adverse reactions

Thinking About Side Effects

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thinking about side effects

I have been thinking a lot about how we characterize the side effects of drugs. Truth be told, that is a topic that I have pondered on a number of occasions since beginning this website. More often than not, we have no idea about the true breadth and depth of these reactions. We think we do, because assuming some semblance of understanding, even an incomplete one, is what allows us to operate in this space, but when we unpeel the layers of that supposed understanding, it is difficult not to be impressed by how little we actually know.

The manufacturers of these products are required to report adverse reactions and side effects before a drug reaches the market and surveil reactions in the broader population after it reaches the market. From here, regulatory agencies, physicians, researchers, and consumers are expected to trust that we know how these drugs do or do not work. Importantly, we are encouraged by this understanding that any negative reactions experienced will be rare, time-limited, and easily mitigated by other medical products. The possibility that there might be side effects not identified by the original research, that ‘rareness’ is relative, and that ill-effects may not be time-limited or easily corrected is difficult to digest. It throws a wrench in the very foundation of the heavily fortified trust in all things modern medicine.

In reality, it is very difficult to ascertain the scope and depth of potential side effects. This is due in part to the complexity of the interactions between the drug, the human, and the totality of his/her environmental exposures and stressors and in part to the economic underpinnings of these endeavors. If one had to include a broader array of variables in a drug trial, no drug would ever be approved, at least not in a timely or cost-efficient manner. Instead, the initial trials utilize the most healthy of participants, perhaps excluding the disease process in question, and all other variables are excluded, both from the subject pool itself and analytically. Who wants to trial a drug on individuals typical of those who would be taking the drug; on individuals with multiple, often chronic comorbidities, for whom both chronic and acute polypharmacy are the norm and not the exception? No one. That would unfavorably skew the data. Better to have a clean subject pool and limit a priori what might be considered an adverse reaction to those that fall within the typically narrow anaphylactic framework and those that are directly related to the purported mechanisms of action of the drug itself. Addressing potential off-target effects must be eliminated or minimized; ditto for potential interactions between the drug and the unique characteristics of the individual. A clean sample and favorable data are the goal.

To that end, adverse reactions research, analyses, and reporting become a ‘see no evil’ approach. If we do not acknowledge the possibility that these reactions exist, then for all intents and purposes, they do not. This means that only the most severe and ‘on-target’ or anaphylactic reactions may be recognized. Any off-target reactions or side effects are labeled as rare and attributed to extraneous variables, unrelated to the drug but entirely related to some inherent weakness of the human who takes the drug.

If confronted with the prospect of negative reactions or even simply negative data e.g. the drug does not work, it is incumbent upon those involved to utilize analytical tools that highlight the good and hide the bad. Data or participant responses that do not fit the desired narrative must be cleaned or removed, post hoc. When that does not work, it is common to select complex statistical methods that no one but the statisticians themselves understand to obfuscate negative findings. Inasmuch as few physicians and even fewer consumers understand even the most basic statistics, this all but eliminates any questions regarding the veracity of the findings. What is written in the abstract or summary is all that will matter. The lede is buried in the stats so that everyone involved might trust in the medication’s safety, trust in their own knowledge, and move comfortably along with their lives.

I admit, this is a cynical perspective, but it is hard-won. After a decade of publishing HM, researching the analytical methodologies employed by drug companies, of investigating the mechanisms of action of many popular and presumed safe drugs, it is difficult not to be jaded. So flimsy are the safety and efficacy data that one is hard-pressed not to question everything. And so here I am amidst a global pandemic for which multiple products have been rushed to market. Pressure to use these products is intense and I and others are left with the sinking feeling that we do not yet know what we think we know about these products or even what we do not know. What we do know is that the developers and manufacturers of these products have a long and well-established history of shady research practices, of burying negative data, of vilifying anyone who questions these practices, and of financing unquestioning support from politicians, ‘thought leaders’, media, and generally, anyone who might be of use. It is not difficult to recognize those same practices at play here but the desire to be safe quells those concerns for most. We’ll take anything and do anything to end this mess, except perhaps ask why we are here in the first place.

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More people than ever are reading Hormones Matter, a testament to the need for independent voices in health and medicine. We are not funded and accept limited advertising. Unlike many health sites, we don’t force you to purchase a subscription. We believe health information should be open to all. If you read Hormones Matter, like it, please help support it. Contribute now.

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This article was published originally on November 4, 2021. 

