A novel synthesis of 6''-[18 F]-fluoromaltotriose as a PET tracer for imaging bacterial infection.

The aim of this study was to develop a positron emission tomography (PET) tracer to visualize and monitor therapeutic response to bacterial infections. In our continued efforts to find maltose based PET tracers that can image bacterial infections, we have designed and prepared 6''-[18 F]fluoromaltotriose as a second generation PET imaging tracer targeting the maltodextrin transporter of bacteria. We have developed methods to synthesize 6''-deoxy-6''-[18 F]fluoro-α-D-glucopyranosyl-(1-4)-O-α-D-glucopyranosyl-(1-4)-O-D-glucopyranose (6''-[18 F]-fluoromaltotriose) as a bacterial infection PET imaging agent. 6''-[18 F]fluoromaltotriose was prepared from precursor, 2'',3'',4''-tri-O-acetyl-6''-O-nosyl-α-D-glucopyranosyl-(1-4)-O-2',3',6'-tri-O-acetyl-α-D-glucopyranosyl-(1-4)-1,2,3,6-tetra-O-acetyl-D-glucopyranose (per-O-acetyl-6''-O-nosyl-maltotriose 4). This method utilizes the reaction between precursor 4 and anhydrous [18 F]KF/Kryptofix 2.2.2 in dimethylformamide (DMF) at 85°C for 10 minutes to yield per-O-acetyl-6''-deoxy-6-'' [18 F]-fluoromaltotriose (7). Successive acidic and basic hydrolysis of the acetyl protecting groups in 7 produced 6''-[18 F]fluoromaltotriose (8). Also, cold 6''- [19 F]fluoromaltotriose was prepared from per-O-acetyl-6''-hydroxymaltotriose via a diethylaminosulfur trifluoride reaction followed by a basic hydrolysis. A successful synthesis of 6''-[18 F]-fluoromaltotriose has been accomplished in 8 ± 1.2% radiochemical yield (decay corrected). Total synthesis time was 120 minutes. Serum stability of 6''-[18 F]fluoromaltotriose at 37°C indicated that 6''-[18 F]-fluoromaltotriose remained intact up to 2 hours. In conclusion, we have successfully synthesized 6''-[18 F]-fluoromaltotriose via direct fluorination of an appropriate precursor of a protected maltotriose.

Major human milk oligosaccharides are absorbed into the systemic circulation after oral administration in rats.

Human milk oligosaccharides (HMO) are involved in many biological functions influencing infant health. Although HMO act locally at the intestine, recent evidence has demonstrated that HMO are partially incorporated into the systemic circulation of breast-fed infants. In the last few years, a large amount of research has been conducted using preclinical models to uncover new biological functions of HMO. The aim of this study was to evaluate the absorption and urine excretion of HMO in rats. We administered a single oral dose of the following HMO: 2'-fucosyllactose (2'-FL), 6'-sialyllactose and lacto-N-neotetraose at different concentrations to adult rats. The time course of absorption of HMO into the bloodstream and their appearance in urine was studied. Our results showed that rats, similar to human infants, are able to effectively absorb a portion of HMO from the intestine into plasma and to excrete them in urine. On the basis of this, we also conducted a specific kinetic absorption study with 2'-FL, the most predominant HMO in human milk, in 9-11-d-old rat pups. Our results confirmed that a significant amount of 2'-FL was absorbed into the systemic circulation and subsequently excreted in urine during lactation in rats in a dose-depended manner. We also found basal levels of these HMO in plasma and urine of adult rats as well as rat pups as a natural result of nursing. Our data suggest that the rat may be a useful preclinical model that provides new insights into the metabolism and functions of HMO.

Effect of a mixture of GOS/FOS® on calcium absorption and retention during recovery from protein malnutrition: experimental model in growing rats.

