Drug Scheduling Research Articles

Drug dispensing practices in private pharmacies in Goa

Background: In India, patients self-order both over-the-counter and prescription-only drugs in pharmacies, although the dispensing of the latter without a prescription is unlawful. Good pharmacy practice (GPP) guidelines have been framed and implemented in the country to help achieve standard practice. However, the quality of dispensing provided is inappropriate, especially in terms of counselling by the pharmacists at the time of dispensing. Aims and Objectives: This study was carried out to assess the drug dispensing practices in private pharmacies and provide data from the state of Goa. Materials and Methods: A questionnaire-based study was conducted among 101 pharmacists in the state of Goa and evaluated for various aspects of dispensing practices. Results: Dispensing without a prescription was 63.4% of the total dispensing encounters. Antihistamines and anti-cough medication, followed by non-steroidal anti-inflammatory drugs and antibiotics were the most commonly dispensed medications without a prescription. Only 18.8% pharmacists explained adverse effects of the drugs and 22.7% explained the dosage and frequency voluntarily while dispensing the medications. Storage and record maintenance also was not being followed as per GPP guidelines. Conclusion: This study revealed an inadequacy in the dispensing practices among the pharmacists in the state. While they are aware of the various schedules of drugs, they do not follow the record keeping as per the current regulations. Therefore, enforcing stringent laws and ensuring that they are followed is necessary along with educational programs for the pharmacists to promote rational drug use.

ACOMPANHAMENTO FARMACOTERAPÊUTICO NO DESFECHO DE PACIENTE COM DOENÇA DE CROHN E MULTIMORBIDADES: RELATO DE CASO

Objective: This case report aimed to assess the viability of pharmacotherapeutic follow-up of a Crohn’s Disease outpatient with multimorbidity, for the implantation of a pharmaceutical care service for inflammatory bowel disease patients in a University Hospital. Method: Data regarding associated pathologies and medication history were collected during six months in pharmaceutical consultations, also information on medical charts with due authorization (no. 510.998). Assessment of drug related problems was done with aid of a drug interaction checker and Naranjo adverse drug reaction probability scale, and also Crohn’s disease activity index used during clinical follow-up. Results: A 49-year-old female CD patient with type 2 diabetes, hypertension and glaucoma was followed-up. It was identified adverse drug reaction to metformin resulting in noncompliance with therapy, with posterior resolution of this problem after intervention with health team and patient education about change in the drug scheduling. Conclusions: Thus, pharmacotherapeutic follow-up effectively contributed to the execution of the right interventions: education regarding therapy, change in the antidiabetic drug scheduling and identification of drug adverse reaction. Pharmacotherapeutic follow-up brings the pharmacist to the healthcare team on managing Crohn’s disease and multimorbidities, enhancing adherence and reducing complications, with aid of pharmaceutical interventions. This case also showed the viability to implant this pharmaceutical service in the hospital, expanding it to other inflammatory bowel disease patients.

Physicians' Attitude Towards Selection of Second Line Therapy with Nilotinib and Dasatinib in Chronic Myeloid Leukemia Patients

