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1.
Pharmacol Res Perspect ; 10(6): e01031, 2022 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-36380704

RESUMO

The translation of new injectable anesthetic drugs from rodent to humans remains slow, despite the realization that reliance on the volatile agents is unsustainable from an environmental perspective. The aim of this study was to investigate the influence of rat sex and strain on the PK and PD of the anesthetic neurosteroid alfaxalone. Forty rats had cannulas inserted under isoflurane anesthesia for drug administration and sampling. Carotid artery blood samples were collected for blood gas analysis, hematology, biochemistry, and plasma concentrations of alfaxalone. Plasma samples were assayed using liquid chromatography-mass spectrometry. Compartmental non-linear mixed effects methods (NLME) models were applied to two rat populations to determine whether body weight, sex, and strain influenced PK parameters. There were significant differences between the sexes for plasma clearance, half-life and mean residence time in Lewis rats, and mean arterial blood pressure was significantly lower in the female rats at 120 min. An initial NLME PK population model was used to design an adjusted alfaxalone infusion for SD females matching plasma concentrations in males and minimizing cardiopulmonary depression but maintaining an appropriate hypnotic effect. A final NLME population model showed that alfaxalone clearance was dependent on both bodyweight and sex, whereas volume of distribution was influenced by strain. NLME PK models offer the advantage of having a single model that describes a population and therefore shares data interpretation between animals unlike the standard deterministic PK approach. This approach can be used to propose bespoke dosing regimens for optimal use of alfaxalone.


Assuntos
Anestésicos , Pregnanodionas , Humanos , Masculino , Feminino , Animais , Ratos , Ratos Endogâmicos Lew , Pregnanodionas/farmacologia , Anestésicos/farmacocinética , Meia-Vida
2.
Biomaterials ; 290: 121820, 2022 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-36194956

RESUMO

Small molecule-drug conjugate (SMDC) shows great potential as a new class of targeted chemotherapeutic agents to tackle cancer. However, its in vivo therapeutic effect is compromised by its poor pharmacokinetic parameters. Herein we describe an approach that enables the precise conjugation of SMDC on N-terminus of the Fc protein to produce a SMDC-Fc bioconjugate (Fc1070) with superior specificity, affinity and potency to tumor cells. In vivo, Fc1070 exhibited an antibody-like pharmacokinetic profile with a long circulation half-life (t1/2 = 79 h) and pro-liver clearance pathway, that is distinct from the parent SMDC (t1/2 = 0.5 h and renal clearance). Intravenous injection of Fc1070 can eliminate the tumor with a single dosing of 7 mg/kg. Coupled with a predefined ligand toolbox, this approach allows the fast generation of other SMDC bioconjugates on demand, thus extending the format easily to other tumor targets. This may provide a general approach for the development of SMDC with enhanced therapeutic properties.


Assuntos
Antineoplásicos , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Meia-Vida , Ligantes
3.
ACS Macro Lett ; 11(11): 1230-1237, 2022 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-36223277

RESUMO

Hydrogen sulfide (H2S) serves as a key gaseous regulator that not only directs many physiological activities, but also manifests therapeutic benefits to many diseases. Developing H2S vehicle platforms for its local delivery and long-acting release is important to achieve target gas therapy. Most of the known H2S-donating polymers contain labile thioester scaffolds within their structures that suffer from the issue of low gas releasing efficiency. Here we present the use of thionoester, a constitutional isomer of thioester, as the functional unit to build a structural platform of cysteine-triggered H2S donor polymer, polythionoester. Simple exchange of the sulfur and oxygen positions in the carbonyl sulfide scaffold makes the polythionoesters undergo a distinct mechanism of H2S production, which can largely improve the gas-releasing efficiency (>80%). Moreover, the thionoester-containing block copolymers can self-assemble into vesicles in an aqueous media. We discover that control over the size effect can adjust the vesicle disassembly rate and gas-releasing kinetics. A tunable half-life of H2S generation (2.6-9.8 h) can be accessed by tailoring the vesicle dimension. This allows such polymersomes to be potential as a gas nanodelivery system for long-lasting gas therapeutics.


