In vivo determination of intestinal calcium absorption, with scandium-47 used as marker

The 47scandium/47calcium ratio technique for studying intestinal absorption of calcium in humans offers the following advantages: neither blood sampling nor complete faecal collection are required, and there is no need for an additional marker or for knowledge of the precise dose of calcium isotope administered. In the study this technique was corrected and modified using a new equation that considerably simplifies the determination procedures. The new method was validated in rats with various intestinal calcium absorption rates. The value of scandium as an unabsorbed intestinal marker was confirmed by the use of 46scandium. A mean recovery of 96% was obtained after intragastric administration. The 47scandium/47calcium ratio technique gave results that correlated well with the faecal 47calcium recovery method over a wide range of intestinal calcium absorption rates obtained by treatment with 1,25-dihydroxycholecalciferol or 1-hydroxyethylidene-1,1-biphosphonate. Taking into account the advantages of the 47scandium/47calcium ratio technique, it appears useful not only in small animals but also in outpatients, particularly children.     

Absorptional function of the small bowel in patients with chronic obstructive bronchitis

The purpose of the study was to evaluate intestinal absorption of fats, proteins and carbohydrates in patients with chronic obstructive bronchitis (COB) depending on the functional condition of the lungs, and clinical manifestation of its disorder. Fat, protein and carbohydrate absorption was studied in 68 COB patients. Lung ventilation was evaluated by means of spirography, pulmonary gas exchange--via measurement of paO2 of arterialized capillary blood by Astrup method. Fat absorption was evaluated using Kamer method and radioindication with 131I-trioleate-glycerine and 131I-oleic acid; protein absorption was determined using 131I-albumin; carbohydrate absorption was determined by d-xylose test. The study demonstrated that deterioration of respiratory and ventilatory pulmonary functions in patients with COB impaired fat, protein and carbohydrate absorption: paO2 > or = 70 mmHg and ventilatory insufficiency (VI) I were associated with an significant reduction of fat absorption by 49% on the average, protein--by 23%, carbohydrates--by 15%; paO2 = 70-40 mmHg and VI II-III--with reduction of these parameters by 104%, 69%, and 41%, respectively. The results show a direct correlation between body weight (BW) deficit and the reduction of fat, protein, and carbohydrate absorption (r = 0.549, 0.707, and 0.482, respectively) in COB patients. The most prominent was the correlation between BW deficit and the reduction of protein absorption. Thus the study of intestinal absorption of fats, proteins and carbohydrates in patients with COB demonstrates not only reduction of absorption, correlating with the degree of the impairment of ventilatory and respiratory pulmonary functions, but also direct correlations between BW deficit and reduction of fat, protein and carbohydrate absorption.     

Holmium as a faecal marker for copper absorption studies in adults

The objective of the present study was to investigate the validity of using holmium as a faecal marker in a copper absorption study using a highly enriched (65)Cu stable isotope label. Ten volunteers (nine female, one male) aged 24-55 years were recruited from the Norwich area to take part in a free-living study. The study was conducted in the Human Nutrition Unit at the Institute of Food Research, Norwich, U.K., and involved feeding breakfast test meals containing foods labelled intrinsically or extrinsically with a highly enriched (65)Cu stable isotope label. A 1 mg oral dose of the rare earth element holmium was administered to volunteers simultaneously with an oral dose of highly enriched (65)Cu stable isotope as a label in the breakfast test meal. Complete faecal collections were made for 10 days after dosing, and the mean percentage holmium recovery (+/- S.D.) was 105 +/- 15%. After correcting for re-excreted copper label, the labelled copper and holmium had similar excretory profiles. It was concluded that holmium is a valid faecal marker in adult human copper absorption studies using stable isotopes.     

