Circling-V ™

Kratom and Drug Design

If humans had designed the medicinal arrangements in plants, I’d have guessed that committees were involved. The mixes, and the proportions, often appear whimsical or arbitrary. For instance, tobacco has Snow White and the Seven Dwarves – nicotine and a handful of minor players, some with anagram names such as cotinine. Cannabis has the 101 Dalmations – or 113 according to one count – of which THC is the lead dog. Then there’s ginseng with a handful of ginsenosides, and their pecking order depends on which species is under the microscope.

Kratom (the leaves of Mitragyna speciose from Southeast Asia) is in the middle of those, with the indole alkaloid mitragynine as the leader in a blend with ~40 related compounds. Structurally they resemble yohimbine, which is more widely found in nature. Yohimbine, in turn, can affect mood-related receptors (dopamine, serotonin) or have adrenaline-like effects.

No surprise, kratom is controversial. Its fans are several million strong in America, and use it for anything from pain relief or opioid withdrawal to energy boosts or libido. And in fact, kratom is well known to be an analgesic, stimulant and mood booster. Some might call that combination ideal. And yet it has marked side effects. The DEA wants to ban this green powder, the FDA wants to regulate it, and the Mayo Clinic calls it unsafe and ineffective.

Oddly, statistics support both sides of the fence. Contra: the stuff causes addiction, seizures, hallucinations, and psychotic symptoms. Pro: serious side effects seem to be mainly from hyper-doses, at which point all bets are off. Even kitchen spices have a history of abuse. I knew locals in Danbury, Ct, who called themselves nutmeggers; the nickname had colonial origins, when the town imported nutmeg in part to get high. Who knew? But back to the topic at hand. Contra: CDC has reported that coroners found 91 fatalities arose by kratom overdoses in an 18-month period. Pro: an outside study found that using kratom alone kills almost nobody.

That got me thinking about the herb’s alkaloid arsenal. The variations likely contribute to the broad effects. I’m guessing that the same chemical diversity accounts for the low lethality, after all, the herb hits on all cylinders without requiring huge amounts of any one contributor. So kratom’s diversification appears to rationalize both its strength and its failure to kill.

Green plant actives aren’t the only group that use safety-in-number. Lanolin (natural wax from wool, used for skin conditions) is said to have as many as 20,000 constituents due to its combinatorial bonding. Petrolatum (like Vaseline®, from petroleum, derived from ancient plants, and used for skin conditions) has two concentration bell curves: maybe a dozen major compounds spiking up, overlaid on a myriad of minor ones with almost a uniform distribution. This isn’t the first time that natural diversity has struck me as a useful example for drug design paradigms. But this time it’s for other reasons. Hopefully, no matter how the laws turn out for kratom, the drug field will take a harder look at the benefits of complexity and chemical permutations in formulation.

Food for Thought

Sunil Mathur and Clare Hoskins, “Drug development: Lessons from nature (Review),” Biomedical Reports, 6:612-614 (2017).

Posted at https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5449954/pdf/br-06-06-0612.pdf

Frank R. Denton III, “Beetle Juice,” Science, 281(5381):1285 (28 August 1998) and 281(5383):1615 (11 September 1998).

Summarized at https://scite.ai/reports/beetle-juice-1y6vWn

Stabilizing Cannabidiol

Cannabidiol is everywhere. I’ve even seen gas stations with big signs outside advertising their CBD products. But there’s an elephant in the check-out line: almost nobody lists the amount of CBD on their labels. There are reasons for that. First, the purified material is still shockingly costly. Thus, many sellers add the minimum to qualify for marketing claims: 0.1%.

But the bigger problem is stability. CBD is one of the least stable ingredients in products, and before you get your hopes up, the other cannabinoids will have similar issues. The problem is aggravated by exposure to air, to heat (such as in delivery trucks in the summer) or if it’s not in dry form. Plants overcome this by ongoing generation of the carboxylic acid derivative, and because their sludgy oils exclude air and other threats. But we don’t have the luxury of keeping the plant alive within a cream or pill. And formulating anaerobically would add cost.

You’d think that with all the groups making CBD products, stabilization would have been figured out by now. Yet in my online hunts few if any of the product teams seem to be equipped for that. In fact, the modest minority that has a chemical background tends to be on the analytical side, as opposed to focusing on the reaction chemistry. So here goes.

For the conditions in retail products a mechanistic chemist wouldn’t expect such species (i.e., terpene phenolics) to suffer much attack from acids or bases. That’s because molecules in this class have no special appetite for protons. Well, that’s not entirely true; strong acid has been reported to yield tetrahydrocannabinol (THC) as a byproduct, but consumer products are unlikely to have the necessary conditions. And the pH for tearing off CBD’s own protons is mainly above 9, which is getting fairly alkaline.

Radicals, though, that’s a different story. Bear in mind that even atmospheric oxygen is a double radical, which is one reason air is so corrosive. It’s an ocean of gas seeping into everything and looking for something to react with. By my count nearly half of CBD’s thirty hydrogen atoms (some more than others) are susceptible to being picked off by a radical. And CBD has two sites on double bonds where it practically invites radicals to plant themselves.

