Showing posts with label High Impact Journals. Show all posts
In in vivo pharmacokinetic studies, itraconazole was found to be a potent clinically important inhibitor of CYP3A4/5 substrates, and fluconazole and voriconazole increased the blood/plasma concentrations of not only CYP3A4/5 substrates but also CYP2C9 substrates. Miconazole was a potent inhibitor of all P450s investigated in vitro, although there are few detailed studies on the clinical significance of this except for CYP2C9. For the echinocandins, no marked inhibition of P450 activities, except for some inhibition of CYP3A4/5 activity, was observed in vitro. The blood/plasma concentrations of concomitant drug metabolism reviews were not markedly affected by coadministration of echinocandins in vivo, suggesting that echinocandins do not cause clinically significant interactions with drugs that are metabolized by P450s via the inhibition of metabolism. The differential effects of these antifungal agents on P450 activities must be considered when clinicians select antifungal agents for patients also receiving other drugs.
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Epigenetic Regulation of Genes Encoding Drug-Metabolizing Enzymes and Transporters; DNA Methylation and Other Mechanisms
The most common epigenetic mechanism of mammalian genome regulation is DNA methylation, which does not change the genetic code but affects gene expression. Owing to its maintenance of the genomic sequence, DNA methylation is expected to offer an explanation for the controversial phenotypes of certain genetic polymorphisms. It has been recognized that DNA methylation plays a role in the transcriptional regulation of some PK/PD genes. In this review, we describe the impact of various epigenetic mechanisms, especially DNA methylation, on the expression (or activity) of drug metabolism enzymes and transporter genes.Allogenic hematopoietic stem cell transplantation (HSCT) is a well established but complex treatment option for malignant and non-malignant disorders in pediatric patients.
For a complete list, click on Bentham Science Publishers’ Journals Impacting Science
For a complete list, click on Bentham Science Publishers’ Journals Impacting Science
A range of rarer Chromosomal disorders copy number variants (CNVs) have been associated with schizophrenia, and both GWAS and CNV studies have provided molecular evidence of genetic overlap between schizophrenia and other disorders. There is increasing interest in phenotypes beyond diagnosis, including further clinical variables and endophenotypes. Next-generation sequencing studies are beginning, with the potential for fast, inexpensive sequencing of the whole genome in large samples, and there is an increasing focus on the functional effects of the candidate risk variants that are being identified.
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Today, we have robust testing strategies to assess the potential for local skin toxicity of chemical exposure. Such methods (e.g. the local lymph node assay for assessing skin sensitisation; skin painting carcinogenicity studies) incorporate skin metabolism of drugs implicitly in the in vivo model system used. In light of recent European legislation (i.e. 7th Amendment to the Cosmetics Directive and Registration Evaluation and Authorisation of existing Chemicals (REACH)), non-animal approaches will be required to reduce and replace animal experiments for chemical risk assessment. It is expected that new models and approaches will need to account for skin metabolism explicitly, as the mechanisms of adverse effects in the skin are deconvoluted. 3D skin models have been proposed as a tool to use in new in vitro alternative approaches. In order to be able to use 3D skin models in this context, we need to understand their metabolic competency in relation to xenobiotic biotransformation and whether functional activity is representative of that seen in human skin.
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The detailed understanding of the binding mode of these compounds to HSP90 has been significantly enhanced by X-ray crystallography of HSP90 constructs co-crystallised with various ligands. Efforts to replace the natural product inhibitors with more drug-like synthetic compounds have mushroomed over the last 4 years. The purines and the 3,4-diarylpyrazoles have proven to be the most successful and their Medicinal Chemistry is reviewed with particular emphasis on structure-based design. Protein/ligand co-crystal structures have shown that conserved water molecules in the active site are a vital part of the hydrogen-bonding network established on binding both natural product and synthetic inhibitors. Medicinal chemists have used this information to develop high affinity lead compounds. Recent research provides the platform for exciting developments in the area of HSP90 inhibition over the next few years.
