Pathological study on mucosal changes in small intestine of rat by oral administration of ricin. I. Microscopical observation

A histological study on small intestine of Wistar rats after oral administration of ricin, a proteinous toxin from castor bean seeds, was carried out. In Experiment I, the jejunum was examined at 1, 2, 5, 10, 15, 20, 24, and 40 hours after oral administration of ricin 30 mg/kg. In Experiment II, ricin was administered at dose of 1, 3, 5, 10, 15, 30, and 60 mg/kg, and after 5 hours the jejunum, mid-portion, and ileum were examined. For comparison, ricin 0.5 mg/kg was administered intraperitoneally and castor bean hemagglutinin (CBH) 30 mg/kg orally. In both experiments, the changes of mucosa were essentially similar dependent on time-lapse and dose respectively, which were atrophy of villus, elongation of crypt, degeneration of epithelium, decrease of goblet cell, fusion of intervillous epithelia, infiltration of neutrophils and eosinophils, and dissociation between epithelium and lamina propria. These changes were most manifest in the jejunum that was contacted with ricin first in a high concentration. In contrast, intraperitoneal administration of ricin caused only dissociation between epithelium and lamina propria and oral administration of CBH caused only milder atrophic changes. The evidences suggest that the mucosal changes by oral administration were caused by direct contact with ricin.     

The central-nervous-system toxicity of long-term oral administration of L-tryptophan to porto-caval-shunted rats.

In a previous paper we have reported that the oral long-term administration of 200 mg/kd of L-tryptophan to rats with a porto-caval shunt causes significant loss of body weight, muscular hypertonicity and aggressivity, as well as marked alteration of the liver structure. We now report that tryptophan administered at the same dosage for the same length of time also induces significant alteration of the central nervous system. These results further demonstrate that high plasma levels of tryptophan are quite well tolerated by control animals but are quite toxic to rats with a porto-caval shunt. We also claim that the brain alterations observed in such animals are not secondary to liver dysfunction but to high levels of plasma tryptophan per se.     

Alumina and zirconia coated vitallium oral endosteal implants in beagles.

The purpose of this study was to assess the addition of a ceramic coating upon a Vitallium implant to increase the implant's biologic acceptability in the oral environment. The mandibular premolar teeth in 9 adult beagle dogs were removed bilaterally and these areas allowed to heal for 6 weeks. Ceramic coating with either Al2O3 or ZrO2 was carried out by flame spray deposition upon Vitallium anchor implants (9 of each), and the implants placed into the 18 healed premolar areas. Clinical and radiographic evaluation was conducted by 2 independent investigators over a 32 week period. Implants which exhibited mobility greater than II on a scale of 0 to III, at intervals of one-half, were judged unsatisfactory. After 19 weeks, all 9 Al2O3 coated implants and 5 ZrO2 coated implants were rated unsatisfactory. After 32 weeks, 4 ZrO2 coated implants were in situ with 0 or I mobility. Radiographically the width of the peri-implant space increased in direct proportion to both time and mobility. Histologic sections demonstrated encapsulating dense fibrous connective tissue which was oriented parallel to both ZrO2 and Al2O3 implants. Results suggest the zirconia used is a superior ceramic coating to the alumina. Neither seemed to increase biologic acceptability over uncoated Vitallium implants.     

A study of parietal gastrointeatinal microflora of rats after oral administration of probiotics

The article is dedicated to one of the topical problems of medical microecology, possibility of modification of parietal gastrointestinal microflora by oral administration of various probiotics, and evaluation of the effects of such modification. The results of the study show that parietal gastrointestinal microflora can be modified by oral administration of probiotics.     

Pharmacokinetic study of paeoniflorin in mice after oral administration of Paeoniae radix extract

A rapid, sensitive and reproducible high-performance liquid chromatographic assay for busulfan in human plasma was developed. After extraction of plasma samples with acetonitrile and methylene chloride, busulfan and the internal standard [1,5-bis(methanesulfonyloxy)pentane] were derivatized with 8-mercaptoquinoline to yield fluorescent compounds which were detected with a fluorescence detector equipped with filters of 360 nm (excitation) and 425 nm (emission). Calibration graphs showed a linear correlation (r>0.9990) over the concentration range of 20-2000 ng/ml. The recovery of busulfan from plasma standards was 70+/-5%. The detection and quantification limits for busulfan in plasma samples were established at 9 ng/ml and 20 ng/ml, respectively. The intra- and inter-assay variations were lower than 8% and 10%, respectively. The applicability of the method was verified by analyzing the plasma concentrations of busulfan in a patient to whom it was administered orally on two different days.     

Hematological changes after long-term aluminum administration to normal adult rabbits.

