Niraparib plus abiraterone acetate with prednisone in patients with metastatic castration-resistant prostate cancer and homologous recombination repair gene alterations: second interim analysis of the randomized phase III MAGNITUDE trial.

BACKGROUND: Patients with metastatic castration-resistant prostate cancer (mCRPC) and BRCA alterations have poor outcomes. MAGNITUDE found patients with homologous recombination repair gene alterations (HRR+), particularly BRCA1/2, benefit from first-line therapy with niraparib plus abiraterone acetate and prednisone (AAP). Here we report longer follow-up from the second prespecified interim analysis (IA2). PATIENTS AND METHODS: Patients with mCRPC were prospectively identified as HRR+ with/without BRCA1/2 alterations and randomized 1 : 1 to niraparib (200 mg orally) plus AAP (1000 mg/10 mg orally) or placebo plus AAP. At IA2, secondary endpoints [time to symptomatic progression, time to initiation of cytotoxic chemotherapy, overall survival (OS)] were assessed. RESULTS: Overall, 212 HRR+ patients received niraparib plus AAP (BRCA1/2 subgroup, n = 113). At IA2 with 24.8 months of median follow-up in the BRCA1/2 subgroup, niraparib plus AAP significantly prolonged radiographic progression-free survival {rPFS; blinded independent central review; median rPFS 19.5 versus 10.9 months; hazard ratio (HR) = 0.55 [95% confidence interval (CI) 0.39-0.78]; nominal P = 0.0007} consistent with the first prespecified interim analysis. rPFS was also prolonged in the total HRR+ population [HR = 0.76 (95% CI 0.60-0.97); nominal P = 0.0280; median follow-up 26.8 months]. Improvements in time to symptomatic progression and time to initiation of cytotoxic chemotherapy were observed with niraparib plus AAP. In the BRCA1/2 subgroup, the analysis of OS with niraparib plus AAP demonstrated an HR of 0.88 (95% CI 0.58-1.34; nominal P = 0.5505); the prespecified inverse probability censoring weighting analysis of OS, accounting for imbalances in subsequent use of poly adenosine diphosphate-ribose polymerase inhibitors and other life-prolonging therapies, demonstrated an HR of 0.54 (95% CI 0.33-0.90; nominal P = 0.0181). No new safety signals were observed. CONCLUSIONS: MAGNITUDE, enrolling the largest BRCA1/2 cohort in first-line mCRPC to date, demonstrated improved rPFS and other clinically relevant outcomes with niraparib plus AAP in patients with BRCA1/2-altered mCRPC, emphasizing the importance of identifying this molecular subset of patients.

Deep, rapid, and durable prostate-specific antigen decline with apalutamide plus androgen deprivation therapy is associated with longer survival and improved clinical outcomes in TITAN patients with metastatic castration-sensitive prostate cancer.

BACKGROUND: The first interim analysis of the phase III, randomized, double-blind, placebo-controlled, multinational TITAN study demonstrated improved overall survival (OS) and radiographic progression-free survival (rPFS) with apalutamide added to ongoing androgen deprivation therapy (ADT) in patients with metastatic castration-sensitive prostate cancer. The final analysis confirmed improvement in OS and other long-term outcomes. We evaluated prostate-specific antigen (PSA) kinetics and the association between PSA decline and outcomes in patients with metastatic castration-sensitive prostate cancer from TITAN. PATIENTS AND METHODS: Patients received apalutamide (240 mg/day) or placebo plus ADT (1 : 1). This post hoc exploratory analysis evaluated PSA kinetics and decline in relation to rPFS (22.7 months' follow-up) and OS, time to PSA progression, and time to castration resistance (44.0 months' follow-up) in patients with or without confirmed PSA decline using a landmark analysis, the Kaplan-Meier method, and Cox proportional hazards model. RESULTS: One thousand and fifty-two patients (apalutamide, 525; placebo, 527) were enrolled. Best confirmed PSA declines (≥50% or ≥90% from baseline or to ≤0.2 ng/ml) were achieved at any time during the study in 90%, 73%, and 68% of apalutamide-treated versus 55%, 29%, and 32% of placebo-treated patients, respectively. By 3 months of apalutamide treatment, best deep PSA decline of ≥90% or to ≤0.2 ng/ml occurred in 59% and 51% of apalutamide- and in 13% and 18% of placebo-treated patients, respectively. Achievement of deep PSA decline at landmark 3 months of apalutamide treatment was associated with longer OS [hazard ratio (HR) 0.35; 95% confidence interval (CI) 0.25-0.48), rPFS (HR 0.44; 95% CI 0.30-0.65), time to PSA progression (HR 0.31; 95% CI 0.22-0.44), and time to castration resistance (HR 0.38; 95% CI 0.27-0.52) compared with no decline (P < 0.0001 for all). Similar results were observed at landmark 6 and 12 months of apalutamide treatment. CONCLUSIONS: Apalutamide plus ADT demonstrated a robust (rapid, deep, and durable) PSA decline that was associated with improved clinical outcomes, including long-term survival.

