RESUMEN
OBJECTIVE: To evaluate psychometric properties of the Chinese version of Dementia Quality of Life Measure - Proxy (C-DEMQoL-Proxy). METHODS: Care home residents aged ≥60 years who were diagnosed with dementia or demonstrated impairment in cognition were recruited from four care facilities in Hong Kong. Caregivers of these participants were also invited to participate. The original DEMQoL-Proxy was translated into Chinese (Cantonese) by a trained translator. The forward-translated version was reviewed by an expert panel of six experienced healthcare professionals. Revisions were made based on comments. The instrument was back-translated to English to check whether further changes were necessary. Demographic data (age, sex, type and severity of dementia, and Mini-Mental State Examination [MMSE] score) were collected from medical records of participants with dementia. Caregivers were interviewed by an occupational therapist or personnel supervised by the occupational therapist using the C-DEMQoL-Proxy and the Chinese version of Quality of Life-Alzheimer's Disease-Proxy (C-QoL-AD-Proxy). Acceptability, reliability, and validity of the C-DEMQoL-Proxy were evaluated using standard psychometric methods. RESULTS: 90 individuals (82.2% women) with dementia aged 72 to 102 years were included. Their diagnosis included Alzheimer's disease (23.3%), vascular dementia (15.6%), mixed and other types of dementias (51.1%), and missing (10%). Severity was mild in 12.2%, moderate in 62.2%, and severe in 25.6%. The mean MMSE score was 12.0 ± 4.9. 20% of the caregivers were family members and the rest were professional carers. The C-DEMQoL-Proxy had good acceptability, with no floor or ceiling effects or missing data. It had good internal consistency (Cronbach alpha = 0.91) and test-retest reliability (intraclass correlation coefficients = 0.83). It was mildly correlated with C-QoL-AD-Proxy (r = 0.29, p < 0.01). Age and sex were not correlated with C-DEMQoL-Proxy scores. C-DEMQoL-Proxy scores were not significantly different between dementia types, severity levels, or between those with higher or lower MMSE scores. CONCLUSION: The C-DEMQoL-Proxy is a valid and reliable instrument to assess health-related quality of life in individuals with dementia.
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Demencia , Calidad de Vida , Encuestas y Cuestionarios , Anciano , Anciano de 80 o más Años , Femenino , Hong Kong , Humanos , Masculino , Apoderado , Psicometría , Reproducibilidad de los Resultados , Instituciones Residenciales , TraduccionesRESUMEN
Okur-Chung syndrome is a neurodevelopmental condition attributed to germline CSNK2A1 pathogenic missense variants. We present 8 unreported subjects with the above syndrome, who have recognizable dysmorphism, varying degrees of developmental delay and multisystem involvement. Together with 6 previously reported cases, we present a case series of 7 female and 7 male subjects, highlighting the recognizable facial features of the syndrome (microcephaly, hypertelorism, epicanthic fold, ptosis, arched eyebrows, low set ears, ear fold abnormality, broad nasal bridge and round face) as well as frequently occurring clinical features including neurodevelopmental delay (93%), gastrointestinal (57%), musculoskeletal (57%) and immunological (43%) abnormalities. The variants reported in this study are evolutionary conserved and absent in the normal population. We observed that the CSNK2A1 gene is relatively intolerant to missense genetic changes, and most variants are within the protein kinase domain. All except 1 variant reported in this cohort are spatially located on the binding pocket of the holoenzyme. We further provide key recommendations on the management of Okur-Chung syndrome. To conclude, this is the second case series on Okur-Chung syndrome, and an in-depth review of the phenotypic features and genomic findings of the condition with suggestions on clinical management.
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Discapacidades del Desarrollo/genética , Discapacidad Intelectual/genética , Trastornos del Neurodesarrollo/genética , Adolescente , Quinasa de la Caseína II/química , Quinasa de la Caseína II/genética , Niño , Preescolar , Discapacidades del Desarrollo/fisiopatología , Cara/fisiopatología , Femenino , Genotipo , Humanos , Discapacidad Intelectual/fisiopatología , Masculino , Anomalías Musculoesqueléticas/genética , Anomalías Musculoesqueléticas/fisiopatología , Mutación Missense/genética , Trastornos del Neurodesarrollo/fisiopatología , Fenotipo , Conformación Proteica , Pliegue de Proteína , Secuenciación del Exoma/métodosRESUMEN
We report the use of combined spinal-epidural analgesia during labour in three parturients with moderately severe mitral stenosis. In each case, rapid analgesia was achieved using intrathecal fentanyl 25 micrograms without major haemodynamic changes. Maintenance analgesia was then established gradually using a dilute epidural infusion of bupivacaine 0.1% and fentanyl 0.0002%, with the avoidance of large or rapid boluses of local anaesthetic. Supplementary analgesia in the latter stages of labour was provided using slow epidural boluses of fentanyl, with or without a low concentration of bupivacaine, which was sufficient to allow controlled instrumental deliveries. We conclude that combined spinal-epidural analgesia is a useful technique for providing analgesia and maintaining haemodynamic stability in parturients with mitral stenosis.
