Current Drug Targets - Immune, Endocrine & Metabolic Disorders - Volume 2, Issue 1, 2002

Volume 2, Issue 1, 2002
-
-
The Evolving Therapy of Rheumatic Diseases, The Future is Now
More LessThere are two main ways in which physicians will be urged to improve the outcome for their patients suffering from rheumatic diseases in the coming era, these are, early diagnosis and timely effective therapy. Current reserch suggests that in rheumatoid arthritis joint damage occurs early, often within the first 2 years and even in the absence of associating severe symptoms, is a call for action for primary care physicians as well as rheumatologists. Similarly in SLE patients, sometimes the treatments are ineffective or too toxic with sepsis or opportunistic infections often limiting their use or resulting in the death of the patient. As primary care physicians are the clinicians most frequently visited by patients with initial symptoms of the disease, they first need to learn when to suspect it as well as its complications, and when to refer the patient appropriately. Rheumatologists need to determine when and how to prescribe the most appropriate treatment, as well as how to incorporate the new drugs which are emerging on the scene. At the same time, earlier initiation of combination therapy with the disease modifying anti-rheumatic therapy holds an area of continued exploration. This new information has modified our approach to patients' management. The age of ”wait and see“ is over.
-
-
-
Hormone Mediation of Immune Responses in the Progression of Diabetes, Rheumatoid Arthritis and Periodontal Diseases
By M. SorryThe crucial role of the immune response is common to diabetes mellitus (DM), rheumatoid arthritis (RA) and periodontal disease. This review identifies advances in this field and exciting paradigms in their management. Uncontrolled hyperglycaemia in diabetic patients results in the formation of advanced glycation end products (AGEs), which are detrimental to cell structure and function. Altered host resistance such as defective migration of PMN, impaired phagocytosis and an exaggerated inflammatory response to microbial products also compromises healing in uncontrolled diabetic patients, further compromised in smokers. Nicotine has well documented effects on the immune response, cell adhesion proteins and apoptosis which affect the severity of disease presentation and response to treatment. Rheumatoid arthritis is a multifactorial disease that results in severe destruction of synovial cartilage and bone. Local secretion of large amounts of TNF-α and IL-1 due to activation of immunocompetent cells characterises the pathophysiology of RA. This has lead to the emergence of TNF-α inhibitors such as etanercept and infliximab in its management. Periodontal disease has a microbial aetiology. But it is similar to RA, in its cyclical pattern of destruction associated with high levels of pro-inflammatory cytokines, which can persist after removal of the antigenic stimulus. Non steroidal anti-inflammatory agents (NSAIDs) have been used as an adjunct to mechanical removal of bacterial antigen, in the management of periodontal disease. The non-reproductive functions of steroid hormones include effects on immunocompetent cells, fibroblasts and osteoblasts, which affect the initiation and progression of inflammatory diseases. Hormone replacement therapy could be another facet in a multifaceted treatment approach in these patients, where indicated.
-
-
-
Clinical Pharmacology of Human Growth Hormone and its Secretagogues
More LessThe regulation of the synthesis and secretion of human growth hormone (hGH), its biologic activity, and its therapeutic use are reviewed. Both the production and secretion of GH are stimulated by hypothalamic GH-releasing hormone (GHRH) and by the endogenous GH secretagogue (GHS) ghrelin, a product of the oxyntic cells located within the fundus of the stomach. Ghrelin and GHRH act synergistically to stimulate GH secretion when administered in vivo, but they act additively when incubated with somatotrophs in vitro. Ghrelin is also found within the hypothalamic arcuate nucleus where it may enhance the release of GHRH and impair that of somatostatin (SRIH) thus contributing to its synergism with GHRH ghrelin is an orexigenic peptide as well as a GHS and appears to play an important role in energy metabolism. SRIH inhibits the secretion but not the synthesis of GH and more effectively that stimulated by GHRH than that by ghrelin. The action of GH is mediated by the GH receptor, a straight chain protein of 620 amino acids with extracellular, transmembrane and cytoplasmic domains. GH has two specific receptor binding sites, (I, II) that bind sequentially to similar acceptor sequences of two GHRs. Activation of the GHR signal transduction pathway begins