RESUMEN
INTRODUCTION: Pain management following major intracranial surgery is often limited by a presumed lack of need and a concern that opioids will adversely affect postoperative outcome and interfere with the neurologic examination. Nevertheless, evidence in adults is accumulating that these patients suffer moderate to severe pain, and this pain is often under-treated. The purpose of this prospective, clinical observational cohort study was to assess the incidence of pain, prescribed analgesics, methods of analgesic delivery, and patient/parent satisfaction in pediatric patients undergoing cranial surgery at three major university children's hospitals. METHODS: After obtaining IRB and parental consent (and when applicable, patient assent), children who underwent cranial surgery for cancer, epilepsy, vascular malformations, and craniofacial reconstruction were studied. Neither intraoperative anesthetic management nor postoperative pain management was standardized, but were based on institutional routine. Patients were evaluated daily by a study investigator and by chart review for pain scores using age appropriate, validated tools (FLACC, Faces Pain Scale-Revised, Wong-Baker Faces Scale or Self-Report on a 0-10 scale), for patient/parent satisfaction using a subset of the NRC Picker satisfaction tool and in adolescents a modified QoR-40, and for the frequency, mode of administration, and type of analgesic provided. Finally, the incidence of opioid-induced side effects, specifically nausea, vomiting, pruritus, altered level of consciousness, and need for emergency diagnostic radiologic studies for altered neurologic examination were recorded. Data are provided as mean ± SD. RESULTS: Two hundred children (98:102 M:F), averaging 7.8 ± 5.8 years old (range 2 months-18.5 years) and 32.2 ± 23.0 kg (range 4.5-111.6 kg) undergoing craniectomy (51), craniotomy (96), and craniofacial reconstruction (53) were studied. Despite considerable variation in mode and route of analgesic administration, there were no differences in average pain score, length of hospital stay, or parental satisfaction with care. Interestingly, opioid-induced side effects were not related to total daily opioid consumption, site of surgery, or method of opioid delivery. The most common side effect was vomiting. No patient developed respiratory depression or altered mental status secondary to analgesic therapy. Regardless of age or procedure, once eating, most patients were treated with oral oxycodone and/or acetaminophen. CONCLUSIONS: Despite considerable variation in modality and route of analgesic administration, there were no differences in average pain score, length of stay, or parental satisfaction with care. Pain scores were low, side effects were minimal, and parental satisfaction was high, providing equipoise for future blinded prospective randomized trials in this patient population.
Asunto(s)
Analgésicos/uso terapéutico , Craneotomía , Manejo del Dolor/métodos , Dolor Postoperatorio/tratamiento farmacológico , Adolescente , Analgésicos/administración & dosificación , Analgésicos/efectos adversos , Niño , Preescolar , Estudios de Cohortes , Vías de Administración de Medicamentos , Femenino , Hospitales Pediátricos/estadística & datos numéricos , Hospitales de Enseñanza/estadística & datos numéricos , Humanos , Lactante , Tiempo de Internación/estadística & datos numéricos , Masculino , Dimensión del Dolor/métodos , Satisfacción del Paciente/estadística & datos numéricos , Estudios Prospectivos , Vómitos/inducido químicamenteRESUMEN
Optimization of the cellular and pharmacological activity of a novel series of PI3 kinase inhibitors targeting multiple isoforms is described.
Asunto(s)
Benzoxazinas/síntesis química , Benzoxazinas/farmacología , Inhibidores de las Quinasa Fosfoinosítidos-3 , Pirazoles/síntesis química , Pirazoles/farmacología , Administración Oral , Animales , Benzoxazinas/química , Técnicas Químicas Combinatorias , Concentración 50 Inhibidora , Isoenzimas/antagonistas & inhibidores , Masculino , Estructura Molecular , Pirazoles/química , Ratas , Ratas Wistar , Relación Estructura-ActividadRESUMEN
Following the identification of a potent IRAK inhibitor through routine project cross screening, a novel class of IRAK-4 inhibitor was established. The SAR of imidazo[1,2-a]pyridino-pyridines and benzimidazolo-pyridines was explored.
Asunto(s)
Quinasas Asociadas a Receptores de Interleucina-1/antagonistas & inhibidores , Inhibidores de Proteínas Quinasas/farmacología , Piridinas/farmacología , Evaluación Preclínica de Medicamentos , Estructura Molecular , Inhibidores de Proteínas Quinasas/síntesis química , Inhibidores de Proteínas Quinasas/química , Piridinas/síntesis química , Piridinas/química , Estereoisomerismo , Relación Estructura-ActividadRESUMEN
A potent IRAK-4 inhibitor was identified through routine project cross screening. The binding mode was inferred using a combination of in silico docking into an IRAK-4 homology model, surrogate crystal structure analysis and chemical analogue SAR.
