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1.
Mol Pharmacol ; 99(4): 286-293, 2021 04.
Artigo em Inglês | MEDLINE | ID: mdl-33547250

RESUMO

Full agonist-mediated activation of free fatty acid receptor 1 (FFAR1/GPR40) alleviates diabetes in rodents. Considering that diabetes is a chronic disease, assessment of treatment durability of chronic exposure to a GPR40 full agonist is pivotal for treating patients with diabetes. However, the physiologic significance of chronic in vitro and in vivo exposure to GPR40 full agonists is largely unclear. Here, we evaluated the in vitro and in vivo effects of chronic treatment with SCO-267, a GPR40 full agonist, on signal transduction and glucose control. In vitro experiments showed that SCO-267 is an allosteric full agonist for GPR40, which activates the Gα q, Gα s, and Gα 12/13 pathways and ß-arrestin recruitment. The calcium signal response was largely sustained in GPR40-overexpressing CHO cells even after prolonged incubation with SCO-267. To evaluate the in vivo relevance of chronic exposure to GPR40 full agonists, SCO-267 (1 and 10 mg/kg) was administered once daily to neonatally streptozotocin-induced diabetic rats for 15-33 days, and glucose control was evaluated. After 15 days of dosing followed by the drug washout period, SCO-267 improved glucose tolerance, most likely by increasing insulin sensitivity in rats. After 33 days, repeated exposure to SCO-267 was highly effective in improving glucose tolerance in rats. Furthermore, chronic exposure to SCO-267 increased pancreatic insulin content. These results demonstrated that even after chronic exposure, SCO-267 effectively activates GPR40 in cells and rats, suggesting the clinical application of SCO-267 in treating chronic diseases including diabetes. SIGNIFICANCE STATEMENT: GPR40 is a validated therapeutic target for diabetes. This study showed that even after chronic exposure, SCO-267, an allosteric GPR40 full agonist, effectively activates GPR40 in cells and rats; these results suggest a durable efficacy of SCO-267 in patients.


Assuntos
Glicemia/efeitos dos fármacos , Diabetes Mellitus Experimental/tratamento farmacológico , Piperidinas/administração & dosagem , Piridinas/administração & dosagem , Receptores Acoplados a Proteínas-G/agonistas , Animais , Glicemia/metabolismo , Células CHO , Cricetinae , Cricetulus , Diabetes Mellitus Experimental/sangue , Relação Dose-Resposta a Droga , Humanos , Masculino , Ratos , Ratos Endogâmicos WKY , Receptores Acoplados a Proteínas-G/metabolismo
2.
Lancet Haematol ; 8(4): e254-e266, 2021 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-33631112

RESUMO

BACKGROUND: Patients with chronic lymphocytic leukaemia and high-risk features have poorer outcomes on ibrutinib than those without high-risk features. The aim of this study was to assess the benefit of adding ublituximab, an anti-CD20 monoclonal antibody, to ibrutinib therapy in this population. METHODS: We did a randomised, phase 3, multicentre study (GENUINE) of patients aged 18 years or older with relapsed or refractory chronic lymphocytic leukaemia with at least one of 17p deletion, 11q deletion, or TP53 mutation, at 119 clinics in the USA and Israel. Eligible patients had received at least one previous chronic lymphocytic leukaemia therapy and had an Eastern Cooperative Oncology Group performance status of 2 or lower. We randomised patients (1:1) using permuted block randomisation with a block size of four and stratified by previous lines of therapy (one vs two or more) to receive ibrutinib alone or ibrutinib in combination with ublituximab. Treatment allocation was not masked to patients or investigators. Ibrutinib was given orally daily at 420 mg for all cycles. Ublituximab was given intravenously in 28-day cycles, with increasing doses during cycle 1 (≤150 mg on day 1, 750 mg on day 2, and 900 mg on days 8 and 15) and continuing at 900 mg on day 1 of cycles 2-6. After cycle 6, ublituximab was given at 900 mg every three cycles. The study was initially designed with co-primary endpoints of progression-free survival and overall response rate but due to protracted patient accrual, the protocol was amended to have a single primary endpoint of independent review committee-assessed overall response rate (defined as the proportion of patients who had a partial response, complete response, or complete response with incomplete marrow recovery according to the 2008 International Workshop on CLL criteria) in the intention-to-treat population. Safety was evaluated in the population of patients who received at least one dose of study treatment. This trial is registered with ClinicalTrials.gov, NCT02301156, and the final analysis is presented. FINDINGS: 224 patients were assessed for eligibility, of whom 126 patients were enrolled and randomly assigned to receive ublituximab plus ibrutinib (n=64) or ibrutinib alone (n=62) between Feb 6, 2015, and Dec 19, 2016. After a median follow-up of 41·6 months (IQR 36·7-47·3), the overall response rate was 53 (83%) of 64 patients in the ublituximab plus ibrutinib group and 40 (65%) of 62 patients in the ibrutinib group (p=0·020). 117 patients, including 59 in the ublituximab plus ibrutinib group and 58 in the ibrutinib group, received at least one dose of treatment and were included in safety analyses. Most adverse events were grade 1 or 2. The most common grade 3 and 4 adverse events were neutropenia (11 [19%] patients in the ublituximab plus ibrutinib group and seven [12%] in the ibrutinib group), anaemia (five [8%] and five [9%]), and diarrhoea (six [10%] and three [5%]). The most common serious adverse events were pneumonia (six [10%] in the ublituximab plus ibrutinib group and four [7%] in the ibrutinib group), atrial fibrillation (four [7%] and one [2%]), sepsis (four [7%] and one [2%]), and febrile neutropenia (three [5%] and one [2%]). Two patients in the ublituximab plus ibrutinib group died due to adverse events (one cardiac arrest and one failure to thrive), neither of which were treatment-related. Five patients in the ibrutinib group died due to adverse events, including one cardiac arrest, one cerebral infarction, one intracranial haemorrhage, one Pneumocystis jirovecii pneumonia infection, and one unexplained death; the death due to cardiac arrest was considered to be treatment-related. INTERPRETATION: The addition of ublituximab to ibrutinib resulted in a statistically higher overall response rate without affecting the safety profile of ibrutinib monotherapy in patients with relapsed or refractory high-risk chronic lymphocytic leukaemia. These findings provide support for the addition of ublituximab to Bruton tyrosine kinase inhibitors for the treatment of these patients. FUNDING: TG Therapeutics.


