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1.
Pharm Res ; 37(2): 17, 2019 Dec 26.
Artigo em Inglês | MEDLINE | ID: mdl-31879800

RESUMO

PURPOSE: Modulating sialylation of therapeutic glycoproteins may be used to influence their clearance and systemic exposure. We studied the effect of low and high sialylated IL4-10 fusion protein (IL4-10 FP) on in vitro and in vivo bioactivity and evaluated the effect of differential sialylation on pharmacokinetic parameters. METHODS: CHO cell lines producing low (IL4-10 FP lowSA) and high sialylated (IL4-10 FP highSA) fusion protein were generated. Bioactivity of the proteins was evaluated in an LPS-stimulated whole blood assay. Pharmacokinetics were studied in rats, analyzing plasma levels of IL4-10 FP upon intravenous injection. In vivo activity was assessed in an inflammatory pain mice model upon intrathecal injection. RESULTS: IL4-10 FP lowSA and IL4-10 FP highSA had similar potency in vitro. The pharmacokinetics study showed a 4-fold higher initial systemic clearance of IL4-10 FP lowSA, whereas the calculated half-life of both IL4-10 FP lowSA and IL4-10 FP highSA was 20.7 min. Finally, both IL4-10 FP glycoforms inhibited persistent inflammatory pain in mice to the same extent. CONCLUSIONS: Differential sialylation of IL4-10 fusion protein does not affect the in vitro and in vivo activity, but clearly results in a difference in systemic exposure. The rapid systemic clearance of low sialylated IL4-10 FP could be a favorable characteristic to minimize systemic exposure after administration in a local compartment.


Assuntos
Anti-Inflamatórios/sangue , Interleucina-10/sangue , Interleucina-4/sangue , Ácido N-Acetilneuramínico/química , Proteínas Recombinantes de Fusão/sangue , Animais , Anti-Inflamatórios/química , Anti-Inflamatórios/farmacologia , Células CHO , Cricetulus , Modelos Animais de Doenças , Glicosilação , Células HEK293 , Humanos , Interleucina-10/química , Interleucina-10/farmacologia , Interleucina-4/química , Interleucina-4/farmacologia , Taxa de Depuração Metabólica , Camundongos Endogâmicos C57BL , Dor/tratamento farmacológico , Ratos Wistar , Proteínas Recombinantes de Fusão/química , Proteínas Recombinantes de Fusão/farmacologia
2.
Emerg Microbes Infect ; 8(1): 1146-1156, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31364945

RESUMO

Estradiol, a major female steroid produced during pregnancy, has been reported to protect ovariectomized animals against H1N1 influenza infections via its anti-inflammatory effects. However, it remains unclear why pregnant women with high gestational estradiol levels are highly susceptible to influenza infections. This study was aimed to investigate the effects of pregnancy level of estradiol on female immunity against H5N1 infection in Balb/c mice. A sex-dependent susceptibility to H5N1 infection (higher morbidity and higher mortality) was observed in both pregnant and non-pregnant female mice as compared to male mice. Subcutaneous implantation of estradiol pellets increased serum estradiol concentrations of non-pregnant female mice to the pregnancy level. These mice were protected from H5N1 infection through downregulation of pulmonary pro-inflammatory cytokines. However, the production of virus-specific antibodies after infection was significantly delayed in estradiol-implanted mice when compared to placebos. Virus-specific IgG-secreting and IL-4-secreting cells were also reduced in estradiol-implanted mice. Similarly, lower antibody titers to seasonal vaccine antigens were found in pregnant women as compared to non-pregnant females without hormone usage. Our results indicate that estradiol levels equivalent to those found during pregnancy have divergent effects on female immunity against influenza, highlighting the importance of vaccination during pregnancy to prevent severe influenza infections.


Assuntos
Anti-Inflamatórios/sangue , Resistência à Doença , Estradiol/sangue , Imunidade Humoral , Virus da Influenza A Subtipo H5N1/imunologia , Infecções por Orthomyxoviridae/imunologia , Complicações Infecciosas na Gravidez/imunologia , Animais , Anti-Inflamatórios/administração & dosagem , Modelos Animais de Doenças , Estradiol/administração & dosagem , Feminino , Imunoglobulina G/sangue , Pulmão/patologia , Masculino , Camundongos Endogâmicos BALB C , Gravidez , Fatores Sexuais
3.
Biopharm Drug Dispos ; 40(7): 250-261, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31256430

RESUMO

Infliximab (IFX) is used as a therapeutic agent for ulcerative colitis (UC) and Crohn's disease (CD). Although the dosage regimen has been established through clinical trial experience, it has yet to be assessed with a pharmacokinetic and pharmacodynamic model. The present study analysed sequential changes of clinical response in patients with ulcerative colitis and Crohn's disease following repeated administrations of infliximab using the pharmacokinetic/pharmacodynamic model. In addition, the dosage regimen presently used for patients with ulcerative colitis was evaluated, as well as the potential efficacy gained by increasing the dose and/or reducing the interval of administration for patients with Crohn's disease. Furthermore, the possibility of evaluating the difference between both diseases with regard to the efficacy of infliximab was investigated. Sequential changes in the clinical response values obtained with our model were in good agreement with the observed values following administration of infliximab in patients with ulcerative colitis and Crohn's disease. The results showed the importance of a loading dose for patients with ulcerative colitis, as well as the efficacy of increasing the dose and reducing the interval for patients with Crohn's disease. Also, the efficacy of infliximab for both diseases is suggested to be similar. In conclusion, our results show a possible modeling scenario that can accommodate the clinical response to infliximab administered for ulcerative colitis and Crohn's disease. Furthermore, it provides confirmation for the present dosage regimens given for these diseases.


