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1.
Molecules ; 25(6)2020 Mar 17.
Artigo em Inglês | MEDLINE | ID: mdl-32192229

RESUMO

The present work represents the in vitro (potency, affinity, efficacy) and in vivo (antinociception, constipation) opioid pharmacology of the novel compound 14-methoxycodeine-6-O-sulfate (14-OMeC6SU), compared to the reference compounds codeine-6-O-sulfate (C6SU), codeine and morphine. Based on in vitro tests (mouse and rat vas deferens, receptor binding and [35S]GTPγS activation assays), 14-OMeC6SU has µ-opioid receptor-mediated activity, displaying higher affinity, potency and efficacy than the parent compounds. In rats, 14-OMeC6SU showed stronger antinociceptive effect in the tail-flick assay than codeine and was equipotent to morphine, whereas C6SU was less efficacious after subcutaneous (s.c.) administration. Following intracerebroventricular injection, 14-OMeC6SU was more potent than morphine. In the Complete Freund's Adjuvant-induced inflammatory hyperalgesia, 14-OMeC6SU and C6SU in s.c. doses up to 6.1 and 13.2 µmol/kg, respectively, showed peripheral antihyperalgesic effect, because co-administered naloxone methiodide, a peripherally acting opioid receptor antagonist antagonized the measured antihyperalgesia. In addition, s.c. C6SU showed less pronounced inhibitory effect on the gastrointestinal transit than 14-OMeC6SU, codeine and morphine. This study provides first evidence that 14-OMeC6SU is more effective than codeine or C6SU in vitro and in vivo. Furthermore, despite C6SU peripheral antihyperalgesic effects with less gastrointestinal side effects the superiority of 14-OMeC6SU was obvious throughout the present study.

2.
Brain Res Bull ; 152: 143-158, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31302238

RESUMO

Interneurons operating with glycine neurotransmitter are involved in the regulation of pain transmission in the dorsal horn of the spinal cord. In addition to interneurons, glycine release also occurs from glial cells neighboring glutamatergic synapses in the spinal cord. Neuronal and glial release of glycine is controlled by glycine transporters (GlyTs). Inhibitors of the two isoforms of GlyTs, the astrocytic type-1 (GlyT-1) and the neuronal type-2 (GlyT-2), decrease pain sensation evoked by injuries of peripheral sensory neurons or inflammation. The function of dorsal horn glycinergic interneurons has been suggested to be reduced in neuropathic pain, which can be reversed by GlyT-2 inhibitors (Org-25543, ALX1393). Several lines of evidence also support that peripheral nerve damage or inflammation may shift glutamatergic neurochemical transmission from N-methyl-D aspartate (NMDA) NR1/NR2A receptor- to NR1/NR2B receptor-mediated events (subunit switch). This pathological overactivation of NR1/NR2B receptors can be reduced by GlyT-1 inhibitors (NFPS, Org-25935), which decrease excessive glycine release from astroglial cells or by selective antagonists of NR2B subunits (ifenprodil, Ro 25-6981). Although several experiments suggest that GlyT inhibitors may represent a novel strategy in the control of neuropathic pain, proving this concept in human beings is hampered by lack of clinically applicable GlyT inhibitors. We also suggest that drugs inhibiting both GlyT-1 and GlyT-2 non-selectively and reversibly, may favorably target neuropathic pain. In this paper we overview inhibitors of the two isoforms of GlyTs as well as the effects of these drugs in experimental models of neuropathic pain. In addition, the possible mechanisms of action of the GlyT inhibitors, i.e. how they affect the neurochemical and pain transmission in the spinal cord, are also discussed. The growing evidence for the possible therapeutic intervention of neuropathic pain by GlyT inhibitors further urges development of drugable compounds, which may beneficially restore impaired pain transmission in various neuropathic conditions.

3.
Front Pharmacol ; 10: 347, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31024314

RESUMO

Reduction of the opioid analgesia in diabetic neuropathic pain (DNP) results from µ-opioid receptor (MOR) reserve reduction. Herein, we examined the antinociceptive and antiallodynic actions of a novel opioid agonist 14-O-methymorphine-6-O-sulfate (14-O-MeM6SU), fentanyl and morphine in rats with streptozocin-evoked DNP of 9-12 weeks following their systemic administration. The antinociceptive dose-response curve of morphine but not of 14-O-MeM6SU or fentanyl showed a significant right-shift in diabetic compared to non-diabetic rats. Only 14-O-MeM6SU produced antiallodynic effects in doses matching antinociceptive doses obtained in non-diabetic rats. Co-administered naloxone methiodide (NAL-M), a peripherally acting opioid receptor antagonist failed to alter the antiallodynic effect of test compounds, indicating the contribution of central opioid receptors. Reduction in spinal MOR binding sites and loss in MOR immunoreactivity of nerve terminals in the spinal cord and dorsal root ganglia in diabetic rats were observed. G-protein coupling assay revealed low efficacy character for morphine and high efficacy character for 14-O-MeM6SU or fentanyl at spinal or supraspinal levels (E max values). Furthermore, at the spinal level only 14-O-MeM6SU showed equal efficacy in G-protein activation in tissues of diabetic- and non-diabetic animals. Altogether, the reduction of spinal opioid receptors concomitant with reduced analgesic effect of morphine may be circumvented by using high efficacy opioids, which provide superior analgesia over morphine. In conclusion, the reduction in the analgesic action of opioids in DNP might be a consequence of MOR reduction, particularly in the spinal cord. Therefore, developing opioids of high efficacy might provide analgesia exceeding that of currently available opioids.

