bluuebunny/crossref_metadata_2025 huggingface dataset:
A Critical Review of Wirebond Visual Inspection Criteria
Authors: Green Thomas
Published: November 2017

Wirebond engineers and technicians primarily rely on three means by which to evaluate the integrity and reliability of a wirebond interconnect. Destruct/non-destruct pull test, ball shear, cross-sections, intermetallic coverage under the ball are tests used to evaluate the mechanical strength as part of process development and in line process controls. Reliability testing and evaluation involves these same tests after prolonged environmental exposure such as, temp cycling, burn-in, humidity testing etc. according to standards such as AEC-Q100. Much has been written about the above. A third and very important consideration in wirebonding is visual inspection of the deformed wire after wirebond formation. The amount of wire squash-out, placement of the bond on the pad relative to nearby circuitry, looping profiles and heel integrity are all very important aspects of wirebond interconnect inspection. Poor workmanship can lead to noncompliant bonds per visual inspection criteria and can directly impact the reliability of the finished product. Bond pad inspection prior to bonding is also a critical aspect that is often overlooked. Historically, MIL-STD-883 has served as a baseline set of visual specs related to wirebond, and package assembly in general. Many company quality documents reference MIL-STD-883 TM 2017 and TM 2010 and/or cut and paste the bond inspection criteria into internal documents. This paper critically reviews the wirebond visual inspection criteria contained in MIL-STD-883 relative to the requirements of a fully optimized modern day wirebond process.
Role of99mTc-(V)DMSA in Detecting Tumor Cell Proliferation
Authors: Al-Saeedi Fatma
Published: November 2017

Pentavalent technetium-99m dimercaptosuccinic acid (99mTc-(V)DMSA) is a tumor-seeking agent which was introduced to evaluate, image, and manage many types of cancers. In this review, the beginning of, and the most recent applications of using this agent was appraised. The relation with tumor cell detection and proliferation was reported and several mechanisms of uptake of99mTc-(V)DMSA in tumor cells are described.
Determination of the Labile Iron Pool of Human Lymphocytes using the Fluorescent Probe, CP655
Authors: Ma Yongmin , Liu Zudong , Hider Robert C , Petrat Frank
Published: November 2017

The present study introduces a method for determining the labile iron pool (LIP) in human lymphocytes. It is measured using the probe CP655, the fluorescence of which is stoichiometrically quenched by the addition of iron. The intracellular CP655 fluorescence in lymphocytes was quenched by increasing intracellular iron concentrations using the highly lipophilic 8-hydroxyquinoline iron complex. Intracellular fluorescence quenching, mediated by the physiological intracellular labile iron, can be recovered on the addition of excess membrane-permeable iron chelator, CP94. The intracellular probe concentration was measured using laser scanning microscopy. An ex situ calibration was performed in a “cytosolic” medium based on the determined intracellular CP655 concentration and probe fluorescence quenching in the presence of iron. The concentration of the LIP of healthy human lymphocytes was determined to be 0.57 ± 0.27 μM. The use of the fluorescent probe CP655 renders it possible to record the time course of iron uptake and iron chelation by CP94 in single intact lymphocytes.
NS-187 (INNO-406), a Bcr-Abl/Lyn Dual Tyrosine Kinase Inhibitor
Authors: Niwa Tomoko , Asaki Tetsuo , Kimura Shinya
Published: November 2017

Protein kinases catalyze the transfer of the γ-phosphoryl group of adenosine triphosphate (ATP) to the hydroxyl groups of protein side chains, and they play critical roles in regulating cellular signal transduction and other biochemical processes. They are attractive targets for today's drug discovery and development, and many pharmaceutical companies are intensively developing various kinds of protein kinase inhibitors. A good example is the recent success with the Bcr-Abl tyrosine kinase inhibitor imatinib mesylate (Gleevec™) in the treatment of chronic myeloid leukemia. Though imatinib has dramatically improved the treatment of Bcr-Abl-positive chronic myeloid leukemia, resistance is often found in patients with advanced-stage disease. Several mechanisms have been proposed to explain this resistance, including point mutations within the Abl kinase domain, amplification of the bcr-abl gene, overexpression of the corresponding mRNA, increased drug efflux mediated by P-glycoprotein, and activation of the Src-family kinase (SFK) Lyn. We set out to develop a novel drug whose affinity for Abl is higher than that of imatinib and whose specificity in inhibiting Lyn is higher than that of SFK/Abl inhibitors such as dasatinib (Sprycel™) or bosutinib (SKI-606). Our work has led to the development of NS-187 (INNO-406), a novel Abl/Lyn dual tyrosine kinase inhibitor with clinical prospects. To provide an overview of how a selective kinase inhibitor has been developed, this review presents chemical-modification studies carried out with the guidance of molecular modeling, the structural basis for the high potency and selectivity of NS-187 based on the X-ray structure of the NS-187/Abl complex, and the biological profiling of NS-187, including site-directed mutagenesis experiments.
Identification of Cysteine Proteases and Screening of Cysteine Protease Inhibitors in Biological Samples by a Two-Dimensional Gel System of Zymography and Reverse Zymography
Authors: Saitoh Eiichi , Yamamoto Shinya , Okamoto Eishiro , Hayakawa Yoshimi , Hoshino Takashi , Sato Ritsuko , Isemura Satoko , Ohtsubo Sadami , Taniguchi Masayuki
Published: November 2017

