Drug Dose Reduction Research Articles

P087 Allele frequency of Thiopurine S-methyltransferase (TPMT) in Hong Kong population

Aim Azathioprine, 6-Mercaptopurine and 6-Thioguanine are commonly used in the management of acute leukemia, autoimmune diseases and as the immunosuppressants in organ transplantation. These drugs belong to the class of thiopurine which can inhibit DNA synthesis and cell proliferation of fast growing lymphocytes by suppressing de novo purine synthesis. Thioguanine nucleotides (TGNs) are the active metabolites in which accumulation of high level cytotoxic TGNs can lead to myelosuppression. It has been demonstrated that Thiopurine S-methyltransferase (TPMT) is the key enzyme responsible for catalytic conversion of TGNs to non-cytotoxic methyl-thioguanine. The TPMT gene is polymorphic and TPMT protein variants with reduced enzyme activity are associated with inefficient removal of TGNs. In this study, we aim to investigate the allele frequency of the most common TPMT variants (TPMT*2 and *3C) in Hong Kong population. Methods Genomic DNA from whole blood was extracted. The presence of TPMT*2 and *3C mutant alleles were determined using Amplification-Refractory Mutation System (ARMS) PCR method. Beta-2-microglobulin was used as the internal control. All mutant alleles were confirmed by Sanger’s sequencing. Hong Kong healthy individuals (n = 300) were included in this study. Rare TPMT alleles were not determined. Results TPMT*1/3C genotype was detected in 9 out of 300 healthy subjects while TPMT*2 allele was absent. The allele frequency of TPMT*3C in Hong Kong population is 1.5%. Conclusions This study provides the first analysis of the allele frequency of TPMT variants in Hong Kong population and our finding is in accordance with the reported frequency range in Chinese population. TPMT*3C is the most common TPMT variant in Hong Kong subjects. The establishment of TPMT genotyping assay for patient requires thiopurine therapy will provide additional information to guide the reduction of drug dose to minimize the risk of myelosuppression.

MANAGEMENT OF DIABETES, OBESITY AND GASTRIC DISORDERS USING THE ‘INTEGRATED APPROACH’ AT HEALTH TOTAL: A CASE STUDY

It has been found that high prevalence of hypertension and Type II diabetes is coincidental to obesity. A well-defined nutrition therapy is one of the most effective methods of managing and slowing down the rate of development of Type II diabetes, gastrointestinal (GI) problems, and hypertension. A healthy diet or plan for the above-mentioned complications should be one that is naturally rich in phytochemicals and low in glycemic index, bad fats, and excess calories. This case study deals with the benefits of an “Integrated approach” in the management of diabetes, hypertension, gastric disorders, and obesity. The “integrated approach” includes patient-specific nutritional therapy, ayurvedic herb support, vitamins and dietary supplements, stress management, and regular exercise. The subject in this study was a 39-year-old obese female with a clinical history of Type II diabetes, borderline hypertension, and GI issues. Apart from these she also complained of low immunity, low energy levels, and high levels of stress. During the 10-month treatment, significant weight loss was achieved along with normalization of blood sugar levels and steady lowering of blood pressure with subsequent improvement in gastric problems and improved energy levels. Hence, the case report aptly illustrates that an integrated approach can help, not only manage diabetes, hypertension, and obesity but also reduce drug dosage and significantly improve quality of life.

Abstract 4908: Exemestane worsens everolimus-associated stomatitis in cancer patients