The effects of long-term aluminum exposure on erythroid parameters were investigated in a rabbit system. Healthy young adult male rabbits were maintained on drinking water containing five mg per L of aluminum citrate; others were treated with an intravenous solution of aluminum maltol, 0.225 mmol of aluminum per week. In the oral study, decreases in the hematocrit, hemoglobin, and red cell count were observed over a 12-month period in those animals on soft water with a low calcium content and containing aluminum citrate; however, no changes were seen in those on hard water containing aluminum citrate nor in rabbits maintained on a normal diet. Small amounts of aluminum were observed in bone marrow macrophages, usually accompanied by iron, in both the orally- and intravenously-treated animals. There was poor correlation between bone marrow aluminum content and length of exposure.     

Reduced number of striatal neurons expressing preprosomatostatin mRNA in rats with oral dyskinesias after long-term haloperidol administration

Neuroleptic-induced oral dyskinesia in rats, a putative analogue to human tardive dyskinesia, may be due to degeneration within the striatum. Using unbiased stereological methods, a decreased number of striatal neurons expressing preprosomatostatin mRNA was observed only in rats that developed pronounced oral dyskinesias after 30 weeks of haloperidol administration. The amount of preprosomatostatin mRNA in each striatal neuron, measured in terms of optical densities of individual neurons, was not affected by haloperidol. A tendency toward a reduction in the number of NADPH-diaphorase positive neurons was observed in rats receiving haloperidol. These results indicate that the mechanism by which neuroleptics induce oral dyskinesias in rats, and perhaps tardive dyskinesia in humans, involves a functional disruption and possibly damage of a subpopulation of interneurons in the striatum.     

Persistent paralysis in critically ill patients after long-term administration of vecuronium.

BACKGROUND. The muscle relaxant vecuronium is sometimes administered to facilitate mechanical ventilation. Neuromuscular paralysis lasting up to seven days may occur after the termination of long-term administration (i.e., more than two days) of vecuronium in critically ill patients. We investigated the role of clinical factors and plasma concentrations of vecuronium and its metabolite in causing this prolonged neuromuscular blockade. METHODS. We studied 16 critically ill adult patients (8 women and 8 men) who had received vecuronium to facilitate mechanical ventilation for at least two consecutive days. Clinical factors and plasma concentrations of vecuronium and 3-desacetylvecuronium, the active metabolite of vecuronium, were compared in patients with and without prolonged neuromuscular blockade. In addition, we performed detailed pharmacokinetic studies in the patients without prolonged neuromuscular blockade. RESULTS. Seven of the 16 patients had prolonged neuromuscular blockade, lasting from six hours to more than seven days, after the termination of vecuronium therapy. These seven patients, six of whom were women, had higher plasma magnesium concentrations and lower arterial blood pH values than the nine patients without prolonged neuromuscular blockade. They also had higher plasma concentrations of 3-desacetylvecuronium and a higher frequency of renal failure (seven of seven patients vs. four of nine patients, P less than 0.03). In the patients without prolonged neuromuscular blockade, the mean (+/- SD) plasma clearance, elimination half-life, and volume of distribution of vecuronium were 2.5 +/- 1.0 ml per kilogram of body weight per minute, 299 +/- 154 minutes, and 1.1 +/- 0.6 liters per kilogram, respectively. CONCLUSIONS. Prolonged neuromuscular blockade after the termination of long-term treatment with vecuronium is associated with metabolic acidosis, elevated plasma magnesium concentrations, female sex, and probably more important, the presence of renal failure and high plasma concentrations of 3-desacetylvecuronium.     

The toxic effects of long-term,oral administration of L-tryptophan in rats with portacaval shunt.

The oral, long-term administration of 200 mg/kg of L-tryptophan to rats previously submitted to a portacaval shunt causes significant loss of body weight, muscular hypertonicity and aggressivity, as well as marked alterations of the liver structure. Conversely, the same treatment is well tolerated by control animals. It is postulated that the derangement of tryptophan metabolism normally occurring in rats with portacaval shunt is by itself insufficient to induce behavioural changes and liver damage, which, on the contrary, develop when tryptophan metabolism is further altered by the administration of the amino acid to the animals for a long period of time.     

