RESUMO
Background: For treating patients with refractory chronic spontaneous urticaria (CSU) resistant to standard doses of 2nd generation H1-antihistamines (H1AH) the International and Japanese guidelines recommend increasing H1AH dose. The latter also recommends switching to a different H1AH. This study explored if the efficacy of the standard dose of bilastine 20 mg is non-inferior to that of double-dose of H1AH in patients with refractory CSU. Methods: This phase IV, multicenter, open-label, randomized, parallel-group trial evaluated the efficacy and safety of switching treatment to bilastine compared to treatment with a 2-fold dose of H1AH in patients with CSU refractory to standard dose H1AH. The primary endpoint was the mean total symptom score (TSS) at Day 5-7 after the start of administration. Results: Treatment efficacy and safety were evaluated in 128 patients (bilastine, n=64; 2-fold dose of H1AH, n=64). The mean TSS at Day 5-7 after the start of administration was smaller than the non-inferiority margin of 0.8, demonstrating non-inferiority of the bilastine switching group to the double-dose H1AH group (0.17 (95% CI -0.32, 0.67)). No difference in Japanese version of Epworth Sleepiness Scale (JESS), DLQI, and urticaria activity score over 7 consecutive days (UAS7) was observed between the two groups. There were no serious adverse events in either group. H1AH-related adverse events occurred in 5 subjects (8 cases) and 2 subjects (3 cases) in the double-dose H1AH and bilastine groups, respectively. Conclusions: Switching treatment to bilastine demonstrated non-inferiority to a double-dose of H1AH in terms of efficacy in patients with CSU refractory to standard dose H1AH with a favorable safety profile. Clinical trial registration: https://jrct.niph.go.jp/latest-detail/jRCTs051180105, identifier jRCTs051180105.
Assuntos
Urticária Crônica , Antagonistas dos Receptores Histamínicos H1 , Piperidinas , Humanos , Masculino , Feminino , Adulto , Urticária Crônica/tratamento farmacológico , Pessoa de Meia-Idade , Piperidinas/uso terapêutico , Piperidinas/efeitos adversos , Piperidinas/administração & dosagem , Resultado do Tratamento , Antagonistas dos Receptores Histamínicos H1/uso terapêutico , Antagonistas dos Receptores Histamínicos H1/administração & dosagem , Antagonistas dos Receptores Histamínicos H1/efeitos adversos , Benzimidazóis/uso terapêutico , Benzimidazóis/efeitos adversos , Benzimidazóis/administração & dosagem , Adulto Jovem , IdosoRESUMO
BACKGROUND: Results of conventional induction chemotherapies in primary central nervous system lymphoma (PCNSL) need to be improved. Ibrutinib, a BTK inhibitor, and lenalidomide, an immunomodulatory drug, have shown promising results at relapse, supporting to further assess their individual use in combination with high-dose methotrexate-based chemotherapy. METHODS: Patients with newly diagnosed PCNSL were randomized to receive four 28-day cycles of ibrutinib or lenalidomide in combination with R-MPV (rituximab, methotrexate, procarbazine, vincristine and prednisone) in a 3 + 3 design. Responders then received a consolidation with R-Cytarabine and an intensive chemotherapy with autologous stem cell transplantation. The objective of the phase IB study was to define the recommended phase II dose (RP2D) based on the dose-limiting toxicity (DLT) occurring during the first induction cycle. RESULTS: Twenty-six patients (median age 52) were randomized. Four DLTs were observed: one grade 5 aspergillosis and pneumocystosis, one grade 4 catheter-related infection and two grade 3 increased alanine aminotransferase levels. RP2D of ibrutinib and lenalidomide were 560 mg daily (D3-14 and D17-28) and 15 mg daily (D1-21) respectively, in combination with R-MPV. In both arms, the most frequent grade ≥3 treatment-related adverse events were hepatic cytolysis, neutropenia and infections. One grade 4 Lyell's syndrome was reported at cycle 2 in the lenalidomide arm. After 4 induction cycles, the overall response rates were 76.9% and 83.3% in the lenalidomide and ibrutinib arm, respectively. CONCLUSION: Targeted induction therapies combining lenalidomide or ibrutinib with R-MPV are feasible for first-line PCNSL. The safety profile is consistent with the known safety profiles of R-MPV and both targeted therapies. The phase II part of the study is ongoing. TRIAL REGISTRATION: NCT04446962.
