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Background & Purpose A new discriminatory system for evaluating the quality of pharmaceuticals is described in this paper as the Pharmaceutical Polygon Fingerprint Matrix system (PharmP-FM). To assess the quality of various pharmaceutical formulations and dosage forms, PharmP-FM uses both qualitative and quantitative fingerprinting techniques. The system expands on the SeDeM expert system, which was initially created to evaluate the suitability of powder for direct compression. PharmP-FM creates a graphical representation of the product's pharmaceutical quality using a set of input parameters. The Performance Index (PI), Normalized Parameter Index (NPI), and Formulation Index (FI) are among the system's output parameters. Methods To evaluate PharmP-FM's performance, the paper examines its application in assessing batch-to-batch variability of weight loss supplement capsules and the quality of multisource brand products of levothyroxine tablets. The findings demonstrate PharmP-FM's capability to identify variations in pharmaceutical quality across these products. Results & Conclusion This paper concludes that PharmP-FM exhibits potential promise as a pharmaceutical quality assessment tool. Its user-friendly nature and adaptability to different formulations and dosage forms make it a versatile discriminatory system. Additionally, PharmP-FM is an open-ended and scalable system that can incorporate additional parameters and accommodate products of varying complexities. The study's results strongly suggest its potential as a potential tool for pharmaceutical quality assessment.
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INTRODUCTION: Coronavirus disease 2019 (COVID-19) outbreak is considered one of the most important public health crises all over the world and in Egypt. Community pharmacists represent the third largest health care professional group after physicians and nurses. Community pharmacists are expected to be fully prepared at the frontline of defending their community needs by limiting the spread of COVID-19 via different pharmaceutical care services. AIM: This study aimed to evaluate the sources of knowledge and readiness of community pharmacists in facing COVID-19 early outbreak in Egypt. METHODS: A descriptive cross-sectional study was performed via a self-administered online google form questionnaire during the early period from 14 April to 3 June 2020. The questionnaire focused on; evaluating education level, sources of information, and readiness of Egyptian community pharmacists in the COVID-19 pandemic crisis. RESULTS: A total of 318 community pharmacists from Egypt participated in this questionnaire. About half of the surveyed pharmacists reported that they were frequently consulted and that their patients were seeking consultation regarding COVID-19 management more than 10 times per day. More than half of the pharmacists reported using social media as a source of information and knew the right social distancing recommendations. Regarding protective measures, only a quarter of pharmacists disclosed the availability of personal protective equipment (PPE). Nevertheless, the majority of pharmacists significantly reported some initial lack of support either inform of recommendations or PPE supply. CONCLUSION: The study revealed the dependence of community pharmacists on social media as the main source of information and the lack of early awareness of evidence-based practice resources. Community pharmacists were in need of more initial support to achieve better satisfaction, patient counselling and infection control. Corrective measures were promptly undertaken to support and satisfy the Egyptian community pharmacists' initial awareness and readiness facing COVID-19.
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COVID-19 , Serviços Comunitários de Farmácia , Estudos Transversais , Egito/epidemiologia , Humanos , Pandemias , Farmacêuticos , SARS-CoV-2RESUMO
BACKGROUND: Brain metastases are an increasing problem in women with invasive breast cancer. Strategies designed to treat brain metastases of breast cancer, particularly chemotherapeutics such as irinotecan, demonstrate limited efficacy. Conventional irinotecan distributes poorly to brain metastases; therefore, NKTR-102, a PEGylated irinotecan conjugate should enhance irinotecan and its active metabolite SN38 exposure in brain metastases leading to brain tumor cytotoxicity. METHODS: Female nude mice were intracranially or intracardially implanted with human brain seeking breast cancer cells (MDA-MB-231Br) and dosed with irinotecan or NKTR-102 to determine plasma and tumor pharmacokinetics of irinotecan and SN38. Tumor burden and survival were evaluated in mice treated with vehicle, irinotecan (50 mg/kg), or NKTR-102 low and high doses (10 mg/kg, 50 mg/kg respectively). RESULTS: NKTR-102 penetrates the blood-tumor barrier and distributes to brain metastases. NKTR-102 increased and prolonged SN38 exposure (>20 ng/g for 168 h) versus conventional irinotecan (>1 ng/g for 4 h). Treatment with NKTR-102 extended survival time (from 35 days to 74 days) and increased overall survival for NKTR-102 low dose (30 % mice) and NKTR-102 high dose (50 % mice). Tumor burden decreased (37 % with 10 mg/kg NKTR-102 and 96 % with 50 mg/kg) and lesion sizes decreased (33 % with 10 mg/kg NKTR-102 and 83 % with 50 mg/kg NKTR-102) compared to conventional irinotecan treated animals. CONCLUSIONS: Elevated and prolonged tumor SN38 exposure after NKTR-102 administration appears responsible for increased survival in this model of breast cancer brain metastasis. Further, SN38 concentrations observed in this study are clinically achieved with 145 mg/m(2) NKTR-102, such as those used in the BEACON trial, underlining translational relevance of these results.
