Homeopathy Seen as Personalised Nanomedicine

Abstract

Among all the discoveries of Hahnemann, potentisation was the most important, though controversial. The curative effect of individualised homeopathic potencies is empirical but inexplicable by the conventional principles of science. This paradox is a highly contentious topic of debate between rationalists and homeopaths. Recent discoveries relating to the nano-particulate nature of homeopathic ultra-high potencies and their potential effect on individual gene expression give new insights into this complex issue. It is concluded that homeopathy may be viewed as ‘personalised nanomedicine’.

Keywords

homeopathy - nanoparticles - potentisation - genetics - personalised nanomedicine

Introduction

In homeopathy, trituration and succussions are involved in the process of potentisation. Samuel Hahnemann's discovery of potentisation gives homeopathy a unique identity. This was not an accidental discovery such as that of gravitational force by Isaac Newton. We know now that potentisation is a landmark in the history of therapeutic medicine. A close study of Hahnemann reveals that this discovery was the outcome of a gradual step-by-step process that began in 1797. He narrated his experience of treating a patient suffering from abdominal colic with the drug Veratrum album in grain doses. Hahnemann prescribed the drug powder containing 4 grains daily for 4 days, but the patient took all the medicine in 2 days.[1] Very shortly, the patient experienced a life-threatening aggravation of his condition.

This experience paved the way for minimising the quantity of medicine prescribed to patients during the 1801 epidemic of scarlet fever in Germany. Hahnemann prescribed one drop of diluted Belladonna as a dose containing, in every drop, a five millionth quantity of a grain. By prescribing the same dose, he achieved excellent results in the cure and prevention of scarlet fever. Hahnemann continued his experiments with other medicines as well, such as: Ignatia (1/1,200,000); Veratrum album (1/4,800,000); Nux Vomica (1/1,200,000 to 1/2,400,000); Pulsatilla (1/80,000); Capsicum (1/1,200,000); Chamomilla (1/85,000,000 to 1/3,840,000,000); Cocculus (1/3,600,000); Belladonna (1/120,000); Drosera (1/200,000); Hyoscyamus (1/100,000,000).[2]

The success in effective therapy using high dilutions encouraged Hahnemann to discover, a decade later, the process of potentisation of drugs based on the centesimal scale. Having discovered the theory of potentisation, Hahnemann started using 30C potency for conducting drug proving experiments and for treating patients. Potentisation is a process in which medicinal substances are triturated or succussed in the medium of sugar or milk or 90% ethyl alcohol in a specific ratio: that is, 1:99 in centesimal scale and 1:9 in decimal scale. A proving experiment was performed preferably with 30C potency.[3] In his last years of life, Hahnemann discovered a wholly new scale: the LM scale, based on 1:50,000 dilution, which ranges from LM1 to LM30.[4]

As he could not scientifically substantiate the process of drug preparation and the therapeutic action of homeopathic potencies, Hahnemann proposed a reasoning that he called a ‘conjecture’ (being doubtful). Hahnemann proposed a hypothesis that, in the process of potentisation, there could be development of hidden ‘dynamic powers’ of the drug substance. Further, he viewed that these dynamic powers of the potency might act on the ‘vital force’ of the patient in its curative action. Even today most homeopaths find it difficult to remove themselves from this hypothetical statement of Hahnemann.

The hypothesis of Avogadro, proposed in 1811, defines the number of atoms in one mole of any substance as equal to 6.022 × 10²³. The term ‘Avogadro's number’ was first used by French physicist Jean Baptiste Perrin in 1909. The accurate determinations of Avogadro's number happened only after the American physicist Robert Millikan measured the charge of an electron. In the initial periods of potentisation, Hahnemann limited the use of potencies to 30C or less, arguing that there was no possibility of any medicinal content in potencies beyond it, but later he approved the experimental evidence of his followers and agreed to use potencies higher than 30C.

