PHARMACEUTICALS AND MEDICDIALS OF ANIMAL ORIGIN*

JOSEPH P. DAILY Armour Pharmaceutical Company

Kankakee, I l l i n o i s

Thrcughout h i s tory , t he inter-dependency between man arid animals has been profound. f o r food. He has often u t i l i z e d animals as a s a c r i f i c e i n h i s re l ig ious ceremonies. Excavations of ancient tombs have revealed the skeletons of animals interred with the skeleton of t h e human. When the skeleton found has been a dog, it is presumed that t h i s animal f r iend was t o guide t h e owner sa fe ly in to t h e next l i fe . In addi t ion t o our dependence on animals f o r nu t r i t i ona l needs, our dependence on animals fo r maintenance of our hea l th is greater today than ever before.

Man has r e l i e d on animals f o r companionship and

Animal t i s s u e ex t rac ts have been used t o meet various needs of Drugs of animal or ig in designed t o meet medicine over t he past century.

t h e present un f i l l ed needs of medicine are under development in both academic and indus t r i a l laborator ies a t this time. One new hormone derived frm animal t i s sue , expected t o be of considerable therapeut ic importance has just recent ly been introduced in to medical prac t ice and w i l l be discussed l a t e r .

Today, many of our major drugs a r e derived d i r e c t l y from animal t i s sue , primarily t h e t i s s u e of c a t t l e and hogs. In general, these tissues provide drugs that a r e agents in t h e regulat ion of functions of the body. They are t h e ca ta lys t s of t h e biochemical reactions of our c e l l s and are such agents as enzymes, vitamins or hormones.

A dhcuss ion of the diseases requir ing such drugs and t h e extent of use of these preparations m y be of i n t e r e s t .

One common general metabolic deficiency occurs in which the pa t ien t is usual ly le tharg ic , loses incentive t o exercise, gains weight, under- goes personal i ty changes, experiences s e n s i t i v i t y t o cold, develops a slow deep-toned speech and dry thickened edematous skin. Medical examination reva ls a lowered metabolic rate and a low serum bound iodine. More def in i t i ve assessment of blood chemistry indicates a lowered triiodothp-mine binding capacity and a low serum thyroxine. The diagnosis is , of course, that t h e pa t ien t i s hypothyroid or myx@,de- matous and this is one of t h e medical conditions t h a t i s almost completely correctable by medication. Similar symptoms a r e sometimes observed i n pa t i en t s who have experienced su rg ica l removal of t h e thyroid o r have undergone extensive radioiodine therapy. The medication in

* Presented a t t h e 29th Annual Reciprocal Meat Conference of the American Meat Science Association, 1976.

t h i s case is thyroid t a b l e t s which are usual ly prepared from pork thyroid t i s sue . Two of the ac t ive ingredients of thyroid glands, tr i iodothyronine and thyroxine have been synthesized and can likewise be administered in t a b l e t form.

Beef thyroid can a l so be used f o r t h i s purpose.

The condition of hypothyroidism is not unusual. It is estirmted that in the United S ta t e s i n 1975, more than 1 b i l l i o n t a b l e t s were administered t o the 3,300,000 persons on thyroid medication. Abuut 59$ of these were obtained from animal t i s sue , t he balance contained the synthet ic hormone.

Just as the thyroid secretes one or two substances and regulates a great number of body functions, ;the adrenal gland secretes a t l e a s t twenty s te ro ids and these likewise a c t d i r e c t l y t o control biochemical react ions a t the c e l l u l a r level . from adrenal t i s s u e and administered as adrenal c o r t i c a l ex t rac t . The advances of chemistry i n the decades of t he 40's and 50's made it possible t o provide some of these s te ro ids synthet ical ly . The pa t ien t benef i t s from the use of these s te ro ids has been espec ia l ly impressive i n t h e treatment of inflammatory conditions i n the f i e l d s or dermatology and rheumatology.

