Recent Patents on Endocrine, Metabolic & Immune Drug Discovery - Volume 10, Issue 2, 2016

Background: Glucose-stimulated insulin secretion (GSIS) from the pancreatic β-cell involves several intracellular metabolic events which lead to the translocation of insulin granules towards the membrane for fusion and release. It is well established that loss of β-cell function and decreased GSIS underlie the pathogenesis of diabetes. Evidence from several laboratories, including our own, demonstrated requisite roles of Rac1 and phagocyte-like NADPH oxidase (Nox2)-derived reactive oxygen species (ROS) in optimal function of the pancreatic β-cell, including GSIS. However, it is becoming increasingly clear that prolonged exposure of β-cells to hyperglycemic conditions, leads to sustained activation of Rac1-Nox2 signaling axis culminating in excessive generation of intracellular ROS (oxidative stress) and β-cell dysregulation and demise. Such “cytotoxic” effects of ROS appear to be mediated via the stress-activated protein kinases/mitogen-activated protein kinases (SAPK/MAPK) signaling pathways. Objective: This review discusses our current understanding of regulation and functions of the conventional MAPKs, namely, ERK1/2, JNK1/2 and p38MAPK. Conclusion: The MAPK pathways are activated in the presence of various stress stimuli including intracellular ROS, via distinct signaling cascades. Once activated, MAPKs participate in specific intracellular signaling processes via interaction with several downstream kinases including the MAPKactivated protein kinases (MAPKAPKs) and transcription factors including c-jun and p53. We have provided an overview of existing evidence in the islet β-cell on the regulatory roles of these MAPKs in mediating cellular responses to alterations in intracellularly generated ROS, which is mediated by the Rac1-Nox2 signaling module. Additionally, we enlisted recent patents developed to improve β-cell function in diabetes and novel pharmacological agents that target oxidative stress and MAPK pathways.

Background: Physiological changes in pregnancy result in increased iodine demand, which may not be met in areas of mild-to-moderate iodine deficiency or borderline sufficiency. As a pregnant woman is the only source of thyroid hormones for her child during early gestation, iodine deficiencyinduced hypothyroxinemia may have deleterious effects on fetal development. Objective: To present the current approach to iodine deficiency and its prophylaxis during pregnancy. Methods: A review of the current literature including patents on iodine deficiency in pregnancy has been performed. Results: Negative influence of severe iodine deficiency on fetal development has been proved, and evidence on a deleterious impact of milder forms of iodine deficiency on cognition of the offspring is rapidly growing. Although the WHO has addressed the issues of monitoring iodine status during pregnancy, prophylactic measures and assessment of their effectiveness, there are some controversies, regarding for example the best methods for control of iodine status. New patents in urinary iodine measurement methods may make iodine nutrition monitoring easier. The main method of iodine prophylaxis, in pregnancy also, is universal salt iodization. However, particularly if there is not sufficient coverage of the households with iodized salt, additional measures, such as oral supplementation with potassium iodide tablets, are necessary in pregnant women to provide adequate iodine nutrition. Iodine supplementation improves maternal thyroid function indices; particularly, it prevents goiter formation. Conclusion: Stronger evidence on beneficial effects of iodine supplementation of mild-to-moderate iodine deficient pregnant women on cognitive function of their children is still needed. It may be provided by randomized controlled trials and international initiatives. Changes in the iodine prophylaxis system should be monitored, both to prevent decreased or excessive iodine intake.

Background: Plants have been known as an integral part of traditional medicine because of their phytoconstituents with their miraculous substances. Tinospora cordifolia (Guduchi/ Giloy) is one such plant having pharmacological functions and medicinal values due to its several constituents such as terpenes, glycosides, alkaloids, steroids and flavonoids. Thus, it has been rightly mentioned in old texts as “Amrita”. Objective: The objective of the present review is to extend the current knowledge, importance and beneficial pharmacological applications of guduchi in humans for safeguarding various health issues. Methods: We extensively reviewed, analyzed and compiled salient information from the published literature available in PubMed and other scientific databases. Results: The present review describes medicinal applications of T. cordifolia in countering various disorders and usages as anti-oxidant, anti-hyperglycemic, antihyperlipidemic, hepatoprotective, cardiovascular protective, neuroprotective, osteoprotective, radioprotective, anti-anxiety, adaptogenic agent, analgesic, anti-inflammatory, antipyretic, a thrombolytic agent, anti-diarrheal, anti-ulcer, anti-microbial and anti-cancer agent. The plant is also a source of micronutrients viz. copper, calcium, phosphorus, iron, zinc and manganese. A special focus has been made on its health benefits in treating endocrine and metabolic disorders and its potential as an immune booster. Several patents have been filed and granted to inventions encompassing T. cordifolia as a major component of therapeutics for ameliorating metabolic, endocrinal and several other ailments, aiding in the betterment of human life expectancy. Conclusion: The information presented would be beneficial for researchers, medical professionals and pharmaceutical companies to design and develop effective medicines, drugs and healthical products exploiting the multiple as well as specific modes of actions of T. cordifolia, and also help in promoting and popularizing this rich herb having promising potentials to prevent and treat various ailments.

