Arzneimittel-Forschung/Drug Research

To survey all bedside-prepared analgesic infusions (two or more drugs within one vehicle) at a 1000-bed general hospital. To evaluate appropriate vehicles and acceptable drug combinations in analgesic infusions with regard to evidence-based therapy. Literature review; computer simulation of pharmacokinetics with MATLAB 6.5; evaluation of pharmacokinetic or pharmacodynamic interactions and dose regimens. Categorisation of 19 infusion combinations used for the management of pain into acceptable and questionable combinations of components in terms of quality assurance evaluation. Diclofenac sodium (CAS 15307-79-6), metamizole sodium (CAS 68-89-3) and tramadol hydrochloride (CAS 36282-47-0) were combined with diazepam (CAS 439-14-5), B-vitamins (CAS 67-03-8, 130-40-5, 58-56-0, 68-19-9, 98-92-0, 137-08-6), lidocaine hydrochloride (CAS 73-78-9), metoclopramide dihydrochloride (CAS 54143-57-6) and pantoprazole sodium (CAS 138786 7-1). The vehicles were Ringer, Ringer lactate, normal saline or an infusion product containing diclofenac sodium and orphenadrine citrate (CAS 4682-36-4). In 37% the vehicle used was not one recommended by the manufacturer or an incompatibility was mentioned in the product information. The combinations of diclofenac sodium or tramadol with diazepam induce a long-lasting sedative effect by diazepam and its metabolite, but only a moderate duration of analgesia. The combination of diclofenac sodium and metamizole sodium is acceptable, although, at a lower dosage of metamizole, the duration of analgesia is shortened. No or insufficient data on therapeutic plasma levels and safe dosages has been reported for lidocaine and B-vitamins. For all of the drug combinations in use, no interactions of clinical relevance are to be expected. In 37% of the nineteen bedside-prepared infusions, the vehicle was not suitable or incompatibilities were cited in the product information. The combinations of metamizole sodium and diclofenac sodium or tramadol in normal saline solution were in accordance with evidence-based medicine. However, changing some infusion regimens might achieve optimisation of pain treatment with respect to duration of analgesia, and the applied number of drugs could be reduced by omitting additives with little clinical effectiveness.

Nemec Karin

Cihal Petra

Timin Evgeny

Kamyar Majid

Lemmens-Gruber Rosa

Arzneimittelforschung

Evidence-based intravenous pain treatment with analgesic infusion regimens

基于证据的静脉镇痛治疗与镇痛输注方案

Hans-Harald Sonnenhang

Frontmatter

前言

A series of phthalazinedione bearing substituted oxadiazole moiety derivatives X(1-7) were synthesized in good yield and evaluated for their possible anticonvulsant activity. The structures of the synthesized compounds were confirmed on the basis of their spectral data and elemental analysis. Their anticonvulsant activities were evaluated by the maximal electroshock induced seizure (MES) and subcutaneous pentylenetetrazole (PTZ) tests. All the tested compounds showed considerable anticonvulsant activities in at least one of the anticonvulsant tests. Moreover, some of the tested compounds exhibited moderate anticonvulsant activities in both MES and PTZ tests. From these results,[3-)2-Alkoxycarbonylmethylthioxadiozol-5-yl)methyl -6-Iodophthalazine - 1,4- (2H,3H)-1,4-dion] (X1-7) derivatives could be recommended as novel structures of broad spectrum anticonvulsants.

M. Zayed

R. Ayyad

Some Novel Anticonvulsant Agents Derived from Phthalazinedione

一些来自邻苯二甲酰二酮的新型抗惊厥药物

G protein-coupled receptor 119 (GPCR 119 (GPR119)) agonists have received considerable attention as a promising therapeutic option for treatment of type 2 diabetes mellitus. GPR119 is one of the GPCRs expressed in pancreatic islet β-cells and its activation enhances stimulation of insulin secretion in a glucose-dependent manner. We have recently described a series of 6-amino-1H-indan-1-ones as potent, selective, and orally bioavailable GPR119 agonists with an amino group that plays important roles not only in their drug-like properties, such as high aqueous solubility, but also in their potent agonistic activity. However, many of these compounds displayed strong to moderate inhibition of human ether-à-go-go related gene channel. Attenuation of the basicity of the amino group by replacing the adjacent benzene ring with electron-deficient heteroaromatic rings provided several heterocyclic cores among which 6-aminofuro[3,2–c]pyridin-3(2H)-one was selected as a promising scaffold. Further optimization around the side chain moiety led to the discovery of 17i, which showed not only strong human GPR119 agonistic activity (EC50=14 nM), but also beneficial effects on gastric emptying and plasma total glucagon-like peptide-1 levels in mice.

