Martin D Lehner

• Dr. rer. nat.
• Group Leader at Bionorica SE

Background The herbal medicinal product Bronchipret® TP film-coated tablets contains a fixed combination of thyme and primula dry extracts (BRO) and has long and successfully been used for the treatment of acute bronchitis. However, the underlying pharmacological mechanisms of action have not been determined so far. We report a tiered approach appl...

Hypersecretion of viscous mucus is one of the hallmark symptoms of acute and chronic bronchitis and typically develops secondary to an inflammation of the airway epithelium. Bronchipret® TP film-coated tablets (BRO), an herbal medicinal product containing a fixed combination of thyme herb and primula root extracts, has been successfully used clinic...

Rational design of a novel template of naphthyridinones rapidly led to PDE4 inhibitors with sub-nanomolar enzymatic potencies. X-ray crystallography confirmed the binding mode of this novel template. We achieved compounds with double-digit picomolar enzymatic potencies through further structure-based design by targeting both the PDE4 enzyme metal-b...

Manchester International Severe Asthma Forum #57 POSTER Tele-monitoring decreases unscheduled outpatient visits in pediatric patients with severe asthma Authors : Mihai Craiu, Iustina Violeta Stan INSMC Alessandrescu-Rusescu, Bucharest, Romania Keywords: Child, Asthma, Virtual-Media, Monitoring, Education Background and Aim: Pediatric asthma p...

The delta isoform of the Phosphatidylinositol 3-kinase (PI3K) has been shown to have an essential role in specific immune cell functions and thus represents a potential therapeutic target for autoimmune and inflammatory diseases. Herein, the optimization of a series of pyrrolotriazinones as potent and selective PI3K inhibitors is described. The m...

Cyclic nucleotide cAMP is an ubiquitous second messenger involved in a plethora of cellular responses to biological agents involving activation of adenylyl cyclase. Its intracellular levels are tightly controlled by a family of cyclic nucleotide degrading enzymes, the PDEs. In recent years, cyclic nucleotide phosphodiesterase type 4 (PDE4) has arou...

Background Phosphatidylinositol 3-kinase delta (PI3Kδ) and Janus-activated kinases (JAK) are both novel anti-inflammatory targets in asthma that affect lymphocyte activation. We have investigated the anti-inflammatory effects of PI3Kδ and JAK inhibition on cytokine release from asthma bronchoalveolar lavage (BAL) cells and T-cell activation, and me...

Lower airway inflammation and mucus hypersecretion are hallmark symptoms of acute bronchitis. Bronchipret® TP (BRO), a fixed combination of thyme and primula dry extracts, previously demonstrated anti-inflammatory activity in the respiratory tract. Here, we report on its capability to normalize goblet cell hyperplasia and MUC5AC production in both...

Increased secretion of viscous mucus is a hallmark symptom of acute bronchitis. Using an in vivo model of bronchoalveolitis we aimed to investigate whether Bronchipret® film-coated tablets (BRO) possess the ability to positively regulate determinants of mucus secretion and consistency. BRO is a herbal medicinal product containing the fixed combinat...

Background/purpose: Acute bronchitis (AB) is a common lung condition characterized by inflammation of the large bronchi in response to infection. Bronchipret(®) syrup (BRO), a fixed combination of thyme and ivy extracts has been effectively used for the treatment of AB. Combining in vivo and mechanistic in vitro studies we aimed to provide a bette...

Aim: Increased secretion of viscous mucus is a hallmark symptom of acute bronchitis. Using an in vivo model of bronchoalveolitis we aimed to investigate whether Bronchipret® film-coated tablets (BRO) possess the ability to positively regulate determinants of mucus secretion and consistency. BRO is a herbal medicinal product containing the fixed com...

Neutrophil infiltration and activation in the lung are important pathophysiological features in COPD, severe asthma and bronchiectasis mostly mediated by CXCL8 and CXCL1 via CXCR1 and CXCR2. No thorough study to date has been performed to compare the anti-inflammatory effect profile of dual CXCR1/2 vs. selective CXCR2 antagonists in relevant human...

In this manuscript, the synthesis and biological activity of a series of pyrazole acetic acid derivatives as CRTh2 antagonists is presented. Biological evaluation in vitro revealed that the pyrazole core showed in several cases a different structure-activity relationship (SAR) to that of related indole acetic acid. A potent series of ortho-sulfonyl...

High throughput screening identified the pyrazole-4-acetic acid substructure as CRTh2 receptor antagonists. Optimisation of the compounds uncovered a tight SAR but also identified some low nanomolar inhibitors.

Despite the sound preclinical database and some promising data from clinical trials, development of PDE4 inhibitors for the treatment of inflammatory or neurological diseases has been hampered by dose-limiting class-related side effects. In the past years, companies opted for different approaches to improve the therapeutic window of their compounds...