Abstract Everolimus is an antitumor drug usually indicated for the treatment of breast, kidney and neuroendocrine malignancies that inhibits the activation of the mammalian Target of Rapamycin (mTOR). Despite the efficacy and success of the treatment, side effects are not uncommon, and stomatitis is quite prevalent. mTOR inhibitor associated stomatitis (mIAS) is described as ulcerated aphthous-like lesions associated with mTOR inhibitors use. mIAS may cause severe pain, leading to nutritional deficiency and general health decline, besides drug dose reduction or suspension. Clinical observation suggested mIAS to be more common among breast cancer patients. Thus, we hypothesized that exemestane could contribute to increase everolimus toxicity in the oral mucosa. We prospectivelly collected clinical data from patients who used everolimus, associated or not with exemestane, from March 2016 to September 2017, and correlated them with information regarding mIAS (date of onset, number of lesions in the oral cavity, grading). We also performed in vitro experiments with Dysplastic Oral Keratinocytes (DOK). Cells were treated with vehicle, everolimus, exemestane or the combination of everolimus and exemestane. Drug induced citotoxicity was evaluated by MTT assay and migration inhibition by scratch wound healing assay. All assays were done in triplicate. Frequencies were compared by Fisher's exact or McNemar test. Log-rank and Wilcoxon tests were employed to compare time to mIAS development. Multivariate ANOVA was used to compare results from in vitro experiments. SPSS and Image J were used to make all statistical analysis. One hundred and thirty patients were evaluated. Mostly were females, with mean age of 60 years, and had previously treated advanced stage (IV) breast cancer. 30.3% developed mIAS. Breast cancer patients (treated with exemestane plus everolimus) had 2.29 higher chance to develop mIAS when compared to neuroendocrine tumos patients (treated with everolimus alone). In vitro experiments showed that the association of everolimus and exemestane increased cell death and migration (wound healing) inhibition of DOK in comparison with cells treated with everolimus or exemestane alone. The clinical data suggests that exemestane increases the risk of developing mIAS, and the in vitro experiments reinforces the idea that exemestane may enhance oral mucosa toxicity mediated by everolimus. Citation Format: Vladmir C. de Lima, Matheus H. de Lima, Fabio A. Alves, Gláucia N. Hajj. Exemestane worsens everolimus-associated stomatitis in cancer patients [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 4908.

Patterns of platinum drug use in an acute care setting: a retrospective study.

Platinum drugs have been in use in cancer treatment for more than 40 years, but little is known about the pattern of their use. The aim of this study was to examine the patterns of platinum drug use, with a secondary aim to describe the occurrence of dose reductions. A retrospective analysis was conducted of oncology pharmacy dispensing records from a single hospital in Australia. Data related to drug choice, regimen and dose reductions were included in this study if the patient had received their last round of chemotherapy between November 2014 and July 2015. Of the 156 patients included in the study, 46% were dispensed a platinum drug during their treatment. The most commonly dispensed drugs were cisplatin (40%), carboplatin (40%) and oxaliplatin (15%), while some patients (5%) received more than one platinum drug. Dose reductions were more common in patients who were treated with a platinum drug (73%) compared with patients treated with non-platinum drugs (55%). The most common reason for a dose reduction was cytopenia. The findings suggest that platinum drugs remain one of the most commonly dispensed drugs to treat cancer patients and most patients receive a dose reduction during treatment.

Accelerated wound healing by injectable star poly(ethylene glycol)-b-poly(propylene sulfide) scaffolds loaded with poorly water-soluble drugs

Injectable hydrogel matrices take the shape of a wound cavity and serve as scaffold for tissue repair and regeneration. Yet these materials are generally hydrophilic, limiting the incorporation of poorly water soluble, hydrophobic drugs. Here we show this shortcoming is circumvented through a star-shaped amphiphilic block copolymer comprising poly(ethylene glycol) and poly (propylene sulfide). This star-shaped amphiphilic polymer self-assembles in an aqueous medium into a physically stable hydrogel and effectively dissolves hydrophobic molecules delivering them at therapeutic doses. The self assembled hydrogel is a robust three-dimensional scaffold in vivo effectively promoting cellular infiltration, reducing inflammation, and wound clsoure. When combined with a hydrophobic BRAF inhibitor that promotes paradoxical mitogen-activated protein kinase (MAPK) activation in keratinocytes and wound closure, our self assembled scaffold supported dermal wound closure at a reduced drug dosage compared to administering the drug in dimethyl sulfoxide (DMSO) without a polymeric matrix. This family of star-shaped amphiphilic polymers delivers poorly water soluble active agents at a fraction of generally required dosage for efficacy and supports three-dimensional cell growth at tissue wounds, showing great promise for novel uses of hydrophobic drugs in tissue repair applications.

Nanostructured Therapeutic Carriers for Tuberculosis Treatment: Approaches & Challenges.

