Small Therapeutic Index Research Articles

Study to Assess the Knowledge and Practice among Cardiac Nurses About Infusion Therapy using Syringe Pump

The use of electronic syringe infusion pumps to administer therapeutic agents is a common practice in hospitals, particularly among patients who require slow injection treatments. For these patients and their practitioners, it is crucial that the administration of drugs (especially for those having a small therapeutic index) via the syringe pump be consistent, predictable, and reliable. The present study was intended to assess the knowledge and practice among cardiac nurses about infusion therapy using syringe pump. The objectives were to assess the knowledge and practice among cardiac nurses about infusion therapy using syringe pump and to find out the association between knowledge and selected variables. The objectives were to assess the knowledge and practice among cardiac nurses about infusion therapy using syringe pump and to find out the association between knowledge and selected variables. The study was done by quantitative approach and research design used was descriptive design. Data was collected from 60 cardiac nurses from SCTIMST Thiruvananthapuram, working in CSICU, CHICU, CHW and CCU. Convenient sampling technique was used for selection of samples. The data was collected using a self-administered questionnaire to assess the cardiac nurses knowledge about infusion therapy using syringe pump and check list to assess the practice. The data was analyzed and interpreted using descriptive and inferential statistics. The present study emphasized to assess the knowledge and practice among cardiac nurses about infusion therapy using syringe pump. Majority (92%) cardiac nurses had good knowledge score (26) with a maximum obtainable score of 9. For practice all participant's (100%) had good practice. There was association between knowledge and selected socio-demographic variables such as age, gender, educational qualification and years of experience.

A single-agent fusion of human IL-2 and anti-IL-2 antibody that selectively expands regulatory T cells

The occurrence of many autoimmune diseases takes root on the disrupted balance among Treg cells, Teff cells, etc. Low-dose interleukin-2 (IL-2) cytokine demonstrates promising clinical efficacy in the expansion of Treg cells and the treatment of autoimmune diseases. However, its clinical application is hindered by the small therapeutic index and short half-life. Previous studies have shown that non-covalent complex of human IL-2 and anti-IL-2 antibody biases cytokine activity towards Treg cells and extends IL-2’s half-life. The clinical translation of such complex is non-trivial. In this study, we discover an anti-human IL-2 antibody and engineer a covalently-linked single-agent fusion of human IL-2 and its antibody that selectively expands Treg cells and exhibits superior disease control activity in animal models of ulcerative colitis and systemic lupus erythematosus, with proper safety profile and good developability. These studies pave the road for its clinical development in diverse autoimmune diseases.

Machine learning algorithms to estimate everolimus exposure trained on simulated and patient pharmacokinetic profiles.

Everolimus is an immunosuppressant with a small therapeutic index and large between‐patient variability. The area under the concentration versus time curve (AUC) is the best marker of exposure but measuring it requires collecting many blood samples. The objective of this study was to train machine learning (ML) algorithms using pharmacokinetic (PK) profiles from kidney transplant recipients, simulated profiles, or both types, and compare their performance for everolimus AUC0‐12h estimation using a limited number of predictors, as compared to an independent set of full PK profiles from patients, as well as to the corresponding maximum a posteriori Bayesian estimates (MAP‐BE). XGBoost was first trained on 508 patient interdose AUCs estimated using MAP‐BE, and then on 500–10,000 rich interdose PK profiles simulated using previously published population PK parameters. The predictors used were: predose, ~1 h, and ~2 h whole blood concentrations, differences between these concentrations, relative deviations from theoretical sampling times, morning dose, patient age, and time elapsed since transplantation. The best results were obtained with XGBoost trained on 5016 simulated profiles. AUC estimation achieved in an external dataset of 114 full‐PK profiles was excellent (root mean squared error [RMSE] = 10.8 μg*h/L) and slightly better than MAP‐BE (RMSE = 11.9 μg*h/L). Using more profiles (n = 10,035) did not improve the ML algorithm performance. The contribution of mixing patient and simulated profiles was significant only when they were in balanced numbers, with ~500 for each (RMSE = 12.5 μg*h/L), compared with patient data alone (RMSE = 18.0 μg*h/L).

A Review: Discovering 1,3,4-oxadiazole and Chalcone Nucleus for Cytotoxicity / EGFR Inhibitory Anticancer Activity.

