RESUMO
PURPOSE: There is currently no gold standard for the management of acute radiation enteritis. We compared the efficacy and safety of Racecadotril, an anti-hypersecretory drug, versus Loperamide, an anti-motility agent, in acute radiation enteritis. METHODS AND MATERIALS: We conducted a randomized, double-masked, non-inferiority trial at a single research institute. Patients receiving curative radiation for pelvic malignancies, who developed grade 2 or 3 diarrhea (as per Common Terminology Criteria for Adverse Events, v 4.0) were included in the study. Patients in the intervention arm received Racecadotril and placebo. Patients in the control arm received Loperamide and placebo. The primary outcome was the resolution of diarrhea, 48 hours after the start of treatment. RESULTS: 162 patients were randomized between 2019 and 2022. On intention-to-treat analysis, 68/81 patients, 84%, (95% CI, 74.1%-91.2%) in the Racecadotril arm and 70/81, 86.4%, (95% CI, 77.0%-93.0%) in the Loperamide arm improved from grade 2 or 3 diarrhea to grade 1 or 0, (P= .66, χ2 test). The difference in proportion was 2.4% (95% CI: -8.5% to 13.4%). Since the upper boundary of the 95% CI crossed our non-inferiority margin of 10% (13.4%) we could not prove the non-inferiority of Racecadotril over Loperamide. Rebound constipation was more in the Loperamide arm compared to Racecadotril (17.3% vs 6.2%; P = .028) CONCLUSIONS: The non-inferiority of Racecadotril to Loperamide in acute radiation enteritis could not be demonstrated. However, Racecadotril can be the preferred drug of choice in acute radiation enteritis because Racecadotril does not affect bowel motility, achieved a high clinical success rate similar to that of Loperamide, and was associated with lesser side effects.
Assuntos
Síndrome Aguda da Radiação , Enterite , Tiorfano , Humanos , Doença Aguda , Síndrome Aguda da Radiação/tratamento farmacológico , Antidiarreicos/efeitos adversos , Diarreia/tratamento farmacológico , Diarreia/etiologia , Método Duplo-Cego , Enterite/etiologia , Enterite/induzido quimicamente , Loperamida/efeitos adversos , Tiorfano/análogos & derivadosRESUMO
Anaplastic lymphoma kinase is a tyrosine kinase receptor protein belonging to insulin receptor superfamily. Gene fusions in anaplastic lymphoma kinase are associated with non-small cell lung cancer development. Hence, they are of immense importance in targeted therapies. Thus, for the treatment of non-small cell lung cancer, effective anaplastic lymphoma kinase inhibitors are of great significance. Therefore, our objective is to find hit compounds that could have better inhibitory activity than the existing anaplastic lymphoma kinase inhibitors. Keeping this in mind, in the present study pharmacophore based virtual screening was performed to identify possible anaplastic lymphoma kinase inhibitors. Initially, a five-point common pharmacophore hypothesis was generated based on twelve anaplastic lymphoma kinase inhibitors using PHASE module of Schrödinger. Subsequently, common pharmacophore hypothesis-based screening was conducted against in-trials subset of ZINC database and a total of 1000 hits were identified. The molecules obtained were further screened by three stages of docking using GLIDE software. The docking results reveal that six hit molecules showed higher glide score in comparison with the reference molecules. Finally, pharmacokinetic properties of the hit molecules were also analysed using QikProp programme. The results indicate that molecules namely videx, dexecadotril, chloramphenicol, naficillin were found to have good pharmacokinetic properties and human oral absorption. Moreover, videx, naficillin and chloramphenicol were found to have significant inhibitory activity for mutant (F1174L) anaplastic lymphoma kinase. It was also found that videx exhibited crucial interactions with the Met1199 residue of the native and mutant anaplastic lymphoma kinase protein. Furthermore, PASS algorithm predicted anti-neoplastic activity for all the four molecules. Thus these hits are found to be promising leads for anaplastic lymphoma kinase inhibitors. We believe that this study will be useful for the discovery and designing of more potent anaplastic lymphoma kinase inhibitors in the near future.
