Each of my discoveries has an interesting story behind it. Here I share the story behind some of my discoveries.
Dipyridamole Eye Drops for Dry Eye Disease
I had been working for more than a decade with researchers at Penn State University on various new uses for the opiate antagonist known as naltrexone. Research showed that it was effective in treating diabetic-related dry eye in rats when combined with the antibiotic Vigamox® (moxifloxacin). During the commercial development of this invention I discovered that naltrexone without Vigamox® had a species-specific effect in treating certain types of human dry eye.
Testing a Different Theory
My colleagues postulated a theory of how this drug was working for dry eye. However, in my opinion the theory didn’t match the known behavior of this drug at the low doses being used. To clarify which theory was correct, I looked for an alternative drug to test; one that based on its related mode of action at very low dose levels would result in similar response patterns. I had been working with one such drug, dipyridamole, in cancer patients. Dipyridamole had been in use already for close to 60 years and there was a huge body of literature about its various mechanisms of action in non-eye disorders.
Following my work, the head of an oncology department of a large hospital was currently prescribing naltrexone drops for cancer-related dry eye patients with reasonably good success. Seeking to improve the results even further, I proposed he try these new dipyridamole eye drops instead. Having ascertained the safety of the dipyridamole eye drops (via data from animal models and self-testing) we further analyzed and optimized the use and dosage levels of dipyridamole.
Effective Relief for Dry Eye
Subsequently some of the patients using the naltrexone drops switched to dipyridamole. In line with my theory, they reported a much greater beneficial effect and were able to discontinue the use of their eye lubricating drops. This was the birth of a breakthrough discovery for treating dry eye. As the quantity of data and evidential experience from patients using these drops grew, I made some surprising discoveries of additional benefits.
Dipyridamole Eye Drops for Pterygium
In the early days I was completely unfamiliar with the eye diseases known as pterygium or pinguecula. In fact, when I first saw these names I had no idea how to even pronounce them.
Not long after my discovery of dipyridamole’s use for dry eye, I was approached by a patient suffering from a pterygium. Her eye doctor, who had diagnosed it, offered her steroid eye drops. She had done some reading on the side effects and risks and wanted to avoid these. I had previously assisted her daughter’s successful fight against an aggressive cancer. Since then I had become the first port of call for any healthcare issue that challenged her family.
She described her symptoms to me and they were typical of dry eye. Indeed, I found that these were common symptoms experienced by most pterygium patients. I suggested she try the dipyridamole drops as they might help.
Surprisingly, the response was rapid and her dry eye symptoms quickly abated as she continued to use the drops. She would regularly email me photos of her eye and I soon noticed that the inflammation of the pterygium appeared to be rapidly receding. After a year of therapy, her pterygium had almost disappeared.
This was a huge leap forward in the treatment of pterygium, a disorder that afflicts up to 24% of the population in equatorial countries, and for which surgery (with poor success rates) has traditionally been the only treatment option.
Fast-acting low-dose Sildenafil Citrate (Viagra®)
Much of my work involves finding solutions for patients when the conventional approach has nothing further to offer. In some instances, these patients in advanced stages of disease cannot tolerate drugs orally. In such situations I have to devise ways of delivering drugs to them by alternative means. Since the intravenous route is sometimes impracticable or the drug may not be available in that form, a transdermal (through the skin) method is preferable.
To achieve effective transport through the skin, the drug must be below a certain molecular size and it must be mixed with a substance that can transport the drug rapidly through the skin. We have a few choices of substances that do this, but typically they work well only with drugs that have been solubilized in water.
One such drug for which I sought a transdermal delivery method was sildenafil citrate (commonly marketed as Viagra®). This drug, originally developed for treating pulmonary hypertension, was subsequently found to treat erectile dysfunction for which it became a bestseller. Since its discovery, about 30 off-label uses have been found for this drug. These include treating wounds, stroke, Raynaud’s phenomenon, altitude sickness – and even (a non-medical use) to keep cut flowers fresh!
Improving a Popular Drug
The challenge I faced was that sildenafil citrate has very poor solubility in water and even less in alcohol. This made its transdermal use challenging.
Together, a pharmacist and I spent long hours experimenting with different solubility enhancers until we discovered a unique method to increase sildenafil citrate’s solubility by 10 to 20 times. We then figured that the increased solubility should permit its oral use at a much lower dose and would help overcome Viagra’s incomplete absorption rate (of ~ 42%) and reduce its side effects.
