Opportunities and Pitfalls in Drug Safety Studies after Marketing Approval An Evaluation with a Focus on Older Patients

In the next decades, the number of older people will rise substantially in Germany. Likewise, drug treatment and polypharmacy will also augment due to the high prevalence of multimorbidity in this subpopulation. Since older people are often excluded from randomized controlled trials prior to drug approval, pharmacoepidemiological safety studies (PSS) based on spontaneous reporting systems and electronic healthcare databases often represent the only opportunity to investigate the safety of drugs in this population. However, these studies have specific methodological challenges related to the clinical characteristics of older patients and the nature of the data sources. Thus, the overall aim of this thesis is to (1) critically assess methodological challenges of PSS based on spontaneous reporting systems and electronic healthcare databases with a focus on older patients and (2) to define further areas of research to enhance their quality. In this context, disproportionality analyses based on spontaneous reports, cohort studies, nested case control studies, and case only designs are introduced as study designs for PSS. Confounding (e.g., by frailty), outcome and exposure misclassification as well as time related biases in PSS are illustrated as selected methodological challenges. These challenges are then discussed in the context of my research articles with a focus on older people, and opportunities to address these challenges are presented. More specifically, the role of spontaneous reporting systems in the detection of adverse drug reactions in older people is critically assessed. Afterwards, drug utilization studies as well as the application of high dimensional propensity score methods and case only designs are discussed as options to overcome the specific problem of confounding by indication and unmeasured confounding in PSS among older people. Further, a detailed review of the patienta s profile is recommended to increase the specificity of the outcome case algorithms in administrative claims databases. Moreover, it is highlighted that sensitivity analyses in drug utilization and safety studies are particularly important in the case of a as neededa treatment among older patients and if information on the prescribed daily dose is missing. Finally, it is highlighted how time related biases can be prevented in cohort and nested case control studies using a time dependent analysis and risk set sampling, respectively. In the conclusion, future research perspectives with regard to PSS in older patients are pointed out as, for instance, the use of semi automated drug safety monitoring based on electronic healthcare databases, the availability of additional medical information in the context of the German a e healtha legislation or the need for external validation studies to study the impact of outcome and drug exposure misclassification

Opportunities and Pitfalls in Drug Safety Studies after Marketing Approval An Evaluation with a Focus on Older Patients

In the next decades, the number of older people will rise substantially in Germany. Likewise, drug treatment and polypharmacy will also augment due to the high prevalence of multimorbidity in this subpopulation. Since older people are often excluded from randomized controlled trials prior to drug approval, pharmacoepidemiological safety studies (PSS) based on spontaneous reporting systems and electronic healthcare databases often represent the only opportunity to investigate the safety of drugs in this population. However, these studies have specific methodological challenges related to the clinical characteristics of older patients and the nature of the data sources. Thus, the overall aim of this thesis is to (1) critically assess methodological challenges of PSS based on spontaneous reporting systems and electronic healthcare databases with a focus on older patients and (2) to define further areas of research to enhance their quality. In this context, disproportionality analyses based on spontaneous reports, cohort studies, nested case control studies, and case only designs are introduced as study designs for PSS. Confounding (e.g., by frailty), outcome and exposure misclassification as well as time related biases in PSS are illustrated as selected methodological challenges. These challenges are then discussed in the context of my research articles with a focus on older people, and opportunities to address these challenges are presented. More specifically, the role of spontaneous reporting systems in the detection of adverse drug reactions in older people is critically assessed. Afterwards, drug utilization studies as well as the application of high dimensional propensity score methods and case only designs are discussed as options to overcome the specific problem of confounding by indication and unmeasured confounding in PSS among older people. Further, a detailed review of the patienta s profile is recommended to increase the specificity of the outcome case algorithms in administrative claims databases. Moreover, it is highlighted that sensitivity analyses in drug utilization and safety studies are particularly important in the case of a as neededa treatment among older patients and if information on the prescribed daily dose is missing. Finally, it is highlighted how time related biases can be prevented in cohort and nested case control studies using a time dependent analysis and risk set sampling, respectively. In the conclusion, future research perspectives with regard to PSS in older patients are pointed out as, for instance, the use of semi automated drug safety monitoring based on electronic healthcare databases, the availability of additional medical information in the context of the German a e healtha legislation or the need for external validation studies to study the impact of outcome and drug exposure misclassification