Assuntos
Sulfeto de Hidrogênio , Polímeros/química , Cisteína , Meia-Vida , Enxofre
4.
Appl Microbiol Biotechnol ; 106(21): 7039-7050, 2022 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-36184689

RESUMO

Interleukin-15 (IL-15) is a promising candidate for cancer immunotherapy due to its potent immune-activating effects. There are several IL-15 molecules currently in clinical trials but facing shortages of poor half-life, circulation instability, or complicated production and quality control processes. The aim of this study is to design a novel IL-15 superagonist to set out the above difficulties, and we constructed F4RLI consisting of the GS-linker spaced IgG4 Fc fragment, soluble IL-15 Rα (sIL-15Rα), and IL-15(N72D). Using a single plasmid transient transfection in HEK293E cells, the matured F4RLI was secreted in the form of homodimer and got purified by an easy step of protein A affinity chromatography. The F4RLI product can significantly stimulate the proliferation of human CD3+CD8+ T cells and NK cells in vitro. Meanwhile, F4RLI greatly extended the half-life and prolonged the exposure of IL-15 in mice nearly by 28- and 200-fold, respectively, in comparison with that of the IL-15 monomer. In vivo, F4RLI vastly expanded mouse splenic CD8+ T lymphocytes, illustrating its potential in tumor immunotherapy. Further studies showed that the combination of F4RLI with the immune checkpoint blocker atezolizumab played a synergistic effect in treating MC38 mouse tumor by increasing the percentage of CD8+ T cells in tumor tissue. Moreover, the combination therapy of F4RLI with the angiogenesis inhibitor bevacizumab resulted in significant tumor growth suppression in a xenograft human HT-29 mouse model. Overall, our results demonstrate a homodimeric IL-15 superagonist F4RLI with advances in manufacturing processes and biopharmaceutical applications for cancer immunotherapy. KEY POINTS: • The homodimeric structure of F4RLI facilitates its easy production processes and quality control. • The fusion with Fc and sIL-15Rα extends the plasma half-life of IL-15 by about 28-fold. • F4RLI can play synergistic antitumor activity with the PD-1/PD-L1 checkpoint inhibitor or angiogenesis inhibitor.


Assuntos
Produtos Biológicos , Interleucina-15 , Receptor de Morte Celular Programada 1 , Animais , Humanos , Camundongos , Inibidores da Angiogênese/farmacologia , Antígeno B7-H1/metabolismo , Bevacizumab/farmacologia , Produtos Biológicos/farmacologia , Linfócitos T CD8-Positivos , Linhagem Celular Tumoral , Meia-Vida , Inibidores de Checkpoint Imunológico/farmacologia , Fragmentos Fc das Imunoglobulinas/genética , Imunoglobulina G/metabolismo , Imunoterapia/métodos , Interleucina-15/agonistas , Receptor de Morte Celular Programada 1/metabolismo , Antineoplásicos/farmacologia
5.
Appl Radiat Isot ; 190: 110480, 2022 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-36209648

RESUMO

Terbium-155 has been identified for its potential for single-photon emission computed tomography (SPECT) in nuclear medicine. For activity measurements, an accurate and precise half-life of this radionuclide is required. However, the currently evaluated half-life of 5.32(6) d with a relative standard uncertainty of 1.1% determines the precision possible. Limited literature for the half-life measurements of this radionuclide is available and all reported investigations are prior to 1970. Further measurements are therefore needed to confirm the accuracy and improve the precision of the half-life for its use in the clinical setting. Two samples produced and mass separated at the CERN-MEDICIS facility have been measured at the National Physical Laboratory by two independent techniques: liquid scintillation counting and high-purity germanium gamma-ray spectrometry. A half-life of 5.2346(36) d has been determined from the weighted mean of the half-lives determined by the two techniques. The half-life reported in this work has shown a relative difference of 1.6% to the currently evaluated half-life and has vastly improved the precision.


