Does Fluid Flow Across the Intestinal Mucosa Affect Quantitative Oral Drug Absorption? Is It Time for a Reevaluation?

Purpose. Hydrophilic and charged solutes have a lower membrane permeability which is due to a lower partition into the lipid membrane (low solubility in the membrane phase) and/or a slower transcellular diffusion coefficient. They are therefore anticipated to be absorbed through the paracellular route, which is a consequence of diffusion and a convective volume flow through the water-filled intercellular space. Methods. Two approaches have been used to investigate the mechanisms underlying the paracellular drug transport across the intestinal mucosa: (a) including water transport by exposing the apical side of the epithelium with a hypotonic solution, and (b) stimulated paracellular transport by widening of tight junction and increased water absorption as a consequence of the sodium-coupled transport of nutrients. Results. Among the first studies that recognized this fluid flux dependent transmucosal transport of drugs, was one published by Oschenfahrt & Winne in 1973 and the one by Kitazawa et al. in 1975. During the last two decades the importance of this paracellular route for drug delivery have been explored in vitro and in situ. Conclusions. The limits concerning molecular weight, shape, ionization and the effect of physiological stimulants, such as luminal concentrations of nutrients, osmolality and motility, are currently under investigation. However, recently published in vivo human data by ourselves and others indicate that the promising results obtained in vitro and in situ for various hydrophilic compounds might not be valid in quantitative aspects in humans, especially not for drugs with a molecular weight over 200.     

Monitoring of skin response to sodium lauryl sulphate: clinical scores versus bioengineering methods

The present trial was designed to evaluate clinical scores (single observer) of sodium lauryl sulphate (SLS)-induced skin irritation in a group of subjects (n = 10) over a 10-day period along with various skin function parameters. In order to avoid significant variations due to secondary phenomena, the following parameters were recorded with non-invasive instruments in this order: skin capacitance (C1; arbitrary units; CM420 Corneometer), transepidermal water loss (TEWL; g/m2.h; Evaporimeter) and laser Doppler flowmetry (CBFV: cutaneous blood flow values; Periflux). All examinations were performed during winter on reclined relaxed subjects present for at least 10 min in a test room with controlled temperature and relative humidity (t degrees: 19.5-20.7 degrees C and RH: 47.3-60.3%). The analysis of differential data (delta = value at tx-value before test; 2-way ANOVA) was made on single parameters as a function of site (volar forearm versus neck) and time (from 24 h after 48-h occlusion with 5% SLS up to 10 days later). The profile of erythema scores over time differed between neck and forearm, but the delta CBFV readings with the laser Doppler instrument did not detect significant site-time interactions. Roughness (blind evaluation with palpating finger) and capacitance readings (delta C1) showed significant differences between sites, but the profile over time was similar in both locations. delta TEWL did not differ according to anatomical location. The reason for different erythema scores on neck and forearm might be related to inherent regional variation of optical properties of the skin or to a substantial contribution of SLS-induced roughness to the readings of erythema.(ABSTRACT TRUNCATED AT 250 WORDS)     

Water imbibition in the rat prostate during castration-induced regression

The present study was conducted to examine changes in water concentration in the ventral prostate of adult rats at different intervals following castration. The prostatic dry weight was obtained by drying the fresh prostate at 70 degrees C for at least 110 hr and the prostatic water content was calculated from its wet and dry weight. Under normal conditions, the prostatic water concentration ranges from 81.9 to 82.7% in uncastrated rats. The prostatic water concentration started to increase at 8 hr postcastration (83.1%) but this increase was not statistically significant. By 16 hr postcastration, the prostatic water concentration (83.8%) became significantly higher than that of the uncastrated animals. In rats of day 1 to day 10 postcastration, the prostate contained significantly more water (84.4%-84.7%) than those in uncastrated animals. By day 21 postcastration, the prostatic water concentration (81.5%) was not significantly different from that of uncastrated rats. Unlike the prostate, the skeletal muscle did not significantly change the water concentration following castration. The 51Cr-EDTA space in the prostate was not significantly different in rats before and after castration. These results indicate that water imbibition in the rat prostate is associated with an active period of prostatic regression and that the change in the 51Cr-EDTA space during prostatic regression is not the major cause of water imbibition in the tissue. Therefore, the present findings suggest that castration-induced water imbibition in the rat prostate is caused by an increase in the intracellular water space.     