Asunto(s)
Diseño de Fármacos , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/farmacología , Imidazoles/síntesis química , Imidazoles/farmacología , Quinasas Asociadas a Receptores de Interleucina-1/antagonistas & inhibidores , Modelos Moleculares , Piridinas/síntesis química , Piridinas/farmacología , Sitios de Unión , Cristalografía por Rayos X , Inhibidores Enzimáticos/química , Imidazoles/química , Conformación Molecular , Estructura Molecular , Piridinas/química , Relación Estructura-ActividadRESUMEN
The synthesis and profile of a series of amides are described. Some of these compounds were potent IRAK-4 inhibitors and two examples were evaluated in vivo.
Asunto(s)
Amidas/síntesis química , Amidas/farmacología , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/farmacología , Quinasas Asociadas a Receptores de Interleucina-1/antagonistas & inhibidores , Modelos Biológicos , Piridinas/síntesis química , Piridinas/farmacología , Bibliotecas de Moléculas Pequeñas/síntesis química , Bibliotecas de Moléculas Pequeñas/farmacología , Amidas/química , Diseño de Fármacos , Inhibidores Enzimáticos/química , Humanos , Estructura Molecular , Piridinas/química , Bibliotecas de Moléculas Pequeñas/química , Relación Estructura-ActividadRESUMEN
The SAR and pharmacokinetic profiles of a series of multi-isoform PI3K inhibitors based on a 3,4-dihydro-2H-benzo[1,4]oxazine scaffold are disclosed.
Asunto(s)
Benzoxazinas/química , Química Farmacéutica/métodos , Oxazinas/síntesis química , Oxazinas/farmacología , Fosfatidilinositol 3-Quinasas/metabolismo , Área Bajo la Curva , Benzoxazinas/farmacología , Cristalografía por Rayos X/métodos , Diseño de Fármacos , Humanos , Inflamación , Concentración 50 Inhibidora , Modelos Químicos , Estructura Molecular , Isoformas de Proteínas , Relación Estructura-ActividadRESUMEN
Since peripheral vascular disease (PVD) is the forerunner of coronary heart disease (CHD), it is vital to detect PVD at an early stage. In the past, the non-invasive ankle arm index (AAI) has been successfully used to predict the susceptibility of PVD/CHD. However, different authors have used different permutations (i.e. highest, average and lowest) of ankle (ASBP) and arm (HSBP) systolic blood pressures to calculate AAI. This study aims to investigate the validity and applicability of different permutations of AAI formulae to predict sub-clinical PVD/CHD in young individuals. The study also investigated whether the use of AAI post-moderate exercise would enhance the predictability of PVD or CHD at an early stage. Individuals from different ethnic background within the UK took part in this study. Following 5min moderate cycle exercise using 50% of heart reserve, the AAI was significantly reduced (P<0.05). It was found that not all the permutations of AAI were acceptable and some over/under estimated AAI compared to currently accepted methodologies. According to the statistical analysis (ANOVA and 95% limits of agreement) calculation of AAI using values of (1) highest ASBP divided by highest HSBP, (2) highest ASBP divided by average HSBP, (3) average ASBP divided by highest HSBP and (4) lowest ASBP divided by average HSBP were within acceptable agreement with the standard method of calculating AAI. Inclusion of these permutations together with the standard method, would give a better predictions of PVD/CHD at an early age.
RESUMEN
This study investigates the contractile response to 5 hydroxytryptamine (5HT) of chorionic artery and vein segments from normotensive (NT) and pre-eclamptic (PE) placentae. It also looked at the effectiveness of ketanserin (KET), a 5HT(2A) receptor antagonist, in reducing 5HT-mediated vasoconstriction. 5HT induced vasoconstriction in all of the vessels was studied. Compared to NT vessels, Emax (%KCl) was significantly reduced in PE arteries (p<0.05) and veins (p<0.0005). The mean Emax for NT arteries was 104.1 (±10.71) whilst PE arteries showed a mean Emax of 57.02 (±12.13). KET produced a statistically significant reduction of Emax in both vessels in NT and the arteries in PE. However the antagonistic effect of KET was not pronounced in PE veins. The EC50 values for NT and PE arteries and veins did not change significantly. There were no noticeable changes in the expression profiles of 5HT(2A) receptor mRNA and protein expressions. The data from this study suggest that in PE, the vascular reactivity of chorionic vessels to 5HT is reduced and it was not due to the altered expression of 5HT(2A) receptors.
Asunto(s)
Corion/irrigación sanguínea , Placenta/irrigación sanguínea , Circulación Placentaria , Preeclampsia/fisiopatología , Receptor de Serotonina 5-HT2A/metabolismo , Serotonina/metabolismo , Vasoconstricción , Adolescente , Adulto , Arterias/efectos de los fármacos , Arterias/metabolismo , Arterias/fisiopatología , Corion/efectos de los fármacos , Corion/metabolismo , Femenino , Regulación de la Expresión Génica , Humanos , Técnicas In Vitro , Ketanserina/farmacología , Placenta/efectos de los fármacos , Placenta/metabolismo , Circulación Placentaria/efectos de los fármacos , Preeclampsia/metabolismo , Embarazo , Tercer Trimestre del Embarazo , ARN Mensajero/metabolismo , Receptor de Serotonina 5-HT2A/química , Receptor de Serotonina 5-HT2A/genética , Antagonistas del Receptor de Serotonina 5-HT2/farmacología , Vasoconstricción/efectos de los fármacos , Venas/efectos de los fármacos , Venas/metabolismo , Venas/fisiopatología , Adulto JovenRESUMEN
The study of non-oxazole containing indole fragments as inhibitors of inosine monophosphate dehydrogenase (IMPDH) is described. The synthesis and in vitro inhibitory values for IMPDH II are discussed.