口服伤寒杆菌前后消化道黏膜上皮内淋巴细胞的作用及其变化规律的实验研究

目的研究口服伤寒杆菌后,大鼠小肠和大肠上皮内淋巴细胞（IEL）的形态学特征及分布特点的变化,为探讨粘膜免疫的机制打下基础。方法给大鼠口服伤寒杆菌,应用免疫组化染色和电镜的方法对大鼠消化道各部分的黏膜IEL表型进行分析,观察其形态特征。结果电镜观察显示大鼠被免疫后肠道淋巴细胞超微结构与对照组相比功能活跃;免疫组化观察到大鼠被免疫后肠道各段IEL的亚群数量明显增加,消化管各部IEL数量有差异。结论服伤寒杆菌后,大鼠小肠和大肠IEL活性明显增强,是免疫反应的形态基础。IEL数量的大量增加,进一步表明淋巴细胞在粘膜免疫中起重要作用。     

Markedly elevated levels of estrone sulfate after long-term oral, but not transdermal, administration of estradiol in postmenopausal women

OBJECTIVE: To compare serum estrone sulfate (E1S) levels in postmenopausal women during long-term treatment with commonly prescribed doses of oral and transdermal estradiol (E2). DESIGN: A retrospective study performed in a University setting in the United States involving 33 healthy postmenopausal women. Two groups of postmenopausal women were studied: group 1 (n = 10) received 1 mg oral micronized E2 daily for 16 months; blood was drawn at 0, 7, and 15 months. Group 2 (n = 23) was randomized into three subgroups. Two of the subgroups (n = 8; n = 7) received E2 delivered at a rate of 0.05 mg/day and 0.1 mg/day, respectively, by transdermal patch, changed twice weekly; the third subgroup received a placebo (without E2) patch for 9 continuous months. Blood samples were drawn at 0, 6, and 9 months. Serum E1S and E2 were quantified by specific radioimmunoassays. Statistical analysis was performed by analysis of variance. RESULTS: After oral E2 treatment, E1S levels increased significantly (p < 0.01) from baseline, reaching an average level of 38.8 ng/mL at 15 months. After transdermal E2 treatment, E1S levels increased significantly, yet to a much lesser extent, reaching levels of 1.8 ng/mL and 3.2 ng/mL after 9 months of treatment with the 0.05 mg/day and 0.1 mg/day patches, respectively. CONCLUSIONS: Markedly elevated levels of E1S were found after long-term oral estrogen treatment. In comparison to the increase in E1S levels after long-term oral estrogen treatment, there was only a small increase in E1S levels after transdermal E2 therapy. This difference may be attributed to the higher dosage of oral E2 that is required because of the low bioavailability compared with the transdermal dosages.     

Interaction of microorganisms with enterocytes after oral administration of pesticides

Intragastral administration of the pesticides Sumi-alpha and Omait to rats significantly increases the number of parietal microorganisms in the jejunum, ileum, and particularly in the cecum. Electron microscopy shows that parietal microorganisms invade goblet cells during secretion and then enter prismatic cells via the lateral plasma membrane. The number of parietal microorganisms entering enterocytes after Sumi-alpha is higher than after less toxic Omait, reaching the maximum 5 h after administration. Translated fromByulleten’ Eksperimental’noi Biologii i Meditsiny, Vol. 123, No. 4, pp. 467–470, April, 1997     

Antithrombin III in patients on long-term oral anticoagulants.

The antithrombin III (AT III) concentration in plasma was measured in 63 patients on oral anticoagulant treatment (mean age 57.7 years), 26 healthy laboratory controls (mean age 28 years), and 21 patients attending the hypertensive clinic who had never been on oral anticoagulants (mean age 50 years). Three methods were used to measure AT III: a coagulation assay, a chromogenic substrate assay, and an immunological assay. In patients on oral anticoagulants, the mean values for AT III in the three assays were: 124%, 107%, and 96% respectively. The mean AT III concentration in laboratory staff was 103.4%, 94%, and 104.1% for the three assays; patients attending the hypertensive clinic had AT III concentrations indistinguishable from those in patients on oral anticoagulants: 117.9%, 110.5%, and 93.9%. The difference between both patient groups and laboratory staff was statistically highly significant, but no difference was demonstrated between patients on anticoagulant treatment and those not receiving it. Our results show that the increase in the functional AT III concentration (measured by coagulation and chromogenic assays) observed in patients on oral anticoagulants is probably due to the effects of age and underlying disease rather than to the anticoagulant treatment itself.     

