Short Bits for a Short Month

Doc Gumshoe on flu shots, penicillin allergies, esketamine,supplements and more...

By Michael Jorrin, "Doc Gumshoe", March 7, 2019

“For such a beastly month as February, 28 days as a rule are plenty,” said the Pirate King.   But you would be surprised at the number of interesting snippets of news in the health-care realm that landed in my inbox during this short month.   I’ll lead off with one that gave me a particular kick.

FDA advisory panel votes to approve J & J’s esketamine

When I was writing the piece about ketamine (“Ketamine: Menace or Miracle”) which posted on January 21st, I had no notion that Johnson & Johnson was working on this agent, which was developed by Janssen Pharmaceuticals, a division of J & J.   Esketamine is an antidepressant delivered by means of a nasal spray, and it is an enantiomer of ketamine. The advisory panel voted 14 to 2 in favor of approving the drug, which makes it highly likely that it will get full FDA approval.   Some advisors expressed the view that esketamine might be the most important drug for treating depression in about 40 years.

… breaking news!

In fact, yesterday (March 5th) as I was writing this (as you see, I’m a bit late in getting it over the net), the FDA did approve esketamine for patients who have not responded to current antidepressants.   It will be marketed under the name Spravato and available only under a controlled distribution plan. Patients will not be able to take the drug at home. It must be taken while the patient is under observation by a health-care provider for at least two hours.   And patients will be cautioned not to drive or operate heavy machinery on the day of treatment.

The plan, at least at the start, is for two treatments per week for four weeks, at a cost of $4,720 to $6,785.   Patients who respond to treatment initially will progress to weekly or semi-weekly treatment at a somewhat lower cost.   However, it is thought that most health insurers will cover esketamine/Spravato.

What is the difference between ketamine and esketamine?   The ketamine molecule can exist in two forms, one of which is the precise mirror image of the other.   The name “esketamine” refers to S-ketamine, one of the two forms of ketamine. The two forms are called enantiomers, dubbed S and R enantiomers, meaning left (sinister) and right (rectus).   All the atoms in the molecule are identical and identically linked, but the two mirror images (like our left and right hands) can have different physiologic effects based on their shapes. One of the enantiomers can precisely bind to a receptor, while the other enantiomer cannot.   For example, esketamine, the S enantiomer, has approximately four times the affinity for the glutamate N-methyl-D-aspartate (NMDA) receptor as its mirror image, R-ketamine. Blocking this receptor is thought to be responsible for the anaesthetic effects of ketamine.

Physicians have been using ketamine as an antidepressant off-label for about 20 years, usually to treat patients who have not responded to treatment with currently-approved antidepressants.   Experience with ketamine as an antidepressant in general supported the view that ketamine was not only effective in previously non-responsive patients, but also that it had a much faster onset of action than traditional antidepressants.

J & J ran three pivotal trials with esketamine, two of which missed their primary endpoints.   However, the evidence from these trials was enough to convince the advisors that the benefits of esketamine conclusively outweighed the risks.   For example, response rates to esketamine were over 60% as early as four and a half hours after a single dose. These benefits were sustained at the 24 hour mark.   About 40% of subjects experienced continued benefits from esketamine after 7 days.

It’s obvious that depression is not something that can be observed and measured accurately from exterior signs, so studies of depression perforce need to rely on some form of patient-reported information.   In the studies with esketamine, the efficacy endpoints were changes in the score from baseline on the Montgomery-Asberg Depression Rating Scale (MADRS). Even though in two of the trials, the primary endpoint was missed, the advisors gave considerable weight to the need for a fast-acting antidepressant that was effective in patients who had previously not responded to treatment.   

Another factor that weighed in favor of a positive vote by the advisors was that esketamine also had reduced thoughts of suicide in the trial subjects.   Suicide risk was assessed using the Suicide Ideation and Behavior Assessment Tool.

The most common adverse events among participants in the esketamine group were nausea, dizziness, dissociation, unpleasant taste, and headache.   (Dissociation is a sense of distance from one’s perceptions and even one’s thoughts, as in “this is all a dream and I’ll soon wake up to the real world.”)

Doc Gumshoe, by the way, is not in the least surprised to see that J & J has stepped in and grabbed this potentially lucrative drug.   As I’ve said several times, Big Pharma has its eyes fixed on any substance, natural or artificial, that could become a genuine drug. If there’s even a hint that psoriasis (for instance) could be treated with an application of something normally used as shoe polish, one of the biggies would be in there figuring it out.   They have the scientific expertise as well as the financial clout. Don’t underestimate them!

