Pharmaceutical pricing, a problem to be solved – Same as software, medicines are no scarce commodity, –Andreas Wildi

Pharmaceutical pricing is a problem to be solved macro-economically, both at home and world wide

This requires a national and international pricing system in which individual drugs could be classified. As part of such a system, we would then measure the value of a drug and assign it with a corresponding price.

As a national and international community, we would then have the chance – here, then and everywhere – of never ever restricting access to effective medicines, and at the same time to struggle until we have solved the price issue.

However, there cannot be such a thing as an expensive drug.

We have every right to stand up for the respect of our patient, and patent, rights. Medicines must be fairly sold domestically and abroad and must be purchased fairly. Same as software, medicines are no scarce commodity.

How is it judged today in Switzerland whether a drug is too expensive?

Again and again, individual medicines are described generally or for certain patients as too expensive and not reimbursed. This is a problem, a problem to be solved.

For [a.o.] the drugs’ pricing responsible are the federal offices for health and social insurance 1) as well as the individual health insurers 2) and cantonal disability insurance agencies.3)


quotes, slightly edited, from: Same as software, medicines are no scarce commodity – Although one of the leading pharmaceutical locations in the world, Switzerland is a high-price island for medicines. In the light of patient, as well as patent, protection, it is high time to questioned pricing of medicines, by Andreas Wildi,4) NZZ 06/23/18

translated from German: So wie Software sind Arzneimittel kein knappes Gut – Obwohl sie zu den führenden Pharmastandorten der Welt zählt, ist die Schweiz bei Medikamenten eine Hochpreisinsel. Im Lichte des Patienten-, aber auch des Patentschutzes muss die Preisfestsetzung grundsätzlich hinterfragt werden, von Andreas Wildi,4) NZZ 23.6.18


1) Federal Office of Public Health FOPH (BAG), bag.admin.ch and Federal Social Insurance Office FSIO (BSV), bsv.admin.ch (de, fr, it, en)

2) health insurance in Switzerland: Health insurance on the web of Swiss authorities online, ch.ch (de, fr, it, rm, en)

3) disability insurance in Switzerland: Disability Insurance DI (IV) at the Information Centre OASI/DI (AHV/IV) website of all compensation and DI offices, ahv-iv.ch (de, fr, it, en)

4) Andreas Wildi is a doctor and lawyer in Zurich and Bern and specializes in Swiss and international compensation and pricing right for pharmaceuticals and medical technology products. He was head of the medication section of the Federal Office of Public Health FOPH (BAG). CV outline at LinkedIn, linkedin.com

 

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1989… The true difference / Der wahre Unterschied / Ten skutečný rozdíl

(en / de / cs)

Capitalism is better than socialism, but it’s worse than I have expected. / Kapitalismus ist besser als Sozialismus, aber schlimmer als ich erwartete. / Kapitalismus je lepší než socialismus, ale horší než jsem čekal.
by Jiří Suchý – Czech actor, songwriter, lyricist and director / tschechischer Schauspieler, Liedermacher, Texter und Regisseur

suchý a molavcová

…inspired et al. to the following…

(en) Capitalism is better than socialism, but worse than I thought – these are the real differences:

  • In socialism, thieves stole toilet paper, soap, pencils. In capitalism, thieves steal factories including those producing toilet paper, soaps and pencils.
  • In socialism, workers got the surplus. In capitalism, they are the surplus.
  • In socialism, many people have stolen, but little, in capitalism few people steal, but a lot.
  • In socialism they wrote about criminals in a black chronicle and they were in jail. In capitalism one writes about them as celebrities and they’re in tax haven.

(de) Kapitalismus ist besser als Sozialismus, aber schlimmer als ich dachte – das sind die wirklichen Unterschiede:

  • Im Sozialismus stahlen die Diebe Toilettenpapier, Seife, Bleistifte. Im Kapitalismus stehlen Diebe Fabriken, auch die in denen Toilettenpapier, Seifen, Bleistifte hergestellt werden.
  • Im Sozialismus erhielten Arbeitskräfte den Überschuss. Im Kapitalismus sind sie der Überschuss.
  • Im Sozialismus haben viele Menschen gestohlen, aber wenig. Im Kapitalismus stehlen wenige, dafür sehr viel.
  • Im Sozialismus schrieb man über Verbrecher in einer schwarzen Chronik und sie sassen im Gefängnis. Im Kapitalismus wird über sie als Prominente geschrieben und sie sitzen in der Steueroase.