Assuntos
Inibidores de Proteínas Quinases/metabolismo , Receptores Proteína Tirosina Quinases/metabolismo , Algoritmos , Quinase do Linfoma Anaplásico , Sítios de Ligação , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/patologia , Domínio Catalítico , Cloranfenicol/química , Cloranfenicol/metabolismo , Bases de Dados de Compostos Químicos , Bases de Dados de Proteínas , Didanosina/química , Didanosina/metabolismo , Avaliação Pré-Clínica de Medicamentos , Humanos , Ligantes , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/patologia , Conformação Molecular , Simulação de Acoplamento Molecular , Mutagênese Sítio-Dirigida , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/uso terapêutico , Receptores Proteína Tirosina Quinases/antagonistas & inibidores , Receptores Proteína Tirosina Quinases/genética , Termodinâmica , Tiorfano/análogos & derivados , Tiorfano/química , Tiorfano/metabolismoRESUMO
Enantioseparation of the antidiarrheal drug, racecadotril, was investigated by liquid chromatography using polysaccharide-type chiral stationary phases in polar organic mode. The enantiodiscrimininating properties of 4 different chiral columns (Chiralpak AD, Chiralcel OD, Chiralpak AS, Chiralcel OJ) with 5 different solvents (methanol, ethanol, 1-propanol, 2-propanol, and acetonitrile) at 5 different temperatures (5-40 °C) were investigated. Apart from Chiralpak AS column the other 3 columns showed significant enantioseparation capabilities. Among the tested mobile phases, alcohol type solvents were superior over acetonitrile, and significant differences in enantioselective performance of the selector were observed depending on the type of alcohol employed. Van't Hoff analysis was used for calculation of thermodynamic parameters which revealed that enantioseparation is mainly enthalpy controlled; however, enthropic control was also observed. Enantiopure standard was used to determine the enantiomer elution order, revealing chiral selector-and mobile-phase dependent reversal of enantiomer elution order. Using the optimized method (Chiralcel OJ stationary phase, thermostated at 10 °C, 100% methanol, flow rate: 0.6 mL/min) baseline separation of racecadotril enantiomers (resolution = 3.00 ± 0.02) was achieved, with the R-enantiomer eluting first. The method was validated according to the ICH guidelines, and its application was tested on capsule and granules containing the racemic mixture of the drug.
Assuntos
2-Propanol/química , Amilose/análogos & derivados , Carbamatos/química , Fenilcarbamatos/química , Polissacarídeos/química , Tiorfano/análogos & derivados , Amilose/química , Cromatografia Líquida de Alta Pressão , Estrutura Molecular , Solventes , Estereoisomerismo , Termodinâmica , Tiorfano/químicaRESUMO
Worldwide, there are about two billion cases of diarrhoeal disease every year and it is the second leading cause of death in children under 5 years of age, killing 1.5 million children annually.(1) The most severe threat posed by diarrhoea is dehydration. In the UK, the incidence of diarrhoea is about one episode per person per year,(2) and approximately 10% of children younger than 5 years old present to healthcare services with gastroenteritis each year.(3) â¾Racecadotril (Hidrasec) is the first in a new class of antidiarrhoeal drug ('enkephalinase inhibitor') that has an antisecretory mechanism and is licensed in adults, children and infants (over 3 months of age) for symptomatic treatment of acute diarrhoea or as complementary treatment when causal treatment is possible.(4-6) Here we review the evidence for racecadotril and its place in the management of acute diarrhoea.
Assuntos
Antidiarreicos/uso terapêutico , Diarreia/tratamento farmacológico , Tiorfano/análogos & derivados , Humanos , Neprilisina/antagonistas & inibidores , Guias de Prática Clínica como Assunto , Ensaios Clínicos Controlados Aleatórios como Assunto , Tiorfano/uso terapêutico , Reino Unido , Organização Mundial da SaúdeRESUMO
Diarrhea is a distressing symptom which limits the quality of life in patients receiving palliative care and is associated with high morbidity and mortality. In patients with AIDS, it is a more common problem than for other entities (e.g., cancer). Loperamide is considered the first choice medication for the symptomatic treatment of diarrhea. This literature review examines the efficacy of loperamide in the symptomatic treatment of diarrhea in palliative care. Two databases (Medline and Embase) were searched through June 2012. A total of 286 studies were identified, but only 7 met the inclusion criteria (1 cohort and 6 experimental studies) in which loperamide (alone or in combination) was tested. There is a lack of significant studies which investigate the efficacy of loperamide in the symptomatic treatment of diarrhea. Two trials indicated superiority of loperamide over placebo. In comparison with octreotide, the results were contradictory. The combination of acetorphan with loperamide was more effective than acetorphan alone, but the combination of loperamide with diphenoxylate was inferior to octreotide. The identified studies revealed methodical problems. A definite recommendation for administration of loperamide can, therefore, not be derived from this work.The English full-text version of this article is available at SpringerLink (under "Supplemental").