4.
Cells ; 8(3)2019 03 15.
Artigo em Inglês | MEDLINE | ID: mdl-30884758

RESUMO

Intestinal dysbiosis is linked to numerous gastrointestinal disorders, including inflammatory bowel diseases. It is a question of debate if coxibs, selective inhibitors of cyclooxygenase (COX)-2, cause dysbiosis. Therefore, in the present study, we aimed to determine the effect of long-term (four weeks) selective inhibition of COX-2 on the small intestinal microbiota in the rat. In order to avoid mucosal damage due to topical effects and inflammation-driven microbial alterations, rofecoxib, a nonacidic compound, was used. The direct inhibitory effect of rofecoxib on the growth of bacteria was ruled out in vitro. The mucosa-sparing effect of rofecoxib was confirmed by macroscopic and histological analysis, as well as by measuring the intestinal levels of cytokines and tight junction proteins. Deep sequencing of bacterial 16S rRNA revealed that chronic rofecoxib treatment had no significant influence on the composition and diversity of jejunal microbiota. In conclusion, this is the first demonstration that long-term selective inhibition of COX-2 by rofecoxib does not cause small intestinal dysbiosis in rats. Moreover, inhibition of COX-2 activity is not likely to be responsible per se for microbial alterations caused by some coxibs, but other drug-specific properties may contribute to it.


Assuntos
Inibidores de Ciclo-Oxigenase 2/farmacologia , Ciclo-Oxigenase 2/metabolismo , Disbiose/patologia , Intestino Delgado/enzimologia , Intestino Delgado/patologia , Lactonas/farmacologia , Sulfonas/farmacologia , Animais , Bactérias/efeitos dos fármacos , Bactérias/crescimento & desenvolvimento , Celecoxib/farmacologia , Dinoprostona/biossíntese , Disbiose/microbiologia , Mucosa Gástrica/efeitos dos fármacos , Mucosa Gástrica/patologia , Microbioma Gastrointestinal/efeitos dos fármacos , Masculino , Testes de Sensibilidade Microbiana , Ratos Wistar , Fatores de Tempo
5.
Brain Res Bull ; 147: 78-85, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30738866

RESUMO

Dipeptidyl-peptidase 4 (DPP4) enzyme is involved in the degradation of many biologically active peptides including opioids. Its role in pain transmission is poorly elucidated. Recently we reported on the spinal antihyperalgesic effects of DPP4 inhibitors, Ile-Pro-Ile (Diprotin A) and vildagliptin in carrageenan-evoked acute inflammatory pain in rats. The present study investigated the effects of intrathecal (it.) diprotin A and vildagliptin in Complete Freund's Adjuvant- (CFA) and formalin induced pain in rats. The former assay can model the subchronic inflammatory pain condition and the later one reflects both acute tonic and inflammatory pain conditions. The involvement of opioid receptor (OR) subtypes, Y1-, and GLP1 receptors were also investigated. In CFA pain model it. diprotin A or vildagliptin dose-dependently inhibits hyperalgesia in ipsilateral while has no effect in contralateral paws. The peak effect was achieved 30 min following drug administration which was used for further analysis. Both compounds showed naltrexone reversible antihyperalgesia. Co-administration of OR-subtype-selective antagonists with diprotin A and vildagliptin revealed involvement of µ and δ > µ opioid receptors, respectively. Co-administered Y1 but not GLP1 receptor antagonists reversed the antihyperalgesic action of both DPP4 inhibitors. In touch-hypersensitivity both compounds were ineffective. In formalin test only diprotin A showed µ and δ OR-mediated antinociception and only in the 2nd phase. This effect was Y1 or GLP-1 receptor antagonist insensitive. In conclusion, diprotin A and vildagliptin display antinociception of different mechanisms of action in subchronic inflammatory pain. Furthermore, the spinal pain relay points of inflammatory pain of acute or subchronic conditions were more effectively affected by diprotin A than vildagliptin which needs future elucidation.

6.
Neurochem Res ; 43(6): 1250-1257, 2018 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-29725918

RESUMO

Opioid analgesics devoid of central side effects are unmet medical need in the treatment of acute pain (e.g. post-operative pain). Recently, we have reported on 14-O-methylmorphine-6-O-sulfate (14-O-MeM6SU), a novel opioid agonist of high efficacy producing peripheral antinociception in subchronic inflammatory pain in certain doses. The present study focused on the antinociceptive effect of 14-O-MeM6SU compared to morphine in formalin test of an early/acute (Phase I) and late/tonic (Phase II) pain phases. Subcutaneous 14-O-MeM6SU (253-1012 nmol/kg) and morphine (3884-31075 nmol/kg) dose dependently reduced the pain behaviors of both phases. Co-administered naloxone methiodide (NAL-M), a peripherally acting opioid antagonist, abolished the antinociceptive effect of 506 nmol/kg 14-O-MeM6SU. On the other hand, the effects of 14-O-MeM6SU (1012 nmol/kg) and morphine (15538 nmol/kg) were only partially affected by NAL-M, indicating the contribution of CNS to antinociception. Locally injected test compounds into formalin treated paws caused antinociception in both phases. Locally effective doses of test compounds were also injected into contralateral paws. Morphine showed effects in both phases, 14-O-MeM6SU in certain doses failed to produce antinociception in either phase. A NAL-M reversible systemic dose of 14-O-MeM6SU and the lowest systemic effective dose of morphine were evaluated for their sedative effects following isoflurane-induced sleeping (righting reflex). In contrast to morphine, 14-O-MeM6SU in certain antinociceptive doses showed no impact on sleeping time. These data highlight that high efficacy opioids of limited CNS penetration in certain doses mitigate somatic and inflammatory pain by targeting MOR at the periphery.