With a line-up like that, even if we strip out 99% of any radical source, the remaining 1% can start the ball rolling. And when they do, they transfer their own radical character to the newly formed CBD derivative. So, we’re off to the races with radical chain reactions. In other words, a trace amount of radical can initiate conversion of all the CBD to byproducts.

Next, consider that many formulas include certain agents that are radical formers. Here we have things like peroxides, sulfhydryl groups (I’m looking at you, proteins and cysteine), metallic nanoparticles, certain metal salts, and the like. And consider paraben preservatives, which exist in ionic form under use conditions and react with air to form radicals.

In theory we could beat the problem by shielding CBD. Oil-in-water emulsions might help. Embedding CBD in a gummy matrix might help. And there are host-guest options such as cyclodextrins to tuck CBD into a tube or some other shell. But the bottom line is, CBD isn’t like some rock that you add and find it still there when you come back. It gets transmogrified.

Food for Thought

Anonymous, “Cannabidiol,” in the federal PubChem database, entry no. 644019. https://pubchem.ncbi.nlm.nih.gov/compound/Cannabidiol

Bacteria as Drug Factories

If organic chemistry had an Olympic event, it would involve finding the easiest way to synthesize natural drugs. Some routes have 30 or 40 steps, and the yields are horrendous because of side reactions all along the way. Various chemists have become organic rock stars by streamlining a synthesis to only a dozen or so steps.

However, though the bench artists bring elegance to the field, a much larger group has more of an engineering mindset – whatever works, and it needs to be fast and cheap. Hence there’s been talk for years about getting genomes to do the work instead. After all, genes make the enzymes that form nature’s production line. And gene work imposes fewer hazards from solvents and the like. But it’s not trivial. Some enzymes need to be in a certain type of operating environment or in a certain spatial relationship relative to other enzymes. And we don’t always know which genes are involved in making the enzymes in the first place.

Biologists at MIT (Jing-ke Weng, Tomáš Pluskal, and their group) are making progress on this. Their recent work is on some of the simpler natural drugs, presumably to shake out the approach before tackling hairier molecules. And their latest coup is engineering bacteria to make kavalactones – the relaxing components in the drink kava. Kava, for ye with botanical leanings, is Piper methysticum in the pepper family. The extract of interest comes from the root. It has six main kavalactones, of which kavain is predominant.

Basically, the compounds are the inverse of caffeine, and even fish relax when they’re exposed to them. Hence the drink provides a substitute for alcohol but without the aggression. If you know a mean drunk, you might want to introduce them to this stuff. Interestingly, kavalactone structures are evocative of the chemical class known as stilbenes, and as such are analogs of resveratrol from grapes. Comparisons to the fruit of the vine have a structural basis.

Now somebody could cite an ugly little acronym, GMO, for the engineered bacteria that produce kavalactones by the new scheme. However not all GMOs represent a rampage in the wild. Bacteria can be cultivated easily in sealed conditions, as in fermentation tanks for yogurt. When the harvest is ready it’s a mere matter of isolating the chemical jewels either from the broth or for instance from dead biomass. And with this method discovery of a potent new natural drug maybe be less likely to leave the host plant on the endangered list – a concern that became very real with taxol.

A critic has noted that the current focus on individual compounds is simplistic: kava is in fact a complex mixture, as are many other natural substances. If the goal is an experience that completely mimics that from kava, I’d agree. But in my mind a far bigger point is that the medicinal industry is ready to make the next leap in drug production. It couldn’t come at a better time, considering the ongoing gold rush to discover new drugs in nature. I doubt that historic synthetic approaches can even come close to keeping up with the rate of discovery. Here’s to living factories for medicine. Cheers!

*Kavain, the dominant kavalactone. Has sedative and anxiolytic properties*

Illustrates chemical structures in kava — *Yangonin, a lesser kavalactone. Binds to the body’s cannabinoid receptors.*

Food for Thought

Tomáš Pluskal et al., “The biosynthetic origin of psychoactive kavalactones in kava,” Nature Plants (July 22, 2019).

https://www.nature.com/articles/s41477-019-0474-0#article-info

Carey Goldberg, “MIT scientists synthesize the feel-good molecules in kava, ‘Nature’s Xanax’,” (August 2, 2019).

https://www.wbur.org/commonhealth/2019/08/02/mit-scientists-kava-whitehead-kavalactones

Medicine in Transition: Fecal Transplants

My parents grew up on rural farms. One day as a kid I was having a grand old time on a hulking fertilizer cart in a granddad’s barnyard. Mom came out of the house and was – to say the least – distressed. It turned out the cart’s technical name was “manure spreader”.

Mom had a fixation on cleanliness, but any residue in the cart was only cow manure: mostly plant matter (lignin is my guess) after being washed by the rains and baked by the sun during weeks of disuse. The stuff is tame. Towns even host discus-throw or shot-put events for hurling dried cow pies / chips / patties. I suppose food-like names reflect society’s tolerance for the material, in fact a common name for horse manure also evokes food – road apples.

But I digress. Human waste seems to be more dangerous. Some discussion of the structure may be helpful so I’ll digress again. Bacteria make up over half of the dry mass. That biome routinely accommodates several hundred species, yet only four phyla (three dozen or so species) represent 99% of the biomatter. For reasons still unclear their ecology tends to gravitate toward one of three main equilibrium states, depending on which is the dominant group – the starch-loving Bacteroides, mucus-eating Prevotella, or sugar-enabling Ruminococcus.

