Worcester Medicine
May/June 2012

Editorial
By Jane Lochrie, MD

Drugs That Make A Difference
"Medical Marijuana" The Cart Before the Horse

By Leonard J. Morse, MD

Medical Marijuana: Evidence of Efficacy
By Evan R. Horton, PharmD

Why FDA Approved Drugs Are Withdrawn from the Market - The Cautionary Story of Xigirs
By Anthony L. Esposito, MD

Old Drugs with New Uses: Focus on Antidotes
By Ryan Attwood, PharmD, BCPS and Jordan Rush, BS

216th Annual Oration
216th Annual Oration of the Worcester District Medical Society 50 Years of Medicine: Less Art, More Science
By Charles Birbara, MD

As I See It
Checkup System Passes Test
By Lynda Young, MD

A Message from the Worcester Free Clinic Coalition
By Melinda Palma and Karen Tenner
Volunteer and Physician Coordinators
Worcester Free Clinic Coalition


Editorial
By Jane Lochrie, MD 

This is my first editorial as Editor of Worcester Medicine.  It is an honor to edit the one of the oldest District Medical Societies' publications. The first publication of Worcester Medicine (formerly Worcester Medical News) was in 1937and it has been continuously published since that time. I welcome your suggestions and would like to see some responses in the form of Letters to the Editor. 

This issue of Worcester Medicine owes a lot to Massachusetts College of Pharmacy and Allied Health Science (MCPHS).  The College opened its doors in downtown Worcester in 2000 and is now composed of five main buildings that consist of 19 Foster Street, MCPHS Online, the Maher Building, The Borysek Living and Learning Center and 10 Lincoln Square.  The Worcester Campus of MCPHS houses several Schools and Programs which include accelerated programs in Nursing and Doctor of Pharmacy, the Masters of Physician Assistant Studies Program for post-baccalaureate students, the Doctor of Physical Therapy Program, and the Doctor of Optometry Program. Approximately 1000 students matriculate in all the programs that are currently offered on the Worcester campus.

Ryan Attwood PharmD, BCPS and Jordan Rush, a third year pharmacy student, focused their article on medications that were used in the past for therapeutic indications and are now being used for antidotes.  The authors caution that these drugs are being used for non- FDA indications and the available data must be evaluated for the drugs’ efficacy and safety.

The mysteries of the pharmaceutical companies and the FDA are unlocked in Dr. Esposito’s article that features the withdrawal of Xigris from the market.  His description of Eli Lilly’s push to have the drug approved to the marketing strategy that stated “It is unethical not to use Xigris” is riveting. He reminds us that “…any new drug should be considered a black box.”

The Point/Counterpoint feature on the legalization of medical marijuana is certainly timely as it will appear as a ballot question in November.  As always, Dr. Morse wrote eloquently, passionately and from the heart. “The medical profession needs to be educated based on clinical studies, not just personal testimony.” Evan Horton, PharmD, makes a powerful argument for the continued research in this area.

Finally, Dr. Birbara’s Oration is a presentation of his scholarly research over the past twenty-two years that has resulted in over fifty publications.  This has benefited many patients in the Worcester community.

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“Medical Marijuana”- The Cart before the Horse
By Leonard J. Morse, MD

In November 2012, Massachusetts voters will be asked to check yes or no on the legalization of marijuana for medical use. Appreciating that most physicians are uninformed about the pharmacology of marijuana, I submitted a Resolution (206) for discussion and action by the Massachusetts Medical Society asking that: “medical marijuana be restricted to medical use only and prescribed by a Drug Enforcement Agency-registered physician,” and that the MMS conduct educational programs “on the pharmacology of marijuana and its many forms as a priority public health effort for all physicians in 2011.”(1) Now, the physicians of Massachusetts may become responsible for prescribing a “legalized,” gateway, addictive drug that is, perhaps, more popular than tobacco among adolescent youth and young adults.

Almost every day, three people (average age of 40) die in Massachusetts from drug overdose. In my opinion, unbridled drug use is the preventable plague of the 21st century. While the population of the United States represents less than five percent of the world’s population, we consume over 60% of its illicit drugs!    

Marijuana (cannabis) is a Schedule I Controlled Substance along with heroin, lysergic acid diethylamide (LSD), peyote, methaqualone and methylenedioxmethamphetamine (“ecstasy”). “The drugs in this Schedule are those that have no accepted medical use in the United States and have high abuse potential” and therefore, may not be prescribed. (2)  Hence, there is a serious disconnect between Federal law and the accepted mandate of legalizing “medical” marijuana.

I attended a Legislative Hearing on House Bill 625 to legalize marijuana for medical purposes on June 28, 2011 and listened to three hours of personal testimony in support of the legislation. The passion was overwhelming. Marijuana warrants medical study to verify its claims. The medical profession and pharmaceutical industry must align to study various preparations of medical cannabis for administration so that an effective product line can be developed similar to other controlled, yet most effective, addictive drugs.  Licensed physicians receive a “Controlled Substance Registration Certificate” from the United States Department of Justice, Drug Enforcement Administration permitting them to prescribe controlled drugs.

