Low-Dose Lactulose as a Prebiotic for Improved Gut Health and Enhanced Mineral Absorption

Although medium and high doses of lactulose are used routinely for the treatment of constipation and hepatic encephalopathy, respectively, a wealth of evidence demonstrates that, at low doses, lactulose can also be used as a prebiotic to stimulate the growth of health-promoting bacteria in the gastrointestinal tract. Indeed, multiple preclinical and clinical studies have shown that low doses of lactulose enhance the proliferation of health-promoting gut bacteria (e.g., Bifidobacterium and Lactobacillus spp.) and increase the production of beneficial metabolites [e.g., short-chain fatty acids (SCFAs)], while inhibiting the growth of potentially pathogenic bacteria (e.g., certain clostridia). SCFAs produced upon microbial fermentation of lactulose, the most abundant of which is acetate, are likely to contribute to immune regulation, which is important not only within the gut itself, but also systemically and for bone health. Low-dose lactulose has also been shown to enhance the absorption of minerals such as calcium and magnesium from the gut, an effect which may have important implications for bone health. This review provides an overview of the preclinical and clinical evidence published to date showing that low-dose lactulose stimulates the growth of health-promoting gut bacteria, inhibits the growth of pathogenic bacteria, increases the production of beneficial metabolites, improves mineral absorption, and has good overall tolerability. Implications of these data for the use of lactulose as a prebiotic are also discussed.

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Proteins as targets for high dilutions of drugs: Interaction between ?-amylase and mercuric chloride.

International Journal of High Dilution Research - ISSN 1982-6206 ◽

10.51910/ijhdr.v17i2.920 ◽

2021 ◽

Vol 17 (2) ◽

pp. 24-25

Author(s):

Nirmal Chandra Sukul ◽

Tandra Sarkar ◽

Atheni Konar ◽

Anirban Sukul

Keyword(s):

Mercuric Chloride ◽

Binding Sites ◽

Low Dose ◽

Soluble Starch ◽

Low Doses ◽

Substrate Interaction ◽

Enzyme Substrate ◽

High Dilutions ◽

High Doses ◽

Mother Tincture

Background: High dilutions of drugs, used in homeopathy, are usually applied by oral route or foliar spray. These dilutions first come in contact with membrane or circulating proteins. Ultra low doses of mercuric chloride, called potencies, promote activity of diastase or ?-amylase in terms of breakdown of starch, a polysaccharide into a disaccharide maltose in a cell-free medium in test tubes. Merc cor or HgCl2 in high doses inhibits the enzyme activity. Aims: To see (i) whether the high and ultra low dose effects of HgCl2 involve different binding sites of the enzyme and (ii) to find an explanation for the low dose effect of HgCl2 in spite of absence of its original molecules. Methodology: Merc cor mother tincture (147 mM HgCl2) in distilled water was used undiluted in this experiment. Merc cor 200c and 1000c were prepared from the mother tincture (MT) by successive dilution with water 1:100 followed by succussion in 200 and 1000 steps, respectively, and finally preserved in 90% EtOH. These potencies and blank 90% ethanol, were diluted with deionized, distilled (DD) water 1:1000 to minimize ethanol content in test solutions. Each test solution or control was mixed with the enzyme 1:10 just before experiment. The control consisted of DD water. An isothermal calorimetry (ITC) instrument was used to measure the interaction between soluble starch and ?-amylase mixed with each potency (200c/1000c) of Merc cor, its mother tincture, ethanol and control. ITC is a thermodynamic technique which helps in measuring directly very small amount of heat evolved during chemical reaction. Soluble starch 90 µM was injected into 300 µl of 15µM ?-amylase at 2 µl / injection. Twenty injections, one every 2 min, were given. The enzyme substrate interaction in terms of heat released (exothermic) or absorbed (endothermic) were monitored by the ITC instrument. All ITC measurements were calculated and analyzed statistically by an in-built software Origin 7. Results and discussion: The data are presented in figures. While Merc cor MT shows endothermic reaction, all its potencies, ethanol and water control show exothermic reactions. There is wide variation in enthalpy (?H), entropy (?S), binding constant (K) and Gibbs free energy change (?G) among the treatments with Merc cor MT, potencies, ethanol and also control. The results indicate that Merc cor MT and its potencies act on different binding sites of the enzyme. The variation in thermodynamic parameters suggest difference in binding interaction between the drug solutions and the enzyme. This in turn influences the enzyme substrate interaction as reported in earlier studies. The potencies are virtually water modified by the starting substance HgCl2. Conclusion: The mother tincture and potencies of mercuric chloride produce different effects on the enzyme substrate interaction. Potencies show wide variation in ?H, ?S, K and ?G values. It appears from the results that the drugs used in homeopathy produce dual action on proteins. At high doses they act on a binding site(s) but at ultra low doses they act on a different binding site(s). Proteins in an organism may serve as targets for initiation of action of homeopathic potencies.