We have developed a two-dimensional (2D-) gel system of zymography and reverse zymography for the detection and characterization of proteases and protease inhibitors. Isoelectric focusing (IEF) agarose gels with pH gradients were employed for separation in the first-dimension and sodium dodecyl sulfate (SDS)-polyacrylamide gel copolymerized with gelatin used for the second dimension. Proteases and protease inhibitors separated by IEF gel were applied on the second gel without trichloroacetic acid (TCA) fixation. Protease activity in the 2D-gel was visualized as transparent spots where gelatin substrate was digested after commassie brilliant blue (CBB) staining. Some of the transparent spots from the skin mucus extract of rainbow trout were determined to be a cysteine protease through use of E-64 or CA-074. In the reverse zymography technique, the gel was incubated with papain solution at 37°C for 18 h. Cysteine protease inhibitors from broad bean seeds were detected as clear blue spots after CBB staining. The amino (N-) terminal sequences of four papain inhibitor spots thus detected were demonstrated to be identical to that of favin β chain, a broad bean lectin. Taken together, our system can be considered to be an efficient technique for discovering and characterizing new proteases and protease inhibitors in biological samples. This is the first report describing a 2D-gel system of zymography and reverse zymography.
Vibratory Reaction Unit for the Rapid Analysis of Proteins and Glycochains
Authors: Sasakura Yukie , Nogami Makoto , Kobayashi Noriko , Kanda Katsuhiro
Published: November 2017

A protein digestion system using immobilized enzymes for protein identification and glycochain analyses has been developed, and a vibration reaction unit for micro-scale sample convection on an enzyme-immobilized solid surface was constructed. BSA as a model substrate was digested by this unit, and was successfully identified by mass spectrometry (MS) analyses. Compared to the conventional liquid-phase digestion, the reaction unit increased the number of matched peptides from 9 to 26, protein score from 455 to 1247, and sequence coverage from 21% to 48%. Glycopeptidase F (NGF), an enzyme that cleaves N-glycans from glycoproteins, was also immobilized and used to remove the glycochains from human immunoglobulin G (IgG). Trypsin and NGF were immobilized on the same solid surface and used to remove glycochains from IgG in single-step. Glycochains were labeled with fluorescent reagent and analyzed by HPLC. Several peaks corresponding to the glycochains of IgG were detected. These results suggested that the single-step digestion system, by immobilized multiple enzymes (trypsin and NGF) would be effective for the rapid structural analysis of glycoproteins.
Solid-Phase Extraction and Reverse-Phase HPLC: Application to Study the Urinary Excretion Pattern of Benzophenone-3 and its Metabolite 2,4-Dihydroxybenzophenone in Human Urine
Authors: Gonzalez Helena , Jacobson Carl-Eric , Wennberg Ann-Marie , Larkö Olle , Farbrot Anne
Published: November 2017

Background

Benzophenone-3 (BZ-3) is a common ultraviolet (UV) absorbing compound in sunscreens. It is the most bioavailable species of all UV-absorbing compounds after topical application and can be found in plasma and urine.

Objectives

The aim of this study was to develop a reverse-phase high performance liquid chromatography (HPLC) method for determining the amounts BZ-3 and its metabolite 2,4-dihydroxybenzophenone (DHB) in human urine. The method had to be suitable for handling a large number of samples. It also had to be rapid and simple, but still sensitive, accurate and reproducible. The assay was applied to study the urinary excretion pattern after repeated whole-body applications of a commercial sunscreen, containing 4% BZ-3, to 25 healthy volunteers.

Methods

Each sample was analyzed with regard to both conjugated/non-conjugated BZ-3 and conjugated/non-conjugated DHB, since both BZ-3 and DHB are extensively conjugated in the body. Solid-phase extraction (SPE) with C8 columns was followed by reverse-phase HPLC. For separation a Genesis C18 column was used with an acethonitrile-water mobile phase and the UV-detector was set at 287 nm.

Results

The assay was linear r 2 > 0.99, with detection limits for BZ-3 and DHB of 0.01 µmol L-1 and 0.16 µmol L-1 respectively. Relative standard deviation (RSD) was less than 10% for BZ-3 and less than 13% for DHB. The excretion pattern varied among the human volunteers; we discerned different patterns among the individuals.

Conclusions

The reverse-phase HPLC assay and extraction procedures developed are suitable for use when a large number of samples need to be analyzed and the method fulfilled our objectives. The differences in excretion pattern may be due to differences in enzyme activity but further studies, especially about genetic polymorphism, need to be performed to verify this finding.
Detecting the Site of Phosphorylation in Phosphopeptides without Loss of Phosphate Group Using MALDI TOF Mass Spectrometry
Authors: Jagannadham Medicharla V. , Nagaraj Ramakrishnan
Published: November 2017

Phosphopeptides with one and four phosphate groups were characterized by MALDI mass spectrometry. The molecular ion of monophosphopeptide could be detected both as positive and negative ions by MALDI TOF with delayed extraction (DE) and in the reflector mode. The tetraphospho peptide could be detected in linear mode. When MS/MS spectra of the monophospho peptides were obtained in a MALDI TOF TOF instrument by CID, b and y ions with the intact phosphate group were observed, in addition the b and y ions without the phosphate group. Our study indicates that it is possible to detect phosphorylated peptides with out the loss of phosphate group by MALDI TOF as well as MALDI TOF TOF instruments with delayed extraction and in the reflector mode.
Understanding Structural Features of Microbial Lipases–-An Overview
Authors: Mala John Geraldine Sandana , Takeuchi Satoru
Published: November 2017