Marijuana should become a Schedule II substance, joining the ranks of other narcotic, stimulant and depressant drugs. Like marijuana, “The drugs in this schedule have a high abuse potential with severe psychic or physical dependence liability and include opium, morphine, codeine Dilaudid, methadone, pantapon, Demerol, cocaine, oxycodone, as well as, non-narcotic drugs such as amphetamine metamphetamine, Preludin, Ritalin, amobarbital, secobarbital and Doriden.”(2)    

The medical profession needs to be educated based on clinical studies, not just personal testimony, and to learn the routes of responsible prescribing. It is inappropriate to prescribe a plant product with varying concentrations of active pharmaceutical compounds so casually dosed as by smoking (3). This is long overdue. In California, certain counties claim over 60% of their income is from growing pristine marijuana. Such widespread use of an addictive drug is irresponsible and leads to predictable yet preventable tragedy. If it is predictable, it is indeed preventable! The United Nations estimates that 190 million people consumed cannabis in 2007, and a new industry has arisen around the cultivating and dispensing of “medical marijuana.”(4)    

Since 1970, 16 states and the District of Columbia have legalized the “medical use” of botanical cannabis. Based on public claims attesting to the wonder of marijuana, the divide between the Federal and state governments continues to broaden. The pharmaceutical industry and the medical profession should become involved in product development, clinical testing, and physician education before medical marijuana becomes legalized.  And physician prescribing should be only by Drug Enforcement Administration licensed professionals as it is for all other controlled substances. 

References:

  1. Morse, L J. “Medical Marijuana,” Late Resolution 206 Massachusetts Medical Society House of Delegates I-10, November 2010.

  2. United States Department of Justice, Drug Enforcement Administration Form-224a (8/96)

  3. Mechoulam, Raphael , “Cannabis-A Valuable Drug That Deserves Better Treatment.” Mayo Clinic Proceedings February 2012:87(2): 107-9.

  4. Bostwick, J. Michael, Blurred Boundaries: “The Therapeutics and Politics of Medical Marijuana.” Mato Clinic Proceedings February 2012:87(2):172-186.

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Medical Marijuana: Evidence of Efficacy
Evan R. Horton, Pharm.D

Marijuana has been a controversial topic, both medically and politically, for decades. The history of cannabis dates back to nearly 3000 B.C., where archeological findings in Asia suggest it was used for medicinal purposes.1 Although federal law identifies the cannabis plant as a Schedule I narcotic, 16 states and the District of Columbia have passed legislation making it legal for patients with legitimate prescriptions from a physician to possess small amounts of marijuana (purchased from dispensaries) or cultivate a certain number of plants.2  An additional 17 states are considering similar bills or ballot initiatives for the upcoming Fall 2012 elections. Based on individual state laws, medical marijuana can be legally prescribed for a number of afflictions including, but limited to: anxiety, spasticity, symptoms of multiple sclerosis (MS), glaucoma, nausea associated with chemotherapy, and anorexia from human immunodeficiency virus (HIV). 

The criminalization of marijuana during the 1920s eliminated the potential for medical research in the United States; however, trials conducted in Canada and Western Europe, where government have taken a softer stance on cannabis, have been able to provide some evidence supporting its use.3  In addition to cannabis, d9-tetrahydrocannibinol (Δ9-THC) extract and Sativex® (extract of Δ9-THC and cannabidiol approved in Canada and Europe), as well as synthetics nabilone and dronabinol, have been studied.

Dronabinol (Marinol®), a Schedule III, and nabilone (Cesamet®), a Schedule II, are FDA-approved for use in nausea and vomiting associated with cancer chemotherapy.4,5  Dronabinol is also indicated for anorexia associated with weight loss in patients with HIV.  Due to the controversy surrounding unapproved pure cannabis and cannabis extract, this review will only focus on studies involving those compounds.

Tourette Syndrome

In response to published case reports on 4 patients with positive self-reported scores following smoking cannabis and a retrospective review of 17 patients, Muller-Vahl and colleagues conducted a randomized (R), double-blind (DB), placebo-controlled (PC), single-dose, cross-over study of 7.5 to 10 mg Δ9-THC followed by a 6-week R, DB, PC trial using 10 mg following dose titration.6  The single-dose trial (n=12) showed improvements in self-reported tics (p=0.015) and obsessive compulsive behaviors (p=0.041), while the 6-week study (n=24) showed significant improvement based on examiner rating scales at weeks 2, 3, and 4 (p<0.05), as well as on self-reported symptoms (p=0.037). Neither study reported serious adverse drug reactions.

Chronic Non-Cancer Pain

Four studies, randomizing a total of 156 patients, examined smoked cannabis for treating neuropathic pain, including two in patients with HIV. All four trials were PC, with three employing a cross-over design and one parallel-group. All showed significant reductions in pain as reported via visual analog scales (VAS) when compared to placebo. In both HIV populations, the approximate NNT for a greater than 30% reduction in pain was 3.5.7  It should be noted that the potency of marijuana varied greatly among each study (range: 2.5 - 9.4% Δ9-THC).

Sativex® has been studied in several chronic pain syndromes. One hundred twenty-five patients with neuropathic pain and allodynia took part in a cross-over trial with self-escalating doses of the oromucosal spray. VAS were significantly decreased with a NNT of 8.5.  Eighteen percent of patients in the Sativex® group, compared to two percent of placebo, withdrew due to side effects.7  A similar study of 48 patients showed similar reductions in pain scores and fewer side effects. Sativex® has also been shown to be effective in the treatment of central pain due to multiple sclerosis and rheumatoid arthritis.

Spasticity from Multiple Sclerosis

Zajicet et al. performed both a 15-week multicenter (33 sites), DB, PC, R trial utilizing both natural and synthetic cannabis extract, followed by a 12-month follow up.8  Six hundred and sixty-seven patients were evaluated and, although objective measures in neither trial showed statistical significance, patient reported ratings of pain and MS symptoms did show improvement. Zajicet conducted a similar 12-week follow-up involving 22 centers and 279 patients. Patients in the cannabis extract group showed significant decreases in spasticity rating scales compared to placebo counterparts (p=0.004). Additional trials of cannabis extract have not showed significant decreases in pain or spasticity versus placebo.

