Current Pharmacy-online News Results

Regulation of inducible BALT formation and contribution to immunity and pathology.

Mucosal Immunol. 2010 Sep 1;
Foo SY, Phipps S

Inducible bronchus-associated lymphoid tissue (iBALT) is an organized tertiary lymphoid structure that is not pre-programmed but develops in response to infection or under chronic inflammatory conditions. Emerging research has shown that iBALT provides a niche for T-cell priming and B-cell education to assist in the clearance of infectious agents, highlighting the prospect that iBALT may be engineered and harnessed to enhance protective immunity against respiratory pathogens. Although iBALT formation is associated with several canonical factors of secondary lymphoid organogenesis such as lymphotoxin-alpha and the homeostatic chemokines, CXCL13, CCL19, and CCL21, these cytokines are not mandatory for its formation, even though they influence its organization and function. Similarly, lymphoid tissue-inducer cells are not a requisite of iBALT formation. In contrast, dendritic cells are emerging as pivotal players required to form and sustain the presence of iBALT. Regulatory T cells appear to be able to attenuate the development of iBALT, although the underlying mechanisms remain ill-defined. In this review, we discuss facets unique to iBALT induction, the cellular subsets, and molecular cues that govern this process, and the contribution of this ectopic structure toward the generation of immune responses in the pulmonary compartment.Mucosal Immunology advance online publication 1 September 2010. doi:10.1038/mi.2010.52.

Anonymous peer assessment of medication management reviews.

Am J Pharm Educ. 2010 Jun 15; 74(5):
Basheti IA, Ryan G, Woulfe J, Bartimote-Aufflick K

OBJECTIVES: To investigate whether pharmacy students' anonymous peer assessment of a medication management review (MMR) was constructive, consistent with the feedback provided by an expert tutor, and enhanced the students' learning experience. DESIGN: Fourth-year undergraduate pharmacy students were randomly and anonymously assigned to a partner and participated in an online peer assessment of their partner's MMR. ASSESSMENT: An independent expert graded a randomly selected sample of the MMR's using a schedule developed for the study. A second expert evaluated the quality of the peer and expert feedback. Students also completed a questionnaire and participated in a focus group interview. Student peers gave significantly higher marks than an expert for the same MMR; however, no significant difference between the quality of written feedback between the students and expert was detected. The majority of students agreed that this activity was a useful learning experience. CONCLUSIONS: Anonymous peer assessment is an effective means of providing additional constructive feedback on student performance on the medication review process. Exposure to other students' work and the giving and receiving of peer feedback were perceived as valuable by students.

A blended learning approach to teaching basic pharmacokinetics and the significance of face-to-face interaction.

Am J Pharm Educ. 2010 Jun 15; 74(5):
Edginton A, Holbrook J

OBJECTIVE: To assess pharmacy students' attitudes towards a blended-learning pharmacokinetics course. DESIGN: Narrated visual presentations and animations that illustrated kinetic processes and guided students through the use of software programs used for calculations were created. Other learning techniques used included online self-assessment quizzes, practice problem sets, and weekly face-to-face problem-solving tutorials. ASSESSMENT: A precourse questionnaire to assess students' level of enthusiasm towards the blended-learning course and to solicit any concerns they had was administered at the beginning of the course. A postcourse questionnaire that included the same 4 Likert-scale items from the precourse questionnaire and follow-up open-ended questions was administered. Individual changes in level of enthusiasm were compared for individuals who completed both the precourse and postcourse questionnaire. Students' concerns about the blended method of learning had decreased postcourse while their enthusiasm for the benefits of blended learning had increased. CONCLUSION: Students' initial concerns about the blended learning experience were focused on their ability to communicate with the instructor about the online components, but shifted to their own time management skills at the end of the course. Face-to-face interactions with each other and with the instructor were more highly rated than online interactions in this course.

Electrochemical Oxidation and Cleavage of Tyrosine- and Tryptophan-Containing Tripeptides.