Assuntos
Adenina/análogos & derivados , Anticorpos Monoclonais/uso terapêutico , Leucemia Linfocítica Crônica de Células B/tratamento farmacológico , Piperidinas/uso terapêutico , Adenina/administração & dosagem , Adenina/efeitos adversos , Adenina/uso terapêutico , Administração Intravenosa , Administração Oral , Tirosina Quinase da Agamaglobulinemia/antagonistas & inibidores , Idoso , Anticorpos Monoclonais/administração & dosagem , Anticorpos Monoclonais/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Feminino , Humanos , Israel/epidemiologia , Masculino , Pessoa de Meia-Idade , Piperidinas/administração & dosagem , Piperidinas/efeitos adversos , Intervalo Livre de Progressão , Inibidores de Proteínas Quinases/uso terapêutico , Segurança , Resultado do Tratamento , Estados Unidos/epidemiologia
3.
Anal Chem ; 93(4): 2144-2151, 2021 02 02.
Artigo em Inglês | MEDLINE | ID: mdl-33470103

RESUMO

Local delivery to the lower gut to treat diseases of the colon has become a topic of special attention. Tissue exposure of locally acting agents is not represented by plasma concentrations. Therefore, reliable methods to measure tissue uptake at the primary site of action (e.g., epithelial layer or lamina propria) are vital. This work investigates the suitability of mass spectrometry imaging (MSI) in quantitatively visualizing intestinal transmural drug distribution. Tofacitinib (Tofa), a drug approved for the treatment of several autoimmune diseases, including ulcerative colitis, was selected as a tool compound for feasibility studies. One- and 7-h postdose sections of the ileum, proximal- and distal-colon from rats that received an oral solution of Tofa were subjected to matrix-assisted laser desorption ionization (MALDI)-MSI. A dilution series of individual concentrations sprayed over an entire tissue section allowed for tissue type-specific quantitation. At 1 h (systemic Tmax), the signal was highest in the ileum, whereas at 7 h, the signal was highest in the colon, when the unabsorbed fraction of the compound reached the colon. A combination of three-dimensional (3D) intensity plots and hematoxylin and eosin (H&E) stains showed a visually observable gradual decrease in Tofa concentration from the lumen toward the muscular layer of the proximal colon. The high luminal concentration of Tofa indicated that flushing of the intestines with saline does not result in complete removal of the drug material from the lumen. This could cause an overestimation of drug concentration in gut tissue homogenates by conventional liquid chromatography-mass spectrometry (LC-MS) methods. This study demonstrates the utility of MSI to differentiate between the lumen and intestinal wall layers and enables proper interpretation of tissue distribution data.


Assuntos
Intestinos/química , Espectrometria de Massas/métodos , Imagem Molecular/métodos , Piperidinas/administração & dosagem , Piperidinas/farmacocinética , Pirimidinas/administração & dosagem , Pirimidinas/farmacocinética , Administração Oral , Animais , Masculino , Piperidinas/química , Inibidores de Proteínas Quinases/administração & dosagem , Inibidores de Proteínas Quinases/farmacocinética , Pirimidinas/química , Ratos , Ratos Sprague-Dawley , Distribuição Tecidual
4.
Life Sci ; 266: 118891, 2021 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-33310047

RESUMO

AIMS: Intervertebral disc (IVD) degeneration (IDD), a common musculoskeletal disease with limited self-healing ability, is challenging to treat. The development of innovative therapies to reverse IDD depends on the elucidation of its regulatory mechanisms. Therefore, the role of Src homology region 2-containing protein tyrosine phosphatase 2 (SHP2) in the pathogenesis of IDD and the therapeutic effect of its small-molecule inhibitor, SHP099, were investigated. MATERIALS AND METHODS: The expression of SHP2 by nucleus pulposus (NP) cells in IVD was investigated in vitro and in vivo, and its molecular mechanism in IDD was explored using transfection technology. Injectable N-isopropylacrylamide-based thermosensitive hydrogels were synthesized for SHP099 delivery. KEY FINDINGS: SHP2 was highly expressed in degenerated IVDs, where its overexpression in NP cells inhibited the expression of Sry-related HMG box-9 (Sox9), leading to the decreased expression of key proteins (collagen II and aggrecan) and consequently to IDD. SHP099 reversed the degeneration of NP cells in vitro. Moreover, its administration in rats via the injectable thermosensitive hydrogel had a therapeutic effect on IDD. SIGNIFICANCE: Our results suggest that SHP2 is a key factor in IDD progression, and SHP099 inhibits both its expression and NP cell degeneration. Therefore, SHP099 delivery via injectable thermosensitive hydrogels is a potential treatment strategy for IDD.