The urologists we work with were happy to try this new fast-acting low-dose formulation in their patients. Their findings: patients who had previously been using Viagra managed to achieve the same effect with half the dose in half the time.
Armed with this surprising outcome, we set out to verify that the molecule (sildenafil citrate) does not change in any way while in the dissolved state we created. We subjected the new solution to Nuclear Magnetic Resonance (NMR) testing, which showed that the molecule remained identical to its powdered form.
Gallium for Stopping Wound Bleeding
Gallium nitrate is a mineral in liquid form approved for use in the treatment of hypercalcemia in cancer patients. Nearly 10 years of close observation had demonstrated the effectiveness of its topical form for successful pain relief in cancer patients with painful bone metastases. I was intrigued by these results and as I was experimenting with various concentrations and dilution methods I had many bottles of gallium around my lab.
One day I cut my thumb very badly while attempting to lift the cover of a can of tuna. The cut was very deep and bleeding profusely. Being the curious experimenter type and wanting to avoid a trip to the emergency room for stitches, I turned to the bottle of gallium I had on my desk. I recalled some reported side effects from its topical use. Could gallium be useful in stopping the bleeding?
An Accidental Discovery
I poured some gallium into a cup and placed my finger in it. Instantly the blood started to coagulate, turn brown and the pain stopped. As I knew that gallium had well-known anti-infective properties as well as wound-healing properties, I kept the finger submerged for about 5 – 10 minutes. The wound appeared to have closed and the process saved me a trip to the ER. The pain had been totally relieved and I dressed it with a plain bandage.
From then on, whenever anyone in my family sustained a serious cut I immediately applied gallium to great effect. One time my daughter fell sustaining a deep gash in her forehead which bled profusely. I applied a gallium-moistened gauze and the bleeding stopped. I then took her to a doctor who became very annoyed. He demanded to know what I had done because he had had to work hard to scrape off the clotted blood in order to be able to clean the wound. Its effectiveness as a coagulant made me realize that gallium had some exciting potential to explore.
In order to accurately measure gallium’s effects, a physician friend and I volunteered as experimental subjects. This physician, a surgeon, used a scalpel to create two cuts on his forearm and on mine. We then applied gallium to one of the wounds on each of us and used a stopwatch to time how quickly the bleeding stopped. We noted a significant reduction of bleeding time by 75%. We published these findings in a medical journal 20111.
How does it Work?
The reduction in bleeding time was exciting, but we still needed to understand how gallium was achieving this effect. This blood clotting property had never been reported previously in the literature. At that time I was working on other projects with my colleagues at the Hospital of Lille, France, and I asked if they could perform some lab testing to uncover the mechanism of action.
The first call I received from the researcher in France was very exciting. “It turns blood into butter”, she said, but still didn’t have any information on the mechanism. Her next report was very subdued. She had performed specialized testing and found that gallium didn’t have any effect on coagulation. To the contrary, it may even have inhibited it.
In fact, this was exciting news as I knew that a serious drawback of other hemostasis products on the market was their ability to cause internal clotting if they were absorbed into the bloodstream. Could we have stumbled onto a solution that avoided this great risk? Our experiments continued and we finally established that while gallium does not inhibit coagulation directly, it leads to flocculation of a blood clotting protein known as fibrinogen. The separated fibrinogen gathers and forms a clot leading to the cessation of bleeding in external wounds. The results of our research were finally published in 2013 in the journal BioMetals2.
Testing Reveals Hidden Benefits
However, another interesting story happened during the testing process. The tests in France were being performed on the spare blood of patients who had been subjected to routine blood tests. One day there was no spare blood in the lab, so one of the researchers volunteered to draw blood for our experiments. Part of the experimental process involved testing for fibrinogen levels before and after the addition of gallium. Surprisingly, this researcher’s pre-gallium fibrinogen level was found to be extremely high.
Elevated fibrinogen is a nonspecific marker for various diseases and an extremely high level usually reflects the presence of a serious condition. This researcher was immediately subjected to a whole-body CT scan which found a 4 cm stomach tumor. One of the other team members, a surgeon, operated and removed it. The pathology showed it to be Castleman’s disease, a rare cancer-like condition.
We had inadvertently discovered that elevated fibrinogen was a way to diagnose Castleman’s disease even before it had spread – something that had never previously been known. This case report was published in the Journal of Clinical and Experimental Hematopathology in 20143.
