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1.
Rev. méd. Chile ; 148(7): 1039-1043, jul. 2020. graf
Article in Spanish | LILACS | ID: biblio-1139408

ABSTRACT

Biological therapy dramatically changed the management of Ulcerative Colitis (UC). However, a significant number of these patients fail to respond or have secondary loss of response to this strategy. In this clinical situation, the options include intensification of anti-TNF therapy, the use of a second anti-TNF or being switched to another drug class. Among the later, tofacitinib, an oral small molecule directed against the JAK/STAT pathway, is safe and effective in inducing and maintaining remission in patients with moderate-severe UC. We report two patients with UC refractory to conventional treatment and biological therapy, who responded successfully to the use of tofacitinib.


Subject(s)
Humans , Male , Middle Aged , Piperidines/therapeutic use , Pyrimidines/therapeutic use , Colitis, Ulcerative/drug therapy , Protein Kinase Inhibitors/therapeutic use , Colitis, Ulcerative/diagnostic imaging , Colonoscopy , Treatment Outcome
2.
Article in Chinese | WPRIM | ID: wpr-878811

ABSTRACT

This article is to investigate the effect of piperine on the small intestine of mice with Parkinson's disease with dementia(PDD). Ninety-six C57 BL/6 mice of SPF grade were randomly divided into 8 groups(male, 12 in each group): normal group, model group, autophagy inhibitor group(6-amino-3-methylpurine, 3 MA, 30 mg·kg~(-1)), autophagy activator group(rapamycin, 1 mg·kg~(-1)), low, medium, and high dose piperine groups(10, 20, 40 mg·kg~(-1)), and medopar group(112.5 mg·kg~(-1)). Except for the normal group, mice in each group were injected subcutaneously with reserpine(0.1 mg·kg~(-1)) once every 48 hours for 40 days. In addition, on the 20 th day of administration, except for the normal group, the mice in the other groups were subjected to bilateral common carotid artery occlusion to finally prepare PDD models. At the same time, each group was given the corresponding drug treatment once a day for 40 days. After the last administration, the behavioral changes of mice were observed by autonomic activity experiment and hot plate experiment. The expression levels of α-synuclein(α-syn) and tyrosine hydroxylase(TH) in the small intestine were detected by immunohistochemistry. The expression levels of beclin-1, microtubule-associated protein 1 light chain 3 B(LC3 B) and p62 in the small intestine were detected by immunofluorescence assay. Hematoxylin-eosin staining was used to observe the pathological morphology of small intestine tissues in each group. Enzyme-linked immunosorbent assay was adopted for detection of β-amyloid precursor protein(APP), p-tau, acetylcholine transferase(ChAT), interleukin-6(IL-6) and tumor necrosis factor-α(TNF-α) in small intestine. Real-time fluorescent quantitative polymerase chain reaction was used to detect the expression of α-syn, TH, beclin-1, microtubule-associated protein 1 light chain 3(LC3), and p62 mRNA and mmu-miR-99 a-5 p in the small intestine. The results of this study showed that, as compared with the model group, the number of activities, the expression levels of ChAT, TH, and p62 were significantly increased in the 3 MA group, the various piperine dose groups, and the medopar group(P<0.05), and their first foot licking time was shortened; APP, p-tau, IL-6, TNF-α, α-syn, beclin-1, LC3 B and mmu-miR-99 a-5 p expression levels were significantly reduced(P<0.05). However, as compared with the model group, the number of activities, ChAT, TH, and p62 expression levels in the rapamycin group were significantly reduced(P<0.05), and the APP, p-tau, IL-6, TNF-α, α-syn, beclin-1, LC3 B and mmu-miR-99 a-5 p expression levels were significantly increased(P<0.05). As compared with the 3 MA group, the number of activities, ChAT, TH, and p62 expression levels were significantly reduced in the low and medium dose piperine groups and rapamycin group(P<0.05); howe-ver, their first foot licking time was significantly prolonged, APP, p-tau, IL-6, TNF-α, α-syn, beclin-1, LC3 B and mmu-miR-99 a-5 p expression levels were increased significantly(P<0.05). As compared with the medopar group, the number of activities, ChAT, TH, and p62 expression levels were significantly reduced in low dose piperine group and rapamycin group(P<0.05), but their first foot licking time was significantly extended, and APP, p-tau, IL-6, TNF-α, α-syn, beclin-1, LC3 B and mmu-miR-99 a-5 p expression levels were significantly increased(P<0.05). In addition, as compared with the normal group, the small intestinal epithelial cells of the model group and the rapamycin group were shed off a lot, with severe damages of intestinal mucosa as well as edema and shedding of the small intestine villi. After administration of the therapeutic interventions, the small intestinal epithelial cells of the 3 MA group, each dose group of piperine, and the medopa group were slightly damaged and the villi were slightly shed off. In summary, piperine has a protective effect on the small intestine of PDD model mice, showing reduced expression of mmu-miR-99 a-5 p, pro-inflammatory factors and autophagy factors, and the mechanism of slowing PDD pathological symptoms may be related to the inhibition of autophagy.


Subject(s)
Alkaloids , Animals , Autophagy , Benzodioxoles , Dementia , Intestine, Small , Male , Mice , Parkinson Disease , Piperidines , Polyunsaturated Alkamides
3.
Article in Chinese | WPRIM | ID: wpr-776559