Assuntos
Hidrogéis/administração & dosagem , Degeneração do Disco Intervertebral/tratamento farmacológico , Núcleo Pulposo/efeitos dos fármacos , Piperidinas/administração & dosagem , Proteína Tirosina Fosfatase não Receptora Tipo 11/antagonistas & inibidores , Pirimidinas/administração & dosagem , Animais , Feminino , Hidrogéis/química , Degeneração do Disco Intervertebral/patologia , Núcleo Pulposo/metabolismo , Piperidinas/química , Pirimidinas/química , Ratos , Ratos Sprague-Dawley , Temperatura
5.
Trials ; 21(1): 1027, 2020 Dec 17.
Artigo em Inglês | MEDLINE | ID: mdl-33334357

RESUMO

OBJECTIVES: This study aims to investigate the efficacy of curcumin-piperine co-supplementation on disease duration, severity and clinical symptoms, and inflammatory mediators in patients with coronavirus (COVID-19). TRIAL DESIGN: This is a randomized, placebo-controlled, double-blind, parallel arm clinical trial. PARTICIPANTS: All patients aged 20-75 years with the diagnosis of Covid-19 based on the PCR test. The exclusion criteria will include an age less than 20 and more than 75 years, current use of warfarin or other anticoagulant drugs, and the presence of sensitivity to herbal products such as turmeric and pepper. This study will be conducted in academic hospitals affiliated to Isfahan University of Medical Sciences, Isfahan, Iran. INTERVENTION AND COMPARATOR: Fifty outpatients will be randomly allocated in a ratio of 1:1 to receive a capsule of curcumin-piperine containing 500 mg curcumin plus 5 mg piperine or matching placebo containing 505 mg maltodextrin twice a daily, after lunch and dinner, over a period of 2 weeks. Similarly, 50 inpatients who are admitted to hospital wards excluding intensive care unit (ICU) will be randomly assigned in a ratio of 1:1 to receive a capsule curcumin-piperine or matching placebo (provided by the Sami Labs company) twice a daily, after lunch and dinner, over a period of 2 weeks. MAIN OUTCOMES: The main outcomes of this study are the efficacy of curcumin-piperine on coronavirus disease's clinical symptoms, duration, severity, and inflammatory mediators after 2 weeks of curcumin-piperine co-supplementation. RANDOMISATION: Randomization sequences will be generated with the use of a random-number table with a permuted block design (block size of 4) and stratification according to the gender variable (male vs. female). These sequences will be prepared by an independent statistician and will be kept in opaque, sealed, numbered envelopes which will be opened only at the time of enrollment. The allocation ratio in intervention and control groups is 1:1. Researchers and all patients will be unaware of the study-group assignment until the completion of data analyses. BLINDING (MASKING): This study is a double-blind clinical trial (participant, researcher). The curcumin-piperine and placebo supplements are packaged in similar numbered drug containers, and the researcher and all patients will be unaware of the study assignment until the end of the study. NUMBERS TO BE RANDOMISED (SAMPLE SIZE): The calculated total sample size is 100 patients, with 25 patients in each group. TRIAL STATUS: The protocol is Version 2.0, May 24, 2020. Recruitment began May 4, 2020, and is anticipated to be completed by April 19, 2021. TRIAL REGISTRATION: This trial has been registered by the title of "Effect of curcumin-piperine co-supplementation on disease duration, severity and clinical signs, and inflammatory factors in patients with coronavirus (COVID-19): A randomized, double-blind, placebo-controlled clinical trial study" in the Iranian Registry of Clinical Trials (IRCT) with code "IRCT20121216011763N46", https://www.irct.ir/trial/47529 . The registration date is May 4, 2020. FULL PROTOCOL: The full protocol is attached as an additional file, accessible from the Trials website (Additional file 1). In the interest in expediting dissemination of this material, the familiar formatting has been eliminated; this Letter serves as a summary of the key elements of the full protocol.


Assuntos
Alcaloides/administração & dosagem , Benzodioxóis/administração & dosagem , Curcumina/administração & dosagem , Suplementos Nutricionais , Piperidinas/administração & dosagem , Alcamidas Poli-Insaturadas/administração & dosagem , Método Duplo-Cego , Hospitalização , Humanos , Irã (Geográfico) , Ensaios Clínicos Controlados Aleatórios como Assunto , Fatores de Tempo , Resultado do Tratamento
6.
Cochrane Database Syst Rev ; 10: CD004730, 2020 10 19.
Artigo em Inglês | MEDLINE | ID: mdl-33075159

