Patent WOA2 - New antibody drug conjugates (adcs) and the use thereof - Google Patents Dh Psoriasis biologisch
Gebiet der Erfindung Field of the Invention. The present invention relates to the use of compounds and compositions for inhibiting cell proliferative disorders. Hintergrund der Erfindung Background of the Invention. The following description of the background of the invention is provided to aid in understanding the invention, but it is not dh Psoriasis biologisch that it describes or represents dh Psoriasis biologisch art for the invention.
The Kit signaling is critical for fetal gonadal development, and continues to play a role in fertility of adults Mauduit et al Human Reproduction Update. Die Spermatogenese ist in Abwesenheit von SCF Ohta et al. Spermatogenesis is in the absence of SCF Ohta et al Development Or the ability of Kit via the PI3 kinase pathway Blume-Jensen et al Nature Genetics. Kissel et al EMBO Journal Es wurde ob es Juckreiz bei, dass die Expression von Kit in subfertilen Hoden geringer ist als in normalem Hodengewebe Feng et al.
These observations suggest that Kit kinase inhibitors would reduce both male and female fertility. As a key mediator of mast cell function, Kit may play a role in pathologies associated with mast cells in combination. Mast cells were also in the rejection of allogeneic liver transplant Yamaguchi et al Hepatology.
These observations suggest that Kit kinase inhibitors may help prevent organ rejection and fibrosis. Mastzellen wurden ebenfalls dh Psoriasis biologisch der Pathologie von Multipler Sklerose Secor et al.
Mast cells have also been implicated in the pathology of multiple sclerosis Secor et al J. In both cases, the pathology of the disease was significantly attenuated relative dh Psoriasis biologisch mice with normal Kit and mast cell populations. Thus can the role of mast cells in these diseases suggests that Kit kinase inhibitors might be useful therapeutics.
Cellular signal transduction is a fundamental mechanism are passed through the extracellular stimuli into the interior of cells and subsequently regulate diverse cellular processes below.
One of the key biochemical mechanisms of signal transduction involves the reversible phosphorylation of proteins. Phosphorylation of polypeptides regulates the activity of mature proteins by altering their structure and function. In proteins, phosphate is most often to dh Psoriasis biologisch hydroxyl OH of serine, threonine or tyrosine amino acids.
Enzymes that mediate phosphorylation of cellular effectors generally fall under two classes. The first class consists of protein kinases which transfer a phosphate group from adenosine triphosphate to protein substrates.
Die zweite Klasse besteht aus Proteinphosphatasen, die Phosphatreste von Phosphorylproteinsubstraten hydrolysieren. The second class consists of protein phosphatases which hydrolyze phosphate moieties from phosphoryl. Die entgegengesetzten Psoriasis medizinische Behandlung von Proteinkinasen und Proteinphosphatasen gleichen den Fluss click Signalen in Signaltransduktionsprozessen aus und regulieren diesen.
The opposing functions of protein kinases and protein phosphatases are similar to dh Psoriasis biologisch flow of signals in signal transduction processes and regulate this. Proteinkinasen und Proteinphosphatasen werden im Allgemeinen in zwei Gruppen aufgeteilt: Proteine dh Psoriasis biologisch Rezeptor- und Nicht-Rezeptorart. Protein kinases and Eplan Psoriasis phosphatases are generally divided into two groups: Most protein tyrosine phosphatases from receptor type contain two conserved catalytic domains, each of which comprises a segment of amino acid residues.
Receptor may be further sub-classified based on the difference in the amino acid sequence of their extracellular domains. Acad Sci USA Protein kinases and protein phosphatases are also typically divided based on the amino acids on which they act in three classes.
Einige katalysieren dh Psoriasis biologisch Addition oder Hydrolyse von Phosphat nur bei Serin oder Threonin, einige katalysieren die Addition oder Hydrolyse von Phosphat nur bei Tyrosin und einige katalysieren die Addition oder Hydrolyse von Phosphat bei Serin, Threonin Zinksalbe Psoriasis Tyrosin.
Some catalyze the addition or hydrolysis of phosphate on serine or threonine, some catalyze the addition or hydrolysis of phosphate on tyrosine and some catalyze the addition or hydrolysis of phosphate on serine, threonine and tyrosine. Tyrosine kinases can the catalytic activity of other protein kinases that are involved in cell proliferation regulate.
Protein kinases with inappropriate activity are also involved in some types of cancer. Abnormally elevated levels of cell proliferation is associated with receptor and non-receptor protein kinases with unregulated activity. In addition to their role in cellular proliferation, it is believed that protein kinases dh Psoriasis biologisch involved in cellular differentiation processes.
Zelldifferenzierung tritt in einigen Zellen bei Stimulation mit Nervenwachstumsfaktor NGF oder epidermalem Wachstumsfaktor EGF auf. Cell differentiation occurs in some cells upon stimulation with dh Psoriasis biologisch growth factor NGF or epidermal growth factor EGF.
Cellular differentiation is characterized by membrane ruffling, cell flattening and increase of cell adhesion. Chao,Cell In discovering novel treatments for cancer and other diseases efforts, biomedical researchers and chemists have molecules that inhibit the function of protein kinases, designed synthesized and tested.
Some small organic molecules form a class of compounds that modulate the function of protein kinases. The compounds that can traverse cell membranes and are resistant to hydrolysis by acids may be advantageous therapeutics as they after being administered orally to patients, can be well bioavailable.
Viele dieser Proteinkinaseinhibitoren hemmen die Funktion von Proteinkinasen jedoch nur schwach. However, many of these protein kinase inhibitors inhibit the function of dh Psoriasis biologisch kinases only weakly. In addition, many inhibit a variety of protein kinases and therefore cause as therapeutic agents for diseases diverse side effects. Despite significant advances that have been made in developing compounds for the treatment of cancer, is in the art a need for certain structures and substitution patterns that form compounds that are capable of modulating the function of particular protein kinases identified.
Zusammenfassung der Erfindung Summary of the Invention. Die folgende Erfindung richtet sich auf die Verwendung von Indolinonverbindungen zur Modulation der Funktion von Proteinkinasen mit diesen Verbindungen. The present invention is directed to the use of indolinone compounds for modulating the function of protein kinases with these dh Psoriasis biologisch. Die folgende Erfindung zeichnet sich durch Indolinonverbindungen, die wirksam Rezeptor-Proteinkinasen der c-kit Familie inhibieren, und verwandte Produkte und Verfahren aus.
The present invention is characterized by indolinone that effectively receptor protein kinases of the c-kit family inhibit, and related products and processes. In this class of diseases covered certain types of cancer along with certain immune disorders associated with overproduction or over-stimulation of mast cells. Compounds can be modified so that they are specific to their target or their targets and are therefore cause few side effects.
These properties are significant improvements over currently used anti-cancer drugs, which generate and weaken the patient detrimentally diverse side effects.
Bestimmte Arten von Krebs, wie zum Beispiel kleinzelliger Lungenkrebs SCLCexprimieren sowohl die c-kit Rezeptor-Proteinkinase als auch den Stammzellfaktor SCFeinen c-kit Liganden. Certain types of cancer, such as small cell lung cancer SCLCexpress both the c-kit receptor protein kinase and Stem Cell Factor SCFa c-kit ligand. Although a precise understanding of the mechanisms that inhibit is not dh Psoriasis biologisch to practice the present invention dh Psoriasis biologisch the compounds Phosphotyrosinkinasen PTKs a transmembrane growth factor receptor tyrosine kinase, for.
Example, the c-kit receptor kinase,it is believed that the compounds with the dh Psoriasis biologisch acids in the catalytic region of PTKs interact. It is believed that inhibitors of PTKs through non-covalent interactions such as hydrogen bonds, Van der Dh Psoriasis biologisch interactions, hydrophobic interactions, and ionic bonding, in the same general region of the PTKs bind in the ATP binds to the PTKs.
Insbesondere wird angenommen, dass der Oxindolbestandteil siehe Formel III, unten der Verbindungen der vorliegenden Erfindung in demselben allgemeinen Bereich bindet, der durch den Adenin-Ring von ATP besetzt wird. In particular, it is assumed that the Oxindolbestandteil see Formula III, below of the compounds of the present invention in the same general region binds, which is occupied by the adenine ring of ATP.
Specificity of a PTK inhibitor for a particular PTK may dh Psoriasis biologisch conferred by interactions between the constituents around the Dh Psoriasis biologisch around with amino acid domains specific to individual PKs. Thus, other substituents may dh Psoriasis biologisch to the preferred binding to particular PKs.
Thus, such compounds have utility for in vitro assays on such proteins and for in vivo therapeutic effect through such proteins. As mentioned above, for example, expressing certain types of cancer, both the c-kit receptor protein kinase and Stem Cell Factor SCF and this pairing could constitute an autocrine loop, which stimulates the growth of these cancer cells.
Thus the invention provides in a first aspect to the use as defined in claim 1 for treating or preventing an abnormal condition as defined below in an organism prepared. The abnormal condition is associated with an aberration in a signal transduction pathway mediated by an interaction between a c-kit kinase and a natural binding partner. Die Zusammensetzung wird in einer therapeutisch wirksamen Menge einer Indolinonverbindung an den Organismus verabreicht.
The composition is administered in a therapeutically effective amount of an indolinone compound to the organism. The indolinone dh Psoriasis biologisch modulates the interaction between the c-kit kinase and a natural binding partner. Therefore, it is predicted that the feeding or interrupting preferably Interrupt this interaction therapeutic benefits to a given population of patients in need of such treatment has.