Some species are quite hazardous, notably C. difficule, but a well-balanced gut biome can whip the troublemakers into shape. Thus, we have fecal microbiota for transplantation (FMTs) – also known as fecal transplants – to achieve rapid control of C. difficule. This summer the FDA issued a warning and tabled clinical trials, noting that an FMT left a patient dead from multi-drug resistant organisms (MDROs). However even as cautions surface, science keeps discovering new medical uses for fecal microbes – from microbial competition and endurance-enhancing lactate metabolism to anti-obesity properties and anti-Alzheimer’s effects.

Some people view the FDA as more hindrance than help on this issue, but really the situation reflects an industry in the making. Wholesale transfers of gut microbes are an efficient way to treat a condition when we don’t understand the health intricacies of that biome. The same situation exists for the appendix. But it is indiscriminate – right up there with using lice to clean wounds. And MDROs are not the only issue – for instance, an FMT can be a prelude to obesity.

Hence new cautions are just a breather while the field gets a better handle on tweaking microbial ecology. Or at least until it begins creating targeted bacterial ferments with controls against drug resistance. Entrepreneurs would even call it a business opportunity, since there’s a clear need and cultivation should provide more uniform products and more predictable results.

A search finds that gut microbes in capsules are already on the drawing board, as probiotics. The thought of swallowing the stuff evokes a visceral reaction, but maybe that’s just me. If it ever comes to that, I’d rather have an enema of artificial feces – say, from mixing ferments with a hydrogel and fiber matrix. Yet either way, Mom would have been horrified.

Food for Thought:

Anonymous (FDA), “important safety alert regarding use of fecal microbiota for transplantation and risk of serious adverse reactions due to transmission of multi-drug resistant organisms,” (June 13, 2019).

https://www.fda.gov/vaccines-blood-biologics/safety-availability-biologics/important-safety-alert-regarding-use-fecal-microbiota-transplantation-and-risk-serious-adverse

D. Grady, “Fecal transplant is linked to a patient’s death, the F.D.A. warns,”” New York Times, (June 13, 2019). https://www.nytimes.com/2019/06/13/health/fecal-transplant-fda.html

M. Arumugam et al., “Enterotypes of the human gut microbiome,” Nature, 473(7346):174-180 (May 12, 2011); Errata: 474(7353):666 (June 30, 2011); 506(7489):516 (February 27, 2014).

https://www.ncbi.nlm.nih.gov/pubmed/21508958

Y. Tian et al., “Fecal microbiota transplantation for ulcerative colitis: a prospective clinical study,” BMC Gastroenterology, 19:116 (2019).

https://bmcgastroenterol.biomedcentral.com/track/pdf/10.1186/s12876-019-1010-4

X. Ding et al., “Long-term safety and efficacy of fecal microbiota transplant in active ulcerative colitis,” Drug Safety 42(7):869-880 (July 2019).

https://link.springer.com/article/10.1007%2Fs40264-019-00809-2

A.S. Patel and J.R. Allegretti, “Commentary: Fecal transplants may hold promise in treating obesity,” Medscape (July 23, 2019).

https://www.medscape.com/viewarticle/915387#vp_2

J. Scheiman et al., “Meta-omics analysis of elite athletes identifies a performance-enhancing microbe that functions via lactate metabolism,” Nature Medicine, 25(7):1104-1109 (July 2019).

https://www.nature.com/articles/s41591-019-0485-4

K. Kowalski and A. Mulak, “Brain-gut-microbiota axis in Alzheimer’s Disease,” Journal of Neurogastroenterology and Motility, 25(1):48-60 (2019).

http://www.jnmjournal.org/journal/view.html?doi=10.5056/jnm18087

N. Alang and C.R. Kelly, “Weight gain after fecal microbiota transplantation,” Open Forum Infectious Diseases, 2(1):0fv004 (February 1, 2015).

https://academic.oup.com/ofid/article/2/1/ofv004/1461242

L. Thomas, “Research into Alternatives to Fecal Microbiota Transplant,” News Medcial Life Sciences (August 23, 2018).

https://www.news-medical.net/health/Research-into-Alternatives-to-Fecal-Microbiota-Transplant.aspx

Micronutrients in the Staples

The World Health Organization uses the term “hidden hunger” to describe a condition that affects a third of the world’s population. Victims of hidden hunger aren’t necessarily starving (though they may be) but they’re undernourished from a dietary deficiency. And that poses health risks. A recent international study addressed this by spraying a cocktail of four minerals onto the surfaces of wheat leaves. The elements then found their way into the grains, from which they can be ingested. The micronutrients were zinc, iodine, selenium and iron. The crop study sites were in China, India, Mexico, Pakistan, South Africa, and Turkey.

