bluuebunny/crossref_metadata_2025_split huggingface dataset:
Supervised versus Uncontrolled Rehabilitation of Patients after Rotator Cuff Repair-Clinical and Neurophysiological Comparative Study
Authors: Lisiński Przemysław , Huber Juliusz , Wilkosz Piotr , Witkowska Alicja , Wytrążek Marcin , Samborski Wlodzimierz , Zagłoba Aleksandra 
Published: February 2012

Purpose The purpose of this study was the evaluation of the effectiveness of supervised rehabilitation in comparison to uncontrolled exercise therapy after surgical reconstruction of rotator cuff interrupted tendons. Methods Twenty two patients with comparable level of disability after the same type of surgery were randomly divided into two equal groups. The first group took part in a supervised therapy and the second one performed simple exercises without supervision. Clinical and neurophysiological examinations were performed prior to rehabilitation and after 20 and 40 days of treatment. The evaluation included the assessment of the pain level with visual analog scale, active range of motion with goniometer, activity of muscle's motor units at rest and during maximal effort with electromyography and transmission of motor fibers in brachial plexus with electroneurography (M-wave stimulation studies). Results In the group of supervised patients the active range of movement changed significantly from 26.4° to 101.5° on average for flexion with adduction while flexion with abduction improved from 21° to 95.5°. Pain sensation changed from 6.4 to 3.2. The mean resting electromyogram amplitude decreased to the greatest degree from 80.9μV to 36.8μV in trapezius muscle while maximal effort electromyogram amplitude increased in this muscle from 381.8μV to 790.9μV. The mean values of amplitudes in electroneurographical suprascapular nerve examinations increased from 536.4μV to 1691μV. No significant differences at P=0.05 were found in these parameters recorded in the patients performing uncontrolled exercises. Conclusion The supervised exercise therapy is more effective than uncontrolled one after the rotator cuff surgical reconstruction.
Treatment of Septic Shock with Continuous HDF Using 2 PMMA Hemofilters for Enhanced Intensity
Authors: Matsumura Yosuke , Oda Shigeto , Sadahiro Tomohito , Nakamura Masataka , Hirayama Yo , Watanabe Eizo , Abe Ryuzo , Nakada Taka-aki , Tateishi Yoshihisa , Oshima Taku , Shinozaki Koichiro , Hirasawa Hiroyuki 
Published: February 2012

Purpose Cytokines play pivotal roles in the pathophysiology of severe sepsis/septic shock, and continuous hemodiafiltration using a polymethylmethacrylate membrane hemofilter (PMMA-CHDF) removes cytokines efficiently and continuously, mainly through adsorption to a hemofilter membrane. The aim of this study was to investigate the clinical efficacy of enhanced intensity PMMA-CHDF in treating refractory septic shock. Methods Seventy-two septic shock patients admitted to the intensive care unit (ICU) underwent critical care including PMMA-CHDF. We employed enhanced intensity PMMA-CHDF to improve the cytokine removal rate by increasing the hemofilter membrane area in 10 refractory septic shock patients (enhanced intensity group, EI group; 2 extracorporeal CHDF circuits using the hemofilter with a larger membrane area of 2.1 m2). Other patients undergoing conventional PMMA-CHDF and matched for severity with the EI group, comprised a matched conventional group (MC group; using a PMMA membrane hemofilter with a membrane area of 1.0 m2; n=15). The case-control comparison was performed between the 2 groups. Results Enhanced intensity PMMA-CHDF significantly increased mean arterial pressure by 23.8% in 1 hour (p=0.037), decreased the blood lactate level by 28.6% in 12 hours (p=0.006), and reduced blood IL-6 level in 24 hours (p=0.005). The ICU survival rate in the EI group was significantly better than that in the MC group (60% vs. 13.3%, p=0.028). Conclusion Enhanced intensity PMMA-CHDF may improve hemodynamics and survival rate in patients with refractory septic shock.
Degradation Effect of Diepoxide Fixation on Porcine Endogenous Retrovirus DNA in Heart Valves: Molecular Aspects
Authors: Cyganek-Niemiec Aleksandra , Strzalka-Mrozik Barbara , Pawlus-Lachecka Lucyna , Wszolek Jolanta , Adamska Jolanta , Kudrjavtseva Julia , Zhuravleva Irina , Kimsa Malgorzata , Okla Hubert , Kimsa Magdalena , Gudek Agnieszka , Mazurek Urszula 
Published: February 2012