Anal Chem. 2010 Aug 20;
Roeser J, Permentier HP, Bruins AP, Bischoff R

Electrochemical oxidation of peptides and proteins has been shown to lead to specific cleavage next to tyrosine (Tyr) and tryptophan (Trp) residues which makes the coupling of electrochemistry to mass spectrometry (EC-MS) a potential instrumental alternative to chemical and enzymatic cleavage. A set of Tyr and Trp-containing tripeptides has been studied to investigate the mechanistic aspects of electrochemical oxidation and the subsequent chemical reactions including peptide bond cleavage, making this the first detailed study of the electrochemistry of Trp-containing peptides. The effect of adjacent amino acids was studied leading to the conclusion that the ratios of oxidation and cleavage products are peptide-dependent and that the adjacent amino acid can influence the secondary chemical reactions occurring after the initial oxidation step. The effect of parameters such as potential and solvent conditions showed that control of the oxidation potential is crucial to avoid dimer formation for Tyr and an increasing number of oxygen insertions (hydroxylations) for Trp, which occur above 1000 mV (vs Pd/H(2)). While the formation of reactive intermediates after the first oxidation step is not strongly dependent on experimental conditions, an acidic pH is required for good cleavage yields. Working under strongly acidic conditions (pH 1.9-3.1) led to optimal cleavage yields (40-80%), whereas no or little cleavage occurred under basic conditions. Online EC-MS allowed determining the optimal potential for maximum cleavage yields, whereas EC-LC-MS/MS revealed the nature and distribution of the reaction products.

Metabolically stabilized long-circulating PEGylated polyacridine peptide polyplexes mediate hydrodynamically stimulated gene expression in liver.

Gene Ther. 2010 Aug 19;
Fernandez CA, Baumhover NJ, Duskey JT, Khargharia S, Kizzire K, Ericson MD, Rice KG

A novel class of PEGylated polyacridine peptides was developed that mediate potent stimulated gene transfer in the liver of mice. Polyacridine peptides, (Acr-X)(n)-Cys-polyethylene glycol (PEG), possessing 2-6 repeats of Lys-acridine (Acr) spaced by either Lys, Arg, Leu or Glu, were Cys derivatized with PEG (PEG(5000 kDa)) and evaluated as in vivo gene transfer agents. An optimal peptide of (Acr-Lys)(6)-Cys-PEG was able to bind to plasmid DNA (pGL3) with high affinity by polyintercalation, stabilize DNA from metabolism by DNAse and extend the pharmacokinetic half-life of DNA in the circulation for up to 2 h. A tail vein dose of PEGylated polyacridine peptide pGL3 polyplexes (1 mug in 50 mul), followed by a stimulatory hydrodynamic dose of normal saline at times ranging from 5 to 60 min post-DNA administration, led to a high level of luciferase expression in the liver, equivalent to levels mediated by direct hydrodynamic dosing of 1 mug of pGL3. The results establish the unique properties of PEGylated polyacridine peptides as a new and promising class of gene delivery peptides that facilitate reversible binding to plasmid DNA, protecting it from DNase in vivo resulting in an extended circulatory half-life, and release of transfection-competent DNA into the liver to mediate a high-level of gene expression upon hydrodynamic boost.Gene Therapy advance online publication, 19 August 2010; doi:10.1038/gt.2010.117.

Pharmacists' online information literacy: an assessment of their use of Internet-based medicines information.

Health Info Libr J. 2010 Sep; 27(3): 208-16
Peterson-Clark G, Aslani P, Williams KA

INTRODUCTION: Pharmacists need effective skills in accessing and using Internet-based medicines information (IBMI) for themselves and their consumers. However, there is limited information regarding how pharmacists use the Internet. OBJECTIVES: To develop and use a research instrument to measure pharmacists' Internet knowledge, search skills, evaluation of and opinions about using IBMI. METHODS: A structured questionnaire examining general Internet knowledge, ability to search for and select pertinent IBMI, evaluation of IBMI, opinions about using IBMI and current Internet use was developed. Exploratory factor analysis was performed to analyse IBMI evaluation. RESULTS: 208 pharmacists responded (response rate 20.6%). There was a large variation in pharmacists' scores. Mean scores were low for General Internet Knowledge (mean 7.91 +/- 3.62; scale 0-16), Search and Selection of IBMI (4.98 +/- 2.91; 0-10) and Opinions on IBMI (44.51 +/- 9.61; 0-80). Four factors [Professionalism of website (4 items; factor loading 0.62-0.87; Cronbach's alpha 0.84), Disclosure (5; 0.37-0.79; 0.73), Appropriateness of content (5; 0.32-0.50; 0.65), Standard of information (6; 0.31-0.48; 0.58)] were extracted from the evaluation scale, explaining 36.89% of the total variance. CONCLUSIONS: A tool was developed to evaluate pharmacists' skills and opinions in using IBMI. A wide range of skills and opinions highlighted the need for training in online information literacy.