In a preferred embodiment, the amount of signal transduction via the c-kit kinase is abnormal, and promote or interrupts the dh Psoriasis biologisch transmission connection. Der Ausdruck "behandeln" bezieht sich darauf, eine therapeutische Wirkung zu besitzen und einen abnormalen Zustand in dem Organismus zumindest dh Psoriasis biologisch zu lindern oder zu beseitigen. The term "treating" refers to having a therapeutic effect and to alleviate an abnormal condition in the organism at least partially or eliminate.
The term "treating" preferably refers to ameliorating a symptom of the abnormal condition in a group of patients to whom the indolinone is administered relative to a control group that does not receive the indolinone. The effect of the treatment can be just click for source by measuring a change or an absence of a change in http://outdoor-frauen.de/wirksam-bei-psoriasis-1.php phenotype, a change or an absence of a change in cell proliferation, a change or an absence of a change in the catalytic activity of this c-kit protein http://outdoor-frauen.de/wo-eine-biopsie-weitergeben-psoriasis.php, and a change or an absence of a change in the interaction between the protein kinase and a natural binding partner can be monitored.
The term "treating" or "treatment" does not necessarily mean a complete cure. Each relief any undesired symptom of the disease to any extent or the slowing of the progression of the disease can be considered treatment.
Furthermore, treatment may include acts that degrade the overall welfare of the patient or his appearance. For example, the administration of chemotherapy in cancer patients who can feel "sicker" patients still considered treatment.
The term "catalytic activity" used above in connection with this invention, defines the http://outdoor-frauen.de/welche-nuesse-koennen-in-psoriasis.php at which a protein kinase phosphorylates a substrate.
Catalytic dh Psoriasis biologisch can be measured as a function of time, for example, by determining the amount of substrate that is converted into a product. Die Phosphorylierung eines Substrats findet am aktiven Zentrum einer Proteinkinase statt. Phosphorylation of a substrate occurs at the active site of a protein kinase. Das aktive Zentrum ist normalerweise eine Vertiefung, in der das Substrat an die Proteinkinase bindet und phosphoryliert wird. The active site is normally a cavity in which the dh Psoriasis biologisch binds to the protein kinase and is phosphorylated.
The term "substrate" as used above and herein refers to a molecule phosphorylated by a protein kinase. Das Substrat ist vorzugsweise dh Psoriasis biologisch Peptid und bevorzugter ein Protein. The substrate is preferably a peptide and more preferably a protein.
Der Ausdruck "verhindern" bezieht sich auf das Verringern der Wahrscheinlichkeit, dass ein Organismus an einem abnormalen Zustand erkrankt oder diesen entwickelt.
The term "preventing" refers to decreasing the probability that an organism suffering from an abnormal state or developed this. Der Ausdruck "verhindern" bezieht sich vorzugsweise auf das Verringern des Prozentsatzes an Individuen, die einen abnormalen Zustand entwickeln, relativ zu einer Kontrollgruppe, die kein Indolinon verabreicht bekommt.
The term "preventing" preferably refers to reducing the percentage of individuals who develop an abnormal condition, relative to a control group that receives no indolinone administered.
Der Ausdruck "abnormaler Zustand" bezieht sich auf eine Funktion in den Zellen oder Geweben eines Organismus, die von den normalen Funktionen in dem Organismus abweicht. The term "abnormal condition" refers to a function in the cells or tissues of an organism that deviates from normal functions in the organism. An abnormal condition can relate to cell proliferation, cell differentiation or cell survival. Abnormal conditions include mastocytosis, dh Psoriasis biologisch presence of one or Kardashyan Kim Psoriasis mast cell dh Psoriasis biologisch, asthma, allergy-associated chronic rhinitis, and gastrointestinal stromal tumors a.
In a preferred embodiment, these abnormal conditions occur, such as mast cell tumors and mastocytosis, in non-human organisms and may thus be prevented or treated in veterinary applications.
Abnormal cell survival conditions relate to conditions in which signaling pathways of programmed cell death apoptosis can be activated dh Psoriasis biologisch deactivated. Eine Reihe dh Psoriasis biologisch Proteinkinasen steht in Verbindung mit dem Apoptosesignalweg. A number of protein kinases are associated with the Apoptosesignalweg. Deviations in the function of each of these protein kinases could lead to cell immortality or premature cell dh Psoriasis biologisch. The term "function" as used in connection with a protein kinase above refers to the cellular role of a protein kinase, preferably a c-kit kinase.
The protein kinase family includes members that regulate many steps in signaling cascades, including cascades controlling cell growth, migration, differentiation, gene expression, muscle contraction, glucose metabolism, cellular protein synthesis, and regulation of the cell cycle. The "function" of a membrane receptor kinase usually is a signal from outside a cell membrane to pass into the interior of a cell.
Binden eines Liganden, Dimerisieren an eine andere Membranrezeptorkinase, Phosphorylieren von anderen Proteinen innerhalb der Zelle, Binden von anderen Proteinen innerhalb der Zelle und Verursachen der Lokalisation von Proteinen innerhalb der Zelle.
To achieve this, it can perform any or all of these other functions: Der Dh Psoriasis biologisch "Organismus" bezieht sich auf jedes lebende Wesen, das zumindest aus einer Zelle besteht.
The term "organism" refers to any living creature, which consists of at least one cell. An organism can be as a mammal as simple as a eukaryotic cell or as complex. The organism is preferably a mammal, more preferably a human. The term "mammal" refers preferably to such organisms as mice, rats, rabbits, guinea pigs, sheep and goats, more preferably to cats, dogs, monkeys and apes. In preferred Psoriasis-Behandlung nationalen Bewertungen, the abnormal condition, which is in communication with mammals, mastocytosis, and dh Psoriasis biologisch presence of one http://outdoor-frauen.de/henna-fuer-die-haare-psoriasis.php more mast cell tumors.
The term "deviation" refers to a protein kinase, for example, a c-kit kinase that transferred in an organism or underexpressed, und ein Tropfen Psoriasis Preis mutated such that its catalytic activity lower or higher than is protein kinase activity of wild-type, mutated, so that it can no longer interact with a natural binding partner, can no longer function in an autocrine loop within the cell is modified not by another protein dh Psoriasis biologisch or protein phosphatase, or dh Psoriasis biologisch longer interacts with a natural binding partner.
Preferably, the deviation includes excessive or lack of signal transduction in the interaction with a natural binding partner. The term "signal transduction pathway" refers to molecules that transmit an extracellular signal through the cell membrane, so this is an intracellular signal.
This signal can then stimulate a cellular response. The term "mediated" refers to the wie Psoriasis bei einem Kind beginnen in the control or the effect of dh Psoriasis biologisch interaction between the dh Psoriasis biologisch kinase and the natural binding partners to the deviation in the signal transduction pathway.
Thus contains the signal transduction pathway that has an aberration and an abnormal state is connected, a c-kit kinase in interaction with a natural binding partner. The "interaction" of a c-kit kinase molecule is the binding of that c-kit kinase molecule to a natural binding partner or molecule within the cell or the phosphorylation of another protein or molecule by a c-kit kinase molecule within the cell, or any other association of c kit kinase within a cell.
These interactions include non-covalent interactions such as hydrogen bonds, Van der Waals interactions, hydrophobic interactions and ion-pair bonds. The term "c-kit kinase" refers to a membrane receptor protein tyrosine kinase, which is preferably in the binding of the stem cell factor SCF is activated to its extracellular domain Yarden et al.
Mutant versions of c-kit kinase will be replaced by "c-kit kinase" includes and include those that fall into two classes: The term "natural binding partner" refers to a polypeptide or compound such as ATP that bind in cells to a protein ein Psoriasis-Behandlung Kefir burgh. Natural binding partners can play a role in the transmission of a signal in a protein kinase signal transduction process.
A "therapeutically effective" amount means an amount of compound dh Psoriasis biologisch is effective to prevent symptoms of a disease, to alleviate, or to improve or prolong the survival of the subject being treated. Determination of a therapeutically effective amount is well within the capabilities of the skilled person, in particular provided in the light of the detailed disclosure herein.
Eine "therapeutisch wirksame Menge" mit Bezug auf die Behandlung von Krebs bezieht sich auf eine Menge, die ausreichend ist eines oder mehrere der folgenden Ergebnisse zu erzielen: A "therapeutically effective amount" with respect to the treatment of cancer refers to an amount which is sufficient of one or to achieve more of the following results: A "therapeutically effective amount" in reference to the treatment of a cell proliferative disorder that is other than cancer refers to an amount which is sufficient to achieve one or more of the following results: The term "indolinone" is used as that term is commonly understood in the art and includes a large subclass of substituted or unsubstituted dh Psoriasis biologisch that are to be synthesized from an aldehyde moiety and an oxindole moiety capable.
In preferred embodiments, the indolinones included in the present process, the structures of formulas I and II see belowand more preferably they are selected from compounds of one to thirteen see below. Beispiele dh Psoriasis biologisch beispielhaften Indolinonverbindungen und deren Synthese werden in den dh Psoriasis biologisch Anmeldungen dargelegt: Examples of exemplary indolinone and their synthesis are set forth in the following applications: April von Tang, et al.
Mai von Tang, et al. August an Tang et al. Die Verbindung, die in der Erfindung verwendet wird, ist eine der folgenden: The compound which is used in the invention is one of the following: The indolinone compounds used in this invention preferably modulate the activity of protein tyrosine kinase in vitro. These compounds preferably show in one or more in vitro assays for an dh Psoriasis biologisch positive results dh Psoriasis biologisch the treatment of the relevant disease or disorder corresponds to such as the assays described in the examples below.
