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3.
Alzheimers Res Ther ; 14(1): 92, 2022 07 08.
Artigo em Inglês | MEDLINE | ID: mdl-35804462

RESUMO

BACKGROUND: Alzheimer's disease (AD) pathology is associated with complex interactions among multiple factors, involving an intertwined network of various signaling pathways. The polypharmacological approach is an emerging therapeutic strategy that has been proposed to overcome the multifactorial nature of AD by targeting multiple pathophysiological factors including amyloid-ß (Aß) and phosphorylated tau. We evaluated a blood-brain barrier penetrating phosphodiesterase 5 (PDE5) inhibitor, mirodenafil (5-ethyl-2-7-n-propyl-3,5-dihydrro-4H-pyrrolo[3,2-d]pyrimidin-4-one), for its therapeutic effects on AD with polypharmacological properties. METHODS: To evaluate the potential of mirodenafil as a disease-modifying AD agent, mirodenafil was administered to test its effects on the cognitive behaviors of the APP-C105 AD mouse model using the Morris water maze and passive avoidance tests. To investigate the mechanisms of action that underlie the beneficial disease-modifying effects of mirodenafil, human neuroblastoma SH-SY5Y cells and mouse hippocampal HT-22 cells were used to show mirodenafil-induced alterations associated with the cyclic guanosine monophosphate (cGMP)/cGMP-dependent protein kinase (PKG)/cAMP-responsive element-binding protein (CREB) pathway, apoptotic cell death, tau phosphorylation, amyloidogenesis, the autophagy-lysosome pathway, glucocorticoid receptor (GR) transcriptional activity, and the Wnt/ß-catenin signaling. RESULTS: Here, mirodenafil is demonstrated to improve cognitive behavior in the APP-C105 mouse model. Mirodenafil not only reduced the Aß and phosphorylated tau burdens in vivo, but also ameliorated AD pathology induced by Aß through the modulation of the cGMP/PKG/CREB signaling pathway, glycogen synthase kinase 3ß (GSK-3ß) activity, GR transcriptional activity, and the Wnt/ß-catenin signaling in neuronal cells. Interestingly, homodimerization and nuclear localization of GR were inhibited by mirodenafil, but not by other PDE5 inhibitors. In addition, only mirodenafil reduced the expression levels of the Wnt antagonist Dickkopf-1 (Dkk-1), thus activating the Wnt/ß-catenin signaling. CONCLUSIONS: These findings strongly suggest that the PDE5 inhibitor mirodenafil shows promise as a potential polypharmacological drug candidate for AD treatment, acting on multiple key signaling pathways involved in amyloid deposition, phosphorylated tau burden, the cGMP/PKG/CREB pathway, GSK-3ß kinase activity, GR signaling, and the Wnt/ß-catenin signaling. Mirodenafil administration to the APP-C105 AD mouse model also improved cognitive behavior, demonstrating the potential of mirodenafil as a polypharmacological AD therapeutic agent.


Assuntos
Doença de Alzheimer , Neuroblastoma , Doença de Alzheimer/patologia , Peptídeos beta-Amiloides/metabolismo , Peptídeos beta-Amiloides/toxicidade , Animais , GMP Cíclico , Modelos Animais de Doenças , Glicogênio Sintase Quinase 3 beta/metabolismo , Humanos , Camundongos , Inibidores da Fosfodiesterase 5/farmacologia , Inibidores da Fosfodiesterase 5/uso terapêutico , Fosforilação , Pirimidinonas , Sulfonamidas , beta Catenina/metabolismo , beta Catenina/uso terapêutico , Proteínas tau/metabolismo
4.
J Pharm Biomed Anal ; 219: 114949, 2022 Sep 20.
Artigo em Inglês | MEDLINE | ID: mdl-35863168

RESUMO

Although ICG-001, chemically synthesised from a bicyclic ß-turn peptidomimetic template, represents various pharmacological activities, no validated determination methods in biological samples have been reported. This study was designed to establish a quantitative determination method for ICG-001 in rat plasma using high-performance liquid chromatography coupled with tandem mass spectrometry (HPLC-MS/MS) to validate the analytical method, including stability, and to characterise its pharmacokinetic behaviour in rats. After simple protein precipitation with acetonitrile, ICG-001 was eluted on a reversed-phase column using a mobile phase of water and acetonitrile (3:7 v/v, including 0.1% formic acid). The protonated precursor ion [M+H]+ and the major fragment ion were confirmed at m/z 549.2 and 141.4, respectively, for ICG-001. ICG-001 was stable under bench and storage conditions. The analytical method met the criteria for Food and Drug Administration-validated bioanalytical methods, and was successfully applied to a pharmacokinetic study for the first time following subcutaneous and intravenous administration.