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Indeed, a particular subtype of balanced rearrangement – inversions – was recently found to be far more common than had been predicted from traditional cytogenetics. Chromosomal disorders inversions alter the orientation of a specific genomic sequence and, unless involving breaks in coding or regulatory regions (and, disregarding complex trans effects, in their close vicinity), appear to be phenotypically silent. Such a surprising finding, which is difficult to reconcile with the classical interpretation of inversions as a mechanism causing subfertility (and ultimately reproductive isolation), motivated a new series of theoretical and empirical studies dedicated to understand their role in human genome evolution and to explore their possible association to complex genetic disorders. With this review, we attempt to describe the latest methodological improvements to inversions detection at a genome wide level, while exploring some of the possible implications of inversion rearrangements on the evolution of the human genome.
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This article describes the importance of heterocyclic nucleus in the development of anticancer drugs. Besides, the attempts have been made to discuss both naturally occurring and synthetic heterocyclic compounds as anticancer agents. In addition, some market selling anticancer heterocyclic compounds have been highlighted. Moreover, the attempts have been made to discuss mechanism of action and recent advances in heterocyclic compounds as anticancer agents. The current challenges and future perspectives of heterocyclic compounds have been discussed. Finally, the suggestions for synthesizing effective, selective, fast and human friendly anticancer agents are discussed in different sections at appropriate places.
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Liver phase II metabolic reactions are also reduced in CRF. On the other hand, intestinal drug disposition is affected in CRF. Increased bioavailability of several drugs has been reported in CRF, reflecting decrease in either intestinal first-pass metabolism of drugs (mediated by P-glycoprotein). Indeed, intestinal CYP450 is also down-regulated secondary to reduced gene expression, whereas, decreased intestinal P-glycoprotein activity has been described. Finally, although the kidneys play a major role in the excretion of drugs, it has the capacity to metabolize endogenous and exogenous compounds. CRF will lead to a decrease in the ability of the kidney to metabolize drugs, but the repercussions on the systemic clearance of drugs is still poorly defined, except for selected xenobiotics. In conclusion, reduced drug metabolism should be taken into account when evaluating the pharmacokinetics of drugs in patients with CRF.
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Since different drug metabolite enantiomers are formed in many metabolic pathways, the other indispensable advantage of CE over HPLC is the possibility of chiral separation without the need of special expensive columns. Recent advances in automated systems have made CE even more popular. The focus of this paper is to review recent studies and advances (mainly from 2000) of drug metabolism reviews by using CE. The review is divided into two parts: (i) principles of CE separation of drugs and their metabolites and (ii) application of CE in drug metabolism studies.
The first part introduces sample preparation, separation and detection modes involved in CE drug metabolism studies. To provide a deeper insight into the achievements, distinction between drug metabolism analysis in vivo and in vitro is made in the second part. Reported methods are discussed and summarized.
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Chemical insults, such as environmental or occupational carcinogenic agents, play a major role in the pathogenesis of many cancers. Many carcinogens exert genotoxic and cytotoxic effects via bioactivation into electrophilic species, a process catalyzed primarily by phase I drug metabolizing enzymes, typically cytochrome P450s. These reactive intermediates can induce DNA and RNA damage, and formation of protein adducts.
The reactive species are often detoxified by phase II drug metabolism enzymes , such as glutathione Stransferases (GSTs), UDP-glucuronosyl transferases (UGTs), sulfotransferase (ST) and N-acetyltransferase (NAT). Phase II enzymes classically conjugate these hydrophobic intermediates to a water-soluble group, thus masking their reactive nature, and allowing subsequent excretion. Therefore, strategies that modulate the levels of phase II enzymes by either pharmacological or nutritional means can lead to enhanced elimination of reactive species.