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Cognitive Testing Post Adverse Reaction: A Lost Opportunity

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In the not too distant past, before sophisticated brain imaging tests became available, it was the job of the neuropsychologist to assess brain function and brain damage based upon an array of cognitive and behavioral tests. These tests measured the functional capacity of different brain regions. They were entirely behavioral and performance based and could, with a fair degree of accuracy, identify whether and where a brain injury was located and the extent of the damage. Results from these tests could then indicate a need for surgical intervention and/or suggest a prognosis and therapeutic options; options that generally involved a cognitive therapy of sorts to retrain or regain lost capacities.

And then, technology caught up; brain imaging became possible and physicians no longer needed the neurocognitive assessment as a diagnostic, but only for rehabilitation purposes once the brain damage was identified. Non-invasive brain imaging was a remarkable technological advancement. How much better and more accurate diagnoses and interventions could be if physicians were able to see the damage in advance, and indeed, at every phase of treatment. No need to delineate the subtle behavioral signs linked to brain injury in order to diagnose, just scan the brain to rule in or rule out trauma and deal with the deficits after the fact.

Functional Cognitive Testing – A Missed Opportunity

I can’t help but wondering though, if we’ve lost something important by switching so completely to visually based diagnoses. For example, what if the damage is at the molecular level and unable to be detected via imaging, or even via current laboratory markers? How do we even know which lab markers to look for if we don’t ascertain that there are in fact decrements in functioning? Do we even recognize brain injuries as extant if they are not visible by current imaging or laboratory techniques?  I have a sense that we don’t. Cognitive deficits, especially those occurring in previously healthy individuals, following an illness, medication, vaccine or even post pregnancy, may be disregarded along with further diagnostic and therapeutic possibilities when the indices of injury exclude assessing functional capacity.

I was reminded of this recently from a patient story. She, and others like her, experienced a loss of reading comprehension post-fluoroquinolone reaction. Medication and vaccine induced cognitive disruptions are not uncommon. In elderly populations they are quite well documented. In the younger adult populations, however, the research is sketchy at best. In the case I mentioned, the patient was a previously healthy, active young woman. After taking a course of fluoroquinolone antibiotics, and in addition to a myriad of other side effects, she reports losing her ability to comprehend text; something that would be quite disabling in our current text-based world.

I lost a lot of my reading comprehension while I was floxed. I could still officially read – if you gave me a short memo that said, “buy milk,” or something like that, I could read it. But reading a novel or complex materials for work became really difficult. I lost track of the content of the beginning of a paragraph by the time I reached the end of the paragraph. I struggled to understand things that I used to be able to read with ease.

Another fluoroquinolone patient describes her deficit:

I remember going into a restaurant a few months after being floxed. I sat down, looked at the menu, and couldn’t understand a single thing. I couldn’t make sense of anything. It was as though trying to read a foreign language. I put it down, and wanted to stand up and start screaming, and breaking glasses and dishes.

Read any of the fluoroquinolone social media and these observations are not uncommon. Similarly, decrements in cognitive function have been reported in our research on the side effects of the HPV vaccine, during and after Lupron treatments, and even with oral contraceptives.

What I find both most interesting and most troubling is that the loss of attentional capacity, loss of short term memory and loss of language comprehension following the administration of a medication or vaccine may be indicative of a broader health issue; one that should be investigated further. No doubt in many patients these deficits were not explored, at least not functionally, as imaging tests are often negative. That is a shame. Functional cognitive assessments, like those common in clinical practice in the past, and yet still in academic research, would more finely delineate the patterns of medication induced cognitive disorders. These tests could tell us the brain regions susceptible to the medication-induced events in the absence imaging or lab markers. In fact, these tests might help us design more appropriate lab markers. More importantly, functional neurocognitive testing could provide clues about the patient’s overall health. Let me explain.

Linking Cognitive Performance to Overall Health

Each of the medications I mentioned above have distinctly different pharmacological mechanisms of action; so different, one might wonder why I would even consider looking for commonalities in their adverse reaction patterns. Initially, I didn’t. But then the data from our research began flowing in, and along with the data, patient stories began arriving. Slowly, pattern similarities began emerging; similarities that I could not explain by solely looking at the drug’s specific mechanisms of action. There had to be an underlying factor or factors that somehow connected these medications and vaccine reactions. What were they? And per the current topic at hand, how might have functional neurocognitive assessments inspired or expedited our understanding? Not all of the pieces to the puzzle are clear, but here are the clues thus far.

Clue 1. Three of the medications we study negatively affect the thyroid (Lupron, Fluoroquinolones and Gardasil). Thyroid influence on central nervous system functioning, cognitive and behavioral performance is well known.

