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Objective: ADAPT+ assessed the long-term safety, tolerability, and efficacy of efgartigimod in adult participants with generalized myasthenia gravis (gMG). Methods: ADAPT+ was an open-label, single-arm, multicenter, up to 3-year extension of the pivotal phase 3 ADAPT study. Efgartigimod was administered in treatment cycles of 4 intravenous infusions (one 10 mg/kg infusion per week). Initiation of subsequent treatment cycles was individualized based on clinical evaluation. Safety endpoints included incidence and severity of adverse events. Efficacy endpoints assessed disease severity using Myasthenia Gravis-Activities of Daily Living (MG-ADL) and Quantitative Myasthenia Gravis (QMG) scores. Results: As of January 2022, 151 participants had rolled over to ADAPT+ and 145 had received ≥1 dose of efgartigimod, of whom, 111 (76.6%) were AChR-Ab+ and 34 (23.4%) were AChR-Ab-. Mean study duration (treatment plus follow-up) was 548 days, and participants received up to 17 treatment cycles, corresponding to 217.6 participant-years of exposure. In the overall population, 123 (84.8%) participants reported ≥1 treatment-emergent adverse event; most frequent were headache (36 [24.8%]), COVID-19 (22 [15.2%]), and nasopharyngitis (20 [13.8%]). Clinically meaningful improvement (CMI) in mean MG-ADL and QMG scores was seen as early as 1 week following the first infusion across multiple cycles in AChR-Ab+ and AChR-Ab- participants. Maximal MG-ADL and QMG improvements aligned with onset and magnitude of total IgG and AChR-Ab reductions. For AChR-Ab+ participants at any time point in each of the first 10 treatment cycles, more than 90% had a maximum reduction of ≥2 points (CMI) in MG-ADL total score; across the 7 cycles in which QMG was measured, 69.4% to 91.3% of participants demonstrated a maximum reduction of ≥3 points (CMI) in QMG total score. Many participants demonstrated improvements well beyond CMI thresholds. In AChR-Ab+ participants with ≥1 year of combined follow-up between ADAPT and ADAPT+, mean number of annualized cycles was 4.7 per year (median [range] 5.0 [0.5-7.6]). Conclusion: Results of ADAPT+ corroborate the substantial clinical improvements seen with efgartigimod in ADAPT and support its long-term safety, tolerability, and efficacy, as well as an individualized dosing regimen for treatment of gMG. Clinical trial registration: https://classic.clinicaltrials.gov/ct2/show/NCT03770403, NCT03770403.
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BACKGROUND: There is an unmet need for treatment options for generalised myasthenia gravis that are effective, targeted, well tolerated, and can be used in a broad population of patients. We aimed to assess the safety and efficacy of efgartigimod (ARGX-113), a human IgG1 antibody Fc fragment engineered to reduce pathogenic IgG autoantibody levels, in patients with generalised myasthenia gravis. METHODS: ADAPT was a randomised, double-blind, placebo-controlled, phase 3 trial done at 56 neuromuscular academic and community centres in 15 countries in North America, Europe, and Japan. Patients aged at least 18 years with generalised myasthenia gravis were eligible to participate in the study, regardless of anti-acetylcholine receptor antibody status, if they had a Myasthenia Gravis Activities of Daily Living (MG-ADL) score of at least 5 (>50% non-ocular), and were on a stable dose of at least one treatment for generalised myasthenia gravis. Patients were randomly assigned by interactive response technology (1:1) to efgartigimod (10 mg/kg) or matching placebo, administered as four infusions per cycle (one infusion per week), repeated as needed depending on clinical response no sooner than 8 weeks after initiation of the previous cycle. Patients, investigators, and clinical site staff were all masked to treatment allocation. The primary endpoint was proportion of acetylcholine receptor antibody-positive patients who were MG-ADL responders (≥2-point MG-ADL improvement sustained