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1.
Intern Med J ; 53(12): 2346-2349, 2023 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-38130050

RESUMO

This cost analysis, from a societal perspective, compared the cost difference of a networked teletrial model (NTTM) with four regional hubs versus conventional trial operation at a single metropolitan specialist centre. The Australian phase 3 cancer interventional randomised controlled trial included 152 of 328 regional participants (patient enrolment 2018-2021; 6-month primary end point). The NTTM significantly reduced (AU$2155 per patient) patient travel cost and time and lost productivity.


Assuntos
Neoplasias , Telemedicina , Humanos , Austrália/epidemiologia , Análise Custo-Benefício , Custos e Análise de Custo , Oncologia , Neoplasias/epidemiologia , Neoplasias/terapia , Ensaios Clínicos Controlados Aleatórios como Assunto , Ensaios Clínicos Fase III como Assunto
2.
AAPS PharmSciTech ; 24(8): 236, 2023 Nov 21.
Artigo em Inglês | MEDLINE | ID: mdl-37989972

RESUMO

Antibody-based therapeutics have recently gained keen attention for the treatment of pulmonary indications. However, systemically administered antibody exposure in the lungs needs to be better understood and remains a topic of interest. In this study, we evaluated the exposure of two different uPAR (urokinase-type plasminogen activator receptor) targeting full-length monoclonal IgGs in plasma and lung epithelial lining fluid (ELF) of mice after IP and IV administration. Antibody AK17 exhibited linear pharmacokinetics (PK) in plasma and ELF at 3 and 30 mg/kg single IV dose. The average plasma and ELF half-lives for AK17 and AK21 ranged between ~321-411 h and ~230-345 h, respectively, indicating sustained systemic and lung exposure of antibodies. The average ELF to the plasma concentration ratio of antibodies was ~0.01 and ~0.03 with IP and IV dosing, respectively, over 2 weeks post single dose. We simultaneously characterized plasma and ELF PK of antibody in mice by developing a minimal lung PBPK model for antibody. This model reasonably captured the plasma and ELF PK data while estimating three parameters. The model accounts for the convective transport of antibody into the tissues via blood and lymph flow. FcRn-mediated transcytosis was incorporated into the model for antibody distribution across the lung epithelial barrier. This model serves as a platform to predict the pulmonary PK of systemically administered antibodies and to support optimal dose selection for desired exposure in the lungs as the site of action.


Assuntos
Pulmão , Receptores de Ativador de Plasminogênio Tipo Uroquinase , Camundongos , Animais , Anticorpos Monoclonais , Antibacterianos
3.
Surg Endosc ; 36(10): 7295-7301, 2022 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-35165760

RESUMO

BACKGROUND: Drain practices in minimally invasive retromuscular ventral hernia repairs have largely been transferred over from open surgery without significant review. We wished to evaluate the role of drains in these repairs. METHODS: Using the Abdominal Wall Reconstruction Surgical Collaborative (AWRSC) registry, patients with ventral hernias who underwent enhanced-view totally extraperitoneal (eTEP) repairs between February 2016 and September 2019 were evaluated. Patients with contamination or active infection within the surgical field, those who underwent an emergent or hybrid repair, or received a concomitant procedure were excluded. Propensity score matching based on the defect size, previous hernia repair status, and the use of posterior component separation (PCS) was used to match patients with drains to patients without drains. We evaluated 180-day outcomes in terms of SSIs, SSOs, and recurrence. RESULTS: 308 patients met the inclusion criteria. After propensity score matching, 48 patients with drains and 72 without drains were included in the analysis cohort. Those with drains were older with a greater likelihood of an incisional hernia, but were broadly similar for other relevant demographic and hernia-related variables. While there was no difference in the incidence of SSOs and SSIs between the two groups, we report a higher risk of SSOs needing procedural intervention (SSOPI) and recurrence, with a lengthened hospital stay in the cohort that received surgical drains. CONCLUSION: The use of surgical drains in "clean" eTEP repairs of ventral hernias appears to be common, with a selection bias for more complex cases. Based on our analysis, we found the use of drains was associated with longer hospital stays. The use of drains did not change the likelihood of suffering an SSI or SSO. However, the incidence of SSOPIs was higher despite the use of drains, which raises questions about their protective role in these repairs.


