RESUMO
BACKGROUND: External beam radiotherapy (EBRT) is the treatment of choice for irresectable meningioma. Due to the strong expression of somatostatin receptors, peptide receptor radionuclide therapy (PRRT) has been used in advanced cases. We assessed the feasibility and tolerability of a combination of both treatment modalities in advanced symptomatic meningioma. METHODS: 10 patients with irresectable meningioma were treated with PRRT (177Lu-DOTA0,Tyr3 octreotate or - DOTA0,Tyr3 octreotide) followed by external beam radiotherapy (EBRT). EBRT performed after PRRT was continued over 5-6 weeks in IMRT technique (median dose: 53.0 Gy). All patients were assessed morphologically and by positron emission tomography (PET) before therapy and were restaged after 3-6 months. Side effects were evaluated according to CTCAE 4.0. RESULTS: Median tumor dose achieved by PRRT was 7.2 Gy. During PRRT and EBRT, no side effects > CTCAE grade 2 were noted. All patients reported stabilization or improvement of tumor-associated symptoms, no morphologic tumor progression was observed in MR-imaging (median follow-up: 13.4 months). The median pre-therapeutic SUV(max) in the meningiomas was 14.2 (range: 4.3-68.7). All patients with a second PET after combined PRRT + EBRT showed an increase in SUV(max) (median: 37%; range: 15%-46%) to a median value of 23.7 (range: 8.0-119.0; 7 patients) while PET-estimated volume generally decreased to 81 ± 21% of the initial volume. CONCLUSIONS: The combination of PRRT and EBRT is feasible and well tolerated. This approach represents an attractive strategy for the treatment of recurring or progressive symptomatic meningioma, which should be further evaluated.
Assuntos
Fracionamento da Dose de Radiação , Neoplasias Meníngeas/diagnóstico por imagem , Neoplasias Meníngeas/radioterapia , Meningioma/diagnóstico por imagem , Meningioma/radioterapia , Octreotida/uso terapêutico , Adulto , Idoso , Terapia Combinada/efeitos adversos , Terapia Combinada/métodos , Progressão da Doença , Estudos de Viabilidade , Feminino , Humanos , Masculino , Neoplasias Meníngeas/complicações , Neoplasias Meníngeas/patologia , Meningioma/complicações , Meningioma/patologia , Pessoa de Meia-Idade , Octreotida/efeitos adversos , Projetos Piloto , Tomografia por Emissão de Pósitrons/efeitos adversos , Tomografia por Emissão de Pósitrons/métodos , Radioterapia de Intensidade Modulada/efeitos adversos , Radioterapia de Intensidade Modulada/métodos , Receptores de Peptídeos/metabolismo , Receptores de Peptídeos/uso terapêuticoRESUMO
A series of etacrynic acid derivatives was synthesized and screened for their in vitro activity against Plasmodium falciparum, as well as their activity against recombinantly expressed falcipain-2 and -3. The two most active compounds of the series displayed IC(50) values of 9.0 and 18.8 microM against Plasmodia.
Assuntos
Antimaláricos/química , Antimaláricos/farmacologia , Cisteína Endopeptidases/efeitos dos fármacos , Inibidores de Cisteína Proteinase/química , Inibidores de Cisteína Proteinase/farmacologia , Ácido Etacrínico/análogos & derivados , Plasmodium falciparum/efeitos dos fármacos , Animais , Antimaláricos/síntese química , Cisteína Endopeptidases/genética , Inibidores de Cisteína Proteinase/síntese química , Estrutura Molecular , Plasmodium falciparum/enzimologia , Proteínas Recombinantes/antagonistas & inibidores , Proteínas Recombinantes/genéticaRESUMO
The coronavirus main protease, M(pro), is considered a major target for drugs suitable to combat coronavirus infections including the severe acute respiratory syndrome (SARS). In this study, comprehensive HPLC- and FRET-substrate-based screenings of various electrophilic compounds were performed to identify potential M(pro) inhibitors. The data revealed that the coronaviral main protease is inhibited by aziridine- and oxirane-2-carboxylates. Among the trans-configured aziridine-2,3-dicarboxylates the Gly-Gly-containing peptide 2c was found to be the most potent inhibitor.
Assuntos
Aziridinas/farmacologia , Peptídeos/farmacologia , Inibidores de Proteases/farmacologia , Síndrome Respiratória Aguda Grave/tratamento farmacológico , Sítios de Ligação , Proteases 3C de Coronavírus , Cisteína Endopeptidases/metabolismo , Humanos , Coronavírus Relacionado à Síndrome Respiratória Aguda Grave/efeitos dos fármacos , Proteínas Virais/metabolismoRESUMO
The coronavirus main protease, M(pro), is considered to be a major target for drugs suitable for combating coronavirus infections including severe acute respiratory syndrome (SARS). An HPLC-based screening of electrophilic compounds that was performed to identify potential M(pro) inhibitors revealed etacrynic acid tert-butylamide (6a) as an effective nonpeptidic inhibitor. Docking studies suggested a binding mode in which the phenyl ring acts as a spacer bridging the inhibitor's activated double bond and its hydrophobic tert-butyl moiety. The latter is supposed to fit into the S4 pocket of the target protease. Furthermore, these studies revealed etacrynic acid amide (6b) as a promising lead for nonpeptidic active-site-directed M(pro) inhibitors. In a fluorimetric enzyme assay using a novel fluorescence resonance energy transfer (FRET) pair labeled substrate, compound 6b showed a K(i) value of 35.3 muM. Since the novel lead compound does not target the S1', S1, and S2 subsites of the enzyme's substrate-binding pockets, there is room for improvement that underlines the lead character of compound 6b.