The structural elucidations of microbial lipases have been of prime interest since the 1980s. Knowledge of structural features plays an important role in designing and engineering lipases for specific purposes. Significant structural data have been presented for few microbial lipases, while, there is still a structure-deficit, that is, most lipase structures are yet to be resolved. A search for ‘lipase structure’ in the RCSB Protein Data Bank ( http://www.rcsb.org/pdb/ ) returns only 93 hits (as of September 2007) and, the NCBI database ( http://www.ncbi.nlm.nih.gov ) reports 89 lipase structures as compared to 14719 core nucleotide records. It is therefore worthwhile to consider investigations on the structural analysis of microbial lipases. This review is intended to provide a collection of resources on the instrumental, chemical and bioinformatics approaches for structure analyses. X-ray crystallography is a versatile tool for the structural biochemists and is been exploited till today. The chemical methods of recent interests include molecular modeling and combinatorial designs. Bioinformatics has surged striking interests in protein structural analysis with the advent of innumerable tools. Furthermore, a literature platform of the structural elucidations so far investigated has been presented with detailed descriptions as applicable to microbial lipases. A case study of Candida rugosa lipase (CRL) has also been discussed which highlights important structural features also common to most lipases. A general profile of lipase has been vividly described with an overview of lipase research reviewed in the past.
Determination of Key Intermediates in Cholesterol and Bile Acid Biosynthesis by Stable Isotope Dilution Mass Spectrometry
Authors: Yoshida Tadashi , Honda Akira , Miyazaki Hiroshi , Matsuzaki Yasushi
Published: November 2017

For more than a decade, we have developed stable isotope dilution mass spectrometry methods to quantify key intermediates in cholesterol and bile acid biosynthesis, mevalonate and oxysterols, respectively. The methods are more sensitive and reproducible than conventional radioisotope (RI), gas-chromatography (GC) or high-performance liquid chromatography (HPLC) methods, so that they are applicable not only to samples from experimental animals but also to small amounts of human specimens. In this paper, we review the development of stable isotope dilution mass spectrometry for quantifying mevalonate and oxysterols in biological materials, and demonstrate the usefulness of this technique.
Pharmacotherapy Update: Risperidone in the Treatment of Schizophrenia
Authors: Raja Michele
Published: November 2017

The paper is a review of the clinical use of risperidone, an antipsychotic introduced in the treatment of schizophrenia in 1994. Randomized controlled trials, naturalistic studies and extensive clinical experience have definitively shown strong efficacy and effectiveness of risperidone in the treatment of schizophrenia and other psychotic disorders. On the basis of available evidence, no other antipsychotic drug has shown superior clinical effectiveness in the treatment of psychotic disorders, with the significant exception of clozapine. The wide use of risperidone in the last 15 years has confirmed a favorable safety index. Some features of risperidone render it uniquely useful in the management of psychotic disorders, including a very wide range of dosage, availability in liquid and long-term injectable forms. Finally, the drug is currently available in generic form, at lower cost. However, risperidone presents major limitations. A substantial number of patients with psychotic symptoms do not respond to risperidone, whatever its dose. Most of these patients will need clozapine. For some risperidone treated patients, extrapyramidal side effects remain a serious concern. Weight gain, metabolic syndrome, and hyperprolactinemia related side effects are frequent and may be severe, unacceptable, and even dangerous in some patients.
Montelukast: Pharmacology, Safety, Tolerability and Efficacy
Authors: Benninger Michael S. , Waters Heather
Published: November 2017

Allergic rhinitis and asthma are common disorders effecting large percentages of the population of Western countries. There are multiple treatment options available for allergic rhinitis and asthma and stepwise approaches to therapy have been recommended. Montelukast is a cysteinyl leukotriene receptor antagonist that has been found to be effective both in the treatment of allergic rhinitis and asthma. This paper will describe the pharmacology, safety, efficacy and tolerability of montelukast. It will examine the comparative efficacy of montelukast to other medications for the treatment of allergic rhinitis and asthma, as well as discuss the recent studies of combination therapy.
A Review of Vinorelbine in the Treatment of Advanced Breast Cancer
Authors: Brunello A. , Roma A. , Basso U. , Jirillo A.
Published: November 2017

Vinorelbine is a semi-synthetic vinca alkaloid that has been shown active in many tumor types and is currently registered for the treatment of advanced breast cancer (ABC) and non-small cell lung cancer (NSCLC), and it is used in other cancer type such as prostate cancer, lymphomas, gynecologic malignancies. This agent has a generally favorable safety profile, and may be suitable for use in special populations such as the elderly and/or frail patient. However, with the taxanes established as standard second line treatment for ABC after failure of an anthracycline, Vinorelbine has been generally relegated for use as third line therapy, in competition with the oral compound Capecitabine. Combination regimens of Vinorelbine and Gemcitabine have been indeed widely studied, and have been demonstrated to be safe and effective. More recently, the exciting results observed with the combination of Vinorelbine and Trastuzumab in patients with Her-2 overexpressing tumors, as well as the development of a reliable formulation and revised schedule of oral Vinorelbine appear to have revived the interest in this compound in the management of this disease. Yet, data from properly designed randomized clinical trials are eagerly awaited to confirm the amount of available data which are mostly based on phase II studies.
Pharmacotherapy of Chronic Hepatitis B in Adults: Focus on Tenofovir Disoproxil Fumarate
Authors: Jain Mamta K. , Zoellner Cindy L. , Garg Kanan
Published: November 2017

