Silver Pharmacology: Past, Present and Questions for the Future

Abstract

Silver pharmacology is at the cross-roads. It has a long history as a chemosterilent but is currently denigrated by some vested interests and other ‘knowledge monopolies’. It deserves better—particularly in these critical times of ever mounting incidence of antibiotic resistance. This reappraisal outlines some approaches to a dispassionate debate as to why we should, or should not, be reconsidering silver as an addition to (not a substitute for) other antibiotics at the front line of medicine. This will require more understanding about (i) the chemistry of silver in a biological environment; (ii) the different physical and bio-reactive properties of ionised silver (Ag(I)) and nanoparticulate metallic silver (Ag^o); (iii) the antibiotic potential of both Ag(I) and Ag^o; and (iv) establishing objective Quality Controls for potential silver therapies. Six appendices (A–F) provide some technical data and focus further upon the need to clearly define (a) procedures for manufacturing nanoparticulate metallic silver (NMS); and (b) the purity and properties of NMS preparations—especially stability, antibiotic efficacy and safety of products offered for clinical evaluation. A further appendix (G) deals with some political considerations currently impeding impartial clinical research on silver therapeutics.

Disclaimer: The author declares no conflict of financial interest with any commercial organisations.

Dedicated to the memory of Douglas Perrin (1922–1998), a physical chemist from New Zealand, with a passionate interest in using metals in medicine.

Appendices

Appendix A: Solubilities of Some Silver Salts/Complexes in Water

Section A, with physiological anions; Section B with some xenobiotic anions S = solubility (gm/L), temperature (T) = 25 °C except as noted.

	Anion	S (g/L)	T
A.	Nitrate	2.57 × 103
	Acetate	11.1
	Nitrite	4.2
	Sulphate	2.2
	Carbonate	3.3 × 10−2
	Phosphate	6.4 × 10−3
	Chloride	1.9 × 10−3
	Chloride	2.1 × 10−1	100
	Stearate	6.5 × 10−4	20
	Oxide (Ag20)	2 × 10−4
	Sulphite	1.4 × 10−4
	Bromide	1.35 × 10−4
	Iodide	2.6 × 10−6
	Cyanide	2.3 × 10−6
	Oxalate	3.6 × 10−11
	Thiocyanate	1.0 × 10−12
	Sulphide	1.5 × 10−14
B.	Perchlorate	5.57 × 103
	Fluoride	>103
	Thiosulphate	7 × 102	20
	Bromate	1.6
	Salicylate	0.95
	Iodate	0.44
	Chromate	3.5 × 10−2
	Azide	2.0 × 10−8
	Arsenate	1.0 × 10−22

1. Notes
2. (i) Silver nitrate, sulphate and acetate are much more water-soluble than silver nitrite, sulphite, carbonate or oxalate.
3. (ii) Stability constants for Ag-L bonding are recorded by Hogfeldt (1982) where L is inorganic and by Perrin (1979) for some organic ligands. These indicate strength of the bonds i.e. dissociation (affinity) constants for Ag-L [Solubility data only provide some indications of bond formation but do not quantify the strength of this bond.]

Appendix B: Reproducible Production of Nano Ag⁰ for Medicinal Use

(also see Laroo 2013)

Some variables that should be recognised and carefully controlled include as follows:

• Cleanliness of glassware, etc.

• Purity of the silver metal (Ag⁰) or silver salts (Ag(I)) which should always be of the highest grade available (>99 %). DIY products using cheaper grades of metallic silver, coinage, silver buckles, etc. will generate toxic products—either containing lead and cadmium (from incomplete refining) or the metals added as hardeners, e.g. copper, nickel, etc.

• Purity of water or other solvents, including content of oxygen and carbon dioxide. Removing chloride ions is essential.

• Physical procedures involved in manufacture. If using

  • Radiant energy (light, gamma rays), define bandwidth and intensity of radiation, duration of exposure, etc.;

  • Microwave energy, define wattage and duration;

  • Heat, define temperature and conditions for cooling;

  • Sonic energy, define key variables;

  • Electro-chemical procedures, define current, voltage, purity of DC supply, temperature control and degree of illumination.

