Infectious Disorders - Drug Targets (Formerly Current Drug Targets - Infectious Disorders) - Volume 8, Issue 2, 2008

Predictive medicine is a new philosophy in healthcare and an attractive subject for currently initiated research activities aimed at a potential application of innovative biotechnologies in the prediction of human pathologies, a development of well-timed prevention and individual therapy-planning. Diabetes care is one of the best examples of an absolute necessity for well-timed prediction, prevention and personalized treatment. Diabetes mellitus frequently results in diverse severe complications, such as retinopathy, nephropathy, silent ischemia, dementia, and cancer - the cascade of chronic complications appearing as “domino-effect”. Promising approaches of differential plasma proteome, detection of circulating nucleic acids and gene expression profiling in circulating leukocytes are currently discussed for development of potent diagnostic, prognostic and therapeutic targets. Minimal invasive insulin administration approaches and/or improvement of pancreatic activity in own insulin production is the main goal of novel drug delivery systems highly desirable for advanced treatment of diabetic patients with both type 1 and type 2 of the disease. High potential of an application of novel gene therapy approaches in diabetes care is expected for such advanced technologies as gene repair by gene replacement therapies.

Diabetes Mellitus (DM) is a serious medical problem that causes long-term systemic complications and considerable associated morbidity. DM can cause retinopathy (DRP), maculopathy, cataract, optic neuropathy, defects of eye muscles. DM is a risk factor for acute infectious conjunctivitis, bacterial keratitis, herpes virus infections and endophtalmitis. Elevated blood glucose induces structural, physiological and hormonal changes which affect retinal capillaries. DRP is recognized by loss of pericyte function and capillary occlusions together leading to breakdown of blood-retinal barrier, edematous changes and proliferation of vessels and fibrous tissue. Depending on stage of DRP, there are different preferable therapeutic approaches applied. In the case of ETDRS, in the area of leakage focal treatment should be performed, while panretinal photocoagulation is applied towards ischemic areas or beginning proliferations. Vitreal haemorrhage followed by fibroproliferative changes or tractional retinal detachment is treated by vitrectomy alone or in combination with ILM peeling. In pathogenesis of DRP, Insulin Growth Factor (IGF-1) can play an important role in production of VEGF (Vascular Endothelial Growth Factor). Hypoxia can up-regulate VEGF expression levels leading to pathologic ocular neovascularisation. An application of intravitreal corticosteroid treatment modulates vascular permeability by suppressing the production of VEGF, reducing both extracellular matrix metalloproteinase activity and basic fibroblast growth factor, decreasing major histocompatibility complex 2 Ag expression levels, and inhibiting activity of inflammatory cells. Clinical effects of treatment using intravitreal corticosteroids are evaluated by reduction of macular thickness and visual improvement. Intravitreal use of Anti-VEGF drugs, Pegaptanib, Ranibizumab and Bevacizumab can modify vasoproliferation, trigger macular edema, and, therefore, influence a prognosis for visual loss.

Diabetes mellitus (DM) is a metabolic disorder. Currently over 230 million patients demonstrate already an epidemic scale of the disease. It is a lifelong progressive disease with a high mortality worldwide: every 10 seconds one patient dies on DM-related consequences. Whereas cardio-vascular complications are well-known for DM, it is relatively new consideration that diabetic patients are highly predisposed to cancer. Particularities of molecular pathomechanisms of cancer in diabetes are currently largely unclear. Disturbed glucose/insulin homeostasis is DM-specific stress factor resulting in increased production of Reactive Oxygen Species (ROS) and oxidative damage to chromosomal and mitochondrial DNA frequently observed in diabetic patients. Long-term accumulation of DNA mutations is wellacknowledged as triggering cancer. DNA-repair is highly energy consuming process which provokes increased mitochondrial activity. Particularly dangerous is a provoked activity of damaged mitochondria which leads to the “vicious circle” lowing energy supply and potentiating ROS production. Mitochondrial dysfunction is the well-acknowledged risk factor for neuro/degenerative diseases - one of possible pathomechanisms for various complications developed secondary to diabetes. At the same time, mitochondrial dysfunction might be implicated in pathomechanisms of diabetes-provoked cancer. There is a growing body of evidence that DM predisposes to almost all cancer types with some particular preferences. Frequently suffering from compromised immune response, diabetic patients is high-risk group for infectious disorders including viral infections. In its turn, viral infections are known to be implicated in cancer pathology. This review considers both stress and viral infections as possible etiology of cancer in diabetes.

