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Purpose: Active hexose-correlated compound (AHCC), a standardized extract of cultured Lentinula edodes mycelia, exerts antitumor effects through anti-inflammatory and immune-modulatory functions. Adjuvant therapy for patients with hepatocellular carcinoma (HCC) who have undergone curative hepatectomy has not been established. The purpose of this study was to evaluate the efficacy and safety of AHCC as adjuvant therapy in patients with advanced HCC after curative hepatectomy., Patients and Methods: The study design was single-armed, non-randomized, open (no one was blinded), and uncontrolled. Patients with HCC who underwent curative hepatectomy were treated with AHCC (1 g) 3 times daily orally for 2 years. The inclusion criteria were HCC diagnosed preoperatively as stages A and B of the Barcelona clinic liver cancer (BCLC) classification and alpha-fetoprotein × protein induced by vitamin K absence or antagonist II (PIVKA-II) ≥ 10 5 for stage A., Results: A total of 29 patients were treated with AHCC, of which 25 (4 patients discontinued) were followed up. The 2-year recurrence-free survival rate after resection was 48% for those without discontinuations and 55.2% for all patients with a history of treatment. Serum albumin levels decreased to a minimum in the first postoperative month and gradually recovered to the preoperative level at 6 months. Almost no change in lymphocyte percentage was observed during follow-up. Inflammation-based prognostic scores were maintained at favorable levels after hepatectomy. Toxicity and adverse events were not observed in any patient., Conclusion: AHCC may be safe and effective in preventing HCC recurrence after curative hepatectomy, and further randomized trials of AHCC for its use in this setting are warranted.This clinical trial was registered in UMIN Clinical Trials Registry (ID UMIN000024396).

Synbiotics, a combination of prebiotics and probiotics, produce synergistic effects to promote gastrointestinal health. Herein, we investigated the synbiotic interaction between the Lactobacillus rhamnosus strain GG (LGG; a probiotic strain) and tagatose (a prebiotic) in a dextran sulfate sodium (DSS)-induced colitis murine model. Initially, body weight, food intake, and clinical features were dramatically decreased after treatment with DSS, and the addition of LGG, tagatose, or both ameliorated these effects. In our pyrosequencing analysis of fecal microbiota, DSS treatment increased the abundance of Proteobacteria and decreased that of Firmicutes. When LGG and tagatose were administered as synbiotics, the gut microbiota composition recovered from the dysbiosis caused by DSS treatment. In particular, the abundance of Bacteroides, Lactobacillus, and Akkermansia was significantly associated with probiotic, prebiotic, and synbiotic treatments. Taken together, our results suggest that LGG and tagatose as synbiotics can alleviate colitis, and synbiotics could be applied as dietary supplements in dairy foods such as yogurt and cheese., (Copyright © 2019 American Dairy Science Association. Published by Elsevier Inc. All rights reserved.)

In the current study, we have tested the nonenzymatic glycation activities of ketohexoses, such as tagatose and psicose. Although tagatose-treated apoA-I (t-A-I) and psicose-treated apoA-I (p-A-I) exerted more inhibitory activity you cupric ion-mediated low-density lipoprotein (LDL) oxidation and oxidized LDL (oxLDL) phagocytosis into macrophage than fructose-treated apoA-I (f-A-I). In the lipid-free state, t-A-I and f-A-I showed more multimerized band without crosslinking. Since t-A-I lost its phospholipid binding ability, the rHDL formation was not as successful as f-A-I. However, injecting t-A-I showed more antioxidant activities in zebrafish embryo under the presence of oxLDL. Three weeks of consumption of fructose (50% of wt in Tetrabit/4% cholesterol) showed a 14% elevation of serum triacylglycerol (TG), while tagatose-administered group showed 30% reduction in serum TG compared to high cholesterol control. Fructose-fed group showed the biggest area of Oil Red O staining with the intensity as strong as the HCD control. However, tagatose-consumed group showed much lesser Oil Red O-stained area with the reduction of lipid accumulation. In conclusion, although tagatose treatment caused modification of apoA-I, the functional loss was not as much severe as the fructose treatment in macrophage cell model, zebrafish embryo, and hypercholesterolemic zebrafish model.

