Wednesday, August 12, 2015

Sometimes a drug is just a specific bit of animal flesh

Although now obsolete, the use of crudely processed chunks of animal flesh in the treatment of disease was widespread in the past. These fleshy parts, usually glands or organs, contain hormones and vitamins necessary for good health that at the time had either not yet been isolated or were difficult/expensive to isolate and use as drugs. They were prepared and administered in several ways: pulverized and snorted, cleaned up a bit and injected, or cooked up and eaten. Unfortunately, the presence of certain proteins along with the desired hormone or vitamin often brought about unexpected harmful effects. Let's take a look at some of these crude drugs.

Antidiuretic hormone via livestock pituitary glands

Antidiuretic hormone (ADH) (aka arginine vasopressin) is a chain of nine amino acids produced in the brain and released into the bloodstream as required. It acts on the kidneys to reduce urine production (a diuretic, such as caffeine or alcohol, does the opposite). This ability makes ADH an effective treatment for pee-related conditions such as diabetes insipidus (producing way too much urine, sometimes due to the brain not making enough ADH), bedwetting, and nocturia (having to wake up at night to pee, which can contribute to insomnia and sleep deprivation).

In the early 20th century, ADH (known as pitressin at the time) was administered by snorting ground up pig and/or cow brain, specifically the hypothalamus and/or posterior lobe of the pituitary gland where the hormone is synthesized and released. These brain bits were cut out, dried using acetone, and ground into a fine powder. This powder was then diluted with an inert soluble powder (e.g. lactose) to produce a snuff.


Pituitary gland (orange dangly thing) at the base of the brain (Source)

At the time of its use, snorting (nasal insufflation) was deemed the best way to get ADH into the bloodstream (it's absorbed through the lining of the inside of the nose). It was easier and more pleasant than injections of purified ADH (needles hurt, y'all), and the hormone was broken down by stomach acid if ingested. Patients would typically take the snuff two to four times daily to treat whatever pee problem was ailing them.

However, it was subsequently observed that snorting a bunch of ground up animal brain wasn't particularly good for your lungs. After being inhaled, if the snuff was fine enough some of the smaller particles could make their way into the deepest parts of the lung, where they would sometimes function as antigens and cause the immune system to mount a harmful inflammatory response. The widespread lung inflammation resulting from the repetitive inhalation of an external antigen is known as hypersensitivity pneumonitis or extrinsic allergic alveolitis, and is typically seen among people exposed to certain airborne substances at work (e.g. dust from mouldy plant matter or chemicals such as isocyanates). The resulting syndrome is usually named after the type of work being done (e.g. farmer's lung, tobacco worker's lung). In this particular case, it came to be called pituitary snuff-taker's lung. Inflammation takes kind of a salting the earth approach to ridding the body of an antigen, so there is usually collateral damage. As the lung becomes damaged, scar tissue is formed. This tissue, being stiff and thickened, makes breathing more difficult, and it usually doesn't go away.

Pituitary snuff was apparently mostly used as a short-term treatment for bedwetting in children. It was taken for substantially longer periods by patients with diabetes insipidus, and it was in these patients that pituitary snuff-taker's lung usually occurred.

Growth hormone via human pituitary glands

In 1909, an Austrian doctor by the name of Bernhard Aschner demonstrated that removing the pituitary gland from a dog resulted in a smaller dog (dwarfism). Just over a decade later, Herbert Evans and Joseph Long at Berkeley produced gigantic rats by injecting them with extracts of the anterior pituitary gland. These changes were eventually determined to be the result of messing with the amount of growth hormone (aka somatotropin) in an animal.

Guinea pig making too much growth hormone, flanked by its parents (Source)

Growth hormone consists of 191 amino acids and is produced and released in the front part of the pituitary gland. It does useful things like increase lean mass and bone density, and is used to treat conditions where growth is stunted in childhood (e.g. Prader-Willi syndrome) as well as in situations where adults develop a deficiency in the hormone due to a pituitary tumour. It's also used by some athletes (and actors) to boost their performance.

Prior to us figuring out how to get bacteria to synthesize a recombinant form of the hormone in the 1980s, its only source was the pituitary glands of human cadavers. As detailed by Maurice Raben, one of the first researchers to use cadaver-derived growth hormone to treat pituitary dwarfism, the hormone was extracted according to the following procedure: (1) use tweezers to peel the tough covering from each gland, (2) dry the unpeeled glands, (3) chop the glands up in a blender, (4) grind the resulting bits into a fine powder using a flour mill, and finally (5) use glacial acetic acid and several solvents to selectively recover growth hormone (removing other hormones found in the pituitary). The final product wasn't completely pure, but it seemed to do the job. Due to the relatively small amount of growth hormone in your average pituitary gland and the much larger amount required to treat people (often over several years), Raben's lab reportedly processed around thirty thousand pituitaries each year, which were obtained from 16 different countries.

