Five favorite molecules

This post was meant to go up yesterday but I was distracted by the lengthy conversation I had with my wife, a physician-scientist, about this very topic.

Many of you who attended the ScienceOnline2010 conference here last January probably met Carmen Drahl, the Princeton-trained chemist who now writes for Chemical & Engineering News and their appropriately-named drug discovery blog, The Haystack, as well as their Newscripts feature.

For the latter, Dr. Drahl pointed us toward a recent “Crosstalks” paper in Chemistry & Biology by Thomas U. Mayer and Andreas Marx of the University of Konstanz (and her interview with the authors) who mused as follows from their abstract:

Which five molecules would you take to a remote island? If you imagine yourself as a castaway on an island you might pick water, glucose, penicillin, and ethanol in combination with aspirin. However, as a scientist, you may ask yourself which molecules impressed you most by their chemical or biological property, their impact on science, or the ingenuity and/or serendipity behind their discovery. Here, we present our personal short list comprising FK506, colchicine, imatinib, Quimi-Hib, and cidofovir. Obviously, our selection is highly subjective and, therefore, we apologize up front to our colleagues for not mentioning their favorite compounds.

The full paper (PDF) is freely available at the time of this post (thank you, Cell Press!) and the science historian in me is delighted by reading it. I’ll be giving this out to my pharmacology students on day one of the upcoming semester and charge them with selecting and justifying a molecule of their own.

But the authors pose two different questions – a) which molecules, drug or not, would you take as the sole occupant of a desert island, and b) which drugs most impress you with their chemistry, biology, or impact on science.

She’s now asking for people to fill out this survey of their own five molecules to take to a desert island (or drop comments on her blogpost).

We approached the question as “what five drugs would you take to a desert island if you were the sole occupant?”

My thought process was to think about what would be most likely to kill you if you were alone as an otherwise reasonably healthy mid-40s dude coming off a bout of pneumonia. Antibiotics and vaccines have arguably had the greatest impact on the leap in life expectancy observed during the 20th century. Vaccines wouldn’t be necessary if you were alone, but antibiotics would be crucial, especially if you fell and broke bones.

But what antibiotic? One probably wouldn’t be encountering highly drug-resistant bugs so would ampicillin be best? Would you want two antibiotics? Perhaps one antibacterial and one antifungal, the latter giving the humid, tropical climate.

For any sort of painful encounter, I’d want morphine. Yes, it’s best injected and I don’t think one would be stranded with syringes as well, but there are oral morphine formulations that have reasonable bioavailability. Perhaps it would be good enough mixed in with coconut milk. If not, I’d take Actiq fentanyl lollipops or hydromorphone.

A good, daily analgesic might help. Aspirin has a lot of advantages despite the evolution of other analgesics like ibuprofen and naproxen.

I’m not sure how my asthma would be on a desert island, but I’d rather not chance it so I’d definitely use up a slot with my rapid-acting beta2-agonist, albuterol.

And if you have a strong, penetrating family history of depression like me, I’d bring an antidepressant – probably escitalopram. Think that’s not necessary? If you can’t even get up and go fishing or build a shelter because you are so paralyzingly depressed, an antidepressant drug could be just as life-saving as a broad-spectrum antibiotic.

Ahh, but malaria – maybe I’ll keep the morphine but give up the naproxen and bring some chloroquine.

This is kind of tough, eh? Some of the choices depend on your own pre-existing conditions.

What five drugs would you bring if stranded on a deserted island?

Even if you comment here, please be sure to put your choices in Carmen’s survey here. She notes that she’ll post some of her results next week.

My voice has been absent from the blogosphere. . .