Assuntos
Adenina , Protocolos de Quimioterapia Combinada Antineoplásica , Neoplasias do Sistema Nervoso Central , Lenalidomida , Piperidinas , Pirazóis , Pirimidinas , Humanos , Lenalidomida/administração & dosagem , Lenalidomida/uso terapêutico , Lenalidomida/efeitos adversos , Adenina/análogos & derivados , Adenina/administração & dosagem , Pessoa de Meia-Idade , Piperidinas/administração & dosagem , Piperidinas/uso terapêutico , Piperidinas/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Masculino , Feminino , Neoplasias do Sistema Nervoso Central/tratamento farmacológico , Idoso , Adulto , Pirimidinas/administração & dosagem , Pirimidinas/uso terapêutico , Pirimidinas/efeitos adversos , Pirazóis/administração & dosagem , Pirazóis/uso terapêutico , Pirazóis/efeitos adversos , Vincristina/administração & dosagem , Vincristina/uso terapêutico , Vincristina/efeitos adversos , Rituximab/administração & dosagem , Rituximab/uso terapêutico , Rituximab/efeitos adversos , Metotrexato/administração & dosagem , Metotrexato/uso terapêutico , Prednisona/administração & dosagem , Prednisona/uso terapêutico , Prednisona/efeitos adversos , Linfoma/tratamento farmacológicoRESUMO
Liposils, synthesized via the liposome templating method, offer a promising strategy for enhancing liposome stability by employing a silica coating. This study focuses on the development of nanocarriers utilizing silica-coated nanoliposomes for encapsulating the poorly water-soluble drug, ibrutinib. Ibrutinib-loaded nanoliposomes were meticulously formulated using the reverse-phase evaporation technique, serving as templates for silica coating, resulting in spherical liposils with an average size of approximately 240 nanometers. Comprehensive characterization of the liposil's physical and chemical properties was conducted using various analytical methods, including dynamic light scattering, transmission electron microscopy, Fourier-transform infrared spectroscopy, and X-ray diffraction analysis. Liposils demonstrated superior performance compared to ibrutinib-loaded nanoliposomes, showing sustained drug release profiles in simulated intestinal fluids and resistance to simulated gastric fluid, as confirmed by dissolution studies. Moreover, ibrutinib liposils exhibited a significant increase in half-life (4.08-fold) and notable improvement in bioavailability (3.12-fold) compared to ibrutinib suspensions, as determined by pharmacokinetic studies in rats. These findings underscore the potential of liposils as nanocarriers for orally delivering poorly water-soluble drugs, offering enhanced stability and controlled release profiles, thereby improving bioavailability prospects and therapeutic efficacy. This approach holds promise for addressing challenges associated with the oral administration of drugs with limited solubility, thereby advancing drug delivery technologies and clinical outcomes in pharmaceutical research and development.
Assuntos
Adenina , Disponibilidade Biológica , Lipossomos , Piperidinas , Pirazóis , Pirimidinas , Adenina/farmacocinética , Adenina/análogos & derivados , Adenina/administração & dosagem , Adenina/química , Piperidinas/farmacocinética , Piperidinas/administração & dosagem , Piperidinas/química , Animais , Administração Oral , Lipossomos/química , Pirimidinas/farmacocinética , Pirimidinas/administração & dosagem , Pirimidinas/química , Ratos , Pirazóis/farmacocinética , Pirazóis/administração & dosagem , Pirazóis/química , Masculino , Sistemas de Liberação de Medicamentos , Liberação Controlada de Fármacos , Nanopartículas/química , Ratos Sprague-Dawley , Dióxido de Silício/químicaRESUMO
BACKGROUND: Clinical amyopathic dermatomyositis is characterized by cutaneous symptoms but lacks muscle symptoms. Anti-melanoma differentiation-associated gene 5 antibodies are frequently found in Japanese patients with clinical amyopathic dermatomyositis. Patients with rapidly progressive interstitial lung disease with positive anti-melanoma differentiation-associated gene 5 antibodies have poor prognoses, and majority of them are treated with combination immunosuppressive therapy; however, the best treatment is yet to be determined. CASE PRESENTATION: A 52-year-old Asian male patient presented with a chief complaint of dyspnea on exertion. He had a typical skin rash and rapidly progressive interstitial pneumonia. Additionally, anti-melanoma differentiation-associated gene 5 antibodies were detected; therefore, he was diagnosed with dermatomyositis-associated interstitial pneumonia. Respiratory failure worsened despite administering steroid pulse therapy, tacrolimus, and cyclophosphamide. Consequently, plasma exchange was performed on day 13 of admission. After a slight improvement, the patient's respiratory failure worsened. Thus, cyclophosphamide was replaced by tofacitinib on day 28. Although respiratory failure improved and the progression of interstitial pneumonia seemed under control, ßD-glucan level increased and Aspergillus antigen was detected on day 49. Micafungin and voriconazole were administered, but the patient succumbed to worsening respiratory failure on day 61. The pathological autopsy revealed multiple nodular lesions with cavity formation in both lungs and the presence of Aspergillus with severe neutrophilic infiltration and necrosis, which supported the diagnosis of invasive pulmonary aspergillosis. CONCLUSION: The patient with anti-melanoma differentiation-associated gene 5 antibody-related rapidly progressive interstitial lung disease, whose disease was difficult to control after the administration of triple immunosuppressive therapy (steroids, tacrolimus, and cyclophosphamide), showed good response with tofacitinib. Unfortunately, the patient died of invasive pulmonary aspergillosis owing to severe immunosuppression; thus, the signs of complications should be promptly detected.