Plasma holotranscobalamin compared with plasma cobalamins for assessment of vitamin B12 absorption; optimisation of a non-radioactive vitamin B12 absorption test (CobaSorb)

BACKGROUND: A recently developed non-radioactive vitamin B(12) absorption test (CobaSorb) was further explored to identify the best marker for reflection of vitamin B(12) absorption and to determine the duration of the test. METHODS: Seventy-eight healthy individuals (age 21-81 years) were given three oral doses of 9 microg vitamin B(12) per day for 5 successive days. Non-fasting blood samples were collected on days 1 to 5 before administration of vitamin B(12) and on day 8. Cobalamins and holotranscobalamin were measured. RESULTS: Performance of the vitamin B(12) absorption test was evaluated in individuals with holotranscobalamin or cobalamins below the 75% percentiles. We used a change greater than 2xCV(day-to-day) in holotranscobalamin (22%) and cobalamins (12%) to indicate a change caused by absorption of vitamin B(12). Among individuals with a baseline holotranscobalamin below the 75% percentile (<75 pmol/L, n=57), 98% had an increase in holotranscobalamin >22% from day 1 to day 3. In contrast, only 72% of the individuals with baseline cobalamins below the 75% percentile (<335 pmol/L, n=57) had an increase in cobalamins >12%. CONCLUSIONS: In healthy individuals with baseline holotranscobalamin <75 pmol/L, vitamin B(12) absorption is well reflected by an increase in holotranscobalamin after 2 days administration of oral vitamin B(12).     

Short-term effects of synthetic human parathyroid hormone-(1--34) administration on bone mineral metabolism in osteoporotic patients.

Since studies in animals and humans have shown that parathyroid hormone can stimulate bone formation and increase trabecular bone, and patients with primary and secondary hyperparathyroidism may exhibit osteosclerosis, we evaluated the effect of short-term administration of human parathyroid hormone, hPTH-(1--34), in patients with osteoporosis. Six patients with osteoporosis underwent detailed studies including blood and urinary measurements of calcium, phosphate, and magnesium; 47Ca kinetic studies; and 18-d balance studies before and during the short-term administration (3--4 wk) of a daily subcutaneous injection of hPTH fragment 1--34 given as 450 or 750 U/dose. The mean fasting plasma calcium values rose slightly after hPTH-(1--34) administration, primarily in the high-dose group. There was no difference in the mean fasting plasma inorganic phosphate levels. The mean daily urinary excretion of calcium and phosphate was significantly increased in patients given the higher dose. In patients given 750 U, net intestinal calcium absorption increased, phosphate absorption increased, calcium balance improved, and phosphate balance improved. In patients given 450 U, calcium balance and phosphate balance worsened. 47Ca kinetic studies showed a minimal increase in bone accretion rate, a decrease in the mean transit time of calcium in the exchangeable pools, and a decrease in the exchangeable-pool size. In all six patients there was an increased renal clearance of 47Ca as a result of hPTH-(1--34) administration. These studies indicate that low doses of parathyroid hormone may promote bone formation, whereas higher doses clearly have an adverse effect on the skeleton.     

Intestinal metabolism of plasma free fatty acids. Intracellular compartmentation and mechanisms of control.

Fatty acid metabolism in intestinal mucosa has been examined primarily in regard to lipid absorption. Since earlier studies suggested intestinal utilization of plasma free fatty acids (FFA), we investigated mucosal metabolism of plasma FFA in rats. Mucosal radioactivity (1 per cent of administered) was maximal 2 min after i.v. [14C]palmitate. Of mucosal 14C, 42 percent was in water-soluble metabolites, including CO2 and ketoacids, 28 percent in phospholipids, and only 16 per cent in triglycerides. The specific activity of mucosal triglyceride fatty acids (TGFA) was 11 times that of serum TGFA, confirming in situ synthesis. Double isotope experiments showed marked differences in the metabolism of fatty acids entering mucosa simultaneously from lumen and plasma. Whereas luminal fatty acids were chiefly esterified to triglyceride, plasma FFA were preferentially oxidized and incorporated into phospholipids. Crypts did not differ from villi, indicating that intestinal metabolism of plasma FFA is related to their site of entry into epithelial cells. Mucosal metabolism of i.v. [14C]palmitate was minimally affected by glucose administration. However, intraduodenal isocaloric ethanol inhibited mucosal oxidation of FFA by 60 per cent, and increased incorporation into triglycerides nearly twofold. During lipid absorption, mucosal uptake of plasma FFA doubled and incorporation into intestinal lymph triglycerides was increased sixfold. These studies demonstrate an intracellular compartmentation of fatty acids in the intestinal epithelium. In contrast to absorbed luminal fatty acids, plasma FFA in the fasting state are both an energy source and a substrate for the synthesis of tissue phospholipid. The fasting contribution of plasma FFA to mucosal and lymph triglyceride is minimal, but it increases during ethanol administration and fat absorption.     