(cs) Kapitalismus je lepší než socialismus, ale horší než jsem si myslel – to jsou skutečné rozdíly mezi kapitalismem a socialismem:

  • V socialismu zloději kradli toaletní papír, mýdlo, tužky. V kapitalismu zloději kradou fabriky včetně těch vyrábějící toaletní papír, mýdla, tužky.
  • V socialismu dělníci dostávali přebytky. V kapitalismu, jsou dělníci přebytkem.
  • V socialismu kradlo hodně lidí, ale málo. V kapitalismu krade málo lidí, ale zato hodně.
  • V socialismu se o zlodějích psalo v černé kronice a seděli v base. V kapitalismu se o zlodějích píše jako o celebritách a sedí v daňovém ráji.

šliter a suchy-3x1

Of disulfiram, the publication of our international team’s work in Nature and nonprofit drugs

» CZECH / ČESKY

Boris Cvek, 23.12.17
based upon Boris Cvek’s interview (in Czech) Významný objev v léčbě rakoviny otevírá nové cesty (A significant discovery in cancer treatment opens new ways) in Hlídací pes (Watchdog) 23.12.17 – slightly edited by –vjr-

Disulfiram (antabuse) and state of today’s research

bcupolDuring the last years we confirmed that disulfiram, also known as antabuse, is effective against cancer at cell level and in animals.

Over the past forty years, dozens of articles have been published on this subject. The problem was that most of them explained the effectiveness of disulfiram in not a clear way. In our article Alcohol-abuse drug disulfiram targets cancer via p97 segregase adaptor NPL4 in the Nature journal, we bring a perhaps definitive explanation. We have shown how disulfiram kills cancer at the level of cells and in animals that have tumors.

jiri-bartekMost of the work was done by Jiří Bártek‘s team of his Olomouc laboratory. Also noteworthy is a study, part of our article, by colleagues from Denmark who have shown that among alcoholics with cancer, those who took disulfiram were healthier.

We also confirmed my old hypothesis that one particular compound produced in the body from disulfiram and copper is responsible for its antitumor activity. Previously, I called it CuET. It is highly remarkable that it accumulates in tumors. This is the dream of all oncologists – to get the cure into the tumor and, on the contrary, not to have it in healthy tissues. Hopefully, this will also be confirmed in humans.

In the cells, this substance causes the degradation of proteins to stop. It prevents the removal of waste, more precisely unnecessary proteins, from the tumor cells. They accumulate inside the cell, which then dies. And it prevents it in a unique way, not described previously. This is probably the greatest scientific contribution of our work.

Model of DSF anti-cancer activity in patients
Fig. 4f

Skrott_et_al-2017-Nature_p5-fig4f_cropped

DSF = disulfiram (tetraethylthiuram disulfide)
DTC = diethyldithiocarbamate
CuET = DTC–copper complex (bis (diethyldithiocarbamate)–copper)

The portability of preclinical research on humans

The main problem of all similar preclinical research, i.e. those performed on cells or animals, is their portability to humans. Even if the preclinical results may give hope, it does not necessarily mean that the substance will work in humans. There may be a vast gap between preclinical and clinical research.

Based on our article in Nature, we can not argue that disulfiram will treat cancer in humans. We can only say that clinical trials of disulfiram in oncology patients are needed. And now we give very strong arguments why to begin with them.

Clinical tests
Editor’s note: Phase II clinical trials already started in Olomouc – Phase II Trial of Disulfiram With Copper in Metastatic Breast Cancer (DISC)

If there was a pharmaceutical company that has patented and owns disulfiram, it would begin clinical trials on a wide range of cancerous diseases based on our findings. But disulfiram has no company to care. It has a long history, it can not be patented and therefore not commercially exploited.

If someone would invest money in the clinical trials, and it would turned out that disulfiram actually cures people, someone could start producing it cheaply and selling it cheaply as well. What we need is public money for clinical tests of disulfiram. And this is, in my opinion, the most important message of our research.

Nonprofit drugsnpd-logo

In the public interest, we need public and/or charitable money. We need disulfiram to get into clinical trials in a nonprofit way. The nonprofit drug development model is, in societies with healthcare based on profit, something totally new. And it well may have the potential to change such healthcare systems globally.

At present, it may seem to be no way to finance clinical trials on large-scale population groups for nonprofit medicines. If there was a way to pay for the trials in a non-commercial way, we could get effective medications that are also very cheap. And in this we see a need for a change in those global healthcare systems, that are dominated by commercial interests.

