pH as a variable in free zinc ion concentration from zinc-containing lozenges.
01 Apr 1988-Antimicrobial Agents and Chemotherapy (American Society for Microbiology)-Vol. 32, Iss: 4, pp 608-609
TL;DR: Eby and Godfrey as discussed by the authors claimed that Zn2+ will be tightly bound to citrate in saliva upon administration of lozenges containing the two ingredients (G. A. Eby, Letter, Antimicrob. Agents Chemother. 32:606-607, 1988).
Abstract: In their letters, Eby and Godfrey claim that Zn2+ will be tightly bound to citrate in saliva upon administration of lozenges containing the two ingredients (G. A. Eby, Letter, Antimicrob. Agents Chemother. 32:606-607, 1988; J. C. Godfrey, Letter, Antimicrob. Agents Chemother. 32:605606, 1988). The lozenges contained citric acid (6), however, and unless several equivalents of base per mole of citric acid are added, citrate will not be produced and tight citrate complexes cannot form. The limited buffer capacity of saliva (1) is insufficient to raise the pH to promote formation of tight complexes. Therefore, much of the zinc added with citric acid in a lozenge is likely to appear as free, unbound Zn2+ in saliva. If a 4.5-g lozenge containing 2% citric acid (6) generates 20 ml of saliva (Godfrey, Letter), the citric acid concentration becomes 23 mM and produces a pH of 2.3. For citric acid (molecular weight, 192) the successive acidity constant pKa values are 3.0, 4.4, and 5.8 (8). Addition of one equivalent or nearly 0.5 mmol of base raises the pH only to 3.7, and even addition of two equivalents of base or almost 1 mmol yields only a pH of 5.1. Thus, due to the acidity of citric acid and the low buffer capacity of saliva, much of the added Zn2+ is likely to remain as the free metal ion. Although ligands present in saliva will bind some Zn2+, the acidity created by adding citric acid reduces their chelating ability. Figure 1 shows the distribution of zinc-citrate species as mole fraction on a zinc basis versus pH for a citric acid-tototal-zinc mole ratio of 1.3, identical to that in the lozenges (6). Stability constants for the Zn2+ and citric acid system
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TL;DR: It is concluded that group 2 ions mainly affect channels by classical screening (a version of Mechanism A) and the transition metals and the Zn group ions mainly bind to the channel and electrostatically modify the gating (Mechanisms B and C), causing larger shifts of the steady-state parameters than the group 1 ions, but also different shifts of activation and deactivation curves.
Abstract: Metal ions affect ion channels either by blocking the current or by modifying the gating. In the present review we analyse the effects on the gating of voltage-gated channels. We show that the effects can be understood in terms of three main mechanisms. Mechanism A assumes screening of fixed surface charges. Mechanism B assumes binding to fixed charges and an associated electrostatic modification of the voltage sensor. Mechanism C assumes binding and an associated non electrostatic modification of the gating. To quantify the non-electrostatic effect we introduced a slowing factor, A. A fourth mechanism (D) is binding to the pore with a consequent pore block, and could be a special case of Mechanisms B or C. A further classification considers whether the metal ion affects a single site or multiple sites. Analysing the properties of these mechanisms and the vast number of studies of metal ion effects on different voltage-gated on channels we conclude that group 2 ions mainly affect channels by classical screening (a version of Mechanism A). The transition metals and the Zn group ions mainly bind to the channel and electrostatically modify the gating (Mechanism B), causing larger shifts of the steady-state parameters than the group 2 ions, but also different shifts of activation and deactivation curves. The lanthanides mainly bind to the channel and both electrostatically and non-electrostatically modify the gating (Mechanisms B and C). With the exception of the ether-a-go-go-like channels, most channel types show remarkably similar ion-specific sensitivities.
91 citations
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TL;DR: There is strong evidence that the zinc lozenge effect on common cold duration is heterogeneous so that benefit is observed with high doses of zinc but not with low doses, and the effects of zinc Lozenge compositions and treatment strategies should be further studied.
