Do Allergy-Induced Endogenous Blood Histamine Fluctuations in Humans Modulate Blood-Brain Barrier Permeability and Psychotropic Drug Efficacy?

December 10, 2015 Leave a comment

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[Draft of December 10, 2015]

Abstract

Simple seasonal allergies, or other allergies, may impact the efficacy of psychotropic drugs in some people, because:

  1. Histamine modulates blood-brain barrier permeability (BBBp) ([5] and refs., [9]).
  2. Psychotropic drug efficacy is determined in part by BBBp.
  3. Human blood-histamine levels vary idiosyncratically as part of the allergic response.
  4. A normal human allergic response can elevate blood histamine levels to 10(-8) M.
  5. Histamine levels of 10(-9) M are sufficient to open the BBB significantly in cats.

That is, allergies cause histamine level fluctuations, which cause BBBp fluctuations, so constant extracranial drug levels may correspond to varying intracranial levels, with widespread clinical implications.

Details

Wide agreement in the literature, going back to the 1990s, supports the observation that endogenous histamine mediates BBBp — e.g., [8] from 1992, [6] from 2000 (authorship overlapping with [8]), and [2], also from 1992.

Schilling and Wahl [7] show that an in vivo blood histamine concentration in cats of 10(-9) M is sufficient to let Na(+)-fluorescein (mw 376 g/mol) through the BBB.

In humans, non-acute histamine concentrations range up to 10(-8) M ([3]; [1], from 1976; and [4]).

The molecular weights of common psychotropics fall within the range that may be impacted by histamine-induced changes in the BBBp: Diazepam (Valium) [285 g/mol], Fluoxetine (Prozac) [309 g/mol], Lorazepam (Ativan) [321 g/mol], Quetiapine (Seroquel) [384 g/mol], Haloperidol (Haldol) [376 g/mol], Sertraline (Zoloft) [306 g/mol], Carbamazepine (Tegretol) [236 g/mol], Paroxetine (Paxil) [329 g/mol], etc.

Case Study

Patient S, suffering from intractable epilepsy and seasonal allergies, was hospitalized 31 times before age 25 for either uncontrolled seizures or intolerable adverse reactions to various AEDs. None of her hospitalizations occurred in May, June, July, or August. (The statistical likelihood of 31 events occurring at random during the same 2/3 of the year is about 5 in a million.)

My hypothesis is that seasonal allergies give S constant histamine levels during the summer but, during the rest of the year, varying histamine levels, and thus varying intracranial AED levels.

Ramifications

Therapeutic dosing for psychotropics may depend on the presence of serum histamine, and may be impacted by allergies, including seasonal allergies.

Therapeutic AED levels, in particular, are often expressed in extracranial blood concentrations. This approach may need to be modified.

Research Suggestions

  • Retroactive patient intake review: Do other epileptics demonstrate seasonal hospital admission patterns?
  • Retroactive patient intake review: Do other patients taking psychotropic drugs demonstrate seasonal hospital admission patterns?
  • Patient study: Measure histamine levels as part of routine AED monitoring.
  • Patient study: Measure histamine levels as part of other psychotropic-drug efficacy monitoring.
  • Basic research: Study BBBp with regard to AEDs/other psychotropics in other mammals, to see if Schilling and Wahl’s results hold for these compounds.

References

[1] Bruce C, R. Weatherstone, A. Seaton, and W. H. Taylor. Histamine levels in plasma, blood, and urine in severe asthma, and the effect of corticosteroid treatment. Thorax. 1976.

[2] Butt AM, Jones HC. Effect of histamine and antagonists on electrical resistance across the blood-brain barrier in rat brain-surface microvessels. Brain Res. 1992 Jan 8;569(1):100-5.

[3] Lin RY, Schwartz LB, Curry A, Pesola GR, Knight RJ, Lee HS, Bakalchuk L, Tenenbaum C, Westfal RE. Histamine and tryptase levels in patients with acute allergic reactions: An emergency department-based study. J Allergy Clin Immunol. 2000 Jul;106(1 Pt 1):65-71.

[4] De Marchi, Sergio M.D., Emanuela Cecchin, M.D., Danilo Villalta, M.D., Grazia Sepiacci, M.D., Gianfranco Santini, M.D., and Ettore Bartoli, M.D. Relief of Pruritus and Decreases in Plasma Histamine Concentrations during Erythropoietin Therapy in Patients with Uremia. N Engl J Med 1992; 326:969-974 April 9, 1992.