Background:One of the main challenges in the treatment of chronic myeloid leukemia (CML) is the selection of second line therapy. While Nilotinib (NILO) and dasatinib (DASA) are available for use as second line treatment for several years, few evidence-based data is available on how physicians make decisions on the use of one drug over another.Aim:We performed a pilot study to describe which factors physicians consider most relevant when deciding therapy with either NILO or DASA in patients who previously failed or were intolerant to Imatinib (IMA) therapy.Patients and methods:Analyses are based on a sample 67 CML patients, recruited as part of a larger international study, who switched from IMA therapy to either NILO (N=36; 53.7%) or DASA (N=31; 46.3%). Patients had to be in second line treatment for at least three months to be eligible for this analysis. Also, in all participating centers, NILO and DASA should have been equally available for use. There were 15 physicians involved in the management of these patients and they were asked to complete an ad-hoc questionnaire investigating reasons based on which they made the decision to either use one drug over another. All questions were phrased as follows: "To what extent have the following issues been determinant to make a decision on which agent (NILO or DASA) to use for this patient?" All answers were rated on a four point likert-scale (ie, not at all, a little, quite a bit and very much). Items investigated were: 1) accessibility of the drug in the hospital; 2) cost of drug; 3) patients' comorbidities; 4) patients' age; 5) patients' personality profile; 6) discussion with patients about Pro and Cons; 7) different treatment schedule of drugs; 8) type of mutation during IMA therapy. Physician characteristics were also collected and analyzed. Other treatment-related variables were investigated such as main reason for changing of TKI (IMA intolerance or resistance), high grade adverse events (AEs) experienced during IMA treatment, or previous duration of IMA therapy.Results:Physicians' experience in treating CML patients was on average 14 years (range 4-32). Patient median age at the time of treatment switch was 47 and 55 years in the NILO and DASA group, respectively. Median time of duration of IMA therapy, before receiving second line therapy, was 1.4 years and 3.3 years for those who switched respectively to NILO or DASA. No differences existed between groups with regard to reasons for switching from IMA therapy (intolerance or resistance) or AEs reported with previous IMA therapy. The top issue considered as most relevant when making the decision was previous discussion with patients on advantages and disadvantages of drugs, being reported as "quite a bit" and "very much" important in 73% of evaluations. Cost of the drug was not considered relevant at all, in the selection of which drug to use, in 97% of the 69 evaluations considered. Also, type of mutation during IMA therapy was considered as of negligible relevance for the decision, but it should not be overlooked that mutations were detected in few patients. Patient's comorbidity or personality profile was quoted as a 'quite a bit' or 'very much' relevant reason for the selection of 2nd line TKI, respectively in 43% or 48% of all questionnaires. Low relevance was assigned to patient age and different treatment schedule: 'not at all' or 'a little' relevance was reported respectively in 64% and 70% of all questionnaires. The analysis of physician-reported grading distribution according to the type of second line treatment did not show any significant difference (no reason lead to a preferential selection of one drug), see table 1.Conclusions:No differences were detectablein selected factors, driving the decision to switch either to NILO or DASA when physicians consider switching from first line IMA therapy. Also, type of TKI selection does not seems to be guided by only one factor. Further research is needed to elucidate on potential reasons underlying clinical decision making in 2nd TKI selection. [Display omitted] DisclosuresEfficace:Seattle Genetics: Consultancy; TEVA: Consultancy, Research Funding; Lundbeck: Research Funding; Bristol Myers Squibb: Consultancy. Rosti:Pfizer: Consultancy, Honoraria, Speakers Bureau; Novartis: Consultancy, Honoraria, Speakers Bureau; BMS: Consultancy, Honoraria, Speakers Bureau; Ariad: Consultancy, Honoraria, Speakers Bureau. Breccia:Celgene: Honoraria; Pfizer: Honoraria; Novartis: Consultancy, Honoraria; Bristol Myers Squibb: Honoraria; Ariad: Honoraria. Baccarani:Novartis: Consultancy, Honoraria, Speakers Bureau; Pfizer: Consultancy, Honoraria, Speakers Bureau; BMS: Consultancy, Honoraria, Speakers Bureau; Ariad: Consultancy, Honoraria, Speakers Bureau.

Epigenetic Targeting with EZH2 and HDAC Inhibitors Is Synergistic in EZH2 Deregulated Lymphomas