These s te ro ids were formerly obtained

Another gland of i n t e re s t is t h e p i t u i t a r y gland. This gland yields a number of regulatory hormones that are used i n human medicine. One of these, adrenocorticotrophic hormone (ACTH), s t imulates t he adrenal t o excrete t h e hormones produced i n the cortex or outer layer of t h a t gland. This hormone, which is peptide in s t ruc ture , i s used t o t r e a t inflammatory diseases i n a =mer similar t o the synthet ic s te ro ids . The hormone has been found espec ia l ly usefu l in rheumatic disorders such as arthrit is , collagen diseases such as lupus erythematosus, dermatologic diseases and a l l e r g i c states such' as bronchial asthma.

It is estimated that i n t h e United States , t h e p i t u i t a r i e s from 60,000,000 hogs are processed annually f o r t h i s hormone and t h a t 16,000,000 human doses of ACTH are administered per year. i s administered by in jec t ion and, unlike the s teroids , in t h e U.S., a l l of t h i s hormone is s t i l l produced from animal t i s s u e .

This hormone

Another hormone from the p i t u i t a r y gland, thyrotropic st imulating hormone (TSH), is used primarily i n diagnosis. thyroid t i s s u e t o produce thyroid hormone. u se fu l i n combination with radioactive iodine t o locate small b i t s of thyroid cancer that have spread t o other pa r t s of t h e body. use of t h e hormone, t h e pa t ien t i s permitted t o d r ink what has become known as the atomic cocktai l , or radioact ive sodium iodide. This radioact ive iodide i s incorporated by the thyroid and by thyroid c e l l s t h a t may have migrated t o other sites in t h e body. Thyrotropic st imulating hormone is then injected f o r 3 t o 7 days and t h e various body sites a r e scanned t o determine rad ioac t iv i ty . If rad ioac t iv i ty is found a t an unexpected location, it indicates that thyroid c e l l s have migrated t o that area and proper s teps can be taken f o r t h e i r

This hormone stimulates It has been found especial ly

In t h i s

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removal or destruct ion. Thyrotropic st imulating hormone is a l s o used f o r other diagnostic procedures r e l a t ing t o thyroid function. It is obtained from beef an ter ior p i t u i t a r y glands.

Enzymes that d iges t protein have found numerous uses in medicine over t h e past two decades. Two proteolyt ic enzymes from the pancreas gland, t ryps in and chymotrypsin, have been administered both by inject ion and o r a l l y t o produce an anti-inflammatory e f f e c t . These same enzymes have been used top ica l ly as debriding agents t o remove dead t i s s u e a t t h e s i t e s of wounds, ulcers and burns.

One of t h e less widely known appl icat ions of proteolyt ic enzymes is in ca ta rac t surgery of t he eye. In t h i s application, t h e enzyme is used t o d iges t t h e zonular f ibe r s t h a t are attached t o t h e lens of t he eye. In t h e employment of t h e enzyme i n ca ta rac t surgery, an incision is mde i n the corneosclera or outer film of t h e eye, and t h e poster ior chamber is then i r r iga t ed with one o r two mi l l i l i t e r s of enzyme solut ion. A f t e r about two or four minutes, enzymatic digest ion has been completed and t h e excess enzyme solut ion is washed away. The lens is then removed mechanically and the incis ion sutured. The use of enzyme solut ion subs tan t ia l ly reduces t h e number of s ca lpe l strokes and the attendant r i s k of t he su rg ica l procedure. It is estimated t h a t approximately 280,000 ca ta rac t operations i n t h e U.S. per year are performed using t h i s e n z p t i c method.

Diabetic ketoacidosis i s a ser ious medical event and the glandular product insu l in is l i f e saving i n this s i tua t ion . Although most insu l in dependent d iabe t ics can be controlled by balancing t h e i r carbohydrate intake, energy output and insul in dosages, imbalances do occur. These a r e more frequent i n t h e pa t ien t group who cannot be taught t o regulate t h e i r insu l in use t o insu l in requirement. Ketoacidosis does sometimes occur in ca re fu l and usual ly well-controlled diabet ics , however, during severe infect ions or other illness.

