Comparison of the Permeability Characteristics of a Human Colonic Epithelial (Caco-2) Cell Line to Colon of Rabbit,Monkey, and Dog Intestine and Human Drug Absorption

The in vitro permeabilities of Caco-2 monolayers and permeabilities in tissue sections from colon of monkey, rabbit, and dog were compared using a series of compounds. The selected compounds differed in their physicochemical properties, such as octanol/water partition coefficient, water solubility, and molecular weight. Their structure included steroids, carboxylic acids, xanthins, alcohols, and polyethylene glycols. A linear permeability relationship was established between Caco-2 and colon tissue from both rabbit and monkey. The results suggest that Caco-2 is twice as permeable as rabbit and five times as permeable as monkey colon. However, no clear relationship could be established between Caco-2 monolayers and dog colon permeability. A relationship between permeability in Caco-2 monolayers and human absorption was found. The results suggest that within certain limits, permeability of Caco-2 monolayers may be used as a predictive tool to estimate human drug absorption.     

DIFFERENCES IN ENDOTHELIUM-DEPENDENT RELAXATION IN VARIOUS ARTERIES FROM WATANABE HERITABLE HYPERLIPIDAEMIC RABBITS WITH INCREASING AGE

1. Endothelium-dependent relaxation in response to acetylcholine (ACh) and the calcium ionophore A 23187 was examined in aorta, coronary, basilar and renal arteries isolated from Watanabe heritable hyperlipidaemic (WHHL) rabbits of 2, 6 and 12 months of age, with normolipidaemic heterozygous WHHL rabbits as controls. 2. In the rings of WHHL rabbit aortae and coronary arteries preconstricted with vasoconstrictors, endothelium-dependent relaxation in response to ACh was attenuated with age compared to the heterozygous WHHL rabbits. A significant negative correlation was found between the total cholesterol content and the relaxation response to ACh in the aortae or coronary arteries from 6 and 12 month old WHHL rabbits. 3. In the rings of basilar arteries, endothelium-dependent relaxations to ACh were not modified with age. Similarly, in the rings of renal arteries, the relaxation response to ACh was not changed with age, but in the 6 and 12 month preparations, after the age of 6 months, a contraction following the relaxation appeared at higher concentrations of ACh (10^?7 to 10^?6 mol/L). The contraction was endothelium-dependent and inhibited by indomethacin. 4. A 23187-induced endothelium-dependent relaxations were also markedly attenuated in the aorta and significantly in the coronary artery with age. 5. Endothelium-independent relaxation to sodium nitroprusside was not changed in all arteries from WHHL rabbits of different ages. 6. These findings indicate that in the aorta and coronary artery of the WHHL rabbit, the endothelium-dependent relaxation to ACh and A 23187 becomes impaired with increasing age (i.e., with the progression of cholesterol deposition in the arterial wall) but is preserved in the basilar and renal artery.     

INTERACTIONS BETWEEN THE CIRCULATORY EFFECTS OF CENTRAL HYPOVOLAEMIA AND ARTERIAL HYPOXIA IN CONSCIOUS RABBITS

1. Eight conscious rabbits were repeatedly subjected to progressive reduction in central blood volume by gradually inflating a thoracic inferior vena caval-cuff so cardiac index (CI) fell at a constant 8.5% of baseline/min. 2. Caval-cuff inflations were performed after 10 min exposure to 100, 21, 12–14 and 8–10% O₂, with and without the addition of 3–4% CO₂, in randomized order. 3. The haemodynamic response to progressive reduction in central blood volume was biphasic. In Phase I, systemic vascular conductance index (SVCI) fell linearly, supporting mean arterial pressure (MAP). When CI had fallen to a critical level, Phase II occurred in which SVCI rose abruptly, MAP plummeted and respiratory drive progressively increased. 4. During Phase I, there were independent linear relationships between Pao₂ (but not Pao₂) and the rates at which SVCI and MAP changed during the progressive fall of CI. The higher the level of Pao₂, the greater was the rate of fall of SVCI and the less the rate of fall of MAP. 5. There was an inverted U-shaped effect of Pao₂, on the level of CI at which Phase II occurred: (a) during hyperoxia (100% O₂), Phase II occurred later than during normoxia (21% O₂); and (b) across the normoxic and hypoxic gas mixtures (21–8% O₂, with and without added CO₂), there was an independent linear relationship between Pao₂ (but not Pao₂ or Pao₂×Pao₂) and the level of CI at which Phase II occurred. That is, the lower the level of Pao₂, the later was the onset of Phase II. This interaction is best explained by an increased level of central sympathetic vasoconstrictor drive during hypoxia.     

The stimulant effect of modafinil on wakefulness is not associated with an increase in anxiety in mice

Modafinil is a new drug used in the treatment of narcolepsy. Its administration in mice induced a dose-dependent increase in locomotor activity. The effects of modafinil were compared with those of dexamphetamine on three tests that assessed the anxiety level (drugs were used at doses which induced a roughly similar stimulation of locomotor activity). Dexamphetamine increased the latency of exploration of a white compartment, increased thigmotaxis in an open-field and decreased the time spent in the open arms of an elevated plus-maze. None of these responses was significantly modified by modafinil. We conclude that modafinil does not share the anxiogenic effects of dexamphetamine.     