. . .because my voice has also been absent from the offline world.
Yes, the final gift to me from LungMutiny2010 is a case of inhaled corticosteroid dysphonia – and another opportunity to cultivate compassion for those with chronic illnesses and permanent loss of physiological functioning.
Here’s a recap: After a three month battle with pneumonia, I returned to the university as much as I could about six weeks ago. I say “as much as I could” because, once again, I was amazed by how little my body would let me do after being confined to bed for ten weeks.
Some days I’d just be doing great and, without warning, hit a wall of complete exhaustion – the kind that even a triple-venti, quadruple-espresso shot beverage couldn’t remedy. Other days I’d wonder why the soles of my feet were red and burning – I had to remind myself that my walk across campus the preceding day was a little much on feet that hadn’t walked, much less seen shoes, for most of the year.
But even as my stamina is on an upward trajectory, I still had laryngitis as my pulmonary symptoms resolved. I kept waiting for it to improve as I tried to talk through the hoarseness.
Then three weeks ago, I lost my voice to all but a whisper.
Fortunately, one of our local academic medical centers maintains a voice care clinic out of their Division of Otolaryngology. I was able to get in within a week to see one of the senior docs in the group and an outstanding team of nurse practitioners and speech pathologists. After lengthy questioning about my allergy/asthma history and the course of my illness to date, they anesthetized my nasal passages with tetracaine spray and viewed my vocal cords with a strobscopic laryngoscope.
The technology was awesome to watch in the recorded video but confirmed that my vocal cords were bright pinkish-red and swollen with irregular edges. “That’s about as bad as we see them around here,” was the quote from my doc as he pointed to the monitor. I forgot to ask if there was a way for me to download some stills to show you here.
Advair Terra Sig.jpgIt seems likely that the large amounts of oral corticosteroids followed by inhaled steroids did a great job helping my lungs heal but set up my vocal cords for a Candida infection (fungal), steroid myopathy, or some combination thereof.
Yes, it’s a major bummer to have what would be called an iatrogenic adverse effect but without these steroids, I’d still be on my back in bed. I make this point because no drug possesses absolute safety. All drugs have a some spectrum of benefits and risks of side effects – the setting in which they are used determines whether those benefits outweigh the risks. I would take these steroids again in a heartbeat. Remember, those who have followed this saga: I was coughing so hard that I was passing out (cough syncope) and I believe I either cracked a rib or tore a tendon from the months of hacking.
I did some reading after another colleague told me of the prevalence of this inhaled steroid side effect. Inhaled corticosteroid dysphonia was first widely described in the literature in 1983 by a group from East Birmingham Hospital in England. In recent years, this adverse reaction seems to have increased in incidence with the introduction of dry power inhalers, usually in the form of the longer-lasting steroid fluticasone.
This 2004 Laryngoscope article from the University of Pennsylvania describes the problem and the pathology quite well.

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Sir James Black (1924-2010) – Physician, Pharmacologist, Gentleman

Have you ever taken one of the now-over-the-counter heartburn relief remedies like Tagamet, Zantac, or Pepcid?
How about the beta-blocker atenolol (Tenormin) or metoprolol (Lopressor) for antihypertensive therapy, or the original less-selective beta-blocker propranolol (Inderal) for migraines, presentation anxiety or stage fright?
Sir James Black - David Levenson Rex Features.jpgIf you answered yes to either question, you owe a debt of gratitude to Sir James Black, the Scottish physician who left us earlier this week at age 85. The best obituary I have seen memorializing Sir James comes from the UK Telegraph.

Black was called the father of analytical pharmacology and was said to have relieved more human suffering than thousands of doctors could have done in careers spent at the bedside. Certainly, no man on earth earned more for the international pharmaceutical industry.
Yet though he became joint winner of the Nobel Prize for Medicine in 1988, Black derived little personal financial benefit from his discoveries. Among businessmen he had a reputation as an irascible maverick and this prickly independence, combined with an antipathy to big institutions, led him to flounce out of jobs whenever he felt corporate short-sightedness was getting in the way of research.

Others can be read at The Independent, The Times, The Guardian, The Scotsman, and BBC News.
It is rare for a scientist to discover one drug that makes it to market. Sir James not only led the discovery of two major drugs, propranolol and cimetidine. As if that were not enough, each drug was a “first-in-class” agent, the first approved drug that acts via a novel mechanism of action.