On this, I wrote in Nonprofit drugs as the salvation for world’s health care systems, published in Drug Discovery Today in 2012, after passing a rigorous review process. In it I also point out that one of the highest incidences of breast cancer occurs in very poor countries, like in Africa, that do not have access to standard oncology treatment.

The argument is very simple. If governments and charities would finance clinical trials of nonprofit drugs, and if these tests were successful, they would help patients all around the world – first of all hundreds of thousands, if not millions, of people in the developing world.

Example of visceral leishmaniasis aka black fever

There is a good example, a drug that was developed in a non-profit way. For curing a disease called visceral leishmaniasis (black fever), a fatal parasitic disease that occurs only in poor regions of India, Bangladesh or Africa.

When researchers found out that this disease could be treated with an “old”, “forgotten” antibiotics paromomycin, Bill and Melinda Gates, together with the World Health Organization and other organizations, agreed to pay for clinical trials. And this medicine works. It helps to cure people, while keeping the price of threating them at a very low level. Curing people of a fatal disease for four euros within three weeks.

There may be a similar opportunity in disulfiram.

Alcohol-abuse drug Antabuse (disulfiram) kills cancer cells

What the report “Alcohol-abuse drug disulfiram targets cancer via p97 segregase adaptor NPL4” Nature 552, 6/14 Dec ’17 (1) is all about

“Alcohol-abuse drug Antabuse kills cancer cells”, writes one of the scientists of an international team(1) in a media release of his university (Alcohol-abuse drug Antabuse kills cancer cellsKarolinska Institutet, 7/12 Dec ’17) about their just published report Alcohol-abuse drug disulfiram targets cancer via p97 segregase adaptor NPL4Nature, 6/14 Dec ’17(1) and continues that the scientist found out, “that the alcohol-abuse drug Antabuse is effective against cancer [and] identifies a potential mechanism of action for the anti-tumour effect.”

The report is about three issues:

  • The, highly interesting, progress in lab work on disufiram, which “fills an important knowledge gap regarding the anti-cancer mechanism of disulfiram and paves the way for future clinical trials,” as “[in] laboratory experiments, the team found that in mice and in the human body, disulfiram becomes metabolised into a molecule that causes a naturally occurring protein NPL4 to clump together with its partner, the body’s p97 enzyme. This process ‘freezes’ and thereby functionally disables the otherwise very mobile and tumour growth-supporting NPL4-p97 duo, resulting in cancer cell death…” (Jiří Bártek in the Karolinska media release)
    NOTE: the first clinical trial just began in Olomouc(2)
     
  • Yet another analyses/report of the records/cases, this time “of cancer patients across Denmark” (over 3000 patients taking Antabuse of over 240,000 cases diagnosed between 2000 and 2013 in Denmark’s cancer registry). This, I think, may/should be “put into perspective” a bit more thoroughly and together with other cases(3), at least as long as the clinical tests are on the way.
     
  • The Nonprofit drugs issues, briefly mentioned by the authors. This theme, as a larger multidisciplinary project, is currently in preparation(4).
Notes, quotes, further reading

(1)

The countries and institutions of the international team…

  • Czech Rep – Palacky University, Olomouc; Charles University, Prague; Psychiatric Hospital, Sternberk
  • Denmark – Danish Cancer Society Research Center, Copenhagen
  • Sweden – Karolinska Institute, Stockholm
  • Switzerland – Kantonsspital St Gallen
  • USA – Caltech, Pasadena, California; Wayne State University, Detroit, Michigan; Amgen, Thousand Oaks, California
  • China – Guangzhou Medical University, Guangzhou

…and their report:

Alcohol-abuse drug disulfiram targets cancer via p97 segregase adaptor NPL4

Zdeněk Škrott+, Martin Mistrík+, Klaus Kaae Andersen, Søren Friis, Dušana Majera, Ján Gurský, Tomáš Oždian, Jiřina Bártková, Zsófia Turi, Pavel Moudrý, Marianne Kraus, Martina Michalová, Jana Václavková, Petr Džubák, Ivo Vrobel, Pavla Poučková, Jindřich Sedláček, Andrea Miklovičová, Anne Kutt, Jing Li, Jana Mattová, Christoph Driessen, Q. Ping Dou, Jørgen Olsen, Marián Hajdúch, Boris Cvek*, Raymond J. Deshaies*, Jiří Bártek* (+contributed equally, *corresponding authors)
Nature 552, 194–199 (14 Dec 2017), doi:10.1038/nature25016, published online: 06 Dec 2017