口服S抗原对抗原诱导性葡萄膜视网膜炎影响的实验研究

目的:观察口服牛视网膜S抗原对Wistar大鼠抗原诱导性葡萄膜视网膜炎(ATU)的影响。方法:用纯化牛视网膜S抗原和福氏完全佐剂的混合乳剂致敏大鼠,14d后接种S抗原于致敏鼠眼玻璃体腔复制AIU模型。观察致敏前后口服S抗原或牛血清白蛋白(BSA)对AIU眼部表现,组织学改变、血清抗体效价、迟发型超敏反应(DTH)、淋巴细胞增殖反应的影响。结果:致敏前后口服BSA对AIU的炎性反应和免疫反应无影响。与口服BSA组比较,预口服S抗原组在AIU第1、3、5d的临床分级参数显著降低,炎症持续时间显著缩短,组织炎性细胞浸润显著减轻,血清特异性抗体滴度降低,DTH显著降低,受S抗原刺激的脾淋巴细胞增殖反应显著降低,加入IL-2共孵育后S抗原刺激的淋巴细胞增殖反应增高。致敏后口服S抗原组在AIU第5d的临床分级参数、炎症持续时间和DTH显著降低,血清特异性抗体滴度降低。结论:口服S抗原可以抑制AIU的炎性反应、细胞免疫反应和体液免疫反应。     

外源质粒DNA经胃肠道途径对小鼠免疫基因的调控作用

目的:研究外源质粒DNA经胃肠道途径对小鼠免疫基因表达的调控作用。方法:给BALB/c小鼠灌胃质粒pcDNA3200μg,分别在灌胃后4h和18h分离脾脏,提取脾脏总RNA。利用Affymetrix基因表达谱芯片对灌胃质粒pcD-NA3后的BALB/c小鼠脾脏进行基因表达谱研究。采用Genmmapp和MAPPFinder软件进行功能聚类分析。结果:灌胃质粒pcDNA3后,大量与免疫应答相关的基因发生上调,这些基因包括转录因子、细胞因子和细胞因子受体、主要组织相容性基因、蛋白酶体基因、补体分子基因和细胞凋亡相关基因;下调的基因主要是免疫球蛋白基因。MAPPFinder分析结果显示大量免疫应答过程发生上调。结论:外源质粒DNA通过胃肠道途径可调控大量免疫基因的表达,对相关基因及免疫应答过程的研究有助于在分子水平上深入了解外源质粒DNA的胃肠道作用机制。     

Azithromycin concentrations in sinus fluid and mucosa after oral administration

The concentrations of azithromycin in sinus fluid and mucosal tissue were determined in a total of 23 patients with acute or chronic sinusitis. Five patients with acute sinusitis and four with chronic sinusitis were administered a five-day course of oral azithromycin (500 mg on day 1, 250 mg on days 2–5, all as single doses), and the remaining 14 patients, all with chronic sinusitis, received single oral doses of azithromycin (500 mg). With the five-day regimen, the mean levels of azithromycin in sinus fluid were markedly higher in patients with acute sinusitis (1.34 µg/ml) than in patients with chronic sinusitis (0.25 µg/ml) 24 h after the first dose. The levels of azithromycin in the sinus fluid increased from the first to the last dose in both patient groups; the mean levels of azithromycin 24 h after the last dose were 2.33 µg/ml in acute sinusitis patients and 0.38 µg/ml in chronic sinusitis patients. In chronic sufferers, the mean levels of azithromycin in the sinus fluid following a single oral dose were 0.25, 0.41, 0.57 and 0.22 µg/ml at 24, 48, 72 and 96 h, respectively, after administration. In these patients the mean sinus drug concentrations were much greater in the mucosal tissue (1.23 µg/g) than in the sinus fluid (0.41 µg/ml) 48 h after administration of the single dose. There were no treatment-related changes in laboratory function tests, and side effects were described as mild to moderate (five patients complained of nausea, abdominal pain or headache). It is concluded that azithromycin penetrates into sinus fluid and tissue, particularly in patients with acute sinusitis, and persists at significant levels for up to four days after administration.     

Pharmacokinetics of ciprofloxacin after oral and intravenous administration in healthy volunteers

The pharmacokinetics of ciprofloxacin (Bay o 9867) was examined after a single oral dose of 250 mg and a single intravenous dose of 100 mg respectively in six healthy male volunteers in an open, randomized crossover study. Although ciprofloxacin concentrations were measured in serum, plasma and urine by HPLC with fluorimetric detection and by microbiological assay, all pharmacokinetic calculations are based on the highly sensitive HPLC method only. The mean serum concentration of ciprofloxacin peaked approximately1 h after the oral dose (0.94 mg/l). The elimination half-life was about 4 h and the renal clearance was 4.75 ml/min·kg; both were independent of the route of administration. The total clearance (9.62 ml/min·kg) was about twofold higher than the renal clearance. The volume of distribution of the central compartment was calculated to be 0.16 l/kg and the total volume at steady state was 2.0 l/kg. About 27 % of the oral dose was excreted in urine, whereas the urinary recovery of the i.v. dose was 46 %. The absolute bioavailability of ciprofloxacin was found to be approximately 60 %. Ciprofloxacin appears to follow first-order, three compartment model kinetics.