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1.  Complexing proteins in botulinum toxin type A drugs: a help or a hindrance? 
Botulinum toxin type A is a high molecular weight protein complex containing active neurotoxin and complexing proteins, the latter of which, it is believed, protect the neurotoxin when in the gastrointestinal tract, and may facilitate its absorption. Comparisons of conventional botulinum toxin type A drugs that include complexing proteins with the complexing protein-free formulation of Xeomin® strongly suggest that complexing proteins do not affect diffusion of the active neurotoxin. Studies of Xeomin have also shown that complexing proteins do not enhance product stability in storage. However, complexing proteins may stimulate antibody development against botulinum toxin type A. Numerous observational studies have been published showing that some patients receiving conventional botulinum toxin may develop neutralizing antibodies, leading to antibody-induced therapy failure. Studies have shown that Xeomin is not associated with the development of neutralizing antibodies in animal models or in patients. In conclusion, complexing proteins do not contribute to the stability of botulinum toxin type A drugs and do not contribute to their therapeutic effects, but may be associated with a secondary nonresponse due to the development of neutralizing antibodies.
doi:10.2147/BTT.S14902
PMCID: PMC3010823  PMID: 21209727
botulinum toxin type A; neurotoxin; complexing proteins; neutralizing antibodies
2.  Gaucher disease: clinical profile and therapeutic developments 
Gaucher disease is a rare inborn error of glycosphingolipid metabolism due to deficiency of lysosomal acid β-glucocerebrosidase; the condition has totemic significance for the development of orphan drugs. A designer therapy, which harnesses the mannose receptor to complement the functional defect in macrophages, ameliorates the principal clinical manifestations in hematopoietic bone marrow and viscera. While several aspects of Gaucher disease (particularly those affecting the skeleton and brain) are refractory to treatment, enzyme (replacement) therapy has become a pharmaceutical blockbuster. Human β-glucocerebrosidase was originally obtained from placenta and the Genzyme Corporation (Allston, MA) subsequently developed a recombinant product. After purification, the enzyme is modified to reveal terminal mannose residues which facilitate selective uptake of the protein, imiglucerase (Cerezyme®), in macrophage-rich tissues. The unprecedented success of Cerezyme has attracted fierce competition: two biosimilar agents, velaglucerase-alfa, VPRIV® (Shire Human Genetic Therapies, Dublin, Ireland) and taliglucerase-alfa (Protalix, Carmiel, Israel), are now approved or in late-phase clinical development as potential ‘niche busters’. Oral treatments have advantages over biological agents for disorders requiring lifelong therapy and additional stratagems which utilize small, orally active molecules have been introduced; these include two chemically distinct compounds which inhibit uridine diphosphate glucose: N-acylsphingosine glucosyltransferase, the first step in the biosynthesis of glucosylceramide – a key molecular target in Gaucher disease and other glycosphingolipidoses. Academic and commercial enterprises in biotechnology have combined strategically to expand the therapeutic repertoire in Gaucher disease. The innovative potential of orphan drug legislation has been realized – with prodigious rewards for companies embracing its humanitarian precepts. In the era before enzyme therapy, bone marrow transplantation was shown to correct systemic disease in Gaucher patients by supplying a source of competent donor macrophages. As a radical advance on cell- or protein-replacement techniques, contemporary methods for transferring genes to autologous hematopoietic stem cells, and to the brain, merit further exploration. At present, the inflated pharmaceutical niche of Gaucher disease appears to be resilient, but if the remaining unmet needs of patients are to be convincingly addressed and commercial development sustained, courageous scientific investment and clinical experimentation will be needed.
doi:10.2147/BTT.S7582
PMCID: PMC3010821  PMID: 21209725
Gaucher disease; orphan diseases; lysosome; macrophage; enzyme therapy; substrate inhibitors; enzyme replacement
3.  Principal long-term adverse effects of imatinib in patients with chronic myeloid leukemia in chronic phase 
Imatinib mesylate (IM), an original Abl tyrosine kinase inhibitor, entered the clinics in 1998 for the treatment of patients with chronic myeloid leukemia (CML). The drug is universally considered the treatment of choice for most, if not all, patients with CML. Importantly, lessons learned from patients with CML have been applied successfully for the treatment of patients with other disorders where IM has since been found to be active by virtue of its ability to target other kinases, such as c-kit in patients with gastrointestinal stromal tumors. IM is associated with mild to moderate toxicity, mostly reversible by dose reduction or discontinuation of the drug. Most adverse effects occur within the first 2 years of starting therapy; however, late effects, many being unique, are now being recognized. In this report, we assess the toxicity associated with IM, with an emphasis on the long-term adverse effects.
