PBI is dedicated to the development and commercialization of safe and therapeutically effective products. We strongly believe that the safety data obtained to date support further clinical use and evaluation of our products and support our assertion that the company’s products are safe and effective when used as directed.
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. Phoenix’s products do not contain plant material. Instead, they contain components of the plant material. The company 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, all the company’s products have been derived from NOEs, and those that have been evaluated in humans have been determined to be safe when used as directed.
In brief, thorough safety (toxicology) studies of PBI 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. Consider the following.
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.
PBI-05204 completed an extensive Phase I trial at the University of Texas M. D. Anderson Cancer Center. Because it was thought that this concentrated form of oleander extract had the potential to possibly produce cardiac arrythmias, every patient was required to undergo constant Holter monitoring, which is a method of constant recording of the heart’s EKG or electrical impulses. Upon completion (2011) of the three-year long Phase I trial with almost 30 patients, there was not a single incidence of cardiotoxicity even though oleandrin (cardiac glycoside) levels (as high as 8 ng/mL) were reached in the patients’ plasma that resulted in antiproliferative responses in tumor growth. Patients were, of course, not allowed onto the clinical trial if there were pre-existing cardiac health issues. A follow up Phase II trial was conducted in advanced pancreatic cancer patients who had failed to respond to conventional chemotherapy and radiotherapy regimens. As in the Phase I trial, no adverse cardiovascular related events were noted.
All of the safety data obtained to date for the above-mentioned products supports the conclusion that they can be safely administered to humans and animals when used as directed.
Please note that PBI neither condones nor recommends the consumption of Nerium oleander plant material nor the use of related homemade extracts due to the likelihood of toxicity.