RESUMEN
Olanexidine gluconate-containing preoperative antiseptic (OLG-C) is colorless, which makes it difficult to determine its area of application. To overcome this drawback, we realized a stable orange-tinted antiseptic (OLG-T) by adding new additives to OLG-C and investigated its pharmaceutical properties compared with OLG-C and povidone iodine (PVP-I). We evaluated the influence of the additives on the antimicrobial activity and adhesiveness of medical adhesives to OLG-T-applied skin by in vitro time-kill/ex vivo micropig skin assays and a peel test using excised micropig skin, respectively. In the in vitro time-kill assay, the bactericidal/fungicidal activity of OLG-T and OLG-C were equivalent. In the ex vivo micropig skin assay, their fast-acting and persistent bactericidal activities against vancomycin-resistant Enterococcus faecalis were higher than that of PVP-I. In the peel test, the adhesion force of the incise drape and the amount of stripped corneocytes on the peeled drape were comparable between OLG-T- and OLG-C-applied skin, but both were less than those of PVP-I-applied skin. The drapes for OLG-T- and OLG-C-applied skin had moderate adhesion force, and the drape-related injuries were expected to be weak. These results suggest that OLG-T performs no worse than OLG-C in terms of its antimicrobial activity and medical adhesive compatibility. Therefore, we expect OLG-T to lead to more convenient preoperative skin preparation and further contribute to lowering surgical site infection rates.
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Antiinfecciosos Locales/administración & dosificación , Compuestos Azo/administración & dosificación , Bacterias/efectos de los fármacos , Biguanidas/administración & dosificación , Colorantes de Alimentos/administración & dosificación , Glucuronatos/administración & dosificación , Piel/efectos de los fármacos , Adhesividad , Animales , Bacterias/crecimiento & desarrollo , Composición de Medicamentos , Femenino , Piel/microbiología , PorcinosRESUMEN
INTRODUCTION/AIMS: There are currently three medications approved for spinal muscular atrophy (SMA), but the use of these medications in combination has not been well described. METHODS: This is a retrospective report of four cases of SMA treated with dual onasemnogene and risdiplam therapy at our institution. RESULTS: Following onasemnogene therapy, all four patients experienced a perceived plateau of therapeutic benefit, at which time daily risdiplam was started. Transient fatigue and weakness was seen in two patients following risdiplam initiation, but this resolved within 1 mo. One patient was hospitalized with severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) and post-viral pneumonia, weeks following risdiplam initiation. No other adverse effects related to onasemnogene and risdiplam combination therapy were identified and all patients experienced objective and subjective improvement. DISCUSSION: Combination therapy with onasemnogene and risdiplam in patients with SMA appears to be well-tolerated. Further large prospective trials are needed to determine whether dual therapy is more efficacious than monotherapy, and to identify rare adverse events that may occur with the use of combination therapy.
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Compuestos Azo/administración & dosificación , Productos Biológicos/administración & dosificación , Pirimidinas/administración & dosificación , Proteínas Recombinantes de Fusión/administración & dosificación , Atrofias Musculares Espinales de la Infancia/diagnóstico , Atrofias Musculares Espinales de la Infancia/terapia , Terapia Combinada/métodos , Quimioterapia Combinada , Femenino , Terapia Genética/métodos , Humanos , Lactante , Masculino , Estudios Retrospectivos , Atrofias Musculares Espinales de la Infancia/fisiopatologíaRESUMEN
Spinal muscular atrophy (SMA) is an inherited lower motor neuron disease. SMA occurs secondary to alterations in the survival motor neuron 1 gene (SMN1), which is the main driver of SMN protein production. The severity of the disease is determined by the number of copies of the SMN2 gene, which is a homolog to SMN1 but not as efficient in protein production. Three medications have recently been approved for the treatment of SMA. Nusinersen is an intrathecal antisense oligonucleotide that alters SMN2 pre-mRNA, onasemnogene abeparvovec-xioi is an intravenous SMN1 gene replacement therapy, and risdiplam is an oral small molecule splicing modifier of SMN2. No head-to-head studies have been conducted comparing these medications, so selection of one of these medications for an individual with SMA can be challenging. In this article we outline the efficacy, safety, and other pertinent factors to consider when selecting a therapy for an individual with SMA. The age of the individual and comorbidities, such as liver or kidney disease, help guide treatment choices. All three of these medications are efficacious, and early initiation is critical for obtaining the best outcomes.