Cancer is reported to be one of the most life-threatening diseases. Major limitations of currently used anticancer agents are drug resistance, very small therapeutic index, and severe, multiple side effects. The current scenario necessitates developing new anticancer agents, acting on novel targets for effectively controlling cancer. The epidermal growth factor receptor is one such target, which is being explored for 1,3,4-oxadiazole and chalcone nuclei. Findings of different researchers working on these scaffolds have been reviewed and analyzed, and the outcomes were summarized. This review focuses on Structure-Activity Relationship studies (SARs) and computational studies of various 1,3,4-oxadiazole and chalcone hybrids/ derivatives reported as cytotoxic/EGFR-TK inhibitory anticancer activity. 1,3,4-oxadiazole and chalcone hybrids/derivatives with varied substitutions are found to be effective pharmacophores in obtaining potent anticancer activity. Having done a thorough literature survey, we conclude that this review will surely provide firm and better insights to the researchers to design and develop potent hybrids/derivatives that inhibit EGFR.

Cell-Penetrating Botulinum Neurotoxin Type A With Improved Cellular Uptake and Therapeutic Index.

Botulinum neurotoxin serotype A (BoNTA) is widely used for treating neuromuscular disorders. Despite of the various marketed products, BoNTA is known to have small therapeutic index ranging from 5 to 15. In the present study, we designed and characterized engineered BoNTA proteins with fusion of cell-penetrating peptides (CPPs). We have shown that CPPs, particularly a recently reported zinc finger protein could improve the cellular uptake and intramuscular therapeutic index of BoNTA. Our study has shed the light on developing next-generation neuromuscular modulators using CPP fusion.

Pharmacology and Mechanism of Action of HSK16149, a Selective Ligand of α2δ Subunit of Voltage-Gated Calcium Channel with Analgesic Activity in Animal Models of Chronic Pain.

Chronic pain is a public health problem because current treatments are unsatisfactory with small therapeutic index. Although pregabalin is effective for treating chronic pain, the clinical use is limited because of its side effects. Therefore, improving its therapeutic index is essential. In this study, HSK16149 was found to be a novel ligand of voltage-gated calcium channel (VGCC) α 2 δ subunit. HSK16149 inhibited [3H]gabapentin binding to the α 2 δ subunit and was 23 times more potent than pregabalin. In two rat models of neuropathic pain, the minimum effective dose (MED) of HSK16149 was 10 mg/kg, and the efficacy was similar to that of 30 mg/kg pregabalin. Moreover, the efficacy of HSK16149 could persist up to 24 hours postadministration at 30 mg/kg, whereas the efficacy of pregabalin lasted only for 12 hours at 30 mg/kg in streptozotocin-induced diabetic neuropathy model, indicating that HSK16149 might be a longer-acting drug candidate. HSK16149 could also inhibit mechanical allodynia in intermittent cold stress model and decrease phase II pain behaviors in formalin-induced nociception model. In addition, the locomotor activity test showed that the MED of HSK16149 was similar to that of pregabalin, whereas in the Rotarod test, the MEDs of HSK16149 and pregabalin were 100 and 30 mg/kg, respectively. These findings indicated that HSK16149 might have a better safety profile on the central nervous system. In summary, HSK16149 is a potent ligand of VGCC α 2 δ subunit with a better therapeutic index than pregabalin. Hence, it could be an effective and safe drug candidate for treating chronic pain. SIGNIFICANCE STATEMENT: As a novel potent ligand of voltage-gated calcium channel α 2 δ subunit, HSK16149 has the potential to be an effective and safe drug candidate for the treatment of chronic pain.