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Antineoplásicos Fitogênicos/farmacologia , Neoplasias Encefálicas/patologia , Neoplasias Encefálicas/secundário , Neoplasias da Mama/patologia , Camptotecina/análogos & derivados , Animais , Antineoplásicos Fitogênicos/administração & dosagem , Antineoplásicos Fitogênicos/química , Barreira Hematoencefálica/efeitos dos fármacos , Barreira Hematoencefálica/metabolismo , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Neoplasias Encefálicas/tratamento farmacológico , Neoplasias Encefálicas/mortalidade , Camptotecina/administração & dosagem , Camptotecina/química , Camptotecina/farmacologia , Linhagem Celular Tumoral , Modelos Animais de Doenças , Monitoramento de Medicamentos , Feminino , Humanos , Irinotecano , Medições Luminescentes , Camundongos , Estrutura Molecular , Permeabilidade , Carga Tumoral/efeitos dos fármacos , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
Glucagon was discovered about a hundred years ago and its role in health and disease is under continuous investigation. Glucagon is a counter regulatory hormone secreted by alpha cells of the pancreas in response to multiple stimuli. Although some of glucagon's actions and its clinical application have been described, clinical experience with glucagon has been historically overshadowed by that of insulin. To date, the role of glucagon's actions in pharmacotherapy has been under explored. Glucagon plays a considerable role as a hormonal regulator via its known actions on the liver. The rise in obesity and diabetes mellitus prevalence is bringing focus to glucagon's known physiological roles and possible clinical applications. Six glucagon products and a glucagon analog are approved for use in the United States. Clinical pharmacology studies provide crucial support of glucagon's actions as evident from comprehensive pharmacokinetics and pharmacodynamics evaluations in humans. Here, we briefly describe the established physiological role of glucagon in humans and its known relationship with disease. We later summarize the clinical pharmacology of available glucagon products with different routes of administration.
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Berberine (BBR) exerts documented protection against neurodegenerative disorders. However, data on the effect of nano-encapsulation on the neuroprotective effect of BBR are lacking. We investigated the effect of BBR loading into chitosan (CS) nanoparticles (NPs) and their surface modification with Tween 80 (T80), polyethylene glycol 4000 (PEG), and miltefosine (MFS) against lipopolysaccharide (LPS)-induced neurodegenerative changes in addition to hepatotoxicity in rats. BBR-NPs were prepared by ionic gelation and characterized for morphology by transmission electron microscopy (TEM), colloidal properties, and entrapment efficiency (EE%). The neuroprotective and hepatoprotective effects of a 14-day pretreatment with four BBR-NPs formulations (4 mg/kg BBR/day) by intraperitoneal (i.p.) injection were challenged by a single i.p. 4 mg/kg dose of LPS on the fifteenth day. Neuroprotective efficacy and potential toxicity of BBR-NPs relative to BBR solution were assessed biochemically and histopathologically. One-way ANOVA followed by Tukey's comparison test was used for statistical analysis. CS nano-encapsulation and surface modification of BBR-NPs altered the neuroprotective and hepatoprotective effects of BBR depending on the physicochemical and/or biological effects of BBR, CS, coating materials, and NP-related features. Similar to the prophylactic and treatment efficacy of NPs for brain delivery, safety of these nanostructures and their individual formulation components warrants due research attention.