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Atrofia Muscular Espinal/tratamiento farmacológico , Fármacos Neuromusculares/administración & dosificación , Oligonucleótidos Antisentido/administración & dosificación , Oligonucleótidos/administración & dosificación , Animales , Compuestos Azo/administración & dosificación , Compuestos Azo/inmunología , Productos Biológicos/administración & dosificación , Productos Biológicos/inmunología , Humanos , Atrofia Muscular Espinal/epidemiología , Atrofia Muscular Espinal/inmunología , Fármacos Neuromusculares/inmunología , Oligonucleótidos/inmunología , Oligonucleótidos Antisentido/inmunología , Pirimidinas/administración & dosificación , Pirimidinas/inmunología , Proteínas Recombinantes de Fusión/administración & dosificación , Proteínas Recombinantes de Fusión/inmunología , Resultado del TratamientoRESUMEN
BACKGROUND: Type 1 spinal muscular atrophy is a rare, progressive neuromuscular disease that is caused by low levels of functional survival of motor neuron (SMN) protein. Risdiplam is an orally administered, small molecule that modifies SMN2 pre-messenger RNA splicing and increases levels of functional SMN protein. METHODS: We report the results of part 1 of a two-part, phase 2-3, open-label study of risdiplam in infants 1 to 7 months of age who had type 1 spinal muscular atrophy, which is characterized by the infant not attaining the ability to sit without support. Primary outcomes were safety, pharmacokinetics, pharmacodynamics (including the blood SMN protein concentration), and the selection of the risdiplam dose for part 2 of the study. Exploratory outcomes included the ability to sit without support for at least 5 seconds. RESULTS: A total of 21 infants were enrolled. Four infants were in a low-dose cohort and were treated with a final dose at month 12 of 0.08 mg of risdiplam per kilogram of body weight per day, and 17 were in a high-dose cohort and were treated with a final dose at month 12 of 0.2 mg per kilogram per day. The baseline median SMN protein concentrations in blood were 1.31 ng per milliliter in the low-dose cohort and 2.54 ng per milliliter in the high-dose cohort; at 12 months, the median values increased to 3.05 ng per milliliter and 5.66 ng per milliliter, respectively, which represented a median of 3.0 times and 1.9 times the baseline values in the low-dose and high-dose cohorts, respectively. Serious adverse events included pneumonia, respiratory tract infection, and acute respiratory failure. At the time of this publication, 4 infants had died of respiratory complications. Seven infants in the high-dose cohort and no infants in the low-dose cohort were able to sit without support for at least 5 seconds. The higher dose of risdiplam (0.2 mg per kilogram per day) was selected for part 2 of the study. CONCLUSIONS: In infants with type 1 spinal muscular atrophy, treatment with oral risdiplam led to an increased expression of functional SMN protein in the blood. (Funded by F. Hoffmann-La Roche; ClinicalTrials.gov number, NCT02913482.).
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Compuestos Azo/administración & dosificación , Fármacos Neuromusculares/administración & dosificación , Pirimidinas/administración & dosificación , Atrofias Musculares Espinales de la Infancia/tratamiento farmacológico , Proteína 1 para la Supervivencia de la Neurona Motora/sangre , Administración Oral , Compuestos Azo/efectos adversos , Compuestos Azo/farmacocinética , Relación Dosis-Respuesta a Droga , Femenino , Humanos , Lactante , Masculino , Fármacos Neuromusculares/efectos adversos , Fármacos Neuromusculares/farmacocinética , Supervivencia sin Progresión , Pirimidinas/efectos adversos , Pirimidinas/farmacocinética , Empalme del ARN , Insuficiencia Respiratoria/etiología , Infecciones del Sistema Respiratorio/etiología , Atrofias Musculares Espinales de la Infancia/complicaciones , Atrofias Musculares Espinales de la Infancia/mortalidad , Proteína 1 para la Supervivencia de la Neurona Motora/genéticaRESUMEN
The prevalence of periodontal disease poses a significant global health burden. Treatments for these diseases, primarily focused on removal and eradication of dental plaque biofilms, are challenging due to limited access to periodontal pockets where these oral pathogens reside. Herein, we report on the development and characterization of nitric oxide (NO)-releasing carboxymethylcellulose (CMC) derivatives and evaluate their in vitro bactericidal efficacy against planktonic Porphyromonas gingivalis and Aggregatibacter actinomycetemcomitans, two prominent periodontopathogens. Bactericidal exposure assays revealed that three of the synthesized NO-releasing polymers were capable of reducing bacterial viability of both species by 99.9% in 2 hr at concentrations of 4 mg ml-1 or lower, reflecting NO's potent and rapid bactericidal action. The NO-releasing CMCs elicited minimal toxicity to human gingival fibroblasts at their bactericidal concentrations following 24-hr exposure.
