Search results for "RAPA"
showing 10 items of 471 documents
A DOTA based bisphosphonate with an albumin binding moiety for delayed body clearance for bone targeting
2016
Radiolabeled bisphosphonates are commonly used in the diagnosis and therapy of bone metastases. Blood clearance of bisphosphonates is usually fast and only 30%-50% of the injected activity is retained in the skeleton, while most of the activity is excreted by the urinary tract. A longer blood circulation may enhance accumulation of bisphosphonate compounds in bone metastases. Therefore, a chemically modified macrocyclic bisphosphonate derivative with an additional human albumin binding entity was synthesized and pharmacokinetics of its complex was evaluated. The DOTA-bisphosphonate conjugate BPAMD was compared against the novel DOTAGA-derived albumin-binding bisphosphonate DOTAGA(428-d-Lys)…
68Ga-BPAMD: PET-imaging of bone metastases with a generator based positron emitter
2012
Abstract Purpose Bone metastases are a serious aggravation for patients suffering from cancer. Therefore, early recognition of bone metastases is of great interest for further treatment of patients. Bisphosphonates are widely used for scintigraphy of bone lesions with 99m Tc. Using the 68 Ge/ 68 Ga generator together with a macroyclic bisphosphonate a comparable PET-tracer comes into focus. Procedures The bisphosphonate DOTA-conjugated ligand BPAMD was labelled with 68 Ga. [ 68 Ga]BPAMD was evaluated in vitro concerning binding to hydroxyapatite and stability. The tracer's in vivo accumulation was determined on healthy rats and bone metastases bearing animals by μ-PET. Results BPAMD was lab…
Calcium antagonist properties of cinnarizine, trifluoperazine and verapamil in guinea-pig normal and skinned trachealis muscle.
1990
In guinea-pig trachealis, depolarized by a K(+)-rich medium, Ca2+ (0.01-10 mM) caused concentration-related spasm. Verapamil (0.5-5 microM), cinnarizine (10-100 microM) and trifluoperazine (16-160 microM) each produced concentration-dependent antagonism of Ca2+ characterized by a rightward and downward displacement of the log concentration-effect curve for Ca2+. The rank order of potencies of these antagonists, measured as the IC75 against Ca2+ (10 mM)-induced contraction of depolarized trachea, was verapamil (5.6 microM) greater than cinnarizine (59 microM) greater than trifluoperazine (91 microM). In skinned trachea, verapamil in concentrations up to 100 microM did not modify the concentr…
Pretreatment with potent P-glycoprotein ligands may increase intestinal secretion in rats.
2001
The expression of P-glycoprotein is induced in cell cultures upon exposure to various inducers. Therefore, the aim of the present study was to evaluate the in-vivo relevance of this observation, i.e. the influence of chronic pretreatments with selected drugs -- all of which are ligands to P-glycoprotein (P-gp) as demonstrated in radioligand binding studies and all of which have some or a considerable effect on P-gp expression in Caco-2 cells -- on the effective intestinal permeabilities of the model compound talinolol in rats employing in-situ single-pass intestinal perfusion of three different gut segments. Talinolol was selected, because it shows high selectivity for one of the exsorptive…
Effects of Calcium Antagonists on Rat Normal and Skinned Fundus
1992
Abstract Calcium chloride (CaCl2) (0·1−25 Mm, in K+-depolarized tissue), KCl (10−112 Mm) and acetylcholine (1 × 10−9 m−1 Mm) produced concentration-dependent contractions of rat isolated fundus. Verapamil (0·01−100 μm), cinnarizine (1−100 μm), trifluoperazine (10−500 μm) and dantrolene (50−250 μm) each produced a concentration-related rightward and downward shift of the log concentration-effect curve for CaCl2. The rank order of potencies of these antagonists, measured as the IC50 against Ca2+ (25 Mm)-induced contraction of depolarized fundus, was verapamil (2.5 μm) > cinnarizine (8·7 μm) > trifluoperazine (85·1 μm) > dantrolene (> 250 μm). Cinnarizine (0·5 Mm) a…
