Cancer research and cannabinoids

Cannabinoids: a review on pre-clinical studies on anti-angiogenesis, apoptosis and reduction of MMP-2 expression inhibiting cancer cell growth

Virginia Thornley, M.D., Neurologist, Epileptologist

June 24, 2018

@VThornleyMD

https://neurologybuzz.com/

Introduction

The surge of recognition of the medical significance of the cannabis sativa can no longer be ignored. Frustrated with the futility of current pharmaceutic agents, their associated side effects and costs, there is a growing tendency for more natriceutic measures of therapy. Shunned by physicians and by the public, there is a growing clamoring of medical marijuana advocates for its use. There is only a small proportion of physicians are qualified to recommend this agent. Prescribing is federally illegal as it is still classified as category I drug. In the state of Florida alone, as of June 2018, out of 75,000 licensed physicians, only 2100 are qualified to recommend it or 2%. Long known for the stigma of its recreational value, its foothold in the medical community is slow-going. Most of the public associates the plant with unseemly, clandestine purposes. The federal law against it stands steadfast, with legislation moving at a molasses pace, even while recognized by state laws. These variables account for the great difficulty procuring this agent which is not only organic and all natural but medical in nature.

However, there is great interest in this plant. The pre-clinical data shows promise but more larger clinical trials are still needed. It seems to be far reaching in its effects and because it is still not well-studied, the vast number of purposes is still largely unknown.

Interest turns towards any anti-neoplastic application it might have. Pre-clinical data has shown some promise, although it may not always translate into human results. The scientific data points towards some benefits in the neoplastic process.

F51D8562-3F50-47FA-8595-1CE460AA6DD9

Endocannabinoid system

In an overview of the endocannabinoid system, there are 2 cannabinoid receptors, CB1 and CB2. The CB1 receptor is abundant in the nervous system and found to a lesser extent in other systems. It is through this receptor that psychoactive properties are activated. The CB2 receptor is found largely in the immune system. Anandamide interacts with the CB1 receptor, of which delta-9-tetrahydrocannabnol is a pharmacomimetic. While 2-AG or di-arachidonoylglycerol is a low affinity agonist at the CB1 receptor. Cannabidiol (CBD)is a mimetic of 2-AG, where 100 times the amount of CBD is needed to get the same effect as THC. It has a full ligand effect on the CB2 receptor. The CB1 receptor is a G-protein coupled receptor. Cannabidiol interacts with the TPRV transient receptor potential channel and the GPR or G-protein receptor family. Expression of the cannabinoid receptors are most notable in areas engaged with memory, motor, learning, emotions and endocrine functions.

Endocannabinoids and the role in cancer

The beneficial effects of cannabinoids on symptoms pertaining to neoplasms such as anorexia, nausea and pain are well-known. Investigations turn towards any effect on the actual neoplastic process.

An upregulation of CB receptors are found in high volume in cancerous processes. The enzymes involved are also at high levels. This suggests that the endocannabinoid system may play a role in the neoplastic process. The frequency of the receptors and amount of enzymes may correlate with the aggressiveness of the type of cancer. This suggests that the endocannabinoid system may be revved up and play a role in promoting a pro-tumor environment.

Conversely, there are studies suggesting that activation of the cannabinoid system may be anti-tumorigenic. Reduction of tumor growth was observed with a  reduction in the endocannabinoid degrading enzymes(1).

While there are some inconsistencies, overall, the anti-tumorigenic effects appear to be better demonstrated in pre-clinical studies.

Effect on tumor cells

Overall, there are more studies that cannabinoids including phytocannabinoids such as tetrahydrocannabinol and cannabidiol and synthetic cannabinoids such as JWH-017 show anti-tumorigenic effects.

In one study, the CB1 receptors were found to inhibit the anti-metastatic nature of the K562 cell line which acts as a chronic myelogenous leukemia model in the study (2).

In glioblastoma multiforme tumors, CB1 and CB2 receptors are both expressed. Altered expressions of the receptors were thought to correlate with the manifestation of gliomas and glioblastoma multiforme. Cannabinoids are thought to manifest anti-proliferative activity against tumor cells by 2 mechanisms: anti-neogenesis of vasculature and promotion of apoptosis (3). In one study of glioma stem cell-like cells from glioma cell lines and glioblastoma multiforme biopsies, there was demonstration of the presence of CB1 and CB2 receptors. CB receptor activation changed the gene expression that controlled the stem cell multiplication and differentiation. in addition, cannabinoids were found to reduce cells with the biomarker nestin which is a neuroepithelial cell progenitor. Cannabinoid treated stem like cells resulted in more differentiation and reduced expression of nestin which promotes glioma formation (3).

42717C61-E774-4D0C-A2EF-214A058AD1F5

Cannabinoids were found to reduce angiogenesis by inhibiting the migration of vascular endothelial cells and by stopping the expression of MMP and proangiogenic factor in neoplastic cells (4). By preventing the increased vasculature cell migration, tumor growth is suppressed. With cannabinoids selectively acting on tumor cells, apoptosis is rendered resulting further in the blocking the growth of cancer cells resulting in the reduction in the proliferation of cancer cells (4). This study is significant because cannabinoids might be developed to achieve effect on reducing proliferation of tumor cells.

