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BACKGROUND: The optimal dosing strategy for rifampicin in treating drug-susceptible tuberculosis (TB) is still highly debated. In the phase 3 clinical trial Study 31/ACTG 5349 (NCT02410772), all participants in the control regimen arm received 600â mg rifampicin daily as a flat dose. Here, we evaluated relationships between rifampicin exposure and efficacy and safety outcomes. METHODS: We analyzed rifampicin concentration time profiles using population nonlinear mixed-effects models. We compared simulated rifampicin exposure from flat- and weight-banded dosing. We evaluated the effect of rifampicin exposure on stable culture conversion at 6 months; TB-related unfavorable outcomes at 9, 12, and 18 months using Cox proportional hazard models; and all trial-defined safety outcomes using logistic regression. RESULTS: Our model-derived rifampicin exposure ranged from 4.57â mg · h/L to 140.0â mg · h/L with a median of 41.8â mg · h/L. Pharmacokinetic simulations demonstrated that flat-dosed rifampicin provided exposure coverage similar to the weight-banded dose. Exposure-efficacy analysis (n = 680) showed that participants with rifampicin exposure below the median experienced similar hazards of stable culture conversion and TB-related unfavorable outcomes compared with those with exposure above the median. Exposure-safety analysis (n = 722) showed that increased rifampicin exposure was not associated with increased grade 3 or higher adverse events or serious adverse events. CONCLUSIONS: Flat-dosing of rifampicin at 600â mg daily may be a reasonable alternative to the incumbent weight-banded dosing strategy for the standard-of-care 6-month regimen. Future research should assess the optimal dosing strategy for rifampicin, at doses higher than the current recommendation.
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Rifampina , Tuberculose , Rifampina/farmacocinética , Rifampina/administração & dosagem , Humanos , Masculino , Adulto , Feminino , Pessoa de Meia-Idade , Tuberculose/tratamento farmacológico , Adulto Jovem , Antituberculosos/farmacocinética , Antituberculosos/administração & dosagem , Antituberculosos/efeitos adversos , Resultado do Tratamento , Adolescente , Relação Dose-Resposta a Droga , IdosoRESUMO
BACKGROUND: In endometrial cancer (EC), preoperative anaemia, thrombocytosis and leucocytosis appear to be associated with worse prognosis. It remains unclear whether these parameters solely reflect tumour aggressiveness, or also impact response to adjuvant treatment. Therefore, our primary aim is to evaluate the prognostic relevance of anaemia, thrombocytosis and leucocytosis on survival in EC. Secondary, to explore their predictive relevance in response to radiotherapy in EC. METHODS: A retrospective multicentre cohort study was performed within 10 hospitals. Preoperative haematological parameters were defined as: Anaemia - haemoglobin <7.45 mmol/L (<12 g/Dl), thrombocytosis - platelets >400 × 109 platelets/L, leucocytosis - leukocytes >10 × 109/L. The relationship of haematological parameters with clinicopathological characteristics, ESGO/ESTRO/ESP risk groups and survival were evaluated. Furthermore, the predictive value of haematological parameters was determined on the overall response to adjuvant radiotherapy and for the ESGO/ESTRO/ESP intermediate-risk group solely receiving radiotherapy. RESULTS: A total of 894 patients were included with a median follow-up of 4.5 years. Anaemia was present in 103 (11.5%), thrombocytosis in 79 (8.8%) and leucocytosis in 114 (12.7%) patients. The presence of anaemia or thrombocytosis was significantly associated with ESGO/ESTRO/ESP high-risk (respectively, P = 0.002 and P = 0.041). In the entire cohort, anaemia remained independently associated with decreased disease-specific survival (HR 2.31, 95% CI (1.19-4.50), P = 0.013) after adjusting for age, the abnormal haematological parameters and ESGO/ESTRO/ESP risk groups. In patients that were treated with adjuvant radiotherapy (n = 239), anaemia was associated with significant reduced 5-year disease-specific and recurrence-free survival (P = 0.005 and P = 0.025, respectively). In ESGO/ESTRO/ESP intermediate risk patients that received solely vaginal brachytherapy (n = 74), anaemia was associated with reduced disease-specific survival (P = 0.041). CONCLUSIONS: Current data demonstrate the importance of preoperative anaemia as independent prognostic factor in patients with EC. Moreover, anaemia seems to be associated with reduced response to radiotherapy. Prospective validation in a larger study cohort is needed to verify anaemia as predictive biomarker