Assuntos
Dor Aguda/tratamento farmacológico , Analgésicos Opioides/administração & dosagem , Analgésicos/administração & dosagem , Codeína/análogos & derivados , Medição da Dor/efeitos dos fármacos , Dor Aguda/metabolismo , Dor Aguda/psicologia , Analgésicos/química , Analgésicos Opioides/química , Animais , Codeína/administração & dosagem , Codeína/química , Relação Dose-Resposta a Droga , Inflamação/tratamento farmacológico , Inflamação/metabolismo , Injeções Subcutâneas , Masculino , Medição da Dor/métodos , Ratos , Ratos Wistar
7.
Peptides ; 99: 205-216, 2018 01.
Artigo em Inglês | MEDLINE | ID: mdl-29038035

RESUMO

In an attempt to design opioid-nociceptin hybrid peptides, three novel bivalent ligands, H-YGGFGGGRYYRIK-NH2, H-YGGFRYYRIK-NH2 and Ac-RYYRIKGGGYGGFL-OH were synthesized and studied by biochemical, pharmacological, biophysical and molecular modelling tools. These chimeric molecules consist of YGGF sequence, a crucial motif in the N-terminus of natural opioid peptides, and Ac-RYYRIK-NH2, which was isolated from a combinatorial peptide library as an antagonist or partial agonist that inhibits the biological activity of the endogenously occurring heptadecapeptide nociceptin. Solution structures for the peptides were studied by analysing their circular dichroism spectra. Receptor binding affinities were measured by equilibrium competition experiments using four highly selective radioligands. G-protein activating properties of the multitarget peptides were estimated in [35S]GTPγS binding tests. The three compounds were also measured in electrically stimulated mouse vas deferens (MVD) bioassay. H-YGGFGGGRYYRIK-NH2 (BA55), carrying N-terminal opioid and C-terminal nociceptin-like sequences interconnected with GGG tripeptide spacer displayed a tendency of having either unordered or ß-sheet structures, was moderately potent in MVD and possessed a NOP/KOP receptor preference. A similar peptide without spacer H-YGGFRYYRIK-NH2 (BA62) exhibited the weakest effect in MVD, more α-helical periodicity was present in its structure and it exhibited the most efficacious agonist actions in the G-protein stimulation assays. The third hybrid peptide Ac-RYYRIKGGGYGGFL-OH (BA61) unexpectedly displayed opioid receptor affinities, because the opioid message motif is hidden within the C-terminus. The designed chimeric peptide ligands presented in this study accommodate well into a group of multitarget opioid compounds that include opioid-non-opioid peptide dimer analogues, dual non-peptide dimers and mixed peptide- non-peptide bifunctional ligands.


Assuntos
Modelos Moleculares , Peptídeos Opioides , Engenharia de Proteínas/métodos , Receptores Acoplados a Proteínas-G/agonistas , Animais , Feminino , Masculino , Camundongos , Peptídeos Opioides/química , Peptídeos Opioides/genética , Peptídeos Opioides/farmacologia , Estrutura Secundária de Proteína , Ratos , Ratos Wistar , Receptores Acoplados a Proteínas-G/genética , Receptores Acoplados a Proteínas-G/metabolismo
8.
Eur J Pharmacol ; 814: 264-273, 2017 Nov 05.
Artigo em Inglês | MEDLINE | ID: mdl-28864212

RESUMO

14-O-methyl (14-O-Me) group in morphine-6-O-sulfate (M6SU) or oxymorphone has been reported to be essential for enhanced affinity, potency and antinociceptive effect of these opioids. Herein we report on the pharmacological properties (potency, affinity and efficacy) of the new compound, 14-O-methylmorphine (14-O-MeM) in in vitro. Additionally, we also investigated the antinociceptive effect of the novel compound, as well as its inhibitory action on gastrointestinal transit in in vivo. The potency and efficacy of test compound were measured by [35S]GTPγS binding, isolated mouse vas deferens (MVD) and rat vas deferens (RVD) assays. The affinity of 14-O-MeM for opioid receptors was assessed by radioligand binding and MVD assays. The antinociceptive and gastrointestinal effects of the novel compound were evaluated in the rat tail-flick test and charcoal meal test, respectively. Morphine, DAMGO, Ile5,6 deltorphin II, deltorphin II and U-69593 were used as reference compounds. 14-O-MeM showed higher efficacy (Emax) and potency (EC50) than morphine in MVD, RVD or [35S]GTPγS binding. In addition, 14-O-MeM compared to morphine showed higher affinity for µ-opioid receptor (MOR). In vivo, in rat tail-flick test 14-O-MeM proved to be stronger antinociceptive agent than morphine after peripheral or central administration. Additionally, both compounds inhibited the gastrointestinal peristalsis. However, when the antinociceptive and antitransit doses for each test compound are compared, 14-O-MeM proved to have slightly more favorable pharmacological profile. Our results affirm that 14-O-MeM, an opioid of high efficacy and affinity for MOR can be considered as a novel analgesic agent of potential clinical value.


Assuntos
Analgésicos/metabolismo , Analgésicos/farmacologia , Codeína/metabolismo , Codeína/farmacologia , Receptores Opioides mu/agonistas , Receptores Opioides mu/metabolismo , Animais , Ligação Competitiva , Trânsito Gastrointestinal/efeitos dos fármacos , Concentração Inibidora 50 , Masculino , Camundongos , Ratos , Especificidade por Substrato , Ducto Deferente/efeitos dos fármacos , Ducto Deferente/metabolismo
9.
Eur J Pharmacol ; 809: 111-121, 2017 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-28502630

