Current Pharmaceutical Biotechnology - Volume 13, Issue 10, 2012

Psoriasis is a common (1-3% of the population worldwide), multifactorial, immune-mediated chronic skin disease. In psoriasis pathogenesis an over-reaction of local innate immune response initiates inflammation with subsequent involvement of adaptive immune response leading to the production of a panel of cytokines, chemokines and growth factors leading to epidermal hyperplasia. Recently, IL-21 has been involved in this process as this cytokine is overexpressed in psoriatic skin and can cause epidermal hyperplasia and inflammation when injected intradermally into mice. Moreover blockade of IL-21 with a human antibody against IL-21 reduces the epidermal thickness and the expression of Th1 and Th17 genes in the well-characterized model of human psoriasis-xenograft mouse. Therefore, the inhibition of this cytokine may be therapeutically effective in the treatment of psoriasis. Here we will review recent data on psoriasis pathogenesis focusing on the role of IL-21 as novel therapeutic target.

Gene therapy is a potential treatment for severe inherited disorders for which there is little hope of finding a conventional cure. These include lethal diseases like immunodeficiencies and metabolic disorders, and non lethal conditions associated to poor quality of life and life-long symptomatic treatments, like muscular dystrophy, cystic fibrosis or thalassemia. Skin adhesion defects belong to both groups. For the non-lethal forms, gene therapy, or transplantation of cultured skin derived from genetically corrected epidermal stem cells, represents a very attractive therapeutic option, and potentially a definitive treatment. Recent advances in gene transfer and stem cell culture technology are making this option closer than ever. This paper critically reviews the progress and prospects of gene therapy for skin adhesion defects, and the factors currently limiting its development.

Pemphigus is a group of rare autoimmune blistering diseases of the skin in which autoantibodies to desmosome cadherins, desmogleins, induce loss of cell-cell adhesion (acantholysis). In addition to steric hindrance and activation of intracellular phosphorylation cascade signaling pathways, apoptosis has been suggested to contribute to the mechanism by which pathogenic IgG induces acantholysis. We review the literature examining the role of apoptosis in pemphigus. Current data recognize a central role of apoptosis in the mechanisms of blister induction. In particular, here we stress the key role of FasL in pemphigus, as it is able to first induce apoptosis, then acantholysis. Being pro-apoptotic molecules important in blister formation, they could represent new specific targets for pemphigus treatment.

Defensins and cathelicidins are anti-microbial peptides (AMPs) that act as natural antibiotics and are part of the innate immune defence in many species. We consider human defensins and LL37, the only human member of the cathelicidin family. In particular, we refer to the human alpha-defensins called human neutrophil peptides (HNP1 through 4), which are produced by neutrophils, HD5 and HD6, mainly expressed in Paneth cells of intestine, the human betadefensins HBD1, HBD2 and HBD3, synthesized by epithelial cells and LL37, which is located in granulocytes, but is also produced by epithelial cells of the skin, lungs, and gut. In the last years, the study of AMPs activity and regulation has allowed to understand the important role of these peptides not only in the innate defence mechanisms against bacteria, viruses, fungi, but also in the regulation of immune cell activation and migration. Complementary studies have disclosed a role for AMPs in modulating many physiological processes that involve non-immune cells, such as activation of wound healing, angiogenesis, cartilage remodeling. Due to the pleiotropic tasks of these peptides, many of them are now being discovered to contribute to immune pathology of chronic diseases that affect skin, gut, joints; this is supported by many examples of immune-mediated pathologies in which their expression is disregulated. In this article we review the current literature that suggests a role for human defensins and LL37 in pathogenic mechanisms of several chronic diseases that are considered of auto-immune or auto-inflammatory origin.

