Recent Patents on Endocrine, Metabolic & Immune Drug Discovery - Volume 2, Issue 1, 2008

Thyroid hormones affect the function of nearly every organ of the body, including lipid homeostasis, regulation of body weight and cardiovascular effects. Application of thyroid hormones for the treatment of metabolic and cardiovascular disorders is not possible due to their side effects, but the discovery of drugs specifically affecting some of these functions may overcome this limitation. In the current review, we outline the physiology of thyroid receptors and summarize patterns of new drugs that bind to different receptors, thereby providing the base for a treatment of patients with metabolic and cardiovascular disorders. More recently, thyrotropin releasing hormone (TRH) has been shown to improve thyroid function in patients with nonthyroidal illness syndrome (NTIS), and may provide a future therapeutic option for critically ill patients. In addition, there is evidence that TRH is involved in central nervous regulation of blood glucose and repair of brain damage. However, therapeutical application of TRH is hampered by its rapid metabolization. Specific long acting analogues may therefore allow better treatment of these conditions. Recent patents on design and therapeutical use of these drugs are summarized in this manuscript.

Eicosanoids have been the major therapeutic targets in rheumatoid arthritis and other degenerative diseases where inflammation is involved. In the past decade, the biological significance of eicosanoids and their potential as therapeutic targets in cancer have also been recognized and is now a focal area of research in many laboratories. Recently, phospholipase A2 (PLA2), the enzyme responsible for arachidonic acid supply to eicosanoid-producing enzymes has attracted attention. It has been proposed that PLA2 inhibition can yield a better therapeutic outcome than inhibition of individual eicosanoid-producing enzymes. In this article, we focus on the rationale for targeting arachidonic acideicosanoid pathways as well as evaluate the recent patents that identify inhibitors of the PLA2 family of enzymes.

Plant sterols and stanols are substances with structural homology to cholesterol, which exhibit hypocholesterolemic properties. They compete cholesterol for intestinal absorption, leading to inhibited entry of cholesterol into circulation and consequently to its lower serum concentration. Since hypercholesterolemia is closely linked with the development of cardiovascular disease (CVD), the cholesterol lowering agents play key-role in preventing CVD. A large body of evidence shows the cholesterol lowering effect of plant sterol and stanol consumption. Due to this significant property the induction of these substances in appropriate amounts in the daily food pattern of mildly hypercholesterolemic patients becomes an exigency since it is an alternative for pharmaceutical treatment. A large number of novel plant sterol and stanol derivatives have been developed with a purpose to find applications in food and pharmaceutical industry. The derivatives provide with two basic advantages: a) enhancement of lipid solubility or acquisition of water solubility with a purpose to extend the usefulness and b) additional beneficial effects for cardiovascular system such as antioxidant, hypotriglyceridemic and antiinflammatory. The article discusses the role of plant sterol and stanol consumption in lowering serum cholesterol concentration and presents patented derivatives of these substances, which can be incorporated into food and pharmaceutical products and exhibit beneficial properties.

Worldwide epidemic of type 2 diabetes mellitus, obesity, dyslipidemia, hypertension and atherosclerosis (i.e. metabolic syndrome) still requires further treatment strategies. Life style change can be regarded as single evidenced option to manage these co-morbid conditions, at the same time. Peroxisome proliferator activated receptors (PPARs) are claimed to play critical roles in metabolic adaptation to changing environmental factors. PPAR alpha and gamma agonists are approved as hypolipidemic and antidiabetic agents, respectively. Combination of PPAR alpha and gamma agonistic effects in a single molecule (i.e. dual PPAR agonists) has been tried to achieve a better multiple cardiovascular risk management. Despite their efficacy, dual PPAR agonists has been discontinued due to safety concerns. New generation of PPAR ligands with a higher safety profile is being actively investigated. Here, we review pursuits for a new PPAR class, and discuss the potential role for selective peroxisome proliferator activated receptor modulators (SPPARMs) as new patented molecules. This article also includes recent patents on this topic.

Hospital prevalence of hyperthyroidism is gradually increasing in urban population of Kinshasa. However, the reasons of this increase are not well known. Objective of this study to search the presence of anti-TSH receptor antibodies in Kinshasa's inhabitants, to identify potential candidates to the Graves' disease and to follow up hyperthyroid patients treated by anti-thyroid drugs. For this, 53 hyperthyroid patients (cases) and 44 euthyroid goiter patients (controls) were included in this study; and 20 healthy free-goiter subjects serums were measured to obtain local references. Thyrotropinbinding inhibiting immunoglobulin assay (TBII) method was used to measure the anti-TSH receptor activity in the serum. Multiple logistic regression analysis was used to identify significant risk factors and their prognostic values. A p. value of 0.05 was considered significative. It shows the prevalence of anti-TSH receptor antibodies in hyperthyroid patients is 94.3%, whereas it is 72.7% in controls; the presence of anti-TSH receptor antibodies multiplies by 4 the risk to hyperthyroidism, especially in the stressed females; and the concentrations of anti-TSH receptor antibodies are higher in hyperthyroid subjects than in controls (p = 0.025); 4) High sensitivity of the dosage (VPN = 99.9%) allows to separate non hyperthyroid persons or those with an non auto-immunological goiter, from the hyperthyroid patients. The present study showed a likely autoimmune origin of hyperthyroidism in urban population of Kinshasa; 2). The presence of anti- TSH receptor antibodies would suggest that the main cause of hyperthyroidism in hyperthyroid patients is Graves' disease, whereas their presence in patients with euthyroid goiter should suggest that they could be potential candidates to Graves' disease. This article also discussed some recent patent related to this field.

