New Generation Of Drugs Research Articles

Myeloid depletion of SOCS3 enhances LPS‐induced acute lung injury through CCAAT/enhancer binding protein δ pathway

Although uncontrolled inflammatory response plays a central role in the pathogenesis of acute lung injury (ALI), the precise molecular mechanisms underlying the development of this disorder remain poorly understood. SOCS3 is an important negative regulator of IL-6-type cytokine signaling. SOCS3 is induced in lung during LPS-induced lung injury, suggesting that generation of SOCS3 may represent a regulatory product during ALI. In the current study, we created mice lacking SOCS3 expression in macrophages and neutrophils (LysM-cre SOCS3(fl/fl)). We evaluated the lung inflammatory response to LPS in both LysM-cre SOCS3(fl/fl) mice and the wild-type (WT) mice (SOCS3(fl/fl)). LysM-cre SOCS3(fl/fl) mice displayed significant increase of the lung permeability index (lung vascular leak of albumin), neutrophils, lung neutrophil accumulation (myeloperoxidase activity), and proinflammatory cytokines/chemokines in bronchial alveolar lavage fluids compared to WT mice. These phenotypes were consistent with morphological evaluation of lung, which showed enhanced inflammatory cell influx and intra-alveolar hemorrhage. We further identify the transcription factor, CCAAT/enhancer-binding protein (C/EBP) δ as a critical downstream target of SOCS3 in LPS-induced ALI. These results indicate that SOCS3 has a protective role in LPS-induced ALI by suppressing C/EBPδ activity in the lung. Elucidating the function of SOCS3 would represent prospective targets for a new generation of drugs needed to treat ALI.

Myeloid Depletion of SOCS3 Enhances LPS‐Induced Acute Lung Injury through CCAAT/Enhancer Binding Protein delta Pathway

ObjectiveSOCS3 is an important negative regulator of IL‐6‐type cytokine signaling. SOCS3 is induced in lung during LPS‐induced lung injury. The objective of this study is to test the hypothesis that SOCS3 is a critical regulator of LPS‐induced ALI.MethodsWe created mice lacking SOCS3 expression in macrophages and neutrophils (LysM‐cre SOCS3fl/fl). We evaluated the lung inflammatory response to LPS in both LysM‐cre SOCS3fl/fl mice and the wild type mice (SOCS3fl/fl). We also determined the role of CCAAT/enhancer‐binding proteins (C/EBP)β and ‐δ in LPS‐induced ALI by using C/EBPβ and ‐δ mutant mice.ResultsLysM‐cre SOCS3fl/fl mice displayed significant increase of the lung permeability index (lung vascular leak of albumin), lung neutrophil accumulation (MPO activity), neutrophils and proinflammatory cytokines/chemokines in bronchial alveolar lavage (BAL) fluids compared to wild‐type mice. These phenotypes were consistent with morphological evaluation of lung, which showed enhanced inflammatory cell influx and intra‐alveolar hemorrhage. We further identify C/EBPδ, but not C/EBPβ, as a critical downstream mediator of SOCS3 in LPS‐induced ALI.ConclusionsResults indicate that SOCS3 has a protective role in LPS‐induced ALI by suppressing C/EBPδ activity in the lung. Elucidating the function of SOCS3 and C/EBPδ would represent prospective targets for a new generation of drugs needed to treat ALI.

Medical Biotechnology: Problems and Prospects in Bangladesh

Biotechnology is the knowledge and techniques of developing and using biological systems for deriving special products and services. The age-old technology took a new turn with the advent of recombinant DNA techniques, and boosted by the development of other molecular biological techniques, cell culture techniques and bioinformatics. Medical biotechnology is the major thrust area of biotechnology. It has brought revolutions in medicine – quick methods for diagnosing diseases, generation of new drugs and vaccines, completely novel approach of treatment are only a few to mention. The industrial and financial bulk of the industry mushroomed very rapidly in the last three decades, led by the USA and western advanced nations. Asian countries like China, India, South Korea, Taiwan and Singapore joined late, but advancing forward in a big way. In all the Asian countries governments supported the initiatives of the expert and entrepreneur community, and invested heavily in its development. Bangladesh has got great potential in developing biotechnology and reaping its fruits. However, lack of commitment and patriotism, and too much corruption and irresponsibility in political and bureaucratic establishment are the major hindrance to the development of biotechnology in Bangladesh. DOI: http://dx.doi.org/10.3329/jemc.v3i1.13873 J Enam Med Col 2013; 3(1): 32-46

Heteronuclear NMR provides an accurate assessment of therapeutic insulin's quality

New generations of drugs are using more and more often therapeutic proteins as the active ingredient, prompting the regulation agencies to adapt their analytical methods. Fast and unambiguous information on the secondary, tertiary and quaternary structure of the protein should be provided to assess the quality of these biodrugs. Recent developments of heteronuclear NMR methods, enabling their use on pharmaceutical formulated unlabeled proteins, provide an efficient way to perform such analysis, a feature that is illustrated here using various commercial formulations of insulins.