CLINICAL PHARMACOLOGY OF FLOROCHINOLONS: A FOCUS ON SAFETY. Review

Fluoroquinolones are effective in the treatment of infections of almost any localization (upper and lower respiratory tract, urinary system, skin and soft tissues, bones and joints, liver and bile ducts, gastrointestinal tract, female genital tract, central nervous system, intra-abdominal), sexually transmitted infections. Resistance is slowly formed to fluoroquinolones. Among the benefits of certain fluoroquinolones are that they can be administered either orally or intravenously. Fluoroquinolones can also be combined with antibacterial agents of other groups. Levofloxacin (the left-turning isomer of ofloxacin) has now become one of the most commonly used antibiotics. This is because the drug exhibits high tissue penetration, creating in the alveolar macrophages, the mucous membranes of the bronchi and fluid lining the respiratory epithelium, a concentration that is significantly higher than the MIC to respiratory pathogens. The literature review presents current insights on the pharmacokinetics, pharmacodynamics, and adverse effects of fluoroquinolones. The risks of tendinitis, tendon ruptures, aortic aneurysm / dissection, QT prolongation, recurrence of C.difficile antibiotic-associated diarrhea, hypo- and hyperglycemic conditions are emphasized. The clinical role of fluoroquinolones inhibitory effect on cytochrome P450 isoenzymes CYP1A2 and CYP2C9 activities, which metabolize many drugs with low therapeutic index (derivatives of sulfonylureas, warfarin, phenytoin, and theophylline etc). Therefore, when deciding on the prescription of fluoroquinolones, especially for elderly patients, the doctor should collect a detailed anamnesis, in particular regarding the administration of drugs with a small therapeutic index, and conduct therapeutic drug monitoring, including monitoring blood glucose levels.

RISK MANAGEMENT OF USE DRUGS WITH NARROW THERAPEUTIC INDEX IN CLINICAL PRACTICE. Review

Relevance. Today, the pharmacotherapy of many diseases is significantly expanded. However, the amount of pathological conditions associated with the use of drugs has increased. Drug related problems in some cases can be fatal and increase health care costs. It is necessary to be able to anticipate in advance the possibility of developing such conditions, to prevent them. Therefore, the analysis of the causes and mechanisms of development of these conditions is relevant.
 Objective. To find out the most common causes of drug related problems and consider the mechanisms of such states.
 Methods. Analysis of scientific publications in PubMed by keywords for the period 2001-2018.
 Results. The therapeutic index is the ratio of the dose that causes toxic effects in 50% of patients to the dose that causes the expected therapeutic effect in 50% of patients. The therapeutic index ≤ 3 is an indicator that defines drugs with narrow (small) therapeutic index. These drugs include insulin, digoxin, warfarin, levothyroxine, aminoglycoside antibiotics, carbamazepine, lithium, phenytoin, etc.
 The risks associated with these drugs are: the use of generic drugs with insufficient bioequivalence, pharmacokinetic interaction and polymorphism of genes of drug metabolism. The main mechanisms of their pharmacokinetic interaction at the stages of absorption (alteration of digestive tract motility, influence on the activity of P-glycoprotein), distribution (competition for blood plasma proteins and tissue proteins), and biotransformation (inhibition or induction of metabolism). The role of polymorphism of genes encoding the activity of isoenzymes cytochrome P450 2C9 and 1A2 and glycoprotein P in the development of adverse drug reactions of drugs with a narrow therapeutic index is presented.
 Conclusion. Risk management of using drugs with a narrow therapeutic index should include therapeutic drug monitoring of especially generic drugs, assessment of the risks of pharmacokinetic interaction, widespread introduction pharmacogenetic tests for determine the polymorphism of the genes of metabolism enzymes and drug transporters in the clinical practice.

INSIGHTS INTO FORMULATION TECHNOLOGIES AND NOVEL STRATEGIES FOR THE DESIGN OF ORALLY DISINTEGRATING DOSAGE FORMS: A COMPREHENSIVE INDUSTRIAL REVIEW

Among the various routes of administration, the oral route remains the most convenient and commonly employed route for drug delivery. The oral conventional drug delivery systems have some drawbacks, such as possibility of gastrointestinal destruction of labile molecules, low absorption of macromolecules, slow onset of action, and unavoidable fluctuation in the concentration of drugs which can either lead to under- or over medication with concomitant adverse effects, especially for drugs with small therapeutic index. Therefore, it became essential to design novel oral drug delivery systems to achieve quick dissolution, absorption, rapid onset of action and reduction of drug dose. Among those novel drug delivery systems are oral disintegrating tablets (ODTs). The purpose of this review article is to report the recent advances in ODT systems with emphasis on their preparations, characterizations and applications.

