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1.
Cancer ; 128(15): 2949-2957, 2022 08 01.
Artículo en Inglés | MEDLINE | ID: mdl-35593736

RESUMEN

BACKGROUND: The survival of patients with high-risk, refractory, relapsed, or metastatic solid tumors remains dismal. A poly(ADP-ribose) polymerase (PARP) inhibitor could be effective for the treatment of pediatric solid tumors with defective homologous recombination. METHODS: This open-label, multicenter phase 1 clinical trial evaluated the safety, tolerability, and efficacy of olaparib, a PARP inhibitor, in pediatric patients with refractory solid tumors to recommend a dose for Phase 2 trials. Olaparib (62.5, 125, and 187.5 mg/m2 twice daily) was administered orally every day (1 cycle = 28 days) using a standard 3 + 3 dose-escalation design. Patients aged 3-18 years with recurrent pediatric solid tumors were eligible. Pharmacokinetic and pharmacodynamic analyses were performed. RESULTS: Fifteen patients were enrolled and received olaparib monotherapy, which was well tolerated. The recommended phase 2 dose for daily administration was 187.5 mg/m2 twice daily. Pharmacokinetics were dose proportional. The area under the concentration-time curve from 0 to 12 h and the peak plasma concentration for 187.5 mg/m2 twice daily in children were comparable to previous data obtained in a 200-mg, twice-daily cohort and lower than those in the 300-mg twice-daily cohort in adults. Pharmacodynamic studies demonstrated substantial inhibition of PARP activity. Two partial responses were observed in patients with Wilms tumor and neuroblastoma. CONCLUSIONS: This report is the first clinical trial to describe the use of a PARP inhibitor as monotherapy in children. Olaparib was well tolerated, with preliminary antitumor responses observed in DNA damage response-defective pediatric tumors. LAY SUMMARY: This Phase 1 trial evaluated the efficacy and safety of olaparib in patients with refractory childhood solid tumors. Olaparib was well tolerated, achieving objective response in 2/15 patients. The DNA damage response was attenuated in nearly one-half of advanced neuroblastoma patients, demonstrating the utility of the PARP inhibitor. The results support further investigation of olaparib as a new treatment for DNA damage-response or repair-defective pediatric cancers.


Asunto(s)
Antineoplásicos , Neuroblastoma , Adulto , Antineoplásicos/efectos adversos , Niño , Humanos , Recurrencia Local de Neoplasia/tratamiento farmacológico , Neuroblastoma/tratamiento farmacológico , Neuroblastoma/genética , Ftalazinas/efectos adversos , Piperazinas , Inhibidores de Poli(ADP-Ribosa) Polimerasas/efectos adversos , Poli(ADP-Ribosa) Polimerasas
2.
BMC Pediatr ; 19(1): 31, 2019 01 26.
Artículo en Inglés | MEDLINE | ID: mdl-30684955

RESUMEN

BACKGROUND: There is no established standard chemotherapy for recurrent pediatric solid tumors such as neuroblastoma and sarcoma. Since some of these tumor cells show dysfunctions in homologous recombination repair, the goal is to conduct a phase I study of olaparib, a poly(ADP-ribose) polymerase inhibitor. In this clinical trial, the aims are to evaluate the safety, tolerability, and efficacy of olaparib in pediatric patients with refractory solid tumors and to recommend a dose for phase II trials. METHODS: In this open-label, multicenter study, olaparib tablets (62.5, 125, and 187.5 mg/m2 b.i.d.) will be administered orally in a standard 3 + 3 dose escalation design. Patients aged 3 to 18 years with recurrent pediatric solid tumors are eligible. Pharmacokinetic and pharmacodynamic analyses will also be performed. DISCUSSION: This study aims to extend the indications for olaparib by assessing its safety and efficacy in pediatric refractory solid tumor patients. TRIAL REGISTRATION: UMIN-CTR ( UMIN000025521 ); Registered on January 4, 2017.