Utilidad y satisfacción de los pacientes de un instrumento educacional en dolor irruptivo oncológico: resultados preliminares

JustificationBreakthrough cancer pain is defined as a transitory exacerbation of pain experienced by the patient who has relatively stable and adequately controlled baseline pain. A new generation of drugs (fentanyl) with transmucosal absorption mimic the characteristics of breakthrough pain by providing an ideal analgesic profile. Good patient education on pain characteristics and the mode of titration of these drugs is essential for a successful approach. ObjectiveTo evaluate the degree of understanding and usefulness that patients give to a titration sheet created to facilitate the use and titration of nasal fentanyl pectin. MethodsTwenty consecutive patients who had completed the titration and had received the titration sheet were included. A survey was used to assess their satisfaction. ResultsOf the 20 patients enrolled, 2 had not consulted the titration sheet because they were happy enough with the verbal instructions given. Of the rest, all had consulted it at least once, 85% considered it very useful and 80% very understandable and 33% suggested minor modifications.

A New Generation of Drugs: Synthetic Peptides Based on Natural Regulatory Peptides

Natural regulatory peptides are biologically active compounds that are produced by various cells and provide a link among the main regulatory systems of the body. The field of research into the biologic activity of endogenous regulatory peptides is extremely vast. These peptides affect the cardiovascular, immune, reproductive, endocrine, digestive, and other systems, alter energy metabolism, and are especially effective in the regulation of the central nervous system. Despite of the wide range of preventive and therapeutic effects of natural regulatory peptides and proteins, their application in clinical practice is difficult. This is primarily because of their extreme instability, as they are rapidly degraded by proteases of the gastrointestinal tract, blood, cerebrospinal fluid, and other biologic media. Compounds with higher stability (i.e., a considerably longer half-life compared with that of natural molecules) and the ability to provide a directional effect on the various body systems were obtained from modifications of endogenous regulatory peptides. Synthetic analogs of regulatory peptides, as a rule, contain only natural amino acids in their composition, and their biodegradation does not lead to the formation of toxic products; thus, they have fewer side effects. This review focuses on the consideration of two synthetic regulatory peptides, Semax and Selank, which were the bases for the creation of new drugs that are used effectively in the treatment of various diseases of the nervous system. The synthetic analog of an adrenocorticotropic hormone 4-10 fragment (ACTH4-10) Semax is a powerful neuroprotective agent that is particularly effective as a therapy for stroke. Selank was synthesized on the basis of the natural immunomodulator tuftsin. Selank is a powerful anxiolytic that is used as a therapy for generalized anxiety disorder and neurasthenia without sedative and muscle-relaxant effects. This review presents the results of research aimed at studying the influence of these peptides on the transcriptome of brain cells. The problems of drugs developed based on the clinical activities of Semax and Selank are discussed separately.

Hepatitis B reactivation related to everolimus

Reactivation of hepatitis B virus (HBV) during chemotherapy is a well known complication in patients with chronic hepatitis B and cancer. The clinical manifestations range from subclinical elevation of liver enzymes to severe, potentially fatal fulminant hepatitis. Reactivation can occur in a patient with previous inactive HBV infection; either an inactive carrier or a patient with resolved hepatitis. Everolimus is a mammalian target of rapamycin (mTOR) inhibitor approved in renal cell carcinoma, neuroendocrine tumours and breast cancer. mTOR inhibitors are a new generation of drugs for targeted treatment; therefore, little about their side effects is known. Here, we report a patient with renal cell carcinoma who experienced a flare of hepatitis B infection during treatment with everolimus. Clinicians should be aware of HBV reactivation in patients who are undergoing treatment with everolimus, and screening for hepatitis B infection and prophylactic antiviral treatment should be considered.

