Current Approaches for Predicting a Lack of Response to Anti-EGFR Therapy in KRAS Wild-Type Patients

Targeting epidermal growth factor receptor (EGFR) has been one of the most effective colorectal cancer strategies. Anti-EGFR antibodies function by binding to the extracellular domain of EGFR, preventing its activation, and ultimately providing clinical benefit. KRAS mutations in codons 12 and 13 are recognized prognostic and predictive biomarkers that should be analyzed at the clinic prior to the administration of anti-EGFR therapy. However, still an important fraction of KRAS wild-type patients do not respond to the treatment. The identification of additional genetic determinants of primary or secondary resistance to EGFR targeted therapy for further improving the selection of patients is urgent. Herein, we review the latest published literature highlighting the most important genes that may predict resistance to anti-EGFR monoclonal antibodies in colorectal cancer patients. According to the available findings, the evaluation of BRAF, NRAS, PIK3CA, and PTEN status could be the right strategy to select patients who are likely to respond to anti-EGFR therapies. In the future, the combination of those biomarkers will help establish consensus that can be introduced into clinical practice.

Saúde pública, inovação farmacêutica e propriedade intelectual: o desenvolvimento de um novo medicamento contra a malária no Brasil

Esta dissertação tem como objetivo estudar a relação entre propriedade intelectual, inovação e saúde pública, com foco na análise do consórcio farmacêutico para desenvolvimento do medicamento combinação em dose fixa artesunato-mefloquina (ASMQ) contra a malária. A concepção dessa iniciativa se insere num momento histórico, final dos anos 1990 e início dos anos 2000, em que estudos apontaram a insuficiência da pesquisa e desenvolvimento para as doenças negligenciadas. Na época, o cenário da malária era particularmente preocupante, dada a disseminação de resistência aos medicamentos disponíveis e à falta de perspectiva do lançamento de novos produtos contra a doença. Para proteger a última classe de antimaláricos eficazes, a saber,os derivados a base de artemisinina, uma estratégia encontrada foi a do recurso à terapia combinada a base de artemisinina (artemisinin based combination therapy ACT). Contudo, dos 4 ACTs recomendados pela OMS em 2001, apenas 1 se encontrava disponível no mercado. O projeto FACT foi então criado, em 2002, com o propósito de desenvolver dois novos ACTs artesunato-mefloquina e artesunato-amodiaquina. O consórcio do ASMQ, por suas especificidades, em particular a produção de inovação por um laboratório público do Sul e a circulação Sul-Sul de conhecimentos e tecnologias , o tornam de interesse para estudos nos campos da bioética e da saúde pública; tendo sido, por isso, escolhido como objeto desta dissertação. O estudo se apoiou em pesquisa bibliográfica, de fundamental relevância para a compreensão dos problemas de acesso e de disponibilidade de novos produtos para doenças negligenciadas, decorrentes de um modelo de inovação farmacêutica sustentado em patentes. De forma complementar, foram feitos: i) trabalho de observação durante a 65a Assembleia Mundial da Saúde, da Organização Mundial da Saúdem, evento de importância para os debates sobre propriedade intelectual e interesse público; e ii) entrevistas com integrantes de equipes das duas principais instituições participantes do consórcio FACT (Farmanguinhos/Fiocruz e DNDi).

Pre-irradiation with low-dose C-12(6+) beam significantly enhances the efficacy of AdCMV-p53 gene therapy in human non-small lung cancer

The combination of ionizing radiation and gene therapy has been investigated. However, there are very few reports about the combination of heavy-ion irradiation and gene therapy. To determine if the pre-exposure to low-dose heavy ion beam enhances the suppression of AdCMV-p53 on non-small lung cancer (NSLC), the cells pre-irradiated or non-irradiated were infected with 20, 40 MOI of AdCMV-p53. Survival fraction and the relative biology effect (RBE) were determined by clonogenic assay. The results showed that the proportions of p53 positive cells in C-12(6+) beam induced AdCMV-p53 infected cells were more than 90%, which were significantly more than those in gamma-ray induced AdCMV-p53 infected cells. The pre-exposure to low-dose 12C6+ beam significantly prevented the G(0)/G(1) arrest and activated G(2)/M checkpoints. The pre-exposure to C-12(6+) beam significantly improved cell to apoptosis. RBEs for the C-12(6+)+ AdCMV-p53 infection groups were 30%-60%,20% -130% and 30%-70% more than those for the C-12(6+)_irradiated only, AdCMV-p53 infected only, and gamma-irradiation induced AdCMVp53 infected groups, respectively. The data suggested that the pre-exposure to low-dose C-12(6+) beam significantly promotes exogenous p53 expression in NSLC, and the suppression of AdCMV-p53 gene therapy on NSLC.

