RESUMEN
OBJECTIVE: The aim of the study was to examine treatment continuation and satisfaction over 1 year among women receiving nomegestrol acetate (NOMAC)/oestradiol (E2) combined oral contraception (COC) in real-world clinical practice. METHODS: The 17ß-Estradiol and Nomegestrol Acetate (BOLERO) Study is an observational, non-interventional, prospective, multicentre cohort study of premenopausal women (aged 18-50 years) who received prescription NOMAC/E2 (2.5 mg/1.5 mg) for contraception during routine clinical practice. Assessments were carried out at enrolment and at 3, 6 and 12 months. Probability of treatment continuation through 12 months (primary outcome) was examined using Kaplan-Meier survival analysis. Secondary outcomes included treatment satisfaction, menstrual cycle-related symptoms, libido and adverse events (AEs). RESULTS: Of 298 enrolled women, 292 were evaluable. The probability of NOMAC/E2 continuation through 12 months was 73.7% (95% confidence interval [CI] 68.0%, 78.5%). Satisfaction with NOMAC/E2 increased from 56.9% (37/65) of women at initial evaluation to 89.2% (58/65) of women at 12 months. Physician ratings at 12 months showed satisfactory to very satisfactory in 84.0% (168/200) of women. Libido was not affected. Menstrual cycle-related symptoms significantly declined from enrolment (6.04 ± 4.32) to 3 months (3.25 ± 3.05) and 12 months (2.62 ± 2.74; p < .0001). Treatment-related AEs were reported by 38.7% (113/292) of women. CONCLUSION: The real-world experience of women receiving NOMAC/E2 indicated very good treatment continuation, high satisfaction and significantly improved menstrual cycle-related symptoms.
Asunto(s)
Conducta Anticonceptiva/estadística & datos numéricos , Anticonceptivos Orales Combinados/administración & dosificación , Estradiol/administración & dosificación , Megestrol/administración & dosificación , Norpregnadienos/administración & dosificación , Cumplimiento y Adherencia al Tratamiento/estadística & datos numéricos , Adolescente , Adulto , Femenino , Humanos , Ciclo Menstrual/efectos de los fármacos , Ciclo Menstrual/psicología , Persona de Mediana Edad , Satisfacción del Paciente , Estudios Prospectivos , Adulto JovenRESUMEN
The unique role of fatty acid amide hydrolase (FAAH) in terminating endocannabinoid (EC) signaling supports its relevance as a therapeutic target. Inhibition of EC metabolizing enzymes elicits indirect agonism of cannabinoid receptors (CBRs) and therapeutic efficacy devoid of psychotropic effects. Based on our previous ligands, and aiming at the discovery of new selective FAAH inhibitors, we developed a series of 12 new compounds characterized by functionalized tricyclic scaffolds. All the developed compounds display negligible activity on monoacylglycerol lipase (MAGL) and CBRs. The most potent FAAH inhibitors of the newly developed series, 6-oxo-5,6-dihydro-4H-benzo[f]pyrrolo[1,2-a][1,4]diazepin-9-yl-6-phenylhexylcarbamate (5 h) and 4-oxo-5,6-dihydro-4H-benzo[f]pyrrolo[1,2-a][1,4]diazepin-9-yl-(6-phenylhexyl)carbamate (5 i) (nanomolar FAAH inhibitors, the latter of which also shows micromolar affinity at the CB1 R), were selected for further studies. Results of cell-based studies on a neuroblastoma cell line (IMR32) demonstrated 5 h, 5 i, and our reference compound 3 ([3-(3-carbamoylpyrrol-1-yl)phenyl] N-(5-phenylpentyl)carbamate) to lack any cytotoxic effect, while all three showed the ability to decrease oxidative stress by reducing the expression of the redox-sensitive transcription factor NF-κB. Encouraged by these data, these compounds were studied in vivo and were dosed orally in a mouse model of neuropathic pain. At 10â mg kg-1 all the compounds were able to relieve the hypersensitivity induced by oxaliplatin.