Assuntos
Medicina Nuclear , Radioisótopos , Meia-Vida , Radioisótopos/análise , Tomografia Computadorizada de Emissão de Fóton Único/métodos , Espectrometria gama
6.
Appl Radiat Isot ; 190: 110507, 2022 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-36228535

RESUMO

The half-lives of 44Sc and 44mSc were measured by following their decay rate using several measurement systems: two ionization chambers and three γ-spectrometry detectors with digital and/or analogue electronics. For 44Sc, the result was the combination of seven half-life values giving a result of 4.042(7) h, which agrees with the last reported value of 4.042(3) h and confirms the near to 2% deviation from the recommended half-life of 3.97(4) h. Scandium-44 is present as an impurity in the production of 44Sc by cyclotron proton irradiation. Its half-life was determined by measurements performed a few days after End of Bomardment (EoB), so that the 44Sc decayed down to a negligible level. Seven measurements were combined to obtain an average of 58.7(3) h, which is in agreement with the recommended value of 58.6(1) h.


Assuntos
Ciclotrons , Escândio , Meia-Vida , Escândio/química
7.
J Nucl Med Technol ; 50(3): 233-239, 2022 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-36215644

RESUMO

Radioiodine therapy has been widely used for ablation of remnant tissue after surgical treatment of differentiated thyroid carcinoma (DTC). Internal dosimetry provides a new approach to choosing the administered activity-an approach that considers the distribution and retention of 131I individually per patient. This study used clinical techniques of internal dosimetry to assess the accumulated activity, internal bone marrow dosimetry, and effective half-life in patients undergoing treatment for DTC. Methods: This was a quantitative, retrospective study analyzing diagnostic documents and images. The internal dosimetry method calculated the dose absorbed by the bone marrow per administered activity of 131I. Calculation of the absorbed dose took into account the accumulated activity, which was obtained through measurements of whole-body images acquired at 4 intervals over 5 d. Results: The median dose absorbed by the bone marrow per administered activity was 0.117 mGy/MBq (range, 0.043-0.152 mGy/MBq). The median whole-body residence time was 22.0 h (range, 12.6-39.4 h). The median effective half-life was 15.6 h (range, 7.6-28.2 h). Conclusion: Internal dosimetry provides information relevant to safe dose limits for DTC radioiodine therapy, especially in advanced cases of the disease for which greater activities may be necessary.


Assuntos
Radioisótopos do Iodo , Neoplasias da Glândula Tireoide , Meia-Vida , Humanos , Radioisótopos do Iodo/uso terapêutico , Radiometria/métodos , Estudos Retrospectivos , Neoplasias da Glândula Tireoide/radioterapia
8.
Sci Rep ; 12(1): 16765, 2022 Oct 06.
Artigo em Inglês | MEDLINE | ID: mdl-36202918

RESUMO

Congenital hyperinsulinism (CHI) is a rare genetic condition characterized by uncontrolled insulin secretion, resulting in hypoglycemia. Although glucagon has lately been regarded as a therapeutic option for CHI, its use is severely hampered by its poor solubility and stability at physiological pH, as well as its short duration of action. To address these constraints, we developed HM15136, a novel long-acting glucagon analog composed of a glucagon analog conjugated to the Fc fragment of human immunoglobulin G4 via a polyethylene glycol linker. In this study, we established that HM15136 was more soluble than natural glucagon (≥ 150 mg/mL vs 0.03 mg/mL). Next, we confirmed that HM15136 activated glucagon receptor in vitro and induced glycogenolysis and gluconeogenesis in rat primary hepatocytes. Pharmacokinetics (PK)/Pharmacodynamics (PD) analysis of HM15136 shows that HM15136 has a markedly longer half-life (36 h vs. < 5 min) and increased bioavailability (90%) compared to native glucagon in mice. Further, HM15136 could effectively reverse acute hypoglycemia induced by insulin challenge, and multiple doses of HM15136 could sustain increased blood glucose levels in CHI rats. In conclusion, our findings indicate that HM15136 promotes sustained elevation of blood glucose, demonstrating the potential for development as a once-weekly therapy for CHI.