for radiotherapy.What is already known on this subject? In endometrial cancer, preoperative abnormal haematological parameters like, anaemia, thrombocytosis and leucocytosis appears to be associated with FIGO advanced-stage and unfavourable outcome.What do the results of this study add? It remains unclear whether anaemia, thrombocytosis or leucocytosis solely reflecting worse prognosis by advanced tumour stage, or also impact response to adjuvant treatment. Current data demonstrate that anaemia is independent associated with decreased disease-specific survival and anaemia seems related with reduced response to radiotherapy and in specific to vaginal brachytherapy in ESGO/ESTRO/ESP intermediate risk patients.What are the implications of these findings for clinical practice and/or further research? Specific applied adjuvant treatment is needed if patients with anaemia have a reduced response to radiotherapy in EC. Prospective validation in a larger study cohort is required to verify anaemia as predictive biomarker for radiotherapy and to further evaluate the prognostic/predictive impact of anaemia in addition to the molecular subgroups.
In this study we focused on three specific blood values before surgery to predict survival outcomes in endometrial cancer patients: low haemoglobin (anaemia), high platelet count (thrombocytosis) and high white blood cell count (leucocytosis). We studied 894 patients with endometrial cancer over about 4.5 years, in which 11.5% had anaemia, 8.8% thrombocytosis and 12.7% leucocytosis. Anaemia was linked to a lower chance of surviving endometrial cancer, even after we considering patients' age, thrombocytosis, leucocytosis and the endometrial cancer risk classification groups. In patients who received radiotherapy after surgery (293 patients), anaemia was linked to a lower change of surviving and cancer coming back within 5 years. In patients within the intermediate endometrial cancer risk classification group who only received specific radiotherapy (74 patients), anaemia was even linked with lower chance of survival. In conclusion, anaemia is an important factor in predicting endometrial cancer outcomes, and it might also make radiotherapy less effective for some patients.
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Anemia , Neoplasias do Endométrio , Trombocitose , Feminino , Humanos , Anemia/etiologia , Biomarcadores , Estudos de Coortes , Neoplasias do Endométrio/complicações , Neoplasias do Endométrio/radioterapia , Neoplasias do Endométrio/cirurgia , Leucocitose , Trombocitose/etiologia , Estudos RetrospectivosRESUMO
INTRODUCTION: Opportunistic salpingectomy (OS) refers to additional removal of the fallopian tubes during abdominal surgery performed for another medical indication, as prevention for ovarian cancer. As OS has been inconsistently implemented, its clinical practice varies worldwide. To reduce this variation, insight is required into current clinical practice and its determinants. Therefore, the study aim was to determine the implementation of counseling and performance of OS between 2015 and 2018, and its patient, surgical, physician, and hospital characteristics. MATERIAL AND METHODS: Retrospective study using electronic medical records from six different Dutch hospitals: two academic, two large teaching, and two non-teaching hospitals. Patients were considered eligible for OS if they underwent elective non-obstetric abdominal surgery for a gynecological indication from January 2015 through December 2018. Primary outcomes were uptake of counseling and performance of OS. Multilevel multivariable logistic regression analyses were conducted to identify characteristics associated with OS. RESULTS: A total of 3214 patients underwent elective non-obstetric abdominal surgery for a gynecological indication and were eligible for OS. Counseling on OS increased significantly from 2.9% in 2015 to 29.4% in 2018. In this period, 440 patients were counseled on OS, of which 95.9% chose OS. Performance of OS increased significantly from 6.9% in 2015 to 44.5% in 2018. Counseling for and performance of OS were more likely in patients who had surgery by laparoscopic approach, were counseled by a gynecological resident, or had more than three contact moments before surgery. Additionally, OS was less likely in patients who had vaginal surgery. CONCLUSIONS: Although the uptake of OS increased from 2015 to 2018, the majority of patients who were eligible for OS were not counseled and did not undergo OS. Its clinical practice varies on patient, surgery, and physician characteristics. Therefore, an implementation strategy tailored to associated determinants is recommended.
