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Synergistic Combination (synergistic + combination)
Selected AbstractsSynergistic Combinations of Anticonvulsant Agents: What Is the Evidence from Animal Experiments?EPILEPSIA, Issue 3 2007Daniël M. Jonker Summary:,Purpose: Combination therapy is often used in the treatment of seizures refractory to monotherapy. At the same time, the pharmacodynamic mechanisms that determine the combined efficacy of antiepileptic drugs (AEDs) are unknown, and this prevents a rational use of these drug combinations. We critically evaluate the existing evidence for pharmacodynamic synergism between AEDs from preclinical studies in animal models of epilepsy to identify useful combinations of mechanisms and to determine whether study outcome depends on the various research methods that are in use. Methods: Published articles were included if the studies were placebo-controlled, in vivo, or ex vivo animal studies investigating marketed or experimental AEDs. The animal models that were used in these studies, the primary molecular targets of the tested drugs, and the methods of interpretation were recorded. The potential association of these factors with the study outcome (synergism: yes or no) was assessed through logistic regression analysis. Results: In total, 107 studies were identified, in which 536 interaction experiments were conducted. In 54% of these experiments, the possibility of a pharmacokinetic interaction was not investigated. The majority of studies were conducted in the maximal electroshock model, and other established models were the pentylenetetrazole model, amygdala kindling, and the DBA/2 model. By far the most widely used method for interpretation of the results was evaluation of the effect of a threshold dose of one agent on the median effective dose (ED50) of another agent. Experiments relying on this method found synergism significantly more often compared with experiments relying on other methods (p < 0.001). Furthermore, experiments including antagonists of the AMPA receptor were more likely to find synergism in comparison with all other experiments (p < 0.001). Conclusions: Intensive preclinical research into the effects of AED combinations has not led to an understanding of the pharmacodynamic properties of AED combinations. Specifically, the majority of the preclinical studies are not adequately designed to distinguish between additive, synergistic, and antagonistic interactions. Quantitative pharmacokinetic,pharmacodynamic studies of selectively acting AEDs in a battery of animal models are necessary for the development of truly synergistic drug combinations. [source] Fire and flame retardants for PVCJOURNAL OF VINYL & ADDITIVE TECHNOLOGY, Issue 3 2003A. William Coaker The flammability performance of PVC plays a significant role in its selection for many applications. Its relatively high chlorine content (56.8%) makes it more resistant to ignition and burning than most organic polymers. In the case of flexible PVC, the plasticizers that contribute flexibility in most instances detract from its resistance to fire. To meet specifications such as oxygen index, heat release, smoke evolution, or extent of burning in cable tests, flame-retardant (FR) and smoke-suppressant (SS) additives are often incorporated. Synergistic combinations of FR and SS additives help PVC formulations meet many stringent FR specifications cost effectively. [source] N-Palmitoyl-4-Hydroxy- L -Proline Palmityl Ester: A Pseudoceramide that Provides Efficient Skin Barrier Repair and ProtectionINTERNATIONAL JOURNAL OF COSMETIC SCIENCE, Issue 1 2006G. Vielhaber Ceramides are the main constituents of the epidermal permeability barrier, and it has been demonstrated that the application of ceramide enriched creams promotes epidermal barrier repair. However, nature-identical ceramides are extremely expensive and difficult to formulate. We therefore developed a new pseudoceramide, N-palmitoyl-4-hydroxy- l -proline palmityl ester (BIO391). Due to its low melting point of £60°C the pseudoceramide BIO391 can easily be incorporated into cosmetic formulations. In addition, it is very safe for use in cosmetics. The efficacy of the pseudoceramide BIO391 was investigated in vivo in a model for detergent-induced barrier disruption. Trans-epidermal water loss, redness, and skin hydration were recorded before and after barrier disruption as well as during the subsequent 9-day treatment with the test products. Barrier repair of skin treated with the pseudoceramide BIO391 was accomplished earlier than that of untreated and vehicle treated skin. Optimum barrier repair was achieved with 1.0% pseudoceramide BIO391 and optimum erythema reduction with 0.5% pseudoceramide BIO391. The optimum dosage could be reduced to 0.1% pseudo-ceramide by synergistic combination with 0.1% (-)-a-bisabolol. In addition, the pseudoceramide BIO391 proved to be as effective as nature-identical ceramides 2 and 3. In summary, N-palmitoyl-4-hydroxy- l -proline palmityl ester is a highly efficient barrier repair agent with efficacy equivalent to that of nature-identical ceramides, and it has excellent formulation properties. [source] Molecular imaging in small animals,roles for micro-CTJOURNAL OF CELLULAR