It has now become clear that the method of drug preparation in homeopathy (potentisation) is very close to the modern method of grinding and milling used in nanotechnology to produce nanoparticles (NPs). Corroborating the findings of others,[5] [6] [7] [8] [9] [10] [11] [12] [13] [14] the author has shown the nano-particulate nature of homeopathic ultra-high dilutions in all the commonly used potencies.[15] [16] [17] [18] [19] [20] His study was conducted with various homeopathic drugs, derived from plants, metals, minerals and nosodes. The presence of original drug substance in the form of NPs in high potencies of metallic and mineral drugs may help to answer the primary question of how homeopathic drug solutions can produce therapeutic action. Therefore, the nanopharmacological[17] therapeutic capability of homeopathic ultra-high dilutions is very relevant and valid.

These findings call for the next phase of deeper enquiry into the therapeutic activity of NPs in the subtle and complex biological system of human beings and other organisms. Scientific evidence is accumulating that homeopathic drugs have the ability to initiate a variety of modifications in the genetic system.[21] [22] [23] [24] [25] [26] [27] [28] [29] [30] [31] [32] [33] [34] [35] [36] [37] [38] [39] [40] [41] [42] [43] [44] [45] For example, Samadder et al have repeatedly reported the regulation of gene expression by potentised homeopathic drugs: for example, they observed that Lycopodium clavatum 5C-15C has anti-cancer effect on HeLa cells in vitro.[23] Another study by Mondal et al implicated DNA interaction in apoptosis induced by Conium maculatum through generation of reactive oxygen species.[24] Saha et al have also reported that homeopathic high potencies of Hydrastis canadensis and Marsdenia cundurango can alter gene expression profiles in HeLa cells in vitro.[27] Das et al have shown that Arsenicum album 30C modulates protein biomarkers and gene expressions in the yeast Saccharomyces cerevisiae after its exposure to arsenite.[33] Olsen observed that ultra-high dilutions of Sodium butyrate could induce gene expression in HEK 293 cells.[45]

Kay and Khuda-Bukhsh proposed the concept of ‘homeo-genomics’.[46] Subsequently, Kay and Rashid discussed the significance of sequence-specific homeopathic DNA therapy and micro-immunotherapy based on a personalised genetic approach.[47] Baldwin et al found that sequence recognition occurs between intact DNA duplexes without any single-stranded elements.[48] The possible interaction of NPs of homeopathic ultra-high dilutions selected on the basis of ‘similia similibus curentur’ (let like be cured by like) with the DNA double helix is intriguing and demands further investigation.

Issues Under Debate

Two serious questions repeatedly raised by critics of homeopathy are to be addressed:

• 1) Does drug content exist in higher potencies?

• 2) What is the basis of the therapeutic action of higher potencies?

From Hahnemann's originally proposed ‘dynamic powers’ of homeopathic potencies, several more recent theories have been developed. These include water memory,[49] [50] [51] formation of clathrates,[52] epitaxy[53] and quantum physical aspects,[54] [55] each of which relies on the dynamic nature of potencies. The silica hypothesis[56] is different in that it proposes the possibility that silicon NPs, leeching from the glassware, act as the therapeutic agents of a homeopathic solution. But the varieties of therapeutic action of homeopathic drugs cannot be confined to only the one type of NP. The discovery of NPs of the original drug materials by Chikramane et al in six metallic homeopathic drugs of 6C, 30C and 200C opened a new era of inquiry into the contents of ultra-high dilutions.[5] However, in validating the homeopathic potencies on the basis of their discoveries, Chikramane et al attempted to explain their findings solely within the limits of Avogadro's number,[57] which has narrowed the scope of enquiries beyond that limit.

The basic concept of homeopathy stands on the strength of homeopathic drug proving experiments. These experiments, on healthy human beings, produce signs and symptoms that disappear with the withdrawal of the drug.[3] The findings of Khuda-Bukhsh et al[21] [22] [23] [24] [25] [26] [27] [28] [29] [30] [31] [32] [33] [34] [35] [36] [37] [38] [39] [40] [41] [42] [43] [44] [45] seem as relevant in the drug proving setting as they do in explaining the therapeutic action of homeopathic potencies. As the homeopathic drugs seem capable of initiating epigenetic changes in the patients that are curative, the same may initiate transient epigenetic modifications during a drug proving experiment. The discovery of immediate early genes (IEGs) may help in conceptualising the science behind such effects. The total number of IEGs is thought to be close to 100, only few of which have been extensively characterised. The expression of IEGs (e.g. c-fos, c-jun, arc) occurs rapidly and transiently on exposure to induced stress and a wide variety of cellular stimuli. The expression of IEGs is low or undetectable in quiescent cells, but is rapidly induced at the transcriptional level within minutes of extracellular stimulation; this transcriptional induction is independent of new protein synthesis.[58] [59] These discoveries offer a new testable hypothesis on homeopathic drug proving.

