Investigational anabolic agents for the treatment of osteoporosis: an update on recent developments

Introduction: Teriparatide, a PTH analogue, was the first anabolic agent to be approved for the treatment of osteoporosis in 2002. Abaloparatide was also recently approved by the FDA. The need for other anabolic agents is still unmet.

Areas covered: In this review, we discuss target molecules and recent advances in the field of anabolic therapy for osteoporosis. PTH and PTHrP analogues binding to the PTH receptor and different routes of administration of teriparatide to avoid the burden of daily subcutaneous injections are discussed. We also review antibodies targeting suppressors of the Wnt pathway such as sclerostin and Dickopff-1.

Expert opinion: The development of alternative ways of administering PTH receptor ligands is a promising field, especially via the transdermal route. Other more promising molecules are still at very early stages of development. FDA recently requested more data on Romosozumab.     

Advances in pharmacotherapy for secondary hyperparathyroidism

Introduction: Secondary hyperparathyroidism is a frequent complication of chronic kidney disease. This review will discuss the various therapeutic options available for the management of hyperparathyroidism.

Areas covered: The main therapeutic strategies available to prevent or slow down the progression of hyperparathyroidism will be detailed here. Reductions in phosphatemia may be achieved by controlling dietary phosphorus, administering phosphorus binders, or increasing the frequency of dialysis sessions. Vitamin D sterols reduce parathyroid hormone (PTH) secretion while normalizing calcium (Ca) and vitamin D levels. Calcimimetics decrease PTH levels, probably with an additional effect on hyperplasia. Percutaneous injections in parathyroids represent an option useful in cases of hyperparathyroidism resistant to pharmacological therapy. Pubmed was searched by combining the terms ‘secondary hyperparathyroidism’ and the name of each one of the drugs reported in this review.

Expert opinion: PTH increases from early stages of renal disease. One of the goals in pre-dialysis is the prevention of hyperphosphatemia and the maintenance of Ca levels in the normal range. The management of hyperparathyroidism in dialysis requires control of phosphorus level. In this stage, the decision to use calcimimetics and vitamin D derivatives should be made according to serum levels of Ca and phosphorus.     

Drug safety evaluation of parathyroid hormone for hypocalcemia in patients with hypoparathyroidism

Introduction: Hypoparathyroidism is a rare disorder characterized by low serum calcium levels and high serum phosphate levels, and low or inappropriately normal levels of parathyroid hormone (PTH). This disease is commonly treated with calcium supplements and active vitamin D metabolites or analogues, but large doses of these supplements are often utilized to relieve the symptoms caused by hypocalcemia, without guarantee of a physiological normalization of calcium-phosphate homeostasis.

Areas covered: Several studies have investigated replacement therapy with recombinant human PTH [rhPTH (1-84) and rhPTH (1-34)] for subjects with hypoparathyroidism. In 2015, The Food and Drug Administration (FDA) approved, in the United States, rhPTH (1–84), named Natpara®, a bioenginerred rhPTH, for the management of chronic hypoparathyroidism not well controlled with conventional therapy. This article evaluates the safety and tolerability of rhPTH (1–84) in patients with chronic hypoparathyroidism, and also describes the studies conducted so far on rhPTH (1-34) used for chronic hypoparathyroidism.

Expert opinion: The research done in this field has shown that replacement treatment with rhPTH is an attractive option for subjects with hypoparathyroidism who are unable to maintain stable and safe serum and urinary calcium levels. However, since therapy with rhPTH is a long-term management option in hypoparathyroidism, more long-term safety data are needed.     

Investigational and experimental GnRH analogs and associated neurotransmitters

Introduction: The GnRH agonistic analogs enable for desensitizing the hypothalamo-pituitary-gonadal axis in malignant and benign conditions where minimizing the production of sex hormones, or blocking ovulation is necessary. The possible indications are prostate cancer, benign prostate hyperplasia, breast cancer, endometriosis, precocious puberty, uterine leiomyomata, assisted reproduction (ART)/in vitro fertilization (IVF), PCOS, minimizing the gonadotoxic effect of chemotherapy in young women, and possibly ovarian cancer.

Areas covered: The aim of the current review is to summarize, giving a critical overview, of the investigational GnRH agonists, and shortly discuss the difference between the GnRH agonists, antagonists, Kisspeptin, and Neurokinin B analogs.