Assuntos
Hiperinsulinismo Congênito , Hiperinsulinismo , Animais , Glicemia/análise , Hiperinsulinismo Congênito/tratamento farmacológico , Glucagon , Meia-Vida , Humanos , Hiperinsulinismo/tratamento farmacológico , Fragmentos Fc das Imunoglobulinas , Insulina/farmacologia , Camundongos , Polietilenoglicóis/farmacologia , Ratos , Receptores de Glucagon , Roedores
9.
Sci Rep ; 12(1): 17876, 2022 Oct 25.
Artigo em Inglês | MEDLINE | ID: mdl-36284200

RESUMO

The broadly neutralizing antibody (bNAb) CAP256-VRC26.25 has exceptional potency against HIV-1 and has been considered for clinical use. During the characterization and production of this bNAb, we observed several unusual features. First, the antibody appeared to adhere to pipette tips, requiring tips to be changed during serial dilution to accurately measure potency. Second, during production scale-up, proteolytic cleavage was discovered to target an extended heavy chain loop, which was attributed to a protease in spent medium from 2-week culture. To enable large scale production, we altered the site of cleavage via a single amino acid change, K100mA. The resultant antibody retained potency and breadth while avoiding protease cleavage. We also added the half-life extending mutation LS, which improved the in vivo persistence in animal models, but did not impact neutralization activity; we observed the same preservation of neutralization for bNAbs VRC01, N6, and PGDM1400 with LS on a 208-virus panel. The final engineered antibody, CAP256V2LS, retained the extraordinary neutralization potency of the parental antibody, had a favorable pharmacokinetic profile in animal models, and was negative in in vitro assessment of autoreactivity. CAP256V2LS has the requisite potency, developability and suitability for scale-up, allowing its advancement as a clinical candidate.


Assuntos
Infecções por HIV , HIV-1 , Animais , Anticorpos Amplamente Neutralizantes , Meia-Vida , Anticorpos Neutralizantes , Anticorpos Anti-HIV , Peptídeo Hidrolases , Aminoácidos
10.
Artigo em Inglês | MEDLINE | ID: mdl-36136094

RESUMO

The aim of the study was to investigate the plasma and muscle pharmacokinetic of enrofloxacin (ENR) and its active metabolite ciprofloxacin (CIP) in Nile tilapia (Oreochromis niloticus) following single intravascular (IV), intraperitoneal (IP), or oral (PO) administration at 30 ± 1 °C. In this study, 234 healthy Nile tilapia (120-150 g) were used. The fish received a single IV, IP, or PO treatment of ENR at a dose of 10 mg/kg. The plasma and muscle tissue concentrations of ENR and CIP were measured using high-performance liquid chromatography with fluorescence detection and were evaluated using non-compartmental analysis. The elimination half-life, volume of distribution at steady state, and total body clearance of ENR were 21.7 h, 2.69 L/kg, and 0.09 L/h/kg, respectively. The peak plasma concentrations of ENR after IP or PO administration were 6.11 and 4.21 µg/mL at 0.25 and 2 h, respectively. The bioavailability of ENR for IP or PO routes was 78% and 86%, respectively. AUC(0-120)muscle/AUC(0-120)plasma ratios following the IV, IP, or PO administrations were 1.43, 1.49, and 1.07, respectively. CIP was detected after all routes, but the AUC0-last ratios of CIP to ENR were <1.0% for plasma and muscle. ENR was detected up to 120 h following the IV, IP, or PO administrations. The long residence time of ENR after single IV, IP, or PO administration ensured the plasma concentration was ≥1 × MIC for bacteria with threshold MIC values of 0.92, 0.72, and 0.80 µg/mL over the whole 120 h observed. However, further studies are necessary to determine the optimum pharmacokinetic/pharmacodynamics data of ENR for the treatment of infections caused by susceptible bacteria in tilapia.


