RESUMO
BACKGROUND: While several studies have examined the treatment of adolescents and young adults (AYAs) with acute lymphoblastic leukemia (ALL), studies of acute myeloid leukemia (AML) are rare. Using national data for Australia, we describe (i) the number and type of treatment centers caring for AYAs, (ii) induction/first-line treatments, and (iii) survival outcomes. PROCEDURE: National population-based study assessing treatment of 15- to 24-year-olds diagnosed with ALL or AML between 2007 and 2012. Treatment details were abstracted from hospital medical records. Treatment centers were classified as pediatric or adult (adult AYA-focused or other adult; and by AYA volume [high/low]). Cox proportional hazard regression analyses examined associations between treatment and overall, event-free, and relapse-free survival outcomes. RESULTS: Forty-seven hospitals delivered induction therapy to 351 patients (181 ALL and 170 AML), with 74 (21%) treated at pediatric centers; 70% of hospitals treated less than two AYA leukemia patients per year. Regardless of treatment center, 82% of ALL patients were on pediatric protocols. For AML, pediatric protocols were not used in adult centers, with adult centers using a non-COG 7+3-type induction protocol (51%, where COG is Cooperative Oncology Group) or an ICE-type protocol (39%, where ICE is idarubicin, cytarabine, etoposide). Exploratory analyses suggested that for both ALL and AML, AYAs selected for adult protocols have worse overall, event-free, and relapse-free survival outcomes. CONCLUSIONS: Pediatric protocols were commonly used for ALL patients regardless of where they are treated, indicating rapid assimilation of recent evidence by Australian hematologists. For AML, pediatric protocols were only used at pediatric centers. Further investigation is warranted to determine the optimal treatment approach for AYA AML patients.
Assuntos
Quimioterapia de Indução/métodos , Leucemia Mieloide Aguda/tratamento farmacológico , Leucemia Mieloide Aguda/mortalidade , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Leucemia-Linfoma Linfoblástico de Células Precursoras/mortalidade , Adolescente , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Austrália , Feminino , Humanos , Masculino , Oncologia/métodos , Pediatria/métodos , Modelos de Riscos Proporcionais , Resultado do Tratamento , Adulto JovemRESUMO
OBJECTIVE: To identify the perceptions of parents of children who died from cancer regarding the palliative and supportive care they received in hospital and in community settings. METHOD: Face-to-face or telephone questionnaires. Setting Tertiary paediatric oncology centres in Western Australia, New South Wales, Queensland and Victoria. PARTICIPANTS: 69 parents. RESULTS: Parents indicated the need for clear and honest information about their child's condition and prognosis throughout the trajectory of illness. Parents also required access to, and advice from, multidisciplinary health professionals when caring for their child at home. Parents preferred to care for their child at home wherever possible throughout the palliative care trajectory of their child's cancer and were well supported by immediate and extended family and friends. However, many families were affected emotionally and financially by the burden of caring for their child with incurable cancer. Families required financial and practical assistance with providing care from their child. Parents wanted and needed more practical resources and information to assist with the management of their child's nutrition and pain, as well as for the support of their other children. CONCLUSION: Care for children and their families should be coordinated by a multidisciplinary team in consultation with children and their families, and should be linked and integrated with the treating hospital in collaboration with community services.
