). With this unique mechanism of action, the research and development of PROTACs that target the Breakpoint Cluster Region Abelson (BCR-ABL) tyrosine kinase (TK) has been increasing dramatically, as they are promising molecules in the treatment of Chronic Myeloid Leukemia (CML), one of the main hematological malignancies, which results from an uncontrolled myeloproliferation due to the constitutive activation of BCR-ABL. AREAS COVERED: This review summarizes the patents/applications published in the online databases like Espacenet or World Intellectual Property Organization regarding PROTACs that promote BCR-ABL degradation. Patents will be described mostly in terms of chemical structure, biochemical/pharmacological activities, and potential clinical applications. EXPERT OPINION: The recent discovery of the enormous potential of PROTACs led to the creation of new compounds capable of degrading BCR-ABL for the treatment of CML. Although still in reduced numbers, and in the pre-clinical phase of development, some compounds have already been shown to overcome some of the difficulties presented by conventional BCR-ABL inhibitors, such as the well-known imatinib. Therefore, it is very likely that some of the present PROTACs will enter future CML therapy in the coming years.

Recent advances in oridonin derivatives with anticancer activity.

Cancer is a leading cause of mortality responsible for an estimated 10 million deaths worldwide in 2020, and its incidence has been rapidly growing over the last decades. Population growth and aging, as well as high systemic toxicity and chemoresistance associated with conventional anticancer therapies reflect these high levels of incidence and mortality. Thus, efforts have been made to search for novel anticancer drugs with fewer side effects and greater therapeutic effectiveness. Nature continues to be the main source of biologically active lead compounds, and diterpenoids are considered one of the most important families since many have been reported to possess anticancer properties. Oridonin is an ent-kaurane tetracyclic diterpenoid isolated from Rabdosia rubescens and has been a target of extensive research over the last few years. It displays a broad range of biological effects including neuroprotective, anti-inflammatory, and anticancer activity against a variety of tumor cells. Several structural modifications on the oridonin and biological evaluation of its derivatives have been performed, creating a library of compounds with improved pharmacological activities. This mini-review aims to highlight the recent advances in oridonin derivatives as potential anticancer drugs, while succinctly exploring their proposed mechanisms of action. To wind up, future research perspectives in this field are also disclosed.

Current clinical practice in corneal crosslinking for treatment of progressive keratoconus in four Nordic countries.

PURPOSE: To evaluate clinical practice in the diagnosis and treatment of progressive keratoconus with corneal crosslinking (CXL) in four Nordic countries. METHODS: A questionnaire was sent to all centres at which keratoconus patients are evaluated and CXL is performed in Sweden, Denmark, Norway and Iceland. Nineteen of 20 centres participated. RESULTS: CXL is performed approximately 1300 times per year in these four Nordic countries with a population of around 21.7 million (2019). In most cases, progression is evaluated using the Pentacam HR, and the maximum keratometry reading (Kmax ) is considered the most important parameter. The most frequently used treatment protocol in Scandinavia is the 9 mW/cm2 epi-off protocol, using hydroxylpropyl methylcellulose riboflavin (HPMC-riboflavin). The participants deemed the following areas to be in most need of improvement: adaptation of the CXL protocol to individual patients (5/19), the development of effective epi-on treatment protocols (4/19), optimal performance of CXL in thin corneas (4/19), improvement of the definition of progression (2/19), and diagnosis of the need for re-treatment (2/19). CONCLUSIONS: We concluded that the diagnosis of progressive keratoconus and the diagnostic equipment used are similar. Treatment strategies are also similar but are suitably different to provide an interesting basis for the comparison of treatment outcomes. The high degree of participation in this survey indicates the possibility of future scientific collaboration on CXL focusing on the areas deemed to need improvement. It would also be of interest to evaluate the possibility of creating a Nordic CXL Registry. The high number of CXL treatments performed ensures sufficient statistical power to solve many questions. Such a registry could be an important contribution to evidence-based care and would allow for longitudinal evaluation.