Assuntos
Ciclídeos , Fluoroquinolonas , Animais , Enrofloxacina/metabolismo , Ciclídeos/metabolismo , Ciprofloxacina/metabolismo , Administração Oral , Músculos/metabolismo , Bactérias/metabolismo , Meia-Vida
11.
Int J Pharm ; 628: 122238, 2022 Nov 25.
Artigo em Inglês | MEDLINE | ID: mdl-36174850

RESUMO

This paper reviews many of the properties of a peptide that need to be considered prior to development as an oral dosage form when co-formulated with a permeation enhancer to improve oral bioavailability, including the importance and implications of peptide half-life on variability in pharmacokinetic profiles. Clinical considerations in terms of food and drug-drug interactions are also discussed. The paper further gives a brief overview how permeation enhancers overcome barriers that limit oral absorption of peptides and thereby improve their oral bioavailability, albeit bioavailabilities are still low single digit and variability is high.


Assuntos
Sistemas de Liberação de Medicamentos , Peptídeos , Administração Oral , Peptídeos/química , Disponibilidade Biológica , Meia-Vida
13.
Molecules ; 27(17)2022 Aug 25.
Artigo em Inglês | MEDLINE | ID: mdl-36080198

RESUMO

A search in PubMed revealed that 72 radionuclides have been considered for molecular or functional targeted radionuclide therapy. As radionuclide therapies increase in number and variations, it is important to understand the role of the radionuclide and the various characteristics that can render it either useful or useless. This review focuses on the physical characteristics of radionuclides that are relevant for radionuclide therapy, such as linear energy transfer, relative biological effectiveness, range, half-life, imaging properties, and radiation protection considerations. All these properties vary considerably between radionuclides and can be optimised for specific targets. Properties that are advantageous for some applications can sometimes be drawbacks for others; for instance, radionuclides that enable easy imaging can introduce more radiation protection concerns than others. Similarly, a long radiation range is beneficial in targets with heterogeneous uptake, but it also increases the radiation dose to tissues surrounding the target, and, hence, a shorter range is likely more beneficial with homogeneous uptake. While one cannot select a collection of characteristics as each radionuclide comes with an unchangeable set, all the 72 radionuclides investigated for therapy-and many more that have not yet been investigated-provide numerous sets to choose between.


Assuntos
Radioisótopos , Meia-Vida , Radioisótopos/uso terapêutico
14.
Eur J Pharm Biopharm ; 179: 126-136, 2022 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-36087879

RESUMO

Co-amorphous technology is an emerging approach for pharmaceutical engineering of drugs and drug leads with improved physicochemical properties and bioavailability. Platensimycin (PTM) is a promising natural antibiotic lead that acts on bacterial fatty acid synthase and exhibits excellent antibacterial activity. Despite great strides to improve its poor pharmacokinetics by medicinal chemistry and nanotechnology, there are no convenient oral delivery systems developed. Here, a co-amorphous system of PTM and berberine chloride (BCL) was developed for oral delivery of PTM. Co-amorphous PTM-BCL was prepared by rotary vacuum evaporation method, and systematically characterized by powder X-ray diffraction, temperature modulated differential scanning calorimetry, Fourier transform infrared spectroscopy (FTIR), and X-ray photoelectron spectroscopy (XPS). Compared with PTM or BCL alone, the equilibrium solubility and dissolution rate of both of them in the co-amorphous systems decreased significantly, showing the characteristics of sustained release. The molecular interactions between PTM and BCL were mediated by strong charged-mediated hydrogen bonds, based on FTIR, XPS, and NMR-based techniques. The co-amorphous PTM-BCL system showed excellent physiochemical stability at room and elevated (40 °C) temperature under dry conditions. The combination of PTM and BCL showed increased killing of a clinical isolated methicillin-resistant Staphylococcus aureus strain in killing checkerboard assays. Finally, co-amorphous PTM-BCL exhibited 2- or 3-fold longer half-life in rats than that of crystalline and amorphous PTM upon oral administration, respectively. Our study suggests a rational approach to realize the full potential of potent antibiotic PTM, which may be conveniently adapted for engineering of other important pharmaceutics.