The diseases tuberculosis, triggered by intracellular pathogens, is a major problem for the global medical professionals. Treatments for these diseases through conventional dosage form consist of long-term therapy with multiple drugs, leading to several side effects and contribute to low patient compliance and drug resistance. The pathogens are found to be situated in the intracellular compartments of the cells, which ultimately results in additional blockades to effective treatment. Therefore, improved and more efficient therapies for such intracellular diseases are required. This review discusses the potential of nanomedicine and related patents to improve intracellular disease chemotherapy. To complete the objective, we searched bibliographic databases of indexed literature using a focused and structured criteria. The quality and characteristics of selected papers were assessed using standard parameters with qualitative analysis having a conceptual framework. Nanoparticle-based drug delivery systems are suitable for the treatment of illnesses, such as tuberculosis. Due to the unique size-dependent properties, nanocarriers such as nanoparticles, liposomes, niosomes and microspheres offer the opportunity to develop new therapeutic and diagnostic tools. The ability to integrate drugs into nanosystems displays a new standard in pharmacotherapy that could be used for cell-targeted drug therapy. Experimental data showed the possibility of intermittent chemotherapy with main antituberculosis drugs by employing nanocarriers. Besides the advantage of the controlled release of medications in organs, the other benefits of the nanocarriers include the possibility of various routes of therapy, reduction in drug dosage and adverse effects, reduced possibility of drug interactions, and drug-resistant targeting. Published literature including patented studies suggests that nanomedicine mediated drug delivery may improve tuberculosis chemotherapy by offering benefits such as targeting to the specific organs, sustained and controlled drug release, tuberculosis diagnosis, drug delivery to the pathogen's intracellular location, and tuberculosis vaccine development. The properties of nanomedicine may prove beneficial in developing improved, efficacious or alternative therapies for tuberculosis diseases.

PCN27 - The Cost-Effectiveness Analysis of Rhtpo Versus Il-11 on The Treatment of Chemotherapy-Induced Thrombocytopenia Patients in China

Thrombocytopenia is a serious clinical conditions after cancer chemotherapy and the condition could result potential drug dose reduction and treatment delay. At the same time, thrombocytopenia can affect the quality of life of patients and increase healthcare cost substantially. In China, recombinant human thrombopoietin (rhTPO) was recommended to treat chemotherapy-induced thrombocytopenia (CIT) by China cancer chemotherapy expert panel in 2014. The objective of this study is to assess the cost-effectiveness of rhTPO versus IL-11 in treating Chinese CIT patients. An economic model was constructed to assess the cost-effectiveness of rhTPO and IL-11 in the treatment of CIT. All data required by the model were derived from literature review and key opinion leader (KOL) survey. The clinical efficacy data were obtained from published literature. Cost data were collected from Chinese leading hospitals located in Beijing, Shanghai, Guangzhou, Jinan, Wuhan and Chengdu with a total of 51 experts interviewed in the 6 cities. A one-way sensitivity analysis was conducted. The total medical cost of rhTPO and IL-11 is RMB 8533.3 and RMB 6820.9 respectively. The incidence rate of grade III thrombocytopenia is 39.7%, 67.6% and grade IV thrombocytopenia is 11.1%, 35.2% respectively of rhTPO and IL-11 group. Compared with IL-11, the increased cost for one grade III thrombocytopenia patient and grade IV thrombocytopenia patient averted by rhTPO is RMB 5990 and RMB 7100 respectively. Both of which are lower than the calculated cost from questionnaires collected from the 51 experts (The cost for one grade III thrombocytopenia patient and grade IV thrombocytopenia patient averted is RMB 6190 and RMB 10650 yuan respectively). With rhTPO cost changing 10% on the basis value, the model shows robustness according to the result. RhTPO is a cost effective treatment compared with IL-11 in China CIT patients. The sensitivity analysis results indicated that the model is robust.

