Enzalutamide: looking back at its preclinical discovery

Introduction: In patients with metastatic prostate cancer (PCa), castration is the standard first-line therapy. However, all patients eventually develop castration-recurrent PCa (CRPC). In these patients who fail the first-line therapy, enzalutamide has emerged as a viable alternative. Enzalutamide is a second-generation small molecule androgen receptor (AR) antagonist that blocks the AR nuclear translocation and DNA binding without any known AR agonist activity.

Areas covered: This review provides an overview of the history of the oral selective AR modulator, enzalutamide, and discusses its discovery and current preclinical experimental results including resistance mechanisms. The article illustrates the history of discovery based on enzalutamide’s mechanism of action. Furthermore, the authors highlight the drug’s clinical development and post-launch developments.

Expert opinion: The landscape of CRPC has changed dramatically over the last few years, as new agents with proven benefit in overall survival have been approved. Compared to the average time of 10 – 15 years for a new drug to go from pre-clinical discovery to registration, enzalutamide obtained FDA approval in < 6 years after its initial characterization. Enzalutamide, a targeted agent of the androgen-AR axis, has shown promising results in CRPC and is generally well tolerated. However, drug resistance inevitably emerges is a severe limitation. The authors believe that further clinical studies that look at its use as either a combinational or sequential therapy could help to address these concerns.     

C-Phycocyanin: an effective protective agent against thymic atrophy by tributyltin

Spirulina platensis, used worldwide as a food supplement, is a natural source of protein, vitamins, carbohydrates and polyunsaturated fatty acids. C-Phycocyanin (C-Pc), its major biliprotein, is known to possess anti-oxidant, anti-inflammatory and radical scavenging properties. Our present study showed that treatment with C-Pc protects the rats from Tributyltin (TBT) induced thymic atrophy. The results reveal TBT-induced oxidative stress mediated apoptosis in rat thymocytes in vivo and its attenuation by C-Pc. This ameliorative effect could be attributed to antioxidant activity of the biliprotein. C-Pc also increased TBTC reduced thymic weight and cellularity as well. TBTC-induced ROS generation and lowered GSH levels were restored by C-Pc, suggesting its radical scavenging properties. The various apoptotic determinants such as mitochondrial membrane potential, Bax/Bcl-2 ratio, caspase-3 activity and apoptotic cell population were effectively modulated by C-Pc treatment. We make this first observation to illustrate the effectiveness of C-Pc in reducing TBTC-induced thymic atrophy. The morphology of thymic tissue was restored to near normal by this biliprotein. The present study, therefore, suggests that C-Pc could serve as an effective natural antioxidant for efficient management of TBTC induced oxidative damage.     

Essential metals and metallothionein in cadmium-induced thymic atrophy and splenomegaly

Cadmium chloride was injected intraperitoneally into mice and the animals were sacrificed 1, 3, and 9 days after the injection. The concentrations and contents of cadmium and six essential metals in the thymus, spleen, kidney, and liver were determined by inductively coupled plasma-atomic emission spectrometry. Although the accumulation of cadmium in the thymus and spleen was as low as 0.05 and 0.2–0.4% of the injected dose, respectively, compared to liver (60%) and kidney (6.5–9.0%), the two immune organs showed dramatic changes of weights; namely severe atrophy of thymus and enlargement of spleen. The concentrations of zinc in the two immune organs did not change during the atrophy or enlargement, though the contents showed significant decrease or increase dependent upon the changes in weights. The concentrations and/or contents of other essential metals also changed with time and the changes depended on organs. The distributions of cadmium in the supernatant fractions of thymus and spleen were determined by high speed liquid chromatography with a flame atomic absorption spectrophotometer. Two cadmium peaks which correspond to the two isometallo-thioneins were eluted exactly at the same retention times as those of liver metallothioneins.     

Strontium ranelate: a look back at its use for osteoporosis

Importance of the field: Osteoporosis is now considered a major health problem in all developed and in most developing (non-African) countries.

Areas covered in this review: In this review, we provide an extensive literature survey (MEDLINE, PubMed, Cochrane Controlled Register), for articles dealing with osteoporosis management and/or strontium ranelate, from 1920 to 2010.

What the reader will gain : The objective is to provide an extensive, unbiased assessment of the available data allowing strontium ranelate to be placed in perspective with other anti-osteoporosis treatments.

Take home message : Owing to a positive benefit-to-risk ratio, strontium ranelate may now be considered a first-line treatment in the management of osteoporosis.     