Assuntos
Serviços de Saúde Comunitária/organização & administração , Neoplasias/psicologia , Cuidados Paliativos/psicologia , Pais/psicologia , Apoio Social , Adulto , Austrália , Cuidadores , Criança , Serviços de Saúde Comunitária/normas , Saúde da Família , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Cuidados Paliativos/organização & administração , Relações Profissional-Família , Cuidados Intermitentes , Estudos Retrospectivos , Adulto JovemRESUMO
PURPOSE: A cancer diagnosis and treatment may have significant implications for a young patient's future fertility. Documentation of fertility-related discussions and actions is crucial to providing the best follow-up care, which may occur for many years post-treatment. This study examined the rate of medical record documentation of fertility-related discussions and fertility preservation (FP) procedures for adolescents and young adults (AYAs) with cancer in Australia. METHODS: A retrospective review of medical records for 941 patients in all six Australian states. Patients were identified through population-based cancer registries (four states) and hospital admission lists (two states). Trained data collectors extracted information from medical records using a comprehensive data collection survey. Records were reviewed for AYA patients (aged 15-24â¯yearsâ¯at diagnosis), diagnosed with acute myeloid leukaemia, acute lymphoblastic leukaemia, central nervous system (CNS) tumours, soft tissue sarcomas (STS), primary bone cancer or Ewing's family tumours between 2007 and 2012. RESULTS: 47.2% of patients had a documented fertility discussion and 35.9% had a documented FP procedure. Fertility-related documentation was less likely for female patients, those with a CNS or STS diagnosis and those receiving high-risk treatments. In multivariable models, adult hospitals with an AYA focus were more likely to document fertility discussions (odds ratio[OR]â¯=â¯1.60; 95%CIâ¯=â¯1.08-2.37) and FP procedures (ORâ¯=â¯1.74; 95%CIâ¯=â¯1.17-2.57) than adult hospitals with no AYA services. CONCLUSIONS: These data provide the first national, population-based estimates of fertility documentation for AYA cancer patients in Australia. Documentation of fertility-related discussions was poor, with higher rates observed in hospitals with greater experience of treating AYA patients.
Assuntos
Documentação/métodos , Preservação da Fertilidade/psicologia , Preservação da Fertilidade/estatística & dados numéricos , Fertilidade/efeitos dos fármacos , Fertilidade/efeitos da radiação , Neoplasias/psicologia , Neoplasias/terapia , Adolescente , Adulto , Austrália , Feminino , Humanos , Masculino , Estudos Retrospectivos , Inquéritos e Questionários , Adulto JovemRESUMO
10 patients with refractory or relapsed soft tissue sarcoma were treated with weekly etoposide (150 mg/m2 on days 1, 2 and 3) and cisplatin (60 mg/m2 on day 2). Toxicity was mainly myelosuppression which resulted in deviation from planned weekly chemotherapy scheduling. With this rapid dose-delivery schedule the tolerated median dose intensities were 161 mg/m2 per week for etoposide and 49 mg/m2 per week for cisplatin. In 9 evaluable patients there were 7 responses, 2 complete and 5 partial, giving a response rate of 78% (confidence interval 51-100%). The combination of etoposide and cisplatin in this schedule produced a higher response rate than reported with previous schedules and is worthy of further evaluation.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Sarcoma/tratamento farmacológico , Neoplasias de Tecidos Moles/tratamento farmacológico , Adolescente , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Criança , Pré-Escolar , Cisplatino/administração & dosagem , Cisplatino/efeitos adversos , Etoposídeo/administração & dosagem , Etoposídeo/efeitos adversos , Feminino , Humanos , Lactente , Masculino , Projetos PilotoRESUMO
Twenty three patients with paediatric soft tissue sarcomas who had relapsed or refractory disease were treated with a rapid schedule of intravenous etoposide (100 mg/m2 daily on three consecutive days, weekly over 3 weeks). The regimen was well tolerated with predictable myelotoxicity. In 19 patients with rhabdomyosarcoma, there was a response rate of 42%. This appears to be better than previously reported with conventional three weekly schedules. These data indicate that for rhabdomyosarcoma, as for some other tumours, a divided dose regimen may be the optimal schedule and is worthy of further evaluation.