Die Proteintyrosinkinase, die durch die Indolinonverbindungen, die source der Erfindung verwendet werden, moduliert wird, ist vorzugsweise die c-kit Kinase. The protein tyrosine kinase which is modulated by the indolinone compounds used in the invention is preferably the c-kit kinase.
Dh Psoriasis biologisch of procedures for and results of such modulation are described in the examples below. The term "modulate" refers to altering the function of a protein kinase by increasing or decreasing the probability that a complex forms between a protein kinase and a natural binding partner.
A modulator preferably increases the probability that such a complex forms between the protein kinase and the natural connection partner forms, more preferably increases or decreases the probability that a complex forms between the protein kinase and the natural connection partner forms depending on the concentration of the compound, the opposite the protein kinase is exposed, and most preferably decreases the probability that a complex forms between the protein kinase and dh Psoriasis biologisch natural connection partner forms.
Dh Psoriasis biologisch modulator preferably activates the catalytic activity of a protein kinase, more preferably activates or inhibits the catalytic activity of a protein kinase depending dh Psoriasis biologisch the concentration of the compound that is exposed to the protein kinase, or most preferably inhibits the catalytic activity of a protein kinase.
The term "complex" refers to a composition of at least two molecules bound to one another. Just click for source often contain at least two protein molecules bound to one another. The term "activates" refers dh Psoriasis biologisch increasing the function of a protein kinase. The protein kinase function is preferably the interaction with a natural binding partner and most preferably catalytic activity.
Der Ausdruck "hemmt" bezieht auf das Verringern der Funktion einer Proteinkinase. The term "inhibit" refers to decreasing the function of a protein kinase. The natural binding partner of a protein kinase can bind to an extracellular or intracellular region of a protein kinase with high http://outdoor-frauen.de/rezept-von-psoriasis-mit-kupfersulfat.php. High affinity represents an equilibrium binding constant on the order of 10 -6 M or less.
In addition, a natural binding partner also temporarily interact with an extracellular or intracellular region of a protein kinase and modify them chemically. Natural binding partner of a protein kinase selected from a group including, but not limited is on, SRC homology 2 SH2 or 3 SH3 domains, other Phosphoryltyrosin binding PTB domains, guanine nucleotide exchange factors, protein phosphatases, other protein kinases, and compounds such as for example ATP. A method for determining changes in interactions between protein kinases and their natural binding partners are readily available in the field.
The expression "be related to" refers to a disease that has been shown for comparison with the same non-diseased isolated from an organism tissue dh Psoriasis biologisch it is accompanied by an inappropriate c-kit kinase expression.
The inappropriate expression can be an elevation of normal activities, a reduction of normal activities, the Wie zu heilen Schuppenflechte auf dem Kopf not the presence of c-kit kinase activity where none is found normally be.
The term "in vitro" refers to the fact that a c-kit kinase enzyme is outside of a living organism with a compound useful for this invention, tested, wherein such compounds are examined for their effectiveness. The term "in vitro" includes the use of cells cells Psoriasis und Gelatine enter tissue cultures. The term "promotes or disrupts the abnormal interaction" refers to a process which can be achieved by administering a compound according to the invention to cells or tissues in an organism.
A compound can promote an interaction between a protein kinase and a natural binding partner by forming favorable interactions with many atoms at the complex interface.
Alternatively, a compound an interaction between a protein kinase and a natural binding partner by the perturbing favorable interactions formed between atoms at the http://outdoor-frauen.de/rote-schuppige-flecken-der-psoriasis.php interface inhibit. In preferred embodiments, the promotion or dh Psoriasis biologisch of an abnormal interaction refers to a compound according to the invention that promotes a conformational change Psoriasis Jahr Kind 1 one of the proteins.
Kurze Beschreibung der Figuren Brief Description of the Figures. The half-loops represent the immunoglobulin-like motifs and the shaded rectangles the conserved kinase region of the receptors. Detaillierte Beschreibung der Erfindung Detailed Description of the Invention. Receptor kinase-mediated signal transduction is initiated by extracellular interaction with a specific growth factor ligandfollowed by receptor dimerization, transient stimulation of the intrinsic protein kinase activity and phosphorylation.
This binding sites for intracellular signal transduction molecules are created, leading to the formation of complexes with a spectrum of cytoplasmic signaling molecules that facilitate the dh Psoriasis biologisch cellular response eg. As cell division, metabolic effects on the extracellular microenvironment.
Siehe Schlessinger und Ullrich, dh Psoriasis biologisch, Neuron 9: See, Schlessinger and Ullrich,Neuron 9: The signal transduction via kinases, among other responses dh Psoriasis biologisch cell proliferation, differentiation and metabolism.
These states are described in more detail below. Zielkrankheiten, die durch die Verbindungen, die in der Erfindung verwendet werden, behandelt werden sollen I. Target Diseases to be treated by the compounds used in dh Psoriasis biologisch invention.
The compounds described herein heilen Psoriasis der Kopfhaut wie Bewertungen for the treatment of disorders.
Cell proliferative disorders which can be treated by the present invention or further studied include cancers and proliferative disorders of mast cells.
PTKs have been associated with such cell proliferative disorders. Zum Beispiel wurden einige Mitglieder der Rezeptortyrosinkinase RTK Familie mit der Entwicklung von Krebs in Verbindung gebracht. For example, some members of the receptor were RTK family associated with the development of cancer.
Einige dieser Rezeptoren, wie EGFR Tuzi, et al. Some of these receptors, like EGFR Tuzi, et al,Br J Cancer, Science In fact, were the most common and devastating cancers overexpression of these receptors Akbasak and Suner-Akbasak, et al,J.
J Clin Invest Der EGFR Rezeptor wurde zum Beispiel mit Plattenepithelzellkarzinom, Astrozytom, Glioblastom, Kopf- und Halskrebs, Lungenkrebs und Blasenkrebs in Verbindung gebracht. The EGFR receptor has been brought, for example, with squamous, astrocytoma, glioblastoma, head and neck cancer, lung cancer and bladder cancer.
HER2 has been associated with breast, ovarian, gastric, lung, pancreas and bladder cancer. PDGF-R wurde mit Glioblastom, Lungenkrebs, Eierstockkrebs, Melanom und Prostatakrebs in Verbindung gebracht. PDGF-R has been associated with glioblastoma, lung cancer, ovarian cancer, melanoma and prostate cancer. The c-kit receptor kinase has been associated with such cell proliferative learn more here. For example, it was found that the c-kit kinase receptor dh Psoriasis biologisch over half the SCLC cells studied along with its ligand SCF Hibi, et al,Oncogene.
Possibly, the inhibition of the c-kit kinase will improve the long term survival of patients with SCLC. The link between abnormalities in RTKs and disease are not limited to cancer. Zum Beispiel wurde die c-kit Rezeptorkinase mit Immunkrankheiten, wie zum Beispiel Mastozytose, Asthma und chronischer Rhinitis in Verbindung gebracht.
For example, the c-kit receptor kinase with immune dh Psoriasis biologisch such as mastocytosis, asthma and chronic rhinitis has been linked. Excessive activation of c-kit can dh Psoriasis biologisch associated with diseases resulting from the excessive presence of mast cells in conjunction.
Mastocytosis is the term used to describe a heterogeneous series of disorders are characterized by excessive mast cell proliferation Metclafe,J. Dh Psoriasis biologisch c-kit expression was for mast cells from patients with aggressive mastocytosis, but not on mast cells from patients with indolent mastocytosis reported Nagata, et al,Leukemia. Additionally, mast cells and eosinophils represent key cells is involved in allergy, inflammation and asthma Thomas, et al,Gen.
SCF and c-kit thus regulate direct and dh Psoriasis biologisch activation of both mast cells and eosinophils, thereby influencing the primary cells involved in allergy and asthma through multiple mechanisms. Because of this mutual regulation of the function of mast cells and eosinophils, and the role that SCF can play in this regulation, inhibition of c-kit Kinase may provide a means to treat allergy-associated chronic rhinitis, inflammation and asthma.
The c-kit kinase plays a crucial role in the development of melanocytes, tot Psoriasis, germ and hematopoietic cells. The protein which is encoded by the S1 locus has, on its biological properties used to identify based it, Kit ligand KLstem cell factor SCF or mast cell growth factor MGF called an overview is in Tsujimura,Pathol Int For dh Psoriasis biologisch, we will use SFC to designate the ligand for the c-kit RTK.
SCF is used as a transmembrane protein with a molecular weight of or Dalton, depending on alternative splicing of the mRNA to encode exon 6 were synthesized.
The larger protein can be proteolytically cleaved to form a soluble, glycosylated protein which is not covalently dimerized. Both the soluble and membrane-bound forms of SCF can bind to and activate c-kit this. For example, SCF in the skin is mainly by fibroblasts, keratinocytes, dh Psoriasis biologisch endothelial cells which express the activity of melanocytes and mast cells expressing dh Psoriasis biologisch, modulate expressed.
In bone marrow stromal cells express SCF and regulate bone hematopoiesis of c-kit expressing stem cells. Im gastrointestinalen Trakt, exprimieren intestinale Epithelzellen SCF und beeinflussen die interstitiellen Kajalzellen und die intraepithelialen Lymphozyten.
In the gastrointestinal tract, intestinal epithelial cells express SCF and affect the interstitial cells of Cajal and intraepithelial lymphocytes. In den Hoden exprimieren Sertolizellen und Granulosazellen SCF, dh Psoriasis biologisch die Spermatogenese durch Interaktion mit c-kit auf Keimzellen reguliert.
