Current Pharmaceutical Biotechnology - Volume 15, Issue 6, 2014

Autoimmune diseases are a large group of diseases with diverse clinical manifestations. They occur due to uncontrolled abnormal immune responses to self tissue and organs. Biologic therapy as a new weapon in the war to against autoimmune diseases is rapidly expanding owning to their specificity, efficacy and safety profiles compared with the traditional non-biologic disease modifying anti-rheumatic drugs (DMARDs). The major targets of these biologic therapies include cytokines, immune cells and some co-stimulation molecules. Cytokines as the targets of biologic therapies are mainly the three classic inflammatory cytokines include tumor necrosis factor (TNF)-α, interleukin (IL)-6 and IL-1. Immune cells targets include B cells and T cells. Though these agents are useful in most patients, the adverse effects accompanied with biologic therapy such as infection and tumor incidence make it quite important to decide appropriately when and how to use these agents. Research in order to define more candidate targets of biologic therapy in autoimmune disease is ongoing. Based on this background, we assembled this special issue for a better understanding of the use of biologics in autoimmune diseases, on aspect of various biologics used in rheumatoid arthritis (RA), lupus, Primary Sjögren’s Syndrome (pSS), autoimmune liver diseases, vasculities, Systemic Sclerosis and polymyositis and dermatomyositis-associated interstitial lung disease. In this special issue, Dashan Wang summarized the biologic agents currently available to treat RA, and the prospective biologic therapies that might be used in the management of RA the in future. Manisha Relan gave an update on the use of biologics in lupus, with a focus on Rituximab, Abatacept, Belimumab, and Epratuzumab. The use of biologics in psoriatic arthritis was summarized by Yan Li. Shiju Chen reviewed the biologics therapy in pSS, focused on the Rituximab in the treatment of pSS to explicate pathogenic function of B cells and assesse its efficacy in sicca symptoms, systemic manifestations and laboratory parameters in pSS patients. Mei Liu provided an overview of emerging biotherapy for autoimmune liver diseases, which gave us a new insight into the treatment strategy in autoimmune liver diseases. Sahana Vishwanath presented a review on biologic agents used in various vasculities. Jingxiu Xuan made a review on the use of biologics in treatment of Systemic Sclerosis. The use of biologics in polymyositis and dermatomyositis was discussed by Yuechi Sun, with a focus on the polymyositis and dermatomyositis- associated interstitial lung disease. This special issue covers many important aspects in the use of biologics in treatment autoimmune diseases, which will surely provide us a better understanding about the role of various biologics in treatment of autoimmune diseases.

Autoimmune liver diseases are chronic inflammatory conditions leading to an etiologically undefined immunemediated attack aimed at hepatocytes and the biliary epithelium. Drugs used in autoimmune liver disease such as ursodeoxycholic acid, prednisolone and azathioprine are not effective in all patients, therefore, new therapeutic approaches are needed for autoimmune liver diseases that are refractory to standard therapy. Biotherapy is a thriving area of research and development, and is used in the treatment of chronic autoimmune liver diseases. However, to date, there is no clinically validated standard biotherapy for autoimmune liver diseases. Thus, future clinical trials are required to evaluate the effectiveness and safety of biotherapy before this approach can be used in routine clinical practice for the therapy of autoimmune liver diseases. This article provides an overview of emerging biotherapy for autoimmune liver diseases.

Systemic lupus erythematosus is more than a heterogeneous autoimmune disease. It is in fact a syndrome of many different clinical genotypes and phenotypes. This review covers the most recently studied monoclonal antibodies and those currently being investigated. The key trials are summarized, including those for biologics on the market for two decades and those just approved for lupus less than two years ago. The focus will be on the following four: Rituximab, Abatacept, Belimumab, and Epratuzumab. It is a challenge to design the perfect trial and study patients with this disease as each has his or her own unique manifestations, biological markers, and underlying genetic background. However, as our understanding of the immune mechanisms involved in lupus increases; novel therapies will emerge that can be utilized for appropriately selected patients.

Interstitial lung disease (ILD) is one of the most common complications of polymyositis (PM) and dermatomyositis (DM). It is always progressive and does not respond to conventional immunosuppressive agent treatment. Biologics are commonly used in treatment of rheumatic diseases. They are also used in polymyositis and dermatomyositis associated interstitial lung disease. This review will focus on the updated use of biologics in PM/DM-ILD.

