Current Pharmaceutical Design

ISSN: 1381-6128

Current Pharmaceutical Design
Volume 14, Number 4, 2008


Contents

Experimental Models for the Study of Drugs Used to Prevent and Treat Vascular Diseases
Executive Editors: C.S. Thompson, D.P. Mikhailidis and K.I. Paraskevas


Editorial Pp. 306-308


Animal Models of Diabetes Mellitus: Relevance to Vascular Complications Pp. 309-324
C.S. Thompson
[Abstract] [Purchase Article]


Experimental Models of Abdominal Aortic Aneurysms: An Overview Pp. 325-337
K.I. Paraskevas, D.P. Mikhailidis and D. Perrea
[Abstract] [Purchase Article]


Apolipoprotein E Knockout Models Pp. 338-351
G. Kolovou, K. Anagnostopoulou, D.P. Mikhailidis and D.V. Cokkinos
[Abstract] [Purchase Article]


Rodent Models of Hemorrhagic Stroke Pp. 352-358
D. Strbian, A. Durukan and T. Tatlisumak
[Abstract] [Purchase Article]


Rodent Models of Ischemic Stroke: A Useful Tool for Stroke Drug Development Pp. 359-370
A. Durukan, D. Strbian and T. Tatlisumak
[Abstract] [Purchase Article]


Models for the Study of Angiogenesis Pp. 371-377
Y. Shiba, M. Takahashi and U. Ikeda
[Abstract] [Purchase Article]


Models for Non-Alcoholic Fatty Liver Disease: A Link with Vascular Risk Pp. 378-384
E. Xirouchakis, A. Sigalas, P. Manousou, V. Calvaruso, M. Pleguezuelo, A. Corbani, S. Maimone, D. Patch and A.K. Burroughs
[Abstract] [Purchase Article]


General Articles


Small Molecules Anti-HIV Therapeutics Targeting CXCR4 Pp. 385-404
F. Grande, A. Garofalo and N. Neamati
[Abstract] [Purchase Article]


Is There A Relationship Between Insulin Resistance and Frailty Syndrome? Pp. 405-410
A.M. Abbatecola and G. Paolisso
[Abstract] [Purchase Article]




Abstracts


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Editorial: Experimental Models for the Study of Drugs Used to Prevent and Treat Vascular Diseases

Vascular disease is a major cause of morbidity and mortality worldwide. Reducing the incidence of deaths due to vascular causes holds implications for national economies worldwide [1]. On this basis, several animal models have been developed to replicate human vascular diseases in order to study their pathophysiology. This issue of the Current Pharmaceutical Design discusses some of these models. In this Editorial we will briefly review each article in this Special Issue and we will also briefly consider a few additional models.

Thompson describes various animal models of diabetes and also highlights those most commonly used to evaluate diabetic micro- and macro-vascular complications [2].

Paraskevas et al. describe the animal models developed for the study of abdominal aortic aneurysms (AAAs) [3]. This review focuses on the pathomechanisms involved in the development of AAAs and the different treatment modalities for their management.

Kolovou et al. describe apolipoprotein E (Apo E) knock out mouse models, which were developed to study atherosclerosis and cardiovascular diseases [4]. The applications of these models in the study of lipoprotein metabolism, arterial wall stiffness and the effect of various diets/drugs are also discussed.

Tatlisumak et al. describe the various animal models for the study of the pathophysiology and management of stroke. In one review, they discuss rodent models of hemorrhagic stroke [5]. In the second review, they discuss models of ischemic stroke [6]. They provide a detailed analysis of why these animal models are important for our understanding of the pathophysiology of stroke and brain ischemia and how they can be used to discover (and test) novel treatment strategies. The advantages and disadvantages of each reported model are also outlined.

Shiba et al. describe models of angiogenesis [7]. They discuss the mechanism of neovascularization and the applications of therapeutic angiogenesis in humans based on animal models.

Xirouchakis et al. describe experimental models of non-alcoholic fatty liver [8]. This condition is associated with both metabolic syndrome and diabetes. Inevitably therefore, there is a link between fatty liver and an increased risk of vascular disease.

In addition, several other models have been developed for the study of vascular disease. This Editorial briefly addresses some of them.

Peripheral Arterial Disease (PAD)
Several animal models for the study of PAD have been described. Lower limb ischemia affects a large percentage of the population. One of the most rapidly growing treatment modalities for the management of PAD is therapeutic angiogenesis [9].

