Purpose. Nerve growth factor efficacy was demonstrated for corneal lesions treatment, and recombi... more Purpose. Nerve growth factor efficacy was demonstrated for corneal lesions treatment, and recombinant human NGF (rhNGF) was approved for neurotrophic keratitis therapy. However, NGF-induced molecular responses in cornea are still largely unknown. We analyzed microRNAs expression in human epithelial corneal cells after time-dependent rhNGF treatment. Methods. Nearly 700 microRNAs were analyzed by qRT-PCR. MicroRNAs showing significant expression differences were examined by DIANA-miRpath v.3.0 to identify target genes and pathways. Immunoblots were performed to preliminarily assess the strength of the in silico results. Results. Twenty-one microRNAs (miR-26a-1-3p, miR-30d-3p, miR-27b-5p, miR-146a-5p, miR-362-5p, mir-550a-5p, mir-34a-3p, mir-1227-3p, mir-27a-5p, mir-222-5p, mir-151a-5p, miR-449a, let7c-5p, miR-337-5p, mir-29b-3p, miR-200b-3p, miR-141-3p, miR-671-3p, miR-324-5p, mir-411-3p, and mir-425-3p) were significantly regulated in response to rhNGF. In silico analysis evidenced ...
A major role for human (h)CXCL8 (interleukin-8) in the pathobiology of myelofibrosis (MF) has bee... more A major role for human (h)CXCL8 (interleukin-8) in the pathobiology of myelofibrosis (MF) has been suggested by observations indicating that MF megakaryocytes express increased levels of hCXCL8 and that plasma levels of this cytokine in MF patients are predictive of poor patient outcomes. Here, we demonstrate that, in addition to high levels of TGF-β, the megakaryocytes from the bone marrow of the Gata1low mouse model of myelofibrosis express high levels of murine (m)CXCL1, the murine equivalent of hCXCL8, and its receptors CXCR1 and CXCR2. Treatment with the CXCR1/R2 inhibitor, Reparixin in aged-matched Gata1low mice demonstrated reductions in bone marrow and splenic fibrosis. Of note, the levels of fibrosis detected using two independent methods (Gomori and reticulin staining) were inversely correlated with plasma levels of Reparixin. Immunostaining of marrow sections indicated that the bone marrow from the Reparixin-treated group expressed lower levels of TGF-β1 than those expres...
Severe Acute Respiratory Syndrome Coronavirus—2 (SARS CoV-2) has resulted in the global spread of... more Severe Acute Respiratory Syndrome Coronavirus—2 (SARS CoV-2) has resulted in the global spread of Coronavirus Disease 2019 (COVID-19) and an increase in complications including Acute Respiratory Distress Syndrome (ARDS). Due to the lack of therapeutic options for Acute Respiratory Distress Syndrome, recent attention has focused on differentiating hyper- and hypo-inflammatory phenotypes of ARDS to help define effective therapeutic strategies. Interleukin 8 (IL-8) is a pro-inflammatory cytokine that has a role in neutrophil activation and has been identified within the pathogenesis and progression of this disease. The aim of this review is to highlight the role of IL-8 as a biomarker and prognostic factor in modulating the hyperinflammatory response in ARDS. The crucial role of IL-8 in lung inflammation and disease pathogenesis might suggest IL-8 as a possible new therapeutic target to efficiently modulate the hyperinflammatory response in ARDS.
Chronic obstructive pulmonary disease (COPD) is a heterogeneous disease with a versatile and comp... more Chronic obstructive pulmonary disease (COPD) is a heterogeneous disease with a versatile and complicated profile, being the fourth most common single cause of death worldwide. Several research groups have been trying to identify possible therapeutic approaches to treat COPD, such as the use of mucoactive drugs, which include carbocysteine. However, their role in the treatment of patients suffering from COPD remains controversial due to COPD’s multifaceted profile. In the present review, 72 articles, published in peer-reviewed journals with high impact factors, are analyzed in order to provide significant insight and increase the knowledge about COPD considering the important contribution of carbocysteine in reducing exacerbations via multiple mechanisms. Carbocysteine is in fact able to modulate mucins and ciliary functions, and to counteract viral and bacterial infections as well as oxidative stress, offering cytoprotective effects. Furthermore, carbocysteine improves steroid respo...