In a significant mouse model study, cannabinoids were found to reduce the activity of metalloproteinase matrix in glioma like cells. C6.9 and C6.4 glioma cell lines were used which are cannabinoid models showing cannabinoid responsive and resistant responses. Biopsy samples of 2 patients with multiforme glioblastoma were used. The cells were treated with tetrahydrocannabinol, JWH-133 a synthetic cannabinoid with CB2 receptor agonist effects and fumonisin.  MMP was measured. The C6.9 cell line was found to have less tumor cell growth and less MMP-2 expression found on western blot using SDS-PAGE when treated with cannabinoids. It selectively reduced MMP-2, other MMP’s remained the same level. In C6.4 cell lines, tumor growth and level of MMP-2 were not affected. The study demonstrates that cannabinoids inhibit tumor cell growth and lowers MMP-2. MMP-2 is expressed in many different cancer lines especially aggressive activity. While the tumor generation is more complex than this, the study adds significant information about tumor genesis and a role of cannabinoids in suppressing cancer growth (5).

In summary

Cannabinoids can affect the aggressiveness of tumors by inhibiting the vascular neogenesis. In addition in the animal model for gliomas, it is demonstrated to suppress cancer cell growth and the expression of MMP-2 which is associated with many neoplastic cell lines. More studies are needed as the neoplastic process is complex. In addition, pre-clinical studies need to be translated into human studies.

References

1.Śledziński, P., Zeyland, J., Słomski, R., Nowak., A.  The current state and future perspectives of cannabinoids in cancer biology. Cancer Biology. 2018; 7(30):765-775

2, Gholizadeh, F., Gharehmani, M.H., Aliebrahimi, S., Shadboorestan, A., Ostad, S.N.  Assessment of cannabinoids agonist and antagonist in invasion potential of K562 cancer cells. Iran Biomed. 2018  (epub ahead of print)

3. McAllister SD, Soroceanu L, Desprez P-Y. The antitumor activity of plant-derived non-psychoactive cannabinoids. Journal of neuroimmune pharmacology : the official journal of the Society on NeuroImmune Pharmacology. 2015;10(2):255-267. doi:10.1007/s11481-015-9608-y.

4. Blazquez, C., Casanova, M.L., Planas, A., del Pulgar, T.G., Villanueva, C., Fernandez-Acenero, M.J., Aragones, J., Huffman, J.W., Jorcano, J.L., Guzman, M. Inhibition of tumor angiogenesis by cannabinoids. FASEB J. 2003, Jan., 17(3):529-531

5. Blazquez, C., Salazar, M., Carracedo, A., Lorente, M., Egia, A., Gonzalez-Feria, L., Haro, A., Velasco, G., Guzman, M. Cannabinoids inihibit glioma cell invasion by down regulating matrix metalloproteinase-2 expression. Neuropharmacology. 2008, Jan. 54(1):235-243

Standard
Uncategorized

2032: A brave new medical world, predictions of the future

Virginia Thornley, M.D., Neurologist, Epileptologist

@VThornleyMD

https://neurologybuzz.com/
June 23, 2018

 

Sometime in the not too distant future, I come up to the front desk otherwise known as the receiving hub. I place my face on the pad where a laser scans the back of my retinas to pull up my information. As my information data is retrieved from the master chip after a few seconds.

As my records are processed through the data processing machine I sit in the laboratory seat where Robot series 2000 comes out. A new model replaces it in a week. It places sensors on my arm where I am punctured with 100% accuracy and automatically the results are processed in a series of pings. Series 2000 informs me in a prerecorded voice “your health care coordinator will be with you in a second.” It beeps while it takes my data from my wearable technology recording my heart rate, rhythm, respiratory rates and blood pressure.

I wait 5 seconds, irritated. This service is unacceptable I will be automating my complaint to the information receiving center. The health care coordinator comes, a new artificial intelligence device telling me everything is good projecting my data in the air with green lighting so I can see. “There are no neoplastic processes. You may continue your genetic treatments,” it says.

Medical cannabis farms quickly skyrocket in value once it is legalized. The people of the land quickly find its amazing ability to cure everything. This is truly a miracle drug everybody has not anticipated, hidden for so many years under stigma and downplay. It quickly develops its potential eradicating seizures, headaches, chronic pain, ADHD, autism, psychosis, inflammation, spasms and at high doses even cures cancer. Those who were able to get a license before the usual regulatory parties come in quickly become billionaires. Farm owners have an increasingly difficult time obtaining licenses to open a nursery as bureaucracy and the exorbitant fees weigh down the application process.

B1F55FBA-970D-4B7D-B96C-BFF117A17DC0

However, chagrined and panicked, business ranks cannot deal with this. Genetic treatments are quickly advertised as the foremost treatment which nobody can afford. Premiums are now $5500 per person before insurance kicks in. Medical marijuana is once again run out of business and once again placed under prohibition for the next 100 years until the next wave of revolutionists rescue it from its slumber.

Disenchanted by the changes in medicine, some doctors start to retire by age 35. The smart ones strike gold when bitcoin and ethereum blow up, as investors cash in. Inital coin offerings have exploded into a huge business. Disenfranchised doctors sick of the way healthcare has turned for the worse open real estate empires or wellness businesses. Physicians are being stealthily accused of having slips in care in order to be placed on the chopping block.