Severe ketoacidosis r e s u l t s i n the pa t ien t becoming cnmatose. In t h i s condition, h i s sk in i s dry and flushed, his t h i r s t i s intense, he frequently vomits, he of ten has abdominal pain, he exhibi ts exaggerated breathing and his breath s m e l l s of acetone. He w i l l fo r tuna te ly respond t o insulin treatment with gradual recovery over a 6 t o I2 hour in t e rva l . Other aspects of h i s metabolic imbalance must a l s o be corrected during t h i s recovery period. For the insu l in dependent diabet ic , insu l in w i l l permit a nearly normal usefu l l i f e . coma, t h i s drug from animal t i s s u e is l i f e saving.

For the d iabe t ic in ketoacidosis

In the U.S., approximately 3,500,000 persons are d iabe t ic and l,l5O,OOO are being treated with insul in . It is estimated that in 1975, 420,000,000 doses of insul in were administered i n t h e U.S.

The therapeut ic products I have mentioned were developed over the past severa l decades. I have mentioned only a few. The l i s t of drugs from animal t i s s u e includes such other important drugs as heparin,

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from intestinal mucosa, b i l e salts from ox g a l l , l i v e r ex t rac ts from beef l i ve r , the spreading enzyme hyaluronidase from b u l l t e s t e s , poster ior p i t u i t a r y hormone from beef p i t u i t a r i e s and glucagon from beef pancreas. All have been introduced in t h i s century and each has a spec ia l place i n medicine.

In 1877, Sir James Paget of England described a bone disease involving abnormal calcium metabolism that he ca l led ' ' os te i t i s deformans ." H i s accounts of t h e disease described wide-spread s k e l e t a l involvement and multiple bone deformity. and i n t h e advanced stages, produced severe bone pain, lead t o spontaneous f rac tures of weakened bone and occasionally t o high output cardiac f a i l u r e due t o increased vascular i ty of the diseased bone. Remodeling of t he involved bone frequently resul ted i n deformity of t he vertebrae, limbs or skull. An in te res t ing s ide observation made by Paget i n h i s o r ig ina l a r t i c l e was t h a t t he hat s i z e of one of h i s pa t ien ts changed each year and from 1844 t o 1876 increased from 22 1/2 inches t o 27 1/2 inches. deformed skull, but deformed spine and legs .

The disease was found t o be progressive

Photographs of t he pa t ien t shared evidence of not only h i s

Over the years, various forms of drug therapy f o r Paget 's disease were investigated. s a t i s f ac to ry .

These =re found t o be non-specific and usua l ly not

In 1962, Dr. Harold Copp and co-workers a t the University of Br i t i sh C o l u b i a discovered the presence of a calcium regulating hormone as a r e s u l t of experiments wherein calcium solut ion was infused intravenously i n t o a dog. then found that this hormone, later named calci tonin, could be extracted from m a m l i a n thyroid t i s sue .

Dr. Paul Munson and co-workers a t Harvard Dental School

Armour Pharrnaceutical Company i n i t i a t e d work directed toward the extract ion and pur i f ica t ion of t h e harmone from pork thyroid t i s s u e and D r . John Pot t s and h i s associates a t Massachusetts General Hospital i n i t i a t e d work directed toward elucidat ion of t h e chemical s t ruc tu re of t h e Armour mater ia l . The hormone was found t o be a peptide containing thir ty- two amino acids . Further work on the pharmacology, toxicology, dosage form development, manufacture, and c l i n i c a l e f f icacy was conducted by Armour i n associat ion with numerous c l i n i c a l invest igators i n the U.S. and Europe. It was found t h a t t h i s hormone, injected on a regular basis e i the r subcutaneously or intramuscularly, t o pa t ien ts with Paget 's disease of t he bone is e f fec t ive in reducing the chemical and many of t he c l i n i c a l manifestations of Paget's disease.

The primary chemical changes associated with Paget's disease a r e an increased excretion of a lka l ine phosphatase and increased excretion of hydroxyproline. Treatment of t h e pa t ien t with ca lc i ton in causes a reduction of both of these chemical indices.

The c l i n i c a l symptoms of bone pain, de te r iora t ing bone s t ruc ture

In some cases, with prolonged treatment it has been found that and abnormal bone remodeling a r e a l s o corrected by administration of t h e drug. t h e irregular d is tor ted Pagetic bone has been re formd in to more normal bone.