Expert opinion: The broad armamentarium of agonists may make it possible, in the future, to expand the indications and uses of these analogs, choosing and specifically tailoring the analog to the required effect, while minimizing side effects.     

Medicinal plants and natural products in amelioration of arsenic toxicity: a short review

Context: Chronic arsenic toxicity (arsenicosis) is considered a serious public health menace worldwide, as there is no specific, safe, and efficacious therapeutic management of arsenicosis.

Objectives: To collate the studies on medicinal plants and natural products with arsenic toxicity ameliorative effect, active pre-clinically and/or clinically.

Methods: Literature survey was carried out by using Google, Scholar Google and Pub-Med. Only the scientific journal articles found on the internet for last two decades were considered. Minerals and semi-synthetic or synthetic analogs of natural products were excluded.

Results: Literature study revealed that 34 medicinal plants and 14 natural products exhibited significant protection from arsenic toxicity, mostly in preclinical trials and a few in clinical studies.

Conclusion: This research could lead to development of a potentially useful agent in clinical management of arsenicosis in humans.     

Predictors of skeletal-related events among cancer patients with bone metastases treated with zoledronic acid: a secondary analysis of a randomized study

Background: The purpose of the current study is to assess the predictors of skeletal-related events (SREs) among advanced cancer patients with bone metastases treated with zoledronic acid within a randomized study.

Research design and methods: This is a secondary analysis of patient-level data of advanced cancer patients with bone metastases who were treated with monthly zoledronic acid in the NCT00330759 clinical trial.

Results: A total of 702 patients were included in the current analysis. In univariate logistic regression analysis, higher body mass index (P = 0.034) and lytic nature of bone metastasis (P = 0.008) were found to be predictive of a higher probability of SREs. When the two factors were included in a multivariate logistic regression model, both of them were predictive of the later development of SREs (P value for higher body mass index = 0.015; P value for lytic bone lesions = 0.005).

Conclusion: Among advanced cancer patients with bone metastases, lytic nature of metastases, as well as higher body mass index, are associated with a higher probability of SREs.

Trial registration number: this clinical trial was registered at clinicaltrials.gov with the number: nct0033     

Inhibitors of α-glucosidase and α-amylase from Cyperus rotundus

Context: A methanol extract of Cyperus rotundus L. (Cyperaceae) rhizomes showed inhibitory activity against α-glucosidase and α-amylase, two enzymes involve in carbohydrate digestion.

Objective: Identification of compounds from C. rotundus rhizomes responsible for the inhibition of α-glucosidase and α-amylase.

Materials and methods: Compounds were identified by a phytochemical investigation using combined chromatographic and spectroscopic methods. α-glucosidase and α-amylase inhibitory activities were evaluated by in vitro enzyme inhibition assays.

Results: A new (2RS,3SR)-3,4′,5,6,7,8-hexahydroxyflavane (1), together with three known stilbene dimers cassigarol E (2), scirpusin A (3) and B (4) were isolated. Compound 2 inhibited both α-glucosidase and α-amylase activities while the flavane 1 only showed effect on α-amylase, and compounds 3 and 4 were active on α-glucosidase. All four compounds showed significant 2,2-diphenyl-1-picrylhydrazyl (DPPH) scavenging activity.

Discussion: The inhibitory activities against α-amylase and α-glucosidase of the C. rotundus rhizomes were reported for the first time. Stilbene dimers are considered as potent inhibitors of α-glucosidase and promising antihyperglycemic agents.

Conclusion: The isolated compounds may contribute to the antidiabetic property of C. rotundus.     

Novel benzopyran derivatives and their therapeutic applications: a patent review (2009–2016)

Introduction: The benzopyran derivatives present a wide variety of biological activity and behaviour. At the same time the benzopyran derivatives support their use as therapeutic agents for multiple diseases. Their structural characteristics correlated to physicochemical properties seem to define the extent of the biological activity.

Areas covered: This review summarizes new patents published on new benzopyran derivatives from 2009 to 2016.

Expert opinion: Many benzopyran derivatives have vivo/vitro biological responses. Their clinical evaluation will be critical to assess therapeutic utility. The compounds containing benzopyran moiety is well defined as lead compounds for design of new more promising molecules.     