RESUMO

Opioid antagonists, naloxone and naltrexone have long been used in clinical practice and research. In addition to their low selectivity, they easily pass through the blood-brain barrier. Quaternization of the amine group in these molecules, (e.g. methylnaltrexone) results in negligible CNS penetration. In addition, zwitterionic compounds have been reported to have limited CNS access. The current study, for the first time gives report on the synthesis and the in vitro [competition binding, G-protein activation, isolated mouse vas deferens (MVD) and mouse colon assay] pharmacology of the zwitterionic compound, naltrexone-14-O-sulfate. Naltrexone, naloxone, and its 14-O-sulfate analogue were used as reference compounds. In competition binding assays, naltrexone-14-O-sulfate showed lower affinity for µ, δ or κ opioid receptor than the parent molecule, naltrexone. However, the µ/κ opioid receptor selectivity ratio significantly improved, indicating better selectivity. Similar tendency was observed for naloxone-14-O-sulfate when compared to naloxone. Naltrexone-14-O-sulfate failed to activate [35S]GTPγS-binding but inhibit the activation evoked by opioid agonists (DAMGO, Ile5,6deltorphin II and U69593), similarly to the reference compounds. Schild plot constructed in MVD revealed that naltrexone-14-O-sulfate acts as a competitive antagonist. In mouse colon, naltrexone-14-O-sulfate antagonized the inhibitory effect of morphine with lower affinity compared to naltrexone and higher affinity when compared to naloxone or naloxone-14-O-sulfate. In vivo (mouse tail-flick test), subcutaneously injected naltrexone-14-O-sulfate antagonized morphine's antinociception in a dose-dependent manner, indicating it's CNS penetration, which was unexpected from such zwitter ionic structure. Future studies are needed to evaluate it's pharmacokinetic profile.


Assuntos
Analgésicos/síntese química , Analgésicos/farmacologia , Naltrexona/síntese química , Naltrexona/farmacologia , Antagonistas de Entorpecentes/síntese química , Antagonistas de Entorpecentes/farmacologia , Receptores Opioides/metabolismo , Animais , Comportamento Animal/efeitos dos fármacos , Técnicas de Química Sintética , Colo/efeitos dos fármacos , Colo/metabolismo , Masculino , Camundongos , Morfina/farmacologia , Naltrexona/análogos & derivados , Ratos , Ratos Wistar , Ducto Deferente/efeitos dos fármacos , Ducto Deferente/metabolismo
10.
Inflammopharmacology ; 25(1): 107-118, 2017 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-27873165

RESUMO

Imidazoline receptors (IRs) have been recognized as promising targets in the treatment of numerous diseases; and moxonidine and rilmenidine, agonists of I1-IRs, are widely used as antihypertensive agents. Some evidence suggests that IR ligands may induce anti-inflammatory effects acting on I1-IRs or other molecular targets, which could be beneficial in patients with inflammatory bowel disease (IBD). On the other hand, several IR ligands may stimulate also alpha2-adrenoceptors, which were earlier shown to inhibit, but in more recent studies to rather aggravate colitis. Hence, this study aimed to analyse for the first time the effect of various I1-IR ligands on intestinal inflammation. Colitis was induced in C57BL/6 mice by adding dextran sulphate sodium (DSS) to the drinking water for 7 days. Mice were treated daily with different IR ligands: moxonidine and rilmenidine (I1-IR agonists), AGN 192403 (highly selective I1-IR ligand, putative antagonist), efaroxan (I1-IR antagonist), as well as with the endogenous IR agonists agmatine and harmane. It was found that moxonidine and rilmenidine at clinically relevant doses, similarly to the other IR ligands, do not have a significant impact on the macroscopic and histological signs of DSS-evoked inflammation. Likewise, colonic myeloperoxidase and serum interleukin-6 levels remained unchanged in response to these agents. Thus, our study demonstrates that imidazoline ligands do not influence significantly the severity of DSS-colitis in mice and suggest that they probably neither affect the course of IBD in humans. However, the translational value of these findings needs to be verified with other experimental colitis models and human studies.


Assuntos
Colite/tratamento farmacológico , Colite/metabolismo , Sulfato de Dextrana/toxicidade , Receptores de Imidazolinas/metabolismo , Imidazolinas/metabolismo , Imidazolinas/uso terapêutico , Animais , Colite/induzido quimicamente , Feminino , Ligantes , Camundongos , Camundongos Endogâmicos C57BL , Resultado do Tratamento
11.
J Pharmacol Exp Ther ; 359(1): 171-81, 2016 10.
Artigo em Inglês | MEDLINE | ID: mdl-27435180

RESUMO

Growing data support peripheral opioid antinociceptive effects, particularly in inflammatory pain models. Here, we examined the antinociceptive effects of subcutaneously administered, recently synthesized 14-O-methylmorphine-6-O-sulfate (14-O-MeM6SU) compared with morphine-6-O-sulfate (M6SU) in a rat model of inflammatory pain induced by an injection of complete Freund's adjuvant and in a mouse model of visceral pain evoked by acetic acid. Subcutaneous doses of 14-O-MeM6SU and M6SU up to 126 and 547 nmol/kg, respectively, produced significant and subcutaneous or intraplantar naloxone methiodide (NAL-M)-reversible antinociception in inflamed paws compared with noninflamed paws. Neither of these doses significantly affected thiobutabarbital-induced sleeping time or rat pulmonary parameters. However, the antinociceptive effects of higher doses were only partially reversed by NAL-M, indicating contribution of the central nervous system. In the mouse writhing test, 14-O-MeM6SU was more potent than M6SU after subcutaneous or intracerebroventricular injections. Both displayed high subcutaneous/intracerebroventricular ED50 ratios. The antinociceptive effects of subcutaneous 14-O-MeM6SU and M6SU up to 136 and 3043 nmol/kg, respectively, were fully antagonized by subcutaneous NAL-M. In addition, the test compounds inhibited mouse gastrointestinal transit in antinociceptive doses. Taken together, these findings suggest that systemic administration of the novel compound 14-O-MeM6SU similar to M6SU in specific dose ranges shows peripheral antinociception in rat and mouse inflammatory pain models without central adverse effects. These findings apply to male animals and must be confirmed in female animals. Therefore, titration of systemic doses of opioid compounds with limited access to the brain might offer peripheral antinociception of clinical importance.


