A mechanistic framework for a priori pharmacokinetic predictions of orally inhaled drugs

The fate of orally inhaled drugs is determined by pulmonary pharmacokinetic (PK) processes such as particle deposition, pulmonary drug dissolution, and mucociliary clearance. Although each single process has been systematically investigated, a quantitative understanding on their interaction remains limited and hence identifying optimal drug and formulation characteristics for orally inhaled drugs is still challenging. To investigate this complex interplay, the pulmonary processes can be integrated into mathematical models. However, existing modeling attempts considerably simplify these processes or are not systematically evaluated against (clinical) data. In this work, we developed a mathematical framework based on physiologically-structured population equations to integrate all relevant pulmonary processes mechanistically. A tailored numerical resolution strategy was chosen and the mechanistic model was evaluated systematically against different clinical datasets. Without any parameter estimation based on individual study data, the developed model simultaneously predicted (1) lung retention profiles of inhaled insoluble particles, (2) particle size-dependent PK of inhaled monodisperse particles, (3) PK differences between inhaled fluticasone propionate and budesonide, and (4) PK differences between healthy volunteers and asthmatic patients. Finally, to identify the most impactful optimization criteria for orally inhaled drugs, we investigated the impact of input parameters on both pulmonary and systemic exposure. Solubility of the inhaled drug did not have any relevant impact on local and systemic PK. Instead, pulmonary dissolution rate, particle size, tissue affinity, and systemic clearance were impactful potential optimization parameters. In the future, the developed prediction framework should be considered a powerful tool to identify optimal drug and formulation characteristics

Dimethyl cis-4-hydroxy­methyl­piperidine-2,6-dicarboxyl­ate

The heterocyclic core of the title compound, C10H17NO5, adopts a chair conformation with its three C substituents positioned equatorially. In the crystal, inter­molecular O—H⋯N hydrogen bonds between neighbouring mol­ecules lead to chains along b. These chains are connected by hydro­phobic inter­actions, forming infinite layers and N—H⋯O=C contacts between mol­ecules of adjacent layers give rise to a three-dimensional structure

Poly[aqua­[μ-4-(4-chloro­phen­yl)-2-thioxo-2,3-dihydro­thia­zol-3-olato]­sodium(I)]

The packing of the title compound, [Na(C9H5ClNOS2)(H2O)]n, in the crystal structure occurs by pairwise attachment of +sc- and −sc-arranged 4-(4-chloro­phen­yl)-2-thioxo-2,3-dihydro­thia­zol-3-olate subunits via S to sodium. Water mol­ecules that are bound in the axial position of the distorted octa­hedral coordination octahedron give rise to a stereogenic center at sodium

tert-Butyl 1-hy­droxy­piperidine-2-carboxyl­ate

The title compound, C10H19NO3, is a disubstituted piperidine bearing substituents in two equatorial positions. One of the substituents is a hy­droxy group bound to nitro­gen and the second a tert-butyl ester group bound to the carbon next to the endocyclic nitro­gen. Enanti­omers of the title compound form hydrogen-bridged dimers across a center of inversion

Poly[ethano­lbis(μ3-2-thio­xo-1,2-dihydro­pyridin-1-olato)dilithium(I)]

The title compound, [Li2(C5H4NOS)2(C2H6O)]n, having two formula units in the asymmetric unit, forms infinite chains of Li2O2 rhombi along b, consisting of four independent Li and O atoms. Metal binding to 2-thio­oxo-1,2-dihydro­pyridin-1-olate occurs in a bidentate fashion via O and S, and in a monodentate manner via the N-oxide O atom. π–π Inter­actions between polymeric chains are evident from centroid-to-centroid distances of pyridine­thione fragments of 3.461 (6)–3.607 (6) Å. The N—O and C—S bond lengths are distinctively different from those in hitherto investigated NiII, ZnII and (H3C)2TlIII complexes of 2-thio­oxo-1,2-dihydro­pyridin-1-olate, but correlate with those reported for 1-hydr­oxy- and 1-alkoxy­pyridine-2(1H)-thio­nes in the solid state

Vergleich einer Zucchinihybridsorte mit einer Zuchtlinie unter Ökolandbau-Bedingungen hinsichtlich der Bildung erster pistillater Blüten- bzw. Früchte