Asunto(s)
Ensayos Clínicos Fase I como Asunto , Recurrencia Local de Neoplasia/tratamiento farmacológico , Ftalazinas/administración & dosificación , Piperazinas/administración & dosificación , Inhibidores de Poli(ADP-Ribosa) Polimerasas/administración & dosificación , Proyectos de Investigación , Administración Oral , Adolescente , Niño , Preescolar , Ensayos Clínicos Fase I como Asunto/métodos , Humanos
3.
Lancet Reg Health West Pac ; 39: 100847, 2023 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-37554997

RESUMEN

Background: Pediatric patients with certain rare diseases are at increased risk of severe respiratory syncytial virus (RSV) infection. However, the prophylactic use of anti-RSV antibody (palivizumab) in these patients is not indicated at present in Japan. Methods: This first-in-the-world multicenter, uncontrolled, open-label, phase II clinical trial was carried out between 28 July 2019 and 24 September 2021 at seven medical institutions in Japan to investigate the efficacy, safety, and pharmacokinetics of palivizumab in 23 subjects recruited from among neonates, infants, or children aged 24 months or younger who had any of the following conditions: pulmonary hypoplasia, airway stenosis, congenital esophageal atresia, inherited metabolic disease, or neuromuscular disease. At least four continuous doses of palivizumab were administered intramuscularly at 15 mg/kg at intervals of 30 days. Findings: Twenty-three enrolled subjects completed the study. No subject required hospitalization for RSV. Adverse events (AE) did not notably differ from the event terms described in the latest interview form. Five severe AEs required unplanned hospitalization, but resolved without RSV infection. Therapeutically effective concentrations of palivizumab were maintained throughout the study period. Interpretation: Palivizumab might be well tolerated and effective in preventing serious respiratory symptoms and hospitalization due to severe RSV infection, indicating the prophylactic use in the pediatric patients included in this study. Funding: Japan Agency for Medical Research and Development (AMED), grant numbers 19lk0201097h0001 (to MM), 20lk0201097h0002 (to MM), 21lk0201097h0003 (to MM), and 22lk0201097h0004 (to MM). AMED did not have any role in the execution of this study, analysis and interpretation of the data, or the decision to submit the results.

4.
Asian J Endosc Surg ; 14(1): 90-93, 2021 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-32346994

RESUMEN

A 58-year-old man had rectal cancer directly invading the urinary bladder and small intestine, without distant metastasis. We successfully performed complete resection using a hybrid approach, including laparoscopic surgery and transanal total pelvic exenteration (TaTPE) with the patient in the prone jackknife (PJK) position. In the PJK position, gravity and pelvic morphology lead to a clear and wide surgical field. This case demonstrates that total pelvic exenteration using laparoscopic surgery and TaTPE in the PJK position provides a better surgical field than either TaTPE or laparoscopic surgery in the supine position. TaTPE in the PJK position may also be useful for curative surgery in locally advanced rectal cancer.


Asunto(s)
Intestino Delgado/cirugía , Exenteración Pélvica , Neoplasias del Recto , Vesículas Seminales/cirugía , Vejiga Urinaria/cirugía , Canal Anal/cirugía , Humanos , Intestino Delgado/patología , Masculino , Persona de Mediana Edad , Invasividad Neoplásica , Posicionamiento del Paciente , Exenteración Pélvica/métodos , Neoplasias del Recto/patología , Neoplasias del Recto/cirugía , Vesículas Seminales/patología , Vejiga Urinaria/patología
5.
Int Cancer Conf J ; 9(3): 107-111, 2020 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-32582512

