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Potential Patient-Reported Toxicities With Disulfiram Treatment in Late Disseminated Lyme Disease

https://www.frontiersin.org/articles/10.3389/fmed.2020.00133/full

Potential Patient-Reported Toxicities With Disulfiram Treatment in Late Disseminated Lyme Disease

Alain Trautmann1*, Hugues Gascan2 and Raouf Ghozzi3*
  • 1Université de Paris, Institut Cochin, INSERM U1016, CNRS UMR8104, Paris, France
  • 2Institut de Génétique et Développement de Rennes (IGDR), Rennes, France
  • 3Centre Hospitalier de Lannemezan, Lannemezan, France

Recently, disulfiram has been proposed as a promising treatment for people suffering from persistent symptoms of Lyme Disease. Disulfiram has several distinct molecular targets. The most well-known is alcohol dehydrogenase, a key enzyme for detoxifying the organism after alcohol ingestion. Other targets and modes of action of disulfiram, that may present problematic side effects, are less commonly mentioned. The French Federation against Tick Borne Diseases (French acronym, FFMVT), which associates three main Lyme patient organizations, MDs and PhDs, has recently been alerted to severe and persistent toxic events in a patient suffering from a late disseminated form of Lyme Disease following disulfiram intake. FFMVT reacted by launching a national call to examine whether other patients in France following a similar treatment could be identified, and what benefits, or side effects could be reported. The statements of 16 patients taking disulfiram have been collected and are presented here. Thirteen out of 16 patients reported toxic events, and seven out of 16 reported benefits for at least part of their symptoms. Based on the collected observations, it seems too early to promote disulfiram as a promising new treatment until the reasons underlying the reported toxicities have been explored, and the results of a well-conducted double blind clinical trial published. The importance of taking into account patient-reported outcomes in Lyme Disease is underlined by the present study.

Introduction

Each year, in the USA, about one person out of 1,000 develops Lyme Disease as declared by the general practitioners, which leads to a total of around 300,000 annual cases (1). Similar frequencies have been reported in Europe, in particular in France (2) and in Germany (3). The patients usually take antibiotics for a few weeks, and in most of cases they recover. However, after several months or even years, a fraction of these properly treated patients, will develop a post-treatment Lyme Disease syndrome (PTLDS) linked to pathogens injected by the tick, usually Borrelia bacteria, often associated with other bacteria like Bartonella, parasites like Babesia, or even viruses. Another group of patients develops a late disseminated form of the disease without having noticed any initial event, like the pathognomonic cutaneous erythema migrans, rendering more difficult the Lyme Disease diagnosis.

There is no consensus for the optimal treatment of these late forms of disease. The major difficulties in their diagnosis and in their treatment are reflected in the number of different names they have been given: late Lyme Disease, persistent Lyme Disease, chronic Lyme Disease, PTLDS, and in France SPPT for “sémiologie persistante polymorphe après morsure de tique” according to the new French government guidelines.

In such a context, there is a desperate need for many people to receive the optimal treatment. Recently, a new treatment has been reported, and many patients are currently trying it despite the fact that the main active compound, disulfiram (DSF), has never been clinically evaluated in the context of a chronic infection, either alone or in combination with antibiotics. In the present work, to try to answer this pressing issue, we have analyzed the scientific literature on DSF and collected patient-reported results in order to inform patients suffering from late forms of Lyme Disease of the potential risks or benefits of DSF treatment.

Methods

After an alert in October 2019 from a patient presenting severe and persistent symptoms after taking DSF, the FFMVT (French Federation against Tick Borne Diseases) decided to launch two actions. One was a thorough analysis of the scientific literature, in order to try to understand the possible causes of such an apparent toxicity. The other one was to collect reported-outcomes from Lyme Disease patients having taken DSF. Three associations of patients, France Lyme, Lympact, Relais de Lyme, sent a standardized questionnaire, prepared by the authors, to their members suffering from PTLDS as described, among others, by J. Aucott (4), or from SPPT, the term used in France by Haute Autorité de Santé (High Health Authority) (https://www.has-sante.fr/portail/jcms/c_2857558/fr/borreliose-de-lyme-et-autres-maladies-vectorielles-a-tiques) and in a case law of the French Council of State (https://www.conseil-etat.fr/fr/arianeweb/CE/decision/2019-12-04/423060).

Concerned patients who were willing to contribute to this enquiry sent back the appropriate information on their clinical status and disease. Information requested included age, sex, health state, dosage and duration of the DSF treatment, concomitant medications, self-reported health improvements and potential toxicities. The answers were collected over a 2-weeks period, and anonymously transferred from patient associations to the authors of the present paper, before being tabulated and analyzed, as presented in Table 1. Note that the Research Integrity Specialist of Frontiers asked us to omit the gender information, and not to indicate the precise age, to reduce the risk for the patients to be indirectly identifiable.

TABLE 1

www.frontiersin.orgTable 1. Responses of 16 patients to DSF treatment (France, July–November 2019).

This enquiry allowed us to rapidly collect the appropriate information for evaluating whether or not reported severe adverse events in a first patient were exceptional or not. However, no definite conclusion can be drawn under such conditions, taking into account the sample size, the different doses of DSF used, and different combinations of concomitant medications used.

Results

The first part of this section will present potential reasons why toxicity is expected in patients taking DSF, and not exclusively following alcohol ingestion. The second part will concern the analysis of 16 patient-reported outcomes collected in November 2019 in France.

DSF, an ALDH Inhibitor

DSF has been clinically used for nearly 70 years, essentially for treating alcohol dependence. DSF inhibits an enzyme that is required for full alcohol degradation, preventing the detoxification that should follow alcohol drinking. This leads to severe nausea and discomfort in DSF-treated patients when they drink alcohol. This induced association between alcohol and severe discomfort is the basis of DSF use for the treatment of alcohol-dependent patients. More than 3,000 scientific publications mention DSF in their title, and most of them are related to alcohol consumption.

After ingestion, alcohol (ethanol) is degraded in two steps:

                                         ADH                                            ALDHEthanol(CH3.CH2.OH)Acetaldehyde(CH3.CHO)Acetate(CH3.COO)

The first reaction is catalyzed by alcohol dehydrogenase (ADH), the second one by aldehyde dehydrogenase (ALDH). The final product, acetate, has no toxicity. By contrast, acetaldehyde (AcH), also known as ethanal, is much more toxic than ethanol. Ethanal is quite volatile, and at low concentration gives off a pleasant smell of green apple, whereas at higher concentrations, its smell becomes pungent. Acute AcH toxicity may involve in particular the nervous system (5). In long term exposure, AcH is also a carcinogen (6). Note that ALDH is only weakly expressed in 30–40% of Asian, individuals, preventing them from properly eliminating alcohol, which explains why many of them have a low tolerance to alcohol.

The potent DSF-induced ALDH inhibition is copper-dependent (7). In vivo, DSF is cleaved, giving rise to diethyldithiocarbamate, an efficient copper chelator (8). Through this mechanism, DSF inhibits copper-dependent enzymes, such as ALDH, abundant in the liver (9), or dopamine β-hydroxylase in the brain (10). The best described effect of DSF, but not the only one, is its toxicity in the presence of alcohol, and sometimes even in its absence, as discussed below.

There are two main places in the organism where the enzymes ADH and ALDH allow the degradation of alcohol to acetate. The first is the ALDH-rich liver, which plays a key role after alcohol drinking. The second, which is seldom mentioned but nevertheless quite important, is the microbiota of the digestive tract, with its billions of bacteria and fungi particularly abundant in the mouth and the large intestine. In some bacteria, the ADH enzymatic activity is significantly stronger than the ALDH one. As a result, in the presence of alcohol, such bacteria, including the commensal ones, trigger an increase in the concentration of toxic AcH (11). This might contribute to a higher frequency of mouth and throat cancers in alcohol-dependent patients (12).

In addition, some anaerobic bacteria and yeasts are able to convert glucose into ethanol (this “alcoholic fermentation” is the basis for the manufacturing of alcoholic beverages). Under certain culture conditions, it is possible, when supplying some of these microorganisms only with glucose, to generate alcohol and then AcH. Thus, the yeast Candida albicans is capable of producing high levels of toxic AcH, after glucose fermentation (11). It can thus be predicted that the toxicity of DSF should be particularly marked in people suffering from candidiasis.

Finally, other bacterial families, such as Lactobacillus, have an ALDH activity larger than that of ADH, which makes them good detoxifiers, by preventing the accumulation of AcH (6).

Other Modes of Action of DSF

Although the DSF toxic effects occurring in the treatment of alcohol-dependent patients have been known for a long time, additional effects have been described more recently. It has been shown in particular that, in vitro, DSF can be cytotoxic for cancer cells (13). These results prompted the launch of three clinical trials including DSF in the treatment in prostate, pancreas and glioblastoma cancers (https://www.cancer.gov/about-cancer/treatment/clinical-trials/intervention/disulfiram). None of these trials, started in 2016 and 2017, has yet given rise to publication.