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Former date rape drug reincarnated as answer to unmet medical needs

Just a quick post on an article that caught my eye: Jazz Pharmaceuticals of Palo Alto, CA, has announced that the US FDA has accepted their new drug application (NDA) filing for JZP-6, or sodium oxybate, for the treatment of pain and fatigue associated with fibromyalgia.
The NDA was based on positive outcomes of two, Phase III clinical trials – those randomized, placebo-controlled double-blind trials that serve as the gold standard for drug efficacy. The company expects an approval decision from FDA by October 2010.
Jazz has already garnered approval for sodium oxybate under the brand name Xyrem® for the treatment of daytime sleepiness in patients with narcolepsy. The company stresses, however, that the drug has not yet been approved for symptoms associated with fibromyalgia.
200px-4-hydroxybutanoic-acid.pngThe item of note here is that sodium oxybate is another name for the sodium salt of gamma-hydroxybutyrate or GHB, a sedative that resembles the inhibitory neurotransmitter GABA but also has its own receptors in the central nervous system. GHB was implicated as far back as the early 1990s on college campuses where young men who lacked any other redeeming qualities to attract women used it to dope the drinks of their dates.
But here we see the study of a drug of abuse giving rise to a useful pharmaceutical, first in narcolepsy and, soon perhaps, for fibromyalgia.
It is a paradox of pharmacology that a sedative like GHB would prevent excessive sleepiness or fatigue. But a similar paradox exists with the use of the stimulant methyphenidate in hyperactivity conditions.
Now that I’ve seen the business reports, I’ll turn to some of my CNS pharmacology colleagues to help explain the neurobiology.
However, this compound demonstrates to me the unanticipated benefits of funding research that aims to investigate drugs of abuse.
Beneficial therapeutic agents come when and where you may least expect them.

Icariin from horny goat weed is structurally unrelated to sildenafil (Viagra®)

In our last post, we discussed a recent USPTO ruling that rejected a claim of the Pfizer patent on the erectile dysfunction drug, sildenafil (Viagra®), to a novel oral treatment for the disorder. The patent appeals panel ruled that the existence of horny goat weed, a traditional Chinese medicine used orally for impotence, was grounds for rejection of the claim.
Frequent commenter daedalus4u pulled out US Patent #6,469,012 (filed Mar 4 1996, issued Oct 22 2002) wherein the relevant claim 24 reads:

A method of treating erectile dysfunction in a male human, comprising orally administering to a male human in need of such treatment an effective amount of a selective cGMP PDE inhibitor, or a pharmaceutically acceptable salt thereof, of a pharmaceutical composition containing either entity.

The claim should never have been allowed in the first place, said daedalus4u, and if upheld would have allowed Pfizer to block sales of horny goat weed. I’m also assuming that upholding claim 24 would have also allowed Pfizer to block sales of follow-on PDE5 inhibitors such as Lilly’s Cialis®. But again, I’m not a patent attorney so I welcome further discussion on this point.
We also heard from my dear old colleague from Adelaide, Professor Ian Musgave. Ian is a pharmacologist who is probably better known in the blogosphere for his astronomy expertise (Astroblog, Southern Sky Watch, and contributing editor to Sky & Space).
But Ian is first and foremost a pharmacologist and raised this point:

Wait a minute, let me get this straight. The patent on Sildenafil, a compound that was rationally designed to specifically inhibit PDE (1) and developed prior to 1996 was invalidated because of a structurally unrelated component of a herbal extract that wasn’t even shown to act on the cGMP/NO system before 2001? (2)

Pfizer is supposed to have time travel? The fact that a herbal treatment alleged to help sexual function would turn out, 5 years after the sildenafil patent had been granted (and the concept of PDE5 inhibitors as treatment for erectile dysfunction wide spread) to have effects on PDE5 could not possibly count as prior art. If so, the 1983 demonstration that the PDE inhibitor papaverine could produce erections would have invalidated the sildenafil patent.

The patent boards ruling is patently rubbish. How can sildenafil “logically flow” from a compound that wasn’t even known to really work, let alone known to inhibit PDE?

(1)Nicholas K. Terrett, Andrew S. Bell, David Brown and Peter Ellis. Sildenafil (VIAGRATM), a potent and selective inhibitor of type 5 cGMP phosphodiesterase with utility for the treatment of male erectile dysfunction. Bioorganic & Medicinal Chemistry Letters
Volume 6, Issue 15, 6 August 1996, Pages 1819-1824
(2)Xin ZC. Kim EK, Tian ZJ, Lin GT, Guo YL. Icariin on relaxation of corpus cavernosm smooth muscle. Chin Sci Bulle 2001; 46: 485-9.