Assuntos
Compostos Bicíclicos Heterocíclicos com Pontes , Espectrometria de Massas em Tandem , Acetonitrilas , Animais , Cromatografia Líquida de Alta Pressão/métodos , Preparações Farmacêuticas , Pirimidinonas , Ratos , Reprodutibilidade dos Testes , Espectrometria de Massas em Tandem/métodos
5.
Eur J Endocrinol ; 187(3): K33-K38, 2022 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-35900324

RESUMO

Introduction: Recently, targeted therapies using BRAFV600E and MEK inhibitors (dabrafenib and trametinib, respectively) have been recommended in BRAF-mutated anaplastic thyroid carcinoma (ATC). Considering the fast development of ATC, droplet digital PCR (ddPCR) performed on fine-needle aspirate (FNA), which is a rapid, reliable, and low-cost method, appears interesting for the detection of BRAFV600E mutation in these patients and allows early initiation of targeted therapies. Results: In our two patients, both presenting extensive cervical masses inaccessible to surgery, ddPCR results were available in less than 24 h. Therefore, dabrafenib and trametinib were started only a few days after first contact. Conclusions: We suggest that ddPCR on FNA be used in non-resectable cervical masses for rapid BRAFV600E mutation detection in the hope that starting targeted therapies early might improve outcomes.


Assuntos
Carcinoma Anaplásico da Tireoide , Neoplasias da Glândula Tireoide , Protocolos de Quimioterapia Combinada Antineoplásica , Humanos , Imidazóis , Mutação , Oximas , Reação em Cadeia da Polimerase/métodos , Proteínas Proto-Oncogênicas B-raf/genética , Piridonas , Pirimidinonas , Carcinoma Anaplásico da Tireoide/tratamento farmacológico , Carcinoma Anaplásico da Tireoide/genética , Carcinoma Anaplásico da Tireoide/patologia , Neoplasias da Glândula Tireoide/tratamento farmacológico , Neoplasias da Glândula Tireoide/genética , Neoplasias da Glândula Tireoide/patologia
6.
Int J Mol Sci ; 23(12)2022 Jun 09.
Artigo em Inglês | MEDLINE | ID: mdl-35742901

RESUMO

Breast cancer (BC) is a heterogeneous disease with different intrinsic subtypes. The most aggressive subtype of BC-triple-negative breast cancer (TNBC) is characterized by high heterogeneity and metastasis rate, poor prognosis and lack of therapeutic targets due to the absence of estrogen receptor, progesterone receptor and human epidermal growth factor receptor 2. Targeted therapies have been approved for many other cancers and even other subtypes of BC, but treatment options for TNBC are still mainly limited to chemotherapy. Therefore, new, more effective treatment regimens are needed. Combined chemotherapy with two or more active agents is considered a promising anti-neoplasm tool in order to achieve better therapeutic response and reduce therapy-related adverse effects. The study demonstrated an antagonistic effect commonly used in TNBC therapy cytostatic drug-paclitaxel (PAX) and sirtuin inhibitor: cambinol (CAM) in BT-549, MDA-MB-468 and HCC1937 TNBC cell lines. The type of pharmacological interaction was determined by a precise and rigorous pharmacodynamic method-isobolographic analysis. The cytotoxic and anti-proliferative effects of CAM used alone or combined with PAX were determined utilizing 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) and 5-bromo-2'-deoxyuridine (BrdU) assays, respectively. Induction of apoptosis in TNBC cell lines after PAX and CAM treatment applied individually or in combination was determined by flow cytometry (FACS) as a number of cells with active caspase-3. It has been observed that both agents used separately inhibit cell proliferation and induce apoptosis; however, applying them in combination ameliorated antiproliferative and pro-apoptotic effects in all analyzed TNBC cell lines. Our results demonstrate that CAM and PAX used in combination act antagonistically, limiting anti-cancer efficacy and showing the importance of preclinical testing.


Assuntos
Sirtuínas , Neoplasias de Mama Triplo Negativas , Apoptose , Linhagem Celular Tumoral , Proliferação de Células , Humanos , Naftalenos , Paclitaxel , Pirimidinonas , Neoplasias de Mama Triplo Negativas/patologia
7.
J Immunother Cancer ; 10(6)2022 06.
Artigo em Inglês | MEDLINE | ID: mdl-35728875