The objective of the current research was to review and update evidence on the dietary effect of the consumption of tagatose in type 2 diabetes, as well as to elucidate the current approach that exists on its production and biotechnological utility in functional food for diabetics. Articles published before July 1, 2017, were included in the databases PubMed, EBSCO, Google Scholar, and Scielo, including the terms "Tagatose", "Sweeteners", "Diabetes Mellitus type 2", "Sweeteners", "D-Tag". D-Tagatose (D-tag) is an isomer of fructose which is approximately 90% sweeter than sucrose. Preliminary studies in animals and preclinical studies showed that D-tag decreased glucose levels, which generated great interest in the scientific community. Recent studies indicate that tagatose has low glycemic index, a potent hypoglycemic effect, and eventually could be associated with important benefits for the treatment of obesity. The authors concluded that D-tag is promising as a sweetener without major adverse effects observed in these clinical studies.

Nanoemulsions are feasible delivery systems of lipophilic compounds, showing potential as edible coatings with enhanced functional properties. The aim of this work was to study the effect of emulsifier type (stearic acid (SA), Tween 80 (T80) or Tween 80/Span 60 (T80/S60)) and emulsification process (homogenization, ultrasound or microfluidization) on nanoemulsion formation based on oxidized corn starch, beeswax (BW) and natural antimicrobials (lauric arginate and natamycin). The response variables were physicochemical properties, rheological behavior, wettability and antimicrobial activity of BW-starch nanoemulsions (BW-SN). The BW-SN emulsified using T80 and microfluidized showed the lowest droplet size (77.6 ± 6.2 nm), a polydispersion index of 0.4 ± 0.0 and whiteness index (WI) of 31.8 ± 0.8. This BW-SN exhibited a more negative ζ-potential: -36 ± 4 mV, and Newtonian flow behavior, indicating great stability. BW-SN antimicrobial activity was not affected by microfluidization nor the presence of T80, showing inhibition of the deteriorative fungi R. stolonifer , C. gloeosporioides and B. cinerea , and the pathogenic bacterium S. Saintpaul. In addition, regardless of emulsifier type and emulsification process, BW-SN applied on the tomato surface exhibited low contact angles (38.5° to 48.6°), resulting in efficient wettability (-7.0 mN/m to -8.9 mN/m). These nanoemulsions may be useful to produce edible coatings to preserve fresh-produce quality and safety., Competing Interests: The authors declare that there is not conflict of interests regarding the publication of this paper.

Context: Gout is a painful disorder which does not have an efficient delivery system for its treatment., Objective: Development and in vitro, in vivo evaluation of allopurinol-loaded nonionic surfactant-based niosomes was envisaged., Materials and Methods: Niosomes were prepared with Span 20 and Tween 20 (1:1 molar ratio) using ether injection method. The formulations were screened for entrapment efficiency, particle size analysis, zeta potential, release kinetics, in vivo activity, and stability studies., Result: Stable, spherical vesicles of average particle size 304 nm with zeta-potential and entrapment efficiency of 22.2 mV and 79.44 ± 0.02%, respectively, were produced. In vitro release study revealed 82.16 ± 0.04% release of allopurinol within 24 h. The niosomal formulation was further evaluated for its antigout potential in monosodium urate (MSU) crystal induced gout animal model. The formulation demonstrated significant uric acid level reduction and enhanced antigout activity when compared with the pure allopurinol., Discussion: The better antigout activity displayed by niosomal formulation could be attributed to sustained release of drug, higher drug solubility within biological fluids, better membrane interaction, smaller size, and presence of cholesterol and surfactant., Conclusions: This study reveals that niosomes can be an efficient delivery system for the treatment of gout.

PELC is a novel emulsion-type adjuvant that contains the bioresorbable polymer poly (ethylene glycol)-block-poly (lactide-co-ε-caprolactone) (PEG-b-PLACL), Span®85 and squalene. To investigate whether PELC is able to enhance CTL responses of antigens for treating tumor, peptides or protein antigens derived from HPV16 E7 were formulated with PELC nanoparticles and CpG oligodeoxynucleotide. We identified that PELC formulation could delay the release of antigens in vitro and in vivo. We assessed the immunogenicity of an H-2D(b)-restricted CTL epitope RAHYNIVTF (RAH) formulated with PELC or PELC/CpG and investigated the ability of these formulations to promote tumor regression. Following a single-dose subcutaneous injection in mice, we found that the RAH peptide formulated with PELC/CpG (RAH/PELC/CpG) resulted in increased numbers of IFN-γ-secreting cells and RAH-specific CD8(+) T cells and an enhanced cytotoxic T cell response compared with RAH formulated with PELC or CpG alone. The tumor-bearing mice received a single-dose injection of RAH/PELC/CpG, which induced complete tumor regression. These results demonstrated that peptide antigen formulated with PELC/CpG nanoparticles is feasible for cancer immunotherapy., (© 2013. Published by Elsevier B.V. All rights reserved.)

