The Many Faces of Hemolysis.

Hemolysis is a problem associated with a variety of red cell pathologies and physiologies not limited to the transfusion of cells. Various pathways lead to the observed outcomes when a hemolytic event occurs. Each event, and the pathway it follows, is based on characteristics of the red cell, the location in which the hemolysis occurs, and the interaction of the immune system. The severity of an event can be predicted with the knowledge of how these 3 factors interface. Although not all hemolytic events are alike, similarities may exist when the pathways overlap.

Development of an Evidence-Based List of Noncytotoxic Vesicant Medications and Solutions.

Infiltration of a vesicant medication, defined as extravasation, may result in significant patient injuries. The first step in preventing extravasation is the identification and recognition of vesicant medications and solutions. Because there is no list of noncytotoxic vesicants as established by a professional organization, the Infusion Nurses Society, as the global authority in infusion nursing, identified the need to address this gap. A task force was formed for the purpose of creating an evidence-based list of noncytotoxic vesicant medications and solutions.

Needle Phobia.

Venipuncture is generally associated with some degree of pain, discomfort, and/or apprehension. Yet most patients accept it with tolerance, even nonchalance. A few, not only pediatric patients, exhibit a higher degree of anxiety and face the procedure with tears, tension, and a variety of bargaining techniques (ie, stick on the count of 3; use only this vein). But for 1 group of people, venipuncture is associated with such fear that avoidance of the procedure is practiced. The end results are detrimental to the patient and may have an impact on society as well. These are patients the American Psychiatric Association classifies as needle phobic. What can a nurse with no training in psychiatry do to assist these patients? To form an appropriate professional response, it's beneficial for practitioners to recognize the different pathways that lead to needle phobia and the issues related to the disorder.

Robust Translation of γ-Secretase Modulator Pharmacology across Preclinical Species and Human Subjects.

The amyloid-ß peptide (Aß)-in particular, the 42-amino acid form, Aß1-42-is thought to play a key role in the pathogenesis of Alzheimer's disease (AD). Thus, several therapeutic modalities aiming to inhibit Aß synthesis or increase the clearance of Aß have entered clinical trials, including γ-secretase inhibitors, anti-Aß antibodies, and amyloid-ß precursor protein cleaving enzyme inhibitors. A unique class of small molecules, γ-secretase modulators (GSMs), selectively reduce Aß1-42 production, and may also decrease Aß1-40 while simultaneously increasing one or more shorter Aß peptides, such as Aß1-38 and Aß1-37. GSMs are particularly attractive because they do not alter the total amount of Aß peptides produced by γ-secretase activity; they spare the processing of other γ-secretase substrates, such as Notch; and they do not cause accumulation of the potentially toxic processing intermediate, ß-C-terminal fragment. This report describes the translation of pharmacological activity across species for two novel GSMs, (S)-7-(4-fluorophenyl)-N2-(3-methoxy-4-(3-methyl-1H-1,2,4-triazol-1-yl)phenyl)-N4-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidine-2,4-diamine (BMS-932481) and (S,Z)-17-(4-chloro-2-fluorophenyl)-34-(3-methyl-1H-1,2,4-triazol-1-yl)-16,17-dihydro-15H-4-oxa-2,9-diaza-1(2,4)-cyclopenta[d]pyrimidina-3(1,3)-benzenacyclononaphan-6-ene (BMS-986133). These GSMs are highly potent in vitro, exhibit dose- and time-dependent activity in vivo, and have consistent levels of pharmacological effect across rats, dogs, monkeys, and human subjects. In rats, the two GSMs exhibit similar pharmacokinetics/pharmacodynamics between the brain and cerebrospinal fluid. In all species, GSM treatment decreased Aß1-42 and Aß1-40 levels while increasing Aß1-38 and Aß1-37 by a corresponding amount. Thus, the GSM mechanism and central activity translate across preclinical species and humans, thereby validating this therapeutic modality for potential utility in AD.

Infusion-related air embolism.

Vascular air embolism as a medically induced complication may be associated with numerous treatments and therapies. In infusion therapy, the risk is associated with venous and arterial catheterization as well as various other invasive procedures and much of the equipment used for them. The manner of air entry and the presentation of symptoms may vary greatly. Appropriate treatment options are dependent on air entry routes. Nurses need to be aware of the common and seldom-considered causes of air embolism to be able to guard against this complication, yet adequately support the patient if it occurs.

Acyl guanidine inhibitors of ß-secretase (BACE-1): optimization of a micromolar hit to a nanomolar lead via iterative solid- and solution-phase library synthesis.

This report describes the discovery and optimization of a BACE-1 inhibitor series containing an unusual acyl guanidine chemotype that was originally synthesized as part of a 6041-membered solid-phase library. The synthesis of multiple follow-up solid- and solution-phase libraries facilitated the optimization of the original micromolar hit into a single-digit nanomolar BACE-1 inhibitor in both radioligand binding and cell-based functional assay formats. The X-ray structure of representative inhibitors bound to BACE-1 revealed a number of key ligand:protein interactions, including a hydrogen bond between the side chain amide of flap residue Gln73 and the acyl guanidine carbonyl group, and a cation-π interaction between Arg235 and the isothiazole 4-methoxyphenyl substituent. Following subcutaneous administration in rats, an acyl guanidine inhibitor with single-digit nanomolar activity in cells afforded good plasma exposures and a dose-dependent reduction in plasma Aß levels, but poor brain exposure was observed (likely due to Pgp-mediated efflux), and significant reductions in brain Aß levels were not obtained.

Therapeutic phlebotomy: a review of diagnoses and treatment considerations.