Do you think you have a penicillin allergy?

If you do, you’re among the 10% of people in the US who think they have a penicillin allergy.   That percentage is even higher – 15% – in older people and hospitalized patients.

However, the key word is “think.”   The reality – the percentage of people who actually do have a real honest-to-goodness penicillin allergy – is much, much lower.   According to a paper in the Journal of the American Medical Association (“Evaluation and Management of Penicillin Allergy: A Review,” Shenoy ES, JAMA 2019 Jan 15;321(2):1888-1999), identifying large numbers of individuals as penicillin resistant leads to significant problems, not just for the individuals themselves, but for the health-care system as a whole.

Most people who are labeled as allergic to penicillin have not been tested for this form of allergy.   In the great majority of cases, the designation as “allergic to penicillin” occurs when an individual receives a dose of one of the penicillin-related drugs and experiences some kind of adverse reaction, which is attributed to the drug, when in fact it may have nothing to do with the drug at all.   The adverse reaction is noted in their medical record as a penicillin allergy and is accepted as a verified fact. Health-care providers in the future will note the supposed penicillin allergy and steer that patient away from those drugs.

The authors of the JAMA paper stress that putting unverified penicillin allergies in a patient’s medical records is contrary to good antimicrobial policy.   It leads to unnecessary use of other broad-spectrum antibiotics that are not only less effective, but also foster the emergence of strains of bacteria that are resistant to antibiotics.   These include methicillin-resistant Staphylococcus aureus, known as MRSA, and also vancomycin-resistant Enterococcus. Broad-spectrum antibiotics also contribute to the emergence of Clostridium difficile (C.diff).

Penicillin is the term sometimes used for a number of related drugs in the much larger group of beta-lactams.   This includes several forms of penicillin itself, along with amoxicillin, ampicillin, methicillin, and several others.   These drugs are among the safest and most effective for a number of the most common illnesses, including respiratory diseases and skin and soft tissue infections.   The drugs used instead of penicillins and related drugs, including fluoroquinolones and cephalosporins, may be both less effective and more associated with side effects.   And because they are broader spectrum than the penicillins, they are more likely to induce resistant strains of those pathogens.

The JAMA paper asserts that true allergic reactions to penicillin, mediated by immunoglobulin E or by T-lymphocytes, are rare.   Dr David Lang, recently elected president of the American Academy of Allergy, Asthma, and Immunology, and chairman of Allergy and Immunology in the respiratory institute at the Cleveland Clinic, was quoted in the NY Times as follows:   “We used to say that nine out of ten people who report a penicillin allergy are skin-test negative.   Now it looks more like 19 out of 20.”

The skin test is easy and fairly reliable.   If a person has had what could be an allergic reaction to one of those penicillin-related drugs, such as amoxicillin, a skin test is recommended.   The test consists of making a small scratch on the patient’s skin, using a needle daubed with a very small quantity of a penicillin reagent. If the patient develops a rash at the site, that confirms the suspicion that the patient is allergic.   Sometimes, if there is doubt as to the signal sent by the scratch test, a second test may be carried out, in which the penicillin reagent is injected under the skin. If these tests are negative, it can be stated with close to 100% accuracy that the tested individual is not allergic to penicillin.   

Responses to penicillin that have a higher probability of being actual allergic reactions would include shortness of breath, local inflammation, hives, or a rash.   But responses such as nausea, vomiting, and headache are common reactions to many drugs, and are not necessarily allergic reactions.

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What does this come down to?   Doc Gumshoe would make the following points:

  1. If you have a mild reaction to an antibiotic in the penicillin family (e. g., amoxicillin), don’t be in a hurry to assume that it’s because you’re allergic.   And don’t assume that because there’s a family history of penicillin allergy, you share that allergy as well.
  2. Even if you once had a real allergic reaction to one of those drugs, don’t assume that a dose of that same drug several years later would result in the -same response.   Allergies can diminish over time.
  3. Rather than going on a regimen with an alternative drug, it would be a good idea to get tested.   Alternatives to drugs in the penicillin family tend to be less effective and also induce the proliferation of resistant pathogens.
  4. Be careful about what goes in your medical records.   Once it’s in there, it is devilishly hard to get it out, and it could cause you harm.

And now, here’s something to keep an eye on.

A universal flu vaccine is getting close to Phase 3

This would be a huge contribution to global health.   Currently, as you know, the flu vaccine has to be reformulated every year.   This means that starting more than six months in advance of the flu season, the vaccine makers have to arrive at a prediction as to which flu strains are going to be the dominant strains in the coming season.   Once this prediction has been made, they need to go into production full speed ahead. More than once, the prediction has been wrong and the vaccine based on that prediction has not been effective in a large number of cases.   And they have to go through this process – which is part guessing game and part rush to the finish line – every single year.