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Analgesia Epidural/métodos , Analgesia Obstétrica/métodos , Estenosis de la Válvula Mitral , Complicaciones Cardiovasculares del Embarazo , Adulto , Analgésicos Opioides/administración & dosificación , Anestésicos Locales/administración & dosificación , Bupivacaína/administración & dosificación , Femenino , Fentanilo/administración & dosificación , Humanos , EmbarazoRESUMEN
DMP 811 exhibited high binding affinity for the angiotensin II subtype receptor AT1 in rat adrenal tissues with an IC50 of 6 nM, but not for the subtype receptor AT2. In the isolated rabbit aorta, DMP 811 inhibited the contractile response to angiotensin II selectively and noncompetitively with a KB value of 0.1 nM. In conscious renal hypertensive rats, DMP 811 decreased blood pressure with i.v. and p.o. ED30s of 0.005 and 0.03 mg/kg, respectively (p.o. ED30 for losartan = 0.59 mg/kg). In conscious furosemide-treated dogs, DMP 811 given either at 0.3 or 1 mg/kg p.o. decreased blood pressure. DMP 811 has oral bioavailabilities of 7 and 29% in rats and dogs, respectively, after a solution dose and 8 and 13%, respectively, after a suspension or capsule dosing. Our study indicates that DMP 811 is a selective and insurmountable AT1 receptor antagonist and is a 20-fold more potent orally-active antihypertensive agent than losartan.
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Antagonistas de Receptores de Angiotensina , Imidazoles/farmacocinética , Tetrazoles/farmacocinética , Animales , Bioensayo , Presión Sanguínea/efectos de los fármacos , Perros , Cobayas , Hipertensión Renovascular , Imidazoles/sangre , Imidazoles/farmacología , Masculino , Conejos , Ensayo de Unión Radioligante , Ratas , Ratas Sprague-Dawley , Tetrazoles/sangre , Tetrazoles/farmacologíaRESUMEN
The 'discovery' of losartan represents three separate discoveries: (1) losartan as the unique biphenyltetrazole molecule and the first of a new chemical class; (2) losartan as a tool to identify AT1-subtype receptors; and (3) losartan as a specific probe for exploring the multiple roles of angiotensin II (Ang II) in normal physiology and pathologic states. Losartan is the first nonpeptide orally active Ang II receptor antagonist to reach clinical trials. Losartan was selected for its affinity for Ang II receptors, functional antagonism of Ang II, lack of agonist properties, and oral anti-hypertensive effects. Losartan has been widely used to define the distribution and function of AT receptor subtypes. Although possible roles of the AT2 subtype have been reported, virtually all of the known effects of Ang II are blocked by losartan. Specific AT1 receptor blockade has been broadly compared with ACE inhibition. Possible differences on the basis of AT1 selectivity, bradykinin potentiating effects and Ang II formed by non-ACE pathways are discussed. Losartan blocks the vascular constrictor effect of Ang II, the Ang II-induced aldosterone synthesis and/or release, and the Ang II-induced cardiovascular 'growth' in vitro and in vivo. In various models of experimental hypertension, losartan prevents or reverses the elevated blood pressure and the associated cardiovascular hypertrophy similar to ACE inhibitors. Likewise, in models of renal failure (for example reduced renal mass, puromycin, ochratoxin), losartan, like ACE inhibition, markedly reduced the elevation in blood pressure, proteinuria or sclerosis. In aortocaval shunt, coronary ligation and ventricular pacing models of heart failure, losartan demonstrated a pathological role for Ang II by reversing the associated haemodynamic findings. In SHR-stroke prone, losartan dramatically increased survival while having a limited effect on blood pressure, suggesting a non-pressure dependent effect of Ang II. These collective data show that Ang II exerts complex pathological effects in experimental models of vascular, cardiac, renal and cerebral disease. The effectiveness of losartan in experimental models of heart failure supports its evaluation in clinical trials with patients with heart failure.