Corneal transplantation in aniridia-related keratopathy with a two-year follow-up period, an uncommon disease with precarious course.

PURPOSE: The purpose of this study is to study the frequency, surgical transplantation technique and outcome in patients with aniridia-related keratopathy (ARK) with two-year follow-up period. METHODS: A retrospective registry-study including all ARK cases performed in Sweden and Denmark between 2001 and 2016 and registered in the Swedish Cornea Transplant Registry. RESULTS: A total of 36 eyes of 26 patients were subjected to corneal transplantation due to ARK during 2001 to 2016. Penetrating keratoplasty (PK) was the procedure of choice in 58.3% (n = 21) of the eyes, followed by a combination of PK and limbal stem cell transplantation in 13.9% (n = 5) and keratolimbal allograft in 13.9% (n = 5). Boston keratoprosthesis was used in 8.3% (n = 3), and anterior lamellar keratoplasty in 5.6% (n = 2). Thirteen of the procedures (36.1%) were retransplantations. Two years after surgery 26 cases were available to follow-up of which 16 of the grafts were functioning (61.5%). The median visual acuity showed a trend of improvement from hand motion to counting fingers. CONCLUSIONS: A majority of the ARK cases (61.5%) had a graft providing useful vision for the patient 2 years after corneal transplantation, but the visual gain was modest at best. Longer follow-up time is required to evaluate functional graft outcomes. Despite the introduction of limbal stem cell transplantation as a suitable treatment, PK was the most common surgical method in the present study.

MDM2-Based Proteolysis-Targeting Chimeras (PROTACs): An Innovative Drug Strategy for Cancer Treatment.

Proteolysis-targeting chimeras (PROTACs) are molecules that selectively degrade a protein of interest (POI). The incorporation of ligands that recruit mouse double minute 2 (MDM2) into PROTACs, forming the so-called MDM2-based PROTACs, has shown promise in cancer treatment due to its dual mechanism of action: a PROTAC that recruits MDM2 prevents its binding to p53, resulting not only in the degradation of POI but also in the increase of intracellular levels of the p53 suppressor, with the activation of a whole set of biological processes, such as cell cycle arrest or apoptosis. In addition, these PROTACs, in certain cases, allow for the degradation of the target, with nanomolar potency, in a rapid and sustained manner over time, with less susceptibility to the development of resistance and tolerance, without causing changes in protein expression, and with selectivity to the target, including the respective isoforms or mutations, and to the cell type, overcoming some limitations associated with the use of inhibitors for the same therapeutic target. Therefore, the aim of this review is to analyze and discuss the characteristics of MDM2-based PROTACs developed for the degradation of oncogenic proteins and to understand what potential they have as future anticancer drugs.

Aniridia-related keratopathy relevant cell signaling pathways in human fetal corneas.

We aimed to study aniridia-related keratopathy (ARK) relevant cell signaling pathways [Notch1, Wnt/ß-catenin, Sonic hedgehog (SHH) and mTOR] in normal human fetal corneas compared with normal human adult corneas and ARK corneas. We found that fetal corneas at 20 weeks of gestation (wg) and normal adult corneas showed similar staining patterns for Notch1; however 10-11 wg fetal corneas showed increased presence of Notch1. Numb and Dlk1 had an enhanced presence in the fetal corneas compared with the adult corneas. Fetal corneas showed stronger immunolabeling with antibodies against ß-catenin, Wnt5a, Wnt7a, Gli1, Hes1, p-rpS6, and mTOR when compared with the adult corneas. Gene expression of Notch1, Wnt5A, Wnt7A, ß-catenin, Hes1, mTOR, and rps6 was higher in the 9-12 wg fetal corneas compared with adult corneas. The cell signaling pathway differences found between human fetal and adult corneas were similar to those previously found in ARK corneas with the exception of Notch1. Analogous profiles of cell signaling pathway activation between human fetal corneas and ARK corneas suggests that there is a less differentiated host milieu in ARK.