A phylogenetic analysis using multidirectional chromosome painting of three species (Uroderma magnirostrum, U. bilobatum and Artibeus obscurus) of subfamily Stenodermatinae (Chiroptera-Phyllostomidae).

The species of genera Uroderma and Artibeus are medium-sized bats belonging to the family Phyllostomidae and subfamily Stenodermatinae (Mammalia, Chiroptera) from South America. They have a wide distribution in the Neotropical region, with two currently recognized species in Uroderma and approximately 20 species in Artibeus. These two genera have different rates of chromosome evolution, with Artibeus probably having retained the ancestral karyotype for the subfamily. We used whole chromosome paint probe sets from Carollia brevicauda and Phyllostomus hastatus on Uroderma magnirostrum, Uroderma bilobatum, and Artibeus obscurus. With the aim of testing the previous phylogenies of these bats using cytogenetics, we compared these results with published painting maps on Phyllostomidae. The genome-wide comparative maps based on chromosome painting and chromosome banding reveal the chromosome forms that characterize each taxonomic level within the Phyllostomidae and show the chromosome evolution of this family. Based on this, we are able to suggest an ancestral karyotype for Phyllostomidae. Our cladistic analysis is an independent confirmation using multidirectional chromosome painting of the previous Phyllostomidae phylogenies.

Chromosomal homologies among vampire bats revealed by chromosome painting (phyllostomidae, chiroptera).

Substantial effort has been made to elucidate karyotypic evolution of phyllostomid bats, mostly through comparisons of G-banding patterns. However, due to the limited number of G-bands in respective karyotypes and to the similarity of non-homologous bands, an accurate evolutionary history of chromosome segments remains questionable. This is the case for vampire bats (Desmodontinae). Despite several proposed homologies, banding data have not yet provided a detailed understanding of the chromosomal changes within vampire genera. We examined karyotype differentiation of the 3 species within this subfamily using whole chromosomal probes from Phyllostomus hastatus (Phyllostominae) and Carollia brevicauda (Carolliinae). Painting probes of P. hastatus respectively detected 22, 21 and 23 conserved segments in Diphylla ecaudata, Diaemus youngi, and Desmodus rotundus karyotypes, whereas 27, 27 and 28 were respectively detectedwith C. brevicauda paints. Based on the evolutionary relationships proposed by morphological and molecular data, we present probable chromosomal synapomorphies for vampire bats and propose chromosomes that were present in the common ancestor of the 5 genera analyzed. Karyotype comparisons allowed us to relate a number of conserved chromosomal segments among the 5 species, providing a broader database for understanding karyotype evolution in the family.

Verificação do prazo de validade de cremes contendo hidroquinona preparados magistralmente: evidências do processo de oxidação / Shelf life testing of compounded hydroquinone creams: evidence of oxidation

A maioria das preparações dermocosméticas clareadoras da pele contém hidroquinona. A tentativa de se obter estabilidade desta substância pode ser considerada um desafio, pois ela sofre decomposição química facilmente, especialmente a auto-oxidação. O objetivo deste trabalho foi verificar o prazo de validade de cremes contendo hidroquinona preparados magistralmente em Presidente Prudente-SP. Para tanto, foram adquiridas em cinco farmácias de manipulação desta cidade três embalagens de creme contendo 2% deste ingrediente, os quais foram submetidos a análises periódicas dentro do prazo de validade vigente. As amostras foram submetidas à avaliação das caracteristicas organolépticas, ao teste de estabilidade por centrifugação, à determinação dos valores de pH e a análises de absorção no ultravioleta a fim de dosar a concentração de hidroquinona no creme. Os resultados obtidos mostraram que os cremes contendo esta substância não cumprem o prazo de validade declarado no rótulo, uma vez que todas as preparações não apresentaram acordância farmacopéica (USP 30) frente aos ensaios de doseamento e pH, embora não haja significância (p > 0,05) no teor de hidroquinona encontrado nos produtos.

