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1.
Sci Rep ; 14(1): 14290, 2024 06 21.
Artigo em Inglês | MEDLINE | ID: mdl-38906992

RESUMO

To investigate the effect and safety of percutaneous endovascular angioplasty (PEA) with optional stenting for the treatment of severe stenosis or occlusion of subclavian artery, patients with severe stenosis ≥ 70% or occlusion of subclavian artery treated with PEA were retrospectively enrolled. The clinical data were analyzed. A total of 222 patients were retrospectively enrolled, including 151 males (68.0%) and 71 females (32.0%) aged 48-86 (mean 63.9 ± 9.0) years. Forty-seven (21.2%) patients had comorbidities. Subclavian artery stenosis ≥ 70% was present in 201 (90.5%) patients and complete subclavian occlusion in 21 (9.5%) cases. Angioplasty was successfully performed in all (100%) patients. Balloon-expandable stents were used in 190 (85.6%) cases, and self-expandable stents in 20 (9.0%) cases. Only 12 (5.4%) cases were treated with balloon dilation only. Among 210 patients treated with stent angioplasty, 71 (33.8% or 71/210) cases underwent balloon pre-dilation, 139 (66.2% or 139/210) had direct deployment of balloon-expandable stents, and 2 (1.0% or 2/210) experienced balloon post-dilation. Distal embolization protection devices were used in 5 (2.3% or 5/222) cases. Periprocedural complications occurred in 3 (1.4%) patients, including aortic dissection in 2 (0.9%) cases and right middle cerebral artery embolism in 1 (0.5%). No hemorrhage occurred. Among 182 (82.0%) patients with 6-month follow-up, restenosis > 70% occurred in 1 (0.5%) patient, and among 68 (30.6%) patients with 12-month follow-up, restenosis > 70% took place in 11 (16.2%) patients. Percutaneous endovascular angioplasty can be safely and efficiently performed for the treatment of severe stenosis ≥ 70% or occlusion of subclavian artery.


Assuntos
Stents , Artéria Subclávia , Humanos , Masculino , Feminino , Idoso , Pessoa de Meia-Idade , Idoso de 80 Anos ou mais , Artéria Subclávia/cirurgia , Estudos Retrospectivos , Stents/efeitos adversos , Resultado do Tratamento , Síndrome do Roubo Subclávio/terapia , Síndrome do Roubo Subclávio/cirurgia , Procedimentos Endovasculares/métodos , Procedimentos Endovasculares/efeitos adversos , Angioplastia/métodos , Angioplastia/efeitos adversos , Constrição Patológica/terapia , Angioplastia com Balão/métodos , Angioplastia com Balão/efeitos adversos , Arteriopatias Oclusivas/terapia , Arteriopatias Oclusivas/cirurgia
2.
Chem Commun (Camb) ; 60(54): 6913-6916, 2024 Jul 02.
Artigo em Inglês | MEDLINE | ID: mdl-38881424

RESUMO

A unique fluorescent sensing probe for UO22+ detection was fabricated with terbium-based metal organic frameworks via introducing specific recognition sites (denoted as Tb-TDPAT). The newly formed Tb-TDPAT presented remarkable detection sensitivity and selectivity towards UO22+, surpassing the need for complex post-modification methods.

3.
Sci Rep ; 14(1): 10945, 2024 05 13.
Artigo em Inglês | MEDLINE | ID: mdl-38740919

RESUMO

To investigate the significance of atherosclerotic plaque location in hybrid surgery comprising both endovascular recanalization approaches and carotid endarterectomy for symptomatic atherosclerotic non-acute long-segment occlusion of the internal carotid artery (ICA), 162 patients were enrolled, including 120 (74.1%) patients in the proximal plaque group and 42 (25.9%) in the distal plaque group. Surgical recanalization was performed in all patients, with successful recanalization in 119 (99.2%) patients in the proximal and 39 (92.9%) in the distal plaque group. The total successful recanalization rate was 97.5% (158/162) with a failure rate of 2.5% (4/162). Periprocedural complications occurred in 5 (4.2% or 5/120) patients in the proximal plaque group, including neck infection in two (1.7%), recurrent nerve injury in 1 (0.8%), and laryngeal edema in 2 (1.7%), and 2 (4.8%) in the distal plaque group, including femoral puncture infection in 2 (4.8%). No severe complications occurred in either group. Univariate analysis showed plaque location was a significant (P = 0.018) risk factor for successful recanalization, and multivariate analysis indicated that the plaque location remained a significant independent risk factor for recanalization success (P = 0.017). In follow-up 6-48 months after the recanalization surgery, reocclusion occurred in two (2.8%) patients in the proximal plaque group and 4 (13.3%) in the distal plaque group. In conclusion, although hybrid surgery achieves similar outcomes in patients with ICA occlusion caused by either proximal or distal atherosclerotic plaques, plaque location may be a significant risk factor for successful recanalization of symptomatic non-acute long-segment ICA occlusion.