Assuntos
Berberina , Staphylococcus aureus Resistente à Meticilina , Adamantano , Aminobenzoatos , Anilidas , Animais , Antibacterianos/farmacologia , Varredura Diferencial de Calorimetria , Cloretos , Preparações de Ação Retardada , Estabilidade de Medicamentos , Ácido Graxo Sintases , Meia-Vida , Pós , Ratos , Solubilidade , Espectroscopia de Infravermelho com Transformada de Fourier , Difração de Raios X
15.
Drug Des Devel Ther ; 16: 3109-3116, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36132333

RESUMO

Albutrepenonacog-alfa (Idelvion®, CSL Behring) is a recombinant fusion protein in which the recombinant FIX (rFIX) links a recombinant human albumin, extending the half-life of rFIX even beyond 100 hours. In 2016, this drug was approved worldwide for the treatment of pediatric and adult persons with hemophilia B (PWH-B). Its efficacy and safety were described in the PROLONG-9FP program and subsequently confirmed in the real-world practice, even if to date there are not many manuscripts that extensively and completely deal with the use of albutrepenonacog-alfa in daily practice, also evaluating its impact on the quality of life of patients treated with this drug; this review therefore aims to analyze all the publications currently available regarding the real-world use of this extended half-life concentrate, also noting which topics need further study and research.


Assuntos
Hemofilia B , Adulto , Criança , Fator IX/uso terapêutico , Meia-Vida , Hemofilia B/tratamento farmacológico , Humanos , Qualidade de Vida , Proteínas Recombinantes de Fusão/efeitos adversos , Albumina Sérica Humana
16.
Semin Thromb Hemost ; 48(8): 904-910, 2022 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-36108649

RESUMO

The availability first in the 1970s of plasma-derived and then in the 1990s of recombinant clotting factor concentrates represented a milestone in hemophilia care, enabling not only treatment of episodic bleeding events but also implementation of prophylactic regimens. The treatment of hemophilia has recently reached new landmarks. The traditional clotting factor replacement therapy for hemophilia has been substituted over the last 10 years by novel treatments such as bioengineered factor VIII and IX molecules with extended half-life and non-factor treatments including the bispecific antibody emicizumab. This narrative review is dedicated to these newer therapies, which are contributing significantly to improving the long-term management of prophylaxis in hemophilia patients. Another section is focused on the current state of gene therapy, which is a promising definitive cure for severe hemophilia A and B.


Assuntos
Hemofilia A , Hemofilia B , Hemostáticos , Humanos , Hemofilia A/tratamento farmacológico , Fator VIII/uso terapêutico , Fatores de Coagulação Sanguínea/uso terapêutico , Meia-Vida , Hemostáticos/uso terapêutico , Terapia Genética , Fator IX/uso terapêutico , Hemofilia B/tratamento farmacológico
17.
Res Vet Sci ; 152: 150-155, 2022 Dec 20.
Artigo em Inglês | MEDLINE | ID: mdl-35973234

RESUMO

Bacterial cystitis is common in dogs and is usually treated with antibiotics. Nitrofurantoin is used for treatment of bacterial cystitis in humans and might provide a feasible treatment option in dogs. The aim of this study was to investigate the nitrofurantoin plasma concentration-time course and potential adverse effects in dogs. Nitrofurantoin (4.4-5.0 mg/kg) was administered orally to eight healthy beagles every 8 h for five days before repeated plasma and urine samples were collected. An additional four beagles served as untreated controls. The nitrofurantoin plasma and urine concentrations were measured using ultra high precision liquid chromatography coupled to tandem mass-spectrometry and further analysed using a non-compartmental pharmacokinetic model. In plasma, the median Cmax was 2.1 µg/mL, tmax was 2 h, the terminal rate constant was 0.9 per h and the terminal half-life was 0.8 h. In urine, median Cmax was 56 µg/mL, tmax was 1 h and the terminal half-life was 4.3 h. No adverse effects were observed clinically or in haematology or biochemistry. The data presented in this study combined with in vitro sensitivity data from common urine pathogens and the lack of observed adverse effects suggest that nitrofurantoin in a standard dosing regimen could be effective in sporadic bacterial cystitis treatment in dogs. Further clinical studies are highly warranted to verify the effectiveness in clinical cases.