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Ginecologia , Neoplasias Ovarianas , Humanos , Feminino , Histerectomia , Estudos Retrospectivos , Neoplasias Ovarianas/prevenção & controle , Neoplasias Ovarianas/cirurgia , SalpingectomiaRESUMO
OBJECTIVES: The purpose of this case study series was to present recruitment and data collection strategies used for Asian American ethnic groups by documenting challenges experienced by researchers in the field of aging. SUMMARY: We compiled four case studies investigating Asian American older adults and/or family caregivers (i.e., Vietnamese, South Asians, Chinese, and Koreans). Each case study employed unique research methods to overcome experienced challenges associated with recruitment and data collection. DISCUSSION: Three constructs were organized for effective recruitment and data collection strategies of this racial group and included (1) forming a bilingual and bicultural research team (research-centered); (2) establishing reciprocal partnerships between researchers and community partners (community-centered); and (3) understanding the historical and cultural backgrounds of targeted ethnic groups (participant-centered). Approaches taken to address the range of challenges and limitations identified in this case study series may also help increase the representation of Asian-American older adults and family caregivers in research. CLINICAL IMPLICATIONS: Successfully including racial and ethnic minority groups in research, especially Asian Americans, may reduce existing racial disparities in mental and physical health. Any barriers and facilitators affecting the research regarding Asian American ethnic groups should continue to be discussed.
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Influenza burden estimates are essential to informing prevention and control policies. To complement recent influenza vaccine production capacity in Vietnam, we used acute respiratory infection (ARI) hospitalization data, severe acute respiratory infection (SARI) surveillance data, and provincial population data from 4 provinces representing Vietnam's major regions during 2014-2016 to calculate provincial and national influenza-associated ARI and SARI hospitalization rates. We determined the proportion of ARI admissions meeting the World Health Organization SARI case definition through medical record review. The mean influenza-associated hospitalization rates per 100,000 population were 218 (95% uncertainty interval [UI] 197-238) for ARI and 134 (95% UI 119-149) for SARI. Influenza-associated SARI hospitalization rates per 100,000 population were highest among children <5 years of age (1,123; 95% UI 946-1,301) and adults >65 years of age (207; 95% UI 186-227), underscoring the need for prevention and control measures, such as vaccination, in these at-risk populations.
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Vacinas contra Influenza , Influenza Humana , Adulto , Idoso , Criança , Hospitalização , Humanos , Influenza Humana/epidemiologia , Vigilância de Evento Sentinela , Vietnã/epidemiologiaRESUMO
The human solute carrier 22A (SLC22A) family consists of 23 members, representing one of the largest families in the human SLC superfamily. Despite their pharmacological and physiological importance in the absorption and disposition of a range of solutes, eight SLC22A family members remain classified as orphans. In this study, we used a multifaceted approach to identify ligands of orphan SLC22A15. Ligands of SLC22A15 were proposed based on phylogenetic analysis and comparative modeling. The putative ligands were then confirmed by metabolomic screening and uptake assays in SLC22A15 transfected HEK293 cells. Metabolomic studies and transporter assays revealed that SLC22A15 prefers zwitterionic compounds over cations and anions. We identified eight zwitterions, including ergothioneine, carnitine, carnosine, gabapentin, as well as four cations, including MPP+ , thiamine, and cimetidine, as substrates of SLC22A15. Carnosine was a specific substrate of SLC22A15 among the transporters in the SLC22A family. SLC22A15 transport of several substrates was sodium-dependent and exhibited a higher Km for ergothioneine, carnitine, and carnosine compared to previously identified transporters for these ligands. This is the first study to characterize the function of SLC22A15. Our studies demonstrate that SLC22A15 may play an important role in determining the systemic and tissue levels of ergothioneine, carnosine, and other zwitterions.