Assuntos
Hérnia Ventral , Hérnia Incisional , Músculos Abdominais/cirurgia , Hérnia Ventral/complicações , Hérnia Ventral/cirurgia , Herniorrafia/métodos , Humanos , Hérnia Incisional/cirurgia , Estudos Retrospectivos , Telas Cirúrgicas/efeitos adversos
4.
Regul Toxicol Pharmacol ; 123: 104960, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-34022260

RESUMO

Cassia occidentalis Linn (CO) is an annual/perennial plant having traditional uses in the treatments of ringworm, gastrointestinal ailments and piles, bone fracture, and wound healing. Previously, we confirmed the medicinal use of the stem extract (ethanolic) of CO (henceforth CSE) in fracture healing at 250 mg/kg dose in rats and described an osteogenic mode of action of four phytochemicals present in CSE. Here we studied CSE's preclinical safety and toxicity. CSE prepared as per regulations of Current Good Manufacturing Practice for human pharmaceuticals/phytopharmaceuticals and all studies were performed in rodents in a GLP-accredited facility. In acute dose toxicity as per New Drug and Clinical Trial Rules, 2019 (prior name schedule Y), in rats and mice and ten-day dose range-finding study in rats, CSE showed no mortality and no gross abnormality at 2500 mg/kg dose. Safety Pharmacology showed no adverse effect on central nervous system, cardiovascular system, and respiratory system at 2500 mg/kg dose. CSE was not mutagenic in the Ames test and did not cause clastogenicity assessed by in vivo bone marrow genotoxicity assay. By a sub chronic (90 days) repeated dose (as per OECD, 408 guideline) study in rats, the no-observed-adverse-effect-level was found to be 2500 mg/kg assessed by clinico-biochemistry and all organs histopathology. We conclude that CSE is safe up to 10X the dose required for its osteogenic effect.


Assuntos
Compostos Fitoquímicos/toxicidade , Extratos Vegetais/toxicidade , Senna , Animais , Etanol , Camundongos , Nível de Efeito Adverso não Observado , Ratos , Roedores , Testes de Toxicidade
5.
Drug Metab Dispos ; 48(5): 368-377, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32086295

RESUMO

Antibody-drug conjugates (ADCs) employ overexpressed cell surface antigens to deliver cytotoxic payloads inside cancer cells. However, the relationship between target expression and ADC efficacy remains ambiguous. In this manuscript, we have addressed a part of this ambiguity by quantitatively investigating the effect of antigen expression levels on ADC exposure within cancer cells. Trastuzumab-valine-citrulline-monomethyl auristatin E was used as a model ADC, and four different cell lines with diverse levels of human epidermal growth factor receptor 2 (HER2) expression were used as model cells. The pharmacokinetics (PK) of total trastuzumab, released monomethyl auristatin E (MMAE), and total MMAE were measured inside the cells and in the cell culture media following incubation with two different concentrations of ADC. In addition, target expression levels, target internalization rate, and cathepsin B and MDR1 protein concentrations were determined for each cell line. All the PK data were mathematically characterized using a cell-level systems PK model for ADC. It was found that SKBR-3, MDA-MB-453, MCF-7, and MDA-MB-468 cells had ∼800,000, ∼250,000, ∼50,000, and ∼10,000 HER2 receptors per cell, respectively. A strong linear relationship (R 2 > 0.9) was observed between HER2 receptor count and released MMAE exposure inside the cancer cells. There was an inverse relationship found between HER2 expression level and internalization rate, and cathepsin B and multidrug resistance protein 1 (MDR1) expression level varied slightly among the cell lines. The PK model was able to simultaneously capture all the PK profiles reasonably well while estimating only two parameters. Our results demonstrate a strong quantitative relationship between antigen expression level and intracellular exposure of ADCs in cancer cells. SIGNIFICANCE STATEMENT: In this manuscript, we have demonstrated a strong linear relationship between target expression level and antibody-drug conjugate (ADC) exposure inside cancer cells. We have also shown that this relationship can be accurately captured using the cell-level systems pharmacokinetics model developed for ADCs. Our results indirectly suggest that the lack of relationship between target expression and efficacy of ADC may stem from differences in the pharmacodynamic properties of cancer cells.


Assuntos
Antineoplásicos Imunológicos/farmacocinética , Imunoconjugados/farmacocinética , Neoplasias/tratamento farmacológico , Oligopeptídeos/farmacocinética , Receptor ErbB-2/metabolismo , Trastuzumab/farmacocinética , Subfamília B de Transportador de Cassetes de Ligação de ATP/análise , Subfamília B de Transportador de Cassetes de Ligação de ATP/metabolismo , Antineoplásicos Imunológicos/análise , Antineoplásicos Imunológicos/uso terapêutico , Catepsina B/análise , Catepsina B/metabolismo , Linhagem Celular Tumoral , Resistencia a Medicamentos Antineoplásicos , Humanos , Imunoconjugados/análise , Imunoconjugados/uso terapêutico , Modelos Biológicos , Neoplasias/imunologia , Neoplasias/patologia , Oligopeptídeos/análise , Oligopeptídeos/uso terapêutico , Receptor ErbB-2/análise , Receptor ErbB-2/antagonistas & inibidores , Trastuzumab/análise , Trastuzumab/uso terapêutico
6.
Reprod Health ; 17(1): 11, 2020 01 21.
Artigo em Inglês | MEDLINE | ID: mdl-31964395