[5] Mayhan, WG. Role of nitric oxide in histamine-induced increases in permeability of the blood-brain barrier. Brain Res 1996 Dec 16;734(1-2)70-6, pubmed ID 9017232.

[6] Patnaik R, Mohanty S, Sharma HS. Blockade of histamine H2 receptors attenuate blood-brain barrier permeability, cerebral blood flow disturbances, edema formation and cell reactions following hyperthermic brain injury in the rat. Acta Neurochir Suppl. 2000;76:535-9.

[7] Schilling L, Wahl M. Opening of the blood-brain barrier during cortical superfusion with histamine. Brain Res. 1994 Aug 8;653(1-2):289-96.

[8] Sharma HS, Nyberg F, Cervos-Navarro J, Dey PK. Histamine modulates heat stress-induced changes in blood-brain barrier permeability, cerebral blood flow, brain oedema and serotonin levels: an experimental study in conscious young rats. Neuroscience. 1992 Sep;50(2):445-54.

[9] Varon, David. Personal Communication: “Of course” histamine modulates BBBp.

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Categories: other

Mi Y’malel Fantasy

December 8, 2015 Leave a comment

A Fantasy based on the traditional melody for Mi Y’malel. Enjoy!





Categories: holidays, Judaism

Let’s Get a Few Things Straight about Hanukkah

December 8, 2015 1 comment

As with so many things, the problem started with Alexander the Great, and, in particular, with what he didn’t do.

Just over 2,300 years ago, Alexander III “The Great” of Macedonia was a young man of 32 who had conquered the known world in just a decade — a feat marked to this day by the names of cities like Alexandria, Egypt, and, 2,000 miles further east, Kandahar, Afghanistan. Alexander’s first wife was seven month’s pregnant, and — in both a literal and figurative marriage of east and west — he had just taken the daughter of the defeated Persian ruler Darius III as a second wife. How could Alexander have known that he wouldn’t live long enough to be a father?

Demonstrating understandable but ill-fated short-sightedness, Alexander had therefore not created a plan of succession, so his death brought huge instability, with various generals and other power brokers vying for control.

Four points define the geography of the ancient world: Greece in the west; Persia (Iran) in the east; Egypt in the south; and Syria, where the journey north from Egypt intersects the east-west trail from Greece to Persia. So power centers were established in those four places. (It is not coincidence that, more than 2,000 years later, Iran, Egypt, Syria, and Greece still dominate the news.)

Jerusalem had the misfortune of lying just off the path from Syria to Egypt, so every time the new Syrian dynasty and the new Egyptian dynasty fought, Jerusalem was part of the battleground. For a while Egypt had the upper hand, and Jerusalem was part of Egypt. Then around 200 BCE, the Syrian ruler Antiochus III “The Great” won Jerusalem and turned it into a Syrian province.

That wouldn’t have been so bad but for the fact that Antiochus III had a son, Antiochus IV. The details are complex — and involve familiar figures like Hannibal — but the upshot is that Antiochus IV was taken into Roman captivity, only to be freed later for another Syrian ruler’s son.

While Antiochus III’s nickname was “The Great,” Antiochus IV was dubbed “The Insane.” And this was not good news at all.

Antiochus IV tried to quash Jewish practice in Jerusalem.

This is the Antiochus against whom the famous Maccabees took up arms.

The Maccabees — led in large part by Judah Maccabee — prevailed. This is the victory we celebrate at Hanukkah.

Because Antiochus IV was from Syria, some people say that the Maccabees fought the Syrians. And because Antiochus IV was part of the Greek dynasty that took over Syria after Alexander the Great’s death, other people say that the Maccabees fought the Greeks. This is why different versions of the Hanukkah story variously refer either to the Syrians or to the Greeks.

So Hanukkah originally commemorated the violent overthrow of violent and unstable Syrian Greek rulers.

Unfortunately, the Maccabees, while able fighters, were less capable rulers. For instance, Simon — one of the five Maccabee brothers — served as high priest of Jerusalem. Then one of his sons, John Hyrcanus I, took over. The reason that Hyrcanus was next, rather than one of Simon’s other two sons, is that Simon’s son-in-law had murdered them, along with Simon himself. And astonishingly, those events were peaceful compared to what would follow.

Later — perhaps because of the dubious optics of a holiday that commemorated overthrowing the government — Hanukkah was recast in terms of the familiar light and darkness, oil and miracles.

But I think those four elements were actually there from the outset. We see from the full story what we already knew: Life is complex and messy. We have periods of light and periods of darkness. The path to the light is often a mundane one that’s based far less in lofty theology and far more in our day-to-day existence.

Oh yes. And, if we look carefully, we find that life is marked by miracles.