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Proteínas de Transporte de Cátions Orgânicos/genética , Transporte Biológico/efeitos dos fármacos , Transporte Biológico/genética , Carnitina/farmacologia , Carnosina/farmacologia , Linhagem Celular , Ergotioneína/farmacologia , Gabapentina/farmacologia , Genômica/métodos , Células HEK293 , Humanos , Ligantes , Filogenia , Transfecção/métodosRESUMO
Mechanistic-understanding-based selection of excipients may improve formulation development strategies for generic drug products and potentially accelerate their approval. Our study aimed at investigating the effects of molecular excipients present in orally administered FDA-approved drug products on the intestinal efflux transporter, BCRP (ABCG2), which plays a critical role in drug absorption with potential implications on drug safety and efficacy. We determined the interactions of 136 oral molecular excipients with BCRP in isolated membrane vesicles and identified 26 excipients as BCRP inhibitors with IC50 values less than 5 µM using 3H-cholecystokinin octapeptide (3H-CCK8). These BCRP inhibitors belonged to three functional categories of excipients: dyes, surfactants, and flavoring agents. Compared with noninhibitors, BCRP inhibitors had significantly higher molecular weights and SLogP values. The inhibitory effects of excipients identified in membrane vesicles were also evaluated in BCRP-overexpressing HEK293 cells at similar concentrations. Only 1 of the 26 inhibitors of BCRP identified in vesicles inhibited BCRP-mediated 3H-oxypurinol uptake by more than 50%, consistent with the notion that BCRP inhibition depends on transmembrane or intracellular availability of the inhibitors. Collectively, the results of this study provide new information on excipient selection during the development of drug products with active pharmaceutical ingredients that are BCRP substrates.
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Membro 2 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/metabolismo , Corantes/metabolismo , Excipientes/metabolismo , Aromatizantes/metabolismo , Proteínas de Neoplasias/metabolismo , Tensoativos/metabolismo , Membro 2 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/antagonistas & inibidores , Membro 2 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/genética , Administração Oral , Corantes/química , Corantes/farmacologia , Composição de Medicamentos/métodos , Avaliação Pré-Clínica de Medicamentos/métodos , Excipientes/química , Excipientes/farmacologia , Feminino , Aromatizantes/química , Aromatizantes/farmacologia , Células HEK293 , Humanos , Concentração Inibidora 50 , Absorção Intestinal/efeitos dos fármacos , Peso Molecular , Proteínas de Neoplasias/antagonistas & inibidores , Proteínas de Neoplasias/genética , Transdução de Sinais/genética , Tensoativos/química , Tensoativos/farmacologia , TransfecçãoRESUMO
BACKGROUND: The development of minimally invasive mitral valve surgery has created the motivation for using this approach in young patients with chronic rheumatic valve disease. We report our recent experience with patients undergoing minimally mitral valve surgery in this group of patients. METHODS: Between July 2014 and June 2018, 142 patients with rheumatic mitral valve dysfunction underwent minimally invasive surgery through a right thoracotomy approach at the University Medical Center of Ho Chi Minh City in Vietnam. Diagnosis was confirmed with transthoracic and transesophageal echocardiography (TTE and TEE). We analyzed the in-hospital and midterm follow-up outcomes of this group. RESULTS: The mean age was 42.6 ± 9.6 years. Sixty patients (42.3%) were male. Sixty-three patients were diagnosed with functional severe tricuspid regurgitation, 29 patients were identified with moderate tricuspid regurgitation, and tricuspid annulus was more than 21 mm/m²). Mitral valve repair was performed in 16 patients (11.3%), and 126 patients underwent mitral valve replacement. Mitral valve repair techniques included annuloplasty, leaflet peeling, and commissurotomy. Thirty-day mortality was 0.7%. Two patients had to be converted to conventional sternotomy, due to left atrial appendage laceration and mitral annular rupture. The overall survival rate was 98.6%. Freedom from reoperation was 97.1%. CONCLUSIONS: In patients with rheumatic valve disease, minimally invasive mitral surgery safely and effectively can be performed with few perioperative complications and good midterm results.