While the vast majority of human pituitaries are safe to use, it has been estimated that about one in ten thousand dead people have something called Creutzfeldt-Jakob disease (CJD). It's caused by weirdly folded proteins that can be transmitted between people and act to alter the structure of the brain, resulting in dementia and other neurological symptoms. At some point it was noticed that patients receiving injections of growth hormone derived from human pituitaries had an unreasonably high likelihood of developing CJD. In particular, the disease was found in many patients under the age of 40, even though it's generally super rare in this age group. We've moved on from human cadavers to tanks of bacteria as our source of growth hormone, so this route of CJD transmission is thankfully toast.

Thyroid hormones via livestock thyroid glands

The thyroid gland is basically a bloody butterfly affixed to the front of your windpipe. It produces two iodine-containing hormones (triiodothyronine and thyroxine) that stimulate the production and breakdown of various substances within the body. They're pretty important, such that not having enough of them (hypothyroidism) can delay growth and intellectual development in children and cause a suite of frustrating symptoms (e.g. fatigue, feeling cold all the time, constipation, swelling, weight gain) in adults.

I can't find a cool enough thyroid pic, so here's a butterfly! (Source)

Thyroid glands from sheep and other livestock were used to treat hypothyroidism as early as 1891. This involved either injecting an extract prepared from the gland under the skin (subcutaneously) or serving the gland up for dinner (and thus avoiding continued injections). I found a case report of a 49 year old woman with hypothyroidism who "was ordered to take half a thyroid, lightly fried and minced, to be taken with currant jelly once a week, and to continue taking the extract once a week." Within a couple of months she was feeling back to normal. Unlike ADH and growth hormone, thyroid hormones aren't peptides and so can be taken orally without much loss due to stomach acid.

Although a synthetic version of thyroxine became available for use in the 1930s, thyroid extract remained a popular treatment for hypothyroidism over the next couple of decades. This was in part due to the perceived high cost and reduced effectiveness of the synthetic hormone.

Vitamin B12 via livestock livers

Anemia, which means not having enough red blood cells to ensure a proper supply of oxygen throughout your body, has many causes, one of which is being deficient in vitamin B12 (pernicious anemia). This vitamin, which contains a cobalt atom at its center, is necessary for bone marrow to effectively produce red blood cells.

In the 1920s, George Hoyt Whipple and Frieda Robscheit-Robbins, working with anemic dogs at the University of California, discovered that feeding them liver could reverse the anemia by stimulating red blood cell production. They attributed this effect to an unknown substance, later determined to be vitamin B12, that was enriched in liver. Building on this finding, doctors fed cooked cow liver to treat patients afflicted with pernicious anemia and noted remarkable recoveries. This had a profound impact (and won Whipple and two others a Nobel Prize) since this form of anemia had previously been a death sentence (pernicious refers to the progressive decline of those afflicted).


References

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Chakera AJ, Pearce SH, Vaidya B. 2012. Treatment for primary hypothyroidism: Current approaches and future possibilities. Drug Design, Development, and Therapy 6:1-11. [Full text]

DeArmond SJ, Prusiner SB. 1995. Etiology and pathogenesis of prion diseases. American Journal of Pathology 146(4):785-811. [Full text]

Fox EL. 1892. A case of myxoedema treated by taking extract of thyroid by the mouth. British Medical Journal 2(1661):941. [Full text]

Goodman L, Gilman A. 1941. The pharmacological basis of therapeutics. Macmillan Company.

Holt KS. 1956. Drug treatment of enuresis; controlled trials with propantheline, amphetamine, and pituitary snuff. Lancet 271(6957):1334-1336.

Mahon WE, Scott DJ, Ansell G, Manson GL, Fraser R. 1967. Hypersensitivity to pituitary snuff with miliary shadowing in the lungs. Thorax 22(1):13-20. [Full text]

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Pepys J, Jenkins PA, Lachmann PJ, Mahon WE. 1966. An iatrogenic autoantibody: Immunological responses to 'pituitary snuff' in patients with diabetes insipidus. Clinical and Experimental Immunology 1(4):377-389. [Full text]

Raben MS. 1957. Preparation of growth hormone from pituitaries of man and monkey. Science 125(3253):883-884. [Full text]

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