doi:10.2147/BTT.S5775
PMCID: PMC3010822  PMID: 21209726
chronic myeloid leukemia; chronic phase; imatinib mesylate
4.  The emerging role of nimotuzumab in the treatment of non-small cell lung cancer 
Current non-small cell lung cancer (NSCLC) chemotherapy and radiotherapy regimens, although showing definite survival benefit, still leave patients with a disappointing 15% 5-year overall survival rate. Because of the need to improve traditional outcomes, research has focused on identifying specific tumorigenic pathways that may serve as therapeutic targets. The most successful strategies to date are those aimed at the epidermal growth factor receptor (EGFR), which is found to be upregulated in 40%–80% of NSCLC. Several tyrosine kinase inhibitors and monoclonal antibodies (mAbs) have been developed that inhibit the EGFR receptor and have demonstrated clinical benefit in trials as single agents and in combination regimens. Here we discuss one such agent, the mAb nimotuzumab, the background of its development, its clinical experience in NSCLC thus far, and the rationale for expanding its use to other NSCLC treatment settings.
doi:10.2147/BTT.S8617
PMCID: PMC2990321  PMID: 21116327
non-small cell lung cancer; chemotherapy; radiotherapy; overall survival; EGFR
5.  Proteasome inhibition and its therapeutic potential in multiple myeloma 
Due to an unmet clinical need for treatment, the first in class proteasome inhibitor, bortezomib, moved from drug discovery to FDA approval in multiple myeloma in an unprecedented eight years. In the wake of this rapid approval arose a large number of questions about its mechanism of action and toxicity as well as its ultimate role in the treatment of this disease. In this article, we briefly review the preclinical and clinical development of the drug as the underpinning for a systematic review of the large number of clinical trials that are beginning to shed some light on the full therapeutic potential of bortezomib in myeloma. We conclude with our current understanding of the mechanism of action of this agent and a discussion of the novel proteasome inhibitors under development, as it will be progress in these areas that will ultimately determine the true potential of proteasome inhibition in myeloma.
doi:10.2147/BTT.S3419
PMCID: PMC2990320  PMID: 21116326
bortezomib; multiple myeloma
6.  Current status of vandetanib (ZD6474) in the treatment of non-small cell lung cancer 
Vandetanib (ZD6474) is an oral small molecule inhibitor of multiple intracellular receptor kinases, including the vascular endothelial growth factor receptor (VEGFR) -2 and epidermal growth factor receptor (EGFR). Both VEGFR and EGFR pathways have emerged as instrumental in the growth and metastasis of multiple malignancies, including non-small cell lung cancer (NSCLC). Indeed, inhibitors of each pathway have been approved by the US Food and Drug Administration for use in advanced NSCLC. As there is considerable cross talk between these pathways, dual inhibition with such agents has become an attractive strategy, with encouraging Phase II clinical trial data to date. The convenience of one oral agent targeting both pathways is clear, and clinical trials have established the maximum tolerated daily dose of vandetanib, with data from randomized Phase III trials emerging. This report will review completed and ongoing NSCLC clinical trials evaluating vandetanib, and speculate on the future of this agent in NSCLC.
PMCID: PMC2943196  PMID: 20859451
Zactima; ZD6474; non-small cell lung cancer; vandetanib
7.  Describing the hexapeptide identity platform between the influenza A H5N1 and Homo sapiens proteomes 
We searched the primary sequence of influenza A H5N1 polyprotein for hexamer amino acid sequences shared with human proteins using the Protein International Resource database and the exact peptide matching analysis program. We find that the viral polyprotein shares numerous hexapeptides with the human proteome. The human proteins involved in the viral overlap are represented by antigens associated with basic cell functions such as proliferation, development, and differentiation. Of special importance, many human proteins that share peptide sequences with influenza A polyprotein are antigens such as reelin, neurexin I-α, myosin-IXa, Bardet–Biedl syndrome 10 protein, Williams syndrome transcription factor, disrupted in schizophrenia 1 protein, amyotrophic lateral sclerosis 2 chromosomal region candidate gene 17 protein, fragile X mental retardation 2 protein, and jouberin. That is, the viral-vs-human overlap involves human proteins that, when altered, have been reported to be potentially associated with multiple neurological disorders that can include autism, epilepsy, obesity, dystonia, ataxia–telangiectasia, amyotrophic lateral sclerosis, sensorineural deafness, sudden infant death syndrome, Charcot-Marie-Tooth disease, and myelination. The present data are discussed as a possible molecular basis for understanding influenza A viral escape from immunosurveillance and for defining anti-influenza immune-therapeutic approaches devoid of collateral adverse events.