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Doenças das Valvas Cardíacas/cirurgia , Valva Mitral/cirurgia , Cardiopatia Reumática/cirurgia , Insuficiência da Valva Tricúspide/cirurgia , Adulto , Conversão para Cirurgia Aberta/estatística & dados numéricos , Ecocardiografia Transesofagiana , Feminino , Doenças das Valvas Cardíacas/diagnóstico por imagem , Implante de Prótese de Valva Cardíaca/estatística & dados numéricos , Humanos , Masculino , Ilustração Médica , Procedimentos Cirúrgicos Minimamente Invasivos/métodos , Valva Mitral/diagnóstico por imagem , Valva Mitral/lesões , Cardiopatia Reumática/diagnóstico por imagem , Esternotomia , Taxa de Sobrevida , Toracotomia/métodos , Insuficiência da Valva Tricúspide/diagnósticoRESUMO
The fungistatic nature and toxicity concern associated with the azole drugs currently on the market have resulted in an increased demand for new azole antifungal agents for which these problematic characteristics do not exist. The extensive use of azoles has resulted in fungal strains capable of resisting the action of these drugs. Herein, we report the synthesis and antifungal activity of novel fluconazole (FLC) analogues with alkyl-, aryl-, cycloalkyl-, and dialkyl-amino substituents. We evaluated their antifungal activity by MIC determination and time-kill assay as well as their safety profile by hemolytic activity against murine erythrocytes as well as cytotoxicity against mammalian cells. The best compounds from our study exhibited broad-spectrum activity against most of the fungal strains tested, with excellent MIC values against a number of clinical isolates. The most promising compounds were found to be less hemolytic than the least hemolytic FDA-approved azole antifungal agent voriconazole (VOR). Finally, we demonstrated that the synthetic alkyl-amino FLC analogues displayed chain-dependent fungal membrane disruption as well as inhibition of ergosterol biosynthesis as possible mechanisms of action.
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Antifúngicos/farmacologia , Fluconazol/farmacologia , Fungos/efeitos dos fármacos , Animais , Antifúngicos/química , Antifúngicos/toxicidade , Candida/efeitos dos fármacos , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Desenho de Fármacos , Eritrócitos/citologia , Eritrócitos/efeitos dos fármacos , Eritrócitos/metabolismo , Fluconazol/química , Fluconazol/toxicidade , Hemólise/efeitos dos fármacos , Camundongos , Testes de Sensibilidade Microbiana , Relação Estrutura-Atividade , Voriconazol/farmacologia , Voriconazol/toxicidadeRESUMO
Cytisine-linked isoflavonoids (CLIFs) inhibited PC-3 prostate and LS174T colon cancer cell proliferation by inhibiting a peroxisomal bifunctional enzyme. A pull-down assay using a biologically active, biotin-modified CLIF identified the target of these agents as the bifunctional peroxisomal enzyme, hydroxysteroid 17ß-dehydrogenase-4 (HSD17B4). Additional studies with truncated versions of HSD17B4 established that CLIFs specifically bind the C-terminus of HSD17B4 and selectively inhibited the enoyl CoA hydratase but not the d-3-hydroxyacyl CoA dehydrogenase activity. HSD17B4 was overexpressed in prostate and colon cancer tissues, knocking down HSD17B4 inhibited cancer cell proliferation, suggesting that HSD17B4 is a potential biomarker and drug target and that CLIFs are potential probes or therapeutic agents for these cancers.