Prophylactic potential of memantine against soman poisoning in rats

BackgroundCarbamates physostigmine and pyridostigmine have been used as a pretreatment against poisoning with nerve agents in order to reversibly inhibit and thus protect from irreversible inhibition a portion of acetylcholinesterase (AChE) in brain and respiratory muscles that is crucial for survival. Memantine, an adamantine derivative, has emerged as a promising alternative to carbamates, since it prevented the fasciculations and skeletal muscle necrosis induced by carbamates and organophosphates, including nerve agents. AimThis experimental study was undertaken in order to investigate and compare the protective and behavioural effects of memantine and standard carbamates physostigmine and pyridostigmine in rats poisoned with soman and treated with atropine, oxime HI-6 and diazepam. Another goal was to elucidate the mechanisms of the antidotal effect of memantine and its potential synergism with standard antidotes against nerve agents. Materials and methodsMale Wistar rats were used throughout the experiments. In dose-finding experiments memantine was administered at dose interval 0–72 mg/kg sc 60 min before sc injection of soman. In time-finding experiments memantine was injected 18 mg/kg sc 0–1440 min before soman. Standard treatment antidotes - atropine 10 mg/kg, HI-6 50 mg/kg and diazepam 2.5 mg/kg – were administered im within 15 s post-exposure. Soman 0.75 LD50 was used to study its inhibitions of neuromuscular transmission on the phrenic nerve-diaphragm preparation in situ and of tissue AChE activity. Behavioural effects of the prophylactic antidotes were investigated by means of the rotarod test. Based on these data therapeutic index and therapeutic width was calculated for all three prophylactic agents. ResultsMemantine pretreatment (18 mg/kg sc) produced in rats poisoned with soman significantly better protective ratios (PRs) than the two carbamates – 1.25 when administered alone and 2.3 when combined with atropine pretreatment and 6.33 and 7.23 with atropine/HI-6 and atropine/HI-6/diazepam post-exposure therapy, respectively. The highest PR of 10.11 obtained in Atr/HI-6-treated rats was achieved after pretreatment with memantine 36 mg/kg. This additional protection lasted for 8 h. All three prophylactic regimens antagonised the soman-induced neuromuscular blockade, but the effect of memantine was fastest. Pretreatment with memantine assured higher AChE activity in brain and diaphragm than in unpretreated rats (46% vs 28% and 68% vs. 38%, respectively). All three prophylactic regimens affected the rotarod performance in rats, but the effect of memantine was relatively strongest. Memantine and pyridostigmine had lowest and highest therapeutic index and therapeutic width, respectively. ConclusionsAlthough memantine assures better and longer-lasting protection against soman poisoning in rats than the two carbamates, its small therapeutic index and narrow therapeutic width seriously limit its potential as a pretreatment agent. Despite its behavioural effects, memantine seems to be beneficial antidote when administered after soman, along with atropine/HI-6/diazepam therapy. Mechanism of the antidotal effect of memantine against soman poisoning appears to be a combination of AChE-protecting and NMDA receptor-blocking action.

SEIZURES WITH ANTI-SEIZURE DRUG

This case study is to report and explore the etiology of a case of refractory seizures due to overdosage of phenytoin tablets. A case report from the Department of Neurology generated through voluntary adverse drug reaction (ADR)reporting stated phenytoin overdosage leading to refractory status epilepticus which did not respond to any of the antiepileptic drugs. A 33-year-old female patient with the history of consumption 15 tablets of phenytoin and a metal ring as part of a suicidal bid a month ago, presented with unconsciousness, persistent seizures, and gangrene of fingers. Magnetic resonance imaging showed generalized atrophic changes of the cerebrum and cerebellum. Electroencephalogram suggested multifocal onset status epilepticus. The patient did not respond to standard emergency treatment of status epilepticus with known antiepileptic drugs and was treated with thiopentone infusion under mechanical ventilation, which controlled her seizures as long as she was maintained under the infusion. Causality analysis using the World Health Organization scale categorizes this ADR as “possible”, as the patient is a known case of seizure disorder with additional cerebral changes. Hence, the disease could have had an influence over the toxic reaction. To conclude, seizures are a rare complication of phenytoin. Seizures can be prevented by evaluating therapeutic plasma concentration of phenytoin. In this case, the patient was on chronic treatment, and due to intentional toxicity, she progressed to a refractory state of seizures. This could have occurred because of the unique kinetic profile of phenytoin, small therapeutic index, genetic variation in drug metabolizing enzymes, and saturated sodium channels.