EFFECTS OF D-600 AND ITS OPTICAL ISOMERS ON FORCE OF CONTRACTION IN CAT PAPILLARY MUSCLES AND GUINEA-PIG AURICLES
1977
Abstract 1 (--)-D-600 and (+)-D-600 exerted concentration-dependent negative inotropic effects in papillary muscles from cats, the potency of (--)-D-600 being about 100 times greater than that of (+)-D-600. The action was more pronounced at high than at low frequencies of stimulation. Time to peak force, relaxation time and therefore also total duration of contraction were not significantly affected by the drugs. 2 The negative inotropic effects of both drugs were not reversible after washing in drug-free solution for 60 min at all concentrations tested. 3 The same negative inotropic effects were seen in guinea-pig left auricles with the racemic mixture of both isomers. 4 Uptake measurement…
Acceleration of glutathione efflux and inhibition of gamma-glutamyltranspeptidase sensitize metastatic B16 melanoma cells to endothelium-induced cyto…
2005
Highly metastatic B16 melanoma (B16M)-F10 cells, as compared with the low metastatic B16M-F1 line, have higher GSH content and preferentially overexpress BCL-2. In addition to its anti-apoptotic properties, BCL-2 inhibits efflux of GSH from B16M-F10 cells and thereby may facilitate metastatic cell resistance against endothelium-induced oxidative/nitrosative stress. Thus, we investigated in B16M-F10 cells which molecular mechanisms channel GSH release and whether their modulation may influence metastatic activity. GSH efflux was abolished in multidrug resistance protein 1 knock-out (MRP-/-1) B16M-F10 transfected with the Bcl-2 gene or in MRP-/-1 B16M-F10 cells incubated with l-methionine, wh…
Human periodontal fibroblast response to a nanostructured hydroxyapatite bone replacement graft in vitro
2007
Abstract Objective The efficacy of nanostructured hydroxyapatite (NHA) for the treatment of osseous defects has been demonstrated in recent studies, even though the underlining biological mechanism is still poorly known. This study examined the alterations in cellular adhesion and mitogenic responses in human periodontal ligament (PDL) cells treated with a novel nanostructured hydroxyapatite bone graft substitute and characterized associated changes in cellular signalling pathways. Methods Cultured PDL cells were stimulated with NHA in a surface coated form. Proliferation was determined by bromodeoxyuridine (BrdU) incorporation and cell adhesion was analysed by a colorimetric assay. In orde…
Different mechanisms of the inhibition of the transient outward current in rat ventricular myocytes.
1994
The mechanism of drug-induced inhibition of the transient outward current, Ito, has been investigated in rat ventricular myocytes using the whole cell patch clamp technique. Ito was activated by 300 ms depolarizing voltage clamp steps in 10 mV increments from −50 mV up to +40 mV. At +40 mV, Ito peaked after about 3 ms, and the time course of inactivation was appropriately described by two time constants, τfast = 17 ms and τslow = 203 ms. Verapamil, quinidine sulfate and nifedipine preferentially depressed Ito at the end of the 300 ms depolarizing voltage clamp step; the inactivation of Ito was accelerated by all drugs, whereas peak Ito was less affected. The time course of drug action at +4…
Vorapaxar in the secondary prevention of atherothrombotic events
2012
BACKGROUND: Thrombin potently activates platelets through the protease-activated receptor PAR-1. Vorapaxar is a novel antiplatelet agent that selectively inhibits the cellular actions of thrombin through antagonism of PAR-1. METHODS: We randomly assigned 26,449 patients who had a history of myocardial infarction, ischemic stroke, or peripheral arterial disease to receive vorapaxar (2.5 mg daily) or matching placebo and followed them for a median of 30 months. The primary efficacy end point was the composite of death from cardiovascular causes, myocardial infarction, or stroke. After 2 years, the data and safety monitoring board recommended discontinuation of the study treatment in patients …