Assuntos
Anti-Inflamatórios/farmacocinética , Anti-Inflamatórios/uso terapêutico , Colite Ulcerativa/tratamento farmacológico , Doença de Crohn/tratamento farmacológico , Infliximab/farmacocinética , Infliximab/uso terapêutico , Modelos Biológicos , Anti-Inflamatórios/sangue , Colite Ulcerativa/metabolismo , Doença de Crohn/metabolismo , Humanos , Infliximab/sangue , Resultado do Tratamento
4.
Gastroenterology ; 157(4): 985-996.e2, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31194979

RESUMO

BACKGROUND & AIMS: Proactive monitoring of drug trough concentrations and antibodies against drugs might help determine whether patients are likely to respond to treatment and increase efficacy. We investigated whether proactive drug monitoring is associated with higher rates of clinical remission in pediatric patients with Crohn's disease (CD). METHODS: We performed a nonblinded, randomized controlled trial of 78 children with CD (6-18 years old; 29% female; mean age, 14.3 ± 2.6 years) who had not received prior treatment with a biologic agent but had responded to adalimumab induction therapy, under scheduled monitoring of clinical and biologic measures (based on clinical factors and levels of C-reactive protein and fecal calprotectin), at pediatric gastroenterology units in Israel from July 2015 through December 2018. The patients were randomly assigned to groups that received proactive monitoring (trough concentrations measured at weeks 4 and 8 and then every 8 weeks until week 72, n = 38) or reactive monitoring (physicians were informed of trough concentrations after loss of response, n = 40). In both groups, doses and intervals of adalimumab were adjusted to achieve trough concentrations of 5 µg/mL. The primary endpoint was sustained corticosteroid-free clinical remission at all visits (week 8 through week 72). RESULTS: The primary endpoint was achieved by 31 children (82%) in the proactive group and 19 children (48%) in the reactive group (P = .002). Sixteen patients in the proactive monitoring group (42%) achieved a composite outcome of sustained corticosteroid-free remission, C-reactive protein ≤0.5 mg/dL, and level of fecal calprotectin ≤150 µg/g compared with 5 patients in the reactive monitoring group (12%) (P = .003). By week 72 of treatment, 33 patients in the proactive monitoring group had received adalimumab intensification (87%) compared with 24 patients in the reactive monitoring group (60%) (P = .001). CONCLUSIONS: In a randomized controlled trial of pediatric patients with CD, we found that proactive monitoring of adalimumab trough concentrations and adjustment of doses and intervals resulted in significantly higher rates corticosteroid-free clinical remission than reactive monitoring (measuring trough concentration after loss of response). Clinicaltrials.gov no.: NCT02256462.


Assuntos
Adalimumab/sangue , Adalimumab/uso terapêutico , Anti-Inflamatórios/sangue , Anti-Inflamatórios/uso terapêutico , Anticorpos/sangue , Doença de Crohn/tratamento farmacológico , Monitoramento de Medicamentos/métodos , Fármacos Gastrointestinais/sangue , Fármacos Gastrointestinais/uso terapêutico , Adalimumab/imunologia , Adalimumab/farmacocinética , Adolescente , Corticosteroides/uso terapêutico , Anti-Inflamatórios/imunologia , Anti-Inflamatórios/farmacocinética , Biomarcadores/sangue , Criança , Doença de Crohn/sangue , Doença de Crohn/diagnóstico , Doença de Crohn/imunologia , Feminino , Fármacos Gastrointestinais/imunologia , Fármacos Gastrointestinais/farmacocinética , Humanos , Israel , Masculino , Modelos Biológicos , Valor Preditivo dos Testes , Indução de Remissão , Fatores de Tempo , Resultado do Tratamento
5.
Gastroenterology ; 157(4): 997-1006.e6, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31175865

RESUMO

BACKGROUND & AIMS: We evaluated the ability of vedolizumab to induce endoscopic and histologic remission in patients with Crohn's disease (CD). METHODS: We performed a prospective study of 110 patients with active CD, based on CD activity index (CDAI) scores >220 and mucosal ulcerations, who received open-label vedolizumab (300 mg) infusions at weeks 0, 2, and 6, and every 8 weeks thereafter through week 52 at tertiary centers in Europe. Patients received an additional infusion at week 10 if their CDAI score had not decreased by 70 points. Patients underwent ileocolonoscopy with collection of biopsies at baseline and weeks 26 and 52; a local and central reader determined simple endoscopic index for CD (SES-CD) scores. Histologic features were assessed by a blinded pathologist at week 26. Serum concentrations of vedolizumab were measured at serial time points. The primary outcome was endoscopic and histologic remission in patients with active CD treated with vedolizumab for 52 weeks. RESULTS: At weeks 26 and 52, 36 patients (29%) and 34 patients (31%), respectively, were in corticosteroid-free clinical remission (CDAI score <150), respectively. Based on intent-to-treat analysis, endoscopic remission (SES-CD score <4) was achieved by 36 patients (33%) and 40 patients (36%) at weeks 26 and 52. Endoscopic responses (decrease in SES-CD score ≥50%) occurred in 44 patients (40%) at week 26 and 5 patients (45%) at week 52. Serum concentrations of vedolizumab were higher at weeks 2, 10, and 22 in patients with lower SES-CD scores. Histologic remission at week 26 was observed in 43 (64%) of 67 patients based on Geboes Score and 37 (66%) of 56 patients based on Robarts Histopathology Index scores in analyses of paired biopsies with inflammation at baseline. Serum concentrations of vedolizumab above 10 mg/L at week 22 were associated with endoscopic remission at week 26. CONCLUSIONS: In a prospective trial, we found that approximately one-third of patients with CD achieve endoscopic remission after 52 weeks of treatment with vedolizumab and two-thirds achieve histologic remission at week 26. Higher serum concentrations of vedolizumab were associated with better outcomes. EUDRACT no: 2014-005376-29.


