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1.
J Alzheimers Dis ; 96(2): 759-766, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-37742657

RESUMO

BACKGROUND: In pre-clinical studies, Bryostatin, MW (molecular weight) 904, has demonstrated synaptogenic, anti-apoptotic, anti-amyloid, and anti-tau tangle efficacies. OBJECTIVE: To identify AD patients who show significant cognitive benefit versus placebo when treated in a trial with chronic Bryostatin dosing. METHODS: In this 6-month 122 AD patient Bryostatin trial, there were two cohorts: the Moderate Cohort (MMSE, Mini-Mental Status Exam: 15-18) and the Moderately Severe Cohort (MMSE 10-14) as pre-specified secondary endpoints. Patient randomization was stratified by baseline SIB to insure balance in baseline cognitive ability between treatment arms. RESULTS: With no safety events noted by the data safety and monitoring board, the Moderately Severe (MMSE 10-14) Bryostatin-treated patients were significantly improved above the placebo patients for Weeks #13 through Week #42. After two cycles of 7 x i.v. Bryostatin doses over a 26-week period, the 10-14 Cohort Severe Impairment Battery (SIB), measured every 2 weeks, showed significant benefit using a Mixed Model Repeated Measures model (MMRM, 2-tailed, p < 0.05) for Weeks #13 through #42, even 16 weeks after dosing completion by Week #26. Placebo 10-14 patients showed no benefit, declining to negative 12.8 points by Week #42. Trend analyses confirmed the MMRM data for this Cohort, with a significant downward slope (equivalent to Cognitive Decline) for the placebo group, p < 0.001, 2-tailed, but no significant decline for the Bryostatin-treated group (p = 0.409, NS), treatment versus placebo p < 0.007. The Moderate Cohort patients showed no significant benefit. CONCLUSIONS: The Bryostatin-treated MMSE 10-14 patients showed no significant cognitive decline throughout the 10-month trial, versus placebo patients' decline of -12.8 SIB points.


Assuntos
Doença de Alzheimer , Transtornos Cognitivos , Humanos , Doença de Alzheimer/tratamento farmacológico , Doença de Alzheimer/complicações , Briostatinas/efeitos adversos , Transtornos Cognitivos/tratamento farmacológico , Método Duplo-Cego , Resultado do Tratamento
2.
J Alzheimers Dis ; 67(2): 555-570, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30530975

RESUMO

BACKGROUND: Bryostatin-activated PKC epsilon pre-clinically induces synaptogenesis, anti-apoptosis, anti-amyloid-ß oligomers, and anti-hyperphosphorylated tau. OBJECTIVES: To investigate bryostatin safety, tolerability, and efficacy to improve cognition in advanced Alzheimer's disease (AD) patients. METHODS: A double-blind, randomized, placebo-controlled Phase II, 12-week trial of i.v. bryostatin for 150 advanced AD patients (55-85) with MMSE-2 of 4-15, randomized 1:1:1 into 20 µg and 40 µg bryostatin, and placebo arms. The Full Analysis Set (FAS) and the Completer Analysis Set (CAS) were pre-specified alternative assessments (1-sided, p < 0.1 for primary efficacy, and 2-sided, p < 0.05 for pre-specified and post hoc exploratory analyses). RESULTS: The safety profile was similar for 20 µg treatment and placebo patients. The 40 µg patients showed safety and drop-out issues, but no efficacy. Primary improvement of Severe Impairment Battery (SIB) scores at 13 weeks was not significant (p = 0.134) in the FAS, although in the CAS, the SIB comparison favored 20 µg bryostatin compared to placebo patients (p < 0.07). Secondary analyses at weeks 5 and 15 (i.e., 30 days post-final dosing) also favored 20 µg bryostatin compared to placebo patients. A pre-specified ANCOVA for baseline memantine blocking bryostatin and positive post-hoc trend analyses were statistically significant (2-sided, p < 0.05). CONCLUSION: Although the primary endpoint was not significant in the FAS, primary and secondary analyses in the CAS, and pre-specified and post-hoc exploratory analyses did favor bryostatin 20 µg compared to the placebo cohort. These promising Phase II results support further trials of 20 µg bryostatin- without memantine- to treat AD.