Animal models of hindlimb ischemia were developed to evaluate the beneficial effects of autologous bone marrow cell infusion [10,11], vascular endothelial growth factor (VEGF) [12] and platelet-derived endothelial cell growth factor (PD-ECGF) [13] for the induction of angiogenesis. Other models were developed for the establishment of diagnostic tests for the evaluation and quantification of angiogenesis [14-17].

These models provide insight in the pathophysiology and management of PAD. Application of these preliminary results in humans holds implications for a different therapeutic approach.

Hyperhomocysteinemia
Hyperhomocysteinemia has been proposed as an independent risk factor for atherothrombotic disease [18-20]. Supplementation with methionine, homocysteine and/or depletion of folic acid and B vitamins can induce mild to severe hyperhomocysteinemia [21,22]. Mice with a heterozygous cystathione β-synthase-deficiency (enzymes responsible for homocysteine metabolism) develop endothelial dysfunction by decreasing vascular nitric oxide bioavailability, thereby leading to impaired vasorelaxation [23,24].

Animal models of hyperhomocysteinemia have extended many of the proposed mechanisms linking this abnormality with atherogenesis. However, the findings reported in animal models are not necessarily reproduced in human studies [25].

Hypertension
Hypertension is an important risk factor for cardiovascular and cerebrovascular disease. Research on pathophysiology and treatment of hypertensive brain damage may benefit from the availability of animal models [26-30].

Spontaneously hypertensive rats represent the most commonly used animal model. In these rats, cerebrovascular changes, brain atrophy, loss of nerve cells in cerebrocortical areas and glial reaction occur. The influence of anti-hypertensive treatment on brain structure and function in animal models of hypertension has also been investigated [26-30].

Animal models for the development and management of hypertension are more extensively discussed elsewhere [26-30].

Hypercholesterolemia, Hypertriglyceridemia and The Metabolic Syndrome
Hypertriglyceridemia is an independent risk factor for coronary artery disease. Many animal models used for the study of hypertension have also other features of the metabolic syndrome. The most frequently used model with genetic hypertension, the spontaneously hypertensive rat, has fasting hyperglycemia, impaired oral glucose tolerance, hyperinsulinemia and hypertriglyceridemia [26-30]. Another genetic model of experimental hypertension is the Dahl salt-sensitive rat [31], which is also used for the study of insulin resistance [32].

Several other models with combination of hypertension, insulin resistance, obesity or diabetes are used, including the Prague hereditary hypertriglyceridemic rat [33,34]. Prague hereditary hypertriglyceridemic rats were developed as a genetic model of human hypertriglyceridemia from a colony of Wistar rats [33,34]. Hereditary hypertriglyceridemic rats are a suitable model for phenotyping and genotyping such complex diseases as hypertension, hypertriglyceridemia and insulin resistance, which represent components of the metabolic syndrome.

Rodent models of hypercholesterolemia have similarly been developed for the study of the metabolic syndrome, dyslipidemia and atherosclerosis [35,36]. Furthermore, lipid-lowering drugs may exert a beneficial effect on non-alcoholic fatty liver disease [37,38].

Renal Function and Renal Artery Stenosis
With the evolution of endovascular procedures for the treatment of arterial stenosis, several animal models were developed to study the consequences and the long-term effects of these techniques. Several aspects of the endovascular approach have been addressed, such as stent positioning and placement [39] or imaging of the lesions [40,41]. These models have assisted the development of accurate techniques for the endovascular approach of renal artery stenosis.

Animal models have also been used for the study of chronic renal insufficiency [42] and renovascular hypertension [43,44]. These models provide insight into the pathomechanisms underlying these complex diseases and the opportunity to test novel drug approaches.

It is hoped that a forthcoming issue of Current Pharmaceutical Design will discuss in greater detail some of the experimental models that are not considered in this issue due to space limitations.

References

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[2] Thompson CS. Animal models of diabetes mellitus: relevance to vascular complications. Curr Pharm Des 2008; 14(4): 309-324.

[3] Paraskevas KI, Mikhailidis DP, Perrea D. Experimental models of abdominal aortic aneurysms: an overview. Curr Pharm Des 2008; 14(4): 325-337.

[4] Kolovou G, Anagnostopoulou K, Mikhailidis DP, Cokkinos DV. Apolipoprotein E knockout models. Curr Pharm Des 2008; 14(4): 338-351.

[5] Strbian D, Durukan A, Tatlisumak T. Rodent models of hemorrhagic stroke. Curr Pharm Des 2008; 14(4): 352-358.