Somatostatin analogs in the treatment of neuroendocrine tumors: current and emerging aspects

Introduction: Neuroendocrine tumors (NETs) harbor somatostatin receptors and there is a strong rationale for using somatostatin analogs (SSAs) for treatment of NETs.

Areas covered: This article discusses i) pharmacology of somatostatin and its analogs; ii) antisecretory and anti-proliferative effects of SSAs in NETs; iii) efficacy and safety of emerging therapeutic regimens with first generation SSAs administered at either high doses or in combination with antineoplastic drugs; iv) efficacy and safety of pasireotide and chimeric molecules; v) efficacy of radionuclide therapy of NETs using SSAs.

Expert opinion: SSAs are the first-line medical therapy for functioning and non-functioning well-differentiated NETs. In patients not responder to first generation SSAs, the increase of drug dose over the conventional regimens, the combination of SSAs with other biotherapies or molecular targeted therapies, the switch to pasireotide or the use of SSAs in radionuclide therapy may improve the therapeutic success.     

Role of osteopontin as a predictive biomarker for anti-EGFR therapy in triple-negative breast cancer

Objective: Effective targeted therapies for patients with triple-negative breast cancer (TNBC) present an unmet clinical need. There is evidence that TNBCs often have increased expression of the epidermal growth factor receptor (EGFR) and of osteopontin (OPN). OPN-mediated signaling can activate EGFR-dependent signaling pathways. Here, we assessed OPN as a potential predictive biomarker for response to anti-EGFR therapy in TNBC.

Research design and methods: Using two different TNBC cell lines, MDA-MB-468 and MDA-MB-231, we investigated the impact of stable expression of OPN on efficacy of the EGFR inhibitor erlotinib in vitro.

Results: We observed that breast cancer cells engineered to overexpress OPN are more sensitive to growth inhibition by erlotinib than control cells. The level of response was related to the level of OPN expression, possibly due to increased phosphorylation status of EGFR Tyr1068.

Conclusions: These results indicate that OPN expression levels are related to sensitivity of TNBC cells to growth inhibition by erlotinib. OPN thus is a promising predictive biomarker for anti-EGFR therapy in breast cancer.     

A review on phytochemical and pharmacological properties of Litsea coreana

Context: Litsea coreana H. Lév. (Lauraceae) is used as an ethnic herb or beverage in China. Substantial studies indicate that it contains a variety of compounds and shows diverse bioactivities with no toxicity.

Objective: This review analyzes and summarizes the ethnopharmacological applications, phytochemistry, and pharmacological activities and molecular mechanisms of L. coreana.

Methods: Related literature (from 1998 to 2016) was obtained and compiled via searching databases including Scopus, Web of Science, Google Scholar, CNKI and PubMed. Keywords (Litsea coreana, hawk tea, eagle tea and laoying cha) were used to select the articles.

Results: Studies indicate that L. coreana contains characteristic polysaccharides, polyphenols, essential oils, and numerious flavonoids, which exhibit remarkable bioactivities, such as hepatoprotection, hyperglycaemia, anti-inflammation, antioxidation and antibacterial, through multiple molecular mechanisms.

Conclusion: This paper provides a systematic review on the phytochemicals and pharmacological activities of L. coreana which should be useful for further study and application of this medicinal herb.     

Taurine reduces blue light-induced retinal neuronal cell apoptosis in vitro

Background: The massive uptake of organic compatible osmolytes is a self-protective response to multiple stressors.

Objective: This study aimed to determine the protective effects of the osmolyte taurine against blue light-induced apoptosis in retinal neuronal cells in vitro.

Methods: Real-time PCR was used to measure osmolyte transport. Radioimmunoassays were performed to measure osmolyte uptake. Cell Counting Kit-8 assays were conducted to measure cellular viability. Flow cytometry analysis was used to measure apoptosis.

Results: Compared with normotonic stress, hypertonic stress-induced uptake of osmolytes, including betaine, myoinositol, and taurine, into the retinal neuronal cells. Blue light increased osmolyte transporter mRNA expression together with osmolyte uptake. Furthermore, taurine significantly suppressed blue light-induced retinal neuronal cell apoptosis.

Conclusion: The compatible osmolyte taurine may have an important role in cell resistance to blue light and cell survival.     