Assuntos
Artéria Carótida Interna , Estenose das Carótidas , Endarterectomia das Carótidas , Placa Aterosclerótica , Humanos , Masculino , Feminino , Idoso , Placa Aterosclerótica/cirurgia , Placa Aterosclerótica/patologia , Placa Aterosclerótica/complicações , Artéria Carótida Interna/cirurgia , Artéria Carótida Interna/patologia , Pessoa de Meia-Idade , Estenose das Carótidas/cirurgia , Estenose das Carótidas/patologia , Estenose das Carótidas/complicações , Endarterectomia das Carótidas/métodos , Resultado do Tratamento , Procedimentos Endovasculares/métodos , Idoso de 80 Anos ou mais , Fatores de Risco
4.
Clin Pharmacol Ther ; 115(6): 1212-1232, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38450707

RESUMO

Adeno-associated virus (AAV) vector-based gene therapy is an innovative modality being increasingly investigated to treat diseases by modifying or replacing defective genes or expressing therapeutic entities. With its unique anatomic and physiological characteristics, the eye constitutes a very attractive target for gene therapy. Specifically, the ocular space is easily accessible and is generally considered "immune-privileged" with a low risk of systemic side effects following local drug administration. As retina cells have limited cellular turnover, a one-time gene delivery has the potential to provide long-term transgene expression. Despite the initial success with voretigene neparvovec (Luxturna), the first approved retina gene therapy, there are still challenges to be overcome for successful clinical development of these products and scientific questions to be answered. The current review paper aims to integrate published experience learned thus far for AAV-based retina gene therapy related to preclinical to clinical translation; first-in-human dose selection; relevant bioanalytical assays and strategies; clinical development considerations including trial design, biodistribution and vector shedding, immunogenicity, transgene expression, and pediatric populations; opportunities for model-informed drug development; and regulatory perspectives. The information presented herein is intended to serve as a guide to inform the clinical development strategy for retina gene therapy with a focus on clinical pharmacology.


Assuntos
Dependovirus , Terapia Genética , Vetores Genéticos , Retina , Doenças Retinianas , Humanos , Dependovirus/genética , Terapia Genética/métodos , Animais , Retina/metabolismo , Doenças Retinianas/terapia , Doenças Retinianas/genética , Técnicas de Transferência de Genes
5.
Anal Chem ; 96(11): 4673-4681, 2024 Mar 19.
Artigo em Inglês | MEDLINE | ID: mdl-38451931

RESUMO

Perfluorooctanesulfonic acid potassium salt (PFOS) residues in ecosystems over long periods are of increasing concern and require a selective and stable optical probe for monitoring. Herein, two functional groups (-F and -NH2) with opposite electronic modulation ability were introduced into Fe/Zn-BDC (denoted as Fe/Zn-BDC-F4 and Fe/Zn-BDC-NH2, respectively) to tailor the coordination environment of the Fe metal center, further regulating the nanozyme activity efficiently. Notably, the peroxidase-like activity is related to the coordination environment of the nanozymes and obeys the following order Fe/Zn-BDC-F4 > Fe/Zn-BDC > Fe/Zn-BDC-NH2. Based on the excellent peroxidase-like activity of Fe/Zn-BDC-F4 and the characteristics of being rich in F atoms, a rapid, selective, and visible colorimetric method was developed for detecting PFOS with a detection limit of 100 nM. The detection mechanism was attributed to various interaction forces between Fe/Zn-BDC-F4 and PFOS, including electrostatic interactions, Fe-S interactions, Fe-F bonds, and halogen bonds. This work not only offers new insights into the atomic-scale rational design of highly active nanozymes but also presents a novel approach to detecting PFOS in environmental samples.