Assessment of hypolactasia and site-specific intestinal permeability by differential sugar absorption of raffinose, lactose, sucrose and mannitol.

The sugar absorption test is a non-invasive test for investigating intestinal permeability by simultaneous measurement of four probe sugars. In this study, we evaluated the utility of raffinose, lactose, sucrose and mannitol as probe sugars and calculated their urinary recovery as a percentage of ingested dose (mol/mol) and the recovery ratios of raffinose/mannitol, lactose/ raffinose and sucrose/raffinose. The reference ranges for these ratios, established from 39 healthy volunteers, are 0.005-0.015, 0.13-0.63 and 0.09-0.47, respectively. This sugar absorption test was performed in three patient groups. i) In 109 patients with aspecific gastrointestinal symptoms of whom intestinal histology was studied by duodenal biopsies: the urinary raffinose/mannitol recovery ratio highly correlated with gradation of duodenal damage; the sensitivity and specificity of the raffinose/mannitol ratio for detection of intestinal damage were 93% and 91%, respectively, using a cut-off level of 0.020. ii) In 70 patients in whom intestinal lactase activity was investigated by the lactose tolerance test: the urinary lactose/raffinose recovery ratio provided high diagnostic accuracy for hypolactasia (sensitivity 81% and specificity 89% at a cut-off level of 0.70). In analogy with the lactose/raffinose ratio, we suppose that the sucrose/raffinose ratio can be used as a marker of hyposucrasia. iii) In 40 patients with localized small intestinal damage, Crohn's disease of the ileum (n = 21) and celiac disease with histologically proven duodenal damage (n = 19): the raffinose/mannitol recovery ratio was increased in 100% of patients with celiac disease and in 81% of patients with Crohn's disease; increased lactose/raffinose recovery ratio (hypolactasia) and increased sucrose/raffinose (hyposucrasia) were present in 89% and 95% of celiac patients and 19% and 0% of Crohn's disease patients, respectively. The combination of the raffinose/mannitol ratio and sucrose/raffinose ratio appears to be an indication of the distribution of intestinal damage.     

Anti-CEA immunoscintigraphy in postoperative follow-up of tumor patients. Differentiated use of various monoclonal antibody preparations

The sensitivity of immunoscintigraphy (ISC) with monoclonal antibodies (Mab) depends on the Mab type, the radiophysical properties of the isotope, the labeling method and the tumor localization. We investigated 38 studies with three different Anti-CEA Mab (In111/I131 BW 431, n = 12; I131 IMACIS-1, n = 11; Tc99m BW 431/26, n = 15) in 35 postoperative tumor patients (31 colorectal, 1 gastric, 2 breast and 1 pancreas cancer) with a total of 62 tumor manifestations. Planar ISC was used in all studies. A dual isotope technique with Tc99m-colloid was applied for imaging of liver metastases in the In111/I131 BW 431/31 and I131 IMACIS-1 studies. Whereas the global sensitivity, ranging from 64-73%, was comparable, the different physiological properties of the Mab preparations caused marked differences in the imaging capabilities of certain tumor localizations, especially in the liver. All Mab underestimated the extent of liver involvement, however, the highest regional sensitivity (75%) was found with the I131 IMACIS-1. In contrast, Mab with the highest physiological liver uptake (In111 BW 431/31, Tc99m BW 431/26) imaged liver metastases in most cases unspecifically as cold spot, yielding a sensitivity of 0-9%. No differences between the Mab were seen in the regional sensitivity with respect to lung metastases, which ranged between 33-40%. All tested Mab showed a high sensitivity in imaging local recurrences ranging between 50% for the I131 IMACIS-1 and 100% for the Tc99m BW 431/26. We conclude, that in postoperative tumor patients anti-CEA ISC with Tc99m BW 431/26 is the method of choice for the detection of local recurrences.(ABSTRACT TRUNCATED AT 250 WORDS)     