Nearly 285 million people worldwide, with 10% being Americans, suffer from diabetes mellitus and its associated comorbidities. This is projected to increase by 6.5% per year, with 439 million inflicted by year 2030. Both morbidity and mortality from diabetes stem from the consequences of microvascular and macrovascular complications. Of the 285 million with diabetes, over a quarter of a million die per year from related complications, making diabetes the fifth leading cause of death in high-income countries. These startling statistics illustrate the therapeutic failure of current diabetes drugs to retard the progression of diabetes. These statistics further illustrate the continual need for further research and development of alternative drugs with novel mechanisms to slow disease progression and disease complications. The treatment algorithm updated in 2008 by American Diabetes Association and the European Association for the Study of Diabetes currently recommends the traditional medications of metformin, either as monotherapy or in combination with sulfonylurea or insulin, as the preferred choice in the tier 1 option. The algorithm only suggests addition of alternative medications such as pioglitazone and incretin-based drugs as second-line agents in the tier 2 "less well-validated" option. However, these traditional medications have not proven to delay the progressive course of diabetes as evidence of increasing need over time for multiple drug therapy to maintain sufficient glycemic control. Because current diabetes medications have limited efficacy and untoward side effects, the development of diabetes mellitus drugs with newer mechanisms of action continues. This article will review the clinical data on the newly available incretin-based drugs on the market, including glucagon-like peptide agonists and of dipeptidyl peptidase type-4 inhibitors. It will also discuss 2 unique medications: pramlintide, which is indicated for both type and type-2 diabetes, and colesevelam, which is approved by the United States Food and Drug Administration for both type-2 diabetes and hyperlipidemia. It will further review the clinical data on the novel emerging agents of sodium-glucose cotransporter-2 inhibitors, tagatose, and succinobucol, all currently in phase III clinical trials. This review article can serve as an aid for clinicians to identify clinical indications in which these new agents can be applied in the treatment algorithm.

Objectives: Catheter-related bloodstream infections (CRBSIs) are common healthcare-associated infections associated with increased morbidity and medical costs. Antiseptic- and antibiotic-coated central venous catheters (CVCs) have been proposed to reduce the incidence of CRBSIs, with variable success. The aim of this study was to determine the in vivo antibiofilm activity of biocompatible and inexpensive compounds, such as cerium nitrate, chitosan and hamamelitannin, against usual agents of CRBSIs., Methods: The antibiofilm effect of cerium nitrate, chitosan and hamamelitannin was tested against Staphylococcus epidermidis, Staphylococcus aureus, Acinetobacter baumannii and Candida albicans in a mouse foreign body infection model, using polyurethane catheter segments. Biofilm formation was assessed with a crystal violet assay to quantify the total biomass, with a tetrazolium reduction assay to quantify the metabolic activity and with scanning electron microscopy., Results: At subinhibitory concentrations, cerium nitrate significantly reduced biofilm formation by C. albicans, chitosan significantly decreased biofilm formation by S. epidermidis and C. albicans, and hamamelitannin significantly inhibited all bacterial biofilms., Discussion: The in vivo antibiofilm effect of cerium nitrate against C. albicans and of chitosan against C. albicans and S. epidermidis, at subinhibitory concentrations, makes them promising alternatives to coat CVCs. Moreover, the microbicidal effect on a wider range of CVC colonizers was previously reported in vitro for both compounds, at higher concentrations. For all bacterial strains, the highest in vivo antibiofilm efficacy was achieved with hamamelitannin. For A. baumannii, this is the first report of in vivo inhibition.