Global Current Trends in Drug Designing for Management of Type-2 Diabetes and Neurodegenerative Disorders

Neurodegenerative diseases (NDs) and Type 2 diabetes (T2D) are progressive disorder often advances with age. T2D is characterized by hyperglycaemia, insulin resistance or relative lack of insulin uptake whereas NDs are characterized by the decline in cognitive function, diffuse deposition of amyloid plaques and neurofibrillary tangles in AD and degeneration of dopaminergic neurons in substantia nigra, leading to a reduction of striatal dopamine (DA) levels in PD. Since conventional drugs fail to surpass the natural CNS protective barriers, therefore, in order to overcome these hurdles, targeted drug delivery is of foremost significance for the treatment of AD and PD. New generation of drugs has discovered through innovative nanotechnology approaches such as polymeric nanoparticles are promising candidates in the investigation of AD because nanoparticles are capable of opening the tight junctions, crossing the BBB. Thus, there is a need to adopt current trend and newer strategies such as nanotechnological, computational and gene therapy approaches for drug design and delivery.

17-AAG Kills Intracellular Leishmania amazonensis while Reducing Inflammatory Responses in Infected Macrophages

BackgroundLeishmaniasis is a neglected endemic disease with a broad spectrum of clinical manifestations. Pentavalent antimonials have been the treatment of choice for the past 70 years and, due to the emergence of resistant cases, the efficacy of these drugs has come under scrutiny. Second-line drugs are less efficacious, cause a range of side effects and can be costly. The formulation of new generations of drugs, especially in developing countries, has become mandatory.Methodology/Principal FindingsWe investigated the anti-leishmanial effect of 17-(allylamino)-17-demethoxygeldanamycin (17-AAG), an HSP90 inhibitor, in vitro. This inhibitor is currently in clinical trials for cancer treatment; however, its effects against intracellular Leishmania remain untested. Macrophages infected with L. amazonensis were treated with 17-AAG (25–500 nM) and parasite load was quantified using optical microscopy. Parasite load declined in 17-AAG-treated macrophages in a dose- and time-dependent manner. Intracellular parasite death became irreversible after 4 h of treatment with 17-AAG, and occurred independent of nitric oxide (NO) and superoxide (O2 −) production. Additionally, intracellular parasite viability was severely reduced after 48 h of treatment. Interestingly, treatment with 17-AAG reduced pro-inflammatory mediator production, including TNF-α, IL-6 and MCP-1, yet IL-12 remained unaffected. Electron microscopy revealed morphological alterations, such as double-membrane vacuoles and myelin figures at 24 and 48 h after 17-AAG treatment.Conclusions/SignificanceThe HSP90 inhibitor, 17-AAG, possesses high potency under low dosage and reduces both pro-inflammatory and oxidative molecule production. Therefore, further studies are warranted to investigate this inhibitor’s potential in the development of new generations of anti-leishmanials.

Czy jest miejsce w pediatrii dla leków antyhistaminowych I generacji?

The first generation antihistamines because of the numerous side effects associated with the lack of selective histamine receptor interaction and the ability to penetrate the central nervous system in the treatment of allergic diseases have been replaced by a newer generation of drugs without these actions. In Poland, but also in many other countries the first generation antihistamines are still used in the treatment of vomiting and coughing. The paper presents the characteristics of the most commonly used the first generation antihistamines and the current indications for use of this drug in children.

Abstract 1641: Concordance between mutations identified by bar-coded multiplexed sequencing of BRAF, NRAS, and KIT in formalin fixed (FFPE) tissue from melanoma patients using the Ion Torrent Personal Genome Machine (PGM) and a real-time PCR assay

Abstract The standard chemotherapy for metastatic melanoma is dacarbazine, however, progression free survival with dacarbazine is a dismal two months. Efforts to improve the treatment of melanoma have focused on specific molecular defects following the discovery that the majority of patients have a mutation in one of three members of the BRAF-MAPK signaling pathway: KIT, BRAF, and RAS. Recent clinical trials have shown promise for drugs that target the molecular defects in melanoma, including the recently approved mutant BRAF inhibitor vemurafenib. As new drugs that target specific mutations move through clinical trials, the opportunity to perform precision medicine is becoming a reality. To deliver on the promise shown by the new generation of drugs it will be necessary to detect specific mutations in patients so they can be matched with the right drug. To this end, we have used an Ion Torrent Personal Genome Machine to sequence the six most commonly mutated codons in melanoma (BRAF 600, NRAS 12 and 13, NRAS 61, KIT 576, and KIT 642) from formalin fixed paraffin embedded tissue of late stage melanoma patients. All six codons of interest were sequenced in forty-six patients and mutations identified by comparison to normal controls. The A375 cell line, containing the known mutation V600E in BRAF was used as a positive control. Samples were sequenced in a multiplexed format using bar coding of the amplicons which allowed 14 patients and two controls to be sequenced simultaneously on each chip. Results were confirmed by real time RT-PCR assay specific for the BRAF V600E mutation. We demonstrate the feasibility of using rapid low cost next-generation sequencing to provide robust detection of mutations in fixed patient samples. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1641. doi:1538-7445.AM2012-1641