Assuntos
Antidiarreicos/uso terapêutico , Diarreia/tratamento farmacológico , Loperamida/uso terapêutico , Cuidados Paliativos , Síndrome da Imunodeficiência Adquirida/complicações , Antidiarreicos/efeitos adversos , Ensaios Clínicos Controlados como Assunto , Diarreia/etiologia , Difenoxilato/efeitos adversos , Difenoxilato/uso terapêutico , Quimioterapia Combinada , Humanos , Loperamida/efeitos adversos , Octreotida/efeitos adversos , Octreotida/uso terapêutico , Tiorfano/efeitos adversos , Tiorfano/análogos & derivados , Tiorfano/uso terapêuticoAssuntos
Aminopiridinas/efeitos adversos , Antidiarreicos/uso terapêutico , Benzamidas/efeitos adversos , Diarreia/tratamento farmacológico , Inibidores de Fosfodiesterase/efeitos adversos , Tiorfano/análogos & derivados , Agonistas de Receptores Adrenérgicos beta 2/administração & dosagem , Agonistas de Receptores Adrenérgicos beta 2/uso terapêutico , Adulto , Aminopiridinas/administração & dosagem , Aminopiridinas/uso terapêutico , Antidiarreicos/administração & dosagem , Antidiarreicos/farmacologia , Benzamidas/administração & dosagem , Benzamidas/uso terapêutico , Criança , AMP Cíclico/metabolismo , Ciclopropanos/administração & dosagem , Ciclopropanos/efeitos adversos , Ciclopropanos/uso terapêutico , Diarreia/induzido quimicamente , Humanos , Neprilisina/antagonistas & inibidores , Doença Pulmonar Obstrutiva Crônica/tratamento farmacológico , Tiorfano/administração & dosagem , Tiorfano/farmacologia , Tiorfano/uso terapêuticoRESUMO
Racecadotril is known as an inhibitor of enkephalinase. Increase of plasma insulin by racecadotril has been observed in rats while the mechanism of the action remains obscure. In the present study, intravenous injection of male Wistar rats with racecadotril significantly decreased blood glucose levels. However, this effect of racecadotril was not modified by naloxone at the dose sufficient to block opioid receptors. Thus, the blood glucose-lowering action of racecadotril might be through an endogenous opioid independent mechanism. Otherwise, we found that C-peptide content was also raised by racecadotril in parallel with the increase of insulin in Wistar rats. Thus, the blood glucose-lowering action of racecadotril was related to insulin secretion, but not through the inhibition of plasma insulin degradation. In addition, racecadotril showed no direct effect on insulin secretion in isolated islets or cultured HIT-T15 beta cells. The increase of plasma insulin and blood glucose-lowering action induced by racecadotril were reduced by pretreatment with atropine and enhanced by physotigmine. Direct inhibition of cholinesterase was not observed in brain homogenates treated with racecadotril. Moreover, actions of racecadotril were significantly reduced in rats receiving hemicholinium-3 at a sufficient dose to decrease endogenous acetylcholine. Activation of cholinergic tone is possibly involved in the blood glucose-lowering effect of racecadotril. Our results suggested that racecadotril increased insulin secretion to lower blood glucose mainly via regulation of parasympathetic tone in Wistar rats.
Assuntos
Insulina/sangue , Neprilisina/antagonistas & inibidores , Tiorfano/análogos & derivados , Acetilcolina/metabolismo , Acetilcolinesterase/metabolismo , Animais , Atropina/farmacologia , Glicemia/efeitos dos fármacos , Encéfalo/efeitos dos fármacos , Encéfalo/enzimologia , Peptídeo C/sangue , Linhagem Celular , Separação Celular , Inibidores da Colinesterase/farmacologia , Relação Dose-Resposta a Droga , Encefalinas/metabolismo , Hemicolínio 3/farmacologia , Insulina/metabolismo , Secreção de Insulina , Células Secretoras de Insulina/efeitos dos fármacos , Células Secretoras de Insulina/metabolismo , Masculino , Antagonistas Muscarínicos/farmacologia , Fisostigmina/farmacologia , Ratos , Ratos Wistar , Receptores Muscarínicos/metabolismo , Tiorfano/administração & dosagem , Tiorfano/farmacologiaRESUMO
RATIONALE: Phosphodiesterase 5 (PDE5) inhibitors (e.g., sildenafil) are selective pulmonary vasodilators in patients with pulmonary arterial hypertension. The mechanism(s) underlying this specificity remains unclear, but studies in genetically modified animals suggest it might be dependent on natriuretic peptide bioactivity. OBJECTIVES: We explored the interaction between PDE5 inhibitors and the natriuretic peptide system to elucidate the (patho)physiological relationship between these two cyclic GMP (cGMP)-regulating systems and potential of a combination therapy exploiting these cooperative pathways. METHODS: Pharmacological evaluation of vascular reactivity was conducted in rat isolated conduit and resistance vessels from the pulmonary and systemic circulation in vitro, and in anesthetized mice in vivo. Parallel studies were undertaken in an animal model of hypoxia-induced pulmonary hypertension (PH). MEASUREMENTS AND MAIN RESULTS: Sildenafil augments vasodilatation to nitric oxide (NO) in pulmonary and systemic conduit and resistance arteries, whereas identical vasorelaxant responses to atrial natriuretic peptide (ANP) are enhanced only in pulmonary vessels. This differential activity is mirrored in vivo where sildenafil increases the hypotensive actions of ANP in the pulmonary, but not systemic, vasculature. In hypoxia-induced PH, combination of sildenafil plus the neutral endopeptidase (NEP) inhibitor ecadotril (which increases endogenous natriuretic peptide levels) acts synergistically, in a cGMP-dependent manner, to reduce many indices of disease severity without significantly affecting systemic blood pressure. CONCLUSIONS: These data demonstrate that PDE5 is a key regulator of cGMP-mediated vasodilation by ANP in the pulmonary, but not systemic, vasculature, thereby explaining the pulmonary selectivity of PDE5 inhibitors. Exploitation of this mechanism (i.e., PDE5 and neutral endopeptidase inhibition) represents a novel, orally active combination therapy for pulmonary arterial hypertension.
