Diflunisal

CAS 22494-42-4

My opinion:

An anti-cancer treatment with great potential relevant for most types of cancers visible on PET/CT. Regarding its effectiveness, this statements says it all: “33 patients were evaluable for metric response, 20 for metabolic and 19 for tumor marker response assessment. For tumor marker follow up 11 % had a CR, 53 % a PR, 26 % a SD of > 3 month and 11 % a PD. For metric follow up 3 % had a CR, 33 % a PR, 39 % a SD of > 3 month and 24 % a PD. For metabolic follow up 10 % had a CR, 35 % a PR, 35 % a SD of > 3 month and 20 % a PD.” (Ref.)

Here CR is complete response, PR is partial remission, SD is stable disease and PD is progressive disease.

Summary

Diflunisal is a salicylic acid derivative (NSAID) and is available in 250 mg and 500 mg tablets. This is a drug similar to aspirin, already used on humans with various medical challenges but not cancer.

Its anti cancer effects have been discovered about 15-20 years ago by Prof. Dr. W. Kreutz, in Germany.
It has been claimed to be:
– Universal cancer therapy: the new cancer therapy works effectively on all solid tumors and metastases
– High selectivity: it acts exclusively on cancer cells
– free of side effects: due to the new target principle and the pH-sensitive active substances used are prevents side effects on normal tissue.
– triggering a pore formation in cancer cells
– All active substances are approved drugs for other diseases
– Good compatibility: The treatment is well tolerated by patients. The drugs are administered intravenously or orally
(Ref.)

There is only one place to my knowledge where this treatment is administrated in IV form to cancer patients. That place is Unifontis in Tunbingen, Germany. This clinic is lead by Prof. Joachim Drevs. I have seen one of his lectures and I was positively impressed. Here you can find a bit more info about the treatment.

Although the IV delivery seems to be preferred, this treatment can also be preformed with oral administration of Diflunisal as discussed below. I prefer the IV route since there may be gastrointestinal issues when administrating such a large amount of Difluinsal (and ASA) during a longer period of time.

Studies in Humans

Update on pilot study on antitumor efficacy of intravenously applied synergistic combinations of diflunisal, PAS, and aspirin in patients with advanced solid tumors. 

Background: Due to chronic hypoxia cancer cells are growing in a more acidic environment compared to physiological tissue. Recent preclinical in vitro and in vivo data have shown direct pH-sensitive anti-tumor activity by pore formation and apoptosis when synergistically acting combinations of Diflunisal, Paraaminosalicylic acid (PAS) and Aspirin were applied. Therefore, a pilot study was performed to evaluate its clinical relevance and its update is presented. Methods: A total of 65 patients (n=65) with advanced solid tumors and the lack of standard treatments were treated with a protocol consisting of 3-5 weeks with 2 daily i.v. infusions of Diflunisal and Aspirin for 4 days per week after they had signed an informed consent form. Response evaluation was assessed by PET/CT differentiating in metabolic and metric (RECIST) response and tumor marker where available. Results: Out of 65 patients treated 8 patients suffered from colorectal cancer, 17 from breast cancer, 6 from ovarian cancer, 3 from lung cancer, 3 from gastric cancer, 3 from glioblastoma, 3 from CUP, 1 from hemangioendothelioma, 1 from pleuramesothelioma, 1 from non-Hodgkin lymphoma, 2 from pancreatic cancer, 1 from choledochus cancer, 3 from prostate cancer, 5 from sarcomas, 2 from head and neck cancer, 1 from melanoma, 1 from cervical cancer, and 1 from thyroid cancer, respectively. Side effects related to the therapy have been fatigue grade I (30%), nausea grade I (13,3%), tinnitus (25%), hypertension (2,5%), dyspnea (3,3%) and burning sensation in tumor areas (65%). 33 patients were evaluable for metric response, 20 for metabolic and 19 for tumor marker response assessment. For tumor marker follow up 11 % had a CR, 53 % a PR, 26 % a SD of > 3 month and 11 % a PD. For metric follow up 3 % had a CR, 33 % a PR, 39 % a SD of > 3 month and 24 % a PD. For metabolic follow up 10 % had a CR, 35 % a PR, 35 % a SD of > 3 month and 20 % a PD. Conclusions: This continuing pilot study confirms a direct pH-sensitive synergistic anti-tumor activity of intravenous Diflunisal, PAS and Aspirin in patients with advanced solid tumors. Therefore, a further evaluation in a controlled clinical phase II study should be performed.

