Current Medicinal Chemistry

ISSN: 0929-8673

Current Medicinal Chemistry
Volume 13, Number 24, 2006

Contents


Genetics of Chronic Obstructive Pulmonary Disease, Beyond a1-Antitrypsin Deficiency Pp. 2857-2873
Fotis Sampsonas, Kiriakos Karkoulias, Alexandros Kaparianos and Kostas Spiropoulos
[Abstract]


Telomerase Inhibition in Cancer Therapeutics: Molecular-Based Approaches Pp. 2875-2888
A.P. Cunningham, W.K. Love, R.W. Zhang, L.G. Andrews and T.O. Tollefsbol
[Abstract]


Current Pharmacological Treatment of Nonalcoholic Fatty Liver Pp. 2889-2900
Piero Portincasa, Ignazio Grattagliano, Vincenzo O. Palmieri and Giuseppe Palasciano
[Abstract]


The Pathophysiology of Oxaliplatin-Induced Neurotoxicity Pp. 2901-2907
Matthew C. Kiernan and Arun V. Krishnan
[Abstract]


Chromatin Remodeling, Cancer and Chemotherapy Pp. 2909-2919
Pranab Dey
[Abstract]


Current Concepts of Immunopathogenesis, Diagnosis and Therapy in Whipple’s Disease Pp. 2921-2926
G. Deriban and T. Marth
[Abstract]


Cimicifugae Rhizoma: From Origins, Bioactive Constituents to Clinical Outcomes Pp. 2927-2951
Jian-Xin Li and Zhi-Yong Yu
[Abstract]


The Synthesis and Antiviral Properties of Acyclic Nucleoside Analogues with a Phosphonomethoxy Fragment in the Side Chain Pp. 2953-2980
A. Khandazhinskaya, M. Yasko and E. Shirokova
[Abstract]




Abstracts


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Genetics of Chronic Obstructive Pulmonary Disease, Beyond a1-Antitrypsin Deficiency
Fotis Sampsonas, Kiriakos Karkoulias, Alexandros Kaparianos and Kostas Spiropoulos

It is known that only 10-20% of smokers develop COPD, implying that apart from environmental features, additional factors such as genetic variability contribute to smoke susceptibility. This proposal is in compatibility with the “Dutch Hypothesis», formulated in the early 60’s. Alpha-1-antitrypsin gene was implicated in the pathogenesis of COPD, especially the homozygous state of z allele. Since then many other genes have stepped forward as possible contributors to COPD development. In the present review we attempt to summarize the majority of these, including the genes of matrix metalloproteinases and their inhibitors, elastin, serpine2, tumor necrosis factor – a, transforming growth factor β, a variety of interleukins and their receptors and antagonists, high affinity IgE receptor , human calcium-activated chloride channel 1, heme oxygenase, vascular endothelial growth factor, microsomal epoxide hydrolase, glutathione S-transferase, cytochrome P45O, superoxide dismutase, vitamin D binding protein, beta2-adrenergic receptor, Toll like receptor, human B defensins, mucins, cystic fibrosis transmembrane regulator, surfactant protein and Nuclear Factor E2 Related Factor 2.


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Telomerase Inhibition in Cancer Therapeutics: Molecular-Based Approaches
A.P. Cunningham, W.K. Love, R.W. Zhang, L.G. Andrews and T.O. Tollefsbol

Current standard cancer therapies (chemotherapy and radiation) often cause serious adverse off-target effects. Drug design strategies are therefore being developed that will more precisely target cancer cells for destruction while leaving surrounding normal cells relatively unaffected. Telomerase, widely expressed in most human cancers but almost undetectable in normal somatic cells, provides an exciting drug target. This review focuses on recent pharmacogenomic approaches to telomerase inhibition. Antisense oligonucleotides, RNA interference, ribozymes, mutant expression, and the exploitation of differential telomerase expression as a strategy for targeted oncolysis are discussed here in the context of cancer therapeutics. Reports of synergism between telomerase inhibitors and traditional cancer therapeutic agents are also analyzed.