Treatment for hepatitis B (HBV), a global disease affecting over 400 million persons, has changed over the past 15 years. Many of the current treatments are oral therapies which suppress HBV viral load and improve liver-related outcomes. However, differences exist in the currently available therapies both in terms of potency and resistance. The newest HBV nucleotide to be approved for the treatment of hepatitis B is tenofovir disoproxil fumarate that when phosphorylated to its active form leads to DNA chain termination. Tenofovir is active against human immunodeficiency virus (HIV) and was approved for its treatment in 2001. It is also active against HBV and was approved for its treatment in 2008. Tenofovir has emerged as an effective and potent therapy against lamivudine resistant strains as well as wild type HBV. Tenofovir resistance to HBV is rare. Long-term use of tenofovir has been associated with renal and bone marrow toxicity in some HIV-infected patients. To date, this is the only oral therapy which is both potent and does not lead to viral resistance in both treatment naïve and experienced patients. Further studies in HBV mono-infected persons are needed to evaluate long-term impact of tenofovir use.
Pharmacotherapy of Fibromyalgia: Focus on Duloxetine
Authors: Serra Eric , Andrejak Michel
Published: November 2017

Context

Fibromyalgia syndrome (FMS) is a frequent medical condition characterized by chronic widespread pain and reduced pain threshold. Associated symptoms include fatigue, non restorative sleep, and psychological distress. As usual in medicine, even if the pathogenesis is unclear, some treatments are useful to help patients.

Objectives

Tricyclic antidepressants were the first drugs used to treat FMS. More recently, among serotonin-norepinephrine reuptake inhibitors, duloxetine was approved by US Food and Drug Administration to treat FMS. Duloxetine is used for the management of major depressive disorder, neuropathic pain, generalized anxiety disorder, and stress incontinence. In the pharmacotherapy of fibromyalgia, a focus is presented on the drug duloxetine.

Results

Mechanism of action, metabolism and pharmacokinetic profile are presented. Clinical studies of Duloxetine showed an acceptable efficacy for this chronic condition: Number Need to Treat (NTT) of 4.7 to 9.9, through two 3-month placebo-controlled trials and two 6-month trials. Evaluation criteria are discussed. Safety of this medication has been found to be satisfactory, with nausea as the most common adverse event, in almost 20% of cases.

Conclusion

Treatment algorithm for duloxetine is presented inside FMS treatment strategy. With duloxetine, it is important to start low and increase slowly to prevent or minimize adverse events: 30 mg/day up to 60 mg/day in the second week and if necessary up to 90-120 mg/day. It is possible to treat for 3 to 6 months, possibly up to 12 months. The drug could be decreased 2 to 4 weeks before stopping, with regular assessments during this time. International recommendations insist on multimodal treatments: drug and non drug. Also effective for anxiety and depression, duloxetine ranks among the first place drugs for FMS.
Pharmacotherapy of Major Depressive Disorder: Focus on Duloxetine
Authors: Muneoka Katsumasa
Published: November 2017

The serotonin-noradrenaline reuptake inhibitor duloxetine is a second-generation antidepressant for the treatment of major depressive disorder (MDD). Its inhibitory potency for serotonin (5-HT) and noradrenaline (NA) reuptake has been demonstrated in animal and in vitro studies. Human studies of peripheral markers of neurotransmission show inhibition of 5-HT reuptake by duloxetine and also support its potency in NA reuptake inhibition. Moreover, a positron emission tomography study in human brains shows that therapeutic doses of duloxetine result in >80% occupancy of 5-HT transporters. Duloxetine is metabolized by hepatic enzymes and cytochromes P450 CYP2D6 and CYP1A2, and plasma duloxetine concentrations increase linearly according to oral dose. In double-blind, randomized, placebo-control studies of MDD, duloxetine-treated patients show significantly increased response and remission rates and significantly longer time to relapse compared to placebo-treated patients. Moreover, duloxetine is efficacious for the treatment of generalized anxiety disorder (GAD) and pain-related diseases such as diabetic peripheral neuropathic pain (DPNP). A daily dose of 60 mg daily seems most effective for treating MDD, GAD and DPNP. Duloxetine is similar in efficacy to fluoxetine, paroxetine and escitalopram for MDD, although escitalopram is better for improving sleep. The most common treatment-emergent side effects of duloxetine are nausea, dry mouth, fatigue and decreased appetite. Studies suggest an association with the incidence of increased sweating or somnolence at higher doses and an association with irritability or anxiety at high plasma levels of duloxetine. Discontinuation rates due to adverse events are higher in patients who receive duloxetine versus placebo in short-term but not long-term studies. Interestingly, there is not a strong correlation between clinical efficacy and plasma levels of duloxetine. Therefore, although duloxetine is safe and tolerated at therapeutic doses of 60-120 mg/day, the dose should be adjusted while the patient is carefully monitored for efficacy and adverse events.
Pharmacotherapy of Oral Mucositis with Palifermin
Authors: Rzepecki Piotr , Oborska Sylwia , Wasko-Grabowska Anna , Mlot Beata , Barzal Justyna
Published: November 2017