Regulation of fluid intake in dogs following water deprivation

Whereas water loss in land living animals occurs continuously, water intake takes place discontinuously. At the normal operating set point of plasma osmolality, urine is more concentrated than plasma due to secretion of vasopressin. Thus animals operate around a state of mild dehydration. As water loss occurs, the severity of dehydration and thirst increase in intensity and at some point water intake occurs. Sufficient water is consumed to return plasma osmolality to the normal operating set point. Food intake and water balance are interdependent as food provides the osmoles which determine obligatory renal solute excretion. When dry food with the same osmotic content was substituted for canned food (water content 74%), dogs increased water intake from 24.2 +/- 4.3 to 62.2 +/- 8.8 ml/kg. Urine output and urine osmolality were unchanged, as under conditions of normal hydration, near maximal urine concentration is achieved. Changing water intake is the only available variable to maintain water balance. During water deprivation, the major renal mechanism appears to be natriuresis. In rehydration, satiety mechanisms ensure appropriate water intake and renal sodium conservation restores sodium balance.     

When poor solubility becomes an issue: From early stage to proof of concept

Drug absorption, sufficient and reproducible bioavailability and/or pharmacokinetic profile in humans are recognized today as one of the major challenges in oral delivery of new drug substances. The issue arose especially when drug discovery and medicinal chemistry moved from wet chemistry to combinatorial chemistry and high throughput screening in the mid-1990s. Taking into account the drug product development times of 8–12 years, the apparent R&D productivity gap as determined by the number of products in late stage clinical development today, is the result of the drug discovery and formulation development in the late 1990s, which were the early and enthusiastic times of the combinatorial chemistry and high throughput screening. In parallel to implementation of these new technologies, tremendous knowledge has been accumulated on biological factors like transporters, metabolizing enzymes and efflux systems as well as on the physicochemical characteristics of the drug substances like crystal structures and salt formation impacting oral bioavailability. Research tools and technologies have been, are and will be developed to assess the impact of these factors on drug absorption for the new chemical entities.

The conference focused specifically on the impact of compounds with poor solubility on analytical evaluation, prediction of oral absorption, substance selection, material and formulation strategies and development. The existing tools and technologies, their potential utilization throughout the drug development process and the directions for further research to overcome existing gaps and influence these drug characteristics were discussed in detail.     

我国城市地下水水质污染状况研究进展

综述了我国城市地下水水质污染状况的研究进展     

Combined treatment with a 5HT1A receptor agonist and a muscarinic acetylcholine receptor antagonist disrupts water maze navigation behavior

The present study was designed to investigate the effects of combined treatment with a serotonin (5-HT)_1A receptor agonist, 8-hydroxy-2-(dipropylamino)-tetralin (8-OH-DPAT), and a muscarinic acetylcholine receptor antagonist, scopolamine, on water maze (WM) navigation. Treatment with either 8-OH-DPAT or scopolamine before daily behavioral training disrupted spatial navigation at medium doses and cue navigation at high doses. Pretraining treatment with a combination of subthreshold doses of 8-OH-DPAT and scopolamine impaired WM spatial and cue navigation, but did not impair the WM performance if the drugs were injected post-training. In trained rats, combined injections of subthreshold doses of 8-OH-DPAT and scopolamine given pretraining did not impair the rats' ability to find the platform in a familiar or in a novel position. The combination of 8-OH-DPAT and scopolamine also disrupted WM navigation in rats with central 5-HT depletion. A combination of a peripheral muscarinic acetylcholine receptor antagonist and 8-OH-DPAT had no effect on WM navigation. These data suggest that combined treatment with drugs blocking muscarinic acetylcholine receptors and activating 5-HT_1A receptors greatly impairs WM learning/performance, but does not impair spatial memory per se.     

施地瑞玛生理性海水鼻腔喷雾器治疗小儿干燥性鼻炎的临床观察

目的:探讨施地瑞玛生理性海水鼻腔喷雾器治疗小儿干燥性鼻炎的疗效。方法:将58例患儿随机分成2组,2组均不使用其他药物。治疗组给予施地瑞玛生理性海水鼻腔喷雾器喷鼻;对照组给予生理性盐水滴鼻液滴鼻,观察2组治疗前后症状、体征及有效率。结果:根据2组的主要症状、体征及疗效,治疗组优于对照组(P<0.05)。结论:生理性海水鼻腔喷雾器治疗小儿干燥性鼻炎,可以缩短病程,改善鼻腔功能,疗效确切,且使用安全、舒适、方便,可以作为治疗小儿干燥性鼻炎的理想药物。     

Effect of water restrictions on the physiological parameters,psychological behavior and brain c-Fos expression in rat

1 Introduction Exposure to hostile stressors causes a series of coor- dinated responses in the body, such as alterations of neu- roendocrine secretion, immune reaction and behavioral manifestation to maintain homeostasis stability and sur-vival of the organisms. Stressors are divided into two main categories: physical, or systemic, and psychological, or emotional / processive. Each stressor might activate a spe- cific central pathway to induce a special neuroendocrine response, even cause stre…