Cleavable cross-linker for protein structure analysis: reliable identification of cross-linking products by tandem MS.

Anal Chem. 2010 Aug 15; 82(16): 6958-68
Müller MQ, Dreiocker F, Ihling CH, Schäfer M, Sinz A

Chemical cross-linking combined with a subsequent enzymatic cleavage of the created cross-linked complex and a mass spectrometric analysis of the resulting cross-linked peptide mixture presents an alternative approach to high-resolution analysis, such as NMR spectroscopy or X-ray crystallography, to obtain low-resolution protein structures and to gain insight into protein interfaces. Here, we describe a novel urea-based cross-linker, which allows distinguishing different cross-linking products by collision-induced dissociation (CID) tandem MS experiments based on characteristic product ions and constant neutral losses. The novel cross-linker is part of our ongoing efforts in developing collision-induced dissociative reagents that allow an efficient analysis of cross-linked proteins and protein complexes. Our innovative analytical concept is exemplified for the Munc13-1 peptide and the recombinantly expressed ligand binding domain of the peroxisome proliferator-activated receptor alpha, for which cross-linking reaction mixtures were analyzed both by offline nano-HPLC/MALDI-TOF/TOF mass spectrometry and by online nano-HPLC/nano-ESI-LTQ-orbitrap mass spectrometry. The characteristic fragment ion patterns of the novel cross-linker greatly simplify the identification of different cross-linked species, namely, modified peptides as well as intrapeptide and interpeptide cross-links, from complex mixtures and drastically reduce the potential of identifying false-positive cross-links. Our novel urea-based CID cleavable cross-linker is expected to be highly advantageous for analyzing protein 3D structures and protein-protein complexes in an automated manner.

Systemic delivery of E6/7 siRNA using novel lipidic particles and its application with cisplatin in cervical cancer mouse models.

Gene Ther. 2010 Aug 12;
Wu SY, Singhania A, Burgess M, Putral LN, Kirkpatrick C, Davies NM, McMillan NA

Small interfering RNA (siRNA) shows great promise in cancer therapy, but its effectiveness in vivo still remains a crucial issue for its transition into the clinics. Although the successful use of polyethylene glycol (PEG)ylated lipidic delivery systems have already been reported, most of the formulation procedures used are labour intensive and also result in unstable end products. We have previously developed a simple yet efficient hydration-of-freeze-dried-matrix (HFDM) method to entrap siRNA within lipid particles, in which the products exhibited superior stability. Here, we show that these HFDM-formulated particles are stable in the presence of serum and can deliver siRNA efficiently to tumours after intravenous administration. Using these particles, around 50% knockdown of the target gene expression was observed in tumours. With the use of siRNA targeting the E6/7 oncogenes expressed in cervical cancer, we showed a 50% reduction in tumour size. This level of tumour growth suppression was comparable to that achieved from cisplatin at the clinically used dose. Overall, our results demonstrate the feasibility of using HFDM-formulated particles to systematically administer E6/7-targeted siRNA for cervical cancer treatment. The simplicity of preparation procedure along with superior product stability obtained from our method offers an innovative approach for the in vivo delivery of siRNA.Gene Therapy advance online publication, 12 August 2010; doi:10.1038/gt.2010.113.

The impact of CYP2D6-predicted phenotype on tamoxifen treatment outcome in patients with metastatic breast cancer.