By 2022,  extenders assume 75% of healthcare authority and no longer require supervision by law. They take care of patients and are therefore, called doctors but because they are not medical doctors they are immune from liability.  Back in 2018, they had comprised 25% of healthcare workers in rural counties. They are a huge boon to the corporates because they are paid half the wages of doctors but do essentially the same thing with less training. It’s a win-win situation for corporate greed and extenders who want autonomy without having to pay the price.

These are the new doctor practitioners. The terminology is a bit confusing to patients but it is of no matter because everybody gets to be called doctor now. With this newfound freedom, these new breeds join together and unionize, setting up shop accepting subsidies from insurance companies. The complex cases are left for the brave remaining doctors of traditional medicine. “You are all on the same team you are all managing patients, therefore, all physician doctors,” corporate management says.

Overburdened with 65 complicated cases a day, malpractice cases easily abound fleecing the remaining steadfast medical physicians.

Medical physicians are slowly and quietly replaced by trainees with now only a 6 hour certification requirement under their belt while they shadow medical physicians for a week and released to the unsuspecting patients. Unbeknownst to the medical doctors they have been training their replacements. Medical doctors slowly release all their power, as it has been quietly and slowly stripped during the past few decades. Burdened by burgeoning work requirements, they have no idea what strikes.

0C2F7A6B-0F89-45B7-9F34-43C9E9C26B98

Then, the corporate heads stop even with the pretense. On National Health Transformation Day, those medical physicians remaining receive pink slips from those that they trained and supervised. How could this be?

By 2028, it is a complete takeover with a few MD’s remaining in genetic research which becomes a trillion dollar industry replacing expensive medications with even more expensive genetic treatments. They are now called genomic project leaders, not even in capitalized letters, to avoid any confusion with the practicing doctors who used to be known as extenders. Basically anybody in contact with a patient is now called doctor just as teams all get trophies there are no losers, no hierarchy and feelings are not hurt.

By 2030, even these doctor practioners or whatever the politically correct term is for extenders become too expensive. In the end, there is a monopoly of healthcare controlled by a single entity. Artificial intelligence overtakes all surgeries and including entering information, gathering blood supplies, obtaining samples, biopsies, everything. Healthcare is more efficient and costlier than ever. Surgery is usurped  by employment of stem cell therapies. Data is entered in a master computer data program and diagnoses are never inaccurate. Medical treatment is now either replacement of genes or stem cell treatment. Pills are unheard of. By now, all of the workers’ wages are devoted entirely to a single care entity. Housing and food is universal, sterile and factory-like in order to contain cost.

Even the doctor replacers are replaced. AI is developed at rapid speeds. The replacements become obsolete. Even the powerful NP and PA unions could not protect them.

There are now 2 classes of people, the masses who can no longer afford healthcare and are now dependent on another system to sustain them and the elitist business class who now controls health, business and the laws of the land.

This is 2032.

Standard
fibromyalgia

Medical marijuana in fibromyalgia: molecular mechanisms and small randomized controlled trials

Virginia Thornley, M.D., Neurologist, Epileptologist

@VThornleyMD

June 17, 2018

Introduction

Fibromyalgia used to be  a condition denoting excessive pain and was previously questionable as there was no testing that could prove or disprove it. Now, the current thought is that it is attributed to hypersensitivity of the nervous system to pain impulses resulting in multiple points of pain in the body.

Endocannabinoid system in pain modulation

The endocannabinoid system is a major chemical neurotransmitter system that has only come to light as to physiology in the last 20 years. The CB1 receptor is found predominantly in the nervous system on which the endogenous endocannabinoid anandamide exerts its effects. The CB2 receptor is found mostly in the immune system on which 2-Arachidonoylglycerol acts. In the nervous system, cannabinoid receptors are seen in the periaqueductal gray area, ventromedial medulla and dorsal horn of the spinal cord which are areas where pain transmission takes place. This suggests that endocannabinoids play a major role in modulation of pain and can impact pain control through manipulation of this system.

Anandamide and and 2-Arachidonoylglycerol are synthesized on demand. It is released immediately after production. 2-AG is formed from a 2 step process. Anandamide has a low affinity to the TPRV1 receptor (2).

1,2-diacylglycerol (DAG) is  a precursor or 2-AG which is formed by hydrolysis of membrane phosphoinositides. DAG is hydrolyzed by 2-AG hydrolase to form 2-AG. 2-AG may be stimulated by activation of G protein receptor such as glutamate receptors. It activates both CB1 and CB2 receptors. Cannabidiol which is found in the cannabis sativa plant is a natural mimetic of 2-AG. Endogenous 2-AG is found 170 times more than Anandamide in the brain. Exogenous 2-AG suppresses nociceptive stimulus (2). 2-AG activity is potentiated with natural 2-acylglycerols which enhances the effects which does not happen when used alone. This is an entourage effect found in the brain where the combination of substances give a combined resulting effect which does not occur if used alone (2).

Mechanisms in pain modulation

Cannabinoids were found to reduce nociceptive transmission at the level of the pain c-fiber responses in the spinal dorsal horn.