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Lupus Erythematosus with Nephritis

PEDIATRICS ◽

10.1542/peds.42.2.369a ◽

1968 ◽

Vol 42 (2) ◽

pp. 369-370

Author(s):

Jerry C. Jacobs

Keyword(s):

Systemic Lupus Erythematosus ◽

Retrospective Analysis ◽

Lupus Erythematosus ◽

Phase 1 study of low-dose prolonged exposure schedules of the hypomethylating agent 5-aza-2′-deoxycytidine (decitabine) in hematopoietic malignancies

Blood ◽

10.1182/blood-2003-03-0687 ◽

2004 ◽

Vol 103 (5) ◽

pp. 1635-1640 ◽

Cited By ~ 572

Author(s):

Jean-Pierre J. Issa ◽

Guillermo Garcia-Manero ◽

Francis J. Giles ◽

Rajan Mannari ◽

Deborah Thomas ◽

...

Keyword(s):

Low Dose ◽

Prolonged Exposure ◽

Phase 1 ◽

Maximum Tolerated Dose ◽

Lymphocytic Leukemia ◽

Myelogenous Leukemia ◽

Low Doses ◽

Phase 1 Study ◽

High Doses ◽

Dose Levels

Abstract Decitabine (5-aza-2′-deoxycytidine) inhibits DNA methylation and has dual effects on neoplastic cells, including the reactivation of silenced genes and differentiation at low doses and cytotoxicity at high doses. We evaluated, in a phase 1 study, low-dose prolonged exposure schedules of decitabine in relapsed/refractory leukemias. Patient cohorts received decitabine at 5, 10, 15, or 20 mg/m2 intravenously over one hour daily, 5 days a week for 2 consecutive weeks, doses 5- to approximately 30-fold lower than the maximum tolerated dose (MTD). There were 2 groups that also received 15 mg/m2 daily for 15 or 20 days. A total of 50 patients were treated (44 with acute myelogenous leukemia [AML]/myelodysplasia [MDS], 5 with chronic myelogenous leukemia [CML], and 1 with acute lymphocytic leukemia [ALL]), and the drug was well tolerated at all dose levels, with myelosuppression being the major side effect. Responses were seen at all dose levels. However, the dose of 15 mg/m2 for 10 days appeared to induce the most responses (11 of 17 or 65%), with fewer responses seen when the dose was escalated or prolonged (2 of 19 or 11%). There was no correlation between P15 methylation at baseline or after therapy and response to decitabine. We conclude that decitabine is effective in myeloid malignancies, and low doses are as or more effective than higher doses.

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ANDROGENIZATION OF THE NEONATAL FEMALE RAT WITH VERY LOW DOSES OF ANDROGEN

Journal of Endocrinology ◽

10.1677/joe.0.0570033 ◽

1973 ◽

Vol 57 (1) ◽

pp. 33-45 ◽

Cited By ~ 16

Author(s):

P. J. SHERIDAN ◽

M. X. ZARROW ◽

V. H. DENENBERG

Keyword(s):

Low Dose ◽

Physiological Effect ◽

Neonatal Rat ◽

Female Rats ◽

High Dose ◽

Female Rat ◽

Low Doses ◽

Minimal Effective Dose ◽

High Doses ◽

Long Acting

SUMMARY The administration of a high dose of androgen on a single day to a neonatal female rat has been shown repeatedly to induce persistent vaginal cornification (PVC). However, this type of treatment does not parallel the continuous androgen secretion present in the male, and the high doses that have been used could represent a pharmacological and not a physiological effect. Experiments were carried out to determine the minimal effective dose of testosterone propionate (TP) needed to cause PVC when the androgen is administered to the neonatal rat for the first 10 days of life or as a long-acting ester. Injection of 1, 3 or 9 μg TP on days 1–10 of life in female rats induced PVC in adulthood. All three doses were found to be more effective than a testicular transplant on day 1. In female rats injected with low doses of TP twice daily for the first 10 days of life, PVC was shown between 90 and 100 days of life in 21 out of 22 animals given 0·5 μg TP/injection, and in eight out of 22 animals given 0·05 μg TP/injection. In an experiment where female rats were given a single injection of 0·1, 1·0 or 10·0 μg TP, or 0·1 or 1·0 μg testosterone cyclopentylpropionate (TC, a long-acting androgen) on the first day after birth, PVC occurred at 90–100 days of age in 15 of the 18 animals which were injected with 10 μg TP, in none of the 17 animals which were injected with 1 μg TP, and in 10 of 11 animals which were injected with 1 μg TC. The effects of all treatments on vaginal opening, first oestrus, ovarian weight, body weight and sexual behaviour are reported. The use and implications of low dose regimens are discussed in relation to the construction of an experimental model for the study of sexual differentiation.