Assuntos
Anti-Inflamatórios/uso terapêutico , Anticorpos Monoclonais Humanizados/uso terapêutico , Doença de Crohn/tratamento farmacológico , Endoscopia Gastrointestinal , Fármacos Gastrointestinais/uso terapêutico , Mucosa Intestinal/efeitos dos fármacos , Cicatrização/efeitos dos fármacos , Corticosteroides/uso terapêutico , Adulto , Anti-Inflamatórios/efeitos adversos , Anti-Inflamatórios/sangue , Anti-Inflamatórios/farmacocinética , Anticorpos Monoclonais Humanizados/efeitos adversos , Anticorpos Monoclonais Humanizados/sangue , Anticorpos Monoclonais Humanizados/farmacocinética , Bélgica , Biópsia , Doença de Crohn/sangue , Doença de Crohn/patologia , Monitoramento de Medicamentos , Feminino , Fármacos Gastrointestinais/efeitos adversos , Fármacos Gastrointestinais/sangue , Fármacos Gastrointestinais/farmacocinética , Humanos , Mucosa Intestinal/patologia , Masculino , Pessoa de Meia-Idade , Países Baixos , Valor Preditivo dos Testes , Estudos Prospectivos , Indução de Remissão , Fatores de Tempo , Resultado do Tratamento
6.
Aust Vet J ; 97(5): 144-148, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-31025330

RESUMO

OBJECTIVE: To quantify the time to clear dexamethasone from plasma and urine of horses following a single nebulisation. DESIGN: Experimental using six Standardbred mares. METHODS: Dexamethasone sodium phosphate (0.04 mg/kg) diluted in 0.9% sodium chloride was administered as an aerosol using a Flexineb E2® nebuliser. Blood samples (0, 2, 4, 6, 8, 10, 12, 24, 32, 48, 72 and 96 h) and urine samples (0, 1, 4, 8, 24, 32, 48, 72 and 96 h) were collected for analysis using liquid chromatography mass spectrometry. RESULTS: Maximum plasma concentrations (tmax ) were reached by the earliest detection point (2 h) after nebulisation (0.6-1.8 ng/mL), but was no longer detectable at 48 h. However, in one horse 0.1 ng/mL was found at 96 h after three consecutive readings of 0 ng/mL. The tmax in urine was reached by the earliest collection point (1 h) after nebulisation (3.2-23.8 ng/mL), but was no longer present in urine at 72 h in five horses, while detectable levels (0.1 ng/mL) were still present at 96 h in one horse. CONCLUSIONS: A single dose of 0.04 mg/kg of DSP administered as an aerosol through a FlexinebE2® mask was no longer detectable in blood at 48 h in six horses tested, but one horse returned a reading of 0.1 ng/mL at 96 h after having no detectable levels. Dexamethasone was not detectable in urine at 72 h in five horses but was detectable at a low concentration (0.1 ng/mL) at 96 h in one horse.


Assuntos
Anti-Inflamatórios/sangue , Anti-Inflamatórios/urina , Dexametasona/sangue , Dexametasona/urina , Cavalos/sangue , Cavalos/urina , Animais , Anti-Inflamatórios/uso terapêutico , Asma/tratamento farmacológico , Asma/veterinária , Dexametasona/uso terapêutico , Feminino , Doenças dos Cavalos/tratamento farmacológico , Nebulizadores e Vaporizadores/veterinária , Projetos Piloto , Distribuição Aleatória
7.
Nano Lett ; 19(6): 3548-3562, 2019 06 12.
Artigo em Inglês | MEDLINE | ID: mdl-31026397

RESUMO

Metastasis is the major cause of high mortality in cancer patients; thus, blocking the metastatic process is of critical importance for cancer treatments. The premetastatic niche, a specialized microenvironment with aberrant changes related to inflammation, allows the colonization of circulating tumor cells (CTCs) and serves as a potential target for metastasis prevention. However, little effort has been dedicated to developing nanomedicine to amend the premetastatic niche. Here this study reports a premetastatic niche-targeting micelle for the modulation of premetastatic microenvironments and suppression of tumor metastasis. The micelles are self-assembled with the oleate carbon chain derivative of metformin and docosahexaenoic acid, two anti-inflammatory agents with low toxicity, and coated with fucoidan for premetastatic niche-targeting. The obtained functionalized micelles (FucOMDs) exhibit an excellent blood circulation profile and premetastatic site-targeting efficiency, inhibit CTC adhesion to activated endothelial cells, alleviate lung vascular permeability, and reverse the aberrant expression of key marker proteins in premetastatic niches. As a result, FucOMDs prevent metastasis formation and efficiently suppress both primary-tumor growth and metastasis formation when combined with targeted chemotherapy. Collectively, the findings here provide proof of concept that the modulation of the premetastatic niche with targeted anti-inflammatory agents provides a potent platform and a safe and clinical translational option for the suppression of tumor metastasis.


Assuntos
Anti-Inflamatórios/administração & dosagem , Ácidos Docosa-Hexaenoicos/administração & dosagem , Metformina/administração & dosagem , Metástase Neoplásica/prevenção & controle , Neoplasias/tratamento farmacológico , Microambiente Tumoral/efeitos dos fármacos , Animais , Anti-Inflamatórios/sangue , Anti-Inflamatórios/uso terapêutico , Ácidos Docosa-Hexaenoicos/sangue , Ácidos Docosa-Hexaenoicos/uso terapêutico , Pulmão/irrigação sanguínea , Metformina/sangue , Metformina/uso terapêutico , Camundongos , Micelas , Metástase Neoplásica/patologia , Neoplasias/patologia , Células Neoplásicas Circulantes/efeitos dos fármacos , Células Neoplásicas Circulantes/patologia , Ratos Sprague-Dawley
8.
J Crohns Colitis ; 13(10): 1248-1256, 2019 Sep 27.
Artigo em Inglês | MEDLINE | ID: mdl-30820530