It was initially thought that these newly discovered effects were also due to the inhibition of ALDH, but this is not always true, and several other DSF targets have been identified. Thus, the protein NLP4, which is necessary for the cellular response to various stresses, is inhibited by DSF-copper complexes (13, 14). In addition, DSF can block an intracellular detoxifying pathway. It can inhibit the proteasome (15), a multi-protein complex required for the elimination of improperly folded proteins. DSF can also block the activation of NF-κB (15, 16), a key molecule in inflammatory stresses, known for inhibiting apoptosis.

In vitro, DSF can neutralize a DNA methyltransferase involved in DNA repair (17). It may also inhibit P-gp, a multidrug pump responsible for the extrusion of toxic molecules, which contributes to cellular resistance to many cytotoxic molecules (18). The effect of DSF on NF-kB, DNA repair, and P-gp may all contribute to the in vitroeffects of DSF against tumor cell lines. The effect of DSF on P-gp has been more particularly studied in fungi and yeasts, offering a possible explanation for the antifungal effect of DSF (19). However, some authors have attributed DSF anti-fungal properties to its capacity to elicit oxidative stress in yeasts (20). Still in vitro, DSF also displayed toxic effect against Plasmodium falciparum, the causative agent of malaria (21), and also against some bacteria (22).

As mentioned previously, DSF can act as a copper chelator, thus inhibiting copper-dependent enzymes. Some bacteria express such enzymes, rendering them sensitive to DSF. However, it is unclear whether the anti-bacterial effect of DSF is due to copper depletion or to direct effects of copper complexation inside bacteria (8, 23).

Most demonstrations of an antibacterial effect of DSF were performed in vitro (24, 25), at concentrations not always compatible with its in vivo use. For instance, one study claims that DSF is toxic to Mycobacterium tuberculosis, including the dormant form, both in vitro and in vivo (24). In fact, the experimental protocol allowed the evaluation of the effect of DSF on the global bacterial load, but showed nothing on in vivo bacterial dormancy. In this study, the efficient dose of DSF would have been equivalent to 1,100 mg of DSF / day for a human of 70 kg, well above the dose tolerated by Lyme Disease patients (see below). Thus, the conclusions of this study still remain to be validated.

In summary, DSF is a pleiotropic drug with multiple targets, without specificity for one molecule or a single pathogen. Most of the reported anti-bacterial effects of DSF have been obtained in vitro, making it difficult to extrapolate for its in vivo use, especially when used in combination with antibiotics.

A Clinical Trial With DSF for Treating Lyme Disease

In March 2019, Pr. Brian Fallon started a clinical trial using DSF and including 24 Lyme Disease patients (https://clinicaltrials.gov/ct2/show/NCT03891667). The results of Professor Fallon’s study should provide important information in the near future. On the clinicaltrials.gov website, the Study Description indicates that DSF is active against Borrelia’s dormant form. However, evidence to support this claim is not provided. The clinical trial document refers to three previous articles (22, 26, 27). In 2016, Pothineni et al. published an in vitrohigh-throughput screening of more than 4,300 drug candidates, against Borrelia burgdorferi grown to its stationary-phase (26). DSF appeared to be a very efficient bactericidal molecule for Borrelia in vitro, but no in vivo results have been reported yet. In 2017, Dr. Long has shown that, in vitro, DSF is cytostatic for Gram-positive bacteria, such as Staphylococcus or Streptococcus, but not for Gram-negative species (22). Finally, in 2019, Dr. Liegner reported three cases of patients who had been treated with DSF after a Lyme Disease that had lasted for several years with heavy treatments (27). For instance, at one point, one patient simultaneously took amoxicillin, clarithromycin, hydroxychloroquine, metronidazole, atovaquone / proguanil, and amitriptyline. After 9 years of illness he took DSF for 3 months: the symptoms of the Lyme Disease seem to have disappeared but the patient had a temporary psychiatric hospitalization. The second patient was on DSF for 6 weeks. The symptoms of the Lyme Disease improved but the treatment was stopped following a syncope, which resulted in a concussion and required hospitalization. In summary, the Liegner study reports three cases in which DSF seems to have been effective against late Lyme Disease, but in two of them neurological problems occurred during the treatment. These three cases have attracted considerable attention and raised great hopes in the Lyme Disease patient communities. However, in a recent talk at the 2019 ILADS Symposium, Dr. Liegner presented data on 30 Lyme Disease patients that he had treated with DSF. In 18 of them, DSF provoked either peripheral neuropathies or psychiatric problems, or both.

DSF Neuronal Toxicity ?

For tens of years, it has been known that DSF can cause occasional and sometimes severe neuropathies (28). In optic neuropathies, with a partial loss of vision, recovery took about 6 months after stopping DSF (29). When DSF is used to treat alcohol dependence, the incidence of undesirable neuropathies has been estimated as 1/15,000 (30). As for the totality of the undesirable effects caused by the DSF, their frequency has been evaluated at 1 per 200–2,000 patients (9).

Are DSF associated neurological disorders (neuropathies or psychiatric problems) related to DSF anti-ALDH activity leading to AcH synthesis? It has been demonstrated that, in vitro, AcH can have an acute toxicity on neurons due to an increase of reactive oxygen species, but this observation has not been extended in vivo (5).

An AcH increased toxicity could theoretically occur even in the absence of alcohol intake, for example in patients with Candida infections, or harboring a high load of microorganisms capable of alcoholic fermentation. Alcoholic fermentation, typically performed by yeasts, should be distinguished from lactic fermentation, more common in anaerobic bacteria. A few cases have been reported of people suffering from Gut Fermentation Syndrome (31, 32). Such patients had up to 2 g/L of alcohol in their blood, without any alcohol intake. This alcohol was produced by fermentation by large colonies of the yeast Saccharomyces cerevisiae in their intestine.

Another DSF target is dopamine β-hydroxylase, a copper-dependent enzyme, responsible for converting dopamine (DA) to norepinephrine (NE) in noradrenergic neurons. This enzyme is mostly expressed in the brain, adrenal gland and liver (https://www.proteinatlas.org/ENSG00000123454-DBH/tissue). By inhibiting dopamine β-hydroxylase, DSF simultaneously reduces NE and elevates DA in these tissues. A link has been established between psychosis and DSF-induced increase of DA in the mesolimbic system (10, 33). Dopamine β-hydroxylase is also expressed in some peripheral sensory neurons and it has been suggested that neurotoxic products of catecholamines metabolism in nociceptors can cause neuronal dysfunction underlying neuropathic pain (34).

Patient-Reported Outcomes

We have recently received from French associations of Lyme patients the results of an enquiry sent to their members suffering from persistent Lyme Disease. The main questions were: have you taken DSF as a treatment for your disease? Which benefits or side effects did you experience? 16 patients have answered.

The clinical features most frequently reported were major fatigue, articular pain and cognition complaints mainly involving memory, whether or not patients were seropositive for Borrelia. The results are presented in Table 1. The conclusions are: 13 out of 16 patients experienced DSF-induced toxic or side effects, mainly concerning the nervous system (neuropathies, headaches, dizziness, difficulty of concentration and expression, sleep disturbance, general pain increase, increase in general fatigue). Several patients reported a more specific increase in their osteo-articular pains, nausea or intestinal disorders.

When taking DSF, some patients simultaneously experienced both negative effects on some symptoms and improvement of others. All in all, 7 out of 16 patients perceived benefits mainly on fatigue and pain, especially after stopping DSF. Others could not differentiate whether partial improvements were due to DSF or to the antibiotics taken during the same period.

Some of DSF toxic effects observed in Lyme patients could be due in part to high initial DSF doses, similar to those used for alcohol-dependent patients. On the other hand, some of these effects could have been due to Jarisch Herxheimer reactions triggered by DSF-induced death of Borrelia. However, some patients, who had already experienced Jarisch Herxheimer reactions before, reported that some of the reactions encountered with DSF treatment were clearly of a different nature. Collectively, these observations suggest that patients with persistent Lyme Disease are more sensitive to the toxicity of DSF than people who have been treated for alcohol dependence, and that in these patients, DSF-induced toxicities are not all related to Jarish Herxeimer reactions.

Discussion

Published scientific articles allow us to draw the conclusion that, in vitro, DSF can undoubtedly kill certain bacteria strains, and that in vivo, DSF can be toxic to both bacteria and the human body. These toxicities can be both acute and long-term.

One can propose different hypotheses to explain these toxicities. They might be mediated by the inhibition of copper-dependent enzymes, such as ALDH or dopamine β-hydroxylase, or the blocking of the NLP4 molecule, or through an oxidative molecule increase, and possibly through yet unidentified mechanisms. Part of these toxicities may also depend on the microbiota, in which some bacterial or yeasts species have a propensity to produce fermentation-derived toxic AcH. It would be worth testing if any intake of bacteria such as Lactobacillus, which have a high ALDH activity, could be used to counter the DSF-induced toxicities.