There are a variety of tricky aspects here. High concentrations of these elements can be toxic to the plant. Also, normally they are absorbed at the roots, yet putting them into fertilizers invites major losses through drainage in the soil, especially at micro-concentrations. Moreover, the plant tends to partition minerals into specialized uses – in particular both iron and zinc have a role in nitrogen metabolism. And there’s something engineers call a mass balance issue: these metals tend to be present at 1000X the concentration in wheat kernels relative to the selenium and iodine – that’s a pretty big difference – which can create real difficulties in obtaining or maintaining a uniform mixture so as to deliver the intended ratios.

The trial had interesting results. After treatment the grain levels jumped by 9X (for iodine), 3X (for selenium), 65% (for zine), and 12% (for iron). Plants have respective transport and partitioning systems for each of these elements, at least from the root. What they would do for foliar (i.e., on-leaf) application was not entirely predictable in advance.

In reviewing the findings, interestingly, a physical chemist or electrochemist could rationalize them by simple diffusion. In general, anions (negative ions) diffuse through water much more easily than cations (positive ions, the metals) do, because cations attract a big cluster of water molecules around them. The cluster migrates about as quickly as dumplings ever do. And the lower the charge, the speedier the migration, regardless of whether the charge is negative or positive. Thus here we have I^-1 > Se^-2 > Zn⁺² > Fe^{+2 or +3}.

That’s just an observation. It could be just coincidence. But if it’s meaningful it suggests that it might be much more efficient to get zinc and iron micronutrients from treated leaves of broadleaf plants, such as spinach, collard greens, cabbage, lettuce, etc. Well, okay, the first two are dark green, meaning they’re already high in iron, but you get my drift. It might be a good way to deliver zinc. Then we wouldn’t be relying on the long diffusion path to the seed, but could ingest the mineral near the source.

Food for Thought

Primary article: C. Zou et al., “Simultaneous biofortification of wheat with zinc, iodine, selenium, and iron through foliar treatment of a micronutrient cocktail in six countries,” J. Agric. Food Chem., 67(29):8096-8106 (July 24, 2019). Abstract posted at: https://pubs.acs.org/doi/10.1021/acs.jafc.9b01829

Ivy’s on My Mind

The three-leaf triads of poison ivy are common in North America except in cities and deserts. Most people I know have had the rash. Native remedies treated it topically with a plant that grew nearby: jewelweed. Modern workers have guessed that jewelweed’s secret was lawsone, a red dye that binds to proteins and is also found in the herbs for making henna. But it turns out, lawsone is ineffective against ivy rash, in fact, jewelweed works only as well as soap.

And that implicates the herb’s saponins, which are suds-forming steroid-like molecules with sugar groups attached. They’re detergents. And what saponins wash off are urushiols, which are allergenic sap oils found in each of poison ivy, poison oak and poison sumac. This is like modern first aid for exposure to ivy: washing that skin within 10-15 minutes.

Why wash? Because even air alone rapidly converts urushiols into reactive quinones, which affix themselves to certain skin proteins. The newly modified proteins then trigger a delayed response by the skin’s network of immune cells. The protein CD1a has now been identified as a key factor for this pathway in mice. Another ivy study in mice found that the protein interleukin-33 (IL-33) facilitates calcium flow into neurons. When investigators blocked either IL-33 or the neuron site, there was less inflammation and scratching. So, drug chemists now have multiple biochemical targets for treatment of ivy rash.

Basically, an allergy-like response causes swelling, and swelling causes the itch. The prior commercial therapies included antihistamines to quench immune responses and cortisone or analgesics to reduce the itch. Some older products contain multivalent metal salts or oxides: these are astringent substances that relieve itch presumably by shrinking skin tissue to normal size. Examples are calamine lotion (zinc oxide and ferric oxide) and Burow’s solution (aluminum sulfate and calcium acetate). Tannin-containing (and thus astringent) extracts such as witch hazel are also used on rash. Beyond that, talc is used as a dry lubricant to reduce chafing.

It would be better if we could prevent the symptoms. Some reports indicate that oral dosing with urushiols may reduce our sensitivity to poison ivy. Eating ivy oils sounds odd but deer do it. And in fact, people eat urushiols in the form of mango fruit, actually mostly in its skin. And cashews and ginkgo have related compounds. [In an odd twist, it matters whether the eater’s first exposure is to ivy or to mangoes.]

Our gastrointestinal tract doesn’t normally absorb substances as oily as these unless they can be saponified (broken down into soaps) by bile or get emulsified (with a soap-like additive). Urushiols can be saponified because their relative acidity is in the same range as for lipids.

An alternative strategy provides molecular cognates that block the immune response. Thus, urushiol analog 5-methyl-3-n-pentadecylcatechol (5-Me-PDC) is a “tolerogen”: it reduces sensitivity to ivy oil, yet is only a slight sensitizer to itself. 5-Me-PDC works both topically and by intravenous injection. And it has relationships between sensitization and cross-reactivity.

Herbal anti-ivy meds don’t yet leverage most of these insights; hopefully they will soon. One option I’d like to see is masking the affected skin proteins with biofilms like bacteria do – except that we don’t how the microbes pull that off.