On the chemical synthesis and drug delivery response of folate receptor-activated, polyethylene glycol-functionalized magnetite nanoparticles

We describe here the chemical synthesis and in vitro drug delivery response of polyethylene glycol (PEG)-functionalized magnetite (Fe3O4) nanoparticles, which were activated with a stable ligand, folic acid, and conjugated with an anticancer drug, doxorubicin. The functionalization and conjugation steps in the chemical synthesis were confirmed using Fourier transform infrared spectroscopy. The drug-release behavior of PEG-functionalized and folic acid-doxorubicin-conjugated magnetic nanoparticles was characterized by two stages involving an initial rapid release, followed by a controlled release. (C) 2007 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.

Construction of hollow DNA/PLL microcapsule as a dual carrier for controlled delivery of DNA and drug

DNA/poly-L-lysine (PLL) capsules were constructed through a layer-by-layer (LbL) self-assembly of DNA and PLL on CaCO3 microparticles, and then used as dual carriers for DNA and drug after dissolution of carbonate cores. The permeability of DNA/PLL microcapsules was investigated with fluorescence probes with different molecular weights by confocal microscopy. The result revealed that the fluorescence probes were able to penetrate the capsule walls even its molecular weight up to 150 kDa. The resultant capsules were used to load drug model molecules-fluorescein isothiocyanate (FITC)-dextran (4 kDa) via spontaneous deposition mechanism.

Multifunctional Hydroxyapatite Nanofibers and Microbelts as Drug Carriers

Luminescent, mesoporous, and bioactive europium-doped hydroxyapatite (HAp:Eu3+) nanofibers and microbelts have been prepared by a combination of sol-gel and electrospinning processes with a cationic surfactant as template. The obtained multifunctional hydroxyapatite nanofibers and microbelts, which have mesoporous structure and red luminescence, were tested as drug carriers by investigating their drug-storage/release properties with ibuprofen (IBU) as model drug. X-ray diffraction, scanning electron microscopy (SEM), transmission electron microscopy (TEM), high-resolution (HR) TEM, FTIR spectroscopy, N-2 adsorption/desorption, photoluminescence (PL) spectra, and UV/Vis spectroscopy were used to characterize the structural, morphological, textural, and optical properties of the resulting samples.

Monodisperse mesoporous superparamagnetic single-crystal magnetite nanoparticles for drug delivery

In this contribution, we report a facile, gram-scale, low-cost route to prepare monodisperse superparamagnetic single-crystal magnetite NPs with mesoporous structure (MSSMN) via a very simple solvothermal method. The formation mechanism of MSSMN is also discussed and we think that Ostwald ripening probably plays an important role in this synthesis process. It is also interestingly found that the size and morphology of mesoporous Fe3O4 NPs can be easily controlled by changing the amount of NaOH and 1,2-ethylenediamine (ETH). Most importantly, the MSSMN can be used as an effective drug delivery carrier. A typical anticancer drug, doxorubicin (Dox), is used for drug loading, and the release behaviors of Dox in two different pH solutions are studied. The results indicate that the MSSMN has a high drug loading capacity and favorable release property for Dox; thus, it is very promising for the application in drug delivery.

Ultrafine PEG-PLA fibers loaded with both paclitaxel and doxorubicin hydrochloride and their in vitro cytotoxicity

By means of "emulsion-electrospinning", both hydrophobic and hydrophilic drugs, paclitaxel (PTX) and doxorubicin hydrochloride (DOX), were successfully loaded into PEG-PLA nanofiber mats to realize multi-drug delivery. The release behaviors of both the drugs from the same fiber mats were ascribed to their solubility properties and distribution status in the fibers. Due to its high hydrophilicity, DOX was easy to diffuse out from the fibers, and its release rate was always faster than that of hydrophobic PTX. Moreover, the release rate of PTX was accelerated by DOX's release from the same drug-loaded fibers. In vitro cytotoxicity against rat Glioma C6 cells indicated that the dual drug combination showed a higher inhibition and apoptosis against C6 cells than a single drug-loaded system, which suggests the promise for multi-drug delivery on combination therapy.