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Aggregatibacter actinomycetemcomitans/efectos de los fármacos , Antibacterianos/farmacología , Compuestos Azo/farmacología , Carboximetilcelulosa de Sodio , Etanolaminas/farmacología , Óxido Nítrico/farmacología , Enfermedades Periodontales/microbiología , Poliaminas/farmacología , Porphyromonas gingivalis/efectos de los fármacos , Propilaminas/farmacología , Antibacterianos/administración & dosificación , Compuestos Azo/administración & dosificación , Compuestos Azo/química , Biopolímeros , Línea Celular , Diaminas/química , Portadores de Fármacos , Sistemas de Liberación de Medicamentos , Etanolaminas/administración & dosificación , Etanolaminas/química , Fibroblastos/efectos de los fármacos , Encía/citología , Humanos , Estructura Molecular , Óxido Nítrico/administración & dosificación , Óxido Nítrico/toxicidad , Poliaminas/administración & dosificación , Poliaminas/química , Propilaminas/administración & dosificación , Propilaminas/química , Especificidad de la Especie , ViscosidadRESUMEN
BACKGROUND: The textile dye mix (TDM) 6.6% pet. contains Disperse Blue (DB) 35, Disperse Yellow 3, Disperse Orange (DO) 1 and 3, Disperse Red 1 and 17, and DB 106 and 124. The most frequent allergen in TDM-positive patients is DO 3. Around 85% of p-phenylenediamine (PPD)-allergic dermatitis patients have shown positive patch test reactions to DO 3. There has been a discussion to exclude DO 3 from TDM 6.6% because of frequent, strong reactions to TDM 6.6% and PPD. OBJECTIVES: To study if DO 3 can be omitted from a TDM. METHODS: Patch tests were performed on 2250 dermatitis patients with TDM 6.6%, TDM 5.6% pet., TDM 7.0% pet., and PPD 1.0% pet.; 122 patients were also patch tested with DO 3 1.0% pet. RESULTS: Among the 2250 patients patch tested, contact allergy prevalence to TDM 6.6% was 2.4%, to TDM 5.6% 1.8%, and to TDM 7.0% 2.0%. Of the 54 TDM 6.6%-positive patients, 55.6% reacted to PPD; as much as 42.2% of PPD-allergic women and 50% of PPD-allergic men reacted to TDM 6.6%. Of the 17 DO 3-positive patients, 94.1% showed a positive reaction to PPD. CONCLUSION: Results indicate that DO 3 can probably be omitted from TDM, but patch testing with TDM 6.6%, TDM 7.0%, DO 3 1.0%, and PPD 1.0% simultaneously is needed to finally decide whether it is possible or not.
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Compuestos Azo/efectos adversos , Colorantes/efectos adversos , Dermatitis Alérgica por Contacto/diagnóstico , Dermatitis Profesional/diagnóstico , Textiles/efectos adversos , Adulto , Compuestos Azo/administración & dosificación , Colorantes/administración & dosificación , Dermatitis Alérgica por Contacto/etiología , Dermatitis Profesional/etiología , Femenino , Humanos , Masculino , Persona de Mediana Edad , Pruebas del Parche/métodosAsunto(s)
Compuestos Azo/administración & dosificación , Aprobación de Drogas/economía , Isoxazoles/administración & dosificación , Pirimidinas/administración & dosificación , Triglicéridos/administración & dosificación , Síndrome de Angelman/tratamiento farmacológico , Ácidos Grasos/metabolismo , Humanos , Atrofia Muscular Espinal/tratamiento farmacológico , Estados UnidosRESUMEN
Hypoxia is an important pathological phenomenon due to uncontrolled cancer cell proliferation and insufficient blood flow, which can be used to design hypoxia-responsive nanocarriers for the intelligent treatment of tumor. However, it is difficult to obtain the response of hypoxia-responsive polymers corresponding to the degree of hypoxia in the tumor sites. Therefore, hypoxia-responsive azobenzene-centered copolymers polyoligo (ethylene glycol) methacrylate-block-poly(ε-caprolactone)-azobenzene-poly(ε-caprolactone)-block-poly oligo (ethylene glycol) (POEGMA-b-PCL-Azo-PCL-b-POEGMA) were synthesized and further self-assembled into spherical micelles. Doxorubicin (DOX) and chlorine e6 (Ce6) were encapsulated inside the micelles. The photodynamic therapy (PDT) of Ce6 could be applied to further amplify the hypoxia condition in the tumor sites through oxygen consumption on laser irradiation (660 nm). Under this condition, the DOX/Ce6-loaded micelles progressively formed spherical micelles with a small size due to the cleavage of azobenzene, thus allowing the controlled release of DOX. The formed smaller micelles could significantly avoid the formation of large aggregates, which is beneficial for clinical application. Moreover, Ce6 would continuously convert oxygen to singlet oxygen (1O2), thus showing toxicity to cancer cells. Both in vitro and intracellular studies confirmed that our "all-in-one" micelles showed a superior synergistic effect of photodynamic therapy and chemotherapy.