Asunto(s)
Amidohidrolasas/antagonistas & inhibidores , Benzodiazepinonas/uso terapéutico , Inhibidores Enzimáticos/uso terapéutico , Neuralgia/tratamiento farmacológico , Animales , Benzodiazepinonas/síntesis química , Benzodiazepinonas/farmacología , Benzodiazepinonas/toxicidad , Línea Celular Tumoral , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/farmacología , Inhibidores Enzimáticos/toxicidad , Humanos , Masculino , Ratones , Simulación del Acoplamiento Molecular , Estructura Molecular , FN-kappa B/metabolismo , Estrés Oxidativo/efectos de los fármacos , Relación Estructura-ActividadRESUMEN
Fatty acid amide hydrolase (FAAH, EC 3.5.1.99) is the main enzyme catabolizing endocannabinoid fatty acid amides. FAAH inactivation promotes beneficial effects upon pain and anxiety without the side effects accompanying agonists of type-1 cannabinoid receptors. Aiming at discovering new selective FAAH inhibitors, we developed a series of compounds (5a-u) characterized by a functionalized heteroaromatic scaffold. Particularly, 5c and 5d were identified as extremely potent, noncompetitive, and reversible FAAH inhibitors endowed with a remarkable selectivity profile and lacking interaction with the hERG channels. In vivo antinociceptive activity was demonstrated for 5c, 5d, and 5n at a dose much lower than that able to induce either striatal and limbic stereotypies or anxiolytic activity, thus outlining their potential to turn into optimum preclinical candidates. Aiming at improving pharmacokinetic properties and metabolic stability of 5d, we developed a subset of nanomolar dialyzable FAAH inhibitors (5v-z), functionalized by specific polyethereal lateral chains and fluorinated aromatic rings.
Asunto(s)
Amidohidrolasas/antagonistas & inhibidores , Analgésicos/síntesis química , Amidohidrolasas/química , Analgésicos/química , Analgésicos/farmacología , Animales , Encéfalo/enzimología , Células CHO , Cricetinae , Cricetulus , Ciclohexanos/síntesis química , Ciclohexanos/química , Ciclohexanos/farmacología , Canal de Potasio ERG1 , Canales de Potasio Éter-A-Go-Go/antagonistas & inhibidores , Furanos/síntesis química , Furanos/química , Furanos/farmacología , Humanos , Hiperalgesia/fisiopatología , Aprendizaje por Laberinto/efectos de los fármacos , Ratones , Modelos Moleculares , Umbral del Dolor , Pirroles/síntesis química , Pirroles/química , Pirroles/farmacología , Ratas , Proteínas Recombinantes/antagonistas & inhibidores , Proteínas Recombinantes/química , Conducta Estereotipada/efectos de los fármacos , Relación Estructura-Actividad , Tiofenos/síntesis química , Tiofenos/química , Tiofenos/farmacologíaRESUMEN
We investigated some pyrrolobenzoxazepinone (PBOs, 3e-i) analogues of early described effective non-nucleoside inhibitors of HIV-1 reverse transcriptase (RT). Enzymological studies of 3e-i enantiomers, with wild type (wt) RT and some drug-resistant mutants, revealed a stereoselective mode of action and selectivity for RT ternary complex. Unexpectedly (+)-3g was found more potent towards the L100I mutant than towards the wt RT, whereas (+)-3h inhibited the K103N mutant and RT wt with comparable potency.