Clue 2. Thyroid damage is linked to cerebellar ataxia, acute and chronic, via white matter demyelination. Cerebellar ataxia has been noted post fluoroquinolone, post Gardasil and post Lupron.

Clue 3. Thyroid damage is linked to peripheral demyelination. Again, all three medications include demyelination syndromes as part of their reaction profiles.

Thyroid dysfunction alone, without any other intervening variables could explain the cognitive and many of the neurological symptoms we were seeing, but was it sufficient to explain all of them? Probably not, there must something else at play. What could it be?

Clue 4. Each of these drugs are linked to mitochondrial damage (mitochondria are an unrecognized target for many pharmaceuticals and environmental agents). These drugs increase the production of reactive oxygen species (ROS) and decrease cellular energetics via changes in mitochondrial functioning. Mitochondrial damage evokes multi-system, seemingly disparate illnesses, much like what we are seeing. Cerebral mitochondrial dysfunction can cause serious cognitive and behavioral symptoms.

Clue 5. Thyroid and mitochondrial health are reciprocally connected. Damage the thyroid and mitochondrial functioning diminishes. Damage the mitochondria and thyroid functioning diminishes. We have two factors that are inherently related.

Thyroid and Mitochondrial Functioning

What factor could initiate a thyroid – mitochondrial cascade and connect completely dissimilar drugs to these reactions; reactions which are often complex, affect multiple physiological systems, but are also integrally dependent upon proper thyroid and/or mitochondrial function (because of their reciprocal relationship)?  Could there be such a connection?  A few more clues.

Clue 6. A heartwrenching patient story: A Long and Complicated History Topped by Levaquin, highlights a particular set of neurological symptoms that every neuropsych student should immediately recognize.

Clue 7.   Patients from the post fluoroquinolone and the Gardasil groups have been identified clinically with thiamine deficiency. I suspect post Lupron patients may also have thiamine deficiencies, but none have been tested yet.

Clue 8. Both the fluoroquinolones and Gardasil increase thiaminase, an enzyme that blocks thiamine. Higher thiaminase means lower thiamine. Oral contraceptives are believed to increase thiaminase and so women using oral contraceptives in combination with a fluoroquinolone and/or the HPV vaccine Gardasil or Cervarix would be at higher risk for thiamine deficiencies.

Drug Induced Thiamine Deficiency, Cognitive Deficits – The Mechanism

It turns out, thiamine deficiency, or more specifically, a medication induced blockade of thiamine may be at the root of these adverse reactions. Thiamine is a co-factor in mitochondrial and cellular energy, the currency of which is adenosine triphosphate (ATP).  Without thiamine, the mitochondria become defunct, as do the cells in which they reside, and they eventually die. High energy organs like the brain, the heart and the GI tract are often affected dramatically. Similarly, given the reciprocal relationship between the thyroid and mitochondrial functioning and their combined influence on cerebral, cardiac and metabolic homeostasis, diminished drugs that attack the thyroid and diminish thiamine may be doubly dangerous.

In most recent work, thiamine deficient syndromes have been expanded to include five conditions, with fair degree of overlap between them.

  1. Gastrointestinal beriberi: abdominal pain, lactic acidosis, vomiting.
  2. Neuritic beriberi: sensorimotor polyneuropathy, peripheral neuropathy (likely multiple B vitamins involved).
  3. Dry beriberi: high output cardiac disruption without edema
  4. Wet beriberi: high output cardiac disruption with edema (dysautonomias, including POTS)
  5. Wernicke’s encephalopathy: mental status changes, ocular abnormalities, gait ataxia

Given the current nutritional trends with high intake of sugar, fats and processed foods, it is likely that when these medications directly block thiamine production, they do so against the backdrop of already suboptimal thiamine intake. When we consider that oral contraceptives block also block thiamine and that women are more likely to already suffer from low thyroid function, the effects of either the fluoroquinolones or Gardasil on the mitochondrial thiamine could be devastating. How many other medications or vaccines affect mitochondrial functioning and/or thyroid health? How many other medications or vaccines contain anti-thiamine components and diminish this critical mitochondrial co-factor?

Loss of Reading Comprehension and Other Missed Opportunities

Thiamine deficient cognitive decline is well characterized and includes the loss of language comprehension, in more severe cases, deficits in language production, cerebellar ataxia, tremors and as it progresses, seizures, coma, and death. All reversible with thiamine replacement. The cognitive deficits reported by patients, post medication or vaccine reaction, when observed alone but especially when taken in combination with the other tell tale signs of incipient thiamine deficiency, could have lead researchers or clinicians to these diagnoses. At the very least, it should have lead clinicians to thyroid dysfunction, but more often than not, this was not the case.