Trials of Sativex in the treatment of MS spasticity and pain have shown similar results to cannabis extract alone. Although patients often self-report symptom improvement, objective measures of spasticity do not significantly improve.8

Glaucoma

One DB, PC, single-dose, cross-over study evaluated the use of inhaled marijuana on intraocular pressure (IOP) in 18 patients with glaucoma.7 Within 60 to 90 minutes, a majority of patients experienced both hypotension followed by a decrease in IOP. The frequency of tachycardia, palpitations, and other adverse effects were a concern to the authors regarding the use of cannabis in this population of patients.

Challenges

Several challenges exist in how to accurately interpret available data surrounding inhaled cannabis trials. There are over 70 psychoactive compounds found in any given strain of cannabis.9  Two strains of medical marijuana, Sativa and Indica, have been primarily used and the differences in their potency may result in variable positive and negative effects. Medical marijuana laws allow for either the purchase of cannabis from dispensaries or the legal cultivation within the home. Both of these options allow for the possibility of genetic alterations through advances in botany, which further complicate the potency of available medical marijuana. Second, the actual amount of cannabinoids that reach the blood stream via alveoli varies based on the individual user’s inhalation/exhalation technique.7  These differences blur the lines of what constitutes an effective dose and may contribute the third challenge, risk of addiction. Finally, physicians must assess the risk of exposure to contaminants such as Aspergillus and heavy metals due to how and where medical marijuana is cultivated.

Oral formulations utilizing Δ9-THC and cannabidiol extracts may decrease some of these challenges, but proponents of inhaled medical marijuana claim that the high number of psychoactive compounds and the reaction caused by burning the dried leaves may add to the efficacy. The argument is that extracts only contain one piece of the cannabis puzzle and may limit the effect that some patients receive from the treatment. Regardless of the political implications, the fact remains that as long as marijuana is classified as a Schedule I narcotic, the scientific information we receive will continue to come from other countries and our knowledge of the true risks and benefits of cannabis will not be fully realized.  

Evan R. Horton, Pharm.D., is Assistant Professor of Pharmacy Practice, Massachusetts College of Pharmacy & Health Sciences – Worcester/Manchester.

References: 

  1. History of Marijuana. Narconon International. http://www.narconon.org/drug-information/marijuana-history.html Accessed 3/20/12.

  2. Marijuana Policy Project. www.mpp.org Accessed   3/20/12.

  3. Leung L. Cannabis and its derivatives: review of medical use. J Am Board Fam Med 2011;24:452-462.

  4. Marinol [package insert]. Solvay Pharmaceuticals. Revised 9/2004; accessed 3/20/12.

  5. Cesamet [package insert]. Meda Pharmaceuticals. Revised 2/2010; accessed 3/25/12

  6. Muller-Vahl K. Cannabinoids reduce symptoms of Tourette’s Syndrome. Expert Opin Pharmacother 2003;4:1717-1725.

  7. Lynch ME, Campbell F. Cannabinoids for treatment of chronic non-cancer pain; a systematic review of randomized trials. Br J Clin Pharmacol 2011;72:735-744.

  8. Zajicek J, Apostu VI. Role of cannabinoids in multiple sclerosis. CNS Drugs 2011;25:187-201.

  9. Ashton CH. Pharmacology and effects of cannabis: a brief review. Br J Psychiatry 2001;178:101-106.

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Why FDA Approved Drugs Are Withdrawn from the Market: The Cautionary Story of Xigris
By Anthony L. Esposito, MD

Physicians practicing at the turn of the 20th century would be dazzled by the variety of therapeutic agents currently available, and they would be awed by the range of human maladies now prevented, controlled or cured by contemporary pharmacologics.  And if they were to seek the source of this river of medicinal marvels, their journeys would certainly take them to the gateways of the nation’s pharmaceutical industry. 

Drug development is a complex, tedious, and expensive process, and pharmaceutical companies must expend an enormous effort to bring a new agent (or new chemical entity) to market.  Years may lapse between the time a compound is created and the time it enters clinical trials; indeed, many drugs fail prior to being tested in humans.  New chemical entities are also abandoned after early clinical trials.  The most common reasons for terminating drug development in Phase I trials are toxicity (43%), lack of efficacy (36%), and pharmacokinetic problems (14%); in Phase III studies, the most common are lack of efficacy (53%) and toxicity (35%), the most frequent of which is hepatotoxicity.  Not surprisingly, the preapproval costs for developing a new chemical entity have been estimated to exceed $500 million dollars. 

In spite of efforts by pharmaceutical companies and the Food and Drug Administration (FDA) to confirm efficacy and to identify toxicities in novel chemical entities, approximately 8% of newly approved drugs acquire a black box warning indicating the potential for a serious adverse drug reaction (ADR) and about 3% are withdrawn from the market, usually within a few years of introduction.  The primary reason for removing an agent from the market is toxicity (94%); the more common ADRs leading to drug withdrawal are hepatic, hematological, and cardiovascular toxicities.

Some of the drugs withdrawn from the market since 2000 and their toxicities are included in Table 1.  Notable are the spectrum of chemical compounds in Table 1 and the variety of diseases or conditions for which the drugs were initially approved.  Also remarkable is the number of deaths associated with some of these agents; for example, drug-associated deaths from rofecoxib (Vioxx), troglitazone (Rezulin), cisapride (Propulsid) and trovafloxacin (Trovan) are reported to have been 27,000, 400, 80, and 6, respectively.  