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Antibióticos Antineoplásicos/administración & dosificación , Compuestos Azo/administración & dosificación , Doxorrubicina/administración & dosificación , Fármacos Fotosensibilizantes/administración & dosificación , Porfirinas/administración & dosificación , Animales , Antibióticos Antineoplásicos/química , Compuestos Azo/química , Hipoxia de la Célula , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Clorofilidas , Doxorrubicina/química , Luz , Ratones , Micelas , Fotoquimioterapia , Fármacos Fotosensibilizantes/química , Fármacos Fotosensibilizantes/efectos de la radiación , Polímeros/administración & dosificación , Polímeros/química , Porfirinas/química , Porfirinas/efectos de la radiación , Especies Reactivas de Oxígeno/metabolismoRESUMEN
Drug diffusion within the skin with a needle-free micro-jet injection (NFI) device was compared with two well-established delivery methods: topical application and solid needle injection. A permanent make-up (PMU) machine, normally used for dermal pigmentation, was utilized as a solid needle injection method. For NFIs a continuous wave (CW) laser diode was used to create a bubble inside a microfluidic device containing a light absorbing solution. Each method delivered two different solutions into ex vivo porcine skin. The first solution consisted of a red dye (direct red 81) and rhodamine B in water. The second solution was direct red 81 and rhodamine B in water and glycerol. We measured the diffusion depth, width and surface area of the solutions in all the injected skin samples. The NFI has a higher vertical dispersion velocity of 3 × 105µm/s compared to topical (0.1 µm/s) and needle injection (53 µm/s). The limitations and advantages of each method are discussed, and we conclude that the micro-jet injector represents a fast and minimally invasive injection method, while the solid needle injector causes notable tissue damage. In contrast, the topical method had the slowest diffusion rate but causes no visible damage to the skin.
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Sistemas de Liberación de Medicamentos/métodos , Inyecciones Subcutáneas/métodos , Agujas , Piel , Administración Cutánea , Animales , Compuestos Azo/administración & dosificación , Colorantes/administración & dosificación , Técnicas In Vitro , Rodaminas/administración & dosificación , PorcinosRESUMEN
Photopharmacology has yielded compounds that have potential to restore impaired visual responses resulting from outer retinal degeneration diseases such as retinitis pigmentosa. Here we evaluate two photoswitchable azobenzene ion channel blockers, DAQ and DAA for vision restoration. DAQ exerts its effect primarily on RGCs, whereas DAA induces light-dependent spiking primarily through amacrine cell activation. Degeneration-induced local field potentials remain a major challenge common to all vision restoration approaches. These 5-10 Hz rhythmic potentials increase the background firing rate of retinal ganglion cells (RGCs) and overlay the stimulated response, thereby reducing signal-to-noise ratio. Along with the bipolar cell-selective photoswitch DAD and second-generation RGC-targeting photoswitch PhENAQ, we investigated the effects of DAA and DAQ on rhythmic local field potentials (LFPs) occurring in the degenerating retina. We found that photoswitches targeting neurons upstream of RGCs, DAA (amacrine cells) and DAD (bipolar cells) suppress the frequency of LFPs, while DAQ and PhENAQ (RGCs) had negligible effects on frequency or spectral power of LFPs. Taken together, these results demonstrate remarkable diversity of cell-type specificity of photoswitchable channel blockers in the retina and suggest that specific compounds may counter rhythmic LFPs to produce superior signal-to-noise characteristics in vision restoration.
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Células Amacrinas/citología , Compuestos Azo/administración & dosificación , Canales Iónicos/antagonistas & inhibidores , Retinitis Pigmentosa/tratamiento farmacológico , Potenciales de Acción/efectos de los fármacos , Células Amacrinas/efectos de los fármacos , Animales , Compuestos Azo/síntesis química , Compuestos Azo/química , Compuestos Azo/farmacología , Modelos Animales de Enfermedad , Femenino , Masculino , Ratones , Estructura Molecular , Células Ganglionares de la Retina/citología , Células Ganglionares de la Retina/efectos de los fármacos , Retinitis Pigmentosa/metabolismoRESUMEN
Determining whether follicle recruitment in the domestic hen is functionally linked to ovulation would inform investigations on the exact time of cyclic recruitment and subsequently, the earliest cellular event mediating recruitment. The objective of the present studies was to determine if the absence of ovulation results in the failure of cyclic recruitment. 3 groups of Hy-Line W-36 hens were studied: no-ovulation, first-ovulation, or late-ovulation within the sequence. Time and occurrence of oviposition and ovulation were documented by video recording and cloacal palpation. To determine the presence of a recently recruited follicle, ovaries were collected during the last hour of photoperiod, and follicles weighing 280 to 900 mg, with yellow yolk incorporated, and diameter of 9 to 12 mm, were considered recently recruited. To compare the amount of yolk uptake in recruited follicles, hens were fed Sudan IV dye 6 h before ovary collection. Percent dyed yolk was quantified from cross-sections of the recruited follicles. To confirm follicle viability, granulosa cell (GC) mitotic activity was assessed via flow cytometry. Initial results indicated the presence of a recently recruited follicle in 10 of 11, 7 of 10, and 9 of 10, no-ovulation, first-ovulation, and late-ovulation ovaries, respectively, with no significant differences in weight (543 ± 62 mg, 456 ± 71 mg, 620 ± 75 mg, respectively). There were no significant differences in yolk incorporation among the most recently recruited follicles with 19.0 ± 2.0%, 18.0 ± 3.7%, and 19.8 ± 3.2% dyed yolk in no-ovulation, first-ovulation, and late-ovulation ovaries, respectively. Finally, there were no significant differences in % GC in the S/G2-M phase of mitosis among recruited follicles (19.0 ± 5.0%, 22.0 ± 4.2%, 15.67 ± 1.0%, in no-ovulation, first-ovulation, and late-ovulation ovaries, respectively), confirming viability of all recruited follicles. We conclude that cyclic recruitment occurs independently of ovulation and propose that the order and timing of cyclic recruitment is predetermined at an earlier stage of follicle development.