Treatment of advanced solid tumours with NSAIDs: Correlation of quantitative monitoring of circulating tumour cells and positron emission tomography-computed tomography imaging

The detection and characterisation of tumour-derived circulating epithelial tumor cells (CETCs) or circulating tumor cells (CTCs) have been a main focus of basic oncological research over previous years. Numerous studies in the past decade have shown that CTCs are a promising tool for the estimation of the risk for metastatic relapse. The present observational study describes treatment results using tumour imaging and the quantification of CTCs. A group of 14 patients with advanced carcinomas was followed during their anticancer treatments. CTC numbers were serially detected and treatment success was estimated by positron emission tomography-computed tomography. A connection was found between tumour remission and a decreasing CTC count in 83%, a connection between stable disease and stable CTC numbers in 78% and a connection between progressive disease (PD) and an increase in CTC count in 50% of cases. In the patients with PD, an incomplete response was observed affecting the CTCs, but not the solid region of the tumour. As a result of this study, it may be concluded that patients with solid tumours benefit from serial quantification of CTCs in addition to imaging, as this combination of techniques provides a more sensitive result than imaging alone.

Anecdotal reports/stories

I have met a men who went through the Diflunisal (or the so called “Diflu”) treatment. He had metastatic pancreatic cancer and was cured after about 3 weeks treatment with Diflu protocol. The man is from US and he wrote a message on a thread on the web. He even shared his e-mail address there so that anyone who likes can contact him and ask about his experience in Germany. The only big challenge is that the price he had to pay was in the range of 30k euro for the three weeks treatment ….

Mechanism

Essentially, the mechanism suggested is based on an interaction of the Diflunisal with the low pH that is found around the tumors. This means that the treatment will be relevant for the tumors that are visible on PET/CT only (which is the case for most cancers) and that the treatment will only be toxic to the tumor cells. Because the toxicity to the tumor cells is activated outside the tumor cell in the low pH environment, there is no chance for the tumor to develop resistance to the treatment. The results is the incorporation of the Diflunisal into the tumor membrane and the formation of a pore like structure that cause the collapse of membrane gradient, leading to cell death. (Ref.) It seems that when using a second salycilate, i.e. Aspirin (ASA) or PAS (p-amino-salicylic acid)  an anti-tuberculosis drug, a synergetic anti-cancer effect can be obtained (Ref.) It has been observed by prof. Krause that PAS and ASA acts on pH below 6.5 and Diflunisal on pH below 7 to induce the pore like formation. Note that the average pH of human blood is 7.36.

The discovery is protected by several patents (see below).

It has been suggested that the pore like structure induced by the salicylates treatment may be further supported by immuno therapies since in this case the immune system will be able to attack the cancer cells (prof Drevs).

Therefore, salicylates harm the cancer cell walls without affecting normal tissue.

Update: a paper published after I wrote this article, indicating a different anticancer mechanisms: Salicylate, diflunisal and their metabolites inhibit CBP/p300 and exhibit anticancer activity  Ancient anti-inflammatory drug salicylic acid has cancer-fighting properties

Other relevant points:

– In patient treatments, where 1000 mg/day of the compounds are administered, corresponding to <0.3 mM interstitial concentrations (identical to Diflunisal to albumin ratio of <2:1), no cancer cell kill takes place but only disturbance of the COX-systems, which leads to proliferation inhibition, i.e. to retardation of tumor growth. (Ref.)
– Diflunisal should be administered to a patient in an amount so that the interstitial concentration of Diflunisal is from 0.55 mM to 1.1 mM, preferably from 0.7 mM to 1.1 mM, more preferably from 0.7 mM to 1.0 mM, e.g. 0.8 mM or 1.0 mM. (Ref.)
– An interstitial concentration of Diflunisal of 1.1 mM corresponds to an oral dose (based on the bodyweight of the patient) of about 55 mg/kg, an interstitial concentration of Diflunisal of 1.0 mM corresponds to an oral dose of about 50 mg/kg, an interstitial concentration of Diflunisal of 0.55 mM corresponds to an oral dose of about 27,5 mg/kg, an interstitial concentration of Diflunisal of 0.7 mM corresponds to an oral dose of 35 mg/kg, an interstitial concentration of Diflunisal of 0.8 mM corresponds to an oral dose of about 40 mg/kg and an interstitial concentration of 0.9 mM corresponds to an oral dose of about 45 mg/kg. The above values are based on a female patient with 65 ml blood per kg, and in case of male patients with e.g. 77 ml blood per kg the dose has to be increased by about 18%. (Ref.)
– It was also found that Diflunisal influx into the cancer cells is mediated by albumin and is coupled to lactate efflux, which means that Diflunisal influx is coupled as an antiport to lactate efflux. This Diflunisal antiport is pH- and concentration-dependent and is ruled by the state of albumin loading with Diflunisal. The Diflunisal antiport can be measured as an accelerated lactate efflux. (Ref.)
– If Diflunisal is orally administered, in most cases the resorption does not occur ad libidum but only up to an amount which leads to a precise measurable concentration in blood of 250 μg/ml, i.e. the resorption of Diflunisal shows saturation behavior. 250 μg/ml corresponds to a 1.00 mM Diflunisal solution. This saturation concentration is reached at 50 mg/kg Diflunisal application. Even if 100 mg/kg Diflunisal is administered, 1.00 mM will not be exceeded. This is guaranteed when Diflunisal application is performed solely orally. It is an outstanding and remarkable feature of Diflunisal that when exclusively administered orally no overdosage can happen because of its resorption saturation behavior at 1.0 mM as outlined above. Therefore, therapy in principle even with a single high oral depot dose could be performed which, however, is not tolerable for most patients. (Ref.)

