Activator bypass experiments

Bufotenine has been found to be behaviorally inactive, or only weakly active, in most animal studies, although at 15 mg/kg, it did produce the head-twitch resonse in mice (43). It was also behaviorally active in experiments in which the blood-brain barrier was bypassed (78). Acylation of the polar hydroxy group of bufotenine increases its lipid solubility (65,74) and apparently enhances its ability to cross the blood-brain barrier (64). For example, O-acetylbufotenine (5-acetoxy-N,N-dimethyltryptamine 54) disrupted conditioned avoidance behavior in rodents (65) and produced tremorigenic activity similar to that elicited by DMT (37) or 5-OMeDMT (59) when administered to mice (64). In this latter study, a comparison of brain levels of bufotenine after administration of O-acetylbufotenine with those of DMT and 5-OMeDMT revealed bufotenine to be the most active of the three agents, based on brain concentration. The pivaloyl ester of bufotenine also appears to possess behavioral activity, since stimulus generalization was observed when this agent was administered to animals trained to discriminate 5-OMeDMT from saline (74). 

An additional general method to reduce bypass is through vacuum deaeration. Miller9 performed experiments on a low-density active blend with and without vacuum deaeration, while holding all other parameters constant, and quantified the bypass for each trial. With the vacuum deaeration engaged, the bypass rate was 2% as compared to the control rate of over 20%. He also observed that the powder feed was uneven and the compact quality was not uniform. Most units are equipped with this capability and it should be considered to minimize bypass for low-dose products. However, vacuum deaeration can cause potency loss, unless the collected material is recirculated to the feed system. 

Accordingly, some effort has been devoted to studying the effects of cisplatin on transcription. In vitro experiments with RNA polymerases demonstrated that productive elongation activity was prematurely terminated by the whole spectrum of cisplatin-DNA adducts, but not by the /ran.y-DDP 1,3-intrastrand adducts [150-152], Selective bypass of trans-DDP adducts was also demonstrated in XPA cells, suggesting that repair of the DNA lesions did not contribute to differential transcription inhibition by the platinum compounds [153], In vivo, hormone-induced chromatin remodeling and subsequent transcription from the MMTV promoter was specifically inhibited by cisplatin [154], In this case, platinum adducts seemed to cause a decrease in the DNA binding of one of the transcription factors, NF1. Several chromatin-associated proteins, such as the linker histone protein HI or... 

Recently, we established that 7-hydroxystaurosporine (UCN-01) is 100,000 fold more potent than caffeine at overcoming the G2 arrest, and dramatically enhances the cytotoxicity of cisplatin in Chinese hamster ovary cells at exactly the same concentrations that bypass the G2 checkpoint [41] [42]. UCN-01 also enhanced the activity of cisplatin in human cell lines, and furthermore, this occurred preferentially in cells with disrupted p53 function [43]. Toxicology experiments have shown that the required doses of UCN-01 are well tolerated in both mice and dogs [44]. Accordingly, UCN-01 would appear to have great potential to be used effectively in combination with cisplatin to enhance cell killing specifically in the tumor. The importance of this strategy for the current discussion is that it emphasizes the... 

As alluded to earlier, in a conventional gravimetric microbalance, it is not possible to determine the true space velocity since an undeterminable, but a large amount of the feed bypasses the catalyst bed. Therefore, the conversion observed in the exit gas cannot be related to the true activity of the catalyst. To demonstrate that the plug-flow-vibration microbalance has overcome this problem we have carried out an experiment in the microbalance and in a conventional fixed bed reactor using 0.3wt%Pt-0.3wt%Re/Al203 under the same conditions 210 kPa, 750 K, = 3 and liquid-weight-hourly space... 

Additional evidence for an alternative pathway for the production of L-fucose came from experiments in mouse lymphoma cell lines blocked in the conversion of GDP-D-[ H]-mannose to GDP-L-[ H]-fucose. Reitman et al. observed that the block could be bypassed by growing the cells in the presence of L-fucose [119]. That this short activation pathway may be a general salvage mechanism is also indicated by the fact that 6-deoxy-D-glucose derivatives could be incorporated into neomycin [71]. The existence of a short activation pathway was recently proven in our laboratories [120] by successful incorporation of l-[2, 3--H2]-rhodinose [121] into landomycin A (12). In this experiment, NMR spectroscopy of the product showed, that only the four protons of the two L-rhodinose moieties were labeled. In a control experiment, d-[2, 2, 3, 3- H4]-rhodinose [121] was fed and, as expected, no incorporation into 12 was observed [120] (Scheme 27). 

These act by a soothing effect mainly on the pharynx and larynx if the solid or liquid preparation is given orally, or on all the airways if it is a vapor. The patient should feel better and experiences the cough as less irritating or painful. The problem is that demulcent activity has never been measured. The only way to do it would be by subjective patient scores (How soothed do you feel ), and even these do not seem to have been used. In addition, a placebo action is difficult to eliminate indeed it seems inevitable in view of the relevant sensations aroused by the herb. To give the solid or liquid agents by capsule would bypass their site of action, and if given as a vapor an appropriate placebo would be hard to select. 

In another study, radiolabeled and fluorescent lipid nanocapsules were synthesized by using a phase inversion process that followed the formation of an o/w microemulsion containing triglycerides, lecithins, and a nonionic surfactant. Results of the experiment revealed that lipid nanocapsules were rapidly accumulated within cells through active and saturating mechanisms. Nanocapsules could bypass the endo-lysosomal compartment with only 10% of the cell-internalized fraction found in isolated lysosomes. When nanocapsules were loaded with paclitaxel, smallest lipid nano capsules (LNCs) also were found to trigger the best cell death activity. ... 

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