Animal studies permeability

Animal studies indicate that the pathogenesis of NSAID small intestinal toxicity involves multiple interactions dependent on enterohepatic circulation, epithelial permeability, neutrophil infiltration and bacterial infection [233]. Several investigations [234-238] have suggested that bacterial flora may play a role in the pathogenesis of NSAID bowel injury and Robert and Asano [239] did show more than 25 years ago that germ-free rats are resis-... 

N,N-Dialkyltryptamines bearing an alkyl substituent on the aromatic nucleus have not been evaluated in man, and only data from animal studies are available. Taborsky et al. (228) found 1-methylation to have variable effects on behavioral activity. This might reflect blood-brain barrier permeability. Methylation at the N1 position of DMT (37), to give 1, N,N-trimethyltryptamine (1-TMT), had... 

In rats exposed for an intermediate duration to an unknown concentration of airborne white phosphorus from the furnace room of a phosphorus factory, an increase in permeability of capillary walls, lesions in the walls of blood vessels, and evidence of impaired microcirculation were observed in the mouth (Ruzuddinov and Rys-Uly 1986). Severe damage to the oral mucosa was also observed in these animals. No information regarding effects on the heart was located in the animal studies. 

In addition to the generally higher permeability of rat skin to that of human skin, the critical factor which is specific for animal studies is that the dosing site must be protected from grooming behavior (leading to oral intake of the... 

Animal studies Table 2 shows solutes that have been used in animal studies. As with the clinical studies, the solutes used are ionized and have small MW, with one exception, insulin. Srinivasan et al. [27] showed that in controlled experiments without ethanol pretreatment of human epidermis, insulin showed no measurable flux however, with ethanol pretreatment, there was a significant increase in the permeability coefficients of insulin. 

PPD induces one of the most severe edema both in humans and animal studies. The edema appears to be grossly specific and selectively localized in the head and neck. It was suggested that the toxic effect of the PPD might be produced by the conversion of the PPD on mucus surfaces to its oxidation product quinondi-mine, which is responsible for intense local irritation [13]. Some authors believed that PPD toxicity is due to some effect either on the blood colloids or on vascular permeability [15]. Also it was believed that the PPD toxicity is due to altered vascular permeability and involvement of the parasympathetic nervous system [13]. Deamination and formation of analine is claimed to be responsible in part for the toxic symptoms [12]. These different views as to the cause of PPD edema appear to be due to the fact that the exact number and nature of the oxidation products is not known [14]. 

In this context, studies on transformants of LLC-PKi cells that expressed P-gp derived from human, monkey, canine, rat, and mouse impressively showed altered efflux activities and rankings depended on the species for substances such as clarithromycin, daunorubicin, digoxin, etoposide, paclitaxel, quinidine, ritonavir, saquinavir, verapamil, and vinblastine [76]. Subsequent experiments confirmed different inhibitory effects of verapamil and quinidine on the transport of daunorubicin, digoxin, and cyclosporin A across LLC-PKi cells with P-gp from different species [77]. These reports clearly pointed out that qualitative statements, whether a substance is a transporter substrate or not, are possible. But it was also underlined that one has to be really careful when applying permeability data of in vitro experiments or in vivo animal studies to human conditions. In general, the functional consequences of species variation may vary from compound to compound, and further studies are needed on this aspect [78]. 

When inadequate in vivo exposure or PK properties are observed, pharmaceutical profiles can be used to troubleshoot the cause of poor in vivo exposure or PK [26]. Assays for solubility, permeability, and stability (metabolic, plasma, acid) can help to track down the inadequate properties responsible for poor in vivo performance. Property optimization synthesis can then be initiated. Subsequent series analogs can be assayed to rank order compounds by properties for subsequent in vivo tests, in order to give the highest likelihood of success. Often animal studies are expensive and time-consuming, especially if they are performed using the animal activity model. Simple in vitro profiling assays can provide information for improved decisions and efficiency. 

Seventy-five percent of drug candidates do not reach the clinical trial phase mainly due to poor pharmacokinetics in animal studies (1). Since so many compounds fail in late stage testing, the current trend is to study the pharmacokinetics of lead compounds as early as possible. One of the most important elements of pharmacokinetics is lipophilicity, or a compound s affinity for fat. Usually, the more water soluble a compound is, the lower its lipophilicity. Low water solubility (high-lipophilicity) compounds have a limited oral bioavailability but are usually easily metabolized. On the other hand, low-lipophilicity compounds have poor membrane permeability since membranes are partly composed of fat. 

Various in vitro and in vivo methods have been used to predict drug absorption including Caco-2 cells, in situ intestinal permeability, whole-animal studies, and more recently chromatographic methods. Compared with in vivo absorption studies, evaluation of intestinal permeability in vitro requires less compound is relatively easy to study, often avoiding complicated surgery is rapid and can allow a wider variety of variables to be controlled. ... 

Ruboxistaurin (LY333531) mesylate is a synthetic compound with a specific inhibitory effect on the PKCP isoforms 1 and 2 in the pancreas and the retina. In animal studies, the compound has been shown to have a stabilizing effect on retinal perfusion, to reduce the permeability of retinal vessels, and to block the neovascular response in retinal vessels during retinal ischemia [5]. Ruboxistaurin is a pro-drug which is administered as tablets and is metabolized to the active compound in the liver. The compound has not been shown to have any appreciable adverse effects, but simultaneous use of... 

The panel of authors who wrote the interim report on dermal absorption (U.S. Environmental Protection Agency, 1992) reviewed several earher experimental studies comparing permeability coefficients of human and animal skin, especially the review by Bronaugh et al. (1982), which was discussed separately in this appendix. No new data were presented in this report. The opinion of this panel was that the numerical differences between human skin and animal skin permeability coefficients vary with the test compound. Thus, they concluded that it was not possible to find a constant factor for adjusting the permeabihty coefficient from a specified animal to reliably represent the permeabihty coefficient for human skin. Major conclusions of this report were that animal skins are generally more permeable than human skin, and that dermal absorption data from animals could be used as a conservative estimate of absorption in humans. 

The most prevalent use of microneedles is in the delivery of drugs. It has been shown that solid microneedles can increase skin permeability to a broad range of molecules and nanoparticles in vitro by up to four orders of magnitude [7]. In vivo animal studies have demrmstrated delivery of oligonucleotides and vaccines (Macroflux ), as well as induction of inunune responses from protein and DNA vaccines [8, 9]. The functionality of hollow microneedles has also been demonstrated, including fluid transport in vitro and microinjection of insulin in diabetic rats to induce reduction of blood glucose levels [10]. Microneedles have also been used to extract interstitial fluid from skin for glucose measurement [11]. 

Shlmamoto and Honjo concluded from animal studies that bromhexlne affects tracheobronchial secretions by an action on central nervous system structures, probably In the areas of the emetic center In the medulla oblongata occurring both as a direct effect and Indirectly via stimulation of the gastric mucous membrane. Other animal tests Indicated bronchial secretions were Increased by bromhexlne as a result of an Improved permeability ratio between the bronchial mucous membrane and Its blood supply. The lytic effect of bromhexlne on human bronchial mucosa, observed vitro by electron microscopy, appears due to Increased secretion... 

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