RESUMEN

In 1982, it was demonstrated that a total mesorectal excision alone could achieve low rectal cancer recurrence rates in the pelvis and high disease-free survival rates. Nowadays, the total mesorectal excision is the gold-standard surgery for rectal cancer. Currently, the transanal total mesorectal excision has attracted attention as a promising alternative to the anterior approach. The transanal approach is superior to the anterior approach, because it facilitates total mesorectal excisions of the lower rectum, improves visualization, and shortens the surgical time. Some factors are particularly favorable for the transanal approach, including lesions in the lower third of the rectum, a narrow pelvis, a large tumor, male sex, and a prostatic enlargement. The transanal total mesorectal excision is commonly performed in the Lloyd-Davies position. However, in the Lloyd-Davies position, the sacral bone prevents the mobilized rectum from moving away from the pelvic base. From the perspective of pelvic morphology, we reasoned that, in the prone jackknife position, the mobilized rectum could spontaneously move toward the head, due to gravity, and this would broaden the pelvic surgical field. Consequently, this position could facilitate the transanal total mesorectal excision. Here, we described a transanal total mesorectal excision performed in the prone jackknife position for treating lower rectal cancer with a prostatic enlargement.

6.
Bioorg Med Chem Lett ; 18(6): 1869-73, 2008 Mar 15.
Artículo en Inglés | MEDLINE | ID: mdl-18313297

RESUMEN

SAR studies were conducted around lead compound 1 using high-throughput parallel solution and solid phase synthesis. Our lead optimization efforts led to the identification of several CCR2b antagonists with potent activity in both binding and functional assays [Compound 71 CCR2b Binding IC(50) 3.2 nM; MCP-1-Induced Chemotaxis IC(50) 0.83 nM; Ca(2+) Flux IC(50) 7.5 nM].


Asunto(s)
Quimiocina CCL2/metabolismo , Quimiotaxis/efectos de los fármacos , Pirrolidinas/farmacología , Receptores CCR2/antagonistas & inhibidores , Calcio/metabolismo , Células Cultivadas , Cromatografía Líquida de Alta Presión , Fluorescencia , Humanos , Riñón/citología , Riñón/efectos de los fármacos , Riñón/metabolismo , Estructura Molecular , Monocitos/efectos de los fármacos , Monocitos/metabolismo , Pirrolidinas/síntesis química , Receptores CCR2/metabolismo , Relación Estructura-Actividad , Transfección
7.
Asian J Endosc Surg ; 10(2): 219-222, 2017 May.
Artículo en Inglés | MEDLINE | ID: mdl-28547933

RESUMEN

We treated a 64-year-old man for rectal cancer with direct invasion to the seminal vesicles and no distant metastases by complete resection with laparoscopy and transanal minimally invasive surgery (TAMIS). We inserted the TAMIS device into the anal canal to above the anorectal ring and dissected to prostate level. High ligation of the inferior mesenteric artery and vein was performed by standard medial laparoscopy. The sigmoid and descending colon were mobilized, and in the postrectal space, we dissected to the space made by TAMIS. The membranous peritoneum was dissected on both sides of the rectum to the cul de sac. The peritoneum was dissected anterolaterally to reveal the seminal ducts, which were ligated and dissected on both sides. The seminal vesicles were dissected from the posterior wall of the bladder to the prostate level. The rectal specimen was now fully mobilized. Lower rectal resection with combined laparoscopy and TAMIS provided a better surgical plane than standard laparoscopy.


Asunto(s)
Adenocarcinoma/cirugía , Laparoscopía/métodos , Neoplasias del Recto/cirugía , Vesículas Seminales/patología , Vesículas Seminales/cirugía , Cirugía Endoscópica Transanal/métodos , Adenocarcinoma/patología , Anciano , Humanos , Masculino , Invasividad Neoplásica , Neoplasias del Recto/patología
8.
J Med Chem ; 55(15): 6700-15, 2012 Aug 09.
Artículo en Inglés | MEDLINE | ID: mdl-22746295

RESUMEN

A novel class of mitogen-activated protein kinase-activated protein kinase 2 (MAPKAP-K2) inhibitors was discovered through screening a kinase-focused library. A homology model of MAPKAP-K2 was generated and used to guide the initial SAR studies and to rationalize the observed selectivity over CDK2. An X-ray crystal structure of a compound from the active series bound to crystalline MAPKAP-K2 confirmed the predicted binding mode. This has enabled the discovery of a series of pyrazolo[1,5-a]pyrimidine derivatives showing good in vitro cellular potency as anti-TNF-α agents and in vivo efficacy in a mouse model of endotoxin shock.