The primary reason why serious ADRs are identified only after novel compounds are introduced into general clinical use is that serious ADRs are often uncommon and thus unobserved until thousands of patients have been exposed; in short, the preapproval studies are underpowered to detect ADRs.  Other factors include the highly selected patients recruited into clinical trials and the finite time study subjects are given the investigational drugs.  By extension, once an agent is available, practitioners may elect to use the drug in patient populations never studied and for conditions beyond those approved.  On occasion, a drug with unique properties will be approved in spite of a serious ADR observed during trials and subsequently withdrawn.  Finally, post-marketing surveillance via the FDA’s Adverse Event Reporting System is largely a voluntary activity, and, as a result, inadequate clinician, industry and patient reporting can lead to delays in identifying ADRs. 

Since the costs of bringing a new compound to market are enormous, the pressures on pharmaceutical companies to generate sales are extraordinary.  As a result, companies aggressively promote the introduction of novel agents by intensively marketing to physicians and consumers, a practice that can yield an explosion in prescription writing and the first-time use of a compound by hundreds of thousands of patients.  Other factors that fuel a marketing surge include a desire to foster favorable prescribing patterns and to blunt the impact of yet-to-be-approved competing agents.  A need to demonstrate robust sales increases to stimulate a rise in stock values has also been cited as playing a role.  Regardless, the rapid exposure of a vast and heterogeneous population to a novel agent may reveal a serious drug problem and, unfortunately, injure large numbers of people.  For example, 19.8 million Americans were exposed to five drugs (terfenadine, bromfenac, fenfluramine, dexfenfluramine and mibefradil) that were all withdrawn in a 12 month period in 1997-1998; in contrast, a total of 12,340 subjects were exposed to these agents during preapproval trials.  

The stories behind the withdrawal of approved medications sometimes read like fiction, and occasionally pharmaceutical industry protagonists appear to play conspiratorial roles.  A brief Google or FDA website search of any of the drugs in Table 1 will provide facts regarding the events leading to a drug’s withdrawal; you as the reader can infer the protagonist’s intent. 

One agent in Table 1, Xigris (drotrecogin alpha or activated protein C), merits special comment, as it is one of the few FDA-approved agents ever withdrawn from the market because of a lack of efficacy.  In brief, severe sepsis results from a cascade of coagulation and immune mediators usually unleashed by a bacterial pathogen and resulting in unfettered and injurious inflammation.  In spite of supportive care and appropriate antimicrobials, severe sepsis is associated with case fatality rates of 30 to 50%.  Since prior studies designed to arrest or temper the dysregulated systems had failed to reduce case fatality rates, the Recombinant Human Activated Protein C Worldwide Evaluation in Severe Sepsis (PROWESS) study published in 2001 was hailed by some as a landmark advance.  In that report, the overall 28 day survival rate for patients with severe sepsis treated with Xigris was 24.7% versus 30.8% for those given placebo (p=0.005); among patients with severe sepsis and a high risk of death, the respective survival rates were 44% and 31%.  The primary ADR was serious bleeding, including intracranial hemorrhage, which occurred more commonly among Xigris treated patients (3.5% versus 2.0%; p=0.06).

Based on data from the PROWESS trial alone, the FDA approved the use of Xigris for patients with severe sepsis and a high risk of death in 2001.  However, the decision to approve was supported by only half of the members of the Anti-Infective Drugs Advisory Committee; the other half had concerns about protocol changes during the trial and bleeding risks.  As a result, the review panel requested further research to address methodological and other concerns with the PROWESS study, and the FDA asked the company developing the drug, Eli Lilly, to perform additional studies in specific patient subgroups, including that for which Xigris had been approved. 

Questions about the validity of the PROWESS data combined with a $6,800 to $8,000 cost per course spawned ambivalence in the medical community, restrictive guidelines in many intensive care units, and lower than expected sales.  In particular, in contrast to Lilly’s predicted annual sales of $300-500 million, actual sales in the first year were about $100 million. 

To promote the use of Xigris, Lilly hired a new public relations firm that developed a marketing strategy anchored on the premise “that it was unethical not to use the drug.”  The marketing campaign was designed to “raise awareness” that life-saving drugs were being “rationed” in intensive care units and to foster and support the creation of sepsis treatment guidelines, which of course would include the use of Xigris.  Lilly gave a $1.8 million dollar grant to establish a Values, Ethics and Rationing Task Force of physicians and ethicists to address the concocted issue of rationing, and the company generously funded the Surviving Sepsis Campaign, which convened experts in infectious diseases and critical care medicine and which led to sepsis management guidelines published in Critical Care Medicine in 2004.  Of note, many professional societies were listed as sponsors of the Surviving Sepsis Campaign Guidelines; reassuringly, the Infectious Diseases Society of America declined to endorse the guidelines, citing among other factors pharmaceutical company sponsorship.  In short, the marketing campaign was designed to drive demand for Xigris.  However, the impact was modest, as annual sales rose to about $200 million.

The fate of Xigris was ultimately determined by the outcome of clinical trials completed after the drug was approved in 2001.  Initially, a survival benefit of activated protein C without an increased risk of serious bleeding appeared to be confirmed in one single-arm, phase-3B, mortality and safety study (ENHANCE US published in 2004).  However, in septic adults with a low risk of death, Xigris failed to show a mortality advantage and was associated with a statistically higher risk of serious hemorrhage (ADDRESS, 2005).  Activated protein C also failed to show a benefit in children with severe sepsis (RESOLVE, 2007) and in adults with septic shock (PROWESS-SHOCK, results released in late 2011).  Of note, the PROWESS-SHOCK study was undertaken at the request of the European Medicines Agency, which is the equivalent of the US FDA and which in 2007 asked Eli Lily to confirm the findings of the 2001 PROWESS study and to substantiate the claim that the benefits of Xigris outweighed its risks.  When the results of PROWESS-SHOCK failed to demonstrate a survival advantage, Eli Lilly withdrew Xigris from the worldwide market in October 2011, and the company discontinued all ongoing clinical trials.