Echinacea biotechnology: advances,commercialization and future considerations

Context: Plants of the genus Echinacea (Asteraceae) are among the most popular herbal supplements on the market today. Recent studies indicate there are potential new applications and emerging markets for this natural health product (NHP).

Objective: This review aims to synthesize recent developments in Echinacea biotechnology and to identify promising applications for these advances in the industry.

Methods: A comprehensive survey of peer-reviewed publications was carried out, focusing on Echinacea biotechnology and impacts on phytochemistry. This article primarily covers research findings since 2007 and builds on earlier reviews on the biotechnology of Echinacea.

Results: Bioreactors, genetic engineering and controlled biotic or abiotic elicitation have the potential to significantly improve the yield, consistency and overall quality of Echinacea products. Using these technologies, a variety of new applications for Echinacea can be realized, such as the use of seed oil and antimicrobial and immune boosting feed additives for livestock.

Conclusions: New applications can take advantage of the well-established popularity of Echinacea as a NHP. Echinacea presents a myriad of potential health benefits, including anti-inflammatory, anxiolytic and antibiotic activities that have yet to be fully translated into new applications. The distinct chemistry and bioactivity of different Echinacea species and organs, moreover, can lead to interesting and diverse commercial opportunities.     

Monoterpenoids from the whole herb of Veronicastrum axillare

Context: Veronicastrum axillare (Sieb. et Zucc.) Yamazaki (Scrophulariaceae) embraces varieties of bioactivities such as anti-inflammatory, anti-pyresis and detoxification activity, while little is known of the phytochemical components of this medicinal plant.

Objective: To isolate and identify bioactive constituents from the whole herb of V. axillare.

Materials and methods: Ethanol extract of the whole herb of V. axillare was subjected to successive column chromatography. Chemical structures of the compounds were elucidated by detailed spectroscopic analyses on the basis of NMR, IR and HR-MS data.

Results: A new monoterpenoid, axillacetal A (1) and a known analogue, tarumal (2), were isolated from the whole herb of V. axillare. The structure of tarumal (2) was also revised according to our NMR data.

Discussion and conclusion: This is the first report on the isolation and authentication of novel chemical constituents from V. axillare.     

Plants in our combating strategies against Mycobacterium tuberculosis: progress made and obstacles met

Context: Traditionally used plants for treating chest-related problems/tuberculosis (TB) have not been evaluated in detail and hence a thorough study is needed in this regard. This knowledge may find application in developing new anti-TB drugs.

Objective: This article elaborates on studying the activity of medicinal plants against different forms of Mycobacterium tuberculosis (Mtb) using different model strains, in vitro and ex vivo assays for studying the tuberculocidal activity and discusses the results from different studies on the activity against different forms of Mtb and human immunodeficiency virus-tuberculosis (HIV-TB) co-infection.

Methods: Scientific databases such as PubMed, Elsevier, Scopus, Google scholar, were used to retrieve the information from 86 research articles (published from 1994 to 2016) related to the topic of this review.

Results: Twenty-three plant species have been reported to possess active molecules against multi-drug resistant (MDR) isolates of Mtb. Seven plants were found to be active against intracellular Mtb and six against dormant bacilli. Seven plants were synergistically effective when combined with anti-TB drugs. Six studies suggest that the beneficial effects of plant extracts are due to their wide array of immuno-modulatory effects manifested by the higher expression of cytokines. Some studies have also shown the dual activity (anti-HIV and anti-TB) of plants.

Conclusion: We emphasize on identifying plants based on traditional uses and testing their extracts/phytomolecules against MDR strains, intracellular Mtb as well as against dormant Mtb. This will help in future to shorten the current therapeutic regimens for TB and also for treating HIV-TB co-infection.     

Inhibition of mTOR kinase as a therapeutic target for acute myeloid leukemia

Introduction: Acute myeloid leukemia (AML), the most common acute leukemia in adults, remains a therapeutic challenge. The phosphatidylinositol 3-kinase/AKT/mammalian target of rapamycin (PI3K/AKT/mTOR) signaling pathway is one of the key aberrant intracellular axes involved in AML.