Cardiovascular risk management of hypertension and hypercholesterolaemia in the Netherlands: from unifactorial to multifactorial approach

About 30years ago, the first Dutch unifactorial guidelines on hypertension and hypercholesterolaemia were developed. These guidelines have been revised several times, often after publication of landmark studies on new generations of drugs. In 1978, cut-off points for pharmacological treatment of hypertension were based on diastolic blood pressure values ≥115mmHg, and in 2000 they were lowered to >100mmHg. From 1997 onwards, cut-off points for systolic blood pressure values >180mmHg were introduced, which became leading. In 1987, cut-offs for hypercholesterolaemia of ≥8mmol/l were set and from 2006 pharmacological treatment was based on a total/HDL cholesterol ratio >8. Around 2000, treatment decisions for hypertension and/or hypercholesterolaemia were no longer based on high levels of individual risk factors, but on a multifactorial approach based on total risk of cardiovascular diseases (CVD), determined by a risk function. In the 2006 multidisciplinary guideline on cardiovascular risk management, the Framingham risk tables were replaced by European SCORE risk charts. A cut-off point of 10% CVD mortality was set in the Netherlands. In 2011, this cut-off point changed to 20% fatal plus nonfatal CVD risk. Nowadays, 'the lower the risk factors, the lower the absolute risk' is the leading paradigm in CVD prevention.

Systemic Therapy for Metastatic Melanoma in 2012: Dawn of a New Era

The 10-year survival rate for patients with metastatic melanoma is less than 10%. Although surgery and radiation therapy have a role in the treatment of metastatic disease, systemic therapy is the mainstay of treatment for these patients. After decades of failed attempts to improve treatment outcomes, recent successes with ipilimumab and vemurafenib have ushered in a new era in systemic therapy. Both ipilimumab and vemurafenib are associated with significant improvements in overall survival of patients in randomized phase III trials, an end point that had proven elusive so far. These breakthroughs not only provide more treatment options for patients with melanoma but also spur the investigation of a new generation of drugs for cancer therapy in general. This article reviews both the current systemic treatment options for metastatic melanoma and promising investigational approaches.

Anti-TNF- therapy may not improve arterial stiffness in patients with AS: a 24-week follow-up

The availability of new-generation drugs has provided significant success reflected by disease activity markers and clinical status in AS, but controversial reports necessitate further assessment of associated increased risk of cardiovascular burden that might persist. Hence this prospective clinical study evaluated the effectiveness of a 24-week anti-TNF-α therapy on vascular stiffness [pulse wave velocity (PWV)] in AS. A total of 28 active AS patients (21 males, 7 females) were enrolled before the start of biologic therapy. Demographic and clinical characteristics were recorded. Arterial stiffness was assessed using PWV. Patients were evaluated before and 24 weeks after anti-TNF-α therapy. The mean disease duration was 8.4 (4.9) years. After 24 weeks of anti-TNF-α therapy, despite significant improvements in patients' symptoms and clinical activity parameters, including BASDAI score [4.9 (0.9) vs 1.9 (0.5), P = 0.0001], ESR [35.5 (23.1) vs 13.8 (9.2) mm/h, P = 0.0001) and CRP level [2.1 (1.6) vs 0.4 (0.3) ng/dl, P = 0.0001], no significant change was seen in arterial stiffness parameters [7.9 (1.3) vs 7.7 (1.3) m/s, P = 0.412]. Significant correlation was determined between arterial stiffness and age, systolic blood pressure and high-density lipoprotein cholesterol levels. Despite significant improvement in markers of disease activity, anti-TNF-α therapy does not seem to improve arterial stiffness, a significant AS-associated cardiovascular burden. Thus, when treating AS, significant end-points other than DASs should also be considered, and any hidden threat like arterial stiffness should be addressed further.