Cognitive deficits in previously high functioning individuals are reported regularly after medication or vaccine reactions. Almost to a tee, most are ignored once imaging tests rule out blatant injury, but they shouldn’t be. These deficits, when functionally assessed, would provide valuable clues regarding the regions of the brain most susceptible to medication or vaccine induced injuries; clues that could identify damage and disease processes well before detected by imaging tests. By dismissing patient complaints of cognitive deficits we lose valuable research, diagnostic, and therapeutic opportunities. And perhaps, even more importantly, when we segregate symptoms by organ or body part and fail to see the inherent connections among symptoms and physiological systems, we miss the opportunity to help patients heal.

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This post was published originally on Hormones Matter on May 21, 2014.

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Dear Epidemiologists, Consider Fluoroquinolones

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fluoroquinolones

Dear Epidemiologists,

I am writing to encourage you to study the long-term and intergenerational adverse-effects of fluoroquinolone antibiotics (Cipro, Levaquin, Avelox, Floxin, and their generic counterparts). It has been noted by both patient groups and the FDA that fluoroquinolones have long-term adverse-effects, yet many patients and physicians are caught off-guard when fluoroquinolone toxicity symptoms are not transient. Fluoroquinolone toxicity symptoms are similar to those of many multi-symptom, chronic, mysterious diseases of modernity, and epidemiological studies are needed in order to determine if the similar symptoms are coincidental, or if they are indicative of a causal relationship between fluoroquinolone use and many of the diseases that fluoroquinolone toxicity resembles.

The Acknowledged Adverse-effects

The musculoskeletal adverse effects of fluoroquinolones are well-known, and fluoroquinolone antibiotics even carry a black box warning noting that they increase the risk of tendon ruptures. Studies have shown that fluoroquinolones also increase the risk of retinal detachment, and a recent (2015) article in JAMA Internal Medicine noted that the risk of aortic aneurysm and dissection is increased with fluoroquinolone use. All these adverse effects point to fluoroquinolones causing collagen synthesis disorders and/or collagen toxicity.

The 2015 BMJ Open article, “Fluoroquinolones and collagen associated severe adverse events: a longitudinal cohort study” goes over the increased risk of tendon ruptures, retinal detachment and aortic aneurysm and dissection in those given fluoroquinolones. The authors conclude that:

“Current fluoroquinolone use was associated with an increased hazard of tendon rupture (HR 3.13, 95% CI 2.98 to 3.28), and increased hazard of aortic aneurysms (HR 2.72, 95% CI 2.53 to 2.93). The relative hazard of these two collagen-associated adverse events were slightly attenuated after multivariate adjustment, but remained clinically meaningful and statistically significant (table 2). The relative hazard of retinal detachment was modest in magnitude, and only statistically significant after multivariate adjustment (table 2). The magnitude of the association of fluoroquinolones and aortic aneurysm events was stronger than the association observed with other aneurysm risk factors such as hypertension and atherosclerosis (table 3).”

Longer-Term Studies are Needed

“Fluoroquinolones and collagen associated severe adverse events: a longitudinal cohort study” is an excellent study, and I commend the authors for their work. However, a couple of drawbacks of it are that the authors only look at patients who are over the age of 65, and the time-period examined is only 30-days post-exposure, though many fluoroquinolone toxicity patients are under the age of 65, and many experience adverse effects months, or even years, after exposure to the fluoroquinolone.

It would be helpful for both patients and physicians if similar studies were conducted looking at the long-term health outcomes for people of various ages after exposure to fluoroquinolones.

Collagen-synthesis Problems and CNS Symptoms

The relationship between other diseases that have to do with disordered collagen synthesis and fluoroquinolone use should also be examined. For example, fluoroquinolone adverse-effects include many central nervous system symptoms, including convulsions, toxic psychosis, suicidal ideation, dizziness, confusion, tremors, hallucinations, depression, anxiety, insomnia, and many other psychiatric symptoms. It is possible that the collagen in the central nervous system is adversely affected by fluoroquinolones, and that fluoroquinolone use is associated with the rise in psychiatric illnesses in the population. It is a hypothesis that should be explored.