***

TOP: *One of the itchiest urushiols*
CENTER: *Its corresponding quinone*
BOTTOM: *5-methyl-3-n-pentadecylcatechol (MPDC)*

Food for Thought:

V. Abrams Motz et al., “The effectiveness of jewelweed, Impatiens capensis, the related cultivar I. balsamina and the compound, lawsone in preventing post poison ivy exposure contact dermatitis,” Journal of Ethnopharmacology, 143(1):314-318 (2012). ABSTRACT: https://www.ncbi.nlm.nih.gov/pubmed/22766473

J.H. Kim et al., “CD1a on Langerhans cells controls inflammatory skin disease,” Nature Immunology (2016). https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5791155/pdf/nihms-800443.pdf

Monash University, “Immune breakthrough: Unscratching poison ivy’s rash,” ScienceDaily (August 23, 2016). http://www.sciencedaily.com/releases/2016/08/160823103242.htm

B. Liu et al., “IL-33/ST2 signaling excites sensory neurons and mediates itch response in a mouse model of poison ivy contact allergy,” Proceedings of the National Academy of Science of the U.S.A., 113(47):E7572-E7579 (Nov. 22, 2016). https://www.pnas.org/content/early/2016/11/04/1606608113/tab-article-info

K. Hershko, I. Weinberg and A. Ingber, “Exploring the mango-poison ivy connection: the riddle of discriminative plant dermatitis,” Contact Dermatitis, 52(1):3-5 (2005). ABSTRACT: https://www.ncbi.nlm.nih.gov/pubmed/15701120

I.S. Dunn et al., “Influence of chemical reactivity of urushiol-type haptens on sensitization and the induction of tolerance,” Cellular Immunology, 97(1):189-196 (1986). ABSTRACT: https://www.ncbi.nlm.nih.gov/pubmed/3742608

E.S. Watson et al., “Immunological studies of poisonous anacardiaceae: production of tolerance in guinea pigs using 3-n-pentadecylcatechol-“modified” autologous blood cells,” Journal of Pharmaceutical Sciences, 70(7):785-789 (1981). ABSTRACT: https://www.ncbi.nlm.nih.gov/pubmed/6455512

J.-L. Stampf et al., “Induction of tolerance to poison ivy urushiol in the guinea pig by epicutaneous application of the structural analog 5-methyl-3-n-pentadecylcatechol,” Journal of Investigative Dermatology, 86(5):535-538 (1986). ABSTRACT: https://www.ncbi.nlm.nih.gov/pubmed/2943824

One-Bout Wonders

Some decades back I had hay fever of epic proportions one weekend. I’d never heard of Chlor-trimeton® but the label sounded good, and the drug worked wonders immediately. That was my one and only real success with it. It didn’t do much later for allergy flare-ups.

Fast-forward twenty years, and someone recommended Echinaceae when I had a cold. Sure, why not? At the time nobody had a better idea (zinc salts weren’t on the horizon yet for colds). Bang! Echinacea was amazing … but only for that one cold.

Now don’t confuse this with bacterial resistance to antibiotics. Resistance happens when drug overuse favors the tiny minority of bacteria that tolerate it. By contrast, colds are viral, and hay fever is an immune response, so those drugs must lose their strength by other mechanisms.

That irreproducibility – and the difficulty of disproving mere coincidence – shows why anecdotal data on drugs meets scientific apathy. No doubt other people have also had one-bout experiences, but any articles on the topic would be an anthology of merely anecdotal data. Even so, the issue may account for the uneven reputations of natural and synthetic drugs.

What does get studied is the gradual fading of efficacy. For instance, biologics lose potency after 6 months of continuous use for psoriasis. Sometimes that is due to flawed protocols: drug doses that are sporadic, too low, or unable to reach the blood effectively. More troublesome is immunogenicity: the immune system sidelines the anti-psoriasis drug.

In other words, a drug allergy arises. When the public hears that term, anyphylaxis and fatalities come to mind, yet in most cases the allergy only marginalizes the compound. Biologics are a special case because their molecules or arrays are big enough to be recognized by the immune system. However smaller drugs can be haptens, that is, they bind to some protein, and then the affected protein is attacked by antibodies and purged.

There’s research on workarounds. Co-administering psoriasis biologics with etanercept (Enbrel®) limits the immune response. Of course, biologic drugs are high-dollar products, so the R&D can afford immunogenicity testing. Not so for over-the-counter natural drugs: we’re lucky if an academic group undertakes a study for a popular plant extract. Yet cosmetic markets find that scores of widely-used plant extracts can trigger allergic reactions in some users.

Few fans of natural medicine would use etanercept or comparable synthetics if they could avoid it, but they may have received similar benefits by serendipity. Herbal compositions often include an immunomodulator such as ginseng root or astragalus root or holy basil. This is typically explained as rebalancing the immune system. I doubt most of those formulators contemplate that the body might treat their product as an insult otherwise. Meaning, instead of correcting defective immunity, those herbs may only ensure the body’s acceptance of the drug.

This gives me hope. All my life I’ve battled with allergies, and several leading hay fever meds have lost their potency. So, I’ll try to find a mild botanical immunomodulator that can work in parallel with antihistamines. Maybe the one-bout wonders can be wonderful again.