RESUMO

BACKGROUND: The Cystic Fibrosis Foundation recommends both short-term and long-acting insulin therapy when cystic fibrosis-related diabetes (CFRD) has been diagnosed. Diagnosis is based on: an elevated fasting blood glucose level greater than 6.94 mmol/L (125 mg/dL); or oral glucose tolerance tests greater than 11.11 mmol/L (200 mg/dL) at two hours; or symptomatic diabetes for random glucose levels greater than 11.11 mmol/L (200 mg/dL); or glycated hemoglobin levels of at least 6.5%. This is an update of a previously published review. OBJECTIVES: To establish the effectiveness of insulin and oral agents for managing diabetes in people with cystic fibrosis in relation to blood sugar levels, lung function and weight management. SEARCH METHODS: We searched the Cochrane Cystic Fibrosis and Genetic Disorders Group's Trials Register comprising references identified from comprehensive electronic database searches and handsearches of relevant journals and abstract books of conference proceedings. We also handsearched abstracts from pulmonary symposia and the North American Cystic Fibrosis Conferences. Date of most recent register search: 10 September 2020. We searched online trials registries; date of most recent searches: 21 March 2020. SELECTION CRITERIA: Randomized controlled trials comparing all methods of pharmacological diabetes therapy in people with diagnosed CFRD. DATA COLLECTION AND ANALYSIS: Two authors independently extracted data and assessed the risk of bias in the included studies. Authors also used GRADE to assess the quality of the evidence. MAIN RESULTS: The searches identified 29 trials (45 references). Four included trials provide results: one short-term single-center cross-over trial (seven adults) comparing insulin with oral repaglinide and no medication in adults with CFRD and normal fasting glucose; one long-term multicenter trial (61 adults with CFRD) comparing insulin with oral repaglinide and placebo; one long-term multicenter trial (67 adults) comparing insulin with oral repaglinide; and one 12-week single-center cross-over trial (20 adults) comparing the long-acting insulin glargine to short-term neutral protamine Hagedorn insulin. Two ongoing trials of newly approved incretin mimics have been noted for possible future inclusion. Downgrading of the quality of the evidence was mainly due to risks of bias across all domains, but particularly due to concerns surrounding allocation concealment and selective reporting. There were also some concerns due to imprecision from small sample sizes and low event rates. Finally, there may be some bias due to the amounts of insulin and repaglinide given not being comparable. Data from one trial comparing insulin to placebo (39 participants) did not show any difference between groups for the primary outcomes of blood glucose levels (very low-quality evidence), lung function (low-quality evidence) or nutritional status (low-quality evidence). Similarly, no differences between groups were seen for the secondary outcomes of number of hypoglycemic episodes (low-quality evidence), secondary infection complications or quality of life (QoL). These results were mirrored in the narrative reports for the second trial in this comparison (seven participants). Data from the one-year trial comparing repaglinide to placebo (38 participants), showed no differences between groups for the primary outcomes of blood glucose levels (very low-quality evidence), lung function (low-quality evidence) and nutritional status (low-quality evidence). Also, no differences were seen between groups for the secondary outcomes of number of hypoglycemic episodes (low-quality evidence), secondary infection complications or QoL. These findings were mirrored in the narrative reports for the second trial (n = 7) in this comparison. Three trials compared insulin to repaglinide (119 participants). Data from one trial (n = 67) showed no difference in blood glucose levels at either 12 months (high-quality evidence) or 24 months; narrative reports from one trial (45 participants) reported no difference between groups, but the second trial (7 participants) reported a beneficial effect of insulin over repaglinide. Two trials (112 participants) found no difference between insulin and repaglinide in lung function or nutritional status (moderate-quality evidence). Two trials (56 participants) reported no difference in the number of hypoglycemic episodes (low-quality evidence). One trial (45 participants) reported no difference between groups in secondary infections and cystic fibrosis QoL. The single trial comparing glargine to neutral protamine Hagedorn insulin did not report directly on the review's primary outcomes, but did report no differences between groups in post-prandial glucose values and weight; neither group reported infectious complications. There was no difference in episodes of hypoglycemia (very low-quality evidence) and while there was no difference reported in QoL, all participants opted to continue treatment with glargine after the trial was completed. Mortality was not reported by any trial in any comparison, but death was not given as a reason for withdrawal in any trial. AUTHORS' CONCLUSIONS: This review has not found any conclusive evidence that any agent has a distinct advantage over another in controlling hyperglycemia or the clinical outcomes associated with CFRD. Given the treatment burden already experienced by people with cystic fibrosis, oral therapy may be a viable treatment option. While some cystic fibrosis centers use oral medications to help control diabetes, the Cystic Fibrosis Foundation (USA) clinical practice guidelines support the use of insulin therapy and this remains the most widely-used treatment method. Randomized controlled trials specifically related to controlling diabetes and its impact on the course of pulmonary disease process in cystic fibrosis continue to be a high priority. Specifically, investigators should evaluate adherence to different therapies and also whether there is benefit in using additional hypoglycemic agents as well as the newly approved incretin mimics. Agents that potentiate insulin action, especially agents with additional anti-inflammatory potential should also be further investigated as adjuvant therapy to insulin.


Assuntos
Fibrose Cística/complicações , Diabetes Mellitus/tratamento farmacológico , Hipoglicemiantes/administração & dosagem , Insulina/administração & dosagem , Administração Oral , Viés , Glicemia/análise , Carbamatos/administração & dosagem , Fibrose Cística/sangue , Diabetes Mellitus/sangue , Diabetes Mellitus/etiologia , Jejum/sangue , Humanos , Hiperglicemia/tratamento farmacológico , Insulina Glargina/administração & dosagem , Insulina Isófana/administração & dosagem , Piperidinas/administração & dosagem , Ensaios Clínicos Controlados Aleatórios como Assunto
7.
Life Sci ; 260: 118430, 2020 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-32931800