RESUMO

BACKGROUND: The randomized phase 3 COMBI-i trial did not meet its primary endpoint of improved progression-free survival (PFS) with spartalizumab plus dabrafenib and trametinib (sparta-DabTram) vs placebo plus dabrafenib and trametinib (placebo-DabTram) in the overall population of patients with unresectable/metastatic BRAF V600-mutant melanoma. This prespecified exploratory biomarker analysis was performed to identify subgroups that may derive greater treatment benefit from sparta-DabTram. METHODS: In COMBI-i (ClinicalTrials.gov, NCT02967692), 532 patients received spartalizumab 400 mg intravenously every 4 weeks plus dabrafenib 150 mg orally two times daily and trametinib 2 mg orally one time daily or placebo-DabTram. Baseline/on-treatment pharmacodynamic markers were assessed via flow cytometry-based immunophenotyping and plasma cytokine profiling. Baseline programmed death ligand 1 (PD-L1) status and T-cell phenotype were assessed via immunohistochemistry; BRAF V600 mutation type, tumor mutational burden (TMB), and circulating tumor DNA (ctDNA) via DNA sequencing; gene expression signatures via RNA sequencing; and CD4+/CD8+ T-cell ratio via immunophenotyping. RESULTS: Extensive biomarker analyses were possible in approximately 64% to 90% of the intention-to-treat population, depending on sample availability and assay. Subgroups based on PD-L1 status/TMB or T-cell inflammation did not show significant differences in PFS benefit with sparta-DabTram vs placebo-DabTram, although T-cell inflammation was prognostic across treatment arms. Subgroups defined by BRAF V600K mutation (HR 0.45 (95% CI 0.21 to 0.99)), detectable ctDNA shedding (HR 0.75 (95% CI 0.58 to 0.96)), or CD4+/CD8+ ratio above median (HR 0.58 (95% CI 0.40 to 0.84)) derived greater PFS benefit with sparta-DabTram vs placebo-DabTram. In a multivariate analysis, ctDNA emerged as strongly prognostic (p=0.007), while its predictive trend did not reach significance; in contrast, CD4+/CD8+ ratio was strongly predictive (interaction p=0.0131). CONCLUSIONS: These results support the feasibility of large-scale comprehensive biomarker analyses in the context of a global phase 3 study. T-cell inflammation was prognostic but not predictive of sparta-DabTram benefit, as patients with high T-cell inflammation already benefit from targeted therapy alone. Baseline ctDNA shedding also emerged as a strong independent prognostic variable, with predictive trends consistent with established measures of disease burden such as lactate dehydrogenase levels. CD4+/CD8+ T-cell ratio was significantly predictive of PFS benefit with sparta-DabTram but requires further validation as a biomarker in melanoma. Taken together with previous observations, further study of checkpoint inhibitor plus targeted therapy combination in patients with higher disease burden may be warranted. TRIAL REGISTRATION NUMBER: NCT02967692.


Assuntos
Biomarcadores Tumorais , Melanoma , Neoplasias Cutâneas , Anticorpos Monoclonais Humanizados , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Antígeno B7-H1/uso terapêutico , Biomarcadores Tumorais/análise , Ensaios Clínicos Fase III como Assunto , Humanos , Imidazóis , Melanoma/tratamento farmacológico , Melanoma/genética , Melanoma/patologia , Oximas , Proteínas Proto-Oncogênicas B-raf/genética , Piridonas , Pirimidinonas , Ensaios Clínicos Controlados Aleatórios como Assunto , Neoplasias Cutâneas/tratamento farmacológico
8.
Int J Clin Pract ; 2022: 6475014, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35685566

RESUMO

Background: Overactive bladder (OAB) is characterized by urgency and frequency with (OAB wet) or without (OAB dry) urge urinary incontinence (UUI). In the phase 3 EMPOWUR trial, vibegron-a selective ß 3-adrenergic receptor agonist for the treatment of OAB-significantly improved daily number of urgency episodes and micturitions vs. placebo (P < 0.01). These post hoc analyses aimed to compare the efficacy of vibegron vs. placebo in OAB dry and wet populations. Methods: Patients were randomly assigned 5:5:4 to receive once-daily vibegron 75 mg, placebo, or tolterodine 4 mg extended release, respectively, for 12 weeks. Baseline criteria for OAB dry included an average of ≥8 micturitions, ≥3 urgency episodes, and <1 UUI episode per diary day and for OAB wet included an average of ≥8 micturitions and ≥1 UUI episode per diary day. Change from baseline in mean daily number of urgency episodes and micturitions was assessed in both populations. Results: Of the 1463 patients included in the full analysis set, 336 (23%) had OAB dry (vibegron, N = 123; placebo, N = 115; and tolterodine, N = 98), and 1127 (77%) had OAB wet (vibegron, N = 403; placebo, N = 405; and tolterodine, N = 319). Vibegron was associated with significant reductions (95% CIs of the least squares mean differences [LSMD] does not include 0) from baseline at week 12 vs. placebo in mean daily urgency episodes for the dry (LSMD [95% CI], ‒1.0 [‒2.0, ‒0.1]) and wet (‒0.6 [‒1.0, ‒0.1]) populations. Vibegron was associated with significant reductions from baseline at week 12 vs. placebo in mean daily micturitions for the dry (LSMD [95% CI], ‒0.8 [‒1.5, ‒ 0.1]) and wet (‒0.5 [‒0.8, ‒0.1]) populations. There were no significant differences in either outcome between tolterodine and placebo for either the dry or wet populations in this study. Conclusions: In this subgroup analysis from the EMPOWUR trial, vibegron was associated with significant reductions compared with placebo in urgency episodes and micturitions in both the OAB dry and wet populations, suggesting that vibegron is similarly efficacious for these endpoints in patients with and without UUI. This trial is registered with NCT03492281.


Assuntos
Bexiga Urinária Hiperativa , Método Duplo-Cego , Humanos , Pirimidinonas , Pirrolidinas , Tartarato de Tolterodina/uso terapêutico , Resultado do Tratamento , Bexiga Urinária Hiperativa/complicações , Bexiga Urinária Hiperativa/tratamento farmacológico , Incontinência Urinária de Urgência
9.
Bioorg Med Chem ; 69: 116832, 2022 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-35752141

RESUMO

A novel series of TGX-221 analogues was prepared that include isosteric replacement of the 4H-pyrido[1,2-a]pyrimidin-4-one with a 4H-benzo[e][1,3]oxazin-4-one scaffold. The compounds that included an CH(CH3)NH type linker showed comparable activity to TGX-221 analogues with the isosterism supported by the comparative SAR analysis. The analogues containing an CH(CH3)O linker were less active but still showed useful SAR including a favoured o-methyl substitution.