The prospective candidate for the universal flu vaccine crown comes from a UK biotech called hVivo, which recently announced Phase 2b results showing that their vaccine was able to significantly reduce the symptoms of mild-to-moderate influenza as compared with placebo.   The vaccine, which for now is called FLU-v, reduced the flu symptoms, potentially relegating influenza to a much milder disease. It also elicited an immunologic response in the trial subjects, suggesting that persons immunized with this vaccine would continue to reject flu infections well beyond the duration of effectiveness of the current generation of vaccines.   

FLU-v is a sterile mixture of four polypeptides that encode the immunoreactive conserved regions within the influenza virus.   What that means is that the vaccine would tend to be effective against any flu strains that had those conserved regions. Of note, the conserved regions persist when the virus mutates, so the vaccine should be effective regardless of mutations.   The Phase 2b study identified 32 healthy male subjects who had not received the seasonal flu vaccine and had no medical history of an influenza-type illness in the past 12 months. Of the 32 subjects, 16 received the FLU-v vaccine and 16 received placebo.   All patients were exposed to influenza H3N2 virus. Patients vaccinated with FLU-v developed substantially increased levels of cellular immunity as well as demonstrating significantly reduced severity of symptoms (P < 0.005). (Pleguezuelos O. Clin Vacc Immunol 2015 122;7:828-835)

Conducting the Phase 3 study will be a major challenge for hVivo, which has formed a partnership with the SEEK Group, another UK pharmaceutical company.   The partnership has been named Imutex, and this new entity is also planning to develop vaccines against other diseases, including the Zika virus. The challenge is not only financial, but logistical: recruiting a sufficient number of healthy volunteers who would submit – for example – to being inoculated with a placebo vaccine and then exposed to the real influenza virus.   At this point, the actual design of the Phase 3 study is not generally known. No doubt the Imutex partners have been trying to figure it out for quite a while. We’ll find out eventually, I trust.

And while we’re on the subject of influenza vaccines …

Getting your flu shot increases your chances of surviving heart failure

The evidence for this meets Doc Gumshoe’s high standards.   It comes from a Danish study (Morin D. Circulation 2018;139:575-586) which examined the records of all patients in Denmark who were 18 years of age or older and had been diagnosed with heart failure between 2003 and 2015.   This cohort consisted of 134,048 individuals, 99.8% of whom were tracked for a median time of 3.7 years.

Influenza vaccination rates in this group ranged from 16% to 54% during the study period.   After adjusting for any variables that might have an effect on heart failure survival, the conclusion of the study was that individuals who had received at least one flu shot during this period had an 18% lower overall risk of death from any cause, and also an 18% lower risk of death from any cardiovascular cause.   These results were judged to be highly significant (P < 0.001).   Annual vaccination, vaccination earlier in the year (before the beginning of flu season), and a greater cumulative number of vaccinations, were factors associated with a greater reduction in the risk of death.

It was noted by the study authors that the death rate risk reduction was in the same range as the reductions associated with drugs that have specific cardiovascular mechanisms of action, such as beta blockers and ACE inhibitors.   These drugs reduce heart failure mortality in patients diagnosed with heart failure by about 20% to 25%.

Dr William Schaffner of Vanderbilt University commented that, “Influenza immunization is inexpensive and quick, and I don’t think that cardiologists can do anything else to benefit their patients that has the immediate impact that influenza vaccination does or is as cheap.   So I think every cardiologist ought to be doing this, starting the day after this paper is published.”

Does the influenza vaccine have any specific cardiovascular benefit?   The Danish study provides no evidence of any specific cardiovascular mechanism.   The likely reason that vaccinated individuals had lower death rates is that for those who already have heart failure symptoms, the added stress of a flu infection may be the difference between life and death.   However, that in no way diminishes the strength of the association, nor the validity of the recommendation – get that flu shot!

And now there is good evidence that flu shots are safe in pregnancy, after all

The doubts as to whether it was safe for pregnant women to get an influenza vaccine arose out of a study by Dr Edward Belongia, who heads the Center for Clinical Epidemiology and Population Health at Wisconsin’s Marshfield Clinic.   This is the third time that Dr Belongia’s team has investigated the relationship between flu shots and miscarriages. The first time, following the 2005 – 06 and 2006 – 07 flu seasons, found no association between flu shots and miscarriages.   But then, after the 2009 influenza pandemic, attention was focused on a new variant of the H1N1 strain, labeled pH1N1. The vaccine for the 2010 – 11 season contained the antigen for that particular strain, and the CDC requested the same team to do a follow-up study to make sure that the new vaccine was also safe in pregnancy.   