On the other hand, many studies have reported that patients with PTLDS have an increased sensitivity to pain, which can affect vision, hearing, touch, and even smell, as reviewed by Batheja et al. (35). These chronic pains can be related multiple to chemical sensitivity and chronic fatigue syndrome, in which the pain sensitivity is modified as well, as reported in Gulf war veterans (36). There is increasing evidence for abnormal sensory processing in these syndromes, with a low “unpleasantness threshold” for multiple types of sensory stimuli (37).

The differences observed for effective concentrations of DSF between alcohol-dependent patients and those suffering from PTDLS or SPPT could also be linked to a such central sensitization often observed in patients suffering from borreliosis (35).

It is necessary to understand why DSF toxicity appears particularly severe and frequent in patients with Lyme Disease, and to rapidly explore the reasons for such DSF toxicity in Lyme Disease animal models. Until we have the first answers to this question, it would be premature to consider DSF as the new miracle molecule for patients suffering from late disseminated Lyme Disease.

Basic Science vs. Social Networks

Case reports are a very useful approach for drawing attention to the possible effectiveness of a new treatment. Undoubtedly, the case report published by Liegner (27) has played such a role. However, the next logical step should have been to examine the potential toxicity of DSF for Lyme patients. This could have been achieved first by using animal models, and then within a standardized clinical trial. These steps were rapidly short-circuited, due to the strong social demand for Lyme Disease treatments. This pressure is exerted largely by social networks, emphasizing their speed and efficiency, but at the same time a lack of analysis and scientific rigor.

Importance of Patient-Reported Outcomes

Following the rapid spread of the idea that DSF could be a major improvement for the treatment of late Lyme Disease, hundreds of patients began using DSF in the hope of treating their disease. At this point, it is important to require, as we do here, on rapid feedback from the patients themselves. No one knows better than patients the severity and importance of secondary toxicities from treatment. They know themselves better than physicians, who sometimes tend to overestimate the benefit/risk ratios (38, 39).

The limitation of the present study is linked to the small number of included patients. This highlights the need for follow-up studies with a larger number of patients to specify the risk/benefit of DSF in late Lyme Disease. The results and experiences reported by the patients should be included in these studies to determine how many of them have truly benefited from DSF treatment. Aiming at distinguishing Jarish Herxheimer reactions due to bacterial die-off and toxic side effects of the drug will be an important issue. More generally, a patient survey will have to be designed to evaluate how many patients have benefited of DSF and how many have not. A long term follow up of the DSF treated patients using an online patient feedback tool will be necessary to determine if they have any relapse or stable remission. All this information is necessary to determine the risk/benefit ratio of DSF for Lyme Disease. This will require a close collaboration between patients, doctors and researchers.

Data Availability Statement

All datasets generated for this study are included in the article/supplementary material.

Ethics Statement

An ethical review process was not required according to national legislation and institutional requirements for the present study. Patient treatment was decided by their physician independently of the study. Patients associations were asked by the authors to collect patient-reported outcomes, which have been transferred anonymously to the authors. All patients that participated to this enquiry were volunteers and have given a written agreement to participate in this study.

21 patients had initially sent a patient-reported outcome. Following your recommendation, they were all asked to give their agreement to participate to this study. No one refused, but five of them did not answer. Therefore, the revised manuscript only presents the 16 cases of patients who sent their written consent.

Author’s Note

AT and HG are members of the scientific council of Fédération Française contre les Maladies Vectorielles à Tiques (FFMVT), and RG is president of FFMVT.

Author Contributions

AT: analysis of the literature. HG, RG, and AT: synthesis and analysis of the patient-reported outcomes. RG: medical advice. AT and HG: writing the manuscript.

Conflict of Interest

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Acknowledgments

We thank Nathalie Torres, Anne Colin, and Pierre Hecker, and the three associations of patients (France Lyme, Lympact, and Relais de Lyme) federated in FFMVT for their invaluable contribution in the collection of patient-reported outcomes. We thank the members of the scientific council of FFMVT for discussion on DSF treatment in late Lyme Disease, and Philippe Ascher, and Boris Barbour for improving the English of the manuscript.

References

1. Tick-borne Disease Working group. 2018 Report to Congress, U.S. Department of Health and Human Services. Available online at: https://www.hhs.gov/ash/advisory-committees/tickbornedisease/reports/index.html (accessed March 24, 2020).

2. Borreliose de Lyme. Surveillance des cas diagnostiqués en médecine générale, 2009–2018, Santé Publique France. Available online at: https://www.santepubliquefrance.fr/maladies-et-traumatismes/maladies-a-transmission-vectorielle/borreliose-de-lyme/donnees/#tabs(accessed March 24, 2020).

3. Lyme-Borreliose. RKI-Ratgeber. Robert Koch Institute (2019). Available online at: https://www.rki.de/DE/Content/Infekt/EpidBull/Merkblaetter/Ratgeber_LymeBorreliose.html#doc2398672bodyText5

4. Rebman AW, Bechtold KT, Yang T, Mihm EA, Soloski MJ, Novak CB, et al. The clinical, symptom, and quality-of-life characterization of a well-defined group of patients with posttreatment lyme disease syndrome. Front Med. (2017) 4:224. doi: 10.3389/fmed.2017.00224

PubMed Abstract | CrossRef Full Text | Google Scholar

5. Cui J, Liu Y, Chang X, Gou W, Zhou X, Liu Z, et al. Acetaldehyde induces neurotoxicity in vitro via oxidative stress- and Ca2+ imbalance-mediated endoplasmic reticulum stress. Oxid Med Cell Longev. (2019) 2019:2593742. doi: 10.1155/2019/2593742

PubMed Abstract | CrossRef Full Text | Google Scholar

6. Salaspuro MP. Acetaldehyde, microbes, and cancer of the digestive tract. Crit Rev Clin Lab Sci. (2003) 40:183–208. doi: 10.1080/713609333

PubMed Abstract | CrossRef Full Text | Google Scholar

7. Shen ML, Lipsky JJ, Naylor S. Role of disulfiram in the in vitro inhibition of rat liver mitochondrial aldehyde dehydrogenase. Biochem Pharmacol. (2000) 60:947–953. doi: 10.1016/s0006-2952(00)00435-4

PubMed Abstract | CrossRef Full Text | Google Scholar

8. Dalecki AG, Haeili M, Shah S, Speer A, Niederweis M, Kutsch O, et al. Disulfiram and copper ions kill Mycobacterium tuberculosis in a synergistic manner. Antimicrob Agents Chemother. (2015) 59:4835–44. doi: 10.1128/AAC.00692-15

PubMed Abstract | CrossRef Full Text | Google Scholar

9. Barth KS, Malcolm RJ. Disulfiram: an old therapeutic with new applications. CNS Neurol Disord Drug Targets. (2010) 9:5–12. doi: 10.2174/187152710790966678

PubMed Abstract | CrossRef Full Text | Google Scholar

10. Spiegel DR, McCroskey A, Puaa K, Meeker G, Hartman L, Hudson J, et al. A case of disulfiram-induced psychosis in a previously asymptomatic patient maintained on mixed amphetamine salts: a review of the literature and possible pathophysiological explanations. Clin Neuropharmacol. (2016) 39:272–5. doi: 10.1097/WNF.0000000000000166

PubMed Abstract | CrossRef Full Text | Google Scholar

11. Moritani K, Takeshita T, Shibata Y, Ninomiya T, Kiyohara Y, Yamashita Y. Acetaldehyde production by major oral microbes. Oral Dis. (2015) 21:748–54. doi: 10.1111/odi.12341

PubMed Abstract | CrossRef Full Text | Google Scholar

12. Goldstein BY, Chang S-C, Hashibe M, La Vecchia C, Zhang Z-F. Alcohol consumption and cancers of the oral cavity and pharynx from 1988 to 2009: an update. Eur J Cancer Prev Off J Eur Cancer Prev Organ ECP. (2010) 19:431–65. doi: 10.1097/CEJ.0b013e32833d936d

PubMed Abstract | CrossRef Full Text | Google Scholar

13. Skrott Z, Mistrik M, Andersen KK, Friis S, Majera D, Gursky J, et al. Alcohol-abuse drug disulfiram targets cancer via p97 segregase adaptor NPL4. Nature. (2017) 552:194–9. doi: 10.1038/nature25016

PubMed Abstract | CrossRef Full Text | Google Scholar

14. Zhang X, Hu P, Ding S-Y, Sun T, Liu L, Han S, et al. Induction of autophagy-dependent apoptosis in cancer cells through activation of ER stress: an uncovered anti-cancer mechanism by anti-alcoholism drug disulfiram. Am J Cancer Res. (2019) 9:1266–81.