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Effects of Low-Dose versus High-Doseγ-Tocotrienol on the Bone Cells Exposed to the Hydrogen Peroxide-Induced Oxidative Stress and Apoptosis

Evidence-based Complementary and Alternative Medicine ◽

10.1155/2012/680834 ◽

2012 ◽

Vol 2012 ◽

pp. 1-10 ◽

Cited By ~ 17

Author(s):

Nizar Abd Manan ◽

Norazlina Mohamed ◽

Ahmad Nazrun Shuid

Keyword(s):

Oxidative Stress ◽

Hydrogen Peroxide ◽

Antioxidant Enzymes ◽

Low Dose ◽

Bone Cells ◽

Dependent Manner ◽

Low Doses ◽

Antioxidant Enzymes Activities ◽

High Doses ◽

Dose Dependent

Oxidative stress and apoptosis can disrupt the bone formation activity of osteoblasts which can lead to osteoporosis. This study was conducted to investigate the effects ofγ-tocotrienol on lipid peroxidation, antioxidant enzymes activities, and apoptosis of osteoblast exposed to hydrogen peroxide (H2O2). Osteoblasts were treated with 1, 10, and 100 μM ofγ-tocotrienol for 24 hours before being exposed to 490 μM (IC50) H2O2for 2 hours. Results showed thatγ-tocotrienol prevented the malondialdehyde (MDA) elevation induced by H2O2in a dose-dependent manner. As for the antioxidant enzymes assays, all doses ofγ-tocotrienol were able to prevent the reduction in SOD and CAT activities, but only the dose of 1 μM of GTT was able to prevent the reduction in GPx. As for the apoptosis assays,γ-tocotrienol was able to reduce apoptosis at the dose of 1 and 10 μM. However, the dose of 100 μM ofγ-tocotrienol induced an even higher apoptosis than H2O2. In conclusion, low doses ofγ-tocotrienol offered protection for osteoblasts against H2O2toxicity, but itself caused toxicity at the high doses.

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Acrylamide-induced changes of granulopoiesis in porcine bone marrow

Journal of Veterinary Research ◽

10.2478/jvetres-2021-0040 ◽

2021 ◽

Vol 0 (0) ◽

Author(s):

Dominika Grzybowska ◽

Anna Snarska

Keyword(s):

Bone Marrow ◽

Cell Morphology ◽

Light Microscope ◽

Low Dose ◽

Low Doses ◽

Cytological Evaluation ◽

High Doses ◽

Induced Changes ◽

The Impact ◽

Experimental Group

Abstract Introduction Due to the widely documented and diverse toxic effects of acrylamide, the authors decided to evaluate the impact of high and low doses of this compound on the process of granulopoiesis in porcine bone marrow. Material and Methods The experiment was conducted on 15 Danish Landrace pigs at the age of 8 weeks. The animals were randomly assigned into three equal groups (n = 5). Control animals received empty gelatine capsules as placebo. Animals in the first experimental group (the LD group) received a low dose of acrylamide of 0.5 μg/kg b.w./day, and animals in the second experimental group (the HD group) received a tenfold higher dose of acrylamide of 5 μg/kg b.w./day. Placebo and acrylamide capsules were administered with feed every morning for 28 days. Bone marrow was collected into tubes without an anticoagulant twice – before the first capsule administration (day 0) and on the 28th day of the study. After drying and staining, bone marrow smears were subjected to detailed cytological evaluation under a light microscope. Results Changes in cell morphology, i.e. degenerative changes in the cellular nuclei, were observed in both experimental groups. Both low and high doses of acrylamide decreased the number of segmented eosinophils, neutrophilic and segmented metamyelocytes, neutrophils, as well as basophils and basophilic metamyelocytes. Conclusion Acrylamide at doses of 0.5 μg/kg b.w./day and 5 μg/kg b.w./day clearly influences porcine granulopoiesis.