Abstract: Background: A number of controlled trials have examined the effect of zinc lozenges on the common cold but the findings have diverged. The purpose of this study was to examine whether the total daily dose of zinc might explain part of the variation in the results. Methods: The Medline, Scopus and Cochrane Central Register of Controlled Trials data bases were searched for placebo- controlled trials examining the effect of zinc lozenges on common cold duration. Two methods were used for analysis: the P-values of the trials were combined by using the Fisher method and the results of the trials were pooled by using the inverse-variance method. Both approaches were used for all the identified trials and separately for the low zinc dose and the high zinc dose trials. Results: Thirteen placebo-controlled comparisons have examined the therapeutic effect of zinc lozenges on common cold episodes of natural origin. Five of the trials used a total daily zinc dose of less than 75 mg and uniformly found no effect. Three trials used zinc acetate in daily doses of over 75 mg, the pooled result indicating a 42% reduction in the duration of colds (95% CI: 35% to 48%). Five trials used zinc salts other than acetate in daily doses of over 75 mg, the pooled result indicating a 20% reduction in the duration of colds (95% CI: 12% to 28%). Conclusions: This study shows strong evidence that the zinc lozenge effect on common cold duration is heterogeneous so that benefit is observed with high doses of zinc but not with low doses. The effects of zinc lozenges should be further studied to determine the optimal lozenge compositions and treatment strategies.
72 citations
Cites background or result from "pH as a variable in free zinc ion c..."
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TL;DR: Properly composed zinc gluconate lozenges may be as effective as zinc acetate loZenges in common cold treatment and there is no evidence that zinc doses over 100 mg/day might lead to greater efficacy in the treatment of the common cold.
Abstract: ObjectiveTo compare the efficacy of zinc acetate lozenges with zinc gluconate lozenges in common cold treatment and to examine the dose-dependency of the effect.DesignMeta-analysis.SettingPlacebo-controlled zinc lozenge trials, in which the zinc dose was > 75 mg/day. The pooled effect of zinc lozenges on common cold duration was calculated by using inverse-variance random-effects method.ParticipantsSeven randomised trials with 575 participants with naturally acquired common colds.Main outcome measureDuration of the common cold.ResultsThe mean common cold duration was 33% (95% CI 21% to 45%) shorter for the zinc groups of the seven included trials. Three trials that used lozenges composed of zinc acetate found that colds were shortened by 40% and four trials that used zinc gluconate by 28%. The difference between the two salts was not significant: 12 percentage points (95% CI: −12 to + 36). Five trials used zinc doses of 80–92 mg/day, common cold duration was reduced by 33%, and two trials used zinc doses ...
61 citations
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TL;DR: From the strong, multiple statistical relationships found, it is inferred that iZn is the active ingredient in zinc lozenges for colds, as it is in vitro against rhinoviruses, and that solution chemistry analytical techniques used at physiological pH are correct means for lozenge iZN analysis.
Abstract: A 7-day reduction in duration of common colds was shown by Eby et al. in 1984 using 23mg zinc gluconate throat lozenges. Over the following 25years, 14 double-blind, placebo-controlled, randomized clinical trials produced widely differing results with about one-half showing success and the remainder showing failure. Positively charged, ionic zinc (iZn), but not bound zinc, is strongly astringent, antirhinoviral, increases interferon-gamma (IFN-gamma) 10-fold, inhibits intercellular adhesion molecule-1 (ICAM-1) and inhibits the release of vasoactive ingredients from mast cell granules. Solution equilibrium chemistry analytical techniques showed lozenge iZn fraction varying from 0% to 100% of total lozenge zinc between trials, with zinc acetate (ZA) releasing 100% iZn, zinc gluconate (ZG) releasing 72% iZn and other zinc compounds releasing much less or none at physiologic pH 7.4. Since only iZn has in vitro benefits, iZn variations are hypothesized to have produced the widely varying clinical results. In support of the iZn hypothesis, lozenge iZn and total daily iZn in trials were found highly correlated with reductions in common cold durations with statistical significance for mean duration (P<0.001) and median duration (P<0.004), while total zinc (iZn plus bound) showed no correlation with changes in duration. Duration reductions (mean 0 days, median 0.43 days) for multi-ligand ZG and ZA lozenges differed significantly from duration reductions (mean 3.37 days, median 2.9 days) for single ligand ZA and ZG lozenges (P<0.001) showing that additive ligands as flavor-masks damaged or eliminated efficacy. Five of 6 trials with lozenges whose zinc compositions had a first stability constant of 1.7 or less succeeded, while only 2 of 9 trials of lozenges with higher stability succeeded (P<0.02). From the strong, multiple statistical relationships found, it is inferred that iZn is the active ingredient in zinc lozenges for colds, as it is in vitro against rhinoviruses, and that solution chemistry analytical techniques used at physiological pH are correct means for lozenge iZn analysis. Zinc lozenges slowly dissolving in the mouth over a 20-30 min period releasing adequate iZn (18 mg) used each 2h are hypothesized to shorten common colds by 6-7 days, which is a cure for the common cold. Due to inadequate lozenge iZn very few of more than 40 different brands of zinc lozenges on the US market are expected to have any effect on the duration or severity of common colds.