Happy Hanukkah.

Categories: holidays, Judaism, spirituality

Twenty-four hours with 5,000 Jews

November 8, 2015 Leave a comment

Dinner with Sonja, my father, and his wife.

Dinner with Sonja, my father, and his wife.

It was a really quick trip, with just barely 24 hours in the Orlando hotel that housed the 5,000 Jews at the URJ Biennial. But it was worth it.

I managed to squeeze in time with good friends and colleagues, dinner with my father, a book signing, a panel presentation, and a pre-announcement announcement. (Look for more on that here soon.)

The Jewish Book Council had brought me down, as part of their partnership with the URJ, for a panel discussion along with Aviya Kushner and Michal Lemberger on “Rereading the Bible: Text, Subtext, and Filling in the Gaps in Between.”

Signing Books for the JBC at the URJ Biennial

Signing Books for the JBC at the URJ Biennial

Joe Biden was scheduled for Saturday evening, by which time I was already en route back to New York. At first I didn’t care that I was missing his address and the inconvenient security that it necessitated. But apparently it was quite an event, with the vice president praising the Jewish commitment to social justice and thanking the Jews for never remaining silent.

We got the idea, of course, from the prophets of the first millennium BCE, whose vision for a better world lives on a hundred generations later.

Fittingly, the taxi driver to the airport had foreshadowed the acknowledgment of that achievement. A woman from Haiti, she heard us talking about this and that, and in response told us how much she admired the Jews and the way they kept their heritage alive.

What a thing to be a part of.

Categories: other

On Camp Eisner, Seeing the Future, and Combating Bullying

July 19, 2015 2 comments

A trip to Eisner offers a glimpse into a glorious future framed by the perspective of our past. What else can you call it when hundreds of children, teens, and young adults from around the world gather in unpretentious worship to sing ancient words as given new voice with modern melodies?

PullQuoteI arrived for Shabbat morning services, held indoors, this time, in deference to the threatening weather. The predominantly musical morning was punctuated by short interpretations of Torah, each one presented by a group of three campers, and each one addressing the topic of promises.

A theme emerged: the promise not to bully. I happen to know that a sign in the dining room proclaims Eisner a bully-free zone. I didn’t know that campers, as part of a pledge they sign when they arrive, promise not to bully.

It seems that the plague of bullying is a modern one. There’s no ancient Jewish discussion of it. There isn’t even a Hebrew word for “bullying.”

But our sages were well aware of the power of words. Gossip, even based in truth, is likened to a capital offense in Judaism. You’re not allowed to speak ill of people behind their backs.

Equally, our tradition forbids unwarranted hostility, proclaims the absolute value of human dignity, and decries enslavement of any sort. Bullying aggressively boxes people into an ignoble cage of powerlessness. The Rabbis — who insisted that even if no one else is behaving well, you must strive to — would have been revolted. So like new melodies for timeless words, Eisner’s campaign against bullying is a new passion born of timeless values.

Visitors often want to bring home the beauty they find at Eisner. The campers at Eisner have suggested a first step: take an Eisner-like anti-bullying pledge.

Giving Students a Jewish Future: Three Clichés for Summer

July 3, 2015 1 comment

A child visits our Sunday religious school planning to stay as briefly as possible. Once in class, she finds she likes school so much that she begs her parents to let her stay until the end.

A Hebrew school student on Wednesday afternoon spontaneously covers the whiteboard with graffiti: “I love this class.”

A student e-mails me to lament a canceled class.

A student guesses the password to my computer because I used a Hebrew word, and he knows it thanks to the effectiveness of his teachers.

A group of students asks if we can please extend the school year because they don’t want classes to end.

These are a few scenes out of many that remain prominent in my mind as I look back on the year now ending. They are, of course, just the tip of the iceberg.

I know. It’s a cliché. And “good writers” don’t use clichés. But I like clichés, because they tend to encapsulate important truths. In this case: the part you see is supported by a much larger part that you don’t.

Much of my job is putting in place the parts of the school-iceberg that you don’t see. The staffing (rare for a religious school, we have a waiting list of teachers who want to teach here), the training, the ambiance (treat everyone with respect), the policies (only make rules about things that matter), the materials, the schedules, the vision. It’s on my mind, because summer is when I focus most on these things.

I’ll meet with the heads of the textbook publishing houses to ask, “what’s your absolutely best material?” I’ll plan content that best matches our faculty and student body. I’ll ask what I can learn from the other religious schools that I’ve visited during the past year. I’ll revisit everything that didn’t work to see if we can do better. I’ll solicit direct feedback from students, teachers, parents, and the leadership. I’ll apply my experience and training to make sure all of our ducks are in a row.