RESUMO

The authors have retracted this article [1] because it contains significant conceptual and textual overlap with unpublished work from another group. Suresh Mehata, Jamie Menzel, Erin Pearson and Kathryn Andersen agree with this retraction. Navaraj Bhattarai, Sharad Kumar Sharma and Mukta Shah did not respond to correspondence regarding this retraction.

7.
Biol Reprod ; 100(4): 917-938, 2019 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-30423016

RESUMO

Endometriosis is a prevalent gynecological disorder that eventually gives rise to painful invasive lesions. Increased levels of transforming growth factor-beta 1 (TGF-B1) have been reported in endometriosis. However, details of the effects of high TGF-B1 on downstream signaling in ectopic endometrial tissue remain obscure. We induced endometriotic lesions in mice by surgical auto-transplantation of endometrial tissues to the peritoneal regions. We then treated endometriotic (ectopic and eutopic endometrial tissues) and nonendometriotic (only eutopic endometrial tissues) animal groups with either active TGF-B1 or PBS. Our results demonstrate that externally supplemented TGF-B1 increases the growth of ectopically implanted endometrial tissues in mice, possibly via SMAD2/3 activation and PTEN suppression. Adhesion molecules integrins (beta3 and beta8) and FAK were upregulated in the ectopic endometrial tissue when TGF-B1 was administered. Phosphorylated E-cadherin, N-cadherin, and vimentin were enhanced in the ectopic endometrial tissue in the presence of TGF-B1 in the mouse model, and correlated with epithelial-mesenchymal transition (EMT) in ovarian endometriotic cells of human origin. Furthermore, in response to TGF-B1, the expression of RHOGTPases (RAC1, RHOC, and RHOG) was increased in the human endometriotic cells (ovarian cyst derived cells from endometriosis patient) and tissues from the mouse model of endometriosis (ectopic endometrial tissue). TGF-B1 enhanced the migratory, invasive, and colonizing potential of human endometriotic cells. Therefore, we conclude that TGF-B1 potentiates the adhesion of ectopic endometrial cells/tissues in the peritoneal region by enhancing the integrin and FAK signaling axis, and also migration via cadherin-mediated EMT and RHOGTPase signaling cascades.


Assuntos
Adesão Celular/efeitos dos fármacos , Movimento Celular/efeitos dos fármacos , Endometriose/patologia , Doenças Peritoneais/patologia , Fator de Crescimento Transformador beta1/farmacologia , Adesividade/efeitos dos fármacos , Animais , Estudos de Casos e Controles , Células Cultivadas , Modelos Animais de Doenças , Progressão da Doença , Relação Dose-Resposta a Droga , Endometriose/sangue , Transição Epitelial-Mesenquimal/efeitos dos fármacos , Transição Epitelial-Mesenquimal/fisiologia , Feminino , Humanos , Camundongos , Doenças Peritoneais/sangue , Proteínas Recombinantes/farmacologia , Fator de Crescimento Transformador beta1/sangue
8.
J Immunol ; 198(7): 2989-2999, 2017 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-28228558

RESUMO

Relatively little is known about factors that initiate immunosuppression in tumors and act at the interface between tumor cells and host cells. In this article, we report novel immunosuppressive properties of the ribosomal protein S19 (RPS19), which is upregulated in human breast and ovarian cancer cells and released from apoptotic tumor cells, whereupon it interacts with the complement C5a receptor 1 expressed on tumor infiltrating myeloid-derived suppressor cells. This interaction promotes tumor growth by facilitating recruitment of these cells to tumors. RPS19 also induces the production of immunosuppressive cytokines, including TGF-ß, by myeloid-derived suppressor cells in tumor-draining lymph nodes, leading to T cell responses skewed toward Th2 phenotypes. RPS19 promotes generation of regulatory T cells while reducing infiltration of CD8+ T cells into tumors. Reducing RPS19 in tumor cells or blocking the C5a receptor 1-RPS19 interaction decreases RPS19-mediated immunosuppression, impairs tumor growth, and delays the development of tumors in a transgenic model of breast cancer. This work provides initial preclinical evidence for targeting RPS19 for anticancer therapy enhancing antitumor T cell responses.