Oral mucositis (OM) is one of the most debilitating and common side effects of intensive anti-cancer treatment. OM is associated with adverse clinical and economic outcomes. In addition to its symptomatic impact, OM increases the likelihood of unplanned breaks or delays in anti-cancer treatment, reduction in dose of chemotherapy, use of feeding tube placement or total parenteral nutrition, the need for an intravenous line, opioid use and hospitalization. Palifermin is a N-truncated recombinant human keratinocyte growth factor (KGF), a member of the fibroblast growth factor (FGF) family, which binds specifically to the human KGF receptor and induces proliferation and differentiation of epithelial cells, including gastrointestinal epithelial cells, hepatocytes, type II pneumocytes, and transitional urothelial cells. It is the first agent approved by the U.S Food and Drug Administration and other regulatory authorities around the world for use in the prevention of oral mucositis caused by high-dose chemotherapy and stem cell transplantation. The following review aims to cover the recent peer-reviewed literature pertaining to the role of palifermin in the prevention of OM in different groups of patients treated with radiation therapy or chemotherapy against cancers.
Pharmacotherapy of Insomnia: Focus on Zolpidem Extended Release
Authors: Monti J.M. , Spence D. Warren , Pandi-Perumal S.R. , Langer Salomon Z. , Hardeland R.
Published: November 2017

The imidazopyridine drug zolpidem ( N,N,6-trimethyl-2[4-methyl-phenyl]imidazo[1,2-a]pyridine-3-acetamide) is a sedative/hypnotic with relative selectivity for α1 subunits of the GABAA receptor/chloride channel complex. Because of this selectivity and regional receptor distribution, zolpidem is less generalized in its CNS depressive actions than benzodiazepines and largely devoid of their major, undesired side- and after-effects, at recommended doses. Zolpidem is rapidly taken up and distributed, binds extensively to plasma proteins, and is readily inactivated by hepatic cytochrome P450 monooxygenases, especially CYP3A4. Zolpidem is thus a rapidly acting agent which provides effective facilitation of sleep onset. However, plasma levels of the immediate release (IR) formulation frequently decline too quickly for effective sleep maintenance. To address this problem zolpidem extended release (ER) has been developed. At age-specific dosages, it increases, in middle-aged and elderly patients, total sleep time and reduces the number of nocturnal awakenings. Both zolpidem IR and ER have favorable toxicological profiles. Adverse effects are moderate, frequently in the incidence range of placebos, and certainly less frequent and severe than those of benzodiazepines. Zolpidem IR and ER are practically devoid of next-day hangover effects and only infrequently cause rebound insomnia of usually short duration. Both variants of zolpidem have a limited potential for dependence and abuse.
Treatment Options in Smoking Cessation: What Place for Bupropion Sustained-Release?
Authors: McCarthy Danielle E , Jorenby Douglas E , Minami Haruka , Yeh Vivian
Published: November 2017

Bupropion SR is approved for the treatment of tobacco dependence in adult smokers. Bupropion SR is an atypical antidepressant that has been shown to double the likelihood of quitting smoking (to roughly 19%-24% six months into a quit attempt), perhaps by acting on dopaminergic and noradrenergic systems and by acting as an antagonist of nicotine acetylcholine receptors. Head-to-head comparisons of bupropion SR and other stop-smoking treatments suggest that bupropion SR is as or more efficacious than nicotine replacement therapies, equally efficacious as nortriptyline, and less efficacious than varenicline. The evidence available regarding the effectiveness of bupropion SR in real-world settings suggests that abstinence rates are similar to those seen in controlled clinical trials. Bupropion SR appears to be safe and efficacious for both men and women and for people with comorbid medical or mental health conditions. Evidence collected to date supports the use of bupropion SR as a safe, tolerable pharmacotherapy for smoking cessation among adult smokers without a predisposition to seizures, but also suggests that benefits in terms of abstinence last only as long as treatment continues. This review focuses on recent evidence regarding bupropion SR effects and highlights important questions regarding the duration of effects, relative efficacy, effectiveness in clinical use, mechanisms of action, and utilization of bupropion SR that remain unanswered.
Pharmacotherapy of Restless Legs Syndrome with Pramipexole
Authors: Manconi Mauro , Ferini-Strambi Luigi
Published: November 2017

The dopamine agonist pramipexole (PRA) ((S)-2-Amino-4,5,6,7-tetrahydro-6-(propylamino) benzothiazole dihydrochloride; molecular formula C10H17N3S-2(HCl), is a D3 selective compound, approved in 1997 for the treatment of Parkinson disease and in 2006 for that of idiopathic restless legs syndrome (RLS). Because of its tolerability, safety and half-life, PRA is favored over levodopa and on the other ergot derivate dopamine agonists, and it is considered nowadays one of the first choices in the therapy of RLS. PRA is rapidly and completely absorbed after oral administration, its protein binding is around 15%, it is almost unaffected by hepatic metabolism and excreted by urine unchanged. PRA has a linear pharmacokinetics, with a half-life ranging between 8 and 14 hours. Double-blind, placebo-controlled studies demonstrated that PRA, even at low dosages and since the first nights of administration, is significantly effective on the typical sensitive symptoms of RLS, on the periodic leg movements during sleep, and in improving the quality of life of patients with RLS. A subjective improvement of sleep quality is usually also reported by the patients, but the polysomnographic assessment gave less solid results on objective sleep parameters. The most common PRA related side effects include headache, nausea and orthostatic hypotension. Data on the long-term therapy of PRA in RLS, and on the efficacy of PRA in symptomatic forms of RLS are warranted to better delineate the role of PRA in RLS treatment.
Ciclesonide in the Management of Asthma
Authors: Gonzalez Daniel , Derendorf Hartmut
Published: November 2017