Chemotherapy-induced peripheral neuropathy (CIPN) and hypersensitivity reactions (HSRs) are among... more Chemotherapy-induced peripheral neuropathy (CIPN) and hypersensitivity reactions (HSRs) are among the most frequent and impairing side effects of the antineoplastic agent paclitaxel. Here, we demonstrated that paclitaxel can bind and activate complement component 5a receptor 1 (C5aR1) and that this binding is crucial in the etiology of paclitaxel-induced CIPN and anaphylaxis. Starting from our previous data demonstrating the role of interleukin (IL)-8 in paclitaxel-induced neuronal toxicity, we searched for proteins that activate IL-8 expression and, by using the Exscalate platform for molecular docking simulations, we predicted the high affinity of C5aR1 with paclitaxel. By in vitro studies, we confirmed the specific and competitive nature of the C5aR1-paclitaxel binding and found that it triggers intracellularly the NFkB/P38 pathway and c-Fos. In F11 neuronal cells and rat dorsal root ganglia, C5aR1 inhibition protected from paclitaxel-induced neuropathological effects, while in p...
Interstitial cystitis (IC)/bladder pain syndrome (BPS) is a chronic bladder disease of unknown et... more Interstitial cystitis (IC)/bladder pain syndrome (BPS) is a chronic bladder disease of unknown etiology characterized by urinary frequency and episodic and chronic pain. Analgesic treatments for IC/BPS are limited, especially for patients with non-Hunner (non-ulcerative) type IC who usually have poor overall outcomes. Here, we demonstrate that oral treatment with DF2755A, a potent and selective inhibitor of chemokine receptors CXCR1/2, can prevent and reverse peripheral neuropathy associated to non-Hunner IC/BPS by directly inhibiting chemokine-induced excitation of sensory neurons. We tested DF2755A antinociceptive effects in a cyclophosphamide (CYP)-induced non-ulcerative IC rat model characterized by severe peripheral neuropathy in the absence of bladder inflammatory infiltrate, urothelial hyperplasia, and hemorrhage. Treatment with DF2755A prevented the onset of peripheral neuropathy and reversed its development in CYP-induced IC rats, showing a strong and long-lasting anti-hype...
Ketoprofen–l-lysine salt (KLS) is a widely used nonsteroidal anti-inflammatory drug. Here, we stu... more Ketoprofen–l-lysine salt (KLS) is a widely used nonsteroidal anti-inflammatory drug. Here, we studied deeply the solid-state characteristics of KLS to possibly identify new polymorphic drugs. Conducting a polymorph screening study and combining conventional techniques with solid-state nuclear magnetic resonance, we identified, for the first time, a salt/cocrystal polymorphism of the ketoprofen (KET)–lysine (LYS) system, with the cocrystal, KET–LYS polymorph 1 (P1), being representative of commercial KLS, and the salt, KET–LYS polymorph 2 (P2), being a new polymorphic form of KLS. Interestingly, in vivo pharmacokinetics showed that the salt polymorph has significantly higher absorption and, thus, different pharmacokinetics compared to commercial KLS (cocrystal), laying the basis for the development of faster-release/acting KLS formulations. Moreover, intrinsic dissolution rate (IDR) and electronic tongue analyses showed that the salt has a higher IDR, a more bitter taste, and a diffe...
L'invention concerne un procede stereoselectif permettant, en une seule etape, de preparer de... more L'invention concerne un procede stereoselectif permettant, en une seule etape, de preparer des endo-3-aminoazabicycloalcanes a partir d'azabicycloalcanones par amination reductrice.