Background: Obesity is a chronic condition with high prevalence and multifaceted aetiology, accompanied by an increased risk of morbidity and mortality. Obesity has several negative effects on the psychological status, and the severity of psychological disorders correlates with the degree of obesity. Objective: Aim of this review is to provide an overview of the literature concerning the psychological distress associated with severe obesity, which contributes to deterioration of the quality of life of affected patients. Methods: Dysfunctional eating behaviours and eating disorders, psychiatric comorbidity, cognition and quality of life will be discussed together with the most common drugs that can be employed to treat the various disorders in this peculiar clinical setting. The effects of bariatric surgery will be also reviewed. Results: Obesity is often the result of pathological behaviours implemented in an eating disorder. Inconsistent results have been reported with regard to the effect of severe obesity on cognition, which recognize a multifaceted aetiology. Serotonergic agents play an important role in the management of patients with obesity and binge episodes, fluoxetine being currently a drug approved for this disorder. The efficacy of lorcaserin, a combination of bupropion and naltrexone, or antiepileptic medications (topiramate and zonisamide) has also been proposed. A neuroprotective role of leptin and oestrogen has been hypothesized. Bariatric surgery is a helpful treatment of morbid obese patients, with long-term favourable results on the psychopathological profile. Conclusion: Psychological, psychoeducational and psychopharmacological treatment can facilitate weight loss in morbid obese subjects with psychopathological comorbidities. A precise definition of the mechanisms affecting appetite, satiety and energy balance is expected to foster the development of new effective antiobesity drugs.

Background: Iodine deficiency (ID) is a major cause of brain damage if not corrected in early pregnancy. Even mild ID leads to measurable neurointellectual impairment. The iodine global network (IGN), previously the international council for the control of iodine deficiency disorders (ICCIDD), has achieved remarkable progress in facilitating iodine nutritional sufficiency in about 70-80% of countries in the world during the past 3 decades or so. Results: At present there are 25 countries with documented iodine deficiency. However, there are still many countries, especially in Europe, with mild iodine deficiency which require active interventional strategies to ensure adequate iodine nutrition. In this context, rigorous monitoring of iodine status is essential to ensure adequate iodisation. Conclusion: The IGN, with 10 world-wide regional coordinators and 100 national coordinators is well placed to implement appropriate strategies to achieve these goals. The recent award of a Horizon 20/20 grant to European stakeholders to harmonise iodine supply in Europe emphasises the commitment of the EU to make improvement in the global iodine health. There are no relevant recent patents for this report.

The natural resources of iodine are seawater, seaweeds and saltpeter-nitrate deposits in Chile. Over 1/3 of the global population is exposed to iodine deficiency, especially in the mountains. Iodine is a component of the thyroid hormones and a strong antioxidant with electric potential of -0.54 V. Iodine as iodide is taken up by the thyroid gland, gastric mucosa, salivary glands and mammary glands in pregnant and breast-feeding women. The transport of iodine to the thyroid gland is regulated by specific enzymes: Natrium Iodine Symporter, Na+/K+ATPase, Pendrin and Apical Iodine Transporter. In the thyrocytes, the thyroid hormones biosynthesis is carried out by iodization of tyrosine to T3 and T4. Secretion of T3 and T4 is regulated by TSH. On the tissue level, the active hormones are T3 and its derivative thyroamine. The most important target is the cardiac muscle, where T3 action results in an increase in the inotropic action and thyroamines exert a negative inotropic and chronotropic effects. The consequences of iodine deficiency are endemic goiter, irreversible brain damage, cretinism, impaired thyroid function and thyroid, gastric and mammary glands cancers. In 1994, the World Health Organization proposed the main strategy for iodine prophylaxis, i.e. Universal Salt Iodization. In Poland, a new model of iodine prophylaxis was introduced in 1996; the model includes obligatory iodization of household salt and neonate formulas and recommendation to take an additional daily dose of iodine for pregnant and breast-feeding women. This model allowed for eliminating endemic goiter in schoolchildren, eradicating cretinism in mountainous areas, and markedly diminished thyroid and gastric cancer incidence. In 2002, WHO classified Poland as a country with a proper daily iodine intake on the population level. No relevant patents were reported for this WHO report.