Br J Cancer. 2010 Aug 10;
Lammers LA, Mathijssen RH, van Gelder T, Bijl MJ, de Graan AJ, Seynaeve C, van Fessem MA, Berns EM, Vulto AG, van Schaik RH

Background:Cytochrome P450 2D6 (CYP2D6) has a crucial role in the metabolic conversion of tamoxifen into the active metabolite endoxifen. In this cohort study, the effect of CYP2D6-predicted phenotype, defined as the combined effect of CYP2D6 genetic variation and concomitant use of CYP2D6-inhibiting medication, on time to breast cancer progression (TTP) and overall survival (OS) in women who use tamoxifen for metastatic breast cancer (MBC) was examined.Methods:We selected patients treated with tamoxifen (40 mg per day) for hormone receptor-positive MBC from whom a blood sample for pharmacogenetic analysis (CYP2D6*3, *4, *5, *6, *10 and *41) was available. Patient charts (n=102) were reviewed to assess TTP and OS, and to determine whether CYP2D6 inhibitors were prescribed during tamoxifen treatment.Results:OS was significantly shorter in patients with a poor CYP2D6 metaboliser phenotype, compared with extensive metabolisers (HR=2.09; P=0.034; 95% CI: 1.06-4.12). Co-administration of CYP2D6 inhibitors alone was also associated with a worse OS (HR=3.55; P=0.002; 95% CI: 1.59-7.96) and TTP (HR=2.97; P=0.008; 95% CI: 1.33-6.67) compared with patients without CYP2D6 inhibitors.Conclusion:CYP2D6 phenotype is an important predictor of treatment outcome in women who are receiving tamoxifen for MBC. Co-administration of CYP2D6 inhibitors worsens treatment outcome of tamoxifen and should therefore be handled with care.British Journal of Cancer advance online publication, 10 August 2010; doi:10.1038/sj.bjc.6605800 www.bjcancer.com.

EphA3 functions are regulated by collaborating phosphotyrosine residues.

Cell Res. 2010 Aug 10;
Shi G, Yue G, Zhou R

Ephrin ligands interact with Eph receptors to regulate a wide variety of biological and pathological processes. Recent studies have identified several downstream pathways that mediate the functions of these receptors. Activation of the receptors by ephrin binding results in the phosphorylation of the receptor tyrosine residues. These phosphorylated residues serve as docking sites for many of the downstream signaling pathways. However, the relative contributions of different phosphotyrosine residues remain undefined. In the present study, we mutated each individual tyrosine residues in the cytoplasmic domain of EphA3 receptor and studied the effects using cell migration, process retraction, and growth cone collapse assays. Stimulation of the EphA3 receptor with ephrin-A5 inhibits 293A cell migration, reduces NG108-15 cell neurite outgrowth, and induces growth cone collapse in hippocampal neurons. Mutation of either Y602 or Y779 alone partially decreases EphA3-induced responses. Full abrogation can only be achieved with mutations of both Y602 and Y779. These observations suggest a collaborative model of different downstream pathways.Cell Research advance online publication 10 August 2010; doi:10.1038/cr.2010.115.

The protein kinase Pak4 disrupts mammary acinar architecture and promotes mammary tumorigenesis.

Oncogene. 2010 Aug 9;
Liu Y, Chen N, Cui X, Zheng X, Deng L, Price S, Karantza V, Minden A

The Pak4 serine/threonine kinase is highly expressed in many cancer cell lines and human tumors. Although several studies have addressed the role for Pak4 in transformation of fibroblasts, most human cancers are epithelial in origin. Epithelial cancers are associated not only with changes in cell growth but also with changes in the cellular organization within the three-dimensional (3D) architecture of the affected tissues. In this study we used immortalized mouse mammary epithelial cells (iMMECs) as a model system to study the role for Pak4 in mammary tumorigenesis. iMMECs are an excellent model system for studying breast cancer, as they can grow in 3D-epithelial cell culture, in which they form acinar structures that recapitulate in vivo mammary morphogenesis. Although Pak4 is expressed at low levels in wild-type iMMECs, it is overexpressed in response to oncogenes, such as oncogenic Ras and Her2/neu. In this study we found that overexpression of Pak4 in iMMECs leads to changes in 3D acinar architecture that are consistent with oncogenic transformation. These include decreased central acinar cell death, abrogation of lumen formation, cell polarity alterations and deregulation of acinar size and cell number. Furthermore, iMMECs overexpressing Pak4 form tumors when implanted into the fat pads of athymic mice. Our results suggest that overexpression of Pak4 triggers events that are important for the transformation of mammary epithelial cells. This is likely to be owing to the ability of Pak4 to inhibit apoptosis and promote cell survival and thus subsequent uncontrolled proliferation, and to its ability to deregulate cell shape and polarity.Oncogene advance online publication, 9 August 2010; doi:10.1038/onc.2010.329.