Assuntos
Etoposídeo/administração & dosagem , Sarcoma/tratamento farmacológico , Adolescente , Criança , Pré-Escolar , Esquema de Medicação , Etoposídeo/efeitos adversos , Feminino , Humanos , Lactente , Infusões Intravenosas , Masculino , Neoplasia Residual/tratamento farmacológico , Rabdomiossarcoma/tratamento farmacológicoRESUMO
The TxA2 receptor antagonist properties of SQ 27,427 [a cyclohexylcarbinol-7-oxabicyclo(2.2.1)heptenoic acid analog] were studied in vitro both in the human platelet and various isolated smooth muscle preparations. SQ 27,427 was found to be a potent inhibitor of human platelet aggregation induced by arachidonic acid, ADP, epinephrine, collagen and the stable TxA2 agonists 9,11-azoPGH2 and SQ 26,655. Inhibition of platelet aggregation was achieved at concentrations of SQ 27,427 which did not alter TxB2 levels. SQ 27,427 was found to weakly inhibit the formation of TxB2 from arachidonic acid and had no effect on the synthesis of PGE2 or PGI2 from arachidonic acid. SQ 27,427 was also found to be a weak stimulator of platelet adenylate cyclase, being 1000 times less potent than PGI2. In isolated smooth muscle experiments, SQ 27,427 was shown to be a potent and specific TxA2 receptor antagonist. It caused competitive antagonism of 9,11-azoPGH2-induced contractions of vascular, respiratory and gastrointestinal smooth muscles. This antagonism was specific, as responses to norepinephrine, serotonin, PGE2, PGI2, PGF2 alpha, histamine, carbachol and KCl were not altered by SQ 27,427.
Assuntos
Plaquetas/metabolismo , Sistema Enzimático do Citocromo P-450 , Ácidos Graxos Monoinsaturados , Ácidos Graxos Insaturados/farmacologia , Oxirredutases Intramoleculares , Músculo Liso/metabolismo , Endoperóxidos de Prostaglandina/farmacologia , Receptores de Superfície Celular/efeitos dos fármacos , Receptores de Superfície Celular/metabolismo , Receptores de Prostaglandina/efeitos dos fármacos , Tromboxano A2/metabolismo , Adenilil Ciclases/sangue , Animais , Bovinos , Epoprostenol/biossíntese , Epoprostenol/metabolismo , Humanos , Técnicas In Vitro , Norepinefrina/farmacologia , Agregação Plaquetária/efeitos dos fármacos , Prostaglandina-Endoperóxido Sintases/metabolismo , Receptores de Tromboxanos , Serotonina/farmacologia , Tromboxano-A Sintase/metabolismoRESUMO
This report presents the early results of a new technique, using a solid-state transducer intracompartmental (STIC) catheter, developed to measure dynamic pressure changes in the anterior compartment of the leg in patients with exercise-induced anterior compartment syndrome. Nine male volunteers (15 limbs) with a history of exercise-induced anterior compartment pain were studied and compared to eleven asymptomatic male controls matched for age, weight and height. After catheter insertion, anterior compartment pressures were recorded with the subjects walking and running on a treadmill and performing several static maneuvers before and after the exercise period. The most statistically significant value between the two groups was the difference in mean pressure during running (P less than 0.001). Presently, all mean running pressures greater than 85 mm Hg are considered abnormal. This new technique offers the investigator the opportunity to measure dynamic intracompartmental pressures in symptomatic patients and provides an objective measurement for selection of patients for fasciotomy.