Doping homogeneity in co-doped materials investigated at different length scales

Doping homogeneity is important for the properties of co-doped phosphors, as it can affect the energy transfer between sensitizer and activator ions. In a case study we apply different methods, that is scanning electron microscopy (SEM) combined with energy dispersive X-ray spectroscopy (EDX) mapping, SEM combined with cathodoluminescence (CL) and solid-state nuclear magnetic resonance (NMR), to study the doping homogeneity of the host system monazite LaPO4 doped with two different lanthanide ions on different length scales. A new criterion for doping heterogeneity in co-doped systems is developed, which is based on the NMR visibility function, which for this purpose is extended to doping with two or more paramagnetic dopants. A deviation from this function is indicative of doping heterogeneity on the length-scale of the blind-spheres of the paramagnetic dopants. A discussion of the advantages and disadvantages of the different methods is presented. The combined approach allows to study doping homogeneity from the nm to the mm scale

Blind spheres of paramagnetic dopants in solid state NMR

Solid-state NMR on paramagnetically doped crystal structures gives information about the spatial distribution of dopants in the host. Paramagnetic dopants may render NMR active nuclei virtually invisible by relaxation, paramagnetic broadening or shielding. In this contribution blind sphere radii r(0) have been reported, which could be extracted through fitting the NMR signal visibility function f (x) = exp(-ar(0)(3)x) to experimental data obtained on several model compound series: La(1-x)Ln(x)PO(4) (Ln = Nd, Sm, Gd, Dy, Ho, Er, Tm, Yb), Sr1-xEuxGa2S4 and (Zn1-xMnx)(3)(PO4)(2)center dot 4H(2)O. Radii were extracted for H-1, P-31 and Ga-71, and dopants like Nd3+, Gd3+, Dy3+, Ho3+, Er3+, Tm3+, Yb3+ and Mn2+. The observed radii determined differed in all cases and covered a range from 5.5 to 13.5 angstrom. While these radii were obtained from the amount of invisible NMR signal, we also show how to link the visibility function to lineshape parameters. We show under which conditions empirical correlations of linewidth and doping concentration can be used to extract blind sphere radii from second moment or linewidth parameter data. From the second moment analysis of La1-xSmxPO4 P-31 MAS NMR spectra for example, a blind sphere size of Sm3+ can be determined, even though the visibility function remains close to 100% over the entire doping range. Dependence of the blind sphere radius r(0) on the NMR isotope and on the paramagnetic dopant could be suggested and verified: for different nuclei, r(0) shows a 3 root gamma-dependence, gamma being the gyromagnetic ratio. The blind sphere radii r(0) for different paramagnetic dopants in a lanthanide series could be predicted from the pseudo-contact term

Effectiveness of oxacillin in treatment of mastitis and concentration and activity of three antimicrobial factors of milkin negative culture results in clinical mastitis