PMCID: PMC2943197  PMID: 20859452
peptide sharing; neurological disorders; host-pathogen relationships; viral escape from immunosurveillance
8.  New and emerging treatment approaches to lupus 
The main goal in systemic lupus erythematosus (SLE) is to achieve remission, as this has a major impact on patient and renal survival. Furthermore, early treatment success has been shown to improve long-term prognosis. Treatment in severe SLE, especially in lupus nephritis, has traditionally been a standardized schematic therapy with cyclophosphamide and prednisolone followed by azathioprine. However, animal and human studies have increased our pathogenetic knowledge of this autoimmune disease with emerging new treatment targets. New and future therapeutic approaches are focused on B-cell depletion, T-cell downregulation and co-stimulatory blockade, cytokine inhibition, or the modulation of complement. Many different biological agents have been used in recent and ongoing studies, but up to now breakthroughs emerging from randomized Phase III trials have been rare. However, the future remains exciting with progress towards safe treatments with which to control the disease in the long run.
PMCID: PMC2943198  PMID: 20859453
systemic lupus erythematosus; lupus nephritis; B-cell depletion; co-stimulatory blockade; cytokine inhibition; monoclonal antibodies
9.  The contribution of cetuximab in the treatment of recurrent and/or metastatic head and neck cancer 
Recurrent and/or metastatic squamous cell carcinoma of the head and neck (HNSCC) continues to be a source of significant morbidity and mortality worldwide. Agents that target the epidermal growth factor receptor (EGFR) have demonstrated beneficial effects in this setting. Cetuximab, a monoclonal antibody against the EGFR, improves locoregional control and overall survival when used as a radiation sensitizer in patients with locoregionally advanced HNSCC undergoing definitive radiation therapy with curative intent. Cetuximab is also active as monotherapy in patients whose cancer has progressed on platinum-containing therapy. In the first-line setting for incurable HNSCC, cetuximab added to platinum-based chemotherapy significantly improves overall survival compared with standard chemotherapy alone. These positive results have had a significant impact on the standard of care for advanced HNSCC. In this review, we will discuss the mechanism of action, clinical data and common toxicities that pertain to the use of cetuximab in the treatment of advanced incurable HNSCC.
PMCID: PMC2921255  PMID: 20714355
cetuximab; squamous cell carcinoma of the head and neck; epidermal growth factor receptor
10.  Rationale for targeted therapies and potential role of pazopanib in advanced renal cell carcinoma 
Advanced renal cell carcinoma (RCC) remains a challenging, major health problem. Recent advances in understanding the fundamental biology underlying one form of RCC, ie, clear cell (or conventional) RCC, have opened the door to a series of targeted agents, such as the tyrosine kinase inhibitors (TKIs), which have become the standard of care in managing advanced clear cell RCC. Among the newest of these agents to receive Food and Drug Administration approval in this disease is pazopanib. This review will summarize what is known about the fundamental biology that underlies clear cell RCC, the data surrounding the previously approved targeted agents for this disease, including not only the TKIs but also the mTOR inhibitors and the vascular endothelial growth factor-specific agent, bevacizumab, and the newest TKI, pazopanib. It will also explore the potential role for pazopanib relative to the other available agents and where it may fit into the armamentarium for treatment of advanced/metastatic RCC.