Molecular imaging in drug development: Update and challenges for radiolabeled antibodies and nanotechnology.

Despite the significant advancement achieved in understanding the molecular mechanisms responsible for cancer transformation and aberrant proliferation, leading to novel targeted cancer therapies, significant effort is still needed to "personalize" cancer treatment. Molecular imaging is an emerging field that has shown the ability to characterize in vivo the molecular pathways present at the cancer cell level, enabling diagnosis and personalized treatment of malignancies. These technologies, particularly SPECT and PET also permit the development of novel radiotheranostic probes, which provide capabilities for diagnosis and treatment with the same agent. The small therapeutic index of most anticancer agents is a limitation in the drug development process. Incorporation of molecular imaging in clinical research may help in overcoming this limitation and favouring selection of patient populations most likely to achieve benefit from targeted therapy. This review will focus on two of the most advanced theranostic approaches with promising potential for application in the clinic: 1) therapeutic monoclonal antibodies which may be linked to a radionuclide for SPECT or PET imaging to guide cancer diagnosis, staging, molecular characterization, and assessment of the response to treatment and 2) multifunctional nanotechnology that allows image guided drug delivery through encapsulation of multiple therapeutic, targeting and imaging agents into a single nanoparticle. Porphysome, a liposome-like nanoparticle, is an example of a novel and promising application of nanotechnology for cancer diagnosis and treatment. These technologies have proven to be effective in preclinical models, warranting further clinical investigation to advance their application for the benefit of cancer patients.

Heparin-induced thrombocytopenia: a tremendous opportunity for randomization.

: Heparin-induced thrombocytopenia and thrombosis (HITT) is both life-threatening with a complex immune-mediated process and clinically challenging to diagnose and treat. What further complicates matters is that thrombocytopenia is a frequently encountered laboratory value but rarely results in clinical signs of HITT. Decades into its initial description, we have anticoagulants with a small therapeutic index and associated high cost. The diagnosis is sometimes equivocal given our current laboratory diagnostics, and can take days to confirm. Furthermore, prior studies that resulted in the approval of anticoagulants for the treatment of heparin-induced thrombocytopenia have been imperfectly designed. Further evaluations of patients with HITT could more adequately define these difficult issues.

Patients' safety: is there a systemic release of gentamicin by gentamicin-coated tibia nails in clinical use?

IntroductionOsteitis is one of the most serious complications in orthopedic surgery. Expert Tibia Nail (ETN) PROtect™ coated with a biodegradable layer of gentamicin-laden polymer was developed for prophylaxis of osteomyelitis. In systemic administration, gentamicin has only a small therapeutic index and serious side effects; it is potentially nephrotoxic as well as ototoxic. It is not yet known if relevant gentamicin concentrations are released into the systemic circulation after implantation of gentamicin-coated nails. In order to evaluate the patients’ risks profiles and increase patient safety, we measured gentamicin levels in pre- and postoperative serum samples of patients undergoing implantation of ETN PROtect.MethodsTwenty-five patients who received ETN PROtect between March 2012 and August 2014 were included in this study. Collection of blood samples occurred before the operation, at weeks 1–4, 3 and 6 months, and up to 1 year after the implantation. Measurement of gentamicin levels in serum samples was performed at the central laboratory of Heidelberg University Hospital. Additionally, laboratory parameters, C-reactive protein, leukocyte number, urea and creatinine concentrations were analyzed in routine controls before and after operating and assessed for systemic side effects.ResultsOver the course of this prospective observational study, we were able to determine that gentamicin-coated nails do not release gentamicin into the systemic circulation above the lowest detectable level of 0.2 mg/dL. There were slight increases in the mean inflammation and renal retention markers, but no gentamicin-associated side effects could be linked to implantation. Furthermore, no allergic reactions could be detected during our study.ConclusionOur findings suggest that there is no relevant release of gentamicin into the systemic circulation causing a systemic effect, and serious side effects due to gentamicin-coated tibia nails should not be feared. Postoperative monitoring of renal function does not seem necessary because of the implantation of ETN PROtect.

The COAG and EU-PACT trials: what is the clinical benefit of pharmacogenetic-guided coumarin dosing during therapy initiation?