Contributions – Zdeněk Škrott, Martin Mistrík, Boris Cvek, Raymond J. Deshaies and Jiří Bártek conceived the study. Zdeněk Škrott and Martin Mistrík performed most biochemical and microscopy experiments and wrote the manuscript. Dušana Majera established the expression cell lines and performed most cytotoxicity tests. Tomáš Oždian, Petr Džubák and Ivo Vrobel performed the HPLC experiments. Klaus Kaae Andersen, Søren Friis and Jørgen Olsen performed the epidemiological analyses. Jiří Bártek performed the immunohistochemical analyses. Jana Václavková and Petr Džubák performed DARTS experiments. Pavel Moudrý performed cell death analyses. Zsófia Turi performed cytotoxicity tests and heat-shock response analyses. Anne Kutt performed cytotoxicity tests. Andrea Miklovičová designed and performed phlebotomies of patients treated with Antabuse. Martina Michalová performed the ITC. Ján Gurský performed FACS analyses, cell death assays and cell sorting. Jindřich Sedláček performed 20S proteasome assays. Jing Li performed 26S proteasome assays. Marianne Kraus and Christoph Driessen performed the cytotoxicity experiments on myeloid- and patient-derived cell lines. Pavla Poučková, Jana Mattová and Marián Hajdúch performed mouse experiments. Jiří Bártek, Boris Cvek, Q. Ping Dou and Raymond J. Deshaies helped to design the experiments, interpreted the data and wrote/edited the manuscript. All authors approved the manuscript.

Acknowledgements, thanks – J. Škvor, M. Zadinová, J. Večerka and D. Doležal for help with animal experiments, Jana Vrbková for statistical analysis, David Friedecký and Tomáš Adam for help with HPLC, Iva Protivánková and M. Grønvig Nielsen for technical assistance.

The authors sum up their findings in the report’s last section:

Model of DSF anti-cancer activity in patients
Fig. 4f

Skrott_et_al-2017-Nature_p5-fig4f_cropped

DSF = disulfiram (tetraethylthiuram disulfide)
DTC = diethyldithiocarbamate
CuET = DTC–copper complex (bis (diethyldithiocarbamate)–copper)

Discussion
Our results help to explain the anti-cancer activity of the alcohol-abuse drug disulfiram.
We propose a model for DSF cytotoxic activity, featuring rapid conversion of DSF into CuET, which accumulates in tumours. After entering cells, CuET binds NPL4 and induces its aggregation, consequently disabling the vital p97–NPL4–UFD1 pathway and inducing a complex cellular phenotype leading to cell death (Fig. 4f). Supporting CuET as the active metabolite is the correlation of CuET concentrations (active in the nanomolar range) with the biological effects and functional impact on the targeted pathway(s) in vivo.
In addition, CuET is the only known metabolite of DSF containing copper ions, a metal that enhances the anti-tumour effects of DSF; it is unlikely that another DSF metabolite could represent the major anti-cancer agent as levels of non-CuET metabolites should be lowered by copper addition.
We also present a method for CuET detection in tissues and plasma, as well as data suggesting that preferential accumulation of CuET in tumours may contribute to cancer cell toxicity, consistent with the high therapeutic tolerability of DSF3, as documented even after years of daily administration at doses comparable to those we used in our mouse experiments.
Considering the numerous studies on DSF and diverse opinions about the potential target of its anti-cancer effects44, identification of NPL4, a key component of the p97–NPL4–UFD1 segregase complex, as the molecular target of CuET is surprising. The CuET–NPL4 interaction leads to rapid formation of protein aggregates and immobilization of this otherwise very mobile multifunctional protein complex, resulting in a severe phenotype, induction of HSR and eventually cell death. While additional potential targets of CuET cannot be excluded, the malfunction of the p97 pathway due to the NPL4–p97 aggregate formation explains the major cell phenotypes and the consequent cell death.
Our work also reconciles the controversial studies6,12, suggesting that the proteasome is the DSF target, by demonstrating that neither 20S nor 26S proteasome, but the processing of ubiquitylated proteins by the NPL4-dependent segregase, is targeted by CuET.
Our results support the notion that the p97–NPL4 pathway is a promising therapeutic target in oncology45,46. Indeed, reports on p97 overabundance correlating with progression and metastasis of carcinomas of the breast, colon and prostate47–49 are consistent with our present nationwide epidemiological analysis, which revealed an association between continued use of DSF and favourable prognosis, an intriguing finding that should be investigated further, particularly given the currently limited therapeutic options for patients with metastatic cancer.
From a broader perspective, our study illustrates the potential of multifaceted approaches to drug repurposing, providing novel mechanistic insights, identification of new cancer-relevant targets and encouragement for further clinical trials, here with DSF, an old, safe and public domain drug4 that might help to save lives of patients with cancer worldwide.