PMCID: PMC2921256  PMID: 20714356
pazopanib; targeted therapy; tyrosine kinase inhibitor; clear cell renal cell carcinoma
11.  Detection and characterization of liver lesions using gadoxetic acid as a tissue-specific contrast agent 
The value of cross-sectional liver imaging is evaluated by the accuracy, sensitivity, and specificity of the specific imaging technique. Magnetic resonance imaging (MRI) has become a key technique for the characterization and detection of focal and diffuse liver disease. More recently, gadoxetic acid, the hepatocyte-specific MR contrast agent, was clinically approved and introduced in many countries. Gadoxetic acid may be considered a “molecular imaging” probe because the compound is actively taken into hepatocytes via the ATP-dependent organic anion transport system in the plasma membrane for the hepatic uptake. The transport of gadoxetic acid from the cytoplasm to the bile is mainly determined by the capacity of the transport protein glutathione-S-transferase. Gadoxetic acid enhances hepatocyte-containing lesions and improves detection of lesions devoid of normal hepatocytes, such as metastases. Innovative rapid MR acquisition techniques with near isotropic 3D pulse sequences with fat saturation parallel the technical progress made by multidetector computed tomography combined with an impressive improvement in tumor–liver contrast when used for gadoxetic acid-enhanced MRI. The purpose of this review is to provide an overview of the development, clinical testing, and applications of this novel MR contrast agent.
PMCID: PMC2921257  PMID: 20714357
hepatocytes; tumor; gadoxetic acid; liver lesions
12.  Prevention of rotavirus gastroenteritis in infants and children: rotavirus vaccine safety, efficacy, and potential impact of vaccines 
Rotavirus infection is the most common cause of severe gastroenteritis globally, with greater than 86% of deaths occurring in low-income and middle-income countries. There are two rotavirus vaccines currently licensed in the United States and prequalified by the World Health Organization. RV1 is a monovalent attenuated human rotavirus strain, given orally in two doses. RV5 is a pentavalent human-bovine reassortant rotavirus vaccine, given orally in three doses. A third rotavirus vaccine, LLV, is a lamb rotavirus strain given orally as a single dose, which is currently available only in China. RV1 and RV5 have been shown to be highly efficacious in developed countries, and initial results from trials in Africa and Asia are promising as well. At least three other vaccines are in development, which are being developed by manufacturers of developing countries. Further studies are needed to clarify issues including administration of oral rotavirus vaccines with breastfeeding and other oral vaccines, and alterations in dosing schedule. Using new data on global diarrheal burden, rotavirus is estimated to cause 390,000 deaths in children younger than 5 years. Should rotavirus vaccines be introduced in the routine immunization programs of all countries, a potential of 170,000 deaths could be prevented annually. The largest impact on mortality would be seen in low-income and middle-income countries, despite poor immunization coverage and lower efficacy. Therefore, international efforts are needed to ensure that rotavirus vaccines reach the populations with highest burden of rotavirus disease.
PMCID: PMC2921258  PMID: 20714358
vaccination; mortality; rotavirus; gastroenteritis
13.  New era in treatment for phenylketonuria: Pharmacologic therapy with sapropterin dihydrochloride 
Oral administration of sapropterin hydrochloride, recently approved for use by the US Food and Drug Administration and the European Commission, is a novel approach for the treatment of phenylketonuria (PKU), one of the most common inborn errors of metabolism. PKU is caused by an inherited deficiency of the enzyme phenylalanine hydroxylase (PAH), and the pathophysiology of the disorder is related to chronic accumulation of the free amino acid phenylalanine in tissues. Contemporary therapy is based upon restriction of dietary protein intake, which leads to reduction of blood phenylalanine levels. This therapy is difficult to maintain throughout life, and dietary noncompliance is commonplace. Sapropterin dihydrochloride is a synthetic version of tetrahydrobiopterin, the naturally occurring pterin cofactor that is required for PAH-mediated phenylalanine hydroxylation. In a subset of individuals with PAH deficiency, sapropterin administration leads to reduction in blood phenylalanine levels independent of dietary protein. For these individuals, sapropterin is an effective novel therapy for PKU.
PMCID: PMC2921259  PMID: 20714359
sapropterin dihydrochloride; phenylketonuria; phenylalanine; tetrahydrobiopterin
14.  Use of clofarabine for acute childhood leukemia 
A second-generation of purine nucleoside analogs, starting with clofarabine, has been developed in the course of the search for new therapeutic agents for acute childhood leukemia, especially for refractory or relapsed disease. Clofarabine is a hybrid of fludarabine and cladribine, and has shown to have antileukemic activity in acute lymphoblastic leukemia as well as in myeloid disorders. As the only new antileukemic chemotherapeutic agent to enter clinical use in the last 10 years, clofarabine was approved as an orphan drug with the primary indication of use in pediatric patients. Toxicity has been tolerable in a heavily pretreated patient population, and clofarabine has been demonstrated to be safe, both as a single agent and in combination therapies. Liver dysfunction has been the most frequently observed adverse event, but this is generally reversible. Numerous Phase I and II trials have recently been conducted, and are still ongoing in an effort to find the optimal role for clofarabine in various treatment strategies. Concomitant use of clofarabine, cytarabine, and etoposide was confirmed to be safe and effective in two independent trials. Based on the promising results when used as a salvage regimen, clofarabine is now being investigated for its potential to become part of frontline protocols.