with attachment of two Janus kinase 2 (JAK2) molecules to the intracellular domains of the GHRs leading to phosphorylation of the tyrosine residues of JAK2 and the GHRs thereafter the signal transduction and activators of transcription (STAT) and Ras mitogen-activated-protein kinase pathways are enhanced. GHRH, SRIH, and ghrelin act through G-protein coupled receptors (GPCR) GHRH activates adenylyl cyclase, cyclic AMP, and protein kinase A pathways, while ghrelin stimulates phospholipase C activity leading to production of inositol 1,4,5-trisphophate and diacylglycerol, increase in cytosolic calcium levels, and GH release SRIH acts though an inhibitory GPCR to prevent depolarization of the somatotroph thus blocking GH secretion. GH has long been used to stimulate linear growth in children with GH deficiency (GHD) it has also been demonstrated to be effective in adults with GHD. The availability of large quantities of recombinant hGH has broadly increased the number of children with short stature being treated with this agent - not always with marked effectiveness. Synthesis of the GHR antagonist pegvisomant has provided another agent with which to treat patients with acromegaly. GHRH also enhances linear growth rate effectively in children with GHD but is less effective than hGH. The discovery of peptidyl and non-peptidyl GH secretagogues (that preceded and led to the identification of ghrelin itself) presents yet other agents for stimulation of endogenous GH secretion that have been useful in diagnostic studies for GHD and for its treatment in small groups of subjects. It is likely that hGH and its secretagoguess will become of increasing clinical usefulness in future decades.
-
-
-
Cell Cycle Dysregulation During Hiv Infection: Perspectives of a Target Based Therapy
Authors: D. Galati, M. Bocchino, M. Paiardini, B. Cervasi, G. Silvestri and G. PiedimonteHuman immunodeficiency virus (HIV) infection is characterized by a severe depletion of both CD4+ and CD8+ T cells, representing the result of virus-mediated killing of infected lymphocytes and the programmed cell death (apoptosis) of the uninfected bystander cells. Since only a small fraction of T lymphocytes are depleted by viral killing, apoptosis represents one of the most important mechanism of T cell death during HIV infection. Several apoptotic pathways can be triggered by the different stimuli: persistent T lymphocyte activation altered death receptor (Fas, TNF-R, TRAIL R1-R2) membrane expression viral proteins as well as gp120, Tat, and Nef host factors such as the unbalance of cytokine synthesis by lymphocyte. Nevertheless, new evidences have demonstrated that the persistent HIV induced T cell activation and proliferation cause a cell cycle dysregulation resulting in a 5-fold increase in apoptotic cells. This perturbation represents a link between HIV infection, T cell activation, accelerated cell turnover and increased apoptosis and may thus represent a new therapeutic target. In fact, Interleukin-2 administration reverts such a cell cycle dysregulation and reduces activation induced T cell apoptosis. Herein we analyze the main HIV-related mechanisms of host cell death, that are dysregulation of the cell cycle and apoptosis induction of T lymphocytes. Finally, the role of cytokines at the site of infection and their association with apoptosis will be discussed to get insights into the immunological perturbations accounting for an accelerated disease progression. Current therapeutic approaches and strategies, like HAART and recombinant cytokines, that may, successfully, improve the immune-system dysregulation, are also discussed
-
-
-
Novel Peptides under Development for the Treatment of Type 1 and Type 2 Diabetes Mellitus
Authors: A.D. Baron, D. Kimm and C. WeyerRecent availability of expanded treatment options for both type 1 and type 2 diabetes has not translated into easier and significantly better glycemic and metabolic management. Patients with type 1 diabetes continue to experience increased risk of hypoglycemic episodes and progressive weight gain resulting from intensive insulin treatment, despite the recent availability of a variety of insulin analog. Given the progressive nature of the disease, most patients with type 2 diabetes inevitably proceed from oral agent monotherapy to combination therapy and, ultimately, require exogenous insulin replacement. Insulin therapy in type 2 diabetes is also accompanied by untoward weight gain. Both type 1 and type 2 diabetes continue to be characterized by marked postprandial hyperglycemia.Two hormones still in development are candidates for pharmacologic intervention, have novel modes of action (some centrally mediated), and show great promise in addressing some of the unmet needs of current diabetes management. Pramlintide acetate, an analog