M. Sakairi

M. Kogami

M. Torii

Y. Kuno

Y. Ohsawa

M. Makino

D. Kataoka

R. Okamoto

T. Miyazawa

M. Inoue

N. Takahashi

S. Harada

N. Watanabe

Synthesis and Biological Evaluation of a 6-Aminofuro[3,2–c]pyridin-3(2H)-one Series of GPR 119 Agonists

6-氨基呋喃[3,2-c]吡啶-3(2H)-酮系列GPR119激动剂的合成与生物学评价

VEGFR-2 tyrosine kinase inhibitors are currently receiving high interest in drug discovery process as anticancer agents. We have used virtual screening techniques in order to discover new scaffolds that can be used for developing new VEGFR-2 kinase inhibitors.Similarity ensemble approach was used to reduce the chemical space of ZINC database to select a subset of compounds. A validated structure-based pharmacophore was developed and adopted to screen the selected subset. Initial hits mapped to the pharmacophore were filtered using docking and scoring. Selected compounds were synthesized and biologically tested. Compound 9 showed very good cytotoxicity profile against the NCI 60 cancer cell lines, while compound 8 showed reasonable inhibition of VEGFR-2 tyrosine kinase.Stepwise virtual screening of databases such as ZINC may result in new scaffolds for developing VEGFR-2 kinase inhibitors.

M. Elsayed

M. El-Araby

R. Serya

K.A. Abouzid

Virtual Screening and Synthesis of New Chemical Scaffolds as VEGFR-2 Kinase Inhibitors

虚拟筛选与新化学骨架的合成作为VEGFR-2激酶抑制剂

Correction to: Wirksamkeit und Verträglichkeit eines pflanzlichen Arzneimittels mit Kapuzinerkressenkraut und Meerrettich bei akuter Sinusitis, akuter Bronchitis und akuter Blasenentzündung im Vergleich zu anderen Therapien unter den Bedingungen der täglichen PraxisArzneimittelforschung 2006; 56(03): 249-257DOI: 10.1055/s-0031-1296717

Karl-Heinz Goos

Uwe Albrecht

Berthold Schneider

Wirksamkeit und Verträglichkeit eines pflanzlichen Arzneimittels mit Kapuzinerkressenkraut und Meerrettich bei akuter Sinusitis, akuter Bronchitis und akuter Blasenentzündung im Vergleich zu anderen Therapien unter den Bedingungen der täglichen Praxis

植物药物毛蕊花和辣根治疗急性鼻窦炎、急性支气管炎和急性膀胱炎的疗效和耐受性在日常实践中与其他疗法的比较

Drei große Bereiche der Medizin erschließen sich der klinischen Immunintervention: die Tumorerkrankungen, die entzündlichen Erkrankungen inklusive der Autoimmunkrankheiten und die Transplantationsmedizin. Für das Paul-Martini-Symposium 2012 konnten herausragende Mediziner und Wissenschaftler in jedem dieser Bereiche gewonnen werden, die eine Bestandsaufnahme über neue immunstimulierende wie suppressive Therapien aus diesen 3 Fachgebieten vornehmen.