PMCID: PMC2898101  PMID: 20631817
clofarabine; pediatric acute lymphoblastic leukemia; pediatric acute myeloid leukemia
15.  Managing idiopathic short stature: role of somatropin (rDNA origin) for injection 
Idiopathic short stature (ISS) is a term that describes short stature in children who do not have growth hormone (GH) deficiency and in whom the etiology of the short stature is not identified. Between 1985 and 2000, more than 40 studies were published regarding GH therapy for ISS. Only 12 of these had data to adult height, of which only 4 were controlled studies. A subsequent placebo-controlled study that followed subjects to adult height indicated that there was a gain of 3.7–7.5 cm in height with GH treatment. In 2003, the US Federal Drug Administration (FDA) approved GH for treatment of short stature. Even before FDA approval, patients with ISS made up about 20% of patients in GH databases, which is largely unchanged since FDA approval. There remains some controversy as to whether GH should be used to treat ISS. This controversy centers on the fact that there has been no definitive demonstration that short stature results in a disadvantage or problems with psychological adjustment, and thus, no demonstration that GH therapy results in improvement in quality of life.
PMCID: PMC2898102  PMID: 20631818
idiopathic short stature; ISS; growth hormone therapy; somatotropin; somatropin; insulin-like growth factor I; IGF-1
16.  Decreasing glioma recurrence through adjuvant cancer stem cell inhibition 
Gliomas remain one of the most challenging solid organ tumors to treat and are marked clinically by invariable recurrence despite multimodal intervention (surgery, chemotherapy, radiation). This recurrence perhaps, is as a consequence of the failure to eradicate a tumor cell subpopulation, termed cancer stem cells. Isolating, characterizing, and understanding these tumor-initiating cells through cellular and molecular markers, along with genetic and epigenetic understanding will allow for selective targeting through therapeutic agents and holds promise for decreasing glioma recurrence.
PMCID: PMC2898103  PMID: 20631819
glioma; cancer stem cells; epigenetic
17.  Distinct expression profiles of Notch-1 protein in human solid tumors: Implications for development of targeted therapeutic monoclonal antibodies 
Biological therapies, such as monoclonal antibodies (mAbs) that target tumor-associated antigens have been considered an effective therapeutic approach in oncology. In considering Notch-1 receptor as a potential target, we performed immunohistochemistry on tissue microarrays to determine 1) whether the receptor is overexpressed in tumor cells as compared to their corresponding normal tissues and 2) the clinical significance of its expression levels in human breast, colorectal, lung and prostate cancers. We found that the expression of Notch-1 protein was overexpressed in primary colorectal adenocarcinoma and nonsmall cell lung carcinoma (NSCLC), but not in primary ductal breast carcinoma or prostate adenocarcinoma. Further analysis revealed that higher levels of Notch-1 protein expression were significantly associated with poorer differentiation of breast and prostate tumors. Strikingly, for NSCLC, the expression levels of Notch-1 protein were found to be inversely correlated with tumor differentiation and progression. For colorectal tumors, however, no correlation of Notch-1 protein expression was found with any tumor clinicopathological parameters, in spite of its overexpression in tumor cells. Our data demonstrated the complexity of Notch-1 protein expression in human solid tumors and further supported the notion that the roles of Notch-1 expression in tumorigenesis are highly context-dependent. The findings could provide the basis for development of distinct therapeutic strategies of Notch-1 mAbs for its applications in the treatment of suitable types of human cancers.