Dose Administration Aid Service in Community Pharmacies: Characterization and Impact Assessment.

Adherence to therapies is a primary determinant of treatment success. Lack of medication adherence is often associated with medical and psychosocial issues due to complications from underlying conditions and is an enormous waste of medical resources. Dose Administration Aid Service (DAAS) can be seen as part of the solution, allowing individual medicine doses to be organized according to the dosing schedule determined by the patient's prescriber. The most recent systematic reviews admit the possibility of a positive impact of this service. In line with this background, the study reported in this paper aimed to characterize DAAS implementation in Portugal and understand the perceptions of pharmacists and owners of community pharmacies regarding the impact of DAAS, preferred methodology types, and State contribution. The study was guided by qualitative description methodology and reported using the consolidated criteria for reporting qualitative research (COREQ) checklist. Data were collected through semi-structured interviews with 18 pharmacists and/or owners of community pharmacies. Using qualitative content analysis, we identified categories that revealed that automated weekly methodology is the preferred methodology, because of its easiness of use and lower cost of preparation. However, the investment cost was felt to be too high by the participants considering the number of potential users for implementation in practice. Participants were also unanimous in recognizing that DAAS has a very positive impact in terms of safety and medication adherence, and the majority agreed that it also helped reduce medication waste. Implications of these findings for medication adherence are discussed.

An inter-day assessment of the ABC parameters in the evaluation of progressive keratoconus.

The progression of keratoconus is commonly determined by comparing the results of corneal tomographic measurements on different occasions. However, investigations on the repeatability of measurements are commonly performed within the same day, thus not taking the inter-day variation into account. The effect of keratoconus disease severity on the measurement error is also seldom considered. In this post hoc investigation, the parameters A, B and C in the Belin ABCD Progression Display were evaluated in relation to disease severity in intra-day and inter-day measurements. Four consecutive measurements were performed on 61 patients with keratoconus on the same day (intra-day). In another cohort, four consecutive measurements were obtained and then repeated 3 days later in 25 patients with keratoconus and 25 healthy controls (inter-day). The results suggest that the diagnosis of disease progression would benefit from inter-day measurements, and the stratification of the parameters A and C according to disease severity. It is also recommended that tomographic systems such as the Pentacam HR be modified to allow the comparison of both single measurements and the mean of replicate measurements of the parameters used in the assessment of progression of keratoconus.

Gene expression profile of extraocular muscles following resection strabismus surgery.

This paper aims to identify key biological processes triggered by resection surgery in the extraocular muscles (EOMs) of a rabbit model of strabismus surgery by studying changes in gene expression. Resection surgery was performed in the superior rectus of 16 rabbits and a group of non-operated rabbits served as control. Muscle samples were collected from groups of four animals 1, 2, 4 and 6 weeks after surgery and processed for RNA-sequencing and immunohistochemistry. We identified a total of 164; 136; 64 and 12 differentially expressed genes 1, 2, 4 and 6 weeks after surgery. Gene Ontology enrichment analysis revealed that differentially expressed genes were involved in biological pathways related to metabolism, response to stimulus mainly related with regulation of immune response, cell cycle and extracellular matrix. A complementary pathway analysis and network analysis performed with Ingenuity Pathway Analysis tool corroborated and completed these findings. Collagen I, fibronectin and versican, evaluated by immunofluorescence, showed that changes at the gene expression level resulted in variation at the protein level. Tenascin-C staining in resected muscles demonstrated the formation of new tendon and myotendinous junctions. These data provide new insights about the biological response of the EOMs to resection surgery and may form the basis for future strategies to improve the outcome of strabismus surgery.

Altered Signaling Pathways in Aniridia-Related Keratopathy.