Association of Dasatinib With Progression-Free Survival Among Patients With Advanced Gastrointestinal Stromal Tumors Resistant to Imatinib

Gastrointestinal stromal tumors (GISTs) are life-threatening when metastatic or not amenable to surgical removal. In a few patients with advanced GISTs refractory to imatinib mesylate, treatment with sunitinib malate followed by regorafenib provides tumor control; however, additional active treatments are needed for most patients. To evaluate the 6-month progression-free survival (PFS), tumor objective response, and overall survival rates in patients with GISTs treated with dasatinib. This single-arm clinical trial used a Bayesian design to enroll patients 13 years or older with measurable imatinib-refractory metastatic GISTs treated at 14 sarcoma referral centers from June 1, 2008, through December 31, 2009. A control group was not included. Patients were followed up for survival for a minimum of 5 years from date of enrollment. Tumor imaging using computed tomography or magnetic resonance imaging was performed every 8 weeks for the first 24 weeks and every 12 weeks thereafter. Tumor response was assessed by local site using the Choi criteria. Treatment was continued until tumor progression, unacceptable toxic effects after reduction in drug dose, or patient or physician decision. Archival tumor tissue was evaluated for expression of the proto-oncogene tyrosine-protein kinase Src (SRC), phosphorylated SRC (pSRC), and succinate dehydrogenase complex iron sulfur subunit B (SDHB) proteins and for mutation in the V-Kit Hardy-Zuckerman 4 feline sarcoma viral oncogene homolog (KIT) and platelet-derived growth factor receptor α (PDGFRA) genes. Data analysis was performed from May 19, 2017, through December 20, 2017. Dasatinib, 70 mg orally twice daily. The primary end point was the 6-month PFS estimate using greater than 30% as evidence of an active drug and less than 10% as evidence of inactive treatment. In this study, 50 patients were enrolled (median age, 60 years; age range, 19-78 years; 31 [62%] male and 19 [38%] female; 41 [82%] white), and 48 were evaluable for response. The estimated 6-month PFS rate was 29% in the overall population and 50% in a subset of 14 patients with pSRC in GISTs. Objective tumor response was observed in 25%, including 1 patient with an imatinib-resistant mutation in PDGFRA exon 18. Dasatinib may have activity in a subset of patients with imatinib-resistant GISTs. Further study is needed to determine whether pSRC is a prognostic biomarker.

Self-assembled amphiphilic zein-lactoferrin micelles for tumor targeted co-delivery of rapamycin and wogonin to breast cancer

Protein-based micelles have shown significant potential for tumor-targeted delivery of anti-cancer drugs. In this light, self-assembled nanocarriers based on GRAS (Generally recognized as safe) amphiphilic protein co-polymers were synthesized via carbodiimide coupling reaction. The new nano-platform is composed of the following key components: (i) hydrophobic zein core to encapsulate the hydrophobic drugs rapamycin (RAP) and wogonin (WOG) with high encapsulation efficiency, (ii) hydrophilic lactoferrin (Lf) corona to enhance the tumor targeting, and prolong systemic circulation of the nanocarriers, and (iii) glutaraldehyde (GLA)-crosslinking to reduce the particle size and improve micellar stability. Zein-Lf micelles showed relatively rapid release of WOG followed by slower diffusion of RAP from zein core. This sequential release may aid in efflux pump inhibition by WOG thus sensitizing tumor cells to RAP action. Interestingly, these micelles showed good hemocompatibility as well as enhanced serum stability owing to the brush-like architecture of Lf shell. Moreover, this combined nano-delivery system maximized synergistic cytotoxicity of RAP and WOG in terms of tumor inhibition in MCF-7 breast cancer cells and Ehrlich ascites tumor animal model as a result of enhanced active targeting. Collectively, GLA-crosslinked zein-Lf micelles hold great promise for combined RAP/WOG delivery to breast cancer with reduced drug dose, minimized side effects and maximized anti-tumor efficacy.

Release of targeted protein nanoparticles from functional bacterial amyloids: A death star-like approach

Sustained release of drug delivery systems (DDS) has the capacity to increase cancer treatment efficiency in terms of drug dosage reduction and subsequent decrease of deleterious side effects. In this regard, many biomaterials are being investigated but none offers morphometric and functional plasticity and versatility comparable to protein-based nanoparticles (pNPs). Here we describe a new DDS by which pNPs are fabricated as bacterial inclusion bodies (IB), that can be easily isolated, subcutaneously injected and used as reservoirs for the sustained release of targeted pNPs. Our approach combines the high performance of pNP, regarding specific cell targeting and biodistribution with the IB supramolecular organization, stability and cost effectiveness. This renders a platform able to provide a sustained source of CXCR4-targeted pNPs that selectively accumulate in tumor cells in a CXCR4+ colorectal cancer xenograft model. In addition, the proposed system could be potentially adapted to any other protein construct offering a plethora of possible new therapeutic applications in nanomedicine.