Assuntos
Infecções Bacterianas , Cistite , Doenças do Cão , Humanos , Cães , Animais , Nitrofurantoína/efeitos adversos , Antibacterianos/efeitos adversos , Antibacterianos/farmacocinética , Infecções Bacterianas/veterinária , Cistite/induzido quimicamente , Cistite/tratamento farmacológico , Cistite/veterinária , Plasma , Administração Oral , Meia-Vida , Doenças do Cão/tratamento farmacológico
18.
Sci Rep ; 12(1): 13925, 2022 08 17.
Artigo em Inglês | MEDLINE | ID: mdl-35978004

RESUMO

Despite a significantly improved dietary iodine supply, solitary toxic thyroid nodules (STN) are still a common clinical problem in former iodine deficient areas. Radioiodine treatment (RIT) is a well-established therapeutic option with few side effects and high success rates. As radioiodine biokinetics are individual for every patient, the necessary activity has to be calculated individually by a pre-therapeutic measurement of the intra-therapeutic effective half-life (EHL) in a radioiodine uptake test (RIUT). A suppressive medication with triiodothyronine (T3) or tetraiodothyronine (T4) is often needed to suppress uptake in normal thyroid tissue. Therefore, the aim of this study was to quantify the possible influence of this medication on intra-therapeutic radioiodine biokinetics. A cohort of 928 patients with STN undergoing RIUT and RIT was analysed. Patients were subdivided into 3 groups. Group T3: medication with T3 (n = 274), group T4: medication with T4 (n = 184) and group NM: no additional medication (n = 470). The T3 and T4 subgroups were further subdivided depending on the dose of thyroid hormone medication. In order to analyse the influence of thyroid hormone medication on individual intra-thyroidal biokinetics, the variance of the determined individual EHL between RIUT and RIT within the single groups and within the subgroups was investigated. EHL was significantly decreased between RIUT and RIT in the T3 and T4 subgroups (EHL: T3: 5.9 ± 1.1 d in RIUT and 3.3 ± 1.4 d in RIT (- 43%) (p < 0.05); T4: 5.9 ± 1.2 d in RIUT and 3.4 ± 1.5 d in RIT (- 42%) (p < 0.05). The decrease of EHL did not differ statistically between T3 or T4. However, both showed a highly significant difference compared to the NM group (p < < 0.05). A further subgroup analysis showed a significant dependence of the decrease in EHL related to the dose of thyroid hormone medication of 35-58% (T3) and 15-67% (T4) (p < 0.05). A significantly reduced EHL compared to RIUT in patients receiving thyroid hormone medication was detected. Moreover, a significant correlation between the dose of thyroid hormone medication (T3 or T4) and the decrease of EHL was found. Therefore, an adaption of the calculated activity should be considered in RIUT to obtain the required radiation dose in RIT of patients suffering from STN.


Assuntos
Iodo , Nódulo da Glândula Tireoide , Meia-Vida , Humanos , Radioisótopos do Iodo/uso terapêutico , Nódulo da Glândula Tireoide/tratamento farmacológico , Tiroxina , Tri-Iodotironina
19.
Vet Microbiol ; 273: 109526, 2022 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-35988378