B1F55FBA-970D-4B7D-B96C-BFF117A17DC0

Randomized controlled trial in fibromyalgia

In one study of 40 patients in a randomized controlled clinical trial, nabilone which is a synthetic cannabinoid was given over a 4 week period. Measures that were evaluated included the visual analog scale for primary outcome and for secondary outcome measure, tender points, secondary outcome measure, Fibromyalgia Impact Questionnaire (FIQ) at weeks 2 and 4 were used. There was statistical difference in treated vs. control groups for pain (P value< 0.02), anxiety (P<0.02 and FIQ (P<0.02). There were more side effects for the treated cohort compared tot he placebo controlled group. This study demonstrates that cannabinoids may be an effective treatment for fibromyalgia (1).

In one paper that reviewed 18 randomized controlled clinical trials of cannabinoids in chronic pain syndromes including fibromyalgia, cannabinoids were found to be an effective type of treatment. Despite the short duration of the trials, pain relief was effective and mild to moderate adverse effects were noted. Larger clinical trials are needed (2).

About

Introduction/Disclaimer

https://neurologybuzz.com/

  1. Skrabek, et al, “Nabilone for the treatment of pain in fibromyalgia,” J. Pain, 2008, Feb., (9)2:164:173
  2. Lynch, et al, “Cannabinoids for treatment of chronic non-cancer pain: a systemic review of randomized trials,” Br. J. Pharmacology, 2011, Nov., 72(5):735-744
Standard
obsessive compulsive disorder

Cannabinoids in obsessive-compulsive disorder: mechanisms and effectiveness in the animal model

Virginia Thornley, M.D., Neurologist, Epileptologist

June 16, 2018

Introduction

Obsessive-compulsive disorder infamously known to the layman as someone who is excessively interested in keeping their environment clean and orderly. It is a neuropsychiatric condition, where thoughts or actions are repetitive. Usually it involves the complex balance of neurotransmitters within the nervous system so that ideas and actions are carried out in a specific manner. When there is an alteration, repetitive loops occur resulting in repetitive thoughts or reverberating loops of motor activity without the usual negative feedback inhibition. Clinically, this results in intrusive thoughts and repetitive actions that are difficult to control.

Because there is a fine orchestration of the interplay of neurotransmitters, many psychiatric agents have been developed  but success is not always complete.

Medical cannabis is emerging as a treatment option recognized as successfully treating many neuropsychiatric conditions. While large clinical randomized controlled trials are sorely lacking. Scientific research is also necessary to understand the exact science on why t might help with neuropsychiatric disorders.

4AB02EC5-BD66-419E-94FD-6DF9628C6B42

Mechanisms of cannabinoids on the CB1 receptor to alleviate repetitive behavior

Anandamide and 2-AG are metabolized by FAAH or fatty acid amide hydrolase and MAGL or monoacyglycerol lipase. FAAH inhibition has been shown to increase anxiolytic effects of endocannabinoid anandamide.

One study sought to seek the effects of FAAH inhibition and MAGL inhibition on the marble burying features of mice (1). Marble burying is a research measure where marble burying is thought to be a sign of anxiety in animals and may correlate with compulsive behavior in mice to alleviate anxiety. Marble burying is an acceptable animal model to demonstrate repetitive behavior and anxiety elicited from mice demonstrating obsessive compulsive disorder (2). Marble burying is not affected by the novelty of the marble or by anxiety. Marble burying is suggested to be a repetitive perseverative type of activity related to digging movements of mice and is a valuable measure in research to evaluate repetitive responses in animals (2).

Benzodiazepines, PF-3845, an FAAH inhibitor and JZL184, a MAGL were found to reduce marble burying activity but did not affect locomotor activity. Delta-9-THC did not reduce marble burying behavior without reducing the locomotor activity (1). In essence, there was significant hypomotility with the marble burying activity.

CAA11F12-A957-4FAF-B74D-6C7D2CE6E613

Reduction of catabolic enyzymes of endocannabinoids may alleviate anxiety

An antogonist at the CB1 receptor negated the reduction of marble burying activity of FAAH and MAGL but not the benzodiazepine. This suggests that the CB1 receptor has anxiolytic properties. Possible treatments would include targeting of the enzymes that break down cannabinoids making the cannabinoids more available.

Cannabidiol effect on obsessive compulsive behavior in the animal model

Cannabidiol was given to mice using the marble burying test which is an animal model demonstrating compulsive behavior. At 15, 30 and 60mg/kg there was effective reduction of marble burying behavior compared to control mice. This study demonstrated that cannabidiol is effective in reducing repetitive perseverative behavior similar to the conditions in obsessive compulsive disorder (3).

In summary

While most of the preliminary data is entirely preclinical, there is scientific evidence that cannabidiol can reduce obsessive-compulsive behavior in the animal model. The mechanism appears to be at the level of the CB1 receptor. While preclinical data does not always translate into positive human results, this concept is promising. Clinical studies are needed.

About

Introduction/Disclaimer

https://neurologybuzz.com/

 

Reference

  1. Kinsey, et al, “Inhibition of endocannabinoid catabolic enzymes elicits anxiolytic-like effects in the marble burying assay,” Pharmacol. Biochem. Behav., 2011 Mar, 98(1)21-7
  2. Thomas, et al, “Marble burying reflects a repetitive and perseverative behavior more than novelty-induced anxiety,” Psychopharmacology, 2010, Jun., 204(2):361-373
  3. Casarotto, et al, “Cannabidiol inhibitory effect on marble-burying behavior:involvement of CB1 receptor,” Behav. Pharmacol, 2010, Jul., 21(4):353-358
Standard
Tourette's Syndrome

Medical cannabis in Tourette’s syndrome: case reports and a small randomized controlled clinical trial

Virginia Thornley, M.D., Neurologist, Epileptologist
June 11, 2018

@VThornleyMD

Introduction
When one hears Tourette’s syndrome the glorified Hollywood impression young person who shouts obscenities comes to mind. It is composed of complex motor or vocal tics generally preceded by a premonitory urge. Vocal tics may consist of coprolalia and echolalia. Motor tics may involve complex actions including copropraxia or simple motor tics. Obsessive compulsive disorder and other neuropsychiatric conditions are often associated with it.