Assuntos
Dermatomiosite , Helicase IFIH1 Induzida por Interferon , Doenças Pulmonares Intersticiais , Piperidinas , Pirimidinas , Humanos , Dermatomiosite/tratamento farmacológico , Dermatomiosite/complicações , Dermatomiosite/imunologia , Masculino , Doenças Pulmonares Intersticiais/tratamento farmacológico , Pessoa de Meia-Idade , Pirimidinas/uso terapêutico , Helicase IFIH1 Induzida por Interferon/imunologia , Piperidinas/uso terapêutico , Piperidinas/administração & dosagem , Autoanticorpos/sangue , Imunossupressores/uso terapêutico , Resultado do Tratamento , Inibidores de Proteínas Quinases/uso terapêuticoRESUMO
ß-site amyloid precursor protein cleaving enzyme (BACE1) represents a key target for Alzheimer's disease (AD) therapy because it is essential for producing the toxic amyloid ß (Aß) peptide that plays a crucial role in the disease's development. BACE1 inhibitors are a promising approach to reducing Aß levels in the brain and preventing AD progression. However, systemic delivery of such inhibitors to the brain demonstrates limited efficacy because of the presence of the blood-brain barrier (BBB). Nose-to-brain (NtB) delivery has the potential to overcome this obstacle. Liposomal drug delivery systems offer several advantages over traditional methods for delivering drugs and nucleic acids from the nose to the brain. The current study aims to prepare, characterize, and evaluate in vitro liposomal forms of donepezil, memantine, BACE-1 siRNA, and their combination for possible treatment of AD via NtB delivery. All the liposomal formulations were prepared using the rotary evaporation method. Their cellular internalization, cytotoxicity, and the suppression of beta-amyloid plaque and other pro-inflammatory cytokine expressions were studied. The Calu-3 Transwell model was used as an in vitro system for mimicking the anatomical and physiological conditions of the nasal epithelium and studying the suitability of the proposed formulations for possible NtB delivery. The investigation results show that liposomes provided the effective intracellular delivery of therapeutics, the potential to overcome tight junctions in BBB, reduced beta-amyloid plaque accumulation and pro-inflammatory cytokine expression, supporting the therapeutic potential of our approach.
Assuntos
Administração Intranasal , Doença de Alzheimer , Secretases da Proteína Precursora do Amiloide , Ácido Aspártico Endopeptidases , Donepezila , Lipossomos , RNA Interferente Pequeno , Doença de Alzheimer/tratamento farmacológico , Humanos , Secretases da Proteína Precursora do Amiloide/antagonistas & inibidores , Ácido Aspártico Endopeptidases/antagonistas & inibidores , RNA Interferente Pequeno/administração & dosagem , Donepezila/administração & dosagem , Sistemas de Liberação de Medicamentos/métodos , Barreira Hematoencefálica/metabolismo , Barreira Hematoencefálica/efeitos dos fármacos , Encéfalo/metabolismo , Encéfalo/efeitos dos fármacos , Piperidinas/administração & dosagem , Piperidinas/farmacocinética , Piperidinas/farmacologia , Mucosa Nasal/metabolismo , Mucosa Nasal/efeitos dos fármacos , Indanos/administração & dosagem , Indanos/farmacocinética , Peptídeos beta-Amiloides/metabolismoAssuntos
Adenina , Protocolos de Quimioterapia Combinada Antineoplásica , Leucemia Linfocítica Crônica de Células B , Piperidinas , Pirazóis , Pirimidinas , Humanos , Leucemia Linfocítica Crônica de Células B/tratamento farmacológico , Leucemia Linfocítica Crônica de Células B/patologia , Pirimidinas/administração & dosagem , Pirimidinas/uso terapêutico , Piperidinas/administração & dosagem , Piperidinas/uso terapêutico , Pirazóis/administração & dosagem , Pirazóis/uso terapêutico , Adenina/análogos & derivados , Adenina/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Inibidores de Proteínas Quinases/uso terapêutico , Inibidores de Proteínas Quinases/administração & dosagem , Nitrilas/administração & dosagem , Nitrilas/uso terapêuticoRESUMO
PURPOSE: This retrospective real-world study compared overall survival (OS) between patients with BRCA wild-type (BRCAwt) recurrent epithelial ovarian cancer (OC) who received niraparib second-line maintenance (2LM) versus active surveillance (AS) using target trial emulation, cloning, inverse probability of censoring weighting (IPCW) methodology to minimize immortal time bias. METHODS: Eligible patients from a United States-based, deidentified, electronic health record-derived database were diagnosed with epithelial OC (January 1, 2011-May 31, 2021), were BRCAwt, and completed second-line (2L) therapy (January 1, 2017-March 2, 2022). Patient data were cloned at index (2L last treatment date), assigned to niraparib 2LM and AS cohorts, and censored when treatment deviated from clone assignment. Follow-up was measured from index to earliest of study end (May 31, 2022), last activity, or death. Median OS (mOS) and hazard ratios were estimated from stabilized IPCW Kaplan-Meier curves and Cox regression models. RESULTS: Overall, 199 patients received niraparib 2LM, and 707 had their care managed with AS. Key characteristics were balanced across cohorts after cloning and stabilized IPCW. Median follow-up was 15.6- and 9.3-months pre-cloning. IPCW mOS was 24.1 months (95% CI: 20.9-29.5) and 18.4 months (95% CI: 15.1-22.8) in niraparib 2LM and AS cohorts, respectively (hazard ratio, 0.77; 95% CI: 0.66-0.89). CONCLUSIONS: This real-world study provides supportive evidence of an OS benefit for patients with BRCAwt recurrent OC who received 2LM niraparib monotherapy compared with those whose care was managed with AS. The analytic strategies implemented were useful in minimizing immortal time bias and measured confounding.