Assuntos
Doença de Alzheimer/tratamento farmacológico , Briostatinas/efeitos adversos , Briostatinas/uso terapêutico , Atividades Cotidianas , Idoso , Idoso de 80 Anos ou mais , Doença de Alzheimer/psicologia , Briostatinas/administração & dosagem , Cognição , Relação Dose-Resposta a Droga , Método Duplo-Cego , Feminino , Humanos , Infusões Intravenosas , Masculino , Testes de Estado Mental e Demência , Pessoa de Meia-Idade , Resultados Negativos , Pacientes Desistentes do Tratamento , Resultado do Tratamento
3.
J Immunol ; 198(3): 1229-1241, 2017 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-27994072

RESUMO

A shock-and-kill approach involving the simultaneous treatment of HIV-1-infected patients with latency-reversing agents (LRAs) and combination antiretroviral therapy was proposed as a means to eradicate viral reservoirs. Currently available LRAs cannot discriminate between HIV-1-infected and uninfected cells. Therefore, the risks and benefits of using broad-spectrum LRAs need to be carefully evaluated, particularly in the CNS, where inflammation and leukocyte transmigration must be tightly regulated. We used a real-time impedance-sensing system to dynamically record the impact of different classes of LRAs on the integrity of tight monolayers of the immortalized human cerebral microvascular endothelial cell line hCMEC/D3. Results show that prostratin and bryostatin-1 can significantly damage the integrity of an endothelial monolayer. Moreover, prostratin and bryostatin-1 induce secretion of some proinflammatory cytokines and an increase of ICAM-1 expression. Additional studies demonstrated that prostratin and bryostatin-1 also affect adhesion and transmigration of CD4+ and CD8+ T cells as well as monocytes in an in vitro human blood-brain barrier (BBB) model. Prostratin and bryostatin-1 could thus be considered as potent regulators of BBB permeability and inflammation that influence leukocyte transport across the BBB. Altogether, these findings contribute to a better understanding of the potential risks and benefits of using a shock-and-kill approach with LRAs on the normal physiological functions of the BBB.


Assuntos
Barreira Hematoencefálica/efeitos dos fármacos , Briostatinas/farmacologia , HIV-1/fisiologia , Leucócitos/efeitos dos fármacos , Ésteres de Forbol/farmacologia , Latência Viral/efeitos dos fármacos , Acetamidas/farmacologia , Azacitidina/análogos & derivados , Azacitidina/farmacologia , Azepinas/farmacologia , Briostatinas/efeitos adversos , Adesão Celular/efeitos dos fármacos , Moléculas de Adesão Celular/análise , Movimento Celular/efeitos dos fármacos , Células Cultivadas , Quimiocina CCL2/fisiologia , Citocinas/metabolismo , Decitabina , Humanos , Inflamação/induzido quimicamente , Molécula 1 de Adesão Intercelular/análise , Leucócitos/fisiologia , Ésteres de Forbol/efeitos adversos , Quinazolinas/farmacologia , Receptores de Superfície Celular/análise
4.
AIDS ; 30(9): 1385-92, 2016 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-26891037

RESUMO

OBJECTIVE: The protein kinase C (PKC) agonist bryostatin-1 has shown significant ex-vivo potency to revert HIV-1 latency, compared with other latency reversing agents (LRA). The safety of this candidate LRA remains to be proven in treated HIV-1-infected patients. METHODS: In this pilot, double-blind phase I clinical-trial (NCT 02269605), we included aviraemic HIV-1-infected patients on triple antiretroviral therapy to evaluate the effects of two different single doses of bryostatin-1 (10 or 20 µg/m) compared with placebo. RESULTS: Twelve patients were included, four in each arm. Bryostatin-1 was well tolerated in all participants. Two patients in the 20 µg/m arm developed grade 1 headache and myalgia. No detectable increases of cell-associated unspliced (CA-US) HIV-1-RNA were observed in any study arm, nor differences in HIV-1 mRNA dynamics between arms (P = 0.44). The frequency of samples with low-level viraemia did not differ between arms and low-level viraemia did not correlate with CA-US HIV-1-RNA levels (P = 0.676). No changes were detected on protein kinase C (PKC) activity and in biomarkers of inflammation (sCD14 and interleukin-6) in any study arm. After the single dose of bryostatin-1, plasma concentrations were under detection limits in all the patients in the 10 µg/m arm, and below 50 pg/ml (0.05 nmol/l) in those in the 20 µg/m arm. CONCLUSION: Bryostatin-1 was safe at the single doses administered. However, the drug did not show any effect on PKC activity or on the transcription of latent HIV, probably due to low plasma concentrations. This study will inform next trials aimed at assessing higher doses, multiple dosing schedules or combination studies with synergistic drugs.