S. Endres

S. Meuer

P. Scriba

Klinische Immunintervention: aktuelle und künftige Ansätze

临床免疫干预：当前与未来方法

C-type lectin receptors (CLRs) that signal via the kinase Syk are an important class of pattern recognition receptors in the innate immune system. They recognize pathogen- and host-derived danger signals and drive several cellular responses, including phagocytosis, the production of reactive oxygen species (ROS), as well as altered gene expression. Best characterized is the role of CLR signaling in anti-fungal immunity, but accumulation evidence indicates additional essential functions for CLR activity in innate immunity against bacteria, viruses or parasites. Moreover, deregulated CLR signaling appears to contribute to inflammatory disease. Crucial for CLR-mediated inflammation and host defence are the engagement of NF-κB signaling pathway and inflammasome activation. NF-κB signaling by CLRs depends on the adapter protein Card9 that upon activation cooperates with Bcl10 and the paracaspase Malt1 to engage the canonical IKK pathway. This mechanism operates independent from CLR-induced ROS production and phagocytosis. Recent findings have indicated that PKCδ is the critical kinase which directly phosphorylates Card9 at Thr231 and which subsequently triggers the signal-induced association of Card9 with Bcl10 and Malt1 and the further recruitment of TAK1 for activation of the canonical NF-κB pathway. Moreover, Syk-mediated CLR signaling upon fungal recognition is crucial for IL-1β generation and is required for both proIL-1β synthesis and activation of the Nlrp3 inflammasome. While proIL-1β synthesis selectively requires the Card9 pathway, inflammasome activation by fungi involves ROS production and potassium efflux. Thus, there is cross talk between Syk-coupled CLRs and Nlrp3, at least in the context of fungal infection. In this symposium I will discuss recent insights into the molecular regulation of CLR-mediated inflammatory effector function and its potential role in human disease together with opportunities to therapeutically manipulate these pathways.

J. Ruland

C-type Lectin Receptors: Signaling and Therapeutic Opportunities

C型凝集素受体：信号传导与治疗机遇

Chronic inflammatory diseases fall into two categories: either "autoimmune" or "auto-inflammatory" [1]. Although nearly all autoimmune diseases have an inflammatory component, as in rheumatoid arthritis, in autoimmune diseases, the primary defect is the auto-reactive T-cell. The term "auto-inflammatory diseases" encompasses several local and systemic diseases due to monocyte dysfunction, each responsive to blocking interleukin-beta (IL-1β) or blocking the IL-1 receptor using the IL-1 receptor antagonist. The best example is Familial Mediterranean Fever since manifestations of this disease include fever, fatigue, painful inflamed serosal and synovial tissues, biochemical markers of systemic inflammation, and hematological responses of neutrophilia [2]. Other auto-inflammatory diseases are due to single amino acid mutations in the protein "cryopyrin" [3] and are called "cryopyrinopathies"; the same syndromes are also termed "cryopyrin associated periodic syndromes" (CAPS). Systemic inflammation can be lethal, and the best example is septic shock. However, septic shock represents exogenously induced inflammation or simply "exogenous inflammation." Although many laboratory studies use bacterial products to stimulate IL-1β production, in the clinical sense, auto-inflammation is the result of IL-1-induced IL-1 or IL-1 induction of other cytokines such as IL-17. Either IL-1α or IL-1β can be the driving component in auto-inflammation. For example, in patients with neonatal onset multi-inflammatory disease (NOMID) treatment with the IL-1 receptor antagonist anakinra drives down not only the manifestations of the disease but also gene expression for IL-1α, IL-1β, TNFα, IL-6 and caspase-1 [4]. The most compelling evidence for the importance of IL-1 in inflammation comes from persons born with a mutation in the gene that codes for the IL-1 receptor antagonist. The syndrome is called DIRA for deficiency of the IL-1 receptor antagonist [5], [6]. At birth, these patients develop lethal inflammation with massive numbers of neutrophils in the skin and high levels of IL-17.

C. Dinarello

Interleukin-1 and the Treatment of Auto-inflammatory Diseases

白细胞介素-1与自身炎症性疾病的治疗

Publication Information	Publisher: Editio Cantor Verlag GmbH，Publishing cycle: ，Journal Type: journal，Open Access Journals: No
Basic data	Year of publication: 1951，Proportion of original research papers: 0.00%，Self Citation Rate:N.A.， Gold OA Rate: 0.00%

Arzneimittel-Forschung/Drug Research

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Evidence-based intravenous pain treatment with analgesic infusion regimens

Frontmatter

Some Novel Anticonvulsant Agents Derived from Phthalazinedione

Synthesis and Biological Evaluation of a 6-Aminofuro[3,2–c]pyridin-3(2H)-one Series of GPR 119 Agonists

Virtual Screening and Synthesis of New Chemical Scaffolds as VEGFR-2 Kinase Inhibitors

Frontmatter

Wirksamkeit und Verträglichkeit eines pflanzlichen Arzneimittels mit Kapuzinerkressenkraut und Meerrettich bei akuter Sinusitis, akuter Bronchitis und akuter Blasenentzündung im Vergleich zu anderen Therapien unter den Bedingungen der täglichen Praxis

Klinische Immunintervention: aktuelle und künftige Ansätze

C-type Lectin Receptors: Signaling and Therapeutic Opportunities

Interleukin-1 and the Treatment of Auto-inflammatory Diseases