Anvirzel® is a proprietary hot water extract of Nerium oleander that has been administered to thousands of patients for the treatment of malignant diseases since at least 1997. The extract has been well characterized and consists of specific plant polysaccharides as well as what is believed to be its most active ingredient, oleandrin. Oleandrin is a type of molecule known as a cardiac glycoside as are other molecules such as digoxin and digitoxin. Oleandrin has the ability to cross the blood brain barrier and once in the brain, it exhibits slow but complete clearance relative to systemic circulation clearance.
Anvirzel® has been shown to be selectively toxic to human malignant cells but not to human normal cells. Oleandrin binds to selected specific cellular tumor cell targets causing cellular downstream changes to certain signal transduction pathways, but not to healthy cells. Anvirzel® has undergone human clinical trials with very promising results, demonstrating activity against difficult to treat human cancers such as melanoma, prostate, and breast cancers as well as certain hematologic malignancies.
Anvirzel®, our oleander based product, contains oleandrin and is effective in the treatment of tumors. This use is species-specific and is correlated with Na, K-ATPase isoforms. Additionally, oleandrin raises the intracellular calcium level, releases cytochrome C from mitochondria, and induces apoptosis through a caspase-dependent pathway.
Also, oleandrin inhibits the release of tumor growth factor bFGF from tumors. bFGF has many tumor-proliferating effects including promoting angiogenesis.
Oleandrin was determined to block the activation of NF-kB, which in turn blocks the cell-survival function of NF-kB. In addition, a non-water-soluble fraction of oleander is able to produce oxygen free-radicals in tumor cells, which may contribute to tumor cell injury and death. Oleandrin, particularly when in the context of oleandrin and oleander extract, is able to cross the blood-brain-barrier.
Anvirzel® is selectively toxic to human malignant cells but not to human normal cells. Oleandrin binds to selected specific cellular tumor cell targets causing cellular downstream changes to certain signal transduction pathways, but not to healthy cells. The selective cytotoxicity against cancer cells is primarily due to the increased expression of the α3-isoform of the Na,K-ATPase enzyme in malignant cells. For example, as colon cells undergo a change from a normal phenotype to a malignant phenotype, they increase expression of the α3 subunit. This then makes the malignant cells unique targets for our products while sparing normal cells.
Our finding of the increased expression of the α3 subunit (in cancer cells) as compared to the α1 subunit (in healthy cells) is in fact the basis for the company’s findings. Ongoing and published research suggests that oleandrin/Anvirzel have antiviral activity. Development continues as the product is nontoxic to normal cells and exhibits multiple antitumor activities such as inducing apoptosis, reducing molecular mechanisms of cell survival, and inhibiting tumor-promoting factor bFGF-2.
Can I combine Anvirzel® with other treatments?
Anvirzel® has been used successfully as a combination therapy with various chemotherapeutic agents, radiotherapy and other alternative treatments.
Anvirzel® and its oleandrin content have anticancer properties that are distinctly different from current standard of care drugs and have shown a strong ability to augment efficacy as well as safety of conventional anticancer treatment. As such, the use of Anvirzel and similar extracts from Nerium oleander are useful when combined with standard of care therapies.
Recent studies have shown a strong effect of oleandrin to inhibit human brain cancer (glioblastoma) in nude mice when combined with radiotherapy (manuscript accepted for publication, March, 2022)
Anvirzel® was approved for use in a Phase I clinical trial completed at Cleveland Clinic. This trial was conducted to assess relative safety of the product for its use in patients with cancer. Patients were randomized to receive this agent by intramuscular injection at doses of 0.1, 0.2, 0.4 ml/m2/day with subsequent patients receiving 0.8 or 1.2 ml/m2/day sequentially. Eighteen patients were enrolled and completed at least one treatment cycle of three weeks. Most patients developed mild injection site pain (78%). Other toxicities included fatigue, nausea, and dyspnea (labored breathing). At completion of the study, there was no evidence of cardiotoxicity, and traditional dose limiting toxicities were not observed. The maximum tolerated dose (MTD) was defined by injection volume as 0.8 ml/m2/day. The study concluded that Anvirzel® can be safely administered at doses up to 1.2 ml/m2/day, with the amount administered intramuscularly limited by volume. The recommended Phase II dose level was 0.8 ml/m2/day.
There are substantial compositional differences between plant material and extracts of that material, because extraction processes are designed to separate desirable compounds, which end up in the extract, from undesirable compounds, which do not end up in the extract. As a result, the plant material and its extracts exhibit substantially different levels of toxicity and therapeutic efficacy. Our products do not contain plant material. Instead, they contain components of the plant material. Salud Integral has developed various extraction processes that provide products with different compositional profiles.
One of the active ingredients in some of the company’s products is oleandrin, which is classified as a cardiac glycoside (CG). One of the key functions of a CG is to inhibit the transmembrane enzyme Na,K‑ATPase, which is responsible for regulating the balance between sodium ions and potassium ions across a cell wall. The enzyme transfers three sodium ions to the cell’s exterior and two potassium ions to the cell’s interior. By inhibiting the enzyme, a CG causes the build-up of sodium ions in the cell’s interior with a consequent increase in calcium ions as well that facilitates cardiac muscle contractility.