Assuntos
Fator Natriurético Atrial/uso terapêutico , Hipertensão Pulmonar/tratamento farmacológico , Piperazinas/uso terapêutico , Sulfonas/uso terapêutico , Vasodilatadores/uso terapêutico , 3',5'-GMP Cíclico Fosfodiesterases/antagonistas & inibidores , Animais , Modelos Animais de Doenças , Sinergismo Farmacológico , Quimioterapia Combinada , Hipertensão Pulmonar/metabolismo , Hipertensão Pulmonar/fisiopatologia , Masculino , Neprilisina/antagonistas & inibidores , Inibidores de Proteases/uso terapêutico , Artéria Pulmonar/efeitos dos fármacos , Artéria Pulmonar/fisiopatologia , Purinas/uso terapêutico , Ratos , Ratos Sprague-Dawley , Citrato de Sildenafila , Tiorfano/análogos & derivados , Tiorfano/uso terapêutico , Resultado do Tratamento , Resistência Vascular/efeitos dos fármacos , Vasodilatação/efeitos dos fármacosRESUMO
Some selected drugs including captopril, fudosteine and racecadotril have been analyzed by infrared (IR) laser desorption/tunable synchrotron vacuum ultraviolet (VUV) photoionization mass spectrometry (PIMS). The molecular ions of captopril and racecadotril are exclusively observed without any fragments at near threshold single-photon ionization (SPI). However, fudosteine easily forms fragments even at a photon energy near the ionization threshold, indicating the instability of its molecular ion. For these drugs, a number of fragments are yielded with the increase of photon energy. The structures of such fragments proposed by IR LD/VUV PIMS are supported by electron ionization time-of-flight mass spectrometry (EI-TOFMS) results. Fragmentation pathways are discussed in detail.
Assuntos
Preparações Farmacêuticas/química , Espectrometria de Massas por Ionização e Dessorção a Laser Assistida por Matriz/métodos , Espectrofotometria Ultravioleta/métodos , Síncrotrons , Anti-Hipertensivos/química , Captopril/química , Cistina/análogos & derivados , Cistina/química , Raios Infravermelhos , Fotoquímica , Inibidores de Proteases/química , Reprodutibilidade dos Testes , Espectrometria de Massas por Ionização por Electrospray , Espectrofotometria Infravermelho , Tiorfano/análogos & derivados , Tiorfano/química , Raios Ultravioleta , VácuoRESUMO
Orally administered racecadotril is rapidly hydrolyzed to the more potent enkephalinase inhibitor thiorphan in vivo. A sensitive and specific liquid chromatography/tandem mass spectrometry method was developed and validated to quantify thiorphan in human plasma using lisinopril as the internal standard. After a simple protein precipitation with methanol, the post-treatment samples were analyzed on a CN column interfaced with a triple-quadruple tandem mass spectrometer using negative electrospray ionization. The method was validated to demonstrate the specificity, lower limit of quantification, accuracy, and precision of measurements. The assay was linear over the concentration range 9.38-600 ng/mL using a 5 microL aliquot of plasma. The correlation coefficients for the calibration curves ranged from 0.9985 to 0.9995. The intra- and inter-day precisions over the entire concentration were not more than 6.33%. Methanol and water (35:65, v/v) is used as the isocratic mobile phase, with 0.1% of formic acid in water. The method was successfully applied for pharmacokinetic study after a single oral administration of 200 mg racecadotril to 20 healthy volunteers.
Assuntos
Cromatografia Líquida de Alta Pressão/métodos , Espectrometria de Massas em Tandem/métodos , Tiorfano/análogos & derivados , Calibragem , Humanos , Neprilisina/antagonistas & inibidores , Padrões de Referência , Reprodutibilidade dos Testes , Sensibilidade e Especificidade , Tiorfano/sangue , Tiorfano/farmacocinéticaRESUMO
Histaminergic neurons located in the posterior hypothalamus (tuberomamillary nucleus, TMN) project widely through the whole brain controlling arousal and attention. They are tonically active during wakefulness but cease firing during sleep. As a homeostatic theory of sleep involves ATP depletion and adenosine accumulation in the brain, we investigated the role of ATP and its analogues as well as adenosine on neuronal activity in the TMN. We show increased firing of rat TMN neurons by ATP, ADP, UTP and 2meSATP, indicating activation of receptors belonging to the P2Y family. Adenosine affected neither membrane potential nor firing of these cells. Single-cell reverse transcriptase-polymerase chain reaction revealed that P2Y1 and P2Y4 are prevailing receptors in TMN neurons. P2Y1 receptor mRNA was detected with a higher frequency in 2-week-old than in 4-week-old rats; in accordance, 2meSATP was more potent than ATP. Semi-quantitative real-time polymerase chain reaction revealed a developmental downregulation of mRNA levels for P2Y1 and P2Y4 receptors. Immunocytochemistry demonstrated neuronal and glial localization of the P2Y1 receptor protein. Network activity measured with multielectrode arrays in primary cultures made from the posterior hypothalamus was enhanced by UTP and 2meSATP (P2Y4 and P2Y1 agonists, respectively). ATP caused an inhibition of firing, which was reversed in the presence of suramin or gabazine [gamma-aminobutyric acid (GABA)A receptor antagonist], indicating that GABAergic neurons are preferentially activated by ATP in this network. Excitation of the wake-active TMN neurons by nucleotides and the lack of adenosine action may be important factors in sleep-wake regulation.
