Current Pharmaceutical Design - Volume 7, Issue 6, 2001

Concurrent with the spread of the western lifestyle, the prevalence of all types of diabetes is on the rise in the worlds population. The number of diabetics is increasing by 4-5 percent per year with an estimated 40-45 percent of individuals over the age of 65 years having either type II diabetes or impaired glucose tolerance. Since the signs of diabetes are not immediately obvious, diagnosis can be preceded by an extended period of impaired glucose tolerance resulting in the prevalence of beta-cell dysfunction and macrovascular complications. In addition to increased medical vigilance, diabetes is being combated through aggressive treatment directed at lowering circulating blood glucose and inhibiting postprandial hyperglycemic spikes. Current strategies to treat diabetes include reducing insulin resistance using glitazones, supplementing insulin supplies with exogenous insulin, increasing endogenous insulin production with sulfonylureas and meglitinides, reducing hepatic glucose production through biguanides, and limiting postprandial glucose absorption with alpha-glucosidase inhibitors. In all of these areas, new generations of small molecules are being investigated which exhibit improved efficacy and safety profiles. Promising biological targets are also emerging such as (1) insulin sensitizers including protein tyrosine phosphatase-1B (PTP-1B) and glycogen synthase kinase 3 (GSK3), (2) inhibitors of gluconeogenesis like pyruvate dehydrogenase kinase (PDH) inhibitors, (3) lipolysis inhibitors, (4) fat oxidation including carnitine palmitoyltransferase (CPT) I and II inhibitors, and (5) energy expenditure by means of beta 3-adrenoceptor agonists. Also important are alternative routes of glucose disposal such as Na + -glucose cotransporter (SGLT) inhibitors, combination therapies, and the treatment of diabetic complications (eg. retinopathy, nephropathy, and neuropathy). With may new opportunities for drug discovery, the prospects are excellent for development of innovative therapies to effectively manage diabetes and prevent its long term complications. This review highlights recent (1997-2000) advances in diabetes therapy and research with an emphasis on small molecule drug design (275 references).

The mechanism of action of the immunosuppressive effects of antithyroid drugs has remained a matter of controversy, despite our earlier contention that such effects in vivo were indirect ie., it was our view that the drugs were acting on the thyroid cells, reducing their thyroid hormone production and other activities, with a consequent reduction in thyrocyte-immunocyte signalling. The reduction in the activation of CD4+ cells,the increased number and activation of CD8+ (and CD8+CDllb+) cells, and the reduction of soluble interleukin-2 receptors, thought once to be direct effects of the medication, are now shown to be due to amelioration of the hyperthyroidism. Thus the reduction in thyroid hormone production induced by the drugs is central to these actions. In addition, the iodination of thyroglobulin is inhibited by these agents, which may affect antigen presentation by the thyrocyte. Furthermore, there is now evidence that the thionamides interfere with thyrocyte expression of such molecules as Class I antigen, interleukin 1 , interleukin-6, prostaglandin E 2 , and heat shock protein. The expression of thyrocyte Class II antigen is probably not inhibited by these drugs, although one group has shown that lectin-stimulated thyrocyte Class II expression is diminished by this treatment this group postulated that this effect might be mediated by reduced interferon gamma production by T lymphocytes, but in vitro experiments do not corroborate this proposal. In any event, the actions as described of the effects of antithyroid drugs on the thyroid cells (particularly normalization of thyroid function) would certainly suffice to explain the diminution of thyroid antibodies (including thyroid stimulating antibody), the reduced immunological response, and the increased remission rate in Graves disease as a consequence of antithyroid drug therapy, without the need to invoke a direct immunosuppressive effect.

Postaglandins(PG) and low-density lipoproteins (LDL) both are playing a key role in atherogenesis. Their interaction at the local vascular level is of central relevance in plaque formation and progression. Details of these complex actions however, still need to be elucidated. Lipoproteins are influencing the PG-production of arterial wall cells and platelets, while PGs in turn have been shown to regulate lipoprotein receptor binding and entry into the arterial wall. Modification of LDL severely influences arterial wall trapping and foam cell formation. During LDL-modification, isoprostanes, a new family of compounds generated by free radical catalysed action, independent of cyclooxygenase, are formed. 8-epi PGF 2a the most well known member exerts a great variety of proatherogenic actions, among them vasoconstriction and platelet activation it also serves as a mitogen and stimulator of endothelin release. The influence of various eicosanoids on lipoprotein modification, however, has not been assessed yet.

Inositol phospholipids represent a small fraction of the phospholipids present in all cellular membranes with remarkable importance in regulating various cell functions. They are synthesized from phosphatidylinositol by sequential phosphorylations on the several hydroxyls of the inositol ring to create polyphos-phoinositides that function either as docking sites to promote formation of molecular signaling complexes, or serve as precursors for soluble inositol polyphosphates that act as diffusible intracellular messengers. Phosphoinositides are involved in the control of many processes, including membrane traffic, endo- and exocytosis, mitogenesis and apoptosis. Pharmacological tools have helped to clarify many details of phosphoinositide metabolism and have unveiled the roles of these lipids in the control of specific signaling pathways. However, because of their pleiotropic functions it has been questionable whether pharmacological manipulation of inositide formation and metabolism can be of therapeutic value. This review briefly summarizes the means by which inositide functions have been pharmacologically manipulated, and discusses possibilities for specifically targeting certain aspects of their regulatory functions.