Assuntos
Células Supressoras Mieloides/imunologia , Neoplasias Experimentais/imunologia , Receptor da Anafilatoxina C5a/imunologia , Proteínas Ribossômicas/imunologia , Animais , Western Blotting , Linhagem Celular Tumoral , Citometria de Fluxo , Humanos , Imunoprecipitação , Camundongos , Linfócitos T/imunologia
9.
Reprod Health ; 16(1): 68, 2019 May 28.
Artigo em Inglês | MEDLINE | ID: mdl-31138253

RESUMO

BACKGROUND: Despite the legalization of abortion services in 2002, unsafe abortion (abortion services conducted by persons lacking necessary skill or in substandard settings or both) continues to be a public health concern in Nepal. There is a lack of national research exploring the characteristics of women who choose to have an abortion. This study assessed abortion in Nepal and its correlates using data from a nationally representative population-based cross-sectional survey. METHODS: We employed data from the Nepal Demographic and Health Survey 2016. Sample selection was based on stratified two-stage cluster sampling in rural areas and three-stage sampling in urban areas. The primary outcome is report of induced abortion in the 5 years preceding the survey, as recorded in the pregnancy history. All values were weighted by sample weights to provide population-level estimates. Bivariate and multivariate logistic regressions were performed using STATA 14 considering cluster sampling design. RESULTS: A total of 12,862 women of reproductive age (15-49 years) were interviewed. Overall, 4% (95% CI: 3.41-4.29) reported an abortion within the last 5 years (and less than 1% had had more than one abortion during that time). A higher proportion of women aged 20-34 years (5.7%), women with primary education (5.1%), women aware of abortion legalization (5.5%), and women in the richest wealth quintile (5.4%) had an abortion in the past 5 years. Compared to women aged < 20 years, women aged 20-34 years had higher odds (AOR: 5.54; 95% CI: 2.87-10.72) of having had an abortion in the past 5 years. Women with three or more living children had greater odds (AOR: 2.24; 95% CI: 1.51-3.31) of having had an abortion than women with no living children. The odds of having an abortion in the past 5 years increased with each wealth quintile, with the richest wealth quintile having almost three-fold greater odds of having had an abortion. No significant association was observed between having an abortion and the ecological zone and place of residence. CONCLUSION: This nationally representative study shows that abortion is associated with women's age, knowledge of abortion legality, wealth status, number of living children, and caste/ethnicity. Targeted interventions to young women, those in the poorest wealth quintile, women from Terai caste groups, and those who reside in Province 2 would be instrumental to address disproportional access to abortion services. Overall, strengthening contraceptive provision and abortion education programs would be cornerstone to improving the health of women and girls in Nepal.


Assuntos
Aborto Induzido/estatística & dados numéricos , Conhecimentos, Atitudes e Prática em Saúde , Inquéritos Epidemiológicos , Aborto Induzido/métodos , Aborto Induzido/psicologia , Adulto , Estudos Transversais , Escolaridade , Características da Família , Feminino , Humanos , Pessoa de Meia-Idade , Nepal , Gravidez , População Rural , Adulto Jovem
10.
BMC Pregnancy Childbirth ; 18(1): 161, 2018 May 11.
Artigo em Inglês | MEDLINE | ID: mdl-29751788

RESUMO

BACKGROUND: We sought to determine if female community health volunteers (FCHVs) and literate women in Nepal can accurately determine success of medical abortion (MA) using a symptom checklist, compared to experienced abortion providers. METHODS: Women undergoing MA, and FCHVs, independently assessed the success of each woman's abortion using an 8-question symptom checklist. Any answers in a red-shaded box indicated that the abortion may not have been successful. Women's/FCHVs' assessments were compared to experienced abortion providers using standard of care. RESULTS: Women's (n = 1153) self-assessment of MA success agreed with abortion providers' determinations 85% of the time (positive predictive value = 90, 95% CI 88, 92); agreement between FCHVs and providers was 82% (positive predictive value = 90, 95% CI 88, 92). Of the 92 women (8%) requiring uterine evacuation with manual vacuum aspiration (n = 84, 7%) or medications (n = 8, 0.7%), 64% self-identified as needing additional care; FCHVs identified 61%. However, both women and FCHVs had difficulty recognizing that an answer in a red-shaded box indicated that the abortion may not have been successful. Of the 453 women with a red-shaded box marked, only 35% of women and 41% of FCHVs identified the need for additional care. CONCLUSION: Use of a checklist to determine MA success is a promising strategy, however further refinement of such a tool, particularly for low-literacy settings, is needed before widespread use.