Assuntos
Analgésicos/administração & dosagem , Analgésicos/farmacologia , Morfina/administração & dosagem , Morfina/farmacologia , Analgésicos/química , Analgésicos/uso terapêutico , Animais , Relação Dose-Resposta a Droga , Interações Medicamentosas , Feminino , Trato Gastrointestinal/efeitos dos fármacos , Trato Gastrointestinal/fisiologia , Masculino , Camundongos , Morfina/química , Morfina/uso terapêutico , Dor/tratamento farmacológico , Ratos , Ratos Wistar , Respiração/efeitos dos fármacos , Tiopental/análogos & derivados , Tiopental/farmacologia
12.
Scand J Gastroenterol ; 51(7): 848-54, 2016 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-26880133

RESUMO

OBJECTIVE: The association between extraintestinal manifestations (EIMs) and disease activity suggest a common pathogenetic link with inflammatory bowel disease (IBD). We report on the association of EIMs and anaemia with long-term disease outcomes, including treatment steps, hospitalization, and surgery in the prospective population-based IBD inception cohort from Veszprem province. METHODS: Data of 678 incident IBD patients (Crohn's disease/ulcerative colitis(CD/UC): 331/347) diagnosed from 1st January 2000 to 31st December 2012 were analyzed (CD: m/f: 176/155, median age at diagnosis: 28, IQR: 21-40 years, disease duration: 6, IQR: 2-9 years; UC: m/f: 200/147, median age at diagnosis: 36, IQR: 26-50 years, duration: 7, IQR: 4-10 years). RESULTS: EIMs were present in 30% of the CD and 17.3% of the UC patients. In CD, female gender (p = 0.02) need for steroid (p  < 0.001) and azathioprine (AZA) (p = 0.02), while in UC, young age at onset (p = 0.03), extensive disease (p = 0.003), female gender (p = 0.07), need for steroids (p < 0.001) and AZA (p = 0.004) and need for IBD-related hospitalization (p = 0.01) were associated with the presence of EIMs. Anaemia was present in 56.7% of the CD and 30.2% of the UC patients. In both CD and UC anaemia was associated with age at onset (pCD = 0.001, pUC = 0.04), disease location/extent (pCD = 0.02, pUC < 0.001), steroid and AZA use (for both pCD,UC < 0.001), need for surgery/colectomy (pCD < 0.001, pUC = 0.002) and hospitalization (pCD = 0.004, pUC < 0.001) and in CD, it was associated with anti TNF therapy(p = 0.002). CONCLUSIONS: The presence of EIMs was associated with disease phenotype in UC and with treatment strategy in both CD and UC. Additionally, anaemia was associated with hospitalization and surgery in both CD and UC, suggesting that EIMs and anaemia may be helpful in stratifying disease severity in IBD.


Assuntos
Doenças Inflamatórias Intestinais/complicações , Adulto , Anemia/complicações , Azatioprina/uso terapêutico , Colite Ulcerativa/complicações , Doença de Crohn/complicações , Feminino , Humanos , Doenças Inflamatórias Intestinais/tratamento farmacológico , Masculino , Pessoa de Meia-Idade , Índice de Gravidade de Doença , Esteroides/uso terapêutico , Adulto Jovem
13.
J Gastrointestin Liver Dis ; 24(3): 287-92, 2015 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-26405700

RESUMO

BACKGROUND AND AIMS: Limited data are available on the hospitalization rates in population-based studies. Since this is a very important outcome measure, the aim of this study was to analyze prospectively if early hospitalization is associated with the later disease course as well as to determine the prevalence and predictors of hospitalization and re-hospitalization in the population-based ulcerative colitis (UC) inception cohort in the Veszprem province database between 2000 and 2012. METHODS: Data of 347 incident UC patients diagnosed between January 1, 2000 and December 31, 2010 were analyzed (M/F: 200/147, median age at diagnosis: 36, IQR: 26-50 years, follow-up duration: 7, IQR 4-10 years). Both in- and outpatient records were collected and comprehensively reviewed. RESULTS: Probabilities of first UC-related hospitalization were 28.6%, 53.7% and 66.2% and of first re-hospitalization were 23.7%, 55.8% and 74.6% after 1-, 5- and 10- years of follow-up, respectively. Main UC-related causes for first hospitalization were diagnostic procedures (26.7%), disease activity (22.4%) or UC-related surgery (4.8%), but a significant percentage was unrelated to IBD (44.8%). In Kaplan-Meier and Cox-regression analysis disease extent at diagnosis (HR extensive: 1.79, p=0.02) or at last follow-up (HR: 1.56, p=0.001), need for steroids (HR: 1.98, p<0.001), azathioprine (HR: 1.55, p=0.038) and anti-TNF (HR: 2.28, p<0.001) were associated with the risk of UC-related hospitalization. Early hospitalization was not associated with a specific disease phenotype or outcome; however, 46.2% of all colectomies were performed in the year of diagnosis. CONCLUSION: Hospitalization and re-hospitalization rates were relatively high in this population-based UC cohort. Early hospitalization was not predictive for the later disease course.


Assuntos
Colite Ulcerativa/epidemiologia , Colite Ulcerativa/terapia , Hospitalização , Adulto , Anti-Inflamatórios/uso terapêutico , Distribuição de Qui-Quadrado , Colectomia , Colite Ulcerativa/diagnóstico , Bases de Dados Factuais , Feminino , Fármacos Gastrointestinais/uso terapêutico , Humanos , Hungria/epidemiologia , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Readmissão do Paciente , Prevalência , Prognóstico , Modelos de Riscos Proporcionais , Estudos Prospectivos , Fatores de Risco , Fatores de Tempo
14.
Brain Res Bull ; 117: 32-8, 2015 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-26235542