Drugs acquiring new black box warnings or drugs withdrawn from the market are a reminder that although pharmaceutical companies, clinical investigators, and the FDA are committed to providing safe and effective therapies, limitations exist in the design of clinical trials and in the review and approval process.  And because post-marketing drug safety surveillance remains a voluntary activity, serious adverse events may not come to light unless practitioners, industry, and consumers report untoward events.  On a broader note, clinicians should perhaps avoid using new drugs when older and equally effective agents are available, and they should inform patients of the limited experience with recently introduced medicines.  In addition, practitioners should be aware of the limitations in the preapproval processes and the post-marketing systems for detecting potential harm, and they should willingly report possible ADRs via the FDA’s MedWatch program.  As the agents in Table 1 illustrate and as Lasser and colleagues conclude, “Any new drug should be considered a black box.
 

References:

  1. Abraham E, Laterre PF, Garg R, et al.  Drotrecogin alfa (activated) for adults with severe sepsis and a low risk of death (ADDRESS study).  N Engl J Med 2005;353:1332-41.  

  2. Bernard GR, Margolis BD, Shanies HM, et al.  The extended evaluation of recombinant human activated protein United States Trial C (ENHANCE US).  A single-arm, phase 3B, multicenter study of drotrecogin alpha (activated) in severe sepsis.  Chest 2004;125:2206-16. 

  3. Brewer T and Colditz G.  Post marketing surveillance and adverse drug reactions: current perspectives and future needs.  JAMA 1999:281:824-9. 

  4. Eichacker PQ, Natanson C and Danner RL.   Surviving Sepsis – Practice guidelines, marketing campaigns and Eli Lilly.  N Engl J Med 2006;355:1640-2. 

  5. Freidman MA, Woodcock J, Lumpkin MM, et al.  The safety of newly approved medicines:  Do recent market removals mean there is a problem?  JAMA 1999;281:1728-34.

  6. Lassar KE, Allen PD, Woolhandler SJ, et al.  Timing of new black box warnings and withdrawals for prescription medications.  JAMA 2002;287:2215-20. 

  7. Nadel S, Goldstein B, Williams MD, et al.  Drotrecogin alfa (activated) in children with severe sepsis:  a multicenter phase III randomized controlled trial (RESOLVE or REsearching severe Sepsis and Organ dysfunction in children: a gLobal perspectiVE).  Lancet 2007;369:836-43.

  8. Regalado R.  To sell pricey drug, Eli Lilly fuels a debate over rationing.  Wall Street Journal September 18, 2003:A1.

  9. Schuster D, Laggner C and Langer T.  Why drugs fail – a study on side effects in new chemical entities.  In:  RJ Vaz, T Klabunde, R Mannhold, H Kubinyi, G Folkers, eds. Antitargets: Prediction and Prevention of Drug Side Effects.  Hoboken, NJ: John Wiley & Sons, Inc., 2008:1-22.

  10. Warren HS, Suffredini AF, Eichacker PQ and Munford RS.   Risks and benefits of activated protein C treatment for severe sepsis.  N Engl J Med 2006;347:1027-30.

  11. Wood AJ.  The safety of new medicines:  the importance of asking the right questions  JAMA 1999;281:1753-4.

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Old Drugs with New Uses:  Focus on Antidotes
By Ryan Attwood, Pharm D, BCPS and Jordan Rush, BS

Medications are often used for off label uses, and it is not uncommon to see older medications being used for new indications. This is especially true in the field of toxicology, where many unlikely agents are used to reverse or mitigate the adverse effects of overdosage or drug toxicity. This article will review some old medications that have recently found a new use as antidotes.

Intravenous lipid emulsion (IVLE) for lipophilic drug toxicity

The administration of IVLE emulsion has long been used to supplement patients receiving intravenous total parental nutrition. The use of IVLE has also recently gained attention as an antidote for several severe lipophilic drug toxicities. Approximately 42 cases of IVLE use for drug toxicity have been reported since June, 2010, with several cases of beta blocker, calcium channel blocker, and antidepressant toxicities reported.1

There are several proposed mechanisms of actions for IVLE therapy. The most widely accepted is the “lipid sink” phenomenon suggested by Weinberg.2,3  This theory suggests that the infusion of the lipid emulsion increases the lipid compartment in the body. The lipophilic drug will then redistribute from the cardiac and brain tissues, through the plasma, and into the circulating lipid droplets. Other proposed mechanisms include an increase in ATP synthesis through fatty acid oxidation and an increase in intracellular calcium levels, leading to increased heart contractility. 2,4

Although there is no definitive dosing protocol established, one source recommends a 1.5 mL/kg 20% lipid emulsion bolus, which can be repeated two additional times in 5 minute intervals if cardiovascular circulation is not restored.2,5 This is then followed by a 0.25 ml/kg/min infusion, with an upper limit of 10 ml/kg for 30 minutes.

There have been few adverse events reported for this use of IVLE therapy. Case reports include an increase in amylase levels and the development of acute lung injury.6,7 Overall, this therapy can be considered safe and is a viable option for patients who have failed traditional overdose protocols.