of the beta cell hormone amylin and the first non-insulin related therapeutic modality for type 1 and type 2 diabetic patients with severe beta cell failure, may be useful as adjunctive therapy to insulin. The principal anti-diabetic effects of pramlintide arise from interactions via its cognate receptors located in the central nervous system resulting in postprandial glucagon suppression, modulation of nutrient absorption rate, and reduction of food intake. Another polypeptide hormone, exendin-4, exerts at least some of its pharmacologic actions as an agonist at the glucagon-like peptide-1 (GLP-1) receptor. GLP-1 and related compounds exhibit multiple modes of action, the most notable being a glucose-dependent insulinotropic effects and the potential to preserve or improve the beta-cell function. The latter effect could potentially halt or delay the progressive deterioration of the diabetic state associated with type 2 diabetes.Physiologically, both amylin and glucagon-like peptide (GLP)-1, along with insulin, are involved in a coordinated and concerted interplay between hormones acting both centrally and peripherally to provide meticulous control over the rate of appearance of exogenous and endogenous glucose and to match that rate to the rate of glucose disappearance. Both hormones are deficient in diabetes. Therapies directed at restoring this complex physiology have the potential to facilitate glucose control and thus minimize the attendant complications of diabetes
-
-
-
Mucosal Immunity - Basic Principles, Ontogeny, Cystic Fibrosis and Mucosal Vaccination
By Z. VancikovaThe mucosal immune system is an integral part of the whole-body immune system, however its regulation, maturation and function are to a great degree independent. Mucosal lymphoid tissue is the largest immune organ of the body, that stands in the first line of defence against foreign invaders. The goal of the immune system is immunity, however immunologic unresponsiveness (tolerance) is a key feature of the mucosal immune system, because the organism must tolerate thousands of ingested and inhaled harmless food and bacterial antigens. The phenomenon of oral tolerance is the unique feature of the mucosal immune system. If abrogated, severe autoimmune diseases like Crohn's disease, ulcerative colitis or coeliac sprue can develop. The quality of mucosal immune responses during newborn and infant age strongly influences the immune reactivity later in life. The most important factors influencing the development of mucosal immune reactivity are the feeding practices and microbial colonization. Manipulation of the mucosal immune system offers interesting possibilities to prevent infection as well as autoimmune diseases directly in the affected tissue, without participation of the whole-body immune system. In this review we present the most recent basic information about the mechanisms of mucosal immunity, ontogeny of mucosal immunity, mucosal tolerance and immunisation and the role of mucosal immunity in an inherited disease in which the main battlefield is the lung mucosa - cystic fibrosis.
-
-
-
Common Treatment of Polycystic Ovarian Syndrome and Major Depressive Disorder: Case Report and Review
Authors: N.L. Rasgon, M.S. Carter, S. Elman, M. Bauer, M. Love and S.G. KorenmanWe present the case of a young woman with treatment-resistant major depression, who presented to the Mood Disorders Clinic with a Hamilton Psychiatric Rating Scale for Depression (HAM-D-21) score of 28, after a year-long treatment with Effexor-XR. The patient also had untreated Polycystic Ovarian Syndrome (PCOS). The resolution of her depressive symptoms resulted from the treatment for PCOS with metformin and spironolactone. The patient remained euthymic 5 months after discontinuation of the antidepressant while continuing therapy for PCOS. We briefly overview of the pertinent literature of the pathophysiology of PCOS and affective disorders, highlighting an overlap in phenotypical presentations between these two disorders. Dysregulation of the hypothalamo-pituitary axis and various end organ systems are implicated in both PCOS and affective disorders. As such, several clinical and biochemical markers are common to both disorders, namely insulin resistance, obesity, and hyperandrogenism. In addition, these metabolic abnormalities are interrelated, causing women with PCOS or affective disorders to get caught in a ”vicious cycle“ of hormonal dysregulation. The case report presented here illustrates how treatment of symptoms such as insulin resistance and hyperandrogenism can lead to remission of major depressive disorder and PCOS. We suggest that through treatment of underlying metabolic defects, both the mood of the patient and the metabolic condition of PCOS can be assisted.
-
Volumes & issues
Most Read This Month
