Recent Patents on Endocrine, Metabolic & Immune Drug Discovery - Volume 8, Issue 2, 2014

Insulin pharmacology has evolved from nonhuman source based extraction of insulin, to use of recombinant technologies for human insulin production, to tailor made synthetic insulin analogues. The delivery techniques of insulin have also improved, from injections to pumps, and to pumps with sensors. However, to achieve the final goal of a closed loop insulin delivery is far from achieved. One of the researches in this direction includes synthetic smart insulins. These are systems with chemical sensors for glucose, linked to reactions that trigger glucose mediated insulin delivery. Interest in this field is high and recent publications and patents show promise. The current review tries to summarize the basic concept of smart insulin as well as cater the recent developments and patents in this direction.

Propolis is a resinous material collected by honeybees from numerous plants and serves as a defense against intruders. Because of its relevant curative properties, it is now gaining popularity in health foods and in cosmetic products. Understanding the underlying molecular mechanisms of phytochemicals has become a good strategy in bioprospection for new anti-inflammatory compounds. The biological activity of propolis derives from its high levels of phenolic acids, while flavonoids are thought to account for the activity of propolis extracts. The comprehension of the relationship between propolis and the immune system has progressed in the last years, recent articles have provided important contributions to this investigation field. Studies have shown that propolis suppressed the “IL-6-induced phosphorylation of signal transducer and STAT3”, an essential cytokine-activated transcription factor in Th17 development. Therefore, action mechanisms of “propolis on Th17 differentiation could be instrumental in controlling disturbed cytokine networks in inflammation, autoimmune diseases, and infections.” The use of propolis has been proposed in some patents as: WO201363714; CN102885854, WO2013142936, US20130266521, and US20130129808, which are related to the treatment of dental diseases; adjuvant in anti-cancer treatment; in cosmetic products; as an anti-inflammatory agent and natural antibiotic. Although there are many publications regarding the propolis efficacy, its applicability to human health and mechanisms of action are not completely understood, creating opportunities for new studies.

The C-X-C chemokine receptor (CXCR)3 and its chemokines (CXCL9, CXCL10, CXCL11) are involved in the pathogenesis of autoimmune thyroiditis (AT), Graves’ disease (GD) and Graves’ Ophthalmopathy (GO). Under the influence of interferon(IFN)γ, the IFNγ-induced protein 10 (IP-10/CXCL10) is secreted by thyrocytes, orbital fibroblasts and preadipocytes. In tissue, Th1 lymphocytes are recruited; hence IFNγ is enhanced, which stimulates CXCL10 secretion reiterating the autoimmune process. The presence of elevated levels of CXCL10 in peripheral liquids is considered a marker of Th1 orientated immune response. High levels of circulating CXCL10 (sCXCL10) have been shown in patients with AT, overall with hypothyroidism. In GD and GO patients high sCXCL10 have been shown particularly in the active disease. A modulatory role of peroxisome proliferator-activated receptor (PPAR)γ or - α agonists on CXCR3 chemokines in AT, GD and GO and the immuno-modulatory effect of methimazole on CXCR3 chemokines in GD have been shown. Further studies are ongoing to explore the use of new molecules that act as antagonists of CXCR3, or block CXCL10, in autoimmune disorders, and many interesting patents have been recently applied.

Melatonin’s function in modulating the circadian cycle of Plasmodium falciparum has been an intense investigation for the past 45 years. The stimulatory effects of melatonin on malaria growth, development and differentiation have been confirmed by numerous studies conducted in the past 40 years but the molecular mechanisms underlying melatonin stimulatory effects have been well understood recently. Melatonin has been identified as a “signal” essential for synchronization of malaria parasitic cell cycle. Melatonin has been shown to modulate the release of intracellular Ca2+ and cAMP in Plasmodium falciparum. In this context, melatonin receptor blocking agent luzindole has been shown to block melatonin’s actions in these intracellular events occurring in human malaria parasites. Recent studies have resulted in the synthesis and development of melatonin derivatives, compounds 7-11 and 12-16. Of these compounds 12, 13 and 14 were able to inhibit the Plasmodium falciparum growth and this serves as a promising lead for the development of future antimalarial compounds that will have rapid antimalarial actions with low toxicity. Some antimalarial drugs that have been patented are also summarized in this review.