Selon la presente invention, des derives de l'acide 4-(trifluoromethanesulfonyloxyphenyl)prop... more Selon la presente invention, des derives de l'acide 4-(trifluoromethanesulfonyloxyphenyl)propionique et une composition pharmaceutique contenant ces composes sont utiles pour inhiber l'activation chimiotactique des neutrophiles (leucocytes PMN) induite par l'interaction de l'interleukine 8 (IL-8) avec les recepteurs membranaires CXCR1 et CXCR2. Ces composes sont utilises dans la prevention et le traitement de pathologies derivees de cette activation. Notablement, ces metabolites sont depourvus d'activite d'inhibition de la cyclo-oxygenase et sont particulierement utiles dans le traitement de pathologies neutrophiles-dependantes, telles que le psoriasis, la colite ulcereuse, le melanome, la bronchopneumopathie chronique obstructive (BPCO), la pemphigoide bulleuse, la polyarthrite rhumatoide, la fibrose idiopathique, la glomerulonephrite ainsi que dans la prevention et le traitement de lesions d'ischemie et de reperfusion.
Mantelli F, Allegretti M, Chao W, Filatori I, Battigello P, Vaja V, Goodman J, Sinigaglia F. Phas... more Mantelli F, Allegretti M, Chao W, Filatori I, Battigello P, Vaja V, Goodman J, Sinigaglia F. Phase I/II randomized, double-masked, vehicle-controlled trial of recombinant human nerve growth factor (rhNGF) eye drops in stage 2/3 neurotrophic keratitis [Abstract]. ARVO Meeting Abstracts (2017).
L'invention porte: sur des (R)-Enantiomeres de sels d'ammonium quaternaire de formule gen... more L'invention porte: sur des (R)-Enantiomeres de sels d'ammonium quaternaire de formule generale (I) dans laquelle: R, R1, R2, R3, X et Z sont tels que definis dans la description; et sur le procede de preparation. Lesdits sels qui inhibent la chimiotaxie des neutrophiles et des monocytes dus a la fraction Ca du complement servent au traitement du psoriasis, du pemphigus et du pemphigoide, de l'arthrite rhumatoide, des pathologie intestinales inflammatoires chroniques dont la rectocolite hemorragique, l'infection aigue des voies respiratoires, la fibrose idiopathique, la fibrose kystique, la broncho-pneumopathie chronique obstructive, et la glomerulonephrite. Les composes de l'invention seront avantageusement utilises pour la prevention et le traitement de lesions dues a l'ischemie et a la reperfusion.
The ongoing coronavirus disease 2019 (COVID-19) pandemic caused by the novel severe acute respira... more The ongoing coronavirus disease 2019 (COVID-19) pandemic caused by the novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) necessitates strategies to identify prophylactic and therapeutic drug candidates to enter rapid clinical development. This is particularly true, given the uncertainty about the endurance of the immune memory induced by both previous infections or vaccines, and given the fact that the eradication of SARS-CoV-2 might be challenging to reach, given the attack rate of the virus, which would require unusually high protection by a vaccine. Here, we show how raloxifene, a selective estrogen receptor modulator with anti-inflammatory and antiviral properties, emerges as an attractive candidate entering clinical trials to test its efficacy in early-stage treatment COVID-19 patients.
The new coronavirus that emerged, called SARS-CoV-2, is the causative agent of the COVID-19 pande... more The new coronavirus that emerged, called SARS-CoV-2, is the causative agent of the COVID-19 pandemic. The identification of potential drug candidates that can rapidly enter clinical trials for the prevention and treatment of COVID-19 is an urgent need, despite the recent introduction of several new vaccines for the prevention and protection of this infectious disease, which in many cases becomes severe. Drug repurposing (DR), a process for studying existing pharmaceutical products for new therapeutic indications, represents one of the most effective potential strategies employed to increase the success rate in the development of new drug therapies. We identified raloxifene, a known Selective Estrogen Receptor Modulator (SERM), as a potential pharmacological agent for the treatment of COVID-19 patients. Following a virtual screening campaign on the most relevant viral protein targets, in this work we report the results of the first pharmacological characterization of raloxifene in re...