Purpose Xenotransplantations of porcine cells, tissues, and organs involve a risk of zoonotic viral infections in recipients, including by porcine endogenous retroviruses (PERVs), which are embedded the genome of all pigs. An appropriate preparation of porcine heart valves for transplantation can prevent retroviral infection. Therefore, the present study focuses on the effect of epoxy compounds and glutaraldehyde on the PERV presence in porcine heart valves prepared for clinical use. Methods Porcine aortic heart valves were fixed with ethylene glycol diglycidyl ether (EDGE) at 5°C and 25°C as well as with glutaraldehyde (GA) for 4 weeks. Salting out was used to isolate genomic DNA from native as well as EDGE- and GA-fixed fragments of valves every week. Quantification of PERV-A, PERV-B, and PERV-C DNA was performed by real-time quantitative polymerase chain reaction (QPCR). Results All subtypes of PERVs were detected in native porcine aortic heart valves. The reduction of the PERV-A, PERV-B, and PERV-C DNA copy numbers was observed in the heart valves which were EDGE-fixed at both temperatures, and in GA-fixed ones in the following weeks. After 7 and 14 days of EDGE cross-linking, significant differences between the investigated temperatures were found for the number of PERV-A and PERV-B copies. PERV DNA was completely degraded within the first week of EDGE fixation at 25°C. Conclusions EDGE fixation induces complete PERV genetic material degradation in porcine aortic heart valves. This suggests that epoxy compounds may be alternatively used in the preparation of bioprosthetic heart valves in future.
Clean Vesical Intermittent Catheterization: Lubrication of Vesical Catheter through Lidocaine or Gentamicine?
Authors: Liotta Raimondo Fausto , Tarantino Maria Lucia 
Published: February 2012

Introduction The patients who undergo intermittent catheterization are at high risk of urinary tract infection. A prophylaxis method for this infection can be represented by the lubrication of urethral catheters with 0.1% gentamycin cream. This study compared the lubrication of urethral catheters with 0.1% gentamycin cream and 2% lidocaine jelly in relation to the quantitative results of the urine culture and incidence of symptomatic urinary tract infection and asymptomatic bacteriuria. Material and Methods Sixteen patients, divided in groups A and B, were studied. Patients in Group A were directed to lubricate the urethral catheter with 0.1% gentamicin cream, whereas in Group B with 2% lidocaine jelly. Urine cultures and urine analysis were carried out every three weeks, for four months, for a total of 5 samples. The presence or absence of bacteria or fungi, the number of colonies and the isolated types, and the leukocyturia were evaluated. Results No significant differences in the presence of significant bacteriuria, symptomatic urinary tract infection and asymptomatic bacteriuria were found between the two groups. Escherichia coli was the most common isolated bacterium in both groups. Conclusions The results of this study, in line with previous works, showed that the lubrication of urethral catheters with 0.1% gentamicin cream is not an effective alternative to reduce significant bacteriuria and prevent urinary infection in patients who undergo clean intermittent catheterization.
Anti-hyperlipidemic Activity of Carissa carandas (Auct.) Leaves Extract in Egg Yolk Induced Hyperlipidemic Rats
Authors: Sumbul S. , Ahmed S. I. 
Published: February 2012

The Purpose of this study was to examine the lipid lowering activity of aqueous: ethanol (1:1) extract of Carissa carandas in Egg yolk induced hyperlipidemic rats. A highly significant increase in the weight of group C (High cholesterol diet) rats was observed when compared with control group N (P<0.01). The extract caused a significant reduction in body weight, Cholesterol, Triglycerides, HDL and LDL in hyperlipidemic rats. Histopathological changes induced by high cholesterol diet were also significantly reduced by the extract. The activity of ethanol and water extract of C. carandas was comparable to that of atorvastatin.
Mechanisms of Cytochrome P450‐Mediated Reactions
Authors: Guengerich F. Peter 
Published: February 2012

AbstractCytochrome P450 (P450) oxidations are the most common reactions involved in the metabolism of drugs. P450 oxidations consist of two phases, oxygen activation and substrate oxidation. The latter phase has a general inherent chemistry. However, owing to rearrangements during and after oxidation, the reactions catalyze diverse processes including carbon hydroxylation, heteroatom oxygenation and dealkylation, epoxidation, and a variety of other transformations. The course of reactions is considered not to be due to inherent chemistry associated with individual P450s but due to the juxtaposition of substrates within active sites.
Cytochrome P450 Polymorphisms
Authors: Zanger Ulrich M. 
Published: February 2012

