NANOTECHNOLOGY HAS BEEN USED IN EVERYTHING IN THIS "PANDEMIC"
https://onlinelibrary.wiley.com/doi/pdfdirect/10.1002/adfm.202107826 (https://doi.org/10.1002/adfm.202107826) Nanoscience versus Viruses: The SARS-CoV-2 Case First published: 13 December 2021
Therapy of viral infections with the use
of nanocarrier-based
drug delivery platforms administered via different ways.
Nanobiosensors for Diagnosis
REMDESIVIR:
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7373689/ Safety profile of the antiviral drug remdesivir: An update Published online 2020 Jul 22
Remdesivir, a broad-spectrum antiviral drug, emerges as a potential candidate for fighting against COVID-19 because of its potent in vitro anti-SARS-CoV-2 activity [1] and encouraging benefits for the infected patients [2].
However, with increasing application, adverse effects of remdesivir have been detected and become a concern of clinicians.
Hepatotoxicity.
In a case series, increased aminotransferases following remdesivir initiation were observed in three COVID-19 patients [4]. Lescure et al. also reported one COVID-19 patient discontinued remdesivir because of alanine aminotransferase elevation and rash, which then decreased within 3 days [5]. According to Grein et al.’s study on compassionate-use remdesivir against COVID-19, 23 % of the patients reported increased hepatic enzymes, and two of them therefore discontinued remdesivir prematurely [2]. A recent randomized controlled trial (RCT) in China also showed that total bilirubin, aspartate and alanine aminotransferase increased, respectively, in 10 %, 5 % and 1 % of COVID-19 patients in the remdesivir group versus 9 %, 12 % and none of COVID-19 patients in the placebo group [6]. More patients in the remdesivir group than the placebo group discontinued the study drug because of aminotransferase or bilirubin increases [6]. However, it should be noted that frequent incident liver injury was observed in COVID-19 patients [7], therefore it is challenging to distinguish whether the elevations in aminotransferases and/or bilirubin attributed to remdesivir or to the underlying diseases. As recommended by European Medicines Agency, remdesivir should not be used with other hepatotoxic drugs and hepatic function monitoring is required during the treatment [8]. Since most COVID-19 patients with liver injury had mild aminotransferases and/or bilirubin increases [7], if abnormality of liver enzymes occur after remdesivir initiation, especially in high levels, adverse drug reactions need to be considered and drug discontinuation is required if necessary.
Gastrointestinal symptoms. According to a case series in which three COVID-19 patients were treated with remdesivir, two had nausea and one suffered from gastroparesis after the treatment initiation [4]. Diarrhea was observed in 9 % of the remdesivir recipients in Grein et al.’s study [2]. Based on a RCT in China, a higher proportion of remdesivir recipients than placebo recipients had dosing prematurely stopped because of anorexia, nausea, and vomiting [6].
Respiratory toxicity.
However, acute respiratory distress syndrome (4 %) and pneumothorax (4 %) were reported after the infusion of remdesivir in Grein et al.’s study [2]. Based on the findings from a RCT in China, more patients in the remdesivir group than the placebo group suffered from respiratory failure or acute respiratory distress syndrome (10 % versus 8 %) and therefore discontinued the study drug (5 % versus 1 %) [6].
Cardiovascular toxicity.
However, one case of hypotension was judged to be potentially related to remdesivir in a RCT of experimental therapies against Ebola [9]. In Grein et al.’s study, hypotension (8 %), atrial fibrillation (6 %) and hypernatremia (6 %) were observed in COVID-19 patients treated with remdesivir [2]. What is more, one case of cardiac arrest was reported in remdesivir group in a RCT in China [6].
Nephrotoxicity.
Grein et al. reported renal impairments, acute kidney injury and hematuria in 8 %, 6 % and 4 % of the remdesivir recipients, respectively [2]. A COVID-19 patient, who was treated by our team in Wuhan in March 2020, suffered from acute renal failure after using remdesivir. This case was also reported in a RCT in China [6]. Therefore, it is important to monitor kidney function during remdesivir treatment, particularly for those with pre-existing renal impairments or those receiving combination therapies with other nephrotoxins.
Reproductive toxicity.
However, the safety of remdesivir in this special group of patients needs to be further evaluated by therapeutic trials which include pregnant women of COVID-19.