Octreotide for sulfonylurea induced hypoglycemia

Octreotide is a long-acting somatostatin analog, a natural hormone found in the body that suppresses the release of various endogenous chemicals and hormones and has long been used in the treatment of acromegaly and the management of some cancer-related side effects. Octreotide’s effect on insulin and glucagon secretion makes it a suitable treatment option for sulfonylurea-induced hypoglycemia.

The traditional approach to sulfonylurea-induced hypoglycemia utilizes dextrose infusions to increase serum glucose levels.8,9  The infusion of glucose causes the body to secrete insulin; however, this results in rebound hypoglycemia. To break this cycle, octreotide has been introduced as a new therapeutic option.

The recommended adult dosing regimen is 50 μg of octreotide subcutaneously every 8-12 hours.9 Octreotide has been effective in cases of pediatric sulfonylurea toxicity as well, with one suggested dosing of 1-1.25 μg/kg.9Currently no adverse reports have been reported. 8,9

Glucagon, insulin and dextrose for beta blocker and calcium channel blocker overdose

Beta blocker and calcium channel blocker overdose is associated with cardiovascular toxicity including conduction disturbances, bradycardia, and cardiogenic shock.10 Management involves agents including atropine, intravenous calcium, inotropes, vasopressors and cardiac pacing to ameliorate these effects.11Two additional therapies, glucagon and insulin / dextrose, are drugs that have long been used for other purposes and are now part of this treatment algorithm.

Glucagon is a 29 amino acid polypeptide which maintains plasma glucose levels during fasting / stress states and has an established use in the management of insulin induced hypoglycemia. It has also been used as an antidote to beta blocker / calcium channel overdose. The proposed mechanism of glucagon’s activity is via activation of adenylate cyclase, resulting in an increase of cyclic AMP and leading to an increase in cardiac inotropy and chronotropy independent of beta receptor activation.12

Glucagon has been shown to be effective in animal models of beta blocker and calcium channel blocker toxicity, and volunteer studies have found that IV glucagon administration is associated with an increase in cardiac index.13,14  Early reports suggest a dose of 50 ug/kg IV (3-5 mg intravenously); however, doses of up to 10 mg have been used.15,16  Glucagon has a relatively short duration of action, and a continuous infusion is sometimes required 17 Tachyphylaxis has been reported and repeat bolus dosing may  be recommended over a continuous infusion.17  Commonly reported adverse effects include gastrointestinal side effects, glucose and electrolyte abnormalities.

Another treatment for beta blocker / calcium channel overdose is the administration of high dose insulin with supplemental dextrose to prevent hypoglycemia. The administration of insulin is associated with increased inotropy and an increased glucose uptake and utilization.19 Typical treatment protocols consist of an initial bolus of 1 unit / kg  intravenous regular insulin followed by a maintenance infusion of 0.5-1 units / kg titrated to clinical response.19  Doses up to 10 units / kg have been reported.20  As expected, hypoglycemia may occur with this therapy and a dextrose bolus is generally recommended if a patient’s serum glucose is less than 200 mg / dl, followed by a maintenance infusion as needed to prevent hypoglycemic events.11  Hypokalemia may also occur and serum potassium should be actively monitored and replaced.  

Conclusion

As many practitioners know, there are often situations where drugs are used for unapproved indications. Quite often the agent may be somewhat novel and work via mechanisms that may be surprising based on the original indication for use.  Although the use of these agents may become widespread, it is important for clinicians to critically evaluate the available data for the drug’s efficacy and safety.

Ryan Attwood PharmD, BCPS is an Assistant Professor of Pharmacy, Department of Pharmacy Practice. Massachusetts College of Pharmacy and Allied Health Science. Worcester. Email:  Ryan.Attwood@mcphs.edu

Jordan Rush BS is a third year pharmacy student at Massachusetts College of Pharmacy and Allied Health Science. Worcester.  Email: Jordan.Rush@my.mcphs.edu

References:

  1. Cave G, Harvey M, Graudins A. Intravenous lipid emulsion as antidote: a summary of published human experience. Emerg Med Australas 2011;23:123-41.

  2. Rothschild L, Bern S, Oswald S, Weinberg G. Intravenous lipid emulsion in clinical toxicology. Scand J Trauma Resusc Emerg Med 2010;18:51.

  3. Weinberg GL, VadeBoncouer T, Ramaraju GA, Garcia-Amaro MF, Cwik MJ. Pretreatment or resuscitation with a lipid infusion shifts the dose-response to bupivacaine-induced asystole in rats. Anesthesiology 1998;88:1071-5.

  4. Huang JM, Xian H, Bacaner M. Long-chain fatty acids activate calcium channels in ventricular myocytes. Proc Natl Acad Sci U S A 1992;89:6452-6.

  5. Weinberg GL. Treatment of local anesthetic systemic toxicity (LAST). Reg Anesth Pain Med 2010;35:188-93.

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  7. Sirianni AJ, Osterhoudt KC, Calello DP, et al. Use of lipid emulsion in the resuscitation of a patient with prolonged cardiovascular collapse after overdose of bupropion and lamotrigine. Ann Emerg Med 2008;51:412-5, 5 e1.

  8. Carr R, Zed PJ. Octreotide for sulfonylurea-induced hypoglycemia following overdose. Ann Pharmacother 2002;36:1727-32.

  9. Lheureux PE, Zahir S, Penaloza A, Gris M. Bench-to-bedside review: Antidotal treatment of sulfonylurea-induced hypoglycaemia with octreotide. Crit Care 2005;9:543-9.

