RESUMO
Neurofibromatosis type 1 (NF1) is a human genetic disorder caused by variants in the NF1 gene. Plexiform neurofibromas, one of many NF1 manifestations, are benign peripheral nerve sheath tumors occurring in up to 50% of NF1 patients. A substantial fraction of NF1 pathogenetic variants are nonsense mutations, which result in the synthesis of truncated non-functional NF1 protein (neurofibromin). To date, no therapeutics have restored neurofibromin expression or addressed the consequences of this protein's absence in NF1 nonsense mutation patients, but nonsense suppression is a potential approach to the problem. Ataluren is a small molecule drug that has been shown to stimulate functional nonsense codon readthrough in several models of nonsense mutation diseases, as well as in Duchenne muscular dystrophy patients. To test ataluren's potential applicability in nonsense mutation NF1 patients, we evaluated its therapeutic effects using three treatment regimens in a previously established NF1 patient-derived (c.2041C > T; p.Arg681X) nonsense mutation mouse model. Collectively, our experiments indicate that: i) ataluren appeared to slow the growth of neurofibromas and alleviate some paralysis phenotypes, ii) female Nf1-nonsense mutation mice manifested more severe paralysis and neurofibroma phenotypes than male mice, iii) ataluren doses with apparent effectiveness were lower in female mice than in male mice, and iv) age factors also influenced ataluren's effectiveness.
Assuntos
Códon sem Sentido , Modelos Animais de Doenças , Neurofibromatose 1 , Neurofibromina 1 , Animais , Códon sem Sentido/efeitos dos fármacos , Camundongos , Masculino , Feminino , Neurofibromatose 1/genética , Neurofibromatose 1/tratamento farmacológico , Neurofibromina 1/genética , Oxidiazóis/farmacologia , Oxidiazóis/uso terapêutico , Humanos , Camundongos Endogâmicos C57BL , Camundongos TransgênicosRESUMO
Chemical agonism of human caseinolytic protease P (HsClpP) is increasingly being recognized as a potential anticancer strategy due to its critical role in maintaining mitochondrial homeostasis. We unveil the discovery of 5-(piperidin-4-yl)-1,2,4-oxadiazole derivatives as a novel class of HsClpP agonists and demonstrate for the first time the application of HsClpP agonists in the treatment of hepatocellular carcinoma (HCC) (Pace, A.; Pierro, P. The new era of 1,2,4-oxadiazoles. Org. Biomol. Chem. 2009, 7 (21), 4337-4348). Compound SL44 exhibited potent HsClpP agonistic activity in the α-casein hydrolysis assay (EC50 = 1.30 µM) and inhibited the proliferation of HCCLM3 cells (IC50 = 3.1 µM, 21.4-fold higher than hit ADX-47273). Mechanistically, SL44 induces degradation of respiratory chain complex subunits and leads to apoptosis in HCC cells. In vivo results demonstrated that SL44 has potent tumor growth inhibitory activity and has a superior safety profile compared to the kinase inhibitor sorafenib. Overall, we developed a novel class of HsClpP agonists that can potentially be used for the treatment of HCC.
Assuntos
Antineoplásicos , Carcinoma Hepatocelular , Proliferação de Células , Neoplasias Hepáticas , Oxidiazóis , Humanos , Carcinoma Hepatocelular/tratamento farmacológico , Carcinoma Hepatocelular/patologia , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/patologia , Animais , Oxidiazóis/química , Oxidiazóis/farmacologia , Oxidiazóis/uso terapêutico , Oxidiazóis/síntese química , Antineoplásicos/farmacologia , Antineoplásicos/química , Antineoplásicos/síntese química , Antineoplásicos/uso terapêutico , Proliferação de Células/efeitos dos fármacos , Camundongos , Relação Estrutura-Atividade , Linhagem Celular Tumoral , Descoberta de Drogas , Camundongos Nus , Apoptose/efeitos dos fármacos , MasculinoRESUMO
BACKGROUND: Amyotrophic lateral sclerosis is a progressive neurodegenerative disorder leading to muscle weakness and respiratory failure. Arimoclomol, a heat-shock protein-70 (HSP70) co-inducer, is neuroprotective in animal models of amyotrophic lateral sclerosis, with multiple mechanisms of action, including clearance of protein aggregates, a pathological hallmark of sporadic and familial amyotrophic lateral sclerosis. We aimed to evaluate the safety and efficacy of arimoclomol in patients with amyotrophic lateral sclerosis. METHODS: ORARIALS-01 was a multinational, randomised, double-blind, placebo-controlled, parallel-group trial done at 29 centres in 12 countries in Europe and North America. Patients were eligible if they were aged 18 years or older and met El Escorial criteria for clinically possible, probable, probable laboratory-supported, definite, or familial amyotrophic lateral sclerosis; had an ALS Functional Rating Scale-Revised score of 35 or more; and had slow vital capacity at 70% or more of the value predicted on the basis of the participant's age, height, and sex. Patients were randomly assigned (2:1) in blocks of 6, stratified by use of a stable dose of riluzole or no riluzole use, to receive oral arimoclomol citrate 1200 mg/day (400 mg three times per day) or placebo. The Randomisation sequence was computer generated centrally. Investigators, study personnel, and study participants were masked to treatment allocation. The primary outcome was the Combined Assessment of Function and Survival (CAFS) rank score over 76 weeks of treatment. The primary outcome and safety were analysed in the modified intention-to-treat population. This trial is registered with ClinicalTrials.gov, NCT03491462, and is completed. FINDINGS: Between July 31, 2018, and July 17, 2019, 287 patients