ABSTRACT

OBJECTIVE@#To observe the effects of AdipoRon orally on the functions of spleen and pancreas in type 2 diabetic mice, in order to present data for clinical application.@*METHODS@#Forty C57/BL6 male mice were randomly divided into 2 groups: normal control group (n=10) and model group (n=30), the former group was fed normally, while the later group was fed with high fat and sugar for 4 weeks.After that, type 2 diabetes model was established in DM group induced by intraperitoneal injection of streptozotocin (STZ, 40 mg/kg).As type 2 diabetes model established successfully, the model mice were randomly divided into three groups (n=10): diabetes mellitus (DM) group, high dose of AdipoRon group (DM + H) and low dose of adiponRon group (DM + L).All the four groups were treated with saline, saline, AdipoRon at the doses of 20 mg/kg and 50 mg/kg by gavages respectively, once a day for 10 days.And then put them to death for collecting blood, pancreas and spleen.Pathological changes of pancreas were observed with a light microscope after HE staining.Protein contents of insulin receptor (INSR), insulin receptor substrate 1( IRS-1) and tumor necrosis factor-α(TNF-α) in pancreatic and spleen tissues were detected by ELISA.The protein level of phosphorylation insulin receptor substrate 1(p-IRS-1) in pancreas was determined by Western blot, and the expression of insulin mRNA in pancreas was tested by RT-PCR.@*RESULTS@#Under the light microscope, it was visible that the pancreatic tissue in NC group was full and closely packed, and the islet was big.Pancreatic tissue of DM mice was incompact and the islet of DM mice was smaller than that of normal mice.As for the mice treated with AdipoRon orally, the pancreatic tissue was full and closely arranged, and the islet was slightly smaller.Compared with NC group, the levels of TNF-α in pancreas and spleen of DM group were increased markedly, the levels of INSR and IRS-1 were decreased, the spleen coefficient, p-IR-1 protein level and insulin mRNA expression in pancreas were decreased, all were significant statistically (P<0.05).Compared with DM group, the levels of TNF-α in pancreas and spleen of AdipoRon groups were decreased, the levels of INSR and IRS-1 in pancreas and spleen of AdipoRon groups were increased, while the spleen coefficient was increased (P<0.05).The p-IRS-1 protein level and insulin mRNA expression in pancreas in DM+H group were increased (P<0.05).Compared with DM + L group, the level of TNF-α was decreased, and the levels of INSR and IRS-1 were significantly increased (P<0.05) in DM + H group (P<0.05).@*CONCLUSION@#Oral administration of AdipoRon can protect the spleen and pancreas of diabetic mice by decreasing the inflammatory response, up-regulating the expression of INSR, and increasing p-IRS-1 level in diabetic mice.


Subject(s)
Animals , Diabetes Mellitus, Experimental , Diabetes Mellitus, Type 2 , Drug Therapy , Inflammation , Insulin , Insulin Receptor Substrate Proteins , Male , Mice , Pancreas , Piperidines , Pharmacology , Random Allocation , Receptor, Insulin , Spleen
4.
Arch. endocrinol. metab. (Online) ; 62(6): 636-640, Dec. 2018. tab, graf
Article in English | LILACS | ID: biblio-983805

ABSTRACT

ABSTRACT Objective: The advent of multikinase inhibitor (MKI) therapy has led to a radical change in the treatment of patients with advanced thyroid carcinoma. The aim of this manuscript is to communicate rare adverse events that occurred in less than 5% of patients in clinical trials in a subset of patients treated in our hospital. Subjects and methods: Out of 760 patients with thyroid cancer followed up with in our Division of Endocrinology, 29 (3.8%) received treatment with MKIs. The median age at diagnosis of these patients was 53 years (range 20-70), and 75.9% of them were women. Sorafenib was prescribed as first-line treatment to 23 patients with differentiated thyroid cancer and as second-line treatment to one patient with advanced medullary thyroid cancer (MTC). Vandetanib was indicated as first-line treatment in 6 patients with MTC and lenvatinib as second-line treatment in two patients with progressive disease under sorafenib treatment. Results: During the follow-up of treatment (mean 13.7 ± 7 months, median 12 months, range 6-32), 5/29 (17.2%) patients presented rare adverse events. These rare adverse effects were: heart failure, thrombocytopenia, and squamous cell carcinoma during sorafenib therapy and squamous cell carcinoma and oophoritis with intestinal perforation during vandetanib treatment. Conclusions: About 3 to 5 years after the approval of MKI therapy, we learned that MKIs usually lead to adverse effects in the majority of patients. Although most of them are manageable, we still need to be aware of potentially serious and rare or unreported adverse effects that can be life-threatening.


Subject(s)
Humans , Male , Female , Adult , Middle Aged , Aged , Young Adult , Piperidines/adverse effects , Quinazolines/adverse effects , Carcinoma/drug therapy , Carcinoma, Medullary/drug therapy , Protein Kinase Inhibitors/adverse effects , Antineoplastic Agents/adverse effects , Oophoritis/chemically induced , Phenylurea Compounds/adverse effects , Quinolines/adverse effects , Thrombocytopenia/chemically induced , Time Factors , Thyroid Neoplasms/drug therapy , Retrospective Studies , Risk Factors , Follow-Up Studies , Kaplan-Meier Estimate , Sorafenib/adverse effects , Heart Failure/chemically induced , Intestinal Perforation/chemically induced
5.
Arq. gastroenterol ; 55(2): 198-200, Apr.-June 2018. graf
Article in English | LILACS | ID: biblio-1038706

ABSTRACT

ABSTRACT Janus kinases inhibitors have already been incorporated into the management of immune-mediated diseases, such as rheumatoid arthritis, and are being investigated for the treatment of psoriasis and inflammatory bowel diseases, both ulcerative colitis and Crohn's disease. Tofacitinib is an oral small-molecule drug that inhibits Janus kinases 1, Janus kinases 3, and, to a lesser extent, Janus kinases 2. This inhibition ends up blocking signals for several inflammatory cytokines that are involved in the pathogenesis of inflammatory bowel diseases and play a role in many immune signaling routes, including lymphocyte activation, function, and proliferation. We report a patient with active ulcerative colitis with primary non-response to three biologics (infliximab, adalimumab and vedolizumab), with different mechanisms of action, who refused surgical treatment and had a favorable response to tofacitinib with clinical and endoscopic remission. No adverse events were observed with the use of the agent. This case illustrates the difficulties we may face regarding the identification of the expression of proper mechanism of action involved in the pathogenesis of ulcerative colitis patients and the importance of having another treatment option with different mechanism of action, like tofacitinib.