Fluoroquinolones and Multi-symptom, Chronic Illnesses

Many patients who have adverse reactions to fluoroquinolones suffer from multi-symptom, often chronic, illness. Fluoroquinolone toxicity has symptoms that are similar to those of autoimmune diseases (including lupus, rheumatoid arthritis and M.S.), neurodegenerative diseases (including ALS and Parkinson’s), and mysterious diseases like fibromyalgia and M.E./chronic fatigue syndrome, and the symptoms often overlap with those of chronic Lyme disease. (Some patient stories that go over the symptoms of fluoroquinolone toxicity can be found on www.fqwallofpain.com). It would be helpful if some epidemiological studies were done to see if fluoroquinolone exposure predisposes people to a diagnosis of an autoimmune, neurodegenerative or other mysterious diseases.

Those who have experienced fluoroquinolone toxicity see the connections between fluoroquinolones and those diseases—because we went from being healthy to suddenly being sick with symptoms of multiple chronic diseases shortly after taking a fluoroquinolone—but our experiences are only anecdotal unless studies confirm our assertions. Epidemiological studies to determine whether or not there is a connection between fluoroquinolone use and autoimmune, neurodegenerative and mysterious diseases would be immensely helpful in showing whether the relationship is causal or anecdotal.

Fluoroquinolones and Diabetes, Heart-disease, and Autism

Fluoroquinolones have been shown to cause dysglycemia and use of fluoroquinolones is correlated with type-2 diabetes. Diabetes is a growing problem that is causing pain and suffering to millions of people worldwide. If even a small percentage of diabetes cases could be prevented through more prudent use of fluoroquinolones, much pain and suffering could be alleviated. Quantifying the relationship between fluoroquinolone use and diabetes via an epidemiological study would be immensely useful.

Given that fluoroquinolones have been shown to increase incidence of aortic dissection and aneurysm, it would be interesting to see if they are associated with heart-disease more generally.

It was noted in the 2013 article in Nature, “Topoisomerases facilitate transcription of long genes linked to autism” that, “chemicals or genetic mutations that impair topoisomerases, and possibly other components of the transcription elongation machinery that interface with topoisomerases, have the potential to profoundly affect expression of long ASD (autism spectrum disorder) candidate genes.” Since fluoroquinolone antibiotics are the most commonly prescribed topoisomerase interrupting drugs, it is worthwhile to look into whether or not they are related (intergenerationally, most likely) to autism.

Longer-Term Studies are Needed

It has been known for many decades that fluoroquinolones have serious and severe adverse-effects, yet very few studies of the long-term effects of fluoroquinolones have been conducted. Fluoroquinolone affected patients have been noting that they have experienced fluoroquinolone toxicity symptoms months, or even years, after administration of the drugs has ceased, and even the FDA has noted that fluoroquinolone associated disability (FQAD) is a consequence of fluoroquinolone use. However, fluoroquinolone studies have primarily concentrated on adverse-effects that occur while the drug is being administered. Long-term, and even intergenerational, epidemiological studies will enlighten us to the true consequences of fluoroquinolones.

Many Questions to Study

How much does fluoroquinolone use increase a person’s risk of getting an autoimmune disease? How much more likely is a person to become diabetic if they use a fluoroquinolone to treat a sinus infection? How much more likely is a person to need a pain medication like Lyrica if they have been prescribed a fluoroquinolone in the past? Are thyroid diseases more common in those who have taken fluoroquinolones than in those who haven’t? Are psychiatric illnesses more common in those who have taken fluoroquinolones? Are people more likely to suffer from heart-disease if they have taken a fluoroquinolone? Are there any intergenerational effects of fluoroquinolones, and, if so, how are they manifesting?

These are all reasonable questions to ask, given the long list of adverse-effects caused by fluoroquinolone antibiotics.

Patients have been screaming about the connections between many of the diseases of modernity and the symptoms of fluoroquinolone toxicity for years, but our screams will only be heard if there is data to back them up. Studies need to be done to get necessary information, so I encourage all scientists who have the access to data and expertise needed, to study fluoroquinolones. People are being hurt by these drugs. Information, data, science and a bit of enlightenment, will help to encourage more prudent and appropriate use of fluoroquinolones, so that the pain caused by them can be minimized.

To all the scientists who have studied fluoroquinolones—your work is appreciated and I hope that it is built upon. Thank you in advance to all those who look further into fluoroquinolone adverse reactions. Your work will be greatly appreciated as well.

Regards,
Lisa Bloomquist
Patient advocate and founder of Floxiehope.com

We Need Your Help

More people than ever are reading Hormones Matter, a testament to the need for independent voices in health and medicine. We are not funded and accept limited advertising. Unlike many health sites, we don’t force you to purchase a subscription. We believe health information should be open to all. If you read Hormones Matter, like it, please help support it. Contribute now.