Oral delivery of macromolecules using intestinal patches: applications for insulin delivery.

Oral drug delivery, though attractive compared to injections, cannot be utilized for the administration of peptides and proteins due to poor epithelial permeability and proteolytic degradation within the gastrointestinal tract. A novel method is described that utilizes mucoadhesive intestinal patches to deliver therapeutic doses of insulin into systemic circulation. Intestinal patches localize insulin near the mucosa and protect it from proteolytic degradation. In vitro experiments confirmed the secure adhesion of patches to the intestine and the release of insulin from the patches. In vivo experiments performed via jejunal administration showed that intestinal insulin patches with doses in the range of 1-10 U/kg induced dose-dependent hypoglycemia in normal rats with a maximum drop in blood glucose levels of 75% observed at a dose of 10 U/kg. These studies demonstrate that reduction in blood glucose levels comparable to that induced by subcutaneous injections can be achieved via enteral insulin absorption with doses only 2-10-fold higher than subcutaneous doses.     

A modified D-xylose absorption test

A modified D-xylose-test is described which enables intestinal absorption to be assessed independently of renal and hepatic function. The speed of appearance of the peak of D-xylose-concentration in plasma after an oral administrated dose and the extent of absorption in the small intestine as a time-function, were analysed by graphic-mathematical evaluation of the kinetics of plasma D-xylose concentration after oral and intravenous administration. Small intestinal functional integrity was assessed in 172 normal individuals (aged from 3 to 96 years), also in 9 patients with coeliac disease. The speed and the extent of D-xylose absorption were significantly reduced in all cases of untreated coeliac disease and during relapse. There were no differences between normal individuals and treated patients. Experience over many years indicates that the modified D-xylose-test is a simple, reliable and inexpensive standard method for detecting changes in intestinal absorption.     

D-xylose absorption and disposition in patients with moderately impaired renal function

D-Xylose kinetics were studied after oral and intravenous administration to 10 patients with impaired renal function, three of whom were being evaluated for intestinal malabsorption. The 0.32 +/- 0.06 L/kg (mean +/- SD) distribution volume of D-xylose in patients with uncomplicated renal impairment was larger than the value of 0.23 +/- 0.04 L/kg that we reported previously for normal subjects (P less than 0.01). Renal clearance was also reduced, averaging 87% of glomerular filtration rate estimated from creatinine clearance, so that the elimination-phase half-life was prolonged to 138 +/- 39 minutes from 75 +/- 11 minutes in normal individuals (P less than 0.01). The 25 gm oral D-xylose dose was 77.4% +/- 14.8% absorbed in the patients with uncomplicated renal impairment, similar to the 69.4% +/- 13.6% absorption reported in normal individuals. However, the absorption half-life was prolonged from 31 +/- 12 minutes in normal subjects to a value of 62 +/- 23 minutes (P less than 0.02). Of the usual clinical indexes of D-xylose absorption, the serum concentration measured 1 hour after the oral dose was best correlated with the extent of D-xylose absorption (r = 0.76; P less than 0.01), and the standard lower normal limit of 0.2 mg/ml was satisfactory.     