***

Cichoric acid (aka chicoric acid): a compound of Echinaceae purpurea thought to assist relief from colds.
It is chemically interesting because of its rotational symmetry and its relationship to cinnamic acid.
The compound was first isolated from chicory (hence the name), but is found in many species, including basil, lemon balm, dandelion leaves, lettuce, ferns, horsetails, and aquatic plants.
Other medicinal effects of cichoric acid: anti-arthritic (anti-inflammatory; also inhibits breakdown of hyaluronic acid in nerves, surface tissue and connective tissue); protects collagen proteins (in skin, nails and hair) from radical-induced damage; and inhibits the integration of HIV genetic code into human code.

Food for Thought

Y.Y.M. Huang, J.S. Ruth and S. Hsu, “Loss of efficacy of secukinumab for psoriasis at 24 to 32 weeks,” Journal of the American Academy of Dermatology, 75(4):e169. (October 2016). https://www.jaad.org/article/S0190-9622(17)30236-0/pdf

Y.Y.M. Huang and S. Hsu, “Loss of efficacy of secukinumab for psoriasis at 24 to 32 weeks: Update and commentary,” Journal of the American Academy of Dermatology, 76(6):e221. (June 2017). https://www.jaad.org/article/S0190-9622(17)30236-0/pdf

Bruce E. Strober, “Why biologic therapies sometimes lose efficacy,” Seminars in Cutaneous Medicine and Surgery, 35(supp. 4):S78-S80 (2016). https://www.globalacademycme.com/cme/dermatology-skin-disease-education-foundation/highlights-skin-disease-education-foundations-12th/why-biologic-therapies-sometimes-lose-efficacy

***

Hawking the Good Stuff

My folks relocated a few weeks before I entered high school. The house we moved into was an inglorious shade of brown mustard that Mom described as pumpkin-colored. She tolerated it until the day when Dad – with farm-bred slyness – called it “cat-manure yellow”. After that she’d settle for nothing but gleaming white, so we slapped on two coats of paint.

Real estate professionals might have picked a euphemism instead – maybe Colonial Ochre. I suspect they had influence where I live now. For instance, my suburb is sometimes thick with turkey hawks – or that’s the name people use. My online search for “turkey hawk” turned up nothing per se. These are turkey vultures, a.k.a. turkey buzzards. And they look like buzzards. Yet that name might imply that dead things stink up the place and attract winged garbage disposals. A hawk, though – that’s a magnificent bird of prey.

I don’t challenge the local names anymore. A long-time Georgian once told me that a certain species was poison oak, because her daddy had called it that. I later realized that’s a regional usage. Standard references show poison ivy leaves as tear-drop-shaped or jagged (botanists would call them entire or serrate), and poison oak leaves with smooth rounded edges (i.e., undulate or crenate). But the old-timers around here call the heart-shaped leaves poison ivy, and the jagged mitten-shaped leaves poison oak. I came across a local patch of true poison oak once; I didn’t ask what they’d call it.

But back to turkey hawks. They’re amazing in their own way. For one thing, even for vultures they have an incredible sense of smell. And they wait two or three days to eat a carcass, but no more. That softens its hide but limits our risk of contagion. Some reports say they also eat grapes and pumpkins – make that grapes and Colonial Ochre fruiting structures. It’s disconcerting to discuss fresh produce and rotting meat in the same sentence – though histories of jerky do it – however there’s evidence that turkey hawks wait until after all the sell-by dates.

Either way, their diet leaves a long list of pathogens around the beaks of turkey hawks and their best friends, black vultures. So, why don’t the birds get sick? Because germs can’t survive a stomach pH of zero. That’s more than 10X the acid concentration that humans have; as corrosive as battery acid. What *does* kill buzzards is liver poisoning from eating carcasses that have drugs (diclofenac) or bullets (they dissolve in acid), and the problem is global.

Another curiosity is that two types of anaerobic bacteria dominate buzzard intestines: Clostridia (as in botulism) and Fusobacteria (as in flesh-eating bacteria), which are also dominant in alligator intestines and, curiously, also in the gastrointestinal tracts of cancer patients. That pairing suggests that the microbes occupy complementary metabolic niches.

One author compared the gut bacteria of vultures to probiotics. That raises a hope that the microbial mutualism there might offer insights for pairing milder organisms in human probiotics. We need a better name for this phenomenon. “Turkey soup”, anyone?

***

Food for Thought

Primary article: M. Roggenbuck et al., “The microbiome of New World vultures,” Nature Communications, 5, Art. No. 5498 (November 25, 2014).

https://www.nature.com/articles/ncomms6498

Commentary on Vulture Digestion: Ewen Callaway, “Microbes help vultures eat rotting meat,” Nature (November 26, 2014).

https://www.nature.com/news/microbes-help-vultures-eat-rotting-meat-1.16345

Clostridia: F. Scaldaferri, V. Petito, and A. Gasbarrini, “Commensal Clostridia: leading players in the maintenance of gut homeostasis,” Gut Pathogens, 5(23):1-8 (2013).

https://gutpathogens.biomedcentral.com/articles/10.1186/1757-4749-5-23

Fusobacteria: A.D. Kostic et al., “Fusobacterium nucleatum potentiates intestinal tumorigenesis and modulates the tumor immune microenvironment,” Cell Host Microbe, 14(2):207-215 (2013).