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  19. Engebretsen KM, Kaczmarek KM, Morgan J, Holger JS. High-dose insulin therapy in beta-blocker and calcium channel-blocker poisoning. Clin Toxicol (Phila) 2011;49:277-83.

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216th Annual Oration of the Worcester District Medical Society
50 Years of Medicine:  Less Art, More Science

By Charles Birbara, MD

This  year, 2012, marks my 50th year as a physician.  During this time, changes in the delivery of medical care have been monumental; take, for instance, the introduction of Medicare, managed care, and the electronic medical  record.   Equally impressive  have been advances in  the treatment of many chronic diseases which all too often resulted in significant long term morbidity and even increased mortality.  Over the past 35 years, I have been fortunate to be involved in many clinical trials of novel agents to treat chronic systemic inflammatory diseases and will recount some of them here.

The destructive processes of all systemic inflammatory disease states are regulated by cytokines, which are small glycoproteins whose primary function is to allow communication between cells  of the immune system.  These are the extracellular communicators which allow macrophages, lymphocytes and dendritic cells to relate to each other.  Cytokines function by binding to specific receptors of the membranes of target cells which then initiate events within these cells, ultimately leading to the production of new messenger RNA and protein.

Tumor necrosis factor-a (TNF) has for years been recognized as a key cytokine in the initiation and progression of the inflammatory process in diseases such as rheumatoid arthritis (RA), psoriasis and Crohn's disease.  Inhibiting its function by binding monoclonal antibodies to its molecular structure stops or curtails the inflammatory process at a very basic level, allowing for symptom resolution and even, in some cases, complete remission.

In the case of RA, the propagating pathology can be very heterogeneous, so that the role of TNF in its pathogenesis may be variable.   In such patients, inhibiting the contribution of cellular elements may be more efficacious than down regulating TNF.  There are two available  FDA approved medications which target lymphocytes and which are capable of inducing clinical improvement and even remission in RA. These are Orencia (abatacept) and Rituxan (rituximab), neither of which has yet demonstrated sufficient efficacy in diseases other than RA to gain FDA approval.

Currently, considerable research dollars are being invested to develop small molecules which, unlike monoclonal antibodies, can be taken orally.  These drugs block intracellular signaling molecules called "kinases" so that the ability of these immune cells to secrete pro-inflammatory  cytokines is blunted.  Unlike monoclonal antibodies which are molecule specific, inhibiting these kinases results in the measured diminution of multiple mediators which contribute to the inflammatory response.  The most advanced of these drugs is" tofacitinib" (Pfizer) which is likely to garner FDA approval for RA  later in 2012.

Over the past 10-15 years, considerable progress has been made in the treatment of the osteoporosis that is so prevalent in our aging population.  While bisphosphonates such as alendronate, risidronate and ibandronate have had a major impact on reducing the incidence of fractures in people with increased bone fragility, there are well-recognized limitations to the use of bisphosphonates over extended time periods.  For this reason, alternatives to currently available medications could have broad clinical appeal.  More recently, denosumab (Prolia), which is given subcutaneously every 6 months and which inhibits the formation and function of osteoclasts, has become available.  Because this molecule does not embed itself in bone, it may well have some advantages with respect to resulting in fewer instances of osteonecrosis of the jaw and atypical femoral fractures which are being increasingly noted with prolonged bisphosphonate use.  On the horizon and well into Phase 3 clinical trials is a Merck compound which inhibits cathepsin K, an enzyme primarily found in osteoclasts and which functions to break down bone matrix.  Multiple studies have demonstrated that inhibition of cathepsin K results in preventing loss of bone strength and decreasing fracture incidence in post menopausal  women.  This medication appears to have an acceptable safety profile, making it likely that it will be commercially available within the next 2 years.

Psoriasis is a systemic inflammatory disease with an incidence of about 2% of the population.  Though striking treatment advances have been made in the past 10 years with the use of TNF inhibitors and monoclonal antibodies directed to IL-12/23 (ustekinumab, Stelara), there is still a significant unmet need in that many patients either fail to respond or lose efficacy to these currently available medications.  In a recent issue of the New England Journal of Medicine (March 29, 2012), clinical trials with monoclonal antibodies inhibiting the function of IL-17 have shown remarkable efficacy in resolution of psoriatic plaque lesions.  Because very few adverse effects were noted in these short Phase 2 trials, further clinical trials are being initiated at this time.  If the currently perceived efficacy and safety profile is maintained in these longer trials, I would expect that these agents will be another significant treatment option for patients who fail to respond to currently available agents.  Clinical Pharmacology Study Group, my clinical trial group, is delighted to have been chosen to participate in the development program of both of these inhibitors of IL-17.

Considerable advances have also been made in the management of tophaceous gout with the recent  FDA  approval of Krystexxa, a recombinant uricase, which has demonstrated a dramatic ability to rapidly decrease serum uric acid and debulk tophi in a matter of weeks.

Charles Birbara, MD, has practiced rheumatology in Worcester since 1970.  He is associate professor of medicine at the University of Massachusetts Medical School and medical director of the Clinical Pharmacology Study Group.

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Ten Years of Health and Medical Preparedness
By Derek Brindisi, MPA and Christopher Montiverdi, MPH, NREMTP

In 1996, the United States Department of Health and Human Services founded the Metropolitan Medical Response System (MMRS) program in response to the increased terrorist threat evidenced by the sarin nerve agent gas attack in the Tokyo Subway system in March, 1995 and the bombing of the Alfred P. Murrah Building in Oklahoma in April of 1995.  The program was designed to enhance and coordinate local and regional response capabilities for highly populated areas that could be targeted by a terrorist attack.  The MMRS concept, organizing principles, and resources are also applicable to the management of large scale incidents such as hazardous materials (HazMat) accidents, epidemic disease outbreaks, and natural disasters requiring specialized and carefully coordinated medical preparation and response.