实验性骨折愈合中骨吸收活动的超微结构观察

将50只家兔造成实验性桡骨骨折,分批取骨痂标本,用光镜和电子显微镜观察表明,在骨折愈合过程中,破骨细胞是骨吸收的主要执行者,巨噬细胞能吞噬死骨,但不能吸收骨质。     

VASOCONSTRICTION IN THE RENAL VASCULAR BED DURING EXERCISE: STUDIES IN CONTROL AND HEART FAILURE RABBITS

1. The effects of graded treadmill exercise on renal blood flow (RBF) were examined in seven rabbits, in which congestive heart failure (CHF) was produced by the administration of doxorubicin, 1 mg/kg, twice weekly for 8 weeks, and in seven controls. A third group of five rabbits underwent doxorubicin treatment with the addition of surgical section of the left renal sympathetic nerve. 2. During submaximal exercise, there was a small reduction in RBF in controls, which was greatly exaggerated in CHF. 3. In both control and heart failure rabbits, there was a precipitous fall in RBF as exercise fatigue developed. 4. Renal sympathectomy ablated these changes in RBF during exercise. 5. It is concluded that in heart failure there is an exaggerated, sympathetically mediated, diversion of blood flow away from the kidney. The onset of exercise fatigue in both normal and heart failure rabbits is accompanied by a marked intensification of this process.     

自身免疫性感音神经性聋豚鼠的子代内耳生理功能研究

目的 :观察自身免疫性感音神经性聋 (ASHL)母豚鼠所产子代内耳生理功能的变化 ,探讨针对内耳的自身免疫因素对子代内耳生理功能的影响及其改变特点。方法 :同种内耳抗原 (CIEAg)持续免疫孕豚鼠 ,采用耳蜗电图 (记录cAP、CM )和眼震电图仪 (记录自发性眼震和冷热空气试验 )测试母鼠和子鼠的听觉和前庭功能 ,并检测血清特异性体液免疫反应。结果 :ASHL模型母豚鼠所产子鼠血清中发现有特异性抗体水平升高 ,部分 (3 /9)出现听觉损伤。非ASHL母鼠和对照组母鼠所产子代未见明显异常。结论 :ASHL雌鼠所产子代可出现感音神经性聋 ,其内耳损伤和功能障碍极可能与针对内耳组织的自身免疫反应 (尤其是体液免疫 )有关 ,从而提示内耳自身免疫因素可能为部分先天性非遗传性感音神经性聋的病因之一。     

改良后的家兔动脉深低温保存实验研究

目的：为探讨家兔动脉在改良的深低温保存后，其作为血管材料替代物的优越性。方法：无菌条件下取新鲜兔动脉，分别给予改良后的营养液经慢速深低温冷冻和快速深低温冷冻处理，6个月后异体和自体移植，12周后，取移植的血管组织，观测其组织活性，组织形态、血管通畅率。结果：改良的营养液保护的血管经慢冻法处理后与自体血管活性相近，经改良的营养液保护的血管，移植前后血管内膜的连续性，血管的组织结构良好；慢冻法处理的血管通畅率比速冻法处理的高，与自体移植组相当。结论：复方氨基酸可以替代传统冷冻保护液中的小牛血清用于血管的深低温保存，降低了该保存技术的成本；快速深低温冷冻保存的动脉血管活力移植效果不如慢速冷冻处理的异体动脉好。     

Rotational tomography of the normal and reconstructed middle ear in temporal bones: an experimental study

Imaging is an essential diagnostic tool in reconstructive middle ear surgery, especially in pre-operative planning. Due to ongoing improvement of imaging quality and development of new imaging techniques like e.g. rotational tomography (RT) post-operative follow-up and immediate evaluation of surgical results may become more important. The aim of this experimental study was to evaluate RT as a new tool for postoperative determination of middle ear anatomy and implant position in temporal bones. RT was performed in ten temporal bone specimen after insertion of different middle ear prostheses concerning material, shape and length (PORP; TORP; Stapes piston). An implantable hearing device (Symphonix Soundbridge®) was also implanted and visualized. For comparison some specimen additionally underwent conventional computed tomography (CT), including the newest technology. Characterization of anatomical structures of the temporal bone using RT was of comparable quality to conventional CT-scans in all investigated specimen while requiring approximately 30% of the CT’s irradiation exposure. Unlike CT the RT showed almost no problems due to metallic artefacts of the implanted prostheses. Furthermore RT enabled a 3-dimensional view of the temporal bone and angle determination of inserted prostheses towards the tympanic membrane and/or the malleus handle. Detailed imaging of the prostheses allowed determination of shape, material and localization within the specimen’s reconstructed middle ear. The new imaging technique of RT allows precise presentation of anatomical structures and middle ear implants in temporal bones. Following these experimental results it will be our future work to evaluate this method in clinical practise.     

Value of digital volume tomography in patients with conductive hearing loss

Digital volume tomography (DVT) is an extension of panoramic tomography. With this diagnostic technique, characterized by high resolution, a narrow section width (0.125 mm) and three-dimensional display, small pathological processes can be well visualized. Twenty-five patients with the history of a progressive hearing loss were examined with DVT (Accu-I-tomo, Morita, Japan). The results were compared with pre- and intraoperative findings to evaluate the diagnostic value of DVT in cases of erosion of the ossicular chain. With high resolution and artifact-free demonstration of the middle ear and the ossicular chain, it was possible to define its continuity preoperatively by DVT in all 25 cases. An intact ossicular chain was found by DVT in 13 cases and was later confirmed by surgery. The predicted erosion of the ossicles was verified in 12 patients, and a tympanoplasty type III was performed. Digital volume tomography is an excellent technique to examine the middle ear cleft and inner ear, and expands the application of diagnostic possibilities in the lateral skull base. Therefore, improvement in preoperative diagnosis is achieved along with more accurate planning of the surgical procedure. Digital volume tomography delivers a small radiation dose with a high resolution and a low purchase price for the equipment.