INTRODUCTION: During growth, protein deprivation impairs epiphyseal growth plate (EGP) height, bone volume (BV) and endochondral ossification. During catch-up growth, Ca availability becomes essential to ensure the extra amount needed to achieve optimal peak bone mass and strength. GOS and FOS improve mineral absorption in the colon. PURPOSE: The effect of a mixture of GOS/FOS® 9:1 added to a 0.5 %Ca (NCa) and a 0.3 %Ca (LCa) diets on Ca, P and Mg absorptions and bone mineralization, density and structure using an experimental model of growing rats recovering from early protein malnutrition was investigated. METHODS: To induce protein malnutrition, rats were fed a low protein diet: 4 % (LPD) during 1 week and then were randomly assigned to recovery groups (R) until day 50 (T = 50) as follows: R0.5 %: NCa; RP0.5 %: NCa + 5.3 % GOS/FOS®; R0.3 %: LCa and RP0.3 %: LCa + 5.3 % GOS/FOS®. Control groups received the 0.5 %Ca or 0.3 %Ca diet from weaning until day 40 or 50. RESULTS: Body weight and length increased in C groups throughout the study; both were arrested in all R during LPD consumption and increased immediately after re-feeding. Independently of dietary Ca content, LS counts, ß-glucosidase and Ca, P and Mg absorption increased, whereas cecum pH, ß-glucuronidase, urease and tryptophanase decreased in RP0.5 %: and RP0.3 %: as compared to the other studied groups (p < 0.01). Prebiotic consumption decreased CTX levels and increased femur Ca, Mg and P contents, total skeleton bone mineral content, proximal tibia and spine BMD, BV, EGP height and hypertrophic zone thickness, stiffness and elastic modulus as compared to recovery groups fed the prebiotic-free diets. CONCLUSION: Under the present experimental conditions, GOS/FOS® mixture induced colonic positive effects, which increased Ca, P and Mg absorption. Thus, consuming the prebiotic-containing diet resulted in an extra amount of minerals that improved bone development in growing rats recovering from protein malnutrition.

Infants Fed a Lower Calorie Formula With 2'FL Show Growth and 2'FL Uptake Like Breast-Fed Infants.

OBJECTIVES: The aim of the present study was to examine the growth and tolerance of infants fed infant formulas with a caloric density closer to human milk (HM) supplemented with human milk oligosaccharides (HMOs) and to study uptake of the HMOs. METHODS: A prospective, randomized, controlled, growth and tolerance study was conducted in healthy, singleton infants (birth weight ≥2490 g), who were enrolled by day of life (DOL) 5. Formula-fed infants were randomized to 1 of 3 formulas with a caloric density of 64.3 kcal/dL. Each formula contained galactooligosaccharides, and the 2 experimental formulas contained varying levels (0.2 and 1.0 g/L) of the HMO 2'-fucosyllactose (2'FL). The 3 formula groups were compared with an HM-fed reference group. Infants were exclusively fed either formula (n = 189) or HM (n = 65) from enrollment to 119 DOL. 2'FL was measured in the blood and urine collected from a subset of infants at DOL 42 and 119, and in HM collected from breast-feeding mothers at DOL 42. RESULTS: There were no significant differences among any groups for weight, length, or head circumference growth during the 4-month study period. All of the formulas were well tolerated and comparable for average stool consistency, number of stools per day, and percent of feedings associated with spitting up or vomit. 2'FL was present in the plasma and urine of infants fed 2'FL, and there were no significant differences in 2'FL uptake relative to the concentration fed. CONCLUSIONS: This is the first report of infants fed 2'FL-fortified formulas with a caloric density similar to HM. Growth and 2'FL uptake were similar to those of HM-fed infants.

Induced fit or conformational selection? The role of the semi-closed state in the maltose binding protein.