Assuntos
Indazóis , Recidiva Local de Neoplasia , Neoplasias Ovarianas , Piperidinas , Humanos , Feminino , Piperidinas/uso terapêutico , Piperidinas/administração & dosagem , Indazóis/uso terapêutico , Indazóis/administração & dosagem , Pessoa de Meia-Idade , Estudos Retrospectivos , Idoso , Neoplasias Ovarianas/tratamento farmacológico , Neoplasias Ovarianas/mortalidade , Carcinoma Epitelial do Ovário/tratamento farmacológico , Carcinoma Epitelial do Ovário/mortalidade , Inibidores de Poli(ADP-Ribose) Polimerases/uso terapêutico , Inibidores de Poli(ADP-Ribose) Polimerases/administração & dosagem , Adulto , Conduta Expectante , Estados Unidos/epidemiologia , Quimioterapia de Manutenção/métodos , Bases de Dados FactuaisAssuntos
Inibidores da Colinesterase , Delírio , Donepezila , Idoso , Feminino , Humanos , Masculino , Inibidores da Colinesterase/efeitos adversos , Inibidores da Colinesterase/administração & dosagem , Delírio/induzido quimicamente , Delírio/tratamento farmacológico , Donepezila/efeitos adversos , Donepezila/administração & dosagem , Quimioterapia Combinada , Indanos/efeitos adversos , Indanos/administração & dosagem , Piperidinas/efeitos adversos , Piperidinas/administração & dosagemRESUMO
INTRODUCTION: Rheumatoid arthritis (RA) is a chronic systemic autoimmune disease characterized by synovial inflammation, joint swelling, and pain involving multiple joints. While biologic disease-modifying antirheumatic drugs (bDMARDs) and targeted synthetic DMARDs (tsDMARDs) are popular treatments for RA, there is limited research on their combined use. This study examined a cohort of RA patients who demonstrated inadequate response to bDMARDs and subsequently initiated combination therapy with tofacitinib and bDMARDs, assessing both the efficacy and safety profile of this therapeutic approach. METHODS: In this study, we retrospectively collected the electronic medical records (EMR) of 62 adult patients with RA who were admitted to the Fourth Affiliated Hospital Zhejiang University School of Medicine between August 2018 and December 2022. All patients had received at least one bDMARD treatment for more than 3 months and still exhibited moderate-to-high disease activity. Tofacitinib 5 mg bid was added to their original biological treatment in 28 cases, and other 34 cases switched to another bDMARD or tsDMARD as control group. Treatment was continued for 24 weeks following the initiation of combination therapy. Changes in DAS28-ESR and ACR20, 50, 70 response rates at week 24 were collected and analyzed from baseline, while changes in C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR) at weeks 4, 8, 12, 24 were also collected and analyzed. RESULTS: After 24 weeks of treatment, the DAS28-ESR score in combined treatment group decreased significantly from a baseline of 5.26 ± 0.90 (3.87-8.31) to 2.67 ± 0.86 (1.41-5.11), with remission achieved by 19 patients (67.9%) and low disease activity achieved by five patients (17.9%). The DAS28-ESR in the control group exhibited a decrease from 5.20 ± 0.77 (3.87-7.23) at baseline to 3.25 ± 1.29 (1.54-5.69). In all, 13 patients (38.2%) achieved remission, while another 11 patients (32.4%) achieved low disease activity. The ACR20, 50, 70 response rates were 85.71%, 75%, and 39.29% in the combined treatment group, whereas it were 75.0%, 53.57%, 21.43% in the control group. Additionally, both ESR and CRP levels decreased significantly during the course of treatment without any reported adverse events leading to discontinuation. CONCLUSION: Our findings offer some evidence, supporting the effectiveness and safety of combining bDMARD with JAKi tofacitinib in RA patients who have an inadequate response to bDMARD monotherapy. This combination effectively manages disease activity while maintaining a relatively low and manageable incidence of adverse events. Further prospective randomized controlled trials with large sample sizes are anticipated to provide evidence-based medical support.
Assuntos
Antirreumáticos , Artrite Reumatoide , Quimioterapia Combinada , Piperidinas , Pirimidinas , Humanos , Artrite Reumatoide/tratamento farmacológico , Artrite Reumatoide/diagnóstico , Pirimidinas/efeitos adversos , Pirimidinas/uso terapêutico , Pirimidinas/administração & dosagem , Masculino , Estudos Retrospectivos , Feminino , Pessoa de Meia-Idade , Piperidinas/efeitos adversos , Piperidinas/administração & dosagem , Piperidinas/uso terapêutico , Antirreumáticos/efeitos adversos , Antirreumáticos/uso terapêutico , Antirreumáticos/administração & dosagem , Resultado do Tratamento , Adulto , Idoso , Inibidores de Proteínas Quinases/efeitos adversos , Inibidores de Proteínas Quinases/uso terapêutico , Inibidores de Proteínas Quinases/administração & dosagem , Fatores de Tempo , Produtos Biológicos/efeitos adversos , Produtos Biológicos/uso terapêutico , Produtos Biológicos/administração & dosagem , Indução de RemissãoRESUMO
BACKGROUND: MAGNITUDE (NCT03748641) demonstrated favourable outcomes with niraparib plus abiraterone acetate plus prednisone (+AAP) versus placebo+AAP in patients with BRCA1/2-altered metastatic castration-resistant prostate cancer (mCRPC). Imbalances in prognostic variables were reported between arms, which impacts estimation of both the clinical benefit and costeffectiveness of niraparib+AAP for healthcare systems. A pre-specified multivariable analysis (MVA) demonstrated improved overall survival (OS) with niraparib+AAP. Here, we used an inverse probability of treatment weighting (IPTW) model to adjust for covariate imbalances and assess time-to-event outcomes. METHODS: IPTW analysis of time-to-event outcomes was conducted using data from patients with BRCA1/2-altered mCRPC (N = 225) in MAGNITUDE. Patients received niraparib+AAP or placebo+AAP. OS, radiographic progression-free survival, time to symptomatic progression, time to initiation of cytotoxic chemotherapy and time to prostate-specific antigen progression were assessed. Weighted Kaplan-Meier curves were generated for each endpoint, and adjusted hazard ratios (HR) were obtained from a weighted Cox model. RESULTS: Improvements in survival outcomes were estimated for niraparib+AAP versus placebo+AAP: unadjusted median OS was 30.4 months versus 28.6 months, respectively (HR: 0.79; 95 % confidence interval [CI]: 0.55, 1.12; p = 0.183). Following IPTW, median OS increased to 34.1 months with niraparib+AAP versus a decrease to 27.4 with placebo (HR: 0.65; 95 % CI: 0.46, 0.93; p = 0.017). Similar improvements were observed for other time-to-event endpoints. CONCLUSIONS: IPTW adjustment provided a more precise estimate of the clinical benefit of niraparib+AAP versus placebo+AAP in patients with BRCA1/2-altered mCRPC. Results were consistent with the pre-specified MVA, and further demonstrated the value of adjusting for baseline imbalances, particularly in smaller studies. TRIAL REGISTRATION: NCT03748641 (MAGNITUDE).