RESUMO Os inibidores das Janus kinases (JAK) têm sido incorporados ao tratamento de doenças imunomediadas, como artrite reumatoide e, além disso, têm sido testados no tratamento da psoríase e doenças inflamatórias intestinais, tanto na retocolite ulcerativa quanto na doença de Crohn. Tofacitinibe é uma droga do grupo das pequenas moléculas de uso oral que inibe as Janus kinases 1 e 3 e, em menor grau, a Janus kinases 2. Esta inibição promove o bloqueio de uma série de citocinas pró-inflamatórias que estão envolvidas na patogênese das doenças inflamatórias intestinais e desempenham importante papel nos processos imunes, tais como ativação, função e proliferação linfocitária. Nesta presente comunicação, relatamos um caso de um paciente portador de retocolite ulcerativa refratária a três agentes biológicos (infliximabe, adalimumabe e vedolizumabe), com diferentes mecanismos de ação, que recusou o tratamento cirúrgico, porém, apresentou boa resposta com o uso de tofacitinibe, com remissão clínica e endoscópica. Não foram evidenciados efeitos colaterais com a droga. O presente caso ilustra as dificuldades que podemos enfrentar em relação à identificação da expressão do correto mecanismo de ação envolvido na patogênese dos pacientes com retocolite ulcerativa e a importância de um novo agente terapêutico com diferente mecanismo de ação, como o tofacitinibe.


Subject(s)
Humans , Male , Adult , Piperidines/therapeutic use , Colitis, Ulcerative/drug therapy , Integrins/therapeutic use , Tumor Necrosis Factor-alpha/therapeutic use , Protein Kinase Inhibitors/therapeutic use , Pyrimidines/therapeutic use , Pyrroles/therapeutic use , Integrins/antagonists & inhibitors , Tumor Necrosis Factor-alpha/antagonists & inhibitors , Infliximab/therapeutic use
6.
Chinese Medical Journal ; (24): 2683-2692, 2018.
Article in English | WPRIM | ID: wpr-775034

ABSTRACT

Background@#Tofacitinib is an oral Janus kinase inhibitor for the treatment of rheumatoid arthritis (RA). This study assessed the efficacy and safety of tofacitinib in Chinese patients with RA enrolled in Phase 3 and long-term extension (LTE) studies.@*Methods@#ORAL Sync was a 1-year, randomized, placebo-controlled, Phase 3 trial. Patients received tofacitinib 5 or 10 mg twice daily (BID) or placebo advanced to tofacitinib 5 or 10 mg BID at 3 or 6 months. All patients remained on ≥1 background conventional synthetic disease-modifying antirheumatic drug. ORAL Sequel is an open-label LTE study (data-cut: March 2015; data collection and analyses were ongoing, and study database was not locked at the time of analysis; study was closed in 2017). Efficacy outcomes: American College of Rheumatology (ACR) 20/50/70 response rates and Disease Activity Score in 28 joints using erythrocyte sedimentation rate (DAS28-4 [ESR]). Patient- and physician-reported outcomes: Health Assessment Questionnaire-Disability Index (HAQ-DI), Patient and Physician Global Assessment of Arthritis, and pain (visual analog scale). Safety was assessed throughout.@*Results@#ORAL Sync included 218 patients; 192 were subsequently enrolled into ORAL Sequel. In ORAL Sync, more patients achieved ACR20 (tofacitinib 5 mg BID, 67.4%; 10 mg BID, 70.6%; placebo, 34.1%) and DAS28-4 (ESR) <2.6 (tofacitinib 5 mg BID, 7.1%; 10 mg BID, 13.1%; placebo, 2.3%) with tofacitinib versus placebo at Month 6. Mean changes from baseline in HAQ-DI were greater with tofacitinib versus placebo at Month 6. In ORAL Sequel, efficacy was consistent to Month 48. Incidence rates for adverse events of special interest in tofacitinib-treated patients were similar to the global population.@*Conclusions@#Tofacitinib significantly reduced signs/symptoms and improved physical function and quality of life in Chinese patients with moderate-to-severely active RA up to Month 48. The safety profile was consistent with the global population.@*Clinical Trial Identifier@#NCT00856544 and NCT00413699.


Subject(s)
Administration, Oral , Adult , Aged , Arthritis, Rheumatoid , Drug Therapy , Asian Continental Ancestry Group , Female , Humans , Male , Middle Aged , Piperidines , Therapeutic Uses , Protein Kinase Inhibitors , Therapeutic Uses , Pyrimidines , Therapeutic Uses , Pyrroles , Therapeutic Uses , Surveys and Questionnaires , Young Adult
7.
Article in English | WPRIM | ID: wpr-773631

ABSTRACT

Ginsenoside Rh2 (Rh2) is one of the major bioactive ginsenosides in Panax ginseng. However, the oral bioavailability of Rh2 is low, with P-glycoprotein (P-gp) and CYP3A4 being reported to be the main factors. The purpose of the present study was to determine the enhancing effect of piperine on the oral bioavailability as well as bioactivity of Rh2. The inhibitory effect of piperine on P-gp and CYP3A4 was determined using a Caco-2 monolayer model and a recombinant CYP3A4 metabolic system, respectively. The pharmacokinetics of oral Rh2 (10 mg·kg) administered alone or in combination with piperine (10 and 20 mg·kg) was performed in rats. The immune boosting effect of Rh2 was assessed in rats by measuring IL-12 level after treated by Rh2 alone or co-administered with piperine. The results indicated that piperine significantly increased the permeability of Rh2 and inhibited the metabolism of Rh2. The pharmacokinetic study results showed that the AUC of Rh2 was significantly increased in combination with piperine at high dose (20 mg·kg) when compared to the control group, with relative bioavailability of 196.8%. The increase of Rh2 exposure led to increased serum levels of IL-12. In conclusion, piperine may be used as a bioenhancer to improve pharmacological effect of Rh2 when given orally.