Ciclesonide is a novel inhaled corticosteroid (ICSs) approved in most countries for the management of persistent asthma. Although inhaled corticosteroids are first-line therapy in the treatment of asthma, long term use and high-doses of these products may result in significant side effects. When developing a new ICSs, the goal is to identify a drug with comparable (or superior) efficacy to active comparators, and an improved safety profile. Ciclesonide is a prodrug which is administered through a hydrofluoroalkane-propellant metered dose inhaler (HFA-MDI). Once it reaches the lungs, the parent compound is metabolized by esterases to desisobutyryl ciclesonide (des-CIC), an active metabolite with a 100-fold greater affinity for the glucocorticoid receptor. Ciclesonide has a unique pharmacokinetic-pharmacodynamic profile which confers an improved therapeutic ratio. Several clinical trials have shown that its efficacy is superior to placebo and similar to several active comparators. However, its high pulmonary deposition and on-site activation minimizes the risk for local side effects. Also, its low oral bioavailability, high hepatic clearance, and extensive plasma protein binding, among other factors, decrease the risk for systemic side effects. Doses of ciclesonide as high as 1280 μg/day (ex-actuator) result in minimal hypothalamic-pituitary-adrenal (HPA) axis suppression, a measure commonly used to assess systemic bioavailability for an ICSs. This review will provide a summary of ciclesonide's role in the management of asthma, including a discussion of relevant clinical trials designed to evaluate its efficacy and safety.
Management Options in Chronic Stable Angina Pectoris: Focus on Ranolazine
Authors: Vadnais David S. , Wenger Nanette K.
Published: November 2017

Chronic stable angina pectoris results from a fixed coronary arterial obstruction causing an imbalance between myocardial oxygen supply and demand. Current therapy aims to reduce cardiovascular events (vasculoprotective) thereby improving survival, and/or relieve ischemic symptoms (antianginal) thereby improving the quality of life. Vasculoprotective therapy consists of lifestyle modification, antiplatelet agents, lipid lowering therapy and angiotensin-converting enzyme (ACE) inhibitors. Conventional antianginal therapy for patients with chronic stable angina consists of beta-blockers, calcium channel blockers and nitrates, with surgical or percutaneous revascularization serving an adjunctive role. Despite the investigation of multiple novel therapies and medications over the past 25 years, arguably the most significant contribution to antianginal therapy during that time involved the recent introduction of ranolazine. Ranolazine acts via a distinctive pathway, inhibiting the late sodium current of the action potential in ischemic myocytes. Multiple studies have demonstrated that ranolazine significantly reduces anginal symptoms and improves exercise performance in patients with chronic stable angina but does not reduce mortality. Ranolazine does not affect either heart rate or blood pressure, a unique property among the current antianginal agents. Despite its QT prolongation, ranolazine has a proven safety profile and is not proarrhythmic. In fact, in a recent large randomized trial, ranolazine reduced the incidence of supraventricular tachycardia, ventricular tachycardia, new-onset atrial fibrillation and bradycardic events. Ranolazine may confer some additional benefits such as a reduction in HbA1c levels and improved left ventricular diastolic function. Ranolazine is now approved for use in chronic stable angina. Current guidelines recommend beta-blockers as the first line antianginal agent due to the proven mortality reduction. However, for patients with bradycardia or hypotension, ranolazine may be considered as initial antianginal therapy.
A Review of Enteric-coated Mycophenolate Sodium for Renal Transplant Immunosuppression
Authors: Newbold Nathan , Riley Brianna , Hardinger Karen
Published: November 2017

Mycophenolic acid inhibits an enzyme, inosine monophosphate dehydrogenase (IMPDH), blocking purine synthesis of lymphocytes and therefore functioning as an effective immunosuppressive agent in transplantation. Currently, there are two available forms of mycophenolic acid (MPA) available; mycophenolate mofetil (MMF) and enteric-coated, delayed-release mycophenolate sodium (EC-MPS). Both products are approved for prophylaxis of organ rejection in renal transplant recipients. The use of MPA may be associated with adverse gastrointestinal effects which can lead to a reduction of the dose or discontinuation of therapy. Enteric-coated MPS was developed to reduce the upper gastrointestinal side effects due to its delayed release in the small intestines. Similar systemic MPA exposure is provided by oral administration of MMF 1000 mg daily and EC-MPS 720 mg, which contain near equimolar MPA content. Clinical trials in renal transplant recipients have demonstrated that EC-MPS is therapeutically equivalent to MMF when used at the time of transplantation and when used for conversion for gastrointestinal complications. The available literature regarding the incidence and severity of gastrointestinal adverse effects and the impact on quality of life remains controversial. Prospective, randomized trials of the available MPA formulations are warranted to further explore the gastrointestinal adverse effect profiles.
Exudative Age-Related Macular Degeneration: Current Therapies and Potential Treatments
Authors: Quiram Polly A. , Song Yahui
Published: November 2017