Assuntos
Acetato de Abiraterona , Protocolos de Quimioterapia Combinada Antineoplásica , Indazóis , Piperidinas , Prednisona , Neoplasias de Próstata Resistentes à Castração , Humanos , Masculino , Indazóis/uso terapêutico , Indazóis/administração & dosagem , Prednisona/administração & dosagem , Prednisona/uso terapêutico , Piperidinas/uso terapêutico , Piperidinas/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Acetato de Abiraterona/administração & dosagem , Acetato de Abiraterona/uso terapêutico , Neoplasias de Próstata Resistentes à Castração/tratamento farmacológico , Neoplasias de Próstata Resistentes à Castração/patologia , Neoplasias de Próstata Resistentes à Castração/mortalidade , Idoso , Pessoa de Meia-Idade , Método Duplo-Cego , Intervalo Livre de Progressão , Idoso de 80 Anos ou maisRESUMO
A 76-year-old woman with a 2-year history of Parkinson's disease presented with dropped head, which had developed rapidly after she had been prescribed donepezil hydrochloride (DNP) at 3â |mg/day. After one month of medication, the extent of the head drop reached 90°. Examination revealed hypertrophy of the left sternocleidomastoid muscle, but no weakness of the extensor muscles in the cervical region. Surface electromyography demonstrated co-|contraction of the sternocleidomastoid and splenius capitus muscles during head flexion and extension. DNP was withdrawn, resulting in immediate amelioration of the head drop, and complete resolution was achieved after two months. Although head drop is often seen in patients with Parkinson's disease, few previous reports have documented DNP as a causative factor. If patients with Parkinson's disease develop head drop, it is important to investigate any history of DNP medication.
Assuntos
Donepezila , Indanos , Doença de Parkinson , Piperidinas , Humanos , Donepezila/administração & dosagem , Idoso , Feminino , Doença de Parkinson/tratamento farmacológico , Piperidinas/administração & dosagem , Piperidinas/efeitos adversos , Indanos/administração & dosagem , Indanos/efeitos adversos , Eletromiografia , Resultado do Tratamento , Inibidores da Colinesterase/administração & dosagem , CabeçaAssuntos
Líquen Plano , Piperidinas , Pirimidinas , Humanos , Pirimidinas/uso terapêutico , Pirimidinas/administração & dosagem , Piperidinas/uso terapêutico , Piperidinas/administração & dosagem , Líquen Plano/tratamento farmacológico , Inibidores de Proteínas Quinases/uso terapêutico , Inibidores de Proteínas Quinases/administração & dosagem , Feminino , Pirróis/uso terapêutico , Pirróis/administração & dosagem , Pessoa de Meia-Idade , Masculino , Administração Tópica , Administração CutâneaRESUMO
BACKGROUND: Remifentanil, an ultra-short-acting µ-opioid receptor agonist, is commonly used for anesthetic management due to excellent adjustability. Remifentanil is known to cause sinus bradycardia, however, because it has a direct negative chronotropic effect on the cardiac conduction system and there is an indirect negative chronotropic effect via the parasympathetic nervous system. CASE PRESENTATION: An 8-year-old Japanese boy was diagnosed with acute hydrocephalus due to a brain tumor in the fourth ventricle and underwent emergency surgery. Imaging examination showed brainstem compression. Endoscopic third ventriculostomy and ventriculoperitoneal shunt surgery were scheduled. Remifentanil was started during induction of general anesthesia, but electrocardiogram showed sinus bradycardia, then Wenckebach-type atrioventricular block, and then complete atrioventricular block. Remifentanil was immediately discontinued, and we administered atropine sulfate. Complete atrioventricular block was restored to sinus rhythm. When remifentanil was restarted, however, the electrocardiogram again showed sinus bradycardia, Wenckebach-type atrioventricular block, and then complete atrioventricular block. Remifentanil was again immediately discontinued, we administered adrenaline, and then complete atrioventricular block was restored to sinus rhythm. Fentanyl was used instead of remifentanil with continuous infusion of dopamine. There has since been no further occurrence of complete atrioventricular block. CONCLUSIONS: This is the first known case of complete atrioventricular block in a pediatric patient with increased intracranial pressure seemingly caused by administration of remifentanil.