Subject(s)
Administration, Oral , Alkaloids , Animals , Benzodioxoles , Biological Availability , Caco-2 Cells , Cytochrome P-450 CYP3A , Metabolism , Drugs, Chinese Herbal , Ginsenosides , Pharmacokinetics , Humans , Interleukin-2 , Metabolism , Panax , Chemistry , Piperidines , Polyunsaturated Alkamides , Rats , Rats, Sprague-Dawley
8.
Article in English | WPRIM | ID: wpr-773563

ABSTRACT

Several chemical compounds can restore pigmentation in vitiligo through mechanisms that vary according to disease etiology. In the present study, we investigated the melanogenic activity of six structurally distinct compounds, namely, scopoletin, kaempferol, chrysin, vitamin D, piperine, and 6-benzylaminopurine. We determined their effectiveness, toxicity, and mechanism of action for stimulating pigmentation in B16F10 melanoma cells and in a zebrafish model. The melanogenic activity of 6-benzylaminopurine, the compound identified as the most potent, was further verified by measuring green fluorescent protein concentration in tyrp1 a: eGFP (tyrosinase-related protein 1) zebrafish and mitfa: eGFP (microphthalmia associated transcription factor) zebrafish and antioxidative activity. All the tested compounds were found to enhance melanogenesis responses both in vivo and in vitro at their respective optimal concentration by increasing melanin content and expression of TYR and MITF. 6-Benzyamino-purine showed the strongest re-pigmentation action at a concentration of 20 μmol·Lin vivo and 100 μmol·Lin vitro, and up-regulated the strong fluorescence expression of green fluorescent protein in tyrp1a: eGFP and mitfa: eGFP zebrafish in vitro. However, its relative anti-oxidative activity was found to be very low. Overall, our results indicated that 6-benzylaminopurine stimulated pigmentation through a direct mechanism, by increasing melanin content via positive regulation of tyrosinase activity in vitro, as well as up-regulating the expression of the green fluorescent protein in transgenic zebrafish in vivo.


Subject(s)
Alkaloids , Chemistry , Pharmacology , Animals , Benzodioxoles , Chemistry , Pharmacology , Benzyl Compounds , Chemistry , Pharmacology , Cholecalciferol , Chemistry , Pharmacology , Flavonoids , Chemistry , Pharmacology , Humans , Kaempferols , Chemistry , Pharmacology , Melanins , Genetics , Metabolism , Monophenol Monooxygenase , Genetics , Metabolism , Pigmentation , Piperidines , Chemistry , Pharmacology , Polyunsaturated Alkamides , Chemistry , Pharmacology , Purines , Chemistry , Pharmacology , Scopoletin , Chemistry , Pharmacology , Vitiligo , Drug Therapy , Metabolism , Zebrafish
9.
Article in Chinese | WPRIM | ID: wpr-776572

ABSTRACT

OBJECTIVE@#To study the effects of adiponin receptor agonist (AdipoRon) on renal injury in type 2 diabetic mice.@*METHODS@#The experiment was carried out on 40 SPF C57/BL6 male mice and they were randomly divided into normal control group (=10) and experimental group (=30). Mice in experimental group were given with high sugar and high fat feed in combination with only an intraperitoneal injection of small dose of streptozotocin to build the model of type 2 diabetes (T2DM), which were randomly divided into three groups, model control group (DM), low dose AdipoRon group (DM + L) and high dose AdipoRon group (DM+H)(=10). Then the change of blood glucose was detected. The serum levels of insulin receptor (INSR), insulin receptor substrate-1 (IRS-1) and tumor necrosis factor-α (TNF-α) in mice were measured by ELASA. Pathological changes of renal tissues were observed with a light microscope after HE staining. The expressions of pancreatic duodenal homebox-1 (PDX-1) and insulin mRNA in renal tissues were detected by RT-PCR. The content of phosphated insulin receptor substrate-1 (p-IRS-1) protein in the kidney was determined by Western blot.@*RESULTS@#Compared with DM mice, blood glucose and TNF-α levels in DM + H mice and DM + L mice were significantly reduced (<0.05), while the expressions of INSR,IRS-1 and the content of p-IRS-1 were increased markedly(<0.05), and the expressions of PDX-1 and insulin mRNA in renal tissue were increased significantly(<0.05, <0.01).@*CONCLUSIONS@#Mice treated with AdipoRon have lower blood glucose and TNF-α levels, and higher protein expression levels of INSR, IRS-1, and higher mRNA expression levels of PDX-1 and insulin, and the content of p-IRS-1. All of these indicate that AdipoRon has a certain effects on renal injury in type 2 diabetic mice.


Subject(s)
Animals , Diabetes Mellitus, Experimental , Diabetes Mellitus, Type 2 , Kidney , Male , Mice , Piperidines
10.
Article in Chinese | WPRIM | ID: wpr-776412

ABSTRACT

A quantitative nuclear magnetic resonance method(qNMR) was established for determination of the absolute content of febrifugine. Proton nuclear magnetic resonance spectroscopy of febrifugine was obtained in DMSO-d₆ with hydroquinone as the internal standard substance on a Bruker Ascend 600 MHz superconducting nuclear resonance spectrometer at 298 K. The specific parameters were as follows: the observing frequency was 600 MHz,spectra width was 7 211 Hz, pulse width was 9.70 μs, pulse sequence was zg30,scan times was 32 and relaxation time was 2 s. The proton signal peaked at δ 7.71 for febrifugine and δ 6.55 for hydroquinone were selected as the quantification peaks. Linear regression of quantitative peak area ratio of febrifugine-hydroquinone versus their mass ratio yielded a correlation coefficient of 0.999 6 and a regression equation of +0.008 6.The linear range of febrifugine was 2.17-17.07 g·L⁻¹,the precision RSD was 0.78%(=6),the repeatability RSD was 1.2%(=6),and the contents of three batches of febrifugine sample were 94.91%,95.09% and 95.52%,respectively. The content of febrifugine was 96.44% determined by high performance liquid chromatography(HPLC). The relative error of the content of febrigugine determinted by qNMR and HPLC methods was 1.27%. The results showed that the internal standard method of proton nuclear magnetic resonance spectroscopy could be used to determine the absolute content of febrifugine.


Subject(s)
Magnetic Resonance Spectroscopy , Piperidines , Protons , Quinazolines
11.
Article in English | WPRIM | ID: wpr-812421

ABSTRACT

Ginsenoside Rh2 (Rh2) is one of the major bioactive ginsenosides in Panax ginseng. However, the oral bioavailability of Rh2 is low, with P-glycoprotein (P-gp) and CYP3A4 being reported to be the main factors. The purpose of the present study was to determine the enhancing effect of piperine on the oral bioavailability as well as bioactivity of Rh2. The inhibitory effect of piperine on P-gp and CYP3A4 was determined using a Caco-2 monolayer model and a recombinant CYP3A4 metabolic system, respectively. The pharmacokinetics of oral Rh2 (10 mg·kg) administered alone or in combination with piperine (10 and 20 mg·kg) was performed in rats. The immune boosting effect of Rh2 was assessed in rats by measuring IL-12 level after treated by Rh2 alone or co-administered with piperine. The results indicated that piperine significantly increased the permeability of Rh2 and inhibited the metabolism of Rh2. The pharmacokinetic study results showed that the AUC of Rh2 was significantly increased in combination with piperine at high dose (20 mg·kg) when compared to the control group, with relative bioavailability of 196.8%. The increase of Rh2 exposure led to increased serum levels of IL-12. In conclusion, piperine may be used as a bioenhancer to improve pharmacological effect of Rh2 when given orally.