A full characterization of the thermodynamic forces underlying ligand-associated conformational changes in proteins is essential for understanding and manipulating diverse biological processes, including transport, signaling, and enzymatic activity. Recent experiments on the maltose binding protein (MBP) have provided valuable data about the different conformational states implicated in the ligand recognition process; however, a complete picture of the accessible pathways and the associated changes in free energy remains elusive. Here we describe results from advanced accelerated molecular dynamics (aMD) simulations, coupled with adaptively biased force (ABF) and thermodynamic integration (TI) free energy methods. The combination of approaches allows us to track the ligand recognition process on the microsecond time scale and provides a detailed characterization of the protein's dynamic and the relative energy of stable states. We find that an induced-fit (IF) mechanism is most likely and that a mechanism involving both a conformational selection (CS) step and an IF step is also possible. The complete recognition process is best viewed as a "Pac Man" type action where the ligand is initially localized to one domain and naturally occurring hinge-bending vibrations in the protein are able to assist the recognition process by increasing the chances of a favorable encounter with side chains on the other domain, leading to a population shift. This interpretation is consistent with experiments and provides new insight into the complex recognition mechanism. The methods employed here are able to describe IF and CS effects and provide formally rigorous means of computing free energy changes. As such, they are superior to conventional MD and flexible docking alone and hold great promise for future development and applications to drug discovery.

Review of the Clinical Experiences of Feeding Infants Formula Containing the Human Milk Oligosaccharide 2'-Fucosyllactose.

Human milk oligosaccharides (HMOs) are the third most abundant solid component in human milk after lactose and lipids. Preclinical research has demonstrated that HMOs and specifically 2'-fucosyllactose (2'-FL) are more than a prebiotic and have multiple functions, including immune, gut, and cognition benefits. Previously, human milk has been the only source for significant levels of HMOs. The most abundant HMO in most mothers' breast milk is 2'-FL. Recently, 2'-FL has been synthesized and shown to be structurally identical to the 2'-FL found in human milk. 2'-FL HMO is now available in some commercial infant formulas. The purpose of this narrative review was to summarize the clinical experiences of feeding infant formula supplemented with the HMO, 2'-FL. Most of these studies investigated standard intact milk protein-based infant formulas containing 2'-FL, and one evaluated a partially hydrolyzed whey-based formula. Collectively, these clinical experiences demonstrated that 2'-FL being added to infant formula was safe, well-tolerated, and absorbed and excreted with similar efficiency to 2'-FL in human milk. Further, infants that were fed formula with 2'-FL had immune benefits, fewer parent-reported respiratory infections, and improved symptoms of formula intolerance. Ultimately, infant formula with 2'-FL supports immune and gut health and is closer compositionally and functionally to human milk.

Difructose anhydride III promotes absorption of the soluble flavonoid alphaG-rutin in rats.

A highly soluble quercetin glycoside, alphaG-rutin, is a glucose adduct of insoluble rutin. We examined the effects of difructose anhydride III (DFAIII; di-D-fructofuranosyl 1,2':2,3'-dianhydride) on intestinal absorption of alphaG-rutin by rat experiments. alphaG-rutin, rutin, quercetin, and the quercetin conjugate appeared in the portal blood after an intubation of alphaG-rutin (100 micromol), DFAIII effected higher portal concentrations of alphaG-rutin in portal cannulated rats. In ligated jejunal and ileal loops of rats, alphaG-rutin, rutin, quercetin, and the quercetin conjugate appeared in the intestinal mesenteric blood at both 30 and 60 min in both loops; the concentration of alphaG-rutin was 1.5-3 times higher when absorbed in the presence DFAIII. In the isolated mucosae of the jejunum and ileum, mucosal-to-serosal passage of alphaG-rutin increased with the addition of 100 micromol of DFAIII. These results indicate that alphaG-rutin is absorbed as the intact form and that DFAIII stimulates its absorption in the small intestine.

Pharmacokinetics of oral antihyperglycaemic agents in patients with renal insufficiency.