Assuntos
Morfolinas , Pirimidinonas , Pirimidinonas/farmacologia , Relação Estrutura-Atividade
10.
Obstet Gynecol ; 139(6): 1070-1081, 2022 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-35675604

RESUMO

OBJECTIVE: To assess the effect of once-daily relugolix combination therapy (relugolix-CT: relugolix 40 mg, estradiol 1 mg, and norethindrone acetate 0.5 mg) compared with placebo on moderate-to-severe pain in women with uterine leiomyomas and heavy menstrual bleeding. METHODS: Two replicate, multinational, double-blind, 24-week, randomized, phase 3 studies (LIBERTY 1 and 2) were conducted in premenopausal women with uterine leiomyoma-associated heavy menstrual bleeding (80 mL or greater per cycle for two cycles or 160 mL or greater during one cycle). A predefined secondary objective was to determine the effect of relugolix-CT on moderate-to-severe uterine leiomyoma-associated pain in the pain subpopulation (women with maximum pain scores of 4 or higher on the 0-10 numerical rating scale at baseline, with pain score reporting compliance of 80% (ie, 28 days or more over the last 35 days of treatment). This key secondary endpoint was defined as the proportion of women achieving minimal-to-no uterine leiomyoma-associated pain (maximum numerical rating scale score 1 or lower) at week 24; menstrual and nonmenstrual pain were evaluated in prespecified secondary analyses. Treatment comparisons were performed in the pooled LIBERTY 1 and 2 pain subpopulation using the Cochran-Mantel-Haenszel test stratified by baseline menstrual blood loss volume. RESULTS: Across both trials, 509 women were randomized to relugolix-CT or placebo (April 2017-December 2018). Of these, 277 (54.4%) met pain subpopulation requirements. With relugolix-CT, 45.2% (95% CI 36.4-54.3) of women achieved minimal-to-no pain compared with 13.9% (95% CI 8.8-20.5) with placebo (nominal P<.001). The proportions of women with minimal-to-no pain during menstrual days and during nonmenstrual days were significantly higher with relugolix-CT (65.0% [95% CI 55.6-73.5] and 44.6% [95% CI 32.3-57.5], respectively) compared with placebo (19.3% [95% CI 13.2-26.7], nominal P<.001, and 21.6% [95% CI 12.9-32.7], nominal P=.004, respectively). CONCLUSION: Over 24 weeks, relugolix-CT significantly reduced moderate-to-severe uterine leiomyoma-associated pain with a more pronounced effect on menstrual pain. These data support that relugolix-CT had clinically meaningful effects on women's experience of uterine leiomyoma-associated pain. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov: LIBERTY 1, NCT03049735; LIBERTY 2, NCT03103087. FUNDING SOURCE: Myovant Sciences GmbH.


Assuntos
Leiomioma , Menorragia , Neoplasias Uterinas , Feminino , Liberdade , Humanos , Leiomioma/complicações , Leiomioma/tratamento farmacológico , Menorragia/tratamento farmacológico , Dor Pélvica/tratamento farmacológico , Compostos de Fenilureia , Pirimidinonas , Ensaios Clínicos Controlados Aleatórios como Assunto , Neoplasias Uterinas/complicações , Neoplasias Uterinas/tratamento farmacológico
11.
Pharmacol Ther ; 236: 108234, 2022 08.
Artigo em Inglês | MEDLINE | ID: mdl-35732246

RESUMO

The retinoblastoma gene (RB) was discovered as the first tumor-suppressor gene. It was subsequently shown to be inactivated in most malignant tumors, particularly at the protein level. Therefore, many activated oncogenes as well as inactivated tumor-suppressor genes inactivate the function of the RB protein. I hypothesized that most of the molecular-targeting agents against activated oncogenes may reactivate the function of RB, and proposed screening systems for agents up-regulating the expression of cyclin-dependent kinase inhibitors, such as p15, p27, and p21, which convert the phosphorylated inactive form of the RB protein to the unphosphorylated active form. I termed this screening as "RB-reactivator screening". Using the screening systems for agents that up-regulate the expression of p15, p27, and p21, we discovered the novel MEK inhibitor trametinib, the novel RAF/MEK inhibitor CH5126766/RO5126766/VS-6766, and the histone deacetylase inhibitor YM753/OBP-801, respectively. Trametinib exerted remarkable effects in patients with advanced BRAF mutant melanoma, and was approved in the USA as the first-in-class MEK inhibitor (trade name: Mekinist) in 2013. The British Pharmacological Society selected trametinib as the Drug Discovery of the Year in 2013. The combination of trametinib and the BRAF inhibitor dabrafenib was approved for advanced BRAF mutant melanoma in the USA, EU, Japan, and many other countries. Additionally, the US Food and Drug Administration (FDA) granted Breakthrough Therapy Designation for the combination of trametinib and dabrafenib in the treatment of patients with advanced BRAF mutant non-small cell lung cancer in 2015, and this combination was subsequently approved in the EU, USA, and Japan. In 2018, this combination was also approved for locally advanced or metastatic BRAF V600-mutant anaplastic thyroid cancer in the USA after it had been granted Breakthrough Therapy Designation by the FDA. I describe here the characterization of our original screening system, RB-reactivator screening, by which these three molecular-targeting agents that advanced into clinical trials were identified.