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Angiotensina II/antagonistas & inhibidores , Antagonistas de Receptores de Angiotensina , Antihipertensivos , Compuestos de Bifenilo , Hipertensión/tratamiento farmacológico , Imidazoles , Tetrazoles , Antihipertensivos/química , Antihipertensivos/farmacología , Antihipertensivos/uso terapéutico , Compuestos de Bifenilo/química , Compuestos de Bifenilo/farmacología , Compuestos de Bifenilo/uso terapéutico , Ensayos Clínicos como Asunto , Humanos , Imidazoles/química , Imidazoles/farmacología , Imidazoles/uso terapéutico , Losartán , Relación Estructura-Actividad , Tetrazoles/química , Tetrazoles/farmacología , Tetrazoles/uso terapéuticoRESUMEN
The identification of the AT1 and AT2 receptor subtypes has stimulated interest in developing balanced angiotensin II receptor antagonists. A series of 5-(3-amidopropanoyl)imidazoles has been prepared which possess balanced affinity for the AT1 and AT2 receptors. XR510 (1), 1-[[2'-[[(isopentoxycarbonyl)amino]sulfonyl]-3- fluoro(1,1'-biphenyl)-4-yl]methyl]-5-[3-(N-pyridin-3- ylbutanamido)propanoyl]-4-ethyl-2-propyl-1H-imidazole, potassium salt, exhibits subnanomolar affinity for both receptor sites. XR510 is very active in lowering blood pressure in renal hypertensive rats and furosemide-treated dogs following oral administration.
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Angiotensina I/metabolismo , Antagonistas de Receptores de Angiotensina , Compuestos de Bifenilo/metabolismo , Compuestos de Bifenilo/farmacología , Imidazoles/síntesis química , Imidazoles/metabolismo , Imidazoles/farmacología , Receptores de Angiotensina/metabolismo , Administración Oral , Animales , Ensayo de Unión Radioligante , Ratas , Relación Estructura-ActividadRESUMEN
ANGIOTENSIN II RECEPTOR ANTAGONISTS: Losartan (DuP 753, MK-954) is the prototype of a new class of orally active, non-peptide angiotensin II receptor antagonists able to inhibit the renin-angiotensin system specifically and selectively without the agonistic effects of the peptide receptor antagonists, e.g. saralasin, or the bradykinin-potentiating effects of the angiotensin converting enzyme (ACE) inhibitors. PRECLINICAL PHARMACOLOGY: The preclinical pharmacology of angiotensin II receptor blockade is exemplified by the experience with losartan. Over 1200 abstracts and papers have been published from studies in which losartan has been used to explore the role of angiotensin II in a wide range of normal and pathological states. Losartan has also proved useful in further defining the heterogeneity of angiotensin II receptors. According to current nomenclature, losartan represents the prototype antagonist of the angiotensin II type 1 (AT1) receptor family (AT1a and AT1b) and does not possess significant affinity for the so-called AT2 receptor. Virtually all of the known actions of angiotensin II, e.g. those defined by angiotensin II itself, saralasin, ACE inhibitors or renin inhibitors, are blocked by losartan, emphasizing the major role of AT1 receptors in mediating the responses of angiotensin II. Although the AT2 receptor has now been cloned, the function of this receptor remains poorly understood. PRECLINICAL STUDIES WITH LOSARTAN: Preclinical studies with losartan have suggested that this agent produces inhibition of the renin-angiotensin system comparable to that of ACE (and renin) inhibitors, without the bradykinin-potentiating effects. In several models of experimental and genetic hypertension losartan has proved to be an orally effective antihypertensive agent with a long duration of action and similar efficacy to that of ACE and renin inhibitors. In animal models of renal disease losartan significantly decreases proteinuria, provides protection against diabetic glomerulopathy and increases survival in stroke-prone spontaneously hypertensive rats. A growing number of experimental studies have also shown that losartan inhibits neointimal proliferation and markedly reduces or prevents cardiovascular hypertrophy/remodeling and cardiac failure mediated by activation of the renin-angiotensin system. Non-peptide AT1 receptor antagonists have added another dimension to the arsenal of drugs manipulating the renin-angiotensin system. These agents do not have the experimental limitations of the peptide antagonists and ACE inhibitors. CONCLUSIONS: Losartan, the first potent and specific AT1 receptor antagonist, is orally active with a long duration of action and therefore has potential for treatment of chronic diseases, such as hypertension and heart failure.