[6] Durukan A, Strbian D, Tatlisumak T. Rodent models of ischemic stroke: a useful tool for stroke drug development. Curr Pharm Des 2008; 14(4): 359-370.

[7] Shiba Y, Takahashi M, Ikeda U. Models for the study of angiogenesis. Curr Pharm Des 2008; 14(4): 371-377.

[8] Xirouchakis E, Sigalas A, Manousou P, Calvaruso V, Pleguezuelo M, Corbani A, et al. Models for non-alcoholic fatty liver disease: a link with vascular risk? Curr Pharm Des 2008; 14(4): 378-384.

[9] Paraskevas KI, Mikhailidis DP. Angiogenesis: a promising treatment option for peripheral arterial disease. Curr Vasc Pharmacol 2008 (In press).

[10] de Nigris F, Williams-Ignarro S, Sica V, D'Armiento FP, Lerman LO, Byrns RE, et al. Therapeutic effects of concurrent autologous bone marrow cell infusion and metabolic intervention in ischemia-induced angiogenesis in the hypercholesterolemic mouse hindlimb. Int J Cardiol 2007; 117: 238-43.

[11] He Y, Luo Y, Tang S, Rajantie I, Salven P, Heil M, et al. Critical function of Bmx/Etk in ischemia-mediated arteriogenesis and angiogenesis. J Clin Invest 2006; 116: 2344-55.

[12] Greve JM, Chico TJ, Goldman H, Bunting S, Peale FV Jr, Daugherty A, et al. Magnetic resonance angiography reveals therapeutic enlargement of collateral vessels induced by VEGF in a murine model of peripheral arterial disease. J Magn Reson Imaging 2006; 24: 1124-32.

[13] Yamada N, Li W, Ihaya A, Kimura T, Morioka K, Uesaka T, et al. Platelet-derived endothelial cell growth factor gene therapy for limb ischemia. J Vasc Surg 2006; 44:1322-8.

[14] Sampath S, Raval AN, Lederman RJ, McVeigh ER. High-resolution 3D arteriography of chronic total peripheral occlusions using a T1-W turbo spin-echo sequence with inner-volume imaging. Magn Reson Med 2007; 57: 40-9.

[15] Dobrucki LW, Sinusas AJ. Imaging angiogenesis. Curr Opin Biotechnol 2007; 18: 90-6.

[16] Alnaeb ME, Alobaid N, Seifalian AM, Mikhailidis DP, Hamilton G. Optical techniques in the assessment of peripheral arterial disease. Curr Vasc Pharmacol 2007; 5: 53-9.

[17] Penuelas I, Aranguren XL, Abizanda G, Marti-Climent JM, Uriz M, Ecay M, et al. (13)N-ammonia PET as a measurement of hindlimb perfusion in a mouse model of peripheral artery occlusive disease. J Nucl Med 2007; 48: 1216-23.

[18] Clarke R, Daly L, Robinson K, Naughten E, Cahalane S, Fowler B, et al. Hyperhomocysteinemia: an independent risk factor for vascular disease. N Engl J Med 1991; 324: 1149-55.

[19] McCully KS. Homocysteine and vascular disease. Nat Med 1996; 2: 386-9.

[20] Selhub J, Jacques PF, Bostom AG, D’Agostino RB, Wilson PW, Belanger AJ, et al. Association between plasma homocysteine concentrations and extracranial carotid-artery stenosis. N Engl J Med 1995; 332: 286-91.

[21] Zhou J, Moller J, Danielsen CC, Bentzon J, Ravn HB, Austin RC, et al. Hyperhomocysteinemia promotes the development of collagen-rich and stable plaques in apoE-deficient mice. Arterioscler Thromb Vasc Biol 2001; 21: 1470-6.

[22] Wang H, Jiang X, Yang F, Gaubatz JW, Ma L, Magera MJ, et al. Hyperhomocysteinemia accelerates atherosclerosis in cystathionine betasynthase and apolipoprotein E double knock-out mice with and without dietary perturbation. Blood 2003; 101: 3901-7.

[23] Eberhardt RT, Forgione MA, Cap A, Leopold JA, Rudd MA, Trolliet M, et al. Endothelial dysfunction in a murine model of mild hyperhomocyst(e)inemia. J Clin Invest 2000; 106: 483-91.