Polyethylene glycol (Macrogol)--an overview of its use in diagnosis and therapy of gastrointestinal diseases

The pharmacological rationale for the use of polyethylene glycol (PEG) in gastroenterology is its inverse relation between molecular mass and intestinal absorbability, with practically no intestinal absorption at molecular masses exceeding 3000, its lack of intestinal enzymatic degradation or bacterial metabolism, and its water binding capacity. PEG is used as a nonabsorbable marker in the evaluation of small intestinal and colonic absorption and secretion, as a marker for intestinal permeability studies, as an essential component of colonic lavage solutions used for the preparation of the colon for diagnostic and therapeutic interventions, and for the treatment of fecal impaction or chronic constipation. Since PEG has been used for decades, there is extensive data documenting its safety in short term use. Although animal experiments have also proved the safety of chronic PEG administration, the increasing use of PEG for the treatment of chronic constipation in the long term requires further surveillance to establish its safety.     

The oral Ca47 test and cynamics of Ca47: comparative evaluation in the study of the digestive absorption of calcium in man

The intestinal absorption of calcium is one of the most important processes regulating calcium metabolism. Its measurement requires the estimation of dietary and faecal calcium over a period of one week, but this procedure is frequently liable to error. The availability of two isotopic procedures contributed to the successful pursuit of measuring intestinal absorption of calcium. In the first procedure the indirect assessment of calcium absorption is based on the kinetic study of plasma radioactivity curve after an intravenous dose of radiocaldium at the same time with a calcium balance study over a period of 6 days, In the second isotopic procedure the calcium absorption is directly calculated from the plasma radioactivity and residual faecal activity following an oral dose of radioactive calcium. We have investigated by the two methods 25 patients (one normal subject and 24 affected by a variety of clinical disorders of calcium metabolism). The excellent agreement, statistically significant, between the data obtained by the two methods suggests that both procedures are adequate to assess intestinal absorption of calcium in man.     

The sugar absorption test in the evaluation of the gastrointestinal intolerance to bisphosphonates: studies with oral pamidronate.

RATIONALE AND AIMS Some bisphosphonates induce gastrointestinal side effects, but the localization in the gastrointestinal tract and the underlying mechanism are unknown. The feasibility of the sugar absorption test was investigated to assess the gastrointestinal effects of oral enteric-coated pamidronate. The sugar absorption test measures the urinary excretion of lactulose, mannitol, and sucrose after oral intake. Increases in the lactulose/mannitol ratio and sucrose excretion indicate increased small intestinal permeability and gastroduodenal disease, respectively. SUBJECTS AND METHODS: Twelve volunteers (5 women and 7 men) participated in a randomized, double-blind, 4-way crossover study. The sugar absorption test was performed 2 hours after the final drug intake following a 3-day course of enteric-coated pamidronate (300 mg daily), placebo, or acetylsalicylic acid (3 g daily). The lactulose/mannitol ratio and sucrose excretion were measured in urine collected for 5 hours after ingestion of the solution. The fourth treatment consisted of intravenous administration of pamidronate. Treatment comparison was with paired t tests after log-transformation. RESULTS: The lactulose/mannitol ratio after pamidronate and acetylsalicylic acid administration was 54% and 118% higher than that after placebo (95% confidence intervals [CI], +8%, +119%, and +69%, +182%). The lactulose/mannitol ratio after pamidronate administration was 29% lower (95% CI, -54%, +3%) than that after acetylsalicylic acid. Compared with placebo the sucrose excretion was 290% higher after acetylsalicylic acid (95% CI, +46%, +518%) but only 8% higher after pamidronate (95% CI, -41%, +97%). The absorption of pamidronate was below 1%, and there was no relationship with the increased lactulose/mannitol ratio. CONCLUSION: Oral enteric-coated pamidronate increases intestinal but not gastroduodenal permeability. There was no relationship between intestinal permeability and absorption of pamidronate. It appears that the sugar absorption test is an appropriate, noninvasive method for evaluation of gastrointestinal effects of bisphosphonates in humans.     