Luminescence functionalization of SBA-15 by YVO4 : Eu3+ as a novel drug delivery system

Luminescence functionalization of the ordered mesoporous SBA-15 silica was realized by depositing a YVO4:Eu3+ phosphor layer on its surface via the Pechini sol-gel process, resulting in the formation of the YVO4:Eu3+@SBA-15 composite material. This material, which combines the mesoporous structure of SBA-15 and the strong red luminescence property of YVO4:Eu3+, can be used as a novel functional drug delivery system. The structure, morphology, porosity, and optical properties of the materials were well characterized by X-ray diffraction, Fourier transform infrared spectroscopy, scanning electron microscopy, transmission electron microscopy, N-2 adsorption, and photoluminescence spectra. As expected, the pore volume, surface area, and pore size of SBA-15 decrease in sequence after deposition of the YVO4:Eu3+ layer and the adsorption of ibuprofen (IBU, drug). The IBU-loaded YVO4:Eu3+@SBA-15 system still shows the red emission of Eu3+ (617 nm, D-5(0)-F-7(2)) under UV irradiation and the controlled drug release property. Additionally, the emission intensity of Eu3+ increases with an increase in the cumulative released amount of IBU in the system, making the extent of drug release easily identifiable, trackable, and monitorable by the change of luminescence. The system has great potential in the drug delivery and disease therapy fields.

High-throughput synergy screening identifies microbial metabolites as combination agents for the treatment of fungal infections

The high mortality rate of immunocompromised patients with fungal infections and the limited availability of highly efficacious and safe agents demand the development of new antifungal therapeutics. To rapidly discover such agents, we developed a high-throughput synergy screening (HTSS) strategy for novel microbial natural products. Specifically, a microbial natural product library was screened for hits that synergize the effect of a low dosage of ketoconazole (KTC) that alone shows little detectable fungicidal activity. Through screening of approximate to 20,000 microbial extracts, 12 hits were identified with broadspectrum antifungal activity. Seven of them showed little cytotoxicity against human hepatoma cells. Fractionation of the active extracts revealed beauvericin (BEA) as the most potent component, because it dramatically synergized KTC activity against diverse fungal pathogens by a checkerboard assay. Significantly, in our immunocompromised mouse model, combinations of BEA (0.5 mg/kg) and KTC (0.5 mg/kg) prolonged survival of the host infected with Candida parapsilosis and reduced fungal colony counts in animal organs including kidneys, lungs, and brains. Such an effect was not achieved even with the high dose of 50 mg/kg KTC. These data support synergism between BEA and KTC and thereby a prospective strategy for antifungal therapy.

Application of Inductive Logic Programming to Structure-Based Drug Design

Enot, D. and King, R. D. (2003) Application of Inductive Logic Programming to Structure-Based Drug Design. 7th European Conference on Principles and Practice of Knowledge Discovery in Databases (PKDD '03). Springer LNAI 2838 p156-167

O mirtilo e suas propriedades terapêuticas

Projeto de Pós-Graduação/Dissertação apresentado à Universidade Fernando Pessoa como parte dos requisitos para obtenção do grau de Mestre em Ciências Farmacêuticas

Paediatric malaria case-management with artemether-lumefantrine in Zambia: a repeat cross-sectional study