Educational program for pharmacists at a multifacility academic medical center.

Am J Health Syst Pharm. 2010 Aug 15; 67(16): 1368-72
Saenz R, Skledar SJ, Yourich B, Mark SM

PURPOSE: An educational program for pharmacists in a multifacility health care setting is described. SUMMARY: The expansion of pharmacy services at a university medical center from a centralized to a decentralized, unit-based model created the need for enhanced education of staff pharmacists. A steering committee with pharmacy department and school of pharmacy representation surveyed educational and professional needs related to the expanded services. Pharmacists indicated that they needed an educational program that was comprehensive, interactive, and accessible to all shifts. Pharmacy school clinical faculty members provided most of the initial educational sessions, which combined didactic presentations and case-based discussion. The needs survey was used in selecting topics that were most relevant to the pharmacists' expanded practice. Each major topic was covered in a series of one-hour sessions held at two-week intervals and scheduled at a time convenient for afternoon-shift pharmacists. Incentives were offered to encourage participation. The live presentations were recorded with video-streaming technology and made available via the Internet to pharmacists on all shifts in all facilities of the health system as well as to faculty members. Since program implementation in 2005, attendance at the live sessions has averaged 25. In postimplementation surveys, pharmacists indicated that the program was meeting their needs and improving patient care. Since 2008, pharmacists have been able to earn continuing-education (CE) credit for the sessions. CONCLUSION: A collaborative educational series with online access, clinical content, and CE credit has been effective in meeting pharmacists' needs in a multifacility health care setting.

Identification of the Position of Mono-O-glucuronide of Flavones and Flavonols by Analyzing Shift in Online UV Spectrum (lambda(max)) Generated from an Online Diode Array Detector.

J Agric Food Chem. 2010 Sep 8; 58(17): 9384-95
Singh R, Wu B, Tang L, Liu Z, Hu M

The beneficial pharmacological effects of flavonoids such as chemoprevention against cancer, aging, and heart diseases are severely limited due to their extensive in vivo glucuronidation by UDP-glucuronosyltransferases (UGTs). UGTs showed regiospecificity (i.e., position preference) in the glucuronidation of the flavonoids based on the substrate's chemical structure. In this paper, glucuronide(s) of 36 flavones and flavonols were generated using an in vitro glucuronidation reaction. UPLC/MS/MS was used to confirm the degree (mono- or di-) of glucuronidation in flavonoids with up to four hydroxyl groups. UV spectra of flavonoids and their respective mono-O-glucuronides were generated using UPLC with an online diode array detector. Analysis of the extent of shift in spectra of glucuronides in band I (300-385 nm) and band II (240-280 nm) regions as reflected by changes in lambda(max) value was used to identify the position of glucuronidation. The data showed that glucuronidation of the 3- and 4'-hydroxyls resulted in band I lambda(max) hypsochromic shifts (or blue shift) of 13-30 and 5-10 nm, respectively. Glucuronidation of the 5-hydroxyl group caused a band II lambda(max) hypsochromic shift of 5-10 nm. In contrast, glucuronidation of the 7-hydroxyl group did not cause any lambda(max) change in band I or II lambda(max), whereas glucuronidation of the 6-hydroxyl group did not cause predictable changes in lambda(max) values. The paper demonstrated for the first time that a rapid and robust analysis method using lambda(max) changes in online UV spectra can be used to pinpoint region-specific glucuronidation of flavones and flavonols with hydroxyl groups at the 4'-, 3-, 5-, and/or 7-position(s).

Analyses of second-generation 'legal highs' in the UK: Initial findings.

