G. W. Muller

Bio: G. W. Muller is an academic researcher from Celgene. The author has contributed to research in topics: Thalidomide & Lenalidomide. The author has an hindex of 4, co-authored 8 publications receiving 381 citations.

Apremilast, a cAMP phosphodiesterase-4 inhibitor, demonstrates anti-inflammatory activity in vitro and in a model of psoriasis.

Abstract: Background and purpose: Apremilast is an orally administered phosphodiesterase-4 inhibitor, currently in phase 2 clinical studies of psoriasis and other chronic inflammatory diseases. The inhibitory effects of apremilast on pro-inflammatory responses of human primary peripheral blood mononuclear cells (PBMC), polymorphonuclear cells, natural killer (NK) cells and epidermal keratinocytes were explored in vitro, and in a preclinical model of psoriasis.

Thalidomide : From tragedy to new drug discovery

Abstract: Analogues of thalidomide have the potential to treat a number of inflammatory and autoimmune diseases

Thalidomide: From Tragedy to New Drug Discovery

Abstract: Analogues of thalidomide have the potential to treat a number of inflammatory and autoimmune diseases

Lenalidomide and pomalidomide strongly enhance tumor cell killing in vitro during antibody-dependent cellular cytotoxicity (ADCC) mediated by trastuzumab, cetuximab and rituximab

Abstract: 3023 Background: Potential mechanisms of action of lenalidomide and pomalidomide (CC-4047) include anti-angiogenic, anti- proliferative and immunomodulatory activities, e.g., enhancement of T cell and NK cell function. Both drugs appear to enhance T cell activation and Th1-type cytokines in cancer patients. Also, both drugs have been shown to enhance rituximab-mediated protection in a mouse lymphoma model. Methods: We have utilized an in vitro ADCC system to assess the ability of these drugs to enhance human NK cell function in response to the approved therapeutic antibodies trastuzumab, cetuximab and rituximab. Results: Pre-treatment of NK cells with either pomalidomide or lenalidomide greatly enhanced IFN-γ production by NK cells in response to IgG in the presence of either IL-2 or IL- 12. In a series of functional ADCC assays, Her2/neu overexpressing breast cancer cells (SKBR3 & MCF-7) pre-coated with trastuzumab, EGFR positive colorectal cancer cells (HCT-116) pre-coated with cetuximab and NHL cell li...

Psoriasis Pathogenesis and Treatment.

Abstract: Research on psoriasis pathogenesis has largely increased knowledge on skin biology in general. In the past 15 years, breakthroughs in the understanding of the pathogenesis of psoriasis have been translated into targeted and highly effective therapies providing fundamental insights into the pathogenesis of chronic inflammatory diseases with a dominant IL-23/Th17 axis. This review discusses the mechanisms involved in the initiation and development of the disease, as well as the therapeutic options that have arisen from the dissection of the inflammatory psoriatic pathways. Our discussion begins by addressing the inflammatory pathways and key cell types initiating and perpetuating psoriatic inflammation. Next, we describe the role of genetics, associated epigenetic mechanisms, and the interaction of the skin flora in the pathophysiology of psoriasis. Finally, we include a comprehensive review of well-established widely available therapies and novel targeted drugs.

Mammalian Cyclic Nucleotide Phosphodiesterases: Molecular Mechanisms and Physiological Functions

Abstract: The superfamily of cyclic nucleotide (cN) phosphodiesterases (PDEs) is comprised of 11 families of enzymes. PDEs break down cAMP and/or cGMP and are major determinants of cellular cN levels and, consequently, the actions of cN-signaling pathways. PDEs exhibit a range of catalytic efficiencies for breakdown of cAMP and/or cGMP and are regulated by myriad processes including phosphorylation, cN binding to allosteric GAF domains, changes in expression levels, interaction with regulatory or anchoring proteins, and reversible translocation among subcellular compartments. Selective PDE inhibitors are currently in clinical use for treatment of erectile dysfunction, pulmonary hypertension, intermittent claudication, and chronic pulmonary obstructive disease; many new inhibitors are being developed for treatment of these and other maladies. Recently reported x-ray crystallographic structures have defined features that provide for specificity for cAMP or cGMP in PDE catalytic sites or their GAF domains, as well as mechanisms involved in catalysis, oligomerization, autoinhibition, and interactions with inhibitors. In addition, major advances have been made in understanding the physiological impact and the biochemical basis for selective localization and/or recruitment of specific PDE isoenzymes to particular subcellular compartments. The many recent advances in understanding PDE structures, functions, and physiological actions are discussed in this review.

Mechanism of action of lenalidomide in hematological malignancies

Abstract: Immunomodulatory drugs lenalidomide and pomalidomide are synthetic compounds derived by modifying the chemical structure of thalidomide to improve its potency and reduce its side effects. Lenalidomide is a 4-amino-glutamyl analogue of thalidomide that lacks the neurologic side effects of sedation and neuropathy and has emerged as a drug with activity against various hematological and solid malignancies. It is approved by FDA for clinical use in myelodysplastic syndromes with deletion of chromosome 5q and multiple myeloma. Lenalidomide has been shown to be an immunomodulator, affecting both cellular and humoral limbs of the immune system. It has also been shown to have anti-angiogenic properties. Newer studies demonstrate its effects on signal transduction that can partly explain its selective efficacy in subsets of MDS. Even though the exact molecular targets of lenalidomide are not well known, its activity across a spectrum of neoplastic conditions highlights the possibility of multiple target sites of action.