Background: There are two components to the clinical efficacy of pediculicides: (i) efficacy against the crawling-stages (lousicidal efficacy); and (ii) efficacy against the eggs (ovicidal efficacy). Lousicidal efficacy and ovicidal efficacy are confounded in clinical trials. Here we report on a trial that was specially designed to rank the clinical ovicidal efficacy of pediculicides. Eggs were collected, pre-treatment and post-treatment, from subjects with different types of hair, different coloured hair and hair of different length., Method: Subjects with at least 20 live eggs of Pediculus capitis (head lice) were randomised to one of three treatment-groups: a melaleuca oil (commonly called tea tree oil) and lavender oil pediculicide (TTO/LO); a eucalyptus oil and lemon tea tree oil pediculicide (EO/LTTO); or a "suffocation" pediculicide. Pre-treatment: 10 to 22 live eggs were taken from the head by cutting the single hair with the live egg attached, before the treatment (total of 1,062 eggs)., Treatment: The subjects then received a single treatment of one of the three pediculicides, according to the manufacturers' instructions. Post-treatment: 10 to 41 treated live eggs were taken from the head by cutting the single hair with the egg attached (total of 1,183 eggs). Eggs were incubated for 14 days. The proportion of eggs that had hatched after 14 days in the pre-treatment group was compared with the proportion of eggs that hatched in the post-treatment group. The primary outcome measure was % ovicidal efficacy for each of the three pediculicides., Results: 722 subjects were examined for the presence of eggs of head lice. 92 of these subjects were recruited and randomly assigned to: the "suffocation" pediculicide (n = 31); the melaleuca oil and lavender oil pediculicide (n = 31); and the eucalyptus oil and lemon tea tree oil pediculicide (n = 30 subjects). The group treated with eucalyptus oil and lemon tea tree oil had an ovicidal efficacy of 3.3% (SD 16%) whereas the group treated with melaleuca oil and lavender oil had an ovicidal efficacy of 44.4% (SD 23%) and the group treated with the "suffocation" pediculicide had an ovicidal efficacy of 68.3% (SD 38%)., Conclusion: Ovicidal efficacy varied substantially among treatments, from 3.3% to 68.3%. The "suffocation" pediculicide and the melaleuca oil and lavender oil pediculicide (TTO/LO) were significantly more ovicidal than eucalyptus oil and lemon tea tree oil pediculicide (EO/LTTO) (P < 0.0001). Ranking: 1. "Suffocation" pediculicide (68.3% efficacy against eggs); 2. Melaleuca oil and lavender oil (44.4%) pediculicide; 3. Eucalyptus oil and lemon tea tree oil (3.3%) pediculicide. The "suffocation" pediculicide and TTO/LO are also highly efficacious against the crawling-stages. Thus, the "suffocation" pediculicide and TTO/LO should be recommended as first line treatments.

The aim of this study is to investigate the mechanism of an action of compound isolated from Vitex negundo in streptozotocin-induced diabetic mice. Light microscopic examination of liver, kidney and pancreatic sections of streptozotocin-induced diabetic mice showed changes like coarsening of acinar cells of endoplasmic reticulum, destruction of β-cells, and alteration in their secretory function were observed in the pancreas. Changes like dilation of vein, unusual concentric arrangement of hepatocytes, and liver fibrosis were observed in the liver. Thickening of tubules and expansion of glomerulus were observed in kidneys. All these altered parameters were reversed close to normal condition upon treatment using idopyranose. The results show the antidiabetic potential of idopyranose. Interestingly, liver, kidney, and pancreatic sections of diabetic mice fed with the isolated 1, 2 di-substituted idopyranose showed regeneration of hepatocytes, nephrocytes, as well as β-cells and acinar region appeared normal with increased numbers of β-cells. To understand the probable mechanism of action of 1, 2 di-substituted idopyranose, we analyzed proinflammatory inducible nitric oxide synthase (iNOS) and nuclear factor-kappa B (NF-κB) expression by immunohistochemistry and the results showed an increased iNOS and NF-κB levels in streptozotocin-induced diabetic liver, kidney and pancreas. Such high iNOS and NF-κB levels were inhibited in 1, 2 di-substituted idopyranose treated mice. The results suggest that 1, 2 di-substituted idopyranose helps in the protection of hepatocytes, nephrocytes and pancreatic β-cells probably by its action against NF-κB and iNOS mediated inflammation in streptozotocin-induced diabetes., (Copyright © 2010 Wiley-Liss, Inc.)

Oral d-tagatose (d-tag) attenuates the rise in plasma glucose during an oral glucose tolerance test in subjects with type 2 diabetes mellitus (DM) and reduces food intake in healthy human subjects. A reduction in food consumption and less weight gain occur in rats fed tagatose. This pilot study explored the metabolic effects of d-tag given daily to 8 human subjects with type 2 DM for 1 year. We hypothesized that this treatment period would lead to weight loss and improvements in glycated hemoglobin and the lipid profile. A 2-month run-in period was followed by a 12-month treatment period when 15 g of oral d-tag was taken 3 times daily with food. No serious adverse effects were seen during the 12-month treatment period. Ten of the initially 12 recruited subjects experienced gastrointestinal side effects that tended to be mild and transient. When 3 subjects were excluded who had oral diabetes, medications added and/or dosages increased during the study and mean (SD) body weight declined from 108.4 (9.0) to 103.3 (7.3) kg (P = .001). Glycated hemoglobin fell nonsignificantly from 10.6% ± 1.9% to 9.6% ± 2.3% (P = .08). High-density lipoprotein cholesterol progressively rose from a baseline level of 30.5 ± 15.8 to 41.7 ± 12.1 mg/dL at month 12 in the 6 subjects who did not have lipid-modifying medications added during the study (P < .001). Significant improvements in body weight and high-density lipoprotein cholesterol in this pilot study suggest that d-tag may be a potentially useful adjunct in the management of patients with type 2 DM., (Copyright © 2010 Elsevier Inc. All rights reserved.)