Other adverse effects. Transient rise in serum amylase was reported in an Ebola-infected patient treated with remdesivir [10]. Grein et al.’s study mentioned rash, multiple-organ-dysfunction syndrome, deep-vein thrombosis, delirium, septic shock, pyrexia as adverse events occurred in remdesivir recipients [2]. Adverse events related to hematologic, circulatory, endocrine and other systems were also detected in the remdesivir group in the RCT in China [6].
The current safety profile of remdesivir is still incomplete. Increasing evidence has witnessed COVID-19 is implicated in injuries of multiple organs including lung, liver, gastrointestinal tract, heart and kidney [7,[11], [12], [13]], hence it is complex to distinguish the underlying causes of adverse events during remdesivir treatment. Moreover, the latest safety data from Grein et al.’s study on compassionate-use remdesivir which reported adverse events in 60 % of the patients and the RCT in China which reported adverse events in 66 % of remdesivir recipients versus 64 % of placebo recipients might be limited by the inclusion criteria, finite sample size and follow-up duration. Since the experience of remdesivir application in the newly emerging COVID-19 is still limited, adverse drug effects need to be paid much attention to.
COMPARE THIS TO THE TOXIC EFFECTS OF NANOTECHNOLOGY:
https://ia902208.us.archive.org/22/items/lipids/2012-02-21_accumulation_of_nanocarriers_in_the_ovary-a_neglected_toxicity_risk.pdf Accumulation of nanocarriers in the ovary: A neglected toxicity risk? - ScienceDirect
Nanocarrier accumulation in the ovaries may also comprise an important toxicity issue in humans but the results might as well open a new field of targeted ovarian therapies.
Although toxicity and potential risks of such carriers have already been studied in detail, many effects are still poorly understood [7]. Unexpected accumulation of drug delivery systems in specific regions after intravenous (i.v.) injection could result in harmful side effects. Therefore, potential accumulation of nanocarriers in various tissues should be investigated during the development of new drug carrier systems. The fate of the carriers in the body depends mainly on their size, charge, shape and flexibility. Carriers larger than 150 nm often accumulate in liver and spleen
all tested nanocarrier batches with diameters between 45 and 350 nm highly accumulated in the ovaries.
https://web.archive.org/web/20190303171221/http://kinampark.com:80/JCRInfo/files/JCR%20151-200,%202012-2015/JCR%20160,%201%202012%20Mader.pdf Toxicity risk of nanocarriers
The biodistribution of the nanoparticles has been studied mainly as a part of the targeted drug delivery, and it is well known that the majority of the administered nanoparticles are cumulated in the liver, lung, spleen, and kidneys [1,2]. One important, but frequently neglected, organ is the ovary. In an article in this issue, Professor Karsten Mäder and his team in cooperation with Dr. Thomas Mueller's group studied the toxicity risk of nanocarriers in the ovary. They detected a high local accumulation of different nanocarrier systems (nanoparticles, nanocapsules and nanoscaled lipid emulsion) in specific locations of rodent ovaries [3].
The results showed that all nanocarrier systems accumulated partially in the ovaries of different mouse species and also of Wistar rats.
https://opus.lib.uts.edu.au/bitstream/10453/146687/2/Applications%20of%20nanocarriers%20as%20drug%20delivery%20vehicles%20for%20active%20phytoconstituents.pdf Applications of Nanocarriers as Drug Delivery Vehicles for Active Phytoconstituents
Received: February 25, 2020 Accepted: April 17, 2020
There are various other factors which should be taken into account with the use of nanocarriers. One of which is the stability of nanoparticles [38]. Nanoparticles tend to aggregate at low drug concentrations and the drug entrapment may vary due to polydispersity [39]. This will ultimately affect their efficiency and solubility in body systems.
Another concern is the long-term risk of toxicity with the use of nanocarriers.
Nanoparticles have been said to affect certain physiological systems because
they generate reactive oxygen species, which might lead to increased oxidative stress and induce inflammation [40,41].
However, toxicity data on the use of nanoparticles are conflicting [42]. Thus, more studies are needed to establish the toxicity of nanoparticles, to further understand their mechanisms and develop solutions to reduce such toxicity risks.