PubMed Abstract | Google Scholar

15. Lövborg H, Oberg F, Rickardson L, Gullbo J, Nygren P, Larsson R. Inhibition of proteasome activity, nuclear factor-KappaB translocation and cell survival by the antialcoholism drug disulfiram. Int J Cancer. (2006) 118:1577–80. doi: 10.1002/ijc.21534

PubMed Abstract | CrossRef Full Text | Google Scholar

16. Yip NC, Fombon IS, Liu P, Brown S, Kannappan V, Armesilla AL, et al. Disulfiram modulated ROS-MAPK and NFκB pathways and targeted breast cancer cells with cancer stem cell-like properties. Br J Cancer. (2011) 104:1564–74. doi: 10.1038/bjc.2011.126

PubMed Abstract | CrossRef Full Text | Google Scholar

17. Paranjpe A, Zhang R, Ali-Osman F, Bobustuc GC, Srivenugopal KS. Disulfiram is a direct and potent inhibitor of human O6-methylguanine-DNA methyltransferase (MGMT) in brain tumor cells and mouse brain and markedly increases the alkylating DNA damage. Carcinogenesis.(2014) 35:692–702. doi: 10.1093/carcin/bgt366

PubMed Abstract | CrossRef Full Text | Google Scholar

18. Sauna ZE, Peng X-H, Nandigama K, Tekle S, Ambudkar SV. The molecular basis of the action of disulfiram as a modulator of the multidrug resistance-linked ATP binding cassette transporters MDR1 (ABCB1) and MRP1 (ABCC1). Mol Pharmacol. (2004) 65:675–84. doi: 10.1124/mol.65.3.675

PubMed Abstract | CrossRef Full Text | Google Scholar

19. Khan S, Singhal S, Mathur T, Upadhyay DJ, Rattan A. Antifungal potential of disulfiram. Nihon Ishinkin Gakkai Zasshi Jpn J Med Mycol.(2007) 48:109–13. doi: 10.3314/jjmm.48.109

PubMed Abstract | CrossRef Full Text | Google Scholar

20. Kwolek-Mirek M, Zadrag-Tecza R, Bartosz G. Ascorbate and thiol antioxidants abolish sensitivity of yeast Saccharomyces cerevisiae to disulfiram. Cell Biol Toxicol. (2012) 28:1–9. doi: 10.1007/s10565-011-9200-z

PubMed Abstract | CrossRef Full Text | Google Scholar

21. Scheibel LW, Adler A, Trager W. Tetraethylthiuram disulfide (Antabuse) inhibits the human malaria parasite Plasmodium falciparum. Proc Natl Acad Sci USA. (1979) 76:5303–7. doi: 10.1073/pnas.76.10.5303

PubMed Abstract | CrossRef Full Text | Google Scholar

22. Long TE. Repurposing thiram and disulfiram as antibacterial agents for multidrug-resistant Staphylococcus aureus infections. Antimicrob Agents Chemother. (2017) 61:e00898-17. doi: 10.1128/AAC.00898-17

PubMed Abstract | CrossRef Full Text | Google Scholar

23. Haeili M, Moore C, Davis CJC, Cochran JB, Shah S, Shrestha TB, et al. Copper complexation screen reveals compounds with potent antibiotic properties against methicillin-resistant Staphylococcus aureus. Antimicrob Agents Chemother. (2014) 58:3727–36. doi: 10.1128/AAC.02316-13

PubMed Abstract | CrossRef Full Text | Google Scholar

24. Horita Y, Takii T, Yagi T, Ogawa K, Fujiwara N, Inagaki E, et al. Antitubercular activity of disulfiram, an antialcoholism drug, against multidrug- and extensively drug-resistant Mycobacterium tuberculosis isolates. Antimicrob Agents Chemother. (2012) 56:4140–5. doi: 10.1128/AAC.06445-11

PubMed Abstract | CrossRef Full Text | Google Scholar

25. Thakare R, Shukla M, Kaul G, Dasgupta A, Chopra S. Repurposing disulfiram for treatment of Staphylococcus aureus infections. Int J Antimicrob Agents. (2019) 53:709–15. doi: 10.1016/j.ijantimicag.2019.03.024

PubMed Abstract | CrossRef Full Text | Google Scholar

26. Pothineni VR, Wagh D, Babar MM, Inayathullah M, Solow-Cordero D, Kim K-M, et al. Identification of new drug candidates against Borrelia burgdorferi using high-throughput screening. Drug Des Devel Ther. (2016) 10:1307–22. doi: 10.2147/DDDT.S101486

PubMed Abstract | CrossRef Full Text | Google Scholar

27. Liegner KB. Disulfiram (Tetraethylthiuram Disulfide) in the treatment of lyme disease and babesiosis: report of experience in three cases. Antibiot Basel Switz. (2019) 8:72. doi: 10.3390/antibiotics8020072

PubMed Abstract | CrossRef Full Text | Google Scholar

28. Frisoni GB, Di Monda V. Disulfiram neuropathy: a review (1971-1988) and report of a case. Alcohol Alcohol Oxf Oxfs. (1989) 24:429–37.

PubMed Abstract | Google Scholar

29. Bessero A-C, Daeppen J-B, Borruat F-X. Optic neuropathy while taking disulfiram. J Fr Ophtalmol. (2006) 29:924–8. doi: 10.1016/s0181-5512(06)70114-0

PubMed Abstract | CrossRef Full Text | Google Scholar

30. Behan C, Lane A, Clarke M. Disulfiram induced peripheral neuropathy: between the devil and the deep blue sea. Ir J Psychol Med. (2007) 24:115–6. doi: 10.1017/S0790966700010454

PubMed Abstract | CrossRef Full Text | Google Scholar

31. Cordell B, McCarthy J. A case study of gut fermentation syndrome (auto-brewery) with Saccharomyces cerevisiae as the causative organism. Int J Clin Med. (2013) 4:309–12. doi: 10.4236/ijcm.2013.47054

CrossRef Full Text | Google Scholar

32. Malik F, Wickremesinghe P, Saverimuttu J. Case report and literature review of auto-brewery syndrome: probably an underdiagnosed medical condition. BMJ Open Gastroenterol. (2019) 6:e000325. doi: 10.1136/bmjgast-2019-000325

PubMed Abstract | CrossRef Full Text | Google Scholar

33. Mohapatra S, Rath NR. Disulfiram induced psychosis. Clin Psychopharmacol Neurosci Off Sci J Korean Coll Neuropsychopharmacol.(2017) 15:68–9. doi: 10.9758/cpn.2017.15.1.68

PubMed Abstract | CrossRef Full Text | Google Scholar

34. Dina OA, Khasar SG, Alessandri-Haber N, Bogen O, Chen X, Green PG, et al. Neurotoxic catecholamine metabolite in nociceptors contributes to painful peripheral neuropathy. Eur J Neurosci. (2008) 28:1180–90. doi: 10.1111/j.1460-9568.2008.06425.x

PubMed Abstract | CrossRef Full Text | Google Scholar

35. Batheja S, Nields JA, Landa A, Fallon BA. Post-treatment lyme syndrome and central sensitization. J Neuropsychiatry Clin Neurosci. (2013) 25:176–86. doi: 10.1176/appi.neuropsych.12090223

PubMed Abstract | CrossRef Full Text | Google Scholar

36. Reid S, Hotopf M, Hull L, Ismail K, Unwin C, Wessely S. Multiple chemical sensitivity and chronic fatigue syndrome in British Gulf War veterans. Am J Epidemiol. (2001) 153:604–9. doi: 10.1093/aje/153.6.604

PubMed Abstract | CrossRef Full Text | Google Scholar

37. Clauw DJ. Potential mechanisms in chemical intolerance and related conditions. Ann N Y Acad Sci. (2001) 933:235–3. doi: 10.1111/j.1749-6632.2001.tb05828.x

PubMed Abstract | CrossRef Full Text | Google Scholar

38. Gravis G, Marino P, Joly F, Oudard S, Priou F, Esterni B, et al. Patients’ self-assessment versus investigators’ evaluation in a phase III trial in non-castrate metastatic prostate cancer (GETUG-AFU 15). Eur J Cancer Oxf Engl. (2014) 50:953–62. doi: 10.1016/j.ejca.2013.11.034

PubMed Abstract | CrossRef Full Text | Google Scholar

39. Di Maio M, Gallo C, Leighl NB, Piccirillo MC, Daniele G, Nuzzo F, et al. Symptomatic toxicities experienced during anticancer treatment: agreement between patient and physician reporting in three randomized trials. J Clin Oncol Off J Am Soc Clin Oncol. (2015) 33:910–5. doi: 10.1200/JCO.2014.57.9334

 

Citation: Trautmann A, Gascan H and Ghozzi R (2020) Potential Patient-Reported Toxicities With Disulfiram Treatment in Late Disseminated Lyme Disease. Front. Med. 7:133. doi: 10.3389/fmed.2020.00133

Received: 10 December 2019; Accepted: 27 March 2020;
Published: 20 April 2020.