The study could, of course, not be prospective.   It compared two groups of women: the cases – 485 women – were those who had experienced spontaneous abortions (i.e., miscarriages), while the controls were those who had given birth at term.   There were two surprising findings: one, women who miscarried were somewhat more likely to have received a flu shot in the previous 28 days; however, there was no association between miscarriage and flu shots in any other time periods during the pregnancy.   That particular association did not reach significance. However, women who had been vaccinated only during the previous flu season did have a somewhat increased number of miscarriages.   The findings by Dr Belongia’s group raised red flags, and the authors asserted that their study could not establish a causal relationship.   (Donahue JG. Vaccine 2017;35:5314-5322)

Consequently, the team went back to work, and conducted a new study, which was larger than the first and specifically designed to examine the question whether flu shots were safe during pregnancy.   An overview of the study findings was recently presented at a meeting of the Advisory Committee on Immunization Practices, which guides vaccination policy for the Centers for Disease Control and Prevention.   It will shortly be submitted to a peer-reviewed journal for publication.

Meantime, Dr Belongia has expressed considerable confidence in the outcome.   “For women right now who are wondering if it’s safe to get a vaccine in early pregnancy, we can say unequivocally, ‘Yes, it is safe!’”

(By the way, for you careful readers who wonder how it is that Dr Belongia is the authority I quote, yet the name on the study is Donahue, please know that the convention for listing study authors is that the lead author’s name goes last.   Dr Belongia is the lead author, but the citation of the study does not necessarily include the lead author. Don’t ask me why.)

Maintaining cognitive function: do vitamin and mineral supplements help?

Sorry to put it that way, but the answer seems to be “No.”   This is based on a Cochrane database that analyzed data from 28 studies with more than 83,000 participants.   Most of these studies were not specifically designed to evaluate the effects of vitamins or supplements on cognition, but included assessments of cognition among other factors.   The purpose of the Cochrane analysis was to assess the effectiveness of vitamin and mineral supplementation in cognitively healthy people in mid and late life. (Rutjes AW. Cochrane Database Sys Rev 12/17/18)

The studies were grouped as to the specific vitamin and/or mineral supplements being employed in the study subjects.   

There were 14 studies with 27,882 participants which compared folic acid, vitamin B12, vitamin B6, or a combination of these to placebo.   These studies found that giving those supplements to healthy adults had little or no effect on cognitive function at any time point up to 5 years, and also probably no effect at 5 to 10 years.

There were 8 studies with 47,840 participants which assessed the effects of antioxidant vitamins: β-carotene, vitamin C, or vitamin E.   There was possibly some evidence of benefit associated with β-carotene after a mean of 18 years of treatment and of vitamin C after 5 years of treatment; however, this evidence was assessed at having a low degree of certainty.   Vitamin E, whether with or without selenium, appeared to have no effect on cognition. Although prostate cancer diagnosis was not one of the goals of the study, it was found that Vitamin E use was linked with a higher incidence of prostate cancer.

There was one study with 4,143 participants which evaluated the effects of vitamin D3 and calcium supplements.   There was no evidence of any effect of this regimen on cognition at any time point up to 10 years.

One trial with 1,072 participants demonstrated that zinc and copper supplements had no effect on overall cognitive function.   

One study with 3,711 participants came to a similar conclusion regarding the effects of selenium supplementation on the incidence of dementia.   

Finally, three trials with 6.306 participants, evaluating the effects of complex vitamins, consisting of B vitamins, antioxidant vitamins, and minerals, were analyzed.   One of these trials specifically looked at overall cognitive function and found that there was little or no effect.

The Cochrane study’s authors admitted that they were disappointed; they had hoped to find a vitamin or mineral supplement, or a combination of these, which could be recommended to a clinician as a means of maintaining cognitive functions and perhaps staving off dementia.

Doc Gumshoe also admits that he is disappointed, but not hugely surprised.   Cognitive function is strongly associated with years spent in school, college, university, etc – the more the better.   It is also associated with activity – dialing down activity seems to dial down cognition. A lot of those “bad habits” – smoking, excessive drinking, etc – are not good for cognition.   But so far, specific links between cognition and nutrition have been elusive. You can eat all the kumquats you want and it won’t make you any smarter.