Psoriatic arthritis (PsA) is an inflammatory arthritis, characterized by mild arthralgia to severe joint deformities. Long term management of these diseases with nonsteroidal anti-inflammatory drugs (NSAIDs) and diseasemodifying antirheumatic drugs (DMARDs) is limited due to lack of efficacy and potential organ toxicity. Recently, the approval of injectable biologics, such as T cell inhibitors and TNF-α antagonist, has changed the treatment of moderateto- severe psoriasis and PsA. Unlike NSAIDs and DMARDs, TNF-α antagonists not only provide unambiguous benefits for the skin and joints, but also prevent the progression of structural damage in peripheral joints. Biological agents in the treatment of PsA have broad prospects. More and more biological agents are being developed for the treatment of PsA. In the current review, we will discuss the progress of biological agents on PsA.

Primary Sjogren’s Syndrome (pSS) is a systemic inflammatory autoimmune of unknown aetiology affecting exocrine glands, particularly the lacrimal and salivary glands. Growing evidence that B-cell depletion therapies are remarkably efficacious in the disorder indicate a major role for B-cell in the immunopathogenesis of pSS. B cell-targeted therapies have raised new therapy promise for they interact with B-cell homeostasis. Anti-CD20 therapy is the unique effective non-symptomatic therapy used in pSS. Growing data suggest Rituximab a promising candidate for pSS therapy. We performed a search for publications on Rituximab in the treatment of pSS to explicate pathogenetic function of B cells and assesse the efficacy in glandular symptoms, systemic manifestations and laboratory parameters in pSS patients. However, the efficiency on glandular manifestations is rather disappointing and controversial. Whether pSS patients with a reasonable residual salivary flow and/or with shorter disease duration will benefit most from Rituximab treatment still remains unclear. Fatigue is the symptom that responds best to Rituximab therapy compared with other systematical involvements. The efficiency in laboratory parameters is unsatisfactory.

The use of biologic agents has revolutionized the management of rheumatoid arthritis (RA) in the past two decades. These biologic agents directly target molecules and cells involved in the pathogenesis of RA. Biologic agents indeed lead to a better prognosis and clinical remission in patients with RA, especially in patients who are not well-controlled with traditional disease-modifying anti-rheumatic drugs (DMARDs). Currently, five TNF inhibitors (infliximab, etanercept, adalimumab, golimumab and certolizumab pegol), an IL-6 receptor antagonist (tocilizumab), an IL-1 receptor antagonist (anakinra), a B cell depleting agent (rituximab) and a T cell co-stimulation inhibitor (abatacept) have been approved for the treatment of RA. With the increased understanding of the pathogenic mechanisms of RA and advantages in manufacturing biotechnology of pharmaceutical companies, a series of novel biologic therapeutic approaches are being developed. In the present paper, we will summarize the biologic agents currently available to treat RA, and the prospective biologic therapies that might be used in the management of RA in future.

Systemic sclerosis (scleroderma) is a heterogeneous autoimmune disorder characterized by collagen overproduction that leads to cutaneous and internal organs sclerosis and pulmonary arterial hypertension. SSc has high morbidity and mortality. SSc pathogenesis is uncertain. At present most therapies of SSc are symptomatic. Effective therapeutic approaches are lacking. Accompanying a growing understanding of SSc pathogenesis, various key mediators are being evaluated as the therapeutic targets. This review described the effects of these key mediators in SSc.

Vasculitides are disease in which injury to blood vessels leads to various degrees and types of organ dysfunction. They are subdivided into different groups dependent on the size of blood vessels involved as well as other particular clinical features. Therapy is dependent upon the size of the blood vessels involved and the nature of the disease. For medium and large vessel vasculitides, glucocorticoids, cyclophosphamide, azathioprine and methotrexate have been the mainstay for induction and maintenance of remission. Because of potential for side effects from standard therapies, various biologic agents have been evaluated in the treatment of ANCA positive vasculitis (AAV), cryoglobulinemic vasculitis, Behcet’s disease and Takayasu’s Arteritis (TAK). In this article, we present a review on biologic agents used in various vasculitides.