Agents that preferentially activate phase II over phase I enzymes can be beneficial as chemopreventives. Compounds, such as isothiocyanates and dithiolthiones have been shown to act as transcriptional activators of phase II enzymes. A consensus enhancer element, known as antioxidant response element (ARE), in the regulatory domains of many phase II genes and an ARE-binding transcription factor nuclear factor E2-related factor 2 (Nrf2) have been implicated in the action of many chemopreventive agents. In this review, we will discuss the mechanisms of regulation of phase II enzymes, including the signal transduction events elicited by chemopreventive agents. We will also summarize the data available for these agents in preclinical models of tumorigenesis. Some chemopreventive agents have progressed to various stages of clinical trials, e.g. biomarker studies in healthy volunteers or in susceptible populations. These clinical data will be reviewed. Finally, we will provide a commentary on implementation of discovery and development programs for novel chemopreventive agents that are based on rational drug design, with lead optimization towards a safe and efficacious regimen in man.
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A youthful Malaysian understudy nursing a broken jaw,
dispensed upon him amid the August 2011 mobs crosswise over Britain,
communicated distress for the individuals who loathed him amid their guise of
going to his help. His sympathy to their activities stood out as truly
newsworthy far and wide. The Prime Minister of Britain made it clear that he
had no such considerations of sympathy around the wrongdoings submitted by the
agitators. His furious political response likewise stood out as truly
newsworthy. The inquiry emerges in the matter of why this rough revolting with
its different degrees of sympathy had happened in any case? An exploratory
answer can be considered to exist identified with a recently developing
therapeutic science.
The numerical relationship between advancing human feeling
and an interminable reality must be experimentally explored through the
utilization of fractal geometrical rationale. Amid the First Kingdom of Egypt,
pictures were made portraying such geometrical rationale being utilized to connection,
empathy to a fanciful boundless in the future. Egyptian symbolic
representations record that in the Second Kingdom, taking after the breakdown
of the First Kingdom through a delayed dry season, the ideas of sympathy, kindness
and equity were melded into political law. Savants from antiquated Greece,
including Pythagoras, made a trip to Egypt to study this geometry of political
morals. That information, structured the premise of the Medical Chemistry
created by the Platonic custom of Greek logic, which was known as the Science
for Ethical Ends.
At the point when a Roman Christian crowd blazed the Great
Library of Alexandria in the fifth Century and killed its overseer, the
mathematician Hypatia, St Augustine declared her utilization of Platonic
fractal rationale to be an agnostic blasphemy and the arithmetic was condemned
as the work of the Devil. Western science got to be so debased with this drivel
that twentieth Century science got to be based upon the Einsteinian world-view,
in which a mistaken understanding of the second law of thermodynamics turned
into the head law administering the greater part of the science. This implied
that it got to be difficult to partner human advancement to unbounded fractal
rationale, in spite of the fact that researchers concurred that such rationale
did for sure stretch out to boundlessness.
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Any new medication treating a specific sickness is not
discovered and delivered overnight, the normal aggregate time for drug
discovery and clinical improvement is around 14 years as when managing any new
medication or chemicals the methodology needs to be intensive and guaranteed
that two vital perspectives are watching: How protected the medication is and
how successful it is at battling an ailment.
Viability
Creating any new medication disclosures will require top to
bottom examination of the ailment and additionally the cosmetics of our bodies
to figure out which proteins are influenced by the disease or even cause the
sickness to happen. The way that these proteins connect with each other can
regularly help achieve an understanding of the ailment and how our bodies
manage them.
When a disclosure has been made that influences or battles
the ailment then refinements will be made to securely expand the Drug Discovery viability in treating the sick. This will mean a harmony between making the
medication sufficiently forceful to treat the ailment rapidly additionally
verify it stays alright for utilization and doesn't create any symptoms.