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Pollos/fisiología , Folículo Ovárico/fisiología , Ovulación/fisiología , Animales , Compuestos Azo/administración & dosificación , Peso Corporal , Femenino , Células de la Granulosa/citología , Mitosis , Oviposición/fisiologíaRESUMEN
BACKGROUND: We examined whether metoclopramide (MCP), a modulator of dopamine and serotonin receptors, alleviated colitis and had synergistic effects when coadministered with 5-aminosalicylic acid (5-ASA) in an experimental model of colitis. METHODS: MCP azo-linked to 5-ASA (5-[4-chloro-2-{2-(diethylamino)ethylcarbamoyl}- 1-methoxyphenyl]azosalicylic acid, MCP-azo-ASA) was synthesized, where 5-ASA was used as a colon-targeting carrier and an anti-colitic agent, and the ability of MCP-azo-ASA to target the colon in vitro and in vivo was evaluated. RESULTS: Our results indicate that MCP-azo-ASA was cleaved to MCP and 5-ASA in the cecal contents, but not in the contents of the small intestine. Oral gavage with equimolar concentrations of MCP-azo-ASA and sulfasalazine (SSZ, a colon-specific prodrug of 5-ASA widely used clinically) demonstrated that the two prodrugs delivered comparable amounts of 5-ASA to the cecum. MCP was barely detected in the blood after oral gavage with MCP-azo-ASA. In a rat model of 2,4-dinitrobenzene sulfonic acid hydrate (DNBS)-induced colitis, MCP-azo-ASA alleviated colonic damage in a dose-dependent manner. Moreover, MCP-azo-ASA reduced the concentrations of inflammatory mediators in the inflamed colon. At low equimolar doses, MCP-azo-ASA, but not SSZ, resulted in significant anti-colitic effects, which indicates that MCP has anti-colitic activity. MCP-azo-ASA had anti-colitic effects equal to those of SSZ at high equimolar doses. CONCLUSION: Thus, our results indicate that MCP-azo-ASA is a colon-specific prodrug of MCP. Targeted delivery of MCP to the colon ameliorated DNBS-induced colitis in rats, and we did not observe any synergistic effects of MCP after co-delivery with 5-ASA.
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Antiinflamatorios no Esteroideos/uso terapéutico , Colitis/tratamiento farmacológico , Colon/efectos de los fármacos , Modelos Animales de Enfermedad , Metoclopramida/uso terapéutico , Profármacos/uso terapéutico , Administración Oral , Animales , Antiinflamatorios no Esteroideos/administración & dosificación , Antiinflamatorios no Esteroideos/síntesis química , Compuestos Azo/administración & dosificación , Compuestos Azo/uso terapéutico , Bencenosulfonatos , Colitis/inducido químicamente , Colitis/patología , Colon/patología , Masculino , Mesalamina/administración & dosificación , Mesalamina/uso terapéutico , Metoclopramida/administración & dosificación , Metoclopramida/síntesis química , Profármacos/administración & dosificación , Profármacos/síntesis química , Ratas , Ratas Sprague-DawleyRESUMEN
AIMS: Risdiplam (RG7916, RO7034067) is an orally administered, centrally and peripherally distributed, survival of motor neuron 2 (SMN2) mRNA splicing modifier for the treatment of spinal muscular atrophy (SMA). The objectives of this entry-into-human study were to assess the safety, tolerability, pharmacokinetics (PK) and pharmacodynamics of risdiplam, and the effect of the strong CYP3A inhibitor itraconazole on the PK of risdiplam in healthy male volunteers. METHODS: Part 1 had a randomized, double-blind, adaptive design with 25 subjects receiving single ascending oral doses of risdiplam (ranging from 0.6-18.0 mg, n = 18) or placebo (n = 7). A Bayesian framework was applied to estimate risdiplam's effect on SMN2 mRNA. The effect of multiple doses of itraconazole on the PK of risdiplam was also assessed using a two-period cross-over design (n = 8). RESULTS: Risdiplam in the fasted or fed state was well tolerated. Risdiplam exhibited linear PK over the dose range with a multi-phasic decline with a mean terminal half-life of 40-69 h. Food had no relevant effect, and itraconazole had only a minor effect on plasma PK indicating a low fraction of risdiplam metabolized by CYP3A. The highest tested dose of 18.0 mg risdiplam led to approximately 41% (95% confidence interval 27-55%) of the estimated maximum increase in SMN2 mRNA. CONCLUSIONS: Risdiplam was well tolerated and proof of mechanism was demonstrated by the intended shift in SMN2 splicing towards full-length SMN2 mRNA. Based on these data, Phase 2/3 studies of risdiplam in patients with SMA are now ongoing.