Subject(s)
Administration, Oral , Alkaloids , Animals , Benzodioxoles , Biological Availability , Caco-2 Cells , Cytochrome P-450 CYP3A , Metabolism , Drugs, Chinese Herbal , Ginsenosides , Pharmacokinetics , Humans , Interleukin-2 , Metabolism , Panax , Chemistry , Piperidines , Polyunsaturated Alkamides , Rats , Rats, Sprague-Dawley
12.
Article in English | WPRIM | ID: wpr-812352

ABSTRACT

Several chemical compounds can restore pigmentation in vitiligo through mechanisms that vary according to disease etiology. In the present study, we investigated the melanogenic activity of six structurally distinct compounds, namely, scopoletin, kaempferol, chrysin, vitamin D, piperine, and 6-benzylaminopurine. We determined their effectiveness, toxicity, and mechanism of action for stimulating pigmentation in B16F10 melanoma cells and in a zebrafish model. The melanogenic activity of 6-benzylaminopurine, the compound identified as the most potent, was further verified by measuring green fluorescent protein concentration in tyrp1 a: eGFP (tyrosinase-related protein 1) zebrafish and mitfa: eGFP (microphthalmia associated transcription factor) zebrafish and antioxidative activity. All the tested compounds were found to enhance melanogenesis responses both in vivo and in vitro at their respective optimal concentration by increasing melanin content and expression of TYR and MITF. 6-Benzyamino-purine showed the strongest re-pigmentation action at a concentration of 20 μmol·Lin vivo and 100 μmol·Lin vitro, and up-regulated the strong fluorescence expression of green fluorescent protein in tyrp1a: eGFP and mitfa: eGFP zebrafish in vitro. However, its relative anti-oxidative activity was found to be very low. Overall, our results indicated that 6-benzylaminopurine stimulated pigmentation through a direct mechanism, by increasing melanin content via positive regulation of tyrosinase activity in vitro, as well as up-regulating the expression of the green fluorescent protein in transgenic zebrafish in vivo.


Subject(s)
Alkaloids , Chemistry , Pharmacology , Animals , Benzodioxoles , Chemistry , Pharmacology , Benzyl Compounds , Chemistry , Pharmacology , Cholecalciferol , Chemistry , Pharmacology , Flavonoids , Chemistry , Pharmacology , Humans , Kaempferols , Chemistry , Pharmacology , Melanins , Genetics , Metabolism , Monophenol Monooxygenase , Genetics , Metabolism , Pigmentation , Piperidines , Chemistry , Pharmacology , Polyunsaturated Alkamides , Chemistry , Pharmacology , Purines , Chemistry , Pharmacology , Scopoletin , Chemistry , Pharmacology , Vitiligo , Drug Therapy , Metabolism , Zebrafish
13.
Biol. Res ; 51: 14, 2018. graf
Article in English | LILACS | ID: biblio-950900

ABSTRACT

BACKGROUND: Neurokinin1 (NK1) receptor has played a vital role in the development of tumor. However, NKP608 as a NK1 receptor antagonist whether has the effect of the resistance of colorectal cancer is still unclear. Thereby, in this study, we investigated the role of NKP608 on human colorectal cancer and explored the underlying mechanism. METHODS: The cell proliferation of colorectal cancer cells was detected by cell counting kit-8 (CCK8) assay, cell migration and invasion were assessed by transwell assay, the apoptotic ratio of cells was assessed by Annexin V-fluorescein isothiocyanate/propidium iodide stained and flow cytometry. The involvement of molecular mechanisms was examined by western blot. RESULTS: In this study, we found that NKP608 inhibited the proliferation, migration/invasion of HCT116 cells. In addition, NKP608 reduced expressions of Wnt-3a, ß-catenin, Cyclin D1, and (vascular endothelial growth factor) VEGF while induced expression of E-Cadherin. Furthermore, flow cytometry analyzed that NKP608 induced apoptosis of HCT116 cells, consistently, western blotting detecting of apoptosis-related proteins revealed that NKP608 downregulated Bcl-2 while upregulated Bax and Active-Caspase-3. CONCLUSIONS: Taken together, our results demonstrated that NKP608 inhibited colorectal cancer cell proliferation, migration and invasion via suppressing the Wnt/ß-catenin signaling pathway. Therefore, NKP608 might represent a promising therapeutic agent in the treatment of colorectal cancer.


Subject(s)
Humans , Piperidines/pharmacology , Quinolines/pharmacology , Colorectal Neoplasms/pathology , Cell Movement/drug effects , Cell Proliferation/drug effects , Wnt Signaling Pathway/drug effects , Neurokinin-1 Receptor Antagonists/pharmacology , Down-Regulation/drug effects , Blotting, Western , Cell Line, Tumor , HCT116 Cells , Flow Cytometry
14.
Rev. Assoc. Med. Bras. (1992) ; 63(9): 753-763, 2017. tab, graf
Article in English | LILACS | ID: biblio-896396