However, additional studies are required to assess and improve the long-term safety of nanosized phytoconstituents to further enhance their use in biomedicine.
https://digital.csic.es/bitstream/10261/218453/1/Toxicity_Garrido_Art2020.pdf Toxicity of Carbon Nanomaterials and Their Potential Application as Drug Delivery Systems: In Vitro Studies in Caco-2 and MCF-7 Cell Lines
Received: 23 July 2020; Accepted: 16 August 2020; Published: 18 August 2020
However, the biomedical applications of carbon nanomaterials arouse serious concerns, as more information on the pharmacokinetics, metabolism, long-term fate and toxicity is Nanomaterials 2020, 10, 1617 3 of 21 essential [27,29,31,39–41].
However, there are widespread concerns on the inherent cytotoxicity of carbon nanomaterials, which remains controversial to this day, with studies demonstrating conflicting results. Carbon nanomaterial-based drug delivery systems are still considered far from being accepted for use in actual clinical settings.
Fundamental studies regarding the impact of size, shape, aggregation degree and functional groups of carbon nanomaterials are needed to provide the design criteria for successful nanomaterial-based strategies.
In the literature, there is a lack of comparative studies, as extensive variations in the nanomaterial source, functionalization, and experimental conditions do not allow direct comparison of the different results.
Several obstacles must be overcome before carbon nanomaterials can be suitable for clinical use. The major challenge and current limitation in this area is still the potential long-term toxicity concerns of carbon nanomaterials.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4618487/ Lipid-Based Nanocarriers for RNA Delivery - PMC (nih.gov)
Toxicity of Cationic Lipids
As mentioned before, cationic lipids are typically included in lipid nanoformulations of RNAi therapeutics to improve RNA encapsulation and stability. Unfortunately, this class of lipid ingredients is also associated with significant toxicity issues [26].
A cationic lipid molecule can disrupt the integrity of a membrane structure as it resembles a detergent. At low concentration, a lipoplex consisting of cationic lipid molecules can irritate the exposed cell and cause cytoplasm vacuolization, reduced number of mitoses and cell shrinkage [28, 39]. When the lipoplex level is sufficiently high, cell lysis and necrosis may be triggered [30]. Cell toxicity may also be induced by interaction of the cationic groups with cellular enzymes such as protein kinase C [31].
At preclinical and clinical levels, systemic toxicities of lipoplexes have also been well-documented.
Issues of PEGylation
However, PEGylation is not without its own drawbacks.
The common practice is to use cationic lipids as previously discussed, but this increases the toxicity.
At this point, the delivery issues and the related toxicity problems have been the biggest obstacles so far.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7898224/ Nanocarriers-Mediated Drug Delivery Systems for Anticancer Agents: An Overview and Perspectives - PMC (nih.gov)
Various novel nanocarrier-mediated drug delivery systems to deliver the chemotherapeutic agents at targeted sites are currently in practice.
Quantum Dots
Nano-sized semiconductor quantum dots are among the novel strategies used in the treatment of different types of cancer.
Carbon Nanotubes
Carbon nanotubes are mostly being applied biological fields as a sensor for diagnostic purpose and for detecting the DNA, proteins and discriminating different types of proteins from serum samples and help in the delivery of vaccines and proteins.125 These delivery systems pose some health dangers because of the insoluble nature in all kinds of solvents.
The nanocarriers' toxicity, especially for QDs, is a significant obstacle for the development of a successful antitumor drug delivery system.
Research is still going on to diminish the toxicity of existing nanocarriers and explore the advanced nanocarriers with a lower toxicity profile.
Nanoparticles have proven to be toxic to human as well as flora and fauna. Nanotoxicology has thus emerged as a new branch of toxicology for studying undesirable effects of nanoparticles. Therefore, development of novel nanoparticles for therapeutics and diagnostics must proceed in tandem with assessment of any toxicological and environmental side effects of these particles. Regulatory authorities should demand for detailed safety and toxicology data in humans and environment before the approval of nanopharmaceuticals.
https://particleandfibretoxicology.biomedcentral.com/articles/10.1186/s12989-019-0299-z Cellular Toxicity and Immunological Effects of Carbon-based Nanomaterials | Particle and Fibre Toxicology | Full Text (biomedcentral.com)
The reported cytotoxicity effects mainly included reactive oxygen species generation, DNA damage, lysosomal damage, mitochondrial dysfunction and eventual cell death via apoptosis or necrosis.