Edited by:

Ying Zhang, Johns Hopkins University, United States

Reviewed by:

Monica E. Embers, Tulane University, United States
John Lambert, University College Dublin, Ireland

Copyright © 2020 Trautmann, Gascan and Ghozzi. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

*Correspondence: Alain Trautmann, alain.trautmann@inserm.fr; Raouf Ghozzi, raouf.ghozzi@ch-lannemezan.fr

____________________

For more:  https://madisonarealymesupportgroup.com/2020/02/12/disulfiram-for-lyme-disease-dr-vrchota/

https://madisonarealymesupportgroup.com/2020/02/14/disulfiram-with-dr-dan-kinderlehrer-md-says-also-hits-bartonella-but-wont-eradicate-it/

https://madisonarealymesupportgroup.com/2019/11/19/if-disulfiram-is-the-cure-for-lyme-disease-should-it-be-prescribed-to-all-lyme-disease-patients/

https://madisonarealymesupportgroup.com/2019/07/26/is-disulfiram-the-magic-bullet-for-chronic-lyme-disease/

https://madisonarealymesupportgroup.com/2019/10/15/disulfiram-psychosis-update/

New Study: HCQ & Zinc Greatly Reduces COVID-19 Health Risk

https://principia-scientific.org/new-study-hydroxychloroquine-zinc-greatly-reduces-covid-19-health-risk/

New Study: Hydroxychloroquine + Zinc Greatly Reduces COVID-19 Health Risk

Written by dcwhispers.com

While the main stream media yet again is pushing recycled headlines about a New York “study” of very ill patients who were NOT actually given the combination of hydroxychloroquine and zinc which concluded these near-death patients did no better or worse when given the drug, another study showing a very different result was largely ignored by these same media outlets.

Imagine that.

Check out this headline coming out of New York as well which showed the combination of hydroxychloroquine and zinc slashed the risk of death from the coronavirus by nearly half.


**Drug Combo With Hydroxychloroquine Promising: NYU Study**

NEW YORK – Researchers at NYU’s Grossman School of Medicine found patients given the antimalarial drug hydroxychloroquine along with zinc sulphate and the antibiotic azithromycin were 44 percent less likely to die from the coronavirus.

“Researchers at NYU’s Grossman School of Medicine found patients given the antimalarial drug hydroxychloroquine along with zinc sulphate and the antibiotic azithromycin were 44 percent less likely to die from the coronavirus.

“Certainly we have very limited options as far as what we have seen work for this infection so anything that may work is very exciting,” said Dr. Joseph Rahimian, Infectious Disease Specialist at NYU Langone Health.”

The study looked at the records of 932 COVID-19 patients treated at local hospitals with hydroxychloroquine and azithromycin.

More than 400 of them were also given 100 milligrams of zinc daily.

Researchers Said The Patients Given Zinc Were One And A Half Times More Likely To Recover, Decreasing Their Need For Intensive Care.

If one were to do an online news search right now for similar studies as above you will find story after story on the recycled New York study that showed no benefit from hydroxychloroquine while this other study (also from New York) that indicates the hydroxychloroquine + zinc combination shows remarkable promise, is receiving almost zero media coverage.

This is the same combination that has been touted by physicians all across America and the world as proving highly effective and yet here in the U.S. there are forces both in government and the media who continue to push this success to the side while also pushing yet more fear and panic of the disease.

Did you know that in Italy, one of the nations hardest hit by Covid 19, once doctors started initiating mass use of hydroxychloroquine and zinc, the death rate plummeted from a high of nearly a thousand a day to less than 200? This drug combination protocol has been repeated in other nations like South Korea, France, Bahrain, Turkey, Brazil, etc., with similar rates of success there as well as outlined in this excerpt from an April 21st scientific journal release:

“On March 23, 2020 a physician (Vladimir Zelenko) in Monroe, New York state, published online similar excellent outcomes on treating his patients with shortness of breath and any patient in the high-risk category with HCQ, azithromycin and zinc sulfate for five days in order to prevent hospitalization.

On April 17, 2020 doctors from a health care provider focused on mostly elderly and chronic patients in Brazil confirmed Raoul’s and Zelenko’s findings reporting that out of 636 symptomatic outpatients of the 224 who refused treatment (control group), 12 were hospitalized (5.4%), and of these 12 hospitalized, 5 patients died (41%) [12]. On the other hand, of the 412 outpatients treated with HCQ and azithromycin, only 8 were hospitalized (1.94%), and no deaths were observed. In case of early treatment (<7 days of symptoms) only 1.17% of treated patients needed hospitalization, while the percentage raised to 3.2% for late treatment (>7 days of symptoms). These outcomes were even more remarkable considering that patients in the treatment groups had higher prevalence of comorbidities including diabetes, immunosuppression state and stroke [12]. “

Again, why is there such push-back going on in the United States from the far-left media to dismiss what appears to be the undeniable effectiveness of hydroxychloroquine + zinc in combatting Covid-19?

Something very weird is going on here and people have been dying by the thousands because of it.

Good news, possibly life-saving news, is being pushed aside while bad news, not matter how flawed or biased, is put front and center in an effort to convince tens of millions that there is currently no real treatment options for the coronavirus even as so much data out there appears to say that is simply not so.

Read more at www.ny1.com

__________________________

**Comment**

For the reason why the media and “authorities” badmouth HCQ:   https://principia-scientific.org/a-tale-of-2-drugs-deep-state-chose-money-power-over-lives/

Excerpt:

Approximately $70 million in U.S. taxpayer funding began Gilead’s partnership with the U.S. Army, Centers for Disease Control and Prevention (CDC) and National Institutes of Health (NIH) to develop remdesivir. Initially for treating Ebola, it failed to show benefit and was shelved. If remdesivir is used to treat COVID-19, Gilead shareholders, not the taxpayers, will profit.

HCQ directly competes with the favored profitable treatment of remdesivir.

In fact the article states that 9 of the 19 experts on the COVID-19 treatment panel have financial interests in Gilead Science.  See the problem?

Early results of the first clinical trial of remdesivir against placebo in coronavirus showed modest benefits, according to The New York Times. Surviving patients given remdesivir were discharged four days sooner than patients given placebo, though no criteria were given for determining improvement. Death rates were not significantly different. About 25% of patients receiving remdesivir had potentially severe side effects, including multiple organ dysfunction, septic shock, acute kidney injury and low blood pressure. Another 23% showed evidence on lab tests of liver damage.

Gilead’s own press release revealed the side effect of acute respiratory failure in 6% of patients in the remdesivir five-day treatment group, and 10.7% of patients in the 10-day treatment group, clearly ominous findings with a drug designed to treat respiratory failure caused by COVID-19.

Dr. Steven Nissen, a Cleveland Clinic cardiologist who has conducted dozens of clinical trials, explained to The New York Times:

The disclosure of trial results in a political setting, before peer review or publication, is very unusual. Scientists will need to see figures on harms associated with the drug in order to assess its benefits. … This is too important to be handled in such a sloppy fashion.”

Going back to 1997, Donald Rumsfeld chaired the Board of Directors at Gilead and after 2001 he held share packages valued at $5-25 Million. Gilead originally developed Tamiflu. George P Shultz, US Secretary of State also was on the board. He sold stocks at a value of more than $7 million. CA governor’s Pete Wilson’s wife also sat on the board.

‘I don’t know of any biotech company that’s’ so politically well-connected [as Gilead],‘ Andrew McDonald, of the analyst firm Think Equity Partners, told Fortune.” (Source: “Virus Mania, How the Medical Industry Continually Invents Epidemics Making Billion Dollar Profits At Our Expense”)

Shunning competing tests and treatments if what the CDC does:  https://madisonarealymesupportgroup.com/2020/04/26/cdc-playbook-learning-from-lyme/

These fraudsters need to go to jail.  Contact your representatives and senators:  https://madisonarealymesupportgroup.com/2020/05/20/cdc-crimes-possible-sherman-provisions-clayton-acts-violated/

 

 

 

 

Morgellons NOT Associated With Fungus

  Approx. 1 Hour 15 Min.

Morgellons NOT Associated With Fungus

May 17, 2020

Interview with microbiologist Marianne Middleveen.

For more:  https://madisonarealymesupportgroup.com/2020/02/24/classification-staging-of-morgellons-disease-lessons-from-syphilis/

Chronic Neurological Lyme Disease Or Co-Morbid Conditions?

https://danielcameronmd.com/chronic-neurological-lyme-disease-dismissed-for-co-morbid-conditions/

CHRONIC NEUROLOGICAL LYME DISEASE OR CO-MORBID CONDITIONS?

man with fatigue holding head

Some patients with chronic neurological Lyme disease continue to have persistent, debilitating symptoms following treatment.

A recent study confirmed the severity of chronic symptoms in this patient population but unfortunately dismissed the symptoms, attributing them to various co-morbid conditions, rather than Lyme disease. [1]

 

The study, “Patient-reported outcome after treatment for definite Lyme neuroborreliosis” by Eikeland and colleagues, describes 258 patients treated for definite Neurologic Lyme disease. Many of them remained symptomatic an average of 5 years after their initial treatment.

According to the authors, a higher proportion of their chronic neurological Lyme disease patients reported severe fatigue. Furthermore, “Mental health-related quality of life was poorer among [neuroborreliosis] NB-treated patients than in normative data.”

