Rationalising Optimal Dosing of Phytotherapeutics For Use In Children: Current Status - Potential Solutions - Actions Needed.

"Children are not small adults with respect to the treatment with medicinal products." This statement of the WHO was the basis for the initiative of the European Commission for the establishment of a paediatric regulation in 2007 to improve the health of children by facilitating the development of medicines for children and adolescents. Seventeen years later, in the field of herbal medicinal products, results are still sobering. Therefore, the Foundation Plants for Health, Society for Medicinal Plants and Natural Products Research, and German Society for Phytotherapy organised a symposium to assess the status quo for the paediatric use of herbal medicinal products (HMPs), to analyse the causes of the current situation, and to discuss strategies for establishing the proof of safe and efficacious HMPs for children.The current situation for HMPs and their use in children is not fulfilling the requirements of legislation. HMPs in paediatrics are effective and safe, but considering the needs of children is necessary. In European countries, the use, registration, and marketing of HMPs are different, depending on the respective national regulations and specific traditions. EU herbal monographs are the best common denominator for such procedures. Emerging safety discussions must be considered. New approaches with real-world data might be a solution. The regulatory framework is to be adapted. Defining rationalised dosing for HMPs can be achieved by the extrapolation of data from adults, by using existing clinical data for children, and by using RWD. Therefore, a strong need for revising restrictions for the use of HMPs in children and rationalising defined dosage regimes is obvious.

Feeding Black Pepper (Piper nigrum) or Exogenous Xylanase Improves the Blood Lipid Profile of Broiler Chickens Fed Wheat-Based Diets.

This study aimed to determine the impact of dietary black peppercorn (BP) and xylanase (XYL) alone or in combination on growth performance, dietary energy, nutrient digestibility and blood lipid profile when fed to male Ross 308 broiler chickens from the ages of 7 to 21 d. A wheat-soy-based basal feed that was formulated to be 0.42 MJ lower in metabolizable energy (ME) was mixed. The basal feed was then split into four batches, with the first batch set aside as the basal control; the second batch was supplemented with freshly milled BP; the third batch was supplemented with XYL; the fourth batch was supplemented with both BP and XYL, as in the previous two batches. Each diet was fed to eight pens, with two birds in a pen, following randomization. Feeding BP reduced bird growth and most of the digestibility coefficients but increased blood high-density lipoprotein (p < 0.05). Dietary XYL increased bird growth, dietary ME and nutrient digestibility (p < 0.05). In addition, XYL increased hepatic carotenoids and coenzyme Q10, but reduced blood low-density lipoprotein (p < 0.05). There were no BP by XYL interactions (p > 0.05) observed. Further research is needed to identify the optimum level of BP in broiler diets.

Prolongation of metallothionein induction combats Aß and α-synuclein toxicity in aged transgenic Caenorhabditis elegans.

Neurodegenerative disorders (ND) like Alzheimer's (AD), Parkinson's (PD), Huntington's or Prion diseases share similar pathological features. They are all age dependent and are often associated with disruptions in analogous metabolic processes such as protein aggregation and oxidative stress, both of which involve metal ions like copper, manganese and iron. Bush and Tanzi proposed 2008 in the 'metal hypothesis of Alzheimer's disease' that a breakdown in metal homeostasis is the main cause of NDs, and drugs restoring metal homeostasis are promising novel therapeutic strategies. We report here that metallothionein (MT), an endogenous metal detoxifying protein, is increased in young amyloid ß (Aß) expressing Caenorhabditis elegans, whereas it is not in wild type strains. Further MT induction collapsed in 8 days old transgenic worms, indicating the age dependency of disease outbreak, and sharing intriguing parallels to diminished MT levels in human brains of AD. A medium throughput screening assay method was established to search for compounds increasing the MT level. Compounds known to induce MT release like progesterone, ZnSO4, quercetin, dexamethasone and apomorphine were active in models of AD and PD. Thioflavin T, clioquinol and emodin are promising leads in AD and PD research, whose mode of action has not been fully established yet. In this study, we could show that the reduction of Aß and α-synuclein toxicity in transgenic C. elegans models correlated with the prolongation of MT induction time and that knockdown of MT with RNA interference resulted in a loss of bioactivity.

Fungal strain matters: colony growth and bioactivity of the European medicinal polypores Fomes fomentarius, Fomitopsis pinicola and Piptoporus betulinus.