RESUMO

Porcine reproductive and respiratory syndrome virus (PRRSV) is an important pathogen. Although tremendous effort has been made for the vaccine development, only modified live vaccines are widely used with arguably limited efficacy. Our previous study showed that the Fc-fused first four Ig-like domains of Sn (Sn4D-Fc) and the SRCR domains 5-9 of CD163 (SRCR59-Fc) can act as PRRSV soluble receptors (VSRs). In this study, we improved the VSR-based anti-PRRSV strategy by taming their Fc domains. Sequence alignment showed that the CH3 domain of pig IgG1 contained five putative amino acids involved in the interaction with the neonatal Fc receptor (FcRn). The M455L/N461S variant of SRCR59-Fc/Sn4D-Fc was created for the higher affinity of FcRn binding. Both rBac-SRCR59-lsFc/Sn4D-lsFc and rBac-SRCR59-Fc/Sn4D-Fc expressing the mutated or wild-type VSRs were generated for conceptual validation. Both immunofluorescence and Western blotting analysis showed that the two rBac vectors could express the encoded VSRs in cells with similar expression levels and anti-PRRSV effects. In the rBac-injected mice, the expression of SRCR59-lsFc/Sn4D-lsFc was significantly prolonged than that of SRCR59-Fc/Sn4D-Fc. Both plasma stability and serum half-life of the purified SRCR59-lsFc/Sn4D-lsFc were significantly improved than that of SRCR59-Fc/Sn4D-Fc. SRCR59-lsFc/Sn4D-lsFc-treated peripheral blood mononuclear cells showed significantly stronger cytotoxicity on PRRSV-infected primary alveolar macrophages than SRCR59-Fc/Sn4D-Fc-treated cells. For the first time, we demonstrated that both half-life and effector function of pig IgG Fc-fused proteins could be significantly improved by taming their CH3 domains. The rBac-SRCR59-lsFc/Sn4D-lsFc could be further developed as a novel anti-PRRSV reagent.


Assuntos
Síndrome Respiratória e Reprodutiva Suína , Vírus da Síndrome Respiratória e Reprodutiva Suína , Doenças dos Roedores , Doenças dos Suínos , Animais , Meia-Vida , Leucócitos Mononucleares , Macrófagos Alveolares , Camundongos , Síndrome Respiratória e Reprodutiva Suína/metabolismo , Síndrome Respiratória e Reprodutiva Suína/prevenção & controle , Vírus da Síndrome Respiratória e Reprodutiva Suína/genética , Domínios Proteicos , Suínos , Doenças dos Suínos/metabolismo
20.
J Clin Endocrinol Metab ; 107(10): e4058-e4062, 2022 09 28.
Artigo em Inglês | MEDLINE | ID: mdl-35914268

RESUMO

CONTEXT: Both FSH and LH circulate as 2 glycoforms, differing in number of glycans: low-N-glycosylated glycoforms, FSHtri and LHdi, and fully N-glycosylated glycoforms, FSHtetra and LHtri. OBJECTIVES: To determine the half-lives of endogenous circulating gonadotropin glycoforms in women during GnRH receptor blockade. DESIGN/PARTICIPANTS: Serum samples were collected in 8 healthy women before and up to 20 hours after administration of the NAL-GLU GnRH antagonist. Three women were in early follicular phase, 2 at mid-cycle phase, and 3 were postmenopausal. MAIN OUTCOME MEASURES: The half-life of each glycoform was estimated by monoexponential decay for FSH (n = 8) and LH (n = 5). Data were analyzed using paired t tests. RESULTS: Half-lives in the circulation of low-N-glycosylated glycoforms of both FSH and LH were shorter than those of the fully N-glycosylated glycoforms (mean; range, FSHtri 343; 116-686 minutes vs FSHtetra 757; 436-1038, minutes, P = 0.0003; LHdi 125, 84-198 minutes vs LHtri 164, 107-235 minutes, P = 0.004). The half-lives of low-and fully N-glycosylated forms of LH were shorter than the corresponding half-lives of FSH glycoforms, P = 0.0008. CONCLUSIONS: For both FSH and LH, low-N-glycosylated glycoforms disappeared from the circulation faster than the fully N-glycosylated. The half-lives of low and fully N-glycosylated forms of LH were shorter than the corresponding half-lives of FSH. The estimated values for half-life in the circulation of total FSH and total LH will depend on the relative amounts of the 2 glycoforms of each hormone and their individual disappearance rates in circulation.


Assuntos
Hormônio Luteinizante , Receptores LHRH , Feminino , Hormônio Foliculoestimulante , Hormônio Liberador de Gonadotropina , Meia-Vida , Humanos , Polissacarídeos
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