Assuntos
Bloqueio Atrioventricular , Hidrocefalia , Remifentanil , Humanos , Masculino , Remifentanil/administração & dosagem , Remifentanil/efeitos adversos , Criança , Bloqueio Atrioventricular/induzido quimicamente , Hidrocefalia/cirurgia , Neoplasias Encefálicas/cirurgia , Anestesia Geral/métodos , Anestesia Geral/efeitos adversos , Piperidinas/efeitos adversos , Piperidinas/administração & dosagem , Analgésicos Opioides/efeitos adversos , Analgésicos Opioides/administração & dosagem , Anestésicos Intravenosos/efeitos adversos , Anestésicos Intravenosos/administração & dosagemRESUMO
BACKGROUND: Allergic rhinitis (AR) or seasonal allergy characterized by sneezing, nasal congestion, nasal itching, and nasal discharge, triggered by immune reactions to environmental allergens. Present day customers also monitor the personal improvements in the area of Evidence-Based natural medicines/supplements. METHODS: A randomized, double-blind, placebo-controlled study was conducted on 65 participants aged 18 to 60 years having 2 or more allergic symptoms like sneezing, rhinorrhoea, nasal obstruction, and nasal itching for a cumulative period greater than 1 hour per day. The study participants received a capsule of NSO (250 mg) with 2.5 mg piperine (BioPerine) as a bioavailability enhancer or a placebo, twice a day, after food for 15 days. The primary objectives were evaluated by mean change in Total Nasal Symptom Score and the duration of AR symptoms per day from baseline to Day 15. Secondary endpoints were changes in Total Ocular Symptoms Score, AR symptom frequency and severity, serum Immunoglobulin E levels, and Patient Global Impression of Change scale. Adverse events were monitored throughout the study. RESULTS: Sixty-five patients were enrolled and all of them completed the study, Nâ =â 33 in NSO and Nâ =â 32 in placebo. A significant reduction in Total Nasal Symptom Score and Total Ocular Symptoms Score was observed in the NSO group compared to the placebo, highlighting the potential of NSO in alleviating AR symptoms. The episodes of AR symptoms per day and the frequency of symptoms in 24 hours reduced significantly in 15 days in both groups, but the extent of improvement was significantly higher in NSO compared to placebo. Improvement in Patient Global Impression of Change was also significantly better in NSO compared to the placebo. Serum Immunoglobulin E levels decreased in NSO but were not significantly different from placebo. No clinically significant changes were observed in vital signs, liver and renal function, lipid profile, hematology, fasting blood sugar, or urine analysis at the end of the study. CONCLUSION: The result of the study demonstrates that NSO 250 mg with 2.5 mg piperine is an effective and well-tolerated supplement for the management of AR symptoms.
Assuntos
Benzoquinonas , Óleos de Plantas , Rinite Alérgica Sazonal , Humanos , Método Duplo-Cego , Adulto , Masculino , Feminino , Pessoa de Meia-Idade , Óleos de Plantas/uso terapêutico , Óleos de Plantas/administração & dosagem , Benzoquinonas/uso terapêutico , Benzoquinonas/administração & dosagem , Benzoquinonas/farmacologia , Rinite Alérgica Sazonal/tratamento farmacológico , Adulto Jovem , Adolescente , Piperidinas/uso terapêutico , Piperidinas/administração & dosagem , Resultado do Tratamento , Imunoglobulina E/sangue , Alcamidas Poli-Insaturadas/uso terapêutico , Alcaloides , Carum , Nigella sativa , BenzodioxóisRESUMO
Rosacea is a chronic inflammatory skin disease characterized by facial erythema and telangiectasia. Despite ongoing research, the pathogenesis of rosacea remains incompletely understood, and current therapies are not entirely satisfactory. The JAK/STAT signaling pathway plays an essential role in immunoregulation, inflammation, and neurovascular regulation. Inhibition of the JAK/STAT pathway appears to hold promise as a potential therapy for rosacea. This study aimed to investigate the effects of the JAK inhibitor tofacitinib on rosacea and to preliminarily explore its therapeutic mechanism. To this end, a rosacea-like mouse model was induced using LL37 and treated with a 2% tofacitinib emulsion. The results demonstrated that topical application of tofacitinib significantly ameliorated rosacea-like phenotype, reduced the infiltration of CD4+ T cells and mast cells, and suppressed dermal angiogenesis. RT-qPCR analysis revealed a reduction in mRNA expression levels of STAT1, STAT4, and STAT5a in skin lesions following topical tofacitinib treatment. Additionally, three patients diagnosed with erythematotelangiectatic rosacea (ETR) were included in the study and treated with oral tofacitinib, leading to a significant improvement in erythema and flushing symptoms. These findings collectively suggest that tofacitinib alleviates LL37-induced rosacea-like skin inflammation in mice and rosacea skin lesions by inhibiting the JAK/STAT signaling pathway.