Assuntos
Aborto Induzido/estatística & dados numéricos , Lista de Checagem/métodos , Avaliação de Resultados em Cuidados de Saúde/métodos , Avaliação de Sintomas/métodos , Aborto Induzido/métodos , Adulto , Agentes Comunitários de Saúde , Autoavaliação Diagnóstica , Feminino , Humanos , Nepal , Gravidez , Reprodutibilidade dos Testes , Resultado do Tratamento , Voluntários , Adulto Jovem
13.
J Immunol ; 194(11): 5529-38, 2015 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-25911761

RESUMO

In contrast to tumor-associated macrophages, myeloid-derived suppressor cells, or inflammatory monocytes, functions of tissue resident macrophages, including alveolar macrophages (AM), in cancer were not well studied. Using a mouse model of breast cancer, we show that AM promote cancer metastasis to the lungs by suppressing antitumor T cells in this organ. AM accumulated in the premetastatic lungs through complement C5a receptor-mediated proliferation but not through recruitment from the circulation. AM preconditioned by breast tumors inhibited Th1 and favored generation of Th2 cells that had lower tumoricidal activity than Th1 cells. In addition, AM reduced the number and maturation of lung dendritic cells by regulating TGF-ß in the lung environment. Depletion of AM reversed immunosuppression imposed by these cells and strengthened local Th1 responses, which significantly reduced lung metastatic burden. C5a receptor deficiency, which also lessens myeloid-derived suppressor cells in the premetastatic niche, synergized with the depletion of AM in preventing metastasis, leading to protection of mice from lung metastases. This study identifies AM as a new component of the premetastatic niche, which is harnessed by tumors to impose immunosuppression, and as a new target for cancer immunotherapies to eliminate or reduce metastasis. Because the lungs are the most common target for hematogenous metastasis, this research offers a plausible explanation for susceptibility of the lungs to cancer metastasis.


Assuntos
Neoplasias Pulmonares/imunologia , Neoplasias Pulmonares/secundário , Macrófagos Alveolares/imunologia , Neoplasias Mamárias Experimentais/patologia , Células Th1/imunologia , Células Th2/imunologia , Animais , Linhagem Celular , Proliferação de Células , Células Dendríticas/imunologia , Feminino , Humanos , Pulmão/imunologia , Macrófagos Alveolares/citologia , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Camundongos Knockout , Receptor da Anafilatoxina C5a/imunologia , Fator de Crescimento Transformador beta/biossíntese , Microambiente Tumoral/imunologia
14.
Toxicol Mech Methods ; 27(5): 376-381, 2017 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-28325086

RESUMO

Non-genotoxic carcinogens may play a significant role in development of cancer. Currently short-term assays for mutagenicity classify genotoxic carcinogens and lack the abilities to detect epigenetic carcinogens. The need to develop an endpoint always remains to recognize potentially carcinogenic agents employing rapid and practical bioassays. For this, the present study utilized TA98 and TA1537 tester strains of Salmonella typhimurium to evaluate four non-genotoxic carcinogenic agents (Coumarin, ß-Myrcene, Bis(2-ethylhexyl) phthalate and trans-anethole). These chemicals were tested individually and in combination with promutagens 2-aminoanthracene (2AA) and benzo(a)pyrene (BP) in presence of metabolic activation system (S9) by plate incorporation method. Exposure to all four test chemicals revealed marked increase of revertant colonies in promutagen combined groups as compared to promutagens alone. However significantly greater fold responses were observed with 2AA combination groups (Coumarin +2AA, ß-Myrcene +2AA, Bis(2-ethylhexyl) phthalate +2AA and trans-anethole +2AA) with TA98 strain as compared with TA1537, which seems to have enhanced the mutagenic response of 2AA in metabolically activated conditions. It is concluded that out of both tester strains TA98 strain of Salmonella typhimurium has the potential to detect non-genotoxic carcinogens when combined with potent promutgens either by inhibiting or modulating activities of liver microsomal enzymes biochemically which may indirectly contribute to neoplastic alterations. Further this simple, short-term alternative assay may provide rapid information during extrapolative toxicology for differentiating genotoxic and non-genotoxic carcinogens.