[24] Weiss N, Heydrick S, Zhang YY, Bierl C, Cap A, Loscalzo J. Cellular redox state and endothelial dysfunction in mildly hyperhomocysteinemic cystathionine beta-synthase-deficient mice. Arterioscler Thromb Vasc Biol 2002; 22: 34-41.

[25] Reddy GS, Wilcken DE. Experimental homocysteinemia in pigs: comparison with studies in sixteen homocystinuric patients. Metabolism 1982; 31: 778-83.

[26] Sabbatini M, Tomassoni D, Amenta F. Influence of treatment with Ca(2+) antagonists on cerebral vasculature of spontaneously hypertensive rats. Mech Ageing Dev 2001; 122: 795-809.

[27] Sabbatini M, Tomassoni D, Amenta F. Hypertensive brain damage: comparative evaluation of protective effect of treatment with dihydropyridine derivatives in spontaneously hypertensive rats. Mech Ageing Dev 2001; 122: 2085-105.

[28] Blezer E, Nicolay K, Goldschmeding R, Koomans H, Joles J. Reduction of cerebral injury in stroke-prone spontaneously hypertensive rats by amlodipine. Eur J Pharmacol 2002; 444: 75-81.

[29] Amenta F, Di Tullio MA, Tomassoni D. Arterial hypertension and brain damage evidence from animal models (review). Clin Exp Hypertens 2003; 25: 359-80.

[30] Amenta F, Tomassoni D. Treatment with nicardipine protects brain in an animal model of hypertension-induced damage. Clin Exp Hypertens 2004; 26: 351-61.

[31] Dahl LK, Heine M, Tassinari L. Effects of chronic excess salt ingestion. Evidence that genetic factors play an important role in susceptibility to experimental hypertension. J Exp Med 1962; 115: 1173-90.

[32] Reaven GM, Twersky J, Chang H. Abnormalities of carbohydrate and lipid metabolism in Dahl rats. Hypertension 1991; 18: 630-5.

[33] Klimes I, Vrana A, Kunes J, Sebokova E, Dobesova Z, Stolba P, et al. Hereditary hypertriglyceridemic rat: a new animal model of metabolic alterations in hypertension. Blood Press 1995; 4: 137-42.

[34] Chen D, Wang MW. Development and application of rodent models for type 2 diabetes. Diabetes Obesity Metab 2005; 8: 307-17.

[35] Aliev G, Burnstock G. Watanabe rabbits with heritable hypercholesterolaemia: a model of atherosclerosis. Histol Histopathol 1998; 13: 797-817.

[36] Russell JC, Proctor SD. Small animal models of cardiovascular disease: tools for the study of the roles of metabolic syndrome, dyslipidemia and atherosclerosis. Cardiovasc Pathol 2006; 15: 318-30.

[37] Deushi M, Nomura M, Kawakami A, Haraguchi M, Ito M, Okazaki M, et al. Ezetimibe improves liver steatosis and insulin resistance in obese rat model of metabolic syndrome. FEBS Lett 2007 Nov 15 [Epub ahead of print].

[38] Athyros VG, Mikhailidis DP, Didangelos TP, Giouleme OI, Liberopoulos EN, Karagiannis A, et al. Effect of multifactorial treatment on non-alcoholic fatty liver disease in metabolic syndrome: a randomised study. Curr Med Res Opin 2006; 22: 873-83.

[39] Kharin SN, Krandycheva VV. Method of experimental constriction of renal artery for modeling of renovascular hypertension in rats. Bull Exp Biol Med 2004; 138: 103-5.

[40] Jackiewicz E, Szczepanska-Sadowska E, Maslinski W. Expression of mineralocorticoid receptors mRNA in the brain, heart and kidney of Sprague Dawley rats with renovascular hypertension. Brain Res Bull 2005; 65: 23-9.

[41] Elgort DR, Hillenbrand CM, Zhang S, Wong EY, Rafie S, Lewin JS, et al. Image-guided and monitored renal artery stenting using only MRI. J Magn Reson Imaging 2006; 23: 619-27.

[42] Misra S, Gordon JD, Fu AA, Glockner JF, Chade AR, Mandrekar J, et al. The porcine remnant kidney model of chronic renal insufficiency. J Surg Res 2006; 135: 370-9.

[43] Park JK, Rhee TK, Cashen TA, Shin W, Schirf BE, Gehl JA, et al. Renal artery stenosis in swine: feasibility of MR assessment of renal function during percutaneous transluminal angioplasty. Radiology 2007; 244: 144-50.