Polypores have been applied in traditional Chinese medicine up to the present day, and are becoming more and more popular worldwide. They show a wide range of bioactivities including anti-cancer, anti-inflammatory, antiviral and immuno-enhancing effects. Their secondary metabolites have been the focus of many studies, but the importance of fungal strain for bioactivity and metabolite production has not been investigated so far for these Basidiomycetes. Therefore, we screened several strains from three medicinal polypore species from traditional European medicine: Fomes fomentarius, Fomitopsis pinicola and Piptoporus betulinus. A total of 22 strains were compared concerning their growth rates, optimum growth temperatures, as well as antimicrobial and antifungal properties of ethanolic fruit body extracts. The morphological identification of strains was confirmed based on rDNA ITS phylogenetic analyses. Our results showed that species delimitation is critical due to the presence of several distinct lineages, e.g. within the Fomes fomentarius species complex. Fungal strains within one lineage showed distinct differences in optimum growth temperatures, in secondary metabolite production, and accordingly, in their bioactivities. In general, F. pinicola and P. betulinus extracts exerted distinct antibiotic activities against Bacillus subtilis and Staphylococcus aureus at minimum inhibitory concentrations (MIC) ranging from 31-125 µg mL-1; The antifungal activities of all three polypores against Aspergillus flavus, A. fumigatus, Absidia orchidis and Candida krusei were often strain-specific, ranging from 125-1000 µg mL-1. Our results highlight that a reliable species identification, followed by an extensive screening for a 'best strain' is an essential prerequisite for the proper identification of bioactive material.

Development of anti-viral agents using molecular modeling and virtual screening techniques.

Computational chemistry has always played a key role in anti-viral drug development. The challenges and the quickly rising public interest when a virus is becoming a threat has significantly influenced computational drug discovery. The most obvious example is anti-AIDS research, where HIV protease and reverse transcriptase have triggered enormous efforts in developing and improving computational methods. Methods applied to anti-viral research include (i) ligand-based approaches that rely on known active compounds to extrapolate biological activity, such as machine learning techniques or classical QSAR, (ii) structure-based methods that rely on an experimentally determined 3D structure of the targets, such as molecular docking or molecular dynamics, and (iii) universal approaches that can be applied in a structure- or ligand-based way, such as 3D QSAR or 3D pharmacophore elucidation. In this review we summarize these molecular modeling approaches as they were applied to fight anti-viral diseases and highlight their importance for anti-viral research. We discuss the role of computational chemistry in the development of small molecules as agents against HIV integrase, HIV-1 protease, HIV-1 reverse transcriptase, the influenza virus M2 channel protein, influenza virus neuraminidase, the SARS coronavirus main proteinase and spike protein, thymidine kinases of herpes viruses, hepatitis c virus proteins and other flaviviruses as well as human rhinovirus coat protein and proteases, and other picornaviridae. We highlight how computational approaches have helped in discovering anti-viral activities of natural products and give an overview on polypharmacology approaches that help to optimize drugs against several viruses or help to optimize the metabolic profile of and anti-viral drug.

Discovery of novel CB2 receptor ligands by a pharmacophore-based virtual screening workflow.

Cannabinoid receptor 2 (CB(2) receptor) ligands are potential candidates for the therapy of chronic pain, inflammatory disorders, atherosclerosis, and osteoporosis. We describe the development of pharmacophore models for CB(2) receptor ligands, as well as a pharmacophore-based virtual screening workflow, which resulted in 14 hits for experimental follow-up. Seven compounds were identified with K(i) values below 25 microM. The CB(2) receptor-selective pyridine tetrahydrocannabinol analogue 8 (K(i) = 1.78 microM) was identified as a CB(2) partial agonist. Acetamides 12 (K(i) = 1.35 microM) and 18 (K(i) = 2.1 microM) represent new scaffolds for CB(2) receptor-selective antagonists and inverse agonists, respectively. Overall, our pharmacophore-based workflow yielded three novel scaffolds for the chemical development of CB(2) receptor ligands.

Crystal forms of torasemide: new insights.

Crystallization from various organic solvents results in three crystal forms of torasemide: monotropically related mod. I (melting point, 158-161 degrees C) and mod. II (melting point, 155-158 degrees C), as well as a pseudopolymorphic crystal form (form A, channel inclusion compound with 1.9-4.2% water and alcohol). Physicochemical properties were determined by thermoanalysis (hot-stage microscopy, differential scanning calorimetry, thermogravimetry), Fourier transform infra-red and Raman spectroscopy, and X-ray powder diffractometry. The hygroscopicity, relative stability, true density, and heat of solutions were determined, respectively. The dissolution behaviour of mod. I and II was investigated as a function of pH, temperature, and in addition to surfactants. Mod. II is nearly three times more soluble than mod. I (mod. I, 0.34 mmol l(-1); mod. II, 0.93 mmol l(-1) at 20 degrees C, pH 4.90) and proved to be highly kinetically stable. By crystallization from 1-butanol, a new compound was synthesized, which was identified as [[4-[(3-Methylphenyl)amino]-3-pyridinyl]sulfonyl]-carbamic acid, butyl ester (TOBC). The most important properties of this torasemide derivative are given. The present results give a thorough physicochemical characterization of the crystal forms of torasemide. They clearly indicate a mistaken identity of mod. II with crystal form A in formerly published articles.