Assuntos
Potenciais de Ação/fisiologia , Hipotálamo Posterior/fisiologia , Receptores Purinérgicos P2/fisiologia , Potenciais de Ação/efeitos dos fármacos , Nucleotídeos de Adenina/farmacologia , Difosfato de Adenosina/análogos & derivados , Difosfato de Adenosina/farmacologia , Animais , Animais Recém-Nascidos , Relação Dose-Resposta a Droga , Interações Medicamentosas , Expressão Gênica/efeitos dos fármacos , Histamina/metabolismo , Hipotálamo Posterior/citologia , Hipotálamo Posterior/efeitos dos fármacos , Imidazóis/farmacologia , Imuno-Histoquímica/métodos , Técnicas In Vitro , Masculino , Metilistaminas/farmacologia , Proteínas Associadas aos Microtúbulos/metabolismo , Antagonistas do Receptor Purinérgico P2 , Fosfato de Piridoxal/análogos & derivados , Fosfato de Piridoxal/farmacologia , RNA Mensageiro/metabolismo , Ratos , Receptores de Glutamato Metabotrópico/metabolismo , Receptores Purinérgicos P2/classificação , Receptores Purinérgicos P2/genética , Reação em Cadeia da Polimerase Via Transcriptase Reversa/métodos , Temperatura , Tiorfano/análogos & derivados , Tiorfano/farmacologiaRESUMO
We examined the influence of cross-bridge cycling kinetics on the length dependence of steady-state force and the rate of force redevelopment (k(tr)) during Ca(2+)-activation at sarcomere lengths (SL) of 2.0 and 2.3 microm in skinned rat cardiac trabeculae. Cross-bridge kinetics were altered by either replacing ATP with 2-deoxy-ATP (dATP) or by reducing [ATP]. At each SL dATP increased maximal force (F(max)) and Ca(2+)-sensitivity of force (pCa(50)) and reduced the cooperativity (n(H)) of force-pCa relations, whereas reducing [ATP] to 0.5 mM (low ATP) increased pCa(50) and n(H) without changing F(max). The difference in pCa(50) between SL 2.0 and 2.3 microm (Delta pCa(50)) was comparable between ATP and dATP, but reduced with low ATP. Maximal k(tr) was elevated by dATP and reduced by low ATP. Ca(2+)-sensitivity of k(tr) increased with both dATP and low ATP and was unaffected by altered SL under all conditions. Significantly, at equivalent levels of submaximal force k(tr) was faster at short SL or increased lattice spacing. These data demonstrate that the SL dependence of force depends on cross-bridge kinetics and that the increase of force upon SL extension occurs without increasing the rate of transitions between nonforce and force-generating cross-bridge states, suggesting SL or lattice spacing may modulate preforce cross-bridge transitions.
Assuntos
Biofísica , Miocárdio/patologia , Tiorfano/análogos & derivados , Trifosfato de Adenosina/química , Trifosfato de Adenosina/metabolismo , Animais , Fenômenos Biofísicos , Cálcio/metabolismo , Nucleotídeos de Desoxiadenina/química , Detergentes/farmacologia , Coração/anatomia & histologia , Cinética , Masculino , Pressão , Ligação Proteica , Ratos , Ratos Sprague-Dawley , Estresse Mecânico , Tiorfano/química , Fatores de TempoRESUMO
The effect of angiotensin-converting enzyme (ACE) and neutral endopeptidase (NEP) inhibition on microvascular plasma leakage (extravasation) was evaluated in a rat model. Progressive inhibition of ACE using captopril caused increased extravasation when lung ACE was inhibited by >55%. In contrast, the selective inhibition of renal NEP by >90% using ecadotril did not increase extravasation. In NEP-inhibited rats, extravasation produced by the ACE inhibitors captopril and lisinopril was markedly enhanced. The dual ACE and NEP inhibitor omapatrilat, at oral doses of 0.03, 0.1, and 0.3 mg/kg, selectively inhibited lung ACE by 19, 61, and 76%, respectively, and did not cause significant extravasation. Doses of 1 and 10 mg/kg omapatrilat, which produced >90% inhibition of ACE and also inhibited renal NEP by 54 and 78%, respectively, significantly increased extravasation. In this model, bradykinin and substance P produced extravasation that could be abolished by the bradykinin 2 (B2) receptor antagonist Hoe 140 (icatibant) or the neurokinin1 (NK1) antagonist CP99994 [(+)-(2S,3S)-3-(2-methoxybenzylamino)-2-phenylpiperidine], respectively. Bradykinin induced extravasation was also partially ( approximately 40%) inhibited by CP99994, indicating that a portion of the response involves B2 receptor-mediated release of substance P. In conclusion, this study is the first to relate the degree of ACE and/or NEP inhibition to extravasation liability in the rat model. Our data clearly demonstrate that ACE inhibitor-induced plasma extravasation is enhanced by concomitant inhibition of NEP. In addition, this study provides further evidence for the role for B2 and NK1 receptors in mediating plasma extravasation in the rat.