RESUMO

AIMS: Previous investigations demonstrated that tramadol, as a painkiller, similar to morphine induces tolerance and dependence. Furthermore, the cannabinoid receptor 1 (CB1R) located in the nucleus accumbens (NAc) plays a critical role in morphine-induced conditioning. Therefore, the main objective of this study was to evaluate the role of NAc CB1R in tramadol induced conditioning and reinstatement. MAIN METHODS: In the present experiment, the effect of NAc CB1 receptors on tramadol induced conditioning was tested by microinjecting of arachidonylcyclopropylamide (ACPA, CB1R agonist) and AM 251 (CB1R inverse agonist) in the NAc during tramadol-induced conditioning in the adult male Wistar rats. In addition, the role of NAc CB1R in the reinstatement was also evaluated by injecting ACPA and AM 251 after a 10-days extinction period. KEY FINDINGS: The obtained data revealed that the administration of tramadol (1,2, and 4 mg/kg, ip) dose-dependently produced conditioned place preference (CPP). Moreover, intra-NAc administration of ACPA (0.25, 0.5, and 1 µg/rat) dose-dependently induced conditioning, while the administration of AM-251 (30, 60, and 120 ng/rat) induced a significant aversion. In addition, the administration of a non-effective dose of AM251 during tramadol conditioning inhibited conditioning induced by tramadol. On the other hand, the administration of ACPA after extinction induced a significant reinstatement. Notably, the locomotor activity did not change among groups. SIGNIFICANCE: Previous studies have shown that tramadol-induced CPP occurs through µ-opioid receptors. The data obtained in the current study indicated that CB1R located in the NAc is involved in mediating conditioning induced by tramadol. Besides, CB1R also plays a vital role in the reinstatement of tramadol-conditioned animals. It might be due to the effect of opioids on enhancing the level of CB1R.


Assuntos
Analgésicos Opioides/efeitos adversos , Condicionamento Psicológico/efeitos dos fármacos , Núcleo Accumbens/efeitos dos fármacos , Receptor CB1 de Canabinoide/fisiologia , Tramadol/efeitos adversos , Analgésicos Opioides/administração & dosagem , Animais , Condicionamento Clássico , Relação Dose-Resposta a Droga , Extinção Psicológica/efeitos dos fármacos , Masculino , Núcleo Accumbens/metabolismo , Piperidinas/administração & dosagem , Piperidinas/farmacologia , Pirazóis/administração & dosagem , Pirazóis/farmacologia , Ratos Wistar , Receptor CB1 de Canabinoide/agonistas , Tramadol/administração & dosagem
8.
PLoS Negl Trop Dis ; 14(8): e0007857, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32866170

RESUMO

Buruli ulcer (BU), caused by Mycobacterium ulcerans, is currently treated with a daily combination of rifampin and either injectable streptomycin or oral clarithromycin. An intermittent oral regimen would facilitate treatment supervision. We first evaluated the bactericidal activity of newer antimicrobials against M. ulcerans using a BU animal model. The imidazopyridine amine telacebec (Q203) exhibited high bactericidal activity whereas tedizolid (an oxazolidinone closely related to linezolid), selamectin and ivermectin (two avermectine compounds) and the benzothiazinone PBTZ169 were not active. Consequently, telacebec was evaluated for its bactericidal and sterilizing activities in combined intermittent regimens. Telacebec given twice a week in combination with a long-half-life compound, either rifapentine or bedaquiline, sterilized mouse footpads in 8 weeks, i.e. after a total of only 16 doses, and prevented relapse during a period of 20 weeks after the end of treatment. These results are very promising for future intermittent oral regimens which would greatly simplify BU treatment in the field.


Assuntos
Antituberculosos/administração & dosagem , Úlcera de Buruli/tratamento farmacológico , Imidazóis/administração & dosagem , Mycobacterium ulcerans/efeitos dos fármacos , Piperidinas/administração & dosagem , Piridinas/administração & dosagem , Animais , Antituberculosos/uso terapêutico , Úlcera de Buruli/microbiologia , Diarilquinolinas , Modelos Animais de Doenças , Quimioterapia Combinada , Feminino , Imidazóis/uso terapêutico , Camundongos , Camundongos Endogâmicos BALB C , Oxazolidinonas , Piperidinas/uso terapêutico , Piridinas/uso terapêutico , Rifampina/análogos & derivados , Tetrazóis
9.
Expert Opin Pharmacother ; 21(15): 1793-1798, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32735148

RESUMO

INTRODUCTION: Schizophrenia has a prevalence of approximately 1% in the general population, with 15.2 per 100,000 persons affected. Iloperidone is a second-generation antipsychotic drug approved for the treatment of schizophrenia in adults. It acts primarily by D2/5HT2a receptor antagonism, with greater affinity for the 5HT2a receptor than for the D2 receptor. AREAS COVERED: This article discusses iloperidone and aims to provide useful information for clinicians to determine which circumstances would best suit the use of iloperidone to treat schizophrenic patients. In this review, the authors briefly discuss schizophrenia and its treatment, before they discuss properties of iloperidone, its indications, approval process, and adverse effects. Finally, the authors review the specific strengths and weaknesses of the medication. EXPERT OPINION: Iloperidone would be an attractive option in patients who are particularly prone to EPS, or who are showing prominent negative symptoms, as well as cognitive deficits. Its availability only in an oral formulation makes it a better option for patients with good medication adherence, and though it could be useful in patients prone to weight gain or hepatic dysfunction on other second generation antipsychotics, it should be used with caution in patients prone to side effects related to alpha adrenergic blockade.