Conclusions
Due to their unique physicochemical properties, carbon nanomaterials are used for widespread applications ranging from industry to biomedicine. In parallel, carbon nanomaterial exposure has also raised concerns over health hazards associated with their properties [66].
It is not yet understood which aspects of carbon nanomaterials, e.g., surface areas, mass concentrations, lengths, dispersibilities, metal impurities, a combination of these features, or some other factors, play a central role in cytotoxicity.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5039077/ Toxicology of Graphene-Based Nanomaterials - PMC (nih.gov)
8. Conclusion and Future Perspective
The studies till date indicate that toxicity of graphene could be dependent on the shape, size, purity, post-production processing steps, oxidative state, functional groups, dispersion state, synthesis methods, route and dose of administration, and exposure times.
Reactive oxidation species mediated cell damage has been postulated as a primary cytotoxicity mechanism of graphene. Graphene sheets with sharp edges could induce direct physical damage and interact with phospholipids leading to membrane destabilization.
https://particleandfibretoxicology.biomedcentral.com/counter/pdf/10.1186/s12989-016-0168-y.pdf Toxicity of graphene-family nanoparticles: a general review of the origins and mechanisms
https://journals.sagepub.com/doi/full/10.1177/2397847317726352
Orally administered gold nanoparticles in mice were captured by the gastrointestinal tract and translocated by blood to other organs such as liver, spleen, kidney, heart, lungs, spleen, and brain.43 Studies in mice suggest that most nanomaterials accumulate in the liver following oral, inhalation, and intravenous exposures.44,45
Hepatotoxicity of nanomaterials
Liver is the primary organ involved in metabolism and detoxification of xenobiotics. Blood carrying toxicants is filtered by liver before being distributed to other parts of the body. The high rate of blood flow to the liver leads to delivery of high concentrations of the toxicant to this organ. The high levels of exposure and the high metabolic activity make liver a major target organ of toxicants. Once the nanomaterial, whether ingested, inhaled, absorbed through the skin or administered by intravenous injections, and medical devices, reaches the circulation, it may be translocated to the liver.
Some studies have suggested that nanoparticles are entrapped by the reticuloendothelial system suggesting liver and spleen as the main target organs.43
Therefore, nanomaterials might be potential hepatotoxicants, and, therefore, hepatotoxicity testing is an important testing strategy for safety assessment of nanomaterials, where appropriate.
Results of limited hepatotoxicity studies reported in the literature demonstrate that nanomaterials might be potential hepatotoxins.
Nephrotoxicity of nanomaterials
Kidney is one of the common target organs for nanomaterial toxicity. It has been reported that kidney is an important target organ for toxicity and the primary organ for clearance nanomaterials.57,58
The results of these studies suggest that certain nanomaterials have the potential to induce nephrotoxicity.
Inhalation toxicity of nanomaterials
Nanoparticles in air can travel great distances by Brownian diffusion. Therefore, inhalation is an important route of human exposure to the airborne nanomaterials. Nanoparticles are deposited in the respiratory tract predominantly by diffusion.60,61 Inhalation of nanoparticles results in depositing the nanoparticles within the alveolar regions of the rat lung.60–62 Once deposited, nanoparticles may cross biological membranes and access tissue that would not normally be exposed to larger particles. Inhaled TiO2 nanoparticles translocate into lung interstitial.61,63 Inhalation of TiO2 nanoparticles resulted in pulmonary overload in rats and mice with inflammation.64
Immunotoxicity of nanomaterials
Nanomaterials can modulate cytokine production.82,83 The available data suggest that through the elicitation of an oxidative stress mechanism, nanoparticles may contribute to pro-inflammatory disease processes in the lung, particularly allergy.82,83
The results of limited studies on immunotoxicity of nanomaterials suggest that certain nanomaterials may have the potential to cause immunotoxicity.
Cardiotoxicity of nanomaterials
The limited studies on cardiotoxic potential of nanomaterials suggest that certain nanomaterials have the potential to induce cardiotoxicity.
Potential mechanisms of nanomaterial toxicity
The mechanism of toxicity of nanomaterials is currently unknown.