Asunto(s)
Antiinflamatorios no Esteroideos/síntesis química , Péptidos y Proteínas de Señalización Intracelular/antagonistas & inhibidores , Proteínas Serina-Treonina Quinasas/antagonistas & inhibidores , Pirazoles/síntesis química , Pirimidinas/síntesis química , Animales , Antiinflamatorios no Esteroideos/farmacocinética , Antiinflamatorios no Esteroideos/farmacología , Línea Celular , Cristalografía por Rayos X , Proteínas de Choque Térmico HSP27/metabolismo , Humanos , Péptidos y Proteínas de Señalización Intracelular/química , Lipopolisacáridos/farmacología , Masculino , Ratones , Ratones Endogámicos C57BL , Modelos Moleculares , Fosforilación , Conformación Proteica , Proteínas Serina-Treonina Quinasas/química , Pirazoles/farmacocinética , Pirazoles/farmacología , Pirimidinas/farmacocinética , Pirimidinas/farmacología , Choque Séptico/metabolismo , Bibliotecas de Moléculas Pequeñas , Estereoisomerismo , Relación Estructura-Actividad , Factor de Necrosis Tumoral alfa/biosíntesis
9.
J Org Chem ; 67(21): 7314-8, 2002 Oct 18.
Artículo en Inglés | MEDLINE | ID: mdl-12375960

RESUMEN

The title compound N,N'-bistosyl-1H,4H-quinoxaline-2,3-dione (TsQD) provides peroxyoxalate chemiluminescence (PO-CL) when reacted with hydrogen peroxide in the presence of fluorophores. The chemiluminescence (CL) efficiency of TsQD was superior to that of other related compounds such as bis(2,4,6-trichlorophenyl) oxalate (TCPO), a typical oxalate for the peroxyoxalate PO-CL, under an aqueous condition. Factors affecting the PO-CL efficiency are discussed from the viewpoint of the structures of the substrates and the electronic nature of the fluorophores. A linear correlation of the logarithmic values evaluated from the CL quantum yields with the oxidation potentials of the aromatic fluorophores supports the involvement of the chemically initiated electron exchange luminescence (CIEEL) mechanism in both TsQD- and TCPO-CL systems. Also, an excellent Hammett relationship was derived from the correlation between the sigma(+) values and the relative singlet excitation yields in TsQD-CL enhanced by a series of fluorescent para,para'-disubstituted distyrylbenzenes.

10.
Bioorg Med Chem Lett ; 14(21): 5407-11, 2004 Nov 01.
Artículo en Inglés | MEDLINE | ID: mdl-15454235

RESUMEN

N,N'-Disubstituted homopiperazine derivatives have been discovered as CC-chemokine receptor 2b (CCR2b) inhibitors with submicromolar activity in the CCR2b binding assay. A 4-substituted benzyl group on one homopiperazine nitrogen was an important moiety for binding affinity to the CCR2b receptor. The SAR for CCR2b binding affinity correlated inversely with the sigma factor of the functional group on this benzyl moiety. Introduction of hydroxy groups to appropriate positions in the 3,3-diphenylpropyl group on the other homopiperazine nitrogen increased CCR2b binding activity. The synthesis of an informer library to search for alternative substructures is also described.


Asunto(s)
Piperazinas/síntesis química , Receptores de Quimiocina/antagonistas & inhibidores , Línea Celular , Quimiocina CCL2/metabolismo , Técnicas Químicas Combinatorias , Diseño de Fármacos , Humanos , Piperazinas/química , Piperazinas/farmacología , Ensayo de Unión Radioligante , Receptores CCR2 , Relación Estructura-Actividad
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