Improved chemo-photothermal therapy of hepatocellular carcinoma using chitosan-coated gold nanoparticles

A green method was used for producing gold nanoparticles (Au NPs) using chitosan as a natural cationic, biodegradable and biocompatible polymer. In this method, chitosan acts as a reducing and stabilizing agent for the synthesis of Au NPs. Different concentrations of chitosan solutions (0.01%, 0.05%, 0.1%, 0.2%, 0.5% and 1%) were applied. In an attempt to mitigate the side effects of anti-cancer drug, 5-fluorouracil (5-FU), through reducing drug doses in photothermal therapy, the formed positively-charged chitosan-wrapped Au NPs were used as a drug delivery system for negatively charged 5-FU to hepatocellular carcinoma cells (HepG2). Au NPs as well as 5-FU@Au nanocomposites were characterized with UV-VIS spectroscopy, particle size, zeta potential, Fourier transform infrared spectroscopy (FTIR), transmission electron microscopy (TEM) and High-Performance Liquid Chromatography (HPLC). The chitosan concentration was shown to be an important parameter for optimizing the dispersion of Au NPs and 5-FU@Au nanocomposites over long time. This stability offers the 5-FU@Au nanocomposites as good candidate for cancer treatment with reduced drug doses in photothermal therapy. A 72% loading-efficiency of 5-FU was obtained. Cytotoxic assay was carried out on HepG2 cell line and it reveals the effectiveness of 5-FU@Au nanocomposites in the presence and absence of laser irradiation compared with the free 5-FU. The cytotoxicity effect of free 5-FU and 5-FU@AuNPs nanocomposites was studied, and it was found that the concentration of 5-FU@Au nanocomposites required to attain 50% of inhibition growth rate was lower than that of free 5-FU in absence of laser radiation and was much lower in presence of laser radiation.

The effect of ultrasound-guided nerve block on the prognosis of patients undergoing laparoscopic cholecystectomy

Objective To investigate the effhect of ultrasound-guided nerve block on the prognosis of patients undergoing laparoscopic cholecystectomy. Methods A total of 150 cases undergoing elective laparoscopic cholecystectomy in our hospital was used as the research object, and randomly divided into control (n=75) and observation (n=75) groups. The control group used punctured local infiltration analgesia, and observation group used the transversus abdominis plane block (TAP) combined with local infiltration analgesia hole. The postoperative awake time, hemodynamic changes, pain score, and analgesic use were compared between two groups. Results The recovery time was significantly reduced in the observation group (9.7±2)minutes compared to the control group (23.9±2.4)minutes. The additional total dose of analgesics and average additional times were significantly lower in the observation group compared to the control group (P 0.05). Conclusions Ultrasound-guided nerve block can obviously reduce postoperative pain, reduce drug use frequency and dosage, significantly improve postoperative outcomes, and does not increase the incidence of adverse drug reactions. It is worthy of clinical reference. Key words: Ultrasonography; Nerve block; Cholecystectomy, laparoscopic; Anesthesia

Lenvatinib in Advanced Radioiodine-refractory Thyroid Cancer: A Snapshot of Real-life Clinical Practice.

We retrospectively analyzed the efficacy and safety of lenvatinib in 12 patients with advanced radioiodine-refractory thyroid cancer in the setting of daily clinical practice. The starting daily dose of lenvatinib was 24 mg, tapered in the case of adverse events. Disease status was periodically evaluated by a single radiologist and safety assessment was regularly performed. After a median follow-up of 13.3 months, 6- and 12-month progression-free survival rates were 63.6% and 54.6%, respectively. Overall survival at 6 and 12 months was 83.3% and 75.0%. Partial response was observed in five patients, while two showed stable disease as their best response. Conversely, progressive disease at first radiological assessment was detected in four patients. All patients experienced at least one adverse event, including systemic and gastrointestinal toxicity, high blood pressure and hand-foot syndrome. In order to manage toxicity, transient drug interruption and dose reduction were required in 10 and 9 cases, respectively. Our data confirm lenvatinib efficacy in patients with advanced thyroid cancer, despite an important toxic profile.