Assuntos
Síndrome do Compartimento Anterior/fisiopatologia , Síndromes Compartimentais/fisiopatologia , Monitorização Fisiológica/métodos , Esforço Físico , Adulto , Animais , Cães , Fasciotomia , Humanos , Masculino , Postura , Transdutores de PressãoRESUMO
Nuclear protein in testis (NUT)-midline carcinoma (NMC) is a rare, aggressive disease typically presenting with a single t(15;19) translocation that results in the generation of a bromodomain-containing protein 4 (BRD4)-NUT fusion. PER-624 is a cell line generated from an NMC patient with an unusually complex karyotype that gave no initial indication of the involvement of the NUT locus. Analysis of PER-624 next-generation transcriptome sequencing (RNA-Seq) using the algorithm FusionFinder identified a novel transcript in which Exon 15 of BRD4 was fused to Exon 2 of NUT, therefore differing from all published NMC fusion transcripts. The three additional exons contained in the PER-624 fusion encode a series of polyproline repeats, with one predicted to form a helix. In the NMC cell line PER-403, we identified the 'standard' NMC fusion and two novel isoforms. Knockdown by small interfering RNA in either cell line resulted in decreased proliferation, increased cell size and expression of cytokeratins consistent with epithelial differentiation. These data demonstrate that the novel BRD4-NUT fusion in PER-624 encodes a functional protein that is central to the oncogenic mechanism in these cells. Genomic PCR indicated that in both PER-624 and PER-403, the translocation fuses an intron of BRD4 to a region upstream of the NUT coding sequence. Thus, the generation of BRD4-NUT fusion transcripts through post-translocation RNA-splicing appears to be a common feature of these carcinomas that has not previously been appreciated, with the mechanism facilitating the expression of alternative isoforms of the fusion. Finally, ectopic expression of wild-type NUT, a protein normally restricted to the testis, could be demonstrated in PER-403, indicating additional pathways for aberrant cell signaling in NMC. This study contributes to our understanding of the genetic diversity of NMC, an important step towards finding therapeutic targets for a disease that is refractory to current treatments.
Assuntos
Carcinoma/genética , Cromossomos Humanos Par 15/genética , Cromossomos Humanos Par 19/genética , Neoplasias Pulmonares/genética , Proteínas Nucleares/fisiologia , Proteínas de Fusão Oncogênica/fisiologia , Neoplasias do Timo/genética , Translocação Genética , Adolescente , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Sequência de Bases , Carcinoma/tratamento farmacológico , Carcinoma/patologia , Diferenciação Celular , Linhagem Celular Tumoral/metabolismo , Linhagem Celular Tumoral/ultraestrutura , Tamanho Celular , Criança , Cromossomos Humanos Par 15/ultraestrutura , Cromossomos Humanos Par 19/ultraestrutura , Resistencia a Medicamentos Antineoplásicos , Éxons/genética , Evolução Fatal , Feminino , Humanos , Hibridização in Situ Fluorescente , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/patologia , Dados de Sequência Molecular , Proteínas Nucleares/antagonistas & inibidores , Proteínas Nucleares/genética , Proteínas de Fusão Oncogênica/antagonistas & inibidores , Proteínas de Fusão Oncogênica/genética , Isoformas de Proteínas/genética , Isoformas de Proteínas/fisiologia , Estrutura Secundária de Proteína , Interferência de RNA , RNA Interferente Pequeno/farmacologia , Alinhamento de Sequência , Homologia de Sequência do Ácido Nucleico , Neoplasias do Timo/patologia , Adulto JovemAssuntos
Hidrazinas/farmacologia , Inibidores de Fosfodiesterase , Pirazóis/farmacologia , Piridinas/farmacologia , Glândulas Suprarrenais/enzimologia , Sulfato de Amônio , Animais , Encéfalo/enzimologia , Cafeína/farmacologia , Ácidos Carboxílicos/farmacologia , Gatos , Bovinos , AMP Cíclico , GMP Cíclico , Ésteres/farmacologia , Hidrólise , Técnicas In Vitro , Cinética , Masculino , Miocárdio/enzimologia , Diester Fosfórico Hidrolases/análise , Ratos , Teofilina/farmacologiaAssuntos