The mucolytic agent S-carboxymethylcysteine is widely used as an expectorant for the treatment of... more The mucolytic agent S-carboxymethylcysteine is widely used as an expectorant for the treatment of numerous respiratory disorders. The metabolic fate of S-carboxymethyl-L-cysteine is complex. Several clinical studies have demonstrated that the metabolism of this agent differs within the same individual, with sulfur oxygenated metabolites generated upon night-time administration. It has been indicated that this drug behaves like a free radical scavenger and that, in this regard, the sulfide is the active species with sulphoxide metabolites (already oxidized) being inactive. Consequently, a night-time consumption of the drug should be more effective upon daytime administration. Still, this diurnal variation in biotransformation (deactivation) is dependent on the genetic polymorphism on which relies the patient population capacities of S-carboxymethyl-L-cysteine sulphoxidation. It has been reported that those cohorts who are efficient sulfur oxidizers will generate inactive oxygenated m...
Retina is a layered structure of the eye, composed of different cellular components working toget... more Retina is a layered structure of the eye, composed of different cellular components working together to produce a complex visual output. Because of its important role in visual function, retinal pathologies commonly represent the main causes of visual injury and blindness in the industrialized world. It is important to develop in vitro models of retinal diseases to use them in first screenings before translating in in vivo experiments and clinics. For this reason, it is important to develop bidimensional (2D) models that are more suitable for drug screening and toxicological studies and tridimensional (3D) models, which can replicate physiological conditions, for investigating pathological mechanisms leading to visual loss. This review provides an overview of the most common retinal diseases, relating to in vivo models, with a specific focus on alternative 2D and 3D in vitro models that can replicate the different cellular and matrix components of retinal layers, as well as injury i...
Purpose. Nerve growth factor efficacy was demonstrated for corneal lesions treatment, and recombi... more Purpose. Nerve growth factor efficacy was demonstrated for corneal lesions treatment, and recombinant human NGF (rhNGF) was approved for neurotrophic keratitis therapy. However, NGF-induced molecular responses in cornea are still largely unknown. We analyzed microRNAs expression in human epithelial corneal cells after time-dependent rhNGF treatment. Methods. Nearly 700 microRNAs were analyzed by qRT-PCR. MicroRNAs showing significant expression differences were examined by DIANA-miRpath v.3.0 to identify target genes and pathways. Immunoblots were performed to preliminarily assess the strength of the in silico results. Results. Twenty-one microRNAs (miR-26a-1-3p, miR-30d-3p, miR-27b-5p, miR-146a-5p, miR-362-5p, mir-550a-5p, mir-34a-3p, mir-1227-3p, mir-27a-5p, mir-222-5p, mir-151a-5p, miR-449a, let7c-5p, miR-337-5p, mir-29b-3p, miR-200b-3p, miR-141-3p, miR-671-3p, miR-324-5p, mir-411-3p, and mir-425-3p) were significantly regulated in response to rhNGF. In silico analysis evidenced ...
A major role for human (h)CXCL8 (interleukin-8) in the pathobiology of myelofibrosis (MF) has bee... more A major role for human (h)CXCL8 (interleukin-8) in the pathobiology of myelofibrosis (MF) has been suggested by observations indicating that MF megakaryocytes express increased levels of hCXCL8 and that plasma levels of this cytokine in MF patients are predictive of poor patient outcomes. Here, we demonstrate that, in addition to high levels of TGF-β, the megakaryocytes from the bone marrow of the Gata1low mouse model of myelofibrosis express high levels of murine (m)CXCL1, the murine equivalent of hCXCL8, and its receptors CXCR1 and CXCR2. Treatment with the CXCR1/R2 inhibitor, Reparixin in aged-matched Gata1low mice demonstrated reductions in bone marrow and splenic fibrosis. Of note, the levels of fibrosis detected using two independent methods (Gomori and reticulin staining) were inversely correlated with plasma levels of Reparixin. Immunostaining of marrow sections indicated that the bone marrow from the Reparixin-treated group expressed lower levels of TGF-β1 than those expres...