Assuntos
Antipsicóticos/uso terapêutico , Isoxazóis/uso terapêutico , Piperidinas/uso terapêutico , Esquizofrenia/tratamento farmacológico , Antipsicóticos/administração & dosagem , Antipsicóticos/efeitos adversos , Humanos , Isoxazóis/administração & dosagem , Isoxazóis/efeitos adversos , Piperidinas/administração & dosagem , Piperidinas/efeitos adversos , Receptor 5-HT2A de Serotonina/metabolismo , Receptores de Dopamina D2/metabolismo , Esquizofrenia/metabolismo , Ganho de Peso/efeitos dos fármacos
10.
Life Sci ; 260: 118261, 2020 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-32795539

RESUMO

AIMS: Rheumatoid arthritis is an autoimmune systemic disorder causing pain, swelling, stiffness, and disability in various joints. This work was designed to evaluate the effect of sitagliptin and tofacitinib on Janus kinase (JAK)/signaling transducer and activator of transcription (STAT) and toll like receptor (TLR-4)/nuclear factor kappa B (NF-κB) signaling pathways in adjuvant induced arthritis in rats. MATERIALS AND METHODS: Severity of arthritis was evaluated and serum was analyzed for inflammatory mediators. The mRNA and protein expression level of the most important members of the two signaling pathways were determined. Lipid profile, transaminases and renal function parameters were assessed. KEY FINDINGS: Sitagliptin and tofacitinib significantly decreased the level of inflammatory parameters, the mRNA and protein expression level of the members of JAK/STAT and TLR-4/NF-κB pathways with more prominent effect of sitagliptin on TLR-4/NF-κB pathway and more expected obvious effect of tofacitinib on JAK/STAT pathway. The combination offered additional anti-inflammatory effect by inhibiting the cross talk between these pathways as inhibition of NF-κB activation decreased the serum level of IL-6 preventing the activation of STAT-3 in tibiotarsal tissues. SIGNIFICANCE: The combination of tofacitinib and sitagliptin normalized serum lipids and blood glucose level which could offer protection against cardiovascular diseases and caused partial reversal of serum transaminases and creatinine levels which can protect against tofacitinb's related hepato and nephrotoxicity. We could conclude that the combination of Sitagliptin with tofacitinib can offer synergistic anti-inflammatory effect and more protective action against side effects of tofacitinib.


Assuntos
Artrite Experimental/tratamento farmacológico , Piperidinas/administração & dosagem , Pirimidinas/administração & dosagem , Pirróis/administração & dosagem , Transdução de Sinais/efeitos dos fármacos , Fosfato de Sitagliptina/administração & dosagem , Receptor 4 Toll-Like/metabolismo , Animais , Anti-Inflamatórios , Glicemia/análise , Sinergismo Farmacológico , Quimioterapia Combinada , Hipoglicemiantes , Interleucina-6/sangue , Janus Quinases/metabolismo , Lipídeos/sangue , Masculino , NF-kappa B/metabolismo , Piperidinas/farmacologia , Inibidores de Proteínas Quinases , Pirimidinas/farmacologia , Pirróis/farmacologia , Ratos , Ratos Sprague-Dawley , Receptor Cross-Talk/efeitos dos fármacos , Fatores de Transcrição STAT/metabolismo , Fator de Transcrição STAT3/metabolismo
11.
Lancet Respir Med ; 8(11): 1132-1143, 2020 11.
Artigo em Inglês | MEDLINE | ID: mdl-32479794

RESUMO

BACKGROUND: We evaluated the efficacy and safety of tepotinib, a potent and highly selective oral MET inhibitor, plus gefitinib in patients with epidermal growth factor receptor (EGFR)-mutant non-small-cell lung cancer (NSCLC) with MET overexpression (immunohistochemistry [IHC]2+ or IHC3+) or MET amplification having acquired resistance to EGFR inhibition. METHODS: In this open-label, phase 1b/2, multicentre, randomised trial (the INSIGHT study), we enrolled adult patients (≥18 years) with advanced or metastatic NSCLC, and Eastern Cooperative Oncology Group performance status of 0 or 1, from academic medical centres and community clinics in six Asian countries. In phase 1b, patients received oral tepotinib 300 mg or 500 mg plus gefitinib 250 mg once daily. In phase 2, patients with EGFR-mutant, T790M-negative NSCLC MET overexpression or MET amplification were randomly assigned (initially in a 1:1 ratio and then 2:1 following a protocol amendment) to tepotinib plus gefitinib at the recommended phase 2 dose or to standard platinum doublet chemotherapy. Randomisation was done centrally via an interactive voice-response system. The primary endpoint was investigator-assessed progression-free survival (PFS). Secondary endpoints included overall survival (OS) and safety. Subgroup analyses were preplanned in patients with high MET overexpression (IHC3+) or MET amplification (mean gene copy number ≥5 or MET to centromere of chromosome 7 ratio ≥2). Efficacy and patient characteristics were assessed on an intention-to-treat basis and safety was assessed for all patients who received at least one dose of study medication. Low recruitment led to early termination of phase 2, so all analyses are considered to be exploratory. This study is registered with ClinicalTrials.gov, NCT01982955, and the European Union Drug Regulating Authorities Clinical Trials Database, Eudra-CT 2016-001604-28. FINDINGS: From Dec 23, 2013, to May 25, 2017, 18 patients were enrolled in phase 1b (n=6 in the 300 mg tepotinib group; n=12 in the 500 mg tepotinib group) and 55 patients in phase 2 (n=31 in the tepotinib plus gefitinib group; n=24 in the chemotherapy group). No dose-limiting toxicities were observed in phase 1b, so tepotinib 500 mg was used as the recommended phase 2 dose. In phase 2, survival outcomes were similar between groups: median PFS was 4·9 months in the tepotinib plus gefitinib group (90% CI 3·9-6·9) versus 4·4 months in the chemotherapy group (90% CI 4·2-6·8; hazard ratio [HR] 0·67, 90% CI 0·35-1·28). Median OS was 17·3 months in the tepotinib plus gefitinib group (12·1-37·3) versus 18·7 months in the chemotherapy group (15·9-20·7; HR 0·69, 0·34-1·41). PFS and OS were longer with tepotinib plus gefitinib than with chemotherapy in patients with high (IHC3+) MET overexpression (n=34; median PFS 8·3 months [4·1-16·6] vs 4·4 months [4·1-6·8]; HR 0·35, 0·17-0·74; median OS 37·3 months [90% CI 24·2-37·3] vs 17·9 months [12·0-20·7]; HR 0·33, 0·14-0·76) or MET amplification (n=19; median PFS 16·6 months [8·3-not estimable] vs 4·2 months [1·4-7·0]; HR 0·13, 0·04-0·43; median OS 37·3 months [90% CI not estimable] vs 13·1 months [3·25-not estimable]; HR 0·08, 0·01-0·51). The most frequent treatment-related grade 3 or worse adverse events were increased amylase (5 [16%] of 31 patients) and lipase (4 [13%]) concentrations in the tepotinib plus gefitinib group and anaemia (7 [30%] of 23 patients) and decreased neutrophil count (3 [13%]) in the chemotherapy group. INTERPRETATION: Despite early study termination, in a preplanned subgroup analysis, our findings suggest improved anti activity for tepotinib plus gefitinib compared with standard chemotherapy in patients with EGFR-mutant NSCLC and MET amplification, warranting further exploration. FUNDING: Merck KGaA.