Nitric oxide (NO) is a key physiological mediator and disturbed regulation of NO release is associated with the pathophysiology of almost all inflammatory diseases. A multitude of inhibitors of NOSs (nitric oxide synthases) have been developed, initially with low or even no selectivity against the constitutively expressed NOS isoforms, eNOS (endoth...

Excessive release of nitric oxide from inducible nitric-oxide synthase (iNOS) has been postulated to contribute to pathology in a number of inflammatory diseases. We recently identified imidazopyridine derivatives as a novel class of potent nitricoxide synthase inhibitors with high selectivity for the inducible isoform. In the present study, we tes...

Treatment of hemodynamic instability in septic shock often demands the administration of vasopressor agents, although these may have deleterious effects on microcirculatory homeostasis. Inhibition of nitric oxide synthase (NOS) has been suggested as an alternative therapeutic approach, as NO formation may be excessively increased in sepsis. To comp...

We have identified imidazopyridine derivatives as a novel class of NO synthase inhibitors with high selectivity for the inducible isoform. 2-[2-(4-Methoxy-pyridin-2-yl)-ethyl]-3H-imidazo[4,5-b]pyridine (BYK191023) showed half-maximal inhibition of crudely purified human inducible (iNOS), neuronal (nNOS), and endothelial (eNOS) NO synthases at 86 nM...

Lipopolysaccharide (LPS) tolerance is a state of refractoriness towards a second stimulation by LPS after a preceding stimulation. LPS is recognized by Toll-like receptor-4 (TLR-4), which belongs to a group of pattern recognition receptors mediating activation of innate immunity by microbial components. To date, it is not known in detail to what ex...

Rheumatoid arthritis (RA) is a disease that is still insufficiently controlled by current treatments. Methotrexate (M7X), a small molecular weight compound, has been the gold standard in the treatment of RA. It has several anti-inflammatory activities, but their contribution to its antiarthritic effects has not yet been established. We conducted a...

Mitogen-activated protein kinase-activated protein kinase 2 (MK2) is one of several kinases activated through direct phosphorylation by p38 mitogen-activated protein kinase. MK2 regulates LPS-induced TNF mRNA translation, and targeted mutation of the MK2 gene renders mice more resistant to D-galactosamine plus LPS-induced liver damage. In the prese...

The atrial natriuretic peptide (ANP) has been suggested to possess immunomodulatory potential because of its property to alter macrophage functions via its guanylate-cylcase- coupled A-receptor (NPR-A), such as inhibiting the expression of inducible nitric oxide synthase or TNF-alpha. The aim of this study was to investigate whether ANP influences...

The atrial natriuretic peptide (ANP) has been suggested to possess immunomodulatory potential because of its property to alter macrophage functions via its guanylate-cylcase- coupled A-receptor (NPR-A), such as inhibiting the expression of inducible nitric oxide synthase or TNF-. The aim of this study was to investigate whether ANP influences COX-2...

We have recently shown that highly purified lipoteichoic acid (LTA) represents a major immunostimulatory principle of Staphylococcus aureus. In order to test whether this translates to other bacterial species, we extracted and purified LTA from 12 laboratory-grown species. All LTA induced the release of TNF-alpha, IL-1beta, IL-6 and IL-10 in human...

We have recently shown that highly purified lipoteichoic acid (LTA) represents a major immunostimulatory principle of Staphylococcus aureus. In order to test whether this translates to other bacterial species, we extracted and purified LTA from 12 laboratory-grown species. All LTA induced the release of TNF-α, IL-1β, IL-6 and IL-10 in human whole b...

Exposure of macrophages to LPS induces a state of hyporesponsiveness to subsequent stimulation with LPS termed LPS desensitization or tolerance. To date, it is not known whether similar mechanisms of macrophage refractoriness are induced on contact with components of Gram-positive bacteria. In the present study, we demonstrate that pretreatment wit...

During infection with gram-negative bacteria, exposure of immune cells to lipopolysaccharide (LPS) from the bacterial cell membrane induces a rapid cytokine response which is essential for the activation of host defenses against the invading pathogens. Administration of LPS to mice induces a state of hyporesponsiveness, or tolerance, characterized...

Lipopolysaccharide (LPS) is a potent immune stimulator which induces many of the pathological sequelae observed during systemic Gram-negative infection. The term endotoxin tolerance describes the phenomenon that the toxicity of LPS is attenuated upon repeated LPS-stimulation. Selective downregulation of certain macrophage activities is considered o...

Publisher Summary This chapter discusses the ratio of reduced to oxidized glutathione (GSH) as an indicator of oxidative stress status and DNA damage. Several methods have been proposed for the determination of GSH status in biological samples. Accurate determination of this status is largely dependent on the prevention of GSH autoxidation during s...