Most skin-lightening cosmetic preparations contain hydroquinone. Improving the stability of hydroquinone can be described as a challenge, as this substance undergoes chemical decomposition easily, especially autoxidation. The objective of this study was to determine the shelf life of hydroquinone creams compounded in Presidente Prudente (SP, Brazil). To this end, 3 tubes of cream containing 2% hydroquinone were purchased in each of 5 pharmacies in this city and subjected to periodic analysis within the recommended shelf life. The cream samples were assessed with respect to organoleptic characteristics, stability under centrifugation, pH and analyzed for hydroquinone content by UV absorption spectroscopy. The results showed that the creams did not exhibit the shelf life stated on the label, since after 45 days none of the preparations were in accord with pharmacopoeial specifications (USP 30) for hydroquinone content and pH, although there was no significant difference (p > 0.05) between the hydroquinone contents of the 5 products.

Desenvolvimento de excipiente específico para cápsulas de nifedipina preparadas magistralmente: parte I / Development of specific excipient for compounded nifedipine capsules. Part I

O presente trabalho tem o objetivo de desenvolver um excipiente específico para cápsula de nifedipina preparada magistralmente, o qual permita o cumprimento dos requisitos farmacopéicos e legais, conforme preconiza a RDC nº 87 de 21 de novembro de 2008. Para isso, foram propostas 6 formulações contendo 10mg de nifedipina, sendo, quatro destas, denominadas A, B, C e D, baseadas na composição de um medicamento industrializado, enquanto as formulações, E e F baseadas em sugestões opcionais de excipientes em função do Sistema de Classificação Biofarmacêutico. Em seguida, estas foram submetidas aos testes de uniformidade de conteúdo e de dissolução utilizando absorção por espectrofotometria na região da ultravioleta (λ = 236nm) para obtenção dos resultados. As amostras (n = 3) se comportaram de forma adequada no teste de uniformidade de conteúdo, entretanto, no teste de dissolução, as formulações não apresentaram uma quantidade satisfatória de ativo dissolvido em 20 min. Pode-se observar uma evolução das formulações quanto à presença de Tween 80 na E, e na F. Entretanto, o aumento na concentração deste agente, não ampliou o perfil de dissolução da nifedipina, pois não houve diferença significativa deste parâmetro entre as duas (E e F). Dentre as fórmulas propostas neste trabalho, concluiu-se que não foi possível determinar uma, que fosse adequada para a aprovação do produto, com a liberação de apenas 20 a 40% do ativo, indicando que há necessidade de novos estudos.

The objective of this study was to develop a specific excipient for extemporaneously compounded nifedipine capsules, which would comply with the specifications of the pharmacopoeia and the legal requisites, set out in Brazilian Health Regulation RDC 87 of November 21, 2008. To this end, 6 formulations for capsules containing 10mg of nifedipine were proposed, the first four (A, B, C and D) being based on the composition of a manufactured medicine, while formulations E and F were based on an alternative excipient, suggested in accordance with the Biopharmaceutical Classification System. After preparation, the formulated capsules were subjected to content uniformity and dissolution tests, using UV absorption spectrophotometry (λ = 236nm) to assay the drug. The samples (n = 3) were found to have adequate content uniformity; however, in the dissolution test, the formulations did not show a satisfactory quantity of dissolved drug in 20 minutes. The formulations E and F were designed with differing amounts of Tween 80. However, increasing the concentration did not improve the dissolution profile of the nifedipine, as there was no significant difference in this parameter between E and F. It was concluded that none of the formulations proposed in this paper could be indicated as suitable for product approval, given that only 20 to 40% of the active component was released, indicating that there is a need for further studies.

Evaluation of nanoparticles loaded with benzopsoralen in rat peritoneal exudate cells.

Psoralens are widely used for the treatment of hyperproliferative skin disease. In this work, we prepared nanoparticles (NP) containing a benzopsoralen (3-ethoxy carbonyl-2H-benzofuro[3,2-f]-1-benzopiran-2-one) by the solvent evaporation technique. We evaluated important NP parameters such as particle size, drug encapsulation efficiency, effect of the encapsulation process over the drug's photochemistry, zeta potential, external morphology, and in vitro release behavior. We also investigated the nanoparticle as a drug delivery system (DDS), as well as its target delivery to the action site, which is a very important parameter to increase the therapeutic use of psoralens and to reduce their side effects. The uptake of benzopsoralen-loaded PLGA nanoparticles by different kinds of cells found in rat peritoneal exudates was also studied. The photodamage promoted by irradiation with UV light revealed morphological characteristics of cell damage such as cytoplasmic vesiculation, mitochondrial damage, and swelling of both the granular endoplasmatic reticulum and nuclear membrane. This encapsulation method maintained the drug's properties and improved drug delivery to the target cell.