• For chemical methods producing NPS from Ag(I) salts, also define

  • Purities of essential reagents used as reductants, dispersants and stabilisers

  • Methods to remove by-products and/or excess reductants: some of these may be physiologically unacceptable e.g. borate or formate or oxalate after using borohydride or formaldehyde or ethylene glycol respectively as the reducing agents. [The much cited Carey-Lea method includes ferrous ions in the mix (Frens and Overboek 1969.]

  • Qualities of essential ‘extras’ e.g. stabilisers/preservatives

  • Operational procedures for any further physical manipulations to separate impurities, enhance potency or lengthen shelf-life (e.g. ultra centrifugation, dialysis, etc.)

• Identify optimal storage conditions: specifying temperature, light sensitivity, nature of containers (plastic, borosilicate or soda glass, etc.)

Note Many methodologies described in the literature focus on NPS production for industrial uses not medicinal purposes. They should be adopted only after recognising the more stringent purities and stability needed for approved medications.

Appendix C: Quality Controls for NPS Products

‘The important thing about knowledge is discrimination, not quantity’.

Peskett (2014)

Note These quality controls can be just as important for understanding toxicities of nano-products. (Warheit et al. 2008) as well as their beneficial pharmaco-activities.

• I. Physico-chemical

  • Analysis for total silver content and purity⁶ and proportion of ionic Ag(I); measure p[Ag].

  • Definition of NPS product by determining:

    • Range of particle sizes

    • Particle charge (volts) and polarity (+ or −) i.e. Zeta potential

    • Particle shape, if transmission electron-microscopy is accessible

    • Acidity/alkalinity i.e. pH

    • Electrical conductivity

    • Light scattering properties and light absorption (400–450 nm)

    • Sorption properties e.g. using fluorescent/fluorogenic indicators

    • Flocculation by anions/cations and acidity⁷

    • By-products present, if not previously removed

    • Additives e.g. stabilisers, anti-flocculants, pharmaceutical adjuncts

    • Light sensitivity

    • Shelf life before obvious deterioration

    • Optimal conditions for storage e.g. dark bottles? and temperature?.

• II. Biological properties in vitro (for quick testing)

  • Stability in physiological media = saline, artificial gastric juice, urine

  • Compatibility with plasma proteins, etc.

  • Toxicity to selected microbes (bacteria,⁸ yeast, protozoa), plant tissues, e.g. germinating radish seeds, to cultured animal cells and whole organisms e.g. brine shrimps⁹

Appendix D: ‘Colloidal Silver ’ (CS): Some Facts and Fallacies

(Note These are items for continuing discussion, not dogmatic truths)

Fallacies

• I. A CS preparation can be a universal treatment for nearly all microbial infections—but where is the detailed evidenced?

• II. It is a ‘good’ medicine because it has traditional origins, ‘mystique’, etc.—but so did apricot kernels (Laetrile) for treating cancer.

• III. It is cheap and easy to manufacture and therefore suitable as a home-made remedy—but so are many poisons e.g. methanol from wood, insecticidal nicotine from tobacco leaves.

• IV. ‘It must be good’, receiving so much attention on the Web—but much of this is advertising and too little is unbiased commentary.

• V. If it were useless, why would the medical establishment want to ‘suppress’ it? [This is a tendentious matter, based more on expediency than principle.]

• VI. ‘It must be safe’, considering the widespread use of silver coinage, cutlery, containers, etc. in our domestic environment—but only rarely are we using unvarnished bulk silver in medicine.

Facts

• (i) Unless defined by composition e.g. purity, particle size, shape and charge, and stability; a CS preparation cannot be expected to successfully interact consistently with a chosen pathogen/other targeted biosystem.