Polyhexamethyleneguanidine phosphate induces severe lung inflammation,fibrosis, and thymic atrophy

Polyhexamethyleneguanidine phosphate (PHMG-P) has been widely used as a disinfectant because of its strong bactericidal activity and low toxicity. However, in 2011, the Korea Centers for Disease Control and Prevention and the Ministry of Health and Welfare reported that a suspicious outbreak of pulmonary disease might have originated from humidifier disinfectants. The purpose of this study was to assess the toxicity of PHMG-P following direct exposure to the lung. PHMG-P (0.3, 0.9, or 1.5 mg/kg) was instilled into the lungs of mice. The levels of proinflammatory markers and fibrotic markers were quantified in lung tissues and flow cytometry was used to evaluate T cell distribution in the thymus. Administration of PHMG-P induced proinflammatory cytokines elevation and infiltration of immune cells into the lungs. Histopathological analysis revealed a dose-dependent exacerbation of both inflammation and pulmonary fibrosis on day 14. PHMG-P also decreased the total cell number and the CD4⁺/CD8⁺ cell ratio in the thymus, with the histopathological examination indicating severe reduction of cortex and medulla. The mRNA levels of biomarkers associated with T cell development also decreased markedly. These findings suggest that exposure of lung tissue to PHMG-P leads to pulmonary inflammation and fibrosis as well as thymic atrophy.     

Immunomodulatory role of piperine in cadmium induced thymic atrophy and splenomegaly in mice

Cadmium being a potent immunotoxicant, affects both humoral and cell mediated immunity. In rodents, it is primarily characterized by marked thymic atrophy and splenomegaly. Cadmium induces apoptosis in mice and suppresses the immune functions. Piperine, major alkaloid of Piper longum Linn. and Piper nigrum Linn. with a long history of medicinal value, has shown anti-apoptotic activity in vitro. Thus, to delineate its role in vivo, piperine (2.5mg/kg/day, oral, 7 days) treated Balb/C mice were administered Cd as CdCl(2) (1.8mg/kg, i.p., once, 4th day). The various biochemical indexes of cell damage such as cytotoxicity (MTT assay), oxidative stress (glutathione, reactive oxygen species), apoptosis (mitochondrial membrane potential, caspase-3 activity, phosphatidylserine externalization, apoptotic DNA, intranucleosomal DNA fragmentation) along with lymphocyte phenotyping, cell proliferative response and cytokine secretion (IL-2 and IFNγ) were assessed in thymic and splenic single cell suspensions. Lowering of body weight gain and cellularity and a loss in cell viability seen in Cd group, were abrogated by piperine treatment. Similarly, oxidative stress and apoptotic markers altered by Cd were also modulated by this alkaloid. In addition, a pronounced inhibition of cell proliferative response, alterations in T- and B-cell phenotypes, cytokine release and morphological changes were restored to normalcy. The present in vivo data corroborating with our previous in vitro findings, provide confirmatory evidence of the immuno-protective efficacy of piperine.     

Getting back to basics: commentary on McSweeney, Murphy, and Kowal (2005)

The review article "Regulation of Drug Taking by Sensitization and Habituation" by F. K. McSweeney, E. S. Murphy, and B. P. Kowal introduces 2 basic principles of behavior, sensitization and habituation, into a comprehensive model for studying drug intake and drug addiction. A key assumption of the model is that the reinforcing effectiveness of drugs sensitize and/or habituate; however, issues with the measurement of reinforcing effectiveness should be carefully considered. In addition, a multidisciplinary approach might broaden this model and increase its power. Other approaches include, but are not limited to, pharmacokinetic-pharmacodynamic modeling and in vivo measures of brain activity.     

Changes in serum glucocorticoid levels and thymic atrophy induced by phenytoin administration in mice

The weights of spleen and thymus were recorded and serum glucocorticoid (GC) levels examined in mice injected intraperitoneally with 60 mg phenytoin (PHT) kg body wt. for 3, 8, and 30 days. In mice injected with PHT, the serum GCs were elevated about 4- to 5-fold in 3 days; the higher levels were maintained and accompanied thymic atrophy throughout the experiment. Moreover, dose-dependent changes in serum GC levels and thymus weight were also observed at 3 days. These results indicate that GCs may play an important role in thymic atrophy induced by PHT.     