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Berberina/administração & dosagem , Quitosana/administração & dosagem , Nanopartículas/administração & dosagem , Doenças Neurodegenerativas/tratamento farmacológico , Fármacos Neuroprotetores/administração & dosagem , Acetilcolinesterase/metabolismo , Peptídeos beta-Amiloides/metabolismo , Animais , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Encéfalo/patologia , Glucose/metabolismo , Glutationa/metabolismo , Lipopolissacarídeos , Fígado/efeitos dos fármacos , Fígado/patologia , Masculino , Doenças Neurodegenerativas/induzido quimicamente , Doenças Neurodegenerativas/metabolismo , Doenças Neurodegenerativas/patologia , Ratos WistarRESUMO
Traditional nutraceuticals and cosmeceuticals hold pragmatic nature with respect to their definitions, claims, purposes and marketing strategies. Their definitions are not well established worldwide. They also have different regulatory definitions and registration regulatory processes in different parts of the world. Global prevalence of nutraceuticals and cosmeceuticals is noticeably high with large market share with minimal regulation compared to traditional drugs. The global market is flooded with nutraceuticals and cosmeceuticals claiming to be of natural origin and sold with a therapeutic claim by major online retail stores such as Amazon and eBay. Apart from the traditional formulations, many manufacturers and researchers use novel formulation technologies in nutraceutical and cosmeceutical formulations for different reasons and objectives. Manufacturers tend to differentiate their products with novel formulations to increase market appeal and sales. On the other hand, researchers use novel strategies to enhance nutraceuticals and cosmeceuticals activity and safety. The objective of this review is to assess the current patents and research adopting novel formulation strategies in nutraceuticals and cosmeceuticals. Patents and research papers investigating nutraceutical and cosmeceutical novel formulations were surveyed for the past 15 years. Various nanosystems and advanced biotechnology systems have been introduced to improve the therapeutic efficacy, safety and market appeal of nutraceuticals and cosmeceuticals, including liposomes, polymeric micelles, quantum dots, nanoparticles, and dendrimers. This review provides an overview of nutraceuticals and cosmeceuticals current technologies, highlighting their pros, cons, misconceptions, regulatory definitions and market. This review also aims in separating the science from fiction in the nutraceuticals and cosmeceuticals development, research and marketing.
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Cosmecêuticos/administração & dosagem , Suplementos Nutricionais , Biotecnologia/métodos , Qualidade de Produtos para o Consumidor , Cosmecêuticos/legislação & jurisprudência , Cosmecêuticos/normas , Suplementos Nutricionais/normas , Humanos , Legislação sobre Alimentos , Patentes como AssuntoRESUMO
INTRODUCTION: Due to the chaos in the legislation in the Middle East, male enhancement nutraceuticals may be sold without any registration or evaluation. These products need to be evaluated with respect to safety and efficacy. Furthermore, cultural and social considerations in the Middle East prevent the use of international evaluations schemes for erectile dysfunction. AIM: Evaluating the safety and efficacy parameters of generic and nutraceutical products for erectile dysfunction in the Middle East through a custom-designed, representable and simple system tailored to the regional culture. METHODS: 74 healthy male volunteers were enrolled into a comparative, simple randomized, single dose, double blind, and crossover clinical study incorporated with a tailored-designed questionnaire. Safety assessment included laboratory analysis for liver functions and measuring blood pressure. MAIN OUTCOME MEASURES: Subjective data regarding safety and efficacy were assessed from the validated questionnaire. Blood pressure was measured. Blood samples were collected to assess the drug/adulterants concentration and liver and kidney functions. RESULTS: All tested nutraceuticals showed undeclared Sildenafil citrate in patients. Questionnaire results showed high inter-patient variability with respect to efficacy and comparable safety profile compared to Viagra®. CONCLUSION: The validated tailored-designed questionnaire effectively assessed the efficacy and safety of male enhancement products. The male enhancement nutraceuticals, sold in Egypt, claimed to be 100% natural are adulterated and of questionable safety profile.