AbstractThe human genome comprises 57 putatively functional, protein‐coding cytochrome P450 (CYP) genes that are grouped according to their sequence similarity into 18 families and 44 subfamilies. Approximately one dozen CYP isozymes of families 1, 2, and 3 are mainly responsible for the metabolism of drugs and other xenobiotics. Large interindividual variability of these enzymes, to which both genetic and nongenetic factors contribute, is an important determinant of drug pharmacokinetics and drug response. This chapter summarizes the functional, clinical, and toxicological relevance of human P450 genetic polymorphism, which affects all drug‐metabolizing CYPs, but to a very different extent.
Flavin‐Containing Monooxygenase: The Role of Flavin‐Containing Monooxgenase in Lead Design and Selection
Authors: Cashman John R. 
Published: February 2012

AbstractThe flavin‐containing monooxygenase (FMO) is a drug‐metabolizing enzyme that oxygenates sulfur‐, nitrogen‐, phosphorous‐ and selenium‐containing compounds. Amines and sulfides are very prevalent in drugs and drug candidates, and FMO could play an important role in drug discovery. Generally, FMO‐mediated metabolism converts compounds to more polar, readily excreted metabolites, and this constitutes a detoxication process. However, sometimes, FMO produces electrophilic metabolites that inhibit other enzyme systems because FMO is quite recalcitrant to inhibition. Because FMO is not readily inhibited or induced, most of its functional variability is not due to environmental factors but due to genetic polymorphisms. Compared with cytochrome P450, drugs and drug candidates that are metabolized by FMO possess less potential for toxicity and adverse drug–drug interactions. Nucleophilic drugs and drug candidates are oxygenated by FMO, and some of these oxygenated metabolites can be readily retroreduced to the parent compound quite efficiently. One class of highly nucleophilic agent that is not oxygenated by FMO includes endogenous physiological nucleophiles such as glutathione or cysteine. The lack of S‐oxygenation of these physiological nucleophiles probably spares the cell from unnecessary consumption of NADPH reductive equivalents as well as from the loss of thiaphile cytoprotective agents such as glutathione. With regard to drug or drug candidate metabolism, introducing a functional group into drug candidates that are metabolized by FMO may be beneficial in drug development and might distribute the metabolism of the drug candidate over a wider set of enzymes as well as potentially provide FMO metabolites that are generally polar, nontoxic, and readily excreted. By avoiding metabolism (and bioactivation) by cytochrome P450, the prospects for increasing druglike properties and decreasing adverse drug–drug interactions of a drug candidate are likely increased. Distributing the metabolism of drugs over a wide range of metabolic processes including FMO might decrease reliance on one metabolic pathway and decrease toxicity and adverse drug–drug interactions.
UDP‐Glucuronosyltransferases: Pharmacogenetics, Functional Characterization, and Clinical Relevance
Authors: Foti Robert S. , Fisher Michael B. 
Published: February 2012

AbstractUDP‐glucuronosyltransferase (UGT)‐catalyzed conjugation reactions play an important role in the metabolism of both xenobiotics and endogenous compounds. The frequency of UGT involvement in xenobiotic drug metabolism has increased as the ability to design out other routes of metabolism (i.e., cytochrome P450) has improved. To this end, the primary goal of this chapter is to serve as a compendium for the significant amount of information surrounding UGTs that has been compiled to date. Where relevant, the chapter covers expression, regulation and polymorphisms, substrates and inhibitors, active site characterization, and finally, clinical relevance of the various UGT isoforms.
ABCDrug Transporters and Their Impact on Drug Disposition/Drug Sensitivity and Resistance
Authors: Wolf Steven J. , Lee Caroline G. 
Published: February 2012