Assuntos
Ecossistema , Potássio , Colorimetria , Peroxidases , Zinco
6.
Mol Ther Methods Clin Dev ; 32(1): 101217, 2024 Mar 14.
Artigo em Inglês | MEDLINE | ID: mdl-38496304

RESUMO

Recombinant adeno-associated virus (AAV) vectors are the leading delivery vehicle used for in vivo gene therapies. Anti-AAV antibodies (AAV Abs) can interact with the viral capsid component of an AAV-based gene therapy (GT). Therefore, patients with preexisting AAV Abs (seropositive patients) are often excluded from GT trials to prevent treatment of patients who are unlikely to benefit1 or may have a higher risk for adverse events outweighing treatment benefits. On the contrary, unnecessary exclusion of patients with high unmet medical need should be avoided. Instead, a risk-benefit assessment that weighs the potential risks due to seropositivity vs. severity of disease and available treatment options, should drive the decision if patient selection is required. Assays for patient selection must be validated according to their intended use following national regulations/standards for diagnostic assays in appropriate laboratories. In this review, we summarize the current process of patient selection, including assay cutoff criteria and related assay validation approaches. We further provide considerations on regulatory requirements for the development of in vitro diagnostic tests supporting market authorization of a corresponding GT.

7.
Anal Chem ; 2024 Feb 08.
Artigo em Inglês | MEDLINE | ID: mdl-38330425

RESUMO

Uranyl ions (UO22+) are recognized as important indicators for monitoring sudden nuclear accidents. However, the interferences coexisting in the complicated environmental matrices impart serious constraints on the reliability of current on-site monitoring methods. Herein, a novel ratiometric method for the highly sensitive and selective detection of UO22+ is reported based on a [Eu(diaminoterephthalic acid)] (Eu-DATP) metal-organic framework. Benefiting from the unique chemical structure of Eu-DATP, energy transfer from DATP to UO22+ was enabled, resulting in the up-regulated fluorescence of UO22+ and the simultaneous down-regulated fluorescence of Eu3+. The limit of detection reached as low as 2.7 nM, which was almost 2 orders of magnitude below the restricted limit in drinking water set by the United States Environmental Protection Agency (130 nM). The Eu-DATP probe showed excellent specificity to UO22+ over numerous interfering species, as the intrinsic emissions of UO22+ were triggered. This unprecedentedly high selectivity is especially beneficial for monitoring UO22+ in complicated environmental matrices with no need for tedious sample pretreatment, such as filtration and digestion. Then, by facilely equipping a Eu-DATP-based sampler on a drone, remotely controlled sampling and on-site analysis in real water samples were realized. The concentrations of UO22+ were determined to be from 16.5 to 23.5 nM in the river water of the Guangzhou downtown area, which was consistent with the results determined by the gold-standard inductively coupled plasma mass spectrometry. This study presents a reliable and convenient method for the on-site analysis of UO22+.

8.
Clin Pharmacol Drug Dev ; 13(3): 307-314, 2024 03.
Artigo em Inglês | MEDLINE | ID: mdl-38189592

RESUMO

The incidence of type 2 diabetes is high, and the existing metformin hydrochloride (MH) tablets of 250 mg cannot meet the demands of the Chinese drug market. This study aimed to evaluate the bioequivalence and safety of generic formulations of MH tablets (test formulation [T], 250 mg/tablet) and innovative products (reference formulation [R], 250 mg/tablet) under fasting conditions. This was an open-label, single-dose, 2-period, 2-sequence crossover, single-center, randomized phase I clinical trial. T and R were considered bioequivalent if the adjusted geometric mean ratios (GMRs) and 90% confidence intervals of the area under the curve (AUC) and maximum concentration (Cmax ) were within the range of 0.8-1.25. Thirty-five participants completed the trial. The T/R adjusted GMRs (95.7% for Cmax , 98.7% for AUC0→t , 98.8% for AUC0→∞ ) were within the acceptable bioequivalence range of 80%-125%. No serious adverse events or suspected or unexpected serious adverse reactions occurred during this trial. The study findings confirmed that generic MH is a well-tolerated and bioequivalent alternative to innovative products under fasting conditions in healthy Chinese participants. (www.chinadrugtrials.org.cn; registration no. CTR20190356).