RESUMO

The therapeutic use of opioids is limited by the development of tolerance to the analgesic effect and the cellular and molecular mechanisms underlying this phenomenon are still not completely understood. For this reason the search for new analgesic derivatives, endowed with lower tolerance, is always an active field. The newly synthesized 14-O-Methylmorphine-6-sulfate (14-O-MeM6SU) shows high efficacy in in vitro assays and a strong analgesic action in the rat tail flick test. The aim of present work was to investigate: the analgesic effect of 14-O-MeM6SU in mouse tail-flick test; the tolerance to analgesic effect of 14-O-MeM6SU compared to morphine in mice, the effects of test compounds on glutamatergic neurotransmission by measuring spontaneous excitatory postsynaptic currents (sEPSCs) of layer V pyramidal cells from rat prefrontal cortices; and the effect of acute and chronic 14-O-MeM6SU treatments on opioid receptor gene expression in SH-SY5Y neuroblastoma cells expressing µ-opioid (MOP) and nociceptin/opioid receptor-like 1 (NOP) receptors. 14-O-MeM6SU was 17 times more potent than morphine in analgesia and had long duration of action in analgesic dose equipotent to morphine. Mice were treated subcutaneously (s.c.) either with 200 µmol/kg morphine or with 14-O-MeM6SU (12 µmol/kg) twice daily for three days. The magnitude of tolerance or cross-tolerance indicated by the shift in antinociceptive ED50 measured was greater for morphine compared to 14-O-MeM6SU. Subsequent to behavioral testing, patch-clamp experiments in layer V pyramidal neurons of rat prefrontal cortical slices in the presence of bicuculline were performed. Both 14-O-MeM6SU (0.1 µM) and morphine (1 µM) decreased the frequency of sEPSCs, indicating reduction of glutamate release. The effect of the novel compound was reversed by the opioid receptor antagonist naloxone, indicating an opioid mediated action. In contrast, the amplitude was not affected. Finally, gene expression data showed a dose dependent down-regulation of MOP receptor after 24h and 48 h exposure to 14-O-MeM6SU. Interestingly, no changes were detected for NOP receptor gene expression. The specific lack of this effect could be related to the lower tolerance development to analgesic effect of 14-O-MeM6SU. Furthermore, 14-O-MeM6SU displayed high intrinsic efficacy possibly an important factor in the observed effects. Further, the observed inhibition of glutamatergic signaling might be attributed also to the reduction of opioid tolerance. Based on our results the development of a new clinically important, safe analgesic agent might be possible.


Assuntos
Analgésicos Opioides/farmacologia , Codeína/análogos & derivados , Morfina/farmacologia , Analgésicos Opioides/efeitos adversos , Animais , Linhagem Celular Tumoral , Codeína/efeitos adversos , Codeína/farmacologia , Relação Dose-Resposta a Droga , Avaliação Pré-Clínica de Medicamentos , Tolerância a Medicamentos , Potenciais Pós-Sinápticos Excitadores/efeitos dos fármacos , Ácido Glutâmico/metabolismo , Humanos , Masculino , Camundongos , Morfina/efeitos adversos , Naloxona/farmacologia , Antagonistas de Entorpecentes/farmacologia , Dor Nociceptiva/tratamento farmacológico , Córtex Pré-Frontal/efeitos dos fármacos , Córtex Pré-Frontal/fisiologia , Células Piramidais/efeitos dos fármacos , Células Piramidais/fisiologia , Ratos Wistar , Receptores Opioides/genética , Receptores Opioides/metabolismo , Receptores Opioides mu/genética , Receptores Opioides mu/metabolismo , Transmissão Sináptica/efeitos dos fármacos , Transmissão Sináptica/fisiologia , Técnicas de Cultura de Tecidos
15.
Scand J Gastroenterol ; 50(3): 306-11, 2015 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-25471148

RESUMO

OBJECTIVE: Patients with inflammatory bowel diseases (IBD) are considered to have an increased risk for venous thromboembolism (VTE). The aim of the present study was to analyze the incidence and risk factors of VTE in a population-based inception cohort in the Veszprem province database between 1977 and 2012. MATERIAL AND METHODS: A total of 1708 incepted IBD patients were included (male/female: 879/829; CD (Crohn's disease): 648, age at onset: 29, interquartile range (IQR): 22-39; UC (ulcerative colitis): 1060, age at onset: 36, IQR: 26-50 years). Both in- and outpatient records were collected and comprehensively reviewed and followed up for a total of 21,369 patient-years. RESULTS: Twenty-two VTE events were identified in 19 patients (6 events in 5 CD and 16 in 14 UC patients). The incidence rate of VTE in IBD was 1.03 per 1000 patient-years. The risk of VTE in UC was associated with extensive location (odds ratio (OR): 3.25, 95% confidence interval (CI): 1.13-9.35), presence of fulminant episode during the disease course (OR: 4.15, 95% CI: 1.28-13.5), smoking (OR: 3.46, 95% CI: 1.14-10.5), and need for steroids (OR: 2.97, 95% CI: 0.99-8.92). CONCLUSION: The incidence of VTE was lower than previously reported. The incidence was higher in males and in UC it was associated with extensive disease, fulminant episodes, corticosteroids-requiring disease and smoking, but not with age at onset.