Assuntos
Piperidinas , Pirimidinas , Rosácea , Transdução de Sinais , Adulto , Animais , Feminino , Humanos , Masculino , Camundongos , Pessoa de Meia-Idade , Administração Oral , Administração Tópica , Linfócitos T CD4-Positivos/efeitos dos fármacos , Linfócitos T CD4-Positivos/imunologia , Modelos Animais de Doenças , Inibidores de Janus Quinases/farmacologia , Inibidores de Janus Quinases/uso terapêutico , Inibidores de Janus Quinases/administração & dosagem , Janus Quinases/metabolismo , Janus Quinases/antagonistas & inibidores , Mastócitos/efeitos dos fármacos , Mastócitos/imunologia , Mastócitos/metabolismo , Piperidinas/farmacologia , Piperidinas/uso terapêutico , Piperidinas/administração & dosagem , Pirimidinas/farmacologia , Pirimidinas/administração & dosagem , Pirimidinas/uso terapêutico , Pirróis/farmacologia , Pirróis/administração & dosagem , Rosácea/tratamento farmacológico , Transdução de Sinais/efeitos dos fármacos , Pele/patologia , Pele/efeitos dos fármacos , Pele/metabolismo , Fatores de Transcrição STAT/metabolismo , Fatores de Transcrição STAT/antagonistas & inibidores , Fator de Transcrição STAT1/metabolismoRESUMO
Inflammatory diseases including rheumatoid arthritis are major health problems. Although different techniques and drugs are clinically available for the diagnosis and therapy of the disease, novel approaches regarding radiolabeled drug delivery systems are researched. Hence, in the present study, it was aimed to design, prepare, and characterize 99mTc-radiolabeled and tofacitinib citrate-encapsulated microsphere loaded poloxamer in situ gel formulations for the intra-articular treatment. Among nine different microsphere formulations, MS/TOFA-9 was chosen as the most proper one due to particle size, high encapsulation efficiency, and in vitro drug release behavior. Poloxamer 338 at a concentration of 15% was used to prepare in situ gel formulations. For intra-articular administration, microspheres were dispersed in an in situ gel containing 15% Poloxamer 338 and characterized in terms of gelation temperature, viscosity, rheological, mechanical, and spreadability properties. After the determination of the safe dose for MS/TOFA-9 and PLX-MS/TOFA-9 as 40 µL/mL in the cell culture study performed on healthy cells, the high anti-inflammatory effects were due to significant cellular inhibition of fibroblasts. In the radiolabeling studies with 99mTc, the optimum radiolabeling condition was determined as 200 ppm SnCl2 and 0.5 mg ascorbic acid, and both 99mTc-MS/TOFA-9 and 99mTc-PLX-MS/TOFA-9 exhibited high cellular binding capacity. In conclusion, although further in vivo experiments are required, PLX-MS/TOFA-9 was found to be a promising agent for intra-articular injection in rheumatoid arthritis.
Assuntos
Artrite Reumatoide , Quitosana , Géis , Microesferas , Piperidinas , Pirimidinas , Artrite Reumatoide/tratamento farmacológico , Artrite Reumatoide/diagnóstico por imagem , Pirimidinas/química , Pirimidinas/administração & dosagem , Pirimidinas/farmacocinética , Piperidinas/química , Piperidinas/administração & dosagem , Piperidinas/farmacocinética , Quitosana/química , Humanos , Tecnécio/química , Injeções Intra-Articulares , Pirróis/química , Pirróis/administração & dosagem , Animais , Poloxâmero/química , Tamanho da Partícula , Liberação Controlada de FármacosAssuntos
Adenina , Protocolos de Quimioterapia Combinada Antineoplásica , Compostos Bicíclicos Heterocíclicos com Pontes , Linfoma de Célula do Manto , Piperidinas , Sulfonamidas , Humanos , Adenina/análogos & derivados , Piperidinas/uso terapêutico , Piperidinas/administração & dosagem , Compostos Bicíclicos Heterocíclicos com Pontes/uso terapêutico , Compostos Bicíclicos Heterocíclicos com Pontes/administração & dosagem , Compostos Bicíclicos Heterocíclicos com Pontes/farmacologia , Sulfonamidas/uso terapêutico , Sulfonamidas/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Linfoma de Célula do Manto/tratamento farmacológico , Linfoma de Célula do Manto/patologia , Pirimidinas/uso terapêutico , Pirimidinas/administração & dosagem , Pirazóis/uso terapêutico , Pirazóis/administração & dosagemRESUMO
Lipid-based formulations (LbFs) have demonstrated success in pharmaceutical applications; however, challenges persist in dissolving entire doses of the drug into defined liquid volumes. In this study, the temperature-induced supersaturation method was employed in LbF to address drug loading and pill burden issues. Supersaturated LbFs (super-LbF) were prepared using the temperature-induced supersaturation method, where the drug load is above its equilibrium solubility. Further, the influence of the drug's physicochemical and thermal characteristics on drug loading and their relevance with an apparent degree of supersaturation (aDS) was studied using two model drugs, ibrutinib and enzalutamide. All the prepared LbFs were evaluated in terms of physical stability, dispersion, and solubilization capacity, as well as pharmacokinetic assessments. Drug re-crystallization was observed in the lipid solution on long-term storage at higher aDS values of 2-2.5. Furthermore, high-throughput lipolysis studies demonstrated a significant decrease in drug concentration across all LbFs (regardless of drug loading) due to a decline in the formulation solvation capacity and subsequent generation of in-situ supersaturation. Further, the in vivo results demonstrated comparable pharmacokinetic parameters between conventional LbF and super-LbF. The short duration of the thermodynamic metastable state limits the potential absorption benefits. However, super-LbFs of Ibr and Enz showed superior profiles, with 1.7-fold and 5.2-fold increased drug exposure compared to their respective crystalline suspensions. In summary, this study emphasizes the potential of temperature-induced supersaturation in LbF for enhancing drug loading and highlights the intricate interplay between drug properties, formulation characteristics, and in vivo performance.