EZH2 is critical in a process known as the Germinal Center (GC) reaction during which B-cells undergo somatic hypermutation and isotype switching in order to develop a large antibody repertoire. EZH2 is a histone methyltransferase serving as the catalytic subunit of the Polycomb Repression Complex 2 (PRC2), which is responsible for tri-methylation of histone 3 lysine 27 (H3K27), a mark of transcriptional repression. EZH2 recruits HDAC1/2 and DNMTs through its cofactor EED to further inhibit transcription. Mutations in EZH2 are found in 7-12% of FL and 22% of GC-DLBCL. EZH2 overexpression secondary to MYC and miRNA dysfunction has also been described. EZH2 also plays a role in T-cell differentiation and has been found in various T-cell malignancies. Histone acetyltransferases (HAT), notably CBP and p300, have also been implicated in B- and T-cell lymphomas and are mutated/deleted in 39% of GC-DLBCL and 41% of FL.Given the presence of EZH2 and HAT dysregulation in lymphoma, we evaluated the potential synergy of EZH2 and HDAC inhibitors co-treatment. Single agent activity for GSK126, an EZH2 inhibitor, and romidepsin, a pan-HDAC inhibitor, was established in a panel of lymphoma cell lines (GC-DLBCL, Non-GC DLBCL, MCL and T-Cell lymphoma, n=21). Cell lines with known EZH2 dysregulation (GC-DLBCL and ATLL) were more sensitive to EZH2 inhibitors as exhibited by lower half maximal effective concentration (EC50) after 6 day exposure (EC50 0.01-16 µM). There was no association between HAT mutation/deletion and romidepsin sensitivity.A panel of lymphoma cell lines was treated for 72 hr with GSK126 and romidepsin using concentrations represented by their EC30-50 (0.5-4.0 µM), and EC20-40 (1.0-4.0 nM), respectively. Synergy was assessed by Excess over Bliss (EOB), where EOB > 10 represents synergy. Simultaneous exposure to GSK126 and romidepsin in GC-DLBCL cell lines demonstrated potent synergy as represented by EOB > 30. Synergy was also present in ATLL cell lines (EOB 28), which are known to have EZH2 dysregulation, as well as non-GC DLBCL cell lines (EOB 47). Although these cell lines do not have EZH2 mutations, some possess relative EZH2 over-expression compared to other lymphomas. Evaluation of drug schedule using GSK126 pretreatment prior to romidepsin exposure did not impact synergy.Compared to single agent activity, the combination of GSK126 (2 µM) and romidepsin (1-4 nM) led to a more pronounced decrease in H3K27 tri-, di-, and mono-methylation and increased acetylation in 4 GC-DLBCL cell lines (OCI-LY7, Pfeiffer, SU-DHL-6, SU-DHL-10) at 24 or 48 hrs. The impact of the combination on the function of the PRC2 complex was assessed via co-immunoprecipation in these cell lines. The combination demonstrated dissociation of the PRC2 complex (EZH2, SUZ12, EED, and RbAp46/48) as compared to single agent exposure. Treatment with the combination also induced dissociation of HDAC2 and DNMT3L. In addition, we observed decreased protein expression of PRC2 complex members and increased p21/CDKN1A, which was more notable in the combination treatment as compared to single agent. This may be due to the removal of HDACs from the p21 transcriptional start site through the disruption of the PRC2 complex and direct inhibition of HDACs, thus leading to increase expression of p21. The combination also led to decreased nuclear localization of EZH2 and its cofactors. Apoptosis was confirmed by caspase 3 and PARP cleavage, and was more potently cleaved after exposure to the combination. Based on the findingthat HDAC2 dissociated from PRC2 complex after treatment with GSK126 and romidepsin, a selective HDAC1/2 inhibitor, ACY-957 (Acetylon Pharmaceuticals), was combined with GSK126 which demonstrated potent synergy in 4 GC-DLBCL cell lines (EOB 37).This data suggests that concomitant inhibition of EZH2 and HDAC is highly synergistic and leads to the dissociation of PRC2 complex. By releasing transcriptional inhibition key tumor suppressors and cell cycle regulators may be re-expressed. Potency of this epigenetic combination may be predicted by gene expression signatures for which RNA-seq libraries are currently in production. Reversing transcriptional inhibition using a combination of EZH2 inhibitors and HDAC inhibitors may lead to a potent treatment option for lymphomas dependent upon EZH2 and HAT activity. [Display omitted] DisclosuresO'Connor:Seattle Genetics: Research Funding; Spectrum: Research Funding; Seattle Genetics: Research Funding; Spectrum: Research Funding; Mundipharma: Membership on an entity's Board of Directors or advisory committees; TG Therapeutics: Research Funding; Mundipharma: Membership on an entity's Board of Directors or advisory committees; TG Therapeutics: Research Funding; Bristol Myers Squibb: Research Funding; Bristol Myers Squibb: Research Funding; Celgene: Research Funding; Celgene: Research Funding. Amengual:Acetylon Pharmaceuticals: Research Funding; Bristol-Myers Squibb: Research Funding.

A stimuli responsive liposome loaded hydrogel provides flexible on-demand release of therapeutic agents.

This paper details the development of a heat responsive liposome loaded hydrogel for the controlled release of pro-angiogenic therapeutics. Lysolipid-based thermosensitive liposomes (LTSLs) embedded in a chitosan-based thermoresponsive hydrogel matrix represents a novel approach for the spatiotemporal release of therapeutic agents. This hydrogel platform demonstrates remarkable flexibility in terms of drug scheduling and sequencing, enabling the release of multiple agents and the ability to control drug dosing in a minimally invasive fashion. The possibility to tune the release kinetics of different drugs independently represents an innovative platform to utilise for a variety of treatments. This approach allows a significant degree of flexibility in achieving a desired release profile via a minimally invasive stimulus, enabling treatments to be tuned in response to changing symptoms and complications.

FTY720 (Fingolimod) Inhibits HIF1 and HIF2 Signaling, Promotes Vascular Remodeling, and Chemosensitizes in Renal Cell Carcinoma Animal Model.