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Compuestos Azo/administración & dosificación , Fármacos Neuromusculares/administración & dosificación , Pirimidinas/administración & dosificación , Empalme del ARN/efectos de los fármacos , Administración Oral , Adolescente , Adulto , Área Bajo la Curva , Compuestos Azo/efectos adversos , Compuestos Azo/farmacocinética , Inhibidores del Citocromo P-450 CYP3A/farmacocinética , Método Doble Ciego , Interacciones Farmacológicas , Voluntarios Sanos , Humanos , Itraconazol/farmacocinética , Masculino , Persona de Mediana Edad , Atrofia Muscular Espinal/tratamiento farmacológico , Atrofia Muscular Espinal/genética , Fármacos Neuromusculares/efectos adversos , Fármacos Neuromusculares/farmacocinética , Pirimidinas/efectos adversos , Pirimidinas/farmacocinética , ARN Mensajero/genética , Proteína 2 para la Supervivencia de la Neurona Motora/genética , Adulto JovenRESUMEN
We report herein, an azo-derivative (AzP1) of FDA approved antineoplastic drug SN-38 (irinotecan analogue) as a theranostic agent with a potential for both tumor hypoxia-specific activation and therapy. The theranostic AzP1 was found to be stable within a biologically relevant pH scale and was chemically inert towards other competitive biological analytes. However, upon treatment with rat-liver microsomes, AzP1 showed a self-calibrated fluorescence enhancement at λemâ¯=â¯560â¯nm. The cytotoxicity profile of AzP1 was tested in various cancer lines. Under hypoxic conditions, prodrug AzP1 exhibited activation to release the parent drug (SN-38) and enhanced cytotoxicity in cancer cells with concomitant fluorescence enhancement at 560â¯nm, which served to monitor both the drug activation and tracing purposes. The therapeutic potential of AzP1 for both tumor-specific activation and suppression of tumor weights was validated in xenograft mouse model. Collectively, the synthetic ease and hypoxia-sensitive activation along with promising therapeutic properties highlight the potential of theranostic AzPI in future cancer treatment programs.
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Antineoplásicos/administración & dosificación , Compuestos Azo/administración & dosificación , Irinotecán/análogos & derivados , Irinotecán/administración & dosificación , Neoplasias/tratamiento farmacológico , Hipoxia Tumoral/efectos de los fármacos , Animales , Caenorhabditis elegans , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Femenino , Humanos , Ratones Endogámicos BALB C , Ratones Desnudos , Microsomas Hepáticos/efectos de los fármacos , Neoplasias/diagnóstico por imagen , Ratas , Nanomedicina TeranósticaRESUMEN
Jietacins, an azoxy antibiotic class of chemicals, were isolated from the culture broth of Streptomyces sp. KP-197. They have a unique structural motif, including a vinyl azoxy group and a long acyclic aliphatic chain, which is usually branched but non-branched in the case of jietacin C. During a drug discovery program, we found that jietacins display potent anthelmintic activity against parasitic nematodes and that jietacin A has a moderate or low acute toxicity (LD50â¯>â¯300â¯mg/kg) and no mutagenic potential in a mini Ames screen. This suggests that jietacins have potential for drug discovery research. In order to create a novel anthelmintic agent, we performed design, synthesis, and biological evaluation of jietacin derivatives against parasitic nematodes. Of these derivatives, we found that a fully synthesized simplified derivative exhibited better anthelmintic activity against three parasitic nematodes than natural jietacins. In addition, it had a better efficacy in vivo through oral administration against a mouse nematode. This indicated that the azoxy motif could prove useful as a template for anthelmintic discovery, possibly creating a class of anthelmintic with novel skeletons, a potential new mode of action, and providing further insight for rational drug design.