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Current Pharmacological Treatment of Nonalcoholic Fatty Liver
Piero Portincasa, Ignazio Grattagliano, Vincenzo O. Palmieri and Giuseppe Palasciano

Nonalcoholic fatty liver disease (NAFLD) is a frequent and potentially progressive chronic liver disease that occurs in subjects who do not abuse alcohol. NAFLD is often associated with obesity, metabolic syndrome and insulin resistance and its more aggressive form, nonalcoholic steatohepatitis (NASH) is a major cause of cryptogenic cirrhosis. NAFLD/NASH are commonly detected because of elevated serum aminotransferase levels, ultrasonographic fatty liver and, at liver histology, steatosis, inflammation, and occasionally fibrosis that may progress to cirrhosis. No established treatment exists for this potentially serious disorder. Current management of NAFLD/NASH is largely conservative and includes diet regimen, aerobic exercise, and interventions towards the associated metabolic abnormalities. The main concern is therefore to decrease liver steatosis and its progression toward steatohepatitis and fibrosis, and the risk of “cryptogenic” cirrhosis. Among the most promising medications, weight reducing drugs, insulin sensitizers and lipid-lowering agents, antioxidants, bile salts, co-factors increasing the mitochondrial transport of fatty acids are being considered. Among them, thiazolidinediones are the most promising drug family that act by activating PPARg nuclear receptors and by regulating both microsomal and peroxisomal lipid oxidative pathways. Pharmacological treatment of obesity and probiotics should be considered as potential therapeutic options. In this review, after summarizing the general background on fatty liver, the most current and attractive pharmacological approaches to the problem of NAFLD/NASH are discussed.


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The Pathophysiology of Oxaliplatin-Induced Neurotoxicity
Matthew C. Kiernan and Arun V. Krishnan

Nerve dysfunction is a common accompaniment of chemotherapy, typically occurring in a dose-dependent manner, so that the higher the dose and the longer the time of exposure, the more likely neuropathy is to occur. With the majority of chemotherapies, the mechanisms of neurotoxicity have not been clearly established. Cessation of therapy may prevent progression to a more severe syndrome and is often necessary even if there has been tumour response. Alternatively dose reduction may slow or halt progression. The clinical investigation of patients with suspected nerve dysfunction related to chemotherapy remains problematic. While routine nerve conduction studies can document the presence of a neuropathy, they do not provide further insight into pathophysiology. In contrast, measurements of nerve excitability by threshold tracking provide complementary information to conventional nerve conduction studies and may be used to infer the activity of a variety of ion channels, energy-dependent pumps and ion exchange processes activated during the process of impulse conduction. The present review will focus on recent developments in clinical rating scales and novel neuro-physiological methods for the clinical investigation of chemotherapy-induced neurotoxicity, and will highlight how such methods may prove useful to study the neurological effects of chemotherapy. Specific emphasis will be placed on oxaliplatin, a platinum-based chemotherapy effective for colorectal cancer that exhibits dose-limiting neurotoxicity.


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Chromatin Remodeling, Cancer and Chemotherapy
Pranab Dey

DNA in eukaryotic nucleus is highly condensed with histone proteins as nucleosomes. Three dimensional arrangements of nucleosomes give rise to the formation of chromatin. Extensive studies in the recent years have highlighted that the structure of chromatin plays a critical role in gene expression. Post translational modifications (such as acetylation, deacetylation, methylation and phosphorylation etc.) of tails of histones may occur with the help of various histone modifier proteins which may lead to architectural changes of nucleosomes and chromatin remodeling. Chromatin remodeling may finally enhance or repress gene transcriptions. The neoplastic cells selectively take the advantages of histone modifications for the cell proliferation, differentiation and evasion of apoptosis. There are enough experimental and clinical evidences that various histone modifiers are linked with many human malignancies. The thorough knowledge of manipulation of histone modifiers by cancer cells may help us to design newer anti-neoplastic drugs in future. There is considerable interest in histone deactylase inhibitors as antineoplastic agents and various clinical trials are in progress. This article reviews a general overview of chromatin remodeling proteins, their role in carcinogenesis and the future potential of the histone deacetylase inhibitors in cancer chemotherapy.