The human sebaceous gland is a microscopic branched type multiacinar gland been present everywhere on the body except on the palms and soles, whereas they are sparsely located on the dorsum of hands and feet. Several medical conditions are related with sebaceous gland pathology, such as acne, sebaceous hyperplasia, sebaceous adenoma and sebaceous carcinoma. Acne is a common, complex, chronic disorder of the human pilosebaceous unit that mostly occurs in adolescence and young adulthood. The sebaceous gland plays an exquisite role in the initiation of the disease. The multifactorial nature of the pathogenesis of acne includes increased sebum production, alteration of the quality of sebum lipids, inflammatory processes, interaction with neuropeptides and dysregulation of the hormone microenvironment, follicular hyperkeratinization and inflammation maintained by Propionbacterium acnes products within the follicle. On the other hand, the sebaceous gland, as a major and critical compartment of human skin, is also affected through ageing, both intrinsic and extrinsic, which lead to distinct clinical and histological changes. Intrinsic ageing of the sebaceous gland is determined primarily by genetic factors and hormonal status, with androgens playing a major role. A clinical manifestation associated with intrinsic ageing changes is skin xerosis. Extrinsic ageing of human sebaceous gland is mainly caused by accumulating UV irradiation, especially UVA. Photoageing of sebaceous gland is expressed with a wide spectrum of benign and malignant sebaceous tumours, such as sebaceous hyperplasia, sebaceous carcinoma and Muir-Torre syndrome. This review will focus on the pathogenesis of the most common sebaceous gland diseases and their molecular pathways which may represent future pharmaceutical targets.

Acetylcysteine has been used to treat acetaminophen overdose for nearly 50 years. While no placebo controlled trials have been conducted, the efficacy of acetylcysteine is accepted for the prevention of hepatic injury when administered early after acetaminophen overdose. Acetylcysteine can be administered as an infusion or oral solution. The duration of treatment varies from 21 to 72 hours, depending on the protocol. Acetylcysteine also prevents death when administered to patients with hepatic failure from acetaminophen.

Aptamers, or nucleic acid ligands, have gained clinical interest over the past 20 years due to their unique characteristics, which are a combination of the best facets of small molecules and antibodies. The high binding affinity and specificity of aptamers allows for isolation of an artificial ligand for theoretically any therapeutic target of interest. Chemical manipulations of aptamers also allow for fine-tuning of their bioavailability, and antidote control greatly expands their clinical use. Here we review the various methods of antidote control of aptamer therapeutics – matched oligonucleotide antidotes and universal antidotes. We also describe the development, recent progress, and potential future therapeutic applications of these types of aptamer-antidote pairs.

Black widow spider (Latrodectus mactans) envenomation has been recognized since antiquity. The syndrome, latrodectism, is characterized by painful muscle rigidity and autonomic disturbances such as tachycardia, hypertension, and diaphoresis. Symptoms typically last for 1-3 days. Treatment has ranged from local folk remedies to administration of specific antivenom. Opioid analgesics combined with muscle relaxants, such as benzodiazepines, are only effective at symptomatic and temporary control. Antivenom is by far the most efficacious therapy available based on symptom resolution, need for subsequent therapy, and hospital admission rates. Fear of allergic type reactions from antivenom administration has limited its use in the United States. A new purified F(ab)2 fragment Latrodectus mactans antivenom, Analatro®, is currently undergoing clinical trials. The product is expected to have similar efficacy and be associated with fewer adverse reactions when compared to the currently available partially purified whole IgG Merck product. This shift in the risk-benefit analysis may ultimately lead to more antivenom administration in significantly envenomated patients.

Cyanide poisoning can present in multiple ways, given its widespread industrial use, presence in combustion products, multiple physical forms, and chemical structures. The primary target of toxicity is mitochondrial cytochrome oxidase. The onset and severity of poisoning depend on the route, dose, physicochemical structure and other variables. Common poisoning features include dyspnea, altered respiratory patterns, abnormal vital signs, altered mental status, seizures, and lactic acidosis. Our present knowledge supports cyanide poisoning treatment based on excellent supportive care with adjunctive antidotal therapy. Multiple antidotes exist and vary in regional availability. All currently marketed antidotes appear to be effective. Antidotal mechanisms include chelation, formation of stable, less toxic complexes, methemoglobin induction, and sulfane sulfur supplementation for detoxification by endogenous rhodanese. Each antidote has advantages and disadvantages. For example, hydroxocobalamin is safer than the methemoglobin inducers in patients with smoke inhalation. Research for new, safer and more effective cyanide antidotes continues.

