Ginkgo biloba is among the most favourite and best explored herbal drugs. Standardized extracts of Ginkgo biloba represent the only herbal alternative to synthetic antidementia drugs in the therapy ...of cognitive decline and Alzheimer's diseases. The clinical efficiency of such standardized Ginkgo biloba extracts (GBE) is still controversial, but authors of numerous international clinical studies recommended the use of GBE in the described therapies.Extracts of Ginkgo biloba are a mixture of substances with a wide variety of physical and chemical properties and activities. Numerous pharmacological investigations lead to the conclusion that the terpene trilactones (TTL) and the flavonoids of GBE are responsible for the main pharmacological effects of the extract in the therapy of cognitive decline. Therefore, the quality of GBE products must be oriented on a defined quantity of TTL and flavonoids. Furthermore, because of their toxic potential the amount of ginkgolic acid should be less than 5 ppm.However, data on pharmacokinetics and bioavailability, especially related to the central nervous system (CNS), which is the target tissue, are relatively rare. A few investigations characterize the TTL and flavonoids of Ginkgo biloba pharmacokinetically in plasma and in the brain. Recent investigations show that significant levels of TTL and Ginkgo biloba flavonoids cross the blood-brain barrier and enter the CNS of rats after oral application of GBE. Knowledge about the pharmacokinetic behaviour of these substances is necessary to discuss the pharmacological results on a more realistic basis.
Monoclonal antibody infusions (mAb‐i) are administered for the treatment of various diseases. They are often transported over long distances from the compounding site to the site of administration. ...However, transport studies are typically carried out with the original drug product but not with compounded mAb‐i. To address this gap, the impact of mechanical stress on the formation of subvisible/nanoparticles in mAb‐i was investigated by dynamic light scattering and flow imaging microscopy. Different mAb‐i concentrations were subjected to vibrational orbital shaking and stored at 2–8°C up to 35 days. The screening revealed that pembrolizumab and bevacizumab infusions show the highest propensity for particle formation. Especially bevacizumab at low concentrations exhibited an increase in particle formation. Because of the unknown health risks associated with the long‐term application of subvisible particles (SVPs)/nanoparticles in infusion bags, stability studies carried out in the frame of licensing application procedures should also focus on SVP formation in mAb‐i. In general, pharmacists should minimize the time of storage and mechanical stress during transport, especially in the case of low‐concentrated mAb‐i. Moreover, if siliconized syringes are used, they should be washed once with saline solution to minimize particle entry.
What happens if monoclonal antibody infusions (mAb‐i) are transported over long distances from the compounding site to the site of administration? Applying mechanical stress to mAb‐i and storage showed increased particle formation in the size ranges ≥1 and ≥2 µm. Stability studies should also focus on subvisible particle formation in mAb‐i. Pharmacists can reduce particle formation by applying siliconized syringes washed once with saline solution.
► 22 Flavonoids were examined for activity against H5N1 influenza A viruses. ► Biochanin A and baicalein exerted the highest potency. ► Biochanin A and baicalein interfered with H5N1 replication. ► ...Biochanin A and baicalein interfered with virus-induced cytokine expression. ► Biochanin A and baicalein differ in their molecular antiviral mechanisms.
From a panel of 22 flavonoids, we identified six compounds (apigenin, baicalein, biochanin A, kaempferol, luteolin, naringenin) that inhibited influenza A nucleoprotein production in human lung epithelial (A549) cells infected with the highly pathogenic avian influenza H5N1 virus strain A/Thailand/Kan-1/04 in non-toxic concentrations. Baicalein (IC50: 18.79±1.17μM, selectivity index 5.82) and biochanin A (IC50 8.92±1.87μM, selectivity index 5.60) were selected for further experiments. Both compounds reduced H5N1 infectious titres (baicalein 40μM: 29-fold reduction, biochanin A 40μM: 55-fold reduction after infection at MOI 0.01), virus-induced caspase 3 cleavage, nuclear export of viral RNP complexes, and enhanced the effects of the neuraminidase inhibitor zanamivir. Biochanin A and baicalein also inhibited the replication of the H5N1 strain A/Vietnam/1203/04. Time of addition experiments indicated that both compounds interfere with H5N1 replication after the adsorption period. Further mechanistic investigations revealed clear differences between these two flavonoids. Only baicalein interfered with the viral neuraminidase activity (39±7% inhibition at 100μM, the maximum concentration tested). In contrast to baicalein, biochanin A affected cellular signalling pathways resulting in reduced virus-induced activation of AKT, ERK 1/2, and NF-kB. Moreover, biochanin A inhibited the virus-induced production of IL-6, IL-8, and IP-10 while baicalein inhibited IL-6 and IL-8 production without affecting IP-10 levels. In primary human monocyte-derived macrophages, only baicalein but not biochanin A impaired H5N1 virus replication. Both flavonoids interfered with the H5N1-induced production of IL-6, IP-10, and TNF-α but not of IL-8 in macrophages. These findings indicate that closely related flavonoids can exert anti-H5N1 effects by different molecular mechanisms.
The bile acid-sensing transcription factor farnesoid X receptor (FXR) regulates multiple metabolic processes. Modulation of FXR is desired to overcome several metabolic pathologies but ...pharmacological administration of full FXR agonists has been plagued by mechanism-based side effects. We have developed a modulator that partially activates FXR in vitro and in mice. Here we report the elucidation of the molecular mechanism that drives partial FXR activation by crystallography- and NMR-based structural biology. Natural and synthetic FXR agonists stabilize formation of an extended helix α11 and the α11-α12 loop upon binding. This strengthens a network of hydrogen bonds, repositions helix α12 and enables co-activator recruitment. Partial agonism in contrast is conferred by a kink in helix α11 that destabilizes the α11-α12 loop, a critical determinant for helix α12 orientation. Thereby, the synthetic partial agonist induces conformational states, capable of recruiting both co-repressors and co-activators leading to an equilibrium of co-activator and co-repressor binding.