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Suplementos Nutricionais/análise , Contaminação de Medicamentos , Medicamentos Genéricos/análise , Disfunção Erétil/sangue , Disfunção Erétil/epidemiologia , Citrato de Sildenafila/análise , Adulto , Estudos Cross-Over , Método Duplo-Cego , Contaminação de Medicamentos/prevenção & controle , Medicamentos Genéricos/metabolismo , Medicamentos Genéricos/uso terapêutico , Egito/epidemiologia , Disfunção Erétil/tratamento farmacológico , Humanos , Masculino , Pessoa de Meia-Idade , Inibidores da Fosfodiesterase 5/análise , Inibidores da Fosfodiesterase 5/sangue , Inibidores da Fosfodiesterase 5/uso terapêutico , Citrato de Sildenafila/sangue , Citrato de Sildenafila/uso terapêutico , Resultado do TratamentoRESUMO
For metastases in the central nervous system, angiogenesis enhances metastatic potential and promotes progression. Primary factors which drive vessel growth are vascular endothelial growth factor (VEGF) and angiopoietin-2. Preclinical models show inhibition of either factor reduces metastases spread and inhibits growth. This work sets out to answer two questions in a preclinical mouse model. First, whether the combined inhibition of VEGF and angiopoietin-2, reduces passive permeability and limits drug uptake into brain metastases; and second, whether this inhibition reduces metastases burden in brain. We observed combinatorial inhibition of VEGF and angiopoietin-2, decreased (p < 0.05) angiogenesis and vascular branching in an aortic ring assay and decreased (p < 0.05) endothelial wound closure times. Using a brain metastases of breast cancer model (induced by intracardiac injections of brain seeking MDA-MB-231Br cells or 4T1Br cells), we observed, similar to VEGF, angiopoetin-2 expression correlates to increased angiogenesis (p < 0.05) and increased lesion permeability. To determine efficacy, animals were administered bevacizumab plus L1-10 (angiopoietin inhibitor) twice per week until neurological symptoms developed. Lesion permeability significantly decreased by â¼50% (p < 0.05) compared to untreated lesions, but remained â¼25% greater (p < 0.0%) than brain. In subsequent experiments, animals were administered similar regimens but sacrificed on day 32. The number of metastatic lesions developed was significantly (p < 0.001) reduced in the bevacizumab group (56%) and combination group (86%). Lesions' size was reduced in bevacizumab treated lesions (â¼67%) and bevacizumab and L1-10 treated lesions (â¼78%) developing area < 0.5 mm2. In summary, combinatorial inhibition of VEGF and angiopoietin reduces lesion permeability and brain metastatic burden.
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Enzymes may offer great potentials in topical pharmaceutical applications provided that treatment conditions are controlled for efficacy and safety. In this study, the effect of alkaline protease produced by recombinant Bacillus subtilis cells on the ex-vivo permeability of rabbit ear skin was investigated under different conditions of enzyme activity (5-60 units) and exposure time (15-60min). Data for transepidermal water loss (TEWL) and permeation of a hydrophilic dye, rhodamine B (Rb), indicated biphasic activity-dependent and exposure time-dependent skin permeability. Maximum effects were obtained at 20 proteolytic units and 30min exposure. Findings proved consistent with histopathological changes indicating progressive stratum corneum (SC) loss and disruption of the dermo-epidermal junction at 20 units and up to 30min exposure time followed by dermal hyalinization at longer exposure. This was associated with progressive loss of skin hair. Applying the identified pretreatment conditions to transdermal delivery of vardenafil in a gel base across dorsal rat skin indicated a significant increase in plasma levels at 30 and 60min with minimal histopathological changes 5days post enzyme treatment. Accordingly, the recombinant B. subtilis alkaline protease offers promise as a pharmaceutical enzyme for transdermal drug delivery bioenhancement and dermatological applications.
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Bacillus subtilis/enzimologia , Proteínas de Bactérias/farmacologia , Sistemas de Liberação de Medicamentos , Endopeptidases/farmacologia , Absorção Cutânea , Administração Cutânea , Animais , Técnicas In Vitro , Permeabilidade , Coelhos , Ratos , Ratos Sprague-Dawley , PeleRESUMO
Erectile dysfunction prevalence globally is noticeably high. This is accompanied by an increase in the use of nutraceuticals for male enhancement. However, the global market is invaded by counterfeit and adulterated nutraceuticals claimed to be of natural origin sold with a therapeutic claim. The objective of this article is to review male enhancement nutraceuticals worldwide with respect to claim, adulterants, and safety. The definition of such products is variable across countries. Thus, the registration procedures differ as well. This facilitates the manipulation of the process, which leads to widespread adulterated and counterfeit products without control. The tele-advertisement and Internet pharmacies aided the widespread sale of male enhancement nutraceuticals, unfortunately, the spurious ones. Finally, based on literature, most of these products were found to be adulterated with active pharmaceutical ingredients (API) and mislabeled as being natural. These products represent a major health hazard for consumers due to lack of clear regulations.