The antioxidant action of Polypodium leucotomos extract and kojic acid: reactions with reactive oxygen species

Two natural products Polypodium leucotomos extract (PL) and kojic acid (KA) were tested for their ability to scavenge reactive oxygen species (ÀOH, ÀO2-, H2O2, ¹O2) in phosphate buffer. Hydroxyl radicals were generated by the Fenton reaction, and the rate constants of scavenging were 1.6 x 10(9) M-1 s-1 for KA and 1.0 x 10(9) M-1 s-1 for PL, similar to that of ethanol (1.4 x 10(9) M-1 s-1). With superoxide anions generated by the xanthine/hypoxanthine system, KA and PL (0.2-1.0 mg/ml) inhibited ÀO2-dependent reduction of nitroblue tetrazolium by up to 30 and 31 percent, respectively. In the detection of ¹O2 by rose bengal irradiation, PL at 1.0 mg/ml quenched singlet oxygen by 43 percent relative to azide and KA by 36 percent. The present study demonstrates that PL showed an antioxidant effect, scavenging three of four reactive oxygen species tested here. Unlike KA, PL did not significantly scavenge hydrogen peroxide

The antioxidant action of Polypodium leucotomos extract and kojic acid: reactions with reactive oxygen species.

Two natural products Polypodium leucotomos extract (PL) and kojic acid (KA) were tested for their ability to scavenge reactive oxygen species (.OH,.O2-, H2O2, 1O2) in phosphate buffer. Hydroxyl radicals were generated by the Fenton reaction, and the rate constants of scavenging were 1.6 x 10(9) M-1 s-1 for KA and 1.0 x 10(9) M-1 s-1 for PL, similar to that of ethanol (1.4 x 10(9) M-1 s-1). With superoxide anions generated by the xanthine/hypoxanthine system, KA and PL (0.2-1.0 mg/ml) inhibited.O2-dependent reduction of nitroblue tetrazolium by up to 30 and 31%, respectively. In the detection of 1O2 by rose bengal irradiation, PL at 1.0 mg/ml quenched singlet oxygen by 43% relative to azide and KA by 36%. The present study demonstrates that PL showed an antioxidant effect, scavenging three of four reactive oxygen species tested here. Unlike KA, PL did not significantly scavenge hydrogen peroxide.

Hypersensitivity reaction associated with acute hepatic dysfunction following a single intravenous dose of procainamide.

Rare cases of hepatotoxicity have been attributed to the antiarrhythmic agent procainamide. We here describe the case of a patient who had a hypersensitivity reaction to procainamide with fever, chills, arthralgia, abdominal pain and acute elevations of serum aminotransferase activities and bilirubin concentration. The reaction occurred after the patient had received a large intravenous dose during cardiac electrophysiological testing. This case should alert physicians to potential hepatotoxic reactions to procainamide, particularly with the increasing popularity of cardiac electrophysiological testing, during which this drug is commonly used.

Determinants of pace-terminable ventricular tachycardia: implications for implantable antitachycardia devices.

The next generation of implantable antitachycardia devices incorporate antitachycardia pacing for the treatment of ventricular tachycardia. To evaluate the potential determinants of pace terminability, we analyzed 62 episodes of induced monomorphic ventricular tachycardia. We found that the tachycardia cycle length and cycle length variability are the major determinants of pace terminability. These findings should be considered in the designing of ventricular tachycardia detection and termination algorithms.

Cirurgia de Burch e suas complicacoes imediatas. / Burch surgery and its immediate complications

Os autores apresentam 85 pacientes com I.U.E. operadas pela tecnica proposta por Burch. Apos descrever os criterios adotados no diagnostico da I.U.E., as indicacoes da via retropubica e os cuidados peroperatorios, apresentam suas complicacoes no pos-operatorio imediato ligadas a cirurgia adotada. As possiveis causas que contribuiram sao analisadas e medidas profilaticas sao propostas