At high concentrations, non-steroidal anti-inflammatory drugs (NSAIDs) can target a number of other cellular processes. For example, they can induce apoptosis independently of cyclooxygenase 1 (COX1) and COX2. Nitric oxide-releasing aspirin can inhibit 5-lipoxygenase, reducing the production of leukotrienes. Specific NSAIDs can activate peroxisome proliferator-activated (PPAR) subtypes α, γ and δ. PPARδ has been shown to interact with the adenomatosis polyposis coli (APC)€“β-catenin signalling pathway that is of particular relevance for colorectal carcinogenesis. NSAIDs also inhibit nuclear factor-κB (NF-κB) signalling. Finally, they can impact the release of prostaglandins from cells through the multidrug-resistance protein 4 (MRP4). (Ref.)

Safety/Toxicity

All drugs used are approved to be used on humans and their profile is similar to that of Aspirin.

Side effects related to the therapy have been fatigue grade I (30%), nausea grade I (13,3%), tinnitus (25%), hypertension (2,5%), dyspnea (3,3%) and burning sensation in tumor areas (65%). http://meetinglibrary.asco.org/content/116352-132

May interact with Acetozolamide (Ref.)

If there is an overdose, NaBic solution IV will help to eliminate: http://c.ymcdn.com/sites/www.aavpt.org/resource/resmgr/imported/aspirin.pdf

Oral LD₅₀ in rat, mouse, and rabbit is 392 mg/kg, 439 mg/kg, and 603 mg/kg, respectively. Symptoms of overdose include drowsiness, nausea, vomiting, diarrhea, hyperventilation, tachycardia, sweating, tinnitus, disorientation, stupor, and coma. The lowest dose without the presence of other medicines which caused death was 15 grams. (Ref.)

Acetylsalicylic acid reduces the excretion of uric acid at a low dosage. In patients at risk this may trigger a gout attack. Ref

For interactions of ASA see the enclosed document (Valproic acid, Digoxin, Hypoglycemic drugs (antidiabetics): the blood sugar level may fall, etc.) Ref

Pharmacokinetics

Diflunisal, a fluorinated salicylate, exhibits analgesic, anti-inflammatory and antipyretic properties, and at high doses inhibits prostaglandin synthesis. It is well absorbed from the intestines and reaches peak plasma levels within 2-3 hours; steady state plasma levels are reached within 3-9 days on a regimen off 500 mg twice daily. Plasma Diflunisal is 99.83% protein bound and it is excreted mostly in the urine as a glucuronide. Diflunisal is generally better tolerated than aspirin and the most frequent adverse reactions are nausea, gastrointestinal discomfort and diarrhea. (Ref.)

In contrast to salicylic acid which has a plasma half-life of 2½ hours, the plasma half-life of diflunisal is 3 to 4 times longer (8 to 12 hours) (Ref.)

Pharmacokinetics and pharmacodynamics of IV ASA: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3964022/

Preparation & Administration

Preparation of IV will be discussed latter.

IV Administration:

• 3-5 weeks administration with daily i.v. infusions 4 days per week (e.g. Monday to Thursday)
• The daily IVs are Diflunisal + ASA or PAS
• Suggested daily combination is Diflu+ASA
• First administrate ASA during about one hour than one hour break and than administrate Diflu during about one hour and a half
• Suggested daily dose of Diflu & ASA:
  ASA: 42 mg/kg/day
  Diflu: 37 mg/kg/day
  
• Administrate via port – that is easier since during the administration via veins in the arm there may be some burning sensation.

Maximum ASA daily dose: 10 vials (5000 mg acetylsalicylic acid) Ref

The suggested administration protocol above is designed based on the (limited) info I have from people treated with Diflu and the published literature. Note that the patents published by prof. Krause suggest a bit different protocol:

IV and/or Oral administration from prof. Krause’s patents:

Oral protocol

“The most preferred dosage scheme is as follows (for a female patient with 65 ml blood per kg body weight, for other patients the dosage scheme can be adapted, if necessary):

	Time	Dose	Variation
	initial dose	about 35 mg/kg
	after about 12 hours	about 30 mg/kg
	after about 3 hours	about 6 mg/kg
	after about 3 hours	about 6 mg/kg	12 mg/kg
	after about 3 hours	about 6 mg/kg
	after about 3 hours	about 6 mg/kg	€‚0 mg/kg
	after about 12 hours	about 30 mg/kg
	after about 3 hours	about 6 mg/kg
	after about 3 hours	about 6 mg/kg	12 mg/kg
	after about 3 hours	about 6 mg/kg
	etc.