Low Dose Naltrexone (LDN) for Crohn’s Disease
I discovered the potential benefit of Low Dose Naltrexone’s (LDN) for the treatment of Crohn’s disease through my readings on the effect of endorphins (endogenous opiates) on intestinal function. Crohn’s disease (as well as other gastrointestinal disorders) has a relatively high placebo response rate. The knowledge that placebo effects are mediated via endorphin production and that the placebo response can be reversed through administration of an opiate-antagonist (such as naltrexone) triggered my interest in the role that endorphins play in health and disease.
The Role of Endorphins
The clear benefits of endorphins led me to explore various ideas of how we could elevate endorphin levels in Crohn’s disease patients. In the early 1980’s, Dr. Ian Zagon and Dr. Pat McLaughlin at Hershey Medical Center discovered a novel method for increasing endorphin production through the administration of very low doses of opiate antagonists. This creates what is called a temporary opiate system blockade, leading to a rebound effect in opiate production and utilization.
By 2002, I had sufficient anecdotal evidence of success from patients who had been trialing this therapy to propose a formal clinical trial in conjunction with Drs. Zagon and McLaughlin. They invited Dr. Jill Smith, then a professor of gastroenterology at Hershey Medical Center, to join as leader of the clinical trial. Our first pilot trial was funded by Penn State University. Following its successful conclusion, the NIH and Broad Foundation funded further advanced trials.
Our study was the first-ever clinical trial on low-dose-naltrexone (LDN) and this established the therapy’s safety. This quickly led to other researchers initiating trials for other autoimmune diseases and eventually for cancer. The clinical studies of LDN caused a rapid expansion of its acceptance and use by doctors worldwide, on an off-label basis. Current estimates suggest that there are over 300,000 users of LDN worldwide.
I launched LDNscience.org in 2010 to disseminate credible scientific information about the use of LDN and counteract the myths and misinformation about its use. LDNscience.org has been successfully serving close to 100,000 visitors annually.
Rituximab for Treating Metastatic Prostate Cancer
This breakthrough scientific discovery started with a very unscientific gut feeling. I was helping a patient with metastatic prostate cancer whose disease presented in an unusual manner. He had diffuse lymphatic involvement coupled with very high PSA levels – in the thousands of nanograms per milliliter of blood (ng/mL). His disease would respond to various therapies and his PSA would drop all the way down to single digits. The medical literature contains very few reports of prostate cancer behaving in such a manner.
Just prior to this, I had witnessed a dramatic response in a lymphoma patient for whom I had assisted in obtaining rituximab as monotherapy. Although the use of rituximab as a single agent (without chemotherapy) wasn’t an established protocol in the treatment of his disease, his doctor agreed to do so because of the patient’s advanced age (over 80), his excellent quality of life (he was an orthopedic physician working full time) and his insistence on avoiding chemotherapy. Treatment with rituximab triggered a rapid reduction in lymph node swelling and resolved the lung problems caused by the chronic blockage of pulmonary circulation that had been plaguing him.
A Hunch and an Exciting Discovery
I had a gut feeling that this drug, rituximab, might help the prostate cancer patient. It seemed safe enough as a single therapy. Indeed, some countries were already using it as a treatment for mononucleosis with no apparent toxicity. The monthly cost of this medication exceeded $15,000, but cost was not an issue for this patient.
Needless to say, the patient’s oncologist wasn’t willing to prescribe this drug without some scientific basis, which I didn’t have. Fortunately, one of the patient’s lymph nodes had been removed a couple of years earlier for pathologic analysis. We obtained the lymph node and tested it at St. George’s University Hospital (in London) for the presence of CD20 – the molecular target of rituximab.
CD20 is an antigen associated with B cells that plays an important role in the immune system response. Certain illnesses lead to a potentially harmful spike in CD20. For this reason CD20 is often used as a test indicator for the presence of particular cancers. Rituximab targets and destroys those B cells that are overloaded with CD20 proteins.
Surprisingly, the lymph nodes tested positive for CD20. To the best of our knowledge, this was the first time that CD20 had been identified in prostate cancer tissue.
Based on these compelling findings the British National Health Service agreed to pay for rituximab therapy. By this time the patient’s situation was deteriorating. Chemotherapy had been discontinued because it was no longer being effective. His PSA was rising by the hundreds each week. Rituximab was started as monotherapy and not only arrested the rise of PSA, but actually led to a significant decline.
Unfortunately, the patient then fractured a vertebra and subsequently died from acidosis induced by pain medication overdose. However, the findings of the breakthrough case were published in 2014 in the medical journal Investigational New Drugs and have since generated interest in performing a clinical trial of rituximab for prostate cancer with a planned clinical trial in the US.