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Inhibidores Enzimáticos/farmacología , IMP Deshidrogenasa/antagonistas & inhibidores , Indoles/farmacología , Carbamatos/química , Carbamatos/farmacología , Cristalografía por Rayos X , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/química , Enlace de Hidrógeno , Indoles/síntesis química , Indoles/química , Modelos Moleculares , Estructura Molecular , Peso Molecular , Oxazoles/farmacología , Compuestos de Fenilurea/química , Compuestos de Fenilurea/farmacología , Sensibilidad y Especificidad , Relación Estructura-ActividadRESUMEN
The elaboration of previously reported indole fragments as inhibitors of inosine monophosphate dehydrogenase (IMPDH) is described. The synthesis, in vitro inhibitory values for IMPDH II, PBMC proliferation and physicochemical properties are discussed.
Asunto(s)
Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/farmacología , IMP Deshidrogenasa/antagonistas & inhibidores , Indoles/síntesis química , Indoles/farmacología , Transporte Biológico Activo/efectos de los fármacos , Células CACO-2 , Proliferación Celular/efectos de los fármacos , Evaluación Preclínica de Medicamentos , Activación Enzimática/efectos de los fármacos , Inhibidores Enzimáticos/química , Humanos , Técnicas In Vitro , Indoles/química , Leucocitos Mononucleares/efectos de los fármacos , Estructura Molecular , Peso Molecular , Relación Estructura-ActividadRESUMEN
The development of a series of novel quinazolinethiones and quinazolinediones as inhibitors of inosine monophosphate dehydrogenase (IMPDH) is described. The synthesis, in vitro inhibitory values for IMPDH II and in vitro inhibitory value for PBMC proliferation are discussed.
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IMP Deshidrogenasa/antagonistas & inhibidores , Quinazolinas/síntesis química , Quinazolinas/farmacología , Células Sanguíneas , Proliferación Celular/efectos de los fármacos , Inhibidores Enzimáticos/síntesis química , Humanos , Concentración 50 Inhibidora , Cetonas/síntesis química , Cetonas/farmacología , Monocitos/efectos de los fármacos , Relación Estructura-Actividad , Tionas/síntesis química , Tionas/farmacologíaRESUMEN
The synthesis and biological activity of a novel series of 7-methoxy-6-oxazol-5-yl-2,3-dihydro-1H-quinazolin-4-ones are described. Some of these compounds were found to be potent inhibitors of inosine 5'-monophosphate dehydrogenase type II (IMPDH II).
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Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/farmacología , IMP Deshidrogenasa/antagonistas & inhibidores , Quinazolinas/química , Quinazolinas/farmacología , Inhibidores Enzimáticos/síntesis química , Humanos , Conformación Molecular , Quinazolinas/síntesis química , Relación Estructura-ActividadRESUMEN
A series of bicyclic heteroaryl ring systems was considered as a replacement for the 3-cyclopentyloxy-4-methoxyphenyl moiety in rolipram resulting in the discovery of 8-methoxyquinoline-5-carboxamides as potent inhibitors of phosphodiesterase type 4 (PDE4).
Asunto(s)
3',5'-AMP Cíclico Fosfodiesterasas/antagonistas & inhibidores , Amidas/uso terapéutico , Antiasmáticos/uso terapéutico , Asma/tratamiento farmacológico , Inhibidores de Fosfodiesterasa/uso terapéutico , Amidas/farmacología , Antiasmáticos/farmacología , Fosfodiesterasas de Nucleótidos Cíclicos Tipo 4 , Humanos , Inhibidores de Fosfodiesterasa/farmacologíaRESUMEN
The synthesis and pharmacological profile of a novel series of 2-substituted 8-methoxyquinolines is described. The 2-trifluoromethyl compound was found to be a potent inhibitor of phosphodiesterase type 4 (PDE4).
Asunto(s)
3',5'-AMP Cíclico Fosfodiesterasas/antagonistas & inhibidores , Inhibidores de Fosfodiesterasa/síntesis química , Inhibidores de Fosfodiesterasa/farmacología , Quinolinas/síntesis química , Quinolinas/farmacología , Animales , Área Bajo la Curva , Fosfodiesterasas de Nucleótidos Cíclicos Tipo 4 , Cobayas , Inhibidores de Fosfodiesterasa/farmacocinética , Quinolinas/farmacocinética , Vómitos/inducido químicamenteRESUMEN
The synthesis and pharmacological profile of a novel series of 7-methoxy-furo[2,3-c]pyridine-4-carboxamides is described. Some of these compounds were found to be potent inhibitors of phosphodiesterase type 4 (PDE4).