BIOCHEMISTRY, Issue S39 2002Erik L. Ritman Abstract X-ray micro-CT is currently used primarily to generate 3D images of micro-architecture (and the function that can be deduced from it) and the regional distribution of administered radiopaque indicators, within intact rodent organs or biopsies from large animals and humans. Current use of X-ray micro-CT can be extended in three ways to increase the quantitative imaging of molecular transport and accumulation within such specimens. (1) By use of heavy elements, other than the usual iodine, attached to molecules of interest or to surrogates for those molecules. The accumulation of the indicator in the physiological compartments, and the transport to and from such compartments, can be quantitated from the imaged spatial distribution of these contrast agents. (2) The high spatial resolution of conventional X-ray attenuation-based CT images can be used to improve the quantitative nature of radionuclide-based tomographic images (SPECT & PET) by providing correction for attenuation of the emitted gamma rays and the accurate delineation of physiological spaces known to selectively accumulate those indicators. Similarly, other imaging modalities which also localize functions in 2D images (such as histological sections subsequently obtained from the same specimen), can provide a synergistic combination with CT-based 3D microstructure. (3) By increasing the sensitivity and specificity of X-ray CT image contrast by use of methods such as: K-edge subtraction imaging, X-ray fluorescence imaging, imaging of the various types of scattered X-ray and the consequences of the change in the speed of X-rays through different tissues, such as refraction and phase shift. These other methods of X-ray imaging can increase contrast by more than an order of magnitude over that due to conventionally-used attenuation of X-ray. To fully exploit their potentials, much development of radiopaque indicators, scanner hardware and image reconstruction and analysis software will be needed. J. Cell. Biochem. Suppl. 39: 116,124, 2002. © 2002 Wiley-Liss, Inc. [source] Thermosensitive and Dissolution Properties in Nanocomposite Polymer HydrogelsMACROMOLECULAR RAPID COMMUNICATIONS, Issue 17 2009Chia-Jung Wu Abstract We investigate the phase transition behavior and dissolution resistant properties of thermo-sensitive nanocomposite hydrogels made from PEO-PPO-PEO triblock copolymer (Pluronic F127) and Laponite silicate nanoparticles. The rapid dissolution properties of F127 copolymer hydrogels usually limit their use as sustained release drug carriers. We overcome this limitation by synergistic combination of nanoparticle gelation characteristics with polymer thermo-sensitivity. We present a proof of concept that the temperature-dependent phase transitions can be shifted as a function of hydrogel composition and that the dissolution of the polymer hydrogels as well as the release of a model drug, albumin, can be significantly slowed down by addition of nanoparticles. The dissolution resistant properties generated will prove useful in the future formulation, processing and application of our polymer hydrogels for sustained release drug delivery carriers. [source] Synergistic interaction between trifluorothymidine and docetaxel is sequence dependentCANCER SCIENCE, Issue 11 2008I.V. Bijnsdorp Docetaxel is a microtubule inhibitor that has actions in the S and G2,M phase of the cell cycle. The pyrimidine trifluorothymidine (TFT) induces DNA damage and an arrest in the G2,M phase. TFT, as part of TAS-102, has been clinically evaluated as an oral chemotherapeutic agent in colon and gastric cancer. The aim of the present study was to determine the optimal administration sequence of TFT and docetaxel and to investigate the underlying mechanism of cytotoxicity. Drug interactions were examined by sulforhodamine B assays and subsequent combination index analyses, and for long-term effects the clonogenic assay was used. A preincubation with docetaxel was synergistic in sulforhodamine B (combination index 0.6,0.8) and clonogenic assays, and was accompanied by a time-dependent cell death induction (17,36%), the occurrence of polynucleation (22%), and mitotic spindle inhibition as determined by flow cytometry and immunostaining. Interestingly, administration of TFT followed by the combination displayed strong antagonistic activity, and was accompanied by less polynucleation and cell death induction than the synergistic combinations. Western blotting showed that the G2,M-phase arrest (25,50%) was accompanied by phosphorylation of Chk2 and dephosphorylation of cdc25c in the synergistic combinations. Together, this indicates that synergistic activity requires docetaxel to initiate mitotic failure prior to the activation of TFT damage signaling, whereas antagonism is a result of TFT cell cycle-arrested cells being less susceptible to docetaxel. Caspase 3 activation was low after docetaxel, suggestive of caspase-independent mechanisms of cell death. Taken together, our models indicate that combination treatment with docetaxel and TFT displays strong synergy when docetaxel is given first, thus providing clues for possible clinical studies. (Cancer Sci 2008; 99: 2302,2308) [source] | |||||||||||||