• (ii) Current silver pharmaceuticals are remarkably non-toxic, in contrast to many inorganic drugs that were once ‘in-vogue’. These latter medications were notoriously toxic with quite dreadful therapeutic indices; vide historic use of mercurials, antimonials, arsenicals and more recently the platinum carcinostats that are all still being used in orthodox/allopathic medicine.

• (iii) Cost is misleading and many qualities may be sacrificed by using (a) impure metallic silver sources, (b) haphazard control of preparative procedures, (c) inadequate checks for impurities and (d) failure to control other essential qualities e.g. stability ex vivo (light, heat, etc.).

• (iv) Drug regulators and the medical fraternity are rightfully concerned to prevent abuse and harm from any antibiotics to both the consumer and the modern environment e.g. the essential microbial population of sewage sludge. Current regulatory procedures for CS and other silver pharmaceuticals seem particularly oppressive (prohibition, etc.); especially when contrasted with the minimal management of proven health risks affecting the whole community, such as alcohol, tobacco, and the over-consumption of sugar, salt, (w6)unsaturated fats; all of which are largely unregulated.

• (v) The safety of (bulk) metallic silver, as in coinage and domestic silverware, is largely irrelevant when considering latent toxicities of ingestible, cationic and nano-metallic silver preparations.

Appendix E: A Summation About NPS: The Good, the Bad, and the Ugly

Good

• Long-term stability without refrigeration

• Potential to adhere to/penetrate bacterial biofilms

• Adjunct to use with planktonic antibiotics, either for synergy or ‘back-up’ therapy

• Cheap. Possible to prepare near/on-site for appropriate infection control

• Restricted diffusion, for maximal topical efficacy (e.g. on skin/gastric ulcers)

• Slow-release source of pharmaco-active Ag(I) = selective toxin?

• Potential for using NPS particles as carriers/delivery systems for other pharmaca (attached covalently or by Coulombic interactions)

Not So Good, often quite Bad in fact

• Inadequate quality controls for safety, purity, stability, antibiotic activities, etc. and risk of adverse reactions.

• Flood of unproven claims on the WWW for pharmaco-efficacy; often misleading and some being nonsense

• Very limited funding for research in an area with poor prospects for high financial returns e.g. from exclusive patents

• Lack of vision by health authorities to help side-step this impasse and also support more studies of silver pharmaceuticals for controlling antibiotic-resistant microbes

Ugly

• Claims that very small silver particles (<2 nm) penetrate the brain, causing firing of the neurones

• Poorly controlled targeting for systemic use

• Ill-founded arguments about environmental toxicities (with much propaganda but too little science)

• Political interference and suppressive tactics to suit vested/misguided interests, rather than patient’s welfare

• Polemics: regulation favouring status quo (basically ‘ban silver’) to the detriment of independent trials to (i) ascertain possible long-term medicinal benefits and (ii) understand safe limits for both individuals and the environment. [Certainly not good science and rather a discredit to Modern Medicine, manipulated or otherwise.]

Note This table is far from complete

Appendix F: Antibiotic Potency , Stability and/or Bio-transformation of Nanoparticulate Silver (NPS): Some Facts and Speculations

Facts

• 1. “One size fits all” is clearly untrue in describing antibiotic activities of NPS products, however carefully prepared to minimise heterogeneity (size, charge density, shape, etc.). So for example, the type of preparations that may be anti-protozoal may have little value as an antiviral.

• 2. NPS (Ag⁰) prepared by chemical procedures, particularly reduction of soluble Ag(I) salts or complexes, such as [Ag(NH₃)₂]⁺, will have their anionic/cationic character largely determined by the preparative conditions.

  Eg AgNO₃ and tribasic citrate salts produce anionic NPS hydrosols, readily aggregated by lanthanum (III) ions i.e. their ‘superficial’ charge is negative.

• 3. By contrast NPS preparations derived without added chemicals e.g. by photo-induced reduction of electrolytically generated Ag(I) cations (Laroo 2013) will most likely be cationic i.e. not aggregated by La(III).