Prof Musgrave is indeed correct in the argument but daedalus4u points out the ruling did not invalidate the Pfizer patent, just the single claim to the pharmaceutical indication.
So that makes more sense to me and now I think I understand.
But in the discussion, Ian gave us another gem in response to a commenter who argued there was a structural resemblance between sildenafil and icariin, the active flavonol glycoside constituent of horny goat weed:

No, not at all. You can stick the benzofuran of the flavonol on top of the methylxanthine moiety of the sildenafil, but the charge distribution and 3D structure is all wrong, the flavonol has these huge sugar moieties which have the wrong charge and stick out in places that should inhibit binding, it lacks the bulky positively charged ring that fits into the PDE5 specific binding pocket. (I have the an image of the 3D structural overlay if anyone want to see them).
Looking at it, icariin does not scream either methylxanthine mimetic or “PDE inhibitor”, in fact I would guess it would be worthless. However, flavonols and flavinoids have a habit of doing things we don’t expect, such as resveratrol being a very decent cannaboid receptor anatgonist, despite looking nothing like cannabinoids of the synthetic antagonists.

In fact, Ian was kind enough to send us two molecular modeling images of the two compounds which I failed to get posted last night that illustrate the vast difference between sildenafil and icariin. This overlay image was generated with RASMOL, with icariin in the wireframe format and sildenafil in stick format:

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Horny Goat Weed (Epimedium spp.) is a limp excuse for Viagra, Cialis

Reuters and Bloomberg reported earlier this week on an ongoing patent battle (read: pissing match) between Pfizer and Eli Lilly & Co. relating to their erectile dysfunction drugs Viagra and Cialis, respectively.
Goat.jpgA US Patent and Trademark Office (USPTO) appeals committee has ruled that an element of Pfizer’s patent on sildenafil, the active chemical in Viagra, is invalid because the drug is insufficiently different from a traditional Chinese medicine called Yin Yang Huo or horny goat weed.
At issue is Pfizer’s claim to a method for treating male erectile dysfunction. The patent appeals panel ruled that the method did not constitute a new invention because of the precedent set by Yin Yang Huo. Moreover, the board ruled that chemicals found in the herbal medicine act by the same mechanism as sildenafil by inhibition of an enzyme called phosphodiesterase-5 (PDE5). Therefore, the panel ruled, “the patent claim was the next logical step up from using the herb.”
I’m not an expert in law but there are untold number of traditional remedies touted for all sorts of sexual enhancement, none of which have the convincing efficacy of the prescription PDE5 inhibitors. We may call the condition “erectile dysfunction” today and the idea of treating it may have existed for centuries but having a compound that can actually do anything about it is an invention. However, I can see the fine distinction if Pfizer claimed that the idea of treating erectile dysfunction was an invention.
You lawyers out there can weigh in but this sounds like a bunch of posturing for market share: worldwide Viagra sales were $2 billion USD last year.
But what is this horny goat weed and why is it being singled out?

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Are testosterone-deficient men responsible for shortages of a life-saving drug for women with breast cancer?

From Monday’s issue of The Press in York, England:

A breast cancer patient from York says she is “disgusted” by a shortage of the drug she and hundreds of other women rely on to reduce the risk of the disease returning.
Mother-of-two Marion Barclay, 45, said the situation became so serious last Friday, she faced the prospect of missing her daily dose of Arimidex tablets.

Marion Barclay Arimidex.jpgThis story is one of several reports on sporadic, worldwide shortages of Arimidex®, the brand of anastrozole sold by AstraZeneca. Anastrozole is a competitive inhibitor of the cytochrome P450 monooxygenase isozyme known as CYP19 or aromatase. Aromatase catalyzes the conversion of testosterone to 17β-estradiol and its inhibition is critical to the long-term management of estrogen receptor-positive breast cancers.
However, the off-label use of anastrozole for men with testosterone deficiency, or hypogonadism, has been a topic discussed at ScienceBlogs since self-help guru James Ray was found in possession of the drug when his Sedona resort room was searched following the deaths of three people in the infamous sweat lodge incident.
Related to this story, a commenter recently criticized endocrinologists in a thread at White Coat Underground saying that:

That is why they don’t know how to use aromatase inhibitors, such as Arimidex (anastrozole), stating it is “only for female breast cancer patients. So why are there between 100 and 1,000 times more men than women on it? Astra Zeneca is laughing all the way to the bank.