3. Iljin, K. et al. High-throughput cell-based screening of 4910 known drugs and drug-like small molecules identfies disulfiram as an inhibitor of prostate cancer cell growth. Clin. Cancer Res. 15, 6070–6078 (2009).
4. Cvek, B. Nonprofit drugs as the salvation of the world’s healthcare systems: the case of Antabuse (disulfiram). Drug Discov. Today 17, 409–412 (2012).

6. Chen, D., Cui, Q. C., Yang, H. & Dou, Q. P. Disulfiram, a clinically used anti-alcoholism drug and copper-binding agent, induces apoptotic cell death in breast cancer cultures and xenografts via inhibition of the proteasome activity. Cancer Res. 66, 10425–10433 (2006).

12. Lövborg, H. et al. Inhibition of proteasome activity, nuclear factor-κB translocation and cell survival by the antialcoholism drug disulfiram. Int. J. Cancer 118, 1577–1580 (2006).

44. Cvek, B. Targeting malignancies with disulfiram (Antabuse): multidrug resistance, angiogenesis, and proteasome. Curr. Cancer Drug Targets 11, 332–337 (2011).
45. Deshaies, R. J. Proteotoxic crisis, the ubiquitin–proteasome system, and cancer therapy. BMC Biol. 12, 94 (2014).
46. Anderson, D. J. et al. Targeting the AAA ATPase p97 as an approach to treat cancer through disruption of protein homeostasis. Cancer Cell 28, 653–665 (2015).
47. Cui, Y. et al. High expression of valosin-containing protein predicts poor prognosis in patients with breast carcinoma. Tumour Biol. 36, 9919–9927 (2015).
48. Yamamoto, S. et al. Expression of valosin-containing protein in colorectal carcinomas as a predictor for disease recurrence and prognosis. Clin. Cancer Res. 10, 651–657 (2004).
49. Tsujimoto, Y. et al. Elevated expression of valosin-containing protein (p97) is associated with poor prognosis of prostate cancer. Clin. Cancer Res. 10, 3007–3012 (2004).


(2)

clinical tests in Olomouc:


(3)

some previous, further cases, reports in:


(4)

on Nonprofit drugs see also:

An old drug for alcoholism finds new life as cancer treatment, –Jocelyn Kaiser

By Jocelyn Kaiser | Science, Dec. 6, 2017, 1:00 PM » THIS ARTICLE IN Science
slightly edited by –vjr–

breast cancer
Breast cancer cells are a target for an alcohol abuse drug.Nature’s Geometry/Science Source

On Alcohol-abuse drug disulfiram targets cancer via p97 segregase adaptor NPL4, Nature 552, 6/14 Dec ’17

“This paper solves a puzzle that has persisted in cancer research for decades,” says cancer biologist Michele Pagano of New York University School of Medicine in New York City, who was not involved in the study.


By age 38, the patient’s breast cancer had spread to her bones, a typically fatal turn of events. She became an alcoholic, and her doctors stopped all cancer treatment, instead giving her a drug to discourage her drinking. She died 10 years later, after an inebriated fall from a window. But an autopsy revealed something unexpected: Her bone tumors had melted away, leaving only a few cancer cells in her marrow.

That 1971 case report,(1) along with numerous lab studies,(2) have suggested that the 6-decade-old drug disulfiram (commercially known as Antabuse), which makes people feel sick from drinking small amounts of alcohol, might also be a cancer fighter. Now, researchers have finally figured out how—by blocking a molecule that is part of a process that gets rid of cellular waste.

Starting in the 1970s, scientists found that disulfiram killed cancer cells and slowed tumor growth in animals. It increased survival in women who had breast tumors removed in a small clinical trial published in 1993,(3) But since then, disulfiram hasn’t gotten much attention for treating cancer, partly because scientists disagreed about how it worked.