were screened, 245 of whom were enrolled in the trial and randomly assigned. The modified intention-to-treat population comprised 239 patients (160 in the arimoclomol group and 79 in the placebo group): 151 (63%) were male and 88 (37%) were female; mean age was 57·6 years (SD 10·9). CAFS score over 76 weeks did not differ between groups (mean 0·51 [SD 0·29] in the arimoclomol group vs 0·49 [0·28] in the placebo group; p=0·62). Cliff's delta comparing the two groups was 0·039 (95% CI -0·116 to 0·194). Proportions of participants who died were similar between the treatment groups: 29 (18%) of 160 patients in the arimoclomol group and 18 (23%) of 79 patients in the placebo group. Most deaths were due to disease progression. The most common adverse events were gastrointestinal. Adverse events were more often deemed treatment-related in the arimoclomol group (104 [65%]) than in the placebo group (41 [52%]) and more often led to treatment discontinuation in the arimoclomol group (26 [16%]) than in the placebo group (four [5%]). INTERPRETATION: Arimoclomol did not improve efficacy outcomes compared with placebo. Although available biomarker data are insufficient to preclude future strategies that target the HSP response, safety data suggest that a higher dose of arimoclomol would not have been tolerated. FUNDING: Orphazyme.
Assuntos
Esclerose Lateral Amiotrófica , Fármacos Neuroprotetores , Humanos , Esclerose Lateral Amiotrófica/tratamento farmacológico , Masculino , Feminino , Método Duplo-Cego , Pessoa de Meia-Idade , Idoso , Fármacos Neuroprotetores/uso terapêutico , Fármacos Neuroprotetores/efeitos adversos , Resultado do Tratamento , Adulto , Hidroxilaminas/uso terapêutico , Hidroxilaminas/efeitos adversos , Hidroxilaminas/farmacologia , Oxidiazóis/uso terapêutico , Oxidiazóis/efeitos adversosRESUMO
The article discusses current issues of the treatment of arterial hypertension. According to presented data, so-called therapeutic nihilism is becoming one of the main barriers to achieving target blood pressure (BP). This nihilism is that despite evidence of the effectiveness of achieving lower BP values, practitioners do not intensify antihypertensive therapy sufficiently to achieve such values. The article specially addresses new criteria for the effectiveness of antihypertensive therapy, which reflect the therapy sustainability. The most commonly used indicator is the duration of the period, during which systolic BP remains in the therapeutic range. The prognostic significance of such indicators is discussed. In these conditions, it is very important to use the most effective antihypertensive drugs for initial antihypertensive therapy, including as a part of combination therapy. This tactic provides more frequent achievement of BP goals without the need for dose adjustment. In this regard, a systematic review was performed, which included sufficiently large randomized studies of the antihypertensive effectiveness of azilsartan medoxomil. This systematic review will provide comprehensive information on a possible role of using the angiotensin II receptor blocker azilsartan as a basic drug for the treatment of a wide range of patients with high BP. Most of the studies included in the systematic review assessed the effectiveness of combination therapy including azilsartan.
Assuntos
Anti-Hipertensivos , Benzimidazóis , Pressão Sanguínea , Hipertensão , Oxidiazóis , Humanos , Oxidiazóis/uso terapêutico , Oxidiazóis/farmacologia , Hipertensão/tratamento farmacológico , Hipertensão/fisiopatologia , Anti-Hipertensivos/uso terapêutico , Benzimidazóis/uso terapêutico , Benzimidazóis/farmacologia , Pressão Sanguínea/efeitos dos fármacos , Pressão Sanguínea/fisiologia , Quimioterapia CombinadaRESUMO
BACKGROUND: Ozanimod showed efficacy and safety in the phase 2 STEPSTONE study conducted in patients with moderately to severely active Crohn's disease. AIMS: This analysis assessed the effects of ozanimod on circulating lymphocytes in Crohn's disease. METHODS: Patients received ozanimod 0.92 mg for 12 weeks. Lymphocyte subtypes were evaluated using multicolor flow analysis on blood samples collected before treatment and on Week 12. Absolute lymphocyte count changes were analyzed by Wilcoxon signed rank tests. Disease activity changes and efficacy outcomes were evaluated at Week 12, and associations with lymphocyte subtype levels were assessed using Spearman's correlation and logistic regression. RESULTS: Reductions in median total T, Th, and cytotoxic T cells occurred at Week 12 (45.4%-76.8%), with reductions in most subtypes of 47.5% to 91.3% (P < 0.001). CD8+ terminally differentiated effector memory cells were largely unaffected (median change, - 19%; P = 0.44). Reductions in median total B cells occurred at Week 12 (76.7%), with reductions in subtypes of 71.4% to 81.7% (P < 0.001). Natural killer and monocyte cell counts were unchanged. Greater baseline levels and changes in nonswitched memory B cells were significantly associated with clinical, endoscopic, and histologic efficacy (P < 0.05, all comparisons). CONCLUSIONS: Ozanimod reduced circulating levels of all B-cell and most T-cell subsets but not monocytes or natural killer cells. Key subsets relevant to immune surveillance were not reduced, supporting the low risk of infection and malignancy with ozanimod in chronic inflammatory diseases. Levels of nonswitched memory B cells were associated with efficacy, providing a potential marker for ozanimod response. TRIAL REGISTRATION: ClinicalTrials.gov: NCT02531113, EudraCT: 2015-002025-19.