[44] Suzuki Y, Ikeno F, Lyons JK, Koizumi T, Yeung AC. Novel stent system for accurate placement in aorto-ostial renal artery disease: preclinical study in porcine renal artery model. Cardiovasc Revasc Med 2007; 8: 99-102.


Kosmas I. Paraskevas
Dimitri P. Mikhailidis
Cecil S. Thompson
Department of Clinical Biochemistry
(Vascular Disease Prevention Clinic)
Royal Free Hospital and
Royal Free University College Medical School
University College London
Pond Street, London NW3 2QG
UK
Tel: +44 (0) 20 7830 2258
Fax: +44 (0) 20 7830 2235
E-mail: MIKHAILIDIS@aol.com


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Animal Models of Diabetes Mellitus: Relevance to Vascular Complications
C.S. Thompson

The prevalence of diabetes mellitus is increasing worldwide at an alarming rate due to population growth, obesity, sedentary lifestyle and aging. Consequently, diabetic microvascular complications (retinopathy and nephropathy) and macrovascular complications (coronary heart disease, peripheral arterial disease and cerebrovascular disease) are also rising.

Traditional oral hypoglycaemic agents only partially prevent the development of these complications. This suggests that selective treatment options that target specific biological pathways (i.e. metabolic factors, intracellular signaling proteins and growth factors) may be a more effective strategy.

Type 1 and Type 2 diabetic animal models have been produced spontaneously by selective inbreeding or by genetic modification, as well as, pharmacological induction. These models have become a safe and reliable option to test the therapeutic potential of novel drugs. They also help to understand the pathophysiology of diabetes mellitus.

This review highlights the most commonly used animal models for the treatment of diabetic micro and macrovascular complications.


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Experimental Models of Abdominal Aortic Aneurysms: An Overview
K.I. Paraskevas, D.P. Mikhailidis and D. Perrea

In the last 50 years, several experimental models of abdominal aortic aneurysms (AAAs) have been described. These models have aided scientists and physicians to understand the pathophysiological mechanisms underlying AAA development and progression. In addition, they have served as means for the development of a number of conservative (such as doxyxycline, marimastat and propranolol) and surgical treatment options for the management of AAAs. In the last few years, experimental models have contributed in the development of novel endovascular techniques for the treatment of AAAs. Animal models of endovascular grafts and percutaneous techniques comprise an essential step for the successful clinical application of these procedures. Additionally, they may comprise part of the training process for vascular surgeons.

The different experimental AAA models are briefly presented and their clinical significance is discussed. Experimental models play an essential role in the field of research for the development of more successful therapeutic alternatives for the management of AAAs.


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Apolipoprotein E Knockout Models
G. Kolovou, K. Anagnostopoulou, D.P. Mikhailidis and D.V. Cokkinos

Atherosclerosis is a multifactorial and long-lasting process in humans. Therefore, animal models where more rapid changes occur can be useful for the study of this process. Among such models are the apolipoprotein (apo) E knock out mice.

Apo E deficient mice show impaired clearing of plasma lipoproteins and they develop atherosclerosis in a short time. The current review considers lipid metabolism and inflammation as well as nutritional and pharmacological agents affecting atherosclerosis, using the apo E knock out mouse model.


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Rodent Models of Hemorrhagic Stroke
D. Strbian, A. Durukan and T. Tatlisumak

Both intracerebral and subarachnoid hemorrhages are associated with high mortality and most survivors are burdened with severe disability. Currently, there is no approved treatment for intracerebral hemorrhage and surgical evacuation was not proven beneficial. Regarding subarachnoid hemorrhage, existing therapies need substantial improvement. Detailed pathophysiologic mechanisms need to be understood in order to develop novel therapeutic strategies. Hemorrhagic stroke models can help achieve both these goals and answer those questions that cannot be addressed in the clinical setting. There are several animal models of intracerebral and subarachnoid hemorrhage, each mimicking fairly reliably different aspects of the condition studied. The similarities and differences among the existing rodent models, model modifications, and some aspects concerning the choice of relevant model are discussed.


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Rodent Models of Ischemic Stroke: A Useful Tool for Stroke Drug Development
A. Durukan, D. Strbian and T. Tatlisumak

Stroke is the third common cause of death and the most common cause of adult disability. Approximately 80% of all strokes are ischemic (brain infarction). The only approved acute therapy is intravenous thrombolysis with tissue plasminogen activator within 3 h of symptom onset but only a small percentage of all ischemic stroke patients can receive this therapy. Therefore, novel therapeutic approaches directed at the pathophysiological mechanisms involved in ischemic brain injury are urgently needed. To this end several experimental stroke models were developed. These models are indispensable for understanding the pathophysiology of brain ischemia and to develop novel drugs and investigative methodology.