This is a peculiar statement because AstraZeneca can only promote the drug in the US for FDA-approved indications. Of course, with their patent on the drug expiring in June 2010 it would not be a surprise if they were seeking approval for a new indication: use in TRT. Indeed, small studies have shown that anastrozole may be effective in managing gynecomastia caused by testosterone conversion to estradiol in men receiving testosterone replacement therapy.
But if “between 100 and 1,000 times more men than women” are currently taking anastrozole, where would that data come from and why would it be publicly available?
And if true, could the alleged masses of men taking anastrozole for testosterone deficiency be indirectly responsible for women with breast cancer facing shortages of a drug essential for their survival?
Photo credit: The Press (York, UK)

Did the patient fail the treatment or did we fail the patient?

While the coffee wasn’t quite ready this morning, I ventured to the Wall Street Journal health page at the Wall Street Journal, one of my frequent first-reads.
I was immediately intrigued by a short article from the excellent Jennifer Corbett Dooren about Roche-Genentech gaining US FDA approval for a new rheumatoid arthritis drug, Actemra.
Actemra (tocilizumab) is a monoclonal antibody that works via a novel mechanism of blocking the receptor for interleukin-6, a pro-inflammatory molecule called a cytokine. What is most important is that Actemra appears to work in patients who have not been helped by other existing drugs such as those like Remicade (infliximab), Enbrel (etanercept), Humira (adalimumab) that block the effects of another cytokine called TNF-alpha.
Rheumatoid arthritis is not just joint aches and pains. It is a very serious disease that can cause not just pain but deformity and progressive disability. Rheumatoid arthritis afflicts 1.3 million people in the US.
But what caught my eye and generated my pre-caffeine ire was in the opening sentence, terminology used in clinical pharmacology and therapeutics, words that I admit to have even uttered myself:

WASHINGTON–The Food and Drug Administration Friday approved a new type of drug by Roche Holding AG’s Genentech unit to treat rheumatoid arthritis in patients who have failed other treatments. [emphasis mine]

I know that we use that phrase because it is seems less cumbersome than saying, “in patients whose disease has not responded to existing drugs.”
But saying that the patient failed the treatment makes it seems that the patient somehow bears responsibility for the lack of their disease to respond to the tools we currently have available. Yes, yes, I know – disease is essentially a patient’s own pathophysiology, where their own homeostatic mechanisms are awry or respond inappropriately to environmental changes or invading organisms.
But jeez, have you ever thought what it sounds like to a patient to hear that they failed the therapy? Could we possibly take any less responsibility for our failure to treat disease? Even if physicians want to use the word “fail” couldn’t they at least shift the blame to us basic scientists who’ve failed to come up with an alternative drug?
As I’m writing this and searching for literature on the medical psychology of using this term, I just realized why I am bothered. If we accept that medicine says, “the patient failed the treatment,” that’s one thing. What troubles me is that I just read the statement in the opening sentence of an article in a highly-regarded business publication crafted by a health and medicine writer whom I respect.
Don’t get me wrong. I’m all for personal responsibility in health. All of us could do a better job of watching what we eat, exercising more, not smoking, drinking alcohol in moderation – the big four factors that could make a greater impact on human disease than the next new wonder drug.
But just because a $10,000/year drug doesn’t work for me and my rheumatoid arthritis, does that really mean that “I failed the treatment?”
I know we’ve got some medical sociologists and psychologists out there reading – I’d be grateful for any commentary or direction to scholarly literature on why we continue to use the term, “the patient failed the treatment.”
One final note
As an amorphous descriptor, Big Pharma has certainly lost a lot of trust of the general public and the scientific community over the past several years from data cover-ups on drug-related deaths to ghostwriting of peer-reviewed journal articles, the latter of which was eloquently addressed by Orac last year. These practices are inexcusable and deserve strong punishment, especially where it is clear that loss of lives was a result of deceptive clinical data submission.
I’ve had the pleasure of training with many outstanding scientists who now work in the industry and, particularly in the field of pharmacology, have come to respect and learn from new colleagues who’ve chosen industrial careers. Several of these people are among the most ethical I know and, as with any other industry, are pained equally if not more by the scandalous cases.
So when good things happen, such as the approval of a new drug that has the potential to help people in pain for whom no other agent has helped, I like to acknowledge the efforts of those folks behind the work.
Let me offer my heartiest congratulations to colleagues at Roche and Genentech on this nail biter after having been asked for more data last year. Addressing these kinds of scientific and regulatory challenges gives me great respect for my colleagues at the bench and in the clinic who have worked to relieve human suffering from this debilitating disease.