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Antihipertensivos/uso terapéutico , Hipertensión/tratamiento farmacológico , Losartán/uso terapéutico , Angiotensina II/fisiología , Bloqueadores del Receptor Tipo 1 de Angiotensina II/uso terapéutico , Animales , Modelos Animales de Enfermedad , Humanos , Hipertensión/fisiopatología , Ratas , Ratas Endogámicas SHR , Insuficiencia Renal/fisiopatología , Sistema Renina-Angiotensina/efectos de los fármacosRESUMEN
We reported previously that blood vessels of domestic fowl contain angiotensin (ANG) receptors on 1) endothelium, mediating vasorelaxation via endothelium-derived relaxing factor and guanosine 3',5'-cyclic monophosphate; 2) vascular smooth muscles, mediating neither relaxation nor contraction; and 3) presumably adrenergic nerve endings, transmitting vasopressor action via a release of norepinephrine. We aimed in the present study to determine fowl vascular ANG receptor subtypes and relate them to function. [Val5]ANG II (native fowl ANG II) increased mean arterial pressure of anesthetized, ganglion-blocker-treated fowl. The dose-pressor response curve for fowl ANG II was not altered by pretreatment (i.v.) with the ANG receptor subtype 1 (AT1) antagonist Dup-753 (losartan, 10 mg/kg) or the subtype 2 (AT2) antagonist PD-123319 (10 mg/kg). Furthermore, cumulative doses (1-20 mg/kg) of losartan or PD-123319 did not selectively inhibit ANG II-induced pressor responses. In reserpine- and prazosin-treated anesthetized fowl, [Val5]ANG II caused dose-dependent vasodepressor actions inhibited by neither losartan (10 mg/kg) nor PD-123319 (10 mg/kg). Likewise, [Val5]ANG II-induced vasorelaxation of fowl aortic rings in vitro was not inhibitable by PD-123319 or losartan (10(-5) M). Specific binding of 125I-labeled ANG II to the aortic endothelium was markedly displaced by ANG II, but not selectively by PD-123319 or losartan. Specific binding of 125I-ANG II ligand to the membrane fraction of aortic smooth muscles was displaced (50% inhibitory concentration) by [Val5]ANG II (3.3 x 10(-8) M) and slightly by PD-123319 (3.7 x 10(-5) M), but not by losartan or EXP-3174, an active metabolite of losartan.(ABSTRACT TRUNCATED AT 250 WORDS)
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Angiotensina II/farmacología , Aorta Abdominal/fisiología , Presión Sanguínea/efectos de los fármacos , Pollos/fisiología , Endotelio Vascular/metabolismo , Receptores de Angiotensina/fisiología , Acetilcolina/farmacología , Angiotensina II/análogos & derivados , Angiotensina II/metabolismo , Antagonistas de Receptores de Angiotensina , Animales , Aorta Abdominal/efectos de los fármacos , Compuestos de Bifenilo/farmacología , Membrana Celular/metabolismo , Relación Dosis-Respuesta a Droga , Femenino , Imidazoles/farmacología , Técnicas In Vitro , Cinética , Losartán , Modelos Cardiovasculares , Contracción Muscular/efectos de los fármacos , Músculo Liso Vascular/efectos de los fármacos , Músculo Liso Vascular/fisiología , Piridinas/farmacología , Receptores de Angiotensina/clasificación , Reserpina/farmacología , Tetrazoles/farmacologíaRESUMEN
In the present study, the properties of angiotensin II (AII) receptors of intact domestic turkey adrenal steroidogenic cells were characterized. AII (but not ACTH) induced an immediate and sustained increase in intracellular Ca2+. In addition, dithiothreitol inhibition of maximal AII-induced aldosterone production was closely correlated with its inhibition of binding suggesting that these receptors are type 1-like and operate through a non-"spare" receptor mode. Equilibrium-binding analysis revealed a single class of binding sites at a concentration of 63,500 sites/cell and having an apparent dissociation constant (Kd) of 1.21 nM. However, the Kd derived from kinetic analyses, 0.27 nM, was lower. Both empirically determined and model-based calculated distributions of bound hormone indicated that at equilibrium, about 30% of hormone-receptor complexes were internalized whereas 70% remained on the surface. This distribution contrasts sharply with that reported for mammalian (rat) adrenocortical cells. In keeping with recent cloning studies, these avian AII receptors of intact adrenal steroidogenic cells discriminated angiotensins and mammalian peptidic and nonpeptidic antagonists differently from mammalian adrenocortical and duck adrenal receptor preparations. Importantly, turkey adrenal steroidogenic cell AII receptors poorly discriminated the nonpeptide antagonists, losartan (DuP 753) (type-1 specific) and PD123177 (type-2 specific). Thus, AII receptors of freshly isolated, intact turkey adrenal steroidogenic cells are pharmacologically distinct from mammalian adrenocortical type-1 receptors.