Assuntos
Diabetes Mellitus Tipo 2 , Metformina , Humanos , Equivalência Terapêutica , Metformina/efeitos adversos , Diabetes Mellitus Tipo 2/tratamento farmacológico , Jejum , Comprimidos , China
9.
Clin Pharmacol Ther ; 115(2): 188-200, 2024 02.
Artigo em Inglês | MEDLINE | ID: mdl-37983584

RESUMO

CAR-T therapies have shown remarkable efficacy against hematological malignancies in the clinic over the last decade and new studies indicate that progress is being made to use these novel therapies to target solid tumors as well as treat autoimmune disease. Innovation in the field, including TCR-T, allogeneic or "off the shelf" CAR-T, and autoantigen/armored CAR-Ts are likely to increase the efficacy and applications of these therapies. The unique aspects of these cell-based therapeutics; patient-derived cells, intracellular expression, in vivo expansion, and phenotypic changes provide unique bioanalytical challenges to develop pharmacokinetic and immunogenicity assessments. The International Consortium for Innovation and Quality in Pharmaceutical Development (IQ) Translational and ADME Sciences Leadership Group (TALG) has brought together a group of industry experts to discuss and consider these challenges. In this white paper, we present the IQ consortium perspective on the best practices and considerations for bioanalytical and immunogenicity aspects toward the optimal development of CAR-T and TCR-T cell therapies.


Assuntos
Neoplasias Hematológicas , Neoplasias , Receptores de Antígenos Quiméricos , Humanos , Linfócitos T , Neoplasias/metabolismo , Imunoterapia Adotiva
10.
Talanta ; 269: 125404, 2024 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-37980819

RESUMO

Monitoring the residual dichlorvos (O,O-dimethyl-O-2,2-dichlorovinylphosphate, DDVP) in food has received extensive attention owing to its large consumption in agriculture. However, the previous sensing methods are not time-efficient enough due to the long incubation time for enzyme inhibition (tens of minutes to hours) or bottlenecked by the complicated procedures for senor fabrication. Herein, a novel sensing strategy is proposed based on the hydrolysis of DDVP into PO43-. By using alkaline phosphatase for hydrolysis, a certain portion of DDVP was transformed to PO43- within only 8 min. Then, the released PO43- was detected by a fluorescent terbium metal-organic framework (Tb-MOF). The coordination of the naked P-O groups to the metal nodes of the Tb-MOF disturbed the antenna effects of its ligands. Thus, DDVP was quantified by the decrease of the fluorescence of Tb ions. Based on this method, DDVP residues on plum surfaces were collected by swabs and successfully detected. The recovery of DDVP was determined in the range from 105 % to 115 %, demonstrating the quantification accuracy of this method. The detection limit reached 4.7 µM, which was lower than the restricted amount in fruit set by the National Standard of China. The present method provides an efficient and user-friendly way for the detection of DDVP and many other organophosphorus pesticides in food.

11.
Front Neurol ; 14: 1226306, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-37900592

RESUMO

Purpose: This study aims to investigate the effect and feasibility of intra-aortic catheter looping via transradial access in angioplasty for symptomatic intracranial severe (>70%) atherosclerotic stenosis or occlusion of large arteries (SISOLAs). Materials and methods: Patients with SISOLAs who underwent transradial endovascular angioplasty using the catheter looping technique in the ascending aorta were retrospectively enrolled. The clinical data and treatment outcomes were analyzed. Results: Fifteen patients aged 48-71 years were enrolled in this study. Left vertebrobasilar artery occlusion was present in 1 (6.7%) patient, severe left middle cerebral artery stenosis in 7 (46.7%) patients, severe left internal carotid artery (ICA) stenosis of the ophthalmic segment in 4 (26.7%) patients, severe left ICA stenosis of the cavernous segment in 2 (13.3%) patients, and severe right middle cerebral artery stenosis in 2 (13.3%) patients. The arterial stenosis ranged from 70 to 92% (mean 86%) before stenting. The looping of a guiding catheter in the ascending aorta via transradial access for angioplasty was successful in all patients (100%). The vertebral artery intracranial segment occlusion was successfully recanalized, while severe stenosis in the remaining 14 patients was successfully eliminated. After endovascular recanalization, the residual stenosis was reduced by 12-26% (median 18%). No puncture-related complications or surgical-related neurological complications occurred in these patients. In the follow-up angiography conducted on 10 (66.7%) patients after 6-25 months, no in-stent restenosis was detected. Conclusion: Intra-aortic guiding catheter looping via transradial access for endovascular angioplasty of SISOLAs is technically safe, feasible, and effective, especially when the transfemoral artery approach is difficult or impossible to undertake.