Yes, I would like to support Hormones Matter. 

Photo by Aaron Burden on Unsplash.

This letter was published previously on Hormones Matter in December 2015.

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SCOTUS Decision on Medication Safety: No Product Liability

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Scotus FDA generic drug ruling

Over two years ago, amidst the DOMA and Voting Rights cases, the Supreme Court of the United States (SCOTUS) quietly ruled in favor of pharmaceutical companies indicating that generic drug makers have no legal obligation to update labeling and warn patients of nasty side-effects should those reactions occur post FDA approval. The case, Mutual Pharmaceutical Co. v Bartlett is a decision that will affect medication safety, healthcare responsibility and states rights for years to come, but few in the media bothered to cover the ruling.

Background of the Case: Mutual Pharmaceutical Co. v Bartlett

In 2004 Karen Bartlett was prescribed a topical NSAID pain-reliever called Sulindac for her shoulder pain. Sulindac is generic version of Merck’s Clinoril that is manufactured by Mutual Pharmaceutical. Shortly thereafter she developed toxic epidermal necrolysis (TEN) – a severe, life threatening and debilitating adverse reaction to the drug. Sulindac caused her skin to peel away from her body, a gruesome, flesh-eating reaction that spread over most of her body.

According to documents discovered later, the drug makers, Merck originally and Mutual for the generic version, knew about the potential for TEN but failed to label it. (Merck has since changed their labeling). Ms. Bartlett sued Mutual under New Hampshire’s design-defect law and was awarded $21 million. Mutual appealed under the auspices that they were not responsible for labeling because that rested with the federal government and the FDA. Since the FDA had not, in its original approval of the drug included the warning, the generic company could not change the labeling without violating federal law. Moreover, even though not labeling the drug violated New Hampshire state law, under which the case was originally brought, state law was in conflict with federal law.

Ms. Bartlett’s case before SCOTUS rested on the fact that Mutual knew about the ‘defect’ and failed to warn consumers. In state court she won. But in the appeal, Mutual contended that even though they knew about the dangers of the drug, as a maker of generic drugs, which are essentially copies of the name-brand drugs, they were not only not responsible for the labeling, Merck and FDA were, Mutual could not change the labeling under federal law. The state’s remedy, and upon which much of the SCOTUS case rested, was to not permit the sale of the ‘defective’ product – the drug – in New Hampshire. In other words, to abide by state law, Mutual should not have sold and not be allowed to sell the product in New Hampshire. SCOTUS again disagreed, effectively forcing the sale of ‘defective’ products’ in states.

There was no question that the drug was responsible for Ms. Bartlett’s injuries, but the since the case rested on the eminence of federal versus state law and the work-around proposed by the state, there was ample precedence for SCOTUS to overturn the lower court’s ruling and they did so, 5-4, mostly along party lines.

SCOTUS documents:

We must decide whether federal law pre-empts the New Hampshire design-defect claim under which respondent Karen Bartlett recovered damages from petitioner Mutual Pharmaceutical, the manufacturer of sulindac, a generic nonsteroidal anti-inflammatory drug (NSAID). New Hampshire law imposes a duty on manufacturers to ensure that the drugs they market are not unreasonably unsafe, and a drug’s safety is evaluated by reference to both its chemical properties and the adequacy of its warnings. Because Mutual was unable to change sulindac’s composition as a matter of both federal law and basic chemistry, New Hampshire’s design-defect cause of action effectively required Mutual to change sulindac’s labeling to provide stronger warnings. But, as this Court recognized just two Terms ago in PLIVA, Inc. v. Mensing, 564 U. S. ___ (2011), federal law prohibits generic drug manufacturers from independently changing their drugs’ labels.

In an opinion written by Justice Alito:

Accordingly, state law imposed a duty on Mutual not to comply with federal law. Under the Supremacy Clause, state laws that require a private party to violate federal law are pre-empted and, thus, are “without effect.” Maryland v. Louisiana, 451 U. S. 725, 746 (1981) .

The Court of Appeals’ solution—that Mutual should simply have pulled sulindac from the market in order to comply with both state and federal law—is no solution. Rather, adopting the Court of Appeals’ stop-selling rationale would render impossibility pre-emption a dead letter and work a revolution in this Court’s pre-emption case law.

Accordingly, we hold that state-law design-defect claims that turn on the adequacy of a drug’s warnings are pre-empted by federal law under PLIVA. We thus reverse the decision of the Court of Appeals below.