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Glándulas Suprarrenales/metabolismo , Receptores de Angiotensina/metabolismo , Pavos , Glándulas Suprarrenales/efectos de los fármacos , Hormona Adrenocorticotrópica/farmacología , Aldosterona/biosíntesis , Angiotensina II/análogos & derivados , Angiotensina II/metabolismo , Angiotensina II/farmacología , Animales , Calcio/metabolismo , Ditiotreitol/farmacología , Radioisótopos de Yodo , Cinética , MasculinoRESUMEN
AT1 and AT2 are the two major receptor subtypes for angiotensin II that have been pharmacologically defined by using the selective ligands losartan and PD123177, respectively. EXP597 (4-[(5-(2-benzoyl)benzyloxycarbonyl-4-ethyl-2-n-propylimidazole-1- yl)methyl]-3-fluoro-2'-isoamyloxycarbonylaminosulfonyl-[1,1']-biph enyl, potassium salt) is a nonpeptide angiotensin II receptor ligand which in the rat adrenal exhibits binding affinities (IC50) of 0.5 and 0.7 nM for angiotensin AT1 and AT2 receptor subtypes, respectively. Further, EXP597 is an insurmountable angiotensin II receptor antagonist in the isolated rabbit aorta and lowers blood pressure in renal hypertensive rats with i.v. and p.o. ED30 values of 0.05 and 0.9 mg/kg, respectively.
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Corteza Suprarrenal/metabolismo , Médula Suprarrenal/metabolismo , Antagonistas de Receptores de Angiotensina , Aorta/metabolismo , Imidazoles/metabolismo , Sistema Renina-Angiotensina/efectos de los fármacos , Sulfonamidas/metabolismo , Administración Oral , Corteza Suprarrenal/efectos de los fármacos , Médula Suprarrenal/efectos de los fármacos , Animales , Aorta/efectos de los fármacos , Unión Competitiva , Compuestos de Bifenilo/metabolismo , Compuestos de Bifenilo/farmacología , Compuestos de Bifenilo/uso terapéutico , Modelos Animales de Enfermedad , Relación Dosis-Respuesta a Droga , Hipertensión Renal/tratamiento farmacológico , Imidazoles/administración & dosificación , Imidazoles/farmacología , Imidazoles/uso terapéutico , Técnicas In Vitro , Inyecciones Intravenosas , Losartán , Masculino , Piridinas/metabolismo , Piridinas/farmacología , Piridinas/uso terapéutico , Conejos , Ensayo de Unión Radioligante , Ratas , Ratas Endogámicas SHR , Ratas Sprague-Dawley , Receptores de Angiotensina/metabolismo , Sulfonamidas/administración & dosificación , Sulfonamidas/farmacología , Sulfonamidas/uso terapéutico , Tetrazoles/metabolismo , Tetrazoles/farmacología , Tetrazoles/uso terapéuticoRESUMEN
The objective of this study was to determine whether the three isoforms of recombinant Ang II receptors (rAT1A, rAT1B and hAT1), stably and individually expressed in CHO cells, could be pharmacologically distinguished by their ligand binding signatures. Competition studies were performed to characterize the inhibition of [125I]Ang II binding to each of the cell membrane preparations by an extensive series of peptide and nonpeptide Ang II analogs. Scatchard plot analyses revealed the following binding characteristics:rAT1A-Kd = 1.27 +/- 0.14 nM; rAT1B- Site 1:Kd = 0.56 +/- 0.11 nM, Site 2: Kd = 126 +/- 23 nM; and hAT1-Site 1:Kd = 1.06 +/- 0.16 nM, Site 2: Kd = 257 +/- 55 nM. The binding of [125I]Ang II in the three preparations was similarly sensitive to inhibition by GTP gamma S. The ligand binding signatures of the three receptor isoforms are essentially the same and are illustrated by the affinity and order of potency of the following ligands: L-158,809 > or = Sar1, Ile8Ang II > saralasin Ang II > or = Ang III > EXP581 > EXP3174 > losartan > or = EXP811 > GR117,289c > EXP6803 > DuP 532 > Ang I >> PD123177. In conclusion, the two rat AT1 receptor isoforms are pharmacologically indistinguishable from each other and from that of the human.