Drug Test Anal. 2010 Aug 5;
Brandt SD, Sumnall HR, Measham F, Cole J

In the UK, mephedrone and other so-called 'legal high' derivatives have recently been classified as Class B, Schedule I under the Misuse of Drugs Act 1971. Since then, alternative products have been advertised on a number of websites. In order to obtain an immediate snapshot of the situation, 24 products were purchased online from 18 UK-based websites over a period of 6 weeks following the ban in April 2010. Qualitative analyses were carried out by gas chromatography ion trap mass spectrometry using electron- and chemical ionization modes, nuclear magnetic resonance spectroscopy, and comparison with reference standards. Overall, the purchased products consisted of single cathinones or cathinone mixtures including mephedrone, butylone, 4-methyl-N-ethylcathinone, flephedrone (4-fluoromethcathinone) and MDPV (3,4-methylenedioxypyrovalerone), respectively. Benzocaine, caffeine, lidocaine, and procaine were also detected. The emphasis was placed on 'Energy 1' (NRG-1), a product advertised as a legal replacement for mephedrone-type derivatives usually claiming to contain naphyrone (naphthylpyrovalerone, O-2482). It was found that 70% of NRG-1 and NRG-2 products appeared to contain a mixture of cathinones banned in April 2010 and rebranded as 'new' legal highs, rather than legal chemicals such as naphyrone as claimed by the retailers. Only one out of 13 NRG-1 samples appeared to show analytical data consistent with naphyrone. These findings also suggest that both consumers and online sellers (unlike manufacturers and wholesalers) are, most likely unknowingly, confronted with the risk of criminalization and potential harm. Copyright (c) 2010 John Wiley & Sons, Ltd.

Targeted Nanoparticles Deliver siRNA to Melanoma.

J Invest Dermatol. 2010 Aug 5;
Chen Y, Bathula SR, Yang Q, Huang L

Melanoma is a severe skin cancer that often leads to death. To examine the potential of small interfering RNA (siRNA) therapy for melanoma, we have developed anisamide-targeted nanoparticles that can systemically deliver siRNA into the cytoplasm of B16F10 murine melanoma cells, which express the sigma receptor. A c-Myc siRNA delivered by the targeted nanoparticles effectively suppressed c-Myc expression in the tumor and partially inhibited tumor growth. More significant tumor growth inhibition was observed with nanoparticles composed of N,N-distearyl-N-methyl-N-2-(N'-arginyl) aminoethyl ammonium chloride (DSAA), a guanidinium-containing cationic lipid, than with a commonly used cationic lipid, 1,2-dioleoyl-3-trimethylammonium-propane (DOTAP). Three daily injections of c-Myc siRNA formulated in the targeted nanoparticles containing DSAA could impair tumor growth, and the ED(50) of c-Myc siRNA was about 0.55 mg kg(-1). The targeted DSAA nanoparticles containing c-Myc siRNA sensitized B16F10 cells to paclitaxel (Taxol), resulting in a complete inhibition of tumor growth for 1 week. Treatments of c-Myc siRNA in the targeted nanoparticles containing DSAA also showed significant inhibition on the growth of MDA-MB-435 tumor. The enhanced anti-melanoma activity is probably related to the fact that DSAA, but not DOTAP, induced reactive oxygen species, triggered apoptosis, and downregulated antiapoptotic protein Bcl-2 in B16F10 melanoma cells. Thus, the targeted nanoparticles containing c-Myc siRNA may serve as an effective therapeutic agent for melanoma.Journal of Investigative Dermatology advance online publication, 5 August 2010; doi:10.1038/jid.2010.222.

[A study of the health food information for cancer patients on Japanese websites]

Yakugaku Zasshi. 2010 Aug; 130(8): 1017-27
Kishimoto K, Yoshino C, Fukushima N

The aim of this paper is to evaluate the reliability of websites providing health food information for cancer patients and, to assess the status to get this information online. We used four common Japanese search engines (Yahoo!, Google, goo, and MSN) to look up websites on Dec. 2, 2008. The search keywords were "health food" and "cancer". The websites for the first 100 hits generated by each search engine were screened and extracted by three conditions. We extracted 64 unique websites by the result of retrieval, of which 54 websites had information about health food factors. The two scales were used to evaluate the quality of the content on 54 websites. On the scale of reliability of information on the Web, the average score was 2.69+/-1.70 (maximum 6) and the median was 2.5. The other scale was matter need to check whether listed to use safely this information. On this scale, the average score was 0.72+/-1.22 (maximum 5) and the median was 0. Three engines showed poor correlation between the ranking and the latter score. But several websites on the top indicated 0 score. Fifty-four websites were extracted with one to four engines and the average number of search engines was 1.9. The two scales were positively correlated with the number of search engines, but these correlations were very poor. Ranking high and extraction by multiple search engines were of minor benefit to pick out more reliable information.