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Alcaloides/farmacologia , Antineoplásicos/farmacologia , Inibidores Enzimáticos/farmacologia , Isoflavonas/farmacologia , Proteína Multifuncional do Peroxissomo-2/antagonistas & inibidores , Alcaloides/química , Antineoplásicos/síntese química , Antineoplásicos/química , Azocinas/química , Azocinas/farmacologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Humanos , Isoflavonas/síntese química , Isoflavonas/química , Estrutura Molecular , Proteína Multifuncional do Peroxissomo-2/metabolismo , Quinolizinas/química , Quinolizinas/farmacologia , Relação Estrutura-AtividadeRESUMO
BACKGROUND: Opioid misuse and dependence are prevalent and rising problems in the United States. Treatment with buprenorphine is a successful treatment option for individuals with opioid dependence. This study describes and preliminarily evaluates a unique delivery system that provides buprenorphine treatment via a shared medical appointment. METHODS: A retrospective medical record review on all 77 opioid-dependent patients referred for a buprenorphine shared medical appointment in a homeless clinic from 2010 to 2012. RESULTS: Most patients were currently homeless (61%), unemployed (92%), had an Axis I psychiatric diagnosis (81%), and had recent polysubstance use (53%). Of the 77 patients, 95% attended at least 1 shared medical appointment. Treatment retention at 12 and 24 weeks was 86% and 70%, respectively. CONCLUSIONS: In a patient population with complex social and mental health histories, buprenorphine treatment via a shared medical appointment had high retention rates. Findings can help guide the development of unique delivery systems to serve real-world complex patients with opioid dependence.
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Instituições de Assistência Ambulatorial , Agendamento de Consultas , Buprenorfina/uso terapêutico , Pessoas Mal Alojadas/psicologia , Tratamento de Substituição de Opiáceos/métodos , Transtornos Relacionados ao Uso de Opioides/tratamento farmacológico , Adulto , Feminino , Humanos , Masculino , Antagonistas de Entorpecentes/uso terapêutico , Aceitação pelo Paciente de Cuidados de Saúde/estatística & dados numéricos , Avaliação de Programas e Projetos de Saúde , Estudos Retrospectivos , Cooperação e Adesão ao Tratamento/estatística & dados numéricos , Adulto JovemRESUMO
Antibiotic resistance is a worldwide problem that needs to be addressed. Staphylococcus aureus is one of the dangerous "ESKAPE" pathogens that rapidly evolve and evade many current FDA-approved antibiotics. Thus, there is an urgent need for new anti-MRSA compounds. Ebselen (also known as 2-phenyl-1,2-benzisoselenazol-3(2H)-one) has shown promising activity in clinical trials for cerebral ischemia, bipolar disorder, and noise-induced hearing loss. Recently, there has been a renewed interest in exploring the antibacterial properties of ebselen. In this study, we synthesized an ebselen-inspired library of 33 compounds where the selenium atom has been replaced by sulfur (ebsulfur derivatives) and evaluated them against a panel of drug-sensitive and drug-resistant S. aureus and non-S. aureus strains. Within our library, we identified three outstanding analogues with potent activity against all S. aureus strains tested (MIC values mostly ⩽2µg/mL), and numerous additional ones with overall very good to good antibacterial activity (1-7.8µg/mL). We also characterized the time-kill analysis, anti-biofilm ability, hemolytic activity, mammalian cytotoxicity, membrane-disruption ability, and reactive oxygen species (ROS) production of some of these analogues.
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Antibacterianos/farmacologia , Azóis/farmacologia , Staphylococcus aureus Resistente à Meticilina/efeitos dos fármacos , Compostos Organosselênicos/farmacologia , Antibacterianos/química , Azóis/síntese química , Azóis/química , Relação Dose-Resposta a Droga , Isoindóis , Testes de Sensibilidade Microbiana , Estrutura Molecular , Compostos Organosselênicos/síntese química , Compostos Organosselênicos/química , Relação Estrutura-AtividadeRESUMO
The rise and emergence of resistance to antifungal drugs by diverse pathogenic fungal strains have resulted in an increase in demand for new antifungal agents. Various heterocyclic scaffolds with different mechanisms of action against fungi have been investigated in the past. Herein, we report the synthesis and antifungal activities of 18 alkylated mono-, bis-, and trisbenzimidazole derivatives, their toxicities against mammalian cells, as well as their ability to induce reactive oxygen species (ROS) in yeast cells. Many of our bisbenzimidazole compounds exhibited moderate to excellent antifungal activities against all tested fungal strains, with MIC values ranging from 15.6 to 0.975µg/mL. The fungal activity profiles of our bisbenzimidazoles were found to be dependent on alkyl chain length. Our most potent compounds were found to display equal or superior antifungal activity when compared to the currently used agents amphotericin B, fluconazole, itraconazole, posaconazole, and voriconazole against many of the strains tested.