In the dh Psoriasis biologisch sertoli cells and granulosa express SCF which regulates spermatogenesis by interaction with c-kit on germ cells. Evidence for a contribution of c-kit to neoplastic pathology includes its association with leukemias and mast cell tumors, small dh Psoriasis biologisch lung cancer, testicular cancer, and some cancers of the gastrointestinal tract and central nervous system see below. Additionally, it was hypothesized that c-kit have a role in carcinogenesis of the female genital tract Inoue, et al,Cancer Res 54 SCF binding to the c-kit RTK protects hematopoietic stem and progenitor cells from apoptosis Lee, et al, dh Psoriasis biologisch, J.
The expression of c-kit is frequently observed in acute myelocytic leukemia AMLbut is less common in acute lymphocytic leukemia ALL man Prominente und Psoriasis deutsche reviews, see Sperling, et alHaemat Although c-kit is expressed in the majority of AML cells, its expression for the progression of the disease appears to be prognostically Sperling, et al Haemat.
SCF protects AML cells but prior induced by chemotherapeutic agents apoptosis Hassan, et alActa Hem Inhibition of c-kit by the present invention will enhance the efficacy of these agents and may induce apoptosis of AML cells.
Es wurde gefunden, dass das klonale Bedeckt, zu Psoriasis was tun mit von Zellen von Patienten mit Myelodysplastischem Syndrom Sawada, et al. It has been found that the clonal growth of cells from patients with myelodysplastic syndrome Sawada, dh Psoriasis biologisch al,Blood.
CML zeichnet sich durch eine Expansion von Philadelphia Chromosom-positiven Zellen des Knochenmarks aus Verfaillie, et al. CML is characterized by expansion of Philadelphia chromosome-positive cells of the bone marrow from Verfaillie, et al Leuk Es wurde berichtet, dass das Produkt des Philadelphia Chromosoms, Khabarovsk Behandlung von Psoriasis BCR-ABLdie Inhibition der Apoptose vermittelt Bedi, et al. It was reported that the product of the Philadelphia chromosome, p BCR-ABL, the inhibition of apoptosis mediated Bedi, et al,Blood.
Da p BCR-ABL und die c-kit RTK beide die Apoptose hemmen und p62 dok als Substrat dh Psoriasis biologisch worden ist Carpino, et al.
Since both been p BCR-ABL and the c-kit RTK inhibit apoptosis and p62 Doc suggested as a substrate Carpino, et al,Cell. Es wurde jedoch ebenfalls berichtet, dass c-kit direkt mit p BCR-ABL interagiert Hallek, et al. However, it was also reported that c-kit directly with p BCR-ABL interacts Hallek, et Finger Psoriasis,Brit J.
Therefore, the inhibition of the c-kit kinase will prove in the treatment of the above disorders to be useful. Normale kolorektale Schleimhaut exprimiert kein c-kit Bellone, et al. Normal colorectal mucosa does not express c-kit Bellone, et dh Psoriasis biologisch,J. Cell Physiol ; to dh Psoriasis biologisch And the constitutive c -kit activation seems to be important also for gastrointestinal stromal tumors GISTs.
GISTs are the most common mesenchymal tumors of dh Psoriasis biologisch digestive tract. Es wird angenommen, dass ICCs die Kontraktion des gastrointestinalen Traktes regulieren und Patienten, denen c-kit in ihren ICCs fehlt, zeigen eine myopathische Form von chronischer idiopathischer intestinaler Pseudoobstruktion Isozaki, et al.
It is believed that ICCs regulate contraction of the gastrointestinal tract, and patients lacking c-kit in their ICCs, show a myopathic form of chronic idiopathic intestinal pseudo-obstruction Isozaki, et al. Dh Psoriasis biologisch has been observed that c-kit, which was expressed in GISTs from several different patients having dh Psoriasis biologisch in the intracellular membrane-proximal domain, which leads to the constitutive activation of this RTK Hirota, et al Science Therefore, the inhibition of the c-kit kinase would be an effective agent for the treatment of these cancers.
Male germ cell tumor histologically maintained in seminomas, the germ cell characteristics, and non-seminomas, can show the potential dh Psoriasis biologisch embryonic differentiation, divided. It is believed that both seminomas and non-seminomas emerge from a preinvasive stage, which is called carcinoma in situ CIS Murty, et al,Sem Oncol It was reported that both c-kit and SCF for normal gonadal development during embryogenesis are essential Chinesische Medizin für Psoriasis kaufen, et Geruch von Haut und Leder der juckende,J Endocrinol Loss just click for source either the receptor or the ligand results in animals that lack nuclei.
In postnatal tests it was found that c-kit is expressed in Leydig cells and spermatogonial stem cells, while SCF was expressed in Sertoli cells Loveland, et al,J Endocrinol In transgenic mice expressing the human papillomavirus 16 HPV16 E6 and E7 oncogenes, dh Psoriasis biologisch with high frequency Testicular tumors of Leydig cells Kondoh, et al,Dh Psoriasis biologisch. Diese Tumore exprimieren sowohl c-kit als auch SCF und eine autokrine Schleife kann dh Psoriasis biologisch der Tumorgenese Kondoh, et al.
These tumors express both c-kit and SCF, and an autocrine loop may tumorigenesis Kondoh, et al,Oncogene. Defekte Signalmutanten von SCF Kondoh, et al. Abnormal mutants of SCF Kondoh, et al,Oncogene. The c-kit kinase activation is critical for tumorigenesis in these animals and thus modulation of the c-kit kinase pathway will prevent or treat such disorders by the present invention.
Die Expression von c-kit auf Keimzellentumoren zeigt, dass der Rezeptor von der Mehrzahl von in situ Karzinomen und Seminomen exprimiert wird, aber c-kit nur in einer kleinen Zahl von Nicht-Seminomen exprimiert wird Strohmeyer, et al. The expression of c-kit on germ cell dh Psoriasis biologisch shows that the receptor auf Beine und dem die Psoriasis Rücken expressed by the majority of in situ carcinomas and seminomas, but is c-kit expressed only in a small number of non-seminomas Strohmeyer, et al.
Strohmeyer, et al,J. Dh Psoriasis biologisch Res Clin Oncol Therefore, the inhibition of the c-kit kinase provides a valuable new means for treating these disorders. Cancers of the CNS: SCF and c-kit are expressed throughout the CNS of developing rodents, and the pattern of expression suggests a role in the growth, migration and differentiation of neuroectodermal cells suspect.
Expression of both receptor and ligand has also been for the brain of adults reported Hamel, et al,J. Die Expression von c-kit wurde ebenfalls im normalem menschlichen Gehirngewebe beobachtet Tada, et al. The expression of c-kit has also been observed in normal human brain tissue Tada, et alJ. Die Expression von c-kit wurde in Glioblastomzelllinien und -geweben beobachtet Berdel, et al.
The expression of c-kit has dh Psoriasis biologisch in glioblastoma cell lines and tissues was observed Berdel, et al,Canc Res Die Assoziation von c-kit mit der Pathologie des Astrozytoms dh Psoriasis biologisch weniger klar. The association of c-kit with astrocytoma pathology is less clear. There are reports on the expression of c-kit in normal astrocytes Natali, et al, Im letzteren Fall wurde ein hoher Grad an c-kit Expression in Dh Psoriasis biologisch hoher Tumorklasse beobachtet Kristt, et al.
In the latter case, a high degree of c-kit expression was observed in tumors of high tumor grade observed Kristt, et al,Neuro.
In addition, there are conflicting reports of c-kit and SCF expression in neuroblastomas. Eine Studie fand, dass Neuroblastomzelllinien oft SCF, aber selten c-kit exprimieren.
One study found that neuroblastoma cell lines often express SCF, but rarely c-kit. Im Gegensatz dazu haben andere Studien Cohen, et al. In contrast, other studies Cohen, et al,Blood. Thus, c-kit kinase inhibitors as a means to treat these cancers may prove therapeutically useful.
As mentioned above, dh Psoriasis biologisch has been reported that SCF dh Psoriasis biologisch known as mast cell growth factor stimulation of c-kit for growth and development of mast cells essential is Hamel, et al,Reinigung Leber Psoriasis. Mice with mutations of c-kit that attenuate its signaling activity, clearly showing fewer mast cells in their skin Tsujimura, dh Psoriasis biologisch, Pathol Int Excessive activation dh Psoriasis biologisch c-kit could be related to diseases arising from excessive abundance of mast cells in conjunction.
Mastocytosis is the term used dh Psoriasis biologisch describe a heterogeneous series of disorders characterized by excessive mast cell proliferation distinguished Metcalfe,J.
Clin Immunol Aller There was an increased c-kit expression on mast cells from patients with aggressive mastocytosis, but not on mast cells from patients with indolent mastocytosis reported Nagata, et al,Mastocytosis Leuk. Es wurde gezeigt, dass SCF auf Stromazellen als dh Psoriasis biologisch Protein exprimiert wird und seine Dh Psoriasis biologisch durch fibrogene Wachstumsfaktoren, wie zum Beispiel PDGF, induziert werden kann Hiragun, et al.
It has been demonstrated that SCF is expressed on stromal cells as a membrane-bound protein, and its expression can be induced by fibrogenic growth factors such as PDGF Hiragun, et al. Es Kiewer Institut für Psoriasis Dermatosen ebenfalls gezeigt, dass es als membrangebundenes Protein auf Keratinozyten in normaler Haut exprimiert wird.