The underlying problem is thought to be related to an imbalance of the neurotransmitters necessary to maintain the fine coordination necessary to avoid excessive motor activity. When that balance is impaired there is less inhibition of motor loop control resulting in reverberating loops and excess movements involving motor groups including muscles controlling speech and body movements. Because the pathophysiology is not entirely clear, these may be some of the most challenging neurological disorders in terms of treatments from a neurological standpoint.

Background on Cannabinoid Mechanisms
With the advent of medical cannabis used in neurological conditions, new indications are discovered. The mechanism is at the level of the endocannabinoid system already inherent within the system. There are 2 receptors, CB1 and CB2. The CB1 receptor is found mostly within the nervous system. The CB2 receptor is mostly in the immune system but is found in other organ systems to a lesser extent. Tetrahydrocannabinol (THC) is a mimetic of Anandamide which works within the endocannabinoid system and has medical properties. THC interacts with the CB1 receptor which is responsible for psychoactive properties most people are familiar with. It is likely at the CB1 receptor where other neurological symptoms are alleviated since this most abundantly found in the nervous system and many neurological symptoms are ameliorated with medical cannabis. Cannabidiol (CBD), which is non-psychoactive, is a pharmacomimetic of 2-AG or diarachidonylglycerol. It is an non-competitive allosteric modulator of the CB1 receptor which alleviates any side effects from THC when they are combined together (1).

37608_434615273840_1627543_n

Clinical Reports
There is one report of a patient treated with nabiximol where there was improvement of tics. There was overall improvement in quality of life and global improvement. There was lessening of premonitory urges. Patients feel the premonitory symptoms are more bothersome. In one study anti-psychotics helped ameliorate the motor tics but did not improve the premonitory symptoms (2). Nabiximol was used in this study where 1 puff contained 2.7mg of THC and 2.5mg of CBD. Assessments included the Yale Global Tic Severity Scale (YGTSS), Tourette’s Syndrome Symptom LIst (TSSL), Modified Rush Video Tic Scale, Premonitory Urge for Tic Scale, Global Clinical Impairment, Visual Analogue Scale for satisfaction for the GTS-Quality of Life. The study showed the best results in the quality of life in terms of alleviating premonitory urges. Larger clinical trials are needed to further this study (2).

In a recent case report, THC (trademark Sativex) was used with success to treat a patient using 10.8mg THC and 10mg CBD daily. Yale Global Tic Severity Scale (YGTSS) and the Original Rush Video Tic Scale were used as measures of evaluation. The results demonstrated effective use of THC in combination with THC for treatment in medically refractory patients (5).

In one single dose, cross over study in 12 patients and a randomized trial in 24 patients spanning 6 weeks was performed (3). The study demonstrated that THC reduces tics without any disruption in cognitive function. Neuropsychological impairment was not seen (3).

In the randomized double blinded placebo-controlled clinical trial of 24 patients, THC of up to 10mg was used in the treated cohort over 6 weeks. Measures used included the Tourette’s Syndrome Clinical Global Impression Scale (TS-CGI), Shapiro Tourette Syndrome Severity Scale (STSS), the Yale Global Tic Severity Scale (YGTSS), Tourette Syndrome Symptom List (TSSL) and the videotape based rating scale. Patients were rated at visits 1 for baseline, visits 3-4 during treatment and visits 5-6 after withdrawal. There was a significant difference between both groups. There was a significant reduction in motor tics, vocal tics and obsessive compulsive disorder. No significant adverse cognitive effects were noted (4).

IMG_5620_preview

More randomized controlled clinical studies are necessary
While there may be a paucity of large clinical trials of the use of medical cannabis in Tourette’s syndrome, tetrahydrocannabinol is a potential therapeutic agent in a neurological disorder where treatment options are very limited and often times unsuccessful. Adverse side effects can preclude treatment using conventional pharmaceutic agents.

While large randomized controlled clinical trials are necessary in providing standard of care, tetrahydrocannabinol has emerged as a potential treatment option used by clinicians who are on the frontlines of treating this debilitating disorder.