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Angiotensina II/metabolismo , Hígado/metabolismo , Receptores de Angiotensina/metabolismo , Animales , Secuencia de Bases , Sitios de Unión , Unión Competitiva , Células CHO , Clonación Molecular , Cricetinae , Cartilla de ADN , Humanos , Cinética , Ligandos , Datos de Secuencia Molecular , Reacción en Cadena de la Polimerasa , ARN Mensajero/biosíntesis , ARN Mensajero/metabolismo , Ratas , Ratas Sprague-Dawley , Receptores de Angiotensina/genética , Homología de Secuencia de AminoácidoRESUMEN
The availability of peptide and non-peptide Ang II receptor antagonists has permitted the study of Ang II receptor heterogeneity. It is now widely recognized that there are at least two distinct Ang II receptor subtypes. AT1 receptors are selective in their recognition of agents such as losartan, DuP 532, L-158,809, SK&F108566, and similar non-peptides. To date, all of the well-known actions of Ang II in mammals are blocked by the AT1 selective antagonists such as losartan and are thus designated as being mediated by the AT1 receptor. Although there have been reports of functional activity mediated through AT2 sites, the pharmacological role for the AT2 receptor has not yet been elucidated. Herein, we report the chemistry and SAR on a novel series of 1,2,3,4-tetrahydrosioquinoline-3-carboxylic acids which have selective affinity for AT2 receptors. The most potent of which (19) has an IC50 of 30 nM for the AT2 receptor in the rat adrenal radioligand binding assay.
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Angiotensina II/metabolismo , Antagonistas de Receptores de Angiotensina , Ácidos Carboxílicos/síntesis química , Ácidos Carboxílicos/farmacología , Isoquinolinas/síntesis química , Isoquinolinas/farmacología , Animales , Sitios de Unión , Ácidos Carboxílicos/química , Isoquinolinas/química , Ratas , Receptores de Angiotensina/metabolismo , Relación Estructura-ActividadRESUMEN
EXP063 (4-[[4-[[3-(N-isopropylamino)-2-hydroxypropyl]oxy]- indole-2-carboxamido]methyl]-2-propyl-1-[(2'-(1H-tetrazol-5-yl)bip henyl-4 - yl)methyl]imidazole-5-carboxylic acid) was designed to possess both the angiotensin II (Ang II) and beta adrenergic receptor antagonistic properties. EXP063 inhibited the specific binding of [125I]Sar1,lle8-Ang II in rat adrenal membranes with Ki values of 3.9 +/- 0.6 nM for the Ang II type 1 and > 1 microM for the Ang II type 2 receptor binding sites. It displaced [3H]dihydroalprenolol in the rat cerebral frontal cortex with a Ki of 80 +/- 13 nM. EXP063 antagonized the contractile effect of Ang II competitively (pA2 = 8.9 +/- 0.1) and selectively in rabbit aorta and guinea pig ileum. EXP063 appears to be a partial beta adrenoceptor agonist as it increased heart rate in vitro and in vivo. At 1 and 10 microM, it inhibited the positive inotropic effect of isoproterenol in guinea pig atria. In pithed rats, EXP063 was more potent in blocking the pressor effect of Ang II than the positive chronotropic effect of isoproterenol. In renal hypertensive rats, EXP063 given i.v. produced a long-lasting decrease in blood pressure for at least 6 hr with an ED30 of 0.53 mg/kg. In summary, this study demonstrates that EXP063 is a novel chemical entity possessing both the Ang II and beta adrenergic receptor blocking properties and, thus, represents a promising agent for the treatment of hypertension and congestive heart failure.
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Antagonistas Adrenérgicos beta/farmacología , Antagonistas de Receptores de Angiotensina , Imidazoles/farmacología , Tetrazoles/farmacología , Animales , Aorta Torácica/efectos de los fármacos , Presión Sanguínea/efectos de los fármacos , Estudios de Factibilidad , Cobayas , Atrios Cardíacos/efectos de los fármacos , Hipertensión Renal/tratamiento farmacológico , Hipertensión Renal/fisiopatología , Íleon/efectos de los fármacos , Técnicas In Vitro , Masculino , Músculo Liso/efectos de los fármacos , Conejos , Ensayo de Unión Radioligante , Ratas , Ratas Sprague-DawleyRESUMEN
The 'angiotensin system' is expressed at the whole body, organ/tissue and cellular levels through the action of angiotensin II at specific receptors. An appreciation of the full scope of the actions of angiotensin II (endocrine, paracrine and autocrine) has been made possible by the discovery of the non-peptide angiotensin II receptor antagonists, losartan (DuP 753/MK954)(AT1-selective) and PD123177 (AT2-selective). Virtually all of the known effects of angiotensin II are blocked by losartan and designated AT1. Selective AT1 receptor blockade with losartan lowers BP in angiotensin II-dependent models of hypertension, reduces cardiac hypertrophy, improves haemodynamics in models of cardiac failure and reduces the intimal response to vascular injury. AT2 sites have been localised in distinct parts of the brain and in foetal tissue. The functional role of the AT2 sites remains controversial, but possible roles in neuronal ion channel function and collagen metabolism in fibroblasts have been reported. AT1 (losartan-sensitive) receptor subtypes have now been cloned from several rat tissues, suggesting that selective agents of the future may be even more specifically targeted. New perspectives in the control of the angiotensin system continue to evolve rapidly as the new receptor antagonists and molecular biology techniques expand our understanding of angiotensin II.