This paper reviews the effects of renal insufficiency on the pharmacokinetics of oral antidiabetic drugs. Of the 3 groups of drugs currently available for the treatment of non-insulin-dependent diabetes mellitus (NIDDM), the sulphonylureas and metformin are, in general, well-tolerated and generally safe. In patients with chronic renal insufficiency, however, care must be exercised in the use of many of these drugs, as accumulation, either of the active drug or of active metabolites, can lead to serious adverse effects such as hypoglycaemia or, with metformin, lactic acidosis. The sulphonylurea drugs, to a greater or lesser degree, are metabolised in the liver to a variety of active or inactive compounds which, in general, are excreted by the kidneys. In addition, varying amounts of parent compound may depend on renal elimination. As a result, sulphonylurea drugs such as tolazamide, acetohexamide, chlorpropamide and glibenclamide (glyburide) are more likely to cause significant hypoglycaemia, as the metabolism of these drugs, compared with other commonly prescribed sulphonylureas, can lead to the accumulation of either the parent drug or the active metabolite in the presence of renal insufficiency. Tolbutamide, glipizide, gliclazide and gliquidone are much less likely to cause hypoglycaemia as their metabolites are either inactive or have minimal hypoglycaemic potency. Metformin is dependent on renal excretion and is not significantly metabolised. As a result, caution is required when treating patients with renal insufficiency where metformin accumulation can occur, with the danger of lactic acidosis. Although the correlation between creatinine clearance (CLCR) and total oral clearance of drug is weaker than the correlation between CLCR and renal clearance (CLR) of metformin, it is clear that renal insufficiency is associated with most cases of metformin-induced lactic acidosis. For this reason, clinicians in general would regard a raised plasma creatinine as a contraindication to metformin treatment. Acarbose, an alpha-glucosidase inhibitor, and a relatively new agent for treating NIDDM, is likely to be safe in patients with impaired renal function, as the drug is not significantly absorbed from the gut, but data on this subject are lacking.

Pharmacokinetic-pharmacodynamic relationships of Acarbose.

Acarbose represents a new pharmacological approach to achieving the metabolic benefits of a slower carbohydrate absorption in diabetes, by acting as a potent, competitive inhibitor of intestinal alpha-glucosidases. Acarbose molecules attach to the carbohydrate binding sites of alpha-glucosidases, with an affinity constant that is much higher than that of the normal substrate. Because of the reversible nature of the inhibitor-enzyme interaction, the conversion of oligosaccharides to monosaccharides is only delayed rather than completely blocked. Acarbose has the structural features of a tetrasaccharide and does not cross the enterocytes after ingestion. Thus, its pharmacokinetic properties are well suited to the pharmacological action directed exclusively towards the intestinal glucosidases. The most important clinical consequence of the delayed carbohydrate digestion caused by acarbose is the attenuation of postprandial increases in blood glucose levels. Other effects have also been described: a decreased beta-pancreatic response to meals, and influences on gut hormone secretion and plasma lipid levels. Gastrointestinal discomfort is frequently reported as an adverse effect of acarbose administration, but incidence usually decreases with time. The suitability of acarbose for improving glucose homeostasis as an adjunct to dietary control or to administration of sulphonylureas or insulin has been extensively studied in patients both with type 1 (insulin-dependent) and type 2 (non-insulin-dependent) diabetes mellitus. Acarbose can be used as first-line therapy in patients with type 2 diabetes which is poorly controlled by diet alone. Moreover, the lack of bodyweight gain or hypoglycaemic effects reported during acarbose treatment may be advantageous for obese or elderly patients. Finally, the reduction in fluctuations of glucose levels throughout the day may help to control type 1 diabetes in patients with 'brittle diabetes'. Long term prospective studies are still needed to confirm these indications and the usefulness of acarbose in conditions other than diabetes, notably reactive hypoglycaemia and dumping syndrome.

Acarbose. A preliminary review of its pharmacodynamic and pharmacokinetic properties, and therapeutic potential.