Purpose: To study the Notch1, Wnt/beta-catenin, sonic hedgehog (SHH), and mammalian target of rapamycin (mTOR) cell signaling pathways in naïve and surgically treated corneas of aniridia cases with advanced aniridia-related keratopathy (ARK). Methods: Two naïve corneal buttons from patients with advanced ARK submitted to penetrating keratoplasty for the first time, one corneal button from an ARK patient that had undergone a keratolimbal allograft (KLAL), two corneal buttons from ARK patients who had previously undergone centered or decentered transplantation, and two adult healthy control corneas were processed for immunohistochemistry in this descriptive study. Antibodies specific against elements of the Notch1 (Notch1; Dlk1; Numb), Wnt/beta-catenin (Wnt5a; Wnt7a; beta-catenin), SHH (glioma-associated oncogene homolog [Gli1]; Hes1), and mTOR (mTOR1; ribosomal protein S6 [rpS6]) signaling pathways were used as well as antibodies against PAX6 and keratin 13 (Krt13). Results: All ARK corneas presented signs of conjunctivalization and analogous signaling pathway changes in the subepithelial pannus and epithelium, with decreased detection of the Notch1 signaling pathway and an increased presence of the Notch1 inhibitors Numb and Dlk1. Increased detections of Wnt/beta-catenin (enhanced presence of Wnt5a, Wnt7a, and beta-catenin), SHH (detection of Gli1 and Hes1), and mTOR (identification of mTOR and rpS6) signaling pathways were found in the subepithelial pannus and epithelium of all ARK corneas, when compared with normal controls. Conclusions: The similarity in pathway alterations found in all ARK corneas, irrespective of limbal stem cell transplantation, further supports the discussion on the role of host-specific factors and limbal stem cell deficiency in ARK.

Aniridia-related keratopathy: Structural changes in naïve and transplanted corneal buttons.

BACKGROUND: To study structural changes in naïve and surgically treated corneas of aniridia patients with advanced aniridia-related keratopathy (ARK). METHODS AND FINDINGS: Two naïve corneal buttons from patients with advanced ARK submitted to penetrating keratoplasty for the first time, one corneal button from an ARK patient that had undergone a keratolimbal allograft (KLAL), two corneal buttons from ARK patients who had previously undergone centered or decentered transplantation and were now retransplanted and two adult healthy donor control corneas were processed for immunohistochemistry. Antibodies against extracellular matrix components in the stroma and in the epithelial basement membrane (collagen I and IV, collagen receptor α11 integrin and laminin α3 chain), markers of fibrosis, wound healing and vascularization (fibronectin, tenascin-C, vimentin, α-SMA and caveolin-1), cell division (Ki-67) and macrophages (CD68) were used. Naïve ARK, KLAL ARK corneas and transplanted corneal buttons presented similar histopathological changes with irregular epithelium and disruption or absence of epithelial basal membrane. There was a loss of the orderly pattern of collagen lamellae and absence of collagen I in all ARK corneas. Vascularization was revealed by the presence of caveolin-1 and collagen IV in the pannus of all ARK aniridia corneas. The changes observed in decentered and centered transplants were analogous. CONCLUSIONS: Given the similar pathological features of all cases, conditions inherent to the host seem to play an important role on the pathophysiology of the ARK in the long run.

Composition, Architecture, and Functional Implications of the Connective Tissue Network of the Extraocular Muscles.

Purpose: We examined the pattern and extent of connective tissue distribution in the extraocular muscles (EOMs) and determined the ability of the interconnected connective tissues to disseminate force laterally. Methods: Human EOMs were examined for collagens I, III, IV, and VI; fibronectin; laminin; and elastin using immunohistochemistry. Connective tissue distribution was examined with scanning electron microscopy. Rabbit EOMs were examined for levels of force transmission longitudinally and transversely using in vitro force assessment. Results: Collagens I, III, and VI localized to the endomysium, perimysium, and epimysium. Collagen IV, fibronectin, and laminin localized to the basal lamina surrounding all myofibers. All collagens localized similarly in the orbital and global layers throughout the muscle length. Elastin had the most irregular pattern and ran longitudinally and circumferentially throughout the length of all EOMs. Scanning electron microscopy showed these elements to be extensively interconnected, from endomysium through the perimysium to the epimysium surrounding the whole muscle. In vitro physiology demonstrated force generation in the lateral dimension, presumably through myofascial transmission, which was always proportional to the force generated in the longitudinally oriented muscles. Conclusions: A striking connective tissue matrix interconnects all the myofibers and extends, via perimysial connections, to the epimysium. These interconnections are significant and allow measurable force transmission laterally as well as longitudinally, suggesting that they may contribute to the nonlinear force summation seen in motor unit recording studies. This provides strong evidence that separate compartmental movements are unlikely as no region is independent of the rest of the muscle.