Assuntos
Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Gefitinibe/administração & dosagem , Regulação Neoplásica da Expressão Gênica/genética , Neoplasias Pulmonares/tratamento farmacológico , Piperidinas/administração & dosagem , Proteínas Proto-Oncogênicas c-met/genética , Piridazinas/administração & dosagem , Pirimidinas/administração & dosagem , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/mortalidade , Carcinoma Pulmonar de Células não Pequenas/patologia , Intervalo Livre de Doença , Resistencia a Medicamentos Antineoplásicos/genética , Receptores ErbB/efeitos dos fármacos , Receptores ErbB/genética , Feminino , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/mortalidade , Neoplasias Pulmonares/patologia , Masculino , Pessoa de Meia-Idade , Mutação , Prognóstico , Modelos de Riscos Proporcionais , Medição de Risco , Análise de Sobrevida , Resultado do Tratamento
14.
Artigo em Inglês | MEDLINE | ID: mdl-32429245

RESUMO

OBJECTIVE: To create a mobile application able to help patients follow medical treatments properly. METHODS: We designed and developed a custom Android/iOS App to remind patients of the pharmaceutical drugs to be taken, of the visits and exams to attend, and to detect their compliance with their personal therapeutic plan. In this paper we describe the App development, UX/UI design, Gamification. TuTOR is an Android and iOS application designed to remind patients of the drugs to be taken, giving them all the information related to their therapeutic plans in a simple and non-invasive way. Thanks to a dedicated back-office, specially designed to meet specific medical information needs, the App can also help physicians detect their patients' compliance with their treatments and modify prescriptions in real time. The App also ensures a state-of-the-art approach to data security and privacy protection. The main feature of TuTOR is the smart therapy assistant, which features dedicated alarms to remind users of taking their prescription drugs. Thanks to the automatic synchronization with a local database, the alert system works even without connection to the Internet. Particular attention was paid during the App's design process: we looked to create an intuitive interface to ensure absolute ease of use, with state-of-the-art visual design aimed at maximizing user experience. Other relevant features include the App's ability to givevisual evidence of the most important drugs to be taken and its note-taking feature, which gives patients the possibility to note down indications on why a specific drug was skipped. The App also keeps track of upcoming medical exams, laboratory tests, and visits on a devoted calendar. It also helps patients by listing therapy contacts, such as physicians' phone numbers, and indicates all medical references by showing, for example, locations of relevant clinics and pharmacies on a map. Thanks to specific visual progress indicators and an innovative gamification approach, the App encourages users to faithfully follow therapy guidelines. With TuTOR, assessing the therapy's state of completion is quick and easy.Thanksto the privacy-by-design approach used, all data managed by the system is compliant with the European Privacy Regulation and it is not available to third parties. EXPECTED RESULTS: A mobile App for medication adherence might increase objectively and subjectively measured adherence.