It is observed that homeopathic drugs of metallic and mineral origin, from 6C to CM in centesimal scale and LM1 to LM30 in 50 millesimal scale, are NPs of smaller size, and that the majority of particles measure less than 10 nm.[16] [17] [18] [20] A critical scale below 10 nm shows that the properties of particles are different and highly potent and modified in comparison to the mass material.[60] NPs of smaller dimensions have the unique ability to penetrate through the cell walls and into the cell nucleus.[61] The peculiar properties of NPs seem mainly due to their high surface to volume ratio.[62]

Toxic substances in high doses can kill, while low doses may stimulate biological systems.[63] The discovery of NPs in homeopathic ultra-high dilutions paves the way for further enquiries into homeopathic drug action. The subtlety and sensitivity of the genetic system make it amenable to the typical ‘butterfly effect’ of Edward Lorenz, with a cascading effect on the chain of physiological and psychological events. The butterfly effect is the sensitive dependence on initial conditions in which a small change in one state can have non-linear impacts on a complex system. It explains the possibility of massive changes at the end by a simple stimulus in the initial condition. This model is highly applicable for many human pathological states, where everything starts from a simple alteration of the coding in genes. A single genetic mutation can cause serious disease conditions: for example, a genetic mutation and its cascading effect in the organism can produce the formation of malignant tumors.[64] In a homeopathic drug proving, a few pills of 30C potency seem capable of initiating a chain of events leading to detectable signs and symptoms in healthy human beings. In homeopathy, many times a single dose of a high potency may initiate a therapeutic action even where pathological changes are established. The scientific basis of homeopathy seems to lie within the subtler levels of human biology.

We know that virtually any step of gene expression can be modulated, from transcriptional initiation, to RNA processing and to the post-translational modification of a protein into the gene regulatory network—a subtle and complex system. It regulates the expression of genes by a multitude of mechanisms such as phosphorylation (temporary modification), methylation (permanent changes), histone acetylation, gene silencing, up-regulation or down-regulation. Homeopathic prescriptions are based on specific characteristic signs and symptoms of mind and body: arguably, therefore, they are the true expressions of the genetic system. The collective clinical experiences of homeopaths across the world show that cures in chronic diseases can be long lasting. Under the conventional bio-molecular system, a quantity of medicines is prescribed on the basis of patient body weight, whereas homeopathic prescriptions contain nanoscale material that may be sufficient in quantity to initiate a therapeutic action.

Nanomedicine as a part of conventional medicine has a short history of two to three decades and is conceived as the medical application of nanotechnology. Current research in nanomedicine is focused on biological devices, nano-electronic biosensors, biological machines, etc. Considerable time and resources are being applied to study the toxicity and environmental impact of nanoscale materials. The concept and utilisation of nanomedicine in the conventional therapeutic mode are focused on delivering drugs to specific cellular tissue using NPs that reduce the wider cytotoxic effect of a chemotherapeutic agent, especially in cancer.[65] The current research approach of nanomedicine is based on the belief that conventional biomolecular medicine is the only true therapeutic approach. It is a paradox that while conventional medicine tries to discover the utility of NPs to transport and deliver drug molecules to kill targeted cells, homeopathically prepared and utilised NPs of potentised substances are used as curative agents. The current discoveries in science and some clinical results of homeopathic medication in acute and chronic diseases unveil the hitherto unknown nano-pharmacological aspect of homeopathic drug potencies and their therapeutic efficacy. It would seem wise to inculcate the nano-pharmacology of homeo-pathy into conventional nanomedicine research to maximise novel and beneficial outcomes in patient care.