Nucleotídeos Cíclicos/farmacologia , Diester Fosfórico Hidrolases/metabolismo , Animais , Encéfalo/enzimologia , Bucladesina/farmacologia , Gatos , AMP Cíclico/metabolismo , GMP Cíclico/farmacologia , Nucleotídeos de Citosina/farmacologia , Hidrólise , Técnicas In Vitro , Nucleotídeos de Inosina/farmacologia , Cinética , Masculino , Miocárdio/enzimologia , Inibidores de Fosfodiesterase , Ratos , Trítio , Nucleotídeos de Uracila/farmacologiaAssuntos
Plaquetas/metabolismo , Epoprostenol/sangue , Prostaglandinas/sangue , 3',5'-AMP Cíclico Fosfodiesterases/antagonistas & inibidores , Ácido Araquidônico , Ácidos Araquidônicos/farmacologia , Epoprostenol/farmacologia , Etazolato/farmacologia , Humanos , Agregação Plaquetária/efeitos dos fármacos , Prostaglandinas E/farmacologiaAssuntos
Falência Renal Crônica/cirurgia , Neoplasias Renais/diagnóstico , Transplante de Rim/efeitos adversos , Tumor de Wilms/diagnóstico , Feminino , Refluxo Gastroesofágico/tratamento farmacológico , Humanos , Lactente , Rim/patologia , Falência Renal Crônica/induzido quimicamente , Neoplasias Renais/induzido quimicamente , Neoplasias Renais/cirurgia , Complicações Pós-Operatórias/diagnóstico , Complicações Pós-Operatórias/cirurgia , Ranitidina/efeitos adversos , Fatores de Tempo , Resultado do Tratamento , Tumor de Wilms/induzido quimicamente , Tumor de Wilms/cirurgiaRESUMO
In this article, we describe a technique for obtaining jejunal biopsies endoscopically using an infant Crosby or Watson capsule. The method is quick, safe, and may be particularly useful if radiological screening is unavailable.
Assuntos
Biópsia/métodos , Jejuno/patologia , Pré-Escolar , Diarreia Infantil/patologia , Gastroscópios , Humanos , Lactente , Mucosa Intestinal/patologia , Desnutrição Proteico-Calórica/patologiaRESUMO
BACKGROUND: Postoperative nausea and vomiting (PONV) may delay discharge from hospital after ambulatory surgery. The antiserotonin agents, ondansetron and granisetron, provide effective prophylaxis against chemotherapy-induced and postoperative nausea and vomiting in adults, but are expensive. We determined the dose-response relation of granisetron and the financial impact of using this drug in preventing PONV after pediatric outpatient surgery. METHODS: In a randomized, double-blind, placebo-controlled study, 97 pediatric outpatients received a placebo or 10 or 40 micrograms.kg-1 granisetron intravenously during a standardized anesthetic. Episodes of postoperative retching, vomiting, and times to discharge readiness were recorded. A decision analysis tree was used to divide each study group into nine mutually exclusive subgroups, depending on the incidence of PONV, need for rescue therapy, and the side effects of antiemetics. Costs and probabilities were assigned to each subgroup, and the cost-effectiveness ratio was determined by dividing the sum of these weighted costs by the number of patients free from both PONV and antiemetic side effects. RESULTS: Granisetron (40 micrograms.kg-1 intravenously) was more effective than a placebo or 10 micrograms.kg-1 granisetron in decreasing the incidence and frequency of postoperative emesis, both in the ambulatory surgery center and during the first 24 h. Patients receiving 40 micrograms.kg-1 granisetron also had shorter times to discharge readiness compared with those receiving a placebo. Administering this dose of granisetron to all high-risk patients would cost the ambulatory care center an additional $99 (95% CI, range $89-$112) per emesis-free patient if nursing labor costs are excluded and $101 (95% CI, range $91-$113) if nursing costs are included. CONCLUSIONS: In this study, 40 micrograms.kg-1 intravenous granisetron (but not 10 micrograms.kg-1) provided effective prophylaxis in children against PONV compared with a placebo, but at a high cost. The effective dose of granisetron for PONV prophylaxis is higher than the Food and Drug Administration-recommended dose for chemotherapy-induced emesis.