Severe Acute Respiratory Syndrome Coronavirus—2 (SARS CoV-2) has resulted in the global spread of... more Severe Acute Respiratory Syndrome Coronavirus—2 (SARS CoV-2) has resulted in the global spread of Coronavirus Disease 2019 (COVID-19) and an increase in complications including Acute Respiratory Distress Syndrome (ARDS). Due to the lack of therapeutic options for Acute Respiratory Distress Syndrome, recent attention has focused on differentiating hyper- and hypo-inflammatory phenotypes of ARDS to help define effective therapeutic strategies. Interleukin 8 (IL-8) is a pro-inflammatory cytokine that has a role in neutrophil activation and has been identified within the pathogenesis and progression of this disease. The aim of this review is to highlight the role of IL-8 as a biomarker and prognostic factor in modulating the hyperinflammatory response in ARDS. The crucial role of IL-8 in lung inflammation and disease pathogenesis might suggest IL-8 as a possible new therapeutic target to efficiently modulate the hyperinflammatory response in ARDS.
Chronic obstructive pulmonary disease (COPD) is a heterogeneous disease with a versatile and comp... more Chronic obstructive pulmonary disease (COPD) is a heterogeneous disease with a versatile and complicated profile, being the fourth most common single cause of death worldwide. Several research groups have been trying to identify possible therapeutic approaches to treat COPD, such as the use of mucoactive drugs, which include carbocysteine. However, their role in the treatment of patients suffering from COPD remains controversial due to COPD’s multifaceted profile. In the present review, 72 articles, published in peer-reviewed journals with high impact factors, are analyzed in order to provide significant insight and increase the knowledge about COPD considering the important contribution of carbocysteine in reducing exacerbations via multiple mechanisms. Carbocysteine is in fact able to modulate mucins and ciliary functions, and to counteract viral and bacterial infections as well as oxidative stress, offering cytoprotective effects. Furthermore, carbocysteine improves steroid respo...
Chemotherapy-induced peripheral neuropathy (CIPN) and hypersensitivity reactions (HSRs) are among... more Chemotherapy-induced peripheral neuropathy (CIPN) and hypersensitivity reactions (HSRs) are among the most frequent and impairing side effects of the antineoplastic agent paclitaxel. Here, we demonstrated that paclitaxel can bind and activate complement component 5a receptor 1 (C5aR1) and that this binding is crucial in the etiology of paclitaxel-induced CIPN and anaphylaxis. Starting from our previous data demonstrating the role of interleukin (IL)-8 in paclitaxel-induced neuronal toxicity, we searched for proteins that activate IL-8 expression and, by using the Exscalate platform for molecular docking simulations, we predicted the high affinity of C5aR1 with paclitaxel. By in vitro studies, we confirmed the specific and competitive nature of the C5aR1-paclitaxel binding and found that it triggers intracellularly the NFkB/P38 pathway and c-Fos. In F11 neuronal cells and rat dorsal root ganglia, C5aR1 inhibition protected from paclitaxel-induced neuropathological effects, while in p...