The mechanism of nanomaterial interaction with cellular organelles is not well understood. Oxidative stress is a major mechanism of toxicity for a wide variety of chemicals. Cellular oxidative stress induces mitochondrial membrane damage, an early indicator of cellular stress. Mitochondrial membrane damage leads to mitochondrial dysfunction, a critical step in cell injury and cell death. Oxidative stress appears to play a major role in the toxicity of nanomaterials. Nanoparticles of various size and chemical composition are able to preferentially localize in mitochondria leading to oxidative stress and cellular damage.55,107
Inflammation which is mediated by production of inflammatory mediators such as cytokines appears to play an important role in the toxicity of nanomaterials.
The limited reported studies suggest that both oxidative stress and inflammation may play important roles in the toxicity of nanomaterials. However, the exact molecular mechanisms of nanotoxicity remain to be fully understood.
etc.
https://www.nature.com/articles/news.200 8.845 Carbon nanotubes: the new asbestos? | Nature
Calls for caution as nanotubes cause precancerous growths in mice.
https://www.nature.com/articles/nnano.2008.111 Carbon nanotubes introduced into the abdominal cavity of mice show asbestos-like pathogenicity in a pilot study | Nature Nanotechnology
Here we show that exposing the mesothelial lining of the body cavity of mice, as a surrogate for the mesothelial lining of the chest cavity, to long multiwalled carbon nanotubes results in asbestos-like, length-dependent, pathogenic behaviour. This includes inflammation and the formation of lesions known as granulomas. This is of considerable importance, because research and business communities continue to invest heavily in carbon nanotubes for a wide range of products5 under the assumption that they are no more hazardous than graphite. Our results suggest the need for further research and great caution before introducing such products into the market if long-term harm is to be avoided.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8353320/ Carbon Nanotubes: A Summary of Beneficial and Dangerous Aspects of an Increasingly Popular Group of Nanomaterials - PMC (nih.gov)
CNTs have characteristics similar to asbestos (size, shape, and biopersistence) and use the same molecular mechanisms and signaling pathways as those involved in asbestos tumorigenesis.
CNTs pose a potential occupational health risk. CNTs are similar in size and shape to asbestos and have the same biopersistence, and several studies on CNTs have focused on the carcinogenicity of these compounds and studied granuloma formation, fibrosis, mesothelial proliferation, and mesothelioma-like growth (13–15).
https://ieeexplore.ieee.org/document/6363471 Nanotechnology And Asbestos: Informing Industry’s Approach To Carbon Nanotubes, Nanoscale Titanium Dioxide, And Nanosilver
CONCLUSION
Nanotechnology – including nanosilver, ultrafine TiO2 and CNTs – may be the most exciting and important technological development of the past century. But it is not without risk. The question of whether, and under what circumstances, these materials may cause disease in humans is still very much open; however, enough is known about the potential dangers that all stakeholders – and juries – will expect industry to mitigate risk and engage in product stewardship right now.
If a mass tort scenario comes to pass, companies that are not affirmatively acting to assess and limit risk today could face punitive damages claims in the future.
Furthermore, industry cannot assume that the Plaintiffs Bar will continue to wait for the science to develop further.
While some courts -- particularly in the federal system -- demand definitive proof of causation in humans, that is not true everywhere.
Personal injury cases involving scientifically-suspect causation evidence are not uncommon, and some courts will allow such cases to proceed to verdict.
Moreover, perceived risk alone may be sufficient to support certain claims.
Finally, industry should assess the risk of exposure for nanomaterial workers and take steps to protect them.
If nanomaterials cause diseases in humans, industry is likely to see it in unprotected worker populations first.
Best nanotech we have is the one GOD gave us, melanin:
https://romanshapoval.substack.com/p/can-we-detox-nanotech-with-sunlight
OMGosh Outraged! You have hung onto the nanotechnology aspect of all this like a pit bull. Thank You!!!! The first abstract you link to, written in 2020 says “Since current safety data about remdesivir is fragmented and limited, we reviewed published studies and official documents regarding remdesivir treatment and summarize the up-to-date safety information, especially in COVID-19 patients.” What shocks me is that Remdesivir was created 2009 and they continue to claim we don’t have a safety profile. And Remdesivir is just one example of nanotechnology. How derelict can our public health system be? Not dereliction…LeeLasik calls it depraved indifference. I think it is murder by proxy. The Malthusians are in the control seat pushing their agenda.