Assuntos
Carcinoma Pulmonar de Células não Pequenas , Descoberta de Drogas , Neoplasias Pulmonares , Melanoma , Piridonas , Pirimidinonas , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Descoberta de Drogas/métodos , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Melanoma/tratamento farmacológico , Melanoma/genética , Quinases de Proteína Quinase Ativadas por Mitógeno/antagonistas & inibidores , Terapia de Alvo Molecular/métodos , Mutação , Oximas/farmacologia , Oximas/uso terapêutico , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/uso terapêutico , Proteínas Proto-Oncogênicas B-raf , Piridonas/farmacologia , Piridonas/uso terapêutico , Pirimidinonas/farmacologia , Pirimidinonas/uso terapêutico , Proteína do Retinoblastoma/genética , Proteína do Retinoblastoma/uso terapêutico
13.
Lancet ; 399(10343): 2267-2279, 2022 06 18.
Artigo em Inglês | MEDLINE | ID: mdl-35717987

RESUMO

BACKGROUND: Endometriosis is a common cause of pelvic pain in women, for which current treatment options are suboptimal. Relugolix, an oral gonadotropin-releasing hormone receptor antagonist, combined with estradiol and a progestin, was evaluated for treatment of endometriosis-associated pain. METHODS: In these two replicate, phase 3, multicentre, randomised, double-blind, placebo-controlled trials at 219 community and hospital research centres in Africa, Australasia, Europe, North America, and South America, we randomly assigned women aged 18-50 years with surgically or directly visualised endometriosis with or without histological confirmation, or with histological diagnosis alone. Participants were eligible if they had moderate to severe endometriosis-associated pain and, during the 35-day run-in period, a dysmenorrhoea Numerical Rating Scale (NRS) score of 4·0 or higher on two or more days and a mean non-menstrual pelvic pain NRS score of 2·5 or higher, or a mean score of 1·25 or higher that included a score of 5 or more on 4 or more days. Women received (1:1:1) once-daily oral placebo, relugolix combination therapy (relugolix 40 mg, estradiol 1 mg, norethisterone acetate 0·5 mg), or delayed relugolix combination therapy (relugolix 40 mg monotherapy followed by relugolix combination therapy, each for 12 weeks) for 24 weeks. During the double-blind randomised treatment and follow-up period, all patients, investigators, and sponsor staff or representatives involved in the conduct of the study were masked to treatment assignment. The co-primary endpoints were responder rates at week 24 for dysmenorrhoea and non-menstrual pelvic pain, both based on NRS scores and analgesic use. Efficacy and safety were analysed in the modified intent-to-treat population (randomised patients who received ≥1 study drug dose). The studies are registered at ClinicalTrials.gov (SPIRIT 1 [NCT03204318] and SPIRIT 2 [NCT03204331]) and EudraCT (SPIRIT 1 [2017-001588-19] and SPIRIT 2 [2017-001632-19]). Eligible patients who completed the SPIRIT studies could enrol in a currently ongoing 80-week open-label extension study (SPIRIT EXTENSION [NCT03654274, EudraCT 2017-004066-10]). Database lock for the on-treatment duration has occurred, and post-treatment follow-up for safety, specificially for bone mineral density and menses recovery, is ongoing at the time of publication. FINDINGS: 638 patients were enrolled into SPIRIT 1 and randomly assigned between Dec 7, 2017, and Dec 4, 2019, to receive relugolix combination therapy (212 [33%]), placebo (213 [33%]), or relugolix delayed combination therapy (213 [33%]). 623 patients were enrolled into SPIRIT 2 and were randomly assigned between Nov 1, 2017 and Oct 4, 2019, to receive relugolix combination therapy (208 [33%]), placebo (208 [33%]), or relugolix delayed combination therapy (207 [33%]). 98 (15%) patients terminated study participation early in SPIRIT 1 and 115 (18%) in SPIRIT 2. In SPIRIT 1, 158 (75%) of 212 patients in the relugolix combination therapy group met the dysmenorrhoea responder criteria compared with 57 (27%) of 212 patients in the placebo group (treatment difference 47·6% [95% CI 39·3-56·0]; p<0·0001). In SPIRIT 2, 155 (75%) of 206 patients in the relugolix combination therapy group were dysmenorrhoea responders compared with 62 (30%) of 204 patients in the placebo group (treatment difference 44·9% [95% CI 36·2-53·5]; p<0·0001). In SPIRIT 1, 124 (58%) of 212 patients in the relugolix combination therapy group met the non-menstrual pelvic pain responder criteria versus 84 (40%) patients in the placebo group (treatment difference 18·9% [9·5-28·2]; p<0·0001). In SPIRIT 2, 136 (66%) of 206 patients were non-menstrual pelvic pain responders in the relugolix combination therapy group compared with 87 (43%) of 204 patients in the placebo group (treatment difference 23·4% [95% CI 13·9-32·8]; p<0·0001). The most common adverse events were headache, nasopharyngitis, and hot flushes. There were nine reports of suicidal ideation across both studies (two in the placebo run-in, two in the placebo group, two in the relugolix combination therapy group, and three in the delayed relugolix combination therapy group). No deaths were reported. Least squares mean percentage change in lumbar spine bone mineral density in the relugolix combination therapy versus placebo groups was -0·70% versus 0·21% in SPIRIT 1 and -0·78% versus 0·02% in SPIRIT 2, and in the delayed relugolix combination group was -2·0% in SPIRIT 1 and -1·9% in SPIRIT 2. Decreases in opioid use were seen in treated patients as compared with placebo. INTERPRETATION: Once-daily relugolix combination therapy significantly improved endometriosis-associated pain and was well tolerated. This oral therapy has the potential to address the unmet clinical need for long-term medical treatment for endometriosis, reducing the need for opioid use or repeated surgical treatment. FUNDING: Myovant Sciences.