Of course, other dosage schemes are also possible, if it is ensured that the interstitial Diflunisal concentration is as disclosed above. Instead of the above mentioned 3 hour intervals four hour, five hour or six hour intervals can be used or 12 hour intervals can be used with adapting the dosage which is given after each interval. The dosage for each interval can also be adapted depending on the patient and in particular on the amount of blood per kg bodyweight of this patient as explained above, and such variations and adaptations are within the knowledge of a skilled person.” (Ref.)

IV protocol

“A suitable initial dose by parenteral, in particular intravenous, administration is from 30 mg/kg i.v. to 40 mg/kg i.v., e.g. about 35 mg/kg i.v., followed after about 12 hours by a dose from 25 mg/kg i.v. to 35 mg/kg i.v., e.g. about 30 mg/kg i.v. followed after about 12 hours by a dose from 25 mg/kg i.v. to 35 mg/kg i.v., e.g. about 30 mg/kg i.v. This dose is administered about every 12 hours.” (Ref.)

IV and Oral protocol

“A suitable combined oral and parenteral dosage scheme is:

• an initial dose from 30 to 40 mg/kg p.o, such as 35 mg/kg p.o,
• after about 12 hours from 25 to 35 mg/kg p.o, e.g. about 30 mg/kg p.o and in addition from 20 to 30 mg/kg i.v., e.g. about 25 mg/kg i.v.
• and then about every 24 hours a dose from 25 to 35 mg/kg p.o, e.g. about 30 mg/kg p.o and in addition a dose from 20 to 30 mg/kg i.v., such as about 25 mg/kg i.v.” (Ref.)

Buffering the stomach content enhances the absorption of diflunisal in man (Ref)

Source & Cost

Diflu can be ordered from western or Chinese chemical suppliers as powder. This should be used to prepare the IV according to the preparation method (to be indicated asap).
Alternatively, Diflu capsules can be found under the following names : Diflunisal, Artrodol, Diflusal, Fluniget, Artrodol, Dolocid, Donobid 250mg and 500mg.

Aspirin IV  can be found at German pharmacies 2.5g costs 47 euro, made by Bayer Vital GmbH

PAS IV can be found at German pharmacies and costs about 63 euro / vial, made by RIEMSER Pharma GmbH

Storage

Store at temperature between 15 and 30 degrees C

Synergists & Antagonists

Immunotherapies

Clinics Treating Patients with Diflunisal

Unifontis – a German expensive clinic lead by a good doctor, Prof. Drevs

Other relevant links:

Diflunisal for the treatment of cancer
Synergistic compositions for the selective control of tumor tissue
Medicaments for the selective treatment of tumour tissues

Ancient anti-inflammatory drug salicylic acid has cancer-fighting properties https://www.sciencedaily.com/releases/2016/05/160531182441.htm

Salicylate, diflunisal and their metabolites inhibit CBP/p300 and exhibit anticancer activity. http://www.ncbi.nlm.nih.gov/pubmed/27244239

Salicylate and acetylsalicylic acid are potent and widely used anti-inflammatory drugs. They are thought to exert their therapeutic effects through multiple mechanisms, including the inhibition of cyclo-oxygenases, modulation of NF-κB activity, and direct activation of AMPK. However, the full spectrum of their activities is incompletely understood. Here we show that salicylate specifically inhibits CBP and p300 lysine acetyltransferase activity in vitro by direct competition with acetyl-Coenzyme A at the catalytic site. We used a chemical structure-similarity search to identify another anti-inflammatory drug, diflunisal, that inhibits p300 more potently than salicylate. At concentrations attainable in human plasma after oral administration, both salicylate and diflunisal blocked the acetylation of lysine residues on histone and non-histone proteins in cells. Finally, we found that diflunisal suppressed the growth of p300-dependent leukemia cell lines expressing AML1-ETO fusion protein in vitro and in vivo. These results highlight a novel epigenetic regulatory mechanism of action for salicylate and derivative drugs.

Disclaimer:

This site is not designed to and does not provide medical advice, professional diagnosis, opinion, treatment or services to you or to any other individual. Through this site and linkages to other sites, I provide general information for educational purposes only. The information provided in this site, or through linkages to other sites, is not a substitute for medical or professional care, and you should not use the information in place of a visit, call consultation or the advice of your physician or other healthcare provider. I am not liable or responsible for any advice, course of treatment, diagnosis or any other information, services or product you obtain through this site. This is just my own personal opinion regarding what we have learned on this road.

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