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Antifúngicos/síntese química , Antifúngicos/farmacologia , Benzimidazóis/síntese química , Benzimidazóis/farmacologia , Antifúngicos/química , Benzimidazóis/química , Espectroscopia de Ressonância Magnética Nuclear de Carbono-13 , Testes de Sensibilidade Microbiana , Espectroscopia de Prótons por Ressonância Magnética , Espécies Reativas de Oxigênio/metabolismo , Leveduras/efeitos dos fármacos , Leveduras/metabolismoRESUMO
Targeted covalent inhibitors (TCIs) are an emerging class of anticancer therapeutics. TCIs are designed to selectively engage their targeted proteins via covalent warheads. From the drug development standpoint, the covalent inhibition mechanism is anticipated to elicit the following theoretical benefits: (i) an extended duration of therapeutic action that is determined by the target protein turnover rate and not necessarily by drug half-life, (ii) a lower therapeutic dose owing to greater pharmacological potency, (iii) lower risk of off-target binding and associated adverse events, and (iv) reduced drug-drug interaction (DDI) liability due to high selectivity and low dose. Elucidating the clinical relevance of these expected benefits requires an integrated assessment of pharmacokinetics (PK), efficacy, safety, and DDI data. In this review, we compared the clinical pharmacology attributes of FDA-approved oncology TCIs within the last 10 years against their reversible inhibitor (RI) counterparts. Our findings indicated that (i) PK half-lives of TCIs were typically shorter and (ii) at their respective recommended clinical doses per drug label, the molar unbound steady state areas under the concentration-time curve (AUCss) of TCIs were lower than those of RIs, but with longer clinically observed durations of response. However, (iii) there was no conclusive evidence supporting improved clinical safety profiles for TCIs, and (iv) DDI perpetrator profiles appeared to be similar between TCIs and RIs. The overall clinical pharmacology comparison of TCI vs. RI surveyed in this paper suggested that at least two of the four forecasted clinical benefits were achieved by TCIs.
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Diamide linked γ-cyclodextrin (γ-CD) dimers are proposed as molecular-scale delivery agents for the anticancer agent curcumin. N,N'-Bis(6(A)-deoxy-γ-cyclodextrin-6(A)-yl)succinamide (66γCD2su) and N,N'-bis(6(A)-deoxy-γ-cyclodextrin-6(A)-yl)urea (66γCD2ur) markedly suppress the degradation of curcumin by forming a strong 1:1 cooperative binding complexes. The results presented in this study describe the potential efficacy of 66γCD2su and 66γCD2ur for intracellular curcumin delivery to cancer cells. Cellular viability assays demonstrated a dose-dependent antiproliferative effect of curcumin in human prostate cancer (PC-3) cells that was preserved by the curcumin-66γCD2su complex. In contrast, delivery of curcumin by 66γCD2ur significantly delayed the antiproliferative effect. We observed similar patterns of gene regulation in PC-3 cells for curcumin complexed with either 66γCD2su or 66γCD2ur in comparison to curcumin alone, although curcumin delivered by either 66γCD2su or 66γCD2ur induces a slightly higher up-regulation of heme oxygenase-1. Highlighting their nontoxic nature, neither 66γCD2su nor 66γCD2ur carriers alone had any measurable effect on cell proliferation or candidate gene expression in PC-3 cells. Finally, confocal fluorescence imaging and uptake studies were used to demonstrate the intracellular delivery of curcumin by 66γCD2su and 66γCD2ur. Overall, these results demonstrate effective intracellular delivery and action of curcumin when complexed with 66γCD2su and 66γCD2ur, providing further evidence of their potential applications to deliver curcumin effectively in cancer and other treatment settings.