Assuntos
Doença de Crohn , Adulto , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Adulto Jovem , Doença de Crohn/tratamento farmacológico , Doença de Crohn/imunologia , Doença de Crohn/sangue , Indanos/uso terapêutico , Contagem de Linfócitos , Subpopulações de Linfócitos/efeitos dos fármacos , Subpopulações de Linfócitos/imunologia , Oxidiazóis/uso terapêutico , Índice de Gravidade de Doença , Moduladores do Receptor de Esfingosina 1 Fosfato/uso terapêutico , Moduladores do Receptor de Esfingosina 1 Fosfato/farmacologia , Resultado do TratamentoRESUMO
INTRODUCTION: In BIPARK-1 and BIPARK-2, addition of once-daily opicapone to levodopa/carbidopa significantly reduced daily "OFF"-time relative to placebo in adults with Parkinson's disease (PD) and motor fluctuations. Diary data from these studies were pooled and analyzed post hoc to characterize "OFF"-times around nighttime sleep and to explore the effects of opicapone 50 mg. METHODS: "OFF" before sleep (OBS), "OFF during the nighttime sleep period" (ODNSP), early morning "OFF" (EMO), and duration of nighttime sleep and awake periods were analyzed descriptively at baseline. Mean changes from baseline to Week 14/15 (end of double-blind treatment) were analyzed using two-sided t-tests in participants with data for both visits. RESULTS: At baseline, 88.3 % (454/514) of participants reported having OBS (34.0 %), ODNSP (17.1 %), or EMO (79.6 %). Those with ODNSP had substantially shorter mean duration of uninterrupted sleep (4.4 h) than the overall pooled population (7.1 h). At Week 14/15, mean decrease from baseline in ODNSP duration was significantly greater with opicapone than with placebo (-0.9 vs. -0.4 h, P < 0.05). In participants with ODNSP at baseline, the decrease in total time spent awake during the night-time sleep period was significantly greater with opicapone than with placebo (-1.0 vs. -0.4 h, P < 0.05), as was the reduction in percent time spent awake during the night-time sleep period (-12.8 % vs. -4.5 %, P < 0.05). CONCLUSION: "OFF"-times around nighttime sleep were common in BIPARK-1 and BIPARK-2. Opicapone may improve sleep by decreasing the amount of time spent awake during the night in patients with PD who have night-time sleep period "OFF" episodes.
Assuntos
Antiparkinsonianos , Levodopa , Oxidiazóis , Doença de Parkinson , Sono , Humanos , Doença de Parkinson/tratamento farmacológico , Doença de Parkinson/fisiopatologia , Doença de Parkinson/complicações , Masculino , Feminino , Método Duplo-Cego , Pessoa de Meia-Idade , Idoso , Sono/efeitos dos fármacos , Sono/fisiologia , Antiparkinsonianos/uso terapêutico , Antiparkinsonianos/administração & dosagem , Antiparkinsonianos/farmacologia , Levodopa/farmacologia , Levodopa/administração & dosagem , Oxidiazóis/farmacologia , Oxidiazóis/administração & dosagem , Oxidiazóis/uso terapêutico , Carbidopa/farmacologia , Carbidopa/administração & dosagem , Combinação de Medicamentos , Vigília/efeitos dos fármacos , Vigília/fisiologiaRESUMO
BACKGROUND: Increasing levodopa (L-dopa)/dopa decarboxylase inhibitor (DDCI) daily dose or adding a catechol-O-methyltransferase (COMT) inhibitor to levodopa/DDCI therapy are strategies used to manage wearing-off symptoms in Parkinson's disease (PD) patients. OBJECTIVES: To evaluate the COMT inhibitor opicapone versus an additional dose of levodopa to treat early wearing-off in PD patients. METHODS: ADOPTION was a randomized, parallel-group, open-label, Phase 4 study conducted in Korea. At baseline, eligible patients were randomized (1:1) to opicapone 50 mg (n = 87) or L-dopa 100 mg (n = 81) (added to current L-dopa/DDCI therapy) for 4 weeks. The main efficacy endpoint was change from baseline to end of study in absolute off time. Other endpoints included changes in on time, in Movement Disorder Society-Unified Parkinson's Disease Rating Scale and 8-item PD Questionnaire scores, and the Clinical and Patient Global Impression of Improvement/Change. RESULTS: The adjusted mean in absolute off time was significantly greater for opicapone 50 mg than for L-dopa 100 mg (-62.1 vs. -16.7 minutes; P = 0.0015). Opicapone-treated patients also reported a greater reduction in the percentage of off time (P = 0.0015), a greater increase in absolute on time (P = 0.0338) and a greater increase in the percentage of on time (P = 0.0015). There were no significant differences in other secondary endpoints. The L-dopa equivalent daily dose was significantly higher in the opicapone group (750.9 vs. 690.0 mg; P = 0.0247), when a 0.5 conversion factor is applied. CONCLUSIONS: Opicapone 50 mg was more effective than an additional 100 mg L-dopa dose at decreasing off time in patients with PD and early wearing-off.