Interstitial cystitis (IC)/bladder pain syndrome (BPS) is a chronic bladder disease of unknown et... more Interstitial cystitis (IC)/bladder pain syndrome (BPS) is a chronic bladder disease of unknown etiology characterized by urinary frequency and episodic and chronic pain. Analgesic treatments for IC/BPS are limited, especially for patients with non-Hunner (non-ulcerative) type IC who usually have poor overall outcomes. Here, we demonstrate that oral treatment with DF2755A, a potent and selective inhibitor of chemokine receptors CXCR1/2, can prevent and reverse peripheral neuropathy associated to non-Hunner IC/BPS by directly inhibiting chemokine-induced excitation of sensory neurons. We tested DF2755A antinociceptive effects in a cyclophosphamide (CYP)-induced non-ulcerative IC rat model characterized by severe peripheral neuropathy in the absence of bladder inflammatory infiltrate, urothelial hyperplasia, and hemorrhage. Treatment with DF2755A prevented the onset of peripheral neuropathy and reversed its development in CYP-induced IC rats, showing a strong and long-lasting anti-hype...
Ketoprofen–l-lysine salt (KLS) is a widely used nonsteroidal anti-inflammatory drug. Here, we stu... more Ketoprofen–l-lysine salt (KLS) is a widely used nonsteroidal anti-inflammatory drug. Here, we studied deeply the solid-state characteristics of KLS to possibly identify new polymorphic drugs. Conducting a polymorph screening study and combining conventional techniques with solid-state nuclear magnetic resonance, we identified, for the first time, a salt/cocrystal polymorphism of the ketoprofen (KET)–lysine (LYS) system, with the cocrystal, KET–LYS polymorph 1 (P1), being representative of commercial KLS, and the salt, KET–LYS polymorph 2 (P2), being a new polymorphic form of KLS. Interestingly, in vivo pharmacokinetics showed that the salt polymorph has significantly higher absorption and, thus, different pharmacokinetics compared to commercial KLS (cocrystal), laying the basis for the development of faster-release/acting KLS formulations. Moreover, intrinsic dissolution rate (IDR) and electronic tongue analyses showed that the salt has a higher IDR, a more bitter taste, and a diffe...
L'invention concerne un procede stereoselectif permettant, en une seule etape, de preparer de... more L'invention concerne un procede stereoselectif permettant, en une seule etape, de preparer des endo-3-aminoazabicycloalcanes a partir d'azabicycloalcanones par amination reductrice.
Selon la presente invention, des derives de l'acide 4-(trifluoromethanesulfonyloxyphenyl)prop... more Selon la presente invention, des derives de l'acide 4-(trifluoromethanesulfonyloxyphenyl)propionique et une composition pharmaceutique contenant ces composes sont utiles pour inhiber l'activation chimiotactique des neutrophiles (leucocytes PMN) induite par l'interaction de l'interleukine 8 (IL-8) avec les recepteurs membranaires CXCR1 et CXCR2. Ces composes sont utilises dans la prevention et le traitement de pathologies derivees de cette activation. Notablement, ces metabolites sont depourvus d'activite d'inhibition de la cyclo-oxygenase et sont particulierement utiles dans le traitement de pathologies neutrophiles-dependantes, telles que le psoriasis, la colite ulcereuse, le melanome, la bronchopneumopathie chronique obstructive (BPCO), la pemphigoide bulleuse, la polyarthrite rhumatoide, la fibrose idiopathique, la glomerulonephrite ainsi que dans la prevention et le traitement de lesions d'ischemie et de reperfusion.
Mantelli F, Allegretti M, Chao W, Filatori I, Battigello P, Vaja V, Goodman J, Sinigaglia F. Phas... more Mantelli F, Allegretti M, Chao W, Filatori I, Battigello P, Vaja V, Goodman J, Sinigaglia F. Phase I/II randomized, double-masked, vehicle-controlled trial of recombinant human nerve growth factor (rhNGF) eye drops in stage 2/3 neurotrophic keratitis [Abstract]. ARVO Meeting Abstracts (2017).