Areas covered: mTOR plays a critical role in sensing and responding to environmental determinants such as nutrient availability, stress, and growth factor concentrations; and in modulating key cellular functions such as proliferation, metabolism, and survival. Although abnormalities of mTOR signaling are strongly associated with neoplastic leukemic proliferation, the role of pharmacologic inhibitors of mTOR in the treatment of AML has not been established.

Expert opinion: Inhibition of mTOR signaling has in general modest growth-inhibitory effects in preclinical AML models and clinical trials. Yet, combination of allosteric mTOR inhibitors with standard chemotherapy or targeted agents has a greater anti-leukemia efficacy. In turn, dual mTORC1/2 inhibitors, and dual PI3K/mTOR inhibitors show greater activity in pre-clinical AML models. Further, understanding the role of mTOR signaling in stemness of leukemias is important because AML stem cells may become chemoresistant by displaying aberrant signaling molecules, modifying epigenetic mechanisms, and altering the components of the bone marrow microenvironment.     

Advances in the treatment options for vitiligo: activated low-dose cytokines-based therapy

Introduction: Vitiligo is a skin disorder characterized by a progressive depigmentation, which is caused by the loss of melanocytes at the cutaneous level. A shift of the immune system with a prevalence of T helper (Th)1/Th17 response instead of a Tregs/Th2 one and may be part of etiology of 10 vitiligo.

Areas covered: This review describes the major points of vitiligo onset and shows the cutting-edge results in the field of low-dose medicine in the treatment of dermatologic diseases and, in particular. in vitiligo. In this review on advances in vitiligo pharmacotherapy, the most pertinent recent publications are reported. Electronic databases such as PubMed were searched for terms ‘low-dose medicine’ or ‘low dose and vitiligo’ or ‘low dose and psoriasis.’

Expert opinion: The availability of a systemic treatment for vitiligo, based on the oral administration of low-dose activated signaling molecules represents an opportunity for the dermatologists to overcome some specific pitfalls of currently available therapeutic protocols.     

Inflammation in Heart Failure: known knowns and unknown unknowns

Introduction: The review deals with inflammation in heart failure (HF). Many data show that systemic inflammation is frequent in HF and implicate that inflammation contributes to damage and dysfunction of the cardiovascular system.

Areas Covered: Experimental data have been mainly obtained in acute laboratory animal models. It is questionable whether animals’ data can be translated into clinical settings with patients with chronic HF who have concomitant pathologies.

The idea of a common inflammatory pathway that characterizes all different forms of clinical HF is unrealistic. It seems realistic that inflammation differs in non-cardiac and cardiac diseases.

Research therapeutic options address the use of inhibitors of cytokines, of agents antagonizing oxidative stress, of MMP and of PI3K signaling pathways.

Expert Opinion: Considering the many unknowns in our knowledge it is not surprising that early trials aimed to antagonize inflammation in HF have been disappointing. We are far away from having solid therapeutic schedules to use immunomodulation in all subtypes of HF. However, modern trials on HF due to virus infections have proven that immunomodulation is therapeutically effective.

We should wisely use the known facts and accept that we have many unknowns. By appropriate selection of the subtypes of HF we may be able to find the appropriate therapy against inflammation in HF.     

Delivery of therapeutic RNA-cleaving oligodeoxyribonucleotides (deoxyribozymes): from cell culture studies to clinical trials

Introduction. Development of efficient in vivo delivery systems remains a major challenge en route to clinical application of antisense technology, including RNA-cleaving molecules such as deoxyribozymes (DNAzymes). The mechanisms of oligonucleotide uptake and trafficking are clearly dependent on cell type and the type of oligonucleotide analogue. It appears likely that each particular disease target would pose its own specific requirements for a delivery method.

Areas covered. In this review we will discuss the available options for DNAzyme delivery in vitro and in vivo, outline various exogenous and endogenous strategies that have been, or are still being, developed and ascertain their applicability with emphasis on those methods that are currently being used in clinical trials.

Expert opinion. The available information suggests that a practical system for in vivo delivery has to be biodegradable, as to minimize concerns over long-term toxicity, it should not accumulate in the organism. Extracellular vesicles may offer the most organic way for drug delivery especially as they can be fused with artificial liposomes to produce hybrid nanoparticles. Chemical modification of DNAzymes holds great potential to apply oligonucleotide analogs that would not only be resistant to nuclease digestion, but also able to penetrate cells without external delivery agents.