Assuntos
Antiparkinsonianos , Levodopa , Oxidiazóis , Doença de Parkinson , Humanos , Doença de Parkinson/tratamento farmacológico , Masculino , Feminino , Idoso , Pessoa de Meia-Idade , Levodopa/uso terapêutico , Levodopa/administração & dosagem , Antiparkinsonianos/uso terapêutico , Antiparkinsonianos/administração & dosagem , Oxidiazóis/uso terapêutico , Oxidiazóis/administração & dosagem , Inibidores de Catecol O-Metiltransferase/uso terapêutico , Inibidores de Catecol O-Metiltransferase/farmacologia , Inibidores de Catecol O-Metiltransferase/administração & dosagem , República da Coreia , Resultado do TratamentoRESUMO
BACKGROUND: Exposure to antibiotics predisposes to dysbiosis and Clostridioides difficile infection (CDI) that can be severe, recurrent (rCDI), and life-threatening. Nonselective drugs that treat CDI and perpetuate dysbiosis are associated with rCDI, in part due to loss of microbiome-derived secondary bile acid (SBA) production. Ridinilazole is a highly selective drug designed to treat CDI and prevent rCDI. METHODS: In this phase 3 superiority trial, adults with CDI, confirmed with a stool toxin test, were randomized to receive 10 days of ridinilazole (200â mg twice daily) or vancomycin (125â mg 4 times daily). The primary endpoint was sustained clinical response (SCR), defined as clinical response and no rCDI through 30 days after end of treatment. Secondary endpoints included rCDI and change in relative abundance of SBAs. RESULTS: Ridinilazole and vancomycin achieved an SCR rate of 73% versus 70.7%, respectively, a treatment difference of 2.2% (95% CI: -4.2%, 8.6%). Ridinilazole resulted in a 53% reduction in recurrence compared with vancomycin (8.1% vs 17.3%; 95% CI: -14.1%, -4.5%; P = .0002). Subgroup analyses revealed consistent ridinilazole benefit for reduction in rCDI across subgroups. Ridinilazole preserved microbiota diversity, increased SBAs, and did not increase the resistome. Conversely, vancomycin worsened CDI-associated dysbiosis, decreased SBAs, increased Proteobacteria abundance (â¼3.5-fold), and increased the resistome. CONCLUSIONS: Although ridinilazole did not meet superiority in SCR, ridinilazole greatly reduced rCDI and preserved microbiome diversity and SBAs compared with vancomycin. These findings suggest that treatment of CDI with ridinilazole results in an earlier recovery of gut microbiome health. Clinical Trials Registration.Ri-CoDIFy 1 and 2: NCT03595553 and NCT03595566.
Assuntos
Antibacterianos , Clostridioides difficile , Infecções por Clostridium , Microbioma Gastrointestinal , Vancomicina , Humanos , Vancomicina/uso terapêutico , Vancomicina/efeitos adversos , Infecções por Clostridium/tratamento farmacológico , Infecções por Clostridium/microbiologia , Masculino , Feminino , Pessoa de Meia-Idade , Método Duplo-Cego , Antibacterianos/uso terapêutico , Antibacterianos/efeitos adversos , Idoso , Clostridioides difficile/efeitos dos fármacos , Microbioma Gastrointestinal/efeitos dos fármacos , Adulto , Resultado do Tratamento , Metaboloma/efeitos dos fármacos , Oxidiazóis/uso terapêutico , Oxidiazóis/efeitos adversos , Disbiose/induzido quimicamente , Benzimidazóis , PiridinasRESUMO
Among the deadliest diseases, cancer is characterized by tumors or an increased number of a specific type of cell because of uncontrolled divisions during mitosis. Researchers in the current era concentrated on the development of highly selective anticancer medications due to the substantial toxicities of conventional cytotoxic drugs. Several marketed drug molecules have provided resistance against cancer through interaction with certain targets/growth factors/enzymes, such as Telomerase, Histone Deacetylase (HDAC), Methionine Aminopeptidase (MetAP II), Thymidylate Synthase (TS), Glycogen Synthase Kinase-3 (GSK), Epidermal Growth Factor (EGF), Vascular Endothelial Growth Factor (VEGF), Focal Adhesion Kinase (FAK), STAT3, Thymidine phosphorylase, and Alkaline phosphatase. The molecular structure of these drug molecules contains various heterocyclic moieties that act as pharmacophores. Recently, 1,3,4- oxadiazole (five-membered heterocyclic moiety) and its derivatives attracted researchers as these have been reported with a wide range of pharmacological activities, including anti-cancer. 1,3,4- oxadiazoles have exhibited anti-cancer potential via acting on any of the above targets. The presented study highlights the synthesis of anti-cancer 1,3,4-oxadiazoles, their mechanism of interactions with targets, along with structure-activity relationship concerning anti-cancer potential.