Ovarian hyperstimulation syndrome (OHSS) is a severe iatrogenic complication of ovulation induction, which has a very serious impact on the patient’s health, as it is often associated with a high morbidity and mortality risk. Indeed, patients classified as having severe OHSS presented with liquid imbalance signs (such as rapid weight gain, tense ascites, respiratory difficulty and progressive oliguria), which are related to the fluid shift from the intravascular space to third space compartments subsequent to an increased capillary permeability. In this way, cardiovascular system findings include decreased intravascular volume, decreased blood pressure, decreased central venous perfusion, and compensatory increased heart rate and cardiac output with arterial vasodilation might be found concomitantly. Notwithstanding that venous thromboembolic phenomena are a possible complication in advanced phases of OHSS, arterial ischemia involving the cerebral circulation is a rare but recently reported problem. The pathogenesis of thromboembolism in OHSS is not fully understood, even though hemoconcentration and blood hyperviscosity seem to play a role in developing thrombotic changes into both venous and arterial system. Interestingly, the presence of cardiac abnormalities in combination with inherited or acquired hypercoagulable state seems to increase the risk of cerebral infarct in these subjects, as recently shown by our group. This review is aimed at investigating the pathomechanism and the management of neurovascular complications related to OHSS, including new treatment options.

Insulin analogues are a major improvement in diabetes pharmacotherapy. Rapid acting insulins have certain advantages over regular insulin, but there is a need to develop even faster acting insulin preparations, which mimic physiological insulin release in a better manner. This review discusses recent developments and patents in the field of Ultra- fast acting insulins. It classifies various approaches towards creation of an Ultra-fast acting insulin profile based upon the method used to achieve a faster onset of action. These include change in formulation of insulin, addition of excipients to insulin, and utilization of novel insulin sites or delivery methods. It examines the current state of evidence, and the developments in the field of newer insulin analogues & delivery methods.

Subclinical hypothyroidism (sHT) is very common in general population, especially in women and older people. sHT individuals may experience symptoms that resemble those observed in overt hypothyroidism, resulting in impaired quality of life (QOL). Asymptomatic patients may suffer a reduction in perceived health status due to the awareness of disease. Cognitive function represents one of the most important domains of the QOL questionnaires. Given the intrinsic relationship between cognitive status and QOL it is worth to address these topics together, in a systematic review of the literature. Thus, we reviewed the English scientific literature available on National Library of Medicine (www.pubmed.com) sine 1980 regarding hypothyroidism, sHT, elderly, L-thyroxine (LT4) therapy, QOL, cognition, brain. We supplemented the search with records from personal files, textbooks, and relevant articles. The possible link, at molecular level, between cognition and thyroid failure was also assessed. Conflicting results on the association between sHT and cognitive and health related QOL impairment are still present, although the most recent, naturalistic studies did not find any significant relationship. Interestingly, a reduction in health related QOL is frequently reported in patients with thyroid autoimmune diseases regardless of thyroid dysfunction. We also report most significant patents on the topic.

Objective: The real benefit of follow-up cervical cytology in women treated for gynecological cancer is unclear. This study was designed to assess the rate of success of cytological examinations in the detection of early vaginal recurrence of gynecological cancer in women found by other methods to have vaginal recurrence of cervical and endometrial cancer. Data Sources: Records of cytological examinations. Study Selection: Thirty-three women treated for early and invasive cervical and endometrial cancer with recurrence in the vaginal vault were retrospectively analyzed. Data Extraction: Records from 1979 to 2010. Data Synthesis: Sixteen women (48.5%) had symptomatic vaginal recurrence associated with distant metastases, whereas 17 (51.5%) had vaginal recurrence only. Cytology was negative in 12 women (36.4%) with both symptomatic and asymptomatic recurrence and positive in the other 21 (63.6%). In 9 of these 21 women (42.9%), the disease was limited to the vaginal vault, whereas the remaining 12 (57.1%) presented with vaginal lesions associated with distant metastases. Cytology was positive in 9 of the 17 (52.9%) women whose recurrence was limited to the vaginal vault and negative in 8 (47.1%). Conclusion: Vaginal cytology yielded false-negative results in almost half of the women with vaginal recurrence of gynecological cancer. Patents of methods used for early diagnosis and detection of immortalization of cervical cancer are also reviewed in this article.

A new method of reduction of autoimmune process activity related to the thyroid in patients without signs of thyroiditis is presented in the article (patent of Ukraine No. 103742). New patents and inventions from different countries of the world related to the problem have been analysed. Materials and Methods: Sixty one patients with a significant disturbance of tolerance to the thyroid antigens in the absence of disturbance of the thyroid function were involved in the research. Twenty two patients with chronic hepatitis C, genotype 1 HCV, receiving antiviral therapy, were also included in the research. Patients were immunized intracutaneously with autoleukocytes for autoimmune process inhibition. After single immunization with autoleukocytes decrease in the level of antibodies against the thyroid antigens was observed in all patients. In some patients without chronic hepatitis C the levels of thyroperoxidase and thyroglobulin antibodies decreased by 50% and more (33.33% and 20.51%, respectively). In patients with ChHC these indices were considerably lower, and the duration of the achieved effect was shorter. However, immunization inhibited activity of immune process in patients with ChHC due to interferon therapy. The suggested method enables to decrease the threat for thyroiditis development even in patients with chronic hepatitis C during antiviral therapy.