Although many of the patients’ symptoms are consistent with those found in chronic neurological Lyme disease, the authors attributed the symptoms to co-morbid illnesses, based on a retrospective review of the medical records.

READ MORE: Six cases of neuroinvasive Lyme disease

The symptoms included: radiating pain, general pain, fatigue, facial palsy, malaise, dizziness and/or unsteadiness, headache, numbness in arm and/or leg, memory and/or concentration problems, paresis in arm and/or leg, and diplopia.

Symptoms due to chronic neurological Lyme disease or co-morbid conditions? CLICK TO TWEET 

Co-morbid conditions listed for these patients included: fibromyalgia, allergies, depression or anxiety, multiple sclerosis, systemic disease sarcoidosis, systemic lupus erythematosus, Sjögren’s syndrome, rheumatoid arthritis, chronic fatigue syndrome, Parkinson’s disease, thyroid dysfunctions, and cancer.

Note: The study was not designed to assess whether the patient, in fact, had the co-morbidity listed in their records or instead had complications of chronic neurological Lyme disease.
References:
  1. Eikeland R, Ljostad U, Helgeland G, et al. Patient-reported outcome after treatment for definite Lyme neuroborreliosis. Brain Behav. 2020:e01595.

____________________

**Comment**

Another worthless study to add to the ever increasing pile of trash.

These poor, sick people were given all sorts of labels: fibromyalgia, lupus, Sjogren’s, RA, CFS, Parkinson’s, cancer – the typical “bad guys,” but ALL were infected with Lyme disease which can cause symptoms indicative of those labels.

It’s very interesting that with Lyme disease, “authorities” want to blame anything other than a persistent borrelia infection, but with COVID-19, those same “authorities” want to blame everything on COVID-19.  This should smell bad to you.  This is not science – it’s biased, narrative-driven propaganda.

For more: Peer-Reviewed Evidence of Persistence of Lyme:MSIDS copy

https://madisonarealymesupportgroup.com/2020/03/09/the-long-term-persistence-of-borrelia-burgdorferi-antigens-dna-in-the-tissues-of-lyme-disease-patient/

https://madisonarealymesupportgroup.com/2017/05/10/body-of-research-showing-borrelia-persists/

https://madisonarealymesupportgroup.com/2020/04/08/how-do-lyme-disease-symptoms-persist-long-term/

https://madisonarealymesupportgroup.com/2019/07/31/post-lyme-disease-syndrome-vs-chronic-lyme-disease-syndrome/

https://madisonarealymesupportgroup.com/2018/04/13/chronic-lyme-post-mortem-study-needed-to-end-the-lyme-wars/

 

Babesia Infection 3 Weeks After Lyme Treatment

https://danielcameronmd.com/lyme-podcast-a-babesia-infection-3-weeks-after-treatment-for-lyme-disease/

LYME PODCAST: A BABESIA INFECTION 3 WEEKS AFTER TREATMENT FOR LYME DISEASE.

A Babesia infection 3 weeks after treatment for Lyme disease.

I will discuss a 67-year-old woman with a Babesia infection 3 weeks after treatment for Lyme disease. Could this delay explain why some patients remain ill or relapse?

Podcast:

https://podcasts.google.com/feed/aHR0cHM6Ly9mZWVkcy5idXp6c3Byb3V0LmNvbS83NzI

Hoversten and her colleague first discussed this case in the British Medical Journal Case Reports  in 2018.

One would expect that tick-borne infections would all occur at the same time.

One would be wrong, as this case illustrates.

A 67-year-old woman from Wisconsin had extensive exposure as an avid gardener and spent a considerable amount of time outdoors.

She did not see a tick. She did see a rash consistent with an erythema migrans rash.

A delay in onset of Babesia may explain why some Lyme disease patients relapse after initially improving with doxycycline or amoxicillin. CLICK TO TWEET

She was prescribed amoxicillin for three-weeks as she was allergic to doxycycline.

Near the end of three-week of amoxicillin, she became ill. Her fever rose to 102.9 F0. She complained of myalgias, dizziness, and fatigue.

Her blood test showed mild anemia, a low platelet count and neutrophil count, and a very high C-reactive protein.

  • neutrophil is a type of white blood cell that helps resolve infections and heal damaged tissues. A low neutrophil count can be seen in tick-borne diseases.
  • A high C-reactive protein is a marker for inflammation but cannot be used to determine what type of inflammation.

She was admitted to the hospital. The doctors thought she might be suffering from sepsis or a tick-borne infection.

  • Sepsis is a life-threatening illness caused by your body’s response to an infection.
  • Her red blood count and platelets continued to drop.
  • She was transferred to a second hospital.
  • There was no evidence of sepsis. The blood cultures were negative after five days.

BABESIA INFECTION

She was diagnosed with the parasite Babesia microti by PCR and by a thin smear of her red blood cells. Typically, Babesia microti is seen on a thick smear of blood. In her case, 0.4% of her red blood cells showed the parasite Babesia microti on a thin smear.

Babesia infections can be severe and, in rare cases, life-threatening. Babesia infections can also be mild or without symptoms. Babesia was more likely to be severe in this woman as she was over 50-years of age and had a history of colon cancer.

She was prescribed a 10-day course of azithromycin and atovaquone. By 5th day of treatment, her fever had resolved, and her platelet count had more than doubled from a low of 17,000 per dl to 42, 000 per dl.

The authors report that the woman remains fatigued after completing treatment.

The authors discussed the nearly three-week gap in time between the woman’s erythema migrans rash and her diagnosis of Babesia. This is not the first case where the onset of Babesia was delayed.

The authors cited two papers describing a 3 to 4-week delay in the onset of Babesia. I described a paper in an earlier podcast where two babies contracted Babesia from their mothers. They did not present with Babesia until after being discharged from the hospital. You can read more about these babies in the article by Saetre and colleagues or listen to my Inside Lyme podcast titled. “Two children who contacted Babesia from their mother.”

This delay may explain why some Lyme disease patients relapse after initially improving with doxycycline or amoxicillin. Treatment for Lyme disease with doxycycline or amoxicillin is not effective for the treatment of Babesia.

What can we learn from this cases?

  1. Babesia infections can occur weeks after the onset of Lyme disease.

What questions does these cases raise?

  1. Should the woman have been evaluated for Babesia infection at the time of the erythema migrans?
  2. Would a Babesia infection have been recognized if the woman had not been diagnosed with Lyme disease?
  3. Should Lyme disease patients be advised to return for follow-up?
  4. Would earlier treatment have avoided the need for hospitalization?
  5. What is the long-term outcome for this woman with a Babesia infection

TREATING TICK-BORNE DISEASE IN MY PRACTICE

In my practice, each individual requires a careful assessment. That is why I order a broad range of blood tests for other illnesses in addition to tick-borne infections. I also arrange consultations with specialists as needed.

Many patients are complex, as highlighted in this Inside Lyme Podcast series.

We need more doctors with skills recognizing Babesia in a patient with Lyme disease. We hope that professionals evaluating individuals with Lyme disease can use this case to remind them to look for Babesia with Lyme disease.

Inside Lyme Podcast Series

This Inside Lyme case series will be discussed on my Facebook and made available on podcast and YouTube.  As always, it is your likes, comments, and shares that help spread the word about this series and our work. If you can, please leave a review on iTunes or wherever else you get your podcasts.

Sign up for our newsletter to keep up with our cases.

_____________________

For more:  

Podcast: Evidence Supporting HCQ & Azithromycin for COVID-19

COVID-19 PODCAST: HYDROXYCHLOROQUINE AND AZITHROMYCIN FOR COVID-19 MAY BE EFFECTIVE AFTER ALL.

Hydroxychloroquine and azithromycin for COVID-19

Welcome to my next Inside Lyme podcast. – I will examine the evidence supporting hydroxychloroquine and azithromycin for COVID-19.

Podcast:

https://podcasts.google.com/feed/aHR0cHM6Ly9mZWVkcy5idXp6c3Byb3V0LmNvbS83NzI

You may be wondering why I am discussing COVID-19 during an Inside Lyme podcast. I am concerned for my children, grandchildren, and my patients. I want to share my understanding of COVID-19 through my eyes as a clinical epidemiologist.

COVID-19 is now a pandemic. We need an effective and safe drug to treat this virus.

Researchers have turned to existing drugs that might be effective without causing significant side effects. Hydroxychloroquine and chloroquine have been prescribed for the treatment and prophylaxis of malaria in addition to the treatment of autoimmune diseases. Hydroxychloroquine and azithromycin have also been prescribed for Lyme disease patients. Hydroxychloroquine and azithromycin have been marketed under the name Plaquenil and Zithromax, respectively in the US.

Both chloroquine and hydroxychloroquine have side effects. The most common side effect of hydroxychloroquine is nausea and diarrhea. In rare cases, hydroxychloroquine can lead to reduced white blood cells, platelets count, anemia, and retinopathy. Retinopathy can lead to color blindness and loss of vision. Both hydroxychloroquine and azithromycin can lead to sudden death from a prolonged QT interval.