Assuntos
Antineoplásicos , Neoplasias , Humanos , Oxidiazóis/farmacologia , Oxidiazóis/uso terapêutico , Fator A de Crescimento do Endotélio Vascular , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Estrutura Molecular , Relação Estrutura-Atividade , Neoplasias/tratamento farmacológicoRESUMO
Sarcopenia is a musculoskeletal disease that reduces muscle mass and strength in older individuals. The study investigates the effects of azilsartan (AZL) on skeletal muscle loss in natural sarcopenic rats. Male Sprague-Dawley rats aged 4-6 months and 18-21 months were selected as young-matched control and natural-aged (sarcopenic) rats, respectively. Rats were allocated into young and old control (YC and OC) and young and old AZL treatment (YT and OT) groups, which received vehicles and AZL (8 mg/kg, orally) for 6 weeks. Rats were then sacrificed after muscle function analysis. Serum and gastrocnemius (GN) muscles were isolated for further endpoints. AZL significantly improved muscle grip strength and antioxidant levels in sarcopenic rats. AZL also restored the levels of insulin, testosterone, and muscle biomarkers such as myostatin and creatinine kinase in sarcopenic rats. Furthermore, AZL treatment improved the cellular and ultrastructure of GN muscle and prevented the shift of type II (glycolytic) myofibers to type I (oxidative) myofibers. The results showed that AZL intervention restored protein synthesis in natural sarcopenic rats by increasing p-Akt-1 and decreasing muscle RING-finger protein-1 and tumor necrosis factor alpha immunoexpressions. In conclusion, the present findings showed that AZL could be an effective intervention in treating age-related muscle impairments.
Assuntos
Envelhecimento , Benzimidazóis , Fibras Musculares de Contração Rápida , Fibras Musculares de Contração Lenta , Oxidiazóis , Ratos Sprague-Dawley , Sarcopenia , Animais , Sarcopenia/prevenção & controle , Sarcopenia/metabolismo , Sarcopenia/tratamento farmacológico , Sarcopenia/patologia , Masculino , Oxidiazóis/farmacologia , Oxidiazóis/uso terapêutico , Envelhecimento/efeitos dos fármacos , Ratos , Benzimidazóis/farmacologia , Benzimidazóis/uso terapêutico , Fibras Musculares de Contração Rápida/efeitos dos fármacos , Fibras Musculares de Contração Rápida/metabolismo , Fibras Musculares de Contração Rápida/patologia , Fibras Musculares de Contração Lenta/efeitos dos fármacos , Fibras Musculares de Contração Lenta/metabolismo , Fibras Musculares de Contração Lenta/patologia , Força Muscular/efeitos dos fármacos , Músculo Esquelético/efeitos dos fármacos , Músculo Esquelético/metabolismo , Músculo Esquelético/patologia , Proteínas Proto-Oncogênicas c-akt/metabolismo , Miostatina/metabolismo , Antioxidantes/farmacologiaRESUMO
Clostridioides difficile is an anaerobic Gram-positive bacterium that colonizes the gut of patients treated with broad-spectrum antibiotics. The normal gut microflora prevents C. difficile colonization; however, dysbiosis by treatment with broad-spectrum antibiotics causes recurrent C. difficile infection (CDI) in 25% of patients. There are no fully effective antibiotics for multiple recurrent CDIs. We report herein that oxadiazole antibiotics exhibit bactericidal activity against C. difficile vegetative cells. We screened a library of 75 oxadiazoles against C. difficile ATCC 43255. The findings from this collection served as the basis for the syntheses of an additional 58 analogs, which were tested against the same strain. We report a potent (MIC50 = 0.5 µg/mL and MIC90 = 1 µg/mL values for 101 C. difficile strains) and narrow-spectrum oxadiazole (3-(4-(cyclopentyloxy)phenyl)-5-(4-nitro-1H-imidazol-2-yl)-1,2,4-oxadiazole; compound 57), which is not active against common gut bacteria or other tested organisms. Compound 57 is selectively bactericidal against C. difficile and targets cell-wall synthesis.