The selection of patient-specific medicines and the modus operandi evolved in the last two centuries make homeopathy a nanomedicine suited individually for each patient.

Homeopaths always relied on the individual nature and peculiarities of patients to choose the right medicine (simillimum) and potency. We know the signs and the symptoms that homeopaths identify in a patient: the characteristics of their personality, reactions to heat/cold, specific cravings and aversions to food and drinks, specific mental likes and dislikes, causative factors, etc. These are the expressions of the genetic system of each individual. Though we know that the genetic codes of all human beings are closely similar, there are quite a few genes that differ per individual, giving them personal identity and individual existence, unique in nature. It seems to me that the totality of the characteristic signs and symptoms of individuals identified by a homeopathic practitioner in the selection of simillimum reflects a part of the ‘genetic blueprint’ mapped out for that person.

Conclusion

From the very beginning, homeopathy has been looked upon with scepticism and sometimes with contempt. Recent scientific discoveries bring into the light hitherto unknown realities of human existence in the fields of health, disease and cure. With the changing milieu of science, from the study of gross matter to the atomic and subatomic levels, medicine and associated therapeutics are likely to undergo changes. Conventional therapeutics have recently coined the idea of ‘personalised medicine’, a concept that has always been the essence of homeopathic medicine.

Accrued over more than 200 years, the methods, experience and research evidence in homeopathy reveal that: (1) homeopathic drug proving is unique and produces temporary signs and symptoms in volunteers; (2) in homeopathic practice, irrespective of the disease diagnosed, patients are administered medicines based on their individual characteristic signs and symptoms, and hence medication is highly personalised; (3) homeopathic potencies could impact on epigenetic programming in patients, leading to cure of a disease; (4) nanoparticles are formed during the process of homeopathic drug potentisation. The above points to the potential of homeopathy as a ‘personalised nanomedicine’ and its important position in the next generation of therapeutic medicine.

Conflict of Interest

None declared.