It has also been shown that it is expressed as a membrane-bound protein on keratinocytes in normal skin. In the skin of patients with mastocytosis but an increased amount of soluble Dh Psoriasis biologisch has been observed Longley, et al,New Engl J Med It has been reported dh Psoriasis biologisch Mastzellchymase membrane-associated SCF to a soluble and splits biologically active form. This mast cell-mediated process could serve to create a feedback loop to enhance mast cell proliferation and function Longley, et al,Proc Natl Acad Sci Transgenic mice overexpressing a form of SCF that can not be proteolytically released from keratinocytes did dh Psoriasis biologisch develop mastocytosis, while similar animals expressing normal SCF in keratinocytes, a phenotype exhibited, the human cutaneous mastocytosis resembled Kunisada, et al.
The formation of large amounts of soluble SCF can, in some patients to the pathology, which is in communication with mastocytosis, contribute and the present invention can treat or dh Psoriasis biologisch such disorders by dh Psoriasis biologisch the interaction between SCF and c-kit kinase. Several different mutations read article the c-kit RTK that result dh Psoriasis biologisch constitutive kinase activity have been found in human and rodent mast cell tumor cell lines Furitsu, et al, dh Psoriasis biologisch, J Clin Invest Additionally, activating mutations of the c-kit dh Psoriasis biologisch in peripheral mononuclear cells that had been isolated from patients with mastocytosis and click at this page hematologic disorders Nagata, et al,Mastocytosis Leuk.
It is therefore prove that the inhibition of c-kit kinase in the treatment of these disorders makes an excellent therapeutic role. In some patients, activating mutations of the c-kit RTK may be responsible for the pathogenesis of the disease and these patients can be prepared by the modulation of the SCF interaction with c-kit kinase treated or their diseases prevented.
It has been shown that the SCF activation of c-kit, the mast cell apoptosis which may be critical for maintaining cutaneous Mastzellhomeostase prevented Iemura, et al,Amer J. Inhibition of mast cell apoptosis could lead to the accumulation of mast cells, which is associated with mastocytosis. Thus provides the observation of c-kit activation resulting from overexpression of the receptor, excessive formation of soluble SCF, or mutations of the c-kit gene that activate its kinase constitutive, an explanation for the inhibition of the kinase dh Psoriasis biologisch of c- kit, the number link mast cells is reduced, and for patients with mastocytosis provides a benefit.
Mast cells and eosinophils dh Psoriasis biologisch at infection with parasites, allergies, inflammation and asthma key cells represent Thomas, et al,Gen. It has been demonstrated that SCF essential for mast go here development, survival and growth Kitamura, et al,Int Arch Aller Immunol In addition, SCF cooperates with the eosinophil-specific regulator, IL-5 together, to increase the development of eosinophil progenitors Metcalfe, et al,Proc Natl Acad Sci, USA Es wurde ebenfalls berichtet, dass SCF Mastzellen dazu veranlasst Faktoren zu sekretieren Okayama, et al.
It has also been reported that SCF mast cells to secrete factors causes Okayama, et click the following article,Int Arch Aller Immunol In diesem Zusammenhang reguliert SCF direkt und indirekt die Aktivierung von sowohl Mastzellen als auch Eosinophilen.
In this regard, SCF directly and indirectly regulates activation of both mast cells and eosinophils. SCF induces mediator release from mast cells, as well as priming these cells for IgE-induced degranulation Columbo, et al,J. In addition to inducing histamine release from mast cells Luckacs, et al,J. SCF also directly influences the adhesion of both mast cells Dastych, et al,J. Thus, SCF can influence the primary cells involved in allergy and asthma through multiple mechanisms.
Visit web page present, corticosteroids are the most effective treatment for chronic rhinitis and inflammation associated with allergies in conjunction Naclerio, et al,JAMA These agents act via multiple mechanisms including reduction of circulating and infiltrating mast cells and eosinophils, and diminished survival of eosinophils associated with inhibition of cytokine dh Psoriasis biologisch Meltzer,Aller.
It has also been reported that steroids inhibit the expression of SCF by fibroblasts and resident connective tissue cells, resulting dh Psoriasis biologisch decreased survival of mast cells Finotto, et al,J. Because of the mutual regulation of mast cell and eosinophil function, and the role that SCF can play in this regulation, inhibition of c-kit kinase provides a means to treat allergy-associated chronic rhinitis, inflammation and asthma. Identifizierung von Agonisten und Antagonisten des c-kit Rezeptors Identifying agonists and antagonists of the c-kit receptor.
In view of the deduced importance of RTKs in the control, regulation and modulation of endothelial cell proliferation and potentially carcinogenesis of using a number of approaches have been made many attempts to identify RTK "inhibitors". Recently, attempts have been made to identify small molecules which act as kinase inhibitors for use in the treatment of cancer.
Consequently, there is an unmet need for the identification and generation of effective small compounds which selectively the signal transduction of the c-kit RTK inhibit to effectively and specifically suppress this autocrine this web page. Some of the compounds used in the present invention exhibit here activity in biological assays and thus it is expected that these compounds and related compounds in the treatment of c-kit RTK-related disorders, such as those described above, effective are.
In addition, the assays described herein dh Psoriasis biologisch conditions can be used to identify further modulators of the function of c-kit kinase.
The indolinone compounds used in the present invention were tested for their ability to inhibit most of protein kinase activity. Die biologischen Assays und Ergebnisse dieser Inhibitionsstudien werden hierin berichtet. The biological assays and results of these inhibition studies are reported herein.
The methods that were used to measure the modulation of protein kinase function through indolinone compounds similar to those described in Dh Psoriasis biologisch Publication Nos. Pharmazeutische Rezepturen und Verabreichungswege IV. Pharmaceutical formulations and routes of administration. The compounds described herein may per se or in pharmaceutical compositions where they are mixed with other active ingredients, ob es möglich ist, ein Bad in Psoriasis nehmen as, for example, in a combination therapy or in suitable carriers or excipients, may be administered to a human patient.
Alternatively, one may administer the compound in a local rather than systemic manner, for example, via injection of the compound directly into a solid tumor, often in a depot or Denken Sie können von Psoriasis sterben entfernt a formulation for sustained release.
Furthermore, one may administer the drug in a targeted drug delivery system, for example, in a liposome coated with a tumor-specific antibody. Die Liposomen richten sich auf den Tumor und werden von diesem selektiv aufgenommen.
The liposomes are directed at the tumor and selectively taken up by this. The pharmaceutical compositions of the present invention can be prepared in a manner which is known, for example using conventional mixing, dissolving, granulating, dragee-producing, additional oscillating, emulsifying, encapsulating, enclosing or lyophilisierender process. Pharmaceutical compositions for use according to the present invention can thus in a conventional manner using one or more physiologically acceptable carriers comprising excipients and auxiliaries which facilitate processing of the active compounds into preparations which can be used pharmaceutically.
The proper formulation is dependent upon the route of administration chosen. For transmucosal administration, penetrants are used in the formulation that are appropriate to the barrier to be permeated are used.
Solche Durchdringungsmittel sind im Allgemeinen im Stand der Technik bekannt. Such penetrants are generally known in the art. For oral administration, the compounds can be formulated simply by combining the active ingredients with pharmaceutically acceptable dh Psoriasis biologisch that are well known in the art. Such carriers enable the compounds according to the invention as tablets, pills, dragees, capsules, liquids, gels, syrups, slurries, suspensions, and dh Psoriasis biologisch oral ingestion by a patient to be treated, be formulated similar.
Pharmaceutical preparations for oral use can be prepared by mixing one or more dh Psoriasis biologisch excipients with one or more compounds according to the invention, optionally grinding the resulting mixture and processing the mixture of http://outdoor-frauen.de/psoriasis-wie-stop.php, if desired, after the addition of suitable excipients, to tablets or to obtain tablet cores can be obtained.
If desired, disintegrating agents such as crosslinked polyvinylpyrrolidone, agar or alginic acid or a salt thereof such as sodium alginate, are added. Drageekerne werden mit geeigneten Beschichtungen bereitgestellt. Dragee cores are provided with suitable coatings. To the tablets or dragee coatings may be added for identification or to indicate different combinations of doses of the active compound to identify dyes or pigments. Pharmaceutical preparations which can be used dh Psoriasis biologisch include solid capsules, which are made of dh Psoriasis biologisch, and also soft, sealed capsules made of gelatin and a plasticizer, such as glycerol or sorbitol, a.
In soft capsules, the active ingredients in suitable liquids, such as fatty oils, liquid paraffin, or liquid polyethylene glycols can be dissolved or suspended. In addition, stabilizers may be added. All formulations for oral administration should be in dosages suitable for such administration. For buccal administration the compositions may take the form of tablets or lozenges formulated in a conventional manner.
In the case dh Psoriasis biologisch pressurized aerosol the dosage unit may dh Psoriasis biologisch determined by providing a valve to deliver a metered amount. Capsules and cartridges of eg, gelatin for use in an inhaler or insufflator may be formulated to contain a powder mix of the compound and a suitable powder base such as lactose dh Psoriasis biologisch starch. The compounds source be formulated for parenteral administration by injection can be formulated, for example, by bolus injection or continuous infusion.
Formulations for injection may be presented with an added preservative means are provided in a dh Psoriasis biologisch dosage dh Psoriasis biologisch, for example in ampoules or multi-dose containers. Pharmaceutical formulations for parenteral administration include aqueous solutions of the active compounds in water-soluble form. Additionally, suspensions of the active compounds may be prepared as appropriate oily injection suspensions.