Importance of the Field: Tagatose is a naturally occurring simple sugar that is a more palatable bulk low-calorie (1.5 kcal/g) sweetener. It was approved as a food additive by the FDA in 2003. Tagatose has been studied as a potential antidiabetic and antiobesity medication. In preliminary studies in humans, tagatose has shown a low postprandial blood glucose and insulin response. Its proposed mechanism of action may involve interference in the absorption of carbohydrates by inhibiting intestinal disaccharidases and glucose transport. It may also act through hepatic inhibition of glycogenolysis., Areas Covered in This Review: This article summarizes tagatose Phase I and II diabetes trials. It describes the pharmacodynamics and possible mechanism of action of this agent. Literature from 1974 to 2009 is reviewed., What the Reader Will Gain: Better understanding of the implications of postprandial hyperglycemia. An appreciation of the liver as a target of glucose control. Increased awareness of tagatose, a sweetener, as a potential new medication that operates through improvement of postprandial hyperglycemia., Take Home Message: Tagatose is currently being studied as a postprandial antihyperglycemic agent that may be safer with regard to hypoglycemia. Ongoing Phase III clinical trials will provide more definitive answers.

A potentially important new drug for treating type 2 diabetes, tagatose, is now in phase 3 clinical trial. The history, development, additional health benefits, mechanisms of action and the potential for the drug are presented in context with a review of the rapidly growing epidemic of type 2 diabetes and treatments for it. An epimer of fructose, the natural hexose tagatose was originally developed by Spherix Incorporated (formerly Biospherics Inc.) as a low-calorie sugar substitute. Only 20% of orally ingested tagatose is fully metabolized, principally in the liver, following a metabolic pathway identical to that of fructose. Following a decade of studies, tagatose became generally recognized as safe for use in foods and beverages under US FDA regulation. The simple sugar is commercially produced by isomerization of galactose, which is prepared from lactose. Early human studies suggested tagatose as a potential antidiabetic drug through its beneficial effects on postprandial hyperglycaemia and hyperinsulinaemia. A subsequent 14-month trial confirmed its potential for treating type 2 diabetes, and tagatose showed promise for inducing weight loss and raising high-density lipoprotein cholesterol, both important to the control of diabetes and constituting benefits independent of the disease. Furthermore, tagatose was shown to be an antioxidant and a prebiotic, both properties cited in the maintenance and promotion of health. No current therapies for type 2 diabetes provide these multiple health benefits. The predominant side effects of tagatose are gastrointestinal disturbances associated with excessive consumption, generally accommodated within 1- to 2-week period. The health and use potentials for tagatose (branded Naturlose((R)) for this use) are given with respect to current type 2 diabetes drugs and markets. Under an FDA-affirmed protocol, Spherix is currently conducting a phase 3 trial to evaluate a placebo-subtracted treatment effect based on a decrease in HbA(1c) levels. Side effects, contraindications and possibly beneficial new findings will be carefully monitored. It is hoped that early results of the trial may become available by mid-2008. If a subsequent NDA is successful, tagatose may fill a major health need.

D-Tagatose has attracted a great deal of attention in recent years due to its health benefits and similar properties to sucrose. D-Tagatose can be used as a low-calorie sweetener, as an intermediate for synthesis of other optically active compounds, and as an additive in detergent, cosmetic, and pharmaceutical formulation. Biotransformation of D-tagatose has been produced using several biocatalyst sources. Among the biocatalysts, L-arabinose isomerase has been mostly applied for D-tagatose production because of the industrial feasibility for the use of D-galactose as a substrate. In this article, the characterization of many L-arabinose isomerases and their D-tagatose production is compared. Protein engineering and immobilization of the enzyme for increasing the conversion rate of D-galactose to D-tagatose are also reviewed.