ABSTRACT

Summary Introduction: Recent animal studies demonstrated immunosuppressive effects of opioid withdrawal resulting in a higher risk of infection. The aim of this study was to determine the impact of remifentanil discontinuation on Post-Anesthesia Care Unit (PACU)-acquired infection after a schedule of sedoanalgesia of at least 6 days. Method: All patients over 18 years of age with a unit admission of more than 4 days were consecutively selected. The study population was the one affected by surgical pathology of any origin where sedation was based on any hypnotic and the opioid remifentanil was used as analgesic for at least 96 hours in continuous perfusion. Patients who died during admission to the unit and those with combined analgesia (peripheral or neuroaxial blocks) were excluded. Bivariate analysis was performed to determine risk factors for infection acquired in the unit. A comparative study between periods of 6 days before and after the cessation of remifentanil was performed. Paired samples test and McNemar test was used for quantitative and categorical variables, respectively. Results: There were 1,789 patients admitted to the PACU during the study and the population eligible was constituted for 102 patients. The incidence rate of PACU-acquired infection was 38 per 1,000 PACU days. Ventilator-associated pneumonia was the most frequently diagnosed PACU-acquired infection. Pseudomona aeruginosa was the most frequently isolated microorganism. Hospital mortality was 36.27%. No statistically significant differences were seen in the incidence of HAI in cancer patients in relation to discontinuation of remifentanil (p=0.068). Conclusion: The baseline state of immunosuppression of cancer patients does not imply a higher incidence of HAI in relation to the interruption of remifentanil. It would be of interest to carry out a multicenter PACU study that included immunological patterns.


Resumo Introdução: Recentes pesquisas utilizando animais demonstraram efeitos imunossupressores depois da suspensão de opiáceos, associados a um maior risco de infecção nosocomial. O objetivo desta investigação foi determinar o impacto da interrupção do opioide remifentanilo em uma Unidade de Reanimação Pós-cirúrgica (URP) nas infecções associadas aos cuidados da saúde depois de uma pauta de sedoanalgesia de ao menos 6 dias. Método: Foram relacionados de forma consecutiva todos os pacientes maiores de 18 anos com internação na unidade superior a 4 dias. A população investigada foi aquela afetada por patologia cirúrgica de qualquer origem, na qual a sedação esteve baseada em qualquer hipnótico e como analgésico, foi utilizado o opioide remifentanilo durante pelo menos 96 horas em perfusão contínua. Foram excluídos os pacientes que faleceram durante a internação na unidade e aqueles com analgesia combinada (bloqueios periféricos ou neuroaxiais). Foi realizada uma análise bivariante para determinar fatores de risco para a infecção adquirida na unidade. Foi realizada uma investigação comparativa entre períodos dos 6 dias anteriores e posteriores à interrupção de remifentanilo. Utilizamos o teste de amostras pareadas e a prova de McNemar para as variáveis quantitativas e categóricas, respectivamente. Resultados: O número de pacientes internados na URP durante o período de investigação foi de 1.789. Depois de aplicar os critérios de inclusão e exclusão, a população elegível ficou constituída por 102 pacientes. A densidade de incidência de infecção de forma global foi de 38 por cada 1.000 dias de internamento. A pneumonia associada à ventilação mecânica foi a infecção adquirida mais frequente e Pseudomona aeruginosa, o micro-organismo mais frequentemente isolado. A mortalidade hospitalar foi de 36,27%. Não foram observadas diferenças estatisticamente significativas na incidência de IACS em pacientes oncológicos em relação à descontinuação de remifentanilo (p=0,068). Conclusão: O estado basal de imunossupressão dos pacientes oncológicos não implica uma maior incidência de IACS em relação à interrupção do remifentanilo. Seria interessante a realização de uma investigação multicêntrica de URP que incluísse padrões imunológicos.


Subject(s)
Humans , Male , Female , Aged , Pain, Postoperative/drug therapy , Cross Infection/etiology , Withholding Treatment , Analgesics, Opioid/administration & dosage , Immunosuppressive Agents/administration & dosage , Neoplasms/surgery , Piperidines/administration & dosage , Midazolam/administration & dosage , Propofol/administration & dosage , Cross Infection/prevention & control , Remifentanil , Middle Aged
15.
Arch. endocrinol. metab. (Online) ; 61(4): 398-402, July-Aug. 2017. tab
Article in English | LILACS | ID: biblio-887574

ABSTRACT

ABSTRACT Medullary thyroid carcinoma (MTC) is a rare neuroendocrine tumor originating from parafollicular C cells of the thyroid and associated with mutations in the proto-oncogene REarranged during Transfection (RET). The prognosis of MTC depends on clinical stage, with a 95.6% 10-year survival rate among patients with localized disease and 40% among patients with advanced disease. Standard chemotherapy and radiotherapy have no significant impact on the overall survival of these patients and two tyrosine kinase receptor inhibitors (TKIs), vandetanib and cabozantinib, have been recently approved for the systemic treatment of locally advanced or metastatic MTC. However, since patients with MTC and residual or recurrent disease may have an indolent course with no need for systemic treatment, and since these drugs are highly toxic, it is extremely important to select the patients who will receive these drugs in a correct manner. It is also essential to carefully monitor patients using TKI regarding possible adverse effects, which should be properly managed when occurring.


Subject(s)
Humans , Piperidines/therapeutic use , Pyridines/therapeutic use , Quinazolines/therapeutic use , Carcinoma, Neuroendocrine/drug therapy , Protein Kinase Inhibitors/therapeutic use , Anilides/therapeutic use , Piperidines/adverse effects , Pyridines/adverse effects , Quinazolines/adverse effects , Thyroid Neoplasms/metabolism , Thyroid Neoplasms/drug therapy , Carcinoma, Neuroendocrine/metabolism , Risk Assessment , Protein Kinase Inhibitors/adverse effects , Anilides/adverse effects
16.
Rev. chil. obstet. ginecol. (En línea) ; 82(2): 163-170, abr. 2017. ilus, graf, tab
Article in Spanish | LILACS | ID: biblio-899894

ABSTRACT

Propósito: Describir la periodicidad del momento de máxima intensidad del dolor de las contracciones uterinas (CUs) durante el trabajo de parto (TDP) para eventualmente permitir el desarrollo de nuevos modelos de administración de analgesia endovenosa. Material y método: Embarazadas de término en TDP, reclutadas desde marzo 2014 por 18 meses, de manera no probabilística consecutiva. Se obtuvo el momento de máximo dolor por autoreporte de las pacientes con cronómetros, previa capacitación. Análisis: Regresión para medidas repetidas de efectos mixtos a los 3-5, 6-7 y 8-10cm de dilatación. La variable respuesta es el intervalo de tiempo desde el momento de máximo dolor de la CU basal al de la contracción siguiente. Resultados: En 64 pacientes, se obtuvo 5 intervalos de tiempo. Para la dilatación de 3-5cm una mediana=140.92 segundos y los coeficientes de regresión (CR) en 4 intervalos de tiempo con respecto al basal de 4.2, 15.9, -2.7 y -5.8 segundos. Para 67cm una mediana=131.16 seg y CR 13.4, 11.3, 2 y -10 seg. Para 8-10cm una mediana=129.3 seg y CR -6.7, 0.49, -2.5 y -7.7 seg. No hubo diferencias significativas entre los coeficientes de regresión. Conclusiones: Con los datos obtenidos podemos señalar que no hubo diferencias estadísticas significativas entre los intervalos de tiempo de los momentos de máximo dolor durante el TDP en fase activa. Esta información es relevante para apoyar el desarrollo de un modelo predictivo del dolor.