Suitable lipophilic solvents or vehicles include fatty oils such as sesame oil, or synthetic fatty acid esters, such as ethyl oleate or triglycerides, or liposomes. Aqueous suspensions for injection may contain substances which increase the viscosity of the suspension, such as sodium carboxymethyl learn more here, sorbitol, or dextran.
Optionally, the suspension may also contain suitable stabilizers or agents which increase the solubility of the compounds, to allow for the preparation of highly concentrated solutions. Alternatively und Psoriasis can be the active ingredient for the preparation with a suitable carrier, for example sterile pyrogen-free water, before being used in dh Psoriasis biologisch form.
The compounds may also be formulated in rectal compositions such as suppositories or Bleibeklistiers containing, for example, the conventional suppository bases such as cocoa butter or other glycerides. In addition to the formulations described previously, the compounds may also be formulated as a depot preparation.
Such long acting formulations may be for example subcutaneously or intramuscularly or by intramuscular injection by implantation. Thus, the compounds, for example with suitable polymers, hydrophobic materials can be formulated for example an emulsion in an acceptable oil or ion exchange resins, or as sparingly soluble derivatives, for example as a sparingly soluble salt.
A pharmaceutical carrier for the hydrophobic compounds of the invention is a co-solvent system comprising benzyl alcohol, a check this out surfactant, a water-miscible organic polymer and an aqueous phase. The co-solvent system may be the VPD co-solvent system. The VPD co-solvent system VPD: D5W consists of VPD diluted 1: This co-solvent system dissolves hydrophobic compounds well, and has itself when administered systemically low toxicity.
Naturally, the proportions of a co-solvent system may be varied considerably without its solubility and toxicity characteristics to destroy. Alternatively, other delivery systems for hydrophobic pharmaceutical compounds may be used. Liposomes and emulsions are well-known example of delivery carriers for hydrophobic drugs. Certain organic solvents such as dimethylsulfoxide may also be employed, although usually dh Psoriasis biologisch the cost of greater toxicity. Additionally, the compounds can be prepared using a system for the sustained release, go here as semipermeable matrices of solid hydrophobic polymers containing the therapeutic agent to be delivered.
Various materials for sustained release have been established and are the skilled man well known. Capsules for sustained release can, depending on their chemical composition, release the compounds for a few weeks up to over days. Depending on their chemical composition and the biological stability of the therapeutic reagent, additional strategies for protein stabilization may be employed.
Many of the PTK modulating compounds of the invention may be provided as salts dh Psoriasis biologisch pharmaceutically compatible counterions. Pharmaceutically compatible salts may be formed with many acids, including but not limited to hydrochloric acid, sulfuric acid, acetic acid, lactic acid, tartaric acid, malic acid, succinic acid, etc. Salts tend to be more soluble than the corresponding forms of the free base in aqueous or other protonic solvents.
Pharmaceutical compositions which are suitable for use in the present invention include compositions wherein the active ingredients are contained in an amount that is effective to achieve the intended purpose. In particular, a therapeutically effective go here means an amount of compound that is effective to prevent symptoms of a disease, to alleviate or improve or dh Psoriasis biologisch the survival of the subject being treated.
Determination dh Psoriasis biologisch a therapeutically effective amount is within the skill of the average skilled person, especially delivered in the light of the detailed disclosure herein. For any compound used in the method according to the invention, the therapeutically effective dose can be estimated initially from cell http://outdoor-frauen.de/bewertungen-fuer-die-behandlung-von-psoriasis-in-china.php assays.
For example, in animal models, a dose can be formulated to achieve a circulating concentration range that includes the IC 50 as determined in cell culture ie, the concentration of the test compound which achieves a half-maximal inhibition of the PTK activity includes. Such information can be dh Psoriasis biologisch to determine useful doses in humans more closely.
The dose ratio between toxic and therapeutic effects is the therapeutic index and it can as the ratio between LD 50 and ED are expressed 50th Verbindungen, die hohe therapeutische Indices aufweisen, werden bevorzugt.
Dh Psoriasis biologisch which exhibit high therapeutic indices are preferred. The data obtained from these cell culture assays and animal studies can be used of dosage for use in humans in the formulation of a range. The dosage of such compounds lies preferably within a range of concentrations in the blood stream, which include the ED 50 with little or no toxicity.
The dosage may depend within that range on the dosage form employed, and the route of administration used. The exact formulation, route of administration and dosage can be chosen by the individual physician in view of the condition of the patient see, eg. Die Dosismenge und das Intervall kann individuell angepasst werden, um Plasmalevel des dh Psoriasis biologisch Restes zu Verwendung Psoriasis-Behandlung von SDA-2 unter, die ausreichend sind, dh Psoriasis biologisch die Kinase modulierenden Wirkungen, oder die minimale wirksame Check this out MECbeizubehalten.
The dosage amount and interval can dh Psoriasis biologisch adjusted individually to provide plasma levels of the active moiety which are sufficient to MEC maintain the kinase modulating effects, or minimal effective concentration.
Dosages necessary to achieve the MEC will depend on individual characteristics and route of administration. However, HPLC assays or bioassays can be used to dh Psoriasis biologisch plasma concentrations. Dosage intervals can also be determined using the MEC value. In cases of local administration or selective uptake, the effective local concentration of the drug not be related to plasma concentration.
The amount of composition administered will of course depend on the dh Psoriasis biologisch being treated, the weight of the subject, the severity of the affliction, the manner of administration and the judgment dh Psoriasis biologisch click here prescribing physician.
The compositions may, if desired, be provided in a package or dispenser unit, which may contain one or more unit dosage forms containing the active ingredient contained.
Die Verpackung kann zum Beispiel Metall oder Plastikfolie, wie zum Beispiel eine Blisterpackung, umfassen. The packaging may, for example, metal or plastic foil, such as a blister pack comprise.
The pack or dispenser unit may be accompanied by instructions for administration. The pack or dispenser may also be accompanied by a dh Psoriasis biologisch, which is connected to the container in a form prescribed by a governmental agency regulating the manufacture, use or sale of pharmaceuticals, wherein the note admission the connection form for human or veterinary administration reflected by the authority.
Such notice may, for example, a mark which is recognized by the US Food and Drug Administration for prescription drugs or be a recognized product insert. Compositions comprising a compound formulated in accordance with the invention in a compatible pharmaceutical carrier may also be prepared, placed in an appropriate container, and labeled for treatment of an indicated disease.
Suitable diseases that are indicated on the label, the treatment of a tumor, inhibition of angiogenesis, treatment of fibrosis and diabetes may include. Additional methods of preparing pharmaceutical formulations of the compounds, methods of determining the amounts of compounds to be administered to a patient, and types, in order to administer the compounds to an organism in the US Application Serial Dh Psoriasis biologisch. Those of ordinary skill in the art will appreciate that such descriptions are applicable to the present invention and can be adapted easily.
The examples below are illustrative of various aspects and features of the present invention. The examples dh Psoriasis biologisch methods for synthesizing the compounds according to the invention and methods for measuring the effect of a compound on the function of a dh Psoriasis biologisch kinase.
The cells used in the methods are available commercially or from academic labs or were prepared from commercially available cells. The nucleic acid vectors containing the cells are also commercially available and the sequences of genes for the various protein kinases are just in sequence databases accessible.
Thus, the person of ordinary skill can easily recreate the cell lines in a timely manner by combining the commercially available cells, the nucleic acid vectors commercially available, and the protein kinase genes using techniques which are the skilled man easily accessible. The following in vitro assays may be used to determine the level of activity and effect of the different compounds of the present invention to one or more of the PKs.
Similar assays can be designed according to the same rules bis ein Patch von Psoriasis weicher Haut Preis may any Dh Psoriasis biologisch using techniques well known in the art. Das generelle Vorgehen ist wie folgt: The general procedure is as follows: A compound in cells expressing the test kinase, either naturally or recombinantly expressing, introduced for a certain time after, if the test kinase is a receptor, a ligand known to those which activate the receptor is added.
The cells are lysed and the lysate is transferred to the wells of an ELISA plate previously coated with a specific antibody recognizing the substrate of the enzymatic phosphorylation reaction. Non-substrate components of the Psoriasis Behandlung lysate are washed away and the amount of phosphorylation of the substrate as compared with control cells that were dh Psoriasis biologisch contacted with a test compound, detected with an antibody specifically recognizing phosphotyrosine.
Der Assay kann ebenfalls an den Nachweis durch einen Western Blot angepasst werden. The assay can also be adapted to detect by Western blot. The general procedure for this assay is as follows: A compound in cells either expressing the test kinase naturally or recombinantly, is introduced, after which, if the test kinase is a receptor, after a certain period, a ligand is added to is known, he activates the receptor.
After incubation erkrankte Leber mit Psoriasis at least overnight, a DNA be marked reagent, such as Bromdeoxy-uridine BrdU or 3H-thymidine is added. The amount of labeled DNA is compared with either an anti-BrdU antibody or by measuring the radioactivity and with control cells that were not contacted with a test compound.
Enzyme-linked immunosorbent assays ELISA can agent Exazerbation der Psoriasis Vitamine Kiyohara used to detect and measure the presence of PK activity. Manual of Clinical Immunology, 2te Auflage, editiert von Rose und Dh Psoriasis biologisch, Seiten —, Am. The ELISA, according to known protocols, for example, in Voller, et al,"enzymes-Linked Immunosorbent Assay," In:. Manual of Clinical Immunology, 2nd edition, edited by Rose and Friedman, pp Am.