Assuntos
Endometriose , Analgésicos Opioides/uso terapêutico , Método Duplo-Cego , Dismenorreia/tratamento farmacológico , Dismenorreia/etiologia , Endometriose/complicações , Endometriose/tratamento farmacológico , Estradiol/uso terapêutico , Feminino , Humanos , Dor Pélvica/tratamento farmacológico , Dor Pélvica/etiologia , Compostos de Fenilureia , Pirimidinonas , Resultado do Tratamento
14.
Cancer Genet ; 266-267: 1-6, 2022 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-35598548

RESUMO

PURPOSE: The present study clarified the sensitivity of the BRAF tyrosine kinase inhibitor mechanism in patients with BRAF compound mutation and predicted the sensitivity using molecular dynamics simulation. METHODS: We examined 16 BRAF tumors with p.V600E-positive non-small-cell lung cancer. RESULTS: One patient (6.2%) had a BRAF p.V600E and p.K601_W604 compound mutation with a good clinical response to dabrafenib and trametinib. Molecular dynamics simulation also complemented the effect. CONCLUSIONS: The combination of a genetic analysis and computational simulation model may help predict the sensitivity for dabrafenib in cases with a rare BRAF compound mutation. The construction of a genomic and simulation fused database is important for the development of personalized medicine in this field.


Assuntos
Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Protocolos de Quimioterapia Combinada Antineoplásica , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/patologia , Humanos , Imidazóis , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , Mutação , Oximas , Proteínas Proto-Oncogênicas B-raf/genética , Piridonas , Pirimidinonas
15.
Environ Microbiol ; 24(7): 3164-3180, 2022 07.
Artigo em Inglês | MEDLINE | ID: mdl-35621047

RESUMO

Solar radiation regulates most biological activities on Earth. Prolonged exposure to solar UV radiation can cause deleterious effects by inducing two major types of DNA damage, namely, cyclobutane pyrimidine dimers (CPDs) and pyrimidine 6-4 pyrimidone photoproducts. These lesions may be repaired by the photoreactivation (Phr) and nucleotide excision repair (NER) pathways; however, the principal UV-induced DNA repair pathway is not known in the fungal genus Pseudogymnoascus. In this study, we demonstrated that an unweighted UV-B dosage of 1.6 kJ m-2 d-1 significantly reduced fungal growth rates (by between 22% and 35%) and inhibited conidia production in a 10 d exposure. The comparison of two DNA repair conditions, light or dark, which respectively induced photoreactivation (Phr) and NER, showed that the UV-B-induced CPDs were repaired significantly more rapidly in light than in dark conditions. The expression levels of two DNA repair genes, RAD2 and PHR1 (encoding a protein in NER and Phr respectively), demonstrated that NER rather than Phr was primarily activated for repairing UV-B-induced DNA damage in these Pseudogymnoascus strains. In contrast, Phr was inhibited after exposure to UV-B radiation, suggesting that PHR1 may have other functional roles. We present the first study to examine the capability of the Arctic and Antarctic Pseudogymnoascus sp. to perform photoreactivation and/or NER via RT-qPCR approaches, and also clarify the effects of light on UV-B-induced DNA damage repair in vivo by quantifying cyclobutene pyrimidine dimers and pyrimidine 6-4 pyrimidone photoproducts. Physiological response data, including relative growth rate, pigmentation and conidia production in these Pseudogymnoascus isolates exposed to UV-B radiation are also presented.