Assuntos
Clostridioides difficile , Infecções por Clostridium , Humanos , Antibacterianos/farmacologia , Antibacterianos/uso terapêutico , Infecções por Clostridium/tratamento farmacológico , Bactérias Gram-Positivas , Oxidiazóis/farmacologia , Oxidiazóis/uso terapêuticoRESUMO
BACKGROUND AND PURPOSE: Motor fluctuations are a significant driver of healthcare resource utilization (HCRU) in people with Parkinson's disease (pwPD). A common management strategy is to include catechol-O-methyltransferase (COMT) inhibition with either opicapone or entacapone in the levodopa regimen. However, to date, there has been a lack of head-to-head data comparing the two COMT inhibitors in real-world settings. The aim of this study was to evaluate changes in HCRU and effect on sleep medications when opicapone was initiated as first COMT inhibitor versus entacapone. METHODS: In this retrospective cohort study, we assessed HCRU outcomes in pwPD naïve to COMT inhibition via UK electronic healthcare records (Clinical Practice Research Datalink and Hospital Episodes Statistics databases, June 2016 to December 2019). HCRU outcomes were assessed before (baseline) and after COMT inhibitor prescription at 0-6 months, 7-12 months and 13-18 months. Opicapone-treated pwPD were algorithm-matched (1:4) to entacapone-treated pwPD. RESULTS: By 6 months, treatment with opicapone resulted in 18.5% fewer neurology outpatient visits compared to entacapone treatment; this effect was maintained until the last follow-up (18 months). In the opicapone group, the mean levodopa equivalent daily dose decreased over the first year and then stabilized, whereas the entacapone-treated group showed an initial decrease in the first 6 months followed by a dose increase between 7 and 18 months. Neither COMT inhibitor had a significant impact on sleep medication use. CONCLUSIONS: This head-to-head study is the first to demonstrate, using 'real-world' data, that initiating COMT inhibition with opicapone is likely to decrease the need for post-treatment HCRU versus initiation of COMT inhibition with entacapone.
Assuntos
Doença de Parkinson , Humanos , Antiparkinsonianos/uso terapêutico , Catecol O-Metiltransferase , Inibidores de Catecol O-Metiltransferase/uso terapêutico , Inibidores de Catecol O-Metiltransferase/farmacologia , Levodopa/uso terapêutico , Oxidiazóis/uso terapêutico , Doença de Parkinson/tratamento farmacológico , Aceitação pelo Paciente de Cuidados de Saúde , Estudos RetrospectivosRESUMO
BACKGROUND: Tumor plasticity processes impact the treatment of different types of cancer; as an effect of this, the bioprospecting of therapies from natural and/or synthetic compounds that can regulate or modulate the immune system has increased considerably. Oxadiazole derivatives are structures that exhibit diverse biological activities. Therefore, this review aimed to evaluate the activity of oxadiazole compounds against tumor cell lines and their possible immune-mediated mechanisms. METHODS: A search in PubMed, Web of Science, and Science Direct databases was carried out on studies published from January 1, 2004, to January 31, 2022, using "oxadiazole" in combination with the other descriptors "cancer" and "macrophage". Only experimental in vitro and in vivo articles were included. A similar search strategy was used in the Derwent Innovation Index database for technology mapping. The search was performed on Drugbank using the descriptor oxadiazole for commercial mapping. RESULTS: 23 oxadiazole studies were included in this review, and some biological activities linked to antitumoral and immunomodulation were listed. Oxadiazole derivatives inhibited tumor cell growth and proliferation, blocked cell cycle, modulated mitochondrial membrane potential, presented immunoregulatory activity by different mechanisms reducing proinflammatory cytokines levels and acted directly as selective inhibitors of the COX enzyme. There was an increase in oxadiazole patent publications in the last 11 years, with emphasis on chemistry, pharmacy and biotechnology applied to microbiology areas. Compounds with 1,2,4-oxadiazole isomer are predominant in patent publications and approved drugs as observed in the technological and commercial mapping. CONCLUSION: Therefore, oxadiazole derivatives are therapeutic molecules that can be considered promising for the development of cancer therapies.
Assuntos
Antineoplásicos , Humanos , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Antineoplásicos/química , Agentes de Imunomodulação , Oxidiazóis/farmacologia , Oxidiazóis/uso terapêutico , Oxidiazóis/química , Linhagem Celular Tumoral , Proliferação de Células , Relação Estrutura-Atividade , Estrutura MolecularRESUMO
Ulcerative colitis (UC) is a chronic inflammatory condition affecting the colon and rectum. Long-term therapy is generally required to achieve and maintain disease control.1 In May 2021 the US Food and Drug Administration approved the use of ozanimod in patients with moderate to severe UC. We describe the first report of the use of ozanimod in real-world clinical practice.