The ea r ly work on ca lc i ton in was conducted on mater ia l obtained from porcine glands. va r i a t ion i n the s t ruc tu re and propert ies of t he hormone, Dr. Copp, t h e o r ig ina l discoverer, found that ca lc i ton in obtained from the u l t i - mobronchial glands of salmon was a t l e a s t twenty times as ac t ive as porcine hormone. Studies of t h i s mater ia l showed that the c l i n i c a l e f f ec t s of salmon ca lc i ton in were nearly iden t i ca l t o those of porcine ca lc i ton in . Because of t he increased potency of the salmon sequence, it w a s considered f eas ib l e t o synthesize t h i s molecule on an economic bas i s .

In the course of work on the species-to-species

Calcitonin obtained from pork thyroid t i s s u e was f irst introduced as a licensed pharmceut ica l product i n to Europe. It i s cur ren t ly being marketed i n the U.K., Spain, France and I t a l y . Calcitonin of salmon sequence is prepared synthe t ica l ly and is now being marketed i n Europe, South Africa and t h e United S ta t e s .

I Comp.red t o hypothyroidism and diabetes, t he incidence of advanced Paget's disease is low. To those pa t ien ts suffer ing f romthe advanced stages of t h e disease, however, t he a v a i l a b i l i t y of t h i s new drug is of major importance.

The professionals i n the pharmaceutical industry a r e dedicated t o providing needed diagnostic and therapeutic agents f o r the maintenance and improvement of human heal th . animal t i s s u e . careers a r e r e l a t ed t o the animal industry f o r providing healthy and uniform animal t i s s u e i n ever increasing quant i t ies . The successful development of pharmaceuticals and medicinals of animal or ig in depends upon work you have done i n the f i e l d of animal science i n the past and the splendid job you a r e now doing.

Many of these agents a re derived from We a r e dependent upon those of you whose professional

We express OUT appreciation.

3

Alpha Chymotrypsin

Ophthalmic Procedures Utilizing Enzyme 280,000

Adrenocorticotrophic Hormone

(ACTH)

Number of Human Doses Per Year (U.S . )

Number of Pituitaries Processed Annually

16 , 000 , 000

60,000,000

184

I

Insul in Medication

Number of Diabetics i n the United States 3#500#000

Diabetics on Insul in Therapy 18150#000

D o s e s of Insul in Administered Annually 4208 0008 000

Thyroid Medication

Number of Pat ients i n the U.S .

Number of Thyroid Tablets P e r Y e a r 1,000 ,000 000

Percent Derived From Animal Tissue

Harold Herrinq: Are there any questions?

John Romans, I l l i n o i s : W h a t percentage of insu l in comes from animals?

Joseph Dailey: Oh, a l l of it. Insul in has been synthesized. It has about 130 amino acid residues. work on it it synthe t ica l ly . A t the moment, t h e r a w materials t o make it synthe- t i c a l l y cost about t en times the pr ice of the insu l in from the animal t i s s u e . So, a l l of it comes from a n h l t i s s u e . There is a world shortage, most of it comes from beef i n the United S ta tes , although some of i t ' s from pork. The insu l in from pork is almost i den t i ca l t o human insul in . In other words, there is only one amino acid difference. Insul in from beef has maybe four or f i v e differences i n amino acids .

Two European commnies are doing It does not appear t o be economically possible t o make

Don Kinsman, Connecticut: On t h a t , is orinase a synthetic?

Joseph Dailey: Yes, i t ' s not insul in l i k e . It is synthet ic and is a small molecular weight drug. Its job is t o conserve t h e insul in t h a t is present r a the r than t o subs t i t u t e f o r insu l in . I a m not t o t a l l y qua l i f ied t o answer t h i s question, but i n general, t he individual must be producing some of h i s own insu l in f o r the orinase t o be e f fec t ive . In the case of insul in , it can be given t o a person who is secret ing no hormone a t a l l .

Don Kinaman: What would be the r e l a t i v e proportion of insulin users t o o r a l an t i -d iabe t ic agents7

Joseph Dailey: I th ink about a t h i r d of t h e d iabe t ics a r e on insul in . Those are generally the mre advanced d iabe t ics .

