An ironic observation by the first synthesiser of thyroxine

[helvella]

Have been looking through some very old papers about thyroid and found one co-authored by Charles Harington, who was very much to the fore in efficient isolation of thyroxine from animal thyroid, and co-inventor of a method of synthesising thyroxine.

The irony from today's perspective lies in this paragraph:

CLXXIX. SOME DERIVATIVES OF THYROXINE.

BY JULIUS NICHOLSON ASHLEY

AND CHARLES ROBERT HARINGTON.

From the Department of Pathological Chemistry, University College Hospital Medical School, London.

(Received October 31st, 1928.)

SINCE thyroxine has been available in the pure condition its therapeutic use has been limited by the fact that it is only possible to elicit with certainty the full physiological activity of the substance when it is administered intravenously. When thyroxine or its sodium salt is administered by the mouth absorption appears to be irregular, and scarcely ever is the full effect of a given dose obtained. Except, therefore, in hospital practice where the intravenous injection offers no difficulties, thyroxine compares unfavourably with crude desiccated thyroid gland as a therapeutic agent. In our opinion thyroxine fails to be absorbed after oral administration owing to its extreme insolubility when in the free condition.

europepmc.org/article/MED/1...

Of course, this comes from almost a century ago. Many things have changed. But the insolubility of thyroxine, right up to the development of levothyroxine sodium oral solutions and gel caps (as in Tirosint), has continued to be an issue.

I do not know if Harington revised this opinion in later years.

[LindaC]

Thank you, hellvella - I've been looking for a document which goes way back... apologies, can't find it yet. I've seen several versions of this Levothyroxine claim: am I splitting hairs here? It seems to me that in 1891 the amazing Newcastle upon Tyne, George Murray did, among others, discover NDT [sheep in this case] and used it with much success.

This is from May 2016: "Thyroxine discovered by Newcastle medic": ***** ****** at Newcastle University, said:

"Everybody knows someone who takes thyroxine tablets. In 1891, a young Newcastle doctor, Dr George Murray, injected an extract from a sheep’s thyroid gland into a patient with symptoms of thyroid under-activity. Over a period of months, the patient got much better. 125 years later around 3% of the population takes thyroxine or thyroid medicines."

Newcastle originally made its big 19th C name, I would say, with NDT and that is so amazing. However Thyroxine, was not isolated until 1913. in pure form in 1914, at the Mayo Clinic by Edward Calvin Kendall from extracts of hog thyroid glands. The hormone was synthesized in 1927 by British chemists Charles Robert Harington and George Barger.

[helvella in reply to LindaC]

This 1926 paper, also by Harington, is pretty damning of Kendall at the Mayo Clinic:

Chemistry of Thyroxine

Isolation of Thyroxine from the Thyroid Gland

Charles Robert Harington

europepmc.org/article/MED/1...

There is no doubt whatsoever that some excellent people have worked at Mayo Clinic. But all too often, when I have read further, they seem immensely skilled at Public Relations. What they have actually done is often a bit less impressive than how it reads.

This is Harington and Barger's paper about synthesising Thyroxine:

Chemistry of Thyroxine: Constitution and Synthesis of Thyroxine.

Harington CR1,

Barger G

The Biochemical Journal, 01 Jan 1927, 21(1):169-183

europepmc.org/article/MED/1...

[LindaC in reply to helvella]

Thank you so much, helvella - most interesting stuff - 'accuracy' as far as is possible, is so much more to appreciate - it's vital - than some P R scam. Newcastle is a fine University [my own 💚] and with some amazing medical achievements, I just happen to think that accuracy wins out every time, in every field, everywhere.

Absolutely agree: there are excellent people at Mayo - everywhere - but it just takes a few to undermine the validity/reliability of methodology/testing... or the apparent ever-growing body of scammers continues to grow. This always reminds me of the painstaking work of Dr John Lowe, sent to UK 'authorities', yet disregarded out of hand in favour of their 'little pet TSH/T4 theories'.

One more time: “Separating the individual from the trend has to be the correct way for a doctor/patient relationship to succeed; many doctors are unnecessarily failing ill patients.”

We are aware that those doctors, a depicted above, are hounded by 'the system'.

NB. 'Zealous proponents of TSH/T4 hypothyroid dx/treatment have no evidence for their stance. The RCP was asked on numerous occasions to cite references to research/ studies showing their, “overwhelming evidence supporting the use of thyroxine (T4 alone)”: to date none has been provided. A Freedom of Information (FOI) request that the RCP provide such evidence was again met with no response. A request was made via the ‘Ask for Evidence’ website, run in association with ‘Sense About Science’ asking for evidence on the safety and efficacy of L-T4 as a treatment for hypothyroidism. This request, directed to the RCP, who eventually responded stating “The RCP’s guidance is based on the opinion of an expert panel temporarily formed for this purpose. The evidence they used to form their individual opinions has not been collated and therefore the RCP cannot provide any evidence list”.' (There is much ignored contrary evidence, even including on bone density + a-fib re T3.) Yet with no record of their decisions or evidence re the basics, the RCP continues. Being above scrutiny is anathema in any field.

“You know an entire field is in trouble when its key authority figures get so publicly drunk on their own self-reinforcing privilege”.

[helvella]

I think levothyroxine is very rarely given by injection but there are case reports - typically of myxoedema coma patients - which mention its use.

[helvella]

You would be OK in Luton:

Intravenous Levothyroxine 200mcg/ml (L-Thyroxine SERB®)

Please note this is a different brand to the one listed in the Medusa IVGUIDE

Dose Conversion & Administration Guide

Parenteral administration of levothyroxine is an option for patients who cannot take medication orallyfor a prolonged period on the recommendation of a consultant or Endocrinologist. Due to the long half-life (6-7 days) most patients will not suffer any sequelae from omission for several days. Levothyroxine for parenteral administration is not available as a licensed product in the UK. We have sourced levothyroxine injection 200micrograms/ml which is licensed in France with an English package leaflet.

Oral to IV Conversion: The intravenous dose of levothyroxine is not the same as the oral dose. There are several recommended conversions ranging from 50 to 80% of the oral dose but the American Association of Clinical Endocrinologists/American Thyroid Association guidelines recommend an intravenous dose 50-70% of the patient’s oral dose.

Example: 125microgram oral = 62.5 to 87.5microgram –round to measurable 60 (0.3ml),70 (0.35ml) or 80micrograms (0.4ml)

bedsformulary.nhs.uk/docs/I...

They appear to blame the variation in dose equivalence on the guideline writers. The truth is, I think, the different absorptions individuals achieve! Which we see every day - changes of make will, if nothing else, tend to affect precise absorption.

[helvella]

Yes - interesting.

But I do wonder if it is a little bit on the PR side? After all, the thyroid gland in our necks has a massive blood supply and is heavily innervated. Might work adequately, might be much better than any other approach, but "normally" is asking a lot.

[annnsandell]

Wow...............

[TaraJR]

linda96 Helsan MikeM46

[helvella]

Given that relocating parathyroids has long been an established procedure, I do really wonder why it is so rarely done.

Anything which has the potential to destroy parathyroids - thyroidectomy or radio-active thyroid treatments, radiation to destroy other tissue in the neck, etc. - seems to allow the possibility of relocating at least one parathyroid ahead of that treatment. Thus preserving at least some parathyroid function.

I imagine an operation to relocate, allow time to check it is functioning and sufficient healing, then do the full operation.