Assuntos
Carcinógenos/toxicidade , Mutagênicos/toxicidade , Salmonella typhimurium/efeitos dos fármacos , Salmonella typhimurium/genética , Ativação Metabólica , Monoterpenos Acíclicos , Derivados de Alilbenzenos , Anisóis/toxicidade , Antracenos/toxicidade , Benzo(a)pireno/toxicidade , Cumarínicos/toxicidade , Dietilexilftalato/toxicidade , Relação Dose-Resposta a Droga , Sinergismo Farmacológico , Microssomos Hepáticos/enzimologia , Microssomos Hepáticos/metabolismo , Monoterpenos/toxicidade , Testes de Mutagenicidade
15.
Mol Pharm ; 13(9): 3247-55, 2016 09 06.
Artigo em Inglês | MEDLINE | ID: mdl-27463245

RESUMO

Nitazoxanide (NTZ) has moderate mycobactericidal activity and is also an inducer of autophagy in mammalian cells. High-payload (40-50% w/w) inhalable particles containing NTZ alone or in combination with antituberculosis (TB) agents isoniazid (INH) and rifabutin (RFB) were prepared with high incorporation efficiency of 92%. In vitro drug release was corrected for drug degradation during the course of study and revealed first-order controlled release. Particles were efficiently taken up in vitro by macrophages and maintained intracellular drug concentrations at one order of magnitude higher than NTZ in solution for 6 h. Dose-dependent killing of Mtb and restoration of lung and spleen architecture were observed in experimentally infected mice treated with inhalations containing NTZ. Adjunct NTZ with INH and RFB cleared culturable bacteria from the lung and spleen and markedly healed tissue architecture. NTZ can be used in combination with INH-RFB to kill the pathogen and heal the host.


Assuntos
Antituberculosos/uso terapêutico , Macrófagos/efeitos dos fármacos , Tiazóis/uso terapêutico , Tuberculose/tratamento farmacológico , Administração por Inalação , Animais , Antituberculosos/administração & dosagem , Autofagia/efeitos dos fármacos , Linhagem Celular , Humanos , Isoniazida/administração & dosagem , Isoniazida/uso terapêutico , Masculino , Camundongos , Nitrocompostos , Planejamento da Radioterapia Assistida por Computador , Rifabutina/administração & dosagem , Rifabutina/uso terapêutico , Tiazóis/administração & dosagem , Tuberculose/metabolismo
16.
Pharm Res ; 33(8): 1899-912, 2016 08.
Artigo em Inglês | MEDLINE | ID: mdl-27095353

RESUMO

PURPOSE: Mycobacterium tuberculosis (Mtb) inhibits host defense mechanisms, including autophagy. We investigated particles containing rapamycin (RAP) alone or in combination with isoniazid (INH) and rifabutin (RFB) for: targeting lung macrophages on inhalation; inducing autophagy; and killing macrophage-resident Mtb and/or augmenting anti-tuberculosis (TB) drugs. METHODS: PLGA and drugs were spray-dried. Pharmacokinetics, partial biodistribution (LC-MS/MS) and efficacy (colony forming units, qPCR, acid fast staining, histopathology) in mice following dry powder inhalation were evaluated. RESULTS: Aerodynamic diameters of formulations were 0.7-4.7 µm. Inhaled particles reached deep lungs and were phagocytosed by alveolar macrophages, yielding AUC0-48 of 102 compared to 0.1 µg/ml × h obtained with equivalent intravenous dose. RAP particles induced more autophagy in Mtb-infected macrophages than solutions. Inhaled particles containing RAP alone in daily, alternate-day and weekly dosing regimens reduced bacterial burden in lungs and spleens, inducing autophagy and phagosome-lysosome fusion. Inhalation of particles containing RAP with INH and RFB cleared the lungs and spleens of culturable bacteria. CONCLUSIONS: Targeting a potent autophagy-inducing agent to airway and lung macrophages alone is feasible, but not sufficient to eliminate Mtb. Combination of macrophage-targeted inhaled RAP with classical anti-TB drugs contributes to restoring tissue architecture and killing Mtb.


Assuntos
Antituberculosos/administração & dosagem , Autofagia/efeitos dos fármacos , Mycobacterium tuberculosis/efeitos dos fármacos , Sirolimo/administração & dosagem , Administração por Inalação , Animais , Antituberculosos/síntese química , Antituberculosos/metabolismo , Autofagia/fisiologia , Avaliação Pré-Clínica de Medicamentos/métodos , Quimioterapia Combinada , Humanos , Ácido Láctico/administração & dosagem , Ácido Láctico/síntese química , Ácido Láctico/metabolismo , Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo , Masculino , Camundongos , Monócitos/efeitos dos fármacos , Monócitos/metabolismo , Mycobacterium tuberculosis/metabolismo , Ácido Poliglicólico/administração & dosagem , Ácido Poliglicólico/síntese química , Ácido Poliglicólico/metabolismo , Copolímero de Ácido Poliláctico e Ácido Poliglicólico , Sirolimo/síntese química , Sirolimo/metabolismo
17.
J Pharmacokinet Pharmacodyn ; 43(6): 567-582, 2016 12.
Artigo em Inglês | MEDLINE | ID: mdl-27670282