About

Introduction/Disclaimer

http://neurologybuzz.com

 

Reference
1. Laprairie, et al, “Cannabidiol is a negative allosteric modulator of the cannabinoid CB1 receptor,” Br. J. Pharmacology, 2015, Oct., 172(20):4790-4805
2. Kanaan, et al, “Significant tic reduction in an otherwise treatment-resistant patient with Gilles de la Tourette syndrome following treatment with nabiximol,: Brain Science, 2017, Apr., 7 (5):47
3. Muller-Vahl,”Cannabinoids reduce symptoms of Tourette’s syndrome,” Expert Opin Pharmacother., 2003, Oct., 4(10):17-1725
4. Muller-Vahl, “Delta-9-Tetrahydrocannabinol (THC) is effective in the treatment of tics in Tourette syndrome: a 6 week randomized trial,” J. Clin Psychiatry, 2003, Apr., 64 (4):459-65
5. Trainor, “Severe motor and vocal tics controlled with Sativex®,” Australas Psychiatry, 2016, Dec, 24 (6):541-544

Standard
stem cell

Mesenchymal stem cell therapy: a viable non-surgical option in lower back pain treatment

Virginia Thornley, M.D., Neurologist, Epileptologist

June 9, 2018

Introduction

Back pain is one of the most common pain disorders encountered by neurologists, neurosurgeons, orthopedic surgeons and pain specialists in the out-patient setting. It is not uncommon for patients to go through an extensive list of medications, steroid injections, physical therapy and even surgery and still remain in unrelenting pain. There is a growing interest in alternative treatments especially with the opioid crisis looming and restriction of strong pain medications. This seeks to review scientific mechanisms behind the success in stem cell treatment. It recaps clinical data. Despite a scarcity of published huge randomized clinical trials, there is a growing and clamoring need for alternative treatments such as stem cell therapy for patients desperately trying to find alleviation from their pain. Trailblazing physicians are using this treatment option in real life practice with growing results.
Back pain is a very common disorder which is especially prevalent in the elderly after wear and tear of long-term activity in conjunction with the natural degenerative changes that come with the aging process. Normally the intervertebral disc complex can withstand compression and shear forces because of the proteoglycans that bind water molecules. This becomes lost with aging. In degenerative disc disease, there are pro-inflammatory molecules.

Pathogenesis of degenerative disc disease
Within the nucleus pulposus, there is no vascular supply except at the end neural plate, has no nerves and is prone to damage. The nucleus pulposus relies on glycolysis for effective disposal of waste products through the endplates. After decades, the nucleus pulposus no longer has notochordal features and is replaced by small chondrocyte like cells. There is replacement of the collagen type 1 and collagen type 2 loss eventually replaced with fibrocartilaginous material. Eventually with time, the endplates have calcification of the small pores where molecules diffuse (1).

 

13925137_10154408559523841_4630279556322234980_n

There are anabolic processes involved as well as catabolic processes including involvement of enzymes, inflammatory mediators, proteinases, aggrecanases. Examples include IL-1 and TNF-alpha. because the disc is avascular this creates an environement of poor regenerative responses with harsh conditions (3).

Some patients may have a genetic predisposition to have flawed extracellular matrix where degenerative disc disease may occur more severely than in other people. Cleavage of proteoglycan can occur with enzymes resulting in loss of height and less ability to reduce compressive and shearing forces. In addition, environmental factors including occupational activities, excessive physical activity impacting the spine may contribute towards degenerative disc disease (1).

Alternative treatment: stem cell therapy
In order to address these issues, various treatments have arisen to try to try to halt the cascade leading to degenerative disc disease. This includes implantation of biomolecules to reduce the catabolic process.

 

 

Stem cell research is gaining more traction as a viable alternative for treatment of this debilitating condition. One study looked at the potential of nucleus pulposus-like cells derived from mesenchymal cells in the rabbit model. From these cells, SOX9, ACAN, COL2, FOXF1, and KRT19 genes were expressed(2). Transplanted nucleus pulposus cells were integrated into the intervertebral disc complex. Improved water content, glycosaminoglycan, and cellularity within the complex was noted. There was a suggestion of biosynthesis with the gene expression of SOX9, ACAn, COL4 (2). This animal study demonstrates that there may be value in nucleus pulposus cells derived from mesenchymal cells may lead to clinical studies where stem cells can be used for back pain.

10562503_10152824035868841_6289734604794227060_o

Injection of mesenchymal stem cells
Injections of mesenchymal stems cells into the disc may reduce the clinical pain and restore disc tissue loss. It may be able to reduce the catabolic microenvirnment (3)

Clinical studies of stem cell use in humans
It appears that stems cells of mesenchymal type derived from adipose or the umbilicus may have the most promise (4).

In one small study of 10 patients, autologous bone marrow mesenchymal cells were were injected in the nucleosus pulposus and followed for a year. After 3 months, there was improvement of pain and disability of 85% of the maximum. After 12 months, there was still high water content within the nucleosus pulposus (5).

Stem cell effects were studied in 2 patients with back pain and leg numbness. Marrow fluid was obtained autologously from the ilium from each patient. Mesenchymal stem cells were cultured in autogenous serum. Fenestration was performed and collagen sponge was applied percutaneously to the affected intervertebral disc complex. After 2 years, the T2 signal was high showing increased disc content in the grafted discs. Clinical symptoms were ameliorated (6).

german tripand old pics 410_preview

Clinical trials
In an open label trial of 26 patients, using the VAS and Oswestbry disability scale, there was reduced pain after percutaneous injection of bone marrow cell concentrate showing autologous mesenchymal stem cells are a viable alternative treatment for back pain (7). They studied the patients through 12 months. Those who received >2000 colony forming fibroblast units/ml had faster and greater pain reduction.

There is one small randomized controlled clinical trial in 24 patients using the Pfirrmann grading scale for degeneration, allogeneic mesenchymal cells were transferred to the clinical cohort. Significant relief of pain was noted compared to the sham group demonstrating that allogeneic transfer may be logistically better than autogenous transfer (8).