Degenerative aortic valve stenosis is the leading cause of heart valve disease in elderly resulting in significant morbidity and mortality. Although aortic stenosis has been recognized as a complex inflammatory and well-regulated process, its exact pathomechanisms are still largely unknown. Assessment by Echocardiography, Electron Beam Computed Tomography and Multislice Computed Tomography is useful for monitoring of disease progression. However, better knowledge of main determinants is essential to enable both prediction and prevention of the disease. It has been suggested that the process of heart valve degeneration is associated with the risk factors of atherosclerosis and shares many histological and molecular characteristics. Morphologic, cellular and sub-cellular examinations of degenerative aortic valves revealed endothelial derangement, inflammatory infiltrates of macrophages, T-lymphocytes and foam cells, non-physiologic lipid / lipoprotein / protein deposits, as well as dramatically altered extra-cellular matrix composition and expression profiles of checkpoint- and ”tissue remodeling“-genes. Metabolic disorder - Diabetes mellitus - is considered to predispose to degenerative valve disease and is associated with faster degeneration of bioprosthetic valves. Oxidative stress is implicated in progressive chronic degenerative processes secondary to diabetes. Moreover, diabetic patients are a high-risk group for infectious disorders. Increased prevalence of infectious endocarditis in patients with type 2 Diabetes mellitus contributes considerably to both acute aortic insufficiency and chronic progressive degeneration of valvular tissue. Cholesterol lowering drugs were demonstrated to be able to retard this progression. This review considers prognostic factors for prediction of progressive degenerative processes and novel targets to prevent calcification of aortic valves.

The presence of DNA and RNA circulating in human plasma and serum is described. The possible sources of the DNA/RNA in blood, their ability to enter other cells and to express in the recipient cells are discussed and the relationship with metastases considered. The possible role(s) of the DNA/RNA in clinical diagnosis, in monitoring treatment and in prognosis are considered for diabetes and oncology.

ATP-binding cassette (ABC) transporters are involved in a variety of physiological processes such as lipid metabolism, ion homeostasis and immune functions. A large number of these proteins have been causatively linked to rare and common human genetic diseases including familial high-density lipoprotein deficiency, retinopathies, cystic fibrosis, diabetes and cardiomyopathies. Furthermore, genetic variations in ABC transporter genes and deregulated expression patterns significantly contribute to drug resistance in human cancer and pancreatic beta cells and alter the pharmacokinetic properties of a variety of drugs. Up-to-date 15 ABC transporters have been identified in human pancreatic beta cells, however only a few of them are identified to date as proteins/genes associated with multidrug resistance (MDR) in diabetes mellitus. Prominent members include the multidrug resistance protein 1 (MRP1/ABCC1), sulfonylurea receptor 1 (SUR1/ABCC8), the multi drug transporter TAP2 and member of the ATP-binding cassette transporter subfamily A (ABCA1). ABCC8 is a subunit of the pancreatic beta-cell K(ATP) channel and plays a key role in the regulation of glucose-induced insulin secretion. Although the physiological role of these transporters to MDR is not yet fully understood, they play an important role in the blood-membrane barrier in pancreatic beta cells. The aim of this article is to provide an overview and to present few examples of drug treatment in MDR in diabetes mellitus associated with function of ABC-transporters.

Advanced drug delivery systems present indubitable advantages for drug administration. During the past three decades, new approaches for the development of new carriers for this topic have been suggested. This led to explosion of publication activity in the area. This article reviews briefly the history of the topic and focuses on general concepts in the issue. One of the most crucial properties of advanced delivery systems is their ability to be well controlled in terms of a carrier structure which is responsible for an optimal drug release. Here we describe new polymerization technologies which consider this particular aspect. A special attention is paid to the preparation of materials by LRP (Living Radical Polymerization) and perspectives of its practical application to the treatment of single diseases. Due to the epidemic scale of Diabetes mellitus, novel drug delivery systems play an important role in and are highly relevant for improved treatment of worldwide permanently growing sub-population of diabetic patients. Type 1 is the insulin-dependent diabetes which accounts for 5 till 10 percent of the whole pool of diabetic cases and currently attracts main attention in research activity devoted to the development of advanced drug delivery systems. Minimal invasive insulin administration approaches and/or improvement of pancreatic activity in own insulin production is the main goal of novel drug delivery systems highly desirable for advanced treatment of diabetic patients with both type 1 and type 2 of the disease.

Both type I and type II diabetes are common diseases with no cure. Both are characterised by chronic hyperglycaemia and can be managed, at least to some extent, by daily proteins treatments. However, in both cases, administration of the protein does not always control glucose levels in a physiologically normal time frame. A variety of different approaches to restore lost insulin in type 1 diabetes by gene therapy have recently been described. Strategies to induce production of new β cells, ameliorate or evade the auto-immune response that leads to β cell destruction, or simply delivering a modified insulin cDNA under the control of glucose-responsive promoters have all resulted in restoration of euglycaemia in a physiologically normal time frame in rodent models of diabetes. In terms of application of gene therapy to type 2 diabetes, delivery of a single protein using a virus vector can also restore euglycaemia in vivo. In addition to these advances, new technologies to permanently modify the genome which could be adapted for the long-term treatment of diabetes are described.