Coumarin derivates are oral anticoagulants commonly prescribed for treatment and prevention of thromboembolism. Due to a small therapeutic index and large inter- and intrapatient differences in dose requirements, treatment with coumarins is challenging, particularly in its starting phase. Extensive evidence suggests that common genetic variants in CYP2C9 and VKORC1 genes together with a number of clinical factors are important determinants of the coumarin dose variability. Pharmacogenetic algorithms comprising both genetic and non-genetic factors were developed to improve the safety of coumarin therapy initiation. Recently, three randomized controlled trials (the COAG and the EU-PACT trials) on pharmacogenetic dosing of warfarin, acenocoumarol and phenprocoumon were published. In these trials different coumarin dosing strategies were compared to investigate whether or not pharmacogenetic testing could be beneficial for coumarin management. The purpose of this review was to present and discuss the design and results of these studies within the context of previously published randomized controlled trials and to address the issues surrounding the incorporation of coumarin pharmacogenetic testing into clinical practice.

Sustained-release protamine sulphate-impregnated microspheres may reduce the frequent administration of recombinant interferon α-2b in ovarian cancer

Parenteral administration of recombinant interferon-α-2b (rINF-α-2b) at a dose of 50×10 IU once a week for 8 weeks is recommended for ovarian cancer. However, short half-life, small therapeutic index and proteolytic degradation cause fluctuations in plasma level and pose barriers in the development of a clinically viable dosage form. Therefore, in the present investigation, fluorescein isothiocynate-tagged rINF-α-2b was loaded into stearic acid (*rINF-α-2b-SMs), pectin (*rINF-α-2b-PMs) and gelatin (*rINF-α-2b-GMs) microspheres. Parameters such as particle size, ζ potential, encapsulation efficiency and in-vitro release were studied to follow the optimization process. The formulation, *rINF-α-2b-GMs of particle size 8.3±2.1 μm with an encapsulation efficiency of 76.0±7.4%, offered 97.4% of *rINF-α-2b release at 288 h. Thus, negatively charged extended-release formulation *rINF-α-2b-GMs was then tethered with a gradient concentration (5-20 mg/ml) of a cationic arginine-rich protein stabilizer, protamine sulphate (Pt). The nanoformulation, *rINF-α-2b-Pt-GMs-15 superimposed with 15 mg/ml of Pt, released 95.0% of *rINF-α-2b at 336 h and was designated as the optimized formulation. The optimized formulation also conserved the primary and secondary structure of *rINF-α-2b as analysed by gel electrophoresis and circular dichroism. Moreover, in-vitro cytotoxicity analysis of SKOV3 cells of the optimized nanoformulation reported significantly (one-way analysis of variance test, P<0.05) lower IC50 (414.3 IU/ml) compared with *rINF-α-2b-GMs (514.3 IU/ml) and pure rINF-α-2b (628.6 IU/ml) at 72 h by offering a prolonged cytotoxic effect. Therefore, *rINF-α-2b-Pt-GMs-15, a promising nanomedicine, warrants further in-depth in-vivo study to scale up the technology for clinical translation.

FAM83B-mediated activation of PI3K/AKT and MAPK signaling cooperates to promote epithelial cell transformation and resistance to targeted therapies

Therapies targeting MAPK and AKT/mTOR signaling are currently being evaluated in clinical trials for several tumor types. However, recent studies suggest that these therapies may be limited due to acquired cancer cell resistance and a small therapeutic index between normal and cancer cells. The identification of novel proteins that are involved in MAPK or AKT/mTOR signaling and differentially expressed between normal and cancer cells will provide mechanistically distinct therapeutic targets with the potential to inhibit these key cancer-associated pathways. We recently identified FAM83B as a novel, previously uncharacterized oncogene capable of hyperactivating MAPK and mTOR signaling and driving the tumorigenicity of immortalized human mammary epithelial cells (HMEC). We show here that elevated FAM83B expression also activates the PI3K/AKT signaling pathway and confers a decreased sensitivity to PI3K, AKT, and mTOR inhibitors. FAM83B co-precipitated with the p85α and p110α subunits of PI3K, as well as AKT, and increased p110α and AKT membrane localization, consistent with elevated PI3K/AKT signaling. In tumor-derived cells harboring elevated FAM83B expression, ablation of FAM83B decreased p110α and AKT membrane localization, suppressed AKT phosphorylation, and diminished proliferation, AIG, and tumorigenicity in vivo. We propose that the level of FAM83B expression may be an important factor to consider when combined therapies targeting MAPK and AKT/mTOR signaling are used. Moreover, the identification of FAM83B as a novel oncogene and its integral involvement in activating PI3K/AKT and MAPK provides a foundation for future therapies aimed at targeting FAM83B in order to suppress the growth of PI3K/AKT- and MAPK-driven cancers.