Asunto(s)
Fármacos Anti-VIH/química , Transcriptasa Inversa del VIH/química , VIH-1 , Oxazepinas/química , Inhibidores de la Transcriptasa Inversa/química , Fármacos Anti-VIH/metabolismo , Fármacos Anti-VIH/farmacología , Farmacorresistencia Viral/efectos de los fármacos , Transcriptasa Inversa del VIH/genética , Transcriptasa Inversa del VIH/metabolismo , VIH-1/genética , VIH-1/metabolismo , Humanos , Concentración 50 Inhibidora , Estructura Molecular , Mutación , Oxazepinas/metabolismo , Oxazepinas/farmacología , Pirroles/química , Pirroles/metabolismo , Pirroles/farmacología , Inhibidores de la Transcriptasa Inversa/metabolismo , Inhibidores de la Transcriptasa Inversa/farmacología , Estereoisomerismo , Relación Estructura-ActividadRESUMEN
Adenosine kinase (AK) catalyzes the phosphorylation of adenosine (Ado) to AMP by means of a kinetic mechanism in which the two substrates Ado and ATP bind the enzyme in a binary and/or ternary complex, with distinct protein conformations. Most of the described inhibitors have Ado-like structural motifs and are nonselective, and some of them (e.g., the tubercidine-like ligands) are characterized by a toxic profile. We have cloned and expressed human AK (hAK) and searched for novel non-substrate-like inhibitors. Our efforts to widen the structural diversity of AK inhibitors led to the identification of novel non-nucleoside, noncompetitive allosteric modulators characterized by a unique molecular scaffold. Among the pyrrolobenzoxa(thia)zepinones (4a-qq) developed, 4a was identified as a non-nucleoside prototype hAK inhibitor. 4a has proapoptotic efficacy, slight inhibition of short-term RNA synthesis, and cytostatic activity on tumor cell lines while showing low cytotoxicity and no significant adverse effects on short-term DNA synthesis in cells.
Asunto(s)
Adenosina Quinasa/antagonistas & inhibidores , Antineoplásicos/síntesis química , Modelos Moleculares , Oxazepinas/síntesis química , Pirroles/síntesis química , Adenosina Quinasa/química , Regulación Alostérica , Sitio Alostérico , Animales , Antineoplásicos/química , Antineoplásicos/farmacología , Apoptosis/efectos de los fármacos , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , ADN/biosíntesis , Ensayos de Selección de Medicamentos Antitumorales , Humanos , Ratones , Oxazepinas/química , Oxazepinas/farmacología , Pirroles/química , Pirroles/farmacología , ARN/biosíntesis , Proteínas Recombinantes/antagonistas & inhibidores , Proteínas Recombinantes/química , Estereoisomerismo , Relación Estructura-ActividadRESUMEN
Among the enzymes involved in the life cycle of HCV, the non-structural protein NS3, with its double function of protease and NTPase/helicase, is essential for the virus replication. Exploiting our previous knowledge in the development of nucleotide-mimicking NS3 helicase (NS3h) inhibitors endowed with key structural and electronic features necessary for an optimal ligand-enzyme interaction, we developed the tetrahydroacridinyl derivative 3a as the most potent NS3h competitive inhibitor reported to date (HCV NS3h K(i)=20 nM).
Asunto(s)
Descubrimiento de Drogas , Hepacivirus/enzimología , Hidrazinas/química , Hidrazinas/farmacología , Pirazinas/química , Pirazinas/farmacología , Quinolinas/química , Quinolinas/farmacología , Proteínas no Estructurales Virales/antagonistas & inhibidores , Unión Competitiva/efectos de los fármacos , Hidrazinas/síntesis química , Unión Proteica , Pirazinas/síntesis química , Quinolinas/síntesis químicaRESUMEN
As a continuation of our efforts to develop innovative ligands for D(3), 5-HT(1A), and 5-HT(2A) receptors with low propensity to block hERG channels, we propose a series bishetero(homo)arylpiperazines 5a-m as novel and potent multifunctional ligands characterized by low occupancy at D(2) and 5-HT(2C) receptors.