Pharmacological exploitation of natural compounds has continued to lead to development of non-synthetic and non-toxic anticancer agents that are promising at ameliorating the menace of neoplastic diseases such as leukemia. This study is an attempt to determine the chemopreventive and antileukemic activities of ethanol extracts of Moringa oleifera leaves on benzene induced leukemia bearing rats. Leukemia was induced by intravenous injection of 0.2 mL benzene solution 48 hourly for 4 weeks in appropriate rat groups. Ethanol extract of Moringa oleifera (EMO) leaves was administered at 0.2 mL of 100 mg/mL to respective treatment rat groups. A standard antileukemic drug (cyclophosphamide) was also used to treat appropriate rat groups. Clinical examination of liver and spleen with hematological parameters were employed to assess the leukemia burden following analysis of the rat blood samples on Sysmex KX-21N automated instrument. Leukemia induction reflected in severe anemia and a marked leukocytosis over the control/baseline group. Liver and spleen enlargements were also observed in group exposed to benzene carcinogen. The in vivo antioxidative potential of EMO was evaluated using Malondialdehyde (MDA) and reduced glutathione (GSH) levels. The liver MDA and GSH levels obtained in benzene induced leukemic rats treated with EMO compared favorably with those obtained in similar treatments with the standard drug (p< 0.05). The extract demonstrated chemopreventive and anti-leukemic activities as much as the standard anti-leukemic drug (p>0.05) by ameliorating the induced leukemic condition in the affected rat groups owing to its bioactive constituents. This study reveals that the extract might be an active, natural and non-toxic anticancer drug lead.

Amphotericin B (AmB) is regarded as a life-saving drug in treating severe systemic fungal infections. However, the poor solubility and permeability limits its oral administration. The main purpose of this study is to evaluate AmB nanosuspensions in enhancing its solubility for the oral application. Magnetic stirring method with very low energy input, as a top-down technology, was firstly used to prepare the drug nanosuspensions. Sodium deoxycholate and carbomer were screened as the stabilizers through a single-factor experiment. Under the optimum conditions, AmB nanosuspensions were spherically shaped with the average particle size of 348.9±21.2 nm. X-ray diffraction analysis and differential scanning calorimetry confirmed that the initial crystalline state was preserved after particle size reduction. Saturated solubility and dissolution rate of AmB nanosuspensions exhibited the better dissolution properties compared with raw drug. Stability study demonstrated that AmB nanosuspensions maintained a good stability at 4oC for 30 days. In conclusion, AmB nanosuspensions potentially improved the oral absorption and magnetic stirring method could be acted as an effective method to produce AmB nanosuspensions.

The paper discussed the protective effect of zinc pretreatment on renal ischemia-reperfusion injury (RIRI) and its mechanism. 50 male ICR mice were randomly divided into five groups: sham-operated group, model group, high-dose group with zinc sulfate pretreatment (60mg/kg body weight), medium-dose group with zinc sulfate pretreatment (30mg/kg body weight) and low-dose group with zinc sulfate pretreatment (15mg/kg body weight). The mice were administrated with zinc sulfate once a day for two weeks, subsequently the RIRI animal models were prepared by ligation of the left renal pedicle 30 minutes. 24h after reperfusion, the kidney tissue was removed and pathological results by HE staining showed that in the model group, kidney surface covered with a large number of red exudates, renal tubular dilatated, disorganized, renal tubular epithelial cell vacuolar degenerated, nuclear pyknosis and necrosis appeared; congestive and necrosis were visible in medullary junction. The pathological changes of renal ischemia- reperfusion were obviously relieved in the animals with medium and low-dose zinc pretreatment. The superoxide dismutase (SOD) activity in the lowdose zinc sulfate pretreatment group was significantly higher than that in the model and high-dose groups (P <0.05). The malondialdehyde (MDA) content of renal tissue, the apoptotic cells percentage in the medium and low dose groups were significantly lower than those in the model group (P <0.05), and MDA content in the low-dose group was significantly lower than that in the medium dose group (P <0.05). The ratio of BCL-2/BAX protein expression in the medium and low dose groups was significantly higher than that in the model group (P<0.05), the ratio in the low groups was significantly higher than that in the medium dose and high dose group by double immunofluorescence staining (P <0.05). In conclusion, zinc has a protective effect on the renal ischemia-reperfusion injury by antioxidant capacity and inhibition of apoptosis in the kidney.

This work extends in vitro screening of antimicrobial activity of the sesquiterpene hydroquinone avarol, a main secondary metabolite of the Mediterranean sponge species Dysidea avara. The antimicrobial activity was in part evaluated by microdilution method against selected bacterial and fungal strains. Additionally, the screening included evaluation of anti-quorum sensing (anti-QS) effects. At a different extent avarol was proven to be active against all the microorganisms tested (MIC 0.002-0.008 mg/mL and MBC 0.004-0.016 mg/mL; MIC 0.004-0.015 mg/mL and MFC 0.008-0.030 mg/mL; respectively). This marine natural product also showed moderate anti-QS effects, reducing Pseudomonas aeruginosa PAO1 biofilm formation (75%), its twitching and protrusions motilities as well as pyocianin production (39%). According to the best of our knowledge, this is the first report both on avarol anti Gram-negative bacterial activity and anti-QS effects.