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Current Concepts of Immunopathogenesis, Diagnosis and Therapy in Whipple’s Disease
G. Deriban and T. Marth

Whipple's disease (WD) is a rare chronic infectious disorder caused by the rod- shaped bacterium Tropheryma whipplei. The disorder is characterized clinically by arthralgia, abdominal pain, diarrhea, malabsorbtion and progressive weight loss. Other important sites of infection include the heart (resulting in the clinical picture of endocarditis and heart failure) and the central nervous system (CNS) (manifestations include confusion, memory loss, focal cranial nerve signs, nystagmus and ophtalmoplegia). The bacterium is presumed to be ubiquitously present. A defect in cellular immune response may predispose patients for an infection with T. whipplei and this might explain the rarity of the disorder despite the ubiquitous bacterial presence. The presumed immunological defect is likely to be quite specific for T. whipplei, since patients are not generally affected by other infections. Decreased production of Interleukin(IL)-12, IL-2 and Interferon (IFN)-γ accompanied by an increased secretion of IL-4 are the main features of this defective immunological response.

The finding of periodic acid-Schiff (PAS)–positive macrophages in the lamina propria of tissue samples obtained by duodenal biopsy usually establishes the diagnosis. The PAS-positive inclusions represent the remnants of the bacteria. Attempts to isolate the causative agent were unsuccessful for nearby 100 years after the first recognition of the disease. In the year 2000, the bacterium was finally successfully grown on a human fibroblast cell line.

Untreated WD patients suffer from a chronic progressive disorder which possibly leads to death. Most patients show a fast clinical improvement to antibiotic therapy, but clinical relapses are described frequently. There is a number of patients, unable to eradicate the bacterium even after several antibiotic treatments and patients with CNS disease, in both of whom alternative therapy strategies are necessary.


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Cimicifugae Rhizoma: From Origins, Bioactive Constituents to Clinical Outcomes
Jian-Xin Li and Zhi-Yong Yu

Cimicifugae Rhizoma, mainly originated from C. acerina, C. dahurica, C. foetida, C. heracleifolia, C. racemosa and C. simplex, has long been used in traditional medicine system. During the past 45 years, a lot of efforts have been dedicated to the studies on their bioactive constituents, pharmacological effects and clinical uses, and a variety of biological activities including relief of hot flash, anti-osteoporosis, anti-human immunodeficiency virus (HIV), antiinflammatory, antidiabetes, antimalaria and vasoactive property have been discovered. Although C. racemosa is widely applied to relieve menopause symptoms in clinic for its hormonal-like action, meaningfully, no estrogenic effect was confirmed up to date. The purpose of this paper is to systematically highlight these achievements and the further therapeutic potential. The origins and distributions of the rhizome are simply listed and phytochemical aspects including over 200 compounds mainly belonging to cycloartane-type triterpenoids have been summarized. The pharmacological characterizations, especially, as a clinically effective phytomedicine, the effects of the rhizoma on menopause symptoms and the clinical applications including possible mechanism have been reviewed in detail. Various in vivo, in vitro studies on the anti-bone resorption effects of the triterpenoids, together with structure-activity relationships are also incorporated to explore the therapeutic potential on osteoporosis, a major public health threat for postmenopausal women.


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The Synthesis and Antiviral Properties of Acyclic Nucleoside Analogues with a Phosphonomethoxy Fragment in the Side Chain
A. Khandazhinskaya, M. Yasko and E. Shirokova

Acyclic nucleoside analogues bearing phosphonomethoxy residues in the side chain (ANP) attract much attention due to a very beneficial combination of biological properties. Intensive work of organic chemists during the last two decades resulted in a large panel of new compounds that were evaluated as potential antiviral drugs. Herein, we present an overview of major chemical structures within the group of acyclic nucleoside analogues containing phosphonomethoxy side fragments and describe main aspects of their synthesis and antiviral potential. We also describe progress in "prodrug" approaches applied to this chemical group to improve pharmacokinetic profiles of the potential candidates. Chemical modifications in the molecule of parental ANP aimed at blocking of phosphonate charges resulted in a set of promising derivatives, two of which have been recently approved for treatment of hepatits B (Hepsera^®) and HIV (Viread^®). The preparation, antiviral properties and some aspects of metabolic transformations and pharmacokinetics of ANP prodrugs are discussed.