for ≥4 weeks) in the first treatment cycle. The primary analysis was done in the modified intention-to-treat population of all acetylcholine receptor antibody-positive patients who had a valid baseline MG-ADL assessment and at least one post-baseline MG-ADL assessment. The safety analysis included all randomly assigned patients who received at least one dose or part dose of efgartigimod or placebo. This trial is registered at ClinicalTrials.gov (NCT03669588); an open-label extension is ongoing (ADAPT+, NCT03770403). FINDINGS: Between Sept 5, 2018, and Nov 26, 2019, 167 patients (84 in the efgartigimod group and 83 in the placebo group) were enrolled, randomly assigned, and treated. 129 (77%) were acetylcholine receptor antibody-positive. Of these patients, more of those in the efgartigimod group were MG-ADL responders (44 [68%] of 65) in cycle 1 than in the placebo group (19 [30%] of 64), with an odds ratio of 4·95 (95% CI 2·21-11·53, p<0·0001). 65 (77%) of 84 patients in the efgartigimod group and 70 (84%) of 83 in the placebo group had treatment-emergent adverse events, with the most frequent being headache (efgartigimod 24 [29%] vs placebo 23 [28%]) and nasopharyngitis (efgartigimod ten [12%] vs placebo 15 [18%]). Four (5%) efgartigimod-treated patients and seven (8%) patients in the placebo group had a serious adverse event. Three patients in each treatment group (4%) discontinued treatment during the study. There were no deaths. INTERPRETATION: Efgartigimod was well tolerated and efficacious in patients with generalised myasthenia gravis. The individualised dosing based on clinical response was a unique feature of ADAPT, and translation to clinical practice with longer term safety and efficacy data will be further informed by the ongoing open-label extension. FUNDING: argenx.
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Anticuerpos Monoclonales Humanizados/uso terapéutico , Anticuerpos Monoclonales/uso terapéutico , Fragmentos Fc de Inmunoglobulinas/uso terapéutico , Miastenia Gravis/tratamiento farmacológico , Actividades Cotidianas , Adulto , Autoanticuerpos/inmunología , Método Doble Ciego , Femenino , Cefalea/tratamiento farmacológico , Humanos , Estudios Longitudinales , Masculino , Persona de Mediana Edad , Miastenia Gravis/inmunología , Receptores Colinérgicos/inmunologíaRESUMEN
In this technical report we describe the thermographic setting protocol suitable for the FLIR T650SC thermal imager (FLIR Systems, Inc., Wilsonville, OR), an instrument that detects electromagnetic radiation in the infrared field which is physiologically emitted from the human body. FLIR T650SC thermal imager processes infrared radiations graphically and analyzes them through a specific software. In biomedicine, infrared thermography is a promising technique amongst other conventional methods used for detecting skin temperature differences considered as a possible sign of disturbances in the human body. Currently, automatic screening of temperature from a safe distance is an instrument utilized in the front line of the SARS CoV2 emergency. The processing method of the thermogram considers an initial setting of constant parameters that cannot be subsequently modified such as temperature range, focusing and image composition. After the acquisition variable values important in the processing and analysis of the thermogram, such as detection of environment temperature, reflected temperature, emissivity, relative humidity and contrast palette, are set in the software. The analysis is performed using the FLIR Tools software. In the biomedical field standardized acquisition of thermograms facilitates the identification of trigger points and areas of hyper- and hypothermia distributed on the skin surface and muscle bundles. The protocol made it possible to create images with the same acquisition method for all patients. The thermal imaging camera is a valid screening tool because its execution is rapid, it is non-invasive, well-tolerated, and at a low cost for patients.