Since May 2002, the City of Worcester’s Metropolitan Medical Response System (WMMRS) has acted as the catalyst for the enhancement of emergency service capabilities relating to the health and medical needs of victims in the event of a Weapons of Mass Destruction (WMD) attack.  This program is designed to strengthen existing emergency response plans and, when necessary, develop new ones to deal with previously unidentified threats. Worcester authorities recognize that the resources of the City and the Greater Worcester Region would be overwhelmed by the reality of mass destruction, disability, and loss of life should a nuclear, chemical, or biological attack occur. 

The City of Worcester Metropolitan Medical Response System program is administered through the City of Worcester’s Division of Emergency Management within the Department of Emergency Communications. The WMMRS, in cooperation with Worcester’s Division of Public Health (WDPH) and the Commonwealth of Massachusetts, continues to integrate and synchronize individual agency response plans.  Realizing the various federal initiatives to combat terrorism and other large scale events, WMMRS has forged several partnerships with the Centers for Disease Control’s Public Health Emergency Preparedness (PHEP) Program, Partnership for the Enhancement of Regional Preparedness (PERP), and the Assistant Secretary for Preparedness and Response’s (ASPR) Hospital Preparedness Program.  Partnerships such as these integrate MMRS, CDC, PERP and ASPR targeting capabilities which create an increased level of awareness, unification, and communication among the major medical preparedness initiatives nationally.

Since its beginning, the WMMRS has matured into a regional initiative encompassing all 74 communities in Central Massachusetts.  WMMRS meets monthly with all ten ASPR funded hospitals and three area health centers in the 74 communities to develop plans to effectively deal with a public health or medical crisis.  Over the years, regional partners have collaborated on the development of a regional medical coordination center where hospitals and emergency medical services can gather to effectively manage the surge of patients should a mass casualty incident (MCI) occur.   This type of collaborative planning with hospitals and first responders allows for consistent training, such as a radiation patient management and the recent Managing Mass Fatalities Seminar held this past fall at the DCU Center. 

For the past nine years the CDC has funded local boards of health to support this critical need for public health preparedness.  WMMRS in many respects has a similar mission with local public health but is funded through the federal Department of Homeland Security.   In conjunction with the Worcester Division of Public Health, WMMRS is working to increase the state of preparedness for the Region II Public Health Coalition.  A major focus for these Boards of Health is to develop a plan where, if necessary, each community would be able to deliver chemoprophylaxis to its respective population within a 48 hour time period following a highly infectious disease outbreak.  For example, in the City of Worcester nine emergency dispensing sites (EDS) have been established to be used for vaccinating or prophylaxis of its 181,000 residents.  These plans were tested during the 2009 influenza season of novel virus H1N1 where WDPH operated over 150 flu clinics. Part of these planning efforts has allowed the WMMRS to continue to develop its cache of pharmaceuticals with antibiotics and chemical anti-dote kits already warehoused locally. 

During the past decade, health and medical professionals have instituted new approaches and have expanded upon well-established, time proven tactics in response to emergencies.  With the possible use of biological agents as an arsenal of assault, the face of terrorism has brought the discipline of public health into a new arena of responsibility.  The WDPH and WMMRS continue to move forward in addressing the evolution of disaster preparedness, depending heavily on effective communication, new technology and ~ above all ~ the expertise of health and medical professionals.

This is but a brief account of what has been occurring in Worcester and Worcester County since September 11th, 2001.

Derek Brindisi, MPA, is Director of Public Health, Worcester Division of Public Health.

Christopher Montiverdi, MPH, NREMTP, is Deputy Director, Division of Emergency Management.

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A Message From the Worcester Free Clinic Coalition
 

Dear Central MA Physicians,

We are writing to ask for your help in supporting the free medical programs in Worcester.  These programs have been providing medical care to those without insurance or with inadequate insurance for over 17 years and we continue to see high patient numbers.  In order to run, the clinics need a licensed physician present at all times. We are grateful for all of the help we have received from UMass Memorial Medical Group physicians and others who have volunteered their time; however, we still have slots to be filled in the coming months. In addition to physicians, the clinics are staffed by nurses, nursing students, medical students and others such as church volunteers.  

There is a clinic each weeknight (Monday- Thursday) from 6:00 pm-8:30pm.  You can volunteer as often or as infrequently as you would like – many of our current volunteers choose to volunteer monthly or quarterly.  Before your first shift, we will give you a tour of the clinic and a brief orientation to the specific clinic with which you will be involved. Experienced students will be at each clinic during all shifts and they will guide you through the logistics and help to answer any questions you may have. 

One of the most common questions that arises from our physician volunteers involves malpractice and liability insurance.  If you are currently practicing, your current insurance may extend to your work at the clinics.  If you are a member of the UMass Memorial Medical Group, we have a process for this.  If you are affiliated with another medical group or are an independent practitioner, please check with your administrator or insurance representative.  If you are a retired physician and not actively doing paid work, Mass Medical Society generously provides coverage for volunteer work.  We are happy to help with your individual situation. 

If you are interested in becoming involved or if you have any questions or concerns, please email us at worcesterfreeclinics@gmail.com.

Best,

Melinda Palma & Karen Tenner
Volunteer and Physician Coordinators
Worcester Free Clinic Coalition

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