Clear cell renal cell carcinoma (ccRCC) is characterized by intratumoral hypoxia and chemoresistance. The hypoxia-inducible factors HIF1α and HIF2α play a crucial role in ccRCC initiation and progression. We previously identified the sphingosine kinase 1/sphingosine 1-phosphate (SphK1/S1P) pathway as a new modulator of HIF1α and HIF2α under hypoxia in various cancer cell models. Here, we report that FTY720, an inhibitor of the S1P signaling pathway, inhibits both HIF1α and HIF2α accumulation in several human cancer cell lines. In a ccRCC heterotopic xenograft model, we show that FTY720 transiently decreases HIF1α and HIF2α intratumoral level and modifies tumor vessel architecture within 5 days of treatment, suggesting a vascular normalization. In mice bearing subcutaneous ccRCC tumor, FTY720 and a gemcitabine-based chemotherapy alone display a limited effect, whereas, in combination, there is a significant effect on tumor size without toxicity. Noteworthy, administration of FTY720 for 5 days before chemotherapy is not associated with a more effective tumor control, suggesting a mode of action mainly independent of the vascular remodeling. In conclusion, these findings demonstrate that FTY720 could successfully sensitize ccRCC to chemotherapy and establish this molecule as a potent therapeutic agent for ccRCC treatment, independently of drug scheduling. Mol Cancer Ther; 15(10); 2465-74. ©2016 AACR.

Metronomic cyclophosphamide activation of anti-tumor immunity: tumor model, mouse host, and drug schedule dependence of gene responses and their upstream regulators.

BackgroundCyclophosphamide (CPA) can activate immunogenic tumor cell death, which induces immune-based tumor ablation and long-term anti-tumor immunity in a syngeneic C57BL/6 (B6) mouse GL261 glioma model when CPA is given on a 6-day repeating metronomic schedule (CPA/6d). In contrast, we find that two other syngeneic B6 mouse tumors, LLC lung carcinoma and B16F10 melanoma, do not exhibit these drug-induced immune responses despite their intrinsic sensitivity to CPA cytotoxicity.MethodsTo elucidate underlying mechanisms, we investigated gene expression and molecular pathway changes associated with the disparate immune responsiveness of these tumors to CPA/6d treatment.ResultsGlobal transcriptome analysis indicated substantial elevation of basal GL261 immune infiltration and strong CPA/6d activation of GL261 immune stimulatory pathways and their upstream regulators, but without preferential depletion of negative immune regulators compared to LLC and B16F10 tumors. In LLC tumors, where CPA/6d treatment is shown to be anti-angiogenic, CPA/6d suppressed VEGFA target genes and down regulated cell adhesion and leukocyte transendothelial migration genes. In GL261 tumors implanted in adaptive immune-deficient scid mice, where CPA/6d-induced GL261 regression is incomplete and late tumor growth rebound can occur, T cell receptor signaling and certain cytokine-cytokine receptor responses seen in B6 mice were deficient. Extending the CPA treatment interval from 6 to 9 days (CPA/9d) − which results in a strong but transient natural killer cell response followed by early tumor growth rebound − induced fewer cytokines and increased expression of drug metabolism genes.ConclusionsThese findings elucidate molecular response pathways activated by intermittent metronomic CPA treatment and identify deficiencies that characterize immune-unresponsive tumor models and drug schedules.Electronic supplementary materialThe online version of this article (doi:10.1186/s12885-016-2597-2) contains supplementary material, which is available to authorized users.

EP 71. Single cell firing patterns in the anterior nucleus of the thalamus relate to therapy response in deep brain stimulation for refractory epilepsy

Introduction: Patients with medically refractory epilepsy treated with deep brain stimulation (DBS) of the anterior nucleus of the thalamus (ANT) vary highly in their therapy response. Proper positioning of the DBS lead is crucial to maximize efficacy and minimize side effects. For a correct implantation, the ANT is anatomically located using pre-operative 3T MRI and perioperative microelectrode recordings (MER). Neurons in the ANT have highly variable, yet characteristic patterns of firing in bursts. During DBS lead implantation, we noted differences among patients’ characteristic burst patterns along the electrode trajectory. In this study, we investigate whether electrophysiological characteristics of the target region could predict therapy response to DBS and could thus be used to improve ANT targeting during DBS surgery. Objectives: To determine whether perioperative neurophysiological characteristics relate to therapy response in DBS for patients with medically refractory epilepsy. Patients and methods: We included ten consecutive epilepsy patients planned for DBS surgery at Maastricht University Medical Center. All patients were diagnosed with medically refractory epilepsy and had incapacitating seizures. Patients failed trials of at least two reasonably tolerated and adequately chosen antiepileptic drug schedules. Using pre-operative 3T MRI, we planned an extraventricular approach to target. The ANT was defined as a grey matter structure at the top of the mamillothalamic tract. Along this trajectory, we performed stereotactic single cell MERs. The anatomical location of the recordings were verified using preoperative 3T MR images. We compared characteristics of the neural signals at different depths along the trajectory between DBS responders and non-responders. Responders were defined as patients with a seizure frequency reduction of more than 50% at one year follow-up. Results: Using MER data from 19 electrode trajectories of ten patients (one unilateral and nine bilateral trajectories), we found high-amplitude neuronal bursts around the target area or ANT. Responders to DBS (n = 5) had higher normalized mean firing rates and mean burst rates near the target area compared to non-responders (n = 5), with a clearer delineation between the target region and surroundings. Electrode trajectories and lead localization did not differ between responders and non-responders. Conclusion: Single cell firing patterns in the ANT relate to therapy response in DBS for patients with medically refractory epilepsy. Analysis of single cell firing patterns using MER may guide targeting or contribute to predicting therapy response to ANT DBS. Further exploration into the use of electrophysiological recordings is warranted to improve targeting or predict outcome in DBS for epilepsy patients.