• References

• 1 Dudgeon RE. The Lesser Writings of Samuel Hahnemann. Indian edition. New Delhi: B Jain Publishers Pvt. Ltd; 1995. -303 -307
• 2 Hahel R. Samuel Hahnemann: His Life and Work. Reprint edition, Vol I, New Delhi: B Jain Publishers Pvt. Ltd; 1992: 310-318
• 3 Goel S. Art and Science of Homeopathic Pharmacy. 2nd ed. Mumbai: Mind Technologies; 2007: 346-361
• 4 Hahnemann S. Organon of Medicine. 6th ed. New Delhi: B Jain Publishers Pvt. Ltd; 1993: 270-276
• 5 Chikramane PS, Suresh AK, Bellare JR, Kane SG. Extreme homeopathic dilutions retain starting materials: a nanoparticulate perspective. Homeopathy 2010; 99: 231-242
• 6 Bell IR, Muralidharan S, Schwartz GE. Nanoparticle characterization of traditional homeopathically - manufactured Gelsemium sempervirens medicines and placebo controls. J Nanomedine Biotherapeutic Discov 2015; 5: 136
• 7 Bell IR, Muralidharan S, Schwartz GE. Nanoparticle characterization of traditional homeopathically–manufactured Silver (Argentum metallicum) medicines and placebo controls. J Nanomed Nanotechnol 2015; 6: 311
• 8 Bell IR, Schwartz GE. Enhancement of adaptive biological effects by nanotechnology preparation methods in homeopathic medicines. Homeopathy 2015; 104: 123-138
• 9 Upadhyay RP, Nayak C. Homeopathy emerging as nanomedicine. Int J High Dilution Res 2011; 10: 299-310
• 10 Konovalov AI, Ryzhkina IS. Highly diluted aqueous solutions: formation of nano–sized molecular assemblies (nanoassociates). Geochem Int 2014; 52: 1207-1226
• 11 Nandy P. A review of basic research on homeopathy from a physicist's point of view. Indian J Res Homeopathy 2015; 9: 141-151
• 12 Kar S, Bandopadhyay P, Chakraborty S. , et al. Derivation of an empirical relation between the size of the nanoparticle and the potency of homeopathic medicines. Int J High Dilution Res 2015; 14: 2-7
• 13 Demangeat JL. Gas nanobubbles and aqueous nanostructures: the crucial role of dynamization. Homeopathy 2015; 104: 101-115
• 14 Elia V, Ausanio G, Gentile F, Germano R, Napoli E, Niccoli M. Experimental evidence of stable water nanostructures in extremely dilute solutions, at standard pressure and temperature. Homeopathy 2014; 103: 44-50
• 15 Rajendran ES. Field Emission Scanning Electron Microscopy (FESEM) and Energy Dispersive Spectroscopy (EDS) studies of centesimal scale potencies of the homeopathic drug Lycopodium clavatum. Am J Homeopath Med 2015; 108: 9-18
• 16 Rajendran ES. An evaluation of Avogadro's number in the light of HRTEM and EDS studies of high dilutions of Ferrum metallicum 6, 30, 200, 1M, 10M and 50Mc. Int J High Dilution Res 2015; 14: 3-9
• 17 Rajendran ES. Nano pharmacological aspect of homeopathic drugs – A comparative study of different scales of ultra-high dilutions based on HRTEM Analysis and NP characterization of homeopathic drug Natrum muriaticum 6C−CM and LM1−LM30. Saudi J Med Pharm Sci 2017; 3: 89-106
• 18 Rajendran ES. Homeopathy a material science! Nanoparticle characterization of Aurum metallicum 6c, 30c, 200c, 1000c, 10000c, 50000c and 100000c. Int J Curr Res 2017; 9: 48923-48927
• 19 Rajendran ES. Homeopathy a nanomedicine – identification and characterization of NPs in Hypericum perforatum 6C, 30C, 200C, 1M, 10M, 50M and CM. Int J Dev Res 2017; 7: 12425-12431
• 20 Rajendran ES. Nanodynamics – Nanoscience, Homeopathy, Physical sciences, Nanomedicine. 1st ed. Cochin: Mohna Publications; 2015: 43-246
• 21 Khuda-Bukhsh AR. Potentized homeopathic drugs act through regulation of gene expression: a hypothesis to explain their mechanism and pathways of action in vitro. Complement Ther Med 1997; 5: 43-46
• 22 Khuda-Bukhsh AR, Bhattacharya SS, Paul S. PLGA Nanoparticle encapsulated plant extract (Gelsemium sempervirens) enhances cellular uptake and increases bioactivity: novel findings from an in vitro study. Tsitol Genet 2009; 14: 15-18
• 23 Samadder A, Das S, Das J, Paul A, Boujedaini N, Khuda-Bukhsh AR. The potentized homeopathic drug, Lycopodium clavatum (5C and 15C) has anti-cancer effect on HeLa cells in vitro. J Acupunct Meridian Stud 2013; 6: 180-187