Assuntos
Antirretrovirais/uso terapêutico , Briostatinas/administração & dosagem , Briostatinas/efeitos adversos , Ativadores de Enzimas/administração & dosagem , Ativadores de Enzimas/efeitos adversos , Infecções por HIV/tratamento farmacológico , Latência Viral/efeitos dos fármacos , Adulto , Método Duplo-Cego , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/epidemiologia , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/patologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Projetos Piloto , Placebos/administração & dosagem , Resultado do Tratamento
5.
Oncologist ; 19(4): 354-5, 2014 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-24674872

RESUMO

BACKGROUND: Temsirolimus, an inhibitor of mammalian target of rapamycin (mTOR) complex 1, is approved for the treatment of metastatic renal cell carcinoma (RCC). Bryostatin-1 inhibits protein kinase C, a downstream effector of mTOR complex 2. We observed antitumor effects with the combination of temsirolimus and bryostatin-1 in RCC cell lines. METHODS. Four cohorts of patients received weekly bryostatin-1 (20 µg/m²) with temsirolimus (10, 15, 25, or 37.5 mg) in 28-day cycles. RESULTS: Thirty patients received a total of 138 cycles across four dose levels. Twenty-five patients had RCC (17 clear cell, 7 papillary, and 1 unclassified). Two sarcoma patients with prior cytotoxic therapy experienced dose-limiting toxicity at 15 mg of temsirolimus (grade 3 neutropenia and grade 3 hypophosphatemia). Subsequently, patients with prior cytotoxic therapy were excluded. Two additional dose-limiting toxicities were noted with 37.5 mg of temsirolimus (grade 3 neutropenia and grade 3 creatinine elevation). Consequently, the maximum tolerated dose was defined as temsirolimus at 25 mg and bryostatin-1 at 20 µg/m² every 28 days. Of the 25 RCC patients, 3 patients had partial responses that lasted for 14 months, 28 months, and ≥ 80 months, respectively. Partial responses were seen in both clear cell and papillary histology. CONCLUSION: This combination of 37.5 mg of temsirolimus with 20 µg/m² of bryostatin-1 was reasonably safe and well tolerated. Durable responses were observed in 3 of 25 patients with RCC.


Assuntos
Briostatinas/uso terapêutico , Carcinoma de Células Renais/tratamento farmacológico , Neoplasias Renais/tratamento farmacológico , Sarcoma/tratamento farmacológico , Sirolimo/análogos & derivados , Antineoplásicos/efeitos adversos , Antineoplásicos/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Briostatinas/efeitos adversos , Carcinoma de Células Renais/mortalidade , Esquema de Medicação , Humanos , Neoplasias Renais/mortalidade , Alvo Mecanístico do Complexo 1 de Rapamicina , Complexos Multiproteicos/antagonistas & inibidores , Proteína Quinase C/antagonistas & inibidores , Inibidores de Proteínas Quinases/efeitos adversos , Inibidores de Proteínas Quinases/uso terapêutico , Sarcoma/mortalidade , Sirolimo/efeitos adversos , Sirolimo/uso terapêutico , Serina-Treonina Quinases TOR/antagonistas & inibidores , Resultado do Tratamento
6.
Am J Hematol ; 84(8): 484-7, 2009 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-19536846

RESUMO

Bryostatin 1, isolated from a marine bryozoan, enhances the efficacy of cytotoxic agents through modulation of the protein kinase C pathway and is active in combination with vincristine for diffuse large B-cell lymphoma. Further, the apoptotic frequency of peripheral blood T lymphocytes as determined by flow cytometry may predict which patients will respond to this combination. We tested the efficacy and safety of bryostatin 1 50 microg/m(2) given over 24 hr and vincristine 1.4 mg/m(2) on days 1 and 15 every 28 days in aggressive B-cell non-Hodgkin lymphoma (NHL) relapsing after autologous stem cell transplantation. End points included tumor response, toxicity, and survival. Responses were correlated with an increase in apoptotic frequency of CD5+ cells by flow cytometry using annexin V staining. Fourteen patients were enrolled with 13 being evaluable for a response. The overall response rate was 31% with two patients achieving a complete response. The most common toxicities were Grade 3 lymphopenia (seven patients), Grade 3 to 4 neutropenia (two patients), and Grade 3 hypophosphatemia (two patients). Median progression-free and overall survivals for all patients were 5.7 and 21.4 months, respectively. One patient demonstrated an increase in T-cell apoptotic frequency, also achieving a complete response. Bryostatin 1 and vincristine have efficacy in select patients with aggressive NHL. Future investigations of agents targeting the protein kinase C pathway may benefit from early response assessment using flow cytometry to evaluate T-cell apoptosis.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Linfoma de Células B/prevenção & controle , Transplante de Células-Tronco , Idoso , Anexina A5/metabolismo , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Apoptose/efeitos dos fármacos , Briostatinas/administração & dosagem , Briostatinas/efeitos adversos , Antígenos CD5/sangue , Intervalo Livre de Doença , Feminino , Humanos , Linfoma de Células B/sangue , Linfopenia/sangue , Linfopenia/induzido quimicamente , Masculino , Pessoa de Meia-Idade , Proteína Quinase C/metabolismo , Recidiva , Taxa de Sobrevida , Linfócitos T/metabolismo , Transplante Autólogo , Vincristina/administração & dosagem , Vincristina/efeitos adversos
7.
Cancer Chemother Pharmacol ; 64(4): 803-10, 2009 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-19221754