I know. It’s another cliché. But three paragraphs later, I still like clichés. In this case, it may not matter which way any particular duck faces, but they do have to be aligned (for travel and for sleep, it turns out). In terms of our school, we face dozens of seemingly arbitrary decisions, but even though each one admits of many successful resolutions, they still have to work together to further a single vision: “Giving students a Jewish future.”

For instance, there are lots of good 4th-grade text books. And lots of people available to teach 4th grade. But there are fewer successful combinations of books and teachers. Our incoming 4th-grade, too, is unique, different from last year’s or next year’s; its particular nature further limits our choices. And the 4th grade has to take its place in a progression from kindergarten to 12th grade; that limits the choices even more. The 4th-grade school duck has to line up with all the other ducks.

In this regard, it’s important to focus on the vision — giving students a Jewish future — and ignore the Siren song of programming.

Yes, I did it. Another cliché. The fabled Greek Siren, half bird and half woman, sang beautifully sweet songs that lured sailors off their safe sailing paths and into destructive island reefs. Many new programs are the same. Though individually attractive, their value is dubious if we let their beauty distract us from our vision. Or to look at things differently: Does a new program bring us closer to giving children a Jewish future? If not, our resources and energy are probably better spent elsewhere.

So even though I’ll examine dozens of new ideas, my enthusiasm will be reserved for a tiny fraction of them — the few programs or undertakings or materials that support the iceberg that lines up our ducks that point away from the Siren song. As I work on next year this summer, that will be my litmus test.

(Okay. So it’s four clichés.)




Originally published in the Vassar Temple monthly bulletin.

Categories: education, Judaism

The Way of the Land: The Value of Doing Good

May 29, 2015 Leave a comment

There are at least two reasons to do something in Judaism.

The first is because we must. We must welcome the stranger, celebrate the holidays, work for a better world, study Torah, even teach our children to swim, according to the Talmud. Each of these requirements is called a mitzvah (plural, mitzvot), though common usage equates that Hebrew word instead with “good deed.”

The legalistic nature of Judaism gives many of these do’s and do-not’s technical names, and then elaborates their nuances. For instance, speaking ill of someone else — gossip — gets the name lashon hara, and we’re not allowed to do it, whether it’s true or not, and no matter how much fun it might be. But what if you feel you need to warn a friend about something? What if you’re just so frustrated that you need to talk things out? What about earning a living as a political humorist who mocks public figures? Details like these are fleshed out in discussions, commentaries, discussions on commentaries, and (yes) commentaries on the discussions. This is what we mean by “Torah” in the broadest sense.

These mitzvot are parallel to modern laws, which likewise dictate appropriate and inappropriate behavior.

By contrast, the second reason to do something in Judaism is because we can. This category goes by the Hebrew name derech eretz, literally “the way of the land.” And it refers to treating one another with the sorts of decency and propriety that can’t be legislated but are nonetheless desirable.

There’s no Jewish law against whistling mirthfully at a funeral, an addition to the Talmud explains, but that doesn’t mean it’s okay. And there’s no Jewish law that requires us to tip a waiter, but that doesn’t mean we should skimp on tips, even though, of course, we’ll get our meal even without purposely paying an extra fifteen or twenty percent for it.

Unlike the American secular approach, though, Jewish derech eretz is on a par with Jewish law. “Derech eretz preceded the Torah,” according to tradition, which is to say, the path to the mitzvot of the Torah is paved with the practice of derech eretz. In America, “there’s no law against it” or “there’s no law making me” are often sound excuses. Not so in Judaism.

Curiously, this same term — “the way of the land” — also means “the way things work,” for better or for worse, as it were. In our hometowns, we are judged by our reputation. But — the Talmud warns — on the road we are judged merely by our clothing. Attire is rarely a reliable indicator of anything substantial, but that’s the way it works. Get used to it. It’s not going to change. Derech eretz.

Reading between the lines, we find a message in the way a single term refers variously to courtesy as well as reality. There’s an unspoken hope that the two concepts merge, that generosity, compassion, and civility become so ingrained in our society that we can’t even imagine things being any other way — a time when going the proverbial extra mile is so common that it’s no longer noteworthy.

Particularly at this season of Shavuot, as we acknowledge anew our acceptance of Torah, let us remember not to be satisfied merely doing the good things that we must. Let us also do the good things that we can.




[Originally published in the Vassar Temple Bulletin, June, 2015.]

Categories: Judaism, spirituality