Hair analysis for the assessment of alcohol or drug abstinence has become a routine procedure in forensic toxicology. Hair coloration leading to loss of incorporated xenobiotics and to false negative ...results has turned out to be a major problem. Currently only colored extracts provide hints of manipulations but not bleaching. A liquid chromatographic–tandem mass spectrometric (LC–MS/MS) method was developed and validated to determine 1H‐pyrrole‐2,3,5‐tricarboxylic acid (PTCA), a major oxidation product of melanin. PTCA was determined in natural hair samples (n = 21) after treatment with 3% hydrogen peroxide (H2O2) for 30 or 40 minutes with concentrations up to 12% for 40 minutes. In another series, 12 natural hair samples were submitted to different coloration procedures (henna, tinting, semi‐permanent and permanent dyeing, bleaching) and the changes in PTCA content were determined. A significant increase in the PTCA content was found for both incubation times and increasing H2O2 concentrations. Coloration with henna or tinting had no influence on PTCA levels detected, but a significant increase was observed after semi‐permanent and permanent dyeing and bleaching. As PTCA concentrations in natural hair were found to be in a range of <2.1–16.4 ng/mg (8.4 ± 3.8 ng/mg, mean ± SD, n = 33), a cut‐off of 20 ng/mg is recommended for the distinction between natural vs. excessively oxidized hair. In case of naturally low melanin content (light‐blond or white hair), no marked increase in PTCA may occur. The present study demonstrated that PTCA is formed during oxidative treatment of melanin in hair, which can be used to detect previous hair coloration including oxidation.
Hair samples of 21 people were treated with different concentrations of hydrogen peroxide. Results were compared with PTCA concentrations of 12 hair samples treated with different hair colorations. Results showed a marked increase of PTCA depending on hydrogen peroxide concentration and treatment time. Therefore PTCA can be used as a direct marker for oxidative hair treatment and may be useful to identify bleached hair samples in laboratory routine.
Current approved drugs for Alzheimer's disease (AD) only attenuate symptoms, but do not cure the disease. The pirinixic acid derivate MH84 has been characterized as a dual ...gamma-secretase/proliferator activated receptor gamma (PPARγ) modulator in vitro. Pharmacokinetic studies in mice showed that MH84 is bioavailable after oral administration and reaches the brain. We recently demonstrated that MH84 improved mitochondrial dysfunction in a cellular model of AD. In the present study, we extended the pharmacological characterization of MH84 to 3-month-old Thy-1 AβPP
mice (harboring the Swedish and London mutation in human amyloid precursor protein (APP)) which are characterized by enhanced AβPP processing and cerebral mitochondrial dysfunction, representing a mouse model of early AD.
Three-month-old Thy-1 AβPP
mice received 12 mg/kg b.w. MH84 by oral gavage once a day for 21 days. Mitochondrial respiration was analyzed in isolated brain mitochondria, and mitochondrial membrane potential and ATP levels were determined in dissociated brain cells. Citrate synthase (CS) activity was determined in brain tissues and MitoTracker Green fluorescence was measured in HEK293-AβPPwt and HEK293-AβPPsw cells. Soluble Aβ
and Aβ
levels were determined using ELISA. Western blot analysis and qRT-PCR were used to measure protein and mRNA levels, respectively.
MH84 reduced cerebral levels of the β-secretase-related C99 peptide and of Aβ40 levels. Mitochondrial dysfunction was ameliorated by restoring complex IV (cytochrome-c oxidase) respiration, mitochondrial membrane potential, and levels of ATP. Induction of PPARγ coactivator-1α (PGC-1α) mRNA and protein expression was identified as a possible mode of action that leads to increased mitochondrial mass as indicated by enhanced CS activity, OXPHOS levels, and MitoTracker Green fluorescence.
MH84 modulates β-secretase processing of APP and improves mitochondrial dysfunction by a PGC-1α-dependent mechanism. Thus, MH84 seems to be a new promising therapeutic agent with approved in-vivo activity for the treatment of AD.
Natural products have long been a source of useful biological activity for the development of new drugs. Their macromolecular targets are, however, largely unknown, which hampers rational drug design ...and optimization. Here we present the development and experimental validation of a computational method for the discovery of such targets. The technique does not require three-dimensional target models and may be applied to structurally complex natural products. The algorithm dissects the natural products into fragments and infers potential pharmacological targets by comparing the fragments to synthetic reference drugs with known targets. We demonstrate that this approach results in confident predictions. In a prospective validation, we show that fragments of the potent antitumour agent archazolid A, a macrolide from the myxobacterium Archangium gephyra, contain relevant information regarding its polypharmacology. Biochemical and biophysical evaluation confirmed the predictions. The results obtained corroborate the practical applicability of the computational approach to natural product 'de-orphaning'.
A 21st century epidemic: As incidence rates of type 2 diabetes mellitus (T2DM) continues to rise, there is a growing need to identify novel therapeutics with improved efficacy and reduced side ...effects. Here, the medicinal chemistry of approved incretin mimetics and DPP‐4 inhibitors is described along with the pharmacological background and late‐stage clinical developments currently in the pipeline.
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