Aim: To describe the timing of the moment of maximum intensity of uterine contraction (UC) pain in labor to possibly enable the development of new models for administering endovenous analgesia. Materials and Methods: Full-term pregnant women in labor, recruited from March 2014 for 18 months, using consecutive nonprobability sampling. The moment of maximum pain was ascertained as self-reported by patients previously trained with chronometers. Analysis: Regression for repeated measurements from mixed results at 3-5, 6-7 and 8-10cm of dilation. The response variable was the time interval from the moment of maximum pain of the baseline UC to the following contraction. Results: In 64 patients, 5 time intervals were obtained. For the dilation of 3-5cm, a median=140.92 seconds and regression coefficients (RC) in 4 time intervals relative to the baseline of 4.2, 15.9, -2.7 and -5.8 seconds. For 6-7cm, a median =131.16 sec and RC 13.4, 11.3, 2 and -10 sec. For 8-10cm, a median =129.3 sec and RC -6.7, 0.49, -2.5 and -7.7 sec. There were no significant differences among the regression coefficients. Conclusions: With the data collected we can report that there were no statistically significant differences between the time intervals of the moments of maximum pain during active labor. This information is relevant to support the development of a predictive model for this pain.


Subject(s)
Humans , Female , Pregnancy , Adolescent , Adult , Piperidines/pharmacokinetics , Analgesia, Patient-Controlled/methods , Labor Pain , Analgesics, Opioid/administration & dosage , Time Factors , Uterine Contraction , Pain Measurement , Predictive Value of Tests , Regression Analysis , Longitudinal Studies , Administration, Intravenous , Analgesics, Opioid/pharmacokinetics , Anesthesia, Obstetrical/methods
17.
An. acad. bras. ciênc ; 89(1): 247-261, Jan,-Mar. 2017. graf
Article in English | LILACS | ID: biblio-886640

ABSTRACT

ABSTRACT Prosopis juliflora is a shrub that has been used to feed animals and humans. However, a synergistic action of piperidine alkaloids has been suggested to be responsible for neurotoxic damage observed in animals. We investigated the involvement of programmed cell death (PCD) and autophagy on the mechanism of cell death induced by a total extract (TAE) of alkaloids and fraction (F32) from P. juliflora leaves composed majoritary of juliprosopine in a model of neuron/glial cell co-culture. We saw that TAE (30 µg/mL) and F32 (7.5 µg/mL) induced reduction in ATP levels and changes in mitochondrial membrane potential at 12 h exposure. Moreover, TAE and F32 induced caspase-9 activation, nuclear condensation and neuronal death at 16 h exposure. After 4 h, they induced autophagy characterized by decreases of P62 protein level, increase of LC3II expression and increase in number of GFP-LC3 cells. Interestingly, we demonstrated that inhibition of autophagy by bafilomycin and vinblastine increased the cell death induced by TAE and autophagy induced by serum deprivation and rapamycin reduced cell death induced by F32 at 24 h. These results indicate that the mechanism neural cell death induced by these alkaloids involves PCD via caspase-9 activation and autophagy, which seems to be an important protective mechanism.


Subject(s)
Animals , Rats , Piperidines/toxicity , Autophagy/physiology , Neuroglia/drug effects , Prosopis/chemistry , Alkaloids/toxicity , Piperidines/isolation & purification , Autophagy/drug effects , Time Factors , Plant Extracts/toxicity , Cell Survival/drug effects , Cells, Cultured , Adenosine Triphosphate/analysis , Neuroglia/physiology , Cell Death/drug effects , Cell Death/physiology , Rats, Wistar , Alkaloids/isolation & purification , Membrane Potential, Mitochondrial/drug effects , Membrane Potential, Mitochondrial/physiology
18.
Yonsei Medical Journal ; : 9-18, 2017.
Article in English | WPRIM | ID: wpr-222311

ABSTRACT

PURPOSE: Rearrangement of the proto-oncogene rearranged during transfection (RET) has been newly identified potential driver mutation in lung adenocarcinoma. Clinically available tyrosine kinase inhibitors (TKIs) target RET kinase activity, which suggests that patients with RET fusion genes may be treatable with a kinase inhibitor. Nevertheless, the mechanisms of resistance to these agents remain largely unknown. Thus, the present study aimed to determine whether epidermal growth factor (EGF) and hepatocyte growth factor (HGF) trigger RET inhibitor resistance in LC-2/ad cells with CCDC6-RET fusion genes. MATERIALS AND METHODS: The effects of EGF and HGF on the susceptibility of a CCDC6-RET lung cancer cell line to RET inhibitors (sunitinib, E7080, vandetanib, and sorafenib) were examined. RESULTS: CCDC6-RET lung cancer cells were highly sensitive to RET inhibitors. EGF activated epidermal growth factor receptor (EGFR) and triggered resistance to sunitinib, E7080, vandetanib, and sorafenib by transducing bypass survival signaling through ERK and AKT. Reversible EGFR-TKI (gefitinib) resensitized cancer cells to RET inhibitors, even in the presence of EGF. Endothelial cells, which are known to produce EGF, decreased the sensitivity of CCDC6-RET lung cancer cells to RET inhibitors, an effect that was inhibited by EGFR small interfering RNA (siRNA), anti-EGFR antibody (cetuximab), and EGFR-TKI (Iressa). HGF had relatively little effect on the sensitivity to RET inhibitors. CONCLUSION: EGF could trigger resistance to RET inhibition in CCDC6-RET lung cancer cells, and endothelial cells may confer resistance to RET inhibitors by EGF. E7080 and other RET inhibitors may provide therapeutic benefits in the treatment of RET-positive lung cancer patients.