RESUMO

PURPOSE: Preclinical data suggested that bryostatin-1 (bryo) could potentiate the cytotoxicity of cisplatin when given prior to this drug. We designed a phase I study to achieve tolerable doses and schedules of bryo and cisplatin in combination and in this sequence. METHODS: Patients with non-hematologic malignancies received bryo followed by cisplatin in several schedules. Bryo was given as an 1 and a 24 h continuous infusion, while cisplatin was always given over 1 h at 50 and 75 mg/m(2); the combined regimen was repeated on an every 3-week and later on an every 2-week schedule. Bryo doses were escalated until recommended phase II doses were defined for each schedule. Patients were evaluated with computerized tomography every 2 cycles. RESULTS: Fifty-three patients were entered. In an every 2-week schedule, the 1-h infusion of bryo became limited by myalgia that was clearly cumulative. With cisplatin 50 mg/m(2) its recommended phase II dose was 30 microg/m(2). In the 3-week schedule, dose-limiting toxicities were mostly related to cisplatin effects while myalgias were tolerable. Pharmacokinetics unfortunately proved to be unreliable due to bryo's erratic extraction. Consistent inhibition of PKC isoform eta (eta) in peripheral blood mononuclear cells was observed following bryo. CONCLUSIONS: Bryo can be safely administered with cisplatin with minimal toxicity; however, only four patients achieved an objective response. Modulation of cisplatin cytotoxicity by bryo awaits further insight into the molecular pathways involved.


Assuntos
Antineoplásicos/uso terapêutico , Briostatinas/uso terapêutico , Cisplatino/uso terapêutico , Neoplasias/tratamento farmacológico , Proteína Quinase C/efeitos dos fármacos , Adulto , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos/administração & dosagem , Antineoplásicos/efeitos adversos , Antineoplásicos/farmacocinética , Briostatinas/efeitos adversos , Briostatinas/farmacocinética , Briostatinas/farmacologia , Cisplatino/efeitos adversos , Cisplatino/farmacocinética , Feminino , Humanos , Masculino , Dose Máxima Tolerável , Pessoa de Meia-Idade , Neoplasias/enzimologia
8.
Trends Biochem Sci ; 34(3): 136-45, 2009 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-19233655

RESUMO

Protein kinase C (PKC) activators possess potent neurotrophic and neuroprotective activity, thus indicating potential applications in treating neurodegenerative diseases, stroke and traumatic brain injury. Although some activators, such as bryostatin and gnidimacrin, have been tested as antitumor agents, others, such as phorbol esters, are potent tumor promoters. All PKC activators downregulate PKC at high concentrations and long application times. However, tumorigenic activators downregulate certain PKC isozymes, especially PKCdelta, more strongly. Tumorigenic activators possess unique structural features that could account for this difference. At concentrations that minimize PKC downregulation, PKC activators can improve long-term memory, reduce beta-amyloid levels, induce synaptogenesis, promote neuronal repair and inhibit cell proliferation. Intermittent, low concentrations of structurally specific, non-tumorigenic PKC activators, therefore, could offer therapeutic benefit for a variety of neurologic disorders.


Assuntos
Carcinógenos/farmacologia , Ativação Enzimática/efeitos dos fármacos , Proteína Quinase C/metabolismo , Sítios de Ligação , Briostatinas/efeitos adversos , Briostatinas/farmacologia , Diterpenos/efeitos adversos , Diterpenos/farmacologia , Regulação para Baixo , Modelos Moleculares , Doenças Neurodegenerativas/tratamento farmacológico , Doenças Neurodegenerativas/metabolismo , Ésteres de Forbol/efeitos adversos , Ésteres de Forbol/farmacologia , Proteína Quinase C/química
9.
Clin Cancer Res ; 12(23): 7059-62, 2006 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-17145828