RESUMO

BACKGROUND AND AIM: Therapeutic drug monitoring is used to optimise adalimumab therapy in patients with Crohn's disease [CD]. However, the interindividual variability in drug absorption and the quantitative effect on drug clearance of anti-adalimumab antibodies [AAA], measured with a drug-resistant assay, are unclear. We aimed to characterise adalimumab population pharmacokinetics [PopPK] and identify determinants of interindividual variability in patients with CD. METHODS: In a prospective multicentre open-label cohort study in 28 patients with CD starting adalimumab therapy peak, intermediate, and trough serum samples were analysed for adalimumab and AAA concentrations using a drug resistant assay. Adalimumab concentration-time data were analysed by non-linear mixed effects modelling and were adequately described by a PopPK model with first-order absorption and one-compartment disposition with linear elimination. Clinical remission at Week 12 [W12] was defined as a Harvey-Bradshaw index ≤4. RESULTS: The absorption rate, volume of distribution, and clearance estimates of a typical patient were respectively 0.343 /day, 7.8 L, and 0.330 L/day. A 4-fold difference in the range of adalimumab concentrations was observed 7 days after the first dose and found to be inversely correlated with baseline lean body weight [LBW], soluble tumour necrosis factor [s-TNF], and s-TNF receptor-1 whereas positive AAA and higher LBW were found to be important predictors of accelerated clearance. An adalimumab concentration at W12 of >7.3 µg/mL was significantly associated with achieving clinical remission at W12. CONCLUSION: Variability in subcutaneous drug absorption is an important contributor to the observed interindividual variability in adalimumab concentrations, in addition to drug clearance [ClinicalTrials.gov NCT02450513].


Assuntos
Adalimumab/sangue , Anti-Inflamatórios/sangue , Doença de Crohn/tratamento farmacológico , Adalimumab/administração & dosagem , Adalimumab/farmacocinética , Adalimumab/uso terapêutico , Adulto , Anti-Inflamatórios/administração & dosagem , Anti-Inflamatórios/farmacocinética , Anti-Inflamatórios/uso terapêutico , Monitoramento de Medicamentos/métodos , Feminino , Humanos , Injeções Subcutâneas , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos
9.
Food Chem Toxicol ; 126: 15-24, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30738132

RESUMO

Morin is a flavonoid has been reported with several pharmacological effects such as, antioxidant, anti-inflammatory, anticancer, antidiabetic, etc. However, morin has low solubility in water, which decreases the bioavailability and limits its clinical application. In this way, to improve the pharmaceutical properties, morin was complexed in hydroxypropyl-ß-cyclodextrin (HP-ß-CD) and its oral bioavailability and anti-inflammatory effects were evaluated. Initially, a phase solubility study was performed, which showed that HP-ß-CD would be the better cyclodextrin for the formation of complexes with morin. The morin/HP-ß-CD inclusion complex (1:1) was prepared by freeze-drying method. The sample obtained was characterized by DSC, FTIR, PXRD, SEM and 1H NMR techniques, evidencing the formation of morin/HP-ß-CD inclusion complex. In addition, complexation efficiency (98.3%) and loading content (17.63%), determined by HPLC demonstrated that morin was efficiently complexed in HP-ß-CD. In vitro dissolution study confirmed that morin/HP-ß-CD inclusion complex increased the solubility and dissolution rate of morin. The oral bioavailability of the morin/HP-ß-CD complex and free morin were evaluated through a pharmacokinetic study in rat plasma. The oral bioavailability of morin complexed with HP-ß-CD was increased by 4.20 times compared with the free morin. Hyperalgesia induced by carrageenan and carrageenan-induced pleurisy were carried out in mice to evaluate the antihyperalgesic and anti-inflammatory activities of free morin and inclusion complex. Morin/HP-ß-CD inclusion complex showed antihyperalgesic effect in inflammatory pain model and anti-inflammatory effect decreasing leukocyte migration and TNF-α levels at a lower dose than free morin. Therefore, the morin/HP-ß-CD inclusion complex improved the solubility, dissolution rate, oral bioavailability, antihyperalgesic and anti-inflammatory effects of morin. In this way, the morin/HP-ß-CD inclusion complex exhibits potential for development of new pharmaceutical product for future clinical applications.


Assuntos
2-Hidroxipropil-beta-Ciclodextrina/química , Anti-Inflamatórios/química , Anti-Inflamatórios/farmacocinética , Flavonoides/química , Flavonoides/farmacocinética , Hiperalgesia/tratamento farmacológico , Hipoglicemiantes/química , Hipoglicemiantes/farmacocinética , Animais , Anti-Inflamatórios/sangue , Disponibilidade Biológica , Varredura Diferencial de Calorimetria , Composição de Medicamentos , Flavonoides/sangue , Humanos , Hiperalgesia/sangue , Hiperalgesia/induzido quimicamente , Hipoglicemiantes/sangue , Masculino , Ratos , Ratos Wistar , Solubilidade , Espectroscopia de Infravermelho com Transformada de Fourier , Difração de Raios X
10.
J Sep Sci ; 42(9): 1702-1709, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30809939

RESUMO

Rapid, simple, and sensitive submicellar liquid chromatography with fluorescence detection was developed and validated to quantify naproxen in plasma and brain samples after oral administration of Naproxen formulations. The method used tramadol as an internal standard. Different submicellar mobile phases with organic phases ranging from 40 to 60% were studied to improve the native fluorescence of the Naproxen and decrease retention times. Separation was done in a Zorbax SB C8 column (250 × 4.6 mm, 5 µm) with a mobile phase containing acidic 0.007 M sodium dodecyl sulfate/acetonitrile (50:50, v/v) at a flow rate of 1 mL/min. Detection was performed with an excitation wavelength of 280 nm and emission of 310 nm and 360 nm for internal standard and Naproxen, respectively. The method was validated by International Conference of Harmonization standards. The method is specific, accurate, and precise (relative standard deviation <3%). Limits of detection and quantification were 0.08 and 0.25 µg/mL, respectively, for biological samples. This method was applied to analyze brain/plasma ratios in mice that had received oral administrations of Naproxen micellar formulations containing 10% w/w of sodium dodecyl sulfate, Cremophor RH 40, or Tween 80. The sodium dodecyl sulfate micelles were faster and more widely distributed in the mouse brains.