In the new study, a Danish-Czech-U.S. team first firmed up the drug’s anticancer effects by combing through Denmark’s unique cancer registry—more than 240,000 cases diagnosed between 2000 and 2013, along with data on the medications each patient took. Of the more than 3000 patients taking Antabuse, the cancer death rate was 34% lower for the 1177 who stayed on the drug compared with those who stopped taking it, the researchers report today in Nature. The drug was an equal opportunity anticancer weapon; its benefits held for prostate, breast, and colon cancer, as well as cancer overall.

The researchers also confirmed that disulfiram slows the growth of breast cancer tumors in mice, particularly if combined with a copper supplement, which was already known to enhance its effects. They then showed that when the mice broke down disulfiram, its main metabolite, ditiocarb, forms a complex with copper that blocks the machinery that cells use to dispose of misfolded and unneeded proteins. “Everything is frozen,” says cancer biologist Jiri Bartek of the Danish Cancer Society Research Center in Copenhagen (and the Karolinska Institute in Stockholm), a co-leader of the study. Partly because of the resulting protein buildup, the cancer cells become stressed and die.

Although some approved cancer drugs and others in development interfere with the same protein cleanup process, known as the ubiquitin-proteasome system, disulfiram targets only a specific molecular complex within this machinery. That could explain why it is so effective, Pagano says. Bartek’s team also solved another puzzle—why normal cells aren’t harmed by disulfiram, even when patients take it for years. For not yet clear reasons, the copper metabolite is 10 times more abundant in tumor tissue compared with other tissues, the group found.

Despite the compelling 1971 anecdote, disulfiram “probably is not a cure” for most cancer patients, cautions cancer biologist Thomas Helleday of the Karolinska Institute in Stockholm. However, the drug could help extend the lives of patients with metastatic cancer—it’s already shown evidence of doing so when combined with chemotherapy in a small lung cancer trial.(4) Bartek and collaborators are now launching trials to test a disulfiram-copper combo as a treatment for metastatic breast (6) and colon cancers and for glioblastoma,(7) a type of brain cancer.

Finding a new use for an approved drug is appealing because the compound has already passed safety testing. However, “big pharma probably won’t be interested” in developing disulfiram for cancer because there’s no patent protection on the drug, Bartek says. Still, if the pending clinical trials provide convincing evidence, Halleday points out, oncologists could go ahead and prescribe it anyway as an inexpensive treatment.


(1)

Spontaneous regression of breast cancer, Prog Clin Biol Res 1977, Lewison EF and (5) on this blog

(2)

next to the Nature paper discussed here see also (5) on this blog

(3)

Sodium dithiocarb as adjuvant immunotherapy for high risk breast cancer: a randomized study, Biotherapy 1993 6(1) 9-12 and (5) on this blog

(4)

A phase IIb trial assessing the addition of disulfiram to chemotherapy for the treatment of metastatic non-small cell lung cancer, Oncologist 2015 Apr 20(4) 366-7 Epub 2015 Mar 16 and (5) on this blog

(5)

Disulfiram (Antabuse) against Cancer on this blog

(6)

phase II clinical trial, with the aim “to establish clinical evidence for introducing disulfiram and cooper as an active therapy for metastatic breast cancer upon failure of conventional systemic and/or locoregional therapies”, are beginning (early 2017) in Olomouc – Phase II Trial of Disulfiram With Copper in Metastatic Breast Cancer (DISC), NCT03323346
(a) NOTE: yet disulfiram should (also) be tested before failure of conventional therapies

(7)

the aim of this clinical trial is “to investigate disulfiram and copper-supplement as add-on treatment in glioblastoma patients with recurrence receiving alkylating chemotherapy, a multicenter RCT including patients in Norway and Sweden, as a proof-of concept study”, in Göteborg (Gothenburg), Trondheim, Skåne (Scania), Stockholm, Linköping, Jönköping, Uppsala and the Örebro County – Disulfiram in Recurrent Glioblastoma, NCT02678975

… more disulfiram tests / studies on clinicaltrials.gov


Science, posted in: Biology, Health, Cancer topic
doi:10.1126/science.aar6850

KaiserJocelyn Kaiser
Jocelyn is a staff writer for Science magazine.
Email Jocelyne

 

 

Disulfiram (Antabuse) against Cancer, –Boris Cvek

Research, case reports, clinical trials

» DEUTSCHAntabuse (disulfiram) against Cancer
a presentation by
 Boris Cvek, Ph.D.
University of Olomouc, Social Health Institute OUSHI
(formerly at the Department of Cell Biology and Genetics)

Research in cells and animals

Many scientific publications have demonstrated that Antabuse (disulfiram), especially when combined with copper (cf. The Active Compound further below), kill cancer cells and is able to suppress tumors in mice.