In the United States, phlebotomies are most often performed for reinfusion of blood to a designated or nondesignated recipient at a later time. These are known, respectively, as autologous or allogenic donations. For a few rare blood disorders, however, phlebotomy is performed as a medical intervention for disease management. These are referred to as therapeutic phlebotomies. Four classifications of blood disorders are discussed here for which symptoms and complications can be managed by the use of therapeutic phlebotomy. The article also offers considerations for setting up a therapeutic phlebotomy program.

Best practices in compound management for preserving compound integrity and accurately providing samples for assays.

Preserving the integrity of the compound collection and providing high-quality materials for drug discovery in an efficient and cost-effective manner are 2 major challenges faced by compound management (CM) at Bristol-Myers Squibb (BMS). The demands on CM include delivering hundreds of thousands of compounds a year to a variety of operations. These operations range from single-compound requests to hit identification support and just-in-time assay plate provision for lead optimization. Support needs for these processes consist of the ability to rapidly provide compounds as solids or solutions in a variety of formats, establishing proper long- and short-term storage conditions and creating appropriate methods for handling concentrated, potent compounds for delivery to sensitive biological assays. A series of experiments evaluating the effects of processing compounds with volatile solvents, storage conditions that can induce freeze/thaw cycles, and the delivery of compounds were performed. This article presents the results of these experiments and how they affect compound integrity and the accuracy of compound management processes.

Continuing controversy of midclavicular catheters.

A review of 50 years of research on catheter tip placement indicates an overwhelming preference for the lower third of the superior vena cava as the appropriate tip location. Despite this evidence, there are still practitioners, physicians, and nurses who advocate tip placement within the axillo-subclavian-innominate vein (also referred to as the midclavicular). This article looks at the arguments presented by practitioners who support midclavicular tip placement. It also reviews some of the research from which the recommendations for superior vena cava placement are derived.

Choosing the right intravenous catheter.

Infusion therapy in the home has been common for many years. The therapies appropriate for home infusion are numerous. The type of access device provided for the infusion is an important consideration for safe and effective care. That choice will take into consideration physician and patient preference and length of therapy. However, paramount to this decision are the characteristics of the infusate. It is essential to know the pH and osmolality of the drug as well as its potential vesicant properties. The nurse needs to act as the patient advocate to ensure that proper catheter selection is made. Patient teaching should be aimed at recognition of complications and immediate interventions to avoid problems.

2-aminothiazole as a novel kinase inhibitor template. Structure-activity relationship studies toward the discovery of N-(2-chloro-6-methylphenyl)-2-[[6-[4-(2-hydroxyethyl)-1- piperazinyl)]-2-methyl-4-pyrimidinyl]amino)]-1,3-thiazole-5-carboxamide (dasatinib, BMS-354825) as a potent pan-Src kinase inhibitor.

2-aminothiazole (1) was discovered as a novel Src family kinase inhibitor template through screening of our internal compound collection. Optimization through successive structure-activity relationship iterations identified analogs 2 (Dasatinib, BMS-354825) and 12m as pan-Src inhibitors with nanomolar to subnanomolar potencies in biochemical and cellular assays. Molecular modeling was used to construct a putative binding model for Lck inhibition by this class of compounds. The framework of key hydrogen-bond interactions proposed by this model was in agreement with the subsequent, published crystal structure of 2 bound to structurally similar Abl kinase. The oral efficacy of this class of inhibitors was demonstrated with 12m in inhibiting the proinflammatory cytokine IL-2 ex vivo in mice (ED50 approximately 5 mg/kg) and in reducing TNF levels in an acute murine model of inflammation (90% inhibition in LPS-induced TNFalpha production when dosed orally at 60 mg/kg, 2 h prior to LPS administration). The oral efficacy of 12m was further demonstrated in a chronic model of adjuvant arthritis in rats with established disease when administered orally at 0.3 and 3 mg/kg twice daily. Dasatinib (2) is currently in clinical trials for the treatment of chronic myelogenous leukemia.

HTS quality control and data analysis: a process to maximize information from a high-throughput screen.

Changes in all aspects of HTS from compound management through to evaluation of hits and leads, strengthened by infrastructure improvements, in both automation and informatics, have made possible increased analysis and implementation of process and quality control throughout HTS. This paper focuses on the process of HTS with an emphasis on quality control, reducing the variability of all the processes that have an impact on the final result, and argue that by increasing the quality of the entire process that data mining of primary screening data is in fact possible and will reduce cycle times to medicinal chemistry.

IV fluid resuscitation.

Infusion therapy specialists are recognized for their technical expertise and their knowledge of the anticipated reactions and adverse effects of many complicated therapies. But when asked the rationale for intravenous fluid selection, many infusion nurses can only shrug their shoulders. Although intravenous fluid selection may seem a complex principle, it is really quite simple. Once the flow of body fluids among fluid compartments is understood, it is easy to follow the intended path of IV fluids. But infusion specialists should be cautious of the manner in which IV fluids are categorized prior to infusion (isotonic, hypotonic, and hypertonic) because these are not always consistent with how they react in the body.

Targeting the MraY and MurG bacterial enzymes for antimicrobial therapeutic intervention.

Assays for two enzymes from Escherichia coli were developed and validated as antibacterial inhibitor screens. The MraY and MurG enzymes were overexpressed and purified as the membrane fraction or to homogeneity, respectively. The MurG enzyme was expressed with a six-histidine tag using an optimized minimal-medium protocol for subsequent purification. Although traditional assays were established, the enzymes were also assayed via a 96-well membrane plate assay and a 384-well scintillation proximity-based assay developed herein. These assays afford a more economical and high-throughput evaluation of inhibitors. A mureidomycin inhibitor mix was used as a control for the assay development and screen validation. Several inhibitors resulting from a high-throughput screen were found and evaluated for potential therapeutic use.