What is in the Product and How to Measure It?

Label claim, as its name implies, assures consumers that the claims printed on the label of a regulated product accurately represent the product within. Ruth et al. reports in “Consistency of label claims of internet-purchased hemp oil and cannabis products as determined using IMS and LC-MS: a market survey” of a qualitative and quantitative study of 23 hemp oil products using two advanced instrument methods: an ion mobility mass spectrometry method and a liquid chromatography high-resolution mass spectrometry method. Cannabis products have become a hotly debated topic due to recent legislative changes. Although several cannabinoid compounds are designated as Schedule I controlled substances by the U.S. Drug Enforcement Administration (USDEA), many state legislatures have legalized marijuana for medical use, recreational use, or both. Schedule I controlled substances are defined by DEA as “drugs with no currently accepted medical use and a high potential for abuse. Schedule I drugs are the most dangerous drugs of all the drug schedules with potentially severe psychological or physical dependence” (USDEA). Regardless of state-level legislation and on-going debate in state legislature, science-driven research forms the background needed by the general public, public health officials, and policy makers to make informed decisions about cannabis products and marijuana. Particularly important from a public health perspective are methods to assess cannabis product content and safety. Ruth et al. found that some commercial products were not consistent with the label claim, foreshadowing future regulatory challenges of the cannabis industry, such as denoting compounds to be sought in testing, testing methods, and the implementation of quality control and quality assurance.https://doi.org/10.21423/jrs-v04n03pi (DOI assigned 5/31/2019)

Variability and singularity arising from poor compliance in a pharmacokinetic model II: the multi-oral case.

We propose a stochastic model for the drug concentration in the case of multiple oral doses and in a situation of poor patient adherence. Our model is able to take into account an irregular drug intake schedule. This article is the second in a series of three. It presents a multi-oral version of the results given in Lévy-Véhel and Lévy-Véhel (J Pharmacokinet Pharmacodyn 40(1):15-39, 2013), that dealt with the multi-IV bolus case. Under the assumption that the irregular dosing schedule follows a Poisson law, we study features of the drug concentration that have practical implications, such as its variability and the regularity of its cumulative probability distribution, which describes its predictive power with respect to the mean behaviour. We consider four variants: continuous-time, with either deterministic or random doses, and discrete-time, also with either deterministic or random doses. Our computations allow one to assess in a precise way the effect of various significant parameters such as the mean rate of intake, the elimination rate, the absorption rate and the mean dose. They quantify how much poor adherence will affect the efficacy of therapy. To appreciate this impact, we provide detailed comparisons with the variability of concentration in two reference situations: a fully adherent patient and a population of fully adherent patients with log-normally distributed pharmacokinetic parameters. Besides, the discrete-time versions of our models reveal unexpected links with objects which have been studied in the mathematical literature under the name of infinite Bernoulli convolutions (Erdós, Am J Math 61:974-975, 1939). This allows us to quantify the fact that, when the random dosing schedule is too sparse, the concentration behaves in a very erratic way. Our results complement the ones in Lévy-Véhel and Lévy-Véhel (J Pharmacokinet Pharmacodyn 40(1):15-39, 2013) and help understanding the consequences of poor adherence. They may have practical outcomes in terms of drug dosing and scheduling.

Abstract 1367: Intra-cerebral pharmacokinetic monitoring of a tyrosine kinase inhibitor (theranostic 18[F]-PET/NIRF labeled dasatinib) delivered via convection-enhanced delivery