Acarbose delays the production of monosaccharides (notably glucose) by inhibiting the alpha-glucosidases associated with the brush-border membrane of the small intestine which are responsible for the digestion of complex polysaccharides and sucrose. In healthy subjects acarbose 100 to 200 mg significantly inhibits postprandial glucose, insulin and triglyceride responses, with some evidence of carbohydrate malabsorption with the higher dose. Clinical trials in patients with non-insulin-dependent diabetes mellitus showed that acarbose improved diabetic control, especially postprandial blood glucose levels, independent of whether the patients were receiving concomitant oral antidiabetic drugs in addition to dietary management. In comparative studies acarbose was significantly superior to placebo, and comparable to biguanides, when used alone or as an adjuvant to sulphonylurea therapy. Trials in patients requiring insulin to control their diabetes demonstrated that acarbose significantly reduced postprandial blood glucose concentrations, resulting in a smoother diurnal blood glucose-time curve and improved symptoms associated with nocturnal hypoglycaemia. Daily insulin requirements were sometimes reduced. In large multicentre trials acarbose up to 600 mg/day for 3 to 12 months improved glycaemic control in approximately 55% of patients with non-insulin-dependent or insulin-dependent diabetes mellitus. Apart from its use in diabetes, encouraging preliminary results have been obtained with acarbose in other therapeutic areas such as dumping syndrome, reactive hypoglycaemia, and types IIb and IV hyperlipoproteinaemias--however, further clinical experience is needed in these settings before clear conclusions can be drawn. No serious side effects have been reported during treatment with acarbose, although it is associated with a high incidence of troublesome gastrointestinal symptoms such as flatulence, abdominal distension, borborygmus and diarrhoea. The incidence of these reactions usually decreases with time. Thus, acarbose represents the first of a new class of oral antidiabetic drugs--the alpha-glucosidase inhibitors. It has proven useful for improving glycaemic control when used as an adjunct to standard therapy involving dietary restriction, oral antidiabetic drugs and/or subcutaneous insulin. That being the case, acarbose should provide the clinician with an interesting treatment option which can be used in a broad range of patients with diabetes mellitus in whom 'traditional' management approaches produce suboptimal glycaemic control.

Acarbose. An update of its pharmacology and therapeutic use in diabetes mellitus.

Acarbose delays digestion of complex carbohydrates and disaccharides to absorbable monosaccharides, by reversibly inhibiting alpha-glucosidases within the intestinal brush border, thereby attenuating postprandial blood glucose peaks. Clinical trials have demonstrated that acarbose generally improves glycaemic control in patients with non-insulin-dependent diabetes mellitus (NIDDM) managed with diet alone, or with other antidiabetic therapy, as evidenced by decreased postprandial plasma glucose and glycosylated haemoglobin levels. It does not appear to directly alter insulin resistance, but may lower postprandial plasma insulin levels. Fasting plasma glucose, triglyceride and/or cholesterol levels may also be decreased. Acarbose also improved metabolic control in patients with insulin-dependent diabetes mellitus (IDDM), frequently decreasing insulin requirements, although further studies are required in this indication. Improved metabolic control appears to delay or prevent long term vascular complications of diabetes, and indeed, acarbose appeared to inhibit development of such complications in preliminary animal studies, but this finding requires confirmation in clinical studies. While acarbose seldom causes systemic adverse effects, it is associated with a high incidence of gastrointestinal disturbances such as flatulence, abdominal distension, borborygmus and diarrhoea, caused by fermentation of unabsorbed carbohydrates. However, these symptoms tend to subside with continued treatment and adherence to an appropriate diet. Thus, acarbose appears to be a worthwhile adjunctive therapeutic option for patients with NIDDM inadequately managed by diet alone, or with pharmacological therapy, and possibly also for patients with IDDM. However, further long term efficacy and tolerability data are required, particularly in the latter indication.