Assuntos
Colite Ulcerativa , Estados Unidos , Humanos , Colite Ulcerativa/tratamento farmacológico , Indanos/uso terapêutico , Oxidiazóis/uso terapêuticoRESUMO
Duchenne Muscular Dystrophy (DMD) includes predictable phases requiring dedicated standard treatments. Therapeutic strategies feature corticosteroids or the more recent gene therapy/stop codon read-through. Ataluren (Translarna®) is an oral drug promoting the readthrough of premature stop codons caused by nonsense mutation (nm) in order to produce full-length dystrophin. It was licensed by EMA in 2014 for ambulatory patients with nmDMD aged ≥ 5 years. Our aim is to report data on long-term ataluren use in Italian patients with nmDMD, with emphasis on continuity of the treatment after loss of ambulation (LoA). Four DMD patients aged between 16 and 24 years who lost ambulation between 12 and 14 years continued to take ataluren after LoA. The oldest patient, aged 24 years, is still taking a few steps. Even in those experiencing motor decline, PUL-test performances were stable and respiratory function satisfactory in all; two patients developed severe cardiomyopathy, stable in one. Therapeutic continuity with ataluren should be offered to all nmDMD patients after LoA given its favourable safety and efficacy profile. However, further research is recommended to identify additional clinically meaningful outcomes and treatment goals following LoA.
Assuntos
Distrofia Muscular de Duchenne , Humanos , Adolescente , Adulto Jovem , Adulto , Distrofia Muscular de Duchenne/terapia , Distrofia Muscular de Duchenne/tratamento farmacológico , Códon sem Sentido , Distrofina/genética , Oxidiazóis/uso terapêutico , CaminhadaRESUMO
Duchenne muscular dystrophy (DMD) is a severe, progressive X-linked recessive disorder, caused by the absence of the dystrophin protein. A resolutive therapy for DMD is not yet available. The first approved drug for DMD patients with nonsense mutations is ataluren, approved for the treatment of children aged ≥ 2 yrs, that seems effective in slowing the disease progression. An earlier introduction of ataluren seems to give better results. We report the case of a 14-year-old DMD patient with a nonsense mutation in exon 70, still ambulant, who started taking ataluren at 12 years and remained stable for the following two years. The patient was on steroid since the age of 6, with beneficial effects. At two-years follow-up, an optimal disease evolution was observed, associated with a constant decrease of creatine kinase blood levels. Despite the late start of the treatment, ataluren seems to have significantly contributed to the stabilization of the functional status in this patient though it cannot be excluded that the result may have been influenced by the previous favorable course of the disease. However, further studies should be planned in patients with similar age treated with ataluren to better evaluate the treatment's results compared to the natural course of the disease.
Assuntos
Distrofia Muscular de Duchenne , Criança , Masculino , Humanos , Adolescente , Distrofia Muscular de Duchenne/tratamento farmacológico , Distrofia Muscular de Duchenne/genética , Distrofia Muscular de Duchenne/metabolismo , Distrofina/genética , Oxidiazóis/uso terapêutico , Códon sem Sentido , ÉxonsRESUMO
Aim: Alzheimer's disease (AD) is the most common neurodegenerative disease whose patients suffered from cognitive impairments. In our study, a novel 1,2,4-Oxadiazole derivative wyc-7-20 was synthesized, which showed low cytotoxicity and potent neuroprotective effect at the cellular level. Improved cognitive impairments, ß-amyloid (Aß) clearance, and tau pathological phenotypes were detected in transgenic animal models after wyc-7-20 treatment. Reversed expressions in AD-related genes were also detected. The results demonstrated wyc-7-20 was potent in AD therapy. Purpose: The pathological complexity of AD increased difficulties in medical research. To explore a new potential medical treatment for AD, a novel 1,2,4-Oxadiazole derivative (wyc-7-20) was designed, synthesized to explore the application in this study. Materials and Methods: Human neuroblastoma (SH-SY5Y) cells and human hepatocellular carcinoma (HepG2) cells were used to detect median lethal dose (LD50). H2O2 and Aß1-42 oligomers (AßOs) were respectively, added into SH-SY5Y cells to detect anti-ROS (reactive oxygen species) and anti-AßOs effects of wyc-7-20. 3×Tg mice were administered with wyc-7-20, and then Y maze test and Morris water maze (MWM) test were applied to detect cognitive improvements. Brain tissue samples were subsequently collected and analyzed using different techniques. Results: wyc-7-20 showed low cytotoxicity and potent neuroprotective effect at the cellular level. Improved cognitive impairments, Aß clearance, and tau pathological phenotypes were detected in transgenic animal models after wyc-7-20 treatment. Reversed expressions in AD-related genes were also detected. Conclusion: wyc-7-20 was potent in AD therapy.