New Glucose-Lowering Agents for Diabetic Kidney Disease.

The prevalence of diabetes mellitus is increasing and is associated with a range of complications including nephropathy. New antidiabetic agents are sought which also have positive effects to diminish diabetic complications. Examples of promising new classes of such agents are glucagon-like peptide-1 receptor agonists, dipeptidyl peptidase-4 inhibitors, and sodium-glucose cotransporter 2 inhibitors. In addition to cardiovascular protective effects such as weight loss and decreased blood pressure of some of these agents, there is evidence for renoprotective effects with these agents. This review elaborates on the main results of renoprotective effects of these 3 treatment classes. In conclusion, currently available trials have demonstrated renoprotective effects for certain glucagon-like peptide-1 receptor agonists, liraglutide and semaglutide, and the sodium-glucose cotransporter 2 inhibitors, empagliflozin and canagliflozin. Dipeptidyl peptidase-4 inhibitors did not show a significant renoprotective effect. Nevertheless, larger studies with respect to renoprotective effects of these 3 drug classes are currently being performed, and thus, no conclusions for all of these agents can yet be made.

Development of a selective and sensitive LC–MS/MS method for the quantification of α-asarone in mouse plasma and its application to pharmacokinetic studies

A simple, sensitive and selective liquid chromatography-tandem mass spectrometric method was developed and validated for the quantification of α-asarone in mouse plasma with its application to pharmacokinetic studies. An electrospray ionization (ESI) with multiple reaction monitoring (MRM) mode was used to monitor the precursor-product ion transitions of 209.1 > 193.9 m/z for α-asarone and 157.8 > 114.0 m/z for allantoin. Chromatographic separation was acquired on a Sepax BR-C18 (5 μm, 120 Å 1.0 × 100 mm) column with an isocratic mobile phase consisting of methanol and 0.1% formic acid (80:20, v/v). The developed bioanalytical method was successfully validated according to the United States Food and Drug Administration (US FDA) guidelines for linearity, selectivity, accuracy, precision, recovery, matrix effect, and stability. The validated method was successfully applied to a pharmacokinetics study of α-asarone along with a combination of pharmacokinetic techniques, including small-volume serial blood sampling in mice, reducing drug doses and the number of animals used, using a simple protein precipitation method and less solvent consumption will enable its use in further bioequivalence studies.

Placebo Effects in the Immune System.

Even though knowledge and systematic application of placebo responses in the immune system are sparse, this topic is of particular importance since it may aim at drug-dose reduction while maintaining therapeutic efficacy of treatment in clinical settings. Placebo responses in the immune system are inducible by associated learning paradigms, such as behaviorally conditioned immunosuppression. One established learning paradigm in both rats and humans is conditioned taste avoidance (CTA), where a novel taste as conditioned stimulus (CS) is paired with the administration of the immunosuppressive drug cyclosporine A (CsA) as unconditioned stimulus. By representing the CS alone at a later time point, the conditioned response is reflected by avoidance behavior toward the taste (CTA). Simultaneously, diminished cytokine production and proliferative capacity of T cells are observed, closely mimicking the pharmacological effects of CsA. This chapter provides an overview on placebo responses in the immune system and delineates actual approaches, translational aspects, and limitations of learning paradigms in clinical settings.

A strategy for effective latent HIV reactivation using subtherapeutic drug doses

Cell state switches underlie a plethora of biological phenomena and disease treatment strategies. Hence the ability to efficiently switch states in a chosen direction is of central importance in a number of scenarios. Increasing the concentration of an effector that results in a given switch is often limited by side effects. Approaches are thus increasingly sought to bypass these constraints, increasing the frequency of state switching without increasing the frequency of the side effect. Here, we employ dynamical systems theory to uncover a simple strategy as to how to maximize the probability of reactivating latent Human immunodeficiency virus (HIV) whilst maintaining minimal side effects. We demonstrate that continuous supply of an effector is significantly more likely to result in a switch with minimal side effects than the same effector supplied in temporally discrete doses. Importantly this continual dosage is likely to occur far below the Minimum effective dose at a concentration that has classically been thought subtherapeutic. We therefore suggest that in many interventional settings there exists potential to reduce drug dose much further than has previously been thought possible yet still maintaining efficacy.