Comparative tolerability profiles of oral antidiabetic agents.

The sulphonylureas and the biguanides are widely used as adjuncts to dietary measures in the treatment of non-insulin-dependent (type 2) diabetes mellitus (NIDDM). Adverse effect profiles differ markedly between the sulphonylureas and biguanides, reflecting differences in chemical structure and mode of action. Sulphonylureas are generally well tolerated, although pharmacokinetic differences between these agents have important clinical implications. The main adverse effect associated with sulphonylureas is hypoglycaemia. This effect is a predictable consequence of the principal pharmacological effect of these drugs, i.e. sensitisation of the islet beta-cell to glucose, resulting in enhanced endogenous insulin secretion. Sulphonylurea-induced suppression of hepatic glucose production may cause profound and protracted hypoglycaemia, especially in elderly patients, in individuals with intercurrent illnesses and reduced caloric intake, or when taken in combination with other compounds with hypoglycaemic potential, e.g. alcohol (ethanol). Sulphonylureas with a longer duration of action, notably chlorpropamide and glibenclamide (glyburide), are more liable to induce serious hypoglycaemia, particularly when drug elimination is reduced by renal impairment. Other drugs such as salicylates may potentiate the actions of sulphonylureas, thereby increasing the risk of hypoglycaemia. Biguanide therapy is associated with alterations in lactate homeostasis which under certain clinical circumstances may result in fatal lactic acidosis. Phenformin is associated with a markedly greater risk of lactic acidosis than metformin. Phenformin has been withdrawn in many countries for this reason. All biguanides must be avoided in patients with renal impairment, hepatic dysfunction and cardiac failure--conditions where drug accumulation or disordered lactate metabolism may predispose to lactic acidosis. Phenformin should not be given to individuals who exhibit a severe, genetically conferred hepatic defect of hydroxylation which impedes metabolism of this drug. Less seriously, the biguanides are associated with a relatively high incidence of gastrointestinal adverse effects which limit compliance. Acarbose, a competitive inhibitor of intestinal alpha-glucosidases, has recently been introduced. In contrast to the sulphonylureas and biguanides, acarbose has not been associated with life-threatening adverse effects. This reflects the low systemic absorption of the drug and, predictably, its principal unwanted effects are gastrointestinal disturbances resulting from iatrogenic carbohydrate malabsorption.

Effects of beano on the tolerability and pharmacodynamics of acarbose.

Acarbose is an alpha-glucosidase inhibitor approved for the treatment of type 2 diabetes mellitus. Acarbose inhibits carbohydrate digestion, allowing an excessive amount of undigested carbohydrate to reach the colon. Bacterial fermentation of the carbohydrate produces intestinal gas, which can cause flatulence and abdominal pain. Beano, an over-the-counter enzyme preparation (alpha-galactosidase), diminishes intestinal gas production by enhancing the breakdown of certain carbohydrates before they reach the lower intestine. This study was undertaken to investigate whether concomitant administration of Beano and acarbose could reduce the flatulence associated with acarbose and, if so, whether Beano would interfere with the effects of acarbose on postprandial serum glucose concentration. In this randomized, double-masked, placebo-controlled, three-period crossover study, 37 patients with type 2 diabetes mellitus received acarbose 100 mg, acarbose 100 mg plus Beano, or placebo. The study population consisted of 20 males and 17 females who ranged in age from 36 to 72 years (mean, 56 years) and in weight from 62 to 142 kg (mean, 92 kg). Each treatment period consisted of 3 days, during which both acarbose and Beano were given at the beginning of each of three meals. There was a 4-day washout interval between each treatment period. The frequency and severity of flatulence were measured using a score compiled from patient diaries. As an additional measure of intestinal gas production, breath hydrogen concentration was measured on day 3 of each treatment period. Postprandial serum glucose concentration was measured at predetermined times after each morning dose to assess pharmacodynamic activity. Patients who took Beano with acarbose had a significantly lower flatulence score than did those who took acarbose alone (0.79 vs 1.09). Consistent with this finding, breath hydrogen concentration was lower after administration of acarbose plus Beano than with acarbose alone (31.2 ppm vs 50.5 ppm). Beano had variable effects on the ability of acarbose to reduce the postprandial serum glucose concentration. Although postprandial serum glucose levels were higher in patients who received acarbose plus Beano than in those who received acarbose alone, both treatments (with or without Beano) resulted in postprandial serum glucose levels that were significantly lower than those seen with placebo. Therefore, although Beano appeared to diminish the activity of acarbose, postprandial serum glucose concentrations still decreased significantly in patients taking Beano with acarbose. Beano has been shown to alleviate the flatulence accompanying acarbose treatment, but it may also interfere with the glucose-lowering effect of acarbose.