And there’s something else about supplements …

776 supplements have been identified as being adulterated with active drugs

We’ve discussed the surprisingly large percentage of supplements where you simply don’t get what you pay for, because they have been adulterated with all kinds of fillers.   In a previous piece about the drugs vs. supplements feud, I referred to the Canadian study that found that of the supplements from 12 marketers, only 2 were exactly as represented on their labels.   Two were totally bogus, and the other 8 were significantly adulterated, sometimes with potentially harmful ingredients.

But this item is different.   What the FDA found was that supplements were adulterated with drugs that had a similar effect to the one that the supplement was supposed to produce.   What that means is that the buyers of supplements, who thought, for example, that they were achieving improved sexual performance through entirely natural substances, were in fact getting the same drugs that the rest of the world used.

The FDA issued warnings to the manufacturers of these supplements – sometimes two and three warnings about the same supplement.   In some cases, the response of the manufacturer was to switch from one adulterated element to another, but not to desist from marketing their adulterated supplement.  

However, the FDA has a data base that keeps track of those adulterated drugs, and that data base was analyzed by researchers who published their results in a paper a few months ago.   (Tucker J. JAMA Netw Open 2018;1(6):e18337)

From 2007 through 2016, 776 adulterated dietary supplements were identified by the FDA and 146 companies were implicated.   The products identified by the FDA as tainted supplements were most often marketed for sexual enhancement (46%), weight loss (41%), or muscle-building (12%).   

The single drug most often found in these adulterated supplements was sildenafil, which you know as Viagra.   Tadalafil, which is the active ingredient in Cialis, was found in about 20% of the sexual enhancement products, and several contained vardenafil, the active ingredient in Levitra.   So these “natural” sexual enhancement supplements were erectile dysfunction drugs in disguise.

In the adulterated weight-loss products, the most frequent ingredient was sibutramine, formerly marketed as Meridia, an obesity drug.   Meridia was withdrawn from the market in 2010 following reports of increased risks of heart attack and stroke.

The muscle-building products mostly contained synthetic steroids or steroid analogues.

The study concluded with the statement that the drug ingredients in these so-called dietary supplements have the potential to cause serious adverse health effects owing to accidental misuse, overuse, or interaction with other medications.   Patients with pre-existing health conditions may also unknowingly be exposed to a drug that is contraindicated for persons with that condition.

Dr Pieter Cohen of Harvard Medical School said, “It’s very hard to explain why the agency would dedicate extensive resources to detecting experimental drugs in supplements, but then, after discovering them, not inform the public or recall the products.”

Preview of coming attractions

The World Health Organization recently put out its list of the ten most serious global health threats.   In my view, some of these combine Good News with Bad News. Doc Gumshoe will devote an entire installment of this serial to a full discussion of the list, but in the meantime, here’s the bare bones:

  • Not vaccinating when you can
  • Drug-resistant superbugs
  • Air pollution and climate change
  • Another global flu pandemic
  • Crises in vulnerable places
  • High-threat pathogens like Ebola
  • Non-transmissible diseases
  • Dengue
  • Weak primary health care
  • HIV

Despite the real advances in healthcare, these could indeed threaten many millions of lives, both worldwide and at home.   As individuals, there certainly are steps that we can take to protect ourselves, but clearly some of these threats can only be addressed at the national or even international level.   

* * * * * * *

As always, I appreciate any and all comments to these pieces, and especially when a comment elicits a vigorous response.   A comment on the most recent Doc Gumshoe sermon, about the supposed Israeli cure for all cancers, triggered a response from a reader who seemed to express the view that investing in anything from Israel was immoral due to Israel’s position on Palestinians.   The commenter used the acronym BDS, which stands for boycott, divest, and sanction.

I have no clear position on Israel, the Palestinians, or the West Bank.   The situation is highly complex, and I don’t know enough about it to arrive at a clear position.   But there is a difference between government of a nation and the accomplishment of that nation’s scientists.   I am certain that many people all over the world strongly disapprove of the political acts of the US government at present, but they would be shooting themselves in the private parts if that disapproval went so far as refusing to acknowledge the benefits brought by scientists in the US.   The work of scientists, whether in the health-care field or any other, belongs to the world and should not be a matter of politics.

My best to all, Michael Jorrin (aka Doc Gumshoe)

[ed note: Michael Jorrin, who I dubbed “Doc Gumshoe” many years ago, is a long-time medical writer (not a doctor) who opines on topics in health and medicine for our readers a couple times a month. He does not typically discuss investments directly, but has agreed to our trading rules. All of his past columns and commentary can be found here.]