Strategies for preventing vision loss in patients with neovascular age-related macular degeneration (ARMD) have evolved over the past decade. Whereas earlier treatments were based on thermal destruction of choroidal neovascularization (CNV), new therapies rely on targeted pharmacologic approaches to reduce the harmful effects of CNV treatment. For the first time in the history of neovascular ARMD treatment, anti-VEGF therapies have consistently improved visual acuity in a subset of patients. Clinical trials continue to investigate the optimal dosing strategies and combination therapies to better refine the treatment of this chronic and debilitating disease.
Management of Multiple Myeloma and Myelodysplastic Syndrome: Focus on Lenalidomide
Authors: Volk Christine , Klein Ulrike
Published: November 2017

Lenalidomide belongs to a group of immunomodulatory drugs (IMiDs), first known with the discovery of thalidomide in the 1950s, and which have then be tested in various malignancies for their clinical potential. It is described that these IMiDs exhibit multiple biologic effects on cytokine and cell-mediated responses. Lenalidomide was developed by chemical modification of thalidomide to enhance the immunomodulatory potency but minimize the dose-limiting neurotoxic effects. This drug seems to have a positive clinical impact on hematologic malignancies including myelodysplastic syndrome, multiple myeloma, and chronic lymphocytic leukemia. Different potential mechanisms are discussed for lenalidomide, including inhibition of angiogenesis, blockade of various cytokines and enhancement of immune system function. Even with strong improvement of the outcome of multiple myeloma, still most patients relapse and, therefore, drugs with new mechanisms of action are urgently needed to overcome this resistance. As for myelodysplastic syndromes, a heterogeneous collection of hematopoietic disorders characterized by cytopenia, treatment options also have increased over the past 10 years, but still supportive care, cell-stimulating agents and chemotherapy with little impact on long-term outcome are offered to patients.

In this review, we discuss the impact of lenalidomide on relapsed myeloma and transfusion dependent MDS as a novel strategy under assessment in preclinical and clinical trials. It was shown that Lenalidomide had clinical potential in both entities and its effectiveness might be enhanced by the rational combination with conventional agents.
Efficacy and safety of fixed-dose Lercanidipine-Enalapril for the treatment of hypertension
Authors: Chatzikyrkou Christos , Haller Hermann , Menne Jan
Published: November 2017

Hypertension is the most important preventable cause of premature death in the developed countries, and the benefits of antihypertensive drugs regarding cardiovascular morbidity and mortality are well established. Nevertheless, adequate control is achieved only in the minority of patients. All official guidelines recommend blood pressure targets of 140/90 mmHg in every patient and even lower in high-risk groups, and support the use of two of more drugs as initial therapy in specific populations. Multiple drugs acting by different, but complementary, mechanisms of action are increasingly implemented in the treatment of hypertension and fixed-dose combinations are gaining popularity. Simplifying therapy is particularly important for elderly patients, who are more likely to have co-morbid conditions and to be taking multiple medications. The once-daily administration of a fixed dose enalapril/lercanidipine effectively reduces blood pressure in patients inadequately controlled by either component, is generally well tolerated and exhibits a favourable metabolic profile.
Tigecycline in the Treatment of Community-Acquired Pneumonia
Authors: Curcio Daniel
Published: November 2017

Tigecycline is a first-in-class glycylcycline, broad-spectrum, intravenous antibacterial developed to overcome the two major mechanisms of tetracycline resistance (ribosomal protection and efflux). The drug has been approved in US for community-acquired bacterial pneumonia in adults. In vitro, tigecycline had good activity against a range of Gram-positive, Gram-negative and atypical community-acquired respiratory tract pathogens implicated in community-acquired pneumonia (CAP), including community-acquired Staphylococcus aureus, penicillin-resistant Streptococus pneumoniae and multidrug-resistant Enterobacteriaceae. Nonetheless, tigecycline shows in vitro low activity against against P. aeruginosa. Tigecycline provides high intrapulmonary concentrations that exceed the MIC90 of most of these respiratory pathogens. The combined results of two well designed, phase III studies demonstrated that tigecycline 100 mg initially, followed by 50 mg every 12 hours for 7-14 days was not inferior to recommended dosages of levofloxacin in the treatment of hospitalized patients with CAP. Clinical cure rates were 89.7% versus 86.3% in the clinically evaluable population and 81.0% versus 79.7% in the clinical modified intent-to-treat population. Tigecycline represents an appropriate choice for empirical monotherapy in the treatment of CAP, mainly in patients with risk factors for infections due to resistant bacteria.
Pharmacotherapy of HIV-1 Infection: Focus on CCR5 Antagonist Maraviroc
Authors: Latinovic Olga , Kuruppu Janaki , Davis Charles , Le Nhut , Heredia Alonso
Published: November 2017