Why This Matters

SCOTUS ruled that manufacturers of generic drugs have no safety or labeling obligations beyond what was expressly given by the brand name company and the FDA approval. If the FDA approved a particular label and adverse events appear later, even when associated with the generic drug, the manufacturer of the generic drug is not liable. The makers of the brand name drug are still liable, but only for their brand name drugs. When an individual is given the generic version rather than the brand name version, even if those two compounds are exactly the same, the individual cannot sue the generic manufacturer per this new ruling, nor can he/she sue the brand name manufacturer, because the adverse event occurred with the generic and the brand name company is not responsible for the generic.

Since the majority of all prescriptions are for generic medications, this ruling effectively absolves drug manufacturers of responsibility for adverse events, once FDA approved.  What’s more, where states could have stepped in and prevented the sale of defective products within their boundaries, this ruling preempts that protection as well. If the federal agencies say it is safe, the states can do nothing. For a conservative court, this is a pretty big usurping of states rights.

Can we sue the FDA for failing to protect consumers?

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More people than ever are reading Hormones Matter, a testament to the need for independent voices in health and medicine. We are not funded and accept limited advertising. Unlike many health sites, we don’t force you to purchase a subscription. We believe health information should be open to all. If you read Hormones Matter, like it, please help support it. Contribute now.

Yes, I would like to support Hormones Matter. 

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Side Effects and Unintended Consequences of Popular Pharmaceuticals

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Lisa Bloomquist

After experiencing an adverse reaction to a popular antibiotic, ciprofloxacin, that involved destruction of my tendons, muscles, and cartilage, as well as my central, peripheral and autonomic nervous systems, I was left with questions that no one seemed to be able to answer – What did ciprofloxacin do to my body?  What happened that made it feel as if a bomb had gone off in me?  Why was I fine after taking ciprofloxacin once, but was far from fine after taking it a second time?  Why can some people tolerate ciprofloxacin and other fluoroquinolone antibiotics with no ill effects, but others can’t and are destroyed by a single prescription?  And the most important question of all – How could I put my body and mind back together again?

I scoured research journals for answers to these questions. The answers that I found were daunting.  I found that ciprofloxacin and other fluoroquinolone antibiotics are topoisomerase interrupters – meaning that they disrupt the enzymatic process of bacterial DNA replication (and mitochondrial DNA replication).  I found that fluoroquinolones deplete intracellular magnesium.  Depletion of intracellular magnesium has multiple health consequences including disruption of more than 300 enzymatic processes.  I realized that both enzyme depletion and magnesium depletion lead to mitochondrial dysfunction.  I found that mitochondrial dysfunction leads to high levels of oxidative stress and that oxidative stress wreaks havoc on multiple areas of health.  I discovered that the carboxylic acid molecule in fluoroquinolones can be metabolized into poisonous metabolites in the liver. I learned how feedback loops between multiple biological systems work together and those compensatory feedback loops make repairing damage difficult.

The more I learned about the complex interactions occurring in my body, the more I realized that the number of unknown factors is far greater than the number of known factors. I realized that, as much as I wanted easy answers and quick solutions, there were none available. Because of the complexity of the human body, as well as individual differences in both genetics and environment, I doubt that easy answers will ever be available. Any one of the many complex systems within the human body can be studied for a lifetime without knowing everything about it. The multiple systems within our bodies are interconnected, difficult to comprehend, poorly understood and truly amazing. Human life is astoundingly, beautifully, mind-bogglingly complex.

Mind Blowing Complexity 

This chart of metabolic pathways shows just one level of biochemical complexity in the human body. Click and take a look. Amazing, isn’t it?  I find the pathways to be both incredibly daunting and beautiful at the same time. As complex as that chart is, it doesn’t include everything. There are additional layers on top of it – genetics, epigenetics, equally complex charts about the microbiome, endocrine system, bioenergetics, etc.

Even though the metabolic pathways in the chart above are known (if they weren’t, they wouldn’t be in the chart), I suspect that the interactions between the metabolic pathways, and the connections between them and other complex systems, are not adequately considered in healthcare. How could they be? These pathways are so mind-blowingly complex, and so interconnected with layer upon layer of feedback and feedforward loops amplifying any disruption and miscalculation, that if we were to properly consider the ramifications of pharmaceutical alterations, no one would dare take most medications. We would recognize the limits of our abilities to predict and treat the inevitable unintended consequences of disturbing the balance within and among these systems. Since pharmaceuticals are a trillion dollar industry, it is safe to say that all of the potential effects of pharmaceuticals on these pathways are not fully considered.