59 citations
References
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Book•
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01 Jan 1961
TL;DR: This handbook presents comprehensive data on blood and other body fluids specifically compiled for reference purposes, in the form of tables, graphs, diagrams, nomograms and line charts.
Abstract: Blood and Other Body Fluids is the first of the biological handbooks to appear under the general direction of the Committee on Biological Handbooks, Federation of American Societies for Experimental Biology. This volume, however, does not inaugurate a new series, but is in fact a continuation of the handbooks prepared under the auspices of the National Academy of Sciences—National Research Council.
This handbook presents comprehensive data on blood and other body fluids specifically compiled for reference purposes. The material is conveniently organized in the form of tables, graphs, diagrams, nomograms and line charts.
729 citations
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TL;DR: Al3+ is expected to complex with oxygen donor ligands, especially phosphates, and it does so in soils, in the gastrointestinal tract, and in cells, and an appreciable fraction occurs as a neutral complex that may pass through membranes and provide a vehicle for Al3+ absorption into the body.
Abstract: The increasing number of roles discovered for Al3+ in physiological processes demands an understanding of how Al3+ interacts with compounds in biological systems. Al3+ is expected to complex with oxygen donor ligands, especially phosphates, and it does so in soils, in the gastrointestinal tract, and in cells. The stability of Al3+ complexes has generally been misjudged because of lack of recognition that free, aqueous Al3+ is not the dominant form in neutral solutions and that the solubility of Al(OH)3 limits the free Al3+ at the plasma pH 7.4 to less than 10(-11) mol/L. In the presence of inorganic phosphate, the permitted free Al3+ is decreased further, through formation of insoluble aluminum phosphate. This precipitate facilitates the elimination of Al3+ from the body. In contrast, citrate solubilizes Al3+, and an appreciable fraction occurs as a neutral complex that may pass through membranes and provide a vehicle for Al3+ absorption into the body. In the blood plasma the most likely small-molecule complex is that with citrate, while the only competitive protein complex is that with transferrin, a protein built to transport Fe3+ but whose sites are only 30% occupied.
586 citations
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TL;DR: Zinc lozenges shortened the average duration of common colds by about 7 days and Side effects or complaints were usually minor and consisted mainly of objectionable taste and mouth irritation.
Abstract: As a possible treatment for common colds, we tested zinc gluconate lozenges in a double-blind, placebo-controlled, clinical trial. One 23-mg zinc lozenge or matched placebo was dissolved in the mouth every 2 wakeful h after an initial double dose. After 7 days, 86% of 37 zinc-treated subjects were asymptomatic, compared with only 46% of 28 placebo-treated subjects (P = 0.0005). Side effects or complaints were usually minor and consisted mainly of objectionable taste and mouth irritation. Zinc lozenges shortened the average duration of common colds by about 7 days.
206 citations
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TL;DR: This paper assesses published stability constants for citrate binding to each metal ion and concludes that ignoring the likely occurrence of a competing 2:1 citrate-Fe3+ complex necessitates adjustments in reported Stability constants for Fe3+ binding to transferrin.
Abstract: Citrate occurs at about 0.1 mM in blood plasma and is the most likely small molecule plasma binder of both Al3+ and Fe3+. This paper assesses published stability constants for citrate binding to each metal ion. From pH 2 to 5 Al3+ forms a neutral complex with citrate that may be absorbed into the body in the upper regions of the gastrointestinal tract. It is especially dangerous to ingest aluminum-containing antacids with citrus fruit or juices. Ignoring the likely occurrence of a competing 2:1 citrate-Fe3+ complex necessitates adjustments in reported stability constants for Fe3+ binding to transferrin. In the blood, plasma transferrin steals both Fe3+ and Al3+ from citrate.
171 citations