Assuntos
Inibidores da Enzima Conversora de Angiotensina/farmacologia , Bradicinina/análogos & derivados , Captopril/farmacologia , Neprilisina/antagonistas & inibidores , Peptidil Dipeptidase A/metabolismo , Plasma/efeitos dos fármacos , Tiorfano/análogos & derivados , Animais , Bradicinina/farmacologia , Relação Dose-Resposta a Droga , Pulmão/efeitos dos fármacos , Pulmão/enzimologia , Masculino , Plasma/fisiologia , Ratos , Ratos Sprague-Dawley , Receptor B1 da Bradicinina/efeitos dos fármacos , Receptor B1 da Bradicinina/fisiologia , Receptor B2 da Bradicinina/efeitos dos fármacos , Receptor B2 da Bradicinina/fisiologia , Receptores da Neurocinina-1/efeitos dos fármacos , Receptores da Neurocinina-1/fisiologia , Substância P/farmacologia , Tiorfano/farmacologiaRESUMO
OBJECTIVE: Activated polymorphonuclear neutrophils (PMNs) are the main source of circulating neutral endopeptidase (NEP). We tested the hypothesis that NEP inhibition could potentiate the effect of atrial natriuretic peptide (ANP) on PMN-vascular cell interactions in vitro. METHODS AND RESULTS: ANP alone and its potentiation by retrothiorphan, the NEP inhibitor, significantly inhibited superoxide, lysozyme, and matrix metalloproteinase (MMP)-9 release by N-formyl-Met-Leu-Phe-stimulated PMNs. Activated PMNs degraded exogenous ANP, which was prevented by NEP inhibition. Hypoxia significantly increased the adhesion of PMNs to endothelial cells and their subsequent MMP-9 release by 60% and 150%, respectively (P<0.01). ANP and its potentiation by retrothiorphan limited PMN adhesion to hypoxic endothelial cells and thus decreased their MMP-9 release (P<0.01). Smooth muscle cells (SMCs) incubated with conditioned medium of N-formyl-Met-Leu-Phe-stimulated PMNs exhibited morphological and biochemical changes characteristic of apoptosis (terminal deoxynucleotidyl transferase-mediated dUTP nick end-labeling positivity, nuclear condensation/fragmentation, poly ADP-ribose polymerase cleavage, and DNA laddering). SMC detachment and subsequent apoptosis could be related to leukocyte elastase-induced pericellular proteolysis, inasmuch as both events are inhibited by elastase inhibitors. ANP and its potentiation by retrothiorphan were able to limit elastase release, fibronectin degradation, and SMC apoptosis. CONCLUSIONS: ANP potentiation by NEP inhibition could limit PMN activation and its consequences on vascular cells.
Assuntos
Fator Natriurético Atrial/farmacologia , Comunicação Celular/efeitos dos fármacos , Músculo Liso Vascular/efeitos dos fármacos , Músculo Liso Vascular/metabolismo , Neutrófilos/efeitos dos fármacos , Neutrófilos/metabolismo , Tiorfano/análogos & derivados , Fator Natriurético Atrial/metabolismo , Adesão Celular/efeitos dos fármacos , Adesão Celular/fisiologia , Comunicação Celular/fisiologia , Degranulação Celular/efeitos dos fármacos , Degranulação Celular/fisiologia , Meios de Cultivo Condicionados/farmacologia , Sinergismo Farmacológico , Endotélio Vascular/citologia , Endotélio Vascular/efeitos dos fármacos , Endotélio Vascular/metabolismo , Inibidores Enzimáticos/farmacologia , Fibronectinas/metabolismo , Humanos , Hipóxia/fisiopatologia , Elastase de Leucócito/metabolismo , Metaloproteinase 9 da Matriz/metabolismo , Músculo Liso Vascular/citologia , Neprilisina/antagonistas & inibidores , Neprilisina/metabolismo , Ativação de Neutrófilo/efeitos dos fármacos , Ativação de Neutrófilo/fisiologia , Neutrófilos/enzimologia , Neutrófilos/patologia , Explosão Respiratória/efeitos dos fármacos , Explosão Respiratória/fisiologia , Tiorfano/farmacologia , Veias Umbilicais/citologiaRESUMO
BACKGROUND: The diuretic actions of endogenously produced atrial natriuretic factor (ANF) may be beneficial in the treatment of chronic heart failure (CHF). Neutral endopeptidase (NEP) is the primary enzyme responsible for the degradation of ANF. The present study investigates the effects of long-term NEP inhibition on the progression of left ventricular (LV) dysfunction and remodeling in dogs with moderate heart failure. METHODS: LV dysfunction was produced in 12 dogs by multiple sequential intracoronary microembolizations. Embolizations were discontinued when LV ejection fraction (EF) was between 30-40%. Two weeks after the last embolization, dogs were randomized to 3 months of oral therapy with the NEP inhibitor ecadotril (100 mg, once daily, n = 6) or to no therapy at all (control, n = 6). RESULTS: During the 3 months of follow-up, LV EF in control dogs decreased from 37 +/- 1% to 28 +/- 1% (P < 0.01) and LV end-diastolic volume (EDV) and end-systolic volume (ESV) increased (EDV: 72 +/- 3 vs. 84 +/- 5 ml, P < 0.01); ESV: 45 +/- 1 vs. 60 +/- 4 ml, P < 0.01). In dogs treated with ecadotril, LV EF (34 +/- 1% vs. 37 +/- 2%), EDV (79+/- 5 vs. 78+/- 6 ml) and ESV (52 +/- 3 vs. 49 +/- 4) remained essentially unchanged after 3 months of therapy. Histomorphometric measurements at the termination of the study showed that ecadotril was associated with significantly reduced cardiomyocyte hypertrophy compared to control. CONCLUSION: Early, long-term NEP inhibition with ecadotril prevents the progression of LV dysfunction and attenuates progressive LV remodeling in dogs with moderate heart failure.