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Low-Dose Pesticides Alter Primary Human Bone Marrow Mesenchymal Stem/Stromal Cells through ALDH2 Inhibition

Cancers ◽

10.3390/cancers13225699 ◽

2021 ◽

Vol 13 (22) ◽

pp. 5699

Author(s):

Amélie Foucault ◽

Noémie Ravalet ◽

Joevin Besombes ◽

Frédéric Picou ◽

Nathalie Gallay ◽

...

Keyword(s):

Stromal Cells ◽

Low Dose ◽

Low Doses ◽

Aldehyde Dehydrogenase 2 ◽

Primitive Hematopoiesis ◽

In Vitro Effects ◽

High Doses ◽

Chlorpyrifos Ethyl ◽

The Impact

(1) Background: The impact of occupational exposure to high doses of pesticides on hematologic disorders is widely studied. Yet, lifelong exposure to low doses of pesticides, and more particularly their cocktail effect, although poorly known, could also participate to the development of such hematological diseases as myelodysplastic syndrome (MDS) in elderly patients. (2) Methods: In this study, a cocktail of seven pesticides frequently present in water and food (maneb, mancozeb, iprodione, imazalil, chlorpyrifos ethyl, diazinon and dimethoate), as determined by the European Food Safety Authority, were selected. Their in vitro effects at low-doses on primary BM-MSCs from healthy volunteers were examined. (3) Results: Exposure of normal BM-MSCs to pesticides for 21 days inhibited cell proliferation and promoted DNA damage and senescence. Concomitantly, these cells presented a decrease in aldehyde dehydrogenase 2 (ALDH2: mRNA, protein and enzymatic activity) and an increase in acetaldehyde levels. Pharmacological inhibition of ALDH2 with disulfiram recapitulated the alterations induced by exposure to low doses of pesticides. Moreover, BM-MSCs capacity to support primitive hematopoiesis was significantly altered. Similar biological abnormalities were found in primary BM-MSCs derived from MDS patients. (4) Conclusions: these results suggest that ALDH2 could participate in the pathophysiology of MDS in elderly people long exposed to low doses of pesticides.

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Modeling of Molecular Mechanisms of Radiation Adaptive Response Formation

East European Journal of Physics ◽

10.26565/2312-4334-2021-2-16 ◽

2021 ◽

Keyword(s):

Adaptive Response ◽

Molecular Mechanisms ◽

Low Dose ◽

Low Doses ◽

Radiation Hormesis ◽

Biological Objects ◽

Mechanisms Of Formation ◽

Radiation Induced ◽

High Doses ◽

Lnt Model

The phenomenon of adaptive response is expressed in the increase of resistance of a biological object to high doses of mutagens under the conditions of previous exposure to these (or other) mutagens in low doses. Low doses of mutagen activate a number of protective mechanisms in a living object, which are called hormetic. Thus, the adaptive response and hormesis are links in the same chain. Radiation hormesis refers to the generally positive effect of low doses of low LET radiation on biological objects. The phenomenology of radiation-induced adaptive response and radiation hormesis for biological objects of different levels of organization is considered; the review of existing theories describing the dose-effect relationship has been reviewed. The hypothesis proposing one of the mechanisms of formation of radiation adaptive response of cells taking into account the conformational structure of chromatin has been submitted. The analysis of modern concepts of the phenomenon of hormesis on the basis of modeling of molecular mechanisms of formation of hormetic reactions to low-dose low LET radiation has been carried out. The parameters that can be used for quantitative and graphical evaluation of the phenomenon of hormesis was considered, and a formula for calculating the coefficient of radiation-induced adaptive response has been proposed. A review of mathematical models describing the radiation relative risk of gene mutations and neoplastic transformations at low-dose irradiation of cohorts has been performed. The following conclusions have been made: radiation hormesis and adaptive response are generally recognized as real and reproducible biological phenomena, which should be considered as very important phenomena of evolutionarily formed biological protection of living organisms from ionizing radiation. The hormesis model of dose-response relationship makes much more accurate predictions of a living object's response to radiation (or other stressors) in the low-dose range than the linear threshold (LNT) model does. The LNT model can adequately describe reactions only in the region of high doses of radiation, and, therefore, extrapolation modeling of biological object’s reactions from the zone of high doses to low doses is not correct.