Abstract Introduction: Convection enhanced delivery (CED) has been recently explored as an advantageous therapeutic strategy for central nervous system (CNS) tumors. One current limitation is the inability to quantitatively monitor distribution of chemotherapeutic agents. The use of surrogate tracers probably underestimates differences in distribution and clearance owing to discordant features between contrast molecules and therapeutic agents, including bioactivity, degradation, conductivity, and diffusivity. Ideally, direct labelling of a therapeutic compound would eliminate these concerns and afford a noninvasive method to monitor critical pharmacokinetic information. This ability would pave the way for designing infusion parameters and drug schedules that are expected to be unique for CED-based therapy. Methods: The small molecule kinase inhibitor dasatinib was modified with a dual-probe technology that utilizes a boronate trap to conjugate 18[F] with a near-infrared fluorophore into a single molecule, 1, allowing for visualization by positron emission tomography (PET) and near-infrared fluorescence (NIRF). The novel boronate trap allows for direct conjugation of 18[F] with minimal disruption of dasatinib's mechanism of action, resulting in a small, versatile probe with potential for other clinically relevant targets. Results: The modified drug was first tested in vitro in a PDGF-B driven p53 deficient DIPG tumor line from Nestin tv-a; p53 floxed mouse. 1 was shown to enter cells on fluorescence microscopy and inhibit cell proliferation. Antagonist drug potency of 1 as evaluated on pontine glioma in ATP-dependent luminescent cell viability, cell-permeant calcein AM, and an MTS cell proliferation assays show that the IC50, of 1 is ∼10nM. In addition, infusions of 1 were performed via CED and intravenous systemic delivery in a RCAS/tv-a PDGF-B driven with p53 deficiency Ntv-a mouse model of high-grade glioma. Compared to systemic delivery, CED was shown to be roughly 230 times more effective in delivery of the infusion to the tumor site. Maximal glioma delivery occurred at 115 min post a 20 min infusion, with clearance occurring with a half-life of 45 min after maximum delivery. Conclusion: Dasatinib was modified to give 1, an agent that can be imaged non-invasively by fluorescence and positron emission tomography (PET). The modified dasatinib showed little modification in biologic activity when compared to unmodified dasatinib and exhibited cytotoxic effects in vitro in glioma cell culture. CED shows a clear benefit to intravenous delivery when the target site is in the CNS. The dual-label probe technology's versatility and minimal biologic profile lends itself to various clinical uses, including the study of different therapeutic agents and delivery routes without the need to rely on surrogate tracers. Citation Format: Melinda Wang, Zhiping Zhou, Hari Krishna Kommidi, Melanie Schweitzer, Mark Chan, Yue Linda Wu, Ranjodh Singh, Richard Ting, Mark M. Souweidane. Intra-cerebral pharmacokinetic monitoring of a tyrosine kinase inhibitor (theranostic 18[F]-PET/NIRF labeled dasatinib) delivered via convection-enhanced delivery. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 1367.

Abstract 852: Modeling the emergence of resistance to chemotherapeutics with virtual tumor

Abstract Drug resistance is a major cause of treatment failure in cancer, and understanding and overcoming mechanisms of resistance is a key challenge in advancing cancer therapy. Although the progression from cytotoxic chemotherapy to drugs aimed at specific molecular targets has improved response rates and reduced adverse effects, in the majority of cases there is still no effective treatment for metastatic disease; resistance constrains the effectiveness of both conventional chemotherapy and targeted agents. Resistance arises from mutations in the genome of cancer cells and/or epigenetic changes. The problem is compounded by considerable intra- and inter-tumour genetic heterogeneity, dictated by the genetic background and history of each cancer cell. It is therefore not surprising that patients with apparently the same cancer can respond differently to the same treatment, and it is becoming increasingly clear that cancer should be managed through personalized medicine. Some steps have already been taken in this direction, such as the development of CancerDR (Cancer Drug Resistance Database), but the approach requires large-scale genomic profiling, which is unlikely to be widespread in clinical practice in the immediate future. In the interim, recent studies have shown that the emergence of drug-resistant disease can at least be delayed through treatment with novel dosing regimens. Physiomics has developed a ‘Virtual Tumour’ (VT) technology that can predict how a tumor will respond to drug exposure. This integrated PK/PD simulation platform can be used to optimize drug dosing and scheduling, and to design new combination therapies. The VT technology integrates pharmacokinetic and pharmacodynamic effects, and models the way individual cells behave within a tumor population. These agent-based methods are particularly suitable for modeling multiple cell populations, and representing the heterogeneity of a clinical tumor. Given the significance of cancer drug resistance, and the form that future cancer therapy is likely to take, Physiomics is actively engaged in developing personalized medicine solutions. As a first step, we have incorporated chemotherapeutic resistance into our VT platform. The VT has been extended by the addition of a resistance module, which has been developed and calibrated using data taken from the literature. This module captures the fundamental mechanism by which resistance arises. Through a case study also derived from the literature, we demonstrate that the extended VT can be applied to model the emergence of resistance in patient-derived xenografts. Furthermore, we show that the VT can be used to identify and optimize therapeutic strategies for delaying the emergence of drug resistance. Our enhanced VT capability represents the first step towards a ground-breaking tool for developing personalized treatment, which is set to revolutionize cancer therapy in the near future, especially for patients with resistant disease. Citation Format: Frances A. Brightman, Eric Fernandez, David Orrell, Christophe Chassagnole. Modeling the emergence of resistance to chemotherapeutics with virtual tumor. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 852.