Assuntos
Colite Ulcerativa/epidemiologia , Doença de Crohn/epidemiologia , Tromboembolia Venosa/epidemiologia , Adulto , Idade de Início , Estudos de Coortes , Feminino , Seguimentos , Humanos , Hungria/epidemiologia , Incidência , Masculino , Pessoa de Meia-Idade , Prognóstico , Fatores de Risco , Distribuição por Sexo , Adulto Jovem
16.
Dig Liver Dis ; 46(5): 405-11, 2014 May.
Artigo em Inglês | MEDLINE | ID: mdl-24495511

RESUMO

BACKGROUND: Limited data are available on paediatric inflammatory bowel diseases in Eastern Europe. Our aim was to analyse disease characteristics in the population-based Veszprem province database between 1977 and 2011. METHODS: 187 (10.5%, ulcerative colitis/Crohn's disease/undetermined colitis: 88/95/4) out of 1565 incident patients were diagnosed with a paediatric onset in this population-based prospective inception cohort. RESULTS: The incidence of Crohn's disease and ulcerative colitis increased from 0 and 0.7 in 1977-1981 to 7.2 and 5.2 in 2007-2011 per 100,000 person years. Ileocolonic location (45%) and inflammatory disease behaviour (61%) were most frequent in Crohn's disease, while azathioprine use was frequent (66%) and surgical resection rates were high (33% at 5 years) in cases with paediatric onset. In ulcerative colitis, 34% of patients were diagnosed with extensive disease, with high rates of disease extension (26% and 41% at 5 and 10 years), fulminant episodes (19.3%) and systemic steroid use (52.3%). The cumulative rate of colectomy was low (6.9%). CONCLUSIONS: The incidence of paediatric inflammatory bowel diseases has rapidly increased in the last three decades in Western Hungary. Ileocolonic disease and a need for azathioprine were characteristic in paediatric Crohn's disease, while paediatric onset ulcerative colitis was characterised by extensive disease and disease extension, while the need for colectomy was low.


Assuntos
Colite Ulcerativa/epidemiologia , Doença de Crohn/epidemiologia , Adolescente , Fatores Etários , Anti-Inflamatórios/uso terapêutico , Azatioprina/uso terapêutico , Criança , Pré-Escolar , Colectomia/estatística & dados numéricos , Colite Ulcerativa/terapia , Doença de Crohn/terapia , Feminino , Humanos , Hungria/epidemiologia , Imunossupressores/uso terapêutico , Incidência , Lactente , Recém-Nascido , Masculino , Fenótipo , Índice de Gravidade de Doença , Fatores Sexuais , Esteroides/uso terapêutico
17.
World J Gastroenterol ; 19(43): 7701-10, 2013 Nov 21.
Artigo em Inglês | MEDLINE | ID: mdl-24282358

RESUMO

AIM: To analyze the difference in disease course and need for surgery in patients with Crohn's disease (CD). METHODS: Data of 506 patients with incident CD were analyzed (age at diagnosis: 31.5 ± 13.8 years). Both hospital and outpatient records were collected prospectively with a complete clinical follow-up and comprehensively reviewed in the population-based Veszprem province database, which includes incident CD patients diagnosed between January 1, 1977 and December 31, 2008. Follow-up data were collected until December 31, 2009. All patients included had at least 1 year of follow-up available. Patients with indeterminate colitis at diagnosis were excluded from the analysis. RESULTS: Overall, 73 patients (14.4%) required resective surgery within 1 year of diagnosis. Steroid exposure and need for biological therapy were lower in patients with early limited surgery (P < 0.001 and P = 0.09). In addition, surgery rates during follow-up in patients with and without early surgery differed significantly after matching on propensity scores (P < 0.001, HR = 0.23). The need for reoperation was also lower in patients with early limited resective surgery (P = 0.038, HR = 0.42) in a Kaplan-Meier and multivariate Cox regression (P = 0.04) analysis. However, this advantage was not observed after matching on propensity scores (P(Logrank) = 0.656, P(Breslow) = 0.498). CONCLUSION: Long-term surgery rates and overall exposure to steroids and biological agents were lower in patients with early limited resective surgery, but reoperation rates did not differ.


Assuntos
Colectomia , Doença de Crohn/cirurgia , Tempo para o Tratamento , Adolescente , Adulto , Produtos Biológicos/uso terapêutico , Distribuição de Qui-Quadrado , Colectomia/efeitos adversos , Colectomia/métodos , Colectomia/mortalidade , Doença de Crohn/diagnóstico , Doença de Crohn/tratamento farmacológico , Doença de Crohn/mortalidade , Progressão da Doença , Feminino , Humanos , Hungria/epidemiologia , Incidência , Estimativa de Kaplan-Meier , Laparoscopia , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Pontuação de Propensão , Modelos de Riscos Proporcionais , Estudos Prospectivos , Reoperação , Estudos Retrospectivos , Fatores de Risco , Esteroides/uso terapêutico , Fatores de Tempo , Resultado do Tratamento , Adulto Jovem
18.
J Gastrointestin Liver Dis ; 22(3): 265-8, 2013 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-24078982

RESUMO

BACKGROUND & AIMS: Since data is limited regarding the risk of colorectal cancer (CRC) in Crohn's disease (CD) patients who present with stenosing disease in the colon, this study was undertaken to assess CRC risk in such patients, using a population-based, Veszprem province database, which includes incidental patients diagnosed between January 1, 1977 and December 31, 2011. METHODS: Data from 640 incidental CD patients were analyzed (M/F ratio: 321/319, age-at-diagnosis: 28 years (IQR: 22-38)). Both hospital and outpatient records were collected and comprehensively reviewed. RESULTS: CRC was diagnosed in six CD patients during a follow-up of 7759 person-years. Sixty-two patients presented with colonic/ileocolonic disease and a stenotic lesion in the colon with a follow-up of 702 person-years (median: 10.5, IQR: 5-16years). Colorectal cancer developed in 6.5% (equalling 0.57/100 person-years), the SIR (6.53, 95% CI: 2.45-17.4) was increased with four patients observed versus 0.61 expected. In a Kaplan-Meier analysis, the probability of developing CRC was 5.5% and 7.5% after 5- and 10 years, respectively, versus 0.4% in patients with other phenotypes (HR: 18.8, p<0.001). A sensitivity analysis included patients with stenosing colonic lesion at diagnosis or during follow-up (n=91, follow-up: 1180 person-years, median: 12, IQR: 6-17years). The probability of developing CRC was 3.6% and 4.9% after 5- and 10 years, respectively. CONCLUSIONS: The risk of CRC in CD patients presenting with or developing a stenotic lesion in the colon is high even after a short disease duration, suggesting the need for careful surveillance.