Role of oxidative stress and apoptosis in cadmium induced thymic atrophy and splenomegaly in mice

Cadmium immunotoxicity in rodents is primarily characterized by marked thymic damage and splenomegaly. To understand the toxicity of Cd on lymphoid cells in vivo, a single dose of Cd as CdCl2 (1.8 mg/kg, i.p.) was administered to male BALB/c mice and cytotoxicity (MTT assay), oxidative stress indicators (glutathione, reactive oxygen species) and apoptotic markers (mitochondrial membrane potential, caspase-3 activity, phosphatidylserine externalization, apoptotic DNA, intranucleosomal DNA fragmentation) were assessed in thymic and splenic single cell suspensions, at various time intervals. Lowering of body weight gain and cellularity and a loss in cell viability was seen in the Cd treated mice. The earliest significant increase in ROS at 18 h, followed by mitochondrial membrane depolarization, caspase-3 activation and GSH depletion at 24h in spleen and later at 48 h in thymus, strongly implicate the possible involvement of ROS. A pronounced inhibition of cell proliferative response at 48 h and 72 h may also be linked to Cd induced apoptosis. The morphological alterations including thymic cortical cell depletion and an increase in red pulp with diminished white pulp in spleen were observed at 48 h and beyond. The splenic cells appeared more susceptible than thymus cells to the adverse effects of Cd. The present study, therefore, demonstrates potentiation of oxidative stress followed by mitochondrial-caspase dependent apoptotic pathway. This may, in part, be responsible for causing suppression of cell proliferative response, thymic atrophy and splenomegaly.     

Atopic dermatitis: understanding the disease and its management

ABSTRACT

Objective: Atopic dermatitis (AD) is a common, chronic, inflammatory skin disease that can significantly reduce the quality of life of not only patients but also entire families. This review will focus on the currently available non-pharmacologic and pharmacologic treatments for the control and management of AD.

Research design and methods: A review of English-language articles from January 1953 to May 2006 was performed within the MEDLINE database. Search terms included, but were not limited to, atopic dermatitis, topical corticosteroids, and topical calcineurin inhibitors. Studies evaluating the diagnosis, physical and psychological burden, and underlying pathophysiology of AD were included. Particular focus was placed on literature presenting key safety and efficacy data from clinical trials involving AD treatment.

Results: Although good skin care and trigger avoidance are fundamental to AD management, most patients also require pharmacologic intervention. Topical therapies comprise the foundation of AD treatment. In particular, topical corticosteroids have been a mainstay in AD treatment for several decades and the newer topical calcineurin inhibitors have become a valuable addition to the therapeutic armamentarium. TCIs are a safe and effective AD treatment; they limit the number of disease flares, extend the time between flares, and provide a steroid-sparing option that may be of particular benefit in the pediatric population. The use of more potent therapies, such as systemic (oral/injected) agents or phototherapy, is typically limited to the treatment of severe, refractory disease. Additionally, owing to the increased risk for bacterial, viral, and fungal infections in patients with AD, topical or systemic antimicrobials are an important component of treatment.

Limitations: Case reports and small-scale studies were typically not included in this analysis and owing to the limited number of trials evaluating TCSs, consensus statements and comprehensive review articles were used to obtain information pertaining to the use of this treatment in AD.

Conclusions: AD is a common, chronic disease requiring a long-term management strategy that incorporates preventive measures and a multipronged treatment approach.     

Further evidence for the involvement of inhibition of cell proliferation and development in thymic and splenic atrophy induced by the peroxisome proliferator perfluoroctanoic acid in mice

We recently demonstrated that severe thymic and splenic atrophy occur upon dietary treatment of mice with potent peroxisome proliferators (PPs), e.g. perfluorooctanoic acid (PFOA), WY-14,643, nafenopin, and di(2-ethylhexyl)phthalate (DEHP). In the present study, we investigated this phenomenon further employing a relative inert PP, PFOA. Comparison of the dose-dependencies and time-courses indicated that the peroxisome proliferative effect occurred prior to atrophy of both the thymus and spleen. However, following withdrawal of PFOA from the diet, the weight of the thymus and spleen rapidly returned to normal within 10 and 5 days, respectively, in contrast to the more persistent peroxisome proliferation. Furthermore, the changes in thymus and spleen weight upon PFOA treatment and the following withdrawal from diet paralleled the changes in total thymocyte and splenocyte counts, respectively. It was found previously that the decreases in the thymocyte populations present in the S and G2/M phases, as well as in the number of CD4+CD8+ cells upon PFOA treatment, were the most dramatic, perhaps reflecting inhibition of thymocyte proliferation in connection with thymocyte development. Here, the recovery of thymocytes began with increases in the populations in these same phases of the cell cycle, with CD4+CD8+ cells recovering most rapidly, lending further support to our previous hypothesis. The possible relationship of these immunotoxic effects of PPs to the changes they cause in fatty acid metabolism is discussed.