Titelblatt, Inhaltsverzeichnis, Lebenslauf 1\. Einleitung 2\. Literatur 3\. Material und Methoden 4\. Ergebnisse 5\. Diskussion 6\. Zusammenfassung 7\. Summary LiteraturverzeichnisDie bedeutsamsten Erreger der Mastitis des Rindes stellen Bakterien dar. Unterstützend zu der körpereigenen Abwehr des Wirtstieres werden im allgemeinen Antibiotika zur Behandlung verwendet. Diese sollten nach Isolierung des Erregers und der Anfertigung eines Antibiogramms gezielt eingesetzt werden. Leider ist dieses nicht in allen Fällen möglich, da in etwa 10-40 % der zu untersuchenden Milchproben aus entzündeten Eutervierteln keine Erreger isoliert werden können. Ziel dieser Arbeit war es, neben der Wirksamkeit von Oxacillin in der Mastitistherapie (Untersuchungsteil 1) eine Erklärung für das Auftreten bakteriologisch negativer Mastitismilchproben zu finden (Untersuchungsteil 1 und 2). Der Untersuchungsteil 1 wurde auf einem Milcherzeugerbetrieb mit ca. 800 melkenden Kühen und 8000 kg gleitendem Herdendurchschnitt durchgeführt. Es wurden Tiere aus allen Laktationsstadien mit klinischen Mastitiden in die Untersuchung aufgenommen. Neben der Erhebung klinischer Befunde an den Tagen 0, 1, 2, 7, 14 und 21 wurde eine mikrobiologische Untersuchung an den Tagen 0, 7, 14 und 21 durchgeführt. In die Untersuchung aufgenommene Tiere wurden mindestens dreimal im Abstand von 24 Stunden mit 1000 mg Oxacillin intrazisternal behandelt. Die Behandlung wurde als klinischer Heilungserfolg eingestuft, wenn der Allgemeinzustand des Tieres ohne besonderen Befund und die Körperinnentemperatur <_ 39,0°C war. Das erkrankte Euterviertel musste frei von akuten entzündlichen Veränderungen, wie vermehrte Wärme, Schmerzhaftigkeit und/ oder Schwellung sein. Die entnommene Milchprobe musste in der grobsinnlichen Beurteilung einen Normalbefund aufweisen. Die klinische Heilungsrate betrug 60,8 % am Tag 14 und 48,1 % am Tag 21. Die Tiere wurden im Durchschnitt 3,4-mal mit 1000 mg Oxacillin alle 24 Stunden intrazisternal behandelt. Die klinische Heilung am Tag 14 bei Mastitiden durch Sc. agalactiae lag bei 66,6 % von insgesamt sechs Tieren. Bei Mastitiden ausgelöst durch S. aureus wurden vier von neun Tieren (44,4 %) geheilt. Die klinischen Heilungsraten unspezifischer Mastitiden zeigten keinen Unterschied zu den klinischen Heilungsraten von Mastitiden, bei denen Erreger in der bakteriologischen Untersuchung isoliert wurden. Die antibakterielle Eigenschaft von Milch wurde von vielen Autoren beschrieben. In der vorliegenden Arbeit wurde untersucht, ob die drei unspezifischen Abwehrfaktoren der Milch Lysozym, Laktoferrin und das Laktoperoxidase- Thiozyanat-Hydrogenperoxid System (LPS) Ursache bakteriologisch negativer Befunde einiger Mastitiden sein können. Der Untersuchungsteil 2 wurde in einem Milchviehbetrieb mit ca. 2.900 Kühen bei einer durchschnittlichen Milchleistung der Herde von ca. 7.100 kg durchgeführt. Aufgenommen wurden Tiere aus allen Laktationsstadien post partum mit einer klinischen Mastitis. Die Tiere wurden klinisch untersucht und Milchproben zur mikrobiologischen Untersuchung und zum Nachweis von Hemmstoffen entnommen. Neben dem klinisch erkrankten Viertel (Versuchsviertel) wurde auch immer das gesunde Viertel der anderen Seite (Kontrollviertel) untersucht. Der Nachweis des Lysozyms erfolgte nach der Lysoplate-Technik basierend auf einer Lyse des im Agar suspendierten Micrococcus lysodeicticus. Beim Nachweis des Laktoferrins handelte es sich um einen Enzyme-linked immunosorbent assay (ELISA) nach Meisel (1990). Der Nachweis der Aktivität des Laktoperoxidase-Thiozyanat-Wasserstoffperoxid Systems (LPS) erfolgte durch eine spektrophotometrische Messung nach Björck und Mullan (1993) auf Grundlage der Entwicklung von Shindler et al. (1976). Die Konzentrationen bzw. Aktivitäten der drei Abwehrfaktoren waren in den erkrankten Vierteln signifikant höher als in den nicht erkrankten Vierteln. Es konnten keine Zusammenhänge zur Milchleistung, zum Laktationsstadium und zur Laktationsnummer festgestellt werden. Die Lysozymkonzentrationen stiegen mit Zunahme der Veränderungen des Euterdrüsengewebes und der grobsinnlichen Sekretbeschaffenheit an. Die Laktoferrinkonzentrationen waren in Eutervierteln mit nur geringen Veränderungen im Drüsengewebe signifikant niedriger als in Eutervierteln mit mittleren oder hochgradigen Veränderungen (p <_ 0,05). Für die LPS-Aktivitäten konnten keine Zusammenhänge zu klinischen Befunden hergestellt werden. Die Untersuchung der drei Faktoren des Abwehrsystems der Milchdrüse in dieser Arbeit ergab keinen Hinweis auf eine Erklärung des Auftretens unspezifischer Mastitiden. Es wurden keine Unterschiede in den Laktoferrinkonzentrationen bzw. LPS-Aktivitäten der Mastitiden mit positivem und negativem Erregernachweis festgestellt. Die Lysozymkonzentrationen der erkrankten Viertel aus denen Erreger isoliert wurden, waren signifikant höher als in den erkrankten Vierteln ohne Erregernachweis (p <_ 0,05).Bacterial infection is the most important cause of mastitis in cattle. Antimicrobial therapy is used for treatment. It should be used after isolation of the causative agent and the determination of its antimicrobial resistance pattern. Unfortunately, this is not possible in all cases, because 10 to 40 % of the milk samples from affected quarters yield no bacterial growth on culture. The objective of this study was to determine efficacy of Oxacillin in the antimicrobial therapy of mastitis (experiment 1) and to evaluate possible reasons for bacteriologically negative mastitis milk samples (experiment 2). Experiment 1 was conducted on a dairy farm with 800 cows in milk with a rolling herd average of 8000 kg per year. Animals from all stages of lactation with clinical mastitis were included in the study. Clinical findings were recorded on days 0, 1, 2, 7, 14 and 21. Milk samples were cultured for microbiological investigation on days 0, 7, 14 and 21. Animals included in the study were treated for at least three times in 24 hour intervals with 1000 mg Oxacillin intramammarily. Cases were classified as clinical cure if the attitude of the animal was back to normal and body temperature was below 39,0°C. The affected quarters had to be free of signs of acute inflammation like increased temperature, pain and/or swelling. The gross appearance of the milk had to be normal. The clinical cure rate was 60.8 % on day 14 and 48.1 % on the day 21. On average animals were treated 3.4 times with Oxacillin. The clinical cure rate on day 14 was 66.6 % (4 of 6 six animals) for mastitis due to Sc. agalactiae and 50 % (4 of 8 cases) for S. aureus mastitis. Clinical cure rates did not differ between cases with and without no bacteria isolated. The antimicrobial activity in milk has been described by many authors. In this study it was evaluated whether lysozyme, lactoferrin and the lactoperoxidase- thiocyanate-peroxide system (LPS) could be the reason for negative culture results in samples for cases of clinical mastitis. Experiment 2 was conducted on a dairy farm with approximately 2900 cows and a rolling herd average of approximataly 7100 kg. Animals from all stages of lactation with clinical mastitis were included in the study. Animals were examined clinically and milk samples were collected for microbiological investigation and to test for inhibitory substances. Lysozyme concentrations were determined using the " lysoplate-technique" which is based on the lysis of Micrococcus lysodeicticus suspended in the agar. Lactoferrin concentrations were measured in an enzyme linked immunosorbent assay (ELISA, Meisel, 1990). Activity of the LPS was determined spectrophotometrically (Shindler et al., 1976; Bjoerck and Mullan, 1993). The concentrations or activities of the three factors were significantly higher in diseased quarters than in quarters without clinical signs of mastitis. No correlations could be determined between the three factors and milk production, parity and stage of lactation. The concentration of lysozyme increased with severity of the clinical signs (local swelling and changes in secretion). The concentration of lactoferrin was significantly lower in quarters with only limited tissue alterations than in quarters with medium or severe alterations (p <_ 0.05). For the LPS-activities no correlation to the severity of clinical signs could be found. Results from this study indicate that the three factors examined did not impair the results of microbiological culture of milk samples from quarters with clinical mastitis. No differences in the concentration of lactoferrin or LPS-activities were found between mastitis with positive and negative culture results. The concentration of lysozyme was even higher in culturally positive samples than in negative samples (p <_ 0.05)