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3772512/

The Combination in Cancer: Y.-Y. Hsieh, “Increased abundance of Clostridium and Fusobacterium in gastric microbiota of patients with gastric cancer in Taiwan,” Scientific Reports, 8, Article No. 158, p. 1-11 (2018)

https://www.nature.com/articles/s41598-017-18596-0

For context on behavior in the gut biome: Hannah M. Wexler, “Bacteroides: the good, the bad, and the nitty-gritty,” Clinical Microbiology Reviews 20(4):593-621 (2007). https://cmr.asm.org/content/cmr/20/4/593.full.pdf

Children & Cancer

A recent study of 200 nations (i.e., the world) estimates that although 400,000 children contract cancer every year, almost 50% are never diagnosed or treated. This is based on a statistical model because registry data is spotty. Only 3% of pediatric cases go undiagnosed in Europe and America, thus the numbers elsewhere are often much worse than the global average.

Having lost a young relative to cancer, I know that grief. The condition may sound rare on a planet of seven-plus billion people, but it isn’t. One child in 330 develops cancer before reaching adulthood; quick math confirms the new numbers are in that ballpark. In my county alone, that would be well over 500 young people this year. The American Cancer Society reports that only accidents are more common than cancer as a cause of death among children.

The story gets worse. Seemingly 92% of all new pediatric cases occur in low- and middle-income countries. I.e., the nations that can least afford therapies or prophylactics have the most cases by far. So, I wondered: since we reach out with vitamins and vaccines in some of those places, what do we do to preempt cancer there? Heck, what do we do for it in our own neighborhoods? According to my reading, mainly we offer nutrition counseling.

Would it be economical to send botanical anti-cancer concentrates to those areas? It could avoid the problem of picky eaters. That isn’t a joke. An African former colleague ate very few vegetables; he called them “twigs and leaves”. And how hard would it be to create a good pill for this? No herb is a fix-all, but some commonly cited natural anti-cancer compounds are listed below. Several of these have been in clinical trials.

Plant Category	Compound
Cruciferous vegetables	indole-3-carbinol
– Cabbage, etc.	brassinin
– Broccoli	sulforane
– Asparagus and mustard	sulforaphane
– Spinach	natural antioxidant mixtures
Tomatoes	lycopene
Tomatillos	withanolides
Carrots	beta-carotenoids
Red grapes; Peanuts	resveratrol
Allium vegetables (garlic; onion)	sulfur compounds
Soybeans	genistein
Green tea	tannins
Citrus fruits	vitamin C
Pomegranates	ellagic acid
Cranberries	myrecitin
Ginger	[6]-gingerol
Ginseng	ginsenosides
Rosemary	carnosol
Cloves	eugenol
Vanilla	vanillin
Aloe	emodin

The key compounds tend to be antioxidants. Because of that, early researchers guessed that those molecules quench byproducts from the reaction of (human) unsaturated lipids with radicals. This makes sense: even oxygen molecules are radicals. But physiology is seldom simple. The compounds listed above ALSO have roles in signaling pathways.* And for instance, radicals mediate the signaling cascades triggered by green tea. Clearly, antioxidants have nuanced roles. In fact, some of them are actually pro-oxidants under some conditions.

But I digress. Different anti-cancer compounds occupy different niches, so we should combine them. A modern rule for well-rounded diets is to eat a variety of fruits and vegetables to obtain all their color categories (green, yellow, orange, red and purple). Unfortunately, the rule is weak at the molecular level. Anticancer compound resveratrol is found in both grapes and peanuts, among other foods. What color is that? Tannins and vitamin C have the same issue.

Never mind. We’ll make arbitrary selections, like Mom did. Let’s say we pick 6 key ingredients for the cancer-preempting pill. Antioxidants are unstable in air, so we’ll smother them in olive oil. Oh, and the ingredients must be bioavailable, which is tricky. Oral doses of (carotene-like) curcuminoids in turmeric aren’t very bioavailable without help.

But we’d find a way. Now, on to the economics. An example is (carotene-like) lycopene, which contributes to the color of tomatoes. For the moment, ignore the fact that the kids may already receive doses of vitamin A that serve the same function. This paragraph is about cost accounting. First, there’s plenty of raw material: America is awash in tomato sauce. But as with most natural products the lycopene concentration is low (~0.1% in fresh tomatoes). Its current bulk price is ~$6,000/kg, ~$170/oz. Copying the daily intake recommendation (15 mg) from related compound Vitamin A yields $0.09 per pill for lycopene cost. For a total of six comparable ingredients the pill cost would be over 50 cents each, before we factor in the costs of excipients, compounding, coating, packaging, shipping or distribution.

Bottom line, by that route we’d be doing well to keep the pill cost down to a buck per day per child all year long on a non-profit basis. Are the kids worth it? Absolutely. But for the same cost, in many parts of the world we could keep their bellies full with nutritious produce.

The analysis isn’t done yet. Pill costs could be slashed if we use cruder extracts and do production abroad. Yet even if we could give pills away for free, most potential donors and non-profit groups won’t get excited about them unless medical associations endorse this approach. That won’t happen until a consensus arises as to which combinations of cancer-preempting natural products are optimal. Alternatively, a windfall from the Gates Foundation might get things moving.