The discovery and development of belimumab: the anti-BLyS-lupus connection.

For the first time in more than 50 years, the US Food and Drug Administration has approved a drug specifically for the treatment of systemic lupus erythematosus (SLE). This drug, belimumab (Benlysta), is a human monoclonal antibody that neutralizes the B-cell survival factor, B-lymphocyte stimulator (BLyS). The approval of belimumab combined a pioneering approach to genomics-based gene discovery, an astute appreciation of translational medicine, a disciplined clinical strategy, a willingness to take calculated risks, a devoted cadre of patients and physicians and a healthy dose of serendipity. Collectively, these efforts have provided a model for the development of a new generation of drugs to treat the broad manifestations of SLE. However, as a substantial percentage of SLE patients do not respond to belimumab, further research is needed to better characterize the pathogenetic mechanisms of SLE, identify additional therapeutic targets, and develop effective and nontoxic novel agents against these targets.

The endocannabinoid system: a key modulator of emotions and cognition

The endocannabinoid system: a key modulator of emotions and cognition

Neuroendocrine Differentiation in the Progression of Prostate Cancer: An Update on Recent Developments

Neuroendocrine (NE) differentiation, either benign or malignant, is the hallmark of prostate cancer (PCa). Clusters of malignant NE cells are found in most prostate cancer cases. NE differentiation is among the non-mutually exclusive theories proposed to explain the progression to androgen independence of PCa. NE differentiation is usually associated with an increased aggressivity and invasiveness of prostate tumors and a poor prognosis. This review aims to present an overview of current knowledge on neuroendocrine differentiation in PCa to improve our understanding of tumour progression and androgen independence. The NE component represents an important therapeutic axis. Development of new generation of drugs that selectively target NE-like cells may lead to the development of new therapeutic modalities for advanced and hormone-refractory PCa.

Spectrofluorometric Analysis of New-Generation Antidepressant Drugs in Pharmaceutical Formulations, Human Urine, and Plasma Samples

Spectrofluorometric analysis for the quantification of new-generation antidepressant drugs belong to the class of selective serotonin reuptake inhibitors and selective norepinephrine reuptake inhibitors is described. Five different drugs, sertraline, paroxetine, citalopram, venlafaxine, and fluoxetine, were analysed for spectrofluorometric detection in pharmaceutical formulations and urine and plasma samples. The calibration curves were found linear between fluorescence intensity and drugs concentration in the range of 5–500 ng/L with coefficients of determination above 0.9985 for all the analytes. The method recoveries were higher than 85% in all the three matrices. The intra- and interday variation coefficients were observed less than 8% and 13%, respectively. The limits of detection (LOD) and limit of quantification (LOQ) were found in the range of 0.016–0.084 ng/L and 0.090–0.285 ng/L, respectively. Additionally, the results were compared statistically for each analyte in all the three matrices and were found equivalent, which signifies the absence of matrix effect. Thus, the method will be applied successfully to the determination of the cited drugs in pure or dosage forms as well as in biological fluids with good accuracy and precision.

Defense peptides of plant immunity

Antimicrobial peptides (AMPs) are natural antibiotics produced by all living organisms to combat pathogens. They are important effector molecules of the immune system both in animals and plants. AMPs are diverse in structure and mode of action. Based on homology of amino acid sequences and 3D structures several AMP families have been distinguished. They are defensins, thionins, lipid transfer proteins, hevein- and knottin-like peptides, and cyclotides. AMPs display broad-spectrum antimicrobial activity and thus show promise for the development of disease- resistant crops by genetic engineering and for the production of new-generation drugs. In this paper, the properties of the main AMP families (defensins and hevein-like peptides) and of a new 4-Cys plant AMP family are reviewed.

Application of BRET technology in interaction of G protein-coupled receptor with β-arrestins: recent progress

G protein-coupled receptors constitute an important super family of cell surface proteins.β-arrestin 1and 2 are widely expressed intracellular adaptor and scaffolding proteins playing important roles in G protein-coupled receptor desensitization,internalization,intracellular trafficking,and G protein-independent signaling.Recent development in bioluminescence resonance energy transfer(BRET)technology makes it possible to monitor the GPCR-β-arrestin complexes in live cells in a real-time manner;and investigators can further elucidate the ever-expanding roles ofβ-arrestins in mediating GPCR function,which will help to develop the new generation of drugs targeting GPCRs.