12.
Phys Chem Chem Phys ; 25(38): 26023-26031, 2023 Oct 04.
Artigo em Inglês | MEDLINE | ID: mdl-37740348

RESUMO

One of the central issues in pattern formation is understanding the response of pattern-forming systems to an external stimulus. While significant progress has been made in systems with only one instability, much less is known about the response of complex patterns arising from the interaction of two or more instabilities. In this paper, we consider the effects of square spatial periodic forcing on oscillatory hexagon patterns in a two-layer coupled reaction diffusion system which undergoes both Turing and Hopf instabilities. Two different types of additive forcings, namely direct and indirect forcing, have been applied. It is shown that the coupled system exhibits different responses towards the spatial forcing under different forcing types. In the indirect case, the oscillatory hexagon pattern transitions into other oscillatory Turing patterns or resonant Turing patterns, depending on the forcing wavenumber and strength. In the direct forcing case, only non-resonant Turing patterns can be obtained. Our results may provide new insight into the modification and control of spatio-temporal patterns in multilayered systems, especially in biological and ecological systems.

13.
AAPS J ; 25(6): 93, 2023 09 28.
Artigo em Inglês | MEDLINE | ID: mdl-37770755

RESUMO

Cell and gene therapies have demonstrated impressive therapeutic efficacy in various human diseases. Nevertheless, cellular immune response directed against these therapeutic agents is an obstacle for achieving long-lasting clinical efficacy. Therefore, it is crucial to develop robust assays to accurately monitor cellular immunogenicity towards these therapies. Enzyme-linked immunospot (ELISpot) assay is one of the primarily used methods for measuring cellular immune response in clinical programs, which requires isolation of the peripheral blood mononuclear cells (PBMCs). The quality of this clinical material is one of the most critical factors that impact the robust assessment of cellular immune responses. The optimal blood sample processing conditions, however, remain poorly understood. In this study, we examined the impact of blood sample processing time on the performance characteristics of ELISpot to measure antigen-specific cellular responses. Blood samples that were processed after overnight delay resulted in a loss of ELISpot signals. We subsequently optimized several parameters of sample processing, and successfully recovered ELISpot signals for the blood samples that are processed within 32 h. Furthermore, several mitigation strategies were employed that would potentially address the impact of granulocyte contamination on detection of antigen-specific cellular responses. Our investigation provides an extension of sample processing window for clinical studies and is significant for resolving the logistical challenge of whole blood sample shipment for timely PBMC preparation in cell/gene therapy clinical studies.


Assuntos
Interferon gama , Leucócitos Mononucleares , Humanos , ELISPOT/métodos , Imunidade Celular
14.
AAPS J ; 25(5): 78, 2023 07 31.
Artigo em Inglês | MEDLINE | ID: mdl-37523051

RESUMO

Interest and efforts to use recombinant adeno-associated viruses (AAV) as gene therapy delivery tools to treat disease have grown exponentially. However, gaps in understanding of the pharmacokinetics/pharmacodynamics (PK/PD) and disposition of this modality exist. This position paper comes from the Novel Modalities Working Group (WG), part of the International Consortium for Innovation and Quality in Pharmaceutical Development (IQ). The pan-industry WG effort focuses on the nonclinical PK and clinical pharmacology aspects of AAV gene therapy and related bioanalytical considerations.Traditional PK concepts are generally not applicable to AAV-based therapies due to the inherent complexity of a transgene-carrying viral vector, and the multiple steps and analytes involved in cell transduction and transgene-derived protein expression. Therefore, we explain PK concepts of biodistribution of AAV-based therapies and place key terminologies related to drug exposure and PD in the proper context. Factors affecting biodistribution are presented in detail, and guidelines are provided to design nonclinical studies to enable a stage-gated progression to Phase 1 testing. The nonclinical and clinical utility of transgene DNA, mRNA, and protein analytes are discussed with bioanalytical strategies to measure these analytes. The pros and cons of qPCR vs. ddPCR technologies for DNA/RNA measurement and qualitative vs. quantitative methods for transgene-derived protein are also presented. Last, best practices and recommendations for use of clinical and nonclinical data to project human dose and response are discussed. Together, the manuscript provides a holistic framework to discuss evolving concepts of PK/PD modeling, bioanalytical technologies, and clinical dose selection in gene therapy.