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OBJECTIVE: To investigate safety and explore efficacy of efgartigimod (ARGX-113), an anti-neonatal Fc receptor immunoglobulin G1 Fc fragment, in patients with generalized myasthenia gravis (gMG) with a history of anti-acetylcholine receptor (AChR) autoantibodies, who were on stable standard-of-care myasthenia gravis (MG) treatment. METHODS: A phase 2, exploratory, randomized, double-blind, placebo-controlled, 15-center study is described. Eligible patients were randomly assigned (1:1) to receive 4 doses over a 3-week period of either 10 mg/kg IV efgartigimod or matched placebo combined with their standard-of-care therapy. Primary endpoints were safety and tolerability. Secondary endpoints included efficacy (change from baseline to week 11 of Myasthenia Gravis Activities of Daily Living, Quantitative Myasthenia Gravis, and Myasthenia Gravis Composite disease severity scores, and of the revised 15-item Myasthenia Gravis Quality of Life scale), pharmacokinetics, pharmacodynamics, and immunogenicity. RESULTS: Of the 35 screened patients, 24 were enrolled and randomized: 12 received efgartigimod and 12 placebo. Efgartigimod was well-tolerated in all patients, with no serious or severe adverse events reported, no relevant changes in vital signs or ECG findings observed, and no difference in adverse events between efgartigimod and placebo treatment. All patients treated with efgartigimod showed a rapid decrease in total immunoglobulin G (IgG) and anti-AChR autoantibody levels, and assessment using all 4 efficacy scales consistently demonstrated that 75% showed a rapid and long-lasting disease improvement. CONCLUSIONS: Efgartigimod was safe and well-tolerated. The correlation between reduction of levels of pathogenic IgG autoantibodies and disease improvement suggests that reducing pathogenic autoantibodies with efgartigimod may offer an innovative approach to treat MG. CLASSIFICATION OF EVIDENCE: This study provides Class I evidence that efgartigimod is safe and well-tolerated in patients with gMG.
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Factores Inmunológicos/uso terapéutico , Miastenia Gravis/tratamiento farmacológico , Receptores Fc/antagonistas & inhibidores , Actividades Cotidianas , Corticoesteroides/uso terapéutico , Adulto , Anciano , Autoanticuerpos/inmunología , Inhibidores de la Colinesterasa/uso terapéutico , Método Doble Ciego , Femenino , Antígenos de Histocompatibilidad Clase I , Humanos , Fragmentos Fc de Inmunoglobulinas/uso terapéutico , Inmunosupresores/uso terapéutico , Masculino , Persona de Mediana Edad , Miastenia Gravis/inmunología , Receptores Colinérgicos/inmunología , Resultado del Tratamiento , Adulto JovenRESUMEN
BACKGROUND: Intravenous Ig (IVIg), plasma exchange, and immunoadsorption are frequently used in the management of severe autoimmune diseases mediated by pathogenic IgG autoantibodies. These approaches modulating IgG levels can, however, be associated with some severe adverse reactions and a substantial burden to patients. Targeting the neonatal Fc receptor (FcRn) presents an innovative and potentially more effective, safer, and more convenient alternative for clearing pathogenic IgGs. METHODS: A randomized, double-blind, placebo-controlled first-in-human study was conducted in 62 healthy volunteers to explore single and multiple ascending intravenous doses of the FcRn antagonist efgartigimod. The study objectives were to assess safety, tolerability, pharmacokinetics, pharmacodynamics, and immunogenicity. The findings of this study were compared with the pharmacodynamics profile elicited by efgartigimod in cynomolgus monkeys. RESULTS: Efgartigimod treatment resulted in a rapid and specific clearance of serum IgG levels in both cynomolgus monkeys and healthy volunteers. In humans, single administration of efgartigimod reduced IgG levels up to 50%, while multiple dosing further lowered IgGs on average by 75% of baseline levels. Approximately 8 weeks following the last administration, IgG levels returned to baseline. Efgartigimod did not alter the homeostasis of albumin or Igs other than IgG, and no serious adverse events related to efgartigimod infusion were observed. CONCLUSION: Antagonizing FcRn using efgartigimod is safe and results in a specific, profound, and sustained reduction of serum IgG levels. These results warrant further evaluation of this therapeutic approach in IgG-driven autoimmune diseases. TRIAL REGISTRATION: Clinicaltrials.gov NCT03457649. FUNDING: argenx BVBA.