AbstractThe “ATP‐binding cassette” superfamily of proteins comprises 49 members, each possessing evolutionarily conserved sequence motifs that lie in the proteins nucleotide (ATP) binding domain. Each member is further classified into seven subclasses (A–G). Most ABC proteins function as membrane‐bound efflux pumps, transporting various small‐molecule substrates from the cytoplasm to the extracellular space; however, there are some exceptions (ABCE and ABCF). A vast array of drugs used in the treatment of diseases such as cancer, HIV, and epilepsy are known substrates of one or more ABC transport pumps. Consequently, the impact of the ABC transport pumps on drug efficacy and resistance has been widely assessed and is explored in this chapter from various perspectives. A focus on cancer drug resistance and the influence of the key ABC proteins ABCB1, ABCC1, ABCC2, and ABCG2 is presented along with a look into the contributions of these proteins to adverse reactions. The chapter concludes with a look into the genetics of the ABC transport pumps, including the genetic regulation of these proteins. The influence of single nucleotide polymorphisms identified within theABCgenes on the efficacy of drugs is discussed in depth. Lastly, the chapter assesses disease states that arise from abnormalities in ABC genes.
Physiologically Based Pharmacokinetic (PBPK) Modeling: Usefulness and Applications
Authors: Maeng Han‐Joo , Chow Edwin C. Y. , Fan Jianghong , Pang K. Sandy 
Published: February 2012

AbstractPhysiologically based pharmacokinetic (PBPK) models are increasingly being used to describe and define more meaningful parameters that relate to physiology, anatomy, and biochemistry in the prediction of pharmacokinetic (PK) profiles and tissue concentration–time profiles of the parent drug and metabolites and to provide mechanistic insight into drug dynamics. Physiological data (blood flow rates and tissue volumes), physical data (protein binding and tissue partition coefficients), and biochemical data (Michaelis–Menten parameters for transporters and enzymes,Vmax/Km) are the information required for building a PBPK model. The whole‐body PBPK model approach is extremely useful to understand sequential metabolism, the kinetics of metabolites, and examine effects of the transporter and enzyme interplay on the blood and target organ exposures of the drug and its metabolites. The application of PBPK models allows one to make predictions of the exposure in target sites, pharmacological activity, or toxicity and the effects of age, pregnancy, disease states, and drug–drug interactions (DDIs). In this chapter, many cases for the application and usefulness of PBPK models are summarized.
ADME of Herbal Dietary Supplements
Authors: PaiBir Sheela , Rahavendran Sadayappan V. 
Published: February 2012

AbstractIn spite of modern medical advances, herbal dietary supplements continue to be widely used for health maintenance, disease prevention, and even disease treatment. The ADME mechanisms for the known herb–drug interactions involve, in most cases, inhibition or induction of hepatic and intestinal drug‐metabolizing enzymes of the cytochrome P450 family, and/or drug transporters. This chapter provides a review of the potential for herb–drug interactions based on literature reports for those herbs that are most popularly used in the United States. Relevant clinical and humanin vitrostudies that have evaluated metabolism‐based or absorption‐based mechanisms to understand the interactions between these herbs and commonly used drugs are also reviewed.
Safety Testing of Drug Metabolites: A Practical Approach for the Implementation of the
MIST
Guidance in
PKDM
Authors: Subramanian Raju , Slatter J. Greg 
Published: February 2012

Abstract
The FDA Safety Testing of Drug Metabolites Guidance and the ICH Requirements for Registration of Pharmaceuticals for Human Use (ICH M3) guidance defined threshholds for metabolite exposure in humans and preclinical species, which (ICH M3) would indicate that preclinical species were exposed adequately to quantitatively significant human metabolites. Proactive, data‐driven, best practices were developed by consensus with key development partners. Nontraditional metabolism approaches such as nonradiometric high resolution‐mass spectrometry (HR‐MS) profiling of plasma metabolites across species were developed to enable timely drug development decision making.
Proteomics in Drug Discovery and Development
Authors: Wang Mu , Witzmann Frank A. 
Published: February 2012

AbstractAided by major technological advances, the field of proteomics has become extremely active in the identification of drug targets that can guide drug development and treatment decisions and ultimately improve treatment outcomes. Proteomics has provided a means for molecular profiling that will assist in the development of tailored therapies. Although the implementation of genomic and proteomic testing in clinical practice is still in its infancy, the rapid development of new technologies and platforms provides hope for personalized medicine. This chapter describes these technologies and platforms, presenting many of their technical aspects along with examples of how they have been implemented in pharmaceutical applications.
Idiosyncratic Drug Reactions
Authors: Wojcinski Zbigniew W. , Uetrecht Jack P. 
Published: February 2012