Platinum based radiochemotherapies: Free radical mechanisms and radiotherapy sensitizers

The radiosensitizing ability of Pt drugs can in the first instance be predicted based on the ease that they undergo activation by electron attachment accompanied by structural modification prior to forming Pt-DNA adducts. Unlike cisplatin, carboplatin and nedaplatin, oxaliplatin does not undergo a facile dissociative electron transfer reaction when an electron is attached. However, oxaliplatin undergoes a facile nucleophilic assisted proton coupled electron transfer (NAPCET), which may be key element of the success of FOLFOX radiochemotherapy against certain cancers. Under acidic conditions, oxaliplatin is a superior radiosensitizer to cisplatin or carboplatin, in the presence of nucleophiles such as water, chloride ions or thiols. Oxaliplatin may also be activated as a platinating agent and radiosensitizer by a minor hydrogen radical free radical mechanism as well as the more dominant NAPCET mechanism. The radiosensitizing synergism that is shown when oxaliplatin is combined with 5-fluorouracil can be due to the formation of a π complex between the two drugs, which is more potent under acidic conditions. These factors have a bearing on Pt based chemotherapy clinical regimes as well as clinical radiochemotherapy regimes, and could be a basis for optimizing how such drug schedules are administered.

HUBUNGAN DUKUNGAN KELUARGA DENGAN KEPATUHAN MINUM OBAT PADA PASIEN TUBERCULOSIS PARU RELAPSE DI RUMAH SAKIT SANTA ELISABETH MEDAN TAHUN 2015

Tuberculosis is a contagious infectious disease caused by mycobacterium tuberculosis. Pulmonary tuberculosis relapse is pulmonary tuberculosis patients who relapse or recurrent back. Support family also processes that occur throughout life, in which the source and type of support affects the life cycle stage family. Goal: This study aimed to identify the relationship with the family support medication adherence in patients with pulmonary tuberculosis relapse in Santa Elisabeth Hospital Medan. Methods: This study Using cross sectional research design, sampling is done by total sampling method with a total sample of 25 respondents. Result: The results of support family size of 52,0% and compliance drink pulmonary tuberculosis drug relapse 52,0%. Conclusion: Di suggest to support compliance is to involve all family members as supervisors drink medication after discharge from the hospital, assisting the patient to consul back and provide health education of patients taking the drug and dosage schedule is recommended by health professionals.

Three Weekly Versus Weekly Cisplatin as Radiosensitizer in Head and Neck Cancer: a Decision Dilemma

Cisplatin-based concurrent chemoradiation plays an undisputed key role as definitive treatment in unresectable patients with locally advanced squamous cell carcinoma head and neck or as an organ preservation strategy. Treatment with 100 mg/m2 3-weekly cisplatin is considered the standard of care but is often associated with several adverse events. The optimum drug schedule of administration remains to be defined and presently, there is insufficient data limiting conclusions about the relative tolerability of one regimen over the other. This review addresses regarding the optimal dose schedule of cisplatin focusing mainly on three-weekly and weekly dose of cisplatin based concurrent chemoradiotherapy in locally advanced head and neck cancer with an emphasis on mucositis, dermatitis, systemic toxicity, compliance, and treatment interruptions. To derive a definitive conclusion, large prospective randomized trials are needed directly comparing standard 3-weekly cisplatin (100 mg/m2) with weekly schedule (30 - 40 mg/m2) of concurrent cisplatin based chemoradiotherapy in locally advanced squamous cell carcinoma head and neck.

Incidence, severity and factors associated with diarrhoea in phase I oncology studies: experience of 1002 consecutive cases.

2568Background: Diarrhea is a common toxicity related to cancer treatment. Diarrhea occurs at different degrees of severity both within and outside the dose limiting toxicity window, influencing the dose and schedule of novel anticancer drugs. We aimed to assess the incidence, severity and factors predisposing to diarrhea in patients (pts) enrolled in phase I studies. Methods: This is a retrospective study of 1002 separate phase I trial pt-cases treated at the Royal Marsden Hospital Drug Development Unit between January 2010 and December 2014. Data were collected from our electronic records for consecutive pts participating in 80 different phase I trials. Results: The incidence of diarrhea was 32.1%. Grade 1-5 diarrhea was reported in 21.9%, 6.3%, 3.1%, 0.1% and 0.1% pt-cases respectively. 69.5% episodes of diarrhea were reported as drug related. 5.6% of pts had a specific trial intervention due to diarrhea such as dose interruption or withdrawal from study. Time on study was not significantly different i...