Studies on human thyroxine-binding globulin (TBG). IX. Some physical, chemical, and biological properties of radioiodinated TBG and partially desialylated TBG.

Thyroxine-binding globulin (TBG) and partially desialylated or slow TBG (STBG) were purified from human serum by affinity chromatography. Purified TBG was identical to TBG present in serum by the criteria of electrophoretic mobility, affinity for thyroxine (T4), and heat-inactivation response. Purified STBG had slower electrophoretic mobility and lower affinity for T4. Both bound T4 in an equimolar ratio, were immunoprecipitable, and had similar inactivation t1/2 at 61 degrees C. TBG and STBG were iodinated by the chloramine-T-catalyzed reaction. An average of from 0.02 to 6 atoms I could be incorporated per molecule of the protein by adjusting the conditions of the reaction (time, protein and iodide concentrations). 125-I, 131-I, and 127-I were used. Iodination increased the anodal mobility of TBG but did not affect the reversible T4-binding, precipitation by antiserum, or the heat-inactivation properties. "Heavily" and "lightly" iodinated TBG had identical disappearance half-times from serum in the rabbit. 15 min after the intravenous administration of [131-I]-STBG and [125-I]TBG mixture to rats, more than 90% of the injected 131-I dose was in the liver, and the liver 131-I/125-I ratio was 32-fold that of serum. Selective uptake of STBG by the liver was also observed in the rabbit and in man. The serum [125-I]STBG/[131-I]TBG ratio declined from 1 to 0.2 in 10 min in the intact rabbit but remained unchanged for 1 h in the acutely hepatectomized animal. In the rabbit, t 1/2 was approximately 3 min for STBG and 0.8-3.4 days for TBG. The radioiodine derived from the iodinated proteins is partly excreted in bile but the bulk was precipitable with specific antibodies. Some isotope in the form of iodide appeared in blood and was excreted in the urine. Since radioiodinated TBG and STBG preserve their biologic and immunologic properties they are useful as tracer materials for metabolic studies. In rat, rabbit, and man STBG is rapidly cleared from serum by the liver. Conversion of TBG to STBG may be the limiting step in the regulation of TBG metabolism.     

A comparison between the semisimultaneous and the stable isotope techniques for bioavailability estimation of terbutaline in humans.

A recently proposed bioavailability estimation procedure, the "semisimultaneous" method, in which the test and reference dose administrations are separated by a short time interval and total concentrations are analyzed, was compared with the stable isotope method for precision and accuracy. By administering isotope-labeled (reference) and unlabeled (test) terbutaline in a semisimultaneous fashion, the bioavailability could be determined with both methods at the same time. The extent and rate of bioavailability of oral terbutaline was determined in eight healthy volunteers by use of both model fitting, AUC methods, and deconvolution. The AUC ratio and the deconvolution methods, by use of the separate isotope data, gave bioavailability estimates of 14.5% +/- 4.1% and 12.2% +/- 3.9%, respectively. According to the semisimultaneous method, bioavailability estimates with the same data sets were 11.8% +/- 4.5% obtained from fitting a model to the data and 11.0% +/- 3.7% by use of a combined model fitting-deconvolution procedure. An excellent agreement between the semisimultaneous and the stable isotope methods was also obtained in the estimation of the rate of absorption.     

The diagnosis of type A and type B niemann-pick disease and detection of carriers using leukocytes and a chromogenic analogue of sphingomyelin

The action of somatostatin on intestinal alkaline phosphatase activity (IAP) in the duodenal juice was examined in 22 subjects undergoing diagnostic secretin-CCK-PZ-tests. Under continuous secretin-CCK-PZ-stimulation there is an increase of IAP which is followed by a period of exhaustion after 1 h of stimulation. The intravenous administration of somatostatin induces a distinct inhibition of IAP which cannot be due to the exhaustion of the enzyme synthesis. As there is a functional relationship between fat absorption and alkaline phosphatase, it is suggested that this inhibition of IAP is one of the mechanisms of the somatostatin-induced inhibition of intestinal fat absorption.     