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The drug discovery is one of the major players involved in
the development of the field of Bioinformatics. Many pharmaceutical companies
have internal teams conducting Bioinformatics research. The pharmaceutical
industry plays a major role in the world economy. The main purpose is to
produce the next major drug. Most drugs are small molecules that are designed
to bind, interact, and modulate the activity of specific biological receptors.
Drug discovery - Historical perspective
Drug Discovery began as an extension of chemistry about a
century ago. In 1865, Kekule formulate the theory of aromatic organic
molecules. Paul Ehlrich applied the selective affinity of dyes for biological
tissues to postulate the existence of Chemoreceptors. This led to birth of
Chemotherapy - a kind of drug treatment. Pharmacology developed a s a separate
stream because of the efforts of Oswald Schmiedeberg at the university of
pharmacology between 1871 and 1918. Penicillin was discovered by Alexander
Fleming in 1929. The characterization of Carboanhydrase in 1933 was followed by
the discovery of Sulphanilamide.
Drug - Definition
A drug is a molecule that interacts with a target biological
molecule in the body and trough such interaction triggers a physiological
effect.
Chemical compound as Drug
A chemical compound to qualify as a drug should have the
following characteristics:
It should beSafeEffectiveStable (both chemically and
metabolically)Deliverable (should be absorbed and should reach the site of
action)Available (by isolation or by synthesis)Novel (patentable)Areas
influencing Drug DiscoveryThere are several approaches to discover new drugs.
They vary from Molecular biology to Combinatorial Chemistry.Some of the
approaches are as follows:-
Molecular biology has profound
influence in Drug Discovery. It applies the concept of genetic information to
biochemical and chemical pathways. The protein drugs such as Recombinant
proteins and Monoclonal antibodies are called as "Biotech Drugs."
Molecular biology can also help us to understand disease processes at molecular
or genetic level and to determine optimal molecular targets for drug
intervention.
High -Throughput Screening (HTS):
In this method of drug discovery, large numbers of
hypothetical targets are incorporated into in-vitro or cell based assays and
exposed to large number of compounds representing numerous variations on a few
chemical themes.
Pharmacogenetic Technology:
Pharmacogenetics is the study of hereditary basis for
differences in a population. Pharmacogenetics makes extensive use of automated
tools for protein and gene sequencing. The DNA sequences of human genome are
not identical and vary from individual to individual.Pharmacogenetics is hence
based on identification of genetic variations (polymorphisms) that alter drug
concentrations and responses.
Conclusion
The years of scientific study in the field of pharmacology,
molecular biology and biotechnology has led to the process of development of
new drugs.Suganya Raphael is an expertise in the field of life
science. she is also working in the area of Content development, Social media
marketing, blogging and article writing.She has completed her M.Phil in Biotechnology.She is also a wife and mother.
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This is the thing that the pharmaceutical organizations make
some statin drugs from - specifically! So why not take it in its common state?
It lives well up to expectations. It lives up to expectations by restricting
the cholesterol response from going ahead. This implies that cholesterol's
generation is backed off accordingly bringing down cholesterol regularly. I
have discovered an incredible exploration article on Pubmed for Red Yeast Rice. The exploration
was carried out by the Center for Human Nutrition and is not one-sided by a
common supplement organization. Here is an alternate study about the
cholesterol-bringing down impacts of an exclusive Chinese red-yeast-rice
dietary supplement.
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People
often think of the word cancer as describing a single disease with a single
cause, like 'flu or HIV. But this is deceptive. Cancer is the name given to a variability
of specific illnesses resulting from one of our body's own cells growing out of
control.There exist more than 200 different types of cancer, each with diverse
causes and symptoms requiring different treatments.
Cancer research journal works on how cancer develops, how it is treated, and how it
is being tackled through ground-breaking research. It is only through research
that cancer is being understood and more effective ways are being discovered to
beat it. Moreover, there are various cancer research journals available which
provide extensive research content on Cancer and its treatment.