 

Possible adverse effects
Concerns include transformation into neoplastic process. This seems to be true with embryonic stem cells which are much earlier seen in the cell lineage. Mesenchymal cells are further down the line as a committed cell type to obviate this. With in vitro culturing, there is concern for cell mutations, but this is less of a concern if it is a same day procedure, autologous and exist as when they were in the body previously. There is concern for extravasation beyond the limit of the disc and if combined with other treatments such as PRP it may promote osteogenesis. In addition, animal models may not replicate the harsh microenvironments of disc pathology where continual torsion and pressure is involved and effects and outcomes might be different (3).

In summary
There is much scientific and animal model data that stem cells remain a viable option for treatment of back pain which is one of the most common problem encountered by neurologists, neurosurgeons, orthopedic surgeons and pain management specialists. While there is much demonstrated in animal studies, clinical trials are still very sparse. This treatment, however, shows promise and despite paucity of clinical trial data, this treatment is gaining traction in practicing clinicians who treat back pain.

Given the failure with medications and even with surgery there is increased interest in alternative treatments including stem cell therapy.

Introduction/Disclaimer

Introduction/Disclaimer

References

1. Rosenberg, et al, “Bedside to bench and back to bedside: translational implications of targeted intervertebral disc therapeutics,” J. Orthop. Translat., 2017, Apr., 10:18-27.
2. Perez-Cruet, et al, “Potential of human nucleus pulposus-like cells derived from umbilical cord to treat degenerative disc disease,” Neurosurgery, 2018, Feb., doi:10.1093/neuros/nyy012
3. Zeckser, et al, “Multipotent stem cell treatment for discogenic low back pain and disc degeneration,” Stem Cell Int., 2016, doi: 10.1155/2016/3908389
4. Knezevic, et al, “Treatment of chronic low back pain – new approaches on the horizon,” J. Pain Res., 2017, May 10, 10:1111-1123
5. Orozco, et al, “Intervertebral dis repair by autologous mesenchymal bone marrow cells: a pilot study,” Transplantation, 2011, Oct., 15, 92 (7):822-8
6. Yoshikawa, et al, “Disc regeneration therapy using marrow mesenchymal cell transplantation: a report of 2 cases,” Spine, 2010, May 15, 35 (11):E475-80
7. Pettiness, et al, “Percutaneous bone cell concentrate reduces discigenic lumbar pain through 12 months,” Stem Cell, 2015, 33(1):146-156
8. Noriega, et al, “Intervertebral disc repair by allogeneic mesenchymal bone marrow cells,” Transplantation, Aug., 2017, 101(8):1945-1951.

 

 

 

 

Standard
Medical Practice

Returning to the sacred patient-physician relationship

Virginia Thornley, M.D., Neurologist, Epileptologist

@VThornleyMD
https://neurologybuzz.com/

June 6, 2018

Introduction

Seeing physician burnout articles every page you swipe on social media, on physician online media groups, and in editorials of national syndicates are becoming the norm. Not to minimize it, it can become fairly discouraging reading about the fate of well-educated healers with only the noblest intentions becoming victims of the healthcare climate that is medicine today. Reading about these issues, one can become disengaged when you are in the throes of working.  It is when one becomes completely removed from the situation when you realize the extent of the dysfunctional system. Yes, the system is terrible, yes, there are too many regulations, too many middlemen, too many people getting in the way of the genuine whole-hearted connection between patient and physician. Where does that leave us and how can we rectify the situation?

Patient-physician relationship: the sacred relationship

It used to be that the relationship was between patient and physician. Patient and physician. There was no such thing as health insurances, no such thing as MOC, no such thing as EMR, no such thing as healthcare professionals. It was patient and physician. Physician and patient. Doctor and patient. Patient and doctor.

There was nothing to separate the physician from caring for his patients. Doctors used to travel with their doctor’s bags to their patient’s home, making house calls, being paid with services or what little the family had on their farms. Doctors took out their trusty stethoscopes and gave a healing balm, sometimes they helped their patients sometimes not, since the remedy was beyond the technology at the time. There was no such thing as malpractice insurance. No such thing as deductibles, no such thing as premiums, no such thing as clicking little boxes that sums up a human’s suffering. The relationship between a doctor and his patient was at its best and humblest-to care for the sick. Not to cure, not to treat but to comfort always. Absolutely nothing stood in the way between doctor and patient. That relationship was pure and untouched.

8C1FC755-C4F4-4BA1-95F7-58283E866CCC

Going back to your roots, back to the patient-physician relationship

How does one go back to this very sacred traditional relationship? If doctors do not realize this is a crisis situation where this very symbolic connection is being threatened by a huge number of many outside forces, they must be hiding under a rock. When one sees hundreds of articles on physician burnout, how to end the patient interview, courses on coding to get the most out of a visit, you know there is something utterly amiss with the system.  There will be the business end of the situation, you do have to pay for staff salaries, paper supplies etc, after all. But the physician-patient relationship is one of the most paramount human connections that cannot and should not be replaced. To heal and to comfort someone during their last few days, to determine if someone no longer has meaningful recovery after suffering from a massive myocardial infarct, to tell a patient they have a glioblastoma multiforme and there is very little chance of recovery, these are sensitive dealings that should not lay on an artificial robot, a medical substitute or a paramedical person. Important discussions like these should be with the physician. In order to have these important discussions, one must first have a relationship. One must never forget why we have entered medicine, to serve our patients. The human connection between a patient and physician is one of trust and hope. But how do we get back there when there are so many compelling factors threatening its very existence?