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Enfermedades Autoinmunes , Fragmentos Fc de Inmunoglobulinas/administración & dosificación , Inmunoglobulina G/sangre , Receptores Fc/antagonistas & inhibidores , Adulto , Animales , Autoanticuerpos/sangre , Enfermedades Autoinmunes/sangre , Enfermedades Autoinmunes/tratamiento farmacológico , Células CHO , Cricetulus , Método Doble Ciego , Femenino , Antígenos de Histocompatibilidad Clase I , Humanos , Fragmentos Fc de Inmunoglobulinas/efectos adversos , Macaca fascicularis , MasculinoRESUMEN
Urinary tract infections (UTIs) are one of the most common bacterial infections in women, often as a recurrent disease. Uropathogenic Escherichia coli (UPEC) is the most common pathotype of extraintestinal pathogenic E. coli (ExPEC) found among patients with UTI. The human intestinal can act as a reservoir of UPEC, with the female urethra being infected by fecal material containing UPEC. Adhesion of bacteria to the epithelial cells of urogenital mucosa is an important mechanism in the pathogenesis of UTI. Alternative nonantibiotic based approaches, such as mechanical barrier protection of the intestinal mucosa have been proposed to reduce bacterial adherence to intestinal epithelium, bacteria proliferation and decrease of the load of UPEC in the intestinal lumen and in the fecal material.
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Infecciones por Escherichia coli/microbiología , Infecciones Urinarias/microbiología , Escherichia coli Uropatógena/fisiología , Animales , Infecciones por Escherichia coli/prevención & control , Femenino , Humanos , Intestinos/microbiología , Recurrencia , Factores de Riesgo , Escherichia coli Uropatógena/genética , Escherichia coli Uropatógena/patogenicidad , VirulenciaRESUMEN
OBJECTIVE: A 5-h phase advance model of insomnia was used to evaluate the efficacy of lorediplon, a new non-benzodiazepine hypnotic. METHODS: Thirty-five male, healthy subjects were included in a five-way randomized cross-over study. During each of the periods, sleep was recorded, and residual effects were measured. All subjects received lorediplon 1, 5, and 10 mg, placebo, and zolpidem 10 mg (i.e., active control). RESULTS: Polysomnographic evaluation revealed that lorediplon (5 and 10 mg) significantly decreased wake after sleep onset (WASO) and increased total sleep time. Analysis by quarters of the night showed a progressive increasing effectiveness of lorediplon 10 mg across the first three quarters. Lorediplon increased non-rapid eye movement slow wave sleep and stage N2 sleep in the second and third quarters. The magnitude of these effects was dose related, with minimal effects seen with 1 mg. No residual effects were observed 13 h post dose. CONCLUSIONS: Lorediplon demonstrated a dose-dependent improvement in sleep, whereas zolpidem showed a more sustained WASO effect. No next-day hangover effects were observed. These sleep effects are also consistent with the pharmacokinetic profile of lorediplon. These results warrant clinical trials in patients with insomnia.
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Hipnóticos y Sedantes/uso terapéutico , Pirazoles/uso terapéutico , Pirimidinas/uso terapéutico , Trastornos del Inicio y del Mantenimiento del Sueño/tratamiento farmacológico , Adulto , Estudios Cruzados , Relación Dosis-Respuesta a Droga , Método Doble Ciego , Humanos , Hipnóticos y Sedantes/efectos adversos , Masculino , Polisomnografía , Pirazoles/efectos adversos , Piridinas/efectos adversos , Piridinas/uso terapéutico , Pirimidinas/efectos adversos , Sueño/efectos de los fármacos , Sueño/fisiología , Trastornos del Inicio y del Mantenimiento del Sueño/fisiopatología , Fases del Sueño/efectos de los fármacos , Encuestas y Cuestionarios , Factores de Tiempo , Resultado del Tratamiento , Población Blanca , Adulto Joven , ZolpidemRESUMEN
Variability is a hallmark of microbial systems. On the one hand, microbes are subject to environmental heterogeneity and undergo changeable conditions in their immediate surroundings. On the other hand, microbial populations exhibit high cellular diversity. The relation between microbial diversity and variability of population dynamics is difficult to assess. This connection can be quantitatively studied from a perspective that combines in silico models and thermodynamic methods and interpretations. The infection process of Plasmodium falciparum parasitizing human red blood cells under laboratory cultivation conditions is used to illustrate the potential of Individual-based models in the context of predictive microbiology and parasitology. Experimental data from several in vitro cultures are compared to the outcome of an individual-based model and analysed from a thermodynamic perspective. This approach allows distinguishing between intrinsic and external constraints that give rise to the diversity in the infection forms, and it provides a criterion to quantitatively define transient and stationary regimes in the culture. Increasing the ability of models to discriminate between different states of microbial populations enhances their predictive capability which finally leads to a better the control over culture systems. The strategy here presented is of general application and it can substantially improve modelling of other types of microbial communities.