Cancer research journal is basic
research into cancer in order to identify causes and develop strategies for deterrence,
analysis, actions and cure. Cancer research ranges from epidemiology, molecular
bioscience to the presentation of clinical trials to evaluate and compare
applications of the various cancer treatments. These applications include radioactivity
therapy, chemotherapy, hormone therapy, surgery, Immunotherapy and treatment of
combined modalities such as chemo-radiotherapy. In mid-1990s, the emphasis in
clinical cancer research shifted towards therapies derived from biotechnology
research, including gene therapy and cancer immuno therapy.
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Drug metabolism also noted as xenobiotic metabolism is
the biochemical alteration of pharmaceutical substances or xenobiotics respectively by living organisms, usually through advanced enzymatic systems. Drug metabolism
often convertslipophilic chemical compounds into more readilyexcretedhydrophilic items. The rate of metabolism
determines the duration and intensity of a drug's pharmacological action.
Established in 1972, drug metabolism reviews is an academic journal that publishes review articles on all facets of drug metabolism investigation. It is the
official journal of the International Society for the Study of Xenobiotics
Current Drug Metabolism works towards to cover all the fresh and outstanding evolutions in
drug metabolism and disposition. This journal provides as an international
forum for the publication of timely reviews and guest edited issues in drug
metabolism. Recent Drug Metabolism is a crucialjournal for academic, clinical, management
and medicinal scientists who wish to be kept
knowledgeable andupdated with the new and most exclusivecreating. The periodical
envelops the following areas:
In vitro systems involving CYP-450; enzyme induction
and inhibition; drug-drug interactions and enzyme kinetics; pharmacokinetics,
toxicokinetics, species scaling and extrapolations; P-glycoprotein and
transport carriers; target organ toxicity and inter individual variability; drug
metabolism and disposition studies; extrahepatic metabolism; phase I and phase
II metabolism; bioactivation, recent developments for the identification of
drug metabolites, adducts and preclinical and clinical summaries of marketed
drugs.
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The carcinogenic potency, and other carcinogens and the
expanse of binding of their ultimate metabolites to DNA and proteins are
correlated with the induction of few cytochrome isozymes. Phase II
drug-metabolizing diverse enzymes inactivate chemical carcinogens into less toxic
or inactive metabolites. Several drugs change the rate of activation of
carcinogens by changing the activities of phases I and II drug-metabolizing
enzymes.
The balance of activation reactions relies on the chemical structure
of the agents, and is subjected to various variables that are a concern of this
body, or genetic background, sex, endocrine status, age, diet, and the
existence of various chemicals. It is significant to perceive that the enzymes
comprise in carcinogen metabolism are also involved in the drug metabolism enzymes of a variety of substrates,
and thus the foreword of specific xenobiotics may change the operating level
and the existence of other chemicals.
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Drug metabolism is
also noted as xenobiotic metabolism is
the biochemical modification of pharmaceutical substances or xenobiotics
respectively by living organisms, usually through unique enzymatic
systems. The increasing
costs and time associated with bringing latest medicines to the market have
developed a need for a fresh paradigm for decreasing the attrition rates of
drug candidates in both preclinical and clinical upbringing stages.
Early
appraisal of drug metabolism and pharmacokinetic (DMPK)
parameters is lately possible due to several higher throughput in vitro and in
vivo screens. This information of DMPK properties should not only lessen the
timelines for the selection of drug candidates but also increase the
probability of their success for development.
The role
of DMPK researchers in the drug research paradigm should not be limited to
screening a great array of compounds during the lead optimization process but
should involve a strive for an understanding of the engagement,
circulation, metabolism, excretion, and possible drug-related toxicities of a
chemical series.
A
specific DMPK research screening paradigm narrates a case study using the
Thrombin Receptor Adversary program. This screening paradigm followed by the
extensive lead optimization process culminated in the selection of SCH 530348,
a potent, careful and orally active thrombin receptor antagonist for the
treatment of thrombosis.
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