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Medicamentos Falsificados , Suplementos Nutricionais/análise , Contaminação de Medicamentos , Rotulagem de Medicamentos/legislação & jurisprudência , Egito , Disfunção Erétil/tratamento farmacológico , Europa (Continente) , Humanos , Internet , Legislação de Medicamentos , Masculino , Oriente Médio , Preparações Farmacêuticas , Inibidores da Fosfodiesterase 5/análise , Inibidores da Fosfodiesterase 5/uso terapêutico , Estados Unidos , United States Food and Drug AdministrationRESUMO
BACKGROUND: Measurement of vascular density has significant value in characterizing healthy and diseased tissue, particularly in brain where vascular density varies among regions. Further, an understanding of brain vessel size helps distinguish between capillaries and larger vessels like arterioles and venules. Unfortunately, few cutting edge methodologies are available to laboratories to rapidly quantify vessel density. NEW METHOD: We developed a rapid microscopic method, which quantifies the numbers and diameters of blood vessels in brain. Utilizing this method we characterized vascular density of five brain regions in both mice and rats, in two tumor models, using three tracers. RESULTS: We observed the number of sections/mm(2) in various brain regions: genu of corpus callosum 161±7, hippocampus 266±18, superior colliculus 300±24, frontal cortex 391±55, and inferior colliculus 692±18 (n=5 animals). Regional brain data were not significantly different between species (p>0.05) or when using different tracers (70kDa and 2000kDa Texas Red; p>0.05). Vascular density decreased (62-79%) in preclinical brain metastases but increased (62%) a rat glioma model. COMPARISON WITH EXISTING METHODS: Our values were similar (p>0.05) to published literature. We applied this method to brain-tumors and observed brain metastases of breast cancer to have a â¼2.5-fold reduction (p>0.05) in vessels/mm(2) compared to normal cortical regions. In contrast, vascular density in a glioma model was significantly higher (sections/mm(2) 736±84; p<0.05). CONCLUSIONS: In summary, we present a vascular density counting method that is rapid, sensitive, and uses fluorescence microscopy without antibodies.
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Encéfalo/irrigação sanguínea , Processamento de Imagem Assistida por Computador/métodos , Microscopia de Fluorescência/métodos , Reconhecimento Automatizado de Padrão/métodos , Animais , Encéfalo/anatomia & histologia , Encéfalo/patologia , Neoplasias Encefálicas/patologia , Linhagem Celular Tumoral , Feminino , Glioma/patologia , Humanos , Masculino , Camundongos Transgênicos , Metástase Neoplásica/patologia , Ratos Endogâmicos F344 , Ratos Sprague-DawleyRESUMO
The global market is invaded by male enhancement nutraceuticals claimed to be of natural origin sold with a major therapeutic claim. Most of these products have been reported by international systems like the Food and Drug Administration (FDA). We hypothesize that these products could represent a major threat to the health of the consumers. In this paper, pharmaceutical evaluation of some of these nutraceutical products sold in Egypt under the therapeutic claim of treating erectile dysfunction, are discussed along with pharmacological evaluation to investigate their safety and efficacy parameters. Samples were analyzed utterly using conventional methods, i.e.: HPLC, HPTLC, NIR, content uniformity and weight variation and friability. The SeDeM system was used for quality assessment. On the basis of the results of this research, the sampled products are adulterated and totally heterogeneous in their adulterant drug content and pharmaceutical quality. These products represent a major safety threat for the consumers in Egypt and the Middle East, especially; the target audience is mostly affected with heart and blood pressure problems seeking natural and safe alternatives to the well-established Phosphodiesterase 5 Inhibitors (PDE-5Is).