RESUMO

PURPOSE: Bryostatin 1 is a macrocyclic lactone with protein kinase C inhibitory activity. Gemcitabine is a nucleotide analogue with a broad spectrum of anticancer activity. Bryostatin 1 enhanced the activity of antitumor agents including gemcitabine in preclinical models. The primary objective of this phase I study was to determine the recommended doses for phase II trials of bryostatin 1 and gemcitabine. EXPERIMENTAL DESIGN: Eligible patients had histologic or cytologic diagnosis of nonhematologic cancer refractory to conventional treatment; life expectancy of >3 months; normal renal, hepatic, and bone marrow function; and a Southwest Oncology Group performance status of 0 to 2. Gemcitabine was administered i.v. over 30 minutes and was followed by bryostatin 1 by i.v. infusion over 24 hours on days 1, 8, and 15 of a 28-day cycle. Bryostatin 1 (microg/m(2)) and gemcitabine (mg/m(2)) doses were escalated as follows: 25/600, 25/800, 25/1,000, 30/1,000, 35/1,000, and 45/1,000, respectively. RESULTS: Thirty-six patients (mean age, 57 years; male/female 15:21) were treated. The median number of treatment cycles per patient was 3 (range, 0-24). Four patients developed dose limiting toxicities: myalgia, 2; myelosuppression, 1; and elevation of serum alanine aminotransferase levels, 1. Ten grade 3 toxicities were observed (anemia, 2; neutropenia, 5; thrombocytopenia, 3). No treatment-related death was seen. The recommended doses for phase II trials for bryostatin 1 and gemcitabine were 35 microg/m(2) and 1,000 mg/m(2), respectively. Two heavily pretreated patients with breast and colon cancer experienced partial responses lasting 22 and 8 months, respectively. Eight patients had stable disease. CONCLUSION: The combination of bryostatin 1 and gemcitabine seemed to be well tolerated with limited grade 3 toxicity. The recommended dose of bryostatin 1 in combination with full doses of gemcitabine was 35 microg/m(2).


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Briostatinas/administração & dosagem , Desoxicitidina/análogos & derivados , Neoplasias/tratamento farmacológico , Adolescente , Adulto , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Briostatinas/efeitos adversos , Desoxicitidina/administração & dosagem , Desoxicitidina/efeitos adversos , Relação Dose-Resposta a Droga , Esquema de Medicação , Feminino , Seguimentos , Humanos , Injeções Intravenosas , Masculino , Dose Máxima Tolerável , Pessoa de Meia-Idade , Neoplasias/diagnóstico , Resultado do Tratamento , Gencitabina
10.
Invest New Drugs ; 24(2): 141-9, 2006 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-16514482

RESUMO

PURPOSE: Bryostatin-1 is a PKC modulator with direct anti-tumor activity and immunomodulatory properties. We combined different doses of Bryostatin-1 with IL-2 to determine effects on clinical response rate and T cell phenotype in patients with advanced kidney cancer. EXPERIMENTAL DESIGN: IL-2 naïve patients were given 11 x 10(6) IU subcutaneously of IL-2 on days 1-4, 8-11, and 15-18 of every 28-day cycle. Twenty four patients were randomized to treatment cohorts of 5, 15 or 25 mcg/m2 of Bryostatin-1 on days 1, 8 and 15, starting in the second cycle. An additional nine, non-randomized patients were given 35 mcg/m2. Lymphocytes were analyzed for number, activation status, and production of IL-2, IL-4 and IFN-gamma. Response evaluation was performed every 3 cycles. RESULTS: Common grade 3 toxicities included fatigue (5), nausea/vomiting (5), myopathy (3), dyspnea (3), and syncope (3). Four patients, in the two highest dose cohorts, demonstrated evidence of tumor shrinkage, although there was only 1 objective PR. The median time to progression was 104 days (95% CI 88-120) and the median survival was 452 days (95% CI = 424-480). There was no significant boosting effect of Bryostatin-1 on lymphocytes. CONCLUSIONS: The addition of Bryostatin-1 to IL-2 was well tolerated, but the overall response rate was low (3.2%), indicating that further studies with this combination are not warranted.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Briostatinas/administração & dosagem , Carcinoma de Células Renais/tratamento farmacológico , Interleucina-2/administração & dosagem , Neoplasias Renais/tratamento farmacológico , Idoso , Idoso de 80 Anos ou mais , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Briostatinas/efeitos adversos , Carcinoma de Células Renais/imunologia , Citocinas/biossíntese , Relação Dose-Resposta a Droga , Feminino , Humanos , Interleucina-2/efeitos adversos , Neoplasias Renais/imunologia , Masculino , Pessoa de Meia-Idade , Metástase Neoplásica , Linfócitos T/efeitos dos fármacos , Linfócitos T/metabolismo , Falha de Tratamento
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