7BA69115-5CCB-42E8-A2D3-A3573B9C9D5C

Acknowledge there is a problem

A basic tenet of remedying a situation is to acknowledge that there is a problem. When one realizes the way one operates is not sustainable, your psyche will address the situation and make changes. If one stays in the limbo, the system can consume you and spit you out. Such are the sad cases of colleagues ruthlessly cut to be replaced with cheap labor by the upper business echelons.  Difficulties coping with this new unsatisfying overburdensome system leads to disillusioned physicians, who previously took pride in their work now reduced to electric circuits, cogs in a machine. And because physicians are perfectionists we feel like failures if we cannot cope. This leads to the worst case scenario which is to take your own life.

B1F55FBA-970D-4B7D-B96C-BFF117A17DC0

We should find pride and satisfaction in what we do. Instead, there are now wellness programs which are a slap in the face placing the blame entirely on the physicians’ shoulders because we are unable to cope. Patients cannot fathom the extent of this medical crisis. All they know is that their physicians keep getting changed because of rapid turnover or a whole encounter is all of 10 minutes to summarize 10 complex problems. The answer lies within ourselves. Nobody can turnaround the situation except ourselves. If we want change we change our whole outlook, whole way of thinking and whole way of practice, it begins within ourselves.

Get rid of the middleman

I used to have a wonderful medical assistant, she did all the pre-questionnaires for me and dutifully entered it into the computer database. As the patient entered my office, I am guilty of saying,”hold on, let me read what my assistant typed” while the patient is seated, gob-smacked, looking at me silently. Looking back I can only shake my head and wonder,”wow, what was I thinking I sound like a cold robot,” which I was. All the boxes were checked perfectly, I did my neurological exam, whipped out my pad, scribbling 5 medications for 5 different symptoms, filled out MRI forms, went over the plan speaking as quickly as possible. Off my patient went on his merry old way, disillusioned and somehow left unfulfilled. Imagine this occurring 20 times a day. I was fried by the end of the day, my patients left dissatisfied and staff went through the office like hotel guests through revolving doors because of the tediousness that is medicine today. When I used to work in hospitals, residents did the pre-work-up as was part of their training, relationships were fleeting, care was in teams and rotations.

003AC0DF-7601-424B-9A3C-ECAD59504CA2

Now, I see new patients for 1 hour, they are now eloquent, unique stories again, not templates that you copy and paste and change with a few details according to the patient. I let them expound until they have nothing left to say. I ask my part, perform my examination which is where the healing touch occurs that every patient subconsciously craves and we go over the plan. I answer all questions until there are no more. It is not uncommon for a patient to shake my hand heartfelt looking me in the eye thanking me. Other times, I receive a warm hug. It is not just as a courtesy gesture but a real expression of appreciation. While I did not cure them I provided so much more, the therapeutic healing relationship that exists between a patient and a doctor that no matter what happens I am now there for them. My heart warms and I modestly reply I didn’t do anything. But deep down I can feel the palpable difference. I have returned to the roots of medicine. I finally understand that this is what it is all about. I now listen to them. I listen to their own unique stories. I make eye contact and take in everything they have to say, the furrowing of their brows, the tone of their voices and I hear what they are saying. I now get comments how they are happy they found me their last doctor only took 5 minutes, while I muse to myself, I used to be that doctor. I remain neutral and non-judgmental, but I am now aware there is a simply better way of practicing now.

2EA61B69-B27A-47A6-8996-C4004E9A6CBC

 

How does one return to your roots

Going back to the basics of communication, human connection, one remembers the reason why you entered medicine. We are slowly replaced by parallel industries where practitioners of dubious training are hailed new miracle healers. Everybody is calling themselves doctors. They spend more time listening and are less regulated. We have lost the art of listening. It has gotten lost in the world of electronic recording, the need to generate copious amounts of data on one patient encounter, in the new team service approach. The unique relationship between doctor and patient is subsequently insidiously altered-soon to be extinct as doctors are slowly being replaced and encroached by other forces. But the solution is very simple, we must return to the country doctor model. Within the very listening provides great comfort. When comfort is achieved we have done our job. We may not cure or treat, but we always comfort. The paradigm shifts back to doctor and patient.

One more time cut out the middleman

I cannot emphasize it enough, cut out the middleman. Anything that keeps you apart from your patient widens the chasm and becomes a barrier, an impediment. Assistants, insurances, computers, physician extenders, these were never around before. When you strip it back down to the bare bones, you return to the rawest, purest form of medicine-the relationship between doctor and patient. Patient and doctor. We should go back to the country doctor model.

It is only then you will realize the depth that is medicine. Only then can we practice medicine the way it is supposed to be…between physician and patient. Patient and physician.

About

https://neurologybuzz.com/

Dr. Virginia Thornley is a Board-Certified Neurologist subspecializing in Epilepsy and Clinical Neurophysiology in private practice. You can follow her on @VThornleyMD. To read more of her writings, visit https://neurologybuzz.com/

Standard