RESUMO

Antibody-drug conjugates (ADCs) are designed to target antigen expressing (Ag+) cells in a tumor. Once processed by the Ag+ cells, ADCs can release cytotoxic drug molecules that can diffuse out of Ag+ cells into the neighboring antigen-negative (Ag-) cells to induce their cytotoxicity. This additional efficacy of ADCs on Ag- cells in the presence of Ag+ cells is known as the 'bystander effect'. Although the importance of this phenomena is widely acknowledged for effective killing of a heterogeneous tumor, the rate and extent of the bystander killing in a heterogeneous system is not quantitatively understood yet. Thus, the objectives of this manuscript were to: (1) synthesize and characterize a tool ADC Trastuzumab-vc-MMAE that is capable of exhibiting bystander effect, (2) quantify the time course of the bystander effect for the tool ADC using in vitro co-culture systems created using mixture of various HER2-expressing cell lines, and (3) develop a pharmacodynamic (PD) model that is capable of characterizing the bystander effect of ADCs. Co-culture studies conducted using GFP labelled MCF7 cells as Ag- cells and N87, BT474, and SKBR3 as Ag+ cells revealed that the bystander effect of ADC increases with increasing fraction of Ag+ cells in a co-culture system, and with increased expression level of target on Ag+ cells. A notable lag time after ADC incubation was also observed prior to significant bystander killing of Ag- cells. Based on our results we hypothesize that there may be other determinants apart from the antigen expression level that can also influence the ability of Ag+ cells to demonstrate the bystander effect in a co-culture system. The co-culture analysis also suggested that the bystander effect of the ADC can dissipate over the period of time as the population of Ag+ cells declines. A novel PD model was developed to mathematically characterize the bystander effect of ADCs by combining two different cell distribution models to represent the population of Ag+ and Ag- cells in a co-culture system. This PD model can be integrated with the systems PK model for ADCs in the future to generate a quantitative framework that is capable of supporting the discovery and development of novel ADCs with optimal bystander killing capabilities.


Assuntos
Anticorpos Monoclonais/farmacologia , Antígenos de Neoplasias/metabolismo , Antineoplásicos/farmacologia , Efeito Espectador/efeitos dos fármacos , Imunoconjugados/farmacologia , Modelos Biológicos , Oligopeptídeos/farmacologia , Trastuzumab/farmacologia , Anticorpos Monoclonais/química , Antígenos de Neoplasias/genética , Antineoplásicos/química , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Técnicas de Cocultura , Proteínas de Fluorescência Verde/genética , Humanos , Imunoconjugados/química , Células MCF-7 , Oligopeptídeos/síntese química , Receptor ErbB-2/antagonistas & inibidores , Receptor ErbB-2/genética , Fatores de Tempo
18.
BMC Womens Health ; 15: 17, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-25783648

RESUMO

BACKGROUND: Despite liberalization of the Nepal abortion law, young women continue to experience barriers to safe abortion services. We hypothesize that marital status may differentially impact such barriers, given the societal context of Nepal. METHODS: We evaluated differences in reproductive knowledge and attitudes by marital status with a probability-based, cross-sectional survey of young women in Rupandehi district, Nepal. Participants (N = 600) were surveyed in 2012 on demographics, romantic experiences, media habits, reproductive information, and abortion knowledge and attitudes. We used logistic regression to assess differences by marital status, controlling for age. RESULTS: Participants, who comprised never-married (54%) and ever-married women (45%), reported good access to basic reproductive health and abortion information. Social desirability bias might have prevented reporting of premarital romantic and sexual activity given that participants reported more premarital activities for their friends than for themselves. Only 45% knew that abortion was legal, and fewer ever-married women were aware of abortion legality. Never-married women expected more negative responses from having an abortion than ever-married women. CONCLUSIONS: Findings highlight the need for providing sexual and reproductive health care information and services to young women regardless of marital status.