Assuntos
Antieméticos/uso terapêutico , Granisetron/uso terapêutico , Náusea/prevenção & controle , Vômito/prevenção & controle , Adolescente , Antieméticos/economia , Criança , Pré-Escolar , Análise Custo-Benefício , Relação Dose-Resposta a Droga , Feminino , Granisetron/economia , Humanos , Masculino , Pais , Complicações Pós-Operatórias/prevenção & controleRESUMO
A series of 9-substituted adenine derivatives inhibited adenylate cyclase activity (ATP pyrophosphate-lyase (cyclizing) EC 4.6.1.1) of a particulate preparation of human blood platelets. A 3--6 fold elevation of adenylate cyclase activity by prostaglandin E1 (PGE1) was inhibited in a concentration-related manner by 9-(tetrahydro-5-methyl-2-furyl) adenine (SQ 22,538), 9-(tetrahydro-2-furyl) adenine (SQ 22,536), 9-cyclopentyladenine (SQ 22,534), 9-furfuryladenine (sQ 4647) and 9-benzyladenine (SQ 218611). The I50 values ranged from 21 microM for SQ 22,538 to 140 microM for SQ 21,611. These same adenine derivatives reversed the inhibition by PGE1 of ADP-induced aggregation and the PGE1-stimulated elevation of adenosine 3':5'-monophosphate (cyclic AMP). The reversal of platelet aggregation inhibition by SQ 22,536 and SQ 4647 was concentration-related with I50 values of 30 microM in each case, whereas SQ 22,534 and SQ 21,611 reversed inhibition by 30% at 100 microM. SQ 22,536, SQ 22,534 and SQ 21,611 also blocked the increase in cyclic AMP levels in a concentration-related manner with I50 values of 1, 4 and 60 microM, respectively. SQ 4647 inhibited the elevation of cyclic AMP by more than 85% at 1000 microM. The adenine derivatives had no effect on platelet aggregation or on cyclic AMP levels in the absence of PGE1. These results provide additional evidence that the inhibition of platelet aggregation by PGE1 is mediated by cyclic AMP.
Assuntos
Adenina/análogos & derivados , Adenilil Ciclases/sangue , Plaquetas/enzimologia , Adenina/farmacologia , Inibidores de Adenilil Ciclases , AMP Cíclico/metabolismo , Relação Dose-Resposta a Droga , Furanos/farmacologia , Humanos , Agregação Plaquetária/efeitos dos fármacos , Prostaglandinas E/farmacologia , Relação Estrutura-AtividadeRESUMO
SQ 28,668 is a thromboxane receptor antagonist. In whole blood and platelet-rich plasma, micromolar concentrations of SQ 28,668 inhibited aggregation of human and porcine platelets induced by arachidonate and U-46,619, and the secondary phase of epinephrine-induced aggregation of human platelets. SQ 28,668 did not inhibit ADP-induced platelet aggregation and did not influence cAMP concentrations. High concentrations of SQ 28,668 inhibited platelet thromboxane synthase (IC50 = 660 microM), but SQ 28,668 did not inhibit cyclooxygenase or prostacyclin synthetase. In anesthetized pigs with pacing-induced tachycardia, placement of a critical stenosis at a focus of coronary vascular injury initiated a reproducible pattern of coronary blood flow reduction, reflecting thrombus formation at the site of injury. Treatment with SQ 28,668 (1.0 mg/kg, i.v.) abolished reductions in coronary blood flow in five of six pigs for 58 +/- 7 min and slowed the rate of blood flow reduction in the sixth. Before SQ 28,668 treatment, the rate of blood-flow reduction averaged 5.3 +/- 0.7 ml/min per min. Thirty and sixty minutes after treatment, the rates of blood-flow reduction averaged 0.6 +/- 0.6 and 2.1 +/- 1.0 ml/min per min, respectively (P less than 0.05). In control pigs, the rate of blood flow reduction before and 30 min after vehicle treatment averaged 5.7 +/- 2.0 and 5.5 +/- 1.6 ml/min per min, respectively (not significant). These findings indicate that SQ 28,668 is an effective antiplatelet agent in vitro and in vivo.