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Suplementos Nutricionais , Contaminação de Medicamentos , Inibidores da Fosfodiesterase 5 , Alanina Transaminase/sangue , Animais , Aspartato Aminotransferases/sangue , Creatinina/sangue , Suplementos Nutricionais/análise , Suplementos Nutricionais/toxicidade , Masculino , Oriente Médio , Inibidores da Fosfodiesterase 5/análise , Inibidores da Fosfodiesterase 5/farmacocinética , Inibidores da Fosfodiesterase 5/farmacologia , Inibidores da Fosfodiesterase 5/toxicidade , Ratos Wistar , Citrato de Sildenafila/análise , Citrato de Sildenafila/farmacocinética , Citrato de Sildenafila/farmacologia , Citrato de Sildenafila/toxicidade , Tadalafila/análise , Ureia/sangue , Dicloridrato de Vardenafila/análise , gama-Glutamiltransferase/metabolismoRESUMO
UNLABELLED: Breast cancer is the most prevalent cancer among women worldwide. However, increased survival is due to the dramatic advances in the screening methods, early diagnosis, and breakthroughs in treatments. Over the course of the last decade, many acquisitions have taken place in this critical field of research in the pharmaceutical industry. Advances in molecular biology and pharmacology aided in better understanding of breast cancer, enabling the design of smarter therapeutics able to target cancer and respond to its microenvironment efficiently. Patents and research papers investigating diagnosis and treatment strategies for breast cancer using novel technologies have been surveyed for the past 15 years. Various nanocarriers have been introduced to improve the therapeutic efficacy of anticancer drugs, including liposomes, polymeric micelles, quantum dots, nanoparticles, and dendrimers. This review provides an overview of breast cancer, conventional therapy, novel technologies in the management of breast cancer, and rational approaches for targeting breast cancer. HIGHLIGHTS: Breast cancer is the most common cancer in women worldwide. However, survival rates vary widely, optimistically heading toward a positive trend. Increased survival is due to the drastic shift in the screening methods, early diagnosis, and breakthroughs in treatments.Different strategies of breast cancer classification and staging have evolved over the years. Intrinsic (molecular) subtyping is essential in clinical trials and well understanding of the disease.Many novel technologies are being developed to detect distant metastases and recurrent disease as well as to assess response to breast cancer management.Intensive research efforts are actively ongoing to take novel breast cancer therapeutics to potential clinical application.Most of the recent research papers and patents discuss one of the following strategies: the development of new drug entities that specifically target the breast tumor cells; tailor designing a novel carrier system that can multitask and multifunction as a drug carrier, targeting vehicle and even as a diagnostic tool, direct conjugation of a therapeutic drug moiety with a targeting moiety, diagnostic moiety or pharmacokinetics altering moiety; or the use of innovative nontraditional approaches such as genetic engineering, stem cells, or vaccinations.
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The observation that approximately 15% of women with disseminated breast cancer will develop symptomatic brain metastases combined with treatment guidelines discouraging single-agent chemotherapeutic strategies facilitates the desire for novel strategies aimed at outright brain metastasis prevention. Effective and robust preclinical methods to evaluate early-stage metastatic processes, brain metastases burden, and overall mean survival are lacking. Here, we develop a novel method to quantitate early metastatic events (arresting and extravasation) in addition to traditional end time-point parameters such as tumor burden and survival in an experimental mouse model of brain metastases of breast cancer. Using this method, a reduced number of viable brain-seeking metastatic cells (from 3,331 ± 263 cells/brain to 1,079 ± 495 cells/brain) were arrested in brain one week postinjection after TGFß knockdown. Treatment with a TGFß receptor inhibitor, galunisertib, reduced the number of arrested cells in brain to 808 ± 82 cells/brain. Furthermore, we observed a reduction in the percentage of extravasated cells (from 63% to 30%) compared with cells remaining intralumenal when TGFß is knocked down or inhibited with galunisertib (40%). The observed reduction of extravasated metastatic cells in brain translated to smaller and fewer brain metastases and resulted in prolonged mean survival (from 36 days to 62 days). This method opens up potentially new avenues of metastases prevention research by providing critical data important to early brain metastasis of breast cancer events.
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Barreira Hematoencefálica , Neoplasias Encefálicas/secundário , Modelos Animais de Doenças , Neoplasias Mamárias Experimentais/patologia , Animais , Encéfalo/patologia , Linhagem Celular Tumoral , Feminino , Humanos , Camundongos , Camundongos Nus , Microscopia de Fluorescência , Metástase Neoplásica , Pirazóis/uso terapêutico , Quinolinas/uso terapêutico , Transdução de Sinais , Fator de Crescimento Transformador beta/metabolismoRESUMO
The blood-brain barrier (BBB) is a specialized vascular interface that restricts the entry of many compounds into brain. This is accomplished through the sealing of vascular endothelial cells together with tight junction proteins to prevent paracellular diffusion. In addition, the BBB has a high degree of expression of numerous efflux transporters which actively extrude compounds back into blood. However, when a metastatic lesion develops in brain the vasculature is typically compromised with increases in passive permeability (blood-tumor barrier; BTB). What is not well documented is to what degree active efflux retains function at the BTB despite the changes observed in passive permeability. In addition, there have been previous reports documenting both increased and decreased expression of P-glycoprotein (P-gp) in lesion vasculature. Herein, we simultaneously administer a passive diffusion marker ((14)C-AIB) and a tracer subject to P-gp efflux (rhodamine 123) into a murine preclinical model of brain metastases of breast cancer. We observed that the metastatic lesions had similar expression (p > 0.05; n = 756-1214 vessels evaluated) at the BBB and the BTB. Moreover, tissue distribution of R123 was not significantly (p > 0.05) different between normal brain and the metastatic lesion. It is possible that the similar expression of P-gp on the BBB and the BTB contribute to this phenomenon. Additionally we observed P-gp expression at the metastatic cancer cells adjacent to the vasculature which may also contribute to reduced R123 uptake into the lesion. The data suggest that despite the disrupted integrity of the BTB, efflux mechanisms appear to be intact, and may be functionally comparable to the normal BBB. The BTB is a significant hurdle to delivering drugs to brain metastasis.