Conditioned control of ingestive behavior by acarbose-induced inhibition of sucrose ingestion in the rat.

It has been reported that the addition of Acarbose, a alpha-glucosidase inhibitor, to a carbohydrate solution blocks a preference that otherwise would be displayed for that solution. One interpretation of those results is that the alteration in preference was caused by the diminished postabsorptive nutritive value of the diet due to the inhibition of hydrolysis of the carbohydrates, and, thus, its absorption. An alternative explanation is that the reduction in the preference was a consequence of an accumulation of undigested carbohydrates in the lumen of the intestine. In the studies reported here, designed to investigate this alternative explanation, it was shown that Acarbose added to a flavored 0.3 M sucrose solution reduced the preference for that solution in a two-bottle preference test. An analysis of the licking behavior of rats ingesting flavored 0.3 M sucrose solutions with and without the addition of Acarbose revealed that the presence of Acarbose in the test solution caused a conditioned reduction in the rate of licking the test solution at the beginning of the meal and, as a result, a reduction in intake of the solution. This conditioned control of the rate of licking was rapidly acquired and was easily reversed. It was also shown that Acarbose increased fluid retention in the small intestine, suggesting that the conditioning may have been based on the accumulation of undigested disaccharides in the intestinal lumen rather than on the diminished postabsorptive nutritive value of the ingested sucrose.(ABSTRACT TRUNCATED AT 250 WORDS)

The effect of a standard oral calcium load given in two different forms on plasma ionized calcium and serum PTH.

A standard dose (1 g, 25.4 mmol) of calcium was administered both as calcium chloride in syrup and as Calcium-Sandoz Syrup (calcium glubionate and calcium galactogluconate) to 10 volunteers. Both dosage forms caused a significant rise in ionized calcium and a significant fall in concentration of serum PTH, the calcium chloride producing significantly greater changes. The urinary excretion of calcium measured over 5 h after calcium chloride was double that after Calcium-Sandoz. Calcium chloride, as expected, also gave rise to a decreased urine pH. Calcium chloride would be the better choice for an oral PTH suppression test.

Absorption and urinary excretion of quercetin, rutin, and alphaG-rutin, a water soluble flavonoid, in rats.

Quercetin, rutin, alphaG-rutin (a water soluble flavonoid), and a mixture of rutin and alphaG-rutin were administered to rats by a single gastric intubation, and their absorption and urinary excretion were examined. The plasma and 24 h urinary levels of aglycons (quercetin and tamarixetin/isorhamnetin) were measured by HPLC after deconjugation with beta-glucuronidase/sulfatase treatment. alphaG-rutin was absorbed more rapidly than quercetin or rutin, and the plasma concentrations of quercetin and tamarixetin/isorhamnetin reached the highest peak level 30 min after dosing. Quercetin, rutin, and the mixture of rutin and alphaG-rutin showed the first peak level 8 h, 8 h, and 30 min after dosing, respectively. The area under the concentration-time curve (AUC) for quercetin in rats administered alphaG-rutin was approximately 4.5- and 2-fold higher than those in rats administered quercetin and rutin, respectively, and was almost the same as that in rats administered a mixture of rutin and alphaG-rutin. The highest 24 h urinary excretion was observed in alphaG-rutin-administered rats. These results suggest that alphaG-rutin is absorbed more efficiently than either quercetin or rutin and that a high plasma concentration can be maintained by supplying rutin and alphaG-rutin in combination.