Assuntos
Colo/patologia , Neoplasias Colorretais/epidemiologia , Doença de Crohn/epidemiologia , Adulto , Distribuição de Qui-Quadrado , Neoplasias Colorretais/diagnóstico , Constrição Patológica , Doença de Crohn/diagnóstico , Feminino , Humanos , Hungria/epidemiologia , Incidência , Estimativa de Kaplan-Meier , Masculino , Fenótipo , Modelos de Riscos Proporcionais , Sistema de Registros , Estudos Retrospectivos , Medição de Risco , Fatores de Risco , Fatores de Tempo , Adulto Jovem
19.
World J Gastroenterol ; 19(14): 2217-26, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-23599648

RESUMO

AIM: To investigate the evolution of disease phenotype in adult and pediatric onset Crohn's disease (CD) populations, diagnosed between 1977 and 2008. METHODS: Data of 506 incident CD patients were analyzed (age at diagnosis: 28.5 years, interquartile range: 22-38 years). Both in- and outpatient records were collected prospectively with a complete clinical follow-up and comprehensively reviewed in the population-based Veszprem province database, which included incident patients diagnosed between January 1, 1977 and December 31, 2008 in adult and pediatric onset CD populations. Disease phenotype according to the Montreal classification and long-term disease course was analysed according to the age at onset in time-dependent univariate and multivariate analysis. RESULTS: Among this population-based cohort, seventy-four (12.8%) pediatric-onset CD patients were identified (diagnosed ≤ 17 years of age). There was no significant difference in the distribution of disease behavior between pediatric (B1: 62%, B2: 15%, B3: 23%) and adult-onset CD patients (B1: 56%, B2: 21%, B3: 23%) at diagnosis, or during follow-up. Overall, the probability of developing complicated disease behaviour was 49.7% and 61.3% in the pediatric and 55.1% and 62.4% in the adult onset patients after 5- and 10-years of follow-up. Similarly, time to change in disease behaviour from non stricturing, non penetrating (B1) to complicated, stricturing or penetrating (B2/B3) disease was not significantly different between pediatric and adult onset CD in a Kaplan-Meier analysis. Calendar year of diagnosis (P = 0.04), ileal location (P < 0.001), perianal disease (P < 0.001), smoking (P = 0.038) and need for steroids (P < 0.001) were associated with presence of, or progression to, complicated disease behavior at diagnosis and during follow-up. A change in disease location was observed in 8.9% of patients and it was associated with smoking status (P = 0.01), but not with age at diagnosis. CONCLUSION: Long-term evolution of disease behavior was not different in pediatric- and adult-onset CD patients in this population-based cohort but was associated to location, perianal disease and smoking status.


Assuntos
Doença de Crohn/epidemiologia , Adolescente , Adulto , Idade de Início , Distribuição de Qui-Quadrado , Doença de Crohn/diagnóstico , Doença de Crohn/terapia , Progressão da Doença , Feminino , Humanos , Hungria/epidemiologia , Incidência , Estimativa de Kaplan-Meier , Masculino , Análise Multivariada , Razão de Chances , Fenótipo , Prognóstico , Modelos de Riscos Proporcionais , Estudos Prospectivos , Fatores de Risco , Fumar/efeitos adversos , Fumar/epidemiologia , Fatores de Tempo , Adulto Jovem
20.
Inflamm Bowel Dis ; 19(5): 1010-7, 2013 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-23399739

RESUMO

BACKGROUND: Previous studies suggest that smoking is an important environmental factor in inflammatory bowel diseases (IBDs), with dichotomous effects in ulcerative colitis (UC) and Crohn's disease (CD). The aim of this study was to analyze the relationship between smoking and IBD risk in a population-based database from Veszprem Province, which included incident cases diagnosed between January 1, 1977, and December 31, 2008. METHODS: Data from 1420 incident patients were analyzed (UC: 914, age at diagnosis: 38.9 years; CD: 506, age at diagnosis: 31.5 years). Both inpatient and outpatient records were collected and comprehensively reviewed. Overall, smoking frequency in the adult general population was 36.1%. RESULTS: Of patients with CD, 47.2% were current smokers at diagnosis. Smoking was more frequent in male patients (P = 0.002) and was associated with an increased risk of CD (odds ratio, 1.96; 95% confidence interval, 1.63-2.37; P < 0.001). In contrast, current smoking was protective against UC (odds ratio, 0.33; 95% confidence interval, 0.27-0.41). The effect of smoking was linked to gender (in CD, more deleterious in male patients) and age at diagnosis and was most prominent in young adults, with a difference already being seen in 18- to 19-year-olds. In CD, a change in disease behavior (P = 0.02), location from ileal or colonic to ileocolonic (P = 0.003), arthritis/arthropathy (P = 0.002), need for steroids (P = 0.06), or AZA (P = 0.038) was more common in current smokers. Smoking in UC was associated with more extensive disease (P = 0.01) and a tendency for decreased need for colectomy (P = 0.06). CONCLUSIONS: Current smoking was associated with the risk of IBD. This effect was linked to gender and age at diagnosis and was most prominent in young adults. No association was observed in pediatric or elderly patients. The deleterious and protective effects of smoking on the course in CD and UC were partially confirmed.


Assuntos
Colite Ulcerativa/etiologia , Doença de Crohn/etiologia , Exposição Ambiental/efeitos adversos , Fumar/efeitos adversos , Adolescente , Adulto , Idoso , Estudos de Coortes , Colite Ulcerativa/epidemiologia , Doença de Crohn/epidemiologia , Feminino , Seguimentos , Humanos , Hungria/epidemiologia , Masculino , Pessoa de Meia-Idade , Prognóstico , Fatores de Risco , Adulto Jovem
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