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Sistema Renina-Angiotensina/efectos de los fármacos , Secuencia de Aminoácidos , Angiotensina II/antagonistas & inhibidores , Antagonistas de Receptores de Angiotensina , Animales , Compuestos de Bifenilo/farmacología , Presión Sanguínea/efectos de los fármacos , Cardiomegalia/prevención & control , Hemodinámica/efectos de los fármacos , Humanos , Imidazoles/farmacología , Losartán , Datos de Secuencia Molecular , Piridinas/farmacología , Sistema Renina-Angiotensina/fisiología , Tetrazoles/farmacologíaAsunto(s)
Angiotensina II/antagonistas & inhibidores , Antagonistas de Receptores de Angiotensina , Antihipertensivos/farmacología , Compuestos de Bifenilo/farmacología , Imidazoles/farmacología , Receptores de Angiotensina/fisiología , Tetrazoles/farmacología , Secuencia de Aminoácidos , Angiotensina II/metabolismo , Angiotensina II/farmacología , Animales , Antihipertensivos/farmacocinética , Antihipertensivos/uso terapéutico , Compuestos de Bifenilo/farmacocinética , Compuestos de Bifenilo/uso terapéutico , Presión Sanguínea/efectos de los fármacos , Clonación Molecular , Hemodinámica/efectos de los fármacos , Humanos , Hipertensión/tratamiento farmacológico , Imidazoles/farmacocinética , Imidazoles/uso terapéutico , Riñón/efectos de los fármacos , Losartán , Datos de Secuencia Molecular , Piridinas/farmacocinética , Piridinas/farmacología , Piridinas/uso terapéutico , Receptores de Angiotensina/química , Tetrazoles/farmacocinética , Tetrazoles/uso terapéuticoRESUMEN
2-Amino-1,4-dihydro-4-(2-[-4[4-(2-methoxyphenyl)-1-piperazinyl]- butylsulfinyl]phenyl)-6-methyl-5-nitro-3-pyridine carboxylic acid methyl ester (XB513) was designed to combine the calcium agonistic and alpha-1 adrenergic receptor antagonistic properties in the same molecule. It inhibited the specific binding of [3H] nitrendipine in rat cardiac ventricular membranes with an IC50 of 1.2 microM, which is 20-fold greater than the standard calcium agonist Bay K 8644. It displaced [3H]prazosin in rat brain membranes with an IC50 of 29 nM. XB513 caused concentration-dependent positive inotropic responses in isolated electrically paced guinea pig left atria with an EC50 of 1.2 microM and was 10 times less potent than Bay K 8644. In rabbit aorta, XB513 inhibited the contractile effect of 16 nM norepinephrine with an IC50 of 89 nM. In an acute heart failure dog model produced by an overdose of propranolol, XB513 at 0.3 to 3 mg/kg i.v. dose-dependently reversed the decreased mean arterial pressure, cardiac output and dP/dt as well as the increased left ventricular end diastolic pressure induced by propranolol. In conscious instrumented dogs, XB513 at 0.1 and 0.3 mg/kg i.v. increased dP/dt and heart rate significantly, with a minor effect on mean arterial pressure. In summary, this study demonstrates that XB513 is a novel chemical entity possessing both calcium agonistic and alpha-1 adrenergic receptor blocking properties and thus may represent a new class of agents for the treatment of congestive heart failure.