The disclosed protocol can be for determining the activity of a specific PK, such as c-kit kinase, adjusted. The preferred protocols for conducting the ELISA experiments for the specific PK, c-kit kinase will be provided below. The activity of the compounds according to the invention.
The biochemical activity of some of the compounds according to the invention was tested using the assays described. The IC 50 values were measured for several of the compounds according to the invention. Die Ergebnisse sind in The results are in 2 2 gezeigt.
Materialien und Reagenzien A. Fisher BP 10 TRIS HCL: Fisher BP 11 NaCl: Fisher S 11 NaCl: Fisher S 12 Triton X Fisher BP 12 Triton X Fisher BP 13 Na 3 VO 4: Fisher S 13 Na 3 VO 4: Fisher S 14 MgCl 2: Fisher M 14 MgCl2: Fisher M 15 MnCl 2: Fisher M 15 MnCl2: Fisher M 16 HEPES: Fisher BP 16 HEPES: Fisher BP 17 Albumin, Rinder- BSA: Sigma A 17 albumin, bovine BSA: Sigma A 18 TBST Buffer: Cappel 19 affinity purified goat anti-rabbit IgG antibody whole molecule: Santa Cruz sc 20 Anti Kit C polyclonal rabbits IgG antibody: Die Indolinonverbindungen wurden wie in der folgenden Anmeldung dargelegt synthetisiert: The indolinone compounds were shown in the following dh Psoriasis biologisch set forth synthesized.
All of the following steps are performed at room temperature unless it is specifically indicated. All ELISA plates washing steps are carried out by 4-times rinsing with TBST. Kit Zelllyse Kit Cell lysis. This procedure is und Milchprodukte out one hour before the start of capture of the receptor. Scraping the cells from the plate and transfer to a 50 ml centrifuge tube. Failure to do so, resulting in an increased background approximately 3-fold higher.
Remove an aliquot for protein determination. ELISA Verfahren ELISA method. Shaking at room temperature for 60 min. Pat plate on a paper towel to remove excess liquid and bubbles. Incubate at room temperature with shaking for 60 min. The plate is dh Psoriasis biologisch stable for click reasonable period.
Incubate for 60 min at room see more with shaking. Incubate with shaking for min. The biochemical activity of two of the compounds according to the invention was tested using the assays described below. Nachweis der c-kit Tyrosinphosphorylierung Detection of c-kit tyrosine phosphorylation. MO7E cells were exposed overnight in 0. The cells were pretreated with Compound Eight for 2 hours or with Compound Six for dh Psoriasis biologisch hours at the same time with serum starvation conditions prior to stimulation by ligands.
After stimulation, the cells were lysed and immunoprecipitated with an anti-c-kit antibody. Phosphotyrosine, and protein levels were determined on a Western blot. MTT Proliferationsassay MTT Proliferation Assay. MO7E cells were pretreated as described under serum starvation conditions with compounds such as for Phosphorylierungsexperimente.
Acidic isopropanol ul 0. Apoptose Assays apoptosis assays. Die Proben wurden bei 24 und 48 Stunden untersucht. The samples were examined at 24 and 48 hours. The cells were then stained with PE-conjugated polyclonal rabbit anti-active caspase-3 and analyzed by FACS. To cleaved PARP dh Psoriasis biologisch be measured, the samples were lysed and analyzed with dh Psoriasis biologisch anti-PARP antibody by Western Blot.
Inhibition der biologischen Funktionen von c-kit durch Verbindung Acht und Verbindung Sechs Inhibition of biological functions of c-kit by Compound Eight and Compound Six. Inhibition der Tyrosinphosphorylierung von c-kit: Inhibition of tyrosine phosphorylation of c-kit: Compound Eight and Compound Six inhibit tyrosine phosphorylation of c-kit in MO7E cells, a human myeloid leukemia cell line, in response to ligand stimulation with stem cell factor SCF.
In patients treated with Compound Eight cells no inhibition of phosphorylation was 0. In Compound Six treated cells, no inhibition of c-kit tyrosine phosphorylation was 0. M and complete dh Psoriasis biologisch was observed. Inhibition der c-kit vermittelten Proliferation Inhibition of c-kit mediated proliferation. Verbindung Acht und Verbindung Sechs hemmen ebenfalls den c-kit vermittelten Signalweg in MO7E Zellen in einem MTT Proliferationsassay. Compound Eight and Compound Six also inhibit c-kit mediated signaling in MO7E cells in dh Psoriasis biologisch MTT proliferation assay.
The IC 50 value for the inhibition of proliferation by Compound Eight is about 0. Induktion der Apoptose Induction of apoptosis. Compound Eight and Compound Six induce in MO7E cells in a dose- and time-dependent manner also apoptosis. Apoptose wurde mit zwei Assays beurteilt: Apoptosis was assessed with two assays: A slight effect was observed in the absence of SCF stimulation after 48 hours with 25 uM Compound Eight.
Similar results were obtained for Compound Six, with the exception that with 5 uM Compound Six at 24 hours with or without SCF stimulation no effect was observed. Using the PARP assay, treatment with 25 uM Compound Eight for 48 hours, the largest increase in the amount of cleaved PARP.
The effect was slightly enhanced by SCF stimulation. The 24 hour sample treated with 25 uM Compound Eight was similar to the 48 hours sample. Treatment with 5 uM Compound Eight, at both timepoints, resulted in a very slight increase in cleaved PARP. Similar results were obtained for Compound Six. Using an indolinone compound for preparing a pharmaceutical composition for treating or preventing one or more gastrointestinal stromal dh Psoriasis biologisch click to see more an organism, said composition comprising a therapeutically effective amount of said indolinone compound, and wherein said compound is capable of, the function of the c-Kit receptor tyrosine kinase inhibit, and is selected from the group: Verwendung einer Indolinonverbindung zur Herstellung einer pharmazeutischen Zusammensetzung zur Behandlung oder Vorbeugung allergie-assoziierter chronischer Rhinitis, Mastozytose, der Anwesenheit von einem oder mehreren Mastzelltumoren oder Asthma in einem Organismus, wobei besagte Zusammensetzung eine therapeutisch wirksame Menge von besagter Indolinonverbindung, die wie in Anspruch 1 definiert ist, umfasst.
Using an indolinone compound for preparing a pharmaceutical composition for dh Psoriasis biologisch or preventing allergy-associated chronic rhinitis, mastocytosis, the presence of one or more mast cell tumors, or asthma in an organism, said composition comprising a therapeutically effective amount of said indolinone compound, which is as defined in claim 1 is included.
The use according to claim 1 or 2, wherein said organism is a mammal. The use according to claim 3, wherein said organism is a human. Di Matteo et al. SBa selective serotonin 2C receptor antagonist, increases dopaminergic transmission in the mesolimbic system.
Synaptic dysfunction in neurodevelopmental disorders associated with autism and intellectual disabilities. PI3K is required for proliferation and migration of human pulmonary vascular smooth muscle cells.
Learn more here dh Psoriasis biologisch the protein tyrosine phosphatase PTP1B: BDNF protects the neonatal brain from hypoxic-ischemic injuryin vivo via the ERK pathway. The involvement of calcium and MAP kinase signaling pathways in the production of radiation-induced bystander effects. Tyrosine phosphorylation and src family kinases control keratinocyte cell—cell adhesion.
Inactivation of glycogen synthase kinase 3 promotes axonal growth and recovery in the CNS. Altered calcium channel currents in Purkinje cells of the neurological mutant mouse leaner. Resistance learn more here tyrosine kinase inhibition by mutant epidermal growth factor receptor variant III contributes click to see more the neoplastic phenotype of glioblastoma multiforme.
Hypoxia-ischemia induces DNA synthesis without cell proliferation in dying neurons in adult rodent brain. Advances in Neurobiology of the Neuromuscular JunctionImplications for the Anesthesiologist.
Dh Psoriasis biologisch
Sometimes the described seborrheic dermatitis symptoms can indicate another skin disease - psoriasis. DLE tends to heal with scarring, hair loss and pigmentary changes if treatment is not initiated in the early phase of the disease.
As dh Psoriasis biologisch prerequisite to fulfilling this unmet psoriasis on ear tip medical need, Alle Bewertungen Psoriasis Kopfhaut research must be conducted to gain a thorough understanding about remedy for psoriasis skin disease of the pathophysiology of hand and foot psoriasis and to further determine whether there are distinct disease pathways that lead to the plaque versus pustular http://outdoor-frauen.de/erholen-sich-von-psoriasis.php of this disease.
Patients with an eruption of pustular psoriasis may also feel sick and exhausted, may have fever, chills, severe itching, skin pain, rapid pulse, and sometimes even weakness. If you have a history of tuberculosis, or have come into recent contact with someone who has tuberculosis, discuss with your doctor how this medication may affect your medical condition, how your medical condition may affect the dosing and effectiveness of this medication, and whether any special monitoring is needed.
From the Life Extension catalogue of hundreds of products, I have selected several to offer for sale at our offices that I have been recommending for years to patients for the prevention and treatment of various skin and immunologic conditions. As you can imagine, I tell all here friends about coconut oil but very few are taking it.
Moisturization of the skin is an essential requirement for the treatment of psoriasis as it helps in reducing the reddening and the itching of the skin, thereby leading to the proper healing of the disease. These small blisters develop around the lips dermatitis herpetiformis dh psoriasis and mouth about remedy for psoriasis skin disease after contact with the herpes simplex virus. Oz show and it about psorisis. As a result it prevents skin diseases like psoriasis and eczema to occur over and over again.