Assuntos
Anti-Inflamatórios/análise , Química Encefálica , Cromatografia Líquida/métodos , Naproxeno/análise , Plasma/química , Animais , Anti-Inflamatórios/sangue , Cromatografia Líquida/instrumentação , Fluorescência , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Naproxeno/sangue
11.
Biomed Pharmacother ; 112: 108644, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30798135

RESUMO

Paeoniflorin-6'-O-benzene sulfonate (CP-25), is a novel derivative of paeoniflorin (Pae) with improved anti-arthritic effects. The aim of this study was to evaluate the therapeutic effects and pharmacokinetics of CP-25 when co-administered with MTX in adjuvant-induced arthritis (AA) rats. AA rats were randomly divided into 6 groups and treated as follows: TGP (50 mg/kg/day, ig), CP-25 (50 mg/kg/day, ig), MTX (0.5 mg/kg, 3 times/week, ig), TGP (50 mg/kg/day, ig) + MTX (0.5 mg/kg, 3 times/week, ig) and CP-25 (50 mg/kg/day, ig) + MTX (0.5 mg/kg, 3 times/week, ig) from days 14 - 35 after induction. Clinical, biochemical, and histological scores were used to assess the severity of arthritis while novel ultra-performance liquid chromatography mass spectrometry (UPLC-MS/MS) was used to detect plasma concentration of CP-25. Co-administration of CP-25 and MTX significantly reduced clinical signs of inflammation, suppressed the serum production of IL-17 compared to TGP (50 mg/kg/day, ig) and MTX (0.5 mg/kg, 3 times/week, ig). Pharmacokinetics studies showed increased AUC0-t, Cmax, and t1/2 of CP-25 while V/F and CL/F decreased when co-administered with MTX. We observed an increase concentration and longer exposure with decreased clearance of CP-25 when combined with MTX, that should be further explored for clinical RA therapy.


Assuntos
Anti-Inflamatórios/farmacocinética , Anti-Inflamatórios/uso terapêutico , Artrite Experimental/tratamento farmacológico , Glucosídeos/farmacocinética , Glucosídeos/uso terapêutico , Metotrexato/uso terapêutico , Monoterpenos/farmacocinética , Monoterpenos/uso terapêutico , Administração Oral , Animais , Anti-Inflamatórios/sangue , Área Sob a Curva , Artrite Experimental/metabolismo , Relação Dose-Resposta a Droga , Esquema de Medicação , Quimioterapia Combinada , Glucosídeos/sangue , Meia-Vida , Masculino , Taxa de Depuração Metabólica , Metotrexato/farmacocinética , Monoterpenos/sangue , Ratos Sprague-Dawley
12.
J Pharm Biomed Anal ; 166: 183-188, 2019 Mar 20.
Artigo em Inglês | MEDLINE | ID: mdl-30654206

RESUMO

Inflachromene (ICM), a novel microglia inhibitor, is under development to treat neuroinflammatory disorders. For the pharmacokinetic evaluation of ICM, we developed quantitative ultra-performance liquid chromatography coupled to tandem mass spectrometry (UPLC-MS/MS) method in rat plasma. Protein precipitation method with acetonitrile (ACN) was used for plasma sample preparation. The analyte and carbamazepine (the internal standard) were separated by the chromatography on an ACQUITY UPLC™ BEH C18 column running gradient mobile phase system made up of 0.1% [v/v] formic acid in water and 0.1% [v/v] formic acid in acetonitrile. For the quantification of ICM, the ion transitions, m/z 378.2→187.1 (ICM) and m/z 237.1→194.1 (IS) were monitored in multiple reaction monitoring (MRM) mode. Standard calibration curve showed excellent linearity with the correlation coefficient (R2) of 0.99 within the concentration range of 0.05-10 µg/mL. The precision and accuracy were within acceptable limits (all < 20%). ICM was degraded time and temperature dependently in rat plasma. The analytical method was successfully utilized in a pharmacokinetic study following intravenous and oral administration of ICM in rats.


Assuntos
Anti-Inflamatórios/sangue , Compostos Heterocíclicos de 4 ou mais Anéis/sangue , Microglia/efeitos dos fármacos , Administração Oral , Animais , Anti-Inflamatórios/administração & dosagem , Anti-Inflamatórios/farmacologia , Área Sob a Curva , Disponibilidade Biológica , Calibragem , Cromatografia Líquida de Alta Pressão , Estabilidade de Medicamentos , Meia-Vida , Compostos Heterocíclicos de 4 ou mais Anéis/administração & dosagem , Compostos Heterocíclicos de 4 ou mais Anéis/farmacologia , Injeções Intravenosas , Ratos Sprague-Dawley , Reprodutibilidade dos Testes , Espectrometria de Massas em Tandem
13.
Cutan Ocul Toxicol ; 38(2): 161-168, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30513212