Oligonucleotide Therapies for the Lung: Ready to Return to the Clinic?

The most promising targets for treating lung diseases are often intracellular molecules recalcitrant to conventional pharmacotherapy. In this respect, antisense oligonucleotides (ASO) would be valuable tools to treat airways disease, as the plurality of their potential mechanisms of action is well-established, their efficiency has been extensively validated in-vitro, and their potential clinical value has been demonstrated with numerous regulatory approvals. Yet in spite of high confidence in the treatment rationale and mechanism of action, it appears that oligonucleotides delivered topically to the lung either rapidly access circulation via epithelial transcytosis or are removed by alveolar macrophages, exerting minimal if any action in the cytosol of cells relevant to lung disease. Moreover, use of cell penetrating peptides, liposomes or nanoparticle delivery systems has not so far been shown to eliminate circulatory clearance, may activate immune responses, or drive macrophage phenotypic changes that, together or in isolation, may present risks to patients.

Ultrasound reverses chemoresistance in breast cancer stem cell like cells by altering ABCG2 expression.

Doxorubicin (DOX) resistance in breast cancer largely results from the breast cancer stem cell like cells (BCSCs) which could be targetted to improve the efficacy of chemotherapy. Cell permeabilization using microbubbles (MBs) and ultrasound (US) have the potential for delivering molecules into the cytoplasm. We aim to evaluate a new methodology of US on BCSCs. First, our findings indicated that ALDHA1+ spheres which were derived from fresh primary breast cancer samples displayed stem cell like features and were resistant to DOX. In patient cohort, we revealed the presence of a variable fraction of ALDHA1+cells in nine out of ten. We, for the first time, showed a new US-MB treatment condition which could be used on ALDHA1+ BCSCs by fluorescence measurement and calcein assay. Next, we demonstrated the efficacy of combined treatment on human BCSCs in vitro and in vivo using DOX and US-MB: the combined treatment with much reduced drug dosage significantly suppressed the stem cell like features of BCSCs and induced BCSCs apoptosis. Furthermore, we suggested that decreased ABCG2 level might be one of the mechanisms by which US-MB medicated DOX treatment. In conclusion, this new US-MB treatment condition has clinical potential in breast cancer therapy by targetting BCSCs; thereby holding benefits for breast cancer patients.

TrpA1 activation in peripheral sensory neurons underlies the ionic basis of pain hypersensitivity in response to vinca alkaloids.

Chemotherapy induced peripheral neuropathy (CIPN), a side effect of many anti-cancer drugs including the vinca alkaloids, is characterized by a severe pain syndrome that compromises treatment in many patients. Currently there are no effective treatments for this pain syndrome except for the reduction of anti-cancer drug dose. Existing data supports the model that the pain associated with CIPN is the result of anti-cancer drugs augmenting the function of the peripheral sensory nociceptors but the cellular mechanisms underlying the effects of anti-cancer drugs on sensory neuron function are not well described. Studies from animal models have suggested a number of disease etiologies including mitotoxicity, axonal degeneration, immune signaling, and reduced sensory innervations but these outcomes are the result of prolonged treatment paradigms and do not necessarily represent the early formative events associated with CIPN. Here we show that acute exposure to vinca alkaloids results in an immediate pain syndrome in both flies and mice. Furthermore, we demonstrate that exposure of isolated sensory neurons to vinca alkaloids results in the generation of an inward sodium current capable of depolarizing these neurons to threshold resulting in neuronal firing. These neuronal effects of vinca alkaloids require the transient receptor potential ankyrin-1 (TrpA1) channel, and the hypersensitization to painful stimuli in response to the acute exposure to vinca alkaloids is reduced in TrpA1 mutant flies and mice. These findings demonstrate the direct excitation of sensory neurons by CIPN-causing chemotherapy drugs, and identify TrpA1 as an important target during the pathogenesis of CIPN.