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Senescencia Celular , Eritrocitos/patología , Eritrocitos/parasitología , Malaria Falciparum/sangre , Malaria Falciparum/parasitología , Plasmodium falciparum/fisiología , Animales , Simulación por Computador , Humanos , Estadios del Ciclo de Vida , Parasitemia/sangre , Parasitemia/parasitología , Plasmodium falciparum/crecimiento & desarrollo , Termodinámica , Factores de TiempoRESUMEN
In spite of advances in prevention and treatment, the burden of cardiovascular diseases is increasing. A fixed-dose combination (FDC) pill, or "polypill," composed of evidence-based drugs has been proposed as a means of improving cardiovascular prevention by reducing cost and increasing patient adherence to treatment. The aim of the FOCUS project, funded by the 7th Framework Programme of the European Commission, is to characterize the factors that underlie inadequate secondary prevention and to test a new FDC. To achieve these goals, a 9-member consortium has been constituted, including institutions from Argentina, France, Italy, Spain, and Switzerland. FOCUS Phase-1 will examine factors potentially related to lack of adequate secondary prevention in 4,000 post-myocardial infarction (MI) patients and analyze the relationship between these factors and patient treatment adherence. Primary end points will be (1) the percentage of patients receiving aspirin, angiotensin-converting enzyme inhibitors, and statins and (2) adherence to treatment measured by the Morisky-Green test. FOCUS Phase-2 is a randomized trial that will compare adherence to treatment in 1,340 post-myocardial infarction patients either receiving an FDC comprising aspirin (100 mg), ramipril (2.5, 5, or 10 mg), and simvastatin (40 mg) or receiving the same 3 drugs separately.
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Inhibidores de la Enzima Convertidora de Angiotensina/administración & dosificación , Aspirina/administración & dosificación , Enfermedades Cardiovasculares/prevención & control , Inhibidores de Hidroximetilglutaril-CoA Reductasas/administración & dosificación , Cumplimiento de la Medicación , Inhibidores de Agregación Plaquetaria/administración & dosificación , Argentina , Combinación de Medicamentos , Europa (Continente) , Humanos , Selección de Paciente , Proyectos de InvestigaciónRESUMEN
A new generation of UV filters has been developed that act by limiting the dose of radiation rather than by blocking a fraction of the solar irradiance on the skin surface. Such progressive sunscreens are based on the photochemical transformation of suitable precursors upon exposure to sunlight. Broadband sunscreens are thus generated "on demand", affording protection when, where, and to the extent that it is needed, providing higher protection to more exposed areas, and increasing the UV blocking capacity as the radiation dose increases. Encapsulation in silica particles isolates the precursors and transformation products, further improving the efficacy, safety, and environmental impact of the use of sunscreens.