Treatment of psoriatic arthritis in a phase 3 randomised, placebo-controlled trial with apremilast, an oral phosphodiesterase 4 inhibitor

Abstract: Objectives Apremilast, an oral phosphodiesterase 4 inhibitor, regulates inflammatory mediators. Psoriatic Arthritis Long-term Assessment of Clinical Efficacy 1 (PALACE 1) compared apremilast with placebo in patients with active psoriatic arthritis despite prior traditional disease-modifying antirheumatic drug (DMARD) and/or biologic therapy. Methods In the 24-week, placebo-controlled phase of PALACE 1, patients (N=504) were randomised (1:1:1) to placebo, apremilast 20 mg twice a day (BID) or apremilast 30 mg BID. At week 16, patients without ≥20% reduction in swollen and tender joint counts were required to be re-randomised equally to either apremilast dose if initially randomised to placebo or remained on their initial apremilast dose. Patients on background concurrent DMARDs continued stable doses (methotrexate, leflunomide and/or sulfasalazine). Primary outcome was the proportion of patients achieving 20% improvement in modified American College of Rheumatology response criteria (ACR20) at week 16. Results At week 16, significantly more apremilast 20 mg BID (31%) and 30 mg BID (40%) patients achieved ACR20 versus placebo (19%) (p Conclusions Apremilast was effective in the treatment of psoriatic arthritis, improving signs and symptoms and physical function. Apremilast demonstrated an acceptable safety profile and was generally well tolerated. Clinical trial registration number NCT01172938.

Structure control of polysaccharide derivatives for efficient separation of enantiomers by chromatography

Abstract: Chirality is a ubiquitous feature in living systems. Today, it is widely recognized that many biologically interesting compounds, such as drugs, agrochemicals, food additives, and fragrances, are chiral and their physiological properties usually rely on their chirality due to the extremely high chiral discrimination ability of enzymes and receptors.1-6 Particularly, the different pharmacological effects between enantiomers are ultimately an important concern in the pharmaceutical field in which only one enantiomer of a chiral drug often exhibits the desirable therapeutic activity, while the other shows an antagonistic function, side effects, or even toxic effects.7-14 During the late 1950s and early 1960s, a racemate of N-phthalylglutamic acid imide, which is a sedative and hypnotic drug known as thalidomide, was administrated to pregnant women and caused the birth of approximately 10 000 babies with malformations. Later, Blaschke pointed out that this teratogenic effect was attributed to the S-(-)isomer.15 Even though the administration of the pure R-(+)isomer could not halt the disaster because thalidomide is unstable in the body and easily undergoes racemization,16-18 this tragedy undoubtedly brought a profound movement in the drug administration and industries. In 1992, the U.S. Food and Drug Administration issued a specific guideline for the production of new chiral drugs,19 which demanded a systematic investigation of the biological behavior of their individual enantiomers and significantly encouraged the development of single enantiomer drugs.20-22 Today, most of the best-selling drugs around the world are administered as single enantiomers with the desired therapeutic activity,23 and the annual sales of single enantiomer drugs are expected to exceed 200 billion dollars in 2008. Furthermore, the preparation of single enantiomers has also become important in the fields of functional materials, such as ferroelectric liquid crystals and organic nonlinear optical molecules.24-26 Based on this historical background, substantial efforts have been undertaken to develop practical techniques for the preparation of enantiomers with a high enantiomeric excess (ee). In general, two approaches are utilized for this objective, asymmetric synthesis and chiral separation. Asymmetric synthesis using chiral sources, such as chiral pools, chiral auxiliaries, asymmetric catalysts, and enzymes, has significantly progressed over the last few decades.27-41 Although the large-scale preparation of enantiomers can be economically attained using this approach, the products do not always show a high ee, and therefore, a further purification step may be inevitable. Additionally, nature produces only one of the enantiomers as a chiral source in most cases. This means that if both enantiomers of the target compounds are required, at least two kinds of chiral sources are necessary for each enantiomer. However, it is sometimes difficult to obtain both of them. On the other hand, the chiral separation approach can easily provide both enantiomers with a high ee. Since Pasteur first isolated two enantiomers of sodium ammonium tartrate using a magnifying glass and a pair of tweezers in 1848,42,43 the innovation of chiral separation techniques has attracted great interest. Basically, chiral separations44 are carried out by (i) crystallization,45-47 (ii) enzymatic kinetic resolution,48-50 and (iii) chromatographic separation.51-53 Specifically, direct chiral separation using chiral stationary phases (CSPs) for high-performance liquid chromatography (HPLC) has significantly evolved during the past few decades and is recognized as the most popular and reliable tool for both the analysis of enantiomer compositions and the preparation of pure enantiomers.51-64 Chiral separations can * To whom correspondence should be addressed. Mailing address: EcoTopia Science Institute, Nagoya University, Furo-cho, Chikusa-ku, Nagoya 4648603, Japan. Phone: +81-52-789-4600. Fax: +81-52-789-3188. E-mail: okamoto@apchem.nagoya-u.ac.jp. † Nagoya University. ‡ Harbin Engineering University. Chem. Rev. 2009, 109, 6077–6101 6077