• 4. The charge densities of NPS particles would largely determine their stability ex vivo, i.e. shelf-life. In theory, the smaller the particles, the greater their ionic character relative to total mass: consequently they will be less likely to spontaneously aggregate. But their shelf life may be no indication of their utility for combating infections in vivo, if they need first to be transformed/bioactivated in vivo (see Item iii below).

• 5. Many reports about the antibiotic potencies of NPS preparations provide few details of how disperse (i.e. size variation) and stable they are. For example, NPS-citrate preparations are intrinsically unstable. Commercial NPS samples, stabilised with citrate and used as reference ‘standards’ for sizing, can aggregate over time with distinctive changes in colour, opacity—and very often biopotency ex vivo. Such deterioration may not always be a negative feature, if it reflects spontaneous transformations that might be accelerated in vivo when used medicinally or ex vivo within the environment after excretion.

Speculations

• (i) Should we be constructing a working concept of NPS ‘metabolism’, considering not only these spontaneous transformations in vitro (see item 5 above) but also the effects of the bio-environment upon an administered polysilver-X NPS complex? This perspective questions the tacit assumption that silver pharmacology is primarily all about the effects of Ag⁰/Ag(I) upon targeted bio-systems; while usually ignoring the reverse interaction i.e. how the internal environment may act upon an NPS preparation to determine pharmaco-activity.

• (ii) If so, the nature of factor(s) X may profoundly influence not only the physico-chemical stability of an NPS preparation ex vivo but also its potential instability (and pharmaceutical value) within the various biosystems it may encounter.

• (iii) Concerning the nature of this factor X: if it is either a potentiator or an inactivator may then determine the medicinal value of an NPS preparation. For example:

  • If X is oxygen, will this oxide/dioxygen ‘film’ be diminished by ‘scrubbing’ with acids in vivo or amplified by H₂O₂ and other bio-oxidants?

  • If X is citrate, will this dissociate and be catabolised in vivo, generating a silver particle more likely to spontaneously aggregate (after losing a particle-stabilising negative charge); perhaps providing a less efficient ‘pay load’ of bio-reactive Ag(I)?

  • If X is ionic Ag(I), will a mobile NPS that is cationic in vitro now be neutralised, even aggregated, by chloride or phosphate ions in vivo?

  • If X is an argentophilic bioligand (Table 4) captured in vivo, will this always immobilise or destroy the value of an NPS product? In some contexts it might possibly increase the hydrophilicity of an NPS preparation, altering its bio-distribution, so changing its efficacy.

  • If X is a particle ‘stabiliser’, may this protective coating be so stable as to isolate a reactive NPS from its targeted biosubstrate? Generalisations about the inefficacy of NPS preparations as an antibiotic in vitro e.g. where X equals PEG or PVP (Xiu et al. 2012) or oleate, may be true in their context but not necessarily valid where X is readily dissociated or metabolised in vivo.

• iv. So how might the nature of X further determine antibiotic activity? As an illustration of this question, here are two examples:

  • (a) The acidic environment of the stomach may determine the anti- Helicobacter pylori activity of an NPS-oxide preparation , to help control gastric ulceration; but the anti-ulcerant effect may not be the same in a different compartment such as within the more alkaline environment of the proximal duodenum. [Even though Helicobacter provokes both stomach and duodenal ulceration.]

  • (b) Some ligands such as esterified ethenoid (unsaturated) fatty acids might reversibly trap some types of NPS at strategic loci, so enhancing their local potency in vivo e.g. within lipid membranes.

• v. Statements that NPS particles are less effective antibiotics for Gram-positive (GP) bacteria than Gram-negative (GN) species—as determined from standard ex vivo bioassays—sometimes may have little meaning for understanding how they might behave in vivo. For example, cationic NPS species might be expected to bind to the anionic polyphosphate teichoic acids within the outer cell wall of GP bacteria. But several reports describe the lesser microbial activity of NPS preparations upon these teichoate-coated bacteria ex vivo. This would not be surprising if the NPS preparations being tested ex vivo were themselves anionic e.g. citrate-coated. But to extrapolate from this hard data to predicting that all NPS preparations would be less useful for treating infections by GP bacteria—without thoroughly evaluating the potency of cationic NPS preparations—may perpetuate a grave error in our perceptions of what are the more useful formulations with which to conduct clinical trials.