AbstractIdiosyncratic drug reactions (IDRs) are adverse drug reactions that are not related to the known pharmacological properties of the drug occur in only a small percentage of the population and do not show any apparent dose–response relationship. The unpredictable nature of IDRs together with the often serious adverse effects encountered pose a major health concern in the development and clinical usage of pharmaceuticals. The mechanism of IDRs is not clearly understood, and although several theories have been proposed, IDRs can be generally categorized mechanistically as either immune mediated or non‐immune‐mediated. There is circumstantial evidence that suggests that most idiosyncratic reactions are hypersensitivity reactions initiated by the formation of chemically reactive metabolites that bind to proteins and induce an immune‐mediated response. Investigations in animal models have had limited success owing to the unpredictability of IDRs in animals, which is similar to the situation in humans. However, IDRs in animals do share some similar characteristics and mechanisms observed in humans supporting the need for further study of animal models.
Gas‐Phase Ion Mobility‐Mass Spectrometry (IM‐MS) and TandemIM‐MS/MSStrategies for Metabolism Studies and Metabolomics
Authors: May Jody C. , Goodwin Cody R. , McLean John A. 
Published: February 2012

AbstractThis chapter describes the current and potential impact of ion mobility‐mass spectrometry (IM‐MS) for addressing the challenges of sample complexity, dynamic range, and throughput for metabolomics experiments. The four primary ion mobility techniques are described with regard to their defining analytical figures‐of‐merit. Tandem MS methods are reviewed, and novel tandem experiments made possible from multi stage activation in IM‐MS instrumentation are discussed in light of the additional information, such experiments provide for the analysis of metabolites.
Analytical Method Development and Validation in Accordance to the Regulatory Guidelines
Authors: Unger Steve E. 
Published: February 2012

AbstractBest practices and detailed requirements to perform LCMS bioanalysis for submission to regulatory agencies are defined in this chapter. The rationale for regulations is discussed, along with recommendations on achieving compliance. Novel drug candidates, new technology, and innovative processes continue to change LCMS bioanalysis. The evolution of global regulatory guidance is also shaping bioanalysis to test assays in a more consistent and thorough manner. Common procedures are now in place for validation and sample analysis of both large and small molecules, allowing consistent review of new drug applications. Influence from GMPs is seen in incurred sample reanalysis and associated out‐of‐specification investigations in bioanalysis. The nature of regulated bioanalysis is ever changing as new methodology and guidance challenges past practices.
Role and Clinical Consequences of HumanUDP‐Glucuronosyltransferases
Authors: Dalvie Deepak K. , Loi Cho‐Ming 
Published: February 2012

AbstractUridine 5′‐diphosphate‐glucuronosyltransferases (UGT) are a family of enzymes that catalyze the conjugation of various drugs and endogenous substances. UGTs contribute to multiple important physiologic functions in the body and serve as an important detoxification pathway for certain drugs. In addition to their abundance in the liver and kidneys, UGTs are also expressed in several other organs including the GI tract. Given their importance in the disposition of drugs and their ubiquitous nature, they have the potential to influence the pharmacokinetics and biological effects of drugs. In addition to detoxification, UGTs are also responsible in metabolically activating compounds to reactive metabolites such as the acyl glucuronides that have the potential to covalently bind to macromolecules and elicit deleterious effects. As the cytochrome P450s (CYPs), UGTs are also subject to genetic polymorphisms and drug‐drug interactions (DDIs), which can impact the clinical development of drugs. This chapter presents an overview of the role and clinical consequences of metabolism of drugs by UGT.
Herb–Drug and Food–Drug Interactions
Authors: Lennard Martin S. 
Published: February 2012

AbstractMedication with plants and herbs has been practiced for thousands of years, and a substantial proportion of the world's population is thought to use herbal medicines. Herbal medicines are likely to be taken with prescribed drugs, leading to the risk of herb–drug interactions. Herbal consumption can not only diminish the therapeutic effect of drugs but also give rise to adverse reactions and toxicity. These clinical effects are caused by changes in (i) pharmacokinetics, particularly through inhibition or induction of the cytochrome P450 drug‐metabolizing enzymes, and (ii) drug receptor sensitivity. There are many instances where food itself and its constituents have been shown to influence the pharmacokinetics of and response to drugs, sometimes causing substantially diminished therapeutic effects or adverse reactions. Much of the published evidence on herb–drug and food–drug interactions is based on case reports or on pharmacokinetic data alone, and these require substantiation by studies measuring the clinical effects of drugs.