Utilization and metabolism of [U-14C]4' galactosyllactose (O-beta-D-galactopyranosyl-(1----4)-O-beta-D-galactopyranosyl-(1----4)- D-glucopyranose) in rats.

O-beta-D-Galactopyranosyl-(1----4)-O-beta-D-galactopyranosyl- (1----4)-D-glucopyranose (designated as 4'GL) are produced from lactose with Cryptococcus laurentii OKN-4. Excretion and metabolism of 4'GL in rats were examined using a radioisotope technique. [U-14c]4'GL was synthesized from [U-14C]lactose by Cryptococcus laurentii OKN-4. The 14CO2 in expired air was counted after oral administration of [U-14C]4'GL or [U-14C]lactose in conventional rats, rats treated with antibiotics and germ-free rats. The rate of 14CO2 excretion from conventional rats given [U-14C]4'GL was slower than that from those administered [U-14C]lactose. When [U-14C]4'GL was orally administered to rats given antibiotics, there was a 2-h delay in 14CO2 excretion, as compared to conventional rats. In germ-free rats, total excretion of 14CO2 from [U-14C]-4'GL decreased to about one-third of that of conventional rats during a 24-h period. Radioactivities in the serum, liver, and carcass of the [U-14C]4'GL oral administration group were lower than those of the [U-14C]lactose oral administration group. Radioactivities in the feces and urine however, were higher in [U-14C]4'GL group than in [U-14C]lactose group.

[Alpha-glucosidase inhibitors: a new therapeutic approach in diabetes and functional hypoglycemia]. / Inhibiteurs des alpha-glucosidases: une nouvelle approche thérapeutique du diabète et des hypoglycémies fonctionnelles.

Acarbose, a potent alpha-glucosidase inhibitor, represents a new concept for the treatment of metabolic disorders, and particularly diabetes mellitus. It slows the absorption kinetics of dietary carbohydrates by reversible competitive inhibition of alpha-glucosidase activity, and so reduces the post-prandial blood glucose increment and insulin response. For these reasons, the drug has been successfully used not only in the treatment of type I or type II diabetes, but also in the management of reactive hypoglycemias and dumping syndrome. In addition, some data suggest a possible role in the treatment of type IV hyperlipidemia. Because of the delay in absorption of oligo- and disaccharides resulting from its administration, a colic bacterial fermentation occurs, accounting for the frequent abdominal discomfort mentioned by the patients. These side effects would be lessened with the second generation glucosidase inhibitors now in progress.

Oligosaccharide promotes bioavailability of a water-soluble flavonoid glycoside, alpha G-rutin, in rats.

This study examined the effects of a nondigestible saccharide, difructose anhydride (DFA) III, and fructooligosaccharides (FOS) on the intestinal absorption and metabolism of alpha G-rutin, a quercetin glycoside in rats during a 2 week feeding period with diets containing 1% alpha G-rutin with or without 1.5 or 3% DFAIII and FOS. Blood concentrations and urinary excretion of quercetin derivatives were largely and dose-dependently increased during the test period with feeding DFA III and FOS. The amounts of quercetin derivatives in the cecal contents and feces were also much higher in both saccharide groups than in the control group. The degradation rate of aglycone, estimated by differences between ingestion and sum of fecal and urinary excretion, were suppressed in the both saccharide groups. Cecal fermentation was dose-dependently modified by the oligosaccharides. It was concluded that suppression of degrading quercetin aglycone in the large intestine has a major role for increasing alpha G-rutin bioavailability by DFA III and FOS feedings.