L'invention porte: sur des (R)-Enantiomeres de sels d'ammonium quaternaire de formule gen... more L'invention porte: sur des (R)-Enantiomeres de sels d'ammonium quaternaire de formule generale (I) dans laquelle: R, R1, R2, R3, X et Z sont tels que definis dans la description; et sur le procede de preparation. Lesdits sels qui inhibent la chimiotaxie des neutrophiles et des monocytes dus a la fraction Ca du complement servent au traitement du psoriasis, du pemphigus et du pemphigoide, de l'arthrite rhumatoide, des pathologie intestinales inflammatoires chroniques dont la rectocolite hemorragique, l'infection aigue des voies respiratoires, la fibrose idiopathique, la fibrose kystique, la broncho-pneumopathie chronique obstructive, et la glomerulonephrite. Les composes de l'invention seront avantageusement utilises pour la prevention et le traitement de lesions dues a l'ischemie et a la reperfusion.
The ongoing coronavirus disease 2019 (COVID-19) pandemic caused by the novel severe acute respira... more The ongoing coronavirus disease 2019 (COVID-19) pandemic caused by the novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) necessitates strategies to identify prophylactic and therapeutic drug candidates to enter rapid clinical development. This is particularly true, given the uncertainty about the endurance of the immune memory induced by both previous infections or vaccines, and given the fact that the eradication of SARS-CoV-2 might be challenging to reach, given the attack rate of the virus, which would require unusually high protection by a vaccine. Here, we show how raloxifene, a selective estrogen receptor modulator with anti-inflammatory and antiviral properties, emerges as an attractive candidate entering clinical trials to test its efficacy in early-stage treatment COVID-19 patients.
The new coronavirus that emerged, called SARS-CoV-2, is the causative agent of the COVID-19 pande... more The new coronavirus that emerged, called SARS-CoV-2, is the causative agent of the COVID-19 pandemic. The identification of potential drug candidates that can rapidly enter clinical trials for the prevention and treatment of COVID-19 is an urgent need, despite the recent introduction of several new vaccines for the prevention and protection of this infectious disease, which in many cases becomes severe. Drug repurposing (DR), a process for studying existing pharmaceutical products for new therapeutic indications, represents one of the most effective potential strategies employed to increase the success rate in the development of new drug therapies. We identified raloxifene, a known Selective Estrogen Receptor Modulator (SERM), as a potential pharmacological agent for the treatment of COVID-19 patients. Following a virtual screening campaign on the most relevant viral protein targets, in this work we report the results of the first pharmacological characterization of raloxifene in re...
The mucolytic agent S-carboxymethylcysteine is widely used as an expectorant for the treatment of... more The mucolytic agent S-carboxymethylcysteine is widely used as an expectorant for the treatment of numerous respiratory disorders. The metabolic fate of S-carboxymethyl-L-cysteine is complex. Several clinical studies have demonstrated that the metabolism of this agent differs within the same individual, with sulfur oxygenated metabolites generated upon night-time administration. It has been indicated that this drug behaves like a free radical scavenger and that, in this regard, the sulfide is the active species with sulphoxide metabolites (already oxidized) being inactive. Consequently, a night-time consumption of the drug should be more effective upon daytime administration. Still, this diurnal variation in biotransformation (deactivation) is dependent on the genetic polymorphism on which relies the patient population capacities of S-carboxymethyl-L-cysteine sulphoxidation. It has been reported that those cohorts who are efficient sulfur oxidizers will generate inactive oxygenated m...
Retina is a layered structure of the eye, composed of different cellular components working toget... more Retina is a layered structure of the eye, composed of different cellular components working together to produce a complex visual output. Because of its important role in visual function, retinal pathologies commonly represent the main causes of visual injury and blindness in the industrialized world. It is important to develop in vitro models of retinal diseases to use them in first screenings before translating in in vivo experiments and clinics. For this reason, it is important to develop bidimensional (2D) models that are more suitable for drug screening and toxicological studies and tridimensional (3D) models, which can replicate physiological conditions, for investigating pathological mechanisms leading to visual loss. This review provides an overview of the most common retinal diseases, relating to in vivo models, with a specific focus on alternative 2D and 3D in vitro models that can replicate the different cellular and matrix components of retinal layers, as well as injury i...
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