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Brain (central nervous system; CNS) metastases pose a life-threatening problem for women with advanced metastatic breast cancer. It has recently been shown that the vasculature within preclinical brain metastasis model markedly restricts paclitaxel delivery in approximately 90% of CNS lesions. Therefore to improve efficacy, we have developed an ultra-small hyaluronic acid (HA) paclitaxel nanoconjugate (â¼5 kDa) that can passively diffuse across the leaky blood-tumor barrier and then be taken up into cancer cells (MDA-MB-231Br) via CD44 receptor-mediated endocytocis. Using CD44 receptor-mediated endocytosis as an uptake mechanism, HA-paclitaxel was able to bypass p-glycoprotein-mediated efflux on the surface of the cancer cells. In vitro cytoxicity of the conjugate and free paclitaxel were similar in that they (i) both caused cell-cycle arrest in the G2-M phase, (ii) showed similar degrees of apoptosis induction (cleaved caspase), and (iii) had similar IC50 values when compared with paclitaxel in MTT assay. A preclinical model of brain metastases of breast cancer using intracardiac injections of Luc-2 transfected MDA-MB-231Br cells was used to evaluate in vivo efficacy of the nanoconjugate. The animals administered with HA-paclitaxel nanoconjugate had significantly longer overall survival compared with the control and the paclitaxel-treated group (P < 0.05). This study suggests that the small molecular weight HA-paclitaxel nanoconjugates can improve standard chemotherapeutic drug efficacy in a preclinical model of brain metastases of breast cancer.
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Antineoplásicos Fitogênicos/farmacologia , Neoplasias Encefálicas/tratamento farmacológico , Neoplasias Encefálicas/secundário , Neoplasias da Mama/tratamento farmacológico , Ácido Hialurônico/farmacologia , Nanoconjugados , Paclitaxel/farmacologia , Animais , Antineoplásicos Fitogênicos/administração & dosagem , Antineoplásicos Fitogênicos/farmacocinética , Antineoplásicos Fitogênicos/uso terapêutico , Neoplasias Encefálicas/patologia , Neoplasias da Mama/mortalidade , Neoplasias da Mama/patologia , Linhagem Celular Tumoral , Avaliação Pré-Clínica de Medicamentos , Feminino , Humanos , Receptores de Hialuronatos/metabolismo , Ácido Hialurônico/administração & dosagem , Ácido Hialurônico/farmacocinética , Células MCF-7 , Neoplasias Mamárias Experimentais , Camundongos Nus , Paclitaxel/administração & dosagem , Paclitaxel/farmacocinética , Paclitaxel/uso terapêuticoRESUMO
Although the formulation of effective topical drug delivery system is one of the most sophisticated pharmaceutical preparations, it has attracted researchers due to many medical advantages associated with it. Topical drug delivery systems can act superficially on skin surface, locally in dermal layer of the skin or transdermally to provide successful delivery of drug molecules to the systemic circulation avoiding the traditional problems and limitations of conventional routes of drug delivery. Many novel formulations have been utilized topically to enhance either permeability or drug targeting to a specific layer of the skin such as Liposomes, ethosomes, transfersomes, niosomes and catezomes. The main problem with all of these formulations is that there is no distinct barrier between the targeting and localization action to a certain layer of the skin and the transdermal action to the circulation of these preparations. Any minimal change in the formulation could transform it from a local targeting preparation to a systemic one. This article deals with the innovations pertaining to the use of various types of liposomal preparations and liposomal like preparations for topical drug delivery and the patents associated with it.