Assuntos
Insuficiência Cardíaca/fisiopatologia , Neprilisina/antagonistas & inibidores , Tiorfano/análogos & derivados , Tiorfano/uso terapêutico , Disfunção Ventricular Esquerda/tratamento farmacológico , Animais , Doença Crônica , Angiografia Coronária , Cães , Insuficiência Cardíaca/complicações , Insuficiência Cardíaca/patologia , Hemodinâmica/efeitos dos fármacos , Miócitos Cardíacos/patologia , Tiorfano/administração & dosagem , Disfunção Ventricular Esquerda/patologia , Disfunção Ventricular Esquerda/fisiopatologia , Remodelação Ventricular/efeitos dos fármacos , Remodelação Ventricular/fisiologiaRESUMO
We investigated the hemodynamic, renal, and hormonal responses to neutral endopeptidase (NEP) inhibition during a 6-h, double-blind, randomized, placebo-controlled study in seven chronic, stable heart transplant patients. Baseline characteristics were similar during both experiments, and no significant changes were observed after placebo. NEP inhibition increased circulating endothelin-1 (from 2.01 +/- 0.1 to 2.90 +/- 0.2 pmol/l; P < 0.01), atrial natriuretic peptide (ANP; from 21.5 +/- 2.7 to 29.6 +/- 3.7 pmol/l; P < 0.01), and the ANP second messenger cGMP. Noteworthy, systemic blood pressure did not increase. Renal plasma flow and glomerular filtration rate remained unmodified after NEP inhibition. Filtration fraction (33 +/- 13%), diuresis (196 +/- 62%), and natriuresis (315 +/- 105%) increased significantly in relation to ANP and cGMP. A strong inverse relationship was observed between excreted cGMP and sodium reabsorption (r = -0.71, P < 0.0001). Thus, despite significantly increasing endothelin-1, NEP inhibition did not adversely influence systemic or renal hemodynamics in transplant patients. ANP, possibly through a tubular action, enhances the natriuresis observed after NEP inhibition.
Assuntos
Pressão Sanguínea/efeitos dos fármacos , Transplante de Coração , Neprilisina/antagonistas & inibidores , Inibidores de Proteases/administração & dosagem , Tiorfano/análogos & derivados , Tiorfano/administração & dosagem , Adulto , Fator Natriurético Atrial/sangue , GMP Cíclico/sangue , GMP Cíclico/urina , Ciclosporina/sangue , Método Duplo-Cego , Endotelina-1/sangue , Taxa de Filtração Glomerular/efeitos dos fármacos , Humanos , Imunossupressores/sangue , Masculino , Pessoa de Meia-Idade , Natriurese/efeitos dos fármacos , Circulação Renal/efeitos dos fármacos , Resistência Vascular/efeitos dos fármacosRESUMO
The intravenous pretreatment with enkephalinase inhibitors KB 101 and acetorphan increased the heart resistance to the arrhythmogenic action of adrenaline (epinephrine), is related to activation of the delta-opioid receptors by endogenous enkephalins. At the same time, the mu-receptors and their endogenous agonists play an insignificant role in development of the antiarrhythmic effect of acetorphan. The enkephalinase inhibitors are a promising group of compounds for the development of new antiarrhythmic drugs, because these agents, in contrast to opiates, do not lead to narcotic addiction.