Die Dauer von der Pflanzung der Zucchinipflanze (Cucurbita pepo L.) bis zu deren Bildung der ersten pistillaten Blüte und schließlich Frucht variiert je nach Umwelt. In diesem Experiment wurden die Tage von der Pflanzung bis zum Beginn der ersten pistillaten Blüte sowie die Bildung der ersten Frucht von zwei verschiedenen Zucchini-Genotypen unter biologischen Anbaubedingungen ausgewertet. Die beiden Genotypen wurden zu drei verschiedenen Zeitpunkten (jeweils einen Monat auseinander) innerhalb einer Anbauphase gepflanzt. Die Gradwachstumstage (GDD) wurden berechnet, um mögliche Unterschiede zwischen den beiden Genotypen zu bewerten. Die erzielten Ergebnisse zeigten Unterschiede zwischen der erforderlichen Anzahl von Tagen und GDD nach dem Pflanzen bis zum Beginn der ersten pistillaten Blüte und Frucht

A Giant Planet Around a Metal-poor Star of Extragalactic Origin

Stars in their late stage of evolution, such as Horizontal Branch stars, are still largely unexplored for planets. We report the detection of a planetary companion around HIP 13044, a very metal-poor star on the red Horizontal Branch, based on radial velocity observations with a high-resolution spectrograph at the 2.2-m MPG/ESO telescope. The star's periodic radial velocity variation of P=16.2 days caused by the planet can be distinguished from the periods of the stellar activity indicators. The minimum mass of the planet is 1.25 Jupiter masses and its orbital semi-major axis 0.116 AU. Because HIP 13044 belongs to a group of stars that have been accreted from a disrupted satellite galaxy of the Milky Way, the planet most likely has an extragalactic origin.Comment: 32 pages, 9 Figure

Impacts of Different Light Spectra on CBD, CBDA and Terpene Concentrations in Relation to the Flower Positions of Different Cannabis Sativa L. Strains

Cannabis is one of the oldest cultivated plants, but plant breeding and cultivation are restricted by country-specific regulations. The plant has gained interest due to its medically important secondary metabolites, cannabinoids and terpenes. Besides biotic and abiotic stress factors, secondary metabolism can be manipulated by changing light quality and intensity. In this study, three morphologically different cannabis strains were grown in a greenhouse experiment under three different light spectra with three real light repetitions. The chosen light sources were as follows: a CHD Agro 400 ceramic metal-halide lamp with a sun-like broad spectrum and an R:FR ratio of 2.8, and two LED lamps, a Solray (SOL) and an AP67, with R:FR ratios of 13.49 and 4, respectively. The results of the study indicated that the considered light spectra significantly influenced CBDA and terpene concentrations in the plants. In addition to the different light spectra, the distributions of secondary metabolites were influenced by flower positions. The distributions varied between strains and indicated interactions between morphology and the chosen light spectra. Thus, the results demonstrate that secondary metabolism can be artificially manipulated by the choice of light spectrum, illuminant and intensity. Furthermore, the data imply that, besides the cannabis strain selected, flower position can have an impact on the medicinal potencies and concentrations of secondary metabolites

Interferon-beta-related tumefactive brain lesion in a Caucasian patient with neuromyelitis optica and clinical stabilization with tocilizumab

Background: Neuromyelitis optica (NMO) is a severely disabling inflammatory disorder of the central nervous system and is often misdiagnosed as multiple sclerosis (MS). There is increasing evidence that treatment options shown to be beneficial in MS, including interferon-β (IFN-β), are detrimental in NMO. Case presentation: We here report the first Caucasian patient with aquaporin 4 (AQP4) antibody (NMO-IgG)-seropositive NMO presenting with a tumefactive brain lesion on treatment with IFN-β. Disease started with relapsing optic neuritis and an episode of longitudinally extensive transverse myelitis (LETM) in the absence of any brain MRI lesions or cerebrospinal fluid-restricted oligoclonal bands. After initial misdiagnosis of multiple sclerosis (MS) the patient received subcutaneous IFN-β1b and, subsequently, subcutaneous IFN-β1a therapy for several years. Under this treatment, the patient showed persisting relapse activity and finally presented with a severe episode of subacute aphasia and right-sided hemiparesis due to a large T2 hyperintensive tumefactive lesion of the left brain hemisphere and a smaller T2 lesion on the right side. Despite rituximab therapy two further LETM episodes occurred, resulting in severe neurological deficits. Therapeutic blockade of the interleukin (IL)-6 signalling pathway by tocilizumab was initiated, followed by clinical and radiological stabilization. Conclusion: Our case (i) illustrates the relevance of correctly distinguishing NMO and MS since these disorders differ markedly in their responsiveness to immunomodulatory and -suppressive therapies; (ii) confirms and extends a previous report describing the development of tumefactive brain lesions under IFN-β therapy in two Asian NMO patients; and (iii) suggests tocilizumab as a promising therapeutic alternative in highly active NMO disease courses