James Ray’s Sedona sweat lodge stash: lessons in polypharmacy and endocrine pharmacology

Sedona - NYT Jeff Topping 04.09.06.jpgOn October 8, 2009, paramedics responded to a 911 call at a mystical retreat being held at Angel Valley Spiritual Retreat Center in West Sedona, Arizona, a stunningly beautiful area known widely as a mecca for New Age enthusiasts. Eyewitness accounts compiled in this October 21 New York Times article describes what medics encountered upon arriving at a 415-square-foot “sweat lodge” on the center’s grounds:

Midway through a two-hour sweat lodge ceremony intended to be a rebirthing experience, participants say, some people began to fall desperately ill from the heat, even as their leader, James Arthur Ray, a nationally known New Age guru, urged them to press on.
“There were people throwing up everywhere,” said Dr. Beverley Bunn, 43, an orthodontist from Texas, who said she struggled to remain conscious in the sweat lodge, a makeshift structure covered with blankets and plastic and heated with fiery rocks.
Dr. Bunn said Mr. Ray told the more than 50 people jammed into the small structure — people who had just completed a 36-hour “vision quest” in which they fasted alone in the desert — that vomiting “was good for you, that you are purging what your body doesn’t want, what it doesn’t need.” But by the end of the ordeal on Oct. 8, emergency crews had taken 21 people to hospitals. Three have since died.

Participants paid $9,695 each to attend a “Spiritual Warrior” retreat led by Mr. Ray, an event that continues to be advertised on the website for James Ray International, Inc.
Yes, the 2010 event is still scheduled for September 18-23, 2010.
But I wouldn’t put up my ten grand just yet because an investigation of Mr. Ray is ongoing and the Yavapati County Sheriff’s Office has recently released the affidavit from a search warrant executed shortly after this tragedy.
This December 30 New York Times article displays the 33-page search affidavit and this January 3 Prescott News article has several photographs and an excellent distillation of the affidavit.
Many other news sources will provide you with details on the circumstances of the tragedy with eyewitness reports and you can read elsewhere of Mr. Ray’s appearances on The Oprah Winfrey Show.
But here we would like to discuss some of the pharmacology associated with the Sedona tragedy. Lynne LaMaster in the Prescott News notes that according to the search warrant documents, investigators were originally looking for:

“A saleable/useable quantity of unlawful drugs including but not limited to marijuana, methamphetamine and peyote, paraphernalia for packaging, manicuring, weighing, distributing, including but not limited to scales, baggies, grinders, bindles, envelopes, seals paraphernalia used to administer the drug, i.e., syringes, cotton swabs, alcohol swabs, spoons, razor blades, tubes.”

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Sir John Crofton, TB combination therapy pioneer – a long and admirable life

Sir John Crofton.jpgDenise Gellene in the New York Times is reporting this morning that Scottish physician, Sir John Crofton, passed away on 3 November at age 97.
Crofton is best known for implementing a combination drug regimen to treat tuberculosis, the insidious lung infection with Mycobacterium tuberculosis which decimated the US early last century and still kills 2 million a year worldwide. The concept of using drug combinations to increase individual drug potency and slow the emergence of resistance is now a mainstay of therapeutic approaches for cancer, HIV, and other infectious diseases.
Gellene reports that Crofton first investigated streptomycin for TB shortly after the drug’s discovery and isolation at Rutgers by Selman Waksman and his then-graduate student, Albert Schatz. Waksman was sole winner of the 1952 Nobel Prize in Physiology or Medicine, with the oversight of Schatz ranked by Scientific American among the top 10 Nobel snubs.
Crofton’s original 1950 letter to the British Medical Journal on use of intermittent doses of streptomycin can be seen in this PDF.
Incidentally, the revered German physician, Robert Koch, was awarded the 1905 Nobel Prize in Physiology or Medicine for the discovery of M. tuberculosis. His medical microbiology criteria, known as Koch’s Postulates, became the rubric for establishing causation of an infectious agent.

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