RESUMO

PURPOSE: Zeaxanthin protects the macula from ocular damage due to light or radiation by scavenging harmful reactive oxygen species. In the present study, zeaxanthin product (OmniXan®; OMX), derived from paprika pods (Capsicum annum; Family-Solanaceae), was tested for its efficacy in the rat retina against photooxidation. METHODS: Forty-two male 8-week-old Wistar rats exposed to 12L/12D, 16L/8D and 24L/0D hours of intense light conditions were orally administrated either 0 or 100 mg/kg BW of zeaxanthin concentration. Retinal morphology was analyzed by histopathology, and target gene expressions were detected with real-time polymerase chain reaction methods. RESULTS: OMX treatment significantly increased the serum zeaxanthin concentration (p < 0.001) and ameliorated oxidative damage by increasing the antioxidant enzyme activities in the retina induced by light (p < 0.001). OMX administration significantly upregulated the expression of genes, including Rhodopsin (Rho), Rod arrestin (SAG), Gα Transducin 1 (GNAT-1), neural cell adhesion molecule (NCAM), growth-associated protein 43 (GAP43), nuclear factor-(erythroid-derived 2)-like 2 (Nrf2) and heme oxygenase (HO-1) and decreased the expression of nuclear factor-κB (NF- κB) and GFAP by OMX treatment rats. The histologic findings confirmed the antioxidant and gene expression data. CONCLUSIONS: This study suggests that OMX is a potent substance that can be used to protect photoreceptor cell degeneration in the retina exposed to intense light.


Assuntos
Anti-Inflamatórios/uso terapêutico , Antioxidantes/uso terapêutico , Luz/efeitos adversos , Degeneração Retiniana/tratamento farmacológico , Zeaxantinas/uso terapêutico , Animais , Anti-Inflamatórios/sangue , Anti-Inflamatórios/farmacologia , Antioxidantes/farmacologia , Biomarcadores/metabolismo , Proteínas do Olho/genética , Regulação da Expressão Gênica/efeitos dos fármacos , Regulação da Expressão Gênica/efeitos da radiação , Masculino , Malondialdeído/metabolismo , Ratos Wistar , Retina/efeitos dos fármacos , Retina/metabolismo , Retina/patologia , Retina/efeitos da radiação , Degeneração Retiniana/genética , Degeneração Retiniana/metabolismo , Degeneração Retiniana/patologia , Zeaxantinas/sangue , Zeaxantinas/farmacologia
14.
J Crohns Colitis ; 13(5): 564-571, 2019 Apr 26.
Artigo em Inglês | MEDLINE | ID: mdl-30500868

RESUMO

BACKGROUND AND AIMS: The impact of severe inflammation on semen quality, including sperm DNA integrity, in men with inflammatory bowel disease [IBD] is unknown, as are the potential effects of anti-tumour necrosis factor-alpha [TNF-alpha] therapy. We investigated the influence of severe active IBD and anti-TNF-alpha treatment on semen quality. METHODS: We prospectively included 20 patients admitted with severe active IBD. Further, 19 patients who initiated and 17 who stopped anti-TNF-alpha therapy were included. Semen samples were obtained during active disease, and on/off treatment. For paired comparisons, samples were collected not less than 3 months after achieving remission, after treatment initiation, or after treatment cessation. Sperm DNA Fragmentation Index [DFI], concentration, morphology, and motility were evaluated. Sex hormones and seminal plasma anti-TNF-alpha drug levels were measured. RESULTS: In patients with severe disease, progressive sperm motility was impaired and increased significantly [from 28.4% to 37.4%, p = 0.045] during remission. There was no difference in DFI [12.5% versus 12.0%, p = 0.55], concentration [55.0 mill/ml versus 70.0 mill/ml, p = 0.39], or normal morphology [4.7% versus 5.1%, p = 0.51] in these patients. During active disease, testosterone was decreased, and normalised after obtaining remission. Patients who started anti-TNF-alpha therapy had a statistically significant, but clinically irrelevant, reduction in DFI after treatment initiation [12.8% versus 10.0%, p = 0.02]. All other semen parameters were unaffected by therapy. Anti-TNF-alpha drugs were excreted in negligible amounts in semen. CONCLUSIONS: Severe active IBD reduces progressive sperm motility and testosterone levels, but sperm DNA integrity is unaffected by active disease. Anti-TNF-alpha therapy does not impair sperm quality.


Assuntos
Adalimumab/uso terapêutico , Anti-Inflamatórios/uso terapêutico , Fragmentação do DNA , Doenças Inflamatórias Intestinais/complicações , Infliximab/uso terapêutico , Análise do Sêmen , Espermatozoides/metabolismo , Fator de Necrose Tumoral alfa/antagonistas & inibidores , Adalimumab/sangue , Adulto , Anti-Inflamatórios/sangue , Fragmentação do DNA/efeitos dos fármacos , Humanos , Doenças Inflamatórias Intestinais/patologia , Infliximab/sangue , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Motilidade Espermática/efeitos dos fármacos , Espermatozoides/efeitos dos fármacos , Testosterona/sangue , Adulto Jovem
15.
Bioelectrochemistry ; 126: 56-63, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30502639

RESUMO

This paper reports the fabrication of an electrochemical DNA biosensor for the electrochemical determination of prednisone (PRD), which is a synthetic corticosteroid. For this purpose, silver nanoparticles (AgNPs) and a new polymer film poly(glyoxal-bis(2-hydroxyanil)) (P(GBHA)) were electrochemically deposited on a glassy carbon electrode (GCE), respectively. Then, an electrochemical DNA biosensor was prepared onto this electrode surface (GCE/AgNPs/P(GBHA)) by the immobilization of dsDNA using a chronoamperometry method. The proposed electrode was characterized by FESEM, XPS, and cyclic voltammetry (CV). The interaction between the PRD and dsDNA immobilized on the GCE/AgNPs/P(GBHA) electrode was investigated via a differential pulse voltammetry (DPV) method and UV-Vis spectrophotometry. The experimental factors affecting the interaction between the PRD concentration and dsDNA were optimized. The fabricated biosensor showed a wide linear response in a PRD concentration range of 1.0-50.0 µg mL-1 depending on both the adenine and guanine base signals. The detection limit based on the guanine and adenine signals was 0.3 µg mL-1 and 0.25 µg mL-1, respectively. The sensor exhibited excellent anti-interferential ability, good stability and reproducibility and was satisfactorily employed for the electrochemical assay of PRD in serum samples. The new DNA biosensor can be utilized for the sensitive, accurate and rapid analysis of PRD.