Substances that aid periodontal regeneration rely on accurate dissemination of active agents to their targets comprising connective tissue and bone. Healing is enhanced by incorporating a carrier agent and a time-release microshape containing the active agent for sustained release and improved uptake at the site of delivery. Chemotherapeutic agents range from antimicrobial, anti-inflammatory and tissue regenerative agents such as platelet rich plasma, enamel matrix proteins, bioactive glass, soy bean based bone fillers, calcium phosphate and brushite cements. Cell recognition of tissue regenerative agents within a vehicular microcapsule for local delivery aid capture of relevant cells at the required site, enhancing its actions and sustenance. Gene based therapies for tissue regeneration promote expression of specific proteins which lead to a steady supply of targeted stimulatory agents over stipulated periods. Techniques of tissue engineering and gene therapy are combined to enhance selective protein expression and expansion of specific cell populations on biodegradable scaffolds acting as carriers for dispensing the required agents. These concepts demonstrate the relevance of optimal targeting and host response which can enhance or detract from the outcome. Future work would aim to provide more consistent results with greater accuracy in targeting and optimal dosing of tissue-active agents. This review also addresses recent patents related to the field.

Massive pulmonary embolism (MPE) is characterized by high mortality. Two thirds of patients die within the first hour of MPE presentation. Significantly lower mortality could be achieved by using the optimal therapeutic dose of plasminogen activators (PAc's). It was expected that Retavase, mutant of wild type t-Pa, would be more efficient in thrombolysis than Activase, due to its longer half-life and enhanced ability to penetrate thrombus due to lack of fibrin attachments. Moreover, the regulation of endogenous TAFIa activity was tested by its inhibition by (PCI). The efficacy and safety in newly developed treatment model of rabbit MPE was tested by PAc's, Activase and Retavase and PCI, direct TAFIa inhibitor. Net clot radioactive thrombi, minced on specific size were injected into left jugular vein simulating MPE. Autologous rabbit blood clot was stabilized for one hour before mincing and injection at room temperature. Treatment was instituted instantly with doses of tested therapeutics divided equally into an immediate bolus and infusion over 60 minutes. Control group was treated with saline. No statistically significant lysis, compared to saline control, was seen in Retavase doses of 0.25, 1mg, 2mg, but significant lysis was seen for the dose of Retavase 0.5mg (p < 0.05). Statisticaly significant lysis (p < 0.05) was seen for all doses of Activase. In dose of Activase 0.5mg was seen high statistical significance (p < 0.001) compared to saline control. Both Activase and Retavase showed a maximum lysis effect at the dose of 0.5mg/kg. The loss of radioactivity in the saline group was considered as endogenous clot lysis. The lytic ability of PCI was similar to Saline innate lung thrombolysis. Statistical significant bleeding, compared to the saline control, was seen for doses of Retavase and Activase, except Activase 0.25 mg. Highly statistical significant bleeding was observed using dose of 0.25 mg Retavase (p = 0.0019) and dose of Activase 2mg (p=0.0041) compared to the saline control. Activase demonstrated distinct thrombolytic capacity over Retavase in rabbit MPE study. PCI inhibitory potential has to be further examined and later tested in higher doses or in combination with lytics to reexamine its TAFIa regulatory potential during MPE. This article also discussed recent patents relevant to the field.

Thrombin activatable fibrinolysis inhibitor (TAFI) is a zymogene that potently inhibits fibrinolysis. It is synthesized by the liver and has an inhibitor role in fibrinolysis through the removal of the carboxy-terminal lysine and arginine residues from partially degraded fibrin polymers. Besides, TAFI has a suppressor effect on conversion of inactive plasminogen to plasmin. Alterations in TAFI pathway have been reported in many conditions. Few data are present in the literature regarding the relationship between TAFI and endocrine disorders. The results from few studies in patients with cardiovascular disease are conflicting. Understanding the role of TAFI in the pathogenesis of endocrine and cardiovascular disorders may hold promise for improving management of these diseases. This paper includes a review of the studies and patents concerned with TAFI pathway and endocrine and cardiovascular problems.

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