Sustained inhibition of HIV-1, the goal of antiretroviral therapy, is often impeded by the emergence of viral drug resistance. For patients infected with HIV-1 resistant to conventional drugs from the viral reverse transcriptase and protease inhibitor classes, the recently approved entry and integration inhibitors effectively suppress HIV-1 and offer additional therapeutic options. Entry inhibitors are particularly attractive because, unlike conventional antiretrovirals, they target HIV-1 extracellularly, thereby sparing cells from both viral- and drug-induced toxicities. The fusion inhibitor enfuvirtide and the CCR5 antagonist maraviroc are the first entry inhibitors licensed for patients with drug-resistant HIV-1, with maraviroc restricted to those infected with CCR5-tropic HIV-1 (R5 HIV-1) only. Vicriviroc (another CCR5 antagonist) is in Phase III clinical trials, whereas the CCR5 antibodies PRO 140 and HGS 004 are in early stages of clinical development. Potent antiviral synergy between maraviroc and CCR5 antibodies, coupled with distinct patterns of resistance, suggest their combinations might be particularly effective in patients. In addition, given that oral administration of maraviroc achieves high drug levels in cervicovaginal fluid, combinations of maraviroc and other CCR5 inhibitors could be effective in preventing HIV-1 transmission. Moreover, since CCR5 antagonists prevent rejection of transplanted organs, maraviroc could both suppress HIV-1 and prolong organ survival for the growing number of HIV-1 patients with kidney or liver failure necessitating organ transplantation. Thus, maraviroc offers an important treatment option for patients with drug-resistant R5 HIV-1, who presently account for >50% of drug-resistance cases.
A Review of Pramlintide in the Management of Diabetes
Authors: Messer Caroline , Green Dina
Published: November 2017

Tight glycemic control in type 1 and type 2 diabetes reduces the risk for microvascular complications, including retinopathy, nephropathy, and neuropathy. Yet, despite intensive insulin regimens, many insulin-dependent patients are unable to achieve euglycemic states. This review will focus on pramlintide, an equipotent amylin analog, and its role in the management of diabetes. Pramlintide lowers glucose through the same mechanisms as amylin: it slows gastric emptying, suppresses the postprandial rise of glucagon in patients with diabetes, and promotes satiety. Long-term clinical trials have shown that the use of pramlintide as an adjunct to insulin minimizes postprandial glucose excursions and reduces both HbA1C and body weight when compared to placebo. Although its effects on HbA1C are modest, pramlintide has gained popularity as a result of its relatively few contraindications, limited side effects, minimal risk for hypoglycemia, and potential for weight loss. The combination of insulin and pramlintide may provide an effective means for patients with diabetes to meet their HbA1C goals.
Fospropofol Disodium Injection: A Review of its Use as a Sedative-hypnotic Agent for Monitored Anesthesia Care (MAC) Sedation in Adult Patients Undergoing Diagnostic or Therapeutic Procedures
Authors: Harris Eric A. , Lubarsky David A. , Candiotti Keith A.
Published: November 2017

Fospropofol, a phosphorylated prodrug version of the popular induction agent propofol, is hydrolyzed in vivo to release active propofol, formaldehyde, and phosphate. Pharmacodynamic studies show fospropofol provides clinically useful sedation and EEG/BIS suppression while causing significantly less respiratory depression than propofol. Pain at the injection site, a common complaint with propofol, was not reported with fospropofol; the major patient complaint was transitory perianal itching during the drug's administration. Although many clinicians believe fospropofol can safely be given by a registered nurse, the FDA mandated that fospropofol, like propofol, must be used only in the presence of a trained anesthesia provider.
Pharmacotherapy Update: Fludarabine in the Treatment of Non-Hodgkin's Lymphoma
Authors: Shvidel Lev , Cohn Mirel , Sigler Erica
Published: November 2017

Fludarabine, a purine nucleoside analogue, is considered as the most active drug in chronic lymphocytic leukemia. This review summarizes current knowledge concerning the mechanism of action, pharmacological properties, clinical activity and toxicity of fludarabine in the treatment of non-Hodgkin's lymphoma. A literature search on fludarabine for lymphomas was undertaken using MEDLINE databases. Clinical data shows that fludarabine alone and as a component of combination chemotherapy is effective in patients with various types of non-Hodgkin's lymphoma, particularly in follicular lymphoma. The most commonly used combinations are with cyclophosphamide and/or mitoxantrone. Fludarabine-based regimens are highly active in both previously untreated and relapsed indolent lymphomas. The results of the chemotherapy are considerably improved with the addition of rituximab. Fludarabine is generally well tolerated. Myelosuppression and infections, including opportunistic varieties, are the most frequent adverse effects. Indications for fludarabine and treatment regimens for lymphoma patients are discussed.
Single Sevikar®: Combination Therapy for the Treatment of Hypertension
Authors: Pimenta Eduardo
Published: November 2017

Hypertension is one of the most important modifiable risk factor for cardiovascular morbidity and mortality and is highly prevalent. Recent guidelines and advisory statements have recommended lower thresholds and goals for patients with hypertension. However, approximately two-thirds of hypertensive patients do not achieve the goals. Poor adherence to anti-hypertensive medication regimens is a common cause of the practice-outcome gap. Monotherapy is also associated with difficulty to control blood pressure (BP) as most of hypertensive patients require 2 or more antihypertensive agents to effectively reduce BP. Therefore, current guidelines have recommended the use of combination therapy early in the management of hypertension or as first-line treatment. Fixed-dose combinations offer many advantages, such as convenience of use and fewer adverse events. Blockage of two or more BP regulatory systems also provides a more effective and physiologic BP reduction. Similar to other combinations, fixed-dose combination tablets containing dihydropyridine calcium channel blockers and angiotensin receptor blockers bring together two distinct and complementary mechanisms of action.