Systemic Effects of AT‐121 as a Safe Analgesic without Abuse Liability in Primates

AT‐121 is a newly developed bifunctional nociceptin/orphanin FQ peptide (NOP)/mu opioid peptide (MOP) receptor agonist that displays full efficacy on NOP receptors and partial efficacy on MOP receptors. The aim of this study was to establish the functional profile of AT‐121 as an analgesic by using several behavioral and physiological assays in rhesus monkeys (Macaca mutatta). Systemic administration of AT‐121 (0.003–0.03 mg/kg) dose‐dependently produced antinociceptive and antihypersensitive effects. Both NOP receptor antagonist J‐113397 (0.1 mg/kg) and MOP receptor antagonist naltrexone (0.03 mg/kg) equally attenuated AT‐121‐induced antinociception. These antagonist studies demonstrate that both NOP and MOP receptor components contribute to the antinociceptive effects exhibited by AT‐121 in primates. More importantly, a full antinociceptive dose (0.03 mg/kg) and a dose 10‐fold higher (0.3 mg/kg) of AT‐121 did not affect physiological functions including respiration, cardiovascular activities, and body temperature as measured by the telemetry probes (DSI, model D70‐PCTR). These findings indicate a wider therapeutic window afforded by AT‐121 as compared to MOP receptor agonists. In addition, AT‐121 did not produce reinforcing effects in monkeys under the progressive‐ratio schedule of drug self‐administration. Following repeated administration of AT‐121, monkeys did not show physiological withdrawal signs precipitated by both NOP and MOP receptor antagonists. Taken together, these translational nonhuman primate studies demonstrate that AT‐121 is an effective and safe analgesic without typical opioid‐associated side effects. Lack of reinforcing effects and acute physical dependence by AT‐121 strongly supports the therapeutic potential of selected bifunctional NOP/MOP agonists as innovative analgesics in humans.Support or Funding InformationSupported by the US‐PHS grants DA‐032568 and DA‐035359 and the US‐DOD grant W81XWH‐13‐2‐0045.

Don’t eat the brown acid: Induced ‘malnovation’ in drug markets

Title II, the Controlled Substances Act (CSA), of the Comprehensive Drug Abuse Prevention and Control Act of 1970 (CDAPCA) created the present system of drug scheduling and regulation. This paper illustrates how the CSA created the incentives for induced ‘malnovation’ (innovation intended to circumvent legislation, and thus foil policymakers’ intended ends) into drug markets, namely “designer drugs.” As a result of this induced malnovation, drug markets have not only increased in the variance of products available that are often sold under similar street names, but there is also a tendency towards creating more dangerous drugs in an attempt to stay outside of the regulation.

Translating neoadjuvant therapy into survival benefits: one size does not fit all.

Neoadjuvant therapy has been established as an effective therapeutic approach for patients with locally advanced breast cancer. Similar outcomes between neoadjuvant and adjuvant chemotherapy have been demonstrated in several trials. Nevertheless, neoadjuvant therapy has some advantages over adjuvant therapy, including tumour downstaging, in vivo assessment of therapeutic efficacy, reduced treatment durations, and the need to enrol fewer patients for clinical trials to reach their preplanned objectives. The number of neoadjuvant trials in patients with breast cancer has increased substantially in the past 5 years, particularly in the context of HER2-positive disease. Substantial improvements in the pathological complete response rate to anti-HER2 therapy, a proposed surrogate end point for long-term clinical benefit, have been observed with neoadjuvant dual-agent HER2 blockade. Thus, it was hypothesized that this approach would provide additional survival benefits over standard-of-care therapy with the anti-HER2 antibody trastuzumab in the adjuvant setting. Emerging data, however, are calling this notion into question. We discuss potential reasons why results of neoadjuvant trials of targeted therapies have not been mirrored in the adjuvant setting, and other than inherent differences in clinical-trial designs and statistical power, we consider how the biology of the disease, patient characteristics, and drug administration and schedule might influence the results.

An automated voice response system for anticoagulant therapy management.

The system described in this paper is aimed at improving the clinical workflow of post-stroke patients under oral anticoagulant therapy (OAT). The system helps both physicians and patients during the periodic control visits necessary to assess the anticoagulation status and the next therapeutic plan. Controls represent a burden for both patients, which after blood drawing must wait for the result, and for physicians, that, after assessing the therapy plan, must communicate it to patients, face-to-face or by telephone. A system is proposed, which embeds an algorithm for the patient-tailored calculation of the drug dosage and scheduling, and an automatic telephone dialogue for the communication of the therapy plan, once it has been validated or adjusted by the physician.