Spherix Inc (formerly Biospherics) is developing tagatose, an orally active lactose derivative for the potential treatment of obesity and type 2 diabetes. The compound is also under investigation for the potential treatment of anemia, hemophilia and medical problems related to infertility, birth weight and excessive maternal food intake. Phase I and II clinical trials have been completed.

Tagatose, a low-calorie, full-bulk natural sugar, has just attained GRAS (Generally Recognized As Safe) status under U.S. Food and Drug Administration (FDA) regulations, thereby permitting its use as a sweetener in foods and beverages. This paper presents all current aspects of tagatose with respect to demonstrated food and beverage applications and the potential health and medical benefits of this unique substance. Summarized studies are referenced to detailed peer-reviewed papers. The safety studies followed the recommendations in the FDA "Red Book." Results were submitted to an Expert Panel for determination of GRAS status under FDA regulation. Small phase 2 clinical trials showed tagatose to be effective in treating type 2 diabetes. The results, buttressed by the references cited, support the efficacy of the various applications disclosed for tagatose. Tagatose has been found to be safe and efficacious for use as a low-calorie, full-bulk sweetener in a wide variety of foods, beverages, health foods, and dietary supplements. It fills broad, heretofore unmet needs for a low-calorie sweetener in products in which the bulk of sugar is important, such as chocolates, chewing gum, cakes, ice cream, and frosted cereals. Its synergism with high-intensity sweeteners also makes it useful in sodas. Various health and medical benefits are indicated, including the treatment of type 2 diabetes, hyperglycemia, anemia, and hemophilia and the improvement of fetal development.

Aim: D-Tagatose (D-tag), a hexose bulk sweetener, does not affect plasma glucose levels when orally administered to rodents. Additionally, D-tag attenuates the rise in plasma glucose after mice are administered oral sucrose. The current study was undertaken to investigate the acute glycaemic effects of oral D-tag alone or in combination with oral glucose in human subjects with and without type 2 diabetes mellitus. Glycaemic responses to D-tag also were investigated in subjects after oral sucrose to examine whether the glucose-lowering effects of D-tag in rodents may result from a direct inhibition of intestinal disaccharidases., Methods: Eight normal and eight subjects with diabetes mellitus were administered 75 g of glucose, 75 g of D-tag, or 75 g of D-tag 30 min prior to a 75 g oral glucose tolerance test (OGTT). Five patients with diabetes mellitus were challenged with a 75 g oral sucrose tolerance test (OSTT) with and without oral pre-treatment with 75 g of D-tag. Patients with diabetes mellitus also received separate 0, 10, 15, 20 and 30 g of D-tag 30 min prior to a 75 g OGTT., Results: Oral loading with D-tag alone led to no changes in glucose or insulin levels in either normal patients or those with diabetes mellitus. Pre-OGTT treatment with 75 g D-tag, however, attenuated the rise in glucose levels in patients with diabetes mellitus (p < 0.02 at 60 and 180 min, and p < 0.01 at 120 min). The glucose area under the curve (AUC) was reduced significantly also by pre-treatment with D-tag in a dose-dependent manner in patients with diabetes mellitus (p < 0.05 for 10 g D-tag, p < 0.001 for 20 g D-tag, and p = 0.0001 for 30 g D-tag). In patients with diabetes mellitus 75 g D-tag similarly attenuated the rise in glucose following an OSTT (p < 0.01 at 30 min, and p < 0.02 at 60 min). Pre-treatment with 75 g D-tag also tended to blunt the rise in insulin following an OGTT in normal patients (p = 0.07 for insulin AUC) but not patients with diabetes mellitus (p = 0.66). Following 75 g of oral D-tag in four normal patients, plasma D-tag levels rose to a mean peak level of 3.6 mg/dl at 90 min. The administration of 75 g D-tag led to diarrhoea, nausea and/or flatulence in 100% of subjects. When D-tag was administered at lower doses ranging from 10 g to 30 g, only three of 10 patients with diabetes mellitus had gastrointestinal symptoms which were much more mild than those evoked by 75 g D-tag., Conclusions: These results show that oral D-tag significantly blunts the rise in plasma glucose seen after oral glucose in patients with diabetes mellitus in a dose-dependent manner without significantly affecting insulin levels. The minimal elevation of plasma D-tag levels in normal patients and the adverse gastrointestinal effects seen following larger doses of D-tag support poor absorption of this hexose and suggest that D-tag may act by attenuating glucose absorption in the intestine. D-tag may be a useful therapeutic adjunct in the management of type 2 diabetes mellitus.