Assuntos
Circulação Coronária/efeitos dos fármacos , Fibrinolíticos , Tromboxano A2/análogos & derivados , Tromboxano A2/antagonistas & inibidores , Ácido 15-Hidroxi-11 alfa,9 alfa-(epoximetano)prosta-5,13-dienoico , Difosfato de Adenosina/farmacologia , Animais , Ácido Araquidônico , Ácidos Araquidônicos/farmacologia , AMP Cíclico/metabolismo , Humanos , Técnicas In Vitro , Masculino , Agregação Plaquetária/efeitos dos fármacos , Endoperóxidos Sintéticos de Prostaglandinas/farmacologia , Prostaglandina-Endoperóxido Sintases/metabolismo , Especificidade da Espécie , Suínos , Tromboxano A2/farmacologia , Tromboxano-A Sintase/metabolismoRESUMO
Small structural changes in a series of 7-oxabicyclo[2.2.1]heptyl acids have produced four types of agents that modify the actions of TXA2 and PG. We showed that SQ 26,655 is a TXA2 receptor agonist, SQ 28,668 and SQ 29,548 are TXA2 receptor antagonists, SQ 28,852 is a CO inhibitor, and SQ 27,986 is a PGI2/PGD2 agonist. SQ 30,077 bound reversibly with high affinity to one site in human platelet membranes. The specific binding of SQ 30,077 is competitively inhibited by the identified TXA2 receptor agonists and antagonists with an order of affinity that correlates well with their functional potencies. SQ 27,986, PDG2 and SQ 28,852 show marginal affinity, indicating that their biological actions are not mediated via the TXA2 receptor.
Assuntos
Ácidos Araquidônicos/metabolismo , Prostaglandinas/farmacologia , Tromboxanos/farmacologia , Ácido Araquidônico , Plaquetas/efeitos dos fármacos , Plaquetas/metabolismo , Humanos , Técnicas In Vitro , Prostaglandinas/metabolismo , Receptores de Prostaglandina/efeitos dos fármacos , Receptores de Prostaglandina/metabolismo , Receptores de Tromboxanos , Tromboxanos/metabolismoRESUMO
7-Oxabicyclo[2.2.1]heptane analogs of prostaglandin (PG) H2 can act as thromboxane (Tx) A2 receptor antagonists or agonists, PGI2 and/or PGD2 receptor agonists, or exhibit a mixture of the above activities. SQ 28,852, a new analog with a hexyloxymethyl omega side chain, is a potent inhibitor of PG synthesis. SQ 28,852 inhibited collagen and arachidonic acid (AA)-induced platelet aggregation and TxB2 and PGE2 formation, but did not block platelet aggregation induced by ADP or the TxA2 mimics, 9,11-azo PGH2, SQ 26,655, and U-46,619. It also blocked conversion of AA to TxB2, PGE2, and 6-keto PGF1 alpha by microsomal preparations of human platelets, bovine seminal vesicles, and bovine aortas, respectively, but did not inhibit the conversion of PGH2 to TxA2 by the platelet microsomal preparation. SQ 28,852 (p.o.) protected mice against the lethal effects of AA (75 mg/kg, i.v.). The I50 values for SQ 28,852, indomethacin and aspirin were 0.025, 0.05 and 15 mg/kg, respectively. Neither SQ 28,852 nor indomethacin protected mice from death caused by 9,11-azo PGH2. SQ 28,852 (0.01 to 1 mg/kg, i.v.) inhibited AA-induced bronchoconstriction in anesthetized guinea pigs for at least 60 min. As an inhibitor of AA-induced bronchoconstriction, SQ 28,852 was 16- and 45-times more potent than indomethacin at 3 and 60 min after i.v. administration, respectively. SQ 28,852 did not inhibit bronchoconstriction induced by histamine or 9,11-azo PGH2, indicating its specificity of action in vivo. SQ 28,852 is the first example of a new class of cyclooxygenase inhibitors whose structure is similar to that of the naturally occurring endoperoxide, PGH2.