BACKGROUND:Zambia was the first African country to change national antimalarial treatment policy to artemisinin-based combination therapy - artemether-lumefantrine. An evaluation during the early implementation phase revealed low readiness of health facilities and health workers to deliver artemether-lumefantrine, and worryingly suboptimal treatment practices. Improvements in the case-management of uncomplicated malaria two years after the initial evaluation and three years after the change of policy in Zambia are reported.METHODS:Data collected during the health facility surveys undertaken in 2004 and 2006 at all outpatient departments of government and mission facilities in four Zambian districts were analysed. The surveys were cross-sectional, using a range of quality of care assessment methods. The main outcome measures were changes in health facility and health worker readiness to deliver artemether-lumefantrine, and changes in case-management practices for children below five years of age presenting with uncomplicated malaria as defined by national guidelines.RESULTS:In 2004, 94 health facilities, 103 health workers and 944 consultations for children with uncomplicated malaria were evaluated. In 2006, 104 facilities, 135 health workers and 1125 consultations were evaluated using the same criteria of selection. Health facility and health worker readiness improved from 2004 to 2006: availability of artemether-lumefantrine from 51% (48/94) to 60% (62/104), presence of artemether-lumefantrine dosage wall charts from 20% (19/94) to 75% (78/104), possession of guidelines from 58% (60/103) to 92% (124/135), and provision of in-service training from 25% (26/103) to 41% (55/135). The proportions of children with uncomplicated malaria treated with artemether-lumefantrine also increased from 2004 to 2006: from 1% (6/527) to 27% (149/552) in children weighing 5 to 9 kg, and from 11% (42/394) to 42% (231/547) in children weighing 10 kg or more. In both weight groups and both years, 22% (441/2020) of children with uncomplicated malaria were not prescribed any antimalarial drug.CONCLUSION:Although significant improvements in malaria case-management have occurred over two years in Zambia, the quality of treatment provided at the point of care is not yet optimal. Strengthening weak health systems and improving the delivery of effective interventions should remain high priority in all countries implementing new treatment policies for malaria.

Accessibility, availability and affordability of anti-malarials in a rural district in Kenya after implementation of a national subsidy scheme.

BACKGROUND: Poor access to prompt and effective treatment for malaria contributes to high mortality and severe morbidity. In Kenya, it is estimated that only 12% of children receive anti-malarials for their fever within 24 hours. The first point of care for many fevers is a local medicine retailer, such as a pharmacy or chemist. The role of the medicine retailer as an important distribution point for malaria medicines has been recognized and several different strategies have been used to improve the services that these retailers provide. Despite these efforts, many mothers still purchase ineffective drugs because they are less expensive than effective artemisinin combination therapy (ACT). One strategy that is being piloted in several countries is an international subsidy targeted at anti-malarials supplied through the retail sector. The goal of this strategy is to make ACT as affordable as ineffective alternatives. The programme, called the Affordable Medicines Facility - malaria was rolled out in Kenya in August 2010. METHODS: In December 2010, the affordability and accessibility of malaria medicines in a rural district in Kenya were evaluated using a complete census of all public and private facilities, chemists, pharmacists, and other malaria medicine retailers within the Webuye Demographic Surveillance Area. Availability, types, and prices of anti-malarials were assessed. There are 13 public or mission facilities and 97 medicine retailers (registered and unregistered). RESULTS: The average distance from a home to the nearest public health facility is 2 km, but the average distance to the nearest medicine retailer is half that. Quinine is the most frequently stocked anti-malarial (61% of retailers). More medicine retailers stocked sulphadoxine-pyramethamine (SP; 57%) than ACT (44%). Eleven percent of retailers stocked AMFm subsidized artemether-lumefantrine (AL). No retailers had chloroquine in stock and only five were selling artemisinin monotherapy. The mean price of any brand of AL, the recommended first-line drug in Kenya, was $2.7 USD. Brands purchased under the AMFm programme cost 40% less than non-AMFm brands. Artemisinin monotherapies cost on average more than twice as much as AMFm-brand AL. SP cost only $0.5, a fraction of the price of ACT. CONCLUSIONS: AMFm-subsidized anti-malarials are considerably less expensive than unsubsidized AL, but the price difference between effective and ineffective therapies is still large.

Progress in intra-articular therapy.

Diarthrodial joints are well suited to intra-articular injection, and the local delivery of therapeutics in this fashion brings several potential advantages to the treatment of a wide range of arthropathies. Possible benefits over systemic delivery include increased bioavailability, reduced systemic exposure, fewer adverse events, and lower total drug costs. Nevertheless, intra-articular therapy is challenging because of the rapid egress of injected materials from the joint space; this elimination is true of both small molecules, which exit via synovial capillaries, and of macromolecules, which are cleared by the lymphatic system. In general, soluble materials have an intra-articular dwell time measured only in hours. Corticosteroids and hyaluronate preparations constitute the mainstay of FDA-approved intra-articular therapeutics. Recombinant proteins, autologous blood products and analgesics have also found clinical use via intra-articular delivery. Several alternative approaches, such as local delivery of cell and gene therapy, as well as the use of microparticles, liposomes, and modified drugs, are in various stages of preclinical development.