Assuntos
Dependovirus , Terapia Genética , Humanos , Dependovirus/genética , Distribuição Tecidual , Desenvolvimento de Medicamentos , Reação em Cadeia da Polimerase
15.
Adv Healthc Mater ; 12(27): e2301157, 2023 10.
Artigo em Inglês | MEDLINE | ID: mdl-37392145

RESUMO

Drug delivery systems (DDSs) capable of sequential multistage drug release are urgently needed for antibacterial applications. Herein, a molecular switch-integrated, photo-responsive nanoplatform is reported based on hollow mesoporous silica nanospheres (HMSN) loaded with silver nanoparticles (Ag NPs), vancomycin (Van), and hemin (HAVH) for bacteria elimination and abscess therapy. Upon near-infrared (NIR) light irradiation, the molecular switch, hemin, can effuse from the mesopores of HMSN, triggering the release of pre-loaded Ag+ and Van, which enables photothermal-modulated drug release and synergistic photothermal-chemo therapy (PTT-CHT). The HAVH_NIR irreversibly disrupts the bacterial cell membrane, facilitating the penetration of Ag+ and Van. It is found that these compounds restrain the transcription and translation of ribosomes and lead to rapid bacterial death. Furthermore, hemin can effectively inhibit excessive inflammatory responses associated with the treatment, promoting accelerated wound healing in a murine abscess model. This work presents a new strategy for antibacterial drug delivery with high controllability and extendibility, which may benefit the development of smart multifunctional nanomedicine for diseases not limited to bacterial infections.


Assuntos
Neuropatia Hereditária Motora e Sensorial , Nanopartículas Metálicas , Nanopartículas , Animais , Camundongos , Abscesso/tratamento farmacológico , Hemina , Prata , Antibacterianos/farmacologia , Vancomicina/farmacologia , Doxorrubicina/farmacologia
16.
Clin Pharmacol Ther ; 114(3): 530-557, 2023 09.
Artigo em Inglês | MEDLINE | ID: mdl-37393588

RESUMO

With the promise of a potentially "single dose curative" paradigm, CAR-T cell therapies have brought a paradigm shift in the treatment and management of hematological malignancies. Both CAR-T and TCR-T cell therapies have also made great progress toward the successful treatment of solid tumor indications. The field is rapidly evolving with recent advancements including the clinical development of "off-the-shelf" allogeneic CAR-T therapies that can overcome the long and difficult "vein-to-vein" wait time seen with autologous CAR-T therapies. There are unique clinical pharmacology, pharmacometric, bioanalytical, and immunogenicity considerations and challenges in the development of these CAR-T and TCR-T cell therapies. Hence, to help accelerate the development of these life-saving therapies for the patients with cancer, experts in this field came together under the umbrella of International Consortium for Innovation and Quality in Pharmaceutical Development (IQ) to form a joint working group between the Clinical Pharmacology Leadership Group (CPLG) and the Translational and ADME Sciences Leadership Group (TALG). In this white paper, we present the IQ consortium perspective on the best practices and considerations for clinical pharmacology and pharmacometric aspects toward the optimal development of CAR-T and TCR-T cell therapies.