• 24 Mondal J, Panigrahi AK, Khuda-Bukhsh AR. Anticancer potential of Conium maculatum extract against cancer cells in vitro: drug-DNA interaction and its ability to induce apoptosis through ROS generation. Pharmacogn Mag 2014; 10 (Suppl. 03) S524-S533
• 25 Khuda-Bukhsh AR. Current trends in high dilution research with particular reference to gene regulatory hypothesis. Nucleus 2014; 57: 3-17
• 26 Samadder A, Khuda-Bukhsh AR. Nanotechnological approaches in diabetes treatment: A new horizon. World J Transl Med 2014; 3: 84-95
• 27 Saha SK, Roy S, Khuda-Bukhsh AR. Ultra-highly diluted plant extracts of Hydrastis canadensis and Marsdenia condurango induce epigenetic modifications and alter gene expression profiles in HeLa cells in vitro. J Integr Med 2015; 13: 400-411
• 28 Mandal SK, Biswas R, Bhattacharyya SS. , et al. Lycopodine from Lycopodium clavatum extract inhibits proliferation of HeLa cells through induction of apoptosis via caspase-3 activation. Eur J Pharmacol 2010; 626: 115-122
• 29 Khuda-Bukhsh AR. Towards understanding molecular mechanisms of action of homeopathic drugs: an overview. Mol Cell Biochem 2003; 253: 339-345
• 30 Khuda-Bukhsh AR, Karmakar SR, Banerjee A. , et al. A follow-up study on the efficacy of the homeopathic remedy Arsenicum album in volunteers living in high risk Arsenic contaminated areas. Indian J Res Homeopathy 2009; 3: 43-51
• 31 Khuda-Bukhsh AR, Sikdar S. Condurango 30C induces epigenetic modification of lung cancer – specific tumour suppressor genes via demethylation. Forsch Komplement Med 2015; 22: 172-179
• 32 Khuda-Bukhsh AR, Bhattacharyya SS, Paul S, Dutta S, Boujedaini N, Belon P. Modulation of signal proteins: a plausible mechanism to explain how a potentized drug Secale cor 30C diluted beyond Avogadro's limit combats skin papilloma in mice. Evid Based Complement Alternat Med 2011; 2011: 286320
• 33 Das D, De A, Dutta S, Biswas R, Boujedaini N, Khuda-Bukhsh AR. Potentized homeopathic drug Arsenicum Album 30C positively modulates protein biomarkers and gene expressions in Saccharomyces cerevisiae exposed to arsenate. Zhong Xi Yi Jie He Xue Bao 2011; 9: 752-760
• 34 Khuda-Bukhsh AR, Chakrabarti J. Effects of sonication on chromosomes of mice, Mus musculus, and modifying effects of a homeopathic drug, Arnica Montana on them. Tsitol Genet 1998; 9: 333-340
• 35 Khuda-Bukhsh AR. An evidence-based evaluation of efficacy of homeopathic drugs in mice during induced hepatocarcinogenesis. Tsitol Genet 2007; 13: 177-185
• 36 Khuda-Bukhsh AR, De A, Das D, Dutta S, Boujedaini N. Analysis of the capability of ultra-highly diluted glucose to increase glucose uptake in arsenite-stressed bacteria Escherichia coli. Zhong Xi Yi Jie He Xue Bao 2011; 9: 901-912
• 37 Marzotto M, Olioso D, Brizzi M, Tononi P, Cristofoletti M, Bellavite P. Extreme sensitivity of gene expression in human SH-SY5Y neurocytes to ultra-low doses of Gelsemium sempervirens. BMC Complement Altern Med 2014; 14: 104-124
• 38 Sunila ES, Kuttan R, Preethi KC, Kuttan G. Dynamized preparations in cell culture. Evid Based Complement Alternat Med 2009; 6: 257-263
• 39 Preethi K, Ellanghiyil S, Kuttan G, Kuttan R. Induction of apoptosis of tumor cells by some potentiated homeopathic drugs: implications on mechanism of action. Integr Cancer Ther 2012; 11: 172-182
• 40 Mukherjee A, Sikdar S, Bishayee K, Boujedaini N, Khuda-Bukhsh AR. Flavonol isolated from ethanolic leaf extract of Thuja occidentalis arrests the cell cycle at G2-M and induces ROS-independent apoptosis in A549 cells, targeting nuclear DNA. Cell Prolif 2014; 47: 56-71
• 41 Bishayee K, Chakraborty D, Gosh D, Boujedaini N, Khuda-Bukhsh AR. Lycopodine triggers apoptosis by modulation 5-lipoxygenase, and depolarizing mitochondrial membrane potential in androgen sensitive and refractory prostate cancer cells without modulating p53 activity; signaling cascade and drug-DNA interaction. Eur J Pharmacol 2013; 698: 110-121