Assuntos
Inibidores de Ciclo-Oxigenase , Sistema Enzimático do Citocromo P-450 , Oxirredutases Intramoleculares , Endoperóxidos de Prostaglandina/farmacologia , Animais , Ácido Araquidônico , Ácidos Araquidônicos/toxicidade , Testes de Provocação Brônquica , Dinoprostona , Epoprostenol/antagonistas & inibidores , Epoprostenol/biossíntese , Humanos , Técnicas In Vitro , Indometacina/farmacologia , Microssomos/metabolismo , Agregação Plaquetária/efeitos dos fármacos , Prostaglandinas E/biossíntese , Tromboxano B2/biossíntese , Tromboxano-A Sintase/antagonistas & inibidoresRESUMO
To determine the prevalence of giardiasis in Gambian children with chronic diarrhoea and to assess their response to treatment, 31 children with chronic diarrhoea and malnutrition were investigated for giardiasis using a combination of serology (specific antigiardia IgM antibody) and microscopy of faeces and jejunal biopsy specimens. Fourteen of 31 children with chronic diarrhoea had giardiasis compared with only four of 33 healthy age and sex matched control children. Four of 15 malnourished children without diarrhoea were giardia positive. Twenty-three children with chronic diarrhoea were reinvestigated after treatment with metronidazole; giardia was found in 11 of them. These results show that giardia is highly prevalent in children with chronic diarrhoea and malnutrition and that the infection does not respond to standard therapeutic measures.
Assuntos
Diarreia/complicações , Giardíase/epidemiologia , Distúrbios Nutricionais/complicações , Animais , Pré-Escolar , Doença Crônica , Estudos Transversais , Diarreia/tratamento farmacológico , Diarreia/parasitologia , Ensaio de Imunoadsorção Enzimática , Fezes/parasitologia , Feminino , Giardia/isolamento & purificação , Giardíase/diagnóstico , Giardíase/tratamento farmacológico , Humanos , Imunoglobulina M/análise , Lactente , Jejuno/parasitologia , Masculino , Distúrbios Nutricionais/parasitologia , PrevalênciaRESUMO
A newly synthesized 9 alpha-homo-9,11-epoxy-5,13-prostadienoic acid analogue, SQ 26, 536, (8(R)9(S)11(R)12(S)-9 alpha-homo-9,11-epoxy-5(Z), 13(E)-15S-hydroxyprostadienoic acid) inhibited arachidonic acid (AA)-induced platelet aggregation with an I50 value of 1.7 microM. SQ 26,536 did not inhibit prostaglandin (PG) synthetase activity of bovine seminal vesicle microsomes or thromboxane (Tx) synthetase activity of lysed human blood platelets. SQ 26,536 also inhibited platelet aggregation induced by epinephrine (secondary phase), 9,11-azoPGH2 and collagen but did not inhibit the primary phase of epinephrine-induced aggregation or ADP-induced platelet aggregation. SQ 26,538 (8(R)9(S)11(R)12(S)-9 alpha-homo-9,11-epoxy-5(Z),13(E)-15R-hydroxyprostadienoic acid), a 15-epimer of SQ 26,536, induced platelet aggregation with an A50 value of 2.5 microM. SQ 26,536 competitively inhibited SQ 26,538-induced platelet aggregation with a Ki value of 3 microM. Neither indomethacin, a PG synthetase inhibitor, nor SQ 80,338 (1-(3-phenyl-2-propenyl)-1H-imidazole), a Tx synthetase inhibitor, inhibited SQ 26,538- or 9,11-azoPGH2-induced platelet aggregation. These data indicate that SQ 26,536 and SQ 26,538 are stable antagonist and agonist, respectively, of the human blood platelet thromboxane receptor.