Effects of Renal Replacement Therapy on Antimicrobial Therapy

Antimicrobial therapy in patients receiving renal replacement therapy (RRT) is challenging due to the varying pharmacokinetic profile of each drug-membrane-technique combination. Renally excreted drugs are usually affected by RRT to a much higher extend than hepatically excreted drugs. However, highly protein bound drugs might be eliminated during RRTs regardless of their usual route of elimination through the formation of a protein membrane within the filter. Beta-lactames pose a good example: most beta-lactames are excreted renally as unchanged drug. However, some betalactames, e.g. flucloxacillin or ceftriaxone adhere to the filter membrane due to their strong protein-drug interaction. Depending on the implemented RRT different administration regimens should be chosen. While beta-lactames may be administered three times daily as well as continuously during continuous RRT, they should be given only once after each hemodialysis session. Aminoglycosides on the other hand should best be given previous to HD to allow for high peak and low through concentrations due to their small therapeutic index and high toxicity. The current Recommendation for glycopeptides in hemodialysis is a post-HD administration. In both groups, aminoglycosides as well as glycopeptides drug monitoring is mandatory. For chinolones the standard dosing intervals should remain unchanged, however they require a significant reduction of the dose, with the exception of moxifloxacin which is excreted hepatically. Until now there are few publications guiding the clinician to the correct dosing schemes in RRT. This review aims to give dosage recommendations for a broad collection of currently used antimicrobial agents and should be applicable for all types of presently employed membranes.

Dosing Done Right: A Review of Common Chemotherapy Calculations

The potential for medication error is great with chemotherapy agents because of their high toxicity profile, small therapeutic index, and numerous dose-limiting adverse effects. The oncology team involved with chemotherapy treatment planning and administration assumes an active role in preventing such events by obtaining and maintaining competency in dose calculations, having knowledge of dose-limiting toxicities, appropriate ordering of drug regimens, and participation in safety verification processes. This article will provide a review of evidence-based formulas and their rationale for use in dosing chemotherapy, case scenarios with practice calculations, and recommendations for safe verification of chemotherapy drug order accuracy.

Cancer chemotherapeutic error in hospitalized patients: Attributable damages and extra costs.

e19529 Background: Medication errors in hospitalized patients are still relatively common with potential dramatic consequences, specialy with antineoplastic drugs because of their high toxicity, their small therapeutic index and health's status of cancer patients. The aim of this study was to assess antineoplastic medication errors (those which have affected patient and those captured before they occur) in terms of frequency, patients harm and cost. Methods: A 1-year prospective study was conducted in a French 1200-bed university hospital detecting medication errors at every step of the anticancer chemotherapy use process. Severity of medication errors and potential consequences of avoided errors were estimated independently by two physicians. A costs analysis was performed by simulation of potential hospital stays and valued at the complete hospital cost of the corresponding diagnosis related groups. Results: Of 6,607 antineoplastic prescriptions charts, 341 presented at least one error (5.16%) corresponding to 449 medication errors of which 436 were captured before administration to patient. Prescription errors represented 91% of errors followed by pharmaceutical errors (8%) and administration errors (1%). In total, 13.4% of avoided errors would have caused a temporary injury, 2.6% a permanent damage and 2.6% would have compromised the vital prognosis of the patient (including 4 to 8 potential deaths). If not avoided, 216 additional hospital days would have been necessary. Thirteen medication errors reached the patient without damages except 2 patients, needing reinforced monitoring. Avoided medication errors would have caused an estimated annual opportunity cost of 92,907€ with 74% attributed to hospital stays and 26% to drugs. Conclusions: This study demonstrates that major medication errors take place in hospital but that a dedicated control quality system allowed capturing most of them before they reach the patient. Potential consequences for patients and cost of medication errors justify the development of preventive actions. No significant financial relationships to disclose.