Asunto(s)
Antihelmínticos/farmacología , Antibacterianos/farmacología , Compuestos Azo/farmacología , Diseño de Fármacos , Nematodos/efectos de los fármacos , Nippostrongylus/efectos de los fármacos , Animales , Antihelmínticos/administración & dosificación , Antihelmínticos/química , Antibacterianos/administración & dosificación , Antibacterianos/química , Compuestos Azo/administración & dosificación , Compuestos Azo/química , Relación Dosis-Respuesta a Droga , Ratones , Estructura Molecular , Pruebas de Sensibilidad Parasitaria , Relación Estructura-ActividadRESUMEN
Aberrant excitatory neurotransmission associated with overproduction of glutamate has been implicated in the development of HIV-associated neurocognitive disorders (HAND). The glutamine antagonist 6-diazo-5-oxo-l-norleucine (DON, 14) attenuates glutamate synthesis in HIV-infected microglia/macrophages, offering therapeutic potential for HAND. We show that 14 prevents manifestation of spatial memory deficits in chimeric EcoHIV-infected mice, a model of HAND. 14 is not clinically available, however, because its development was hampered by peripheral toxicities. We describe the synthesis of several substituted N-(pivaloyloxy)alkoxy-carbonyl prodrugs of 14 designed to circulate inert in plasma and be taken up and biotransformed to 14 in the brain. The lead prodrug, isopropyl 6-diazo-5-oxo-2-(((phenyl(pivaloyloxy)methoxy)carbonyl)amino)hexanoate (13d), was stable in swine and human plasma but liberated 14 in swine brain homogenate. When dosed systemically in swine, 13d provided a 15-fold enhanced CSF-to-plasma ratio and a 9-fold enhanced brain-to-plasma ratio relative to 14, opening a possible clinical path for the treatment of HAND.
Asunto(s)
Aminocaproatos/farmacología , Compuestos Azo/farmacología , Diazooxonorleucina/farmacología , Trastornos Neurocognitivos/tratamiento farmacológico , Nootrópicos/farmacología , Profármacos/farmacología , Aminocaproatos/administración & dosificación , Aminocaproatos/síntesis química , Animales , Compuestos Azo/administración & dosificación , Compuestos Azo/síntesis química , Sangre/metabolismo , Encéfalo/metabolismo , Diazooxonorleucina/administración & dosificación , Estabilidad de Medicamentos , Femenino , Ácido Glutámico/metabolismo , Glutaminasa/antagonistas & inhibidores , Infecciones por VIH/complicaciones , Humanos , Masculino , Ratones Endogámicos C57BL , Trastornos Neurocognitivos/etiología , Nootrópicos/administración & dosificación , Nootrópicos/síntesis química , Profármacos/administración & dosificación , Profármacos/síntesis química , Porcinos , Carga Viral/efectos de los fármacosRESUMEN
As a potent radiosensitizer nitric oxide (NO) may be a putative adjuvant in the treatment of malignant gliomas which are known for their radio- and chemoresistance. The NO donor prodrug JS-K (O2-(2.4-dinitrophenyl) 1-[(4-ethoxycarbonyl) piperazin-1-yl] diazen-1-ium-1,2-diolate) allows cell-type specific intracellular NO release via enzymatic activation by glutathione-S-transferases overexpressed in glioblastoma multiforme. The cytotoxic and radiosensitizing efficacy of JS-K was assessed in U87 glioma cells in vitro focusing on cell proliferation, induction of DNA damage, and cell death. In vivo efficacy of JS-K and repetitive irradiation were investigated in an orthotopic U87 xenograft model in mice. For the first time, we could show that JS-K acts as a potent cytotoxic and radiosensitizing agent in U87 cells in vitro. This dose- and time-dependent effect is due to an enhanced induction of DNA double-strand breaks leading to mitotic catastrophe as the dominant form of cell death. However, this potent cytotoxic and radiosensitizing effect could not be confirmed in an intracranial U87 xenograft model, possibly due to insufficient delivery into the brain. Although NO donor treatment was well tolerated, neither a retardation of tumor growth nor an extended survival could be observed after JS-K and/or radiotherapy.
Asunto(s)
Compuestos Azo/administración & dosificación , Glioblastoma/tratamiento farmacológico , Glioblastoma/radioterapia , Donantes de Óxido Nítrico/administración & dosificación , Piperazinas/administración & dosificación , Animales , Proliferación Celular/efectos de los fármacos , Proliferación Celular/efectos de la radiación , Daño del ADN/efectos de los fármacos , Daño del ADN/efectos de la radiación , Relación Dosis-Respuesta a Droga , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Regulación Neoplásica de la Expresión Génica/efectos de la radiación , Glioblastoma/patología , Humanos , Ratones , Óxido Nítrico/metabolismo , Fármacos Sensibilizantes a Radiaciones/administración & dosificación , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
DON (6-diazo-5-oxo-l-norleucine), a glutamine antagonist, was demonstrated to exhibit analgesic, antibacterial, antiviral and anticancer properties. The study was performed to characterize its in vitro and in vivo genetic toxicity potential. DON was tested in the bacterial reverse mutation assay (Ames test) using Salmonella typhimurium tester strains (TA98, TA100, TA1535 and TA1537) and Escherichia coli tester strain (WP2 uvrA) with and without S9 and also with reductive S9. In addition, DON was tested for the chromosome aberrations in Chinese hamster ovary (CHO) cells with or without S9 to evaluate the clastogenic potential. Furthermore, DON was also evaluated for its in vivo clastogenic activity by detecting micronuclei in polychromatic erythrocyte (PCE) cells in bone marrow collected from the male mice dosed intravenously with 500, 100, 10, 1 and 0.1 mg/kg at 24 and 48-h post-dose. The Ames mutagenicity assay showed no positive mutagenic responses. However, the in vitro chromosome aberration assay demonstrated dose dependent statistically positive increase in structural aberrations at 4 and 20-h exposure without S9 and also at 4-h exposure with S9. The in vivo micronucleus assay also revealed a statistically positive response for micronucleus formation at 500, 100 and 10 mg/kg at 24 and 48-h post-dose. Thus, DON appears to be negative in the Ames test but positive in the in vitro chromosome aberration assay and in the in vivo micronucleus assay. In conclusion, the results indicate DON is a genotoxic compound with a plausible epigenetic mechanism.