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Protección Radiológica/métodos , Protectores Solares/farmacología , Relación Dosis-Respuesta a Droga , Descubrimiento de Drogas , Estabilidad de Medicamentos , Ésteres/química , Ésteres/farmacología , Estudios de Factibilidad , Filtración , Procesos Fotoquímicos , Protectores Solares/químicaRESUMEN
The pharmaceutical development of a cardiovascular polypill presents several unique challenges. The selection of the type and number of active drugs to be incorporated requires important consideration of clinical, pharmaceutical and commercial issues, and the final decision with regard to the polypill's components depends on how these issues are prioritized. Once the drug combination has been chosen, developers must determine which pharmaceutical formulation should be used. The most appropriate method of drug delivery can vary markedly and depends on the characteristics of the drugs to be combined. Finally, careful consideration of how to gather the type of information required by regulatory agencies before a particular polypill can be approved for use in the general population is crucial. Although the association of multiple, active ingredients in a single dosage form would represent a major step forward in the prevention of cardiovascular conditions, a careful evaluation of all the above-mentioned variables and a well thought-out development plan is mandatory to maximize the chances of success.
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Fármacos Cardiovasculares/administración & dosificación , Enfermedades Cardiovasculares/tratamiento farmacológico , Fármacos Cardiovasculares/economía , Enfermedades Cardiovasculares/prevención & control , Química Farmacéutica , Esquema de Medicación , Aprobación de Drogas , Combinación de Medicamentos , Composición de Medicamentos , Costos de los Medicamentos , Industria Farmacéutica/economía , Humanos , Propiedad Intelectual , Resultado del TratamientoRESUMEN
The efficacy of a new torasemide prolonged release (PR) formulation to torasemide immediate release (IR) was compared in a randomized noninferiority double-blind trial. Patients with newly diagnosed mild-to-moderate hypertension or unresponsive or poor tolerability to previous antihypertensive monotherapy received 5 mg/day of torasemide-PR (n = 219) or torasemide-IR (n = 223) for 12 weeks (uptitration to 10 mg/day if no response at 4 or 8 weeks). Mean diastolic blood pressure (DBP) reduction in the torasemide-PR group (11.6 +/- 7.1 mmHg, 95% confidence interval [CI] 10.6-12.5) versus torasemide-IR (11.3 +/- 7.5 mmHg, 95% CI 10.2-12.3) met the noninferiority criterion of a nonsided 97.5% CI lower than the preestablished margin of 2 mmHg. A significantly higher percentage of patients in the torasemide-PR group achieved adequate BP control after 8 and 12 weeks. Ambulatory 24-h BP monitoring (ABPM) measurements in a subset of 100 patients showed greater daytime SBP reductions in the torasemide-PR group (128.4 +/- 9.9 mmHg vs. 133.5 +/- 10.4 mmHg, P < 0.05). Safety and tolerability of both formulations were similar.
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Antihipertensivos/uso terapéutico , Presión Sanguínea/efectos de los fármacos , Diuréticos/uso terapéutico , Hipertensión/tratamiento farmacológico , Sulfonamidas/uso terapéutico , Adulto , Anciano , Antihipertensivos/efectos adversos , Monitoreo Ambulatorio de la Presión Arterial , Preparaciones de Acción Retardada , Diuréticos/efectos adversos , Método Doble Ciego , Femenino , Humanos , Hipertensión/fisiopatología , Masculino , Persona de Mediana Edad , Índice de Severidad de la Enfermedad , España , Sulfonamidas/efectos adversos , Factores de Tiempo , Torasemida , Resultado del Tratamiento , Micción/efectos de los fármacosRESUMEN
In this work we describe the synthesis and biological evaluation of the tacrine-1,4-dihydropyridine (DHP) hybrids (3-11). These multipotent molecules are the result of the juxtaposition of an acetylcholinesterase inhibitor (AChEI) such as tacrine (1) and a 1,4-DHP such as nimodipine (2). Compounds 3-11 are very selective and potent AChEIs and show an excellent neuroprotective profile and a moderate Ca2+ channel blockade effect. Consequently, these molecules are new potential drugs for the treatment of Alzheimer's disease.