SrAlSi4N7:Eu2+

The new nitridoalumosilicate phosphor SrAlSi4N7:Eu2+ has been synthesized under nitrogen atmosphere at temperatures up to 1630°C in a radio-frequency furnace starting from Sr metal, α-Si3N4, AlN, and additional Eu metal. The crystal structure of the host compound SrAlSi4N7 has been solved and refined on the basis of single-crystal and powder X-ray diffraction data. In the solid, there is a network structure of corner-sharing SiN4 tetrahedra incorporating infinite chains of all edge-sharing AlN4 tetrahedra running along [001] (SrAlSi4N7: Pna21 (No. 33), Z = 8, a = 11.742(2) Å, b = 21.391(4) Å, c = 4.966(1) Å, V = 12.472(4) Å3, 2739 reflections, 236 refined parameters, R1 = 0.0366). The Eu2+-doped compound SrAlSi4N7:Eu2+ shows typical broadband emission originating from dipole-allowed 4f6(7FJ)5d1 → 4f7 (8S7/2) transitions in the orange-red spectral region (λmax = 632 nm for 2% Eu doping level, 450 nm excitation) with a spectral width of FWHM = 2955 (± 75) cm−1 and a Stokes shift ΔS = 4823 (± 100) cm−1. The luminescence properties make the phosphor an attractive candidate material as red component in trichromatic warm white light LEDs with excellent color rendition properties