Exophiala phaeomuriformis keratitis in a subarctic climate region: a case report.

PURPOSE: To report a case of Exophiala phaeomuriformis mycotic keratitis in a patient from a subarctic climate region. Dematiaceous fungi (black yeasts) have been gaining importance as corneal keratitis and ulcer causative agents in certain regions, but no cases have been described in Scandinavia. METHODS: Case report of a patient with a persistent corneal erosion that eventually presented a brown-pigmented infiltrate. The patient had a history of several months of topical therapy comprising medication for glaucoma, corticosteroids and antibiotics. A therapeutic contact lens was used, and amniotic membrane transplantation was performed before the development of the pigmented infiltrate. RESULTS: Exophiala phaeomuriformis was identified on the microbiological cultures from the surgically obtained infiltrate scrapes. The patient responded to topical amphotericin and fluconazole, the erosion was cured and a stromal scar subsided. During follow-up, sequential slit-lamp images and anterior segment optical coherence tomography (OCT) scans were obtained. CONCLUSION: This is the first described case of keratitis caused by E. phaeomuriformis in a subarctic region, the first in Europe and, to our knowledge, the second reported case in the literature. It is important to remember that superficial corneal brown-pigmented infiltrates should raise the suspicion of an unusual fungal infection even in this climate. This is particularly important in patients with ocular surface disease treated with steroids and antibiotics for a long time.

CHOROIDAL THICKNESS IN DIABETIC PATIENTS WITHOUT DIABETIC RETINOPATHY.

PURPOSE: To compare choroidal thickness (CT) between diabetic patients without diabetic retinopathy and a nondiabetic group. To explore how CT relates to disease duration, mean arterial pressure, glycemia, glycosylated hemoglobin, intraocular pressure, and ocular pulse amplitude. METHODS: Choroidal thickness was assessed using a spectral-domain optical coherence tomography and enhanced depth mode at 13 locations (subfoveal and 3 measurements 500 µm apart in 4 directions-nasal, temporal, superior, and inferior). Linear regression models were used. RESULTS: One hundred seventy-five patients were recruited (125 diabetic patients without diabetic retinopathy and 50 nondiabetic patients). In diabetic patients, although without statistical significance, CT showed a trend to be thicker in all locations (6.16-24.27 µm). Choroidal thickness was negatively associated with age (P < 0.001) in both groups, but only in the diabetic group, it was positively associated to ocular pulse amplitude (with a mean increase between 8.5 µm and 11.6 µm for each millimeter of mercury increase in ocular pulse amplitude). Diabetic patients' CT seems to stabilize after 150 months of diabetes, increase with higher glycemia levels (>160 mg/dL) while showing no fluctuation with glycosylated hemoglobin and mean arterial pressure. CONCLUSION: There seems to be a thickening of the choroid in diabetic patients without diabetic retinopathy. Moreover, this tissue may be functionally different in diabetes, as the pattern of associations seems to differ between groups.