PMCID: PMC2898104  PMID: 20631820
Notch-1; target therapy; tissue microarray; immunohistochemistry
18.  Everolimus: the first approved product for patients with advanced renal cell cancer after sunitinib and/or sorafenib 
Everolimus (RAD001, Afinitor® Novartis) is the first oral inhibitor of mTOR (mammalian target of rapamycin) to reach the oncology clinic. Everolimus 10 mg daily achieves complete inhibition of its target at below the maximum tolerable dose for most patients. A phase III randomized placebo-controlled trial has examined the impact of everolimus in patients with clear cell renal cancers and progressive disease on or within 6 months of the VEGFR tyrosine kinase inhibitors sunitinib and/or sorafenib. The primary endpoint of progression-free survival was increased from median 1.9 to 4.9 months (hazard ratio 0.33, P < 0.001) and 25% were still progression-free after 10 months of everolimus therapy. There was a delay in time to decline of performance status and trends to improvement in quality of life, disease-related symptoms, and overall survival despite crossover of the majority of patients assigned to placebo. In 2009, everolimus was approved in the US and Europe as the only validated option for this indication. Toxicities are usually mild to moderate and can be managed with dose reduction or interruption if necessary. Opportunistic infections and non-infectious pneumonitis are seen as a class effect. Management of common practical management issues are discussed. Clinical trials are in progress to examine additional roles for everolimus in renal cancer, alone and in combination with other agents.
PMCID: PMC2880340  PMID: 20531964
everolimus; drug therapy; advanced renal cancer
19.  Critical appraisal of canakinumab in the treatment of adults and children with cryopyrin-associated periodic syndrome (CAPS) 
The cryopyrin-associated syndromes (CAPS) include three autosomal-dominant syndromes, that are caused by a mutation in the NLRP3 gene on chromosome 1, encoding the cryopyrin protein. These syndromes, familial cold autoinflammatory syndrome, Muckle-Wells syndrome and neonatal-onset multisystem inflammatory disease, are characterized by urticaria-like rash, fever, central nervous system inflammation, an arthropathy and a risk of the development of amyloidosis in a respectively escalating degree of severity between the various syndromes. Recently the role of cryopyrin in the regulation of interleukin (IL)-1 production and activation was described and anti IL-1 therapies were found to be very effective in treating these syndromes. There are several types of anti IL-1 medications based on different mechanisms of antagonizing IL-1. This paper focuses on the efficacy and safety of canakinumab, a long-acting humanized anti IL-1 antibody, in treating these syndromes.
PMCID: PMC2880341  PMID: 20531965
canakinumab; cryopyrin-associated periodic syndromes; biologics; treatment; autoinflammatory diseases
20.  Management of patients with advanced non-small cell lung cancer: role of gefitinib 
Gefitinib is the first epidermal growth factor receptor tyrosine-kinase inhibitor approved for the treatment of advanced non-small cell lung cancer (NSCLC). Its failure to improve survival in a placebo-control study, however, led to its withdrawal in the United States though it is available in many other countries Subsequent studies nevertheless showed comparable efficacy for gefitinib and docetaxel in the second-line therapy. Gefitinib significantly improved progression-free survival compared to chemotherapy in patients with activating mutations in the epidermal growth factor receptor tyrosine kinase mutations. This review will discuss the results of these large randomized studies and discuss the role of gefitinib in the treatment of advanced NSCLC.
PMCID: PMC2880342  PMID: 20531966
gefitinib; non-small cell lung cancer
21.  Hepatitis B virus and Homo sapiens proteome-wide analysis: A profusion of viral peptide overlaps in neuron-specific human proteins 
The primary amino acid sequence of the hepatitis B virus (HBV) proteome was searched for identity spots in the human proteome by using the Protein Information Resource database. We find that the HBV polyprotein shares sixty-five heptapeptides, one octapeptide, and one nonapeptide with the human proteins. The viral matches are disseminated among fundamental human proteins such as adhesion molecules, leukocyte differentiation antigens, enzymes, proteins associated with spermatogenesis, and transcription factors. As a datum of special interest, a number of peptide motifs are shared between the virus- and brain-specific antigens involved in neuronal protection. This study may help to evaluate the potential cross reactions and side effects of HBV antigen-based vaccines.