Assuntos
Aborto Induzido , Aborto Legal , Conhecimentos, Atitudes e Prática em Saúde , Estado Civil/estatística & dados numéricos , Comportamento Sexual/estatística & dados numéricos , Adolescente , Estudos Transversais , Feminino , Acessibilidade aos Serviços de Saúde , Humanos , Modelos Logísticos , Nepal , Gravidez , Adulto Jovem
19.
Pharm Biol ; 53(1): 147-57, 2015 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-25237891

RESUMO

CONTEXT: Withania somnifera (Linn.) Dunal (Solanaceae), a clinically used herbal drug in Ayurveda, shows potent antioxidant, anti-inflammatory, pro-apoptotic, and cardioprotective effects. However, the efficacy of W. somnifera in pulmonary hypertension (PH), a cardiopulmonary disorder, remains unexplored. OBJECTIVE: The present study investigates the effect of W. somnifera root powder on monocrotaline (MCT)-induced PH in rats. MATERIALS AND METHODS: In preventive studies, W. somnifera root powder (50 and 100 mg/kg/d, p.o.) was administered from day 1 following single administration of MCT (60 mg/kg, s.c.) in Sprague-Dawley (SD) rats. After 35 d, right ventricular pressure (RVP) was measured in anesthetized rats. Various physical markers of right ventricular hypertrophy (RVH) were measured in isolated hearts. Markers of endothelial function, inflammation, and oxidative stress were estimated in lung homogenate. Vasoreactivity of pulmonary arteries was also studied. In therapeutic treatment, W. somnifera (50 and 100 mg/kg/d, p.o.) was administered from day 21 to 35 post-MCT administration. RESULTS: Preventive treatment with 50 and 100 mg/kg W. somnifera significantly reduced the RVP (32.18 ± 1.273 mm Hg and 29.98 ± 1.119 mm Hg, respectively, versus 42.96 ± 1.789 mm Hg of MCT) and all markers of RVH in MCT-challenged rats. There was an improvement in inflammation, oxidative stress and endothelial dysfunction, and attenuation of proliferative marker and apoptotic resistance in lungs. Therapeutic treatment with W. somnifera (100 mg/kg) also reduced RVP and RVH. DISCUSSION: This study demonstrated that W. somnifera significantly protected against MCT-induced PH due to its antioxidant, anti-inflammatory, pro-apoptotic, and cardioprotective properties.


Assuntos
Anti-Hipertensivos/uso terapêutico , Cardiotônicos/uso terapêutico , Hipertensão Pulmonar/prevenção & controle , Monocrotalina/farmacologia , Preparações de Plantas/uso terapêutico , Withania/química , Administração Oral , Animais , Anti-Hipertensivos/administração & dosagem , Anti-Hipertensivos/química , Cardiotônicos/administração & dosagem , Cardiotônicos/química , Relação Dose-Resposta a Droga , Endotélio Vascular/efeitos dos fármacos , Endotélio Vascular/fisiopatologia , Coração/efeitos dos fármacos , Hipertensão Pulmonar/induzido quimicamente , Pulmão/efeitos dos fármacos , Pulmão/patologia , Masculino , Ayurveda , Tamanho do Órgão/efeitos dos fármacos , Preparações de Plantas/administração & dosagem , Preparações de Plantas/química , Raízes de Plantas/química , Pós , Ratos Sprague-Dawley
20.
J Appl Toxicol ; 34(6): 576-94, 2014 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-24777877

RESUMO

Early assessment of the toxicity potential of new molecules in pharmaceutical industry is a multi-dimensional task involving predictive systems and screening approaches to aid in the optimization of lead compounds prior to their entry into development phase. Due to the high attrition rate in the pharma industry in last few years, it has become imperative for the nonclinical toxicologist to focus on novel approaches which could be helpful for early screening of drug candidates. The need is that the toxicologists should change their classical approach to a more investigative approach. This review discusses the developments that allow toxicologists to anticipate safety problems and plan ways to address them earlier than ever before. This includes progress in the field of in vitro models, surrogate models, molecular toxicology, 'omics' technologies, translational safety biomarkers, stem-cell based assays and preclinical imaging. The traditional boundaries between teams focusing on efficacy/ safety and preclinical/ clinical aspects in the pharma industry are disappearing, and translational research-centric organizations with a focused vision of bringing drugs forward safely and rapidly are emerging. Today's toxicologist should collaborate with medicinal chemists, pharmacologists, and clinicians and these value-adding contributions will change traditional toxicologists from side-effect identifiers to drug development enablers.


Assuntos
Toxicologia/métodos , Pesquisa Translacional Biomédica/métodos , Alternativas aos Testes com Animais , Animais , Biomarcadores/análise , Células Cultivadas , Comportamento Cooperativo , Previsões , Humanos , Comunicação Interdisciplinar , Modelos Animais , Segurança do Paciente , Medição de Risco , Toxicogenética , Toxicologia/tendências , Pesquisa Translacional Biomédica/tendências
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