Background: Gynecomastia may occur physiologically in the neonatal period, during puberty, and in old age. It may also develop in association with various pathologic states. The challenge for the physician is to distinguish physiological gynecomastia from those with an underlying pathology. Objective: To review in depth the pathophysiology, clinical manifestations, and treatment of gynecomastia. Method: A PubMed search was completed in Clinical Queries using the key term “gynecomastia”. Patents were searched using the key term “gynecomastia” from www.google.com/patents, www.uspto.gov, and www.freepatentsonline.com. Results: Gynecomastia is caused by an imbalance between the stimulatory effect of estrogen and the inhibitory effect of androgen at the breast tissue level. Clinically, gynecomastia is characterized by the presence of a firm or rubbery, discrete, subareolar ridge of glandular tissue that is symmetrical in shape, freely movable, and nonadherent to skin or underlying tissue. Since most cases of physiological gynecomastia regress spontaneously with time, reassurance is all that is necessary. For pathological gynecomastia, treatment should be directed at the underlying cause, if possible. If gynecomastia persists in spite of the above measures, pharmacologic therapy and reduction mammoplasty may be considered. Recent patents related to the management of gynecomastia are discussed. Conclusion: The majority of cases are physiological and do not require treatment other than reassurance. For pathological cases, the underlying cause should be treated if possible. If gynecomastia persists in spite of the above measures and treatment becomes necessary, tamoxifen is the treatment of choice. Reduction mammoplasty may be considered for resistant cases.

Background: Iodine deficiency has been one of the most prevalent micronutrient deficiencies in the world, causing many health disorders, particularly in pregnant women and children. Despite increased salt iodization in some countries and regions, the process has lacked global coordination and sustainability, two prerequisites for reaching the aim of eliminating iodine deficiency. This goal can be reached only by evidence-based, effectively monitored joint and committed actions of all countries. Objective: The aim of the article is to present the role of WHO in leading and coordinating public health actions aiming elimination of iodine deficiency. Results: WHO was given a mandate to coordinate such public health actions, including developing and strengthening relevant public health legislation, issuing technically sound and evidence-based norms and standards, and monitoring the health situation and trends. Conclusion: WHO has coordinated and fostered collaboration between countries, international organizations, scientific associations and non-governmental organization to reach the goal of eliminating iodine deficiency. No recent patents are discussed for this WHO report.

Background: Paracoccidioidomycosis (PCM) is a systemic mycosis caused by dimorphic fungi Paracoccidioides brasiliensis and Paracoccidioides lutzii. It is prevalent in Latin American, mainly in Brazil. Therefore, PCM has fundamental impact on the Brazilian global economy, especially in public health system, since it is affecting economical active population in different country regions. Objective: The present study aimed to standardize the Real Time-Polymerase Chain Reaction (rt-PCR) for an efficient and safe PCM diagnosis amplifying the recombinant protein PB27 gene, only expressed by specimens of Paracoccidioides genus. Methods: To standardize a methodology of rt-PCR using species-specific primers and probe designed for annealing in this specific region of the fungi´s genome, amplifying the recombinant protein PB27 gene, only expressed by specimens of Paracoccidioides genus. Followed by design in silico, experiments were performed in vitro to determine rt-PCR specificity, efficiency and genome detection limit. Results: The primers and probe sequences were deposited in Brazilian Coordination of Technological Innovation and Transfer (CTIT), under patent reference number BR1020160078830. The present study demonstrated the rt-PCR applicability for support on diagnosis of paracoccidioidomycosis, presenting low cost, which makes it affordable for public health services in developing countries as Brazil. It is noteworthy that it is necessary to validate this methodology using clinical samples before to use as a safe method of diagnosis. A review of all patents related to this topic was performed and it was shown that, to date, there are no records of patent on kits for paracoccidioidomycosis´s diagnostic. Indeed, there is still a lot to go to reach this goal. Conclusion: The reaction developed was standardized and patented, opening perspectives to molecular diagnosis development for paracoccidioidomycosis, since rt-PCR can be applied to a broad spectrum of infectious diseases. It would need to be tested in biological samples in order to validate this method and then generate a diagnostic kit for Paracoccidioidomycosis.