Revisão sistemática e análise de custo- minimização de lipegfilgrastim na profilaxia da neutropenia e da neutropenia febril relacionadas à quimioterapia citotóxica / Systematic review and cost-minimization analysis of lipegfilgrastim in the prophylaxis of neutropenia and febrile neutropenia related to cytotoxic chemotherapy

Objetivo: Realizar avaliação econômica de lipegfilgrastim, fator de crescimento de longa duração (G-CSF), com os demais medicamentos da classe terapêutica disponíveis para a diminuição da duração da neutropenia grave (NG) e da incidência de neutropenia febril (NF), em pacientes adultos tratados com quimioterapia citotóxica para neoplasias malignas. Métodos: Revisão sistemática da literatura de evidências científicas sobre a eficácia e a segurança de lipegfilgrastim e análise de custo-minimização em comparação com pegfilgrastim ou filgrastim sob a perspectiva do Sistema Suplementar no Brasil. A análise incluiu tempo de tratamento de estudos clínicos, custo de infusão/ honorários médicos e custo com aquisição de medicamentos, distribuídos em três perspectivas: cenário 1 (conservador), cenário 2 (moderado) e cenário 3 (mundo real). Resultados: Seis estudos foram incluídos na análise, sendo três estudos randomizados e três revisões sistemáticas. O lipegfilgrastim resultou numa duração média de NG significativamente menor ao placebo e não inferior ao pegfilgrastim. Um estudo que comparou indiretamente lipegfilgrastim com filgrastim não encontrou diferenças estatisticamente significativas em redução de duração de NG e incidência de NF. O lipegfilgrastim apresentou redução de custos diretos de -R$ 3.673,50/paciente comparado com pegfilgrastim em todos os cenários avaliados e, na comparação com filgrastim, observou-se redução de -R$ 57.403,40; -R$ 19.183,67 e de -R$ 42,50/paciente nos cenários 1, 2 e 3, respectivamente. Conclusões: Lipegfilgrastim apresentou perfil de custo-minimização favorável em comparação com pegfilgrastim ou filgrastim, e surge como uma importante alternativa para o tratamento da redução da duração da neutropenia e da incidência da neutropenia febril durante a realização de tratamento quimioterápico, que pode representar economia de recursos para o Sistema de Saúde Suplementar.

jective: To develop an economic evaluation of lipegfilgrastin, long acting G-CSF, compared to other available G-CSF to reduce the duration of severe neutropenia (SN) and the incidence of febrile neutropenia (FN) in adult patients treated with cytotoxic chemotherapy for cancer in the Brazilian private Health System. Methods: Systematic literature review of scientific evidence evaluating the efficacy and safety of lipegfilgrastin and cost-minimization analysis comparing to pegfilgrastin or filgrastin in the Brazilian private Health System. The analysis includes time of treatment with filgrastin from clinical trials (scenario 1) or real world data (scenario 2 and 3) and considers direct medical costs. Results: Six studies were included in the analysis: three randomized controlled trials and three systematic reviews. Lipegfilgrastin resulted in a statistically significant reduction of median SN duration compared to placebo and non-inferior compared to pegfilgrastin. A study that performed an indirect comparison of lipegfilgrastin and filgrastin did not find any difference statistically significant reduction of SN duration and FN incidence. Lipefilgrastin resulted in a cost-difference of -R$ 3.673,50/patient compared to pegfilgrastin in all scenarios and -R$ 57.403,40; -R$ 19.183,67 and -R$ 42,50/patient compared to filgrastin in scenario 1, 2 and 3 respectively. Conclusions: Lipegfilgrastim showed a favorable cost-minimization profile compared to pegfilgrastin or filgrastin and is an important alternative treatment in reducing the duration of neutropenia and the incidence of febrile neutropenia during the course of chemotherapy, and may result in resource savings for the Brazilian Private Health System.

Open-Angle Glaucoma: Drug Development Pipeline during the Last 20 Years (1995-2015).