Assuntos
Adenina , Benzamidas , Química Farmacêutica , Lipídeos , Nitrilas , Feniltioidantoína , Piperidinas , Solubilidade , Temperatura , Nitrilas/química , Nitrilas/administração & dosagem , Piperidinas/química , Piperidinas/administração & dosagem , Piperidinas/farmacocinética , Benzamidas/química , Benzamidas/farmacocinética , Adenina/análogos & derivados , Adenina/química , Adenina/administração & dosagem , Feniltioidantoína/farmacocinética , Feniltioidantoína/administração & dosagem , Lipídeos/química , Animais , Química Farmacêutica/métodos , Composição de Medicamentos/métodos , Masculino , Pirimidinas/farmacocinética , Pirimidinas/química , Pirimidinas/administração & dosagem , Estabilidade de Medicamentos , Cristalização/métodos , Pirazóis/química , Pirazóis/farmacocinética , Pirazóis/administração & dosagem , Lipólise/efeitos dos fármacos , RatosRESUMO
BACKGROUND: Tofacitinib is an oral Janus kinase inhibitor for the treatment of ulcerative colitis (UC). We aimed to identify the safety and effectiveness of tofacitinib in patients with UC in routine clinical settings in Korea. METHODS: This open-label, observational, prospective, post-marketing surveillance study was conducted at 22 hospitals in the Republic of Korea. Patients with moderate to severe active UC who received tofacitinib were included and followed up for up to 52 weeks. Tofacitinib was administered at a dosage of 10 mg twice daily for at least 8 weeks, followed by 5 or 10 mg twice daily at the investigator's discretion based on clinical evaluation according to the approved Korean label. Safety including adverse events (AEs) and effectiveness including clinical remission, clinical response, and endoscopic mucosal healing were evaluated. Safety analysis set was defined as all patients registered for this study who received at least one dose of tofacitinib according to the approved Korean label and followed up for safety data. Effectiveness analysis set included patients in the safety analysis set who were evaluated for overall effectiveness assessment and excluded patients who had received tofacitinib less than 8 weeks. RESULTS: A total of 110 patients were enrolled, of whom 106 patients were included in the safety population. The median duration of treatment was 370 days and the treatment duration ranged from 16 to 684 days for the safety population. AEs occurred in 42 patients (39.6%). Serious AEs (SAEs) occurred in 7 patients (6.6%) and of them, there were 2 cases of serious infections. These serious infections were reported as Adverse Event of Special Interest (AESI) in this study and no other AESI were reported. There were no cases of death during the study period. Clinical remission rates were 40.0%, 46.7%, 57.6%, and 55.1% at 8, 16, 24, and 52 weeks, and clinical response rates were 77.8%, 87.9%, 56.6%, and 81.4% at each visit, respectively. Endoscopic mucosal healing rates were 58.7% at 16 weeks and 46.2% at 52 weeks. CONCLUSION: Tofacitinib was effective in Korean patients with moderate to severe active UC and the safety findings were consistent with the known safety profile of tofacitinib. This study confirmed the safety and effectiveness of tofacitinib in Korean patients with moderate to severe active UC in routine clinical settings. TRIAL REGISTRATION: This study is registered in the ClinicalTrials.gov under the identifier NCT04071405, registered on 28 August 2019.
Assuntos
Colite Ulcerativa , Piperidinas , Vigilância de Produtos Comercializados , Pirimidinas , Humanos , Pirimidinas/efeitos adversos , Pirimidinas/uso terapêutico , Pirimidinas/administração & dosagem , Piperidinas/efeitos adversos , Piperidinas/uso terapêutico , Piperidinas/administração & dosagem , Colite Ulcerativa/tratamento farmacológico , Masculino , Feminino , Adulto , Estudos Prospectivos , Pessoa de Meia-Idade , República da Coreia , Pirróis/efeitos adversos , Pirróis/uso terapêutico , Pirróis/administração & dosagem , Resultado do Tratamento , Inibidores de Janus Quinases/efeitos adversos , Inibidores de Janus Quinases/uso terapêutico , Inibidores de Janus Quinases/administração & dosagem , Idoso , Inibidores de Proteínas Quinases/efeitos adversos , Inibidores de Proteínas Quinases/uso terapêutico , Inibidores de Proteínas Quinases/administração & dosagem , Adulto Jovem , Indução de RemissãoRESUMO
Depression and anxiety are prevalent neuropsychiatric conditions among patients with Parkinson's disease (PD), which may manifest prior to motor symptoms. As levodopa, a prominent treatment for PD motor symptoms, provides few benefits for mood-related abnormalities, tackling non-motor symptoms is particularly important. AdipoRon (Ad), an adiponectin agonist, has demonstrated neuroprotective effects by suppressing neuroinflammatory responses and activating the AMPK/Sirt-1 signaling pathway. This study looked at the potential advantages and underlying mechanisms of intranasal Ad in a rat model of PD induced by 6-hydroxydopamine (6-OHDA). We found that Ad at doses of 1 and 10 µg for 21 days exhibited anxiolytic- and antidepressant effects in the open field (OF) test, elevated plus maze (EPM), sucrose splash test, and forced swimming test in a PD model caused by a unilateral 6-OHDA injection into the medial forebrain bundle (MFB). The Ad also lowered the levels of corticosterone in the blood, decreased inflammasome components (NLRP3, caspase 1, and IL-1ß), and increased Sirt-1 protein levels in the prefrontal cortex (PFC) of PD rats. We conclude that Ad ameliorates anxious and depressive-like behaviors in the PD rat model through stimulating the AMPK/Sirt-1 signaling and blocking the NLRP3 inflammasome pathways in the PFC.