A. W . Kotula, Meat Science Research Lab.: For years, t h e medical profession has been seeking t o f ind a cure f o r improper bone growth i n children when one l eg s tops growing and the other one continues. Would ca lc i ton in work i n th i s instance and is anybody doing anything in that area?

Joseph Dailey: Calcitonin probably would not be appropriate for that . The mechanism of calci tonin is t o block the calcium coming from the bone. A s you probably know, a l l the calcium is absorbed ora l ly , and there is a very rapid turnover of calcium i n t o t h e bone, calcium out of the bone. For example, i n a rat, if we block the calcium coming out of the bone, and t h a t ' s w h a t calci tonin does, we can get a 10 percent drop in serum calcium i n one hour. In children, t h i s is likewise very rapid. In adul ts , i t ' s very slow. The calci tonin was t r i e d In Paget's Disease f i rs t , because t h a t i s a very high turnover calcium disease. Another in te res t ing disease which is much more wide spread is Osteoperosis, where there is a general demineralization of calcium from the bone. It would be nice t o s t o p the calcium coming out i n osteoperosis, and thus maintain a norm1 balance r a the r than a continuous negative balance. That's under study, but i t ' s not an appraved indication a t the moment. The condition you speak of , I think, would not be appropriate f o r calci tonin.

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Melvin Hunt, Kansas State: Do you have any do l l a r value of these types of products t h a t are used i n the United States?

Joseph Dailey: No, I don ' t , The e t h i c a l pharmaceutical business i n the United S ta tes (by e t h i c a l I mean essent ia l ly those items t h a t are sold by prescr ipt ion) is about 3 b i l l i o n dol la rs a t the manufacturers leve l . of that is from na tura l products through animal t i s sue . I don't have those f igures exactly.

I don ' t know, but I would have t o guess, that under 10 percent

Paul Lewis, Arkansas: Can the pancreas from c a t t l e be frozen f o r storage for insulin? How long can it be stored?

Joseph Dailey: Yes, pancreas glands are stored frozen and they can be stored f o r a considerable period of time. insul in can be obtained from pancreas glands, but the economics a r e such in t h i s country tha t that's seldom done. European countries. But it de f in i t e ly can be stored f o r years.

Both enzymes and the

It's done i n some of the

Harold Herring, Armour: Paget's Disease, and is there any par t icu lar ethnic group that is affected by Paget's Disease?

What is the incidence or frequency of

Joseph Dailey: I guess t h a t there are ethnic groups t h a t a r e affected by Paget's Disease. It appears t o have high incidence i n the United S ta tes and i n North and Central Europe. be of any importance in Japan. The incidence of it is about 2 percent of the population over the age of 40. However, severe Paget's Disease is much more rare than tha t . the x-ray people. They w i l l often be taking x-rays f o r some other purpose, and they w i l l see a deformed bone. In most cases it can be caught before it reaches the advanced stage. Unt i l calci tonin, there w a s nothing t h a t could be done f o r it. pa t ien ts are showing up now that there 's a cure avai lable

It does not appear t o

Paget's Disease is usually picked up by

So many, many more Paget's

Harold Herring: To continue w i t h t h i s morning's program on By- products Ut i l iza t ion , we've got f o r OUT next topic , "Batch, Continuous and Lar Temperature Rendering .'I

country, we're very for tunate t o have Mr. L. G . Hansen give the presen- t a t i o n . M r . Hansen is the Vice President and Manager of the Northern Division of Peterson Manufacturing Company of Emeryvi l le , Cal i fornia . He was born and raised near Missoula, Montana, on a farm. from Montana College i n Bozeman w i t h a B.S. Degree i n Indus t r ia l Engineering. cal led Northrup, King and Company. He a l s o worked fo r an a i r c r a f t fabr icat ion group w i t h Boeing Aircraf t . of Edible and Inedible Rendering f o r Peterson Manufacturing Plants i n northeran California.

Since Mr , Peterson is out of the

He graduated

He previously worked for a seed processing firm that w a s

He is presently General Manager