PMCID: PMC2880343  PMID: 20531967
HBV proteome; human proteome; similarity analysis; viral versus human proteome overlapping; vaccine-related cross-reactions
22.  Potential role of ustekinumab in the treatment of chronic plaque psoriasis 
Psoriasis is a relatively common, chronic and disabling skin disease, with an immune-related pathogenesis and a genetic background which may be triggered by several environmental factors including smoking and infections. There is no cure but several treatment options are available. The treatment of psoriasis is far from being satisfactory due to impractical modalities of topical treatment and suboptimal safety profile of the systemic treatments available. In the last few years, parallel to an improved understanding of the disease pathogenesis, there has been a boost in research on new agents for the treatment of psoriasis. Ustekinumab, a monoclonal antibody targeting the p40 subunit of interleukin (IL)-12 and IL-23, is one such new agent. Psoriasis and its management are briefly reviewed before focusing on the evidence for ustekinumab in the treatment of chronic plaque psoriasis through a systematic search of the main registries of ongoing trials up to December 2009. Ustekinumab proved to be very effective short term in the control of clinical manifestations in psoriasis compared with placebo and with etanercept. Long-term and comparative data are still limited. There is a need for continuing research on the long-term effectiveness and safety of the drug.
PMCID: PMC2880344  PMID: 20531968
ustekinumab; chronic plaque psoriasis
23.  Palliative treatment of malignant ascites: profile of catumaxomab 
Malignant ascites is the abnormal accumulation of fluid in the peritoneal cavity associated with several intrapelvic and intra-abdominal malignancies. The development of ascites leads to significant symptoms and poor quality of life for the cancer patient. Available therapies for palliation include treatment of the underlying disease, but when there are no treatment options, the use of diuretics, implantation of drainage catheters, and surgical shunting techniques are considered. None of these symptom palliation options affect the course of disease. The development of trifunctional antibodies, which attach to specific overexpressed surface markers on tumor cells, and trigger an immune response leading to cytoreductive effects, represents a new approach to the management of malignant ascites. The purpose of this review is to highlight current therapies for malignant ascites and review data as to the effectiveness of a new trifunctional antibody, catumaxomab.
PMCID: PMC2880345  PMID: 20531969
catumaxomab; ascites; trifunctional
24.  Management of chronic immune thrombocytopenic purpura: targeting insufficient megakaryopoiesis as a novel therapeutic principle 
Traditionally, anti-platelet autoantibodies accelerating platelet clearance from the peripheral circulation have been recognized as the primary pathopysiological mechanism in chronic immune thrombocytopenia (ITP). Recently, increasing evidence supports the co-existence of insufficient megakaryopoiesis. Inadequate low thrombopoietin (TPO) levels are associated with insufficient proliferation and differentiation of megakaryocytes, decreased proplatelet formation, and subsequent platelet release. Recently two novel activators of TPO receptors have been made available: romiplostim and eltrombopag. In several phase III studies, both agents demonstrated increase of platelet counts in about 80% of chronic ITP patients within 2 to 3 weeks. These agents substantially broaden the therapeutic options for patients with chronic ITP although long-term results are still pending. This review will provide an update on the current conception of underlying mechanisms in ITP and novel, pathophysiologically based treatment options.
PMCID: PMC2880346  PMID: 20531970
immune thrombocytopenia; romiplostim; eltrombopag; megakaryopoiesis
25.  Safety and immunogenicity of Salmonella typhimurium expressing C-terminal truncated human IL-2 in a murine model 
Salmonella enterica serovar Typhimurium preferentially colonizes tumors in vivo and has proven to be an effective biologic vector. The attenuated S. enterica Typhimurium strain χ4550 was engineered to express truncated human interleukin-2 and renamed SalpIL2. Previously, we observed that a single oral administration of SalpIL2 reduced tumor number and volume, while significantly increasing local and systemic natural killer (NK) cell populations in an experimental metastasis model. Here we report that in nontumor-bearing mice, a single oral dose of SalpIL2 resulted in increased splenic cytotoxic T and NK cell populations that returned to control levels by 4 weeks post oral administration. Though SalpIL2 was detected in mouse tissues for up to 10 weeks, no prolonged alterations in peripheral blood serum chemistry or complete blood cell counts were observed. Similarly, comparative histopathological analysis of tissues revealed no significant increase in pyogranulomas in SalpIL2-treated animals with respect to saline controls. In Rag-1 knockout mice, which have severely impaired B and T cell function, SalpIL2 reduced growth of hepatic metastases. Furthermore, SalpIL2 altered expression of several proinflammatory cytokines and chemokines in the serum of mice with pulmonary osteosarcoma metastases. These data further suggest that SalpIL2 is avirulent and induces a cell-mediated antitumor response.
PMCID: PMC2846145  PMID: 20376175
Salmonella Typhimurium; natural killer cells; interleukin-2

Results 1-25 (31)