Asunto(s)
Antagonistas Adrenérgicos alfa/farmacología , Agonistas de los Canales de Calcio/farmacología , Dihidropiridinas/farmacología , Piperazinas/farmacología , Antagonistas Adrenérgicos alfa/química , Animales , Agonistas de los Canales de Calcio/química , Dihidropiridinas/química , Perros , Femenino , Cobayas , Corazón/efectos de los fármacos , Corazón/fisiología , Íleon/efectos de los fármacos , Íleon/fisiología , Técnicas In Vitro , Masculino , Contracción Muscular/efectos de los fármacos , Contracción Miocárdica/efectos de los fármacos , Piperazinas/química , Conejos , Ensayo de Unión Radioligante , Ratas , Ratas Sprague-Dawley , Relación Estructura-ActividadRESUMEN
The objective of this study was to determine whether the binding signature of the cloned rat AT1A receptor transfected into Chinese hamster ovary cells could be distinguished from that of the endogenous AT1B receptor expressed in rat adrenal cortex. An extensive series of peptide and nonpeptide Ang II analogs was used for the characterization. The binding of [125I]Ang II to the recombinant AT1A receptors was quite sensitive to inhibition by GTP gamma S. Scatchard analysis of the competition of Ang II revealed two populations of binding sites (site 1: KD = 3.05 +/- 0.27 nM and a maximum binding (Bmax) of 134 +/- 26 fmol/mg protein; site 2: KD = 253 +/- 77 nM and Bmax = 1.05 +/- 0.19 pmol/mg protein). The ligand binding signature of the AT1A receptor is defined by the affinity (Ki = nM) and order of potency of the following ligands: saralasin (2.07) > Ang II (3.35) > losartan (14) > Ang III (20) > GR 117289C (28) > EXP6803 (160) > Ang I (281) > PD123177 (> 10,000). This binding signature of the cloned AT1A receptors appears to be similar to that displayed by rat adrenal cortical cells where AT1B is predominantly expressed. These findings suggest that AT1A and AT1B receptors may not be easily distinguishable by the currently available ligand agonists or antagonists. Consequently, AT1A or AT1B may be considered as isoforms rather than subtypes of the AT1 receptors.
Asunto(s)
Músculo Liso Vascular/metabolismo , Receptores de Angiotensina/metabolismo , Corteza Suprarrenal/metabolismo , Angiotensina I/metabolismo , Angiotensina III/metabolismo , Animales , Secuencia de Bases , Unión Competitiva , Compuestos de Bifenilo/metabolismo , Células CHO , Cricetinae , Guanosina 5'-O-(3-Tiotrifosfato)/farmacología , Imidazoles/metabolismo , Losartán , Datos de Secuencia Molecular , Ácidos Nicotínicos/metabolismo , Piridinas/metabolismo , Ratas , Receptores de Angiotensina/química , Proteínas Recombinantes/metabolismo , Saralasina/metabolismo , Tetrazoles/metabolismo , TransfecciónRESUMEN
The renin-angiotensin system (RAS) has been demonstrated to be a key element in blood pressure regulation and fluid volume homeostasis. Since angiotensin II (AII) is the effector molecule of the RAS, the most direct approach to block this system is to antagonize AII at the level of its receptor. Therefore, at Du Pont Merck the working hypothesis has been that the identification of metabolically stable and orally effective AII-receptor antagonists would constitute a new and superior class of agents useful in treating hypertension and congestive heart failure. Our program began with a detailed pharmacologic evaluation of some simple N-benzylimidazoles, originally described by Takeda Chemical Industries in Osaka, Japan. They were found to be a series of weak but selective AII-receptor antagonists with a competitive mode of action. We embarked on a program aimed to design and synthesize more potent and orally effective nonpeptide antagonists, while attempting to preserve their selective affinity for the AII receptor. The first major breakthrough in our efforts to increase the potency of these compounds came with the development of a series of N-benzylimidazole phthalamic acid derivatives. Although effective at lowering blood pressure when administered intravenously, the phthalamic acids were devoid of oral activity. The first orally active AII antagonists came with the discovery of the biphenyl carboxylic acids. Although these compounds are absorbed after oral dosing, their bioavailability was less than desired. In the hope of improving the oral absorption of these biphenyls, we investigated a variety of acidic groups as bioisosteric replacements for the carboxylic acid. The key to the discovery of nonpeptide AII-receptor antagonists with improved oral activity and duration of action resulted from replacing the carboxylic acid group with the isosteric but more lipophilic tetrazole ring. Hence, our efforts culminated in the discovery of losartan (2-n-butyl-4-chloro-5-hydroxymethyl-1-[(2'-(1H-tetrazol-5-yl) biphenyl-4-yl)methyl]imidazole, potassium salt), a highly potent angiotensin type 1 (AT1) selective receptor antagonist with a long duration of action. Losartan is currently undergoing clinical investigation for the treatment of hypertension. The history, including the rationale for the design of the compounds, and ensuing structure-activity relationships of losartan and related analogs will be described. Many of the newer compounds exceed the potency of losartan, and the best compounds in the series rival the affinity of the endogenous ligand, AII, for its receptor.(ABSTRACT TRUNCATED AT 400 WORDS)