贻贝粘蛋白创面修复敷料体外细胞毒性的检测方法

背景：在贻贝粘蛋白创面修复敷料的体外细胞毒性检测中,由于蛋白分子表面带正电荷,1∶9的浸提比会使细胞聚团而导致测定产生误差,影响测定结果。 目的：在已有标准的基础上,根据贻贝粘蛋白特殊的性质及使用状态,改进贻贝粘蛋白创面修复敷料的浸提比例或前处理方法。 方法：①浸提液法：将贻贝粘蛋白创面修复敷料与细胞培养液分别以1∶9、1∶131浸提比例制备浸提液,分别以贻贝粘蛋白创面修复敷料浸提液、天然乳胶浸提液、高密度聚乙烯浸提液及细胞培养液培养L929小鼠成纤维细胞。②直接接触法：分别以蒸馏水、贻贝粘蛋白创面修复敷料溶液、二甲基亚砜及细胞培养液培养L929小鼠成纤维细胞。 结果与结论：采用浸提比1∶9测定样品体外细胞毒性时,细胞产生聚团作用,不适用于样品毒性的检测;调整浸提比为1∶131后,絮凝作用和细胞聚团现象明显降低,提高了检测结果的可信度,显示样品无细胞毒性。直接接触法显示样品无细胞毒性。采用经调整过的浸提液法或直接接触法均可适用于贻贝粘蛋白创面修复敷料体外细胞毒性的检测。     

The pharmacokinetics of baclofen derived from intestinal infusion

The pharmacokinetics of baclofen, a centrally acting muscle relaxant, have been elucidated in man. The pharmacokinetic disposition was determined form plasma concentration-time data and urinary recovery after the administration of rate-limiting intestinal infusions and an oral bolus dose. Based on comparisons between the plasma concentration-time profiles from the intestinal infusions and the oral bolus doses, relative regression parameter assignments were made. The intestinal absorption of baclofen after intestinal infusion was very rapid, such that baclofen disposition was well characterized by an open two-compartment pharmacokinetic model with zero-order input. Intravenous administration of baclofen was precluded from this study because of the potential for severe adverse reactions. The average distribution phase constant (alpha) was 1.29 hours-1 and the average elimination phase constant (beta) was 0.191 hours-1. Average volume of the central compartment (Vc/F), volume of the body compartment (Varea/F), systemic clearance (CL/F), and renal clearance were 28.8 L, 59.0 L, 180 ml/min, and 103 ml/min, respectively. Pharmacokinetics were dose proportional in the dose range studied. The use of these pharmacokinetic parameters as determined in normal subjects in therapeutic management is particularly relevant, because baclofen is targeted to a patient population subject to renal dysfunction.     

Effect of Neomycin on Cholesterol Metabolism in the Germ-Free Pig

Abstract The effect of neomycin sulphate in an oral dose of 1.5 g daily was studied in germ-free piglets given a preliminary intravenous dose of labelled cholesterol. Combined urinary and faecal pools were assayed for radioactivity and the faecal excretion of neutral sterols and bile acids was calculated by the isotopic balance method. During the administration of neomycin there was only a slight and transient decrease in serum cholesterol, but the faecal excretion of endogenous neutral sterols was more than doubled. There was also a significant rise in faecal fat excretion, although bile acid excretion remained unchanged. Examination of the morphology of the small intestinal mucosa by both light and electron microscopy showed no evidence that neomycin had caused any damage to either absorptive or crypt cells. The only abnormality found was the presence in macrophages in the lamina propria of dense inclusions which exhibited a paracrystalline structure at very high magnification; they were not found in control germ-free animals. These findings demonstrate that neomycin exerts an effect on lipid metabolism which is independent of its antibiotic actions and which is not secondary to mucosal damage.