The cumulative cardiac toxicity of the anthracycline antibiotics and their propensity to produce severe tissue injury following extravasation from a peripheral vein during intravenous administration remain significant problems in clinical oncologic practice. Understanding of the free radical metabolism of these drugs and their interactions with iron proteins led to the development of dexrazoxane, an analogue of EDTA with intrinsic antineoplastic activity as well as strong iron binding properties, as both a prospective cardioprotective therapy for patients receiving anthracyclines and as an effective treatment for anthracycline extravasations. In this review, the molecular mechanisms by which the anthracyclines generate reactive oxygen species and interact with intracellular iron are examined to understand the cardioprotective mechanism of action of dexrazoxane and its ability to protect the subcutaneous tissues from anthracycline-induced tissue necrosis.

The accidental or intentional release of plutonium or americium can cause acute and long term adverse health effects if they enter the human body by ingestion, inhalation, or injection. These effects can be prevented by rapid removal of these radionuclides by chelators such as calcium or zinc diethylenetriaminepentaacetate (calcium or zinc DTPA). These compounds have been shown to be efficacious in enhancing the elimination of members of the actinide family particularly plutonium and americium when administered intravenously or by nebulizer. The efficacy and adverse effects profile depend on several factors that include the route of internalization of the actinide, the type, and route time of administration of the chelator, and whether the calcium or zinc salt of DTPA is used. Current and future research efforts should be directed at overcoming limitations associated with the use of these complex drugs by using innovative methods that can enhance their structural and therapeutic properties.

More than 90% of all fatal mushroom poisonings worldwide are due to amatoxin containing species that grow abundantly in Europe, South Asia, and the Indian subcontinent. Many cases have also been reported in North America. Initial symptoms of abdominal cramps, vomiting, and a severe cholera-like diarrhea generally do not manifest until at least six to eight hours following ingestion and can be followed by renal and hepatic failure. Outcomes range from complete recovery to fulminant organ failure and death which can sometimes be averted by liver transplant. There are no controlled clinical studies available due to ethical reasons, but uncontrolled trials and case reports describe successful treatment with intravenous silibinin (Legalon® SIL). In nearly 1,500 documented cases, the overall mortality in patients treated with Legalon® SIL is less than 10% in comparison to more than 20% when using penicillin or a combination of silibinin and penicillin. Silibinin, a proven antioxidative and anti-inflammatory acting flavonolignan isolated from milk thistle extracts, has been shown to interact with specific hepatic transport proteins blocking cellular amatoxin re-uptake and thus interrupting enterohepatic circulation of the toxin. The addition of intravenous silibinin to aggressive intravenous fluid management serves to arrest and allow reversal of the manifestation of fulminant hepatic failure, even in severely poisoned patients. These findings together with the available clinical experience justify the use of silibinin as Legalon® SIL in Amanita poisoning cases.

Rapid decontamination of the skin is the single most important action to prevent dermal absorption of chemical contaminants in persons exposed to chemical warfare agents (CWA) and toxic industrial chemicals (TICs) as a result of accidental or intentional release. Chemicals on the skin may be removed by mechanical means through the use of dry sorbents or water. Recent interest in decontamination systems which both partition contaminants away from the skin and actively neutralize the chemical has led to the development of several reactive decontamination solutions. This article will review the recently FDA-approved Reactive Skin Decontamination Lotion (RSDL) and will summarize the toxicity and efficacy studies conducted to date. Evidence of RSDL's superior performance against vesicant and organophosphorus chemical warfare agents compared to water, bleach, and dry sorbents, suggests that RSDL may have a role in mass human exposure chemical decontamination in both the military and civilian arenas.