Plerixafor: A chemokine receptor-4 antagonist for mobilization of hematopoietic stem cells for transplantation after high-dose chemotherapy for non-Hodgkin's lymphoma or multiple myeloma.

Clin Ther. 2010 May; 32(5): 821-43
Steinberg M, Silva M

BACKGROUND: Autologous hematopoietic stem cell (HSC) transplantation is used to facilitate hematopoietic recovery after administration of high-dose chemotherapy in patients with Hodgkin's disease, non-Hodgkin's lymphoma (NHL), multiple myeloma (MM), leukemias, and some solid tumors. There are limitations to the existing methods of mobilizing CD34+ HSC with chemotherapy and/or granulocyte colony-stimulating factor (G-CSF). Plerixafor, a bicyclam molecule that acts as a pure antagonist of chemokine receptor-4, is approved by the US Food and Drug Administration for use in combination with G-CSF for mobilization of CD34+ HSC in patients with NHL or MM. OBJECTIVE: This review presents information on plerixafor, including its mechanism of action in mobilizing stem cells, pharmacokinetics, clinical efficacy, adverse effects, and pharmacoeconomic considerations. METHODS: MEDLINE, EMBASE (1996-June 2009), and International Pharmaceutical Abstracts (1970-June 2009) were searched on July 9, 2009, using the key words plerixafor and AMD3100 for reports relating to HSC mobilization. The search was updated on September 20, 2009, and again on January 30, 2010. The reference lists of identified articles were examined for additional abstracts and other sources of information. The journal Blood was searched online to identify abstracts presented at Annual Meetings of the American Society of Hematology. RESULTS: After administration of plerixafor, HSC migrate from the bone marrow into the peripheral blood, permitting collection by apheresis. Clinical trials in humans have found that the combination of G-CSF + plerixafor facilitates mobilization of HSC. In patients with MM without extensive previous treatment who were undergoing a first mobilization, the use of G-CSF + plerixafor was reported to double counts of circulating peripheral CD34+ HSC and thus double the number of CD34+ HSC collected in half as many apheresis procedures, although rates of engraftment, graft durability, transplantation, and survival outcomes were not significantly improved. In patients with Hodgkin's disease or NHL, in whom limited success in mobilization is expected, G-CSF + plerixafor also facilitated or improved mobilization with improved apheresis yields, again without significant improvement in outcomes. Common (> or = 20%) adverse events of plerixafor used in combination with G-CSF include diarrhea (37%), nausea (34%), injection-site reactions (34%), fatigue (27%), and headache (22%). Plerixafor 0.24 mg/kg SC is administered on the evening of the fourth day of G-CSF dosing, approximately 11 hours before the first apheresis session. Daily doses of plerixafor can be repeated up to 3 times on consecutive days to achieve adequate HSC collection. The average wholesale price of a 24-mg vial of plerixafor is $7500. CONCLUSIONS: Plerixafor is an effective agent for mobilizing CD34+ HSC. Long-term treatment outcomes are being studied in patients undergoing autologous transplantation of HSC mobilized with G-CSF + plerixafor.

Association between HTR2C gene polymorphisms and the metabolic syndrome in patients using antipsychotics: a replication study.