Asunto(s)
Compuestos Azo/toxicidad , Aberraciones Cromosómicas/efectos de los fármacos , Células Precursoras Eritroides/efectos de los fármacos , Glutamina/antagonistas & inhibidores , Mutágenos/toxicidad , Neurotransmisores/toxicidad , Norleucina/análogos & derivados , Activación Metabólica , Animales , Arocloros/farmacología , Compuestos Azo/administración & dosificación , Compuestos Azo/metabolismo , Células CHO , Cricetinae , Cricetulus , Relación Dosis-Respuesta a Droga , Contaminantes Ambientales/farmacología , Masculino , Mesocricetus , Ratones Endogámicos ICR , Pruebas de Micronúcleos , Microsomas Hepáticos/efectos de los fármacos , Microsomas Hepáticos/enzimología , Microsomas Hepáticos/metabolismo , Pruebas de Mutagenicidad , Mutágenos/administración & dosificación , Mutágenos/metabolismo , Neurotransmisores/administración & dosificación , Neurotransmisores/metabolismo , Norleucina/administración & dosificación , Norleucina/metabolismo , Norleucina/toxicidad , Ratas Sprague-Dawley , Pruebas de Toxicidad AgudaRESUMEN
This study estimated the theoretical maximum daily intake (TMDI) of Sunset Yellow (SY) synthetic food dye by the Brazilian population through food consumption data from the Household Budget Survey (HBS) of the Brazilian Institute of Geography and Statistics (IBGE, 2008/09). The study covered the population in urban and rural areas in the five regions of the country, and from different age groups, in order to verify if it were possible to exceed the acceptable daily intake (ADI) of SY, which is 4.0 mg kg-1 body weight. This was assessed by cross-checking food products containing this dye from the largest supermarket chains in Brazil with data from the HBS-IBGE 2008/09. These data showed that the average consumption of SY per capita did not exceed the ADI in any of the aforementioned population groups. However, when considering food consumption in urban and rural areas (279 and 260 mg of SY day-1), in the five regions of the country (260-338 mg of SY day-1), and for adolescents (332 mg SY day-1), it is noted that part of the population could be exceeding the recommended ADI, which may pose health risks. Although it is unlikely that individuals will exceed the SY ADI, this may occur in some cases, especially for younger people.
Asunto(s)
Compuestos Azo/administración & dosificación , Compuestos Azo/análisis , Encuestas sobre Dietas , Suplementos Dietéticos , Administración Oral , Adolescente , Adulto , Brasil , Niño , Femenino , Humanos , Masculino , Persona de Mediana Edad , Nivel sin Efectos Adversos Observados , Medición de Riesgo , Adulto JovenRESUMEN
AIM: To develop a human in vitro model of non-alcoholic fatty liver disease (NAFLD), utilising primary hepatocytes cultured in a three-dimensional (3D) perfused platform. METHODS: Fat and lean culture media were developed to directly investigate the effects of fat loading on primary hepatocytes cultured in a 3D perfused culture system. Oil Red O staining was used to measure fat loading in the hepatocytes and the consumption of free fatty acids (FFA) from culture medium was monitored. Hepatic functions, gene expression profiles and adipokine release were compared for cells cultured in fat and lean conditions. To determine if fat loading in the system could be modulated hepatocytes were treated with known anti-steatotic compounds. RESULTS: Hepatocytes cultured in fat medium were found to accumulate three times more fat than lean cells and fat uptake was continuous over a 14-d culture. Fat loading of hepatocytes did not cause any hepatotoxicity and significantly increased albumin production. Numerous adipokines were expressed by fatty cells and genes associated with NAFLD and liver disease were upregulated including: Insulin-like growth factor-binding protein 1, fatty acid-binding protein 3 and CYP7A1. The metabolic activity of hepatocytes cultured in fatty conditions was found to be impaired and the activities of CYP3A4 and CYP2C9 were significantly reduced, similar to observations made in NAFLD patients. The utility of the model for drug screening was demonstrated by measuring the effects of known anti-steatotic compounds. Hepatocytes, cultured under fatty conditions and treated with metformin, had a reduced cellular fat content compared to untreated controls and consumed less FFA from cell culture medium. CONCLUSION: The 3D in vitro NAFLD model recapitulates many features of clinical NAFLD and is an ideal tool for analysing the efficacy of anti-steatotic compounds.