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Acetilcolinesterasa/química , Dihidropiridinas/química , Fármacos Neuroprotectores/farmacología , Tacrina/química , Acetilcolinesterasa/metabolismo , Enfermedad de Alzheimer/tratamiento farmacológico , Animales , Antioxidantes/farmacología , Calcio/metabolismo , Canales de Calcio/química , Proliferación Celular/efectos de los fármacos , Células Cultivadas , Anguilas/metabolismo , Humanos , Peróxido de Hidrógeno/farmacología , L-Lactato Deshidrogenasa/metabolismo , Neuroblastoma/metabolismo , Neuroblastoma/patología , Fármacos Neuroprotectores/síntesis química , Fármacos Neuroprotectores/química , Relación Estructura-ActividadRESUMEN
Among the known non-benzodiazepine hypnotic drugs, Zolpidem (1a), Indiplon (2a) and Zaleplon (2b) have shown high affinity and selectivity for the alpha(1) subunit of the GABA-A receptor. Our group has performed pharmacophoric and ADMET-prediction studies to evaluate a virtual library of new molecules based on privileged structures. Among these, we have synthesized a library of N-substituted indoles and a library of N-substituted benzimidazoles. Afterwards, in vitro screening and in vivo spontaneous motor activity in mice has revealed molecules with good in vitro affinities for the alpha(1) receptor and potent in vivo induction of sedation.
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Bencimidazoles/química , Bencimidazoles/farmacología , Agonistas de Receptores de GABA-A , Indoles/química , Indoles/farmacología , Modelos Moleculares , Bencimidazoles/síntesis química , Evaluación Preclínica de Medicamentos , Indoles/síntesis química , Espectroscopía de Resonancia MagnéticaRESUMEN
Among the known non-benzodiazepinic hypnotic drugs acting on the alpha1 subunit of the GABA-A receptor, Zolpidem, Zaleplon and Indiplon have showed high affinity and selectivity. Following a design methodology including pharmacophoric requirements and ADME-predicted properties, we have synthesized a library of 3-amino-4,5-dihydro-1H-pyrazolo[3,4-b]pyridin-6(7H)-ones and their N1-alkyl derivatives as new scaffolds for designing non-benzodiazepine BZ receptor ligands.
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Diseño de Fármacos , Hipnóticos y Sedantes/síntesis química , Piridonas/síntesis química , Animales , Benzodiazepinas/química , Benzodiazepinas/farmacología , Hipnóticos y Sedantes/química , Hipnóticos y Sedantes/farmacología , Masculino , Pirazoles/química , Piridinas/química , Piridinas/farmacología , Piridonas/química , Piridonas/farmacología , Ratas , Ratas Sprague-Dawley , Receptores de GABA-A/efectos de los fármacos , Relación Estructura-Actividad , Tiofenos/química , Tiofenos/farmacología , ZolpidemRESUMEN
Peripheral tachykinins (TKs) are believed to play a role in the pathogenesis of inflammatory bowel diseases (IBD). In this study we investigated changes induced by central administration of two natural TK receptor agonists, NK(1) (PG-SPI) and NK(3) (PG-KII), on trinitrobenzene sulphonic acid (TNBS)- and dextran sodium sulphate (DSS)-induced experimental colitis in rats. Colitis was induced by instilling a single intracolonic dose of TNBS 50 mgkg(-1) (0.5 ml in 50% ethanol) or by oral administration of 5% DSS for 7 days. Each group of rats was intracerebroventricularly injected daily with PG-SPI and PG-KII (0.5, 5, and 50 microgkg(-1)). On day 3, TNBS-treated animals were killed and the severity of gut inflammation was evaluated by measuring myeloperoxidase (MPO) activity, interleukin-1beta (IL-1beta) production and by scoring macroscopic and histologic colonic damage. DSS-treated animals were checked daily for the length of survival and for stool consistency and faecal blood. In the TNBS group, PG-SPI and PG-KII increased scores for the severity of colonic damage, stimulated the production of IL-1beta and increased granulocyte infiltration into the colon (MPO activity). In the DSS group, PG-SPI and PG-KII decreased the percentage of surviving animals, and increased the number of rats that developed loose stools and blood in the faeces and the MPO activity. These results indicate that centrally injected NK(1) and NK(3) tachykinin receptor agonists play a proinflammatory role in experimentally-induced colitis in rats.