ANTIVIRAL EFFECTS OF HYDROXYCHLOROQUINE AND CHLOROQUINE

Hydroxychloroquine and chloroquine have shown some antiviral benefits in vitro (Wang, 2020, letter) Both have been studied for other related viruses, including Severe Acute Respiratory Syndrome (SARS) and Middle East Respiratory Syndrome (Mers).

Chloroquine improved outcomes in a series of small studies in China. Gao and colleagues discussed the finding in the journal BioScience Trends .

“Thus far, results from more than 100 patients have demonstrated that chloroquine phosphate is superior to the control treatment in inhibiting the exacerbation of pneumonia, improving lung imaging findings, promoting a virus negative conversion, and shortening the disease course according to the news briefing.”

These findings led the State Council in China to approve chloroquine for COVIID-19

Hydroxychloroquine and azithromycin for COVID-19 may be effective after all. CLICK TO TWEETUnfortunately, this series of Chinese trials do not appear to have been published. It is hard to discuss these Chinese trials until they are published.

FIRST FRENCH CLINICAL TRIAL BY GAUTRET AND COLLEAGUES

Gautret and colleagues published a French trial evaluating the benefit and risks of hydroxychloroquine and Zithromax for the treatment of COVID-19.

The authors prescribed 600 mg of hydroxychloroquine to 26 patients with COVID-19. Two were asymptomatic. Ten had upper tract respiratory infections, and six had lower tract respiratory infections. The doctors prescribed azithromycin to 6 of their patients with COVID-19 to prevent bacterial superinfection.

The authors were able to show a significant reduction in the viral load in nasopharyngeal samples of their COID-19 patients treated with hydroxychloroquine compared to COVID-19 patients who were not treated.

The authors were able to show even a greater reduction in viral load in the six COVID-19 patients when Zithromax was added.

Only one of the 26 patients treated with hydroxychloroquine was dropped from the study due to an adverse event. That patient dropped out due to nausea.

The authors explained why they decided to share their findings early.

“For ethical reasons and because our first results are so significant and evident, we decide to share our findings with the medical community, given the urgent need for an effective drug against SARS-CoV-2 in the current pandemic context.”

FLAWS IN THE FIRST FRENCH TRIAL BY GAUTRET

The Gautret trial was small and flawed. They should have used controls from the same hospital with the same characteristics as the 26 treated patients. Instead, they enrolled 16 controls were from other centers.

The Gautret trial did not evaluate whether a reduction or elimination of the COVID-19 virus in saliva would prevent outcomes important to patients such as a transfer to an intensive care unit or death. Four of the 26 patients treated with hydroxychloroquine did poorly. Three were transferred to the intensive care unit. One died. None of the patients with a COVID—19 infection developed a QT prolongation.

The Gautret trial was not designed to determine if the absence if COVID-19 from the saliva meant the absence of COVID-19 from other tissues.

The Gautret trial could not determine if the benefits seen for the six COVID-19 patients treated with azithromycin were from an antiviral effect or an antibiotic effect.

SECOND FRENCH TRIAL

A recently published second French trial by Gautret and colleagues added further support for the hydroxychloroquine with azithromycin.

“In 80 in-patients receiving a combination of hydroxychloroquine and azithromycin we noted a clinical improvement in all but one 86 year-old patient who died, and one 74-year-old patient still in intensive care unit.”

PLANNED TRIALS

Researchers at the University of Minnesota are planning on a trial “to see whether malaria treatment hydroxychloroquine can prevent or reduce the severity of the coronavirus disease (COVID-19)” writes Gabe Gutierrez and Dennis Romero in NBCNews.

COULD CUTTING THE COVID-19 VIRAL LOAD BE HELPFUL?

Yes, according to Gautret. “hydroxychloroquine and azithromycin “can play a role in controlling the disease epidemic by limiting the duration of virus shedding, which can last for several weeks in the absence of specific treatment.” write Gautret.

COULD HYDROXYCHLOROQUINE AND AZITHROMYCIN FOR INDIVIDUALS WITH COVID-19 BE HELPFUL?

Yes, according to both Gautret trials. Hydroxychloroquine and azithromycin lowered the COVID-19 viral load patient. Moreover, most of the patients with a COVID-19 infection were improved or discharged in the second Gautret trial.

COULD HYDROXYCHLOROQUINE AND AZITHROMYCIN PREVENT COVID-19 INFECTION?

Neither Gautret trials assessed whether hydroxychloroquine with azithromycin would be effective for prophylaxis before an infection. The study only enrolled hospitalized patients already infected with the COVID-19 virus.

WHAT NOW?

For now, researchers and politicians are divided on whether to recommend hydroxychloroquine and azithromycin for the prevention and treatment of COVID-19. There is growing pressure on doctors to wait for science.

Doctors have patients who are sick now. Doctors have patients who want to prevent getting COVID-19.

“The Food and Drug Administration (FDA) on Sunday issued an emergency-use authorization for a pair of anti-malaria drugs as health officials work to combat the rapid spread of the novel coronavirus.” writes Jusin Wise in The Hill.

Stay tuned.

References:
  1. Wang M, Cao R, Zhang L, Yang X, Liu J, Xu M, Shi Z, Hu Z, Zhong W, Xiao G. Remdesivir and chloroquine effectively inhibit the recently emerged novel coronavirus (2019-nCoV) in vitro. Cell Res. 2020 Mar;30(3):269-271.
  2. Gautret P, Lagier JC, Parola P, Hoang VT, Meddeb L, Mailhe M, Doudier B, Courjon J, Giordanengo V, Vieira VE, Dupont HT, Honoré S, Colson P, Chabrière E, La Scola B, Rolain JM, Brouqui P, Raoult D. Hydroxychloroquine and azithromycin as a treatment of COVID-19: results of an open-label non-randomized clinical trial. Int J Antimicrob Agents. 2020 Mar 20:105949.
  3. Cai J, Xu J, Lin D, Yang Z, Xu L, Qu Z, Zhang Y, Zhang H, Jia R, Liu P, Wang X, Ge Y, Xia A, Tian H, Chang H, Wang C, Li J, Wang J, Zeng M. A Case Series of children with 2019 novel coronavirus infection: clinical and epidemiological features. Clin Infect Dis. 2020 Feb 28. pii: ciaa198
  4. Gao J, Tian Z, Yang X. Breakthrough: Chloroquine phosphate has shown apparent efficacy in treatment of COVID-19 associated pneumonia in clinical studies. Biosci Trends. 2020 Mar 16;14(1):72-73.
  5. Gautret P, Lagier JC, Parola P, and colleagues. Clinical and microbiological effect of a combination of hydroxychloroquine and azithromycin in 80 COVID-19 patients with at least a six-day follow up: an observational study. To be published as of 3/20/20.
  6. Clinical trials on coronavirus drugs may take only months, researcher says. Gabe Gutierrez and Dennis Romero, From NBCNew.com Last accessed 3/29/20.

_____________

**Comment**

I posted this recently, but “authorities” have been bad-mouthing HCQ because many of them are getting financial kick-backs from Gilead Science, the manufacturer of the anti-viral Remdesivir, which bombed for Ebola, so they dug it out of the drug graveyard and are repurposing it for COVID-19.  HCQ is a direct competitor and the CDC/NIH won’t have it.  They diss any test or treatment that competes with their own.  It’s all about profits. This is why nothing will change until these people can not have patents and conflicting interests.  See:  https://madisonarealymesupportgroup.com/2020/05/08/update-cdc-playbook-learning-from-lyme/

When I compare how the media writes about the anti-viral drug Remdesivir vs HCQ, it isn’t surprising to learn that NIAID is working with Gilead to conduct Phase II human trials on on it.  Dr. Fauci, who is supposed to be a gate-keeper of public health, often does business with Big Pharma:  https://www.fort-russ.com/2020/04/shedding-light-on-the-dishonorable-record-of-dr-fauci-a-real-mengele/

Please see Dr. Eric Berg‘s FB video explaining HCQ vs Remdesivir:  https://www.facebook.com/135796882846/posts/10158628517062847/?sfnsn=mo&d=n&vh=e

Even the White House economic adviser got into a massive argument with Fauci over his ongoing resistance to the use of hydroxychloroquine to treat COVID-19:  https://madisonarealymesupportgroup.com/2020/04/08/peter-navarro-explodes-at-fauci-in-heated-showdown-over-hydroxychloroquine/

https://principia-scientific.org/a-tale-of-2-drugs-deep-state-chose-money-power-over-lives/

Excerpt:

Approximately $70 million in U.S. taxpayer funding began Gilead’s partnership with the U.S. Army, Centers for Disease Control and Prevention (CDC) and National Institutes of Health (NIH) to develop remdesivir. Initially for treating Ebola, it failed to show benefit and was shelved. If remdesivir is used to treat COVID-19, Gilead shareholders, not the taxpayers, will profit.