This review considers the most commonly used ischemic stroke models (including preconditioning models) in rodents emphasizing their advantages and disadvantages. Since none of the models can perfectly simulate human stroke, researchers must interpret experimental findings carefully.


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Models for the Study of Angiogenesis
Y. Shiba, M. Takahashi and U. Ikeda

Cardiovascular disease remains a principal cause of mortality in Western countries. Novel strategies for enhancing angiogenesis (such as gene or cell therapy) provide alternative choices for patients without any current treatment options. This progress has contributed towards understanding the mechanisms underlying vascular formation. The establishment of new experimental models could lead to the development of new treatments.

This article overviews the diverse models for the study of angiogenesis.


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Models for Non-Alcoholic Fatty Liver Disease: A Link with Vascular Risk
E. Xirouchakis, A. Sigalas, P. Manousou, V. Calvaruso, M. Pleguezuelo, A. Corbani, S. Maimone, D. Patch and A.K. Burroughs

Non alcoholic fatty liver disease (NAFLD) is often part of the metabolic syndrome which includes central obesity, dyslipidaemia, insulin resistance/type 2 diabetes mellitus and hypertension. In turn, NAFLD may be associated with an increased vascular risk.

Several experimental models which express histological steatosis or steatohepatitis with fibrosis have been described. This review identifies those models of NAFLD with features of vascular risk.


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Small Molecules Anti-HIV Therapeutics Targeting CXCR4
F. Grande, A. Garofalo and N. Neamati

HIV cellular entry is a multistep process that requires the interaction of a viral envelope glycoprotein (gp120) and a host receptor (CD4) followed by binding to a co-receptor. The CC-chemokine receptor 5 (CCR5) and CXC-chemokine receptor 4 (CXCR4) have been identified as the major HIV co-receptors and therefore are promising targets for the development of new anti-HIV drugs. CXCR4 is also involved in several diseases such as angiogenesis, metabolic and neurological disorders, rheumatoid arthritis and in different forms of metastatic cancer. Herein, we present a review focusing on small molecule CXCR4 antagonists. These compounds are divided into 11 classes that include cyclic penta- and tetrapeptides, diketopiperazine mimetics, bicyclams, non-bicyclams, tetrahydroquinolines, thiazolylisothiourea derivatives, benzodiazepines, alkyl amine analogs and non-peptides derivatives, dipicolylamine-zinc(II) complexes, ampelopsin and distamycin analogs. The most advanced CXCR4 antagonists documented are bicyclam derivatives, which are specific CXCR4 antagonists and exhibit potency in the nanomolar range. Further development of selective CXCR4 antagonists continues to be crucial for the design of second generation of anti-HIV drugs. We aim to provide a comprehensive summary of diverse structural templates that could be useful for optimization and discovery of novel CXCR4 antagonists.


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Is There A Relationship Between Insulin Resistance and Frailty Syndrome?
A.M. Abbatecola and G. Paolisso

Due to the fact that the percentage of aged subjects in the populations of industrialized countries is dramatically increasing, the scientific community has been obligated to focus their attention on age related disease states and peculiar consequences of aging such as, frailty. Frailty is defined as a syndrome of decreased reserve and resistance to stressors and is clinically expressed as muscle weakness, poor exercise tolerance, factors related to body composition, sarcopenia, and lower extremity mobility. Some biochemical markers of frailty in older persons, including pro-inflammatory markers, hormones and free radicals have been suggested. However, there is growing evidence that a rise in insulin resistance [IR] occurs as individuals age and IR is not only considered a simple metabolic finding, but has been identified as a major risk factor for many age-related diseases due to altered lipid metabolism, increased inflammatory state, impaired endothelial functioning, pro-thrombotic status and atherosclerosis. Considering that IR is related to many of the clinical features of frailty such as, skeletal muscle weakness, lower extremity mobility disability, cognitive decline and body composition changes, we will analyze the relationships among IR and such individual components while highlighting potential pathophysiologic mechanisms of IR on the activation of the downward spiral of the frailty syndrome in older persons. In particular, we will address the issue that IR may also be considered a pivotal biological component of some clinical aspects of the frailty syndrome in aging individuals.