The figure below, from our research now being prepared for publication (NOTE, Dec’17 – in between published: Nature, Dec 6/14 2017, doi:10.1038/nature25016, see Alcohol-abuse drug Antabuse (disulfiram) kills cancer cells), shows mice with a metastasis of human breast cancer, most effectively suppressed by the active compound.

antabuse-boris-cvek-01
gluCu = food supplement containing copper | Mock = control group

Case report by Dr. Lewison (Prog. Clin. Biol. Res. 12, 47-53, 1977)

Spontaneous regression of breast cancer, Prog Clin Biol Res 1977, Lewison EF

In 1977, Dr. Lewison from Johns Hopkins University in the USA published a case report of a patient with metastasizing breast cancer who became an alcoholic. Between 1961-1971 she used Antabuse (Disulfiram) and became cancer-free. She died in 1971 – not because of cancer, but by falling from a window while heavily drunk.

“However, in 1961 she became a severe alcoholic and it was necessary to discontinue all hormone therapy and Antabuse was started [for treatment of alcoholism]. Over the next 10 years, from 1961 to 1971, complete resolution of all bone lesions in the spine, skull, pelvis and ribs gradually occurred and the patient remained clinically free of cancer with no further hormone therapy, chemotherapy, or radiation therapy. Frequent psychiatric care was required and she remained on and off Antabuse therapy for her continued drinking problem. She died in 1971 when she accidentally fell from a third floor window. The coroner’s report showed a high blood alcohol level and residual nests of metastatic carcinoma in the bone marrow.”

Ditiocarb clinical trial (Biotherapy 6, 9-13, 1993)

Sodium dithiocarb as adjuvant immunotherapy for high risk breast cancer: a randomized study, Biotherapy 1993 6(1) 9-12

In 1993, French scientists published a phase II clinical trial of a drug called Ditiocarb. This compound is produced after ingestion of Antabuse. They used very low doses – 700 mg weekly, in comparison to a standard Antabuse dosage of 250-500 mg daily.

Sixty-four women with non-metastatic high risk breast cancer after surgery were divided into two equal groups. The first group were placed on standard chemo + placebo, while the second were on the same chemo + Ditiocarb. The drugs were taken for 9 months. After 5 years, 55% of patients were alive in the first group compared to 81% of patients in the second group.

It is to be expected that with higher doses, and after longer treatment, the effect might be much stronger. Our hypothesis is that the active compound (which occurs in the body after Ditiocarb reaction with copper, cf. The Active Compound below) was able to destroy micro metastases in some patients – even at such low doses and after only 9 months.

Case report from Utah (Mol. Cancer Ther. 3, 1049-1060, 2004)

In 2004, scientists from Utah published a case report of a patient with melanoma metastasis in the liver, which – by using a combination of disulfiram and zinc – shrank after a few months and disappeared after three and a half years.

antabuse-boris-cvek-02

Today, the fact that the active compound is a copper combination is already known (in fact, the zinc compound does not exist in human body and disulfiram prefers copper that is naturally occurring in the body).

Disulfiram clinical trial (Oncologist 20, 366-367, 2015)

A phase IIb trial assessing the addition of disulfiram to chemotherapy for the treatment of metastatic non-small cell lung cancer, Oncologist 2015 Apr 20(4) 366-7 Epub 2015 Mar 16

In 2015, the Oncologist journal published results of a clinical trial from Israel, where 40 patients with metastatic lung cancer were divided into two equal groups (of 20 each). The first group were placed on standard chemo, while the second group were on standard chemo + disulfiram (just 120 mg daily). Patients from the second group survived 3 months longer on average and, most importantly, two survived for a long time. The figure further shows that all the patients from the first group died after two years.

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The active compound

We have various experimental evidence, now prepared for publication, showing that the active compound is a complex of Ditiocarb and copper; which occurs under normal conditions after Antabuse ingestion in the human body.

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Phase II and phase III clinical trials

To get approval from state authorities for Antabuse to be used normally in oncology, we need to conduct further and larger clinical trials  – i.e. phase II clinical trials (hundreds of patients) and phase III in particular (thousands of patients). We need such trials to examine various cancers and to combine Antabuse with various standard chemo drugs.