Synthesis, Structure, and Dynamics of Tris(η5-cyclopentadienyl)lanthanides and Bis(η5-cyclopentadienyl)[bis(trimethylsilyl)amido]cerium(III)

The crystal structures of tris(η5-cyclopentadienyl)lanthanides (Ln = Ce, Dy, Ho) have been determined using different X-ray diffraction methods. Cp3Ce and Cp3Ho (Cp = cyclopentadienyl) crystal data needed special solution and refinement methods, due to the occurrence of intrinsic twinning in these species. Our results do not agree with the previously published cell constants of Cp3Ho. The space group and unit cell parameters of Cp3Dy have been derived from powder diffraction experiments. High-resolution 13C solid-state NMR data of Cp3La are presented, giving evidence of the dynamics and bonding situation of the Cp ligands. Cp3Ce turned out to be a reactive reagent for the synthesis of bis(η5-cyclopentadienyl)[bis(trimethylsilyl)amido]cerium(III)

Unprecedented Zeolite-Like Framework Topology Constructed from Cages with 3-Rings in a Barium Oxonitridophosphate

A novel oxonitridophosphate, Ba19P36O6+xN66-xCl8+x(x≈4.54), has been synthesized by heating a multicomponent reactant mixture consisting of phosphoryl triamide OP(NH2)3, thiophosphoryl triamide SP(NH2)3, BaS, and NH4Cl enclosed in an evacuated and sealed silica glass ampule up to 750°C. Despite the presence of side phases, the crystal structure was elucidated ab initio from high-resolution synchrotron powder diffraction data (λ=39.998 pm) applying the charge flipping algorithm supported by independent symmetry information derived from electron diffraction (ED) and scanning transmission electron microscopy (STEM). The compound crystallizes in the cubic space group Fm3c (no. 226) with a = 2685.41(3) pm and Z = 8. As confirmed by Rietveld refinement, the structure comprises all-side vertex sharing P(O,N)4 tetrahedra forming slightly distorted 3846812 cages representing a novel composite building unit (CBU). Interlinked through their 4-rings and additional 3-rings, the cages build up a 3D network with a framework density FD = 14.87 T/1000 Å3 and a 3D 8-ring channel system. Ba2+ and Clˉ as extra-framework ions are located within the cages and channels of the framework. The structuralmodel is corroborated by 31P double-quantum(DQ) /single-quantum (SQ) and triple-quantum (TQ) /single-quantum (SQ) 2D correlation MAS NMR spectroscopy. According to 31P{1H} C-REDOR NMR measurements, the H content is less than one H atom per unit cell

Ba2AlSi5N9

Ba2AlSi5N9 was synthesized starting from Si3N4, AlN, and Ba in a radio-frequency furnace at temperatures of about 1725°C. The new nitridoalumosilicate crystallizes in the triclinic space group P1 (no. 1), a=9.860(1) Å, b=10.320(1) Å, c=10.346(1) Å, α=90.37(2)°, β=118.43(2)°; γ=103.69(2)°, Z=4, R1=0.0314. All synthesized crystals were characteristically twinned by reticular pseudomerohedry with twin law (1 0 0, −0.5 −1 0, −1 0 −1). The crystal structure of Ba2AlSi5N9 was determined from single-crystal X-ray diffraction data of a twinned crystal and confirmed by Rietveld refinement both on X-ray and on neutron powder diffraction data. Statistical distribution Si/Al is corroborated by lattice energy calculations (MAPLE). 29Si and 27Al solid-state NMR are in accordance with the crystallographic results. Ba2AlSi5N9 represents a new type of network structure made up of TN4 tetrahedra (T = Si, Al). Highly condensed layers of dreier rings with nitrogen connecting three neighboring tetrahedral centers occur which are further crosslinked by dreier rings and vierer rings. The dreier rings consist of corner-sharing tetrahedra, whereas some of the vierer rings exhibit two pairs of edge-sharing tetrahedra. In the resulting voids of the network there are eight different Ba2+ sites with coordination numbers between 6 and 10. Thermogravimetric investigations confirmed a thermal stability of Ba2AlSi5N9 up to about 1515°C (He atmosphere). Luminescence measurements on Ba2AlSi5N9:Eu2+ (2 mol % Eu2+) with an excitation wavelength of 450 nm revealed a broadband emission peaking at 584 nm (FWHM=100 nm) originating from dipole-allowed 4f6(7F)5d1 → 4f7(8S7/2) transitions