Assuntos
Neoplasias , Farmacologia Clínica , Receptores de Antígenos Quiméricos , Humanos , Receptores de Antígenos de Linfócitos T , Linfócitos T , Neoplasias/terapia , Imunoterapia Adotiva/efeitos adversos
17.
Clin Pharmacol Drug Dev ; 12(6): 611-624, 2023 06.
Artigo em Inglês | MEDLINE | ID: mdl-37125450

RESUMO

JNJ-64264681 is an irreversible covalent inhibitor of Bruton's tyrosine kinase. This phase 1, first-in-human, 2-part (single-ascending dose [SAD]; multiple-ascending dose [MAD]) study evaluated the safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD; Bruton's tyrosine kinase occupancy [BTKO]) of JNJ-64264681 oral solution in healthy participants. For SAD (N = 78), 6 increasing doses of JNJ-64264681 (4-400 mg) or placebo were evaluated in fasted males. The effects of sex, food, and a capsule formulation were evaluated in separate cohorts. For MAD (N = 27), sequential cohorts of male and female participants received 36/100/200 mg JNJ-64264681 once daily for 10 days. JNJ-64264681 exposure (peak concentration; area under the concentration-time curve) was less than dose proportional from 4 mg to 36 mg. Dose-normalized area under the concentration-time curves following the 36 mg and 100 mg doses were generally similar. The mean terminal half-life was 1.6-13.2 hours. With multiple doses, steady state was achieved by day 2. A semimechanistic PK/PD model was developed using the first 5 SAD cohorts' data to predict %BTKO in MAD cohorts. PK/PD model guided dose-escalation, and all participants in the 200/400 mg single-dose cohorts achieved ≥90% BTKO at 4 hours after dosing (peak) with prolonged occupancy. As BTKO data became available from MAD cohorts, it was found that observed BTKO data were consistent with model predictions. JNJ-64264681 showed no safety signals of concern. Overall, safety, tolerability, PK, BTKO, and PK/PD modeling guided the rationale for dose selection for the subsequent first-in-patient lymphoma studies.


Assuntos
Tirosina Quinase da Agamaglobulinemia , Feminino , Humanos , Masculino , Área Sob a Curva , Relação Dose-Resposta a Droga , Método Duplo-Cego , Meia-Vida , /farmacologia
18.
Front Neurol ; 14: 1128960, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-37181573

RESUMO

Purpose: The study aimed to investigate the feasibility and effect of transradial access with intra-aortic catheter looping for the treatment of intracranial aneurysms. Materials and methods: This retrospective one-center study was performed on patients with intracranial aneurysms which were embolized through transradial access with intra-aortic catheter looping because of the difficulty of transfemoral access or transradial access without intra-aortic catheter looping. The imaging and clinical data were analyzed. Results: A total of 11 patients were enrolled, including seven (63.6%) male patients. Most patients were associated with one or two risk factors of atherosclerosis. There were nine aneurysms in the left internal carotid artery system and two aneurysms in the right internal carotid artery system. All 11 patients had complications with different anatomic variations or vascular diseases, which made endovascular operation via the transfemoral artery difficult or a failure. The right transradial artery approach was adopted in all patients, and the success rate of intra-aortic catheter looping was 100%. Embolization of intracranial aneurysms was successfully completed in all patients. No instability of the guide catheter was encountered. No puncture site complications or surgical-related neurological complications occurred. Conclusion: Transradial access with intra-aortic catheter looping for embolization of intracranial aneurysms is technically feasible, safe, and efficient as an important supplementary approach to the routine transfemoral access or transradial access without intra-aortic catheter looping.

20.
Chem Sci ; 13(46): 13948-13955, 2022 Nov 30.
Artigo em Inglês | MEDLINE | ID: mdl-36544738

RESUMO

Despite the excellent luminescent properties of lanthanide clusters (LnCs), their suprastructures that inherit their characteristic luminescent properties are scarcely reported. Herein, novel and highly luminescent suprastructures are synthesized via a two-step assembly method to incorporate LnCs in covalent organic frameworks (COFs). COFs are pre-synthesized and decorated with rigid anchoring groups on their nanochannel walls, which provide one-dimensional confined spaces for the subsequent in situ assembly of luminescent LnCs. The confined LnCs are termed nanoparticles (NPs) to distinguish them from the pure LnCs. Secondary micropores with predictable sizes are successfully formed between the walls of the nanochannels and the orderly aligned NPs therein. By using a small organic ligand that can efficiently sensitize Ln(iii) cations in the assembly processes, the obtained composites show high quantum yields above 20%. The fluorescence can even be effectively maintained across nine pH units. The secondary micropores further enable the unambiguous discrimination of six methinehalides and ultrasensitive detection of uranyl ions. This study provides a new type of luminescent material that has potential for sensing and light emitting.

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