Normally, clinical trials are funded by pharmaceutical companies. However, Antabuse is not patentable. The advantage is that it is affordable (hundreds of Dollars/Euros per patient per year), yet the weakness is that it is not interesting for business. Therefore, Antabuse clinical trials must be paid by charities and governments in the public interest. We want to finance such clinical trials.

If large phase III clinical trials show that Antabuse is able to cure some cancers, it would be, as an inexpensive drug, affordable even for patients in low-income countries.

First steps and further progress – including fast-track approval

In Olomouc, where we have experience with Antabuse research, there are oncologists who are willing to conduct Antabuse clinical trials. In collaboration with them, we have designed a phase II clinical trial of 100 patients with metastatic breast cancer and 100 patients with metastatic lung cancer (500 mg Antabuse + 2 mg copper daily).

In all patients, overall survival will be determined, and if their tumors shrink, do not grow, or grow further. The results will be of value for the identification of patients who are most sensitive to Antabuse therapy, and for further research as to why some patients are more sensitive than others.

We would also like to conduct further trials in patients with different cancers. In the case of positive results, we would design phase III clinical trials and talk to the FDA and EMA to win a fast-track approval of Antabuse for metastatic cancer where it is curable. Negative results would instigate phase II clinical trials of Antabuse in combination with standard chemo.

Why test Antabuse in Olomouc?

In Olomouc we have a team of oncologists led by prof. Bohuslav Melichar, head of the Oncology Unit of the Teaching Hospital, ready to conduct clinical trials of Antabuse in patients with metastatic breast/lung cancer and other cancers – as soon as sufficient funding is found.

Preliminary/rough cost estimate of the 100 + 100 trial
(subject to review / amendments)

  • Wages of physicians (2 physicians), coordinator and supervisor of clinical trial
    some € 80,000 per year – for 2 years € 160,000
  • Material (Antabuse, copper supplementation, materials used for standard health care in hospitals), other services and non-material costs (examination of patients, insurance according to law),
    some € 120,000 per year – for 2 years € 240,000

  • Overall cost of 1 phase II clinical trial of 100 + 100 patients
    some € 200,000 per year – for 2 years € 400,000

This project is the result of our long-term scientific research of Antabuse anti-cancer activity here in Olomouc. So far, there is only one team, besides us, focused on Antabuse application in oncology, (prof. Weiguang Wang in UK), but they are working on some patentable formulation of disulfiram.

Our strategy fits perfectly into the mission of Olomouc University Social Health Institute (OUSHI). It is not “only” about curing patients, but we have an ambition to contribute to changing healthcare systems globally, to make them more affordable with “nonprofit drugs”. More about this idea can be found in the article “Nonprofit drugs as the salvation for world‘s health care systems: the case of Antabuse” by B. Cvek, published in Drug Discovery Today.


CONTACTBoris Cvek, Ph.D. / Prof. Peter Tavel, Ph.D. (UP / Olomouc University (CZ)

PROPOSED/POSSIBLE PARTNERS*Prof. Ray Deshaies (California Institute of Technology, Pasadena CA (USA) / Prof. Vikas Sukhatme (Dana-Farber/Harvard Cancer Research, Boston MA (USA) / Prof. Jiří Bártek (UP, Olomouc (CZ), Danish Cancer Society Research Center, Copenhagen (DK), Karolinska Institutet, Stockholm (S) / Prof. Ping Dou (Barbara Ann Karmanos Cancer Institute, Detroit MI (USA) / Prof. Christoph Driessen (Kantonsspital St. Gallen (CH), SAKK (CH) / Prof. Pavla Poučková (1st Medical Faculty Charles University, Prague (CZ)
*chronologically, as we have “found” them and with whom we currently (2015/16) work together on our Nature publication

No more wars, no more killings, by states – how to… Is Europe already so far?

In the middle of the 19th century, in the middle of Europe, the elites of what became multicultural Switzerland, decided not to participate in any wars. One of the questions this society asked: “How to be secure without wars?”

In the middle of the 20th century, the elites of what became EU decided not to fight each other – yet to go to any wars they wish to. One of the questions the EU did not ask yet: “How to be secure without wars?”

Another question asked by those people, in the middle of the 19th century, in the middle of Europe: “How to participate all in shaping all things common together?”

I think these two questions should be asked by today’s elites of Europe. Yet who are the elites of today? All the people? Is Europe already that far?