Assuntos
Antiarrítmicos/farmacologia , Inibidores Enzimáticos/farmacologia , Neprilisina/antagonistas & inibidores , Fenilalanina/análogos & derivados , Tiorfano/análogos & derivados , Animais , Arritmias Cardíacas/induzido quimicamente , Arritmias Cardíacas/prevenção & controle , Antígenos CD13/antagonistas & inibidores , Dissulfetos/farmacologia , Epinefrina , Masculino , Fenilalanina/farmacologia , Ratos , Ratos Wistar , Receptores Opioides delta/agonistas , Receptores Opioides mu/agonistas , Tiorfano/farmacologiaRESUMO
OBJECTIVE: Cyclosporine (CysA), a potent immunosuppressant, is associated with hypertension and nephrotoxicity. Neutral endopeptidase (NEP) degrades vasoactive peptides, including the natriuretic peptides and endothelin-1 (ET-1). We conducted the present study to determine whether or not the NEP inhibitor, ecadotril, prevents cyclosporine-induced hypertension and to clarify the mechanisms responsible for the hypotensive effects of ecadotril. DESIGN AND METHODS: We studied the chronic effects of ecadotril (30 mg/kg per day) on blood pressure; the production of ET-1 and C-type natriuretic peptide (CNP); endothelial nitric oxide synthase (eNOS) activity; and the expression of messenger RNA (mRNA), for each substance in blood vessels of CysA-induced hypertensive rats. RESULTS: CysA (25 mg/kg per day) given for 4 weeks increased the blood pressure from 116 +/- 14 mmHg to 159 +/- 15 mmHg, in rats. This increase was blunted by the co-administration of ecadotril (blood pressure: 134 +/- 14 mmHg). CysA increased plasma NEP activity. CysA increased the production of ET-1 and the expression of ET-1 mRNA without affecting CNP synthesis and endothelin converting enzyme (ECE)-1 mRNA expression. CysA decreased the eNOS activity and eNOS mRNA levels. Addition of the NEP inhibitor decreased the synthesis of ET-1 and ET-1 mRNA levels and increased the eNOS activity and the eNOS mRNA levels. Vascular CNP synthesis and ECE-1 mRNA expression in rats treated with ecadotril did not differ from those in rats treated with CysA and ecadotril. CONCLUSION: These results indicate that chronic NEP inhibition may prevent the CysA-induced hypertension by decreasing local ET-1 synthesis and partly increasing vascular nitric oxide production.
Assuntos
Ciclosporina/toxicidade , Inibidores Enzimáticos/toxicidade , Hipertensão/enzimologia , Neprilisina/antagonistas & inibidores , Inibidores de Proteases/farmacologia , Tiorfano/análogos & derivados , Tiorfano/farmacologia , Animais , Pressão Sanguínea/efeitos dos fármacos , Pressão Sanguínea/fisiologia , Southern Blotting , Sondas de DNA/química , Endotelina-1/sangue , Endotelina-1/genética , Endotélio Vascular/efeitos dos fármacos , Endotélio Vascular/metabolismo , Hipertensão/induzido quimicamente , Hipertensão/fisiopatologia , Masculino , Peptídeo Natriurético Tipo C/sangue , Peptídeo Natriurético Tipo C/genética , Óxido Nítrico Sintase/sangue , Óxido Nítrico Sintase/genética , Óxido Nítrico Sintase Tipo III , Reação em Cadeia da Polimerase , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Ratos , Ratos Endogâmicos WKYRESUMO
Our purpose was to determine, in patients with metastatic colorectal carcinoma treated with irinotecan single-agent after 5-FU failure, the most significant predictive parameters for tumour response, progression-free survival and toxicity. Between October 1992 and April 1995, 455 patients with 5-FU resistant metastatic colorectal carcinoma entered four consecutive phase II trials. The first two studies assessed tumour response, the other two were randomized studies which assessed the efficacy of racecadotril to prevent irinotecan-induced diarrhoea. Due to homogeneous main eligibility criterias, data from those studies could be pooled for statistical analysis. Potential clinical and biological predictive factors (PF) for toxicity, tumour growth control, e.g. response or stabilization and progression-free survival (PFS), were studied in multivariate analysis. 363 patients were evaluable for response, 432 were evaluable for PFS, 368 for neutropenia and 416 for delayed diarrhoea, respectively. Normal baseline haemoglobin level (Hb), time since diagnosis of colorectal carcinoma, grade 3 or 4 neutropenia or diarrhoea at first cycle and a low number of organs involved were the most PF for tumour growth control (P<0.05). Significant prognostic variables for PFS were WHO Performance Status, liver and lymph-node involvement, time since diagnosis, age and CEA value (P < or =0.02). Six groups of patients based on the number of unfavourable prognostic factors are presented. Baseline bilirubin, haemoglobin level, number of organs involved and time from diagnosis were PF for neutropenia; PS, serum creatinine, leukocyte count, time from 5-FU progression and prior abdominopelvic irradiation were PF for delayed diarrhoea (P< or =0.05). These PF should help clinicians to anticipate for a given patient the probability to observe a response/stabilization or a toxicity. These results should also be prospectively confirmed in ongoing or future trials using irinotecan, both as a single agent and in combination with other drugs.