Asunto(s)
Antipsicóticos/síntesis química , Piperazinas/síntesis química , Receptor de Serotonina 5-HT1A/metabolismo , Receptor de Serotonina 5-HT2A/metabolismo , Receptores de Dopamina D3/metabolismo , Animales , Antipsicóticos/farmacocinética , Antipsicóticos/farmacología , Canal de Potasio ERG1 , Canales de Potasio Éter-A-Go-Go/antagonistas & inhibidores , Canales de Potasio Éter-A-Go-Go/metabolismo , Humanos , Ligandos , Ratones , Modelos Moleculares , Piperazinas/farmacocinética , Piperazinas/farmacología , Relación Estructura-ActividadRESUMEN
We investigated the pharmacological profile of a novel series of quinoxaline-based 5-HT(3) receptor ligands bearing an extra basic moiety on the piperazine N-4. High affinity and selectivity were dependent on the electronic properties of the substituents, and at cardiac level 3a and 3c modulated chronotropy but not inotropy. In von Bezold-Jarisch reflex test 3a-c were partial agonists while 3i was a full agonist. Preliminary pharmacokinetic studies indicated that 3a is a brain penetrating agent.
Asunto(s)
Pirroles/síntesis química , Quinoxalinas/síntesis química , Agonistas del Receptor de Serotonina 5-HT3 , Animales , Barrera Hematoencefálica/metabolismo , Agonismo Parcial de Drogas , Cobayas , Frecuencia Cardíaca/efectos de los fármacos , Técnicas In Vitro , Ligandos , Contracción Miocárdica/efectos de los fármacos , Pirroles/química , Pirroles/farmacología , Quinoxalinas/farmacocinética , Quinoxalinas/farmacología , Ratas , Reflejo/efectos de los fármacos , Antagonistas del Receptor de Serotonina 5-HT3 , Relación Estructura-ActividadRESUMEN
The synthesis and the biological characterization of novel highly selective pyrroloquinoxaline 5-HT(3) receptor (5-HT(3)R) ligands are described. In functional and in vivo biological studies the novel quinoxalines modulated cardiac parameters by direct interaction with myocardial 5-HT(3)Rs. The potent 5-HT(3)R ligands 4h and 4n modulate chronotropy (right atrium) but not inotropy (left atrium) at the cardiac level, being antagonist and partial agonist, respectively. Preliminary pharmacokinetic studies indicate that (S)-4n and 4a, representatives of the novel 5-HT(3)R ligands, possess poor blood-brain barrier permeability, being the prototypes of peripherally acting 5-HT(3)R modulators endowed with a clear-cut pharmacological activity at the cardiac level. The unique properties of 4h and 4n, compared to their previously described centrally active N-methyl analogue 5a, are mainly due to the hydrophilic groups at the distal piperazine nitrogen. These analogues represent novel pharmacological tools for investigating the role of peripheral 5-HT(3)R in the modulation of cardiac parameters.
Asunto(s)
Corazón/efectos de los fármacos , Miocardio/metabolismo , Pirroles/síntesis química , Pirroles/farmacología , Quinoxalinas/síntesis química , Quinoxalinas/farmacología , Receptores de Serotonina 5-HT3/efectos de los fármacos , Receptores de Serotonina 5-HT3/metabolismo , Animales , Barorreflejo/efectos de los fármacos , Fenómenos Químicos , Femenino , Cobayas , Atrios Cardíacos/efectos de los fármacos , Atrios Cardíacos/metabolismo , Masculino , Ratones , Modelos Moleculares , Pirroles/farmacocinética , Quinoxalinas/farmacocinética , Quipazina/análogos & derivados , Quipazina/síntesis química , Ratas , Ratas Sprague-Dawley , Receptores de Serotonina/metabolismo , Agonistas del Receptor de Serotonina 5-HT3 , Relación Estructura-ActividadRESUMEN
Starting from the prototypic compound 4, we describe new, potent, and broad-spectrum pyrrolobenzo(pyrido)oxazepinones antivirals. A biochemical and enzymological investigation was performed for defining their mechanism of inhibition at either recombinant HIV-1 RT wild type and non-nucleoside reverse transcriptase inhibitors (NNRTIs)-resistant mutants. For the novel compounds (S)-(+)-5 and (S)-(-)-7, a clear-cut stereoselective mechanism of enzyme inhibition was found. Molecular modeling studies were performed for revealing the underpinnings of this behavior.