Background: Animal-derived antivenoms have been used to treat snake envenomation for more than 100 years. Major technological advantages in the past 30 years have produced antivenoms that are highly purified and chemically modified to reduce the risk of acute hypersensitivity reactions. Like all pharmaceutical manufacture, commercial-scale antivenom production requires making trade-offs between cost, purity, pharmacokinetic profile, and production yield. Scope: This article reviews the current state of the art for antivenom production and development. Particular attention is paid to controversies and trade-offs used to achieve a balance between improved safety and pharmacokinetic performance.

It has long been demonstrated that a subset of patients with Sjogren's syndrome (SS) develop ectopic lymphoid structures (ELS) in the salivary glands (SG). These structures are characterised by periductal clusters of T and B lymphocytes, development of high endothelial venules and differentiation of follicular dendritic cells (FDC) networks. Evidence in patients with and animal models of SS demonstrated that the formation and maintenance of ELS in the SG is critically dependent on the ectopic expression of lymphotoxins (LT) and lymphoid chemokines CXCL13, CCL19, CCL21 and CXCL12. Several cell types, including resident epithelial, stromal and endothelial cells as well as different subsets of infiltrating immune cells, have been shown to be capable of producing some of these factors during chronic inflammation in SS. In this review we focus on the cellular and molecular mechanisms regulating the formation of ELS in SS SG, with particular emphasis on the role of lymphoid chemokines. In addition, we summarise accumulating data in support of the notion that ELS in SS represent functional niches whereby autoreactive B cells undergo affinity maturation, clonal selection and differentiation into autoantibody producing cells, thus contributing to autoimmunity over and above secondary lymphoid organs. Furthermore, we review the emerging role of ELS and lymphoid chemokines in driving extranodal B cell lymphomagenesis in SS and we focus on recent evidence suggesting that ELS identify subsets of SS patients at increased risk of developing systemic manifestations and lymphoma.

Primary Sjogren's Syndrome (PSS) is characterized by dryness of the eyes and mouth due to lymphocytic infiltration of secretory exocrine glands. As well as disabling dryness, patients commonly have fatigue and arthralgia and an associated reduction in quality of life. The condition principally affects adult women and is relatively common - approximately 1:1000 to 1:250 adult women are estimated to have the condition in European/North American studies. Current therapy is principally symptomatic with the use of artificial tears and oral gels, pastilles and sprays. Medications to stimulate residual glandular secretion can be helpful for appropriate individuals. A proportion of patients also develop extraglandular features such as skin vasculitis, or lung, neurological, haematological or other systemic involvement. Conventional general immunosuppressive therapies such as corticosteroids or disease-modifying drugs, have been used in some patients with these clinical features. Biologic therapies specifically directed against molecules involved in disease pathogenesis represent a potentially more effective approach to therapeutic intervention in rheumatic diseases including PSS. The greatest experience in PSS is with rituximab, an anti-B-cell monoclonal antibody already in use for the treatment of B-cell lymphoma and rheumatoid arthritis. A randomised placebo controlled study is currently recruiting in France and a further study is planned in the UK. This review discusses the utility of biologic therapies in PSS, potential challenges for their use, the available data on rituximab and the potential role for other biologic therapies currently in development, or in clinical trials, in other autoimmune conditions.

T cells are implicated in both local and systemic pathophysiology of primary Sjogren's syndrome (PSS). Lymphocytic infiltrates in exocrine glands are dominated by CD4+ T cells, some contributing to ectopic lymphoid tissue, others, unusually, exhibiting cytotoxic potential. Cytokine secretion patterns are complex, with Th1 and Th17 components implicated in pathology. Circulating T cells exhibit phenotypes consistent with hyperactivation, cytokine imbalance, and homeostatic alterations; CD4 lymphopenia is recognized as a risk factor for developing lymphoma. Evidence of oligoclonal expansion is found locally and systemically. Functional alterations (e.g. cytokine secretion profile, migratory potential, target cell interactions) are less clearly defined. Attempts at T cell-targeted therapy of PSS have been limited, although therapy targeted at other arms of the immune response may also affect T cells. A better understanding of T-cell dysregulation in PSS is required in order to understand its contribution to disease, aid prognosis, and improve therapeutic interventions aimed at this aspect of the disease.