RESUMO
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.
Assuntos
Analgésicos/uso terapêutico , Craniotomia , Manejo da Dor/métodos , Dor Pós-Operatória/tratamento farmacológico , Adolescente , Analgésicos/administração & dosagem , Analgésicos/efeitos adversos , Criança , Pré-Escolar , Estudos de Coortes , Vias de Administração de Medicamentos , Feminino , Hospitais Pediátricos/estatística & dados numéricos , Hospitais de Ensino/estatística & dados numéricos , Humanos , Lactente , Tempo de Internação/estatística & dados numéricos , Masculino , Medição da Dor/métodos , Satisfação do Paciente/estatística & dados numéricos , Estudos Prospectivos , Vômito/induzido quimicamenteRESUMO
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.
Assuntos
Desenho de Fármacos , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/farmacologia , Imidazóis/síntese química , Imidazóis/farmacologia , Quinases Associadas a Receptores de Interleucina-1/antagonistas & inibidores , Modelos Moleculares , Piridinas/síntese química , Piridinas/farmacologia , Sítios de Ligação , Cristalografia por Raios X , Inibidores Enzimáticos/química , Imidazóis/química , Conformação Molecular , Estrutura Molecular , Piridinas/química , Relação Estrutura-AtividadeRESUMO
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.
Assuntos
Amidas/síntese química , Amidas/farmacologia , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/farmacologia , Quinases Associadas a Receptores de Interleucina-1/antagonistas & inibidores , Modelos Biológicos , Piridinas/síntese química , Piridinas/farmacologia , Bibliotecas de Moléculas Pequenas/síntese química , Bibliotecas de Moléculas Pequenas/farmacologia , Amidas/química , Desenho de Fármacos , Inibidores Enzimáticos/química , Humanos , Estrutura Molecular , Piridinas/química , Bibliotecas de Moléculas Pequenas/química , Relação Estrutura-AtividadeRESUMO
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.
Assuntos
Quinases Associadas a Receptores de Interleucina-1/antagonistas & inibidores , Inibidores de Proteínas Quinases/farmacologia , Piridinas/farmacologia , Avaliação Pré-Clínica de Medicamentos , Estrutura Molecular , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/química , Piridinas/síntese química , Piridinas/química , Estereoisomerismo , Relação Estrutura-AtividadeRESUMO
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.
Assuntos
Inibidores Enzimáticos/farmacologia , IMP Desidrogenase/antagonistas & inibidores , Indóis/farmacologia , Carbamatos/química , Carbamatos/farmacologia , Cristalografia por Raios X , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Ligação de Hidrogênio , Indóis/síntese química , Indóis/química , Modelos Moleculares , Estrutura Molecular , Peso Molecular , Oxazóis/farmacologia , Compostos de Fenilureia/química , Compostos de Fenilureia/farmacologia , Sensibilidade e Especificidade , Relação Estrutura-AtividadeRESUMO
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.
Assuntos
Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/farmacologia , IMP Desidrogenase/antagonistas & inibidores , Indóis/síntese química , Indóis/farmacologia , Transporte Biológico Ativo/efeitos dos fármacos , Células CACO-2 , Proliferação de Células/efeitos dos fármacos , Avaliação Pré-Clínica de Medicamentos , Ativação Enzimática/efeitos dos fármacos , Inibidores Enzimáticos/química , Humanos , Técnicas In Vitro , Indóis/química , Leucócitos Mononucleares/efeitos dos fármacos , Estrutura Molecular , Peso Molecular , Relação Estrutura-AtividadeRESUMO
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.
Assuntos
IMP Desidrogenase/antagonistas & inibidores , Quinazolinas/síntese química , Quinazolinas/farmacologia , Células Sanguíneas , Proliferação de Células/efeitos dos fármacos , Inibidores Enzimáticos/síntese química , Humanos , Concentração Inibidora 50 , Cetonas/síntese química , Cetonas/farmacologia , Monócitos/efeitos dos fármacos , Relação Estrutura-Atividade , Tionas/síntese química , Tionas/farmacologiaRESUMO
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).
Assuntos
Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , IMP Desidrogenase/antagonistas & inibidores , Quinazolinas/química , Quinazolinas/farmacologia , Inibidores Enzimáticos/síntese química , Humanos , Conformação Molecular , Quinazolinas/síntese química , Relação Estrutura-AtividadeRESUMO
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).
Assuntos
3',5'-AMP Cíclico Fosfodiesterases/antagonistas & inibidores , Antiasmáticos/síntese química , Antiasmáticos/farmacologia , Furanos/síntese química , Furanos/farmacologia , Inibidores de Fosfodiesterase/síntese química , Inibidores de Fosfodiesterase/farmacologia , Piridinas/síntese química , Piridinas/farmacologia , Animais , Antiasmáticos/farmacocinética , Sítios de Ligação , Nucleotídeo Cíclico Fosfodiesterase do Tipo 4 , Furanos/farmacocinética , Cobaias , Indicadores e Reagentes , Inibidores de Fosfodiesterase/farmacocinética , Piridinas/farmacocinética , Rolipram/metabolismo , Relação Estrutura-AtividadeRESUMO
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).
Assuntos
3',5'-AMP Cíclico Fosfodiesterases/antagonistas & inibidores , Amidas/uso terapêutico , Antiasmáticos/uso terapêutico , Asma/tratamento farmacológico , Inibidores de Fosfodiesterase/uso terapêutico , Amidas/farmacologia , Antiasmáticos/farmacologia , Nucleotídeo Cíclico Fosfodiesterase do Tipo 4 , Humanos , Inibidores de Fosfodiesterase/farmacologiaRESUMO
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).