Early results of the first clinical trial of remdesivir against placebo in coronavirus showed modest benefits, according to The New York Times. Surviving patients given remdesivir were discharged four days sooner than patients given placebo, though no criteria were given for determining improvement. Death rates were not significantly different. About 25% of patients receiving remdesivir had potentially severe side effects, including multiple organ dysfunction, septic shock, acute kidney injury and low blood pressure. Another 23% showed evidence on lab tests of liver damage.

Gilead’s own press release revealed the side effect of acute respiratory failure in 6% of patients in the remdesivir five-day treatment group, and 10.7% of patients in the 10-day treatment group, clearly ominous findings with a drug designed to treat respiratory failure caused by COVID-19.

Dr. Steven Nissen, a Cleveland Clinic cardiologist who has conducted dozens of clinical trials, explained to The New York Times:

The disclosure of trial results in a political setting, before peer review or publication, is very unusual. Scientists will need to see figures on harms associated with the drug in order to assess its benefits. … This is too important to be handled in such a sloppy fashion.”

Going back to 1997, Donald Rumsfeld chaired the Board of Directors at Gilead and after 2001 he held share packages valued at $5-25 Million. Gilead originally developed Tamiflu. George P Shultz, US Secretary of State also was on the board. He sold stocks at a value of more than $7 million. CA governor’s Pete Wilson’s wife also sat on the board.

‘I don’t know of any biotech company that’s’ so politically well-connected [as Gilead],‘ Andrew McDonald, of the analyst firm Think Equity Partners, told Fortune.” (Source: “Virus Mania, How the Medical Industry Continually Invents Epidemics Making Billion Dollar Profits At Our Expense”)

It’s looking very much like the CDC is helping Gilead reclaim its losses on Remdesivir’s failure in Ebola.  Let’s just whip it back out for COVID-19, the public won’t notice!

For more:  https://madisonarealymesupportgroup.com/2020/05/11/what-are-sars-covid2-patients-really-dying-from/  Details are given within this link as to WHY HCQ works so well in COVID-19.  This is NOT a virus which causes interstitial pneumonia as we’ve been told, but rather it causes disseminated intravascular coagulation (DIC).  

https://madisonarealymesupportgroup.com/2020/04/04/efficacy-of-hydroxychloroquine-in-patients-with-covid-19-results-of-a-randomized-clinical-trial/

https://madisonarealymesupportgroup.com/2020/04/24/dr-oz-interviews-dr-didier-raoult-on-hydroxychloroquine-study-for-covid-19/

Dr. Zelenko, a New York doctor, has successfully treated 1,450 COVID-19 patients with a 99% success rate using a cocktail of hydroxychloroquine, Zinc Sulfate and Azithromycin:  https://techstartups.com/2020/04/21/dr-vladimir-zelenko-now-treated-1450-coronavirus-patients-2-deaths-using-hydroxychloroquine-99-99-success-rate-latest-video-interview/  Video with Zelenko in link.

https://madisonarealymesupportgroup.com/2020/04/08/peter-navarro-explodes-at-fauci-in-heated-showdown-over-hydroxychloroquine/

 

 

 

 

 

 

What Are SARS COVID2 Patients Really Dying From?

 Approx. 13 Min. (You can click on subtitles to read in English)

April 27, 2020

By Dr. Harry Ambrose

What Are SARS COVID2 Patients Really Dying From?

All the facts seem to point out that the death of the patients by the Sars Cov-2 virus is not an interstitial pneumonia that has been talked about so much in the media. There is a real cause which we explain in detail and chronologically in this chapter, and about which not much is said in the official journalistic media.

___________________

**Comment**

I’ve loosely transcribed the audio from Spanish to English.  In short, SARS COVID2 patients are not dying from interstitial pneumonia (which is why ventilators aren’t working and often cause more harm than good) but rather from DIC (disseminated intravascular coagulation) – a medical term for blood clotting causing a lack of oxygen.

Here’s the loose transcript:

Autopsies revealed a number of micro-thrombi, generalized venous, this means that in the capillaries, blood clotting occurred with obstruction blood flow, this caused the inability of oxygen to reach the alveoli, and for more mechanical respirator than the patient had, he was going to die anyway, because he had occluded blood vessels that carry oxygenated blood to the lungs, they also found micro throbs, in the heart, brain, and kidneys.  Which means the patients did not die of interstitial pneumonia as told initially, they died from a blood condition called disseminated intravascular coagulation (DIC) also found in the x-rays of the lungs that interstitial pneumonia can be easily confused with images caused by micro thombus.

These discoveries of Italian pathologists in more than 50 autopsies performed in Bergamo and Milan Italy, center of the largest number of cases in that country, was corroborated by another more recent study in the U.S. by the doctor specializing in pathology, Sharon Fox and collaborators, in April in New Orleans, but only in 4 patients.

So in total 74 autopsies and other Chinese studies by Dr. Ning Tang etal., between Feb and March that confirm these facts.  Increased D-dimers in the blood and coagulopathy indicators are related with worse prognosis of hospitalized patients.

SARS, COVID2 was invented in a British lab (Pirbright Institute) from a U.S. patent (Bickerton et al.) which has 4 genetic inserts:
  • HIV
  • Malaria
  • TB
  • most likely Dengue or Zika, which most likely were carried out in the biosafety lab in Wuhan China, and then escaped or were released.

Of these diseases Malaria, Dengue, Zika, and HIV can cause Thrombocytopenia, which means decreased platelets and formation of micro clots or thrombus, which produces purpuric lesions on the skin, which results in red dots on the limbs, that have been reported in some patients asymptomatic but infected with COVID-19 – mainly in young people, and the worst cases are capable of inducing coagulation, Disseminated Intravascular, which is a systemic event triggered by damage in the blood vessels, caused by inflammation.  This has two consequences:

  • Severe, localized micro thrombus formation OR
  • Generalized or localized bleeding

The video states that while some scholars will say “severe infections can trigger DIC,” which is true, but among those infectious processes are HIV, Malaria, ZIKA, and Dengue, which is irrefutable. 

It shouldn’t be surprising that the genetic codes inserted into the new SARS invention, COVID2 are those of these pathologies.

The first action when the patient stops being asymptomatic and before hospitalization should be blood studies to analyze coagulation because DIC must be avoided at all costs. 

  • Prothrombin time or PT, which measures the external path of the cascade of coagulation
  • Partial thromboplastin time, of PTT, which measures intrinsic and common pathway, the amount of D-dimers,
  • Level of fibrinogen, platelet count and hematocrit will show quickly what is happening.

This clotted blood is mainly in the lungs, heart, brain and kidney.  It is feasible that many died of hemorrhagic vascular brain ischemia, others with kidney failure, and others with heart disease such as myocardial infarction or failure of cardiac dilation of the heart.

Pathologist Sharon Fox found dilation of the right ventricle that means the heart was dilated, by the effort of pumping blood to the lungs that were occluded by micro thrombus, covered by platelet accumulation, and exudates inflammatory, characteristic of coagulopathy or DIC.

Another study just published by Wuhan General Hospital by Zhang et al., in more than 300 hospitalized patients from Jan 1999 to March 2020, the scale levels, D-dimers like prognostic factor of higher or lower mortality, and the conclusion was that patients with increased elevation of this blood factor had a greater risk of dying.

All of this evidence points to the fact patients are dying of micro thrombus (DIC) in the lungs, mainly, without ruling out heart, brain, and kidneys, NOT by interstitial pneumonia as reported and continues being reported today.

These studies raises a very suspicious question:

Who told these researchers in Wuhan, China to study  D-dimers specifically just 12 days after the pandemic was declared?  This is suspicious and indicates they already knew it was a disease that causes DIC and had probably done autopsies prior to December and they knew which blood element was indicated.  

This proves that this plague came long before they gave the alert, allowing it to spread widely.

And, they already knew about the micro thrombus and coagulopathies as the vital element in the the cause of mortality. 

It took 3 months and thousands of people dying until the studies presented in this video happened.  A harsh reality of what went on.

Dr. Harry Abrose, et al.

__________________

This also explains why hydroxychlorquine (HCQ), an antimalarial (along with zinc)is working, as well as Azithromycin as it stops the growth of bacteria like TB.
Dr. Haridopolos (FL Board of Medicine) states the following about hydroxychloroquine:
  • alkalizes the blood, reducing the virus’ ability to replicate
  • causes 02 to dissociate from hemoglobin, similarly as carbon monoxide replaces the 02 molecule
  • reduces cytokine storm

“Hydroxychloroquine prevents the virus from binding to the hemoglobin which causes the oxygen to plummet and desaturate, and it prevents the iron from getting released from the hemoglobin molecule and causing damage in the lungs,” said Melbourne Family Dr. Stephanie Haridopolos.  https://www.fox35orlando.com/news/hydroxychloroquine-what-is-it-and-why-the-debate-in-the-fight-against-covid-19

Evidently, HCQ also improves the following:

Most of these issues are involved with COVID2, showing why HCQ would be a good choice.