• 42 Bishayee K, Paul A, Ghosh S. , et al. Condurango-glycoside-A fraction of Gonolobus condurango induces DNA damage associated senescence and apoptosis via ROS-dependent p53 signalling pathway in HeLa cells. Mol Cell Biochem 2013; 382: 173-183
• 43 Friso S, Choi SW, Girelli D. , et al. A common mutation in the 5,10-methylenetetrahydrofolate reductase gene affects genomic DNA methylation through an interaction with folate status. Proc Natl Acad Sci U S A 2002; 99: 5606-5611
• 44 Baylin SB, Herman JG, Graff JR, Vertino PM, Issa JP. Alterations in DNA methylation: a fundamental aspect of neoplasia. Adv Cancer Res 1998; 72: 141-196
• 45 Olsen S. Effects of ultra-high dilutions of sodium butyrate on viability and gene expression in HEK 293 cells. Homeopathy 2017; 106: 32-36
• 46 Kay PH, Khuda-Bukhsh AR. The contribution of homeogenomic and homeogenetic studies in the support of the practice of homeopathy. Indian J Res Homeopathy 2016; 10: 101-107
• 47 Kay P, Rashid S. The development of new sequence specific homeopathic DNA remedies for health promotion and disease protection. Positive Health Online 2015; 220: 1-9
• 48 Baldwin GS, Brooks NJ, Robson RE. , et al. DNA double helices recognize mutual sequence homology in a protein free environment. J Phys Chem B 2008; 112: 1060-1064
• 49 Davenas E, Beauvais F, Amara J. , et al. Human basophil degranulation triggered by very dilute antiserum against IgE. Nature 1988; 333: 816-818
• 50 Chaplin MF. The memory of water: an overview. Homeopathy 2007; 96: 143-150
• 51 Teixeira J. Can water possibly have a memory? A sceptical view. Homeopathy 2007; 96: 158-162
• 52 Anagnostatos GS. Small water clusters (clathrates) in homeopathic preparation process. In: Endler PC, Schulte J. , eds. Ultra High Dilution–Physiology and Physics. Dordrecht, the Netherlands: Kluwer Academic Publishers; 1994: 121-128
• 53 Rao ML, Roy R, Bell IR, Hoover R. The defining role of structure (including epitaxy) in the plausibility of homeopathy. Homeopathy 2007; 96: 175-182
• 54 Walach H, Jonas WB, Ives J, van Wijk R, Weingärtner O. Research on homeopathy: state of the art. J Altern Complement Med 2005; 11: 813-829
• 55 Davydov AS. Energy and electron transport in biological systems. In: Ho MW, Popp FA, Warnke U. , eds. Bioelectrodynamic and Biocommunication. Singapore: World Scientific Publishing Co Pvt. Ltd; 1994: 411-420 , Chap 17
• 56 Anick DJ, Ives JA. The silica hypothesis for homeopathy: physical chemistry. Homeopathy 2007; 96: 189-195
• 57 Chikramane PS, Kalita D, Suresh AK, Kane SG, Bellare JR. Why extreme dilutions reach non-zero asymptotes: a nanoparticulate hypothesis based on froth flotation. Langmuir 2012; 28: 15864-15875
• 58 Trnecková L, Rotllant D, Klenerová V, Hynie S, Armario A. Dynamics of immediate early gene and neuropeptide gene response to prolonged immobilization stress: evidence against a critical role of the termination of exposure to the stressor. J Neurochem 2007; 100: 905-914
• 59 Sheng M, Greenberg ME. The regulation and function of c-fos and other immediate early genes in the nervous system. Neuron 1990; 4: 477-485
• 60 Alivisatos AP. Semiconductor clusters, Nanocrystals, and Quantum Dots. Science 1996; 271: 933-937
• 61 Verma A, Stellacci F. Effect of surface properties on nanoparticle – cell interactions. Small 2010; 6: 12-21
• 62 Biener J, Wittstock A, Baumann TF, Weissmüller J, Baumer M, Hamza AV. Surface chemistry in nanoscale materials. Materials (Basel) 2009; 2: 2404-2428
• 63 Calabrese EJ, Baldwin LA. Hormesis: the dose-response revolution. Annu Rev Pharmacol Toxicol 2003; 43: 175-197
• 64 Davies H, Bignell GR, Cox C. , et al. Mutations of the BRAF gene in human cancer. Nature 2002; 417: 949-954
• 65 Ranganathan R, Madanmohan S, Kesavan A. , et al. Nanomedicine: towards development of patient-friendly drug-delivery systems for oncological applications. Int J Nanomedicine 2012; 7: 1043-1060