Assuntos
Aminofenóis/química , Anti-Inflamatórios/sangue , Técnicas Biossensoriais/métodos , Ácidos Nucleicos Imobilizados/química , Nanopartículas Metálicas/química , Polímeros/química , Prednisona/sangue , Prata/química , Carbono/química , DNA/química , Técnicas Eletroquímicas/métodos , Eletrodos , Humanos
16.
J Vet Pharmacol Ther ; 42(1): 37-44, 2019 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-30242850

RESUMO

Devil's claw is used for the treatment of inflammatory symptoms and degenerative disorders in horses since many years, but without the substantive pharmacokinetic data. The pharmacokinetic parameters of harpagoside, the main active constituent of Harpagophytum procumbens DC ex Meisn., were evaluated in equine plasma after administration of Harpagophytum extract FB 8858 in an open, single-dose, two-treatment, two-period, randomized cross-over design. Six horses received a single dose of Harpagophytum extract, corresponding to 5 mg/kg BM harpagoside, and after 7 days washout period, 10 mg/kg BM harpagoside via nasogastric tube. Plasma samples at certain time points (before and 0-24 hr after administration) were collected, cleaned up by solid-phase extraction, and harpagoside concentrations were determined by LC-MS/MS using apigenin-7-glucoside as internal standard. Plasma concentration-time data and relevant parameters were described by noncompartmental model through PKSolver software. Harpagoside could be detected up to 9 hr after administration. Cmax was found at 25.59 and 55.46 ng/ml, t1/2 at 2.53 and 2.32 hr, respectively, and tmax at 1 hr in both trials. AUC0-inf was 70.46 and 117.85 ng hr ml-1 , respectively. A proportional relationship between dose, Cmax and AUC was observed. Distribution (Vz /F) was 259.04 and 283.83 L/kg and clearance (CL/F) 70.96 and 84.86 L hr-1  kg-1 , respectively. Treatment of horses with Harpagophytum extract did not cause any clinically detectable side effects.


Assuntos
Anti-Inflamatórios/farmacocinética , Glicosídeos/farmacocinética , Harpagophytum , Extratos Vegetais/farmacologia , Piranos/farmacocinética , Animais , Anti-Inflamatórios/administração & dosagem , Anti-Inflamatórios/sangue , Estudos Cross-Over , Feminino , Glicosídeos/sangue , Cavalos/sangue , Cavalos/metabolismo , Intubação Gastrointestinal/veterinária , Masculino , Extratos Vegetais/administração & dosagem , Piranos/sangue , Distribuição Aleatória
18.
Dig Dis Sci ; 64(3): 846-854, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30426297

RESUMO

OBJECTIVES: (a) To evaluate the diagnostic accuracy of anti-TNF trough levels to predict mucosal healing in inflammatory bowel disease (IBD); (b) to determine the best cut-off point to predict mucosal healing in IBD patients treated with anti-TNF. METHODS: This is a multicenter, prospective study. IBD patients under anti-TNF treatment for at least 6 months that had to undergo an endoscopy were included. Mucosal healing was defined as: Simple endoscopic score for Crohn's Disease < 3 for Crohn's disease (CD), Rutgeerts score < i2 for CD in postoperative setting, or Mayo endoscopic score ≤ 1 for ulcerative colitis (UC). Anti-TNF concentrations were measured using SMART ELISAs at trough. RESULTS: A total of 182 patients were included. Anti-TNF trough levels were significantly higher among patients that had mucosal healing than among those who did not. The area under the curve of infliximab for mucosal healing was 0.63 (best cutoff value 3.4 µg/mL), and for adalimumab 0.60 (best cutoff value 7.2 µg/mL). In the multivariate analysis, having anti-TNF drug levels above the cutoff values [odds ratio (OR) 3.1]) and having UC instead of CD (OR 4) were associated with a higher probability of having mucosal healing. Additionally, the need for an escalated dosage (OR 0.2) and current smoking habit (OR 0.2) were also associated with a lower probability of mucosal healing. CONCLUSIONS: There was an association between anti-TNF trough levels and mucosal healing in IBD patients; however, the accuracy of the determination of infliximab and adalimumab concentrations able to predict mucosal healing was suboptimal.


Assuntos
Adalimumab/uso terapêutico , Anti-Inflamatórios/uso terapêutico , Produtos Biológicos/uso terapêutico , Colite Ulcerativa/tratamento farmacológico , Doença de Crohn/tratamento farmacológico , Infliximab/uso terapêutico , Mucosa Intestinal/efeitos dos fármacos , Fator de Necrose Tumoral alfa/antagonistas & inibidores , Cicatrização/efeitos dos fármacos , Adalimumab/sangue , Adalimumab/farmacocinética , Adulto , Anti-Inflamatórios/sangue , Anti-Inflamatórios/farmacocinética , Produtos Biológicos/sangue , Produtos Biológicos/farmacocinética , Colite Ulcerativa/sangue , Colite Ulcerativa/diagnóstico , Colite Ulcerativa/imunologia , Doença de Crohn/sangue , Doença de Crohn/diagnóstico , Doença de Crohn/imunologia , Monitoramento de Medicamentos/métodos , Endoscopia Gastrointestinal , Ensaio de Imunoadsorção Enzimática , Feminino , Humanos , Infliximab/sangue , Infliximab/farmacocinética , Mucosa Intestinal/imunologia , Mucosa Intestinal/patologia , Masculino , Pessoa de Meia-Idade , Valor Preditivo dos Testes , Estudos Prospectivos , Espanha , Fatores de Tempo , Resultado do Tratamento , Fator de Necrose Tumoral alfa/imunologia
19.
Eur J Gastroenterol Hepatol ; 31(2): 187-191, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30543573