Assuntos
Artrite Reumatoide , Adesão à Medicação , Aplicativos Móveis , Piperidinas , Inibidores de Proteínas Quinases , Pirimidinas , Pirróis , Adolescente , Adulto , Artrite Reumatoide/tratamento farmacológico , Segurança Computacional , Feminino , Humanos , Piperidinas/administração & dosagem , Gravidez , Inibidores de Proteínas Quinases/administração & dosagem , Pirimidinas/administração & dosagem , Pirróis/administração & dosagem , Adulto Jovem
16.
Psychopharmacology (Berl) ; 237(6): 1783-1793, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32296859

RESUMO

RATIONALE: Patients diagnosed with schizophrenia typically receive life-long treatments with antipsychotic drugs (APDs). However, the impact of chronic APDs treatment on neuroplastic mechanisms in the brain remains largely elusive. OBJECTIVE: Here, we focused on blonanserin, a second-generation antipsychotic (SGA) that acts as an antagonist at dopamine D2, D3, and serotonin 5-HT2A receptors, and represents an important tool for the treatment of schizophrenia. METHODS: We used rats to investigate the ability of chronic treatment blonanserin to modulate the activity of brain structures relevant for schizophrenia, under baseline conditions or in response to an acute forced swim session (FSS). We measured the expression of different immediate early genes (IEGs), including c-Fos, Arc/Arg 3.1, Zif268 and Npas4. RESULTS: Blonanserin per se produced limited changes in the expression of these genes under basal conditions, while, as expected, FSS produced a significant elevation of IEGs transcription in different brain regions. The response of blonanserin-treated rats to FSS show anatomical and gene-selective differences. Indeed, the upregulation of IEGs was greatly reduced in the striatum, a brain structure enriched in dopamine receptors, whereas the upregulation of some genes (Zif268, Npas4) was largely preserved in other regions, such as the prefrontal cortex and the ventral hippocampus. CONCLUSIONS: Taken together, our findings show that chronic exposure to blonanserin modulates selective IEGs with a specific anatomical profile. Moreover, the differential activation of specific brain regions under challenging conditions may contribute to specific clinical features of the drug.


Assuntos
Antipsicóticos/administração & dosagem , Encéfalo/efeitos dos fármacos , Genes Precoces/efeitos dos fármacos , Piperazinas/administração & dosagem , Piperidinas/administração & dosagem , Estresse Psicológico/tratamento farmacológico , Animais , Encéfalo/fisiologia , Esquema de Medicação , Genes Precoces/fisiologia , Masculino , Ratos , Ratos Sprague-Dawley , Receptores Dopaminérgicos/metabolismo , Esquizofrenia/tratamento farmacológico , Esquizofrenia/genética , Estresse Psicológico/genética , Estresse Psicológico/psicologia
17.
J Oncol Pharm Pract ; 26(5): 1190-1199, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32279595

RESUMO

Mantle cell lymphoma is a rare subtype of B-cell non-Hodgkin's lymphomas that is generally classified as an aggressive lymphoma requiring front-line chemo-immunotherapy with stem cell rescue. Despite effective treatment, many patients relapse or are refractory to front-line therapy. In addition, these patients may also develop drug resistance requiring novel modalities for subsequent lines. Bruton's tyrosine kinase inhibitors have demonstrated a well-tolerated safety and efficacy profile across several B-cell malignancies. Ibrutinib, acalabrutinib, and zanubrutinib are FDA-approved as treatment options for patients with Mantle cell lymphoma following one prior line of therapy. Various factors should be considered which include the adverse event profile of these agents and ability to adhere to therapy. In this article, we review the role of Bruton's tyrosine kinase inhibitors for the management of Mantle cell lymphoma and review the clinical pharmacology, pharmacokinetics, safety and efficacy, and future directions.


Assuntos
Antineoplásicos/uso terapêutico , Linfoma de Célula do Manto/tratamento farmacológico , Inibidores de Proteínas Quinases/uso terapêutico , Tirosina Quinase da Agamaglobulinemia/antagonistas & inibidores , Benzamidas/administração & dosagem , Humanos , Imunoterapia , Piperidinas/administração & dosagem , Pirazinas/administração & dosagem , Pirazóis/administração & dosagem , Pirimidinas/administração & dosagem
19.
Anticancer Res ; 40(3): 1395-1403, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-32132036

RESUMO

BACKGROUND/AIM: The aim of the study was to examine the efficacy of the combination of anaplastic lymphoma kinase (ALK) inhibitors with other inhibitors for the treatment of ALK-positive lymphomas. This approach is predicted to be an alternative way for suppressing ALK-positive anaplastic large cell lymphoma (ALCL). MATERIALS AND METHODS: We treated ALK-positive ALCL cell lines, KARPAS-299 and SU-DHL-1, with the ALK inhibitor alectinib and the mammalian target of rapamycin (mTOR) inhibitor everolimus. RESULTS: The ALK inhibitor alectinib had a selective ALK-dependent inhibitory effect on ALK-positive cancer cell proliferation. Treatment with alectinib or everolimus inhibited target molecules, and their combination augmented their inhibitory effect on the mTOR pathway. Furthermore, the combination treatment significantly inhibited cell proliferation and induced cell cycle arrest at the G0/G1 phase in ALK-positive ALCL cells. CONCLUSION: The combination of both inhibitors synergistically inhibits ALK-positive ALCL cell growth via the ALK/mTOR pathway.


Assuntos
Quinase do Linfoma Anaplásico/antagonistas & inibidores , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Carbazóis/farmacologia , Everolimo/farmacologia , Linfoma Anaplásico de Células Grandes/tratamento farmacológico , Linfoma Anaplásico de Células Grandes/enzimologia , Piperidinas/farmacologia , Quinase do Linfoma Anaplásico/biossíntese , Carbazóis/administração & dosagem , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Processos de Crescimento Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Crizotinibe/administração & dosagem , Crizotinibe/farmacologia , Sinergismo Farmacológico , Everolimo/administração & dosagem , Humanos , Células Jurkat , Linfoma Anaplásico de Células Grandes/patologia , Piperidinas/administração & dosagem , Inibidores de Proteínas Quinases/administração & dosagem , Inibidores de Proteínas Quinases/farmacologia
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