Pharmacogenomics J. 2010 Aug 3;
Risselada AJ, Vehof J, Bruggeman R, Wilffert B, Cohen D, Al Hadithy AF, Arends J, Mulder H

In two previous studies we found an association between HTR2C polymorphisms and the prevalence of the metabolic syndrome in patients using antipsychotics. In this study, we set out to replicate our findings in a third separate sample of patients. Data for this cross-sectional study came from the ongoing Pharmacotherapy Monitoring and Outcome survey study, investigating the association between schizophrenia and metabolic or cardiovascular risk factors. Primary end point was the prevalence of the metabolic syndrome. Primary determinants were two polymorphisms in the HTR2C gene: rs3813929 (-759 C/T) and rs1414334:C>G. Carriership of the variant rs1414334 C-allele was significantly associated with an increase prevalence of the metabolic syndrome (odds ratio (OR) 3.73; 95% confidence interval (CI) 1.29-10.79, P=0.015). No association was found between the HTR2C -759 C/T polymorphism and the metabolic syndrome. This study confirms previous findings that the variant C-allele of the rs1414334 polymorphism is associated with the metabolic syndrome.The Pharmacogenomics Journal advance online publication, 3 August 2010; doi:10.1038/tpj.2010.66.

Recombinant activated factor VIIa treatment for refractory hemorrhage in infants.

J Perinatol. 2010 Jul 29;
Dang CN, Katakam LI, Smith PB, Cotten CM, Goldberg RN, Chandler N, Thornburg CD, Bidegain M

Objective:Report clinical response to recombinant factor VIIa in a cohort of critically ill infants.Study Design:We identified all infants who received factor VIIa in the Duke Neonatal Intensive Care Unit between January 2005 and July 2008. Hematological data and volume of blood transfusions before and after factor VIIa treatment were compared. The precipitating diagnosis for each factor VIIa use, and the ensuing clinical outcomes of bleeding, thrombosis and mortality were noted.Result:We identified 18 infants with median birth weight of 880 g and median gestational age of 26 weeks. One to six doses of factor VIIa (90 mcg kg(-1) per dose) were administered, with 13 (72%) infants receiving a single dose. Hemostasis was achieved in 13 (72%) of the infants. Prothrombin time and activated partial thromboplastin time significantly decreased following treatment with factor VIIa. Volume of plasma transfusions significantly decreased following treatment with factor VIIa (P=0.02). Thrombosis occurred in one (11%) infant. Six (33%) infants died within 72 h of treatment, and overall mortality was 10/18 (56%).Conclusion:Treatment with factor VIIa at doses of 90 mcg kg(-1) improved coagulation studies and decreased the need for plasma transfusions in a group of critically ill infants without significant risk. Factor VIIa may be an effective addition to current treatment modalities for refractory hemorrhage in infants.Journal of Perinatology advance online publication, 29 July 2010; doi:10.1038/jp.2010.85.

Vascular protection in diabetic stroke: role of matrix metalloprotease-dependent vascular remodeling.

J Cereb Blood Flow Metab. 2010 Jul 28;
Elgebaly MM, Prakash R, Li W, Ogbi S, Johnson MH, Mezzetti EM, Fagan SC, Ergul A

Temporary focal ischemia causes greater hemorrhagic transformation (HT) in diabetic Goto-Kakizaki (GK) rats, a model with increased cerebrovascular matrix metalloprotease (MMP) activity and tortuosity. The objective of the current study was to test the hypotheses that (1) diabetes-induced cerebrovascular remodeling is MMP dependent and (2) prevention of vascular remodeling by glucose control or MMP inhibition reduces HT in diabetic stroke. Control and GK rats were treated with vehicle, metformin, or minocycline for 4 weeks, and indices of remodeling including vascular tortuosity index, lumen diameter, number of collaterals, and middle cerebral artery (MCA) MMP activity were measured. Additional animals were subjected to 3 hours MCA occlusion/21 hours reperfusion, and infarct size and HT were evaluated as indices of neurovascular injury. All remodeling markers including MMP-9 activity were increased in diabetes. Infarct size was smaller in minocycline-treated animals. Both metformin and minocycline reduced vascular remodeling and severity of HT in diabetes. These results provide evidence that diabetes-mediated stimulation of MMP-9 activity promotes cerebrovascular remodeling, which contributes to greater HT in diabetes. Metformin and minocycline offer vascular protection, which has important clinical implications for diabetes patients who are at a fourfold to sixfold higher risk for stroke.Journal of Cerebral Blood Flow & Metabolism advance online publication, 28 July 2010; doi:10.1038/jcbfm.2010.120.