Assuntos
Doença de Alzheimer , Neuroblastoma , Doenças Neurodegenerativas , Fármacos Neuroprotetores , Doença de Alzheimer/metabolismo , Peptídeos beta-Amiloides/metabolismo , Animais , Modelos Animais de Doenças , Humanos , Peróxido de Hidrogênio , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Neuroblastoma/tratamento farmacológico , Doenças Neurodegenerativas/tratamento farmacológico , Fármacos Neuroprotetores/farmacologia , Fármacos Neuroprotetores/uso terapêutico , Oxidiazóis/farmacologia , Oxidiazóis/uso terapêutico , Espécies Reativas de Oxigênio , Proteínas tau/metabolismoRESUMO
BACKGROUND: Ozanimod, an oral sphingosine 1-phosphate receptor modulator currently approved for the treatment of moderately to severely active ulcerative colitis and relapsing multiple sclerosis, showed clinical, endoscopic, and histological benefit in the phase 2 STEPSTONE trial for Crohn's disease (CD). We aim to describe the trial design of the YELLOWSTONE phase 3 program evaluating the safety and efficacy of ozanimod in patients with moderately to severely active CD. METHODS: The YELLOWSTONE program consists of phase 3, randomized, double-blind, placebo-controlled induction (NCT03440372 and NCT03440385) and maintenance (NCT03464097) trials and an open-label extension (OLE) study (NCT03467958). Patients with inadequate response or intolerance to ≥1 CD treatment are randomized to receive daily ozanimod 0.92 mg (equivalent to ozanimod HCl 1 mg) or placebo for 12 weeks during induction. Those who respond to ozanimod are rerandomized to continue ozanimod or placebo maintenance therapy for 52 weeks. Patients who do not meet criteria for maintenance, experience relapse during maintenance, or complete maintenance or ≥ 1 year of STEPSTONE are eligible for open-label treatment for up to 234 weeks. Efficacy endpoints include clinical, endoscopic, and histologic outcomes. RESULTS: Expected 2023 (induction studies), 2024 (maintenance study), and 2026 (OLE). CONCLUSION: YELLOWSTONE will provide pivotal phase 3 data on the safety and efficacy of ozanimod in patients with moderately to severely active CD using state-of-the-art methods, including centrally read endoscopic and histologic measurements, along with subjective assessments of symptom control based on the Crohn's Disease Activity Index. These studies could enable approval of ozanimod as a new CD therapy. CLINICAL TRIAL REGISTRATION NUMBERS: NCT03440372, NCT03440385, NCT03464097, NCT03467958.
Assuntos
Doença de Crohn , Humanos , Doença de Crohn/tratamento farmacológico , Doença de Crohn/induzido quimicamente , Oxidiazóis/farmacologia , Oxidiazóis/uso terapêutico , Indanos/uso terapêutico , Indanos/farmacologia , Fatores Imunológicos/uso terapêuticoRESUMO
Hepatitis B virus (HBV) infection is a public health threat worldwide and characterized by a dysfunctional immune response. In the present work, a new series of benzimidazole substituted 1, 2, 4-oxadiazole compounds were designed as immunomodulatory anti-HBV agents. Data showed compound 11o displayed significant in vitro anti-HBV activities against wild-type and nucleos(t)ide analogues-resistant HBV with IC50 values of 0.53 and 0.44 µM, respectively. In contrast, nucleos(t)ide analogue lamivudine is only effective for wild-type HBV (IC50 < 0.1 µM) but not effective for resistant HBV (IC50 > 100 µM). Dual-luciferase reporter gene and ELISA assay revealed that 11o exhibited a dose-dependent effect on inducing TLR8-regulated NF-κB activity, and could promote the secretion of cytokines TNF-α and IL-12 in supernatant from human PBMC cells. Molecular docking studies found that 11o formed tight interactions with binding pocket residues located at the dimer interface of TLR8. Considering the potent in vitro anti-HBV activity, effective TLR8-agonistic potency, and relatively safe profile with a selectivity index (SI) value high above 37, compound 11o deserves further investigation as a potential immunomodulatory anti-HBV agent.
Assuntos
Vírus da Hepatite B , Hepatite B , Humanos , Receptor 8 Toll-Like , Simulação de Acoplamento Molecular , Oxidiazóis/farmacologia , Oxidiazóis/uso terapêutico , Leucócitos Mononucleares , Antivirais/química , Hepatite B/tratamento farmacológico , Benzimidazóis/farmacologia , Benzimidazóis/uso terapêuticoRESUMO
Dipeptidyl peptidase-IV (DPP-IV) inhibitors, often known as gliptins, have been used to treat type 2 diabetes mellitus (T2DM). They may be combined with other medications as an additional treatment or used alone as a monotherapy. In addition to insulin, sulfonylureas, thiazolidinediones, and metformin, these molecules appear as possible therapeutic options. Oxadiazole rings have been employed in numerous different ways during drug development efforts. It has been shown that including them in the pharmacophore increases the amount of ligand that may be bound. The exceptional hydrogen bond acceptor properties of oxadiazoles and the distinct hydrocarbon bonding potential of their regioisomers have been established. Beside their anti-diabetic effects, oxadiazoles display a wide range of pharmacological properties. In this study, we made the assumption that molecules containing oxadiazole rings may afford a different approach to the treatment of diabetes, not only for controlling glycemic levels but also for preventing atherosclerosis progression and other complications associated with diabetes. It was observed that oxadiazole fusion with benzothiazole, 5-(2,5,2-trifluoroethoxy) phenyl, ß-homophenylalanine, 2-methyl-2-{5-(4-chlorophenyl), diamine-bridged bis-coumarinyl, 5-aryl-2-(6'-nitrobenzofuran-2'-yl), nitrobenzofuran, and/or oxindole leads to potential anti-diabetic activity.