• vi. By contrast, GN bacteria carrying a relatively high content of lipids within their cell coating, may either preferentially take up and bond with hydrophobic NPS particles (with low charge density) or ‘capture’ cationic NPS particles that may disrupt the stabilising effects of their anionic membrane phospholipids.

In Conclusion

Beware of simplistic generalisations about potencies of antimicrobial NPS preparations which implicitly assume that they are always ‘naked’ silver particles. In fact they are more likely to be complex entities, represented here as NPS-X. So in the absence of essential details about (a) their bio-evaluation ex vivo (e.g. with or without using agar plates) and (b) their physical stability, chemical constitution (noting what factor X might be) and natural lability—we may be dealing with ‘rogue products’. This is certainly no basis for a scientifically grounded antibiotic revolution, as yet.

Appendix G: Political Considerations

This ought not to be part of any scientific enquiry into the merits or hazards of any drug, new or old. The facts, the theories, the clinical evaluations, etc. should all be dispassionately considered—without interference or censorship from either vested interests or poorly informed government regulators. At present, silver therapeutics is not allowed this freedom. There are several reasons for this situation. Here are three:

• 1. Governmental regulations concerning use of, and claims for, medicinal silver are presented in the following e-publications.

  http://www.fda.gov/ohrms/dockets/98fr/081799a.txt

  http://www.gpo.gov/fdsys/pkg/FR-1999-08-17/pdf/99-21253.pdf

  http://nccam.nih.gov/health/silver and for Australia https://www.tga.gov.au/colloidal-silver-related-products

  They are dogmatic, deny medicinal claims and even punitive if you disagree. This is not a good state of affairs for progressing the healing arts, especially those with traceable histories of their benefits exceeding possible harm and supported by unambiguous scientific observations. But wisely considered, these current regulations concerning the medical use of silver should catalyse a genuine debate about how to unshackle laboratory and clinical research on silver pharmaceuticals—to move beyond a negative risk-averse mindset (i.e. ‘thou shalt not….’). This needs to be replaced by a climate of open and honest enquiries about what may be beneficial to humankind (and animals) and about what may not be so (especially for the environment).

  Recently, we have seen other traditional therapies decriminalised e.g. cannabis for cancer pain. So why not silver therapeutics, especially if they might save lives from infections that are currently antibiotic-resistant? [But how will we ever know this under the present suppressant regulations?]

• 2. The power of industrial lobbyists (Angell 2004; Goldacre 2012).

  The influence of pharmaceutical companies upon the ‘education’ of physicians and operations of various drug-regulatory agencies has inverted some of the functions of these agencies [They were originally established to prevent harm to the public, not to seemingly protect monopolistic interests at the expense of public wellbeing.]

  We are left with the unsatisfactory status of alternative/traditional therapies, like those using silver and without patent protection. They are the subject of considerable misinformation and rarely funded to provide the evidence demanded by these lobbyists, insisting they be treated as ‘new drugs’—even when historically shown to be much more acceptable and rather cheaper than many licensed/patented alternates. This is another aspect of the ‘rhetoric versus reality’ (Angell 2004) as practised by Big Pharma to destroy its competition.

• 3. ‘Consumer protection’

  In theory, this is a very good thing but so often it is captured by vested interests and debased in practise.¹⁰ It is naive to believe official dogmas that such alternate/traditional therapies are nearly always either unproven(!) (but see Bone and Mills 2013) or too dangerous to be licensed—even when Quality Assured.

  Agencies minding our health need to do their own homework; if necessary sponsor and publish their own research and (for a change) listen to non-industrial advocates sometimes.