Assuntos
Dímeros de Pirimidina , Raios Ultravioleta , Regiões Antárticas , Dano ao DNA , Reparo do DNA , Pigmentação , Dímeros de Pirimidina/metabolismo , Pirimidinonas , Esporos Fúngicos/metabolismo
16.
EBioMedicine ; 80: 104069, 2022 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-35605429

RESUMO

BACKGROUND: We conducted an exploratory study to assess the safety tolerability, and anti-fibrotic effects of PRI-724, a CBP/ß-catenin inhibitor, in patients with hepatitis C virus (HCV)- and hepatitis B virus (HBV)-induced cirrhosis. METHODS: This multicentre, open-label, non-randomised, non-placebo-controlled phase 1/2a trial was conducted at three hospitals in Japan. Between July 27, 2018, and July 13, 2021, we enrolled patients with HCV- and HBV-induced cirrhosis classified as Child-Pugh (CP) class A or B. In phase 1, 15 patients received intravenous infusions of PRI-724 at escalating doses of 140, 280, and 380 mg/m2/4 h twice weekly for 12 weeks. In phase 2a, 12 patients received the recommended PRI-724 dose. The primary endpoints of phases 1 and 2a were the frequency and severity of adverse events and efficacy in treating cirrhosis based on liver biopsy. This study was registered at ClinicalTrials.gov (no. NCT03620474). FINDINGS: Three patients from phase 1 who received the recommended PRI-724 dose were evaluated to obtain efficacy and safety data in phase 2a. Serious adverse events occurred in three patients, one of which was possibly related to PRI-724. The most common adverse events were diarrhoea and nausea. PRI-724 did not decrease hepatic fibrosis with any statistical significance, either by ordinal scoring or measurement of collagen proportionate area at 12 weeks; however, we observed statistically significant improvements in liver stiffness, Model for End-stage Liver Disease score, and serum albumin level. INTERPRETATION: Intravenous administration of 280 mg/m2/4 h PRI-724 over 12 weeks was preliminarily assessed to be well tolerated; however, further evaluation of anti-fibrotic effects in patients with cirrhosis is warranted. FUNDING: AMED, Ohara Pharmaceutical.


Assuntos
Doença Hepática Terminal , Hepatite C Crônica , Hepatite C , Herpesvirus Cercopitecino 1 , Antivirais/efeitos adversos , Compostos Bicíclicos Heterocíclicos com Pontes , Doença Hepática Terminal/induzido quimicamente , Hepacivirus , Hepatite C/tratamento farmacológico , Hepatite C Crônica/tratamento farmacológico , Humanos , Cirrose Hepática/complicações , Cirrose Hepática/diagnóstico , Cirrose Hepática/tratamento farmacológico , Pirimidinonas , Índice de Gravidade de Doença , Resultado do Tratamento , beta Catenina
17.
Melanoma Res ; 32(4): 299-301, 2022 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-35635528

RESUMO

The effect of serine/threonine-protein kinase B-Raf/mitogen-activated protein kinase (BRAF/MEK) inhibitors on the immune system is not clearly described, but rare cases of autoimmune phenomena have been reported. The clinical case we present below is the first report of a necrotizing myopathy related to dabrafenib/trametinib treatment. A 48-year-old man started dabrafenib/trametinib for stage IV BRAF-V600E mutated cutaneous melanoma. After the first month, he presented with grade 3 pyrexia (Common Terminology Criteria for Adverse Events [CTCAE] v.5.0.) and increased creatinine-kinase levels. A diagnosis of immune-mediated necrotizing myopathy, antisignal recognition particle (anit-SRP) positive, was made. At disease progression, dabrafenib/trametinib was restarted, triggering a new episode of grade 2 pyrexia and myositis. Treatment was changed to encorafenib/binimetinib without repeating pyrexia or limiting creatinine-kinase elevation, presenting even a loss of anti-SRP antibodies. Given the temporal relationship, the fact that re-exposition induced a new worsening of the myopathy and the loss of the anti-SRP antibodies after changing treatment, we infer that there possibly is a clear relationship between dabrafenib/trametinib treatment and the myopathy.


Assuntos
Melanoma , Miosite , Neoplasias Cutâneas , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Creatinina/uso terapêutico , Febre/etiologia , Humanos , Imidazóis/efeitos adversos , Masculino , Melanoma/etiologia , Pessoa de Meia-Idade , Quinases de Proteína Quinase Ativadas por Mitógeno , Mutação , Miosite/induzido quimicamente , Oximas/efeitos adversos , Inibidores de Proteínas Quinases/efeitos adversos , Proteínas Proto-Oncogênicas B-raf/genética , Piridonas , Pirimidinonas/efeitos adversos , Neoplasias Cutâneas/etiologia
18.
Eur J Pharmacol ; 926: 175017, 2022 Jul 05.
Artigo em Inglês | MEDLINE | ID: mdl-35588870