Subject(s)
Adenocarcinoma/drug therapy , Cell Line, Tumor , Cetuximab/pharmacology , Drug Resistance, Neoplasm/drug effects , Epidermal Growth Factor/metabolism , Gene Rearrangement , Hepatocyte Growth Factor/pharmacology , Humans , Indoles/pharmacology , Lung Neoplasms/drug therapy , MAP Kinase Signaling System , Mutation , Niacinamide/analogs & derivatives , Phenylurea Compounds/pharmacology , Piperidines/pharmacology , Protein Kinase Inhibitors/therapeutic use , Proto-Oncogene Proteins c-ret/antagonists & inhibitors , Pyrroles/pharmacology , Quinazolines/pharmacology , RNA, Small Interfering/pharmacology , ErbB Receptors/genetics , Signal Transduction/drug effects , fms-Like Tyrosine Kinase 3/metabolism
19.
Article in Chinese | WPRIM | ID: wpr-300831

ABSTRACT

To investigate the effects of neuronal histamine on spatial memory acquisition impairment in rats with pentylenetetrazole-kindling epilepsy, and to explore its mechanisms.A subconvulsive dose of pentylenetetrazole (35 mg/kg) was intraperitoneally injected in rats every 48 h to induce chemical kindling until fully kindled. Morris water maze was used to measure the spatial memory acquisition of the rats one week after fully pentylenetetrazole-kindled, and the histamine contents in different brain areas were measured spectrofluorometrically. Different dosages of hitidine (the precursor of histamine), pyrilamine (H1 receptor antagonist), and zolantidine (H2 receptor antagonist) were intraperitoneally injected, and their effects on spatial memory acquisition of the rats were observed.Compared with control group, escape latencies were significantly prolonged on Morris water maze training day 2 and day 3 in pentylenetetrazole-kindling epilepsy rats (all<0.05); and the histamine contents in hippocampus, thalamus and hypothalamus were decreased significantly (all<0.05). Escape latencies were markedly shortened on day 3 by intraperitoneally injected with histidine 500 mg/kg, and on day 2 and day 3 by intraperitoneally injected with histidine 1000 mg/kg in pentylenetetrazole-kindling epilepsy rats (all<0.05). The protection of histidine was reversed by zolantidine (10 and 20 mg/kg), but not by pyrilamine.Neuronal histamine can improve the spatial memory acquisition impairment in rats with pentylenetetrazole-kindling epilepsy, and the activation of H2 receptors is possibly involved in the protective effects of histamine.


Subject(s)
Animals , Benzothiazoles , Pharmacology , Brain Chemistry , Epilepsy , Hippocampus , Chemistry , Histamine H1 Antagonists , Pharmacology , Histamine H2 Antagonists , Pharmacology , Histidine , Pharmacology , Hypothalamus , Chemistry , Kindling, Neurologic , Physiology , Memory Disorders , Drug Therapy , Pentylenetetrazole , Phenoxypropanolamines , Pharmacology , Piperidines , Pharmacology , Pyrilamine , Pharmacology , Rats , Rats, Sprague-Dawley , Receptors, Histamine H2 , Physiology , Spatial Memory , Spectrometry, Fluorescence , Thalamus , Chemistry
20.
Article in Chinese | WPRIM | ID: wpr-300433

ABSTRACT

<p><b>OBJECTIVE</b>To compare the efficacy and safety of different analgesic and sedative treatments in children with mechanical ventilation in the pediatric intensive care unit (PICU).</p><p><b>METHODS</b>Eighty children with mechanical ventilation in the PICU who needed analgesic and sedative treatments were equally and randomly divided into midazolam group and remifentanil+midazolam group. The sedative and analgesic effects were assessed using the Ramsay Scale and the Face, Legs, Activity, Cry and Consolability (FLACC) Scale. The following indices were recorded for the two groups: vital signs, ventilator parameters, organ function, total doses of remifentanil and midazolam, duration of mechanical ventilation, length of PICU stay, PICU cost, and incidence of adverse events.</p><p><b>RESULTS</b>Satisfactory sedation was achieved in the two groups, but the remifentanil+midazolam group had a significantly shorter time to analgesia and sedation than the midazolam group. The remifentanil+midazolam group had a significantly higher percentage of patients with grade 3-4 on the Ramsay Scale and a significantly lower dose of midazolam than the midazolam group (P<0.05). Both groups showed decreases in heart rate (HR), mean arterial pressure (MAP), and spontaneous breathing frequency (RRs) after treatment. However, the remifentanil+midazolam group had significantly greater decreases in HR at 3-24 hours after treatment and MAP and RRs at 3-12 hours after treatment than the midazolam group (P<0.05). Compared with the midazolam group, the remifentanil+midazolam group had significantly higher ventilator tidal volume and transcutaneous oxygen saturation at 6 and 12 hours after treatment and significantly lower end-tidal carbon dioxide partial pressure at 6 and 12 hours after treatment (P<0.05). The remifentanil+midazolam group had significantly shorter time to awake, extubation time, duration of mechanical ventilation, and length of PICU stay than the midazolam group (P<0.05). There were no significant differences in PICU cost, incidence of adverse events, and hepatic and renal functions before and after treatment between the two groups (P>0.05). Both groups showed a significant decrease in fasting blood glucose level after treatment (P<0.05).</p><p><b>CONCLUSIONS</b>For children with mechanical ventilation in the PICU, remifentanil+midazolam treatment can rapidly achieve analgesia and sedation, improve the effect of mechanical ventilation, and reduce the dose of sedative compared with midazolam alone, and is well tolerated.</p>


Subject(s)
Analgesics , Therapeutic Uses , Blood Glucose , Female , Humans , Hypnotics and Sedatives , Therapeutic Uses , Infant , Intensive Care Units, Pediatric , Male , Midazolam , Therapeutic Uses , Piperidines , Therapeutic Uses , Respiration, Artificial
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