CGs are not foreign to the human body. In fact, ouabain is a naturally occurring CG found in humans, and it is not harmful to us in the small concentrations at which it asserts it biological activity.
The extent to which the CG inhibits the Na,K‑ATPase enzyme is determined by the dose of CG administered. At low doses, a CG can exhibit a range of therapeutic activities, but at very high doses, a CG may be toxic. This dosing range is called the “therapeutic window”. In the case of the company’s products, the doses required for efficacy are below the toxic dose. Of importance are recent published articles indicating antiviral effects of oleandrin and extracts containing them. The concentrations of oleandrin required to produce prophylactic as well as therapeutic antiviral effects have been shown to be even less than that necessary for anticancer effects.
Because CGs represent a structurally diverse class of compounds, they vary widely in their relative biological activities, so their respective therapeutic windows are not the same. This means that the therapeutic window of one CG will be different than the therapeutic window of another CG. Even so, safe and effective therapies employing CGs are well known.
For example, ouabain is approved for use in France and Germany for treating heart failure.
Digoxin, one of the oldest medications in the field of cardiotherapy, is a CG extracted from the Digitalis lanata (foxglove) plant, which is well-recognized as a “poisonous” plant. Digoxin exhibits severe toxicity in animals and humans when not used as directed. Even so, Dr. William Withering was the first to successfully use extracts of foxglove for treatment of his patients with ‘dropsy’ (congestive heart failure). Following determination of its safe-dosing levels, Digoxin is now widely prescribed for the treatment of various heart conditions such as atrial fibrillation, atrial flutter, and heart failure. Digoxin is even on the WHO’s List of Essential Medicines, and in 2019 it was the most commonly prescribed medication in the U.S. Digoxin is administered by mouth or by injection into a vein.
Digitoxin is another digitalis-derived CG, which is prescribed for the treatment of heart failure.
It is evident that plant derived CGs have gained wide acceptance in the pharmaceutical industry, because they can be safely administered and are therapeutically effective when used as directed. It is only when CGs are administered at high doses, those above the therapeutic window, that adverse events and toxicity occur.
Oleandrin is another plant derived CG. It is found in extracts obtained from Nerium species plants, in particular Nerium oleander. Even though they can be toxic when used improperly, Nerium oleander extracts (NOEs) have been used safely in traditional medicines for centuries, as long as they are used as directed. To date, Salud Integral has had no reports of toxicity from patients using any of our oleander derived products.
In brief, thorough safety (toxicology) studies of our products and PBI nerium oleander based related products have been conducted in rodents (mice and rats), canines, hamsters, and/or monkeys, all to better understand the safe dose levels and effects of our products and to meet stringent FDA requirements before any product can be introduced into humans. Safety studies in animals have been conducted for ANVIRZEL®, PBI-05204, PBI-06150, and PBI-07343, all of which were found to have safe dosing ranges in animals.
More specifically, the company has developed packages of in vitro data, in vivo animal data, and in vivo human data demonstrating the safety and anticancer activity of NOEs. The in vitro and animal data were accepted by the FDA when the agency approved evaluation of two of the company’s products (PBI-05204 and ANVIRZEL®) for use in human clinical trials. Confirmation of safe use of PBI-05204 and ANVIRZEL® in humans was obtained from those clinical trials. The lack of significant cardiotoxicities within these trials points to the safe use (with appropriate guidelines) of these agents for diseases in addition to congestive heart failure.
All of the safety data obtained to date for our oleander based products supports the conclusion that they can be safely administered to humans and animals when used as directed.
What are the observed Side Effects?
No negative side effects have been reported by clinicians and patients undergoing Anvirzel® therapy. The “Common Thread” running through almost all of the clinical records of the patient population using ANVIRZEL® has been the marked improvement in the “quality of life” of those patients. This includes, but is not limited to, homeostasis, marked improvement in pain management with elimination of or marked reduction in use of analgesics, positive response to antibiotics, increased appetite with concomitant weight gain, and increase in energy with reduction of fatigue.
How do I take Anvirzel®?
Place the Anvirzel Tablet under your tongue and wait until the tablet is fully dissolved. Once the tablet is dissolved you may swallow the fluid mixed with your saliva.
How do I store unused boxes of Anvirzel®?
The container and storage conditions need to be intact without exposing it to long periods of sunlight. Our product is lyophilized in a high-quality pharmaceutical form and does not contain water. If you store our product as we mention above, it will keep its properties for up to 3 years of shelf life. Store the unused boxes of Anvirzel® tablets in a cool, dry place at a temperature below 30°C / 86°F. Do not expose to direct sunlight.
Can I use Anvirzel® if I have a history of heart disease, myocardial infarction, or ventricular cardiac arrhythmias?
We recommend that you consult a physician before using Anvirzel® if you have a history of heart disease, myocardial infarction, or ventricular cardiac arrhythmias. This is because Anvirzel® can enhance the effects of digoxin, a digitalis heart medication.
Are there any contraindications when taking Anvirzel®?
We do not recommend the use of Anvirzel® if you are currently taking any digitalis heart medications, such as digoxin. If you are taking digoxin, please consult your physician before taking Anvirzel®.