RESUMO

It has been recently proposed that repeated bladder ischemia/reperfusion induced by chronic pelvic ischemia may lead to detrusor overactivity, followed by lower urinary tract symptoms. Vibegron is a selective ß3-adrenoceptor agonist approved for the treatment of overactive bladder. Several studies have tested ß3-adrenoceptor agonists using animal models with detrusor overactivity related to bladder ischemia/reperfusion. However, whether ß3-adrenoceptor agonists directly affect ischemia/reperfusion-evoked detrusor overactivity is unclear. Therefore, we examined whether bladder anoxia/reoxygenation could enhance spontaneous bladder contractions (SBCs) and investigated the effect of vibegron on enhanced SBCs. Isolated whole bladders from rats were incubated with Krebs solution aerated with 95% N2 + 5% CO2 for 5 h (anoxia). Subsequently, the bathing solution was replaced with an oxygen-saturated solution (reoxygenation). Anoxia/reoxygenation caused enhancement of the amplitude but not the frequency of SBC compared with that before reoxygenation. Vibegron (0.3-30 µM) inhibited this increase in SBC amplitude, but not the frequency, in a dose-dependent manner. The inhibitory effect of vibegron was not affected by pretreatment with the adenylyl cyclase inhibitor SQ22536 (100 µM) or protein kinase A inhibitor KT5720 (1 µM) and was not accompanied by considerable changes in cyclic adenosine monophosphate (cAMP) content in the bladder. In contrast, the large conductance potassium channel inhibitor iberiotoxin (100 nM) suppressed the inhibitory effect of vibegron. These results suggest that bladder ischemia/reperfusion induces SBC enhancement and vibegron directly inhibits detrusor overactivity via the large conductance potassium channel, which involves ß3-adrenoceptor, rather than the cAMP signaling pathway.


Assuntos
Pirimidinonas , Pirrolidinas , Bexiga Urinária Hiperativa , Bexiga Urinária , Agonistas de Receptores Adrenérgicos beta 3/farmacologia , Animais , Hipóxia/metabolismo , Canais de Potássio/metabolismo , Pirimidinonas/farmacologia , Pirrolidinas/farmacologia , Ratos , Receptores Adrenérgicos/metabolismo , Bexiga Urinária/efeitos dos fármacos , Bexiga Urinária/metabolismo , Bexiga Urinária Hiperativa/tratamento farmacológico , Bexiga Urinária Hiperativa/etiologia , Bexiga Urinária Hiperativa/metabolismo , Urodinâmica
19.
Molecules ; 27(9)2022 Apr 21.
Artigo em Inglês | MEDLINE | ID: mdl-35566029

RESUMO

Alteration of insect growth regulators by the action of inhibitors is becoming an attractive strategy to combat disease-transmitting insects. In the present study, we investigated the larvicidal effect of 1,2,3-triazolyl-pyrimidinone derivatives against the larvae of the mosquito Anopheles arabiensis, a vector of malaria. All compounds demonstrated insecticidal activity against mosquito larvae in a dose-dependent fashion. A preliminary study of the structure-activity relationship indicated that the electron-withdrawing substituent in the para position of the 4-phenyl-pyrimidinone moiety enhanced the molecules' potency. A docking study of these derivatives revealed favorable binding affinity for the sterol carrier protein-2 receptor, a protein present in the intestine of the mosquito larvae. Being effective insecticides against the malaria-transmitting Anopheles arabiensis, 1,2,3-triazole-based pyrimidinones represent a starting point to develop novel inhibitors of insect growth regulators.


Assuntos
Anopheles , Inseticidas , Malária , Animais , Proteínas de Transporte , Inseticidas/química , Inseticidas/farmacologia , Hormônios Juvenis/farmacologia , Larva , Simulação de Acoplamento Molecular , Controle de Mosquitos , Mosquitos Vetores , Pirimidinonas/farmacologia
20.
Mol Microbiol ; 117(6): 1384-1404, 2022 06.
Artigo em Inglês | MEDLINE | ID: mdl-35510686

RESUMO

Bacterial opportunistic pathogens make diverse secondary metabolites both in the natural environment and when causing infections, yet how these molecules mediate microbial interactions and their consequences for antibiotic treatment are still poorly understood. Here, we explore the role of three redox-active secondary metabolites, pyocyanin, phenazine-1-carboxylic acid, and toxoflavin, as interspecies modulators of antibiotic resilience. We find that these molecules dramatically change susceptibility levels of diverse bacteria to clinical antibiotics. Pyocyanin and phenazine-1-carboxylic acid are made by Pseudomonas aeruginosa, while toxoflavin is made by Burkholderia gladioli, organisms that infect cystic fibrosis and other immunocompromised patients. All molecules alter the susceptibility profile of pathogenic species within the "Burkholderia cepacia complex" to different antibiotics, either antagonizing or potentiating their effects, depending on the drug's class. Defense responses regulated by the redox-sensitive transcription factor SoxR potentiate the antagonistic effects these metabolites have against fluoroquinolones, and the presence of genes encoding SoxR and the efflux systems it regulates can be used to predict how these metabolites will affect antibiotic susceptibility of different bacteria. Finally, we demonstrate that inclusion of secondary metabolites in standard protocols used to assess antibiotic resistance can dramatically alter the results, motivating the development of new tests for more accurate clinical assessment.


Assuntos
Antibacterianos , Complexo Burkholderia cepacia , Antibacterianos/metabolismo , Antibacterianos/farmacologia , Complexo Burkholderia cepacia/metabolismo , Humanos , Fenazinas/metabolismo , Fenazinas/farmacologia , Pseudomonas aeruginosa/metabolismo , Piocianina/metabolismo , Pirimidinonas , Triazinas
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