Pharmaceuticals Disrupt Biochemical Pathways

Every pharmaceutical has an effect on those pathways. When the drug interacts with the metabolic pathways as expected, all parties involved are pleased. When the drug interacts in unexpected or unwanted ways, we say that there are “side-effects.” I wonder though, are there really side-effects, or is that just a more palatable expression about the limits of our understanding (and attention)? One could argue that if we paid more attention to the broader biological systems involved in human health, those “side-effects” would be entirely predictable. But we don’t. Instead we focus our medication efforts on narrowly defined targets, destroying a particular pathogen or amplifying or diminishing a specific cell cycle function, all the while ignoring that those processes are conserved systemically. Perturbations in one organism or one function, necessarily affects the entire system. Nothing happens in isolation.

If we were to consider the potential for drugs to initiate systemic reactions, and if the effects of drugs on metabolic pathways were properly regarded, fluoroquinolones and many other drugs and vaccines would not be on the market. But we don’t. Instead, we choose to believe that side-effects are rare and won’t happen to us. Those beliefs are bolstered by decades of marketing to physicians and patients, promoting the safety and efficacy of each drug, often long after science and the legal system have disputed those claims.

Fluoroquinolones, the drugs I know most about, deplete intracellular magnesium (note how many times you see Mg in the chart) and disrupt vital enzymatic processes (which are kind of important). Can you even imagine there not being unintended consequences to depleting vital minerals from a system that is as complex and interconnected as cellular biochemistry and metabolic pathways that determine human health?  I cannot imagine it, because after learning about how fluoroquinolones react in the body, I know too much to believe the marketing propaganda about any drug. Before my adverse reaction, however, I never gave the safety of antibiotics a second thought. It appears neither did my doctor, nor the millions of other physicians who have made the fluoroquinolone class of antibiotics the most prescribed and profitable antibiotics ever.

I know that there are some very smart scientists out there; people who are far more intelligent than I, who have a much better grasp of biochemistry – so why aren’t the dangers of fluoroquinolones more well-known? Why aren’t the side-effects entirely predictable? Why did I have to figure out all of this on my own, without help from the physician who prescribed the medication or the physicians I saw post reaction? Sadly, I have come to believe that most physicians and patients alike don’t want to recognize the complexity of human health; preferring instead to believe in our own intellectual supremacy. And as much as I appreciate the scientists who are doing the work on which I have based my assertions, I don’t think that there is anyone who understands the complex biochemical feedback loops sufficiently to guarantee that there won’t be unintended consequences when disrupting part of the system with a pharmaceutical.

Unintended Consequences

How can one avoid the unintended consequences that come with disruption of the biochemical interactions described in this chart?  Individualized medicine that takes into consideration genetic predispositions is one place to start, but it requires that we recognize the complexity of interacting systems and abandon our silver bullet approach to medicine. From where I sit, this is a long way off. Individualized medicine based on genetic predispositions barely exists. If we consider the complexity of a lifetime of environmental exposures, predicting how a particular drug will react in given individual is complex, if not impossible. For me, the most feasible way to avoid unintended disruptions and feedback loops is to avoiding pharmaceuticals (or at least use them very sparingly). Each medication has side-effects and unintended consequences. All drugs disrupt the very biochemical feedback loops necessary for keeping us healthy.

Avoid the Cause in Order to Avoid the Effect

Perhaps, I am the medical equivalent of a Luddite. Perhaps, I over-emphasize the harm done by pharmaceuticals and underestimate the good done by them because I was hurt by a drug. I see the unintended consequences of disrupting the delicate balance of biochemical pathways everywhere. All of the diseases of modernity can be traced to a disruption on the chart above (or maybe a disruption on the endocrine system chart, or the microbiome chart, or the epigenetics chart). People are sick; not cells in a petri dish – people. They are sick and they are suffering because of disruptions in their biochemistry.

These systems are complex. The feedback loops between systems amplify the complexity and make mistakes and miscalculations difficult (impossible) to correct.

Disruptions in our biochemistry result in disease.

We live in a world of unintended consequences. Does anyone else see it?

Information about Fluoroquinolone Toxicity

Information about the author, and adverse reactions to fluoroquinolone antibiotics (Cipro/ciprofloxacin, Levaquin/levofloxacin, Avelox/moxifloxacin and Floxin/ofloxacin) can be found on Lisa Bloomquist’s site, www.floxiehope.com.

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