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The Effects of Increasing Doses of Ranitidine on Gastric pH in Children

The Journal of Pediatric Pharmacology and Therapeutics ◽

10.5863/1551-6776-9.4.259 ◽

2004 ◽

Vol 9 (4) ◽

pp. 259-264 ◽

Cited By ~ 1

Author(s):

Seema Khan ◽

Theresa M. Shalaby ◽

Susan R. Orenstein

Keyword(s):

Low Dose ◽

Ph Monitoring ◽

Phase 1 ◽

Randomized Study ◽

Gastric Ph ◽

Fixed Dose ◽

High Dose ◽

Low Doses ◽

The Mean ◽

High Doses

BACKGROUND Ranitidine is widely used for gastroesophageal reflux disease (GERD) in children, but optimal dosing is unclear. We compared effects of weight-based doses of oral ranitidine on gastric pH in children with clinical GERD. METHODS Children ages 4–11 years with clinical GERD were enrolled in a multi-center prospective randomized study comparing a fixed dose of ranitidine (Zantac 75) with placebo after an overnight fast; gastric pH was measured for 6 h after the fixed dose (Phase 1). Of the six enrollees from our center, four received active drug during Phase 1; 12 h after the fixed dose, these four children received ranitidine 5 mg/kg (maximum 150 mg) and gastric pH was measured for another 6–12 hours (Phase 2). This report details the effects of two dose ranges (Low Dose, < 3 mg/kg/dose, and High Dose, ≥ 3 mg/kg/dose) on gastric pH in children. RESULTS The four children were 6.9–11.3 years old and weighed 20.4–49.5 kg. The Low Doses were 1.5–2.7 mg/kg; the High Doses were 3–5 mg/kg. Although the mean percentage of time with gastric pH > 4 during the entire 6 hours following dosing was similar after Low and High Dose (50% vs. 57%, NS), during the last two hours of this interval the mean percentage of time with gastric pH > 4 was only 29% for Low Dose vs. 89% for High Dose (P = 0.006). Moreover, during those two hours, none of the Low Doses kept gastric pH above 4 for > 60% of the time, while all of the High Doses kept pH above 4 for > 60% of the time (P = 0.03). In three of four patients who underwent extended (9–12 h) gastric pH monitoring after High Dose ranitidine, gastric pH was above 4 for more than 40% of total time. CONCLUSIONS Doses of ranitidine ≥ 3 mg/kg/dose may be required for acid suppression lasting beyond 6 hours.

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Effect of low dose ASV with supportive care in poisonous snake bites in Marathwada region, Aurangabad, Maharashtra, India

International Journal of Scientific Reports ◽

10.18203/issn.2454-2156.intjscirep20151500 ◽

2015 ◽

Vol 1 (8) ◽

pp. 307

Author(s):

Mangala S. Borkar ◽

Chandrakant G. Lahane ◽

Akshay A. Kashid ◽

Swati U. Chavan ◽

Sandeep G. Uppod

Keyword(s):

Low Dose ◽

Fresh Frozen Plasma ◽

Average Dose ◽

Low Doses ◽

Number Of Patients ◽

Snake Bites ◽

Significant Difference ◽

Male Preponderance ◽

Fresh Frozen ◽

High Doses

Background: Due to a large number of patients and severe scarcity of ASV with patches of unavailability and unaffordable high cost, low doses of ASV had to be compulsorily used for treatment of poisonous snakebites. The main objective is to study the effectiveness of low dose ASV (total <50 ml) in the management of poisonous snake bites in the scenario of global ASV scarcity.Methods: Patients of snake bites with signs of envenomation were included in this observational, prospective study. Immediately, low dose (30 to 50 ml) of ASV was started after carefully testing intravenously. The patients were kept under intensive observation with supportive management (artificial ventilation, neostigmine-atropine, blood and fresh frozen plasma, as needed). Results: In the study of 309 patients, slight male preponderance was seen (161 males and 148 females).144 patients had vasculotoxic, 122 patients had neurotoxic and 43 patients had mixed type (both vasculotoxic and neurotoxic) of envenomation. Average dose of ASV given was 35.30 ml. 297 patients survived, 12 died. In 42 cases having both neurological and vasculotoxic (mixed) snake bite, 7 patients (16.66%) died. Among 122 neuroparalytic cases, 5 (4.0983%) died. We did not get any mortality in the 145 cases of vasculotoxic snake bites. There was no statistically significant difference in the outcome of the patients whether they received higher or low doses of ASV.Conclusions: There was no significant difference in the outcome of poisonous snake bites whether low dose (<50 ml) or high doses (>50 ml) of ASV were given and practically all the victims who came on time, survived with low doses of ASV. This is very important in developing countries like India where there is high incidence of poisonous snake bites and scarcity of ASV.

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