Six derivatives of sixteen-membered macrolides possessing 4-O-acyl-alpha-L-cladinose as a neutral sugar were synthesized via 3"-methylthiomethyl ether intermediates in reasonable yield. Introduction of a methyl group on the 3"-hydroxyl group of midecamycin A1 was effective for enhancing its antibacterial activity. All these derivatives exhibited excellent therapeutic effects in mice, and some of them showed improved pharmacokinetics compared with the natural antibiotics (mycarose type) in mice. Facile synthesis of 9-O-acylated analogues are also described.

Restriction of dietary energy extends life and reduces incidences of disease in animals. These benefits would likely extend to humans. However, diet restriction in animals imposes reductions of 30-50% in food intake, which is probably unacceptable to humans. Low-energy sweeteners used in beverages offer minor reductions in energy intake. However, they lack the bulk required for baked goods and other sugar-rich foods. Full-bulk sweeteners providing about one-half the energy of sugar are under development for such uses. Laxation limits their acceptable dose. Even within such limitations, they can help achieve the health benefits for humans indicated by diet restriction. D-Tagatose, a new candidate sweetener, is nearly as sweet as sucrose and has the bulk of sucrose, yet provides zero available energy. We discuss its potential contribution to human diet restriction along with its specific effect in delaying the aging effects of glycosylation.

The development of substances that could be employed as male contraceptives would be of worldwide importance. As yet, however, it has not proved possible to find a substance which provides reliable contraception during use, whose effects are reversible following discontinuation, and which has minimal side-effects. Furthermore, the possibility of mutagenic effects and adverse effects on libido or sexual potency must be excluded and systemic application must be possible. The drugs gossypol, alpha-chlorohydrin and hexose derivates, which are presented in detail in this article, partly fulfil these requirements but are still a long way from representing an ideal compound for use as a male contraceptive. However, studies of these drugs may indicate ways of achieving the ultimate goal. The drugs showed interesting properties, which suggest that they may be used for purposes other than male contraception.

Results of the application of gelvisol in 74 patients with toxic goiter enabled the author to recommend the drug to be included in the preoperative preparing of the patients along with other usual medication. The effect of gelvisol caused quicker normalization of functions of main organs and systems.

There is evidence to suggest that the extra nuclear cell constituents are the part of the cell which contains all the biochemical mechanisms responsible for implementing all cell functions. These functions include control of cell division, growth, response to injury, replacement of effete cells, maintenance of anatomical and spatial cellular relations and specific cellular function and structure. The energy to perform these functions is derived from the aerobic metabolism of glucose. The energy required for nuclear division appears to be wholly or partly derived from the anaerobic metabolism of glucose. Ethyl alcohol interferes with the aerobic metabolic pathways and thus disrupts or diminishes all aerobically activated cell functions. The speed of all activities motivated by aerobic glycolysis can be increased by appropriate electrical stimulations delivered from any of a range of electromagnetic radiation frequencies tested. In addition to the stimulant effect on aerobic metabolic processes, 434 MHz can stimulate the anaerobic glucose metabolism of cancer with consequent stimulation of cancer growth rate. 434 MHz appears to deliver energy to the anaerobic cancer metabolism by causing a resonance phenomenon amongst one or more of the substrates which comprise the first few stages of glycolysis. This phenomenon permits the selective delivery of electromagnetic radiation energy to cancer cells which, if sufficiently intense, causes injury to cancer cells without harm to the normal cells except when the latter are in the phase of anaerobic metabolism which occurs at some stage of the mitotic cycle. Streptokinase, ethanol and glucose analogues increase the lethal effects on cancers undergoing therapy with 434 MHz radiation and observations of such responses suggest a theoretical basis to explain the rare spontaneous remissions of human cancer. Cancer appears to protect its glucose supplies by elevating the blood glucose levels above normal and by some mechanism which reduces the effectiveness of the body's control of its fasting glucose level. The serum fibrinogen level rises when cancer involves the abdominal viscerae, particularly the liver. A raised serum fibrinogen level appears to be a direct indication that the liver must be included in the treatment regime if longer survival is desired. If the level cannot be corrected then death of that individual appears assured.