Otherwise, preemptive extracts will remain the prize of buyers who can afford them.

***

*As to signaling pathways triggered by plant foods for cancer prevention, a recent abstract mentions nuclear factor kappa B, cyclooxygenase-2, signal transducer and activator of transcription 3, Akt, mitogen activated protein kinase/extracellular regulated kinase, Bcl-2, caspases, poly (ADP-ribose) polymerase, matrix metalloproteinase 2/9, and cyclin D1.

*Lycopene, a fat-soluble symmetric tetraterpene*

Food for Thought

Z.J. Ward et al., “Estimating the total incidence of global childhood cancer: a simulation-based analysis,” The Lancet, (February 26, 2019). For a summary and commentary, see https://www.sciencedaily.com/releases/2019/02/190226184140.htm.

A.R. Khuda-Bukhsh, S. Das, and S.K. Saha, “Molecular approaches toward targeted cancer prevention with some food plants and their products: inflammatory and other signal pathways,” Nutr. Cancer, 66(2):104-205 (2014). ABSTRACT: https://www.researchgate.net/publication/259498052_Molecular_Approaches_Toward_Targeted_Cancer_Prevention_with_Some_Food_Plants_and_Their_Products_Inflammatory_and_Other_Signal_Pathways

On Rats & Multiplication

Here in the South we get our share of troubling wildlife: fire ants, black widows, brown recluses, the occasional scorpion, and all four types of North American poisonous snakes. Then there are the gators, black bears, and other predators in the hinterlands. Of course, the assortment out west is sobering, too: grizzlies and brown bears are nothing to sneeze at.

Still, in the suburbs where I live the species that cause the most headaches are mundane. Cockroaches are a nuisance, but rats take the prize. The rodents show up inside gardens, crawl spaces, walls, ceilings, attics, and woe to you if rats get into your ductwork. After a while, everything starts to look like a rat. There’s Rattus rattus (ground rats), squirrels (tree rats), bats (air rats), children (rug rats), athletes (gym rats), politicians – no, no, let’s keep this edifying, though I note that Germans refer to their town hall as the Rat•haus.

Recently I learned that plantings may contribute more than food to our rat population. A study found that drinking a water extract from the fruit of either fig (Ficus carica), cinnamon, or fumitory (also known as earth smoke; poppy family) can double or triple the likelihood that adult rats will try to make little ones. The fig nearly matched the best-known synthetic drug for that purpose (sildenafil/Viagra®), used by humans. I suspect the rat study was less interested in animating rodents than in gauging the potential effects on humans. Research is sneaky that way.

So, this gives me a new criterion for which plant species get inflicted upon my yard. You see, three Ficus carica trees have materialized on my lawn since the study was first published, because the effect wasn’t on our personal radar until now. Hopefully one of the neighborhood red-tailed hawks will spot any fig-loving rats yet leave foolhardy small terriers alone.

Now if you’re like me – and I won’t pretend that’s a good thing – you’re wondering which molecules inspire a rat. After a high-level analysis, the authors vaguely credited the flavonoids in each of the three plant species. You remember flavonoids. They’re antioxidants, made famous in chocolate. Oddly, no one knows the molecular source of chocolate’s charm for Valentine’s Day, though its efficacy is never in doubt. In light of flavonoids’ oft-studied drug effects and thousands of structural variants, they were a fair guess as to rats.

So how can I leverage these insights? I’ll keep cinnamon at bay. That’s easy; it’s mainly East Asian. And don’t drop cinnamon sticks on my property; the spice makes elderly rats frisky. The fumitory is also distant – mainly in North Africa, West Asia, and continental Europe. It turns out sycamore fig trees are okay, but my family is already committed to F. carica.

Which other plants should I ban from my yard? Many species have never been tested for their effects on rats, but happily a cottage industry is trying to close the gap. And those researchers publish plausible data on rat behavior, no matter what the doubters tell you. So here are two tips. Skip the date palms. They’d clutter up your lawn, anyway. And skip plants that have a certain reputation for human behavior – e.g., tongkat ali – as rat physiology is similar.

Of course, rat problems may fall off if a bear takes up residence. My online searches for natural products to manage a bear’s mood have turned up only meals and pepper spray. Hmm.

***Skeletal core for a flavone, one of the main types of flavonoid.***

Food for Thought

G.Z. Mukhtar et al., “Cinnamomun cassia, Ficus carica and Fumaria officinalis possesses aphrodisiac activity in male Wistar rats,” Annals of Experimental Biology, 3(3):14-17 (2015). https://www.scholarsresearchlibrary.com/articles/cinnamomun-cassia-ficus-carica-and-fumaria-officinalis-possesses-aphrodisiac-activity-in-male-wister-rats.pdf

U. Tijjani et al., “Aphrodisiac effect of aqueous stem bark extract of Ficus sycomorus on female Wistar rats,” Nigerian Journal of Basic and Applied Science, 26(1): 70-79 (June, 2018). https://www.ejmanager.com/mnstemps/97/97-1505123814.pdf?t=1551055379

S. Kotta, S.H. Ansari, and J. Ali, “Exploring scientifically proven herbal aphrodisiacs,” Pharmacognosy Reviews, 7(13):1-10 (2013). https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3731873/