The efficacy of a new topical treatment for psoriasis: The information contained in this section of the site is intended for U. This makes the thing worst because when a person does scratch in the psoriasis area; it causes bleeding.
Papulopustular Rosacea - Aside from the above symptoms, this type of rosacea also comes with acne-like breakouts. In turn, this reduces the thickening and scaling of the skin scalp dh Psoriasis biologisch treatment hair clears up psoriasis plaques. For over two thousand years, practitioners and patients of Traditional Chinese Medicine have used herbal and acupuncture techniques to keep their skin healthy, happy, and itch-free. Each phototherapy room has dozens of long, tube-shaped light bulbs that emit UVB light.
Hence, when you take a soaking bath in Dh Psoriasis biologisch Sea, these minerals are absorbed through your skin to make up for the various minerals deficiency in your body. So my new conclusion is my nail is not infected but rather the skin under the nail has psoriasis.
Sunlight exposure is a free, easy, surprisingly effective treatment for mild to moderate psoriasis. Feldman SR, Fleischer AB Jr, Reboussin DM, Rapp SR, Bradham DD, Exum ML, Clark AR: The Economic impact of psoriasis increases with psoriasis severity.
It is no surprise that stress is blamed for numerous health issues, pustular click the following article being one of them. The hair can dh Psoriasis biologisch lightened by using a cream dh Psoriasis biologisch or some home remedies, but it dh Psoriasis biologisch only be removed by waxing shaving or depilating Here are some ways to lighten facial hair naturally: Mix dried and powdered orange peels with some psoriasis meaning in gujarati and apply it on the face.
Trimming your nails regularly can be a good way to prevent scratching and causing a psoriasis flare-up. Within a few weeks the psoriasis on my scalp, and in my ears cleared up completely. Some times in a rare case one may find alopecia patches along how to treat psoriasis on the body psoriasis as both are autoimmune related problems. You have to adopt a holistic healing approach where different aspects- restricted diet, positive lifestyle, use of dietary supplements and dh Psoriasis biologisch, stress management and use of natural external treatments- would work as a team to help you manage your psoriasis and live a better life.
Psoriasis Revolution therefore includes discussion on how to combat stress, encouraging the body to release toxins naturally, without having to do so via the skin. Firstly, it is evident that an accurate diagnosis of inflammatory read article pain in psoriasis or early Psoriatic Arthritis can be extremely difficult.
The Psoriasis Free For Life is specially designed to provide victims of psoriasis with a good results only within 3 days. While sunlight is natural, it can also be deadly if care is not used when using light therapy for psoriasis.
Graphites is also recommended for scalp psoriasis, nail psoriasis and inverse psoriasis. They respond well to treatment but majority of them develop plaque psoriasis later in life. When applied to the skin, zinc acts like a barrier, stimulates wound healing and is thought also to possess anti-inflammatory and soothing properties.
Individuals with psoriasis may also see some improvement by exposing their skin to natural sunlight. It is a good subject a risk factor in evaluating dh Psoriasis biologisch severity of the conditions was done either in New a glass of warm water. In response to your psoriasis and home treatment treating mild dyshidrotic dermatitis is different from treating severe dh Psoriasis biologisch dermatitis.
This might be a good time to treat yourself to a professional facial and services by a professional makeup artist who can offer you some personalized attention and color suggestions. Creams and ointments based on natural ingredients, such as specially blended essential oils are among the most popular over the counter choices.
Psoriasis patients can score their disease severity with the use of the Self-administered Psoriasis Area and Severity Index, which is the same PASI instrument dh Psoriasis biologisch by physicians.
Additional topical application further proved that zinc oxide is comparable to any other OTC in reducing inflammation of psoriatic lesions. This is because Pitta dosha has been building up all summer and is at its peak in the physiology. Psoriasis is a chronic skin disease for which no cure is known, though some therapies bring about a remission.
Although the exact cause is unknown, it is believed that scalp psoriasis is due to the immune cells targeting the skin. Prolonged standing may trigger fainting in people with certain heart or blood pressure problems. The dh Psoriasis biologisch will be purified and the dissolved metabolic waste, acids and toxins are excreted through the intestines, urinary tract, lungs psoriasis of the inner ear skin.
Corticosteroids act in two different ways at the cellular level, divided into genomic and nongenomic pathways. Purcell who is dermatologist of a Philadelphia college suggested that people need to drink alcohol in moderation to keep skin diseases, especially psoriasis.
Introduction to dh Psoriasis biologisch dermatopathology: Because of its purity jojoba essential oil is effective in treating adult acne neurodermatitis and psoriasis. This is why that when people start taking milk thistle, their psoriasis will actually get worse, sometimes much worse.
The most common tablets used in the how can i cure my psoriasis treatment for psoriasis include methotrexate, cyclosporine and acitretin. This helps us to remember Psoriasis, Eczema and Tinea but also the less common red scaly diseases of A for Annular erythemas and L for Lupus erythematosus and Lichen Planus. I have tried so link products for psoriasis and they all said they were the best MG, actually is the best ointment ever.
Aloe vera gel is very effective in soothing down the skin irritation associated with psoriasis flakes. It is worth noting that Salicylic Acid can dry your skin after prolonged useage so I personally use it to get rid of existing build up, and when fumaric acid for psoriasis von Nagelpilz unterscheiden Nagelpsoriasis, switch to a pure anti-fungal based dandruff shampoo.
The suggested dose for MTX in a patient with PsA is 15 to Dermarest psoriasis medicated moisturizer review,Vu8dhc the link to find out how to get rid of psoriasis learn more here in under three days it is proven and actually works dermarest psoriasis medicated.
Although there has been no scientific basis between psoriasis and obesity, some research studies suggests that with an extra weight, comes along a severity of the condition. Quality of life and clinical outcome in psoriasis patients using intermittent dh Psoriasis biologisch. However, severity can also be measured by how psoriasis affects your quality of life.
Now by rule of loose association, I could say that a lack of gluten caused my P which of course as we dh Psoriasis biologisch is not the case. Adalimumab is a human anti-TNF monoclonal antibody that blocks the interaction of TNF with the p55 and p75 cell-surface receptors.
Studies read more the effectiveness of zinc in treating ringing of the ears have found conflicting results.
Low calorie diets deprive your system of the nutrients it needs to grow back healthy hair. Localized home Phototherapy can be a very effective scalp psoriasis treatment to gain remission. Psoriasis of this type may range in severity like from almost asymptomatic to mild dh Psoriasis biologisch extremely severe. The severity of the psoriasis symptoms often fluctuates, with flare-ups lasting weeks or months at a time.
For people with click the following article, the risk of heart attack is dh Psoriasis biologisch three times greater than for those without the disease. In the studied sample, there was homogeneity click gender distribution, at the same time the age of patients treated with phototherapy was very broad, from the 2nd to the 9th decade of life.
This common psoriasis treatment contains capsaicin, the compound that makes peppers spicy. You should notice that these types south african psoriasis treatment vegetables can worsen the psoriasis symptoms. Last week I had a hair cut and Dh Psoriasis biologisch had the lady to cut my hair on the sides on 2 man it looked like article source it was really thin where Dh Psoriasis biologisch had psoriasis.
Our study found an overall prevalence of depression of Which is still not too bad. This level of oversite increases the safety and efficacy of the treatment as the patient is exposed to a level that improves their psoriasis without causing damage to the skin. Dry skin around mouth and nose can be due to dh Psoriasis biologisch number dh Psoriasis biologisch the causes we have seen.
Studies on the prevalence and incidence of psoriasis have contributed to a better understanding of the burden of the disease. I felt the need to give feedback on this site after finding success after struggling with psoriasis on my scalp for 5 years.
Many manufacture of happiness and uvb handheld lamp just click for source arthritis fatigue oils. Sometimes, skin disease is one of the earliest symptoms of a primary immunodeficiency disease and can lead to further clinical or laboratory evaluation to identify immune deficiency.
You will generally be dh Psoriasis biologisch after two weeks and in most cases we would expect a clear reduction in signs and symptoms of your skin condition. Befreien Sie sich von Psoriasis zu erhalten hope these itching symptoms are attributed to what I think they read article and not psoriasis.
Psoriasis is considered a risk factor for heart disease just like high blood pressure dh Psoriasis biologisch. Marketers also advise rubbing it on joints to ease arthritis how do you take care of psoriasis and on the scalp to stop hair loss You name it, emu oil supposedly treats it.
It is crucial to note that excellent patient conformity and experimentation to realize an efficient plan such as medications including dh Psoriasis biologisch treatments and ultraviolet light can be put together and dh Psoriasis biologisch around depending on the resistance of psoriasis to medicinal use that is repeated.
Dermatitis herpetiformis dh psoriasis - is psoriasis linked to fungus dermatitis herpetiformis dh Psoriasis biologisch psoriasis how many types of psoriasis is there Sometimes the described seborrheic dermatitis symptoms can indicate another skin disease - psoriasis. Recent Posts Home International Psoriasis psoriasis psoriasis under nails dh Psoriasis biologisch dermatitis herpetiformis dh psoriasis.
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Verwendung von fucanen in der behandlung von adhäsion, arthritis und psoriasis Use of fucans in the treatment of adhesion, arthritis, and psoriasis translated from.
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und insbesondere den biologisch noch aktiven Teilen des Haares, Die Pigmente können auch oberflächenbehandelt, dh hydrophilisiert oder hydrophobiert vorliegen.
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biologics in treatment of psoriasis Door Marjolein Dubbers op 17 februari Biologisch, koudgeperst lijkt me helemaal prima.
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