OBJECTIVES: To analyse drug development for open-angle glaucoma during the last 20 years. METHODS: Research was performed by referring to clinical trials registered at the International Clinical Trials Registry Platform (ICTRP). A search for the condition "open-angle glaucoma" with the intervention "drug" was performed. We included trials registered from 01/01/1995 to 01/01/2015, only involving studies in phases 1, 2, and 3. Only studies resorting to novel treatment strategies (either novel drugs or yet-untested fixed associations of approved medication) were considered. RESULTS: We recorded 158 studies for the condition of open-angle glaucoma with a drug-based intervention; 65 of the studies reported phase 2 trials and 74 reported phase 3 trials. Pharmaceutical companies were the primary sponsors of 95.3% of the trials. Most of the studies (66.5%, n = 105) involved a new drug, and the remainder (33.5%, n = 53) tested fixed drug associations. The bulk of the trials (n = 99, 62.7%) involved the use of prostaglandin analogues, either as a comparator or a study drug. In descending order of frequency, the studies conducted involved Rho-kinase inhibitors (n = 15), carbonic anhydrase inhibitors (n = 14), ß-blockers (n = 7), angiostatic steroids (n = 6), α2-adrenergic agonists (n = 4), 5-HT2A receptor agonists (n = 4), and NMDA receptor antagonists (n = 2). A cyclin-dependent kinase inhibitor, an LIM-domain kinase 2 inhibitor, an A1 adenosine receptor agonist, catechin, macrolide, saffron, and seawater were each tested in 1 clinical trial. CONCLUSION: Research into the medical treatment of glaucoma indicates the use of prostaglandin analogues. However, there are a significant number of trials testing other drug classes, particularly Rho-kinase inhibitors. This new focus could lead to a potential increase in the number of therapeutical options for the management of glaucoma in the future.

Macular Ganglion Cell Layer and Peripapillary Retinal Nerve Fibre Layer Thickness in Patients with Unilateral Posterior Cerebral Artery Ischaemic Lesion: An Optical Coherence Tomography Study.

The purpose of this study is to evaluate the macular ganglion cell layer (GCL) and peripapillary retinal nerve fibre layer (RNFL) thickness in patients with unilateral posterior cerebral artery (PCA) ischaemic lesions using spectral-domain optical coherence tomography (SD-OCT). A prospective, case-control study of patients with unilateral PCA lesion was conducted in the neuro-ophthalmology clinic of Centro Hospitalar Lisboa Central. Macular and peripapillary SD-OCT scans were performed in both eyes of each patient. Twelve patients with PCA lesions (stroke group) and 12 healthy normal controls were included in this study. Peripapillary RNFL comparison between both eyes of the same subject in the stroke group found a thinning in the superior-temporal (p = 0.008) and inferior-temporal (p = 0.023) sectors of the ipsilateral eye and nasal sector (p = 0.003) of the contralateral eye. Macular GCL thickness comparison showed a reduction temporally in the ipsilateral eye (p = 0.004) and nasally in the contralateral eye (p = 0.002). Peripapillary RNFL thickness was significantly reduced in both eyes of patients with PCA compared with controls, affecting all sectors in the contralateral eye and predominantly temporal sectors in the ipsilateral eye. A statistically significant decrease in macular GCL thickness was found in both hemiretinas of both eyes of stroke patients when compared with controls (p < 0.05). This study shows that TRD may play a role in the physiopathology of lesions of the posterior visual pathway.

Diabetic choroidopathy: a review of the current literature.

Diabetic retinopathy is an increasingly prevalent disease, and a leading contributor to the burden of all-cause blindness worldwide. In addition to retinal changes, choroidal abnormalities are common in patients with diabetes. The first studies concerning this vascular structure were based on histologic, indocyanine angiography and laser Doppler flowmetry techniques, but the development of new optical coherence tomography (OCT) technologies and imaging software for enhanced depth imaging (EDI)-OCT in recent years has made it possible to provide more detailed images of the choroidal anatomy and topography.In diabetic patients, several choroidal changes have been described in the literature throughout the years; the recent focus is choroidal thickness, which is significantly different from that in healthy patients. However, understanding choroidal manifestations of diabetic eye disease remains a real challenge, and this gap is hindering efforts towards better defining choroidal evaluation as a predictive factor for disease evolution and treatment response.This review aims to summarize the recent literature concerning changes in choroidal structure in diabetic patients, the relationship to diabetic retinal disease progression, and finally, the current and potential application of the measurement of variations in choroidal thickness for patient management.