Local destruction of malignant growths was achieved rapidly by creating around their cells a strongly hypertonic environment. Various hexoses, injected in and around tumors at 37 degrees, were utilized to produce the osmotic disturbance. Homeostatic correction of the osmotic disturbance was prevented by local ischemia, induced by vasoconstriction, and maintained soon afterwards by thrombosis. Of the few vasoactive agents tested for this purpose, serotonin was the safest and most effective. It worked better when mixed with the hexose than when injected separately s.c. at a distance. The best response to treatment was obtained from tumors which were unattached to deep structures, poorly vascularized, and resistant to an increase of internal pressure, whereas special precautions had to be taken with friable neoplasms to avoid dissemination of metastases. Under certain conditions, by causing acute tumor necrosis, a single treatment achieved a high ratio of cure; in which a favorable immune response to dramatic reduction of tumor burden and to resorbed lysed material perhaps played a part.

The synthesis of alpha-D-glucopyranosyl 1-(methylenediphosphonate) (11), alpha-D-galactopyranosyl 1-(methylenediphosphonate) (14), and alpha-D-mannopyranosyl 1-(methylenediphosphonate) (17) has been accomplished. [(Di-phenoxyphosphinyl)methyl]phosphonic acid (diphenyl-MDP) (5), synthesized by two different procedures, was fused with beta-D-glucopyranose pentaacetate followed by catalytic hydrogenation to give 2,3,4,6-tetra-O-acetyl-alpha-D-glucopyranosyl methylenediphosphonate (glucose-MDP) (10). The anomeric configuration of 10 was assigned on the basis of NMR spectral studies. Condensation of 10 with 2',3'-di-O-acetyladenosine was accomplished by using 1-(mesitylene-2-sulfonyl)-3-nitro-1,2,4-triazole (MSNT) as coupling agent, and removal of the blocking groups gave adenosine 5'-[(alpha-D-glucopyranosylhydroxyphosphinyl)methyl]phosphonate (20). Uridine 5'-[(alpha-D-galactopyranosylhydroxyphosphinyl)methyl] phosphonate (23) and guanosine 5'-[(alpha-D-mannopyranosylhydroxyphosphinyl)methyl]phosphonate (26) were similarly prepared. Using a specific glycoprotein galactosyltransferase (EC 2.4.1.38) assay, uridine 5'-[(alpha-D-galactopyranosylhydroxyphosphinyl)methyl]phosphonate (23) demonstrated competitive inhibition with an apparent Ki of 97 microM. The adenosine analogue did not inhibit the enzyme. None of the above compounds show any in vitro antitumor or antiviral activity. Such specific inhibitors of glycosyltransferases may serve as specific probes to study various glycosyltransferases that might be involved in the process of metastasis.

In this study, 28 patients with maintained beta-blockade underwent coronary artery bypass grafting. Twelve of these patients, who received preoperative infusion of carbohydrate-phosphate solution, had a smaller cumulated leakage of CK-B compared to the others, suggesting reduced myocardial damage.

In the paper, the results of clinical applications of a complex peroral therapeutic solution--gelvisol for symptomatic treatment of generalized malignant tumors of the breast, lung and thyroid are summarized. The solution was administered in a dose of 50-60 ml 5-6 times a day during 12-14 days. A positive effect was manifested in the improved general condition of patients, better appetite, less intoxication of the organisms, better functioning of the liver and kidneys.

4-Deoxy-4-fluoro-alpha-D-sorbose (6) was prepared in crystalline form by the action of potassium hydrogen fluoride on 3,4-anhydro-1,2-O-isopropylidene-beta-D-psicopyranose (3) followed by deacetonation. Under identical conditions, 3,4-anhydro-1,2-O-isopropylidene-beta-D-tagatopyranose (7) underwent epoxide migration to give 4,5-anhydro-1,2-O-isopropylidene-beta-D-fructopyranose (12), which after deacetonation yielded 4-deoxy-4-fluoro-D-tagatose (15) and 5-deoxy-5-fluoro-alpha-L-sorbopyranose (16), the latter as the crystalline, free sugar. The action of glycol-cleavage reagents on the isopropylidene acetals of the deoxyfluoro sugars was consistent with the assigned structures. The structures were established by 13-C n.m.r. studies of the free deoxyfluoro sugars 6 and 16 and of the isopropylidene acetal 13, and by 1-H n.m.r. studies on the acetylated isopropylidene acetals 5 diacetate, 13 diacetate, and 14 diacetate. 5-Deoxy-5-fluoro-L-sorbose (16) was biologically active, producing in mice effects characteristic of deoxyfluorotrioses and of fluoroacetate. 4-Deoxy-4-fluoro-D-tagatose (15) and 4-deoxy-4-fluoro-D-sorbose (6) produced no apparent effects in mice up to a dose of 500mg/kg. The implications of these findings with respect to transport, phosphorylation, and the action of aldolase on ketohexoses are discussed.