RESUMO

BACKGROUND: Infliximab trough levels (IFX-TLs) and antibodies to infliximab (ATIs) have been suggested as useful markers for the optimization of treatment in inflammatory bowel disease (IBD). We aimed to estimate the patterns over time of IFX-TLs and ATIs in IBD patients on maintenance treatment with IFX. METHODS: Two different measurements of IFX-TLs and ATIs were performed (ELISA; Eagle BioSciences) at a 10-month interval using serum samples of consecutive patients on maintenance treatment with IFX. Certain biomarkers [hemoglobin, erythrocyte sedimentation rate, C-reactive protein (CRP), platelets, albumin] measured at the same time as well as clinical disease activity and quality of life were assessed. RESULTS: Among a total of 86 IBD patients under maintenance treatment with IFX, 64 [49 Crohn's disease, 15 ulcerative colitis (UC), 42 men, mean age 44.2±15.2 years, 41 in combination therapy with immunomodulator, six in intensified dose], with two available measurements of IFX-TLs and ATIs (A and B), were included in the study. The median levels of IF-TLs were 5.07 (interquartiles range: 1.60-12.73) µg/ml in measurement A and 4.68 (1.19-7.83) µg/ml in measurement B (P<0.0001). Patients whose dose was intensified after the first measurement showed an increase in their median IFX-TLs from 1.47 to 8.5 µg/ml, whereas patients with stable IFX dose showed a significant reduction in the median IFX-TLs from 5.65 to 3.8 µg/ml (P<0.0001). In the logistic regression analysis, the decrease in IFX-TL was correlated significantly and independently with the increase in CRP [odds ratio 5.2 (1.4-19.0), P=0.01]. CONCLUSION: IBD patients on maintenance treatment with IFX show decreasing patterns of IFX-TLs over time associated with increasing patterns of CRP levels.


Assuntos
Anti-Inflamatórios/farmacocinética , Colite Ulcerativa/tratamento farmacológico , Doença de Crohn/tratamento farmacológico , Fármacos Gastrointestinais/farmacocinética , Infliximab/farmacocinética , Adulto , Anti-Inflamatórios/administração & dosagem , Anti-Inflamatórios/sangue , Biomarcadores/sangue , Proteína C-Reativa/metabolismo , Colite Ulcerativa/sangue , Colite Ulcerativa/diagnóstico , Doença de Crohn/sangue , Doença de Crohn/diagnóstico , Monitoramento de Medicamentos/métodos , Quimioterapia Combinada , Ensaio de Imunoadsorção Enzimática , Feminino , Fármacos Gastrointestinais/administração & dosagem , Fármacos Gastrointestinais/sangue , Humanos , Mediadores da Inflamação/sangue , Infliximab/administração & dosagem , Infliximab/sangue , Quimioterapia de Manutenção , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Indução de Remissão , Resultado do Tratamento
20.
Intern Med J ; 49(4): 513-518, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30091273

RESUMO

BACKGROUND: Therapeutic drug monitoring of anti-tumour necrosis factor (TNF) drugs and anti-drug antibodies (ADA) is now recommended in the treatment of inflammatory bowel disease. However, assay types and drug concentration thresholds are still debated. AIM: To correlate inflammatory bowel disease activity in a New Zealand cohort with trough concentrations of infliximab and adalimumab, and ADA using locally developed competitive-binding enzyme-linked immunosorbent assays (ELISA) to establish threshold concentrations. METHODS: Patients with ulcerative colitis (UC) and Crohn disease (CD) from Christchurch and Dunedin on anti-TNF drugs >12 weeks were enrolled. Trough blood samples were assayed for drug and ADA concentrations. Other data included quality of life, blood count, C-reactive protein, albumin, renal function and disease activity indices. RESULTS: Of 103 patients, 53 were on infliximab (36 CD, 15 UC and 2 unclassified) and 50 adalimumab (48 CD and 2 UC). Median (range) infliximab and adalimumab concentrations were 10.5 (0-41) and 9.61 mg/L (0-30). CD remission, Crohn Disease Activity Index <150, correlated with infliximab and adalimumab concentration in CD (infliximab, P = 0.03; adalimumab, P = 0.04), with too few UC patients for analysis. Receiver operator curve analysis suggested a threshold value of 5.1 mg/L for distinguishing active disease from remission for infliximab and 7.3 mg/L for adalimumab in CD. Of 13 patients with infliximab <2 mg/L, 10 were ADA positive by homogeneous mobility shift assay (HMSA), including five with neutralising antibodies using ELISA. Of six with adalimumab <2 mg/L, three were ADA positive using HMSA, including one with neutralising antibodies. CONCLUSION: Using the New Zealand ELISA assay, threshold concentrations of 5 mg/L for infliximab and 7 mg/L for adalimumab are suggested to aid dosing decisions, consistent with results internationally. Both neutralising (ELISA) and non-neutralising ADA (HMSA) are associated with low drug concentrations.


Assuntos
Adalimumab/sangue , Monitoramento de Medicamentos/métodos , Doenças Inflamatórias Intestinais/tratamento farmacológico , Infliximab/sangue , Fator de Necrose Tumoral alfa/antagonistas & inibidores , Adalimumab/uso terapêutico , Adolescente , Adulto , Idoso , Anti-Inflamatórios/sangue , Anti-Inflamatórios/uso terapêutico , Anticorpos Neutralizantes/sangue , Ligação Competitiva , Ensaio de Imunoadsorção Enzimática , Feminino , Fármacos Gastrointestinais/sangue , Fármacos Gastrointestinais/uso terapêutico , Humanos , Infliximab/uso terapêutico , Masculino , Pessoa de Meia-Idade , Nova Zelândia , Curva ROC , Adulto Jovem
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