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Curcumina/química , Curcumina/farmacologia , Diamida/química , Neoplasias da Próstata/tratamento farmacológico , gama-Ciclodextrinas/química , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Expressão Gênica/efeitos dos fármacos , Expressão Gênica/genética , Heme Oxigenase-1/genética , Heme Oxigenase-1/metabolismo , Humanos , Masculino , Neoplasias da Próstata/genética , Neoplasias da Próstata/metabolismo , Regulação para Cima/efeitos dos fármacos , Regulação para Cima/genéticaRESUMO
This critical review covers the developments in anion recognition and sensing using Zn(II)-dipicolylamine functionalized receptors over the past decade with emphasis on recent rapid advances in the last five years.
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Aminas/química , Técnicas Biossensoriais/métodos , Técnicas de Química Analítica/instrumentação , Compostos Organometálicos/química , Ácidos Picolínicos/química , Zinco/química , Sequência de Aminoácidos , Animais , Ânions/análise , Ânions/química , Linhagem Celular , Humanos , Dados de Sequência MolecularRESUMO
Botulinum toxin-A (BTX) administration into muscle is an established treatment for conditions with excessive muscle contraction. However, botulinum therapy has short-term effectiveness, and high-dose injection of BTX could induce neutralizing antibodies against BTX. Therefore, prolonging its effects could be beneficial in a clinical situation. Insulin-like growth factor-1 receptor (IGF1R) and its ligands, insulin-like growth factor (IGF) -I and II, regulate the physiological and pathological processes of the nervous system. It has been suggested that IGF1R is involved in the process after BTX administration, but the specific regeneration mechanism remains unclear. Therefore, this study aimed to determine how inhibition of IGF1R signaling pathway affects BTX-induced muscle paralysis. The results showed that anti-IGF1R antibody administration inhibited the recovery from BTX-induced neurogenic paralysis, and the synaptic components at the neuromuscular junction (NMJ), mainly post-synaptic components, were significantly affected by the antibody. In addition, the wet weight or frequency distribution of the cross-sectional area of the muscle fibers was regulated by IGF1R, and sequential antibody administration following BTX treatment increased the number of Pax7+-satellite cells in the gastrocnemius (GC) muscle, independent of NMJ recovery. Moreover, BTX treatment upregulated mammalian target of rapamycin (mTOR)/S6 kinase signaling pathway, HDAC4, Myog, Fbxo32/MAFbx/Atrogin-1 pathway, and transcription of synaptic components, but not autophagy. Finally, IGF1R inhibition affected only mTOR/S6 kinase translational signaling in the GC muscle. In conclusion, the IGF1R signaling pathway is critical for NMJ regeneration via specific translational signals. IGF1R inhibition could be highly beneficial in clinical practice by decreasing the number of injections and total dose of BTX due to the prolonged duration of the effect.
Assuntos
Toxinas Botulínicas , Fator de Crescimento Insulin-Like I , Junção Neuromuscular , Fibras Musculares Esqueléticas , Anticorpos Neutralizantes/farmacologiaRESUMO
2-Methylquinazolin-4(3H)-one was prepared by the reaction of anthranilic acid, acetic anhydride, and ammonium acetate. The reaction of 2-methylquinazolin-4(3H)-one with N-aryl-2-chloroacetamides in acetone in the presence of potassium carbonate gave nine N-aryl-2-(2-methyl-4-oxoquinazolin-3(4H)-yl)acetamide compounds. The structures of these compounds were elucidated on the basis of their IR, 1H nuclear magnetic resonance (NMR), 13C NMR, and high-resolution mass spectrometry (HR-MS) spectral data. These synthesized compounds containing the 2-methyl-3,4-dihydroquinazolin-4-one moiety exhibited activity against Aedes aegypti mosquito larvae with LC50 values of 2.085-4.201 µg/mL after 72 h exposure, which is also confirmed using a quantitative structure-activity relationship (QSAR) model. Interestingly, these compounds did not exhibit toxicity to the nontarget organism Diplonychus rusticus. In silico molecular docking revealed acetylcholine binding protein (AChBP) and acetylcholinesterase (AChE) to be potential molecular targets. These data indicated the larvicidal potential and environmental friendliness of these N-aryl-2-(2-methyl-4-oxoquinazolin-3(4H)-yl)acetamide derivatives.